DE4229048A1 - New ester(s) of 9-chloro-prostaglandin(s) - useful in treatment of glaucoma and as diuretic agents - Google Patents
New ester(s) of 9-chloro-prostaglandin(s) - useful in treatment of glaucoma and as diuretic agentsInfo
- Publication number
- DE4229048A1 DE4229048A1 DE4229048A DE4229048A DE4229048A1 DE 4229048 A1 DE4229048 A1 DE 4229048A1 DE 4229048 A DE4229048 A DE 4229048A DE 4229048 A DE4229048 A DE 4229048A DE 4229048 A1 DE4229048 A1 DE 4229048A1
- Authority
- DE
- Germany
- Prior art keywords
- chloro
- cyclohexyl
- pentanor
- dihydroxy
- ester
- 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.)
- Withdrawn
Links
- 150000002148 esters Chemical class 0.000 title claims abstract description 17
- 208000010412 Glaucoma Diseases 0.000 title abstract description 5
- 239000002934 diuretic Substances 0.000 title abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 8
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims abstract description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 7
- 239000002798 polar solvent Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 150000001718 carbodiimides Chemical class 0.000 claims description 3
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 2
- 230000004913 activation Effects 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 29
- -1 soln. Substances 0.000 abstract description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 10
- 230000004087 circulation Effects 0.000 abstract description 6
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 241000700159 Rattus Species 0.000 abstract description 3
- 239000006210 lotion Substances 0.000 abstract description 3
- 239000002674 ointment Substances 0.000 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 239000006071 cream Substances 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract description 2
- 230000004406 elevated intraocular pressure Effects 0.000 abstract 1
- 235000019439 ethyl acetate Nutrition 0.000 abstract 1
- 239000011505 plaster Substances 0.000 abstract 1
- VZAWCLCJGSBATP-UHFFFAOYSA-N 1-cycloundecyl-1,2-diazacycloundecane Chemical compound C1CCCCCCCCCC1N1NCCCCCCCCC1 VZAWCLCJGSBATP-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 230000004410 intraocular pressure Effects 0.000 description 6
- PPNCOQHHSGMKGI-UHFFFAOYSA-N 1-cyclononyldiazonane Chemical compound C1CCCCCCCC1N1NCCCCCCC1 PPNCOQHHSGMKGI-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000021190 leftovers Nutrition 0.000 description 1
- 230000029860 luteolysis Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 230000008326 skin blood flow Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nanotechnology (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Gegenstand der vorliegenden Erfindung sind Ester von 9-Chlor-Prostaglandin-Derivaten und diese enthaltene pharmazeutische Präparate.The present invention relates to esters of 9-chloro-prostaglandin derivatives and pharmaceutical preparations containing them.
Aus EP 299 914 sind 9-Chlor-3-oxa-prostaglandin-Derivate der allgemeinen FormelFrom EP 299 914 9-chloro-3-oxa-prostaglandin derivatives of the general formula
worin
Z die Restewherein
Z the leftovers
Hal ein α- oder β-ständiges Chlor- oder Fluoratom,
R1 den Rest CH2OH oder COOR2 mit R2 in der Bedeutung eines Wasserstoffatoms,
eines Alkyl- oder Cycloalkyl-, Aryl- oder heterocyclischen Restes oder R1 den
Rest CONHR3 mit R3 in der Bedeutung eines Säurerestes oder des Restes R2 und
A eine -CH2-CH2-, eine trans -CH=CH- oder eine -C≡C-Gruppe
W eine freie oder funktionell abgewandelte Hydroxymethylengruppe oder eine freie
oder funktionell abgewandelteHal is an α or β chlorine or fluorine atom,
R 1 represents the radical CH 2 OH or COOR 2 with R 2 meaning a hydrogen atom, an alkyl or cycloalkyl, aryl or heterocyclic radical or R 1 den
Radical CONHR 3 with R 3 meaning an acid radical or the radical R 2 and
A is a -CH 2 -CH 2 -, a trans -CH = CH- or a -C≡C group
W is a free or functionally modified hydroxymethylene group or a free or functionally modified
wobei die jeweiligen OH-Gruppen α- oder β-ständig sein
können,
D und E gemeinsam eine direkte Bindung oder
D eine geradkettige mit 1-10, eine verzweigtkettige mit 2-10 oder eine ringförmige
Alkylengruppe mit 3-10 C-Atomen, die gegebenenfalls durch Fluoratome
substituiert sein können und
E ein Sauerstoff- oder Schwefelatom, eine direkte Bindung, eine -C≡C-Bindung
oder eine -CR6=CR7-Gruppe darstellt, wobei R6 und R7 sich unterscheiden und ein
Wasserstoffatom, ein Chloratom oder eine C1-C4-Alkylgruppe bedeuten,
R4 eine freie oder funktionell abgewandelte Hydroxygruppe,
R5 ein Wasserstoffatom, eine Alkyl-, eine Halogen-substituierte Alkyl-, eine
Cycloalkyl-, eine gegebenenfalls substituierte Aryl- oder eine heterocyclische
Gruppe, und falls R2 die Bedeutung eines Wasserstoffatoms hat,deren Salze mit
physiologisch verträglichen Basen bedeuten und deren Cyclodextrinclathrate
bekannt,
jedoch werden die Ester der vorliegenden Erfindung weder im einzelnen genannt noch
besonders hervorgehoben.where the respective OH groups can be α- or β-permanent,
D and E together have a direct bond or
D is a straight-chain with 1-10, a branched chain with 2-10 or a ring-shaped alkylene group with 3-10 C-atoms, which can optionally be substituted by fluorine atoms and
E is an oxygen or sulfur atom, a direct bond, a -C≡C bond
or represents a -CR 6 = CR 7 group, where R 6 and R 7 differ and denote a hydrogen atom, a chlorine atom or a C 1 -C 4 alkyl group,
R 4 is a free or functionally modified hydroxy group,
R 5 is a hydrogen atom, an alkyl, a halogen-substituted alkyl, a cycloalkyl, an optionally substituted aryl or a heterocyclic group, and if R 2 has the meaning of a hydrogen atom, their salts mean with physiologically compatible bases and their cyclodextrin clathrates
is known, but the esters of the present invention are neither mentioned in detail nor particularly emphasized.
