US20220106351A1 - Heterodimer compositions and methods for the treatment of ocular disorders - Google Patents
Heterodimer compositions and methods for the treatment of ocular disorders Download PDFInfo
- Publication number
- US20220106351A1 US20220106351A1 US17/554,808 US202117554808A US2022106351A1 US 20220106351 A1 US20220106351 A1 US 20220106351A1 US 202117554808 A US202117554808 A US 202117554808A US 2022106351 A1 US2022106351 A1 US 2022106351A1
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- United States
- Prior art keywords
- formula
- radical
- alkyl
- compound
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 104
- 238000000034 method Methods 0.000 title claims abstract description 51
- 238000011282 treatment Methods 0.000 title abstract description 16
- 208000022873 Ocular disease Diseases 0.000 title abstract description 11
- 239000000833 heterodimer Substances 0.000 title description 27
- 150000003180 prostaglandins Chemical class 0.000 claims abstract description 66
- -1 article Substances 0.000 claims description 321
- 125000000217 alkyl group Chemical group 0.000 claims description 287
- 150000001875 compounds Chemical class 0.000 claims description 261
- 229910052739 hydrogen Inorganic materials 0.000 claims description 254
- 239000001257 hydrogen Substances 0.000 claims description 254
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 196
- 125000005647 linker group Chemical group 0.000 claims description 194
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 162
- 229910052736 halogen Inorganic materials 0.000 claims description 158
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 115
- 125000005843 halogen group Chemical group 0.000 claims description 105
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 94
- 150000003839 salts Chemical class 0.000 claims description 91
- 125000002947 alkylene group Chemical group 0.000 claims description 89
- 150000002367 halogens Chemical group 0.000 claims description 82
- 125000003545 alkoxy group Chemical group 0.000 claims description 81
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 62
- 239000007943 implant Substances 0.000 claims description 51
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 49
- 125000001153 fluoro group Chemical group F* 0.000 claims description 36
- 201000010099 disease Diseases 0.000 claims description 30
- 208000035475 disorder Diseases 0.000 claims description 19
- 125000001188 haloalkyl group Chemical group 0.000 claims description 18
- WWSWYXNVCBLWNZ-QIZQQNKQSA-N fluprostenol Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC(O)=O)OC1=CC=CC(C(F)(F)F)=C1 WWSWYXNVCBLWNZ-QIZQQNKQSA-N 0.000 claims description 15
- 229960001160 latanoprost Drugs 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 13
- HNPFPERDNWXAGS-LZCJLJQNSA-N (e)-7-[3,5-dihydroxy-2-(3-hydroxy-5-phenylpentyl)cyclopentyl]hept-5-enoic acid Chemical compound C=1C=CC=CC=1CCC(O)CCC1C(O)CC(O)C1C\C=C\CCCC(O)=O HNPFPERDNWXAGS-LZCJLJQNSA-N 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 claims description 11
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 claims description 6
- 229960002470 bimatoprost Drugs 0.000 claims description 6
- BKVUSNOUTQMSBE-XCMGCKIWSA-N propan-2-yl 4-[(3s,5ar,6r,7r,8as)-6-[(e,3r)-4-(2,5-difluorophenoxy)-3-hydroxybut-1-enyl]-7-hydroxy-3,4,5,5a,6,7,8,8a-octahydro-2h-cyclopenta[b]oxepin-3-yl]butanoate Chemical compound C([C@H](O)/C=C/[C@H]1[C@H](O)C[C@H]2[C@@H]1CC[C@@H](CO2)CCCC(=O)OC(C)C)OC1=CC(F)=CC=C1F BKVUSNOUTQMSBE-XCMGCKIWSA-N 0.000 claims description 6
- 229950000863 sepetaprost Drugs 0.000 claims description 6
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 claims description 5
- 229960002368 travoprost Drugs 0.000 claims description 5
- KIQXRQVVYTYYAZ-VKVYFNERSA-N (z)-7-[(1r,2r,3r,5s)-2-[(e)-3,3-difluoro-4-phenoxybut-1-enyl]-3,5-dihydroxycyclopentyl]hept-5-enoic acid Chemical compound OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 KIQXRQVVYTYYAZ-VKVYFNERSA-N 0.000 claims description 4
- YFHHIZGZVLHBQZ-KDACTHKWSA-N 17-phenyl-trinor-prostaglandin F2alpha Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC(O)=O)CC1=CC=CC=C1 YFHHIZGZVLHBQZ-KDACTHKWSA-N 0.000 claims description 4
- 229960004458 tafluprost Drugs 0.000 claims description 3
- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 abstract description 90
- 230000004410 intraocular pressure Effects 0.000 abstract description 39
- 208000010412 Glaucoma Diseases 0.000 abstract description 37
- 206010061218 Inflammation Diseases 0.000 abstract description 17
- 230000004054 inflammatory process Effects 0.000 abstract description 17
- 229940094443 oxytocics prostaglandins Drugs 0.000 abstract description 11
- 206010064930 age-related macular degeneration Diseases 0.000 abstract description 8
- 230000001225 therapeutic effect Effects 0.000 abstract description 8
- 238000002347 injection Methods 0.000 abstract description 7
- 239000007924 injection Substances 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 6
- 238000001356 surgical procedure Methods 0.000 abstract description 6
- 208000000208 Wet Macular Degeneration Diseases 0.000 abstract description 5
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 5
- 208000002780 macular degeneration Diseases 0.000 abstract description 5
- 208000002177 Cataract Diseases 0.000 abstract description 4
- 206010012688 Diabetic retinal oedema Diseases 0.000 abstract description 4
- 201000011190 diabetic macular edema Diseases 0.000 abstract description 4
- 208000011325 dry age related macular degeneration Diseases 0.000 abstract description 4
- 208000004644 retinal vein occlusion Diseases 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 208000010217 blepharitis Diseases 0.000 abstract 1
- 150000003254 radicals Chemical class 0.000 description 375
- 125000004043 oxo group Chemical group O=* 0.000 description 126
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 105
- 239000003814 drug Substances 0.000 description 89
- 229940079593 drug Drugs 0.000 description 85
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 66
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 60
- 229910052799 carbon Inorganic materials 0.000 description 53
- 229960001232 anecortave Drugs 0.000 description 51
- 125000003342 alkenyl group Chemical group 0.000 description 50
- 239000000243 solution Substances 0.000 description 49
- 239000007787 solid Substances 0.000 description 46
- 229910052760 oxygen Inorganic materials 0.000 description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 43
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 41
- 239000012091 fetal bovine serum Substances 0.000 description 41
- 125000000304 alkynyl group Chemical group 0.000 description 40
- 239000008188 pellet Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- 239000008194 pharmaceutical composition Substances 0.000 description 38
- 125000003118 aryl group Chemical group 0.000 description 37
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
- 125000003282 alkyl amino group Chemical group 0.000 description 34
- YUWPMEXLKGOSBF-GACAOOTBSA-N Anecortave acetate Chemical compound O=C1CC[C@]2(C)C3=CC[C@]4(C)[C@](C(=O)COC(=O)C)(O)CC[C@H]4[C@@H]3CCC2=C1 YUWPMEXLKGOSBF-GACAOOTBSA-N 0.000 description 33
- 125000001769 aryl amino group Chemical group 0.000 description 33
- 239000000047 product Substances 0.000 description 33
- 239000000126 substance Substances 0.000 description 33
- 239000012453 solvate Substances 0.000 description 31
- 238000003786 synthesis reaction Methods 0.000 description 31
- 150000003573 thiols Chemical class 0.000 description 31
- 0 *C([6*])(C[5*])CCC1C([1*])C([2*])C([3*])C1CCCCCC[4*] Chemical compound *C([6*])(C[5*])CCC1C([1*])C([2*])C([3*])C1CCCCCC[4*] 0.000 description 30
- 238000002844 melting Methods 0.000 description 29
- 230000008018 melting Effects 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
- 239000003795 chemical substances by application Substances 0.000 description 28
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- 125000001424 substituent group Chemical group 0.000 description 27
- 125000004432 carbon atom Chemical group C* 0.000 description 25
- 238000012545 processing Methods 0.000 description 25
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- 125000001072 heteroaryl group Chemical group 0.000 description 24
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- 238000004587 chromatography analysis Methods 0.000 description 19
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 19
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- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 17
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 16
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- 101100347605 Arabidopsis thaliana VIII-A gene Proteins 0.000 description 15
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- 238000013270 controlled release Methods 0.000 description 15
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 15
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 13
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- YUOZKOLALXNELS-SQVYRKCQSA-N tiomesterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@H](SC(=O)C)CC3=CC(=O)C[C@H](SC(C)=O)[C@]3(C)[C@H]21 YUOZKOLALXNELS-SQVYRKCQSA-N 0.000 description 1
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- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
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- 229960000312 trenbolone Drugs 0.000 description 1
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- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
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- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 229960002249 ulobetasol Drugs 0.000 description 1
- LEHFPXVYPMWYQD-XHIJKXOTSA-N ulobetasol Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CCl)(O)[C@@]2(C)C[C@@H]1O LEHFPXVYPMWYQD-XHIJKXOTSA-N 0.000 description 1
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- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
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Images
Classifications
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
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- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- A61K47/554—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
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- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
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- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
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- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
Definitions
- Prostaglandins are a front-line medication in the treatment of glaucoma and can be used in the treatment of other ocular disorders.
- prostaglandins are useful for lowering intraocular pressure (IOP), a major risk factor in glaucoma.
- IOP intraocular pressure
- prostaglandins are ophthalmically formulated and delivered in the form of eye drops.
- frequent ophthalmic administration of prostaglandins is often required. For example, latanoprost given once a day has been reported to have a mean IOP lowering of about 35%.
- D1 is a processable group (also referred to herein as a processable radical)
- L is a linker
- D2 is a drug (also referred herein as a drug radical).
- L is a hydrolyzable linker or bond, such that when the compound of formula D1-L-D2 is (e.g., ophthalmically) administered (or when present in or otherwise exposed to an aqueous environment, such as a buffering solution, tears, serum, or the like), D1 and D2 are released (e.g., in their free, non-radical form).
- the (e.g., covalent) joining of a group D1 to an active agent D2 (e.g., non-processable active agent) through a linker L (e.g., D1-L-D2) provides a compound comprising an otherwise non-processable drug (e.g., D2-L-D2 (e.g., D2-D2)) in a processable form.
- a drug such as a prostaglandin
- a processable group such as a steroid or other radical of a formula described herein, such as Formula (I)).
- the processable group D1 may or may not itself be processable when in free form, but when combined with D2 (e.g., through a linker L) provides a solid (e.g., at a physiological temperature) that is processable (e.g., at a temperature above a physiological temperature).
- a platform for providing compounds and implants e.g., with high drug content, low excipient content (e.g., that would otherwise need to be removed), and other benefits, such as described herein) that provide long-lasting release of therapeutics (e.g., prostaglandins, steroids, beta-blockers, and/or the like) in biological and therapeutic applications, such as in ocular (e.g., implant) administration.
- therapeutics e.g., prostaglandins, steroids, beta-blockers, and/or the like
- compounds provided herein are processable into forms (e.g., implants, coatings, or other bodies), such as that are capable of being administered to (e.g., an eye of) an individual in need thereof.
- forms e.g., implants, coatings, or other bodies
- such compounds are processable without the need for additional excipients or materials (e.g., controlled release polymers, matrices, or other components).
- the no or low amounts of additional excipients or materials facilitates high levels of drug delivery, while limiting impact of drug delivery (e.g., a small implant can have high quantities of drug).
- such compounds are administered to (e.g., implanted into) an individual, such that sustained and/or otherwise controlled (e.g., local) delivery of the drug is achieved.
- delivery of the compounds e.g., in the form of an implant, coating, etc.
- compounds, formulations, and implants provided herein facilitate the long term delivery of drugs to an individual in need thereof, such as without the need for frequent dosing.
- prostaglandins are often formulated and administered as eye drops, such as with daily administration.
- the group D1 is also an active agent or drug (e.g., radical thereof).
- D1 and D2 are both effective in the treatment of a single indication, such that administration of a compound herein provides a combination therapeutic effect.
- D1 is a steroid and D2 is a prostaglandin.
- the anti-inflammatory effect of the steroid and the ocular pressure lowering effect of the prostaglandin both provide therapeutic effect.
- D1 is an anti-inflammatory (e.g., steroid) and reduces or minimizes an inflammatory response to the implant.
- compositions comprising compounds described herein, and methods of making and using compounds provided herein.
- methods of using the compounds provided herein include methods of treating disorders in individuals in need thereof, such as disorders treatable by a drug D2 (e.g., in its free form).
- methods of treatment provided herein comprise methods of treating ocular disorders, such as glaucoma. It is to be understood that disclosures of methods provided herein explicitly include disclosures of pharmaceutical compositions comprising (e.g., an effective amount) of a compound provided herein for such uses.
- a compound comprising a first radical and a second radical, the first radical comprising the structure of Formula (I):
- each R a , R b , and R c is independently selected from the group consisting of oxo, halogen, —CN, —NO 2 , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.
- any one of R a , R b , or R c are taken together with another of R a , R b , or R c to form a substituted or an unsubstituted cycloalkyl or heterocycloalkyl.
- X 1 , X 2 , X 3 , and X 4 are each independently selected from the group consisting of a bond and Q y , wherein each Q is independently selected from the group consisting of —O—, —NR—, —S(R) x —, and —C(R) z —.
- y is 1-3.
- each x is independently 0-5.
- each z is independently 1 or 2 (e.g., depending on degree of saturation).
- each of m, n, and o are independently 0-6.
- each R is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, and thiol (e.g., wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted), or each R is taken together with another R to form an oxo.
- the second radical is a therapeutically active agent (or drug).
- the first radical e.g., steroid
- the second radical e.g., prostaglandin
- either the first radical, the second radical, or both the first radical and the second radical is not a steroid.
- the second radical is a drug.
- the drug is a prostaglandin.
- the prostaglandin is selected from the group consisting of latanoprost, latanoprost acid, travoprost, travoprost acid, tafluprost, tafluprost acid, bimatoprost, bimatoprost acid, sepetaprost, and sepetaprost acid, or a fragment or radical of any of the foregoing.
- X 1 is Q 1 .
- X 2 is a bond.
- X 3 is Q 2 .
- X 4 is Q 1 .
- X 1 and X 4 are each Q 1 .
- X 2 is a bond and X 3 is Q 2 .
- Q is —C(R) 1 — or —C(R) 2 —.
- X 1 and X 4 are each independently —C(R) 1 — or —C(R) 2 —.
- X 2 is a bond and X 3 is —C(R) 2 C(R) 2 —, —C(R)C(R) 2 —, or —C(R)C(R)—.
- X 1 and X 4 are each —C(R) 2 —, and X 2 is a bond and X 3 is —C(R) 2 C(R) 2 — or —C(R)C(R) 2 —.
- each R is independently hydrogen, halogen, alkyl, heteroalkyl, hydroxy, amino (e.g., dihydroamino, alkylamino, or arylamino), or taken together with another R to form an oxo.
- each R is independently hydrogen, halogen, alkyl, hydroxy, or taken together with another R to form an oxo.
- each R is independently hydrogen or halogen.
- each R is independently hydrogen or alkyl.
- each R is independently hydrogen or hydroxy.
- each R is independently hydrogen or taken together with another R to form an oxo.
- the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol of R is optionally substituted.
- R combines with one of R a , R b , or R c to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
- R is amino and combines with one of R a , R b , or R c to form an optionally substituted heterocycloalkyl.
- R is amino and combines with one of R a or R c to form a heterocycloalkyl substituted with optionally substituted alkyl.
- a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IA):
- each R a , R b , and R c are independently selected from the group consisting of oxo, halogen, —CN, —NO 2 , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.
- each of m, n, and o are independently 0-6.
- any one of R a , R b , or R c are taken together with another of R a , R b , or R c to form a substituted or an unsubstituted cycloalkyl or heterocycloalkyl.
- the second radical is a therapeutically active agent (or drug) and the first radical (e.g., steroid) being different than the second radical (e.g., prostaglandin).
- the first radical, the second radical, or both the first radical and the second radical is not a steroid.
- pharmaceutical salts or solvates of a compound of Formula (IA) are also provided in certain embodiments herein.
- both the first radical and the second radical have a structure of Formula (I) or Formula (IA).
- the first radical has a structure of Formula (I) or Formula (IA) and the second radical does not have a structure of Formula (I) or Formula (IA).
- the structure of Formula (I) or Formula (IA) has a melt and/or glass transition temperature at a temperature of at least 20° C. (e.g., at least 25° C., at least 30° C., at least 37° C., at least 40° C., at least 50° C., at least 100° C., or more) in its free form.
- n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, each R b is independently hydrogen, halogen, alkyl, heteroalkyl, hydroxy, amino (e.g., dihydroamino, alkylamino, or arylamino), or taken together with another R b to form an oxo. In some embodiments, each R b is independently hydrogen, halogen, alkyl, hydroxy, or taken together with another R b to form an oxo. In some embodiments, each R b is independently hydrogen or halogen. In some embodiments, each R b is independently hydrogen or alkyl. In some embodiments, each R b is independently hydrogen or hydroxy. In some embodiments, each R b is independently hydrogen or taken together with another R b to form an oxo.
- the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol of R b is optionally substituted.
- R b combines with one of R a , R b , or R c to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.
- R b is amino and combines with one of R a or R c to form an optionally substituted heterocycloalkyl.
- R b is amino and combines with one of R a or R c to form a heterocycloalkyl substituted with optionally substituted alkyl.
- one of R c is taken together with another R c to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl. In some embodiments, one of R c is taken together with another R c to form an optionally substituted cycloalkyl.
- one of R c is taken together with another R c to form a cycloalkyl substituted with one or more substituent, each substituent selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, alkoxy, amino, thiol, or heterocycloalkyl is optionally substituted.
- substituent selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycl
- R a , R b , and R c are each optionally and independently substituted with one or more groups, each group independently selected from —OH, oxo, alkyl (e.g., alkenyl), heteroalkyl, cycloalkyl, or alkoxy, wherein the alkyl, heteroalkyl, cycloalkyl, or alkoxy, is further optionally substituted.
- the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of each R a , R b , or R c is, independently, substituted or not substituted.
- each group is independently not substituted or substituted with any one or more substituent described herein.
- each group is independently not substituted or substituted with one or more substituent, wherein each substituent is selected from the group consisting of —OH, oxo, alkyl, heteroalkyl, cycloalkyl, or alkoxy, wherein the alkyl, heteroalkyl, cycloalkyl, or alkoxy, is further optionally substituted.
- the substituted or unsubstituted cycloalkyl or heterocycloalkyl are each optionally and independently substituted with one or more groups, each group independently selected from —OH, oxo, alkyl (e.g., alkenyl, alkynyl), —S-alkyl, —NH-alkyl, halogen, heteroalkyl, cycloalkyl, or alkoxy, wherein the alkyl (e.g., —S-alkyl, —NH— alkyl), heteroalkyl, cycloalkyl, or alkoxy, is further optionally substituted.
- substituted or unsubstituted cycloalkyl or heterocycloalkyl are, independently, substituted or not substituted. In some embodiments, each group is independently not substituted or substituted with any one or more substituent described herein.
- each group is independently not substituted or substituted with one or more substituent, wherein each substituent is selected from the group consisting of —OH, oxo, alkyl (e.g., alkenyl, alkynyl), —S-alkyl, —NH-alkyl, halogen, heteroalkyl, cycloalkyl, or alkoxy, wherein the alkyl (e.g., —S-alkyl, —NH-alkyl), heteroalkyl, cycloalkyl, or alkoxy, is further optionally substituted.
- alkyl e.g., alkenyl, alkynyl
- —S-alkyl e.g., —NH-alkyl
- heteroalkyl e.g., —NH-alkyl
- cycloalkyl e.g., cycloalkyl, or alkoxy
- the cycloalkyl (e.g., of Formula (I) or Formula (IA)) is substituted with oxo, —OH, optionally substituted alkyl, or optionally substituted alkoxy.
- the alkyl is substituted with one or more halogen, oxo, —OH, alkyl (e.g., alkenyl), —S-alkyl, —NH-alkyl, alkoxy, wherein the alkyl (e.g., —S— alkyl, —NH-alkyl) or alkoxy is further optionally substituted.
- the alkyl is methyl.
- a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IB):
- each R a , R b , R c , and R d are independently selected from the group consisting of oxo, halogen, —CN, —NO 2 , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.
- each of m, n, o, and p are independently 0-6.
- any one of R a , R b , R c , and R d are taken together with another of R a , R b , R c , and R d to form a substituted or an unsubstituted cycloalkyl or heterocycloalkyl.
- the second radical is a therapeutically active agent (or drug) and the first radical (e.g., steroid) being different than the second radical (e.g., prostaglandin).
- the first radical, the second radical, or both the first radical and the second radical is not a steroid.
- pharmaceutical salts or solvates of a compound of Formula (IB) are also provided in certain embodiments herein.
- Ring B of any one of Formula (I), Formula (IA), or Formula (IB) is an optionally substituted cycloalkyl. In some embodiments, Ring B of any one of Formula (I), Formula (IA), or Formula (IB) does not comprise a heteroatom within the ring (e.g., Ring B is optionally substituted cycloalkyl). In some embodiments, Ring B of any one of Formula (I), Formula (IA), or Formula (IB) comprises only single bonds. In some embodiments, Ring B of any one of Formula (I), Formula (IA), or Formula (IB) comprises at least one double bond.
- Ring B of any one of Formula (I), Formula (IA), or Formula (IB) is attached to at least one ring (e.g., Ring A and/or Ring C) that comprises at least one double bond.
- Ring A comprises at least one double bond.
- Ring C comprises at least one double bond.
- Ring A and Ring C each independently comprise at least one double bond.
- Ring B of any one of Formula (I), Formula (IA), or Formula (IB) is attached to at least one ring (e.g., Ring A and or Ring C) that is aromatic.
- Ring B of any one of Formula (I) or Formula (IA) is aromatic.
- Ring A, Ring B, and Ring C of any one of Formula (I) or Formula (IA) are each aromatic.
- m is 4. In some embodiments, m is 3. In some embodiments, m is 2. In some embodiments, m is 1. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, o is 5. In some embodiments, o is 4. In some embodiments, o is 3. In some embodiments, o is 2. In some embodiments, o is 1. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.
- each R a , R b , R c , and R d are independently selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, thiol, or heterocycloalkyl is optionally substituted.
- each R a is independently selected from —OH, oxo, halogen, alkyl, or alkoxy, wherein the alkyl or alkoxy is optionally substituted.
- each R b is independently selected from —OH, oxo, halogen, or optionally substituted alkyl.
- each R c is independently selected from —OH, oxo, or optionally substituted alkyl.
- each R d is independently selected from —OH, oxo, alkyl (e.g., alkenyl or alkynyl), heteroalkyl, or each R d is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted.
- the substituted alkyl of R d is —COOH, —(C ⁇ O)alkyl, —(C ⁇ O)Oalkyl, —O(C ⁇ O)Oalkyl, —(C ⁇ O)Salkyl, wherein the alkyl is optionally substituted with —OH or halogen.
- one R d is taken together with another R d to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl.
- the alkyl of any one of R a , R b , R c , or R d is C 1 -C 3 alkyl. In some embodiments, the alkyl of any one of R a , R b , R c , or R d is substituted with oxo and further optionally substituted with alkyl, hydroxy, halogen, heteroalkyl, alkoxy, thioether, wherein the alkyl, alkoxy, thioether, or heteroalkyl is further optionally substituted. In some embodiments, the alkoxy of any one of R a , R b , R c , or R d is C 1 -C 3 alkoxy.
- Ring A is aromatic. In some embodiments, Ring A comprises at least one double bond. In some embodiments, Ring A comprises one double bond. In some embodiments, Ring A comprises two double bonds. In some embodiments, Ring B comprises at least one double bond. In some embodiments, Ring B comprises one double bond. In some embodiments, Ring C comprises one double bond. In some embodiments, Ring D comprises one double bond. In some embodiments, Ring A comprises at least one double bond and each of Ring B, Ring C, and Ring D consist of single bonds. In some embodiments, Ring A is aromatic and each of Ring B, Ring C, and Ring D consist of single bonds. In some embodiments, Ring A comprises at least one double bond and at least one of Ring B, Ring C, or Ring D comprises a double bond.
- Ring A is aromatic and at least one of Ring B, Ring C, or Ring D comprises a double bond. In some embodiments, Ring A comprises at least one double bond and Ring B comprises a double bond. In some embodiments, Ring A comprises at least one double bond and Ring C comprises a double bond. In some embodiments, Ring A comprises at least one double bond and Ring D comprises a double bond.
- a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IC):
- R a is hydrogen, —OH, or oxo.
- each R d ′ is independently selected from hydrogen, —OH, halogen, C 1 -C 3 alkyl, and alkoxy.
- R a ′′ is absent, hydrogen, or C 1 -C 3 alkyl.
- R b is absent, hydrogen, halogen, or C 1 -C 3 alkyl.
- R b ′ is hydrogen, halogen, —OH, oxo, or C 1 -C 3 alkyl.
- R b ′′ is hydrogen or —OH.
- each R c is independently hydrogen, —OH, oxo, or C 1 -C 3 alkyl.
- each R c ′ is independently hydrogen or C 1 -C 3 alkyl.
- R c ′′ is hydrogen, —OH, C 1 -C 3 alkyl, or —C( ⁇ O)H.
- each R d is independently hydrogen, —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or each R d is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted.
- R d ′ is hydrogen, —OH, C 1 -C 3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl.
- one R d is taken together with R d ′ to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl.
- either the first radical, the second radical, or both the first radical and the second radical is not a steroid.
- the second radical is a therapeutically active agent (or drug) and the first radical (e.g., steroid) being different than the second radical (e.g., prostaglandin.
- the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) consists of single bonds. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises at least one double bond. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises one double bond. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises two double bonds. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises three double bonds.
- the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises at least one aromatic ring. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises one aromatic ring.
- R d is —OH.
- R a is —OH and attached to a fully saturated cycloalkyl.
- R a is —OH and attached to an aryl.
- R a is oxo.
- R a is oxo and is adjacent to at least one double bond.
- R a is oxo and is adjacent to one double bond.
- R a is oxo and is adjacent to two double bonds.
- each R a ′ is independently hydrogen or halogen (e.g., fluoro or chloro). In some embodiments, each R a , is independently hydrogen or C 1 -C 3 alkyl. In some embodiments, each R a , is independently hydrogen or C 1 -C 3 alkoxy. In some embodiments, each R a ′ is attached to a single bond. In some embodiments, each R a , is hydrogen. In some embodiments, at least one R a ′ is attached to a double bond. In some embodiments, one R a , is attached to a double bond. In some embodiments, each R a , is attached to a double bond.
- each R a is independently hydrogen or C 1 -C 3 alkyl and attached to a single bond.
- each R a ′ is independently hydrogen or halogen, and one R a , is attached to a double bond.
- each R a is hydrogen and attached to a single bond.
- each R a is hydrogen and attached to a double bond.
- each R a is attached to an aryl and independently hydrogen or C 1 -C 3 alkoxy.
- each R a is hydrogen and attached to an aryl.
- R a ′′ is absent. In some embodiments, R a ′′ is hydrogen. In some embodiments, R a ′′ is C 1 -C 3 alkyl. In some embodiments, R a is —OH or oxo, each R a , is independently hydrogen or C 1 -C 3 alkyl, and R a ′′ is C 1 -C 3 alkyl. In some embodiments, R a is —OH or oxo, each R a , is independently hydrogen or C 1 -C 3 alkoxy, and R a ′′ is C 1 -C 3 alkyl.
- R a is oxo, each R a , is independently hydrogen or halogen (e.g., fluoro or chloro), and R a ′′ is C 1 -C 3 alkyl (e.g., methyl).
- R a is oxo, each R a ′ is independently hydrogen or C 1 -C 3 alkyl (e.g., methyl), and R a ′′ is C 1 -C 3 alkyl (e.g., methyl).
- R a is oxo, each R a , is hydrogen, and R a ′′ is C 1 -C 3 alkyl (e.g., methyl).
- R a is —OH, each R a , is independently hydrogen or C 1 -C 3 alkoxy (e.g., methoxy), and R a ′′ is absent.
- R a is —OH, each R a , is hydrogen, and R a ′′ is C 1 -C 3 alkyl (e.g., methyl).
- R a is —OH, each R a ′ is hydrogen, and R a ′′ is absent.
- R b is absent. In some embodiments, R b is hydrogen. In some embodiments, R b is halogen (e.g., fluoro or chloro). In some embodiments, R b ′ is hydrogen. In some embodiments, R b ′ is halogen (e.g., fluoro or chloro). In some embodiments, R b ′ is —OH. In some embodiments, R b ′ is -oxo. In some embodiments, R b ′ is C 1 -C 3 alkyl (e.g., methyl).
- R b ′ is hydrogen, halogen (e.g., fluoro or chloro), or C 1 -C 3 alkyl (e.g., methyl) and attached to a single bond. In some embodiments, R b ′ is hydrogen or C 1 -C 3 alkyl (e.g., methyl) and attached to a double bond. In some embodiments, R b ′′ is hydrogen. In some embodiments, R b ′′ is —OH.
- R b is hydrogen or halogen (e.g., fluoro or chloro)
- R b ′ is hydrogen, halogen (e.g., fluoro or chloro), or C 1 -C 3 alkyl (e.g., methyl)
- R 1′ is hydrogen.
- R b is hydrogen or halogen (e.g., fluoro or chloro)
- R b ′ is hydrogen or halogen (e.g., fluoro or chloro)
- R b ′′ is hydrogen.
- R b is halogen (e.g., fluoro or chloro), R b ′ is halogen (e.g., fluoro or chloro), and R b ′′ is hydrogen.
- R b is halogen (e.g., fluoro or chloro)
- R b ′ is hydrogen
- R b ′′ is hydrogen.
- R b is hydrogen
- R b ′ is halogen (e.g., fluoro or chloro)
- R 1′ is hydrogen.
- R b is hydrogen, R b ′ is C 1 -C 3 alkyl (e.g., methyl), and R 1′ is hydrogen.
- R b is hydrogen, R b ′ is hydrogen, and R 1′ is —OH. In some embodiments, R b is hydrogen, R b ′ is oxo, and R b ′′ is hydrogen. In some embodiments, R b , R b ′, and R b ′′ are each hydrogen.
- each R c is independently hydrogen or —OH. In some embodiments, each R c is independently hydrogen or oxo. In some embodiments, each R c is hydrogen. In some embodiments, each R c ′ is hydrogen. In some embodiments, each R c ′ is C 1 -C 3 alkyl. In some embodiments, R c ′ is hydrogen. In some embodiments, R c ′ is C 1 -C 3 alkyl. In some embodiments, R c ′′ is —C( ⁇ O)H.
- each R c is hydrogen, each R c ′ is hydrogen, and R c ′ is C 1 -C 3 alkyl. In some embodiments, each R c is independently hydrogen or —OH, each R c ′ is hydrogen, and R c ′′ is C 1 -C 3 alkyl. In some embodiments, each R c is independently hydrogen or oxo, each R c ′ is hydrogen, and R c ′′ is C 1 -C 3 alkyl. In some embodiments, each R c is independently hydrogen or —OH, each R c ′ is hydrogen, and R c ′′ is —C( ⁇ O)H. In some embodiments, each R c is independently hydrogen or —OH, each R c ′ is C 1 -C 3 alkyl, and R c ′ is hydrogen.
- one R d is absent and R d ′ and the other R d are attached to a double bond. In some embodiments, the R d ′ and the other R d attached to a double bond are each hydrogen.
- one R d is hydrogen and the other R d is —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted.
- one R d is alkyl and the other R d is —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted.
- one R d is optionally substituted alkoxy and the other R d is —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted.
- one R d is —OH and the other R d is —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted.
- each R d is independently hydrogen or —OH.
- each R d is independently optionally substituted alkyl or —OH.
- each R d is independently —COOH or —OH. In some embodiments, each R d is independently —COOH or optionally substituted alkoxy. In some embodiments, each R d is taken together to form an oxo. In some embodiments, each R d is taken together to form an optionally substituted alkenyl. In some embodiments, the alkenyl is substituted with —COOH and alkyl. In some embodiments, the alkyl comprises saturated and unsaturated carbon bonds. In some embodiments, each R d is independently optionally substituted alkyl or hydrogen. In some embodiments, the alkyl consists of saturated carbon bonds.
- the alkyl is substituted with C 1 -C 3 alkyl and alkyl further substituted with —COOH. In some embodiments, the alkyl is substituted with C 1 -C 3 alkyl and alkyl further substituted with —OH.
- R d ′ is hydrogen. In some embodiments, R d ′ is —OH. In some embodiments, R d ′ is C 1 -C 3 alkyl (e.g., alkylene or alkenyl). In some embodiments, the C 1 -C 3 alkyl is methyl. In some embodiments, the C 1 -C 3 alkyl is CHCH. In some embodiments, R d ′ is heteroalkyl. In some embodiments, the heteroalkyl is —O(C ⁇ O)C 1 -C 3 alkyl.
- one R d is taken together with R d ′ to form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In some embodiments, one R d is taken together with R d ′ to form a heterocycloalkyl substituted with one or more alkyl groups. In some embodiments, one R d is optionally substituted alkyl and the other R d is taken together with R d ′ to form a heterocycloalkyl substituted with one or more alkyl groups. In some embodiments, the alkyl is substituted with oxo and —OH.
- the alkyl is substituted with oxo and alkyl further substituted with halogen (e.g., fluoro or chloro).
- the heterocycloalkyl is an optionally substituted dioxolane.
- the optionally substituted dioxolane is 2,2-dimethyl-1,3-dioxolane.
- the optionally substituted dioxolane is 1,4-dioxaspiro[4.4]nonane.
- each R d is independently hydrogen or optionally substituted alkyl and R d ′ is hydrogen. In some embodiments, each R d is independently hydrogen or optionally substituted alkyl and R d ′ is C 1 -C 3 alkyl. In some embodiments, each R d is independently optionally substituted alkyl and R d ′ is hydrogen. In some embodiments, each R d is independently —OH or optionally substituted alkyl and R d ′ is hydrogen. In some embodiments, each R d is independently —COOH or optionally substituted alkoxy and R d ′ is hydrogen.
- each R d is independently —OH or optionally substituted alkyl and R d ′ is C 1 -C 3 alkyl. In some embodiments, each R d is independently —OH or optionally substituted alkyl and R d ′ is —OH. In some embodiments, each R d is independently —OH or optionally substituted alkyl and R d ′ is alkyl (e.g., alkenyl). In some embodiments, each R d is independently hydrogen or —OH and R d ′ is hydrogen. In some embodiments, each R d is independently —OH or —COOH and R d ′ is hydrogen. In some embodiments, each R d and R d ′ are hydrogen.
- each R d is optionally substituted alkenyl and R d ′ is optionally substituted alkoxy. In some embodiments, each R d is taken together to form an oxo and R d ′ is hydrogen. In some embodiments, one R d is optionally substituted alkyl and the other R d is taken together with R d ′ is to form an optionally substituted heterocycloalkyl.
- the alkyl or heteroalkyl of R d or R d ′ is substituted with one or more of the group consisting of —SH, —OH, —COOH, oxo, halogen, amino (e.g., dihydroamino, alkylamino, or arylamino), alkyl (e.g., alkenyl, alkynyl), heteroalkyl, ester, amide, sulfonic acid, and sulfone.
- one R d is taken together with R d ′ to form substituted heterocycloalkyl.
- the alkyl of R d is substituted with oxo and alkyl further substituted with hydroxyl. In some embodiments, the alkyl of R d is substituted with oxo and alkyl further substituted with halogen (e.g., fluorine or chlorine). In some embodiments, the alkyl of R d is substituted with oxo and C 1 -C 3 alkyl. In some embodiments, the alkyl of R d is substituted with oxo and alkyl further substituted with alkoxy further substituted with oxo and C 1 -C 3 alkyl.
- halogen e.g., fluorine or chlorine
- the alkyl of R d is substituted with alkyl and alkyl further substituted with oxo and amino further substituted with alkyl further substituted with sulfonic acid. In some embodiments, the alkyl of R d is substituted with oxo and thiol (e.g., thioether) further substituted with C 1 -C 3 alkyl further substituted with halogen (e.g., fluorine or chlorine). In some embodiments, the alkyl of R d is substituted with —OH.
- the alkyl of R d is substituted with oxo and hydroxyl (e.g., ether) further substituted with C 1 -C 3 alkyl further substituted with halogen (e.g., fluorine or chlorine).
- the alkoxy of R d is substituted with oxo and alkoxy further substituted with alkyl.
- the C 1 -C 3 alkyl is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some embodiments, the C 1 -C 3 alkyl is methyl. In some embodiments, the C 1 -C 3 alkoxy is methoxy, ethyoxy, propyoxy, or isopropoxy. In some embodiments, the C 1 -C 3 alkyl is methoxy.
- the first radical and the second radical are joined by a linker (e.g., a bond).
- the first radical is joined to the second radical through any one of R a , R b , R c , or R d of the first radical.
- the first radical is joined to the second radical through any one of R a , R b , R c , or R d , and the R a , R b , R c , or R d through which the first radical is joined to the second radical comprises a hydroxyl radical (e.g., when together with the linker or second radical (where the linker is a bond), forms an ether), a thiol radical (e.g., when together with the linker or second radical (where the linker is a bond), forms a thioether), or a carboxylate radical (e.g., when taken together with the linker or second radical (where the linker is a bond), forms an ester or carbonate).
- a hydroxyl radical e.g., when together with the linker or second radical (where the linker is a bond)
- a thiol radical e.g., when together with the linker or second radical (where the linker is a bond)
- connection between the thiol radical forms a thioester, a disulfide, or a thiocarbonate.
- connection between the carboxylate radical forms an anhydride.
- the first radical is joined to the second radical through any one of R a , R b , R c , or R d , and the R a , R b , R c , or R d through which the first radical is joined to the second radical comprises an amino radical (e.g., when together with the linker or second radical (where the linker is a bond), forms an amide, carbamate, or thiocarbamate).
- the R a , R b , R c , or R d through which the first radical is joined to the second radical comprises a hydroxyl radical which together with the linker or with the second radical forms an ether. In some embodiments, the R a , R b , R c , or R d through which the first radical is joined to the second radical comprises a thiol radical which together with the linker or the second radical forms a thioether. In some embodiments, the R a , R b , R c , or R d through which the first radical is joined to the second radical comprises a carboxylate radical which together with the linker or the second radical forms an ester or a carbonate.
- the first radical has a structure of Formula (I), Formula (IA), Formula (IB), or Formula (IC) and the second radical does not have a structure of Formula (I), Formula (IA), Formula (IB), or Formula (IC).
- the structure of Formula (I), Formula (IA), Formula (IB), or Formula (IC) has a melt and/or glass transition temperature at a temperature of at least 20° C. (e.g., at least 25° C., at least 30° C., at least 37° C., at least 40° C., at least 50° C., at least 100° C., or more) in its free form.
- both the first radical and the second radical consist of the three-membered ring system of Formula (I), Formula (IA), Formula (IB), or Formula (IC).
- the first radical is a central nervous system (CNS) agent.
- the radical of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is a steroid, an opioid agonist, an opioid antagonist, an adrenergic receptor antagonist (e.g., ⁇ -blocker, ⁇ -1 blocker), or a serotonergic antagonist (e.g., serotonin 5-HT3 receptor antagonist).
- the first radical is an anti-inflammatory agent, an anti-psychotic agent (e.g., typical anti-psychotic, a typical antipsychotic, schizophrenia, or the like), or the like.
- the IOP lowering agent is a beta-blocker.
- the beta-blocker is timolol.
- the second radical is an intraocular pressure (IOP) lowering agent.
- the first radical is an anti-inflammatory agent and the second radical is an intraocular pressure (IOP) lowering agent.
- the first radical is an IOP lowering steroid (e.g., anecortave) or benign steroid (e.g., cholesterol) and the second radical is an IOP lowering agent.
- the IOP lowering agent is a prostaglandin.
- the first radical is a solid (e.g., having a melting point of at least 30° C.) in its free form.
- the second radical is a liquid (e.g., having a melting point of less than 30° C.) in its free form.
- the first radical is a steroid (e.g., dexamethasone, anecortave, etc.).
- the steroid is a corticosteroid (e.g., glucocorticoid or mineral corticoid), a sex steroid, a neurosteroid, an aminosteroid, or a secosteroid.
- the second radical is not a steroid (or does not have a structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC)).
- the first radical is a steroid and the second radical is a prostaglandin.
- the second radical has a structure of Formula (II):
- R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted.
- any one of R 1 , R 2 , R 3 , R 4 , or R 5 are taken together to form an optionally substituted cycloalkyl or heterocycloalkyl.
- X is selected from the group consisting of —O—, —NR—, —S(R) a —, and —C(R) b —.
- a is independently 0-2.
- b is independently 1 or 2. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound of Formula (II).
- X is S, —C(R) 1 —, or —C(R) 2 —. In some embodiments, X is S attached to a single bond. In some embodiments, X is —CH— or —CH 2 —.
- R 4 is alkyl substituted with one or more groups, each group being independently selected from —C( ⁇ O)OC 1 -C 3 alkyl, —COOH, —CONH 2 , —CONHC 1 -C 3 alkyl, and/or alkyl (e.g., alkylene or alkenyl).
- R 4 is alkyl substituted with —COOH.
- R 4 is alkyl substituted with —C( ⁇ O)OC 1 -C 3 alkyl.
- R 4 is alkyl substituted with —CONH 2 .
- R 4 is alkyl substituted with —CONHC 1 -C 3 alkyl.
- the alkyl of R 4 comprises at least one double bond. In some embodiments, the alkyl of R 4 comprises one double bond. In some embodiments, the alkyl of R 4 comprises two double bonds. In some embodiments, the two double bonds form an allene.
- R 5 is alkyl substituted with one or more groups, each group being independently selected from halogen, —OH, oxo, alkyl (e.g., alkynyl), alkoxy, aryl, and aryloxy, wherein alkyl (e.g., alkynyl), aryl, or aryloxy is optionally substituted.
- the alkyl is substituted with one or more groups, each group being independently selected from halogen, —OH, oxo, alkyl (e.g., alkynyl), aryl, or aryloxy, wherein the alkyl (e.g., alkynyl), aryl, or aryloxy is optionally substituted.
- the aryl or aryloxy is substituted with one or more halogen groups.
- the aryl or aryloxy is unsubstituted.
- the second radical has a structure of Formula (IIA):
- each is independently a single bond or a double bond.
- R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted.
- Formula (IIA) comprises three double bonds. In some embodiments, Formula (IIA) comprises two double bonds. In some embodiments, Formula (IIA) comprises one double bond.
- R 1 and R 3 are each independently —OH or oxo. In some embodiments, R 1 is oxo, R 2 is hydrogen, and R 3 is —OH. In some embodiments, R 3 is oxo, R 2 is hydrogen, and R 1 is —OH. In some embodiments, R 1 and R 3 are each —OH and R 2 is hydrogen.
