AU2001256560A1 - Thienodibenzoazulene compounds as tumor necrosis factor inhibitors - Google Patents
Thienodibenzoazulene compounds as tumor necrosis factor inhibitorsInfo
- Publication number
- AU2001256560A1 AU2001256560A1 AU2001256560A AU2001256560A AU2001256560A1 AU 2001256560 A1 AU2001256560 A1 AU 2001256560A1 AU 2001256560 A AU2001256560 A AU 2001256560A AU 2001256560 A AU2001256560 A AU 2001256560A AU 2001256560 A1 AU2001256560 A1 AU 2001256560A1
- Authority
- AU
- Australia
- Prior art keywords
- dibenzo
- azulene
- ylmethoxy
- dithia
- hydrochloride
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims description 61
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 title description 4
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 title description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 100
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 78
- 238000006243 chemical reaction Methods 0.000 claims description 65
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 30
- 239000011541 reaction mixture Substances 0.000 claims description 28
- 230000008569 process Effects 0.000 claims description 27
- 238000004440 column chromatography Methods 0.000 claims description 25
- 238000010992 reflux Methods 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 238000000746 purification Methods 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- -1 ciano Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 6
- 102000004127 Cytokines Human genes 0.000 claims description 6
- 108090000695 Cytokines Proteins 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 230000001575 pathological effect Effects 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000006193 alkinyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 238000004587 chromatography analysis Methods 0.000 claims description 5
- 239000005550 inflammation mediator Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 239000002609 medium Substances 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 150000007860 aryl ester derivatives Chemical class 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003610 charcoal Substances 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000004970 halomethyl group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 239000012454 non-polar solvent Substances 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 238000003408 phase transfer catalysis Methods 0.000 claims description 2
- 239000003444 phase transfer catalyst Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims 4
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 claims 1
- SQNXZINOQZHERU-UHFFFAOYSA-N 1-[2-(13-oxa-3-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2(6),4,7,9,11,14,16-octaen-4-ylmethoxy)ethyl]pyrrolidine hydrochloride Chemical compound Cl.C=1C(C2=CC=CC=C2OC2=CC=CC=C22)=C2SC=1COCCN1CCCC1 SQNXZINOQZHERU-UHFFFAOYSA-N 0.000 claims 1
- JQDGMCDEGXIBGU-UHFFFAOYSA-N 1-[2-[(17-chloro-13-oxa-3-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),2(6),4,7,9,11,15,17-octaen-4-yl)methoxy]ethyl]pyrrolidine Chemical compound S1C=2C3=CC(Cl)=CC=C3OC3=CC=CC=C3C=2C=C1COCCN1CCCC1 JQDGMCDEGXIBGU-UHFFFAOYSA-N 0.000 claims 1
- WCSAFFKZIJBSBC-UHFFFAOYSA-N 1-[2-[(17-chloro-3,13-dithiatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),2(6),4,7,9,11,15,17-octaen-4-yl)methoxy]ethyl]pyrrolidine hydrochloride Chemical compound Cl.S1C=2C3=CC(Cl)=CC=C3SC3=CC=CC=C3C=2C=C1COCCN1CCCC1 WCSAFFKZIJBSBC-UHFFFAOYSA-N 0.000 claims 1
- BTPOOJLYRXTZLT-UHFFFAOYSA-N 1-[2-[(17-fluoro-3,13-dithiatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),2(6),4,7,9,11,15,17-octaen-4-yl)methoxy]ethyl]pyrrolidine hydrochloride Chemical compound Cl.S1C=2C3=CC(F)=CC=C3SC3=CC=CC=C3C=2C=C1COCCN1CCCC1 BTPOOJLYRXTZLT-UHFFFAOYSA-N 0.000 claims 1
- TXWAOMXXXNTOBQ-UHFFFAOYSA-N Cl.C12=CC(F)=CC=C2OC2=CC=CC=C2C2=C1SC(COCCCN(C)C)=C2 Chemical compound Cl.C12=CC(F)=CC=C2OC2=CC=CC=C2C2=C1SC(COCCCN(C)C)=C2 TXWAOMXXXNTOBQ-UHFFFAOYSA-N 0.000 claims 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- 150000004678 hydrides Chemical class 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 229910052703 rhodium Inorganic materials 0.000 claims 1
- 239000010948 rhodium Substances 0.000 claims 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims 1
- 229910052707 ruthenium Inorganic materials 0.000 claims 1
- 239000000047 product Substances 0.000 description 77
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- 238000005160 1H NMR spectroscopy Methods 0.000 description 63
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000000243 solution Substances 0.000 description 40
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 37
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 37
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 36
- 102000000589 Interleukin-1 Human genes 0.000 description 25
- 108010002352 Interleukin-1 Proteins 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000002158 endotoxin Substances 0.000 description 17
- 229920006008 lipopolysaccharide Polymers 0.000 description 16
- 230000028327 secretion Effects 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- LQLJZSJKRYTKTP-UHFFFAOYSA-N 2-dimethylaminoethyl chloride hydrochloride Chemical compound Cl.CN(C)CCCl LQLJZSJKRYTKTP-UHFFFAOYSA-N 0.000 description 14
- LJQNMDZRCXJETK-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine;hydron;chloride Chemical compound Cl.CN(C)CCCCl LJQNMDZRCXJETK-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 13
- 238000012360 testing method Methods 0.000 description 12
- NBJHDLKSWUDGJG-UHFFFAOYSA-N 4-(2-chloroethyl)morpholin-4-ium;chloride Chemical compound Cl.ClCCN1CCOCC1 NBJHDLKSWUDGJG-UHFFFAOYSA-N 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 description 9
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 230000006433 tumor necrosis factor production Effects 0.000 description 7
- GXMSLNZIHPZWAI-UHFFFAOYSA-N 5-thiatetracyclo[12.4.0.02,6.08,13]octadeca-1(18),2,6,8,10,12,14,16-octaene Chemical class S1CC=C2C3=C(C4=C(C=C12)C=CC=C4)C=CC=C3 GXMSLNZIHPZWAI-UHFFFAOYSA-N 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000012546 transfer Methods 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000011725 BALB/c mouse Methods 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000000160 carbon, hydrogen and nitrogen elemental analysis Methods 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 108010008165 Etanercept Proteins 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000018276 interleukin-1 production Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 210000003024 peritoneal macrophage Anatomy 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000002917 arthritic effect Effects 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 229960000403 etanercept Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 229960000598 infliximab Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 230000004963 pathophysiological condition Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 210000003200 peritoneal cavity Anatomy 0.000 description 2
- 239000000651 prodrug Chemical group 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- KAANTNXREIRLCT-UHFFFAOYSA-N 1-(triphenyl-$l^{5}-phosphanylidene)propan-2-one Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)C)C1=CC=CC=C1 KAANTNXREIRLCT-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- RZGJWVFLDKZTTI-UHFFFAOYSA-L Cl[Cr](=O)(=O)OC1=CC=CC=N1 Chemical compound Cl[Cr](=O)(=O)OC1=CC=CC=N1 RZGJWVFLDKZTTI-UHFFFAOYSA-L 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 description 1
- 101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- RHHSGLPWDHEVIR-UHFFFAOYSA-L O[Cr](O[Cr](OC1=CC=CC=N1)(=O)=O)(=O)=O Chemical compound O[Cr](O[Cr](OC1=CC=CC=N1)(=O)=O)(=O)=O RHHSGLPWDHEVIR-UHFFFAOYSA-L 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 206010036030 Polyarthritis Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000002009 alkene group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 150000004677 hydrates Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- 229960003676 tenidap Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Description
THIENODIBENZOAZULENE COMPOUNDS AS TUMOR NECROSIS FACTOR INHIBITORS
Technical Field
The present invention relates to new derivatives of 1-thiadibenzoazulene, their pharmacologically acceptable salts, solvates and prodrug forms, processes for the preparation thereof and their antiinflammatory effects and particularly to the inhibition of the production of the tumor necrosis factor-α (TNF-α) and of interleukin-1 (IL-1) and to their analgetic action.