Aus EP 30 377 sind 9-Chlor-Prostaglandin-DerivateFrom EP 30 377 are 9-chloro-prostaglandin derivatives
worin
das 9-Chloratom α- oder β-ständig sein kann,
R1 den Rest OR2 mit R2 in der Bedeutung eines Wasserstoffatoms, Alkyl,
Cycloalkyl, Aryl oder eines heterocyclischen Restes oder den Rest NHR3 mit R3 in der
Bedeutung eines Säurerestes oder Wasserstoffatoms und
A eine -CH2-CH2- oder cis -CH=CH-Gruppe,
B eine -CH2-CH2-,= trans -CH=CH-oder eine -C≡C-Gruppe,
W eine freie oder funktionell abgewandelte Hydroxymethylengruppe oder eine freie
oder funktionell abgewandeltewherein
the 9-chlorine atom can be α- or β-permanent,
R 1 represents the radical OR 2 with R 2 in the meaning of a hydrogen atom, alkyl,
Cycloalkyl, aryl or a heterocyclic radical or the radical NHR 3 with R 3 in the meaning of an acid radical or hydrogen atom and
A is a -CH 2 -CH 2 - or cis -CH = CH group,
B is a -CH 2 -CH 2 -, = trans -CH = CH - or a -C≡C group,
W is a free or functionally modified hydroxymethylene group or a free or functionally modified
wobei die OH-Gruppe α- oder β-
ständig sein kann,
D und E gemeinsam eine direkte Bindung oder
D eine geradkettige oder verzweigtkettige Alkylengruppe mit 1-10 C-Atomen, die
gegebenenfalls durch Fluoratome substituiert ist, und
E ein Sauerstoff- oder Schwefelatom oder eine direkte Bindung und
R4 eine freie oder funktionell abgewandelte Hydroxygruppe,
R5 eine Alkyl-, eine Halogen substituierte Alkyl-, Cycloalkyl-, eine gegebenenfalls
substituierte Aryl- oder heterocyclische Gruppe und
falls R1 die Bedeutung einer Hydroxylgruppe hat, deren Salze mit physiologisch
verträglichen Basen bedeuten,
bekannt,
jedoch werden auch dort die Ester dieser Erfindung weder im einzelnen genannt noch
besonders hervorgehoben.where the OH group can be α- or β-,
D and E together have a direct bond or
D is a straight-chain or branched-chain alkylene group with 1-10 C atoms, which is optionally substituted by fluorine atoms, and
E is an oxygen or sulfur atom or a direct bond and
R 4 is a free or functionally modified hydroxy group,
R 5 is an alkyl, a halogen-substituted alkyl, cycloalkyl, an optionally substituted aryl or heterocyclic group and if R 1 is a hydroxyl group, the salts of which mean with physiologically compatible bases,
known, however, the esters of this invention are neither mentioned in detail nor particularly emphasized there.
9-ChIor-Prostaglandin-Derivate sind pharmakologisch und medizinisch wertvolle Wirkstoffe, deren Herstellung und Anwendung z. B. zur Zytoprotektion, Ulkusheilung, Hemmung der Magensäuresekretion, Luteolyse, Blutdrucksenkung, oder Plättchenaggregationshemmung in EP 299 914, EP 30 377 und WO 86/05488 beschrieben sind. Diese Substanzen besitzen gegenüber den entsprechenden natürlichen Prostaglandinen bei ähnlichem Wirkungsspektrum eine wesentlich verbesserte Spezifität und längere Wirkung.9-chlorine prostaglandin derivatives are pharmacologically and medically valuable Active ingredients, their manufacture and application z. B. for cytoprotection, ulcer healing, Inhibition of gastric acid secretion, luteolysis, lowering blood pressure, or Inhibition of platelet aggregation is described in EP 299 914, EP 30 377 and WO 86/05488 are. These substances have compared to the corresponding natural ones Prostaglandins with a similar spectrum of activity a significantly improved specificity and longer impact.
Es wurde nun gefunden, daß die erfindungsgemäßen Ester überraschenderweise besonders für die lokale Anwendung geeignet sind, sowie diuretische Wirkung zeigen und die Nierendurchblutung fördern.It has now been found that the esters according to the invention are surprisingly special are suitable for local use, as well as show diuretic activity and the Promote kidney circulation.