- R 4 is —C( ⁇ O)OC 1 -C 3 alkyl, —COOH, —CONH 2 , or —CONHC 1 -C 3 alkyl. In some embodiments, R 4 is —COOH. In some embodiments, R 4 is —CONH 2 .
- R 5 is alkyl or aryloxy, wherein the alkyl and aryloxy are optionally substituted.
- R 5 is alkyl.
- the alkyl is butyl or hexyl.
- R 5 is alkyl substituted with optionally substituted aryl or optionally substituted alkyl.
- the alkyl is substituted with unsubstituted aryl.
- the alkyl is substituted with alkyl (e.g., but-2-yne).
- R 5 is unsubstituted aryloxy.
- R 5 is aryloxy substituted with one or more alkyl (e.g., —CF 3 ) or halo (fluoro or chloro) groups. In some embodiments, the aryloxy is substituted with —CF 3 .
- R 6 and R 6′ are each fluoro. In some embodiments, R 6 is H or methyl and R 6′ is —OH. In some embodiments, R 6 is H and R 6′ is —OH. In some embodiments, R 6 is methyl and R 6′ is —OH. In some embodiments, R 6 and R 6′ are taken together to form an oxo.
- R 3 and R 4 of Formula (II) are taken together to form an optionally substituted cycloalkyl or heterocycloalkyl. In some embodiments, R 3 and R 4 of Formula (II) are taken together to form heterocycloalkyl substituted with optionally substituted alkyl (e.g., alkenyl). In some embodiments, R 3 and R 4 of Formula (II) are taken together to form a heterocycloalkyl substituted with alkyl (e.g., alkenyl) substituted with —COOH or —C( ⁇ O)OC 1 -C 3 alky.
- the heterocycloalkyl is substituted with alkyl further substituted with —COOH or —C( ⁇ O)OC 1 -C 3 alkyl. In some embodiments, the heterocycloalkyl is substituted with alkenyl further substituted with alkyl, which is further substituted with —COOH or —C( ⁇ O)OC 1 -C 3 alkyl. In some embodiments the alkyl or alkenyl is substituted with —COOH.
- the second radical has a structure of Formula (IIB):
- R 1 , R 2 , and R 5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted.
- R 6′′ is oxo or —OH.
- Y 1 and Y 2 are each independently a bond or alkylene.
- G is O or CH 2 .
- g is 1 or 2.
- R 10 is alkyl or H. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound of Formula (IIB).
- G is O and Y 1 is a bond.
- Y 2 is methylene.
- g is 1.
- G is O and Y 1 is a alkylene.
- Y 2 is a bond.
- g is 2.
- R 1 is oxo or —OH. In some embodiments, R 1 is —OH. In some embodiments, R 1 is —OH and R 2 is hydrogen. In some embodiments, R 6′′ is —OH. In some embodiments, R 5 is alkyl. In some embodiments, R 5 is substituted aryl.
- G is O, Y 1 is a bond, Y 2 is methylene, g is 1, R 1 is —OH, R 2 is hydrogen, R 5 is alkyl, R 6′′ is —OH, and R 10 is H.
- G is O, Y 1 is a methylene, Y 2 is a bond, g is 2, R 1 is —OH, R 2 is hydrogen, R 5 is substituted aryl, R 6′′ is —OH, and R 10 is H or C 1 -C 3 alkyl.
- R 5 is selected from one or more of the group consisting of —O—, —OH, halogen, alkyl (e.g., alkynyl), aryl, wherein the alkyl (e.g., alkynyl) and aryl are optionally substituted with one or more of alkyl (e.g., fluoroalkyl), halogen, and —OH.
- R 5 is optionally substituted aryl or optionally substituted —O-aryl.
- R 5 is alkyl or aryloxy, wherein the alkyl and optionally substituted aryloxy. In some embodiments, R 5 is alkyl.
- the alkyl is butyl or hexyl.
- R 5 is unsubstituted aryloxy. In some embodiments, the aryloxy is substituted with one or two —F. In some embodiments, R 5 is an aryl or O-aryl, each of which is unsubstituted. In some embodiments, R 5 is an aryl or O-aryl, each of which is substituted with one or more of halogen or haloalkyl (e.g., trifluoroalkyl, e.g., trifluoromethyl).
- halogen or haloalkyl e.g., trifluoroalkyl, e.g., trifluoromethyl
- a compound comprising a first radical or a second radical, wherein the first radical has a structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) and the second radical has a structure of any one of Formula (II), Formula (IIA), or Formula (IIB).
- the first radical e.g., having a structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC)
- the second radical e.g., Formula (II), Formula (IIA), or Formula (IIB)
- the linker is a bond.
- provided herein is a compound comprising a steroid. In some embodiments, provided herein is a compound comprising a prostaglandin. In some embodiments, provided herein is a compound comprising a linker (e.g., hydrolyzable linker). In some embodiments, the linker adjoins (e.g., covalently) the steroid and the prostaglandin. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound.
- each R d , R b , R c , and R d are independently selected from the group consisting of oxo, halogen, —CN, —NO 2 , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted.
- any one of R a , R b , R c , and R d are taken together with another of R d , R b , R c , and R d to form an substituted or unsubstituted cycloalkyl or heterocycloalkyl.
- each of m, n, o, and p are independently 0-6.
- R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted.
- L is a linker.
- any one of the groups of Formula (III) are as provided elsewhere herein (e.g., as in for Formula (IB) or Formula (II)).
- R a is hydrogen, —OH, or oxo.
- each R a ′ is independently selected from hydrogen, —OH, halogen, C 1 -C 3 alkyl, and alkoxy.
- R a ′′ is absent, hydrogen, or C 1 -C 3 alkyl.
- R b is absent, hydrogen, halogen, or C 1 -C 3 alkyl.
- R b ′ is hydrogen, halogen, —OH, oxo, or C 1 -C 3 alkyl.
- R b ′′ is hydrogen or —OH.
- each R c is independently hydrogen, —OH, oxo, or C 1 -C 3 alkyl.
- each R c ′ is independently hydrogen or C 1 -C 3 alkyl.
- R c ′′ is hydrogen, —OH, C 1 -C 3 alkyl, or —C( ⁇ O)H.
- each R d is independently hydrogen, —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or each R d is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted.
- R d ′ is hydrogen, —OH, C 1 -C 3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl.
- one R d is taken together with R d ′ to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl.
- R 1 , R 2 , R 3 , R 4 , and R 6 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted.
- R 6 and R 6′ are each independently hydrogen, halogen, alkyl, or R 6 and R 6′ are taken together to form an oxo.
- R a is hydrogen, —OH, or oxo.
- each R d ′ is independently selected from hydrogen, —OH, halogen, C 1 -C 3 alkyl, and alkoxy.
- R d ′′ is absent, hydrogen, or C 1 -C 3 alkyl.
- R b is absent, hydrogen, halogen, or C 1 -C 3 alkyl.
- R b ′ is hydrogen, halogen, —OH, oxo, or C 1 -C 3 alkyl.
- R b ′′ is hydrogen or —OH.
- each R c is independently hydrogen, —OH, oxo, or C 1 -C 3 alkyl.
- each R c ′ is independently hydrogen or C 1 -C 3 alkyl.
- R c ′′ is hydrogen, —OH, C 1 -C 3 alkyl, or —C( ⁇ O)H.
- each R d is independently hydrogen, —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or each R d is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted.
- R d ′ is hydrogen, —OH, C 1 -C 3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl.
- one R d is taken together with R d ′ to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl.
- R 1 , R 2 , and R 5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted.
- R 6′′ is oxo or —OH.
- Y 1 and Y 2 are each independently a bond or alkylene.
- G is O or CH 2 .
- g is 1 or 2.
- R 1′ is alkyl or H.
- L is a linker.
- a hydroxyl radical or a carboxylate radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a hydroxyl radical or a carboxylate radical of another of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) through a linker.
- a hydroxyl radical or a carboxylate radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a hydroxyl radical or a carboxylate radical of any one of Formula (II), Formula (IIA), or Formula (IIB) through a linker.
- a hydroxyl radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a hydroxyl radical of any one of Formula (II), Formula (IIA), or Formula (IIB) through a linker.
- a hydroxyl radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a carboxylate radical of any one of Formula (II), Formula (IIA), or Formula (IIB) through a linker.
- a carboxylate radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a hydroxyl radical of any one of Formula (II), Formula (IIA), or Formula (IIB) through a linker.
- a carboxylate radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a carboxylate radical of any one of Formula (II), Formula (IIA), or Formula (IIB) through a linker.
- the linker is a bond. In some embodiments, the linker is oxo.
- any one of R a , R a ′, R b , R b ′, R b ′′, R c , R c ′′, R d , or R d ′ is an ester radical, a hydroxyl radical, or a carboxylate radical
- any one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6′ , R 6′′ , or R 10 is an amide radical, a thiol radical, a hydroxyl radical, or a carboxylate radical.
- any one of R a , R a ′, R b , R b ′, R b ′′, R c , R c ′′, R d , or R d ′ is an ester radical, a hydroxyl radical, or a carboxylate radical
- any one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6′ , R 6′′ , or R 10 is a hydroxyl radical or a carboxylate radical.
- any radical of R a , R a ′, R b , R b ′, R b ′′, R c , R c ′′, R d , or R d ′ is adjoined to any radical of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6′ , R 6′′ , or R 10 by a linker.
- any radical of R a , R a ′, R b , R b ′, R b ′′, R c , R c ′′, R d , or R d ′ is adjoined to any radical of R 4 , R 5 , R 6 , R 6′ , R 6′′ , or R 10 by a linker.
- any radical of R a , R b , R c , or R d is adjoined to any radical of R 4 , R 5 , R 6 , R 6′ , R 6′′ , or R 10 by a linker.
- any radical of R d or R d ′ is adjoined to any radical of R 4 , R 5 , R 6 , R 6′ , R 6′′ , or R 10 by a linker.
- a radical of R d is adjoined to any radical of R 4 , R 6 , R 6′ , R 6′′ , or R 10 by a linker.
- a radical of R d is adjoined to a radical of R 4 or R 10 by a linker.
- a radical of of R d is adjoined to any radical of R 6 , R 6′ , or R 6′′ by a linker.
- the linker is oxo. In some embodiments, the linker is a bond.
- the linker is a bond, alkyl, heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy is optionally substituted.
- the alkyl, heteroalkyl, or alkoxy are each independently substituted with one or more groups, each group being independently selected from the group consisting of —O—, —S—, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl.
- the linker is alkyl (alkylene) and the alkyl (alkylene) is substituted with one or more groups selected from —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl.
- the linker is an unsubstituted alkyl (alkylene).
- the linker is heteroalkyl (heteroalkylene) and the heteroalkyl (heteroalkylene) is substituted with one or more groups selected from halo or alkyl.
- the linker is unsubstituted heteroalkyl (heteroalkylene).
- the linker is a bond.
- the linker comprises one or more linker group, each linker group being independently selected from a bond, alkyl, cycloalkyl, heteroalkyl, or alkoxy, wherein the alkyl, cycloalkyl, heteroalkyl, or alkoxy is optionally substituted.
- the linker is a bond, alkyl, cycloalkyl, heteroalkyl, or alkoxy, wherein the alkyl, cycloalkyl, heteroalkyl, or alkoxy is optionally substituted.
- the alkyl, cycloalkyl, heteroalkyl, or alkoxy are each independently substituted with one or more substitutent, each substituent being independently selected from the group consisting of —O— (e.g., —OH), —S— (e.g., —SH), silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl.
- —O— e.g., —OH
- —S— e.g., —SH
- silicone amino
- optionally substituted alkyl e.g., alkenyl, alkynyl, branched (e.g., polypropylene
- haloalkyl optionally substituted heteroalkyl (e.g, polyTHF)
- the linker comprises one or more linker group, each linker group being independently selected from alkyl (alkylene) and cycloalkyl (cycloalkylene).
- the linker is alkyl (alkylene) or cycloalkyl (cycloalkylene).
- the alkyl (alkylene) or cycloalkyl (cycloalkylene) is unsubstituted or substituted with one or more substituent, each substituent being independently selected from the group consisting of —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl.
- the linker comprises an unsubstituted or substituted alkylene-cycloalkylene-alkylene.
- the linker comprises at least one oxo. In some embodiments, the linker is oxo. In some embodiments, the linker comprises at least one carbamate. In some embodiments, the linker is a carbamate. In some embodiments, the linker comprises at least one ester. In some embodiments, the linker is an ester.
- the linker comprises one or more linker groups selected from oxo, —O—, —S—, unsubstituted alkylene, C ⁇ O(CH 2 CH 2 ) n C ⁇ O, C ⁇ O(CHCH) n C ⁇ O, C ⁇ O(OCH 2 CH 2 O) n C ⁇ O, O(CH 2 CH 2 O) n , and C ⁇ O(CH 2 CH 2 O) n , (CH(CH 3 )C( ⁇ O)O) n , wherein n is 1-20.
- the linker is a bond, unsubstituted alkylene, C ⁇ O(CH 2 CH 2 ) n C ⁇ O, C ⁇ O(CHCH) n C ⁇ O, C ⁇ O(OCH 2 CH 2 O) n C ⁇ O, O(CH 2 CH 2 O) n , C ⁇ O(CH 2 CH 2 O) n , (CH(CH 3 )C( ⁇ O)O) n , and C ⁇ O(CH 2 CH 2 ) n C ⁇ O(CH(CH 3 )C( ⁇ O)O) n , wherein n is 1-20. In some embodiments, n is 1-10. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.
- the linker comprises one or more linker group, each linker group being independently selected from the group consisting of a bond, —O—, —O(C ⁇ O)—, —O(C ⁇ O)—O—, —S—, unsubstituted alkylene, unsubstituted cycloalkylene, C ⁇ O(CH 2 CH 2 ) n C ⁇ O, C ⁇ O(CHCH) n C ⁇ O, C ⁇ O(OCH 2 CH 2 O) n C ⁇ O, O(CH 2 CH 2 O) n , and C ⁇ O(CH 2 CH 2 O) n , and (CH(CH 3 )C( ⁇ O)O) n , wherein n is 1-20.
- the linker is a bond, unsubstituted alkylene, unsubstituted alkylene-cycloalkylene-alkylene, C ⁇ O(CH 2 CH 2 ) n C ⁇ O, C ⁇ O(CHCH) n C ⁇ O, C ⁇ O(OCH 2 CH 2 O) n C ⁇ O, O(CH 2 CH 2 O) n , and C ⁇ O(CH 2 CH 2 O) n , (CH(CH 3 )C( ⁇ O)O) n , C ⁇ O(CH 2 CH 2 ) n C ⁇ O(CH(CH 3 )C( ⁇ O)O) n , wherein n is 1-20. In some embodiments, n is 1-10. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.
- the linker is hydrolyzed in a buffered solution. In some embodiments, the linker is hydrolytically labile. In some embodiments, the linker is hydrolyzed by water. In some embodiments, the linker is hydrolyzed by an enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a protease or an esterase). In some embodiments, the enzyme is an esterase.
- the enzyme is a hydrolase (e.g., a protease or an esterase). In some embodiments, the enzyme is an esterase.
- the first radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- the first radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- the second radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- the second radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- the first radical is a hydroxyl radial. In some embodiments, the second radical is a hydroxyl radial. In some embodiments, the first radical is a carboxyl radical. In some embodiment, the second radical is a carboxyl radical.
- R 7 is hydrogen or halogen. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro. In some embodiments, R 8 is a hydrogen or a C 1 -C 4 alkyl. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl, ethyl, propyl or butyl. In some embodiments, R 8 is methyl, ethyl, or butyl. In some embodiments, R 8 is methyl. In some embodiments, R 7 is hydrogen and R 8 is methyl. In some embodiments, R 9 is absent, hydrogen or hydroxyl. In some embodiments, R 9 is hydrogen.
- R 9 is hydroxyl. In some embodiments, R 9 is absent. In some embodiments, L is a linker. In some embodiments, L is a linker described herein. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker group, each linker group being independently selected from the group consisting of an alkylene, cycloalkylene and —O—. In some embodiments, PG is a prostaglandin radical. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VI).
- a compound provided herein has the structure of formula (VI-A):
- R 7 is hydrogen or halogen. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro. In some embodiments, R 8 is a hydrogen or a C 1 -C 4 alkyl. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl, ethyl, propyl or butyl. In some embodiments, R 8 is methyl, ethyl, or butyl. In some embodiments, R 8 is methyl. In some embodiments, R 7 is hydrogen and R 8 is methyl. In some embodiments, L is a linker. In some embodiments, L is a bond.
- L comprises one or more linker group, each linker group being independently selected from the group consisting of an alkylene, cycloalkylene or —O—.
- PG is a prostaglandin radical. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VI-A).
- a compound provided herein has the structure of formula (VI-B):
- R 7 is hydrogen or halogen. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro. In some embodiments, R 8 is a hydrogen or a C 1 -C 4 alkyl. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl, ethyl, propyl or butyl. In some embodiments, R 8 is methyl, ethyl, or butyl. In some embodiments, R 8 is methyl. In some embodiments, R 7 is hydrogen and R 8 is methyl. In some embodiments, R 9 is absent, hydrogen or hydroxyl. In some embodiments, R 9 is hydrogen.
- R 9 is hydroxyl. In some embodiments, R 9 is absent. In some embodiments, L is a linker. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker group, each linker group being independently selected from the group consisting of an alkylene, cycloalkylene or —O—. In some embodiments, PG is a prostaglandin radical. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VI-B).
- a compound provided herein has the structure of formula (VI-C):
- L is a linker. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker group, each linker group being independently selected from the group consisting of an alkylene, cycloalkylene or —O—. In some embodiments, PG is a prostaglandin radical. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VI-B).
- PG prostaglandin
- G is OH and Y 1 is hydrogen. In some embodiments, G together with Y 1 form —O—CH 2 —. In some embodiments, Y 2 is a bond or —CH 2 —. In some embodiments, g is 1 or 2. In some embodiments, Z is —O— or —CH 2 —. In some embodiments, R 6 and R 6′ are each independently hydrogen, halogen or OH. In some embodiments, R 11 is —OR 13 , or —NR 13′ R 13′′ . In some embodiments, R 13 , R 13′ and R 13′′ are each independently hydrogen or a C 1 -C 3 alkyl.
- each R 12 is independently halogen or haloalkyl. In some embodiments, u is 0-5. In some embodiments, R 6 and R 6′ are each fluoro. In some embodiments, R 6 is OH and R 6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH 2 —. In some embodiments, each R 12 is F and u is 2. In some embodiments, CF 3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R 11 is OH. In some embodiments, R 11 is —NHCH 2 CH 3 . In some embodiments, R 11 is —OCH(CH 3 ) 2 .
- the prostaglandin (PG) radical provided herein has the formula (VII-A):
- Z is —O— or —CH 2 —.
- R 6 and R 6′ are each independently hydrogen, halogen or OH.
- R 11 is —OR 13 , or —NR 13 , R 13′′ .
- R 13 , R 13′ and R 13′′ are each independently hydrogen or a C 1 -C 3 alkyl.
- each R 12 is independently halogen or haloalkyl.
- u is 0-5.
- R 6 and R 6′ are each independently fluoro.
- R 6 is OH and R 6′ is hydrogen.
- Z is —O—.
- Z is —CH 2 —.
- R 12 is F and u is 2.
- CF 3 and u is 1.
- u is 0.
- u is 1.
- u is 2.
- u is 3.
- u is 4.
- u is 5.
- R 11 is OH.
- R 11 is —NHCH 2 CH 3 .
- R 11 is —OCH(CH 3 ) 2 .
- the prostaglandin (PG) radical has the formula (VII-B):
- Z is —O— or —CH 2 —.
- R 6 and R 6′ are each independently hydrogen, halogen or OH.
- R 11 is —OR 13 , or —NR 13′ R 13′′ .
- R 13 , R 13′ and R 13′′ are each independently hydrogen or a C 1 -C 3 alkyl.
- each R 12 is independently halogen or haloalkyl.
- u is 0-5.
- R 6 and R 6′ are each independently fluoro.
- R 6 is OH and R 6′ is hydrogen.
- Z is —O—.
- Z is —CH 2 —.
- R 12 is F and u is 2.
- CF 3 and u is 1.
- u is 0.
- u is 1.
- u is 2.
- u is 3.
- u is 4.
- u is 5.
- R 11 is OH.
- R 11 is —NHCH 2 CH 3 .
- R 11 is —OCH(CH 3 ) 2 .
- the radical e.g., a PG radical
- the radical is attached to a linker (e.g., L) provided herein.
- the PG radical is attached to a linker (e.g., L) and the linker is further attached to a steroid radical (e.g., provided herein).
- R 11 is a radical (e.g., a hydroxyl radical or an amino radical) attached to a linker (e.g., a radical of a linker) provided herein (e.g., and the linker (e.g., another radical of the linker) is further attached to a steroid radical provided herein).
- R 6 or R 6′ is a radical (e.g., a hydroxyl radical) attached to a linker (e.g., a radical of a linker) provided herein (e.g., and the linker (e.g., another radical of the linker) is further attached to a steroid radical provided herein).
- a linker e.g., a radical of a linker
- the linker e.g., another radical of the linker
- R 6 and R 6′ are each independently hydrogen, halogen or OH.
- R n is —OR 13 or —NR 13′ R 13′′ .
- each R 12 is independently halogen or haloalkyl.
- R 13 , R 13′ and R 13′′ are each independently hydrogen or a C 1 -C 3 alkyl.
- u is 0-5.
- R 6 and R 6′ are each independently fluoro.
- R 6 is OH and R 6′ is hydrogen.
- Z is —O—.
- Z is —CH 2 —.
- R 12 is F and u is 2.
- R 12 is CF 3 and u is 1.
- u is 0.
- u is 1.
- u is 2.
- u is 3.
- u is 4. In some embodiments, u is 5. In some embodiments, R 11 is OH. In some embodiments, R 11 is —NHCH 2 CH 3 . In some embodiments, R 11 is —OCH(CH 3 ) 2 .
- Provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VIII).
- L is a linker.
- A is a steroid radical.
- Z is —O— or —CH 2 —.
- R 6 and R 6′ are each independently hydrogen, halogen or OH;
- R 11 is —OR 13 , or —NR 13′ R 13′′ .
- each R 12 is independently halogen or haloalkyl.
- R 13 , R 13′ and R 13′′ are each independently hydrogen or a C 1 -C 3 alkyl.
- u is 0-5.
- R 6 and R 6′ are each independently fluoro.
- R 6 is OH and R 6′ is hydrogen.
- Z is —O—. In some embodiments, Z is —CH 2 —. In some embodiments, R 12 is F and u is 2. In some embodiments, R 12 is CF 3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R 11 is OH. In some embodiments, R 11 is —NHCH 2 CH 3 . In some embodiments, R 11 is —OCH(CH 3 ) 2 . Provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VIII-A).
- L is a linker.
- A is a steroid radical.
- Z is —O— or —CH 2 —.
- R 6 and R 6′ are each independently hydrogen, halogen or OH.
- R 11 is —OR 13 , or —NR 13′ R 13′′ .
- each R 12 is independently halogen or haloalkyl.
- R 13 , R 13′ and R 13′′ are each independently hydrogen or a C 1 -C 3 alkyl.
- u is 0-5.
- R 6 and R 6′ are each independently fluoro.
- R 6 is OH and R 6′ is hydrogen.
- Z is —O—.
- Z is —CH 2 —.
- R 12 is F and u is 2.
- R 12 is CF 3 and u is 1.
- u is 0.
- u is 1.
- u is 2.
- u is 3.
- u is 4.
- u is 5.
- R 11 is OH.
- R 11 is —NHCH 2 CH 3 .
- R 11 is —OCH(CH 3 ) 2 .
- Provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VIII-B).
- R 11 is a radical (e.g., a hydroxyl radical or an amino radical) attached to L.
- R 6 or R 6′ is a radical (e.g., a hydroxyl radical) attached to L.
- L is a bond.
- L comprises one or more linker group, each linker group being independently selected from the group consisting of an alkylene, cycloalkylene or —O—.
- A has the structure:
- R 7 is hydrogen or halogen.
- R 8 is a hydrogen or a C 1 -C 4 alkyl.
- R 9 is absent, hydrogen or hydroxyl.
- R 7 is hydrogen.
- R 7 is fluoro.
- R 8 is hydrogen.
- R 8 is methyl, ethyl, propyl or butyl.
- R 8 is methyl, ethyl or butyl.
- R 8 is methyl.
- R 9 is hydroxyl.
- A has the structure:
- R 7 is hydrogen or halogen.
- R 8 is a hydrogen or a C 1 -C 4 alkyl.
- R 9 is absent, hydrogen or hydroxyl.
- R 7 is hydrogen.
- R 7 is fluoro.
- R 8 is hydrogen.
- R 8 is methyl, ethyl, propyl or butyl.
- R 8 is methyl, ethyl or butyl.
- R 8 is methyl.
- A has the structure:
- R 7 is hydrogen or halogen.
- R 8 is a hydrogen or a C 1 -C 4 alkyl.
- R 9 is absent, hydrogen or hydroxyl.
- R 7 is hydrogen.
- R 7 is fluoro.
- R 8 is hydrogen.
- R 8 is methyl, ethyl, propyl or butyl.
- R 8 is methyl, ethyl or butyl.
- R 8 is methyl.
- R 9 is hydroxyl.
- A has the structure:
- each is independently a single bond or a double bond.
- G is OH and Y 1 is hydrogen. In some embodiments, G together with Y 1 form —O—CH 2 —. In some embodiments, Y 2 is a bond or —CH 2 —. In some embodiments, g is 1 or 2.
- Z is —O— or —CH 2 —.
- R 6 and R 6′ are each independently hydrogen, halogen or OH. In some embodiments, each R 12 is independently halogen or haloalkyl. In some embodiments, u is 0-5. In some embodiments, Z is —O— or —CH 2 —.
- R 6 and R 6′ are each independently hydrogen, halogen or OH. In some embodiments, each R 12 is independently halogen or haloalkyl. In some embodiments, R 6 and R 6′ are each fluoro. In some embodiments, R 6 is OH and R 6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH 2 —. In some embodiments, R 12 is F and u is 2. In some embodiments, R 12 is CF 3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (IX).
- each is independently a single bond or a double bond.
- L is a linker. In some embodiments, L is a bond. In some embodiments, L is —(C ⁇ O)—, or —O— (C ⁇ O)—.
- G is OH and Y 1 is hydrogen. In some embodiments, G together with Y 1 form —O—CH 2 —. In some embodiments, Y 2 is a bond or —CH 2 —. In some embodiments, g is 1 or 2. In some embodiments, Z is —O— or —CH 2 —.
- R 6 and R 6′ are each independently hydrogen, halogen or OH.
- each R 12 is independently halogen or haloalkyl. In some embodiments, u is 0-5. In some embodiments, Z is —O— or —CH 2 —. In some embodiments, R 6 and R 6′ are each independently hydrogen, halogen or OH. In some embodiments, each R 12 is independently halogen or haloalkyl. In some embodiments, R 6 and R 6′ are each independently fluoro. In some embodiments, R 6 is OH and R 6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH 2 —. In some embodiments, R 12 is F and u is 2. In some embodiments, R 12 is CF 3 and u is 1.
- u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (X).
- a compound provided herein comprises a steroid attached to a second agent (e.g., a prostaglandin) through an optional linker (e.g., travoprost-anecortave), as such, forming a heteroalkyl bond (e.g., an ester, a carbonate, etc.), such as, whereby upon cleavage (e.g., hydrolysis) of the heteroalkyl bond, the steroid and/or second agent are released in their free form.
- a second agent e.g., a prostaglandin
- an optional linker e.g., travoprost-anecortave
- a steroid radical e.g., a first radical
- a hydroxyl radical e.g., anecortave desacetate radical
- a second radical e.g., a prostaglandin radical
- a hydroxyl radical e.g., a carboxylic radical, etc.
- a pharmaceutical composition comprising any compound provided herein, such as a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), or a pharmaceutically-acceptable salt thereof.
- the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient.
- intraocular ophthalmic administration is administration in the eye, such as intraocular, intracameral, intravitreal, suprachoroidal, punctal, retrobulbar, or subconjunctival.
- Another embodiment provides the pharmaceutical composition, wherein the pharmaceutical composition is suitable for subcutaneous administration. Another embodiment provides the pharmaceutical composition, wherein the pharmaceutical composition is suitable for intraspinal administration.
- Another embodiment provides a pharmaceutical implant or article comprising any compound provided herein, such as a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable salt thereof.
- the implant or article comprises at least 50 wt. % (at least 60 wt. %, at least 70 wt. %, at least 80 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %, or the like) of the compound and/or pharmaceutically acceptable salt thereof.
- an article or implant provided herein comprises at least 50 wt. % of a compound as described herein.
- an article or implant provided herein comprises at least 70 wt. % of a compound as described herein.
- an article or implant provided herein comprises at least 90 wt. % of a compound as described herein.
- an article or implant provided herein comprises at least 95 wt. % of a compound as described herein. In some instances, an article or implant provided herein comprises at least 99 wt. % of a compound as described herein. In some instances, an article or implant provided herein comprises an additional component, such as up to 20 wt. %, 15 wt. %, 10 wt. %, 5 wt. %, 1 wt. %, 0.1 wt. %, 0.01 wt. %, or less of the additional component. In some embodiments, an article or implant provided herein comprises up to 5 wt. % (e.g., up to 1 wt. %, up to 0.1 wt.
- an article or implant provided herein comprises up to 5 wt. % (e.g., up to 1 wt. %, up to 0.1 wt. %, or less) of an impurity, such as residual from a manufacturing process, such as provided herein. In some embodiments, an article or implant provided herein comprises up to 5 wt. % (e.g., up to 1 wt. %, up to 0.1 wt. %, or less) of a steroid (as described herein).
- the implant or article releases a (e.g., active) group therefrom, such as when implanted into or otherwise administered to an individual (or when placed into an aqueous medium (e.g., aqueous buffer solution), serum, or other physiological medium, such as at a physiological temperature, such as 37° C.).
- a (e.g., active) group released is the free form of the first radical and/or the second radical.
- a (e.g., active) group released from the compound is an active fragment or metabolite of the first and/or second radical.
- the implant or article undergoes surface erosion to release the compound, the first radical, and/or the second radical (or an (e.g., active) fragment or radical thereof).
- first radical and the second radical are released from the pharmaceutical implant or article at near zero-order in solution (e.g., buffer solution, serum, biological environment, in vivo, or the like).
- the first radical and the second radical (or an (e.g., active) fragment or metabolite thereof) are released from the pharmaceutical implant or article at 37° C. in 100% bovine serum or at 37° C. in phosphate buffered saline (PBS) at a rate such that t 10 is greater than or equal to 1/10 of t50.
- PBS phosphate buffered saline
- a compound or a pharmaceutical composition comprising any compound provided herein, such as a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable salt thereof.
- the composition further comprises an amount of a free form of any radical provided herein, or a combination thereof, such as a free form of a radical having the (e.g., steroid) structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X) (such as wherein the free form is the structure, wherein the free form (e.g., —COO— or —O— thereof) has a negative charge (e.g., as —O ⁇ ) or an H (e.g
- a composition provided herein comprises a (e.g., weight or molar) ratio of a compound provided herein to a free form of any radical provided herein, or a combination thereof, such as a free form of a radical having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), or a pharmaceutically acceptable salt thereof (e.g., wherein the free form is the structure, wherein the free form (e.g., —COO— or —O— thereof) has
- the relative amount of the free form of the radical is 0% to about 50%, such 0% to about 20%, 0% to about 10%, about 0.1% to about 10%, about 0.1% to about 5%, less than 5%, less than 2.5%, less than 2%, or the like (percentages being weight/weight or mole/mole percentages).
- compounds provided herein release free form of any radical provided herein, or a combination thereof, such as a free form of a structure of a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X) (e.g., wherein the free form (e.g., —COO— or —O— thereof) has a negative charge (e.g., as —O ⁇ ) or H (e.g., as —OH), rather than being connected to a linker
- provided herein is a method of treating an ophthalmic disease or disorder in a patient in need thereof, comprising administering to the patient a composition comprising any compound provided herein, such as a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable salt thereof.
- a composition comprising any compound provided herein, such as a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable salt thereof.
- Another embodiment provides the method wherein the ophthalmic disease or disorder is glaucoma.
- ophthalmic disease or disorder is selected from the group consisting of ocular inflammation, diabetic macular edema, posterior inflammation, anterior inflammation, macular degeneration (e.g., wet macular degeneration (AMD)), post-cataract surgery, and retinal vein occlusion.
- macular degeneration e.g., wet macular degeneration (AMD)
- post-cataract surgery e.g., post-cataract surgery
- retinal vein occlusion e.g., retinal vein occlusion
- a composition provided herein comprises a compound provided herein in a therapeutically effective amount (e.g., at a concentration effective to treat an ophthalmic disease or disorder in an individual in need thereof, the method comprising administering to the individual a compound, pharmaceutically acceptable salt, implant, article, or composition having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (V), Formula (V),
- a composition provided herein (e.g., used in a method provided herein) comprises a compound provided herein in a therapeutically effective amount (e.g., at a concentration effective to treat glaucoma, inflammation, and/or lower intraocular pressure) in the eye.
- a (e.g., pharmaceutical and/or ophthalmic) composition provided herein comprises about 0.1 wt. % to about 10 wt. % of a compound provided herein.
- FIG. 1 shows the chemical structure for a prodrug ester and an active pharmaceutical ingredient for a prostaglandin (e.g., travaprost ( FIG. 1A ) and travoprost acid ( FIG. 1B ), respectively) and a steroid (e.g., anecortave acetate ( FIG. 1C ) and anecortave desacetate ( FIG. 1D ), respectively) exemplified herein.
- a prostaglandin e.g., travaprost ( FIG. 1A ) and travoprost acid ( FIG. 1B ), respectively
- a steroid e.g., anecortave acetate ( FIG. 1C ) and anecortave desacetate ( FIG. 1D ), respectively
- FIG. 2 shows the chemical structure ( FIG. 2A ) and the heat processed pellet ( FIG. 2B ) of a steroid-prostaglandin heterodimer (travoprost-anecortave, Compound 1) exemplified herein.
- FIG. 2C shows the drug release profile for Compound 1 (pellet) in fetal bovine serum (FBS) over 15 days.
- FIG. 2D represents the 15-day progression of the surface erosion drug release profile for the pellet of Compound 1 in FBS.
- FIG. 3 shows the chemical structure ( FIG. 3A ) and the heat processed pellet ( FIG. 3B ) of a steroid-prostaglandin heterodimer (travoprost-dexamethasone, Compound 2) exemplified herein.
- FIG. 3C shows the drug release profile for Compound 2 (pellet) in phosphate-buffered saline (PBS) over 30 days.
- FIG. 3D represents the 30-day progression of the (e.g., surface erosion) drug release profile and swelling profile for the pellet of Compound 2 in PBS.
- FIG. 4 shows the chemical structure for a prodrug ester and an active pharmaceutical ingredient for a prostaglandin (e.g., latanoprost ( FIG. 4A ) and latanoprost acid ( FIG. 4B ), respectively) exemplified herein.
- a prostaglandin e.g., latanoprost ( FIG. 4A ) and latanoprost acid ( FIG. 4B ), respectively
- FIG. 5 shows the chemical structure ( FIG. 5A ) and the heat processed pellet ( FIG. 5B ) of a steroid-prostaglandin heterodimer (latanoprost-dexamethasone, Compound 3) exemplified herein.
- FIG. 5C shows the drug release profile for Compound 3 (pellet) in fetal bovine serum (FBS) over 30 days.
- FIG. 5D represents the 30-day progression of the (e.g., surface erosion) drug release profile and swelling profile for the pellet of Compound 3 in FBS.
- FIG. 6 shows the chemical structure ( FIG. 6A ) of a steroid-prostaglandin heterodimer (latanoprost-estrone, Compound 4) exemplified herein.
- FIG. 6B shows the drug release profile for Compound 4 (coating on polymeric substrate) in fetal bovine serum (FBS) over 8 days.
- FIG. 6C represents the 7-day progression of the surface coating drug release of Compound 4 in FBS.
- FIG. 7 shows the chemical structure ( FIG. 7A ) and the heat processed pellet ( FIG. 7B ) of a steroid-prostaglandin heterodimer (bimatoprost-anecortave, Compound 5) exemplified herein.
- FIG. 7C shows the drug release profile for Compound 5 (pellet) in fetal bovine serum (FBS) over 25 days.
- FIG. 7D represents the 28-day progression of the (e.g., surface erosion) drug release profile for the pellet of Compound 5 in FBS.
- FIG. 8 shows the chemical structure ( FIG. 8A ) and the heat processed pellet ( FIG. 8B ) of a steroid-prostaglandin heterodimer (latanoprost-anecortave, Compound 6) exemplified herein.
- FIG. 8C shows the drug release profile for each of latanoprost acid ( ⁇ ) and anecortave desacetate (o) (pellet) in fetal bovine serum (FBS) over 30 days.
- FIG. 8D represents the 28-day progression of the (e.g., surface erosion) drug release profile for the pellet of Compound 6 in FBS.
- FIG. 9 shows the chemical structure ( FIG. 9A ) and the heat processed pellet ( FIG. 9B ) of a steroid-prostaglandin heterodimer (tafluprost-anecortave, Compound 7) exemplified herein.
- FIG. 9C shows the drug release profile for Compound 7 (pellet) in fetal bovine serum (FBS) over 30 days.
- FIG. 9D represents the 28-day progression of the (e.g., surface erosion) drug release profile for the pellet of Compound 7 in FBS.
- FIG. 10 shows an extruded rod of a steroid-prostaglandin heterodimer (bimatoprost-anecortave, Compound 5) exemplified herein ( FIG. 10A ).
- FIG. 10B shows the drug release profile of Compound 5 (extruded rod) in fetal bovine serum (FBS) over 30 days.
- FIG. 10C represents the 30-day progression of the (e.g., surface erosion) drug release profile for the extruded rod of Compound 5 in FBS.
- FIG. 11 shows an extruded rod of a steroid-prostaglandin heterodimer (travoprost-anecortave, Compound 1) exemplified herein ( FIG. 11A ).
- FIG. 11B shows the drug release profile of Compound 1 (extruded rod) in fetal bovine serum (FBS) over 30 days.
- FBS fetal bovine serum
- FIG. 12 shows an extruded rod of a steroid-prostaglandin heterodimer (latanoprost-anecortave, Compound 6) exemplified herein ( FIG. 12A ).
- FIG. 12B shows the drug release profile of Compound 6 (extruded rod) in fetal bovine serum (FBS) over 70 days.
- FIG. 12C represents the 70-day progression of the (e.g., surface erosion) drug release profile for the extruded rod of Compound 6 in FBS.
- FIG. 13 shows an extruded rod of a steroid-prostaglandin heterodimer (tafluprost-anecortave, Compound 7) exemplified herein ( FIG. 13A ).
- FIG. 13B shows the drug release profile of Compound 7 (extruded rod) in fetal bovine serum (FBS) over 100 days.
- FIG. 13C represents the 100-day progression of the (e.g., surface erosion) drug release profile for the extruded rod of Compound 7 in FBS.
- FIG. 14 shows an extruded rod of a steroid-prostaglandin heterodimer (bimatoprost-anecortave, Compound 5) exemplified herein in a rabbit eye.
- FIG. 15 shows the chemical structure ( FIG. 15A ) and the heat processed pellet ( FIG. 15B ) of a steroid-prostaglandin heterodimer (travoprost-cyclohexanedimethanol-anecortave, Compound 8) exemplified herein.
- FIG. 15C shows the drug release profile for Compound 8 (pellet) in fetal bovine serum (FBS) over 8 days.
- FIG. 16 shows the chemical structure of a steroid-prostaglandin heterodimer (travoprost-naltrexone, Compound 9) exemplified herein.
- FIG. 17 shows the chemical structure of a steroid-prostaglandin heterodimer (timolol-deoxycholic acid, Compound 10) exemplified herein.
- FIG. 18 shows purity of Compound 5 before (pre-sterilization) or post sterilization of Compound 5 in ethylene oxide, or by gamma-radiation or E-beam.
- FIG. 19 shows the chemical structure ( FIG. 19A ) and the heat processed pellet ( FIG. 19B ) of a steroid-prostaglandin heterodimer (Bimatoprost (C 15 )-anecortave, Compound 11) exemplified herein.
- Amino refers to the —NH 2 radical (dihydroamino).
- Alkylamino refers to an amino group which is substituted by one or more alkyl groups as defined herein.
- Arylamino referrers to an amino group which substituted by one or more aryl groups as defined herein.
- Niro refers to the —NO 2 radical.
- Oxa refers to the —O— radical.
- Oxo refers to the ⁇ O radical.
- Thioxo refers to the ⁇ S radical.
- Oximo refers to the ⁇ N—OH radical.
- “Hydrazino” refers to the ⁇ N—NH 2 radical.
- Haldrogen refers to the “H” radical.
- Alkyl generally refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl). Unless otherwise stated, alkyl is saturated or unsaturated (e.g., an alkenyl, which comprises at least one carbon-carbon double bond, or alkynyl, which comprises at least one carbon-carbon triple bond). Disclosures provided herein of an “alkyl” are intended to include independent recitations of a saturated “alkyl,” or unsaturated alkyl (alkenyl, alkynyl), unless otherwise stated.
- Alkyl groups described herein are generally monovalent, but may also be divalent (which may also be described herein as “alkylene” or “alkylenylene”, or alkynylene groups).
- an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl).
- an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl).
- an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl).
- an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl).
- an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl).
- an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl).
- the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
- the alkyl is attached to the rest of the molecule by a single bond.
- alkyl groups are each independently substituted or unsubstituted.
- alkyl includes a specific and explicit recitation of an unsaturated “alkyl” group.
- an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t
- Alkoxy refers to a radical bonded through an oxygen atom of the formula —O-alkyl, where alkyl is an alkyl chain as defined above.
- Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is optionally substituted as described for “alkyl” groups.
- Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkenyl is optionally substituted as described for “alkyl” groups.
- Alkylene or “alkylene chain” generally refers to a straight or branched divalent alkyl group linking the rest of the molecule to a radical group, such as having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, i-propylene, n-butylene, and the like. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted as described for alkyl groups herein.
- article generally refers to a pharmaceutical composition that is machined, molded, heat-processed, emulsion-processed, electrospun, electrosprayed, blow molded, or extruded to form a fiber, fiber mesh, woven fabric, non-woven fabric, film, surface coating, pellet, cylinder, rod, microparticle, nanoparticle, or another shaped article.
- Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
- the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hückel theory.
- the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
- aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R
- Alkyl or aryl-alkyl refers to a radical of the formula —R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
- the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
- the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
- Carbocyclyl or “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing single C—C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds).
- saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- An unsaturated carbocyclyl is also referred to as “cycloalkenyl.”
- monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
- Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
- carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R
- Carbocyclylalkyl refers to a radical of the formula —R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
- Carbocyclylalkenyl refers to a radical of the formula —R c -carbocyclyl where R c is an alkenylene chain as defined above. The alkenylene chain and the carbocyclyl radical is optionally substituted as defined above.
- Carbocyclylalkynyl refers to a radical of the formula —R c -carbocyclyl where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
- Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula —O—R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
- Halo or “halogen” refers to bromo, chloro, fluoro or iodo substituents.
- Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
- the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
- heteroalkyl refers to an alkyl group as defined above in which one or more skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriate number of substituents or valencies—for example, —CH 2 — may be replaced with —NH— or —O—).
- each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, selenium, or other suitable heteroatom.
- each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g.
- a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C 1 -C 18 heteroalkyl. In some embodiments, a heteroalkyl is a C 1 -C 12 heteroalkyl.
- a heteroalkyl is a C 1 -C 6 heteroalkyl. In some embodiments, a heteroalkyl is a C 1 -C 4 heteroalkyl. Representative heteroalkyl groups include, but are not limited to —OCH 2 OMe, or —CH 2 CH 2 OMe. In some embodiments, heteroalkyl includes alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl, as defined herein. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted as defined above for an alkyl group.
- Heteroalkylene refers to a divalent heteroalkyl group defined above which links one part of the molecule to another part of the molecule. Unless stated specifically otherwise, a heteroalkylene is optionally substituted, as defined above for an alkyl group.
- Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
- heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
- heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(
- N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
- An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
- C-heterocyclyl or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
- a C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
- Heterocyclylalkyl refers to a radical of the formula —R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain.
- the heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
- Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula —O—R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain.
- the heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
- Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
- the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hückel theory.
- Heteroaryl includes fused or bridged ring systems.
- the heteroatom(s) in the heteroaryl radical is optionally oxidized.
- heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
- heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl (benzothion
- heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—R a , —R b —OC(O)—R
- N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
- An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
- a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- Heteroarylalkyl refers to a radical of the formula —R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
- Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula —O—R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
- the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
- the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
- geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
- positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.
- optionally substituted groups are each independently substituted or unsubstituted.
- substituted groups may be substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t R a (where t is 1 or 2), —
- reference to any atom includes reference to isotopes thereof.
- reference to H includes reference to any isotope thereof, such as a 1 H, 2 H, 3 H, or mixtures thereof.
- anecortave herein refer to “anecortave” in the desacetate form of FIG. 1D ; however, where applicable, recitations of “anecortave” include disclosure of each of the “desacetate” and “acetate” forms.
- opioid or “opiate,” as used interchangeably herein, generally refers to a ligand that binds to an opioid receptor, such as, for example, the delta ( ⁇ )-opioid receptor (DOR), the kappa ( ⁇ )-opioid receptor (KOR), mu ( ⁇ )-opioid receptor (MOR), nociceptin opioid receptor (NOR), zeta ( ⁇ )-opioid receptor (ZOR), or any combination thereof.
- the opioid is an opioid agonist, an opioid antagonist, or a mixed opioid agonist/antagonist of an opioid receptor.
- the opioid agonist is a partial opioid agonist or an inverse opioid agonist.
- the opioid is an opioid radical.
- the opioid radical is joined to a radical of a therapeutically active agent by a linker, as described herein, forming an opioid dimer.
- the opioid dimer is a heterodimer as described above.
- an opioid radical is joined to a second radical, which is not an opioid radical, such as, for example, a radical of a therapeutically active agent (e.g., a steroid), by a linker described herein, forming an opioid heterodimer.
- a first opioid radical such as, for example, a partial opioid agonist
- a second opioid radical which is a different opioid radical than the first opioid radical, such as, for example, an opioid antagonist, by a linker described herein, forming a heterodimer.
- pellet refers to the shape of the pharmaceutical compositions of the disclosure that is rounded, spherical, cylindrical, or a combination thereof.
- the pellet has a mean diameter from about 0.2 to 5 mm, e.g., from about 0.2 to 1 mm, from about 0.2 to 2 mm, from about 0.3 to 3 mm, from about 1.5 to 5 mm, from about 2 to 5 mm, from about 2.5 to 5 mm, from about 3 to 5 mm, from about 3.5 to 5 mm, from about 4 to 5 mm, or from about 4.5 to 5 mm.
- “Pharmaceutically acceptable salt” includes both acid and base addition salts.
- a pharmaceutically acceptable salt of any one of the pharmacological agents described herein is intended to encompass any and all pharmaceutically suitable salt forms.
- Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
- acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
- Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
- Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
- “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al
- treat include reducing, alleviating, abating, ameliorating, relieving, or lessening the symptoms associated with a disease, disease state, or indication (e.g., glaucoma) in either a chronic or acute therapeutic scenario.
- treatment includes a reduction of intraocular pressure.
- treatment of a disease or disease state described herein includes the disclosure of use of such compound or composition for the treatment of such disease, disease state, or indication.
- API active pharmaceutical ingredient
- Pharmaceutical formulation of an API that is a liquid at room temperature often requires, for example, excipients (e.g., stabilizers, additives, adjuvants, etc.) or conjugation to another molecule (e.g., a polymer) to stabilize and/or produce a processable and/or storable product.
- excipients e.g., stabilizers, additives, adjuvants, etc.
- another molecule e.g., a polymer
- APIs that are solids at room temperature are often used for pharmaceutical formulations, avoiding the additional processing and formulation for producing medicinal products from liquid APIs; albeit, still incurring significant cost to formulation to a final medicinal product. Therefore, the cost of formulating solid or liquid APIs as well as the limited processability of liquid APIs limit the efficacy and/or adoption of potentially beneficial therapeutics.
- modified-release pharmaceuticals can improve patient compliance.
- extended-release (ER) dosage forms such as sustained-release (SR) or controlled-release (CR) dosage forms, may facilitate compliance with a therapeutic regimen in some instances.
- SR and CR dosage forms are generally designed to liberate an API at a certain rate, such as to maintain a particular drug concentration over a period of time.
- SR maintains drug release over a sustained period but not at a constant rate
- CR maintains drug release over a sustained period at a more consistent (e.g., nearly constant) rate (e.g., zero-order).
- a more consistent rate e.g., nearly constant
- zero-order e.g., zero-order
- dosage forms often include controlled release excipients (e.g., polymers) and/or controlled release matrices to facilitate controlled release.
- controlled release formulations can be even more difficult to develop.
- many controlled release forms have limited durations of active release (e.g., 24-hour release windows), so patient compliance remains an issue.
- compounds described herein are solids at body temperature (e.g., about 37° C., or lower).
- compounds provided herein comprise a first group or radical (e.g., a structure provided in any one of Formula (I), Formula (IA), Formula (IB), Formula (IB′) Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V)) (e.g., covalently) joined (e.g., conjugated) to a second group.
- the first group is a radical of Formula (I), Formula (IA), Formula (IB), Formula (IB′) or Formula (IC).
- the second group is a group that is itself not processable itself in free form (e.g., has a melting temperature that is higher than its degradation temperature, is generally insoluble, such as in aqueous media, or is otherwise not suited for processing).
- the second group is a group that is not processable in dimer form (e.g., when conjugated directly to itself or via a linker, such as described herein).
- the second group is a group that has a melting point and/or glass transition temperature of less than 50° C., less than 40° C., less than 37° C., or the like. Generally, such compounds, even if solid at room temperature, may not be suitable for use as implants due to the possibility of melting or deformation in a physiological environment.
- the compound is formed into an implantable article (e.g., a pellet), such as using methods described herein (e.g., as described in the examples).
- the implantable article has a (e.g., zero-order) controlled release rate over an extended period (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 12 weeks, 52 weeks, or more) in an aqueous medium (e.g., a buffer solution, serum, biological environment (e.g., in the eye), in vivo, or the like).
- an aqueous medium e.g., a buffer solution, serum, biological environment (e.g., in the eye), in vivo, or the like.
- a compound provided herein is administered to an individual suffering an acute or a chronic disease or condition (e.g., as a therapy for the acute or chronic disease or condition) in any suitable manner (e.g., route of administration, such as by implanting, and/or frequency of dosing), such as a single dose or a series of doses (e.g., once or twice every 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 12 weeks, 52 weeks, or more).
- compounds e.g., conjugates
- processable compounds described herein are used to improve treatment options and/or patient compliance for chronic diseases and/or disorders.
- the processable compounds described herein are used to improve treatment options and/or patient compliance for ophthalmology, neurology, post-surgical medicine, orthopedics, and pain management.
- a processable compound is a compound that can be processed with heat or solvent to form a solid, such as with little (e.g., less than 20 wt. %, less than 10 wt. %, or less than 5 wt. %) or no addition of further excipient.
- the solid prepared following processing is an amorphous solid or a solid having a highly amorphous morphology (e.g., as discussed in more detail herein).
- a processable compound provided herein is a solid at room (e.g., 20° C.) and/or physiological temperature (e.g., 37° C.).
- the compound is thermally processable, such as having a melt or glass transition temperature of at least 37° C., at least 40° C., at least 50° C., at least 60° C., at least 70° C., at least 100° C., or the like. In some embodiments, it is beneficial for the compound to be solid at room temperature, but processable at a temperature that is not prohibitively high. In some embodiments, a compound provided herein has a melt and/or glass transition temperature of less than 200° C., less than 150° C., less than 140° C., less than 130° C., less than 125° C., less than 120° C., or the like.
- the compounds have any suitable morphology, such as to facilitate processing and/or pharmacodynamic effects (e.g., release profile).
- the compound (or implant or pharmaceutical composition comprising the compound) is amorphous (or comprises a highly amorphous content).
- a compound (e.g., morphology) provided herein is a solid, such as at a physiological temperature (e.g., having a melting point (T m ) and/or glass transition temperature (T g ) of at least 37° C.).
- T m melting point
- T g glass transition temperature
- the compound is a crystalline solid, film, glass, or amorphous solid (e.g., at a temperature of at least 37° C.).
- the compound (or composition, article, or coating comprising the compound) has a crystallinity of at most 15% (e.g., determined by PXRD, DSC, or polarized light microscopy). In some embodiments, the compound (or composition, article, or coating comprising the compound) is substantially non-crystalline (e.g., determined by PXRD, DSC, or polarized light microscopy). In some embodiments, the compound (or composition, article, or coating comprising the compound) is amorphous (e.g., determined by PXRD, DSC, or polarized light microscopy).
- the compound e.g., morphology
- T m thermal melting point
- T g glass transition temperature
- T g glass transition temperature
- the compound has a melting point of at least 37° C.
- the compound has a melting point of at least 100° C.
- either one or both of the first and/or second radicals (or (e.g., active) fragments or metabolites thereof) of the compounds (e.g., drug conjugates) and (e.g., active) agents are released (e.g., in their free form), the release being controlled release and/or extended release.
- either one or both of the first and/or second radicals of the compounds and agents are released (e.g., in their free form) for at least 15 days (e.g., in solution, buffer solution, serum, biological environment, in vivo, or the like).
- processable agents e.g., compounds formed from a processable group (e.g., a radical that makes a non-processable radical processable when linked or joined thereto) and a non-processable moiety (e.g., a radical that, if in its free form, would not be processable, such as by thermal techniques, e.g., because of a melting point that is below a physiological temperature).
- a processable group e.g., a radical that makes a non-processable radical processable when linked or joined thereto
- a non-processable moiety e.g., a radical that, if in its free form, would not be processable, such as by thermal techniques, e.g., because of a melting point that is below a physiological temperature.
- the processable agents described herein are processable into a solid (e.g., at a temperature of at least 20° C., 25° C., 30° C., 37° C., or more).
- conjugates provided herein represent a significant advance in the art, e.g., as processable compounds suitable for being formed into or formulated into controlled and/or extended release articles, coatings, or other pharmaceutical compositions that are beneficial for treating acute and/or chronic diseases or disorders, such as with infrequent (e.g., a single, or weekly, monthly, or less frequent) administration.
- infrequent e.g., a single, or weekly, monthly, or less frequent
- a compound comprising a first radical and a second radical, the first radical comprising the structure of Formula (I):
- a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IA):
- a compound comprising a first radical and a second radical, the first radical or the second radical comprising a structure of Formula (IB′):
- a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IB):
- heteroatom e.g., O, S, or N
- a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IC):
- the alkyl or heteroalkyl of R d is substituted with one or more of the group consisting of —SH, —OH, —COOH, oxo, halogen, amino, alkyl (e.g., alkenyl, alkynyl), heteroalkyl, ester, amide, sulfonic acid, and sulfone.
- one R d is taken together with R d ′ to form substituted heterocycloalkyl.
- the first radical and the second radical are joined by a linker (e.g., a bond).
- the first radical is joined to the second radical through any one of R a , R b , R c , or R d of the first radical.
- the first radical is joined to the second radical through any one of R a , R b , R c , or R d , and the R a , R b , R c , or R d through which the first radical is joined to the second radical comprises a hydroxyl radical (e.g., when together with the linker or second radical (where the linker is a bond), forms an ether), a thiol radical (e.g., when together with the linker or second radical (where the linker is a bond), forms a thioether), or a carboxylate radical (e.g., when taken together with the linker or second radical (where the linker is a bond), forms an ester or carbonate).
- a hydroxyl radical e.g., when together with the linker or second radical (where the linker is a bond)
- a thiol radical e.g., when together with the linker or second radical (where the linker is a bond)
- the R a , R b , R c , or R d through which the first radical is joined to the second radical comprises a hydroxyl radical which together with the linker or with the second radical forms an ether. In some embodiments, the R a , R b , R c , or R d through which the first radical is joined to the second radical comprises a thiol radical which together with the linker or the second radical forms a thioether. In some embodiments, the R a , R b , R c , or R d through which the first radical is joined to the second radical comprises a carboxylate radical which together with the linker or the second radical forms an ester or a carbonate.
- both the first radical and the second radical have the structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC). In some embodiments, both the first radical and the second radical have the structure of any one of Formula (I), Formula (IA), or Formula (IB′). In some embodiments, both the first radical and the second radical have the structure of Formula (I) or Formula (IA). In some embodiments, both the first radical and the second radical have the structure of Formula (I). In some embodiments, both the first radical and the second radical have the structure of Formula (IA).
- the first radical and the second radical are joined by a linker (e.g., a hydrolysable linker).
- a linker e.g., a hydrolysable linker
- the linker is a bond.
- the first radical has a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC).
- the second radical has a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC).
- the second radical e.g., which is not processable in its free form, not processable in dimer form, and/or is liquid or malleable at physiological temperature
- the second radical does not have a structure of any one of a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC).
- the radical of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC) is a steroid, an opioid agonist, an opioid antagonist, an adrenergic receptor antagonist (e.g., ⁇ -blocker, ⁇ -1 blocker), or a serotonergic antagonist (e.g., serotonin 5-HT3 receptor antagonist).
- the first radical and/or the second radical is an anti-inflammatory agent, an anti-psychotic agent (e.g., typical anti-psychotic, a typical antipsychotic, schizophrenia, or the like), or the like.
- the first radical and/or the second radical is a beta-blocker, which may be used to treat intra-ocular pressure in the eye.
- the beta-blocker is timolol.
- the beta-blocker is levobunolol, metipranolol or carteolol.
- the beta-blocker is selected from the group consisting of Dichloroisoprenaline, Propranolol, Bucindolol, Carteolol, Carvedilol, Labetalol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Celiprolol, Metoprolol, Nebivolol, Esmolol, Butaxamine, ICI-118,551, SR 59230A, Nebivolol, Acebutolol, pindolol, labetalol, mepindolol, oxprenolol, celiprolol, and penbutolol.
- the beta-blocker is selected from the group consisting of Betaxolol
- the first radical is a solid (e.g., having a melting point of at least 30° C.) in its free form.
- the second radical is a liquid (e.g., having a melting point of less than 30° C.) in its free form.
- the first radical or the second radical is a steroid (e.g., dexamethasone, anecortave (e.g., anecortave desacetate), etc.).
- the first radical is or is derived from anecortave (e.g., anecortave acetate or anecortave desacetate).
- the first radical is a steroid (e.g., dexamethasone, anecortave (e.g., anecortave desacetate), etc.).
- the steroid is a corticosteroid (e.g., glucocorticoid or mineral corticoid), a sex steroid, a neurosteroid, an aminosteroid, or a secosteroid.
- the second radical is not a steroid.
- the second radical is a radical that does not have a structure of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC).
- the steroid is a glucocorticoid.
- the glucocorticoid is selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, loprednol, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate
- the steroid is a mineralocorticoid.
- the mineralocorticoid is selected from the group consisting of aldosterone, fludrocortisone, deoxycorticosterone, and corticosterone, or the like.
- the mineralocorticoid is canrenone (e.g., potassium canrenoate), drospirenone, eplerenone, spirolactone, or a metabolite thereof (e.g., 7 ⁇ -thiomethylspironolactone, canrenone, 6 ⁇ -hydroxy-7 ⁇ -thiomethylspironolactone, and 7 ⁇ -thiospironolactone).
- the steroid is an anabolic steroid.
- the anabolic steroid is selected from the group consisting of androisoxazole, androstenediol, bolandiol, bolasterone, clostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methandriol, methenolone, methyltrienolone, nandrolone, norbolethone, oxymesterone, stenbolone, and trenbolone, or the like.
- the steroid is an androgenic steroid.
- the androgenic steroid is selected from the group consisting of boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17- ⁇ -methyltestosterone 3-cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal, testosterone proprionate, testosterone enanthate tiomesterone dehydroepiandrosterone (DHEA), androstenedione, androstenediol, androsterone, dihydrotestosterone (DHT), and androstanolone, or the like.
- DHEA dehydroepiandrosterone
- DHT dihydrotestosterone
- the steroid is a progestin steroid.
- the progestin steroid is selected from the group consisting of progesterone, norethisterone, norethisterone acetate, gestodene, levonorgestrel, allylestrenol, anagestone, desogestrel, dimethisterone, dydrogesterone, ethisterone, ethynodiol, ethynodiol diacetate, etonogestrel, gestodene, ethinylestradiol, haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17-alpha-hydroxyprogesterone, lynestrenol, medroxyprogesterone, melengestrol, norethindrone, norethynodrel, norgesterone, gestonorone, norgestimate, norgestrel, le
- the steroid is an estrogen steroid.
- the estrogen steroid is selected from the group consisting of estradiol, estrone, eguilenin, equilin, estradiol benzoate, estriol, ethinyl estradiol, mestranol, moxestrol, mytatrienediol, quinestradiol, and quinestrol, or the like.
- the steroid is selected from the group consisting of abiraterone, cyproterone acetate, dutasteride, enzalutamide, finasteride, galeterone, fusidic acid, cholesterol, 11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, obeticholic acid, tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone, 5 ⁇ -dihydrocorticosterone, 5 ⁇ -dihydropregesterone, flugestone, prebediolone, chlormadinone acetate, medrogestone, and segesterone acetate, or the like.
- the steroid is an anti-angiogenic or an intraocular pressure (IOP) lowering steroid.
- the anti-angiogenic or intraocular pressure (IOP) lowering steroid is selected from the group consisting of anecortave acetate, anecortave (e.g., anecortave desacetate), 11-epicortisol, 17 ⁇ -hydroxyprogesterone, tetrahydrocortexolone, and tetrahydrocortisol, or the like.
- the anti-angiogenic or IOP lowering steroid is anecortave desacetate.
- the steroid is a cholic acid-related bile acid steroid.
- the cholic acid-related bile acid steroid is selected from the group consisting of deoxycholic acid, apocholic acid, dehydrocholic acid, glycochenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, hyodeoxycholic acid, lithocholic acid, ⁇ -muricholic acid, ⁇ -muricholic acid, ⁇ -muricholic acid, w-muricholic acid, taurochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurolithocholic acid, and tauroursodeoxycholic acid, or the like.
- the steroid is a neurosteroid.
- the neurosteroid is selected from the group consisting of alphaxalone, alphadolone, hydroxydione, minaxolone, tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone, ganoxolone, 3 ⁇ -androstanediol, epipregnanolone, isopregnanolone, and 24(S)-hydroxycholesterol, or the like.
- the steroid is a steroid pheromone.
- the steroid pheromone is selected from the group consisting of androstadienol, androstadienone, androstenol, androstenone, estratetraenol, 5-dehydroprogesterone, 6-dehydro-retroprogesterone, allopregnanolone, and hydroxyprogesterone caproate, or the like.
- the steroid is a steroid metabolite.
- the steroid metabolite is selected from the group consisting of tetrahydrotriamcinolone, cortienic acid, 11-dehydrocorticosterone, 11 ⁇ -hydroxypregnenolone, ketoprogesterone, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone, and progesterone, or the like.
- the steroid is a progestin.
- the progestin is selected from the group consisting of allopregnone-3 ⁇ ,20 ⁇ -diol, allopregnone-3 ⁇ ,20 ⁇ -diol, allopregnane-3 ⁇ ,21-diol-11,20-dione, allopregnane-3 ⁇ ,17 ⁇ -diol-20-one, 3,20-allopregnanedione, 3 ⁇ ,11 ⁇ ,17 ⁇ ,20 ⁇ ,21-pentol, allopregnane-3 ⁇ ,17 ⁇ ,20 ⁇ ,21-tetrol, allopregnane-3 ⁇ ,11 ⁇ ,17 ⁇ ,21-tetrol-20-one, allopregnane-3 ⁇ ,11 ⁇ ,17 ⁇ ,21-tetrol-20-one, allopregnane-3 ⁇ ,11 ⁇ ,17 ⁇ ,21-tetrol-20-one, allopregnane-3 ⁇ ,11 ⁇ ,17 ⁇ ,21-tetrol-20-one, allo
- first radical and the second radical are joined by a linker (e.g., hydrolyzable linker). In some embodiments, the first radical and the second radical are joined by a bond.
- linker e.g., hydrolyzable linker
- the linker is a bond, alkyl, heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy is optionally substituted.
- the alkyl, heteroalkyl, or alkoxy are each independently substituted with one or more groups, each group being independently selected from the group consisting of a bond, —O—, —S—, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl.
- the linker is a bond.
- the linker is alkyl (alkylene) and the alkyl (alkylene) is substituted with one or more groups selected from —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl.
- the linker is alkyl (alkylene) and the alkyl (alkylene) is an unsubstituted alkylene.
- the linker is heteroalkyl (heteroalkylene) and the heteroalkyl (heteroalkylene) is substituted with one or more groups selected from halo or alkyl.
- the linker is heteroalkyl (heteroalkylene) and is the heteroalkyl (heteroalkylene) an unsubstituted heteroalkylene.
- the linker comprises one or more linker groups selected from a bond, —O—, —S—, unsubstituted alkylene, C ⁇ O(CH 2 CH 2 ) n C ⁇ O, C ⁇ O(CHCH) n C ⁇ O, C ⁇ O(OCH 2 CH 2 O) n C ⁇ O, O(CH 2 CH 2 O) n , and C ⁇ O(CH 2 CH 2 O) n , (CH(CH 3 )C( ⁇ O)O) n , wherein n is 1-20.
- the linker is a bond, unsubstituted alkylene, C ⁇ O(CH 2 CH 2 ) n C ⁇ O, C ⁇ O(CHCH) n C ⁇ O, C ⁇ O(OCH 2 CH 2 O) n C ⁇ O, O(CH 2 CH 2 O) n , and C ⁇ O(CH 2 CH 2 O) n , (CH(CH 3 )C( ⁇ O)O) n , C ⁇ O(CH 2 CH 2 ) n C ⁇ O(CH(CH 3 )C( ⁇ O)O) n , wherein n is 1-20.
- the linker is a bond.
- the linker is hydrolyzed in a buffered solution. In some embodiments, the linker is hydrolyzed by an enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a protease or an esterase).
- a hydrolase e.g., a protease or an esterase
- the first radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- the first radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- the disclosure provides a compound, or pharmaceutically acceptable salt thereof, having a structure provided in Table 1.
- the compound, or pharmaceutically acceptable salt thereof, provided in Table 1 is a solid at a temperature of at least 20° C. (e.g., at least 30 C, at least 37 C, at least 40 C, at least 50 C, at least 70 C, at least 100 C, or the like).
- the compound, or pharmaceutically acceptable salt thereof, provided in Table 1 is processable at a temperature of at least 20° C. (e.g., as described in the examples).
- the compound, or pharmaceutically acceptable salt thereof, provided in Table 1 is processable into an article (e.g., machined, molded, emulsion-processed, electrospun, electrosprayed, blow molded, or extruded to form a fiber, fiber mesh, woven fabric, non-woven fabric, film, surface coating, pellet, cylinder, rod, microparticle, nanoparticle, or another shaped article) at a temperature of at least 20° C.
- the compound, or pharmaceutically acceptable salt thereof, provided in Table 1 comprises both a first radical and a second radical.
- the compound in Table 1 is processable when the first radical, and the second radical are joined by a linker.
- the linker is a bond.
- the disclosure provides a compound (e.g., conjugate, such as a heterodimeric conjugate), or pharmaceutically acceptable salt thereof, having a structure provided in Table 2.
- parent conjugate compounds that do not form a processable solid are shown in Table 2.
- the compound, or pharmaceutically acceptable salt thereof, provided in Table 2 is not a solid at a temperature of at least 20° C.
- the compound, or pharmaceutically acceptable salt thereof, provided in Table 2 is not processable at a temperature of at least 20° C.
- the compound, or pharmaceutically acceptable salt thereof, provided in Table 2 is not processable into an article, as described herein, at a temperature of at least 20° C.
- the compound, or pharmaceutically acceptable salt thereof, provided in Table 2 comprises both a first radical and a second radical.
- the heterodimeric conjugate in Table 2 is not processable when the first radical and the second radical are joined by a linker.
- the linker is not a bond.
- the linker is alkyl, heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy is optionally substituted with one or more groups, each group being independently selected from the group consisting of a bond, —O—, —S—, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl.
- alkyl e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl
- optionally substituted heteroalkyl e.g, polyTHF
- cycloalkyl optionally substituted cycloalkyl
- Intraocular diseases are a group of diseases including, but not limited to, glaucoma, ocular inflammation, diabetic macular edema, posterior inflammation, anterior inflammation, macular degeneration (e.g., wet macular degeneration (AMD) and dry AMD), post-cataract surgery, and retinal vein occlusion. Prominent aspects of intraocular diseases are increased intraocular pressure and inflammation.
- the intraocular disease is a macular degeneration.
- the intraocular disease is wet AMD.
- the intraocular disease is dry AMD.
- glaucoma is a group of eye diseases, which result in damage to the optic nerve and cause vision loss. Glaucoma is one of the leading causes of blindness globally, and there is currently no cure for glaucoma. Glaucoma management is limited to avoiding glaucomatous damage and nerve damage as well as preserving visual field and total quality of life. This management system relies on diagnostic techniques and follow-up examinations as well as judicious selection of treatments for the individual patient.
- Therapeutic strategies for glaucoma are limited to pharmaceutical agents (e.g., intraocular pressure (IOP) lowering agents, e.g., prostaglandins), surgery (e.g., implants), laser therapy, or any combination thereof.
- IOP intraocular pressure
- the reported rates of nonadherence to topical glaucoma medication vary widely from 16% to 67%, and it is estimated that less than a third of patients remained on their initial therapy after 12 months (Robin et al, Exp. Rev. Ophth. (2019); 14:4-5, 199-210). Poor compliance with medications and follow-up visits is a major reason for vision loss in glaucoma patients.
- Ocular hypertension is one of the major risk factors for glaucoma, and lowering it is a major goal of glaucoma treatment.
- Intraocular pressure is a function of the production of aqueous humor by the ciliary processes of the eye as well as it's drainage through the trabecular meshwork.
- the drainage mechanisms are hindered and/or blocked, causing an increase in IOP.
- inflammation blocks outflow of aqueous humor through the trabecular meshwork, causing secondary glaucoma. This inflammation is often difficult to treat because anti-inflammatory steroids (e.g., corticosteroids), which restrict blood flow to the eye, often raise the IOP further.
- anti-inflammatory steroids e.g., corticosteroids
- Described herein are compounds that navigate the balance between reducing the IOP (e.g., with an IOP lowering agent such as a prostaglandin or an IOP lowering steroid) as well as reducing inflammation (e.g., with a corticosteroid).
- an IOP lowering agent such as a prostaglandin or an IOP lowering steroid
- reducing inflammation e.g., with a corticosteroid.
- described herein are compounds that significantly increase patient compliance by reducing the number of administrations of API (e.g., once per month).
- Described herein are processable agents for glaucoma formed from a processable moiety and a non-processable moiety.
- the processable agents for glaucoma described herein are processable into a solid (e.g., at a temperature of at least 20° C., 25° C., 30° C., 37° C., or more).
- the processable agents for glaucoma described herein have a controlled release profile (e.g., zero order) and/or an extended release profile (e.g., at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 15 days, 30 days, or more) in solution (e.g., buffer solution, serum, biological environment, in vivo, or the like).
- the compounds for glaucoma described herein are useful to treat both acute and chronic diseases or disorders.
- the compounds for glaucoma are tested, in certain embodiments, using the assays and methods described herein (e.g., as described in the examples).
- the compounds for glaucoma described herein represent a significant advance in the art as the processable agents produce a controlled and extended release profile that is beneficial for treating acute and/or chronic forms of glaucoma with a single administration.
- a heteromeric conjugate comprising a first radical and a second radical.
- both the first radical and the second radical have the structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC).
- the first radical is an anti-inflammatory agent.
- the second radical is selected from the group consisting of a non-steroidal anti-inflammatory (NSAID), an intraocular pressure (IOP) lowering agent, a beta blocker, a Rho kinase inhibitor, a carbonic anhydrase inhibitor, an ⁇ -adrenergic agonist, tyrosine kinase inhibitor, neuroprotective agent, anti-oxidant, anti-microbial, anti-viral, or the like.
- the second radical is an IOP lowering agent.
- the first radical is an anti-inflammatory agent and the second radical is an IOP lowering agent.
- the first radical is an IOP lowering steroid (e.g., anecortave (e.g., anecortave desacetate)) or benign steroid (e.g., cholesterol) and the second radical is an IOP lowering agent.
- the IOP lowering agent is a prostaglandin.
- the first radical is a steroid and the second radical is a prostaglandin.
- the first radical has the structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC).
- the second radical has a structure of Formula (II):
- R 4 is alkyl substituted with one or more of —COOH, —CONH 2 , and alkyl (e.g., alkylene or alkenyl).
- X is S, —C(R) 1 —, or —C(R) 2 —.
- X is —CH— or —CH 2 —.
- the second radical has a structure of Formula (IIA):
- R 6 and R 6′ are each independently fluoro. In some embodiments, R 6 is H or methyl and R 6′ is —OH. In some embodiments, R 6 and R 6′ are taken together to form an oxo. In some embodiments, R 1 and R 3 are each independently —OH or oxo. In some embodiments, R 3 and R 4 are taken together to form a heterocycloalkyl substituted with alkyl (e.g., alkenyl) substituted with —COOH.
- alkyl e.g., alkenyl
- the second radical has a structure of Formula (IIB):
- R 1 is oxo or —OH.
- R 2 is hydrogen.
- R 5 is selected from one or more of the group consisting of —O—, —OH, halogen, alkyl (e.g., alkynyl), aryl, wherein the alkyl (e.g., alkynyl) and aryl are optionally substituted with one or more of alkyl (e.g., fluoroalkyl), halogen, and —OH.
- R 5 is optionally substituted aryl or optionally substituted —O-aryl.
- first radical and the second radical are joined by a linker (e.g., hydrolyzable linker). In some embodiments, the first radical and the second radical are joined by a bond.
- linker e.g., hydrolyzable linker
- a compound comprising:
- any one of Re, R a ′, R b , R b ′, R b ′′, R c , R c ′′, R d , or R d ′ is an ester radical, a hydroxyl radical, or a carboxylate radical
- any one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6′ , R 6′′ , or R 10 is a thiol radical, a hydroxyl radical, or a carboxylate radical.
- any one of Re, R a ′, R b , R b ′, R b ′′, R c , R c ′, R d , or R d ′ is adjoined to any one of R 2 , R 3 , R 4 , R 5 , R 6 , R 6′ , R 6′′ , or R 10 by a linker.
- any one of R d , R a ′, R b , R b ′, R b ′′, R c ′′, R d , or R d ′ is adjoined to any one of R 4 , R 5 , R 6 , R 6′ , R 6′′ , or R 10 by a linker.
- any one of R d or R d ′ is adjoined to any one of R 4 , R 5 , R 6 , R 6′ , R 6′′ , or R 10 by a linker.
- the linker is a bond.
- the linker is a bond, alkyl, heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy is optionally substituted.
- the alkyl, heteroalkyl, or alkoxy are each independently substituted with one or more groups, each group being independently selected from the group consisting of a bond, —O—, —S—, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl.
- the linker is a bond.
- the linker is alkyl (alkylene) and the alkyl (alkylene) is substituted with one or more groups selected from —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl.
- the linker is alkyl (alkylene) and the alkyl (alkylene) is an unsubstituted alkylene.
- the linker is heteroalkyl (heteroalkylene) and the heteroalkyl (heteroalkylene) is substituted with one or more groups selected from halo or alkyl.
- the linker is heteroalkyl (heteroalkylene) and is the heteroalkyl (heteroalkylene) an unsubstituted heteroalkylene.
- the linker comprises one or more linker groups selected from a bond, —O—, —S—, unsubstituted alkylene, C ⁇ O(CH 2 CH 2 ) n C ⁇ O, C ⁇ O(CHCH) n C ⁇ O, C ⁇ O(OCH 2 CH 2 O) n C ⁇ O, O(CH 2 CH 2 O) n , and C ⁇ O(CH 2 CH 2 O) n , (CH(CH 3 )C( ⁇ O)O) n , wherein n is 1-20.
- the linker is a bond, unsubstituted alkylene, C ⁇ O(CH 2 CH 2 ) n C ⁇ O, C ⁇ O(CHCH) n C ⁇ O, C ⁇ O(OCH 2 CH 2 O) n C ⁇ O, O(CH 2 CH 2 O) n , and C ⁇ O(CH 2 CH 2 O) n , (CH(CH 3 )C( ⁇ O)O) n , C ⁇ O(CH 2 CH 2 ) n C ⁇ O(CH(CH 3 )C( ⁇ O)O) n , wherein n is 1-20.
- the linker comprises one or more linker group, each linker group being independently selected from the group consisting of a bond, alkyl, cycloalkyl, heteroalkyl, or alkoxy, wherein the alkyl, cycloalkyl, heteroalkyl, or alkoxy is optionally substituted.
- the alkyl, cycloalkyl, heteroalkyl, or alkoxy are each independently substituted with one or more substituent, each substituent being independently selected from the group consisting of —O— (e.g., —OH), —S— (e.g., —SH), silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl.
- —O— e.g., —OH
- —S— e.g., —SH
- silicone amino
- optionally substituted alkyl e.g., alkenyl, alkynyl, branched (e.g., polypropylene
- haloalkyl optionally substituted heteroalkyl (e.g, polyTHF)
- the linker comprises one or more linker group, each linker group being independently selected from the group consisting of alkyl (alkylene) and cycloalkyl (cycloalkylene), and the alkyl (alkylene) or cycloalkyl (cycloalkylene) is unsubstituted or substituted (e.g., with one or more substituent each substituent being independently selected from the group consisting of —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl).
- the linker comprises an unsubstituted or substituted alkylene-cycloalkylene-alkylene.
- the linker comprises one or more linker group, each linker group being independently selected from the group consisting of a bond, —O—, —O(C ⁇ O)—, —O(C ⁇ O)—O—, —S—, unsubstituted alkylene, unsubstituted cycloalkylene, C ⁇ O(CH 2 CH 2 ) n C ⁇ O, C ⁇ O(CHCH) n C ⁇ O, C ⁇ O(OCH 2 CH 2 O) n C ⁇ O, O(CH 2 CH 2 O) n , and C ⁇ O(CH 2 CH 2 O) n , and (CH(CH 3 )C( ⁇ O)O) n , wherein n is 1-20.
- the linker is a bond, unsubstituted alkylene, unsubstituted alkylene-cycloalkylene-alkylene, C ⁇ O(CH 2 CH 2 ) n C ⁇ O, C ⁇ O(CHCH) n C ⁇ O, C ⁇ O(OCH 2 CH 2 O) n C ⁇ O, O(CH 2 CH 2 O) n , and C ⁇ O(CH 2 CH 2 O) n , (CH(CH 3 )C( ⁇ O)O) n , C ⁇ O(CH 2 CH 2 ) n C ⁇ O(CH(CH 3 )C( ⁇ O)O) n , wherein n is 1-20. In some embodiments, n is 1-10. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.
- the linker is hydrolyzed in a buffered solution. In some embodiments, the linker is hydrolyzed by an enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a protease or an esterase).
- a hydrolase e.g., a protease or an esterase
- the first radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- the second radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- the second radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- the second radical is a radical of a drug.
- the drug is a prostaglandin.
- the prostaglandin is selected from the group consisting of latanoprost, latanoprost acid, travoprost, travoprost acid, tafluprost, tafluprost acid, bimatoprost, bimatoprost acid, sepetaprost, and sepetaprost acid, or a fragment or radical of any of the foregoing.
- the second radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- the disclosure provides a compound for glaucoma, or pharmaceutically acceptable salt thereof, having a structure provided in Table 3.
- parent conjugate compounds that form articles e.g., pellets), using methods described in the examples herein, are shown in Table 3.
- the compound for glaucoma, or pharmaceutically acceptable salt thereof, provided in Table 3 is a solid at a temperature of at least 20° C.
- the compound for glaucoma, or pharmaceutically acceptable salt thereof, provided in Table 3 is processable at a temperature of at least 20° C.
- the compound for glaucoma, or pharmaceutically acceptable salt thereof, provided in Table 3 is processable into an article, as described herein, at a temperature of at least 20° C.
- the compound for glaucoma, or pharmaceutically acceptable salt thereof, provided in Table 3 comprises a first radical that is processable in its free form and a second radical that is not processable in its free form.
- the compound for glaucoma in Table 3 is processable when the first radical that is processable in its free form and the second radical that is not processable in its free form are joined by a linker.
- the linker is a bond.
- the linker comprises one more linker group, each linker group being independently selected from the group consisting of a bond, alkyl or cycloalkyl, wherein the alkyl or cycloalkyl may optionally be substituted.
- the linker forms, together with the first and/or the second radical, an ether.
- the linker forms, together with the first and/or the second radical, an ester.
- the linker forms, together with the first and/or second radical, a carbonate.
- Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.
- the compound described herein has a structure provided in any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V).
- the compounds as described herein is administered as a pure chemical.
- the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, Pa. (2005)).
- a pharmaceutically suitable or acceptable carrier also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, Pa. (2005)).
- One embodiment provides a pharmaceutical composition comprising any compound provided herein, such as a compound that has the structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- Another embodiment provides the pharmaceutical composition, wherein the pharmaceutical composition is suitable for ophthalmic administration.
- intraocular ophthalmic administration is intraocular, subretinal, superciliary, forniceal, into Schlemm's canal, inside a bleb, intracameral, intravitreal, suprachoroidal, punctal, retrobulbar, or subconjunctival.
- synthetic materials
- any article or implant provided herein such as containing a compound as described by any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), (or pharmaceutically acceptable salt thereof) is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as, for example, impurities, synthetic materials (e.g., unreacted starting materials (e.g., a steroid provided herein in its free form), hydrolyzed materials (e.g., a steroid provided herein in its free
- any compound provided herein such as the compound as described by any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), (or pharmaceutically acceptable salt thereof) is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as impurities, unreacted intermediates or byproducts (e.g., synthesis by-products or processing by-products, such as produced by heat processing, solvent processing, and/or sterilization).
- other organic small molecules such as impurities, unreacted intermediates or byproducts (e.
- the implant or article comprises at least 50 wt. % (at least 60 wt.
- the implant or article releases (such as by surface erosion) the compound, the first radical, and/or the second radical (and/or other (e.g., active) fragment or metabolite of the compound).
- release is at or near zero-order (e.g., in an aqueous medium, such as in a buffer solution, serum, biological environment, in vivo, or the like, such as at a physiological temperature (e.g., 37° C.).
- the first radical and the second radical are released from the pharmaceutical implant or article at 37° C. in 100% bovine serum or at 37° C. in phosphate buffered saline (PBS) at a rate such that t 10 is greater than or equal to 1/10 of t 50 .
- the first radical and the second radical are released from the pharmaceutical implant or article at 37° C. in mixture of fetal bovine serum (FBS) and phosphate buffered saline (PBS) (e.g., 1% FBS in PBS) at a rate such that t 10 is greater than or equal to 1/10 of t 50 .
- FBS fetal bovine serum
- PBS phosphate buffered saline
- certain forms of pharmaceutical compositions described herein provide a controllable surface area.
- the controllable surface area is injected, does not require removal after completion of drug release, and allows for tailoring of drug release rates for a given indication.
- methods provided herein do not require (or comprise) removal of an article or implant, or residual materials or components thereof (e.g., because the implant is completely or almost completely (e.g., bio- or physiologically) degraded or degradable (e.g., at least 80 wt. %, at least 85 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %, at least 99 wt. %, or the like)).
- the implants, articles, or compositions described herein are amorphous.
- the implants, articles, or compositions described herein are formed by heat-based and solvent based processing methods.
- heat processing methods include heat molding, injection molding, extrusion, 3D printing, melt electrospinning, fiber spinning, fiber extrusion, and/or blow molding.
- solvent processing include coating, micro printing, dot printing, micropatterning, fiber spinning, solvent blow molding, emulsions, electrospraying, and electrospinning.
- processing methods to form an intermediate glassy state of any of the above heat and solvent based methods as well as heat and solvent based methods that lead to glassy state material with no defined shape e.g. spray drying, lyophilization, powder melting, etc.
- glassy state generally refers to an amorphous solid including greater than 70%, 80%, 90%, 95%, 98%, or 99% (w/w) of compositions, articles, or implants described herein.
- the compositions, articles, or implants described herein exhibit a glass transition temperature above 38° C.
- the level of crystallinity is, for example, from 0-15% (e.g., less than 1%, 0-1%, 0-3%, 0-5%, 0-7%, 0-9%, 0-10%, or 0-13%).
- glass formulations are formed using heat processing or solvent processing methods described herein (e.g., in the examples).
- the pharmaceutical compositions described herein are prepared by electrospinning.
- the pharmaceutical compositions of the disclosure are dissolved in a solvent (e.g., acetone) at concentrations ranging from, e.g., 10-30% w/v, and are electrosprayed to form micro- and nanoparticles.
- the solution is loaded into a syringe and injected at a rate (e.g., 0.5 mL/h) onto a stationary collection plate.
- a potential difference e.g., 18 kV
- a concentration of 10% w/v is used to obtain nanoparticles.
- a concentration of 30% w/v is used to obtain micro particles.
- compositions of the disclosure are dissolved in a solvent (e.g., THF, or 1:1 ratio of DCM/THF).