Prior Art
Hitherto, 1-thiadibenzoazulenes, which are substituted in position 2 with methyl, methyl ketone, nitro group or a derivative of carboxylic group (Cagniant P. and Kirsch G., C. R. Hebd. Sceances Acad.Sci, 1976, 283:638-686) have been described in the literature. According to our knowledge and available literature data, however, neither 1-thiadibenzoazulene derivatives of general formula I nor any possible methods of their preparation have been decribed so far. It is also not known either that 1- thiadibenzoazulenes possess an anti-inflammatory effect.
In 1975 TNF-α was defined as an endotoxine-induced serum factor causing tumor necrosis in vitro and in vivo (Carswell E. A. et al., Proc. Natl. Acad. Sci. U.S.A. 1975, 72:36666-3670). In addition to antitumor activity, TNF-α has several other biologic activities, which are important in the homeostasis of organism as well as in pathophysiological conditions. The main sources of TNF-α are monocytes- macrophages, T-lymphocytes and mast cells.
The finding that anti-TNF-α antibodies (cA2) are effective in the treatment of patients suffering from rheumatoid arthritis (RA) (Elliott M. et al., Lancet 1994, 344:1105- 1110) intensified the interest to find new TNF-α inhibitors as possible potent medicaments for RA. Rheumatoid arthritis is an autoimmune chronic inflammatory disease characterized by irreversible pathological changes of the joints. In addition to
RA, TNF-α antagonists are also applicable to several pathological conditions and diseases such as spondylitis, osteoarthritis, gout and other arthritic conditions, sepsis, septic shock, toxic shock syndrome, atopical dermatitis, contact dermatitis, psoriasis, glomerulonephritis, lupus erhythematosus, scleroderma, asthma, cachexia, chronic obstructive lung disease, congestive heart failure, insulin resistance, lung fibrosis, multiple sclerosis, Chron's disease, ulcerative colitis, viral infections and AIDS.
Proof of biological importance of TNF-α was obtained in in vivo experiments in mice having inactivated genes for TNF-α or its receptor. Such animals were resistant to collagen-induced arthritis (Mori L. et al., J. Immunol. 1996, 757:3178-3182) and to endotoxin-induced shock (Pfeffer K. et al., Cell 1993, 73:457-467). In experiments with animals having an increased TNF-α level a chronic inflammatory polyarthritis appeared (Georgopoulos S. et al., J. Inflamm. 1996, 4(5:86-97; Keffer J. et al., EMBO J. 1991, 70:4025-4031), which was palliated by inhibitors of TNF-α production. The treatment of such inflammatory and pathologic conditions usually includes the application of nonsteroid antiinflammatory medicaments, in severe cases, however, gold salts, D-penicillinamine or methotrexate are administered. Said medicaments act symptomatically and do not stop the pathological process. New approaches in theraphy of rheumatoid arthritis have been established upon medicaments such as tenidap, leflunomide, cyclosporine, FK-506 and biomolecules neutralizing the activity of TNF-α. Presently, the fusion protein ofthe soluble TNF receptor named etanercept (Enbrel, Immunex/Wyeth) and mouse and human cimeric monoclonal antibody named infliximab (Remicade, Centocor) are available on the market. In addition to RA- therapy, etanercept and infliximab are also approved for the treatment of Chron's disease (Exp. Opin. Invest Drugs 2000, 9, 103).
In RA-therapy, in addition to the inhibition of TNF-α secretion, it is also important to inhibit IL-1 secretion since IL-1 represents an important cytokine in cell regulation, immunoregulation and in the pathophysiological conditions such as inflammation (Dinarello C. A. et al, Rev. Infect. Disease,l9S4, 6:51). Known biological activities of IL-1 are: activation of T-cells, induction of elevated temperature, stimulation of prostaglandine or collagenase secretion, chemotaxis of neutrophils and reduction of
iron level in plasma (Dinarello C. A., J. Clinical Immunology, 1985, 5:287). There are known two receptors to which IL-1 can be bound: IL-1RI and IL-1RII. IL-1RI transfers the signal intracellularly, while IL-1RII is present on the cell surface and does not transfer the signal within the cell. Since IL1-RII binds both IL-1 and IL1-RI, it can act as a negative regulator of IL-1 effect. In addition to the mentioned mechanism of regulation of signal transfer, another natural IL-1 receptor antagonist (IL-lra) is present in cells. This protein binds to IL-1RI but does not transfer any signal. Yet its potency in the inhibition of signal transfer is not great, therefore it must be present in a 500 times higher concentration than IL-1 in order to break the signal transfer. Recombinant human IL-lra (Amgen) was clinicaly tested (Bresnihan B. et al., Arthrit. Rheum. 1996, 39:73) and the obtained results demonstrated an improvement of the symptoms in 472 patients suffering from RA with respect to a placebo. These results indicate the importance of inhibition of IL-1 activity in the treatment of diseases such as RA where the production of IL-1 is inhibited. Due to the synergistic action of TNF-α and IL-1, dibenzoazulenes can be used in the treatment of conditions and diseases connected with an increased secretion of TNF-α and IL-1.
According to the known and established prior art, 1-thiadibenzoazulene compounds representing the subject of the present invention, their pharmacologically acceptable salts, hydrates, prodrug forms and pharmaceutical preparations comprising them have hitherto not been described. Moreover, no compound representing the subject of the present invention has been described either as an anti-inflammatory substance or as an inhibitor of TNF-α and IL-1 secretion or an analgetic.