Die Erfindung betrifft Ester von 9-Chlor-Prostaglandinen der allgemeinen Formel IThe invention relates to esters of 9-chloro prostaglandins of the general Formula I.
worin
X Sauerstoff oder CH2, und
R1 einen gegebenenfalls substituierten Q-C3-Alkyl-, Cyclopentyl-,
Cyclohexyl-, Phenyl- oder Benzyl-Rest
bedeuten und deren Cyclodextrinclathrate.wherein
X is oxygen or CH 2 , and
R 1 is an optionally substituted QC 3 alkyl, cyclopentyl, cyclohexyl, phenyl or benzyl radical
mean and their cyclodextrin clathrates.
Als Alkylgruppen R1 sind gerade oder verzweigte Alkylgruppen mit 2-3 C-Atomen zu betrachten, wie Ethyl, Propyl, und Isopropyl. Die Alkylgruppen R1 können gegebenenfalls mehrfach substituiert sein durch Halogenatome, Hydroxygruppen, Alkoxygruppen, Dialkylamino- und Trialkylammoniumgruppen, oder gegebenenfalls substituierte Aryl bzw. Aroylgruppen. Bevorzugt ist die Monosubstitution. Als Substituenten seien beispielsweise genannt Fluor, Chlor oder Brom, Hydroxy, Methoxy, Dimethylamino, Trimethylammonium, Phenyl. Als bevorzugte Substituenten sind Fluor, Hydroxy, und Methoxy zu nennen. Besonders bevorzugt ist der Hydroxy-Substituent.Straight or branched alkyl groups with 2-3 carbon atoms, such as ethyl, propyl and isopropyl, are to be considered as alkyl groups R 1 . The alkyl groups R 1 may optionally be substituted several times by halogen atoms, hydroxyl groups, alkoxy groups, dialkylamino and trialkylammonium groups, or optionally substituted aryl or aroyl groups. Mono substitution is preferred. Examples of substituents are fluorine, chlorine or bromine, hydroxy, methoxy, dimethylamino, trimethylammonium, phenyl. Preferred substituents are fluorine, hydroxy and methoxy. The hydroxy substituent is particularly preferred.
Die Phenyl- und Benzylgruppe in R1 kann substituiert sein durch 1-3 Halogenatome, eine Phenylgruppe, 1-2 Methylgruppen, 1-2 Methoxygruppen, 1-2 Chlormethyl-, Fluormethyl-, oder Trifluormethylgruppen, oder 1-2 Carboxylgruppen. Bevorzugt sind die Substituenten in 3- und 4-Stellung am Phenylring, zum Beispiel Fluor, Chlor, Alkoxy oder Trifluormethyl oder in 4-Stellung Hydroxy.The phenyl and benzyl group in R 1 can be substituted by 1-3 halogen atoms, a phenyl group, 1-2 methyl groups, 1-2 methoxy groups, 1-2 chloromethyl, fluoromethyl or trifluoromethyl groups, or 1-2 carboxyl groups. The substituents in the 3- and 4-position on the phenyl ring are preferred, for example fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position hydroxy.
Die Cyclopentyl- und die Cyclohexylgruppe R1 kann durch Alkylgruppen mit 1-4 C- Atomen substituiert sein wie z. B. Methylcyclopentyl, Methylcyclohexyl.The cyclopentyl and the cyclohexyl group R 1 can be substituted by alkyl groups with 1-4 C atoms such as. B. methylcyclopentyl, methylcyclohexyl.
Die Erfindung betrifft ferner ein Verfahren zur Herstellung von Estern der 9-Chlor prostaglandine der Formel I dadurch gekennzeichnet, daß man in an sich bekannter Weise eine Verbindung der Formel IIThe invention further relates to a process for the preparation of esters of 9-chlorine prostaglandins of the formula I, characterized in that in a manner known per se a compound of formula II
worin X die oben angegebene Bedeutung hat,
A.
entweder in Gegenwart einer geeigneten Base in einem polaren Lösungsmittel mit einer
Verbindung der allgemeinen Formel IIIwhere X has the meaning given above,
A.
either in the presence of a suitable base in a polar solvent with a compound of general formula III
Hal-R1 (III)Hal-R 1 (III)
worin R1 die oben angegebenen Bedeutung hat, jedoch nicht Phenyl bedeutet, und Hal für
Chlor, Brom oder Iod steht,
bei Temperaturen zwischen -80°C und 100°C umsetzt, und den entstandenen Ester isoliert
oder
B.
in Gegenwart einer geeigneten Base in einem polaren Lösungsmittel nach Aktivierung mit
einem Carbodiimid wie z. B. Dicyclohexylcarbodiimid mit Phenol bei Temperaturen
zwischen -30°C und 50°C umsetzt und den entstandenen Ester isoliert.wherein R 1 has the meaning given above but does not mean phenyl, and Hal represents chlorine, bromine or iodine,
at temperatures between -80 ° C and 100 ° C, and the resulting ester is isolated or
B.
in the presence of a suitable base in a polar solvent after activation with a carbodiimide such as. B. dicyclohexylcarbodiimide with phenol at temperatures between -30 ° C and 50 ° C and the resulting ester isolated.