- a solvent e.g., THF, or 1:1 ratio of DCM/THF.
- the solution is loaded into a syringe and injected at a rate (e.g., 0.5 mL/h) onto a cylindrical mandrel rotating at a particular rotational speed, e.g., 1150 rpm, to obtain aligned fibers, or onto a stationary collector surface to obtain unaligned fibers.
- a potential difference e.g., 18 kV or 17 kV is maintained between the needle and collecting surface for aligned and random fibers.
- fibers are prepared from the melt at elevated temperatures, the glassy state intermediate, or from the solution by dissolving the pharmaceutical compositions described herein in a solvent (e.g., DCM, THF, or chloroform).
- a solvent e.g., DCM, THF, or chloroform.
- the viscous melt, intermediate, or solution is fed through a spinneret and fibers are formed upon cooling (melt or heat spinning) or following solvent evaporation with warm air as the compound exits the spinneret (dry spinning).
- wet spinning and gel spinning are used to produce the fibers disclosed herein.
- Heat spinning describes a process that is similar to the melt spinning, but performed with a glassy state intermediate and heated above the glass transition temperature (T g ), obtaining the viscous fluid to extrude/spin instead of the melt.
- T g glass transition temperature
- tweezers may be dipped into melted material or concentrated solutions and retracted slowly in order to pull fibers. The rate of pulling and distance pulled may be varied to yield fibers and columnar structures of different thickness.
- micro-particles or nano-particles made from the pharmaceutical composition are formed using an emulsion process.
- the pharmaceutical composition is dissolved in an organic solvent (e.g. DCM, THF, etc.).
- a surfactant e.g. SDS, PVA, etc.
- the resulting mixture is stirred for the appropriate time at room temperature to form an emulsion.
- the emulsion is subsequently added to Milli-Q water under stirring for an appropriate time (e.g., 1 h) to remove residual solvent.
- the resulting micro- or nano-particles may be collected by centrifugation and dried.
- injectable cylinders or rods made from a pharmaceutical composition described herein is formed by heat extrusion.
- the pharmaceutical composition is loaded into a hot melt extruder, heated to a temperature above the melting point (e.g., for crystalline compositions) or glass transition temperature (e.g., for pre-melted or amorphous compositions), and extruded using (i) a compressive force to push the material through the nozzle and (ii) a tensile force (or gravity) to pull the material out of the extruder.
- the extrudate may be cut to the desired length for suitable drug dosing for a medical indication.
- a milling process is used to reduce the size of an article described to form sized particles, e.g., beads, in the micrometer (microbeads) to nanometer size range (nanobeads).
- the milling process may be performed using a mill or other suitable apparatus.
- dry and wet milling processes such as, for example, jet milling, cryo-milling, ball milling, media milling, sonication, and homogenization are used in methods described herein.
- heating of the milled microparticle above the T g is performed to achieve a spherical shape.
- particles with non-spherical shapes are used as milled.
- a composition described herein has a limited window (e.g., short timeframe of seconds to minutes) of thermal stability, whereby the purity of the dimer is affected (e.g., minimally) at elevated temperatures.
- an intermediate glassy state form e.g., film, surface coating, pellet, micro-particles, or other shaped article
- heat or solvent processing is used to remove or reduce the crystallinity of the material to form a glassy state composition.
- the glassy state composition is heat processed at a lower temperature (e.g., processing just above the glass transition temperature (T g ), and below the melt temperature (T m )).
- the lower temperature allows for a longer timeframe for heat processing the glassy state material into the final shaped article, while reducing the impact of processing conditions on the purity of the prodrug dimer in the article.
- the injection formulation is an solid formulation.
- the injection formulation is a non-aqueous formulation.
- the pharmaceutical compositions described herein provide an article (e.g., as described herein) with a controlled release profile (e.g., by surface erosion).
- the surface erosion allows the article to maintain its physical form, while gradually decreasing in size as the surface erodes (e.g., at a constant rate), rather than by, for example, bulk erosion that is characteristic of some polymer-based drug release vehicles (e.g., polylactic/glycolic acid).
- the surface erosion inhibits burst release and/or reduces the formation of inflammatory particulates (e.g., no or minimal crystalline particulates are formed or released from the articles when drug is released as described herein).
- compositions described herein are delivered over a period of time.
- a slower and steadier rate of delivery e.g., release of less than 10% of the first radical or the second radical in their free form (as a percentage of the total drug, the first radical or the second radical in their free form, present in the article) at 37° C. in 100% bovine serum over 5 days
- the drug release is tailored to avoid side effects of slower and longer release of the drug by engineering the article to provide constant release over a comparatively shorter period of time.
- the drug release is tailored for dose and duration suitable for the indication or administration method.
- the release rate is related to, for example, the drug configuration of the dimer.
- the drug release rate from an article described herein is modulated by the cleavage of dimer-linker bond through hydrolysis or enzymatic degradation.
- the linking moiety e.g., the linker
- the drug release rate is controlled by a functional group on the composition described herein to conjugate through to the linker, for example, a primary vs. a secondary hydroxyl group.
- the release rate from a dimer is related to percentage of the loaded dimer compared to the final drug dimer formulation (e.g., by using a pharmaceutical excipient (e.g., bulking agent/excipient).
- the release rate is controlled by the size of a microbead.
- drug release is tailored based on the solubility of drug dimer (e.g., through selection of appropriate drug and/or linker) that will influence the rate of surface erosion (e.g., dissolution/degradation) from the article.
- drug release is affected by changes in surface area of the formulation, e.g., by changing the diameter of the microbeads. By adjusting the vide supra factors, dissolution, degradation, diffusion, and controlled release may be varied over wide ranges. For example, release may be designed to be initiated over minutes to hours, and may extend over the course of days, weeks, months, or years.
- a heat processed pellet e.g., FIGS. 2B, 3B, 5B, 7B, 8B, 9B, 15B, and 19B
- rod e.g., FIGS. 10A, 11A, 12A, and 13A
- a heterodimer e.g., a steroid-prostaglandin heterodimer
- FIGS. 2A, 3A, 5A, 6A, 7A, 8A, 9A, 15A, and 19A exemplified herein.
- a drug release profile of a pellet e.g., FIGS.
- FIGS. 10B, 10C, 11B, 12B, 12C, 13B, and 13C fetal bovine serum (FBS), phosphate-buffered saline (PBS), or a combination thereof over a period (e.g., an extended period is time) of time (e.g., 15 days, 30 days, 60 days, 90 days, 120 days, 365 days, or more).
- FBS fetal bovine serum
- PBS phosphate-buffered saline
- the release profile of a composition provided herein is measured as the change (e.g., increase) in concentration of one or more drug (e.g., a steroid and/or a prostaglandin) in a solution over a period of time.
- the release profile of a composition provided herein is measured as an increase in concentration of a steroid over a period of time.
- FIG. 8C illustrates release of both steroid and prostaglandin in FBS. As is illustrated, both steroid and prostaglandin have similar release profiles.
- steroid and prostaglandin are directly linked, there should be an identical release profile.
- the steroid and prostaglandin appear to have slightly differing release profile at many time points, e.g., as a function of greater difficulty in detecting one of the chromophores (e.g., prostaglandin or steroid) over the other of the chromophores (e.g., steroid or prostaglandin).
- Other figures demonstrating drug release illustrate release of prostaglandins, which may be overestimated or underestimated as a result of detection methods.
- other figures demonstrate that the various compounds provided herein and illustrated therein demonstrate release of prostaglandin (and, implicitly, steroid).
- the release profile of a composition provided herein is measured as an increase in concentration of a prostaglandin over a period of time.
- the release profile of a composition provided herein is measured as an increase in concentration of a steroid and a prostaglandin over a period of time (e.g., FIG. 8B ).
- the increase in concentration of one drug (e.g., a steroid) over a period of time corresponds with the increase in concentration of another drug (e.g., a prostaglandin) over a period of time.
- drug release e.g., of prostaglandins
- HPLC and UV techniques e.g., poor chromophores
- released amounts e.g., in particular for sustained release applications where released amounts of prostaglandin analogs are present at low amounts.
- an increase of steroid concentration in solution over a period of time is used to quantify a drug (e.g., prostaglandin) release profile.
- a pharmaceutical composition containing a dimer described herein is administered to a subject by the following non-limiting examples oral, sublingual, nasal, intradermal, subcutaneous, intramuscular, rectal, vaginal, intravenous, intraarterial, intracisternal, intraperitoneal, intravitreal, periocular, topical (as by powders, creams, ointments, or drops), buccal and inhalational administration.
- the articles described herein are administered parenterally as injections (intravenous, intramuscular, or subcutaneous), or locally as injections (intraocularly or into a joint space).
- the formulations described herein are admixed under sterile conditions with a pharmaceutically acceptable carrier, preservatives and/or buffers.
- the implant, article, or composition described herein is suitable for ophthalmic administration, subcutaneous administration, or intraspinal administration.
- the ophthalmic administration is intraocular, subretinal, superciliary, forniceal, into Schlemm's canal, inside a bleb, intracameral, intravitreal, suprachoroidal, punctal, retrobulbar, or subconjunctival.
- the implant, article, or composition described herein is a coating on a device.
- the device is a contact lenses, a microshunt device, microinvasive glaucoma surgery (MIGS) device, an intraocular lenses, or the like.
- MIGS microinvasive glaucoma surgery
- the dose of the composition comprising at least one compound as described herein differ, depending upon the patient's (e.g., human) condition, that is, general health status, age, and other factors.
- compositions are administered in a manner appropriate to the disease to be treated (or prevented).
- An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form and/or potency of the active ingredient, and the method of administration.
- an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity).
- Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
- compositions described herein are combined with a pharmaceutically suitable or acceptable carrier (e.g., a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier.
- a pharmaceutically suitable or acceptable carrier e.g., a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier.
- exemplary excipients are described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, Pa. (2005)).
- provided herein is a method of treating an ophthalmic, neurological, orthopedic, acute or chronic pain, or post-operative disease or disorder in a patient in need of thereof, comprising administering to the patient any compound provided herein, or a pharmaceutically acceptable salt thereof, or a (e.g., pharmaceutical) composition comprising any compound provided herein, or a pharmaceutically acceptable salt thereof, such as a compound having a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V) Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X).
- a pharmaceutically acceptable salt thereof such as a compound having a structure of any one of Formula (I), Formula
- provided herein is a method of treating an ophthalmic disease or disorder in a patient in need of thereof, comprising administering to the patient any compound provided herein, or a pharmaceutically acceptable salt thereof, or a (e.g., pharmaceutical) composition comprising any compound provided herein, or a pharmaceutically acceptable salt thereof, such as a compound having a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V) Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X).
- a pharmaceutically acceptable salt thereof such as a compound having a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB
- intraocular ophthalmic administration is intraocular, subretinal, superciliary, forniceal, into Schlemm's canal, inside a bleb, intracameral, intravitreal, suprachoroidal, punctal, retrobulbar, or subconjunctival.
- Methods involving treating a subject may include preventing a disease, disorder or condition from occurring in the subject which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition.
- Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected (e.g., such treating the pain of a subject by administration of an agent even though such agent does not treat the cause of the pain).
- the ophthalmic disease or disorder is selected from glaucoma, ocular inflammation, diabetic macular edema, posterior inflammation, anterior inflammation, macular degeneration (e.g., wet macular degeneration (AMD) or dry AMD), post-cataract surgery, and retinal vein occlusion.
- the ocular disease or disorder is glaucoma.
- Samples (20.0 mg) are dissolved in acetonitrile (10.0 mL) to make 2 mg/mL solution.
- solvent A was Water+0.05% trifluoroacetic acid (TFA);
- solvent B was Acetonitrile+0.05% TFA;
- the flow rate was 1.0 mL/min;
- the detection method was UV @242 nm and UV Spectra from 190 to 400 nm.
- Compound powder was prepared neat in a glass capillary tube, and melting temperature was measured manually with standard glass capillary tube melting point apparatus.
- Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Starting materials were purchased from commercial sources or synthesized according to the methods described herein or using literature procedures.
- travoprost (1 g, 2.00 mmol) in MeOH (16 mL) was added 1M NaOH (aq) (16 mL, 16 mmol) and the mixture stirred for 16 h. The mixture was quenched into 0.5M HCl (aq) (32 mL, 16 mmol) and the aqueous extracted with DCM (2 ⁇ 100 mL). The DCM layers were combined dried (MgSO 4 ) and concentrated to give travoprost acid (916 mg, 100%) as a colorless oil.
- Dexamethasone (314 mg, 0.80 mmol, 1.0 equiv) was dissolved in THF (20 mL) under nitrogen and phosgene solution (2.86 mL of a 1.4 M solution in toluene, 4.0 mmol, 5 equiv) was added dropwise with stirring. The mixture was stirred at room temperature overnight. Concentration of the mixture afforded the dexamethasone chloroformate as a thick oil which was dissolved in DCM (50 mL).
- Triethylene glycol (1.07 mL, 1.20 g, 8 mmol, 10 equiv) and pyridine (130 ⁇ L, 126 mg, 1.60 mmol, 2.0 equiv) were added and the mixture stirred for 2 h.
- the reaction solution was washed with water (2 ⁇ 50 mL) and the DCM layer concentrated onto normal phase silica (2 g) and purified by automated normal phase chromatography (ethyl acetate-hexane). The product containing fractions were combined and concentrated in vacuo to give the dexamethasone-triethyleneglycol ester intermediate as an off-white glassy solid (296 mg, 0.52 mmol, 65%).
- Anecortave desacetate (640 mg, 1.86 mmol) was dissolved in dry THF (40 mL) under nitrogen and phosgene solution (6.64 mL of a 1.4 M solution in toluene, 9.29 mmol) was added dropwise with stirring. The mixture was stirred at room temperature overnight. Concentration of the mixture afforded anecortave chloroformate as a pale yellow solid (740 mg, 98%) that was used without further purification or analysis.
- a compound of the disclosure was formed into a pellet in the glassy state by heat molding. Crystalline powder of the conjugate compound was melted between 85° C. to 110° C. and pressed into a cylindrical mold of ⁇ 1 mm height ⁇ 1 mm diameter.
- Compound 4 was formed into a thin film coating on a polymer surface by solvent casting. Compound 4 was dissolved in acetone at 50 mg/ml. 20 ⁇ l was cast onto a Dacron coupon and left to air dry at room temperature overnight followed by 2 h under vacuum at 50° C.
- a compound of the disclosure was formed into a rod in the glassy state by heat extrusion.
- the conjugate compound was initially melted at a temperature up to 140° C.
- the resulting material was then loaded into a heat extruder with a 30G die head, heated between 70° C. to 125° C., and pressure was applied to a piston to form extrudate from the extruder.
- the extrudate was cut to different lengths.
- Heat-molded pellets or extruded rods of Compounds of the disclosure were assessed in either fetal bovine serum (FBS), phosphate buffered saline (PBS), or 1% FBS in PBS (v/v).
- FBS fetal bovine serum
- PBS phosphate buffered saline
- 1% FBS in PBS v/v.
- Heat-molded pellets or extruded rods were placed in 20 ml glass vials, to which was added 2 ml of release buffer. Samples were incubated at 37° C. with constant agitation at 115 rpm. At intervals up to 14 days in length, release buffer was assessed for released drug and then fully replaced with 2 ml of fresh buffer.
- acetonitrile was added to precipitate proteins and extract drug release products. Samples were analyzed by high performance liquid chromatography (HPLC) to quantify drug products.
- HPLC high performance liquid chromatography
- Compound 5 was formed into rods by melt extrusion and cut to length. The resulting implants were loaded into the lumen of needles and terminally sterilized by ethylene oxide, gamma irradiation, and E-beam. Following sterilization, samples were dissolved in a suitable solvent and assessed for changes in purity due to sterilization by HPLC.
- FIG. 18 shows purity of compound 5 before (pre-sterilization) or post sterilization of Compound 5 in ethylene oxide, or by gamma-radiation or E-beam.
- Compound 5 was formed into rods by melt extrusion and were cut to 1, 1.5 or 2 mm length. The resulting implants were loaded in the lumen of needles, terminally sterilized, and injected into the anterior chamber of rabbits. Implants settled into the inferior iridocorneal angle and were visualized by anterior chamber optical coherence tomography.
- Compound 6 was formed into rods by melt extrusion and were cut to 1.5 mm length. The resulting implants were loaded in the lumen of needles, terminally sterilized, and injected into the anterior chamber of rabbits. Implants settled into the inferior iridocorneal angle and were visualized by anterior chamber optical coherence tomography.
- FIG. 14 shows an extruded rod steroid-prostaglandin heterodimer (bimatoprost-anecortave, Compound 5) exemplified herein in a rabbit eye.
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Abstract
Description
- This application is a continuation of U.S. patent application Ser. No. 17/350,888, filed on Jun. 17, 2021, which is a continuation of International Application No. PCT/1132021/000332 filed on Apr. 29, 2021, which claims the benefit of U.S. Provisional Application No. 63/019,182, filed May 1, 2020, which are hereby incorporated by reference in their entirety herein.
- Prostaglandins (prostaglandin analogs) are a front-line medication in the treatment of glaucoma and can be used in the treatment of other ocular disorders. In some instances, prostaglandins are useful for lowering intraocular pressure (IOP), a major risk factor in glaucoma. Typically, prostaglandins are ophthalmically formulated and delivered in the form of eye drops. To provide efficacy, however, frequent ophthalmic administration of prostaglandins is often required. For example, latanoprost given once a day has been reported to have a mean IOP lowering of about 35%.
- Provided in certain embodiments herein are compounds comprising a first radical (D1) and a second radical (D2) (e.g., having the formula: D1-L-D2). In certain instances, D1 is a processable group (also referred to herein as a processable radical), L is a linker, and D2 is a drug (also referred herein as a drug radical). In certain embodiments, L is a hydrolyzable linker or bond, such that when the compound of formula D1-L-D2 is (e.g., ophthalmically) administered (or when present in or otherwise exposed to an aqueous environment, such as a buffering solution, tears, serum, or the like), D1 and D2 are released (e.g., in their free, non-radical form). In certain instances, the (e.g., covalent) joining of a group D1 to an active agent D2 (e.g., non-processable active agent) through a linker L (e.g., D1-L-D2), provides a compound comprising an otherwise non-processable drug (e.g., D2-L-D2 (e.g., D2-D2)) in a processable form. In certain instances, a drug (such as a prostaglandin) is joined with a processable group (such as a steroid or other radical of a formula described herein, such as Formula (I)). In certain instances, the processable group D1 may or may not itself be processable when in free form, but when combined with D2 (e.g., through a linker L) provides a solid (e.g., at a physiological temperature) that is processable (e.g., at a temperature above a physiological temperature).
- Provided in certain instances herein is a platform for providing compounds and implants (e.g., with high drug content, low excipient content (e.g., that would otherwise need to be removed), and other benefits, such as described herein) that provide long-lasting release of therapeutics (e.g., prostaglandins, steroids, beta-blockers, and/or the like) in biological and therapeutic applications, such as in ocular (e.g., implant) administration.
- In some instances, compounds provided herein (e.g., joining a non-processable drug, such as a prostaglandin, radical to a processable, such as a steroid, radical, such as through a (e.g., hydrolyzable) linker) are processable into forms (e.g., implants, coatings, or other bodies), such as that are capable of being administered to (e.g., an eye of) an individual in need thereof. In some instances, such compounds are processable without the need for additional excipients or materials (e.g., controlled release polymers, matrices, or other components). In certain instances, the no or low amounts of additional excipients or materials facilitates high levels of drug delivery, while limiting impact of drug delivery (e.g., a small implant can have high quantities of drug).
- In certain instances, such compounds (or implants comprising such compounds) are administered to (e.g., implanted into) an individual, such that sustained and/or otherwise controlled (e.g., local) delivery of the drug is achieved. In some instances, delivery of the compounds (e.g., in the form of an implant, coating, etc.) facilitate delivery of a drug component or radical thereof for an extended period of time, such as for weeks, months, or more. In certain instances, compounds, formulations, and implants provided herein facilitate the long term delivery of drugs to an individual in need thereof, such as without the need for frequent dosing. For example, as discussed herein, prostaglandins are often formulated and administered as eye drops, such as with daily administration. In some instances, without rigid compliance to frequent administration is required to maintain (e.g., optimal) therapeutic efficacy. With the compounds provided herein, however, long term delivery of such drugs can be achieved from weeks, months, or more, with infrequent administration (e.g., once a year, twice a year, or the like).
- In some embodiments, the group D1 is also an active agent or drug (e.g., radical thereof). In certain embodiments, D1 and D2 are both effective in the treatment of a single indication, such that administration of a compound herein provides a combination therapeutic effect. For example, in some embodiments, D1 is a steroid and D2 is a prostaglandin. In certain embodiments, such as in therapies for the treatment of glaucoma, the anti-inflammatory effect of the steroid and the ocular pressure lowering effect of the prostaglandin both provide therapeutic effect. In some embodiments, such as wherein the compound is formulated as or with an implant, D1 is an anti-inflammatory (e.g., steroid) and reduces or minimizes an inflammatory response to the implant.
- Provided in certain embodiments herein are compounds, such as described herein, (e.g., pharmaceutical) compositions comprising compounds described herein, and methods of making and using compounds provided herein. In some embodiments, methods of using the compounds provided herein include methods of treating disorders in individuals in need thereof, such as disorders treatable by a drug D2 (e.g., in its free form). In some embodiments, methods of treatment provided herein comprise methods of treating ocular disorders, such as glaucoma. It is to be understood that disclosures of methods provided herein explicitly include disclosures of pharmaceutical compositions comprising (e.g., an effective amount) of a compound provided herein for such uses.
- Provided in certain embodiments herein is a compound comprising a first radical and a second radical, the first radical comprising the structure of Formula (I):
- In certain embodiments, is a single bond or a double bond. In some embodiments, each Ra, Rb, and Rc is independently selected from the group consisting of oxo, halogen, —CN, —NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. In certain embodiments, any one of Ra, Rb, or Rc are taken together with another of Ra, Rb, or Rc to form a substituted or an unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, X1, X2, X3, and X4 are each independently selected from the group consisting of a bond and Qy, wherein each Q is independently selected from the group consisting of —O—, —NR—, —S(R)x—, and —C(R)z—. In some embodiments, y is 1-3. In certain embodiments, each x is independently 0-5. In some embodiments, each z is independently 1 or 2 (e.g., depending on degree of saturation). In certain embodiments, each of m, n, and o are independently 0-6. In certain embodiments, each R is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, and thiol (e.g., wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted), or each R is taken together with another R to form an oxo. In some embodiments, the second radical is a therapeutically active agent (or drug). In certain embodiments, the first radical (e.g., steroid) is different than the second radical (e.g., prostaglandin). In some embodiments, either the first radical, the second radical, or both the first radical and the second radical is not a steroid. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (I).
- In some embodiments, the second radical is a drug. In some embodiments, the drug is a prostaglandin. In some embodiments, the prostaglandin is selected from the group consisting of latanoprost, latanoprost acid, travoprost, travoprost acid, tafluprost, tafluprost acid, bimatoprost, bimatoprost acid, sepetaprost, and sepetaprost acid, or a fragment or radical of any of the foregoing.
- In some embodiments, X1 is Q1. In some embodiments, X2 is a bond. In some embodiments, X3 is Q2. In some embodiments, X4 is Q1. In some embodiments, X1 and X4 are each Q1. In some embodiments, X2 is a bond and X3 is Q2. In some embodiments, Q is —C(R)1— or —C(R)2—. In some embodiments, X1 and X4 are each independently —C(R)1— or —C(R)2—. In some embodiments, X2 is a bond and X3 is —C(R)2C(R)2—, —C(R)C(R)2—, or —C(R)C(R)—. In some embodiments, X1 and X4 are each —C(R)2—, and X2 is a bond and X3 is —C(R)2C(R)2— or —C(R)C(R)2—.
- In some embodiments, each R is independently hydrogen, halogen, alkyl, heteroalkyl, hydroxy, amino (e.g., dihydroamino, alkylamino, or arylamino), or taken together with another R to form an oxo. In some embodiments, each R is independently hydrogen, halogen, alkyl, hydroxy, or taken together with another R to form an oxo. In some embodiments, each R is independently hydrogen or halogen. In some embodiments, each R is independently hydrogen or alkyl. In some embodiments, each R is independently hydrogen or hydroxy. In some embodiments, each R is independently hydrogen or taken together with another R to form an oxo.
- In some embodiments, the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol of R is optionally substituted. In some embodiments, R combines with one of Ra, Rb, or Rc to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl. In some embodiments, R is amino and combines with one of Ra, Rb, or Rc to form an optionally substituted heterocycloalkyl. In some embodiments, R is amino and combines with one of Ra or Rc to form a heterocycloalkyl substituted with optionally substituted alkyl.
- In some embodiments, provided herein is a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IA):
- In some embodiments, is a single bond or a double bond). In some embodiments, each Ra, Rb, and Rc are independently selected from the group consisting of oxo, halogen, —CN, —NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. In some embodiments, each of m, n, and o are independently 0-6. In some embodiments, any one of Ra, Rb, or Rc are taken together with another of Ra, Rb, or Rc to form a substituted or an unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, the second radical is a therapeutically active agent (or drug) and the first radical (e.g., steroid) being different than the second radical (e.g., prostaglandin). In some embodiments, either the first radical, the second radical, or both the first radical and the second radical is not a steroid. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound of Formula (IA).
- In some embodiments, both the first radical and the second radical have a structure of Formula (I) or Formula (IA). In some embodiments, the first radical has a structure of Formula (I) or Formula (IA) and the second radical does not have a structure of Formula (I) or Formula (IA). In some embodiments, the structure of Formula (I) or Formula (IA) has a melt and/or glass transition temperature at a temperature of at least 20° C. (e.g., at least 25° C., at least 30° C., at least 37° C., at least 40° C., at least 50° C., at least 100° C., or more) in its free form.
- In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, each Rb is independently hydrogen, halogen, alkyl, heteroalkyl, hydroxy, amino (e.g., dihydroamino, alkylamino, or arylamino), or taken together with another Rb to form an oxo. In some embodiments, each Rb is independently hydrogen, halogen, alkyl, hydroxy, or taken together with another Rb to form an oxo. In some embodiments, each Rb is independently hydrogen or halogen. In some embodiments, each Rb is independently hydrogen or alkyl. In some embodiments, each Rb is independently hydrogen or hydroxy. In some embodiments, each Rb is independently hydrogen or taken together with another Rb to form an oxo.
- In some embodiments, the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol of Rb is optionally substituted. In some embodiments, Rb combines with one of Ra, Rb, or Rc to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl. In some embodiments, Rb is amino and combines with one of Ra or Rc to form an optionally substituted heterocycloalkyl. In some embodiments, Rb is amino and combines with one of Ra or Rc to form a heterocycloalkyl substituted with optionally substituted alkyl.
- In some embodiments, one of Rc is taken together with another Rc to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl. In some embodiments, one of Rc is taken together with another Rc to form an optionally substituted cycloalkyl. In some embodiments, one of Rc is taken together with another Rc to form a cycloalkyl substituted with one or more substituent, each substituent selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, alkoxy, amino, thiol, or heterocycloalkyl is optionally substituted.
- In some embodiments, Ra, Rb, and Rc (e.g., of Formula (I) or Formula (IA)) are each optionally and independently substituted with one or more groups, each group independently selected from —OH, oxo, alkyl (e.g., alkenyl), heteroalkyl, cycloalkyl, or alkoxy, wherein the alkyl, heteroalkyl, cycloalkyl, or alkoxy, is further optionally substituted. In certain embodiments, the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl of each Ra, Rb, or Rc (e.g., of Formula (I) or Formula (IA)) is, independently, substituted or not substituted. In some embodiments, each group is independently not substituted or substituted with any one or more substituent described herein. In specific embodiments, each group is independently not substituted or substituted with one or more substituent, wherein each substituent is selected from the group consisting of —OH, oxo, alkyl, heteroalkyl, cycloalkyl, or alkoxy, wherein the alkyl, heteroalkyl, cycloalkyl, or alkoxy, is further optionally substituted.
- In some embodiments, the substituted or unsubstituted cycloalkyl or heterocycloalkyl (e.g., of Formula (I) or Formula (IA)) are each optionally and independently substituted with one or more groups, each group independently selected from —OH, oxo, alkyl (e.g., alkenyl, alkynyl), —S-alkyl, —NH-alkyl, halogen, heteroalkyl, cycloalkyl, or alkoxy, wherein the alkyl (e.g., —S-alkyl, —NH— alkyl), heteroalkyl, cycloalkyl, or alkoxy, is further optionally substituted. In certain embodiments, substituted or unsubstituted cycloalkyl or heterocycloalkyl are, independently, substituted or not substituted. In some embodiments, each group is independently not substituted or substituted with any one or more substituent described herein. In specific embodiments, each group is independently not substituted or substituted with one or more substituent, wherein each substituent is selected from the group consisting of —OH, oxo, alkyl (e.g., alkenyl, alkynyl), —S-alkyl, —NH-alkyl, halogen, heteroalkyl, cycloalkyl, or alkoxy, wherein the alkyl (e.g., —S-alkyl, —NH-alkyl), heteroalkyl, cycloalkyl, or alkoxy, is further optionally substituted. In some embodiments, the cycloalkyl (e.g., of Formula (I) or Formula (IA)) is substituted with oxo, —OH, optionally substituted alkyl, or optionally substituted alkoxy. In some embodiments, the alkyl is substituted with one or more halogen, oxo, —OH, alkyl (e.g., alkenyl), —S-alkyl, —NH-alkyl, alkoxy, wherein the alkyl (e.g., —S— alkyl, —NH-alkyl) or alkoxy is further optionally substituted. In some embodiments, the alkyl is methyl.
- In some embodiments, provided herein is a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IB):
- In some embodiments, is a single bond or a double bond). In some embodiments, each Ra, Rb, Rc, and Rd are independently selected from the group consisting of oxo, halogen, —CN, —NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. In some embodiments, each of m, n, o, and p are independently 0-6. In some embodiments, any one of Ra, Rb, Rc, and Rd are taken together with another of Ra, Rb, Rc, and Rd to form a substituted or an unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, the second radical is a therapeutically active agent (or drug) and the first radical (e.g., steroid) being different than the second radical (e.g., prostaglandin). In some embodiments, either the first radical, the second radical, or both the first radical and the second radical is not a steroid. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound of Formula (IB).
- In some embodiments, Ring B of any one of Formula (I), Formula (IA), or Formula (IB) is an optionally substituted cycloalkyl. In some embodiments, Ring B of any one of Formula (I), Formula (IA), or Formula (IB) does not comprise a heteroatom within the ring (e.g., Ring B is optionally substituted cycloalkyl). In some embodiments, Ring B of any one of Formula (I), Formula (IA), or Formula (IB) comprises only single bonds. In some embodiments, Ring B of any one of Formula (I), Formula (IA), or Formula (IB) comprises at least one double bond. In some embodiments, Ring B of any one of Formula (I), Formula (IA), or Formula (IB) is attached to at least one ring (e.g., Ring A and/or Ring C) that comprises at least one double bond. In some embodiments, Ring A comprises at least one double bond. In some embodiments, Ring C comprises at least one double bond. In some embodiments, Ring A and Ring C each independently comprise at least one double bond. In some embodiments, Ring B of any one of Formula (I), Formula (IA), or Formula (IB) is attached to at least one ring (e.g., Ring A and or Ring C) that is aromatic. In some embodiments, Ring B of any one of Formula (I) or Formula (IA) is aromatic. In some embodiments, Ring A, Ring B, and Ring C of any one of Formula (I) or Formula (IA) are each aromatic.
- In some embodiments, m is 4. In some embodiments, m is 3. In some embodiments, m is 2. In some embodiments, m is 1. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, o is 5. In some embodiments, o is 4. In some embodiments, o is 3. In some embodiments, o is 2. In some embodiments, o is 1. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.
- In some embodiments, each Ra, Rb, Rc, and Rd are independently selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, thiol, or heterocycloalkyl is optionally substituted. In some embodiments, each Ra is independently selected from —OH, oxo, halogen, alkyl, or alkoxy, wherein the alkyl or alkoxy is optionally substituted. In some embodiments, each Rb is independently selected from —OH, oxo, halogen, or optionally substituted alkyl. In some embodiments, each Rc is independently selected from —OH, oxo, or optionally substituted alkyl. In some embodiments, each Rd is independently selected from —OH, oxo, alkyl (e.g., alkenyl or alkynyl), heteroalkyl, or each Rd is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted. In some embodiments, the substituted alkyl of Rd is —COOH, —(C═O)alkyl, —(C═O)Oalkyl, —O(C═O)Oalkyl, —(C═O)Salkyl, wherein the alkyl is optionally substituted with —OH or halogen. In some embodiments, one Rd is taken together with another Rd to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl.
- In some embodiments, the alkyl of any one of Ra, Rb, Rc, or Rd is C1-C3 alkyl. In some embodiments, the alkyl of any one of Ra, Rb, Rc, or Rd is substituted with oxo and further optionally substituted with alkyl, hydroxy, halogen, heteroalkyl, alkoxy, thioether, wherein the alkyl, alkoxy, thioether, or heteroalkyl is further optionally substituted. In some embodiments, the alkoxy of any one of Ra, Rb, Rc, or Rd is C1-C3 alkoxy.
- In some embodiments, Ring A is aromatic. In some embodiments, Ring A comprises at least one double bond. In some embodiments, Ring A comprises one double bond. In some embodiments, Ring A comprises two double bonds. In some embodiments, Ring B comprises at least one double bond. In some embodiments, Ring B comprises one double bond. In some embodiments, Ring C comprises one double bond. In some embodiments, Ring D comprises one double bond. In some embodiments, Ring A comprises at least one double bond and each of Ring B, Ring C, and Ring D consist of single bonds. In some embodiments, Ring A is aromatic and each of Ring B, Ring C, and Ring D consist of single bonds. In some embodiments, Ring A comprises at least one double bond and at least one of Ring B, Ring C, or Ring D comprises a double bond. In some embodiments, Ring A is aromatic and at least one of Ring B, Ring C, or Ring D comprises a double bond. In some embodiments, Ring A comprises at least one double bond and Ring B comprises a double bond. In some embodiments, Ring A comprises at least one double bond and Ring C comprises a double bond. In some embodiments, Ring A comprises at least one double bond and Ring D comprises a double bond.
- In some embodiments, provided herein is a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IC):
- In some embodiments, is a single bond or a double bond. In some embodiments, Ra is hydrogen, —OH, or oxo. In some embodiments, each Rd′ is independently selected from hydrogen, —OH, halogen, C1-C3 alkyl, and alkoxy. In some embodiments, Ra″ is absent, hydrogen, or C1-C3 alkyl. In some embodiments, Rb is absent, hydrogen, halogen, or C1-C3 alkyl. In some embodiments, Rb′ is hydrogen, halogen, —OH, oxo, or C1-C3 alkyl. In some embodiments, Rb″ is hydrogen or —OH. In some embodiments, each Rc is independently hydrogen, —OH, oxo, or C1-C3 alkyl. In some embodiments, each Rc′ is independently hydrogen or C1-C3 alkyl. In some embodiments, Rc″ is hydrogen, —OH, C1-C3 alkyl, or —C(═O)H. In some embodiments, each Rd is independently hydrogen, —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or each Rd is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted. In some embodiments, Rd′ is hydrogen, —OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl. In some embodiments, one Rd is taken together with Rd′ to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, either the first radical, the second radical, or both the first radical and the second radical is not a steroid. In some embodiments, the second radical is a therapeutically active agent (or drug) and the first radical (e.g., steroid) being different than the second radical (e.g., prostaglandin. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound of Formula (IC).
- In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) consists of single bonds. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises at least one double bond. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises one double bond. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises two double bonds. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises three double bonds. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises at least one aromatic ring. In some embodiments, the structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises one aromatic ring.
- In some embodiments, Rd is —OH. In some embodiments, Ra is —OH and attached to a fully saturated cycloalkyl. In some embodiments, Ra is —OH and attached to an aryl. In some embodiments, Ra is oxo. In some embodiments, Ra is oxo and is adjacent to at least one double bond. In some embodiments, Ra is oxo and is adjacent to one double bond. In some embodiments, Ra is oxo and is adjacent to two double bonds.
- In some embodiments, each Ra′ is independently hydrogen or halogen (e.g., fluoro or chloro). In some embodiments, each Ra, is independently hydrogen or C1-C3 alkyl. In some embodiments, each Ra, is independently hydrogen or C1-C3 alkoxy. In some embodiments, each Ra′ is attached to a single bond. In some embodiments, each Ra, is hydrogen. In some embodiments, at least one Ra′ is attached to a double bond. In some embodiments, one Ra, is attached to a double bond. In some embodiments, each Ra, is attached to a double bond. In some embodiments, each Ra, is independently hydrogen or C1-C3 alkyl and attached to a single bond. In some embodiments, each Ra′ is independently hydrogen or halogen, and one Ra, is attached to a double bond. In some embodiments, each Ra, is hydrogen and attached to a single bond. In some embodiments, each Ra, is hydrogen and attached to a double bond. In some embodiments, each Ra, is attached to an aryl and independently hydrogen or C1-C3 alkoxy. In some embodiments, each Ra, is hydrogen and attached to an aryl.
- In some embodiments, Ra″ is absent. In some embodiments, Ra″ is hydrogen. In some embodiments, Ra″ is C1-C3 alkyl. In some embodiments, Ra is —OH or oxo, each Ra, is independently hydrogen or C1-C3 alkyl, and Ra″ is C1-C3 alkyl. In some embodiments, Ra is —OH or oxo, each Ra, is independently hydrogen or C1-C3 alkoxy, and Ra″ is C1-C3 alkyl. In some embodiments, Ra is oxo, each Ra, is independently hydrogen or halogen (e.g., fluoro or chloro), and Ra″ is C1-C3 alkyl (e.g., methyl). In some embodiments, Ra is oxo, each Ra′ is independently hydrogen or C1-C3 alkyl (e.g., methyl), and Ra″ is C1-C3 alkyl (e.g., methyl). In some embodiments, Ra is oxo, each Ra, is hydrogen, and Ra″ is C1-C3 alkyl (e.g., methyl). In some embodiments, Ra is —OH, each Ra, is independently hydrogen or C1-C3 alkoxy (e.g., methoxy), and Ra″ is absent. In some embodiments, Ra is —OH, each Ra, is hydrogen, and Ra″ is C1-C3 alkyl (e.g., methyl). In some embodiments, Ra is —OH, each Ra′ is hydrogen, and Ra″ is absent.
- In some embodiments, Rb is absent. In some embodiments, Rb is hydrogen. In some embodiments, Rb is halogen (e.g., fluoro or chloro). In some embodiments, Rb′ is hydrogen. In some embodiments, Rb′ is halogen (e.g., fluoro or chloro). In some embodiments, Rb′ is —OH. In some embodiments, Rb′ is -oxo. In some embodiments, Rb′ is C1-C3 alkyl (e.g., methyl). In some embodiments, Rb′ is hydrogen, halogen (e.g., fluoro or chloro), or C1-C3 alkyl (e.g., methyl) and attached to a single bond. In some embodiments, Rb′ is hydrogen or C1-C3 alkyl (e.g., methyl) and attached to a double bond. In some embodiments, Rb″ is hydrogen. In some embodiments, Rb″ is —OH.
- In some embodiments, Rb is hydrogen or halogen (e.g., fluoro or chloro), Rb′ is hydrogen, halogen (e.g., fluoro or chloro), or C1-C3 alkyl (e.g., methyl), and R1′ is hydrogen. In some embodiments, Rb is hydrogen or halogen (e.g., fluoro or chloro), Rb′ is hydrogen or halogen (e.g., fluoro or chloro), and Rb″ is hydrogen. In some embodiments, Rb is halogen (e.g., fluoro or chloro), Rb′ is halogen (e.g., fluoro or chloro), and Rb″ is hydrogen. In some embodiments, Rb is halogen (e.g., fluoro or chloro), Rb′ is hydrogen, and Rb″ is hydrogen. In some embodiments, Rb is hydrogen, Rb′ is halogen (e.g., fluoro or chloro), and R1′ is hydrogen. In some embodiments, Rb is hydrogen, Rb′ is C1-C3 alkyl (e.g., methyl), and R1′ is hydrogen. In some embodiments, Rb is hydrogen, Rb′ is hydrogen, and R1′ is —OH. In some embodiments, Rb is hydrogen, Rb′ is oxo, and Rb″ is hydrogen. In some embodiments, Rb, Rb′, and Rb″ are each hydrogen.
- In some embodiments, each Rc is independently hydrogen or —OH. In some embodiments, each Rc is independently hydrogen or oxo. In some embodiments, each Rc is hydrogen. In some embodiments, each Rc′ is hydrogen. In some embodiments, each Rc′ is C1-C3 alkyl. In some embodiments, Rc′ is hydrogen. In some embodiments, Rc′ is C1-C3 alkyl. In some embodiments, Rc″ is —C(═O)H.
- In some embodiments, each Rc is hydrogen, each Rc′ is hydrogen, and Rc′ is C1-C3 alkyl. In some embodiments, each Rc is independently hydrogen or —OH, each Rc′ is hydrogen, and Rc″ is C1-C3 alkyl. In some embodiments, each Rc is independently hydrogen or oxo, each Rc′ is hydrogen, and Rc″ is C1-C3 alkyl. In some embodiments, each Rc is independently hydrogen or —OH, each Rc′ is hydrogen, and Rc″ is —C(═O)H. In some embodiments, each Rc is independently hydrogen or —OH, each Rc′ is C1-C3 alkyl, and Rc′ is hydrogen.
- In some embodiments, one Rd is absent and Rd′ and the other Rd are attached to a double bond. In some embodiments, the Rd′ and the other Rd attached to a double bond are each hydrogen.
- In some embodiments, one Rd is hydrogen and the other Rd is —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted. In some embodiments, one Rd is alkyl and the other Rd is —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted. In some embodiments, one Rd is optionally substituted alkoxy and the other Rd is —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted. In some embodiments, one Rd is —OH and the other Rd is —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, wherein the alkyl or heteroalkyl is optionally substituted. In some embodiments, each Rd is independently hydrogen or —OH. In some embodiments, each Rd is independently optionally substituted alkyl or —OH. In some embodiments, each Rd is independently —COOH or —OH. In some embodiments, each Rd is independently —COOH or optionally substituted alkoxy. In some embodiments, each Rd is taken together to form an oxo. In some embodiments, each Rd is taken together to form an optionally substituted alkenyl. In some embodiments, the alkenyl is substituted with —COOH and alkyl. In some embodiments, the alkyl comprises saturated and unsaturated carbon bonds. In some embodiments, each Rd is independently optionally substituted alkyl or hydrogen. In some embodiments, the alkyl consists of saturated carbon bonds. In some embodiments, the alkyl is substituted with C1-C3 alkyl and alkyl further substituted with —COOH. In some embodiments, the alkyl is substituted with C1-C3 alkyl and alkyl further substituted with —OH.