Technical Solution
The present invention relates to compounds represented by the general formula I, 1- thiadibenzoazulene derivatives, to their pharmacologically acceptable salts and solvates represented by formula I
wherein
X can represent CH2 or a heteroatom such as O, S, S(=0), S(=0)2 or NR13, wherein Rι3 means hydrogen, C1-6 alkyl,
alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl or arylsulfonyl and Rls R2, R3, R4, R5, R^, R7, Rs, R9 independently from each other represent substituents that can be hydrogen, halogens (fluorine, chlorine or bromine); or C1-C7 alkyls, alkenyls, aryls or heteroaryls; or can represent different groups: halomethyl, hydroxy, C1-C7 alkoxy or aryloxy, C1-C7 alkylthio or arylthio, C1-C7 alkylsulfonyl, ciano, amino, mono- and di-Cι-C7 substituted amines, derivatives of carboxylic group (C1-C7 carboxylic acids and their anhydrides, Cx-C7 unsubstituted, mono-, di-substituted amides, C1-C7 alkyl or aryl esters), C1-C7 derivatives of carbonyl group (CrC7 alkyl or aryl carbonyls), and R10 can represent substituents such as: C2- C15 alkyls, C2-C15 alkenyls, C2-Cι5 alkinyls, aryls or heteroaryls, C Cι5 haloalkyls, Cr C15 hydroxyalkyls, Ci-C15 alkyloxy, C1-C15 alkylthio, C3-C15 alkylcarbonyls, C2-Cι5 alkylcarboxylic acid, C2-C15 alkylsters, C1-C15 alkylsulfonyls, C1-C15 alkylarylsulfonyls, arysulfonyls and CrC15 alkylamines represented by the general formula
-(CH2)n-A wherein n means 1-15, and one or more methylene groups can be substituted with an oxygen or sulfur atom, and
A represents a five- or six-membered, saturated or unsaturated ring with one, two or three heteroatoms, or
wherein Rπ and R12 independently from each other represent hydrogen, C1-C7 alkyl, alkenyl, alkinyl, aryl or heteroaryl, or a heterocycle with 1-3 heteroatoms.
The terms as used in the present invention are defined as stated below unless otherwise specified.
"Alkyl" means a monovalent alkane (hydrocarbon), wherefrom a radical is derived, which can be a straight-chain, a branched-chain or a cyclic hydrocarbon or a combination of straight-chain and cyclic hydrocarbons and of branched-chain and cyclic hydrocarbons. The preferred straight-chain or branched-chain alkyls include methyl, ethyl, propyl, fcopropyl, butyl, sec-butyl and t-butyl. The preferred cycloalkyls include cyclopentyl and cyclohexyl. Alkyl also represents a straight-chain or branched-chain alkyl group containing a cycloalkyl portion or being broken by it.
"Alkenyl" means a hydrocarbon radical being a straight-chain, a branched-chain or a cyclic hydrocarbon or a combination of straight-chain and cyclic hydrocarbons and of branched-chain and cyclic hydrocarbons, which has at least one double carbon-carbon bond. Particularly ethenyl, propenyl, butenyl and cyclohexenyl are meant. As stated above under the definition of "alkyl", also alkenyl can be a straight-chain, a branched- chain or a cyclic one, and a portion of alkenyl group can contain double bonds and it can also be substituted when a substituted alkenyl group is of interest. Alkenyl also represents a straight-chain or a branched-chain alkenyl group containing a cycloalkenyl portion or being broken by it.
"Alkinyl" means a hydrocarbon radical, which is a straight-chain or a branched-chain one and contains at least one and at most three triple carbon-carbon bonds. Particularly ethinyl, propinyl and butinyl groups are meant.
"Aryl" means an aromatic ring such as phenyl, substituted phenyl or similar groups as well as fused rings such as naphtyl etc. Aryl contains at least one ring with at least 6
carbon atoms or two rings having together 10 carbon atoms and alternating double (resonant) bonds between carbon atoms (particularly phenyl and naphtyl). Aryl groups can be additionally substituted with one or two substituents such as halogens (fluorine, chlorine and bromine), hydroxy, C C7 alkyls, C1-C7 alkoxy or aryloxy, C1-C7 alkylthio or arylthio, alkylsulfonyl, ciano or amino groups.
"Heteroaryl" means a monocyclic or a bicyclic aromatic hydrocarbon containing at least one heteroaom such as O, S or N with carbon and nitrogen representing the binding sites for the basic formula. Heteroaryl can be additionally substituted with a halogen or CF3 group and a lower alkyl such as methyl, ethyl or propyl. Heteroaryl means an aromatic and a partly aromatic group with one or more heteroatoms. Examples of this type are thiophene, pyrrole, imidazole, pyridine, oxazole, thiazole, pyrazole, tetrazole, pyrimidine, pyrazine and triazine.
Another object of the present invention relates to a process for the preparation of dibenzoazulene derivatives represented by formula I. These compounds can be prepared from thiophene esters of the general formula I, wherein all radicals and symbols have the above-defined meanings i.e. where radicals Rls R2, R3, R , R5, R , R7, R8 and R9 have the above-defined meanings and R10 means ethoxycarbonyl (Cagniant P. and Kirsch G., C. R. Hebd. Sceances Acad. Set, 1976, 283:683-686). By means of further reactions these esters are converted into other substituents defined as Rio. These reactions include the reduction of an ester to the corresponding alcohol or aldehyde, alkylation and other nucleophilic reactions on the ethoxycarbonyl group (Scheme 1).
Scheme 1
The reduction of the ethoxycarbonyl group is performed by the use of metal hydrides to obtain an alcohol (Rw = hydroxymethyl). The reaction is performed in suitable nonpolar solvents (preferably in aliphatic ethers) at a temperature from 0 to 36°C within a period of 1 to 5 hours. The isolation and purification ofthe compounds can be performed by recrystallization or column chromatography.
By the reaction of an alcohol of the general formula I wherein Rι0 represents hydroxymethyl and of a chloride ofthe formula II
Cl-(CH2)n-A II
wherein the symbols n and A have the above-defined meanings, ω-amino ethers ofthe general formula I are obtained.
The stated reactions are performed at a temperature from 20 to 100 °C within a period of 1 to 24 hours under the conditions of phase-transfer catalysis in a two-phase system (preferably 50% NaOH-toluene) and in the presence of a phase-transfer catalyst (preferably benzyl-triethyl-ammonium-chloride, benzyl-triethyl-ammonium-bromide, cetyl-trimethyl-bromide). Subsequently to the treatment of the reaction mixture, the obtained products are isolated by recrystallization or chromatography on a silica gel column.
By the oxidation of an alcohol ofthe general formula I wherein Rι0 = hydroxymethyl with pyridinyl dichromate or pyridinyl chlorochromate, an aldehyde the general formula I wherein Rι0 = CHO is obtained. The reaction is performed in dichloromethane at room temperature within a period of 2 to 5 hours. The obtained aldehyde is purified by passing through a column of florisil or silica gel.
The reaction of an aldehyde of the general formula I wherein Rι0 - CHO with different corresponding phosphorus-ylides results in the formation of compounds of the general formula I, wherein Rio has the above-defined meanings and which have an alkene functionality in the position 2 of the chain defining R10. These reactions are performed in anhydrous solvents such as toluene, benzene or hexane at the reflux temperature of the solvent within a period of 3 to 5 hours. The obtained products are purified by column chromatography.
By the hydrogenation of the compounds I, wherein R10 contains one or more double carbon-carbon bonds, compounds ofthe general formula I wherein Rio has a saturated chain are obtained. These reactions are usually performed with 5% Pd on active
charcoal under a hydrogen pressure from 6.7x104 to 4.0x105 Pa in ethanol, ethyl acetate or other suitable solvents. By filtration and evaporation of the solvents saturated products are obtained, which can be purified to the desired purity by recrystallization or column chromatography on silica gel.
The pharmaceutically suitable salts of the compounds representing a subject of the present invention include salts with inorganic acids (hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids) or organic acids (tartaric, acetic, trifluoroacetic, citric, maleic, lactic, fumaric, benzoic, succinic, methanesulfonic and p-toluenesulfonic acids).