Als Base für die Umsetzung von Verbindungen der allgemeinen Formel II mit Verbindungen der allgemeinen Formel III oder mit Phenol sind die dem Fachmann bekannten Basen, z. B. Diazabicyclononan, Diazabicycloundecen, Diisopropylethylamin, N,N-Dimethylaminopyridin, Pyridin, Triethylamin, Kaliumcarbonat oder Cäsiumcarbonat besonders geeignet.As a base for the reaction of compounds of general formula II with Compounds of the general formula III or with phenol are the person skilled in the art known bases, e.g. B. diazabicyclononane, diazabicycloundecene, diisopropylethylamine, N, N-dimethylaminopyridine, pyridine, triethylamine, potassium carbonate or cesium carbonate particularly suitable.
Die Umsetzungen können in polaren Lösungsmitteln, z. B. Aceton, Acetonitril, Chloroform, Diethylether, Dimethylformamid, Dimethylsulfoxid, Methylenchlorid oder Tetrahydrofuran erfolgen.The reactions can be carried out in polar solvents, e.g. B. acetone, acetonitrile, Chloroform, diethyl ether, dimethylformamide, dimethyl sulfoxide, methylene chloride or Tetrahydrofuran take place.
Die Einführung der Estergruppe CO2R1, bei welcher R1 eine Alkylgruppe mit 2-3 C- Atomen darstellt, erfolgt nach den dem Fachmann bekannten Methoden. Die Carboxy verbindungen können beispielsweise auch mit Diazokohlenwasserstoffen in an sich bekannter Weise umgesetzt werden. Die Veresterungen mit Diazokohlenwasserstoffen erfolgt z. B. dadurch, daß man eine Lösung des Diazokohlenwasserstoffes in einem inerten Lösungsmittel, vorzugsweise in Diethylether, mit der Carboxyverbindung in dem gleichen oder in einem anderen Lösungsmittel, wie z. B. Methylenchlorid, vermischt. Nach beendeter Umsetzung in 1 bis 30 Minuten wird das Lösungsmittel entfernt und der Ester in üblicher Weise gereinigt. Diazoalkane sind entweder bekannt oder können nach bekannten Methoden hergestellt werden [Org. Reactions Bd. 8, Seite 389-394 (1954)].The introduction of the ester group CO 2 R 1 , in which R 1 represents an alkyl group with 2-3 C atoms, takes place according to the methods known to the person skilled in the art. The carboxy compounds can, for example, also be reacted with diazo hydrocarbons in a manner known per se. The esterifications with diazo hydrocarbons take place, for. Example, that a solution of the diazo hydrocarbon in an inert solvent, preferably in diethyl ether, with the carboxy compound in the same or in a different solvent, such as. B. methylene chloride mixed. When the reaction has ended in 1 to 30 minutes, the solvent is removed and the ester is purified in the customary manner. Diazoalkanes are either known or can be prepared by known methods [Org. Reactions Vol. 8, pages 389-394 (1954)].
Die Einführung der Estergruppe CO2R1, bei welcher R1 eine Alkylgruppe mit 2-3 C- Atomen darstellt, die gegebenenfalls auch substituiert sein kann, kann auch in der nachstehenden Weise erfolgen. Die Carboxyverbindungen werden beispielsweise mit dem entsprechenden Alkylhalogenid, bevorzugt Alkylbromid oder Alkyliodid, in Gegenwart einer Base, wie beispielsweise Triethylamin, Diazabicyclononan (DBN), Diazabicycloundecan (DBU) in einem inerten Lösungsmittel, wie beispielsweise Acetonitril, Tetrahydrofuran, Methylenchlorid oder Dimethylformamid bei Temperaturen zwischen -80°C und 100°C, vorzugsweise bei 0°C bis 30°C, verestert.The introduction of the ester group CO 2 R 1 , in which R 1 represents an alkyl group with 2-3 C atoms, which can optionally also be substituted, can also be carried out in the following manner. The carboxy compounds are, for example, with the corresponding alkyl halide, preferably alkyl bromide or alkyl iodide, in the presence of a base, such as triethylamine, diazabicyclononane (DBN), diazabicycloundecane (DBU) in an inert solvent, such as acetonitrile, tetrahydrofuran, methylene chloride or dimethylformamide at temperatures between - 80 ° C and 100 ° C, preferably at 0 ° C to 30 ° C, esterified.
Die Einführung der Estergruppe CO2R1, bei welcher R1 eine substituierte oder unsubstituierte Phenylgruppe darstellt, erfolgt nach den dem Fachmann bekannten Methoden. Beispielsweise werden die Carboxyverbindungen mit den entsprechenden Phenylhydroxyverbindungen mit einem Carbodiimid z. B. Dicyclohexylcarbodiimid in Gegenwart einer geeigneten Base, beispielsweise Diazabicyclononan (DBN), Diazabicycloundecen (DBU), Diisopropylethylamin, N,N-Dimethylaminopyridin (DMAP), Pyridin, Triethylamin, Cäsiumcarbonat oder Kaliumcarbonat in einem inerten polaren Lösungsmittel umgesetzt. Als Lösungsmittel kommen Aceton, Acetonitril, Chloroform, Diethylether, Dimethylformamid, Dimethylsulfoxid, Essigester, Ethylenchlorid, Methylenchlorid, oder Tetrahydrofuran, vorzugsweise Chloroform in Frage. Die Reaktion wird bei Temperaturen zwischen -30°C und +50°C, vorzugsweise bei Temperaturen zwischen 0°C und Raumtemperatur, durchgeführt.The introduction of the ester group CO 2 R 1 , in which R 1 represents a substituted or unsubstituted phenyl group, takes place according to the methods known to the person skilled in the art. For example, the carboxy compounds with the corresponding phenylhydroxy compounds with a carbodiimide z. B. dicyclohexylcarbodiimide in the presence of a suitable base, for example diazabicyclononane (DBN), diazabicycloundecene (DBU), diisopropylethylamine, N, N-dimethylaminopyridine (DMAP), pyridine, triethylamine, cesium carbonate or potassium carbonate in an inert polar solvent. Acetone, acetonitrile, chloroform, diethyl ether, dimethylformamide, dimethyl sulfoxide, ethyl acetate, ethylene chloride, methylene chloride or tetrahydrofuran, preferably chloroform, are suitable as solvents. The reaction is carried out at temperatures between -30 ° C and + 50 ° C, preferably at temperatures between 0 ° C and room temperature.