- In some embodiments, Rd′ is hydrogen. In some embodiments, Rd′ is —OH. In some embodiments, Rd′ is C1-C3 alkyl (e.g., alkylene or alkenyl). In some embodiments, the C1-C3 alkyl is methyl. In some embodiments, the C1-C3 alkyl is CHCH. In some embodiments, Rd′ is heteroalkyl. In some embodiments, the heteroalkyl is —O(C═O)C1-C3 alkyl.
- In some embodiments, one Rd is taken together with Rd′ to form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In some embodiments, one Rd is taken together with Rd′ to form a heterocycloalkyl substituted with one or more alkyl groups. In some embodiments, one Rd is optionally substituted alkyl and the other Rd is taken together with Rd′ to form a heterocycloalkyl substituted with one or more alkyl groups. In some embodiments, the alkyl is substituted with oxo and —OH. In some embodiments, the alkyl is substituted with oxo and alkyl further substituted with halogen (e.g., fluoro or chloro). In some embodiments, the heterocycloalkyl is an optionally substituted dioxolane. In some embodiments, the optionally substituted dioxolane is 2,2-dimethyl-1,3-dioxolane. In some embodiments, the optionally substituted dioxolane is 1,4-dioxaspiro[4.4]nonane.
- In some embodiments, each Rd is independently hydrogen or optionally substituted alkyl and Rd′ is hydrogen. In some embodiments, each Rd is independently hydrogen or optionally substituted alkyl and Rd′ is C1-C3 alkyl. In some embodiments, each Rd is independently optionally substituted alkyl and Rd′ is hydrogen. In some embodiments, each Rd is independently —OH or optionally substituted alkyl and Rd′ is hydrogen. In some embodiments, each Rd is independently —COOH or optionally substituted alkoxy and Rd′ is hydrogen. In some embodiments, each Rd is independently —OH or optionally substituted alkyl and Rd′ is C1-C3 alkyl. In some embodiments, each Rd is independently —OH or optionally substituted alkyl and Rd′ is —OH. In some embodiments, each Rd is independently —OH or optionally substituted alkyl and Rd′ is alkyl (e.g., alkenyl). In some embodiments, each Rd is independently hydrogen or —OH and Rd′ is hydrogen. In some embodiments, each Rd is independently —OH or —COOH and Rd′ is hydrogen. In some embodiments, each Rd and Rd′ are hydrogen. In some embodiments, each Rd is optionally substituted alkenyl and Rd′ is optionally substituted alkoxy. In some embodiments, each Rd is taken together to form an oxo and Rd′ is hydrogen. In some embodiments, one Rd is optionally substituted alkyl and the other Rd is taken together with Rd′ is to form an optionally substituted heterocycloalkyl.
- In some embodiments, the alkyl or heteroalkyl of Rd or Rd′ is substituted with one or more of the group consisting of —SH, —OH, —COOH, oxo, halogen, amino (e.g., dihydroamino, alkylamino, or arylamino), alkyl (e.g., alkenyl, alkynyl), heteroalkyl, ester, amide, sulfonic acid, and sulfone. In some embodiments, one Rd is taken together with Rd′ to form substituted heterocycloalkyl.
- In some embodiments, the alkyl of Rd is substituted with oxo and alkyl further substituted with hydroxyl. In some embodiments, the alkyl of Rd is substituted with oxo and alkyl further substituted with halogen (e.g., fluorine or chlorine). In some embodiments, the alkyl of Rd is substituted with oxo and C1-C3 alkyl. In some embodiments, the alkyl of Rd is substituted with oxo and alkyl further substituted with alkoxy further substituted with oxo and C1-C3 alkyl. In some embodiments, the alkyl of Rd is substituted with alkyl and alkyl further substituted with oxo and amino further substituted with alkyl further substituted with sulfonic acid. In some embodiments, the alkyl of Rd is substituted with oxo and thiol (e.g., thioether) further substituted with C1-C3 alkyl further substituted with halogen (e.g., fluorine or chlorine). In some embodiments, the alkyl of Rd is substituted with —OH. In some embodiments, the alkyl of Rd is substituted with oxo and hydroxyl (e.g., ether) further substituted with C1-C3 alkyl further substituted with halogen (e.g., fluorine or chlorine). In some embodiments, the alkoxy of Rd is substituted with oxo and alkoxy further substituted with alkyl.
- In some embodiments, the C1-C3 alkyl is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some embodiments, the C1-C3 alkyl is methyl. In some embodiments, the C1-C3 alkoxy is methoxy, ethyoxy, propyoxy, or isopropoxy. In some embodiments, the C1-C3 alkyl is methoxy.
- In some embodiments, the first radical and the second radical are joined by a linker (e.g., a bond). In some embodiments, the first radical is joined to the second radical through any one of Ra, Rb, Rc, or Rd of the first radical. In some embodiments, the first radical is joined to the second radical through any one of Ra, Rb, Rc, or Rd, and the Ra, Rb, Rc, or Rd through which the first radical is joined to the second radical comprises a hydroxyl radical (e.g., when together with the linker or second radical (where the linker is a bond), forms an ether), a thiol radical (e.g., when together with the linker or second radical (where the linker is a bond), forms a thioether), or a carboxylate radical (e.g., when taken together with the linker or second radical (where the linker is a bond), forms an ester or carbonate). In some embodiments, the connection between the thiol radical forms a thioester, a disulfide, or a thiocarbonate. In some embodiments, the connection between the carboxylate radical forms an anhydride. In some embodiments, the first radical is joined to the second radical through any one of Ra, Rb, Rc, or Rd, and the Ra, Rb, Rc, or Rd through which the first radical is joined to the second radical comprises an amino radical (e.g., when together with the linker or second radical (where the linker is a bond), forms an amide, carbamate, or thiocarbamate).
- In some embodiments, the Ra, Rb, Rc, or Rd through which the first radical is joined to the second radical comprises a hydroxyl radical which together with the linker or with the second radical forms an ether. In some embodiments, the Ra, Rb, Rc, or Rd through which the first radical is joined to the second radical comprises a thiol radical which together with the linker or the second radical forms a thioether. In some embodiments, the Ra, Rb, Rc, or Rd through which the first radical is joined to the second radical comprises a carboxylate radical which together with the linker or the second radical forms an ester or a carbonate.
- In some embodiments, the first radical has a structure of Formula (I), Formula (IA), Formula (IB), or Formula (IC) and the second radical does not have a structure of Formula (I), Formula (IA), Formula (IB), or Formula (IC). In some embodiments, the structure of Formula (I), Formula (IA), Formula (IB), or Formula (IC) has a melt and/or glass transition temperature at a temperature of at least 20° C. (e.g., at least 25° C., at least 30° C., at least 37° C., at least 40° C., at least 50° C., at least 100° C., or more) in its free form.
- In some embodiments, both the first radical and the second radical consist of the three-membered ring system of Formula (I), Formula (IA), Formula (IB), or Formula (IC). In some embodiments, the first radical is a central nervous system (CNS) agent. In some embodiments, the radical of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is a steroid, an opioid agonist, an opioid antagonist, an adrenergic receptor antagonist (e.g., β-blocker, α-1 blocker), or a serotonergic antagonist (e.g., serotonin 5-HT3 receptor antagonist). In some embodiments, the first radical is an anti-inflammatory agent, an anti-psychotic agent (e.g., typical anti-psychotic, a typical antipsychotic, schizophrenia, or the like), or the like. In some embodiments, the IOP lowering agent is a beta-blocker. In some embodiments, the beta-blocker is timolol.
- In some embodiments, the second radical is an intraocular pressure (IOP) lowering agent. In some embodiments, the first radical is an anti-inflammatory agent and the second radical is an intraocular pressure (IOP) lowering agent. In some embodiments, the first radical is an IOP lowering steroid (e.g., anecortave) or benign steroid (e.g., cholesterol) and the second radical is an IOP lowering agent. In some embodiments, the IOP lowering agent is a prostaglandin.
- In some embodiments, the first radical is a solid (e.g., having a melting point of at least 30° C.) in its free form. In some embodiments, the second radical is a liquid (e.g., having a melting point of less than 30° C.) in its free form. In some embodiments, the first radical is a steroid (e.g., dexamethasone, anecortave, etc.). In some embodiments, the steroid is a corticosteroid (e.g., glucocorticoid or mineral corticoid), a sex steroid, a neurosteroid, an aminosteroid, or a secosteroid. In some embodiments, the second radical is not a steroid (or does not have a structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC)). In some embodiments, the first radical is a steroid and the second radical is a prostaglandin.
- In some embodiments, the second radical has a structure of Formula (II):
- In some embodiments, is a single bond or a double bond. In some embodiments, R1, R2, R3, R4, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted. In some embodiments, any one of R1, R2, R3, R4, or R5 are taken together to form an optionally substituted cycloalkyl or heterocycloalkyl. In some embodiments, X is selected from the group consisting of —O—, —NR—, —S(R)a—, and —C(R)b—. In some embodiments, a is independently 0-2. In some embodiments, b is independently 1 or 2. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound of Formula (II).
- In some embodiments, X is S, —C(R)1—, or —C(R)2—. In some embodiments, X is S attached to a single bond. In some embodiments, X is —CH— or —CH2—.
- In some embodiments, R4 is alkyl substituted with one or more groups, each group being independently selected from —C(═O)OC1-C3alkyl, —COOH, —CONH2, —CONHC1-C3alkyl, and/or alkyl (e.g., alkylene or alkenyl). In some embodiments, R4 is alkyl substituted with —COOH. In some embodiments, R4 is alkyl substituted with —C(═O)OC1-C3alkyl. In some embodiments, R4 is alkyl substituted with —CONH2. In some embodiments, R4 is alkyl substituted with —CONHC1-C3alkyl. In some embodiments, the alkyl of R4 comprises at least one double bond. In some embodiments, the alkyl of R4 comprises one double bond. In some embodiments, the alkyl of R4 comprises two double bonds. In some embodiments, the two double bonds form an allene.
- In some embodiments, R5 is alkyl substituted with one or more groups, each group being independently selected from halogen, —OH, oxo, alkyl (e.g., alkynyl), alkoxy, aryl, and aryloxy, wherein alkyl (e.g., alkynyl), aryl, or aryloxy is optionally substituted. In some embodiments, the alkyl is substituted with one or more groups, each group being independently selected from halogen, —OH, oxo, alkyl (e.g., alkynyl), aryl, or aryloxy, wherein the alkyl (e.g., alkynyl), aryl, or aryloxy is optionally substituted. In some embodiments, the aryl or aryloxy is substituted with one or more halogen groups. In some embodiments, the aryl or aryloxy is unsubstituted.
- In some embodiments, the second radical has a structure of Formula (IIA):
- In some embodiments, each is independently a single bond or a double bond. In some embodiments, R1, R2, R3, R4, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted.
- In some embodiments, Formula (IIA) comprises three double bonds. In some embodiments, Formula (IIA) comprises two double bonds. In some embodiments, Formula (IIA) comprises one double bond.
- In some embodiments, R1 and R3 are each independently —OH or oxo. In some embodiments, R1 is oxo, R2 is hydrogen, and R3 is —OH. In some embodiments, R3 is oxo, R2 is hydrogen, and R1 is —OH. In some embodiments, R1 and R3 are each —OH and R2 is hydrogen.
- In some embodiments, R4 is —C(═O)OC1-C3alkyl, —COOH, —CONH2, or —CONHC1-C3alkyl. In some embodiments, R4 is —COOH. In some embodiments, R4 is —CONH2.
- In some embodiments, R5 is alkyl or aryloxy, wherein the alkyl and aryloxy are optionally substituted. In some embodiments, R5 is alkyl. In some embodiments, the alkyl is butyl or hexyl. In some embodiments, R5 is alkyl substituted with optionally substituted aryl or optionally substituted alkyl. In some embodiments, the alkyl is substituted with unsubstituted aryl. In some embodiments, the alkyl is substituted with alkyl (e.g., but-2-yne). In some embodiments, R5 is unsubstituted aryloxy. In some embodiments, R5 is aryloxy substituted with one or more alkyl (e.g., —CF3) or halo (fluoro or chloro) groups. In some embodiments, the aryloxy is substituted with —CF3.
- In some embodiments, R6 and R6′ are each fluoro. In some embodiments, R6 is H or methyl and R6′ is —OH. In some embodiments, R6 is H and R6′ is —OH. In some embodiments, R6 is methyl and R6′ is —OH. In some embodiments, R6 and R6′ are taken together to form an oxo.
- In some embodiments, R3 and R4 of Formula (II) are taken together to form an optionally substituted cycloalkyl or heterocycloalkyl. In some embodiments, R3 and R4 of Formula (II) are taken together to form heterocycloalkyl substituted with optionally substituted alkyl (e.g., alkenyl). In some embodiments, R3 and R4 of Formula (II) are taken together to form a heterocycloalkyl substituted with alkyl (e.g., alkenyl) substituted with —COOH or —C(═O)OC1-C3alky. In some embodiments, the heterocycloalkyl is substituted with alkyl further substituted with —COOH or —C(═O)OC1-C3alkyl. In some embodiments, the heterocycloalkyl is substituted with alkenyl further substituted with alkyl, which is further substituted with —COOH or —C(═O)OC1-C3alkyl. In some embodiments the alkyl or alkenyl is substituted with —COOH.
- In some embodiments, the second radical has a structure of Formula (IIB):
- In some embodiments, is a single bond or a double bond. In some embodiments, R1, R2, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted. In some embodiments, R6″ is oxo or —OH. In some embodiments, Y1 and Y2 are each independently a bond or alkylene. In some embodiments, G is O or CH2. In some embodiments, g is 1 or 2. In some embodiments, R10 is alkyl or H. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound of Formula (IIB).
- In some embodiments, G is O and Y1 is a bond. In some embodiments, Y2 is methylene. In some embodiments, g is 1. In some embodiments, G is O and Y1 is a alkylene. In some embodiments, Y2 is a bond. In some embodiments, g is 2.
- In some embodiments, R1 is oxo or —OH. In some embodiments, R1 is —OH. In some embodiments, R1 is —OH and R2 is hydrogen. In some embodiments, R6″ is —OH. In some embodiments, R5 is alkyl. In some embodiments, R5 is substituted aryl.
- In some embodiments, G is O, Y1 is a bond, Y2 is methylene, g is 1, R1 is —OH, R2 is hydrogen, R5 is alkyl, R6″ is —OH, and R10 is H. In some embodiments, G is O, Y1 is a methylene, Y2 is a bond, g is 2, R1 is —OH, R2 is hydrogen, R5 is substituted aryl, R6″ is —OH, and R10 is H or C1-C3alkyl.
- In some embodiments, R5 is selected from one or more of the group consisting of —O—, —OH, halogen, alkyl (e.g., alkynyl), aryl, wherein the alkyl (e.g., alkynyl) and aryl are optionally substituted with one or more of alkyl (e.g., fluoroalkyl), halogen, and —OH. In some embodiments, R5 is optionally substituted aryl or optionally substituted —O-aryl. In some embodiments, R5 is alkyl or aryloxy, wherein the alkyl and optionally substituted aryloxy. In some embodiments, R5 is alkyl. In some embodiments, the alkyl is butyl or hexyl. In some embodiments, R5 is unsubstituted aryloxy. In some embodiments, the aryloxy is substituted with one or two —F. In some embodiments, R5 is an aryl or O-aryl, each of which is unsubstituted. In some embodiments, R5 is an aryl or O-aryl, each of which is substituted with one or more of halogen or haloalkyl (e.g., trifluoroalkyl, e.g., trifluoromethyl).
- In certain embodiments, provided herein is a compound comprising a first radical or a second radical, wherein the first radical has a structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) and the second radical has a structure of any one of Formula (II), Formula (IIA), or Formula (IIB). In some embodiments, the first radical (e.g., having a structure of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC)) and the second radical (e.g., Formula (II), Formula (IIA), or Formula (IIB)) are joined by a linker (e.g., hydrolyzable linker). In some embodiments, the linker is a bond.
- In certain embodiments, provided herein is a compound comprising a steroid. In some embodiments, provided herein is a compound comprising a prostaglandin. In some embodiments, provided herein is a compound comprising a linker (e.g., hydrolyzable linker). In some embodiments, the linker adjoins (e.g., covalently) the steroid and the prostaglandin. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound.
- In certain aspects, provided herein is a compound having the structure of Formula (III):
- In some embodiments, is a single bond or a double bond. In some embodiments, each Rd, Rb, Rc, and Rd are independently selected from the group consisting of oxo, halogen, —CN, —NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. In some embodiments, any one of Ra, Rb, Rc, and Rd are taken together with another of Rd, Rb, Rc, and Rd to form an substituted or unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, each of m, n, o, and p are independently 0-6. In some embodiments, R1, R2, R3, R4, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted. In some embodiments, L is a linker. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound of Formula (III).
- In some embodiments, the optional substitution of any one of the groups of Formula (III) are as provided elsewhere herein (e.g., as in for Formula (IB) or Formula (II)).
- In certain aspects, provided herein is a compound having the structure of Formula (IV):
- In some embodiments, is a single bond or a double bond. In some embodiments, Ra is hydrogen, —OH, or oxo. In some embodiments, each Ra′ is independently selected from hydrogen, —OH, halogen, C1-C3 alkyl, and alkoxy. In some embodiments, Ra″ is absent, hydrogen, or C1-C3 alkyl. In some embodiments, Rb is absent, hydrogen, halogen, or C1-C3 alkyl. In some embodiments, Rb′ is hydrogen, halogen, —OH, oxo, or C1-C3 alkyl. In some embodiments, Rb″ is hydrogen or —OH. In some embodiments, each Rc is independently hydrogen, —OH, oxo, or C1-C3 alkyl. In some embodiments, each Rc′ is independently hydrogen or C1-C3 alkyl. In some embodiments, Rc″ is hydrogen, —OH, C1-C3 alkyl, or —C(═O)H. In some embodiments, each Rd is independently hydrogen, —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or each Rd is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted. In some embodiments, Rd′ is hydrogen, —OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl. In some embodiments, one Rd is taken together with Rd′ to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, R1, R2, R3, R4, and R6 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted. In some embodiments, R6 and R6′ are each independently hydrogen, halogen, alkyl, or R6 and R6′ are taken together to form an oxo. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound of Formula (IV).
- In certain aspects, provided herein is a compound having the structure of Formula (V):
- In some embodiments, is a single bond or a double bond. In some embodiments, Ra is hydrogen, —OH, or oxo. In some embodiments, each Rd′ is independently selected from hydrogen, —OH, halogen, C1-C3 alkyl, and alkoxy. In some embodiments, Rd″ is absent, hydrogen, or C1-C3 alkyl. In some embodiments, Rb is absent, hydrogen, halogen, or C1-C3 alkyl. In some embodiments, Rb′ is hydrogen, halogen, —OH, oxo, or C1-C3 alkyl. In some embodiments, Rb″ is hydrogen or —OH. In some embodiments, each Rc is independently hydrogen, —OH, oxo, or C1-C3 alkyl. In some embodiments, each Rc′ is independently hydrogen or C1-C3 alkyl. In some embodiments, Rc″ is hydrogen, —OH, C1-C3 alkyl, or —C(═O)H. In some embodiments, each Rd is independently hydrogen, —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or each Rd is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted. In some embodiments, Rd′ is hydrogen, —OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl. In some embodiments, one Rd is taken together with Rd′ to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, R1, R2, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted. In some embodiments, R6″ is oxo or —OH. In some embodiments, Y1 and Y2 are each independently a bond or alkylene. In some embodiments, G is O or CH2. In some embodiments, g is 1 or 2. In some embodiments, R1′ is alkyl or H. In some embodiments, L is a linker. Also provided in certain embodiments herein are pharmaceutical salts or solvates of a compound of Formula (V).
- In some embodiments, a hydroxyl radical or a carboxylate radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a hydroxyl radical or a carboxylate radical of another of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) through a linker. In some embodiments, a hydroxyl radical or a carboxylate radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a hydroxyl radical or a carboxylate radical of any one of Formula (II), Formula (IIA), or Formula (IIB) through a linker. In some embodiments, a hydroxyl radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a hydroxyl radical of any one of Formula (II), Formula (IIA), or Formula (IIB) through a linker. In some embodiments, a hydroxyl radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a carboxylate radical of any one of Formula (II), Formula (IIA), or Formula (IIB) through a linker. In some embodiments, a carboxylate radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a hydroxyl radical of any one of Formula (II), Formula (IIA), or Formula (IIB) through a linker. In some embodiments, a carboxylate radical of any one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is attached to a carboxylate radical of any one of Formula (II), Formula (IIA), or Formula (IIB) through a linker. In some embodiments, the linker is a bond. In some embodiments, the linker is oxo.
- In some embodiments, any one of Ra, Ra′, Rb, Rb′, Rb″, Rc, Rc″, Rd, or Rd′ is an ester radical, a hydroxyl radical, or a carboxylate radical, and any one of R1, R2, R3, R4, R5, R6, R6′, R6″, or R10 is an amide radical, a thiol radical, a hydroxyl radical, or a carboxylate radical. In some embodiments, any one of Ra, Ra′, Rb, Rb′, Rb″, Rc, Rc″, Rd, or Rd′ is an ester radical, a hydroxyl radical, or a carboxylate radical, and any one of R1, R2, R3, R4, R5, R6, R6′, R6″, or R10 is a hydroxyl radical or a carboxylate radical. In some embodiments, any radical of Ra, Ra′, Rb, Rb′, Rb″, Rc, Rc″, Rd, or Rd′ is adjoined to any radical of R1, R2, R3, R4, R5, R6, R6′, R6″, or R10 by a linker. In some embodiments, any radical of Ra, Ra′, Rb, Rb′, Rb″, Rc, Rc″, Rd, or Rd′ is adjoined to any radical of R4, R5, R6, R6′, R6″, or R10 by a linker. In some embodiments, any radical of Ra, Rb, Rc, or Rd is adjoined to any radical of R4, R5, R6, R6′, R6″, or R10 by a linker. In some embodiments, any radical of Rd or Rd′ is adjoined to any radical of R4, R5, R6, R6′, R6″, or R10 by a linker. In some embodiments, a radical of Rd is adjoined to any radical of R4, R6, R6′, R6″, or R10 by a linker. In some embodiments, a radical of Rd is adjoined to a radical of R4 or R10 by a linker. In some embodiments, a radical of of Rd is adjoined to any radical of R6, R6′, or R6″ by a linker. In some embodiments, the linker is oxo. In some embodiments, the linker is a bond.
- In some embodiments, the linker is a bond, alkyl, heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy is optionally substituted. In some embodiments, the alkyl, heteroalkyl, or alkoxy are each independently substituted with one or more groups, each group being independently selected from the group consisting of —O—, —S—, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl. In some embodiments, the linker is alkyl (alkylene) and the alkyl (alkylene) is substituted with one or more groups selected from —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, the linker is an unsubstituted alkyl (alkylene). In some embodiments, the linker is heteroalkyl (heteroalkylene) and the heteroalkyl (heteroalkylene) is substituted with one or more groups selected from halo or alkyl. In some embodiments, the linker is unsubstituted heteroalkyl (heteroalkylene). In some embodiments, the linker is a bond.
- In some embodiments, the linker comprises one or more linker group, each linker group being independently selected from a bond, alkyl, cycloalkyl, heteroalkyl, or alkoxy, wherein the alkyl, cycloalkyl, heteroalkyl, or alkoxy is optionally substituted. In some embodiments, the linker is a bond, alkyl, cycloalkyl, heteroalkyl, or alkoxy, wherein the alkyl, cycloalkyl, heteroalkyl, or alkoxy is optionally substituted. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, or alkoxy are each independently substituted with one or more substitutent, each substituent being independently selected from the group consisting of —O— (e.g., —OH), —S— (e.g., —SH), silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl. In some embodiments, the linker comprises one or more linker group, each linker group being independently selected from alkyl (alkylene) and cycloalkyl (cycloalkylene). In some embodiments, the linker is alkyl (alkylene) or cycloalkyl (cycloalkylene). In some embodiments, the alkyl (alkylene) or cycloalkyl (cycloalkylene) is unsubstituted or substituted with one or more substituent, each substituent being independently selected from the group consisting of —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, the linker comprises an unsubstituted or substituted alkylene-cycloalkylene-alkylene.
- In some embodiments, the linker comprises at least one oxo. In some embodiments, the linker is oxo. In some embodiments, the linker comprises at least one carbamate. In some embodiments, the linker is a carbamate. In some embodiments, the linker comprises at least one ester. In some embodiments, the linker is an ester.
- In some embodiments, the linker comprises one or more linker groups selected from oxo, —O—, —S—, unsubstituted alkylene, C═O(CH2CH2)nC═O, C═O(CHCH)nC═O, C═O(OCH2CH2O)nC═O, O(CH2CH2O)n, and C═O(CH2CH2O)n, (CH(CH3)C(═O)O)n, wherein n is 1-20. In some embodiments, the linker is a bond, unsubstituted alkylene, C═O(CH2CH2)nC═O, C═O(CHCH)nC═O, C═O(OCH2CH2O)nC═O, O(CH2CH2O)n, C═O(CH2CH2O)n, (CH(CH3)C(═O)O)n, and C═O(CH2CH2)nC═O(CH(CH3)C(═O)O)n, wherein n is 1-20. In some embodiments, n is 1-10. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.
- In some embodiments, the linker comprises one or more linker group, each linker group being independently selected from the group consisting of a bond, —O—, —O(C═O)—, —O(C═O)—O—, —S—, unsubstituted alkylene, unsubstituted cycloalkylene, C═O(CH2CH2)nC═O, C═O(CHCH)nC═O, C═O(OCH2CH2O)nC═O, O(CH2CH2O)n, and C═O(CH2CH2O)n, and (CH(CH3)C(═O)O)n, wherein n is 1-20. In some embodiments, the linker is a bond, unsubstituted alkylene, unsubstituted alkylene-cycloalkylene-alkylene, C═O(CH2CH2)nC═O, C═O(CHCH)nC═O, C═O(OCH2CH2O)nC═O, O(CH2CH2O)n, and C═O(CH2CH2O)n, (CH(CH3)C(═O)O)n, C═O(CH2CH2)nC═O(CH(CH3)C(═O)O)n, wherein n is 1-20. In some embodiments, n is 1-10. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.
- In some embodiments, the linker is hydrolyzed in a buffered solution. In some embodiments, the linker is hydrolytically labile. In some embodiments, the linker is hydrolyzed by water. In some embodiments, the linker is hydrolyzed by an enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a protease or an esterase). In some embodiments, the enzyme is an esterase.
- In some embodiments, the first radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- In some embodiments, the first radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- In some embodiments, the second radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- In some embodiments, the second radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- In some embodiments, the first radical is a hydroxyl radial. In some embodiments, the second radical is a hydroxyl radial. In some embodiments, the first radical is a carboxyl radical. In some embodiment, the second radical is a carboxyl radical.
- In certain embodiments, provided herein is a compound having the structure of Formula (VI):
- In some embodiments, is a single bond or a double bond. In some embodiments, R7 is hydrogen or halogen. In some embodiments, R7 is hydrogen. In some embodiments, R7 is fluoro. In some embodiments, R8 is a hydrogen or a C1-C4 alkyl. In some embodiments, R8 is hydrogen. In some embodiments, R8 is methyl, ethyl, propyl or butyl. In some embodiments, R8 is methyl, ethyl, or butyl. In some embodiments, R8 is methyl. In some embodiments, R7 is hydrogen and R8 is methyl. In some embodiments, R9 is absent, hydrogen or hydroxyl. In some embodiments, R9 is hydrogen. In some embodiments, R9 is hydroxyl. In some embodiments, R9 is absent. In some embodiments, L is a linker. In some embodiments, L is a linker described herein. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker group, each linker group being independently selected from the group consisting of an alkylene, cycloalkylene and —O—. In some embodiments, PG is a prostaglandin radical. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VI).
- In some embodiments, a compound provided herein has the structure of formula (VI-A):
- In some embodiments, is a single bond or a double bond. In some embodiments, R7 is hydrogen or halogen. In some embodiments, R7 is hydrogen. In some embodiments, R7 is fluoro. In some embodiments, R8 is a hydrogen or a C1-C4 alkyl. In some embodiments, R8 is hydrogen. In some embodiments, R8 is methyl, ethyl, propyl or butyl. In some embodiments, R8 is methyl, ethyl, or butyl. In some embodiments, R8 is methyl. In some embodiments, R7 is hydrogen and R8 is methyl. In some embodiments, L is a linker. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker group, each linker group being independently selected from the group consisting of an alkylene, cycloalkylene or —O—. In some embodiments, PG is a prostaglandin radical. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VI-A).
- In some embodiments, a compound provided herein has the structure of formula (VI-B):
- In some embodiments, is a single bond or a double bond. In some embodiments, R7 is hydrogen or halogen. In some embodiments, R7 is hydrogen. In some embodiments, R7 is fluoro. In some embodiments, R8 is a hydrogen or a C1-C4 alkyl. In some embodiments, R8 is hydrogen. In some embodiments, R8 is methyl, ethyl, propyl or butyl. In some embodiments, R8 is methyl, ethyl, or butyl. In some embodiments, R8 is methyl. In some embodiments, R7 is hydrogen and R8 is methyl. In some embodiments, R9 is absent, hydrogen or hydroxyl. In some embodiments, R9 is hydrogen. In some embodiments, R9 is hydroxyl. In some embodiments, R9 is absent. In some embodiments, L is a linker. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker group, each linker group being independently selected from the group consisting of an alkylene, cycloalkylene or —O—. In some embodiments, PG is a prostaglandin radical. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VI-B).
- In some embodiments, a compound provided herein has the structure of formula (VI-C):
- In some embodiments, L is a linker. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker group, each linker group being independently selected from the group consisting of an alkylene, cycloalkylene or —O—. In some embodiments, PG is a prostaglandin radical. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VI-B).
- In certain embodiments, provided herein is a compound having a prostaglandin (PG) radical of the formula (VII).
- In some embodiments, is a single bond or a double bond. In some embodiments, G is OH and Y1 is hydrogen. In some embodiments, G together with Y1 form —O—CH2—. In some embodiments, Y2 is a bond or —CH2—. In some embodiments, g is 1 or 2. In some embodiments, Z is —O— or —CH2—. In some embodiments, R6 and R6′ are each independently hydrogen, halogen or OH. In some embodiments, R11 is —OR13, or —NR13′R13″. In some embodiments, R13, R13′ and R13″ are each independently hydrogen or a C1-C3 alkyl. In some embodiments, each R12 is independently halogen or haloalkyl. In some embodiments, u is 0-5. In some embodiments, R6 and R6′ are each fluoro. In some embodiments, R6 is OH and R6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH2—. In some embodiments, each R12 is F and u is 2. In some embodiments, CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R11 is OH. In some embodiments, R11 is —NHCH2CH3. In some embodiments, R11 is —OCH(CH3)2.
- In some embodiments, the prostaglandin (PG) radical provided herein has the formula (VII-A):
- In some embodiments, Z is —O— or —CH2—. In some embodiments, R6 and R6′ are each independently hydrogen, halogen or OH. In some embodiments, R11 is —OR13, or —NR13, R13″. In some embodiments, R13, R13′ and R13″ are each independently hydrogen or a C1-C3 alkyl. In some embodiments, each R12 is independently halogen or haloalkyl. In some embodiments, u is 0-5. In some embodiments, R6 and R6′ are each independently fluoro. In some embodiments, R6 is OH and R6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH2—. In some embodiments, R12 is F and u is 2. In some embodiments, CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R11 is OH. In some embodiments, R11 is —NHCH2CH3. In some embodiments, R11 is —OCH(CH3)2.
- In some embodiments, the prostaglandin (PG) radical has the formula (VII-B):
- In some embodiments, Z is —O— or —CH2—. In some embodiments, R6 and R6′ are each independently hydrogen, halogen or OH. In some embodiments, R11 is —OR13, or —NR13′R13″. In some embodiments, R13, R13′ and R13″ are each independently hydrogen or a C1-C3 alkyl. In some embodiments, each R12 is independently halogen or haloalkyl. In some embodiments, u is 0-5. In some embodiments, R6 and R6′ are each independently fluoro. In some embodiments, R6 is OH and R6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH2—. In some embodiments, R12 is F and u is 2. In some embodiments, CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R11 is OH. In some embodiments, R11 is —NHCH2CH3. In some embodiments, R11 is —OCH(CH3)2.
- In some embodiments, the radical (e.g., a PG radical) is attached to a linker (e.g., L) provided herein. In some embodiments, the PG radical is attached to a linker (e.g., L) and the linker is further attached to a steroid radical (e.g., provided herein). In some embodiments, R11 is a radical (e.g., a hydroxyl radical or an amino radical) attached to a linker (e.g., a radical of a linker) provided herein (e.g., and the linker (e.g., another radical of the linker) is further attached to a steroid radical provided herein). In some embodiments, R6 or R6′ is a radical (e.g., a hydroxyl radical) attached to a linker (e.g., a radical of a linker) provided herein (e.g., and the linker (e.g., another radical of the linker) is further attached to a steroid radical provided herein).
- In certain embodiments, provided herein is a compound having the structure of Formula (VIII):
- In some embodiments, is a single bond or a double bond. In some embodiments, L is a linker. In some embodiments, A is a steroid radical. In some embodiments, G is OH and Y1 is hydrogen. In some embodiments, G together with Y1 form —O—CH2—. In some embodiments, Y2 is a bond or —CH2—. In some embodiments, g is 1 or 2. In some embodiments, Z is —O— or —CH2—. In some embodiments, R6 and R6′ are each independently hydrogen, halogen or OH. In some embodiments, Rn is —OR13 or —NR13′R13″. In some embodiments, each R12 is independently halogen or haloalkyl. In some embodiments, R13, R13′ and R13″ are each independently hydrogen or a C1-C3 alkyl. In some embodiments, u is 0-5. In some embodiments, R6 and R6′ are each independently fluoro. In some embodiments, R6 is OH and R6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH2—. In some embodiments, R12 is F and u is 2. In some embodiments, R12 is CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R11 is OH. In some embodiments, R11 is —NHCH2CH3. In some embodiments, R11 is —OCH(CH3)2. Provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VIII).
- In certain embodiments, provided herein is a compound having the structure of Formula (VIII-A):
- In some embodiments, L is a linker. In some embodiments, A is a steroid radical. In some embodiments, Z is —O— or —CH2—. In some embodiments, R6 and R6′ are each independently hydrogen, halogen or OH; R11 is —OR13, or —NR13′R13″. In some embodiments, each R12 is independently halogen or haloalkyl. In some embodiments, R13, R13′ and R13″ are each independently hydrogen or a C1-C3 alkyl. In some embodiments, u is 0-5. In some embodiments, R6 and R6′ are each independently fluoro. In some embodiments, R6 is OH and R6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH2—. In some embodiments, R12 is F and u is 2. In some embodiments, R12 is CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R11 is OH. In some embodiments, R11 is —NHCH2CH3. In some embodiments, R11 is —OCH(CH3)2. Provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VIII-A).
- In certain embodiments, provided herein is a compound having the structure of Formula (VIII-B):
- In some embodiments, L is a linker. In some embodiments, A is a steroid radical. In some embodiments, Z is —O— or —CH2—. In some embodiments, R6 and R6′ are each independently hydrogen, halogen or OH. In some embodiments, R11 is —OR13, or —NR13′R13″. In some embodiments, each R12 is independently halogen or haloalkyl. In some embodiments, R13, R13′ and R13″ are each independently hydrogen or a C1-C3 alkyl. In some embodiments, u is 0-5. In some embodiments, R6 and R6′ are each independently fluoro. In some embodiments, R6 is OH and R6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH2—. In some embodiments, R12 is F and u is 2. In some embodiments, R12 is CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R11 is OH. In some embodiments, R11 is —NHCH2CH3. In some embodiments, R11 is —OCH(CH3)2. Provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (VIII-B).
- In some embodiments, R11 is a radical (e.g., a hydroxyl radical or an amino radical) attached to L. In some embodiments, R6 or R6′ is a radical (e.g., a hydroxyl radical) attached to L. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker group, each linker group being independently selected from the group consisting of an alkylene, cycloalkylene or —O—.
- In certain embodiments, A has the structure:
- In some embodiments, is a single bond or a double bond. In some embodiments, R7 is hydrogen or halogen. In some embodiments, R8 is a hydrogen or a C1-C4 alkyl. In some embodiments, R9 is absent, hydrogen or hydroxyl. In some embodiments, R7 is hydrogen. In some embodiments, R7 is fluoro. In some embodiments, R8 is hydrogen. In some embodiments, R8 is methyl, ethyl, propyl or butyl. In some embodiments, R8 is methyl, ethyl or butyl. In some embodiments, R8 is methyl. In some embodiments, R9 is hydroxyl.
- In certain embodiments, A has the structure:
- In some embodiments, is a single bond or a double bond. In some embodiments, R7 is hydrogen or halogen. In some embodiments, R8 is a hydrogen or a C1-C4 alkyl. In some embodiments, R9 is absent, hydrogen or hydroxyl. In some embodiments, R7 is hydrogen. In some embodiments, R7 is fluoro. In some embodiments, R8 is hydrogen. In some embodiments, R8 is methyl, ethyl, propyl or butyl. In some embodiments, R8 is methyl, ethyl or butyl. In some embodiments, R8 is methyl.
- In certain embodiments, A has the structure:
- In some embodiments, is a single bond or a double bond. In some embodiments, R7 is hydrogen or halogen. In some embodiments, R8 is a hydrogen or a C1-C4 alkyl. In some embodiments, R9 is absent, hydrogen or hydroxyl. In some embodiments, R7 is hydrogen. In some embodiments, R7 is fluoro. In some embodiments, R8 is hydrogen. In some embodiments, R8 is methyl, ethyl, propyl or butyl. In some embodiments, R8 is methyl, ethyl or butyl. In some embodiments, R8 is methyl. In some embodiments, R9 is hydroxyl.
- In certain embodiments, A has the structure:
- In certain embodiments, provided herein is a compound having the structure of Formula (IX):
- In certain embodiments, each is independently a single bond or a double bond. In some embodiments, G is OH and Y1 is hydrogen. In some embodiments, G together with Y1 form —O—CH2—. In some embodiments, Y2 is a bond or —CH2—. In some embodiments, g is 1 or 2. In some embodiments, Z is —O— or —CH2—. In some embodiments, R6 and R6′ are each independently hydrogen, halogen or OH. In some embodiments, each R12 is independently halogen or haloalkyl. In some embodiments, u is 0-5. In some embodiments, Z is —O— or —CH2—. In some embodiments, R6 and R6′ are each independently hydrogen, halogen or OH. In some embodiments, each R12 is independently halogen or haloalkyl. In some embodiments, R6 and R6′ are each fluoro. In some embodiments, R6 is OH and R6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH2—. In some embodiments, R12 is F and u is 2. In some embodiments, R12 is CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (IX).
- In certain embodiments, provided herein is a compound having the structure of Formula (X):
- In certain embodiments, each is independently a single bond or a double bond. In some embodiments, L is a linker. In some embodiments, L is a bond. In some embodiments, L is —(C═O)—, or —O— (C═O)—. In some embodiments, G is OH and Y1 is hydrogen. In some embodiments, G together with Y1 form —O—CH2—. In some embodiments, Y2 is a bond or —CH2—. In some embodiments, g is 1 or 2. In some embodiments, Z is —O— or —CH2—. In some embodiments, R6 and R6′ are each independently hydrogen, halogen or OH. In some embodiments, each R12 is independently halogen or haloalkyl. In some embodiments, u is 0-5. In some embodiments, Z is —O— or —CH2—. In some embodiments, R6 and R6′ are each independently hydrogen, halogen or OH. In some embodiments, each R12 is independently halogen or haloalkyl. In some embodiments, R6 and R6′ are each independently fluoro. In some embodiments, R6 is OH and R6′ is hydrogen. In some embodiments, Z is —O—. In some embodiments, Z is —CH2—. In some embodiments, R12 is F and u is 2. In some embodiments, R12 is CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. Also provided in certain embodiments herein are pharmaceutically-acceptable salts or solvates of a compound of Formula (X).
- In some embodiments, a compound provided herein comprises a steroid attached to a second agent (e.g., a prostaglandin) through an optional linker (e.g., travoprost-anecortave), as such, forming a heteroalkyl bond (e.g., an ester, a carbonate, etc.), such as, whereby upon cleavage (e.g., hydrolysis) of the heteroalkyl bond, the steroid and/or second agent are released in their free form. In some embodiments, a steroid radical (e.g., a first radical) provided herein (e.g., a hydroxyl radical (e.g., anecortave desacetate radical)) is attached to an optional linker or a second radical (e.g., a prostaglandin radical) (e.g., a hydroxyl radical, a carboxylic radical, etc.) provided herein to form a compound provided herein.
- In some aspects, provided herein is a pharmaceutical composition comprising any compound provided herein, such as a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), or a pharmaceutically-acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient. Another embodiment provides the pharmaceutical composition, wherein the pharmaceutical composition is suitable for ophthalmic administration. Another embodiment provides the pharmaceutical composition, wherein the pharmaceutical composition is suitable for intraocular ophthalmic administration. In some embodiments, intraocular ophthalmic administration is administration in the eye, such as intraocular, intracameral, intravitreal, suprachoroidal, punctal, retrobulbar, or subconjunctival.
- Another embodiment provides the pharmaceutical composition, wherein the pharmaceutical composition is suitable for subcutaneous administration. Another embodiment provides the pharmaceutical composition, wherein the pharmaceutical composition is suitable for intraspinal administration.
- Another embodiment provides a pharmaceutical implant or article comprising any compound provided herein, such as a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable salt thereof.
- In some embodiments, the implant or article comprises at least 50 wt. % (at least 60 wt. %, at least 70 wt. %, at least 80 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %, or the like) of the compound and/or pharmaceutically acceptable salt thereof. In some instances, an article or implant provided herein comprises at least 50 wt. % of a compound as described herein. In some instances, an article or implant provided herein comprises at least 70 wt. % of a compound as described herein. In some instances, an article or implant provided herein comprises at least 90 wt. % of a compound as described herein. In some instances, an article or implant provided herein comprises at least 95 wt. % of a compound as described herein. In some instances, an article or implant provided herein comprises at least 99 wt. % of a compound as described herein. In some instances, an article or implant provided herein comprises an additional component, such as up to 20 wt. %, 15 wt. %, 10 wt. %, 5 wt. %, 1 wt. %, 0.1 wt. %, 0.01 wt. %, or less of the additional component. In some embodiments, an article or implant provided herein comprises up to 5 wt. % (e.g., up to 1 wt. %, up to 0.1 wt. %, or less) a first radical in its free form (e.g., a steroid (such as described herein)), a second radical in its free form (e.g., a prostaglandin (such as described herein), or a combination thereof (e.g., as an impurity, such as residual from a manufacturing process, such as provided herein). In some embodiments, an article or implant provided herein comprises up to 5 wt. % (e.g., up to 1 wt. %, up to 0.1 wt. %, or less) of an impurity, such as residual from a manufacturing process, such as provided herein. In some embodiments, an article or implant provided herein comprises up to 5 wt. % (e.g., up to 1 wt. %, up to 0.1 wt. %, or less) of a steroid (as described herein).