A further subject of the present invention is the use of the compounds of the present invention in the treatment of inflammatory diseases and conditions, particularly of all diseases and conditions induced by an excessive secretion of TNF-α and IL-1.
An effective dose of the cytokine or inflammation mediator production inhibitors of the present invention or of pharmaceutically acceptable salts thereof is useful in the production of medicaments for the treatment and prophylaxis of any pathological condition or disease induced by an excessive unregulated production of cytokines or inflammation mediators.
More specifically, the present invention relates to an effective dose of TNF-α inhibitors, which can be determined by common methods.
Further, the present invention relates to pharmaceutical preparations containing an effective nontoxic dose of compounds of the present invention as well as pharmaceutically acceptable carriers and solvents.
The preparation of the pharmaceutical preparations can include mixing, granulating, tabletting and dissolving the ingredients. Chemical carriers can be in solid or liquid form. Solid carriers can be lactose, sucrose, talc, gelatine, agar, pectin, magnesium
stearate, fatty acids etc. Liquid carriers can be syrups, oils such as olive, sunflower seed or soybean oils, water etc. Similarly, carriers may also contain a component for a sustained release of the active component such as glyceryl monostearate or glyceryl distearate. Several forms of pharmaceutical compositions can be prepared. If a solid carrier is used these forms can include tablets, solid gelatinous capsules, powders or granules that can be administered orally in capsules. The amount of the solid carrier can vary but mainly it is in the range from 25 mg to 1 g. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatinous capsules, sterile injectable liquids such as ampules, or nonaqueous liquid suspensions.
The compounds of the present invention can be administered orally, parenterally, topically, intranasally, intrarectally and mtravaginally. "Parenterally" means intraveneous, intramuscular and subcutaneous administrations. The corresponding preparations ofthe compounds ofthe present invention can be used in the prophylaxis as well as in the treatment of several diseases and pathological inflammatory conditions caused by an excessive nonregulated production of cytokines or inflammation mediators, foremost TNF-α. They include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic pathological conditions and diseases, eczema, psoriasis as well as other inflammatory conditions of skin such as burns induced by UV radiation (sun rays and similar UV sources), inflammatory eye diseases, Chron's disease, ulcerative cholitis and asthma.
The inhibitory effect of the compounds of the present invention on the secretion of TNF-α and IL-1 was determined by the following in vitro and in vivo experiments:
Determination of TNF-α and IL-1 secretion in mononuclear cells of human peripheral blood in vitro
Peripheral blood mononuclear cells (PMBC) were prepared from heparinized whole blood after separation of PMBC on Ficoll-Hypaque (Amersham-Pharmacia). For the determination of TNF-α level 3.5-5x104 cells were cultured in a total volume of 200 μl within a period of 18 to 24 hours on microtiter flat bottom plates (96 wells, Falcon) in RPMI 1640 medium supplemented with 10% of heat-inactivated human AB serum (Hrvatski zavod za transfuzijsku medicinu, Zagreb), 100 units/ml of penicillin, 100 mg/ml of streptomycine and 20 mM HEPES (GIBCO). The cells were incubated at 37°C in an atmosphere with 5% C02 and 90% moisture. The cells in a negative control were cultured only in the medium (NC), while the secretion of TNF-α in a positive control was stimulated by the addition of 1 μg/ml lipopolysaccharide (LPS, E. coli serotype 0111 :B4, SIGMA) (PC) and the effect ofthe tested substances on TNF-α secretion was tested after their addition to cell cultures stimulated with LPS (TS). The TNF-α level in the cell supernatant was determined by ELISA according to the manufacturer's (R&D Systems) suggestions. The test sensitivity was <3pg/ml TNF-α. The determination of IL-1 level was performed as described for TNF-α determination, only that lxlO5 cells/well and O.lng/ml of LPS were used. IL-1 level was determined by ELISA (R&D Systems). The percentage inhibition of TNF-α or IL-1 production was calculated by the following equation:
% inhibition = [1-(TS-NC)/(PC-NC)]* 100. IC-50 value was defined as the concentration ofthe substance at which 50% of TNF-α production was inhibited. The compounds demonstrating IC-50 in concentrations of 20 μM or lower were considered active.
Determination of TNF-α and IL-1 secretion by mouse peritoneal macrophages in vitro
For obtaining peritoneal macrophages, male BALB/c mice at an age of 8 to 12 weeks were injected i.p. with 300 μg of zimozane (SIGMA) dissolved in a phosphate buffer (PBS) in a total volume of 0.1 ml/mouse. After 24 hours the mice were subjected to euthanasia according to the Laboratory Animals Welfare Act. The peritoneal cavity was washed with 5 ml of sterile saline. The obtained peritoneal macrophages were washed twice with sterile saline and after the last centrifugation (800 g) they were resuspended in RPMI 1640. For the determination of TNF-α secretion, 5x104 cells/well were cultured in a total volume of 200 μl within a period of 18 to 24 hours on microtiter flat bottom plates (96 wells, Falcon) in RPMI 1640 medium supplemented with 10% of heat-inactivated fetal calf serum (FCS), 100 units/ml of penicillin, 100 mg/ml of streptomycine, 20 mM HEPES and 50 μM 2-β mercaptoethanol (all of GIBCO). The cells were incubated at 37°C in an atmosphere with 5% C02 and 90% moisture. The cells in a negative control were cultured only in the medium (NC), while the secretion of TNF-α in a positive control was stimulated by the addition of 1 μg/ml lipopolysaccharide (LPS, E. coli serotype 0111:B4, SIGMA) (PC) and the effect of the tested substances on TNF-α secretion was tested after their addition to cell cultures stimulated with LPS (TS). The TNF-α level in the cell supernatant was determined by ELISA according to manufacturer's (R&D Systems, Biosource) suggestions. The determination of IL-1 level was performed as described for TNF-α determination, only that 1x10s cells/well and 0.1 ng/ml of LPS were used. The IL-1 level was determined by ELISA (R&D Systems). The percentage inhibition of TNF-α or IL-1 production was calculated by the following equation:
% inhibition = [1-(TS-NC)/(PC-NC)]*100. IC-50 value was defined as the concentration ofthe substance at which 50% of TNF-α production was inhibited. The compounds demonstrating IC-50 in concentration of 10 μM or lower were considered active.
In vivo model of LPS-induced exccessive secretion of TNF-α or IL-1 in mice
TNF-α or IL-1 secretion in mice was induced according to the previously described method (Badger A. M. et al., J. ofPharmac. and Env. Therap. 1996, 279:1453-1461). In the test male BALB/c mice at an age of 8 to 12 weeks in groups of 6 to 10 animals were used. Animals were treated p.o. either only with the solvent (in a negative and a positive control) or with solutions of the substance 30 minutes prior to the i.p. treatment with LPS (E.coli serotype 0111:B4, Sigma) in a dose of 25 μg/animal. Two hours later the animals were euthanized by means of an i.p. injection of Roumpun (Bayer) and Ketanest (Park-Davis). A blood sample from each animal was collected in a "vacutaner" tube (Becton Dickinson) and the plasma was separated according to the manufacturer's suggestions. The TNF-α level in the plasma was determined by ELISA (Biosource, R&D Systems) according to the process prescribed by the manufacturer. The test sensitivity was <3pg/ml TNF-α. The IL-1 level was determined by ELISA (R&D Systems). The percentage inhibition of TNF-α or IL-1 production was calculated by the following equation:
% inhibition - [1-(TS-NC)/(PC-NC)]* 100. The compounds demonstrating a 30% or higher inhibition of TNF-α production at a dose of 10 mg/kg were considered active.