Die für die Synthese der Ester benötigten Ausgangsmaterialien sind nach Vorschriften aus EP 299 914 und WO 86/05488 zu erhalten.The starting materials required for the synthesis of the esters are made according to regulations EP 299 914 and WO 86/05488.
Cyclodextrinclathrate können analog einer Vorschrift in WO 87/05294 erhalten werden.Cyclodextrin clathrates can be obtained analogously to a regulation in WO 87/05294.
Die erfindungsgemäßen Ester eignen sich besonders für die lokale Anwendung wie z. B. zur Förderung der Hautdurchblutung oder zur Behandlung erhöhten Augeninnendruckes (Glaukom) sowie zur Förderung der Nierendurchblutung oder zur Verwendung als Diuretikum.The esters according to the invention are particularly suitable for local application such as. B. to promote blood circulation to the skin or to treat increased intraocular pressure (Glaucoma) as well as to promote kidney circulation or to use as Diuretic.
Bei Kaninchen bewirkt die lokale Applikation der Verbindungen eine Senkung des Augeninnendruckes.In rabbits, the local application of the compounds causes a reduction in the Intraocular pressure.
Bei Affen mit experimentellem Glaukom bewirkt die lokale Applikation der Verbindungen eine Normalisierung des pathologisch erhöhten Augeninnendruckes.In monkeys with experimental glaucoma, the local application of the compounds causes a normalization of the pathologically increased intraocular pressure.
Die Einzeldosis der Verbindungen für die Anwendung zur Behandlung erhöhten Augeninnendruckes ist 1 ng-100 µg / Auge, einmal oder mehrmals täglich, wenn sie am menschlichen Patienten lokal verabreicht werden.The single dose of compounds for use in treatment increased The intraocular pressure is 1 ng-100 µg / eye, once or several times a day when it is on administered to human patients locally.
Für die lokale Applikation für die Anwendung zur Behandlung erhöhten Augeninnendruckes sind beispielsweise Lösungen, Lotionen oder Salben geeignet.Increased for local application for treatment application Intraocular pressure, for example, solutions, lotions or ointments are suitable.
Die Dosis der Verbindungen bei lokaler Anwendung ist 5-500 ng/cm2, wenn sie am menschlichen Patienten verabreicht werden.The dose of the compounds when used locally is 5-500 ng / cm 2 when administered to the human patient.
Für die lokale Applikation für die Anwendung zur Förderung der Hautdurchblutung sind beispielsweise Lösungen, Lotionen, Salben, Cremes oder Pflaster geeignet.For local application for use to promote skin circulation for example, solutions, lotions, ointments, creams or plasters.
Die Erfindung betrifft auch Arzneimittel auf Basis der Verbindungen der Formel I, sowie deren Cyclodextrinclathrate, mit den üblichen Hilfs- und Trägerstoffen. The invention also relates to medicaments based on the compounds of the formula I, and their cyclodextrin clathrates, with the usual auxiliaries and carriers.
Die erfindungsgemäßen Wirkstoffe sollen in Verbindung mit den in der Galenik bekannten und üblichen Hilfsstoffen, z. B. zur Herstellung von Präparaten zur Förderung der Haut- oder Nierendurchblutung, zur Behandlung des erhöhten Augeninnendruckes (Glaukom) oder zur Verwendung als Diuretikum dienen.The active compounds according to the invention are intended to be used in conjunction with those known in galenics and usual auxiliaries, e.g. B. for the preparation of preparations for promoting the skin or renal blood flow, to treat increased intraocular pressure (glaucoma) or serve as a diuretic.
Die folgenden Beispiele sollen die Erfindung näher erläutern, ohne daß damit eine Begrenzung vorgenommen werden soll.The following examples are intended to explain the invention in greater detail, without any Limitation should be made.
Zu 250 mg (5Z,13E)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-
16,17,18,19,20-pentanor-5,13-prostadiensäure gibt man 6.25 ml einer Lösung aus
Acetonitril, Diazabicycloundecan (DBU) und Iodethan (50 ml Acetonitril, 0.8 ml DBU,
0.8 ml Iodethan) und rührt 22 Stunden bei 24°C unter Argon. Anschließend verdünnt man
mit 150 ml Essigester, wäscht einmal mit 5%iger Natriumhydrogencarbonat-Lösung,
dreimal mit je 10 ml einer Mischung aus gesättigter Natriumchlorid-Lösung und Wasser
(1 : 1), trocknet über Natriumsulfat und engt im Vakuum ein. Das Rohprodukt reinigt man
durch Säulenchromatographie an Kieselgel. Mit Hexan / 0-80% Essigester als
Elutionsmittel erhält man 129 mg der Titelverbindung als farbloses Öl.