- In certain embodiments, the implant or article releases a (e.g., active) group therefrom, such as when implanted into or otherwise administered to an individual (or when placed into an aqueous medium (e.g., aqueous buffer solution), serum, or other physiological medium, such as at a physiological temperature, such as 37° C.). In some instances, a (e.g., active) group released is the free form of the first radical and/or the second radical. In certain instances, a (e.g., active) group released from the compound is an active fragment or metabolite of the first and/or second radical. In some embodiments, the implant or article undergoes surface erosion to release the compound, the first radical, and/or the second radical (or an (e.g., active) fragment or radical thereof). In some embodiments, first radical and the second radical are released from the pharmaceutical implant or article at near zero-order in solution (e.g., buffer solution, serum, biological environment, in vivo, or the like). In some embodiments, the first radical and the second radical (or an (e.g., active) fragment or metabolite thereof) are released from the pharmaceutical implant or article at 37° C. in 100% bovine serum or at 37° C. in phosphate buffered saline (PBS) at a rate such that t10 is greater than or equal to 1/10 of t50.
- In some embodiments, a compound or a pharmaceutical composition comprising any compound provided herein, such as a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition further comprises an amount of a free form of any radical provided herein, or a combination thereof, such as a free form of a radical having the (e.g., steroid) structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X) (such as wherein the free form is the structure, wherein the free form (e.g., —COO— or —O— thereof) has a negative charge (e.g., as —O−) or an H (e.g., as —OH), rather than being connected to a linker and/or other (first or second) radical). In some embodiments, a composition provided herein comprises a (e.g., weight or molar) ratio of a compound provided herein to a free form of any radical provided herein, or a combination thereof, such as a free form of a radical having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), or a pharmaceutically acceptable salt thereof (e.g., wherein the free form is the structure, wherein the free form (e.g., —COO— or —O— thereof) has a negative charge (e.g., as —O−) or an H (e.g., as —OH)), rather than being connected to a linker and/or other (first or second) radical, of about 1:99 to about 100:0 (e.g., the amount of the free form of the radical relative to the overall amount of free form of the radical plus the conjugate is between 0% (weight or molar) and 99%). In some embodiments, the relative amount of the free form of the radical is 0% to about 50%, such 0% to about 20%, 0% to about 10%, about 0.1% to about 10%, about 0.1% to about 5%, less than 5%, less than 2.5%, less than 2%, or the like (percentages being weight/weight or mole/mole percentages). Further, in some instances, compounds provided herein release free form of any radical provided herein, or a combination thereof, such as a free form of a structure of a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X) (e.g., wherein the free form (e.g., —COO— or —O— thereof) has a negative charge (e.g., as —O−) or H (e.g., as —OH), rather than being connected to a linker and/or other (first or second) radical)), such as when administered to an individual (e.g., ocular (e.g., intraocular), subcutaneous, or intraspinal administration).
- In certain embodiments, provided herein is a method of treating an ophthalmic disease or disorder in a patient in need thereof, comprising administering to the patient a composition comprising any compound provided herein, such as a compound having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable salt thereof. Another embodiment provides the method wherein the ophthalmic disease or disorder is glaucoma. Another embodiment provides the method wherein the ophthalmic disease or disorder is selected from the group consisting of ocular inflammation, diabetic macular edema, posterior inflammation, anterior inflammation, macular degeneration (e.g., wet macular degeneration (AMD)), post-cataract surgery, and retinal vein occlusion.
- In certain embodiments, provided herein is a method of treating a medical indication or abnormality (e.g., ocular or neurological disease and/or disorder), the method comprising administering a therapeutically effective amount of a compound or composition provided herein. In some embodiments, a composition provided herein (e.g., used in a method provided herein) comprises a compound provided herein in a therapeutically effective amount (e.g., at a concentration effective to treat an ophthalmic disease or disorder in an individual in need thereof, the method comprising administering to the individual a compound, pharmaceutically acceptable salt, implant, article, or composition having the structure of any one of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X). In some embodiments, a composition provided herein (e.g., used in a method provided herein) comprises a compound provided herein in a therapeutically effective amount (e.g., at a concentration effective to treat glaucoma, inflammation, and/or lower intraocular pressure) in the eye. In certain embodiments, a (e.g., pharmaceutical and/or ophthalmic) composition provided herein comprises about 0.1 wt. % to about 10 wt. % of a compound provided herein.
- The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:
-
FIG. 1 shows the chemical structure for a prodrug ester and an active pharmaceutical ingredient for a prostaglandin (e.g., travaprost (FIG. 1A ) and travoprost acid (FIG. 1B ), respectively) and a steroid (e.g., anecortave acetate (FIG. 1C ) and anecortave desacetate (FIG. 1D ), respectively) exemplified herein. -
FIG. 2 shows the chemical structure (FIG. 2A ) and the heat processed pellet (FIG. 2B ) of a steroid-prostaglandin heterodimer (travoprost-anecortave, Compound 1) exemplified herein.FIG. 2C shows the drug release profile for Compound 1 (pellet) in fetal bovine serum (FBS) over 15 days.FIG. 2D represents the 15-day progression of the surface erosion drug release profile for the pellet ofCompound 1 in FBS. -
FIG. 3 shows the chemical structure (FIG. 3A ) and the heat processed pellet (FIG. 3B ) of a steroid-prostaglandin heterodimer (travoprost-dexamethasone, Compound 2) exemplified herein.FIG. 3C shows the drug release profile for Compound 2 (pellet) in phosphate-buffered saline (PBS) over 30 days.FIG. 3D represents the 30-day progression of the (e.g., surface erosion) drug release profile and swelling profile for the pellet ofCompound 2 in PBS. -
FIG. 4 shows the chemical structure for a prodrug ester and an active pharmaceutical ingredient for a prostaglandin (e.g., latanoprost (FIG. 4A ) and latanoprost acid (FIG. 4B ), respectively) exemplified herein. -
FIG. 5 shows the chemical structure (FIG. 5A ) and the heat processed pellet (FIG. 5B ) of a steroid-prostaglandin heterodimer (latanoprost-dexamethasone, Compound 3) exemplified herein.FIG. 5C shows the drug release profile for Compound 3 (pellet) in fetal bovine serum (FBS) over 30 days.FIG. 5D represents the 30-day progression of the (e.g., surface erosion) drug release profile and swelling profile for the pellet of Compound 3 in FBS. -
FIG. 6 shows the chemical structure (FIG. 6A ) of a steroid-prostaglandin heterodimer (latanoprost-estrone, Compound 4) exemplified herein.FIG. 6B shows the drug release profile for Compound 4 (coating on polymeric substrate) in fetal bovine serum (FBS) over 8 days.FIG. 6C represents the 7-day progression of the surface coating drug release ofCompound 4 in FBS. -
FIG. 7 shows the chemical structure (FIG. 7A ) and the heat processed pellet (FIG. 7B ) of a steroid-prostaglandin heterodimer (bimatoprost-anecortave, Compound 5) exemplified herein.FIG. 7C shows the drug release profile for Compound 5 (pellet) in fetal bovine serum (FBS) over 25 days.FIG. 7D represents the 28-day progression of the (e.g., surface erosion) drug release profile for the pellet ofCompound 5 in FBS. -
FIG. 8 shows the chemical structure (FIG. 8A ) and the heat processed pellet (FIG. 8B ) of a steroid-prostaglandin heterodimer (latanoprost-anecortave, Compound 6) exemplified herein.FIG. 8C shows the drug release profile for each of latanoprost acid (●) and anecortave desacetate (o) (pellet) in fetal bovine serum (FBS) over 30 days.FIG. 8D represents the 28-day progression of the (e.g., surface erosion) drug release profile for the pellet ofCompound 6 in FBS. -
FIG. 9 shows the chemical structure (FIG. 9A ) and the heat processed pellet (FIG. 9B ) of a steroid-prostaglandin heterodimer (tafluprost-anecortave, Compound 7) exemplified herein.FIG. 9C shows the drug release profile for Compound 7 (pellet) in fetal bovine serum (FBS) over 30 days.FIG. 9D represents the 28-day progression of the (e.g., surface erosion) drug release profile for the pellet ofCompound 7 in FBS. -
FIG. 10 shows an extruded rod of a steroid-prostaglandin heterodimer (bimatoprost-anecortave, Compound 5) exemplified herein (FIG. 10A ).FIG. 10B shows the drug release profile of Compound 5 (extruded rod) in fetal bovine serum (FBS) over 30 days.FIG. 10C represents the 30-day progression of the (e.g., surface erosion) drug release profile for the extruded rod ofCompound 5 in FBS. -
FIG. 11 shows an extruded rod of a steroid-prostaglandin heterodimer (travoprost-anecortave, Compound 1) exemplified herein (FIG. 11A ).FIG. 11B shows the drug release profile of Compound 1 (extruded rod) in fetal bovine serum (FBS) over 30 days. -
FIG. 12 shows an extruded rod of a steroid-prostaglandin heterodimer (latanoprost-anecortave, Compound 6) exemplified herein (FIG. 12A ).FIG. 12B shows the drug release profile of Compound 6 (extruded rod) in fetal bovine serum (FBS) over 70 days.FIG. 12C represents the 70-day progression of the (e.g., surface erosion) drug release profile for the extruded rod ofCompound 6 in FBS. -
FIG. 13 shows an extruded rod of a steroid-prostaglandin heterodimer (tafluprost-anecortave, Compound 7) exemplified herein (FIG. 13A ).FIG. 13B shows the drug release profile of Compound 7 (extruded rod) in fetal bovine serum (FBS) over 100 days.FIG. 13C represents the 100-day progression of the (e.g., surface erosion) drug release profile for the extruded rod ofCompound 7 in FBS. -
FIG. 14 shows an extruded rod of a steroid-prostaglandin heterodimer (bimatoprost-anecortave, Compound 5) exemplified herein in a rabbit eye. -
FIG. 15 shows the chemical structure (FIG. 15A ) and the heat processed pellet (FIG. 15B ) of a steroid-prostaglandin heterodimer (travoprost-cyclohexanedimethanol-anecortave, Compound 8) exemplified herein.FIG. 15C shows the drug release profile for Compound 8 (pellet) in fetal bovine serum (FBS) over 8 days. -
FIG. 16 shows the chemical structure of a steroid-prostaglandin heterodimer (travoprost-naltrexone, Compound 9) exemplified herein. -
FIG. 17 shows the chemical structure of a steroid-prostaglandin heterodimer (timolol-deoxycholic acid, Compound 10) exemplified herein. -
FIG. 18 shows purity ofCompound 5 before (pre-sterilization) or post sterilization ofCompound 5 in ethylene oxide, or by gamma-radiation or E-beam. -
FIG. 19 shows the chemical structure (FIG. 19A ) and the heat processed pellet (FIG. 19B ) of a steroid-prostaglandin heterodimer (Bimatoprost (C15)-anecortave, Compound 11) exemplified herein. - As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may “consist of” or “consist essentially of” the described features.
- “Amino” refers to the —NH2 radical (dihydroamino). “Alkylamino” refers to an amino group which is substituted by one or more alkyl groups as defined herein. “Arylamino” referrers to an amino group which substituted by one or more aryl groups as defined herein.
- “Cyano” refers to the —CN radical.
- “Nitro” refers to the —NO2 radical.
- “Oxa” refers to the —O— radical.
- “Oxo” refers to the ═O radical.
- “Thioxo” refers to the ═S radical.
- “Imino” refers to the ═N—H radical.
- “Oximo” refers to the ═N—OH radical.
- “Hydrazino” refers to the ═N—NH2 radical.
- “Hydrogen” refers to the “H” radical.
- “Alkyl” generally refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). Unless otherwise stated, alkyl is saturated or unsaturated (e.g., an alkenyl, which comprises at least one carbon-carbon double bond, or alkynyl, which comprises at least one carbon-carbon triple bond). Disclosures provided herein of an “alkyl” are intended to include independent recitations of a saturated “alkyl,” or unsaturated alkyl (alkenyl, alkynyl), unless otherwise stated. Alkyl groups described herein are generally monovalent, but may also be divalent (which may also be described herein as “alkylene” or “alkylenylene”, or alkynylene groups). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. In general, alkyl groups are each independently substituted or unsubstituted. Each recitation of “alkyl” provided herein, unless otherwise stated, includes a specific and explicit recitation of an unsaturated “alkyl” group. Similarly, unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —OC(O)—N(Ra)2, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tRa (where t is 1 or 2) and —S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).
- “Alkoxy” refers to a radical bonded through an oxygen atom of the formula —O-alkyl, where alkyl is an alkyl chain as defined above.
- “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is optionally substituted as described for “alkyl” groups.
- “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkenyl is optionally substituted as described for “alkyl” groups.
- “Alkylene” or “alkylene chain” generally refers to a straight or branched divalent alkyl group linking the rest of the molecule to a radical group, such as having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, i-propylene, n-butylene, and the like. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted as described for alkyl groups herein.
- The term “article,” as used herein, generally refers to a pharmaceutical composition that is machined, molded, heat-processed, emulsion-processed, electrospun, electrosprayed, blow molded, or extruded to form a fiber, fiber mesh, woven fabric, non-woven fabric, film, surface coating, pellet, cylinder, rod, microparticle, nanoparticle, or another shaped article.
- “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —Rb—ORa, —Rb—OC(O)—Ra, —Rb—OC(O)—ORa, —Rb—OC(O)—N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O)ORa, —Rb—C(O)N(Ra)2, —Rb—O—Rc—C(O)N(Ra)2, —Rb—N(Ra)C(O)ORa, —Rb—N(Ra)C(O)Ra, —Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)tRa (where t is 1 or 2), —Rb—S(O)tORa (where t is 1 or 2) and —Rb—S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
- “Aralkyl” or “aryl-alkyl” refers to a radical of the formula —Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
- “Carbocyclyl” or “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing single C—C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). Examples of saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —Rb—ORa, —Rb—OC(O)—Ra, —Rb—OC(O)—ORa, —Rb—OC(O)—N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O)ORa, —Rb—C(O)N(Ra)2, —Rb—O—Rc—C(O)N(Ra)2, —Rb—N(Ra)C(O)O Ra, —Rb—N(Ra)C(O)Ra,—Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)tRa (where t is 1 or 2), —Rb—S(O)tORa (where t is 1 or 2) and —Rb—S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
- “Carbocyclylalkyl” refers to a radical of the formula —Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
- “Carbocyclylalkenyl” refers to a radical of the formula —Rc-carbocyclyl where Rc is an alkenylene chain as defined above. The alkenylene chain and the carbocyclyl radical is optionally substituted as defined above.
- “Carbocyclylalkynyl” refers to a radical of the formula —Rc-carbocyclyl where Rc is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
- “Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
- “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo substituents.
- “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
- The term “heteroalkyl” refers to an alkyl group as defined above in which one or more skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriate number of substituents or valencies—for example, —CH2— may be replaced with —NH— or —O—). For example, each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, selenium, or other suitable heteroatom. In some instances, each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, or —N(aryl)- or having another substituent contemplated herein), or sulfur (e.g. —S—, —S(═O)—, or —S(═O)2—). In some embodiments, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C1-C18 heteroalkyl. In some embodiments, a heteroalkyl is a C1-C12 heteroalkyl. In some embodiments, a heteroalkyl is a C1-C6 heteroalkyl. In some embodiments, a heteroalkyl is a C1-C4 heteroalkyl. Representative heteroalkyl groups include, but are not limited to —OCH2OMe, or —CH2CH2OMe. In some embodiments, heteroalkyl includes alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl, as defined herein. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted as defined above for an alkyl group.
- “Heteroalkylene” refers to a divalent heteroalkyl group defined above which links one part of the molecule to another part of the molecule. Unless stated specifically otherwise, a heteroalkylene is optionally substituted, as defined above for an alkyl group.
- “Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —Rb—ORa, —Rb—OC(O)—Ra, —Rb—OC(O)—ORa, —Rb—OC(O)—N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O)ORa, —Rb—C(O)N(Ra)2, —Rb—O—Rc—C(O)N(Ra)2, —Rb—N(Ra)C(O)ORa, —Rb—N(Ra)C(O)Ra, —Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)tRa (where t is 1 or 2), —Rb—S(O)tORa (where t is 1 or 2) and —Rb—S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
- “N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
- “C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
- “Heterocyclylalkyl” refers to a radical of the formula —Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
- “Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
- “Heteroaryl” refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6α,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —Rb—ORa, —Rb—OC(O)—Ra, —Rb—OC(O)—ORa, —Rb—OC(O)—N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O)ORa, —Rb—C(O)N(Ra)2, —Rb—O—Rc—C(O)N(Ra)2, —Rb—N(Ra)C(O)ORa, —Rb—N(Ra)C(O)Ra, —Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)tRa (where t is 1 or 2), —Rb—S(O)tORa (where t is 1 or 2) and —Rb—S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
- “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- “C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- “Heteroarylalkyl” refers to a radical of the formula —Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
- “Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
- The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.
- In general, optionally substituted groups are each independently substituted or unsubstituted. Each recitation of an optionally substituted group provided herein, unless otherwise stated, includes an independent and explicit recitation of both an unsubstituted group and a substituted group (e.g., substituted in certain embodiments, and unsubstituted in certain other embodiments). Unless otherwise stated, substituted groups may be substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —OC(O)—N(Ra)2, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tRa (where t is 1 or 2) and —S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).
- The compounds disclosed herein, reference to any atom includes reference to isotopes thereof. For example, reference to H includes reference to any isotope thereof, such as a 1H, 2H, 3H, or mixtures thereof.
- Generally, recitations of “anecortave” herein refer to “anecortave” in the desacetate form of
FIG. 1D ; however, where applicable, recitations of “anecortave” include disclosure of each of the “desacetate” and “acetate” forms. - The term “opioid” or “opiate,” as used interchangeably herein, generally refers to a ligand that binds to an opioid receptor, such as, for example, the delta (δ)-opioid receptor (DOR), the kappa (κ)-opioid receptor (KOR), mu (μ)-opioid receptor (MOR), nociceptin opioid receptor (NOR), zeta (ζ)-opioid receptor (ZOR), or any combination thereof. In some embodiments, the opioid is an opioid agonist, an opioid antagonist, or a mixed opioid agonist/antagonist of an opioid receptor. In some embodiments, the opioid agonist is a partial opioid agonist or an inverse opioid agonist. In some embodiments, the opioid is an opioid radical. In some embodiments, the opioid radical is joined to a radical of a therapeutically active agent by a linker, as described herein, forming an opioid dimer. In some embodiments, the opioid dimer is a heterodimer as described above. In some embodiments, an opioid radical is joined to a second radical, which is not an opioid radical, such as, for example, a radical of a therapeutically active agent (e.g., a steroid), by a linker described herein, forming an opioid heterodimer. In some embodiments, a first opioid radical, such as, for example, a partial opioid agonist, is joined to a second opioid radical, which is a different opioid radical than the first opioid radical, such as, for example, an opioid antagonist, by a linker described herein, forming a heterodimer.
- The term “pellet,” as used herein, refers to the shape of the pharmaceutical compositions of the disclosure that is rounded, spherical, cylindrical, or a combination thereof. In some embodiments, the pellet has a mean diameter from about 0.2 to 5 mm, e.g., from about 0.2 to 1 mm, from about 0.2 to 2 mm, from about 0.3 to 3 mm, from about 1.5 to 5 mm, from about 2 to 5 mm, from about 2.5 to 5 mm, from about 3 to 5 mm, from about 3.5 to 5 mm, from about 4 to 5 mm, or from about 4.5 to 5 mm.
- “Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the pharmacological agents described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
- “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.
- The terms “treat,” “treating,” or “treatment” as used herein, include reducing, alleviating, abating, ameliorating, relieving, or lessening the symptoms associated with a disease, disease state, or indication (e.g., glaucoma) in either a chronic or acute therapeutic scenario. In one embodiment, treatment includes a reduction of intraocular pressure. Also, treatment of a disease or disease state described herein includes the disclosure of use of such compound or composition for the treatment of such disease, disease state, or indication.
- Often the final hurdle of drug development, producing a final medicinal product from an active pharmaceutical ingredient (API) that is a solid or a liquid at room temperature is an extensive and costly process. Pharmaceutical formulation of an API that is a liquid at room temperature often requires, for example, excipients (e.g., stabilizers, additives, adjuvants, etc.) or conjugation to another molecule (e.g., a polymer) to stabilize and/or produce a processable and/or storable product. Instead, APIs that are solids at room temperature are often used for pharmaceutical formulations, avoiding the additional processing and formulation for producing medicinal products from liquid APIs; albeit, still incurring significant cost to formulation to a final medicinal product. Therefore, the cost of formulating solid or liquid APIs as well as the limited processability of liquid APIs limit the efficacy and/or adoption of potentially beneficial therapeutics.
- Furthermore, patient compliance is an often unresolved issue in the clinic. In some instances, modified-release pharmaceuticals can improve patient compliance. For example, extended-release (ER) dosage forms, such as sustained-release (SR) or controlled-release (CR) dosage forms, may facilitate compliance with a therapeutic regimen in some instances. SR and CR dosage forms are generally designed to liberate an API at a certain rate, such as to maintain a particular drug concentration over a period of time. For example, SR maintains drug release over a sustained period but not at a constant rate, while CR maintains drug release over a sustained period at a more consistent (e.g., nearly constant) rate (e.g., zero-order). Despite their ability to extend the dosing of an active, such dosage forms can be difficult to develop. Moreover, such dosage forms often include controlled release excipients (e.g., polymers) and/or controlled release matrices to facilitate controlled release. In the case of liquid or otherwise low melting point active agents, controlled release formulations can be even more difficult to develop. Moreover, even in the best circumstances, many controlled release forms have limited durations of active release (e.g., 24-hour release windows), so patient compliance remains an issue.
- Provided in certain embodiments herein are processable compounds that address the burden of medicinal product formulation as well as patient compliance. In certain embodiments, compounds described herein are solids at body temperature (e.g., about 37° C., or lower). In certain embodiments, compounds provided herein comprise a first group or radical (e.g., a structure provided in any one of Formula (I), Formula (IA), Formula (IB), Formula (IB′) Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V)) (e.g., covalently) joined (e.g., conjugated) to a second group. In some embodiments, the first group is a radical of Formula (I), Formula (IA), Formula (IB), Formula (IB′) or Formula (IC). In some embodiments, the second group is a group that is itself not processable itself in free form (e.g., has a melting temperature that is higher than its degradation temperature, is generally insoluble, such as in aqueous media, or is otherwise not suited for processing). In certain embodiments, the second group is a group that is not processable in dimer form (e.g., when conjugated directly to itself or via a linker, such as described herein). In some embodiments, the second group is a group that has a melting point and/or glass transition temperature of less than 50° C., less than 40° C., less than 37° C., or the like. Generally, such compounds, even if solid at room temperature, may not be suitable for use as implants due to the possibility of melting or deformation in a physiological environment. In some embodiments, the compound is formed into an implantable article (e.g., a pellet), such as using methods described herein (e.g., as described in the examples). In some embodiments, the implantable article has a (e.g., zero-order) controlled release rate over an extended period (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 12 weeks, 52 weeks, or more) in an aqueous medium (e.g., a buffer solution, serum, biological environment (e.g., in the eye), in vivo, or the like). In some embodiments, a compound provided herein (or implant comprising such a compound) is administered to an individual suffering an acute or a chronic disease or condition (e.g., as a therapy for the acute or chronic disease or condition) in any suitable manner (e.g., route of administration, such as by implanting, and/or frequency of dosing), such as a single dose or a series of doses (e.g., once or twice every 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 12 weeks, 52 weeks, or more).
- In certain instances, compounds (e.g., conjugates) provided herein are used to improve treatment options and/or patient compliance for acute diseases and/or disorders. In some instances, processable compounds described herein are used to improve treatment options and/or patient compliance for chronic diseases and/or disorders. In some embodiments, the processable compounds described herein are used to improve treatment options and/or patient compliance for ophthalmology, neurology, post-surgical medicine, orthopedics, and pain management.
- Provided herein are compounds (e.g., conjugates) that are processable (e.g., into an article). A processable compound is a compound that can be processed with heat or solvent to form a solid, such as with little (e.g., less than 20 wt. %, less than 10 wt. %, or less than 5 wt. %) or no addition of further excipient. In certain instances, the solid prepared following processing is an amorphous solid or a solid having a highly amorphous morphology (e.g., as discussed in more detail herein). In certain instances, a processable compound provided herein is a solid at room (e.g., 20° C.) and/or physiological temperature (e.g., 37° C.). In some instances, the compound is thermally processable, such as having a melt or glass transition temperature of at least 37° C., at least 40° C., at least 50° C., at least 60° C., at least 70° C., at least 100° C., or the like. In some embodiments, it is beneficial for the compound to be solid at room temperature, but processable at a temperature that is not prohibitively high. In some embodiments, a compound provided herein has a melt and/or glass transition temperature of less than 200° C., less than 150° C., less than 140° C., less than 130° C., less than 125° C., less than 120° C., or the like.
- In some embodiments, the compounds have any suitable morphology, such as to facilitate processing and/or pharmacodynamic effects (e.g., release profile). In certain embodiments, the compound (or implant or pharmaceutical composition comprising the compound) is amorphous (or comprises a highly amorphous content). In some embodiments, a compound (e.g., morphology) provided herein is a solid, such as at a physiological temperature (e.g., having a melting point (Tm) and/or glass transition temperature (Tg) of at least 37° C.). In some embodiments, the compound is a crystalline solid, film, glass, or amorphous solid (e.g., at a temperature of at least 37° C.). In some embodiments, the compound (or composition, article, or coating comprising the compound) has a crystallinity of at most 15% (e.g., determined by PXRD, DSC, or polarized light microscopy). In some embodiments, the compound (or composition, article, or coating comprising the compound) is substantially non-crystalline (e.g., determined by PXRD, DSC, or polarized light microscopy). In some embodiments, the compound (or composition, article, or coating comprising the compound) is amorphous (e.g., determined by PXRD, DSC, or polarized light microscopy). In some embodiments, the compound (e.g., morphology) has a thermal melting point (Tm) that is greater than or equal to the glass transition temperature (Tg). In some embodiments, the compound has a melting point of at least 37° C. In some embodiments, the compound (e.g., morphology) has a melting point of at least 100° C. In some embodiments, either one or both of the first and/or second radicals (or (e.g., active) fragments or metabolites thereof) of the compounds (e.g., drug conjugates) and (e.g., active) agents are released (e.g., in their free form), the release being controlled release and/or extended release. In some embodiments, either one or both of the first and/or second radicals of the compounds and agents are released (e.g., in their free form) for at least 15 days (e.g., in solution, buffer solution, serum, biological environment, in vivo, or the like).
- Described in certain embodiments herein are processable agents (e.g., compounds) formed from a processable group (e.g., a radical that makes a non-processable radical processable when linked or joined thereto) and a non-processable moiety (e.g., a radical that, if in its free form, would not be processable, such as by thermal techniques, e.g., because of a melting point that is below a physiological temperature). In some embodiments, the processable agents described herein are processable into a solid (e.g., at a temperature of at least 20° C., 25° C., 30° C., 37° C., or more). In some embodiments, provided herein are compounds useful in therapies for treating acute, chronic, or both disease or condition. In some instances, the conjugates provided herein represent a significant advance in the art, e.g., as processable compounds suitable for being formed into or formulated into controlled and/or extended release articles, coatings, or other pharmaceutical compositions that are beneficial for treating acute and/or chronic diseases or disorders, such as with infrequent (e.g., a single, or weekly, monthly, or less frequent) administration.
- In certain aspects, provided herein is a compound comprising a first radical and a second radical, the first radical comprising the structure of Formula (I):
-
- wherein:
- is a single bond or a double bond;
- each Ra, Rb, and Rc are independently selected from the group consisting of oxo, halogen, —CN, —NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted;
- or any one of Ra, Rb, or Rc are taken together with another of Ra, Rb, or Rc to form a substituted or an unsubstituted cycloalkyl or heterocycloalkyl;
- X1, X2, X3, and X4 are each independently selected from the group consisting of a bond and Qy, wherein each Q is independently selected from the group consisting of —O—, —NR—, —S(R)x—, and —C(R)z—;
- each of m, n, and o are independently 0-6;
- each x is independently 0-5;
- each y is independently 1-3;
- each z is independently 1 or 2;
- each R is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, and thiol (e.g., wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted), or one R is taken together with another R to form an oxo; and
- the second radical being a therapeutically active agent (or drug) and the first radical (e.g., steroid) being different than the second radical (e.g., prostaglandin);
- wherein, either the first radical, the second radical, or both the first radical and the second radical is not a steroid,
- or a pharmaceutically-acceptable salt or solvate thereof.
- In some embodiments, provided herein is a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IA):
-
- wherein:
- is a single bond or a double bond;
- each Ra, Rb, and Rc are independently selected from the group consisting of oxo, halogen, —CN, —NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted;
- or any one of Ra, Rb, or Rc are taken together with another of Ra, Rb, or Rc to form a substituted or an unsubstituted cycloalkyl or heterocycloalkyl;
- each of m, n, and o are independently 0-6; and
- the second radical being a therapeutically active agent (or drug) and the first radical (e.g., steroid) being different than the second radical (e.g., prostaglandin);
- wherein, either the first radical, the second radical, or both the first radical and the second radical is not a steroid,
- or a pharmaceutically-acceptable salt or solvate thereof.
- In some embodiments, provided herein is a compound comprising a first radical and a second radical, the first radical or the second radical comprising a structure of Formula (IB′):
-
- wherein:
- is a single bond or a double bond;
- each Ga is independently selected from the group consisting of oxo, halogen, —CN, —NO2, azide, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryloxy, ester, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, hydrazone, oxime, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, alkoxy, aryloxy, hydrazone, or heterocycloalkyl is optionally substituted;
- or a first Ga is taken together with another Ra to form an optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- each G1 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl are optionally substituted;
- G2 is hydrogen, hydroxy, alkyl, heteroalkyl, alkoxy, cycloalkyl, or heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, alkoxy, or heterocycloalkyl are optionally substituted;
- s is 0-8; and
- q is 1 or 2,
- or a pharmaceutically-acceptable salt or solvate thereof.
- In some embodiments, provided herein is a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IB):
-
- wherein:
- is a single bond or a double bond;
- each Ra, Rb, Rc, and Rd are independently selected from the group consisting of oxo, halogen, —CN, —NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted;
- or any one of Ra, Rb, Rc, and Rd are taken together with another of Re, Rb, Rc, and Rd to form a substituted or an unsubstituted cycloalkyl or heterocycloalkyl;
- each of m, n, o, and p are independently 0-6; and
- the second radical being a therapeutically active agent (or drug) and the first radical (e.g., steroid) being different than the second radical (e.g., prostaglandin);
- wherein, either the first radical, the second radical, or both the first radical and the second radical is not a steroid,
- or a pharmaceutically-acceptable salt or solvate thereof.
- In some embodiments, Ring A, B, C, or D of Formula (I), Formula (IA), or Formula (IB), each optionally and independently comprise one or more heteroatom (e.g., O, S, or N) within the ring.
- In some embodiments, provided herein is a compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IC):
-
- wherein:
- is a single bond or a double bond; Ra is hydrogen, —OH, or oxo;
- each Ra′ is independently selected from hydrogen, —OH, halogen, C1-C3 alkyl, and alkoxy;
- Ra″ is absent, hydrogen, or C1-C3 alkyl;
- Rb is absent, hydrogen, halogen, or C1-C3 alkyl;
- Rb′ is hydrogen, halogen, —OH, oxo, or C1-C3 alkyl;
- Rb″ is hydrogen or —OH;
- each Rc is independently hydrogen, —OH, oxo, or C1-C3 alkyl;
- each Rc′ is independently hydrogen or C1-C3 alkyl;
- Rc″ is hydrogen, —OH, C1-C3 alkyl, or —C(═O)H;
- each Rd is independently hydrogen, —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or each Rd is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted;
- Rd′ is hydrogen, —OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl;
- or one Rd is taken together with Rd′ to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl; and
- the second radical being a therapeutically active agent (or drug) and the first radical (e.g., steroid) being different than the second radical (e.g., prostaglandin);
- wherein, either the first radical, the second radical, or both the first radical and the second radical is not a steroid,
- or a pharmaceutically-acceptable salt or solvate thereof.
- In some embodiments, the alkyl or heteroalkyl of Rd is substituted with one or more of the group consisting of —SH, —OH, —COOH, oxo, halogen, amino, alkyl (e.g., alkenyl, alkynyl), heteroalkyl, ester, amide, sulfonic acid, and sulfone. In some embodiments, one Rd is taken together with Rd′ to form substituted heterocycloalkyl.
- In some embodiments, the first radical and the second radical are joined by a linker (e.g., a bond). In some embodiments, the first radical is joined to the second radical through any one of Ra, Rb, Rc, or Rd of the first radical. In some embodiments, the first radical is joined to the second radical through any one of Ra, Rb, Rc, or Rd, and the Ra, Rb, Rc, or Rd through which the first radical is joined to the second radical comprises a hydroxyl radical (e.g., when together with the linker or second radical (where the linker is a bond), forms an ether), a thiol radical (e.g., when together with the linker or second radical (where the linker is a bond), forms a thioether), or a carboxylate radical (e.g., when taken together with the linker or second radical (where the linker is a bond), forms an ester or carbonate).
- In some embodiments, the Ra, Rb, Rc, or Rd through which the first radical is joined to the second radical comprises a hydroxyl radical which together with the linker or with the second radical forms an ether. In some embodiments, the Ra, Rb, Rc, or Rd through which the first radical is joined to the second radical comprises a thiol radical which together with the linker or the second radical forms a thioether. In some embodiments, the Ra, Rb, Rc, or Rd through which the first radical is joined to the second radical comprises a carboxylate radical which together with the linker or the second radical forms an ester or a carbonate.
- In some embodiments, both the first radical and the second radical have the structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC). In some embodiments, both the first radical and the second radical have the structure of any one of Formula (I), Formula (IA), or Formula (IB′). In some embodiments, both the first radical and the second radical have the structure of Formula (I) or Formula (IA). In some embodiments, both the first radical and the second radical have the structure of Formula (I). In some embodiments, both the first radical and the second radical have the structure of Formula (IA). In some embodiments, the first radical and the second radical (e.g., that have the structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC)) are joined by a linker (e.g., a hydrolysable linker). In some embodiments, the linker (e.g., a hydrolysable linker) is a bond.
- In some embodiments, the first radical has a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC). In some embodiments, the second radical has a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC). In some embodiments, the second radical (e.g., which is not processable in its free form, not processable in dimer form, and/or is liquid or malleable at physiological temperature) does not have a structure of any one of a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC).
- In some embodiments, the radical of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC) is a steroid, an opioid agonist, an opioid antagonist, an adrenergic receptor antagonist (e.g., β-blocker, α-1 blocker), or a serotonergic antagonist (e.g., serotonin 5-HT3 receptor antagonist). In some embodiments, the first radical and/or the second radical is an anti-inflammatory agent, an anti-psychotic agent (e.g., typical anti-psychotic, a typical antipsychotic, schizophrenia, or the like), or the like.
- In some embodiments, the first radical and/or the second radical is a beta-blocker, which may be used to treat intra-ocular pressure in the eye. In some embodiments, the beta-blocker is timolol. In other embodiments, the beta-blocker is levobunolol, metipranolol or carteolol. In some embodiments, the beta-blocker is selected from the group consisting of Dichloroisoprenaline, Propranolol, Bucindolol, Carteolol, Carvedilol, Labetalol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Celiprolol, Metoprolol, Nebivolol, Esmolol, Butaxamine, ICI-118,551, SR 59230A, Nebivolol, Acebutolol, pindolol, labetalol, mepindolol, oxprenolol, celiprolol, and penbutolol. In some embodiments, the beta-blocker is selected from the group consisting of Betaxolol, carteolol, levobunolol, timolol, metipranolol.
- In some embodiments, the first radical is a solid (e.g., having a melting point of at least 30° C.) in its free form. In some embodiments, the second radical is a liquid (e.g., having a melting point of less than 30° C.) in its free form.
- In some embodiments, the first radical or the second radical is a steroid (e.g., dexamethasone, anecortave (e.g., anecortave desacetate), etc.). In some embodiments, the first radical is or is derived from anecortave (e.g., anecortave acetate or anecortave desacetate). In some embodiments, the first radical is a steroid (e.g., dexamethasone, anecortave (e.g., anecortave desacetate), etc.). In some embodiments, the steroid is a corticosteroid (e.g., glucocorticoid or mineral corticoid), a sex steroid, a neurosteroid, an aminosteroid, or a secosteroid. In some embodiments, the second radical is not a steroid. In certain embodiments, the second radical is a radical that does not have a structure of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC).
- In some embodiments, the steroid is a glucocorticoid. In some embodiments, the glucocorticoid is selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, loprednol, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fluclorolone, fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone pivalate, flunisolide, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, meprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, and ulobetasol, or the like.
- In some embodiments, the steroid is a mineralocorticoid. In some embodiments, the mineralocorticoid is selected from the group consisting of aldosterone, fludrocortisone, deoxycorticosterone, and corticosterone, or the like. In some embodiments, the mineralocorticoid is canrenone (e.g., potassium canrenoate), drospirenone, eplerenone, spirolactone, or a metabolite thereof (e.g., 7α-thiomethylspironolactone, canrenone, 6β-hydroxy-7α-thiomethylspironolactone, and 7α-thiospironolactone).
- In some embodiments, the steroid is an anabolic steroid. In some embodiments, the anabolic steroid is selected from the group consisting of androisoxazole, androstenediol, bolandiol, bolasterone, clostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methandriol, methenolone, methyltrienolone, nandrolone, norbolethone, oxymesterone, stenbolone, and trenbolone, or the like.
- In some embodiments, the steroid is an androgenic steroid. In some embodiments, the androgenic steroid is selected from the group consisting of boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17-α-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal, testosterone proprionate, testosterone enanthate tiomesterone dehydroepiandrosterone (DHEA), androstenedione, androstenediol, androsterone, dihydrotestosterone (DHT), and androstanolone, or the like.
- In some embodiments, the steroid is a progestin steroid. In some embodiments, the progestin steroid is selected from the group consisting of progesterone, norethisterone, norethisterone acetate, gestodene, levonorgestrel, allylestrenol, anagestone, desogestrel, dimethisterone, dydrogesterone, ethisterone, ethynodiol, ethynodiol diacetate, etonogestrel, gestodene, ethinylestradiol, haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17-alpha-hydroxyprogesterone, lynestrenol, medroxyprogesterone, melengestrol, norethindrone, norethynodrel, norgesterone, gestonorone, norgestimate, norgestrel, levonorgestrel, norgestrienone, norvinisterone, pentagestrone, M ENT (7-methyl-19-testosterone); norelgestromin, and trimigestone drospirenone, tibolone, and megestrol, or the like.
- In some embodiments, the steroid is an estrogen steroid. In some embodiments, the estrogen steroid is selected from the group consisting of estradiol, estrone, eguilenin, equilin, estradiol benzoate, estriol, ethinyl estradiol, mestranol, moxestrol, mytatrienediol, quinestradiol, and quinestrol, or the like.
- In some embodiments, the steroid is selected from the group consisting of abiraterone, cyproterone acetate, dutasteride, enzalutamide, finasteride, galeterone, fusidic acid, cholesterol, 11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, obeticholic acid, tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone, 5α-dihydrocorticosterone, 5α-dihydropregesterone, flugestone, prebediolone, chlormadinone acetate, medrogestone, and segesterone acetate, or the like.
- In some embodiments, the steroid is an anti-angiogenic or an intraocular pressure (IOP) lowering steroid. In some embodiments, the anti-angiogenic or intraocular pressure (IOP) lowering steroid is selected from the group consisting of anecortave acetate, anecortave (e.g., anecortave desacetate), 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, and tetrahydrocortisol, or the like. In some embodiments, the anti-angiogenic or IOP lowering steroid is anecortave desacetate.
- In some embodiments, the steroid is a cholic acid-related bile acid steroid. In some embodiments, the cholic acid-related bile acid steroid is selected from the group consisting of deoxycholic acid, apocholic acid, dehydrocholic acid, glycochenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, hyodeoxycholic acid, lithocholic acid, α-muricholic acid, β-muricholic acid, γ-muricholic acid, w-muricholic acid, taurochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurolithocholic acid, and tauroursodeoxycholic acid, or the like.
- In some embodiments, the steroid is a neurosteroid. In some embodiments, the neurosteroid is selected from the group consisting of alphaxalone, alphadolone, hydroxydione, minaxolone, tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone, ganoxolone, 3α-androstanediol, epipregnanolone, isopregnanolone, and 24(S)-hydroxycholesterol, or the like.
- In some embodiments, the steroid is a steroid pheromone. In some embodiments, the steroid pheromone is selected from the group consisting of androstadienol, androstadienone, androstenol, androstenone, estratetraenol, 5-dehydroprogesterone, 6-dehydro-retroprogesterone, allopregnanolone, and hydroxyprogesterone caproate, or the like.
- In some embodiments, the steroid is a steroid metabolite. In some embodiments, the steroid metabolite is selected from the group consisting of tetrahydrotriamcinolone, cortienic acid, 11-dehydrocorticosterone, 11β-hydroxypregnenolone, ketoprogesterone, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone, and progesterone, or the like.
- In some embodiments, the steroid is a progestin. In some embodiments, the progestin is selected from the group consisting of allopregnone-3α,20α-diol, allopregnone-3β,20β-diol, allopregnane-3β,21-diol-11,20-dione, allopregnane-3β,17α-diol-20-one, 3,20-allopregnanedione, 3β,11β,17α,20β,21-pentol, allopregnane-3β,17α,20β,21-tetrol, allopregnane-3α,11β,17α,21-tetrol-20-one, allopregnane-3β,11β,17α,21-tetrol-20-one, allopregnane-3β,17α,20β-triol, allopregnane-3β,17α,21-triol-11,20-dione, allopregnane-3β,11β,21-triol-20-one, allopregnane-3β,17α,21-triol-20-one, allopregnane-3α-ol-20-one, allopregnane-3β-ol-20-one, pregnanediol, 3,20-pregnanedione, 4-pregnene-20,21-diol-3,11-dione, 4-pregnene-11β,17α,20,21-tetrol-3-one, 4-pregnene-17α,20β,21-triol-3,11-dione, 4-pregnene-17α,20β,21-triol-3-one, and pregnenolone, or the like.
- In some embodiments, the first radical and the second radical are joined by a linker (e.g., hydrolyzable linker). In some embodiments, the first radical and the second radical are joined by a bond.