Writhing test for analgetic activity
In this test, pain is induced with an injection of an irritant, usually acetic acid, into the peritoneal cavity of mice. The animals respond by the characteristic writhings, which gave the name ofthe test. (Collier H. O. J. et al, Pharmac. Chemother., 1968, 32:295- 310; Fukawa K. et al., J. Pharmacol. Metk, 1980, 4:251-259; Schweizer A. et al, Agents Actions, 1988, 23:29-31). This test is suitable for the determination of analgetic activity of compounds. Process: male BALB/c mice (Charles River, Italy) at an age of 8 to 12 weeks were used. To a control group methyl cellulose was administered p.o. 30 minutes prior to i.p. administration of acetic acid in a concentration of 0.6%, .whereas to the test groups a standard (acetyl salicylic acid) or test substances in
methylcellulose were administered p.o. 30 minutes prior to i.p. administration of 0.6% acetic acid (volume 0.1 ml/ 10 g). Mice were individually placed under glass funnels und the number of writhings of each animal was recorded during a period of 20 minutes. The percentage inhibition of writhings was calculated according to the equation:
% inhibition = (mean value of number of writhings in the control group - number of writhings in the test group)/number of writhings in the control group* 100.
The compounds demonstrating the same or better analgetic activity than acetyl salicylic acid were considered active.
In vivo model of LPS-induced shock in mice
Male BALB/c mice at an age of 8 to 12 weeks (Charles River, Italy) were used. LPS isolated from Serratie marcessans (Sigma, L-6136) was diluted in sterile saline. The first LPS injection was administered intradermally in a dose of 4μg/mouse. 18 to 24 hours later LPS was administered i.v. in a dose of 200 μg/mouse. To a control group two LPS injections were administered in the above described manner. The test groups were administered the substances p.o. half an hour prior to each LPS administration. The survival after 24 hours was observed.
The compounds resulting in a 40% or better survival at a dose of 30 mg/kg were considered active.
The compounds of Examples 1, 5, 19 and 21 demonstrate activity in at least two investigated tests. These results, however, only illustrate the biological activity of the compounds and do not limit the present invention in any way.
Preparation processes with Examples
The present invention is illustrated but in no way limited by the following Examples.
Example A Preparation of alcohol
To a suspension of LiAlH in dry ether (10 mmole/15 ml of dry ether) an ether solution of an ester (2 mmole/15 ml dry ether) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. Subsequently, when all ester was consumed in the reaction (the course of the reaction was followed by thin layer chromatography), the excess of LiAlH4 was decomposed by the addition of diethyl ether and water. The obtained white precipitate was filtered off and, after drying over anhydrous Na2S0 , the filtrate was evaporated under the reduced pressure. The crude product was purified by column chromatography.
According to the process of Example A and starting from corresponding esters, dibenzoazulene alcohols represented by the formula I, wherein Ri, R5, Rβ, R7, R8 and R9 = H, and R2, R3, R and X have the meanings as illustrated in Table 1, were prepared.
Table 1
The compounds decribed in Examples 1-5 were prepared from alcohol 1 and the corresponding chloroalkyldialkyamine hydrochloride according to the process described in Example 1.
Example 1
Dimethyl-[3-(8-oxa-l-thia-dibenzo[e,Λ]azulene-2-ylmethoxy)-propyl]-amine hydrochloride
To a solution of 3-dimethylaminopropylchloride hydrochloride (2.2 g, 0.014 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.1 g, 0.44 mmole) and a toluene solution of alcohol 1 (0.28 g, 0.001 mole) were added. The reaction mixture was heated under vigorous stirring and reflux for 4 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.25 g) was isolated. By the addition of concentrated hydrochloric acid into the cold ethanol solution of amine, a crystalline product, m.p. 162-165°C, was obtained.
C, H, N, S analysis: C 65.45 (calc. 65.74); H 6.12 (calc. 6.02); N 3.89 (calc. 3.48); S 8.52 (calc. 7.98)
1H NMR (ppm, CDC13): 2.18 (m, 2H); 2.79 (d, 6H); 3.15 (m, 2H); 3.68 (t, 2H); 4.71 (s, 2H); 7.15-7.58 (m, 9H), 12.29 (s, IH).
Example 2
Dimethyl-[2-(8-oxa-l-thia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]-amine hydrochloride
By the reaction of alcohol 1 (0.45 g, 0.0015 mole) and 2-dimethylaminoethylchloride hydrochloride (3.05 g, 0.021 mole), an oily product (0.3 g) was obtained, which was converted into the hydrochloride, m.p. 203°C.
C, H, N analysis: C 64.85 (calc. 65.02); H 5.80 (calc. 5.72); N 3.48 (calc. 3.61).
1H NMR (ppm, CDC13): 2.89 (s, 6H); 3.27 (m, 2H); 4.07 (m, 2H); 4.78 (s, 2H); 7.16-
7.47 (m, 9H); 12.5 (s, IH).
Example 3
4-[2-(8-oxa-l-thia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride
By the reaction of alcohol 1 (0.45 g, 0.0015 mole) and 4-(2-chloroethyl)-morpholine hydrochloride (3.9 g, 0.021 mole), an oily product (0.34 g) was obtained, which was converted into the hydrochloride, m.p. 164°C.
C, H, N analysis: C 63.57 (calc. 64.25); H 5.76 (calc. 5.6); N 3.79 (calc. 3.26).
1H NMR (ppm, CDC13): 2.99 (bs, 2H); 3.23 (m, 2H); 3.55 (d, 2H); 3.94 (d, 2H); 4.14
(m, 2H); 4.27 (m, 2H); 4.75 (s, 2H); 7.14-7.44 (m, 9H); 13.16 (s, IH).
Example 4
l-[2-(8-oxa-l-thia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride
By the reaction of alcohol 1 (0.45 g, 0.0015 mole) and l-(2-chloroethyl)-piperidine monohydrochloride (3.86 g, 0.021mole), an oily product (0.48 g) was obtained, which was converted into the hydrochloride, m.p. 179°C.
C, H, N analysis: C 67.53 (calc. 67.35); H 6.30 (calc. 6.12); N 3.61 (calc. 3.27).
1H NMR (ppm, CDC13): 1.83 (m, 4H); 2.25 (m, 2H); 2.74 (m, 2H); 3.18 (m, 2H); 3.6
(m, 2H); 4.10 (m, 2H); 4.73 (s, 2H); 7.13-7.5 (m, 9H); 12.15 (s, IH).
Example 5 l-[2-(8-oxa-l-thia-dibenzo[e,/ϊ]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride
By the reaction of alcohol 1 (0.45 g, 0.0015 mole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (3.6 g, 0.021 mole), an oily product (0.41 g) was obtained, which was converted into the hydrochloride, m.p. 203-205°C.
C, H, N analysis: C 67.12 (calc. 67.35); H 6.03 (calc. 5.84); N 3.91 (calc. 3.38).