IR (CHCl3): 3608, 3410 (br.), 3020, 3000, 2980, 2928, 2857, 1726, 1450, 1376, 1245,
1095, 1085, 973 cm-1.To 250 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5,13-prostadienoic acid are added 6.25 ml of a solution of acetonitrile, diazabicycloundecane (DBU) and iodoethane (50 ml acetonitrile, 0.8 ml DBU, 0.8 ml iodoethane) and stir for 22 hours at 24 ° C under argon. Then diluted with 150 ml of ethyl acetate, washed once with 5% sodium hydrogen carbonate solution, three times with 10 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as the eluent, 129 mg of the title compound are obtained as a colorless oil.
IR (CHCl 3 ): 3608, 3410 (br.), 3020, 3000, 2980, 2928, 2857, 1726, 1450, 1376, 1245, 1095, 1085, 973 cm -1 .
Zu 100 mg (5Z,13E)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-
16,17,18,19,20-pentanor-5,13-prostadiensäure gibt man 2.5 ml einer Lösung aus
Acetonitril, Diazabicycloundecan (DBU) und 2-Iodpropan (50 ml Acetonitril, 0.8 ml
DBU, 0.8 ml 2-Iodpropan) und rührt 22 Stunden bei 24°C unter Argon. Anschließend
verdünnt man mit 70 ml Essigester, wäscht zweimal mit je 10 ml einer Mischung aus
gesättigter Natriumchlorid-Lösung und Wasser (1 : 1), trocknet über Natriumsulfat und engt
im Vakuum ein. Das Rohprodukt reinigt man durch Säulenchromatographie an Kieselgel.
Mit Hexan / 0-80% Essigester als Elutionsmittel erhält man 50.1 mg der Titelverbindung
als farbloses Öl.
IR (CHCl3): 3609, 3415 (br.), 3030, 3000, 2983, 2928, 2857, 1723, 1453, 1377, 1247,
1207, 1085, 973 cm-1.
To 100 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5,13-prostadienoic acid are added 2.5 ml of a solution of acetonitrile, diazabicycloundecane (DBU) and 2-iodopropane (50 ml acetonitrile, 0.8 ml DBU, 0.8 ml 2-iodopropane) and stirred for 22 hours at 24 ° C under argon. Then it is diluted with 70 ml of ethyl acetate, washed twice with 10 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as the eluent, 50.1 mg of the title compound are obtained as a colorless oil.
IR (CHCl 3 ): 3609, 3415 (br.), 3030, 3000, 2983, 2928, 2857, 1723, 1453, 1377, 1247, 1207, 1085, 973 cm -1 .
Zu 92 mg (5Z,13E)-(9R,11R,15S)-9-Chlor-3-oxa-15-cyclohexyl-11,15-dihydroxy-
16,17,18,19,20-pentanor-5,13-prostadiensäure gibt man 2.3 ml einer Lösung aus
Acetonitril, Diazabicycloundecan (DBU) und Iodethan (50 ml Acetonitril, 0.8 ml DBU,
0.8 ml Iodethan) und rührt 18 Stunden bei 24°C unter Argon. Dann nochmals mit 0.73 ml
einer Lösung aus 100 mg DBU in 10 ml Acetonitril versetzt und weitere 20 Stunden bei
24°C unter Argon gerührt. Anschließend verdünnt man mit 70 ml Essigester, wäscht
einmal mit 10 ml einer 5%iger Natriumhydrogencarbonat-Lösung, dreimal mit je 10 ml
einer Mischung aus gesättigter Natriumchlorid-Lösung und Wasser (1 : 1), trocknet über
Natriumsulfat und engt im Vakuum ein. Das Rohprodukt reinigt man durch
Säulenchromatographie an Kieselgel. Mit Hexan / 0-80% Essigester als Elutionsmittel
erhält man 75.5 mg der Titelverbindung als farbloses Öl.
IR (CHCl3): 3605, 3415 (br.), 3030, 2997, 2985, 2926, 2853, 1745, 1447, 1380, 1300,
1273, 1125, 1020, 997, 972 cm-1.To 92 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5,13 -prostadienic acid is added 2.3 ml of a solution of acetonitrile, diazabicycloundecane (DBU) and iodoethane (50 ml acetonitrile, 0.8 ml DBU, 0.8 ml iodoethane) and stirred for 18 hours at 24 ° C under argon. Then again 0.73 ml of a solution of 100 mg DBU in 10 ml acetonitrile was added and the mixture was stirred for a further 20 hours at 24 ° C. under argon. Then diluted with 70 ml of ethyl acetate, washed once with 10 ml of a 5% sodium hydrogen carbonate solution, three times with 10 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as the eluent, 75.5 mg of the title compound are obtained as a colorless oil.
IR (CHCl 3 ): 3605, 3415 (br.), 3030, 2997, 2985, 2926, 2853, 1745, 1447, 1380, 1300, 1273, 1125, 1020, 997, 972 cm -1 .