- In some embodiments, the linker is a bond, alkyl, heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy is optionally substituted. In some embodiments, the alkyl, heteroalkyl, or alkoxy are each independently substituted with one or more groups, each group being independently selected from the group consisting of a bond, —O—, —S—, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl. In some embodiments, the linker is a bond. In some embodiments, the linker is alkyl (alkylene) and the alkyl (alkylene) is substituted with one or more groups selected from —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, the linker is alkyl (alkylene) and the alkyl (alkylene) is an unsubstituted alkylene. In some embodiments, the linker is heteroalkyl (heteroalkylene) and the heteroalkyl (heteroalkylene) is substituted with one or more groups selected from halo or alkyl. In some embodiments, the linker is heteroalkyl (heteroalkylene) and is the heteroalkyl (heteroalkylene) an unsubstituted heteroalkylene. In some embodiments, the linker comprises one or more linker groups selected from a bond, —O—, —S—, unsubstituted alkylene, C═O(CH2CH2)nC═O, C═O(CHCH)nC═O, C═O(OCH2CH2O)nC═O, O(CH2CH2O)n, and C═O(CH2CH2O)n, (CH(CH3)C(═O)O)n, wherein n is 1-20. In some embodiments, the linker is a bond, unsubstituted alkylene, C═O(CH2CH2)nC═O, C═O(CHCH)nC═O, C═O(OCH2CH2O)nC═O, O(CH2CH2O)n, and C═O(CH2CH2O)n, (CH(CH3)C(═O)O)n, C═O(CH2CH2)nC═O(CH(CH3)C(═O)O)n, wherein n is 1-20. In some embodiments, the linker is a bond.
- In some embodiments, the linker is hydrolyzed in a buffered solution. In some embodiments, the linker is hydrolyzed by an enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a protease or an esterase).
- In some embodiments, the first radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- In some embodiments, the first radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- In certain embodiments, the disclosure provides a compound, or pharmaceutically acceptable salt thereof, having a structure provided in Table 1. In some embodiments, the compound, or pharmaceutically acceptable salt thereof, provided in Table 1 is a solid at a temperature of at least 20° C. (e.g., at least 30 C, at least 37 C, at least 40 C, at least 50 C, at least 70 C, at least 100 C, or the like). In some embodiments, the compound, or pharmaceutically acceptable salt thereof, provided in Table 1 is processable at a temperature of at least 20° C. (e.g., as described in the examples). In some embodiments, the compound, or pharmaceutically acceptable salt thereof, provided in Table 1 is processable into an article (e.g., machined, molded, emulsion-processed, electrospun, electrosprayed, blow molded, or extruded to form a fiber, fiber mesh, woven fabric, non-woven fabric, film, surface coating, pellet, cylinder, rod, microparticle, nanoparticle, or another shaped article) at a temperature of at least 20° C. In some embodiments, the compound, or pharmaceutically acceptable salt thereof, provided in Table 1 comprises both a first radical and a second radical. In some embodiments, the compound in Table 1 is processable when the first radical, and the second radical are joined by a linker. In some embodiments, the linker is a bond.
-
TABLE 1 Compound Number Structure Name 1 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate 2 2- ((8S,9R,10S,11S,13S,14S, 16R,17R)-9-fluoro-11,17- dihydroxy-10,13,16- trimethyl-3-oxo- 6,7,8,9,10,11,12,13,14, 15,16,17-dodecahydro- 3H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate 3 2- ((8S,9R,10S,11S,13S,14S, 16R,17R)-9-fluoro-11,17- dihydroxy-10,13,16- trimethyl-3-oxo- 6,7,8,9,10,11,12,13,14, 15,16,17-dodecahydro- 3H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5- phenylpentyl)cyclopentyl) hept-5- enoate 4 (8R,9S,13S,14S)-13- methyl-17-oxo- 7,8,9,11,12,13,14,15,16, 17-decahydro-6H- cyclopenta[a]phenanthren- 3-yl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5- phenylpentyl)cyclopentyl) hept-5- enoate 5 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((S,E)-3- hydroxy-5-phenylpent-1- en-1-yl)cyclopentyl)hept- 5- enoate 6 2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5- phenylpentyl)cyclopentyl) hept-5- enoate 7 2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-2-((E)-3,3- difluoro-4-phenoxybut-1- en-1-yl)-3,5- dihydroxycyclopentyl) hept-5- enoate 8 (4-((((2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2- oxoethoxy)carbonyl)oxy) methyl)cyclohexyl)methyl (Z)-7-((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate 9 (4R,4aS,7aR,12bS)-3- (cyclopropylmethyl)-4a- hydroxy-7-oxo- 2,3,4,4a,5,6,7,7a- octahydro-1H-4,12- methanobenzofuro[3,2- e]isoquinolin-9-yl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate 10 (S)-1-(tert-butylamino)- 3-((4-morpholino-1,2,5- thiadiazol-3- yl)oxy)propan-2-yl(R)-4- ((3R,5R,8R,9S,10S,12S,13 R,14S,17R)-3,12- dihydroxy-10,13- dimethylhexadecahydro- 1H- cyclopenta[a]phenanthren- 17-yl)pentanoate 11 (S,E)-1-((1R,2R,3S,5R)-2- ((Z)-7-(ethylamino)-7- oxohept-2-en-1-yl)-3,5- dihydroxycyclopentyl)-5- phenylpent-1-en-3-yl(2- ((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl) carbonate 12 2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-(3- oxodecyl)cyclopentyl) hept-5-enoate 13 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((S,E)-3- hydroxyoct-1-en-1- yl)cyclopentyl)hept-5- enoate 14 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl 4- ((3R,5aS,6S,7S,8aR)-6- ((S,E)-4-(2,5- difluorophenoxy)-3- hydroxybut-1-en-1-yl)-7- hydroxyoctahydro-2H- cyclopenta[b]oxepin-3- yl) butanoate 15 (8R,9S,13S,14S)-13- methyl-17-oxo- 7,8,9,11,12,13,14,15,16, 17-decahydro-6H- cyclopenta[a]phenanthren- 3-yl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate 16 1-(tert-butylamino)-3- ((4-morpholino-1,2,5- thiadiazol-3- yl)oxy)propan-2-yl(2- ((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl) carbonate 17 (4R,4aS,7aR,12bS)-3- allyl-4a-hydroxy-7-oxo- 2,3,4,4a,5,6,7,7a- octahydro-1H-4,12- methanobenzofuro[3,2- e]isoquinolin-9-yl(2- ((8S,9S,10R,11S,13S,14S, 17R)-11,17-dihydroxy- 10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14, 15,16,17- tetradecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl) carbonate 18 1-((4R,4aS,7aR,12bS)-3- allyl-4a-hydroxy-7-oxo- 2,3,4,4a,5,6,7,7a- octahydro-2H-4,12- methanobenzofuro[3,2- e]isoquinolin-9-yl)8-(2- ((8S,9S,10R,11S,13S,14S, 17R)-11,17-dihydroxy- 10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14, 15,16,17- tetradecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl) octanedioate 19 1-(tert-butylamino)-3- ((4-morpholino-1,2,5- thiadiazol-3- yl)oxy)propan-2-yl(4R)- 4- ((3R,5S,7R,8R,9S,10S, 12S,13R,14S,17R)-3,7,12- trihydroxy-10,13- dimethylhexadecahydro- 1H- cyclopenta[a]phenanthren- 17-yl) pentanoate 20 1-(tert-butylamino)-3- ((4-morpholino-1,2,5- thiadiazol-3- yl)oxy)propan-2-yl(Z)-2- ((3R,4S,5S,8S,9S,10S,11R, 13R,14S,16S)-16- acetoxy-3,11-dihydroxy- 4,8,10,14- tetramethylhexadecahydro- 17H- cyclopenta[a]phenanthren- 17-ylidene)-6- methylhept-5- enoate 21 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(E)-4- (2-((5-bromoquinoxalin- 6-yl)amino)-4,5-dihydro- 1H-imidazol-1-yl)but-3- enoate 22 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(E)-4- ((((4S,6S)-4-(ethylamino)- 6-methyl-7,7-dioxido- 5,6-dihydro-4H- thieno[2,3-b]thiopyran- 2- yl)sulfonyl)imino) butanoate 23 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(E)-4- (4-(isoquinolin-5- ylsulfonyl)-1,4-diazepan- 1-yl)but-3-enoate 24 (Z)-4-(4-(4- chlorophenyl)-4- hydroxypiperidin-1-yl)-1- (4-fluorophenyl)but-1- en-1-yl(2- ((8S,9S,10R,11S,13S,14S, 17R)-11,17-dihydroxy- 10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13, 14,15,16,17- tetradecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl) carbonate - In some embodiments, the disclosure provides a compound (e.g., conjugate, such as a heterodimeric conjugate), or pharmaceutically acceptable salt thereof, having a structure provided in Table 2. In other embodiments, parent conjugate compounds that do not form a processable solid are shown in Table 2. In some embodiments, the compound, or pharmaceutically acceptable salt thereof, provided in Table 2 is not a solid at a temperature of at least 20° C. In some embodiments, the compound, or pharmaceutically acceptable salt thereof, provided in Table 2 is not processable at a temperature of at least 20° C. In some embodiments, the compound, or pharmaceutically acceptable salt thereof, provided in Table 2 is not processable into an article, as described herein, at a temperature of at least 20° C.
- In some embodiments, the compound, or pharmaceutically acceptable salt thereof, provided in Table 2 comprises both a first radical and a second radical. In some embodiments, the heterodimeric conjugate in Table 2 is not processable when the first radical and the second radical are joined by a linker. In some embodiments, the linker is not a bond. In some embodiments, the linker is alkyl, heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy is optionally substituted with one or more groups, each group being independently selected from the group consisting of a bond, —O—, —S—, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl.
-
TABLE 2 Compound Number Structure Name 25 1- ((8S,9R,10S,11S,13S,14S, 16R,17R)-9-fluoro-11,17- dihydroxy-10,13,16- trimethyl-3-oxo- 6,7,8,9,10,11,12,13,14, 15,16,17-dodecahydro- 3H- cyclopenta[a]phenanthren- 17-yl)-1,4-dioxo- 3,5,8,11- tetraoxatridecan-13-yl (Z)-7-((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5- phenylpentyl)cyclopentyl) hept-5-enoate 26 4-acetamidophenyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate 27 ((3R,5R,7R)-adamantan- 1-yl)methyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate 28 2-(2-(2-(((Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5- phenylpentyl)cyclopentyl) hept-5- enoyl)oxy)ethoxy)ethoxy) ethyl(Z)-7- ((1S,2S,3S,5R)-3,5- dihydroxy-2-((S)-3- hydroxy-5- phenylpentyl)cyclopentyl) hept-5-enoate 29 propyl(Z)-7- ((1R,2R,3R,5S)-2- ((3R,18S)-20- ((1S,2S,3R,5S)-3,5- dihydroxy-2-((Z)-7-oxo-7- propoxyhept-2-en-1- yl)cyclopentyl)-5,16- dioxo-3,18-diphenethyl- 4,6,9,12,15,17- hexaoxaicosyl)-3,5- dihydroxycyclopentyl) hept-5- enoate 30 propyl(Z)-7- ((1R,2R,3R,5S)-2-((R)-3- ((ethoxycarbonyl)oxy)-5- phenylpentyl)-3,5- dihydroxycyclopentyl) hept-5-enoate - Intraocular diseases are a group of diseases including, but not limited to, glaucoma, ocular inflammation, diabetic macular edema, posterior inflammation, anterior inflammation, macular degeneration (e.g., wet macular degeneration (AMD) and dry AMD), post-cataract surgery, and retinal vein occlusion. Prominent aspects of intraocular diseases are increased intraocular pressure and inflammation. In some embodiments, the intraocular disease is a macular degeneration. In some embodiments, the intraocular disease is wet AMD. In some embodiments, the intraocular disease is dry AMD.
- In some embodiments, glaucoma is a group of eye diseases, which result in damage to the optic nerve and cause vision loss. Glaucoma is one of the leading causes of blindness globally, and there is currently no cure for glaucoma. Glaucoma management is limited to avoiding glaucomatous damage and nerve damage as well as preserving visual field and total quality of life. This management system relies on diagnostic techniques and follow-up examinations as well as judicious selection of treatments for the individual patient.
- Therapeutic strategies for glaucoma are limited to pharmaceutical agents (e.g., intraocular pressure (IOP) lowering agents, e.g., prostaglandins), surgery (e.g., implants), laser therapy, or any combination thereof. The reported rates of nonadherence to topical glaucoma medication vary widely from 16% to 67%, and it is estimated that less than a third of patients remained on their initial therapy after 12 months (Robin et al, Exp. Rev. Ophth. (2019); 14:4-5, 199-210). Poor compliance with medications and follow-up visits is a major reason for vision loss in glaucoma patients.
- Ocular hypertension (increased intraocular pressure (IOP)) is one of the major risk factors for glaucoma, and lowering it is a major goal of glaucoma treatment. Intraocular pressure is a function of the production of aqueous humor by the ciliary processes of the eye as well as it's drainage through the trabecular meshwork. In glaucoma, the drainage mechanisms are hindered and/or blocked, causing an increase in IOP. Furthermore, inflammation blocks outflow of aqueous humor through the trabecular meshwork, causing secondary glaucoma. This inflammation is often difficult to treat because anti-inflammatory steroids (e.g., corticosteroids), which restrict blood flow to the eye, often raise the IOP further. Described herein are compounds that navigate the balance between reducing the IOP (e.g., with an IOP lowering agent such as a prostaglandin or an IOP lowering steroid) as well as reducing inflammation (e.g., with a corticosteroid). In some embodiments, described herein are compounds that significantly increase patient compliance by reducing the number of administrations of API (e.g., once per month).
- Described herein are processable agents for glaucoma formed from a processable moiety and a non-processable moiety. The processable agents for glaucoma described herein are processable into a solid (e.g., at a temperature of at least 20° C., 25° C., 30° C., 37° C., or more). The processable agents for glaucoma described herein have a controlled release profile (e.g., zero order) and/or an extended release profile (e.g., at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 15 days, 30 days, or more) in solution (e.g., buffer solution, serum, biological environment, in vivo, or the like). The compounds for glaucoma described herein are useful to treat both acute and chronic diseases or disorders. The compounds for glaucoma are tested, in certain embodiments, using the assays and methods described herein (e.g., as described in the examples). The compounds for glaucoma described herein represent a significant advance in the art as the processable agents produce a controlled and extended release profile that is beneficial for treating acute and/or chronic forms of glaucoma with a single administration.
- Provided herein is a heteromeric conjugate comprising a first radical and a second radical. In some embodiments, both the first radical and the second radical have the structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC). In some embodiments, the first radical is an anti-inflammatory agent. In some embodiments, the second radical is selected from the group consisting of a non-steroidal anti-inflammatory (NSAID), an intraocular pressure (IOP) lowering agent, a beta blocker, a Rho kinase inhibitor, a carbonic anhydrase inhibitor, an α-adrenergic agonist, tyrosine kinase inhibitor, neuroprotective agent, anti-oxidant, anti-microbial, anti-viral, or the like. In some embodiments, the second radical is an IOP lowering agent. In some embodiments, the first radical is an anti-inflammatory agent and the second radical is an IOP lowering agent. In some embodiments, the first radical is an IOP lowering steroid (e.g., anecortave (e.g., anecortave desacetate)) or benign steroid (e.g., cholesterol) and the second radical is an IOP lowering agent. In some embodiments, the IOP lowering agent is a prostaglandin. In some embodiments, the first radical is a steroid and the second radical is a prostaglandin.
- In certain aspects, the first radical has the structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), or Formula (IC).
- In some embodiments, the second radical has a structure of Formula (II):
-
- wherein:
- R1, R2, R3, R4, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted;
- or any one of R1, R2, R3, R4, or R5 are taken together to form an optionally substituted cycloalkyl or heterocycloalkyl;
- X is selected from the group consisting of —O—, —NR—, —S(R)a—, and —C(R)b—;
- a is independently 0-2; and
- b is independently 1 or 2,
- or a pharmaceutically acceptable salt or solvate thereof.
- In some embodiments, R4 is alkyl substituted with one or more of —COOH, —CONH2, and alkyl (e.g., alkylene or alkenyl). In some embodiments, X is S, —C(R)1—, or —C(R)2—. In some embodiments, X is —CH— or —CH2—.
- In some embodiments, the second radical has a structure of Formula (IIA):
-
- wherein:
- R1, R2, R3, R4, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted; and
- R6 and R6′ are each independently hydrogen, halogen, alkyl, or R6 and R6′ are taken together to form an oxo,
- or a pharmaceutically acceptable salt or solvate thereof.
- In some embodiments, R6 and R6′ are each independently fluoro. In some embodiments, R6 is H or methyl and R6′ is —OH. In some embodiments, R6 and R6′ are taken together to form an oxo. In some embodiments, R1 and R3 are each independently —OH or oxo. In some embodiments, R3 and R4 are taken together to form a heterocycloalkyl substituted with alkyl (e.g., alkenyl) substituted with —COOH.
- In some embodiments, the second radical has a structure of Formula (IIB):
-
- wherein:
- R1, R2, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted;
- R6″ is oxo or —OH;
- Y1 and Y2 are each independently a bond or alkylene;
- G is O or CH2;
- g is 1 or 2; and
- R10 is alkyl or hydrogen,
- or a pharmaceutically acceptable salt or solvate thereof.
- In some embodiments, R1 is oxo or —OH. In some embodiments, R2 is hydrogen. In some embodiments, R5 is selected from one or more of the group consisting of —O—, —OH, halogen, alkyl (e.g., alkynyl), aryl, wherein the alkyl (e.g., alkynyl) and aryl are optionally substituted with one or more of alkyl (e.g., fluoroalkyl), halogen, and —OH. In some embodiments, R5 is optionally substituted aryl or optionally substituted —O-aryl.
- In some embodiments, the first radical and the second radical are joined by a linker (e.g., hydrolyzable linker). In some embodiments, the first radical and the second radical are joined by a bond.
- In certain aspects, provided herein is a compound comprising:
-
- a) a steroid;
- b) a prostaglandin; and
- c) a linker (e.g., hydrolyzable linker), wherein the linker adjoins (e.g., covalently) the steroid and the prostaglandin,
- or a pharmaceutically acceptable salt or solvate thereof.
- In certain aspects, provided herein is a compound having the structure of Formula (III):
-
- wherein:
- is a single bond or a double bond;
- each Ra, Rb, Rc, and Rd are independently selected from the group consisting of oxo, halogen, —CN, —NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, or thiol, wherein the alkyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted;
- or any one of Ra, Rb, Rc, and Rd are taken together with another of Ra, Rb, Rc, and Rd to form an substituted or unsubstituted cycloalkyl or heterocycloalkyl;
- each of m, n, o, and p are independently 0-6;
- each R is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, and thiol, or is taken together with another R to form an oxo;
- R1, R2, R3, R4, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted; and
- L is a linker,
- or a pharmaceutically-acceptable salt or solvate thereof.
- In certain aspects, provided herein is a compound having the structure of Formula (IV):
-
- wherein:
- is a single bond or a double bond;
- Rd is hydrogen, —OH, or oxo;
- each Ra′ is independently selected from hydrogen, —OH, halogen, C1-C3 alkyl, and alkoxy;
- Ra″ is absent, hydrogen, or C1-C3 alkyl;
- Rb is absent, hydrogen, halogen, or C1-C3 alkyl;
- Rb′ is hydrogen, halogen, —OH, oxo, or C1-C3 alkyl;
- Rb″ is hydrogen or —OH;
- each Rc is independently hydrogen, —OH, oxo, or C1-C3 alkyl;
- each Rc′ is independently hydrogen or C1-C3 alkyl;
- Rc″ is hydrogen, —OH, C1-C3 alkyl, or —C(═O)H;
- each Rd is independently hydrogen, —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or each Rd is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted;
- Rd′ is hydrogen, —OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl;
- or one Rd is taken together with Rd′ to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;
- R1, R2, R3, R4, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted; and
- R6 and R6′ are each independently hydrogen, halogen, alkyl, or R6 and R6′ are taken together to form an oxo,
- or a pharmaceutically acceptable salt or solvate thereof.
- In certain aspects, provided herein is a compound having the structure of Formula (V):
-
- wherein:
- is a single bond or a double bond;
- Rd is hydrogen, —OH, or oxo;
- each Ra′ is independently selected from hydrogen, —OH, halogen, C1-C3 alkyl, and alkoxy;
- Ra″ is absent, hydrogen, or C1-C3 alkyl;
- Rb is absent, hydrogen, halogen, or C1-C3 alkyl;
- Rb′ is hydrogen, halogen, —OH, oxo, or C1-C3 alkyl;
- Rb″ is hydrogen or —OH;
- each Rc is independently hydrogen, —OH, oxo, or C1-C3 alkyl;
- each Rc′ is independently hydrogen or C1-C3 alkyl;
- Rc″ is hydrogen, —OH, C1-C3 alkyl, or —C(═O)H;
- each Rd is independently hydrogen, —OH, —COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or each Rd is taken together to form an oxo, wherein the alkyl or heteroalkyl is optionally substituted;
- Rd′ is hydrogen, —OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl;
- or one Rd is taken together with Rd′ to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;
- R1, R2, and R5 are each independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted;
- R6″ is oxo or —OH;
- Y1 and Y2 are each independently a bond or alkylene;
- G is O or CH2;
- g is 1 or 2;
- R10 is alkyl or H; and
- L is a linker,
- or a pharmaceutically acceptable salt or solvate thereof.
- In some embodiments, any one of Re, Ra′, Rb, Rb′, Rb″, Rc, Rc″, Rd, or Rd′ is an ester radical, a hydroxyl radical, or a carboxylate radical, and any one of R1, R2, R3, R4, R5, R6, R6′, R6″, or R10 is a thiol radical, a hydroxyl radical, or a carboxylate radical. In some embodiments, any one of Re, Ra′, Rb, Rb′, Rb″, Rc, Rc′, Rd, or Rd′ is adjoined to any one of R2, R3, R4, R5, R6, R6′, R6″, or R10 by a linker. In some embodiments, any one of Rd, Ra′, Rb, Rb′, Rb″, Rc″, Rd, or Rd′ is adjoined to any one of R4, R5, R6, R6′, R6″, or R10 by a linker. In some embodiments, any one of Rd or Rd′ is adjoined to any one of R4, R5, R6, R6′, R6″, or R10 by a linker. In some embodiments, the linker is a bond.
- In some embodiments, the linker is a bond, alkyl, heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy is optionally substituted. In some embodiments, the alkyl, heteroalkyl, or alkoxy are each independently substituted with one or more groups, each group being independently selected from the group consisting of a bond, —O—, —S—, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl. In some embodiments, the linker is a bond. In some embodiments, the linker is alkyl (alkylene) and the alkyl (alkylene) is substituted with one or more groups selected from —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, the linker is alkyl (alkylene) and the alkyl (alkylene) is an unsubstituted alkylene. In some embodiments, the linker is heteroalkyl (heteroalkylene) and the heteroalkyl (heteroalkylene) is substituted with one or more groups selected from halo or alkyl. In some embodiments, the linker is heteroalkyl (heteroalkylene) and is the heteroalkyl (heteroalkylene) an unsubstituted heteroalkylene. In some embodiments, the linker comprises one or more linker groups selected from a bond, —O—, —S—, unsubstituted alkylene, C═O(CH2CH2)nC═O, C═O(CHCH)nC═O, C═O(OCH2CH2O)nC═O, O(CH2CH2O)n, and C═O(CH2CH2O)n, (CH(CH3)C(═O)O)n, wherein n is 1-20. In some embodiments, the linker is a bond, unsubstituted alkylene, C═O(CH2CH2)nC═O, C═O(CHCH)nC═O, C═O(OCH2CH2O)nC═O, O(CH2CH2O)n, and C═O(CH2CH2O)n, (CH(CH3)C(═O)O)n, C═O(CH2CH2)nC═O(CH(CH3)C(═O)O)n, wherein n is 1-20.
- In some embodiments, the linker comprises one or more linker group, each linker group being independently selected from the group consisting of a bond, alkyl, cycloalkyl, heteroalkyl, or alkoxy, wherein the alkyl, cycloalkyl, heteroalkyl, or alkoxy is optionally substituted. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, or alkoxy are each independently substituted with one or more substituent, each substituent being independently selected from the group consisting of —O— (e.g., —OH), —S— (e.g., —SH), silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl. In some embodiments, the linker comprises one or more linker group, each linker group being independently selected from the group consisting of alkyl (alkylene) and cycloalkyl (cycloalkylene), and the alkyl (alkylene) or cycloalkyl (cycloalkylene) is unsubstituted or substituted (e.g., with one or more substituent each substituent being independently selected from the group consisting of —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl). In some embodiments, the linker comprises an unsubstituted or substituted alkylene-cycloalkylene-alkylene. In some embodiments, the linker comprises one or more linker group, each linker group being independently selected from the group consisting of a bond, —O—, —O(C═O)—, —O(C═O)—O—, —S—, unsubstituted alkylene, unsubstituted cycloalkylene, C═O(CH2CH2)nC═O, C═O(CHCH)nC═O, C═O(OCH2CH2O)nC═O, O(CH2CH2O)n, and C═O(CH2CH2O)n, and (CH(CH3)C(═O)O)n, wherein n is 1-20. In some embodiments, the linker is a bond, unsubstituted alkylene, unsubstituted alkylene-cycloalkylene-alkylene, C═O(CH2CH2)nC═O, C═O(CHCH)nC═O, C═O(OCH2CH2O)nC═O, O(CH2CH2O)n, and C═O(CH2CH2O)n, (CH(CH3)C(═O)O)n, C═O(CH2CH2)nC═O(CH(CH3)C(═O)O)n, wherein n is 1-20. In some embodiments, n is 1-10. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.
- In some embodiments, the linker is hydrolyzed in a buffered solution. In some embodiments, the linker is hydrolyzed by an enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a protease or an esterase).
- In some embodiments, the first radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- In some embodiments, the second radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- In some embodiments, the second radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- In some embodiments, the second radical is a radical of a drug. In some embodiments, the drug is a prostaglandin. In some embodiments, the prostaglandin is selected from the group consisting of latanoprost, latanoprost acid, travoprost, travoprost acid, tafluprost, tafluprost acid, bimatoprost, bimatoprost acid, sepetaprost, and sepetaprost acid, or a fragment or radical of any of the foregoing.
- In some embodiments, the second radical is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of:
- In some embodiments, the disclosure provides a compound for glaucoma, or pharmaceutically acceptable salt thereof, having a structure provided in Table 3. In some embodiments, parent conjugate compounds that form articles (e.g., pellets), using methods described in the examples herein, are shown in Table 3. In some embodiments, the compound for glaucoma, or pharmaceutically acceptable salt thereof, provided in Table 3 is a solid at a temperature of at least 20° C. In some embodiments, the compound for glaucoma, or pharmaceutically acceptable salt thereof, provided in Table 3 is processable at a temperature of at least 20° C. In some embodiments, the compound for glaucoma, or pharmaceutically acceptable salt thereof, provided in Table 3 is processable into an article, as described herein, at a temperature of at least 20° C. In some embodiments, the compound for glaucoma, or pharmaceutically acceptable salt thereof, provided in Table 3 comprises a first radical that is processable in its free form and a second radical that is not processable in its free form. In some embodiments, the compound for glaucoma in Table 3 is processable when the first radical that is processable in its free form and the second radical that is not processable in its free form are joined by a linker. In some embodiments, the linker is a bond. In some embodiments, the linker comprises one more linker group, each linker group being independently selected from the group consisting of a bond, alkyl or cycloalkyl, wherein the alkyl or cycloalkyl may optionally be substituted. In some embodiment the linker forms, together with the first and/or the second radical, an ether. In some embodiment the linker forms, together with the first and/or the second radical, an ester. In some embodiment the linker forms, together with the first and/or second radical, a carbonate.
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TABLE 3 Compound Number Structure Name 1 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate 2 2- ((8S,9R,10S,11S,13S,14S, 16R,17R)-9-fluoro-11,17- dihydroxy-10,13,16- trimethyl-3-oxo- 6,7,8,9,10,11,12,13,14,15,16,17- dodecahydro- 3H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy)but- 1-en-1- yl)cyclopentyl)hept-5- enoate 3 2- ((8S,9R,10S,11S,13S,14S,16R,17R)- 9-fluoro-11,7- dihydroxy-10,13,16- trimethyl-3-oxo- 6,7,8,9,10,11,12,13,14,15,16,17- dodecahydro- 3H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5- phenylpentyl)cyclopentyl) hept-5- enoate 4 (8R,9S,13S,14S)-13- methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17- decahydro-6H- cyclopenta[a]phenanthren- 3-yl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5- phenylpentyl)cyclopentyl) hept-5- enoate 5 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((S,E)-3- hydroxy-5-phenylpent-1- en-1-yl)cyclopentyl)hept- 5- enoate 6 2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo- 2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5- phenylpentyl)cyclopentyl) hept-5- enoate 7 2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo- 2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-2-((E)-3,3- difluoro-4-phenoxybut-1- en-1-yl)-3,5- dihydroxycyclopentyl)hept- 5- enoate 8 (4-((((2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo- 2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2- oxoethoxy)carbonyl)oxy) methyl)cyclohexyl)methyl) (Z)-7-((1R,2R,3R,55)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate 9 (4R,4aS,7aR,12bS)-3- (cyclopropylmethyl)-4a- hydroxy-7-oxo- 2,3,4,4a,5,6,7,7a- octahydro-1H-4,12- methanobenzofuro[3,2- e]isoquinolin-9-yl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate 10 (S)-1-(tert-butylamino)- 3-((4-morpholino-1,2,5- thiadiazol-3- yl)oxy)propan-2-yl(R)-4- ((3R,5R,8R,9S,10S,12S,13R,14S,17R)- 3,12- dihydroxy-10,13- dimethylhexadecahydro- 1H- cyclopenta[a]phenanthren- 17-yl)pentanoate 11 (S,E)-1-((1R,2R,3S,5R)-2- ((Z)-7-(ethylamino)-7- oxohept-2-en-1-yl)-3,5- dihydroxycyclopentyl)-5- phenylpent-1-en-3-yl(2- ((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl) carbonate - The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), Crescent Chemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI America (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.), and Wako Chemicals USA, Inc. (Richmond, Va.).
- Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.
- Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the dual-acting meibomian gland dysfunction pharmacological agent described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.
- In some embodiments, the compound described herein has a structure provided in any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), or Formula (V). In certain embodiments, the compounds as described herein is administered as a pure chemical. In other embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa. (2005)).
- One embodiment provides a pharmaceutical composition comprising any compound provided herein, such as a compound that has the structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Another embodiment provides the pharmaceutical composition, wherein the pharmaceutical composition is suitable for ophthalmic administration. Another embodiment provides the pharmaceutical composition, wherein the pharmaceutical composition is suitable for intraocular ophthalmic administration. In some embodiments, intraocular ophthalmic administration is intraocular, subretinal, superciliary, forniceal, into Schlemm's canal, inside a bleb, intracameral, intravitreal, suprachoroidal, punctal, retrobulbar, or subconjunctival.
- In some embodiments, any composition provided herein, such as containing a compound as described by any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), (or pharmaceutically acceptable salt thereof) comprises an optional additional component, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other molecules, such as, for example, impurities, synthetic materials (e.g., unreacted starting materials (e.g., a steroid provided herein in its free form), hydrolyzed materials (e.g., a steroid provided herein in its free form), unreacted intermediates, or the like) or byproducts (e.g., synthesis by-products or processing by-products, such as produced by heat processing, solvent processing, and/or sterilization).
- In some embodiments, any article or implant provided herein, such as containing a compound as described by any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), (or pharmaceutically acceptable salt thereof) is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as, for example, impurities, synthetic materials (e.g., unreacted starting materials (e.g., a steroid provided herein in its free form), hydrolyzed materials (e.g., a steroid provided herein in its free form), unreacted intermediates, or the like) or byproducts (e.g., synthesis by-products or processing by-products, such as produced by heat processing, solvent processing, and/or sterilization).
- In certain embodiments, any compound provided herein, such as the compound as described by any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), (or pharmaceutically acceptable salt thereof) is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as impurities, unreacted intermediates or byproducts (e.g., synthesis by-products or processing by-products, such as produced by heat processing, solvent processing, and/or sterilization).
- In certain embodiments, any compound provided herein, such as the compound as described by any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), (or pharmaceutically acceptable salt thereof) is a pharmaceutical implant or article. In some embodiments, the implant or article comprises at least 50 wt. % (at least 60 wt. %, at least 70 wt. %, at least 80 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %, or the like) of the compound and/or pharmaceutically acceptable salt thereof. In some embodiments, the implant or article releases (such as by surface erosion) the compound, the first radical, and/or the second radical (and/or other (e.g., active) fragment or metabolite of the compound). In some embodiments, release is at or near zero-order (e.g., in an aqueous medium, such as in a buffer solution, serum, biological environment, in vivo, or the like, such as at a physiological temperature (e.g., 37° C.). In some embodiments, the first radical and the second radical are released from the pharmaceutical implant or article at 37° C. in 100% bovine serum or at 37° C. in phosphate buffered saline (PBS) at a rate such that t10 is greater than or equal to 1/10 of t50. In some embodiments, the first radical and the second radical are released from the pharmaceutical implant or article at 37° C. in mixture of fetal bovine serum (FBS) and phosphate buffered saline (PBS) (e.g., 1% FBS in PBS) at a rate such that t10 is greater than or equal to 1/10 of t50.
- In some embodiments, certain forms of pharmaceutical compositions described herein (e.g., fibers, fiber meshes, woven fabrics, non-woven fabrics, pellets, cylinders, rods, hollow tubes, microparticles (e.g., microbeads), nanoparticles (e.g., nanobeads), or other shaped articles) provide a controllable surface area. In some embodiments, the controllable surface area is injected, does not require removal after completion of drug release, and allows for tailoring of drug release rates for a given indication. In certain embodiments, methods provided herein do not require (or comprise) removal of an article or implant, or residual materials or components thereof (e.g., because the implant is completely or almost completely (e.g., bio- or physiologically) degraded or degradable (e.g., at least 80 wt. %, at least 85 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %, at least 99 wt. %, or the like)).
- In some embodiments, the implants, articles, or compositions described herein are amorphous. In some embodiments, the implants, articles, or compositions described herein are formed by heat-based and solvent based processing methods. Non-limiting examples of heat processing methods include heat molding, injection molding, extrusion, 3D printing, melt electrospinning, fiber spinning, fiber extrusion, and/or blow molding. Non-limiting examples of solvent processing include coating, micro printing, dot printing, micropatterning, fiber spinning, solvent blow molding, emulsions, electrospraying, and electrospinning. In some embodiments, processing methods to form an intermediate glassy state of any of the above heat and solvent based methods as well as heat and solvent based methods that lead to glassy state material with no defined shape (e.g. spray drying, lyophilization, powder melting, etc.).
- The term “glassy state,” as used herein, generally refers to an amorphous solid including greater than 70%, 80%, 90%, 95%, 98%, or 99% (w/w) of compositions, articles, or implants described herein. In some embodiments, the compositions, articles, or implants described herein exhibit a glass transition temperature above 38° C. In the glassy state, as measured by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), or polarized light microscopy (PLM), the level of crystallinity is, for example, from 0-15% (e.g., less than 1%, 0-1%, 0-3%, 0-5%, 0-7%, 0-9%, 0-10%, or 0-13%). In some embodiments, glass formulations are formed using heat processing or solvent processing methods described herein (e.g., in the examples).
- In some embodiments, the pharmaceutical compositions described herein are prepared by electrospinning. In some embodiments, the pharmaceutical compositions of the disclosure are dissolved in a solvent (e.g., acetone) at concentrations ranging from, e.g., 10-30% w/v, and are electrosprayed to form micro- and nanoparticles. In some embodiments, the solution is loaded into a syringe and injected at a rate (e.g., 0.5 mL/h) onto a stationary collection plate. In some embodiments, a potential difference (e.g., 18 kV) is maintained between the needle and collecting surface. For example, in certain embodiments, a concentration of 10% w/v is used to obtain nanoparticles. In other embodiments, a concentration of 30% w/v is used to obtain micro particles.
- The pharmaceutical compositions of the disclosure are dissolved in a solvent (e.g., THF, or 1:1 ratio of DCM/THF). In some embodiments, the solution is loaded into a syringe and injected at a rate (e.g., 0.5 mL/h) onto a cylindrical mandrel rotating at a particular rotational speed, e.g., 1150 rpm, to obtain aligned fibers, or onto a stationary collector surface to obtain unaligned fibers. In some embodiments, a potential difference (e.g., 18 kV or 17 kV) is maintained between the needle and collecting surface for aligned and random fibers.
- In other embodiments, fibers are prepared from the melt at elevated temperatures, the glassy state intermediate, or from the solution by dissolving the pharmaceutical compositions described herein in a solvent (e.g., DCM, THF, or chloroform). As used herein, “melt spinning” describes heat processing from the melt state, “heat spinning” describes heat processing from the glassy state, and “wet”, “dry”, and “gel” spinning describe solution processing.
- In some embodiments, the viscous melt, intermediate, or solution is fed through a spinneret and fibers are formed upon cooling (melt or heat spinning) or following solvent evaporation with warm air as the compound exits the spinneret (dry spinning). In some embodiments, wet spinning and gel spinning are used to produce the fibers disclosed herein. “Heat spinning,” as used herein, describes a process that is similar to the melt spinning, but performed with a glassy state intermediate and heated above the glass transition temperature (Tg), obtaining the viscous fluid to extrude/spin instead of the melt. Alternatively, tweezers may be dipped into melted material or concentrated solutions and retracted slowly in order to pull fibers. The rate of pulling and distance pulled may be varied to yield fibers and columnar structures of different thickness.
- In some embodiments, micro-particles or nano-particles made from the pharmaceutical composition are formed using an emulsion process. In some embodiments, the pharmaceutical composition is dissolved in an organic solvent (e.g. DCM, THF, etc.). In some embodiments, a surfactant (e.g. SDS, PVA, etc.) is added (e.g. 1%) to the solution/mixture. In some embodiments, the resulting mixture is stirred for the appropriate time at room temperature to form an emulsion. In some embodiments, the emulsion is subsequently added to Milli-Q water under stirring for an appropriate time (e.g., 1 h) to remove residual solvent. The resulting micro- or nano-particles may be collected by centrifugation and dried.
- In some embodiments, injectable cylinders or rods made from a pharmaceutical composition described herein is formed by heat extrusion. In some embodiments, the pharmaceutical composition is loaded into a hot melt extruder, heated to a temperature above the melting point (e.g., for crystalline compositions) or glass transition temperature (e.g., for pre-melted or amorphous compositions), and extruded using (i) a compressive force to push the material through the nozzle and (ii) a tensile force (or gravity) to pull the material out of the extruder. The extrudate may be cut to the desired length for suitable drug dosing for a medical indication.
- In some embodiments, a milling process is used to reduce the size of an article described to form sized particles, e.g., beads, in the micrometer (microbeads) to nanometer size range (nanobeads). The milling process may be performed using a mill or other suitable apparatus. In some embodiments, dry and wet milling processes, such as, for example, jet milling, cryo-milling, ball milling, media milling, sonication, and homogenization are used in methods described herein. In some embodiments, heating of the milled microparticle above the Tg is performed to achieve a spherical shape. In some embodiments, particles with non-spherical shapes are used as milled.
- In certain embodiments, a composition described herein has a limited window (e.g., short timeframe of seconds to minutes) of thermal stability, whereby the purity of the dimer is affected (e.g., minimally) at elevated temperatures. In some embodiments, an intermediate glassy state form (e.g., film, surface coating, pellet, micro-particles, or other shaped article) is made to avoid decomposition. In some embodiments, heat or solvent processing is used to remove or reduce the crystallinity of the material to form a glassy state composition. In some embodiments, the glassy state composition is heat processed at a lower temperature (e.g., processing just above the glass transition temperature (Tg), and below the melt temperature (Tm)). In some embodiments, the lower temperature allows for a longer timeframe for heat processing the glassy state material into the final shaped article, while reducing the impact of processing conditions on the purity of the prodrug dimer in the article.
- Exemplary processing details are provided in the Examples.
- In some embodiments, the processable compound as described by any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), is formulated for administration by injection. In some instances, the injection formulation is an solid formulation. In some instances, the injection formulation is a non-aqueous formulation.
- In certain aspects, the pharmaceutical compositions described herein provide an article (e.g., as described herein) with a controlled release profile (e.g., by surface erosion). In some embodiments, the surface erosion allows the article to maintain its physical form, while gradually decreasing in size as the surface erodes (e.g., at a constant rate), rather than by, for example, bulk erosion that is characteristic of some polymer-based drug release vehicles (e.g., polylactic/glycolic acid). In some embodiments, the surface erosion inhibits burst release and/or reduces the formation of inflammatory particulates (e.g., no or minimal crystalline particulates are formed or released from the articles when drug is released as described herein). In some embodiments, compositions described herein are delivered over a period of time. For example, a slower and steadier rate of delivery (e.g., release of less than 10% of the first radical or the second radical in their free form (as a percentage of the total drug, the first radical or the second radical in their free form, present in the article) at 37° C. in 100% bovine serum over 5 days) results in a reduction in the frequency with which the pharmaceutical composition is administered to a subject and/or improve the safety profile of the drug. In some embodiments, the drug release is tailored to avoid side effects of slower and longer release of the drug by engineering the article to provide constant release over a comparatively shorter period of time. In some embodiments, the drug release is tailored for dose and duration suitable for the indication or administration method.
- In some embodiments, the release rate is related to, for example, the drug configuration of the dimer. In some embodiments, the drug release rate from an article described herein is modulated by the cleavage of dimer-linker bond through hydrolysis or enzymatic degradation. In some embodiments, the linking moiety (e.g., the linker) affects drug release rate. In some embodiments, the drug release rate is controlled by a functional group on the composition described herein to conjugate through to the linker, for example, a primary vs. a secondary hydroxyl group. In some embodiments, the release rate from a dimer is related to percentage of the loaded dimer compared to the final drug dimer formulation (e.g., by using a pharmaceutical excipient (e.g., bulking agent/excipient). In some embodiments, the release rate is controlled by the size of a microbead. In some embodiments, drug release is tailored based on the solubility of drug dimer (e.g., through selection of appropriate drug and/or linker) that will influence the rate of surface erosion (e.g., dissolution/degradation) from the article. In other embodiments, drug release is affected by changes in surface area of the formulation, e.g., by changing the diameter of the microbeads. By adjusting the vide supra factors, dissolution, degradation, diffusion, and controlled release may be varied over wide ranges. For example, release may be designed to be initiated over minutes to hours, and may extend over the course of days, weeks, months, or years.