1H NMR (ppm, CDC13): 2.02 (m, 2H); 2.18 (m, 2H); 2.91 (m, 2H); 3.27 (m, 2H); 3.81
(m, 2H); 4.08 (m, 2H); 4.75 (s, 2H); 7.12-7.5 (m, 9H); 12.7 (s, IH).
The compounds described in Examples 6-10 were prepared from alcohol 2 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 6.
Example 6
[3-(9-chloro-8-oxa-l-thia-dibenzo[e,Λ]azulene-2-ylmethoxy)-propyl]-dimethyl- amine
To a solution of 3-dimethylaminopropylchloride hydrochloride (2.37 g, 0.015 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.25 g) and a toluene solution of alcohol 2 (0.2 g, 0.64 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 3 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.11 g) was isolated.
1H NMR (ppm, CDC13): 1.93 (m, 2H); 2.39 (s, 6H); 2.59 (m, 2H); 3.64 (m, 2H); 4.72 (s, 2H); 7.05-7.56 (m, 8H).
Example 7
[2-(9-chloro-8-oxa-l-thia-dibenzo[e,/t]azulene-2-ylmethoxy)-ethyl]-dimethyl- amine
By the reaction of alcohol 2 (0.2 g, 0.64 mmole) and 2-dimethylaminoethylchloride hydrochloride (2.6 g, 0.015 mole), an oily product (0.15 g) was obtained.
1H NMR (ppm, CDC13): 2.42 (s, 6H); 2.72 (m, 2H); 3.74 (m, 2H); 4.76 (s, 2H); 7.08- 7.55 (m, 8H).
Example 8 4-[2-(9-chloro-8-oxa-l-thia-dibenzo[e, r]azulene-2-ylmethoxy)-ethyl]-morpholine
By the reaction of alcohol 2 (0.2 g, 0.64 mmole) and 4-(2-chloroethyl)-morpholine hydrochloride (2.8 g, 0.015 mole), an oily product (0.19 g) was obtained.
1H NMR (ppm, CDC13): 2.51 (m, 4H); 3.71 (m, 8H); 4.75 (s, 2H); 7.08-7.56 (m, 8H).
Example 9 l-[2-(9-chloro-8-oxa-l-thia-dibenzo[e, e]azulene-2-ylmethoxy)-ethyl]-piperidine
By the reaction of alcohol 2 (0.2 g, 0.64 mmole) and l-(2-chloroethyl)-piperidine monohydrochloride (2.76 g, 0.015 mole), an oily product (0.13 g) was obtained.
Example 10 l-[2-(9-chloro-8-oxa-l-thia-dibenzo[e,Λ]azuIene-2-ylmethoxy)-ethyl]-pyrrolidine
By the reaction of alcohol 2 (0.2 g, 0.64 mmole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (2.55 g, 0.015 mole), an oily product (0.15 g) was obtained.
!H NMR (ppm, CDC13): 2.02 (m, 2H); 2.2 (m, 2H); 2.94 (m, 2H); 3.32 (m, 2H); 3.87 (m, 2H); 4.11 (m, 2H); 4.79 (s, 2H); 7.07-7.56 (m, 8H).
The compounds described in Examples 11-15 were prepared from alcohol 3 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 11.
Example 11
[3-(ll-chloro-8-oxa-l-thia-dibenzo[e, r]azulene-2-ylmethoxy)-propyl]-dimethyl- amine
To a solution of 3-dimethylaminopropylchloride hydrochloride (2.2 g, 0.014 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.25 g) and a toluene solution of alcohol 3 (0.19 g, 0.6 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 5 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.18 g) was isolated.
1H NMR (ppm, CDC13): 2.05-2.14 (m, 2H); 2.63 (s, 6H); 2.91 (t, 2H); 3.71 (t, 2H); 4.74 (s, 2H); 7.2-7.5 (m, 8H).
Example 12
[2-(ll-chloro-8-oxa-l-thia-dibenzo[e,A]azulene-2-yImethoxy)-ethyl]-dimethyl- amine
By the reaction of alcohol 3 (0.19 g, 0.6 mmole) and 2-dimethylaminoethylchloride hydrochloride (2.01 g, 0.014 mole), an oily product (0.2 g) was obtained.
1H NMR (ppm, CDC13): 2.46 (s, 6H); 2.80 (t, 2H); 3.78 (t, 2H); 4.76 (s, 2H); 7.19-7.5 (m, 8H).
Example 13 4-[2-(ll-chloro-8-oxa-l-thia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-morpholine
By the reaction of alcohol 3 (0.19 g, 0.6 mmole) and 4-(2-chloroethyl)-morpholine hydrochloride (2.8 g, 0.015 mole), an oily product (0.3 g) was obtained.
1H NMR (ppm, CDC13): 2.61-2.84 (m, 6H); 3.82 (m, 6H); 4.77 (s, 2H); 7.2-7,48 (m, 8H).
Example 14 l-[2-(ll-chloro-8-oxa-l-thia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]-piperidine
By the reaction of alcohol 3 (0.19 g, 0.6 mmole) and l-(2-chloroethyl)-piperidine monohydrochloride (2.76 g, 0.015 mole), an oily product (0.21 g) was obtained.
1H NMR (ppm, CDC13): 1.43 (m, 2H); 1.85 (m, 2H); 2.25 (m, 2H); 2.75 (m, 2H); 3.14 (m, 2H); 3.65 (m, 2H); 4.01-4.15 (m, 2H); 4.84 (s, 2H); 7.15-7.65 (m, 8H).
Example 15 l-[2-(ll-chloro-8-oxa-l-thia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-pyrrolidine
By the reaction of alcohol 3 (0.19 g, 0.6 mmole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (2.55 g, 0.015 mole), an oily product (0.25 g) was obtained.
1H NMR (ppm, CDC13): 1.8-2.2 (m, 8H); 2.9-3.25 (m, 2H); 3.98 (m, 2H); 4.8 (s, 2H); 7.19-7.45 (m, 8H).
The compounds described in Examples 16-20 were prepared from alcohol 4 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 16.
Example 16
[3-(ll-fluoro~8-oxa-l-thia~dibenzo[e, ι]azulene-2-yImethoxy)-propyI]- dimethylamine hydrochloride
To a solution of 3-dimethylaminopropylchloride hydrochloride (2.2 g, 0.014 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g) and a toluene solution of alcohol 4 (0.2 g, 0.63 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 4 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.14 g) was isolated.
Example 17
[2-(ll-fluoro-8-oxa-l-thia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-dimethyl- amine hydrochloride
By the reaction of alcohol 4 (0.2 g, 0.63 mmole) and 2-dimethylaminoethylchloride hydrochloride (2.01 g, 0.014 mole), an oily product (0.24 g) was obtained, which was converted into the hydrochloride, m.p. 178-179°C.
C, H, N, S analysis: C 61.53 (calc. 62.14); H 5.19 (calc. 5.21); N 3.72 (calc. 3.45); S 8.15 (calc. 7.90).
1H NMR (ppm, CDC13): 2.91 (d, 6H); 3.28 (m, 2H); 4.10 (m, 2H); 4.79 (s, 2H); 6.97- 7.5 (m, 8H); 12.75 (s, IH).