Zu 190 mg (5Z,13E)-(9R,11R,15S)-9-Chlor-3-oxa-15-cyclohexyl-11, 15-dihydroxy-
16,17,18,19,20-pentanor-5,13-prostadiensäure gibt man 4.7 ml einer Lösung aus
Acetonitril, Diazabicycloundecan (DBU) und 2-Iodpropan (50 ml Acetonitril, 0.8 ml
DBU, 0.8 ml 2-Iodpropan) und rührt 18 Stunden bei 24°C unter Argon. Anschließend
verdünnt man mit 70 ml Essigester, wäscht zweimal mit je 20 ml einer Mischung aus
gesättigter Natriumchlorid-Lösung und Wasser (1 : 1), trocknet über Natriumsulfat und engt
im Vakuum ein. Das Rohprodukt reinigt man durch Säulenchromatographie an Kieselgel.
Mit Hexan / 0-80% Essigester als Elutionsmittel erhält man 83.1 mg der Titelverbindung
als farbloses Öl.
IR (CHCl3): 3605, 3410 (br.), 3030, 3000, 2983, 2925, 2853, 1738, 1448, 1376, 1125,
1102, 997, 973 cm-1.
To 190 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11, 15-dihydroxy-16,17,18,19,20-pentanor-5,13 -prostadienic acid is added 4.7 ml of a solution of acetonitrile, diazabicycloundecane (DBU) and 2-iodopropane (50 ml acetonitrile, 0.8 ml DBU, 0.8 ml 2-iodopropane) and stirred for 18 hours at 24 ° C under argon. Then it is diluted with 70 ml of ethyl acetate, washed twice with 20 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as the eluent, 83.1 mg of the title compound are obtained as a colorless oil.
IR (CHCl 3 ): 3605, 3410 (br.), 3030, 3000, 2983, 2925, 2853, 1738, 1448, 1376, 1125, 1102, 997, 973 cm -1 .
Die Hautdurchblutung wurde mit der nichtinvasiven Laser-Doppler Methode bestimmt. Die Messungen wurden 4 Stunden nach der lokalen Applikation der Substanzen auf der Bauchhaut von narkotisierten (Urethan) haarlosen Ratten (für diese Untersuchungen wurden weibliche Ratten (Wister, hairless) mit einem Körpergewicht von 220-250 g verwendet) durchgeführt. Als Lösungsmittel wurde Isopropylmyristat in Ethanol verwendet ( 5/95; v/v).The blood flow to the skin was determined using the non-invasive laser Doppler method. The measurements were taken 4 hours after the local application of the substances on the Belly skin of anesthetized (urethane) hairless rats (female rats (Wister, hairless) with a Body weight of 220-250 g used) carried out. When Solvent isopropyl myristate in ethanol was used (5/95; v / v).
Claims (7)
X Sauerstoff oder CH2,
R1 einen gegebenenfalls substituierten Q-C3-Alkyl-, Cyclopentyl-, Cyclohexyl-, Phenyl- oder Benzyl-Rest
bedeuten und deren Cyclodextrinclathrate.1. Esters of 9-chloro-prostaglandins of the general formula I wherein
X is oxygen or CH 2 ,
R 1 is an optionally substituted QC 3 alkyl, cyclopentyl, cyclohexyl, phenyl or benzyl radical
mean and their cyclodextrin clathrates.
A.
entweder in Gegenwart einer geeigneten Base in einem polaren Lösungsmittel mit einer Verbindung der allgemeinen Formel IIIHal-R1 (III)worin R1 die oben angegebenen Bedeutung hat, jedoch nicht Phenyl bedeutet, und Hal für Chlor, Brom oder Iod steht,
bei Temperaturen zwischen -80°C und 100°C umsetzt, und den entstandenen Ester isoliert und gegebenenfalls in das Cyclodextrinclathrat überführt oder
B.
in Gegenwart einer geeigneten Base in einem polaren Lösungsmittel nach Aktivierung mit einem Carbodiimid wie z. B. Dicyclohexylcarbodiimid mit Phenol bei Temperaturen zwischen -30°C und 50°C umsetzt und den entstandenen Ester isoliert und gegebenenfalls in das Cyclodextrinclathrat überführt.2. Process for the preparation of esters of 9-chloro-prostaglandins of the formula I. characterized in that a compound of formula II where X is oxygen or CH 2 ,
A.
either in the presence of a suitable base in a polar solvent with a compound of the general formula IIIHal-R 1 (III) in which R 1 has the meaning given above but does not mean phenyl, and Hal represents chlorine, bromine or iodine,
at temperatures between -80 ° C and 100 ° C, and the resulting ester isolated and optionally converted into the cyclodextrin clathrate or
B.