- In some instances, provided herein is a heat processed pellet (e.g.,
FIGS. 2B, 3B, 5B, 7B, 8B, 9B, 15B, and 19B ) or rod (e.g.,FIGS. 10A, 11A, 12A, and 13A ) of a heterodimer (e.g., a steroid-prostaglandin heterodimer) (e.g.,FIGS. 2A, 3A, 5A, 6A, 7A, 8A, 9A, 15A, and 19A ) exemplified herein. In some instances, provided herein is a drug release profile of a pellet (e.g.,FIGS. 2C, 2D, 3C, 3D, 5C, 5D, 6B, 6C, 7C, 7D, 8C, 8D, 9C, 9D, and 15C ) or a rod (FIGS. 10B, 10C, 11B, 12B, 12C, 13B, and 13C ) provided herein in fetal bovine serum (FBS), phosphate-buffered saline (PBS), or a combination thereof over a period (e.g., an extended period is time) of time (e.g., 15 days, 30 days, 60 days, 90 days, 120 days, 365 days, or more). In some instances, the release profile of a composition provided herein (e.g., a steroid-prostaglandin heterodimer derived pellet) is measured as the change (e.g., increase) in concentration of one or more drug (e.g., a steroid and/or a prostaglandin) in a solution over a period of time. In some instances, the release profile of a composition provided herein (e.g., a steroid-prostaglandin heterodimer derived pellet) is measured as an increase in concentration of a steroid over a period of time.FIG. 8C illustrates release of both steroid and prostaglandin in FBS. As is illustrated, both steroid and prostaglandin have similar release profiles. It is expected that because steroid and prostaglandin are directly linked, there should be an identical release profile. However, the steroid and prostaglandin appear to have slightly differing release profile at many time points, e.g., as a function of greater difficulty in detecting one of the chromophores (e.g., prostaglandin or steroid) over the other of the chromophores (e.g., steroid or prostaglandin). Other figures demonstrating drug release illustrate release of prostaglandins, which may be overestimated or underestimated as a result of detection methods. However, other figures demonstrate that the various compounds provided herein and illustrated therein demonstrate release of prostaglandin (and, implicitly, steroid). As such this data demonstrates a platform for providing compounds and implants (e.g., with high drug content, low excipient content (e.g., that needs to be removed), and other benefits, such as described herein) that provide long-lasting release of prostaglandins (and steroid) under desirable conditions. In some instances, the release profile of a composition provided herein (e.g., a steroid-prostaglandin heterodimer derived pellet) is measured as an increase in concentration of a prostaglandin over a period of time. In some instances, the release profile of a composition provided herein (e.g., a steroid-prostaglandin heterodimer derived pellet) is measured as an increase in concentration of a steroid and a prostaglandin over a period of time (e.g.,FIG. 8B ). In some instances, the increase in concentration of one drug (e.g., a steroid) over a period of time corresponds with the increase in concentration of another drug (e.g., a prostaglandin) over a period of time. In some instances, drug release (e.g., of prostaglandins) is difficult to analyze by HPLC and UV techniques (e.g., poor chromophores), which may, for instance, result in over-or under estimation of released amounts (e.g., in particular for sustained release applications where released amounts of prostaglandin analogs are present at low amounts). In some instances, an increase of steroid concentration in solution over a period of time is used to quantify a drug (e.g., prostaglandin) release profile. - In some embodiments, a pharmaceutical composition containing a dimer described herein is administered to a subject by the following non-limiting examples oral, sublingual, nasal, intradermal, subcutaneous, intramuscular, rectal, vaginal, intravenous, intraarterial, intracisternal, intraperitoneal, intravitreal, periocular, topical (as by powders, creams, ointments, or drops), buccal and inhalational administration. In certain instances, the articles described herein are administered parenterally as injections (intravenous, intramuscular, or subcutaneous), or locally as injections (intraocularly or into a joint space). In some embodiments, the formulations described herein are admixed under sterile conditions with a pharmaceutically acceptable carrier, preservatives and/or buffers.
- In some embodiments, the implant, article, or composition described herein is suitable for ophthalmic administration, subcutaneous administration, or intraspinal administration. In some embodiments, the ophthalmic administration is intraocular, subretinal, superciliary, forniceal, into Schlemm's canal, inside a bleb, intracameral, intravitreal, suprachoroidal, punctal, retrobulbar, or subconjunctival.
- In some instances, the implant, article, or composition described herein is a coating on a device. In some instances, the device is a contact lenses, a microshunt device, microinvasive glaucoma surgery (MIGS) device, an intraocular lenses, or the like.
- The dose of the composition comprising at least one compound as described herein differ, depending upon the patient's (e.g., human) condition, that is, general health status, age, and other factors.
- Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form and/or potency of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
- In other embodiments, the compositions described herein are combined with a pharmaceutically suitable or acceptable carrier (e.g., a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier. Exemplary excipients are described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa. (2005)).
- In certain aspects, provided herein is a method of treating an ophthalmic, neurological, orthopedic, acute or chronic pain, or post-operative disease or disorder in a patient in need of thereof, comprising administering to the patient any compound provided herein, or a pharmaceutically acceptable salt thereof, or a (e.g., pharmaceutical) composition comprising any compound provided herein, or a pharmaceutically acceptable salt thereof, such as a compound having a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V) Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X). In certain aspects, provided herein is a method of treating an ophthalmic disease or disorder in a patient in need of thereof, comprising administering to the patient any compound provided herein, or a pharmaceutically acceptable salt thereof, or a (e.g., pharmaceutical) composition comprising any compound provided herein, or a pharmaceutically acceptable salt thereof, such as a compound having a structure of any one of Formula (I), Formula (IA), Formula (IB′), Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V) Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X). Another embodiment provides the method wherein the pharmaceutical composition is in the form of a solid suitable for intraocular ophthalmic administration (e.g., injection). In some embodiments, intraocular ophthalmic administration is intraocular, subretinal, superciliary, forniceal, into Schlemm's canal, inside a bleb, intracameral, intravitreal, suprachoroidal, punctal, retrobulbar, or subconjunctival.
- Methods involving treating a subject may include preventing a disease, disorder or condition from occurring in the subject which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected (e.g., such treating the pain of a subject by administration of an agent even though such agent does not treat the cause of the pain).
- Another embodiment provides the method wherein the ophthalmic disease or disorder is selected from glaucoma, ocular inflammation, diabetic macular edema, posterior inflammation, anterior inflammation, macular degeneration (e.g., wet macular degeneration (AMD) or dry AMD), post-cataract surgery, and retinal vein occlusion. In some embodiments, the ocular disease or disorder is glaucoma.
- Samples (20.0 mg) are dissolved in acetonitrile (10.0 mL) to make 2 mg/mL solution. For the system: solvent A was Water+0.05% trifluoroacetic acid (TFA); solvent B was Acetonitrile+0.05% TFA; the flow rate was 1.0 mL/min; and the detection method was UV @242 nm and UV Spectra from 190 to 400 nm. The samples were loaded onto an Agilent 1100 series HPLC with either (i) a Phenomenex Gemini-NX C18 Column (5 μm; 110 Å; 250×4.6 mm; 00G-4454-E0) or (ii) Phenomenex SecurityGuard Analytical Guard Column (KJO-4282) with
Gemini C18 4×3.0 mm Guard Cartridge (AJO-7597). The solvent gradient profile is shown in Table 4 -
TABLE 4 Time (min) % A Solvent % B Solvent 0 80 20 40 16 84 42 0 100 50 0 100 - Compounds (10 mg) were dissolved in 666 uL of either CDCl3 or DMSO-d6 and loaded in an 8-inch length, 5 mm diameter NMR tube. The instrument was a
Varian Mercury 400 NMR spectrometer. Proton NMR spectra were obtained with 16 scans using the default method. FIDs were processed with MestRe-C software. - Compounds were dissolved in acetonitrile at 1 mg/ml and used directly for analysis on an Agilent 6538 QTOF, using ESI MS+ as ion source.
- Compound powder was prepared neat in a glass capillary tube, and melting temperature was measured manually with standard glass capillary tube melting point apparatus.
- 5-10 mg of compounds were weighed in an aluminum pan. Using a Hitachi Differential Scanning calorimeter DSC7020, samples were heated from room temperature to 110-150° C. at 10° C./min, cooled to −30° C. at 10° C./min, and heated again to 110-150° C. at 10° C./min.
- Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Starting materials were purchased from commercial sources or synthesized according to the methods described herein or using literature procedures.
-
- To a stirred solution of travoprost (1 g, 2.00 mmol) in MeOH (16 mL) was added 1M NaOH(aq) (16 mL, 16 mmol) and the mixture stirred for 16 h. The mixture was quenched into 0.5M HCl(aq) (32 mL, 16 mmol) and the aqueous extracted with DCM (2×100 mL). The DCM layers were combined dried (MgSO4) and concentrated to give travoprost acid (916 mg, 100%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39 (1H, t, J=8 Hz), 7.22 (1H, d, J=8 Hz), 7.15 (1H, s), 7.08 (1H, d, J=8 Hz), 5.70 (2H, m), 5.40 (2H, m), 4.98 (1H, heptet, J=6.5 Hz), 4.52 (1H, m), 3.97 (3H, m), 3.25 (2H, br s), 2.60 (1H, br s), 2.38 (1H, m), 2.30-1.96 (7H, m), 1.76 (1H, dd, J=16, 4 Hz), 1.65 (2H, quintet, J=7), 1.55 (1H, m).
-
- To a stirred suspension of anecortave acetate (3.0 g, 7.76 mmol) in methanol (80 mL) was added potassium hydroxide solution (77.5 mL of a 0.2M solution, 15.52 mmol) and the mixture stirred overnight. The reaction mixture was quenched into ice water (400 mL), stirred and filtered to collect the precipitate which was dissolved in DCM (300 mL), washed with water (300 mL) and dried over sodium sulfate to give anecortave desacetate (1.0 g, 37%). 1H NMR (400 MHz, DMSO-d6) δ 5.66 (s, 1H); 5.52 (d, 1H, J=5 Hz), 5.28 (s, 1H, OH), 4.60 (t, J=5 Hz, 1H, OH), 4.31 (AB, 2H, J=19 Hz, Δv=82.5 Hz, further split (J=5 Hz) by OH), 2.60 (m, 3H), 2.50 (m, 1H), 2.25 (m, 3H), 2.05 (m, 3H), 1.80 (m, 2H), 1.55 (m, 2H), 1.22 (m, 1H), 1.20 (s, 3H), 1.02 (q, 1H, J=12 Hz), 0.49 (s, 3H).
-
- To a stirred solution of travoprost acid (180 mg, 0.393 mmol) in dry pyridine (20 mL) under nitrogen was added anecortave desacetate (406 mg, 1.18 mmol), 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred overnight. The mixture was concentrated and the residue dissolved in DCM (100 mL), the solution washed with 0.5 M hydrochloric acid (100 mL), water (100 mL), dried (MgSO4) and concentrated onto 5 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient). Product containing fractions were combined, extracted with DCM, dried (MgSO4) and concentrated to give the product as an off-white solid (102 mg, 33%). Melting point: 78-80° C. HPLC retention time: 31.7 min, ESI MS+ Found, C44H55F3NaO9 + Exact Mass: 807.3684. 1H NMR (400 MHz, DMSO-d6) δ 7.45 (1H, t, J=8 Hz), 7.20 (3H, m), 5.62 (1H, s), 5.55-5.40 (6H, m), 5.20 (1H, s, OH), 5.11 (1H, br s), 4.95 (1H, d, J=12 Hz), 4.80 (1H, d, J=12 Hz), 4.48 (1H, br s), 4.31 (2H, m), 3.85 (3H, m), 3.64 (1H, m), 2.60 (2H, m), 2.38 (1H, m), 2.25 (3H, m), 2.20 (3H, m), 2.05 (3H, m), 1.95 (3H, m), 1.80 (6H, m), 1.55 (3H, m), 1.41 (1H, m), 1.22 (1H, m), 1.20 (3H, s), 1.02 (1H, q, J=12 Hz), 0.49 (3H, s).
-
- To a stirred solution of travoprost acid (180 mg, 0.393 mmol) and dexamethasone (1.54 g, 3.93 mmol) in dry THF (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 10 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient), product containing fractions were combined, extracted with DCM, dried (MgSO4) and concentrated to give a solid which was further purified by normal phase Biotage automated chromatography (hexane-ethyl acetate gradient). Product containing fractions were combined and concentrated to give the product as an off-white solid (120 mg, 37%). Melting point: 80° C. HPLC retention time: 30.5 min, ESI MS+ Found, C45H56F4NaO10 + Exact Mass: 855.3707. 1H NMR (400 MHz, DMSO-d6) δ 7.45 (1H, t, J=8 Hz), 7.20 (4H, m), 6.20 (1H, d), 5.99 (1H, s), 5.60-5.35 (4H, m), 5.20 (1H, m), 5.11 (1H, d), 4.95 (1H, d, J=12 Hz), 4.76 (1H, d, J=12 Hz), 4.50 (1H, d), 4.31 (2H, m), 4.05 (1H, m), 3.89 (3H, m), 3.64 (1H, m), 3.59 (1H, m), 2.83 (1H, m), 2.60 (1H, m), 2.38 (1H, m), 2.25 (3H, m), 2.20 (3H, m), 2.05 (3H, m), 1.95 (3H, m), 1.78 (2H, m), 1.60-1.40 (4H, m), 1.30 (1H, m), 1.21 (3H, s), 1.02 (1H, q, J=12 Hz), 0.82 (3H, s), 0.78 (3H, d).
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- To a stirred solution of latanoprost (1 g, 2.31 mmol) in MeOH (16 mL) was added 1M NaOH(aq) (18.5 mL, 18.5 mmol) and the mixture stirred for 16 h. The mixture was quenched into 0.5M HCl(aq) (37 mL, 18.5 mmol) and the aqueous extracted with DCM (2×100 mL). The DCM layers were combined dried (MgSO4) and concentrated to give latanoprost acid (902 mg, 100%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (1H, br s), 7.23 (2H, m), 7.12 (3H, m), 5.42 (1H, m), 5.23 (1H, m), 4.39 (2H, m), 4.20 (1H, m), 3.82 (1H, m), 3.60 (1H, m), 3.36 (1H, m), 2.60 (1H, m), 2.52 (1H, m), 2.15 (3H, m), 1.98 (4H, m), 1.60-1.25 (10H, m), 1.20 (1H, m).
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- To a stirred solution of latanoprost acid (153 mg, 0.393 mmol) and dexamethasone (1.54 g, 3.93 mmol) in dry THF (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 10 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient), product containing fractions were combined, extracted with DCM, dried (MgSO4) and concentrated to give a solid which was further purified by normal phase Biotage automated chromatography (hexane-ethyl acetate gradient). Product containing fractions were combined and concentrated to give the product as an off-white solid (102 mg, 34%). Melting point: 78° C. HPLC retention time: 30.8 min, ESI MS+ Found, C45H62FO9 + Exact Mass: 765.4378 1H NMR (400 MHz, DMSO-d6) δ 7.35-7.05 (6H, m), 6.20 (1H, d), 5.99 (1H, s), 5.50-5.25 (3H, m), 5.10 (1H, s), 5.00 (1H, d), 4.80 (1H, d), 4.40 (2H, d), 4.21 (2H, m), 3.85 (1H, m), 3.61 (1H, m), 2.83 (2H, m), 2.60 (4H, m), 2.38 (4H, m), 2.11 (6H, m), 1.75 (1H, m), 1.60-1.20 (18H, m), 1.02 (1H, q, J=12 Hz), 0.82 (3H, s), 0.78 (3H, d).
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- To a stirred solution of latanoprost acid (153 mg, 0.393 mmol) and estrone (318 mg, 1.179 mmol) in dry THF (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 10 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient), product containing fractions were combined, extracted with DCM, dried (MgSO4) and concentrated to give a solid which was further purified by normal phase Biotage automated chromatography (hexane-ethyl acetate gradient). Product containing fractions were combined and concentrated to give the product as an off-white solid (28 mg, 11%). Melting point: 65° C. HPLC retention time: 35.9 min, ESI MS+ Found, C41H54NaO6+ Exact Mass: 665.3818 1H NMR (400 MHz, DMSO-d6) δ 7.23 (2H, m), 7.12 (3H, m), 7.04 (1H, d), 6.51 (1H, m), 6.45 (1H, m), 5.42 (1H, m), 5.23 (1H, m), 4.39 (2H, m), 4.20 (1H, m), 3.82 (1H, m), 3.60 (1H, m), 3.36 (1H, m), 2.75 (2H, m), 2.60 (1H, m), 2.52 (1H, m), 2.42 (1H, m), 2.30 (1H, m), 2.15 (4H, m), 2.05 (1H, m), 1.98 (4H, m), 1.92 (2H, m), 1.74 (1H, m), 1.60-1.25 (16H, m), 1.20 (1H, m), 0.81 (3H, s).
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- Dexamethasone (314 mg, 0.80 mmol, 1.0 equiv) was dissolved in THF (20 mL) under nitrogen and phosgene solution (2.86 mL of a 1.4 M solution in toluene, 4.0 mmol, 5 equiv) was added dropwise with stirring. The mixture was stirred at room temperature overnight. Concentration of the mixture afforded the dexamethasone chloroformate as a thick oil which was dissolved in DCM (50 mL). Triethylene glycol (1.07 mL, 1.20 g, 8 mmol, 10 equiv) and pyridine (130 μL, 126 mg, 1.60 mmol, 2.0 equiv) were added and the mixture stirred for 2 h. The reaction solution was washed with water (2×50 mL) and the DCM layer concentrated onto normal phase silica (2 g) and purified by automated normal phase chromatography (ethyl acetate-hexane). The product containing fractions were combined and concentrated in vacuo to give the dexamethasone-triethyleneglycol ester intermediate as an off-white glassy solid (296 mg, 0.52 mmol, 65%). This was dissolved in DCM (50 mL) and latanoprost acid (202 mg, 0.52 mmol), 4-(dimethylamino)pyridine (127 mg, 1.04 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (198 mg, 1.04 mmol) were added and the mixture was stirred overnight. The reaction solution was washed with water (2×50 mL) and the DCM layer concentrated onto reverse phase silica (2 g) and purified by automated reverse phase chromatography (acetonitrile-water). The product containing fractions were concentrated in vacuo to give the dexamethasone-triethyleneglycol-latanoprost as a colourless oil (49 mg, 0.052 mmol, 10%). HPLC retention time: 33.9 min, ESI MS+ Found, C52H74FO14+ Exact Mass: 941.5063 1H NMR (400 MHz, DMSO-d6) δ 7.35-7.05 (6H, m), 6.20 (1H, d), 5.99 (1H, s), 5.50-5.25 (3H, m), 5.10 (1H, s), 5.00 (1H, d), 4.80 (1H, d), 4.40 (2H, d), 4.21 (6H, m), 3.85 (1H, m), 3.65 (4H, m), 3.61 (1H, m), 3.57 (4H, s), 2.83 (2H, m), 2.60 (4H, m), 2.38 (4H, m), 2.11 (6H, m), 1.75 (1H, m), 1.60-1.20 (18H, m), 1.02 (1H, q, J=12 Hz), 0.82 (3H, s), 0.78 (3H, d).
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- To a stirred solution of travoprost acid (180 mg, 0.393 mmol) and acetaminophen (297 mg, 1.97 mmol) in dry THF (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 5 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient), product containing fractions were combined, extracted with DCM, dried (MgSO4) and concentrated to give travoprost-acetaminophen ester (139 mg, 60%) as a colourless oil. HPLC retention time: 22.6 min, ESI MS+ Found, C31H37F3NO7 + Exact Mass: 592.2522. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (1H, s, NH), 7.57 (2H, d, J=8 Hz), 7.45 (1H, t, J=8 Hz), 7.22 (2H, m), 7.15 (1H, s), 6.98 (2H, d), 5.70 (2H, m), 5.40 (2H, m), 4.98 (1H, heptet, J=6.5 Hz), 4.52 (1H, m), 3.97 (3H, m), 3.25 (2H, br s), 2.60 (1H, br s), 2.38 (1H, m), 2.30-1.96 (10H, m), 1.76 (1H, dd, J=16, 4 Hz), 1.65 (2H, quintet, J=7), 1.55 (1H, m).
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- To a stirred solution of travoprost acid (180 mg, 0.393 mmol) and 1-Adamantanemethanol (327 mg, 1.97 mmol) in dry THF (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 5 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient), product containing fractions were combined, extracted with DCM, dried (MgSO4) and concentrated to give travoprost-acetaminophen ester (71 mg, 30%) as a colourless oil. HPLC retention time: 40.3 min, ESI MS+ Found, C34H46F3O6 + Exact Mass: 607.3246. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (1H, t, J=8 Hz), 7.22 (2H, m), 7.15 (1H, s), 5.60-5.40 (3H, m), 5.20 (1H, m), 5.10 (1H, d J=8.0 Hz), 4.52 (1H, m), 4.30 (2H, m), 3.88 (3H, m), 3.63 (1H, m), 3.56 (2H, s), 2.93 (1H, m), 2.20-1.80 (10H, m), 1.70-1.40 (15H, m), 1.25 (1H, m).
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- To a solution of latanoprost acid (202 mg, 0.52 mmol) and triethylene glycol (42 uL, 39 mg, 0.26 mmol) in DCM (50 mL) was added 4-(dimethylamino)pyridine (127 mg, 1.04 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (198 mg, 1.04 mmol) were added and the mixture was stirred overnight. The reaction solution was washed with water (2×50 mL) and the DCM layer concentrated onto reverse phase silica (2 g) and purified by automated reverse phase chromatography (acetonitrile-water). The product containing fractions were concentrated in vacuo to give the latanoprost-triethyleneglycol-latanoprost as a colourless oil (37 mg, 0.042 mmol, 8%). HPLC retention time: 30.2 min, ESI MS+ Found, C52H79O12+ Exact Mass: 895.5972 1H NMR (400 MHz, DMSO-d6) δ 7.23 (4H, m), 7.12 (6H, m), 5.42 (2H, m), 5.23 (2H, m), 4.39 (4H, m), 4.25-4.20 (6H, m), 3.82 (2H, m), 3.65 (4H, m), 3.60-3.55 (6H, m), 3.36 (2H, m), 2.60 (2H, m), 2.52 (2H, m), 2.15 (6H, m), 1.98 (8H, m), 1.60-1.25 (20H, m), 1.20 (2H, m).
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- To a stirred solution of latanoprost (222.0 mg, 0.51 mmol) in dry DCM (20 mL) was added n-butylboronic acid (60.1 mg, 0.59 mmol) and the mixture stirred at reflux for 1 h under nitrogen atmosphere. The mixture was concentrated and the residue redissolved in dry DCM, the mixture heated to reflux for 3 h, concentrated to give the 9, 11-boronate of latanoprost (254 mg, 100%) as a clear colourless oil which was and used directly without further purification. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.28-7.17 (m, 2H), 7.17-7.03 (m, 3H), 5.49-5.27 (m, 2H), 4.93 (ddd, J=15.2, 7.6, 4.9 Hz, 1H), 4.28-4.13 (m, 1H), 4.07-3.90 (m, 1H), 3.65-3.46 (m, 1H), 2.78-2.67 (m, 1H), 2.67-2.41 (m, 1H), 2.28-2.11 (m, 4H), 2.09-1.98 (m, 2H), 1.91-1.79 (m, 1H), 1.79-1.53 (m, 7H), 1.53-1.38 (m, 3H), 1.38-1.07 (m, 12H), 0.89-0.75 (m, 3H), 0.64-0.52 (m, 2H). To a solution of 9, 11-boronate of latanoprost (254 mg, 0.51 mmol) in dry DCM (25 mL) was added pyridine (164 uL, 162 mg, 2.04 mmol) and triethylene glycol bis(chloroformate) (52 uL, 70 mg, 0.255 mmol, 0.5 equiv) and the mixture stirred for 4 h, methanol (5 mL) was added and the mixture stirred overnight. The mixture was concentrated onto 1 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient), product containing fractions were combined, extracted with DCM, dried (MgSO4) and concentrated to give latanoprost-TEG-latanoprost carbonate dimer (68 mg, 25%) as a colourless oil. HPLC retention time: 48.2 min, ESI MS+ Found, C60H91O16+ Exact Mass: 1067.6307 1H NMR (400 MHz, DMSO-d6) δ 7.23 (4H, m), 7.12 (6H, m), 5.42 (2H, m), 5.23 (2H, m), 4.39 (4H, m), 4.25-4.20 (6H, m), 3.82 (2H, m), 3.65 (4H, m), 3.60-3.55 (6H, m), 3.36 (2H, m), 2.60 (2H, m), 2.52 (2H, m), 2.15 (6H, m), 1.98 (8H, m), 1.60-1.25 (20H, m), 1.20 (2H, m), 1.00 (12H, d).
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- To a solution of 9, 11-boronate of latanoprost (254 mg, 0.51 mmol) in dry DCM (25 mL) was added pyridine (82 uL, 81 mg, 1.02 mmol) and ethylchloroformate (48 uL, 55 mg, 0.51 mmol) and the mixture stirred for 4 h, methanol (5 mL) was added and the mixture stirred overnight. The mixture was concentrated onto 1 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient), product containing fractions were combined, extracted with DCM, dried (MgSO4) and concentrated to give latanoprost-15-ethyl carbonate (154 mg, 60%) as a colourless oil. HPLC retention time: 34.8 min, ESI MS+ Found, C29H45O7+ Exact Mass: 505.3165 1H NMR (400 MHz, DMSO-d6) δ 7.23 (2H, m), 7.12 (3H, m), 5.42 (1H, m), 5.23 (1H, m), 4.80 (1H, m), 4.60 (1H, m), 4.39 (2H, m), 4.20 (1H, m), 4.03 (2H, m), 3.82 (1H, m), 3.60 (1H, m), 2.60 (1H, m), 2.52 (1H, m), 2.15 (2H, m), 1.98 (4H, m), 1.80-1.25 (10H, m), 1.20 (4H, m), 1.16 (6H, d).
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- To a stirred solution of bimatoprost acid (1.0 g, 2.57 mmol) in dry pyridine (120 mL) under nitrogen was added anecortave desacetate (1.77 g, 5.14 mmol), 4-(dimethylamino)pyridine (0.62 g, 5.14 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.99 g, 5.14 mmol) and the mixture was stirred for 4 d at 37° C. The mixture was concentrated and the residue dissolved in DCM (150 mL), the solution washed with 0.5 M hydrochloric acid (150 mL), water (100 mL), dried (MgSO4) and concentrated onto 5 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient) followed by normal phase Biotage automated chromatography (hexanes-ethyl acetate). Product containing fractions were combined, concentrated, redissolved in MeCN (50 mL) and concentrated to give the product as an off-white solid (445 mg, 24%). Melting point: 110-115° C. HPLC retention time: 29.7 min, ESI MS+ Calculated for C44H58NaO8 +; 737.4024, Found: 737.4020. 1H NMR (400 MHz, DMSO-d6) δ 7.25 (t, J=7.5 Hz, 2H), 7.20-7.10 (m, 3H), 5.66 (d, J=1.5 Hz, 1H), 5.58-5.17 (m, 6H), 4.97 (d, J=17.6 Hz, 1H), 4.84 (d, J=17.6 Hz, 1H), 4.65 (d, J=4.6 Hz, 1H), 4.49 (d, J=5.8 Hz, 1H), 4.34 (d, J=5.0 Hz, 1H), 3.92 (td, J=6.4, 3.5 Hz, 2H), 3.67 (ddd, J=13.6, 6.9, 4.0 Hz, 1H), 2.72-2.42 (m, 4H), 2.37-1.92 (m, 16H), 1.88-1.75 (m, 3H), 1.75-1.62 (m, 2H), 1.62-1.49 (m, 3H), 1.44 (ddd, J=14.1, 5.7, 2.4 Hz, 1H), 1.40-1.21 (m, 5H), 1.07-0.93 (m, 1H), 0.48 (s, 3H).
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- To a stirred solution of latanoprost acid (1.0 g, 2.56 mmol) in dry pyridine (60 mL) under nitrogen was added anecortave desacetate (1.76 g, 5.12 mmol), 4-(dimethylamino)pyridine (0.62 g, 5.12 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.99 g, 5.14 mmol) and the mixture was stirred for 4 d at 37° C. The mixture was concentrated and the residue dissolved in DCM (150 mL), the solution washed with 0.5 M hydrochloric acid (150 mL), water (100 mL), dried (MgSO4) and concentrated onto 4 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient) followed by normal phase Biotage automated chromatography (hexanes-ethyl acetate). Product containing fractions were combined, concentrated, redissolved in MeCN (50 mL) and concentrated to give the product as an off-white solid (415 mg, 23%). Melting point: 122-124° C. HPLC retention time: 31.4 min, ESI MS+ Calculated for C44H60NaO8 +; 739.4180, Found: 737.4183. 1H NMR (400 MHz, DMSO-d6) δ 7.25 (t, J=7.5 Hz, 2H), 7.21-7.10 (m, 3H), 5.65 (d, J=1.6 Hz, 1H), 5.55-5.42 (m, 3H), 5.36-5.25 (m, 1H), 4.99 (d, J=17.6 Hz, 1H), 4.85 (d, J=17.6 Hz, 1H), 4.45-4.34 (m, 2H), 4.20 (d, J=5.4 Hz, 1H), 3.94-3.84 (m, 1H), 3.68-3.57 (m, 1H), 3.38 (d, J=9.8 Hz, 1H), 2.75-2.51 (m, 5H), 2.50-2.42 (m, 4H), 2.41-1.91 (m, 10H), 1.83 (dt, J=11.7, 7.5 Hz, 3H), 1.69-1.31 (m, 12H), 1.30 (s, 3H), 1.23 (tt, J=9.3, 5.5 Hz, 1H), 1.07-0.93 (m, 1H), 0.48 (s, 3H).
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- To a solution of tafluprost acid (800 mg, 1.95 mmol) and anecortave desacetate (1.34 g, 3.90 mmol) in dry pyridine (50 mL) was added DMAP (476 mg, 3.90 mmol) and EDCl (747 mg, 3.90 mmol) at 0° C., then stirred at 20° C. for 10 h. The reaction mixture was poured into DCM (50 mL), washed with 1M aqueous HCl (3×100 mL), the organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [water (0.225% FA)-ACN]; B %: 35%-80%, 23 min) to give the product (600 mg, 42%) as an off-white solid. Melting point: 107-110° C. HPLC retention time: 33.8 min, ESI MS+ Calculated for C43H54F2NaO8 +; 759.3684, Found: 759.3690. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (t, J=7.8 Hz, 2H) 6.92-7.05 (m, 3H) 6.09 (br dd, J=15.7, 8.9 Hz, 1H) 5.77 (dt, J=15.7, 11.2 Hz, 1H) 5.65 (s, 1H) 5.49-5.55 (m, 2H) 5.39-5.48 (m, 1H) 5.22-5.31 (m, 1H) 4.93-5.02 (m, 1H) 4.79-4.89 (m, 1H) 4.73 (d, J=5.9 Hz, 1H) 4.47 (d, J=4.8 Hz, 1H) 4.33 (br t, J=12.9 Hz, 2H) 3.92 (br d, J=3.8 Hz, 1H) 3.75 (quin, J=6.9 Hz, 1H) 2.53-2.69 (m, 3H) 1.90-2.37 (m, 15H) 1.74-1.87 (m, 3H) 1.55 (quin, J=7.2 Hz, 3H) 1.39-1.49 (m, 2H) 1.25-1.37 (m, 4H) 0.92-1.07 (m, 1H) 0.48 (s, 3H)
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- Anecortave desacetate (640 mg, 1.86 mmol) was dissolved in dry THF (40 mL) under nitrogen and phosgene solution (6.64 mL of a 1.4 M solution in toluene, 9.29 mmol) was added dropwise with stirring. The mixture was stirred at room temperature overnight. Concentration of the mixture afforded anecortave chloroformate as a pale yellow solid (740 mg, 98%) that was used without further purification or analysis.
- To a stirred suspension of 1,4-cyclohexanedimethanol (2.48 g, 1.72 mmol) in dry CH2Cl2 (30 mL) was added anecortave chloroformate (700 mg, 1.72 mmol) and dry pyridine (1.08 mL, 13.4 mmol). The solution was stirred at room temperature for 16 h, concentrated and the yellow residue re-dissolved in CH2Cl2 (50 mL). The solution was washed with 0.5 M hydrochloric acid (2×50 mL), water (50 mL), dried (MgSO4) and evaporated to give anecortave-CDM as a pale yellow solid (701 mg, 79%). HPLC retention time: 27.4 min. ESI MS+ calculated for C30H42NaO2 +; 537.2823, Found: 537.2830. 1H NMR (400 MHz, DMSO-d6) δ 5.66 (1H, s), 5.54-5.51 (2H, m), 5.04 (1H, d, J=17.8, Hz), 4.83 (1H, d, J=17.8 Hz), 4.37-4.29 (1H, m), 4.02 (1H, d, J=7.2 Hz), 3.92 (1H, d, J=6.4 Hz), 3.30-3.25 (1H, m), 3.22-3.17 (1H, m), 2.68-2.43 (3H, m), 2.36-2.18 (3H, m), 2.12-1.94 (4H, m), 1.87-1.69 (5H, m), 1.61-1.48 (2H, m), 1.45-1.28 (5H, m), 1.30 (3H, s), 1.06-0.79 (3H, m), 0.52-0.46 (3H, m).
- A stirred solution of travoprost acid (200 mg, 0.436 mmol) in dry MeCN (10 mL) under nitrogen was stirred at −15° C. (ice/salt bath). N-Methylmorpholine (96.8 μL, 0.872 mmol) and isobutyl chloroformate (57.8 μL, 0.436 mmol) were added and the solution stirred for 10 mins. The solution was then added dropwise to a suspension of anecortave-CDM (453 mg, 0.872 mmol) in dry MeCN (20 mL) under nitrogen at −15° C. (ice/salt bath). After 10 mins stirring, the mixture was warmed to room temperature and stirred for 3 hours. The mixture was concentrated onto reverse phase silica (3 g) and purified by automated reverse phase chromatography (aqueous-MeCN). The product containing fractions were concentrated in vacuo to give the product as a colorless solid (53 mg, 13%). For thermal property measurements, the solid was dissolved in DCM and concentrated in vacuo to give a colorless solid. Melting point: not observed (Tg=˜43° C.). HPLC retention time: 37.8 min. ESI MS+ calculated for C53H69F3NaO12 +; 977.4633, Found: 977.4640. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (1H, t, J=8.0 Hz), 7.26-7.19 (2H, m), 7.18 (1H, s), 5.65 (1H, s), 5.58-5.38 (5H, m), 5.26-5.18 (1H, m), 5.10 (1H, d, J=4.8 Hz), 5.02 (1H, dd, J=17.8, 1.79 Hz), 4.82 (1H, d, J=17.8 Hz), 4.52 (1H, d, J=5.8 Hz), 4.35-4.26 (2H, m), 4.01 (1H, d, J=7.2 Hz), 3.96-3.86 (5H, m), 3.78 (1H, d, J=6.5 Hz), 3.71-3.63 (1H, m), 2.66-2.42 (3H, m), 2.35-2.25 (2H, m), 2.25-2.10 (6H, m), 2.10-2.03 (2H, m), 2.00-1.92 (5H, m), 1.83-1.65 (5H, m), 1.60-1.26 (12H, m), 1.29 (3H, s), 1.05-0.81 (3H, m), 0.47 (3H, s).
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- To a stirred solution of travoprost acid (122 mg, 0.27 mmol) and naltrexone.HCl (100 mg, 0.27 mmol) in dry DCM (20 mL) under nitrogen was added 4-(dimethylamino)pyridine (132 mg, 1.08 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (104 mg, 0.54 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 2 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient), product containing fractions were combined and concentrated, the residue dissolved in MTBE (20 mL) and concentrated to give travoprost-naltrexone ester (84 mg, 40%) as a glassy white solid. Melting point: 56° C. HPLC retention time: 17.6 min, ESI MS+ Calculated for C43H51F3NO9 +; 782.3516, Found: 782.3512. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (t, J=7.9 Hz, 1H), 7.32-7.15 (m, 3H), 6.80 (d, J=8.2 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 5.64-5.39 (m, 3H), 5.34-5.23 (m, 1H), 5.11 (d, J=4.8 Hz, 2H), 4.90 (s, 1H), 4.53 (d, J=5.8 Hz, 1H), 4.36 (d, J=4.9 Hz, 1H), 4.31 (p, J=5.3 Hz, 1H), 3.93 (dq, J=8.9, 4.8 Hz, 2H), 3.69 (p, J=7.4 Hz, 1H), 3.16 (d, J=5.6 Hz, 1H), 3.09-3.06 (m, 1H), 2.97-2.84 (m, 2H), 2.70-2.53 (m, 2H), 2.43-2.30 (m, 4H), 2.26-1.89 (m, 8H), 1.77 (td, J=9.7, 5.8 Hz, 1H), 1.62 (p, J=7.3 Hz, 2H), 1.49-1.20 (m, 4H), 1.10 (s, 1H), 0.87 (dtd, J=14.1, 6.9, 4.0 Hz, 1H), 0.58-0.42 (m, 2H), 0.19-0.09 (m, 2H).
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- To a stirred solution of timolol free base (316 mg, 1.0 mmol) and deoxycholic acid (393 mg, 1.0 mmol) in dry DCM (20 mL) under nitrogen was added 4-(dimethylamino)pyridine (244 mg, 2.0 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (384 mg, 2.0 mmol) and the mixture was stirred for 2 d. The mixture was concentrated onto 1 g reverse phase silica. Purification was performed by reverse phase Biotage automated chromatography (aqueous-MeCN gradient), product containing fractions were combined and concentrated, the residue dissolved in MTBE (20 mL) and concentrated to give timolol-deoxycholic ester (242 mg, 35%) as a glassy white solid. Melting point: 73° C. HPLC retention time: 36.2 min, ESI MS+ Calculated for C37H63N4O6 +; 691.4463, Found: 691.4464 1H NMR (400 MHz, DMSO-d6) δ 5.11 (qd, J=6.3, 2.8 Hz, 1H), 4.61 (dd, J=11.4, 2.8 Hz, 1H), 4.51-4.41 (m, 2H), 4.19 (d, J=4.1 Hz, 1H), 3.77 (d, J=3.8 Hz, 1H), 3.68 (t, J=4.8 Hz, 4H), 3.48-3.34 (m, 5H), 2.70 (d, J=6.3 Hz, 2H), 2.33 (ddd, J=14.4, 9.0, 4.9 Hz, 1H), 2.16 (dq, J=15.5, 8.1 Hz, 1H), 1.86-1.41 (m, 11H), 1.38-1.11 (m, 11H), 1.11 (s, 1H), 1.08-0.93 (m, 11H), 0.90 (d, J=6.2 Hz, 3H), 0.84 (s, 3H), 0.55 (s, 3H).
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- To a stirred solution of bimatoprost amide (100 mg, 0.241 mmol) in dry pyridine (3 mL) under nitrogen was added anecortave chloroformate (196 mg, 0.482 mmol). The yellow solution was stirred for 4 days, concentrated and re-dissolved in CH2Cl2 (5 mL). The mixture was concentrated onto reverse phase silica (2 g) and purified by automated reverse phase chromatography (aqueous-MeCN). The product containing fractions were concentrated to give a solid that was further purified by normal phase Biotage automated chromatography (hexane-ethyl acetate gradient). The product containing fractions were concentrated in vacuo to give the product as a colorless solid (23 mg, 12%). Melting point: not observed (Tg=˜60° C.). HPLC retention time: 30.5 min. ESI MS+ calculated for C47H63NNaO9 +; 808.4395, Found: 808.4397. 1H NMR (400 MHz, DMSO-d6) 7.68 (1H, t, J=5.7 Hz, NH), 7.30-7.22 (2H, m), 7.19-7.12 (3H, m), 5.65 (1H, s), 5.55-5.38 (5H, m), 5.33-5.26 (1H, m), 5.03 (1H, d, J=17.8 Hz), 4.82-4.76 (2H, m), 4.70-4.64 (2H, m), 3.98-3.89 (2H, m), 3.07-2.99 (2H, qd, J=7.2, 5.7 Hz), 2.67-2.43 (6H, m), 2.38-2.15 (5H, m), 2.15-1.89 (10H, m), 1.86-1.63 (3H, m), 1.59-1.21 (8H, m), 1.29 (3H, s), 0.98 (3H, t, J=7.2 Hz), 0.47 (3H, s).
- A compound of the disclosure was formed into a pellet in the glassy state by heat molding. Crystalline powder of the conjugate compound was melted between 85° C. to 110° C. and pressed into a cylindrical mold of ˜1 mm height×1 mm diameter.
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Compound 4 was formed into a thin film coating on a polymer surface by solvent casting.Compound 4 was dissolved in acetone at 50 mg/ml. 20 μl was cast onto a Dacron coupon and left to air dry at room temperature overnight followed by 2 h under vacuum at 50° C. - A compound of the disclosure was formed into a rod in the glassy state by heat extrusion. The conjugate compound was initially melted at a temperature up to 140° C. The resulting material was then loaded into a heat extruder with a 30G die head, heated between 70° C. to 125° C., and pressure was applied to a piston to form extrudate from the extruder. The extrudate was cut to different lengths.
- Drug release from heat-molded pellets or extruded rods of Compounds of the disclosure were assessed in either fetal bovine serum (FBS), phosphate buffered saline (PBS), or 1% FBS in PBS (v/v). Heat-molded pellets or extruded rods were placed in 20 ml glass vials, to which was added 2 ml of release buffer. Samples were incubated at 37° C. with constant agitation at 115 rpm. At intervals up to 14 days in length, release buffer was assessed for released drug and then fully replaced with 2 ml of fresh buffer. For FBS release conditions, acetonitrile was added to precipitate proteins and extract drug release products. Samples were analyzed by high performance liquid chromatography (HPLC) to quantify drug products.
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Compound 5 was formed into rods by melt extrusion and cut to length. The resulting implants were loaded into the lumen of needles and terminally sterilized by ethylene oxide, gamma irradiation, and E-beam. Following sterilization, samples were dissolved in a suitable solvent and assessed for changes in purity due to sterilization by HPLC. - For example,
FIG. 18 shows purity ofcompound 5 before (pre-sterilization) or post sterilization ofCompound 5 in ethylene oxide, or by gamma-radiation or E-beam. -
Compound 5 was formed into rods by melt extrusion and were cut to 1, 1.5 or 2 mm length. The resulting implants were loaded in the lumen of needles, terminally sterilized, and injected into the anterior chamber of rabbits. Implants settled into the inferior iridocorneal angle and were visualized by anterior chamber optical coherence tomography. -
Compound 6 was formed into rods by melt extrusion and were cut to 1.5 mm length. The resulting implants were loaded in the lumen of needles, terminally sterilized, and injected into the anterior chamber of rabbits. Implants settled into the inferior iridocorneal angle and were visualized by anterior chamber optical coherence tomography. - For example,
FIG. 14 shows an extruded rod steroid-prostaglandin heterodimer (bimatoprost-anecortave, Compound 5) exemplified herein in a rabbit eye.
Claims (21)
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US17/350,888 US11279729B2 (en) | 2020-05-01 | 2021-06-17 | Heterodimer compositions and methods for the treatment of ocular disorders |
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2021
- 2021-04-29 CN CN202180047539.0A patent/CN115956083A/en active Pending
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