Example 18
4-[2-(ll-fluoro-8-oxa-l-thia-dibenzo[e,Λ]azuϊene-2-ylmethoxy)-ethyl]-morpholine hydrochloride
By the reaction of alcohol 4 (0.2 g, 0.63 mmole) and 4-(2-chloroethyl)-morpholine hydrochloride (2.6 g, 0.014 mole), an oily product (0.25 g) was obtained, which was converted into the hydrochloride, m.p. 207-208°C.
C, H, N, S analysis: C 61,28 (calc. 61.67); H 5.33 (calc. 5.18); N 3.36 (calc. 3.13); S 7.44 (calc. 7.16).
1H NMR (ppm, CDC13): 3.05 (m, 2H); 3.25 (m, 2H); 3.57 (d, 2H); 3.97 (d, 2H); 4.19 (m, 2H); 4.35 (m, 2H); 4.79 (s, 2H); 7.0-7.47 (m, 8H).
Example 19 l-[2-(ll-fluoro-8-oxa-l-thia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride
By the reaction of alcohol 4 (0.2 g, 0.63 mmole) and l-(2-chloroethyl)-piperidine monohydrochloride (2.6 g, 0.014 mole), an oily product (0.2 g) was obtained, which was converted into the hydrochloride, m.p. 122-124°C.
1H NMR (ppm, CDC13): 1.95 (m, 4H); 2.17 (m, 2H); 2.27 (m, 2H); 2.75 (m, 2H); 3.12 (m, 2H); 3.65 (d, 2H); 4.78 (s, 2H); 6.98-7,68 (m, 8H); 12.2 (s, IH).
Example 20 l-[2-(ll-fluoro-8-oxa-l-thia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride
By the reaction of alcohol 4 (0.2 g, 0.63 mmole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (2.4 g, 0.014 mole), an oily product (0.27 g) was obtained, which was converted into the hydrochloride, m.p. 210°C.
C, H, N, S analysis: C 63.02 (calc. 63.95); H 5.42 (calc. 5.37); N 3.48 (calc 3.24); S 7.62 (calc. 7.42).
1H NMR (ppm, CDC13): 2.09 ( , 2H); 2.17 (m, 2H); 2.94 (m, 2H); 3.31 (m, 2H); 3.85 (m, 2H); 4.10 (m, 2H); 4.79 (s, 2H); 6.97-7.48 (m, 8H); 12.3 (s, IH).
The compounds described in Examples 21-25 were prepared from alcohol 5 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 21.
Example 21
[3-(l,8-dithia-dibenzo[e,A]azulene-2-ylmethoxy)-propyl]-dimethylamine hydrochloride
To a solution of 3-dimethylaminopropylchloride hydrochloride (2.2 g, 0.012 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g, 0.65 mmole) and a toluene solution of alcohol 5 (0.33 g, 0.0011 mole) were added. The reaction mixture was heated under vigorous stirring and reflux for 5 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.32 g) was isolated. By the addition of concentrated hydrochloric acid into the cold ethanol solution of amine, a crystalline product was obtained.
C, H, N, S analysis: C 62.74 (calc. 63.21); H 5.83 (calc. 5.79); N 3.63 (calc. 3.35); S 15.51 (calc. 15.34).
1H NMR (ppm, CDC13): 2.20 (m, 2H); 2,80 (d, 6H); 3.17 (m, 2H); 3.72 (m, 2H); 4.73 (s, 2H); 7.11-7.63 (m, 9H); 12.27 (s, IH).
Example 22
[2-(l,8-dithia-dibenzo[e,A]azuIene-2-ylmethoxy)-ethyI]-dimethylamine hydrochloride
By the reaction of alcohol 5 (0.25 g, 0.84 mmole) and 2-dimethylaminoethylchloride hydrochloride (2.7 g, 0.019 mole), an oily product (0.22 g) was obtained, which was converted into the hydrochloride, m.p. 151°C .
1H NMR (ppm, CDC13): 2.90 (m, 6H); 3.28 (m, 2H); 4.12 (m, 2H); 4.80 (s, 2H); 7.23- 7.66 (m, 9H); 12.7 (s, IH).
Example 23
4-[2-(l,8-dithia-dibenzo[e,/ι]azulene-2-yImethoxy)-ethyI]-morpholine hydrochloride
By the reaction of alcohol 5 (0.25 g, 0.84 mmole) and 4-(2-chloroethyl)-morpholine hydrochloride (3.47 g, 0.019 mole), an oily product (0.3 g) was obtained, which was converted into the hydrochloride, m.p. 178-183°C.
C, H, N, S analysis: C 59,76 (calc. 61.93); H 5.30 (calc. 5.42); N 3.35 (calc. 3.14); S 13.89 (calc. 14.38).
1H NMR (ppm CDC13): 3.05 (m, 2H); 3.25 (m, 2H); 3.55 (m, 2H); 4.0 (m, 2H); 4.15- 4.38 (m, 4H); 4.7 (s, 2H); 7.22-7.65 (m, 9H); 13.25 (s, IH).
Example 24 l-[2-(l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride
By the reaction of alcohol 5 (0.25 g, 0.84 mmole) and l-(2-chloroethyι)-piρeridine monohydrochloride (3.3 g, 0.018 mole), an oily product (0.17 g) was obtained, which was converted into the hydrochloride, m.p. 173°C.
1H NMR (ppm, CDC13): 1.46 (m, 2H); 1.95 (m, 4H); 2.27 (m, 2H); 2.85 (m, 2H); 3.32 (m, 2H); 3.68 (m, 2H); 4.12 (m, 2H); 7.22-7.35 (m, 9H); 10.97 (s, IH).
Example 25 l-[2-(l,8-dithia-dibenzo[e,/ ]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride
By the reaction of alcohol 5 (0.25 g, 0.84 mmole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (3.1 g, 0.019 mole), an oily product (0.2 g) was obtained, which was converted into the hydrochloride.
The compounds described in Examples 26-30 were prepared from alcohol 6 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 26.
Example 26
[3-(ll-fluoro-l,8-dithia-dibenzo[e,Λ]azulene-2-ylmethoxy)-propyl]-dimethyI- amine hydrochloride
To a solution of 3-dimethylaminopropylchloride hydrochloride (1.8 g, 0.011 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g) and a toluene solution of alcohol 6 (0.25 g, 0.8 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 5 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.18 g) was isolated. By the addition of concentrated hydrochloric acid into the cold ethanol solution of amine, a crystalline product was obtained, m.p. 209-214°C.
1H NMR (ppm, CDC13): 2.30 (m, 2H); 2.88 (d, 6H); 3.24 (m, 2H); 3.80 (m, 2H); 4.82 (s, 2H); 7.08 (m, IH); 7.28-7.71 (m, 7H); 12.5 (s, IH).
Example 27
[2-(ll-fluoro-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride
By the reaction of alcohol 6 (0.21 g, 0.67 mmole) and 2-dimethylaminoethylchloride hydrochloride (1.5 g, 0.01 mole), an oily product (0.22 g) was obtained, which was converted into the hydrochloride, m.p. 151-155°C.
1H NMR (ppm, CDC13): 2.23 (s, 6H); 3.03 (m, 2H); 4.22 (m, 2H); 4.87 (s, 2H); 7.06- 7.12 (m, IH); 7.23-7.73 (m, 7H); 12.5 (s, IH).