in the presence of a suitable base in a polar solvent after activation with a carbodiimide such as. B. dicyclohexylcarbodiimide with phenol at temperatures between -30 ° C and 50 ° C and the resulting ester isolated and optionally converted into the cyclodextrin clathrate.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4229048A DE4229048A1 (en) | 1992-08-31 | 1992-08-31 | New ester(s) of 9-chloro-prostaglandin(s) - useful in treatment of glaucoma and as diuretic agents |
| PCT/DE1993/000809 WO1994005631A1 (en) | 1992-08-31 | 1993-08-31 | 9-chloroprostaglandin esters and amides and their use in the preparation of drugs |
| DE59308617T DE59308617D1 (en) | 1992-08-31 | 1993-08-31 | 9-CHLORINE PROSTAGLANDIN ESTERS AND AMIDES AND THEIR USE FOR THE PRODUCTION OF MEDICINAL PRODUCTS |
| ES93918946T ES2118248T3 (en) | 1992-08-31 | 1993-08-31 | 9-CHLORINE-PROSTAGLANDINE ESTERS AND AMIDES AND THEIR USE TO PREPARE MEDICINES. |
| AT93918946T ATE166642T1 (en) | 1992-08-31 | 1993-08-31 | 9-CHLORINE-PROSTAGLANDIN ESTERS AND AMIDES AND THEIR USE FOR THE PRODUCTION OF MEDICINAL PRODUCTS |
| EP93918946A EP0656889B1 (en) | 1992-08-31 | 1993-08-31 | 9-chloroprostaglandin esters and amides and their use in the preparation of drugs |
| DK93918946T DK0656889T3 (en) | 1992-08-31 | 1993-08-31 | 9-chloro-prostaglandin esters and amides and their use in the manufacture of drugs |
| JP6506751A JPH08500597A (en) | 1992-08-31 | 1993-08-31 | 9-Chloro-prostaglandin-ester and 9-chloro-prostaglandinamide and the use of said 9-chloro-prostaglandin-ester and 9-chloro-prostaglandinamide for the manufacture of a medicament |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4229048A DE4229048A1 (en) | 1992-08-31 | 1992-08-31 | New ester(s) of 9-chloro-prostaglandin(s) - useful in treatment of glaucoma and as diuretic agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE4229048A1 true DE4229048A1 (en) | 1994-03-03 |
Family
ID=6466903
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE4229048A Withdrawn DE4229048A1 (en) | 1992-08-31 | 1992-08-31 | New ester(s) of 9-chloro-prostaglandin(s) - useful in treatment of glaucoma and as diuretic agents |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE4229048A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995006634A1 (en) * | 1993-08-31 | 1995-03-09 | Schering Aktiengesellschaft | New 9-chloro-prostaglandin derivatives |
| US5627209A (en) * | 1993-12-15 | 1997-05-06 | Alcon Laboratories, Inc. | Use of certain 9-haloprostaglandins to treat glaucoma and ocular hypertension |
| US5721273A (en) * | 1993-12-15 | 1998-02-24 | Alcon Laboratories, Inc. | Use of certain 9-halo-13,14-dihydroprostaglandins to treat glaucoma and ocular hypertension |
| US5807892A (en) * | 1994-09-30 | 1998-09-15 | Alcon Laboratories, Inc. | Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1026652A3 (en) * | 1979-12-10 | 1983-06-30 | Шеринг Аг (Фирма) | Process for preparing derivatives of 9-chloroprostane or their salts |
| DE3510978A1 (en) * | 1985-03-22 | 1986-09-25 | Schering AG, Berlin und Bergkamen, 1000 Berlin | NEW 9-HALOGEN PROSTAGLANDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| EP0299914A1 (en) * | 1987-07-17 | 1989-01-18 | Schering Aktiengesellschaft | 9-Halogen (Z) prostaglandin derivatives, process for their production and their use as medicines |
| DE4036140A1 (en) * | 1990-11-09 | 1992-05-14 | Schering Ag | 9-HALOGEN-11SS-HYDROXY-PROSTAGLANDIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
-
1992
- 1992-08-31 DE DE4229048A patent/DE4229048A1/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1026652A3 (en) * | 1979-12-10 | 1983-06-30 | Шеринг Аг (Фирма) | Process for preparing derivatives of 9-chloroprostane or their salts |
| DE3510978A1 (en) * | 1985-03-22 | 1986-09-25 | Schering AG, Berlin und Bergkamen, 1000 Berlin | NEW 9-HALOGEN PROSTAGLANDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| EP0299914A1 (en) * | 1987-07-17 | 1989-01-18 | Schering Aktiengesellschaft | 9-Halogen (Z) prostaglandin derivatives, process for their production and their use as medicines |
| DE4036140A1 (en) * | 1990-11-09 | 1992-05-14 | Schering Ag | 9-HALOGEN-11SS-HYDROXY-PROSTAGLANDIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995006634A1 (en) * | 1993-08-31 | 1995-03-09 | Schering Aktiengesellschaft | New 9-chloro-prostaglandin derivatives |
| US5627209A (en) * | 1993-12-15 | 1997-05-06 | Alcon Laboratories, Inc. | Use of certain 9-haloprostaglandins to treat glaucoma and ocular hypertension |
| US5721273A (en) * | 1993-12-15 | 1998-02-24 | Alcon Laboratories, Inc. | Use of certain 9-halo-13,14-dihydroprostaglandins to treat glaucoma and ocular hypertension |
| US6344581B1 (en) | 1993-12-15 | 2002-02-05 | Alcon Manufacturing, Ltd. | Method of prostaglandin synthesis |
| US6531614B2 (en) | 1993-12-15 | 2003-03-11 | Alcon Manufacturing, Ltd. | Method of prostaglandin synthesis |
| US5807892A (en) * | 1994-09-30 | 1998-09-15 | Alcon Laboratories, Inc. | Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| OM8 | Search report available as to paragraph 43 lit. 1 sentence 1 patent law | ||
| 8127 | New person/name/address of the applicant |
Owner name: SCHERING AG, 13353 BERLIN, DE |
|
| 8141 | Disposal/no request for examination |