Example 28
4-[2-(ll-fluoro-l,8-dithia-dibenzo[e, (]azulene-2-ylmethoxy)-ethyl]-morpholme hydrochloride
By the reaction of alcohol 6 (0.21 g, 0.67 mmole) and 4-(2-chloroethyl)-morpholine hydrochloride (1.9 g, 0.01 mole), an oily product (0.15 g) was obtained, which was converted into the hydrochloride, m.p. 168-170°C.
1H NMR (ppm, CDC13): 3.05 (m, 4H); 3.65 (m, 2H); 4.05 (m, 2H); 4.28 (m, 4H); 4.87 (s, 2H); 7.09 (m, IH); 7.23-7.74 (m, 7H); 13.25 (s, IH).
Example 29 l-[2-(ll-fluoro-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride
By the reaction of alcohol 6 (0.21 g, 0.67 mmole) and l-(2-chloroethyl)-piperidine monohydrochloride (1.9 g, 0.01 mole), an oily product (0.2 g) was obtained, which was converted into the hydrochloride, m.p. 214-216°C.
Example 30 l-[2-(ll-fluoro-l,8-dithia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride
By the reaction of alcohol 6 (0.21 g, 0.67 mmole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (1.8 g, 0.01 mole), an oily product (0.17 g) was obtained, which was converted into the hydrochloride, m.p. 202-205°C.
1H NMR (ppm, CDC13): 2.14 (m, 2H); 2.24 (m, 2H); 3.01 (m, 2H); 3.85 (m, 2H); 3.93 (m, 2H); 4.21 (m, 2H); 4.88 (s, 2H); 7.09 (m, IH); 7.24-7.69 (m, 7H); 12.7 (s, IH).
The compounds described in Examples 31-35 were prepared from alcohol 7 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 31.
Example 31
[3-(ll-chloro-l,8-dithia-dibenzo[e,Λ]azulene-2-ylmethoxy)-propyl]-dimethyl- amine hydrochloride
To a solution of 3-dimethylaminopropylchloride hydrochloride (1.7 g, 0.011 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g) and a toluene solution of alcohol 7 (0.25 g, 0.75 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 3 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.17 g) was isolated, which was converted into the hydrochloride, m.p. 199-200°C.
1H NMR (ppm, CDC13): 2.31 (m, 2H); 2.89 (d, 6H); 3.25 (m, 2H); 3.80 (m, 2H); 4.8 (s, 2H); 7.26-7.69 (m, 8H); 12.5 (s, IH).
Example 32
[2-(ll-chloro-l,8-dithia-dibenzo[e,Λ]azuIene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride
By the reaction of alcohol 7 (0.25 g, 0.75 mmole) and 2-dimethylaminoethylchloride hydrochloride (1.5 g, 0.011 mole), an oily product (0.2 g) was obtained, which was converted into the hydrochloride, m.p. 165-167°C.
1H NMR (ppm, CDC13): 2.98 (s, 6H); 3.35 (m, 2H); 4.2 (m, 2H); 4.87 (s, 2H); 7.29- 7.68 (m, 8H); 12.55 (s, IH).
Example 33
4-[2-(ll-chloro-l,8-dithia-dibenzo[e,Λ]azuIene-2-ylmethoxy)-ethyl]-morpholine hydrochloride
By the reaction of alcohol 7 (0.2 g, 0.61 mmole) and 4-(2-chloroethyl)-morpholine hydrochloride (1.9 g, 0.01 mole), an oily product (0.21 g) was obtained, which was converted into the hydrochloride, m.p. 190°C.
1H NMR (ppm, CDC13): 3.08 (m, 2H); 3.32 (m, 2H); 3.63 (m, 2H); 4.05 (m, 2H); 4.25 (m, 4H); 4.87 (s, 2H); 7.29-7,69 (m, 8H); 13.25 (s, IH).
Example 34 l-[2-(ll-chloro-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride
By the reaction of alcohol 7 (0.2 g, 0.61 mmole) and l-(2-chloroethyl)-piperidine monohydrochloride (1.9 g, 0.01 mole), an oily product (0.43 g) was obtained, which was converted into the hydrochloride, m.p. 184-185°C.
1H NMR (ppm, CDC13): 1.51 (m, 3H); 2.23 (m, 7H); 3.07 (m, 2H); 3.18 (m, 2H); 4.23 (m, 2H); 7.32-7.74 (m, 8H); 12.3 (s, IH).
Example 35 l-[2-(ll-chloro-l,8-dithia-dibenzo[e, r]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride
By the reaction of alcohol 7 (0.2 g, 0.61 mmole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (1.8 g, 0.01 mole), an oily product (0.27 g) was obtained, which was converted into the hydrochloride, m.p. 238°C.
1H NMR (ppm, CDC13): 2.14 (m, 2H); 2.29 (m, 2H); 3.01 (m, 2H); 3.38 (m, 2H); 3.93 (m, 2H); 4.25 (m, 2H); 4.88 (s, 2H); 7.28-7.69 (m, 8H); 12.7 (s, IH).
The compounds described in Examples 36-40 were prepared from alcohol 8 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 36.
Example 36
[3-(ll-bromo-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-propyl]-dimethyl- amine hydrochloride
To a solution of 3-dimethylaminopropylchloride hydrochloride (1.7 g, 0.011 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g) and a toluene solution of alcohol 8 (0.23 g, 0.61 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 3 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.25 g) was isolated, which was converted into the hydrochloride, m.p. 170-176°C.
1H NMR (ppm, CDC13): 2.28 (m, 2H); 2.88 (d, 6H); 3.25 (m, 2H); 3.79 (m, 2H); 4.81 (s, 2H); 7.28-7.71 (m, 8H); 12.5 (s, IH).
Example 37
[2-(ll-bromo-l,8-dithia-dibenzo[e,A]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride
By the reaction of alcohol 8 (0.23 g, 0.61 mmole) and 2-dimethylaminoethylchloride hydrochloride (1.5 g, 0.01 mole), an oily product (0.31 g) was obtained, which was converted into the hydrochloride, m.p. 147-150°C.
1H NMR (ppm, CDC13): 2.22 (s, 6H); 2.97 (m, 2H); 4.22 (m, 2H); 4.86 (s, 2H); 7.28- 7.72 (m, 8H); 12.25 (s, IH).
Example 38 4-[2-(ll-bromo-l,8-dithia-dibenzo[e,/f]azulene-2-ylmethoxy)-ethyl]-morpholine
By the reaction of alcohol 8 (0.23 g, 0.61 mmole) and 4-(2-chloroethyl)-morpholine hydrochloride (2.2 g, 0.012 mole), an oily product (0.11 g) was obtained.
Example 39 l-[2-(ll-bromo-l,8-dithia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]-piperidine
By the reaction of alcohol 8 (0.23 g, 0.61 mmole) and l-(2-chloroethyl)-piperidine monohydrochloride (2.2 g, 0.012 mole), an oily product (0.09 g) was obtained.
Example 40 l-[2-(ll-bromo-l,8-dithia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]-pyrrolidine
By the reaction of alcohol 8 (0.23 g, 0.61 mmole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (2.2 g, 0.012 mole), an oily product (0.17 g) was obtained.
1H NMR (ppm, CDC13): 2.02 (m, 4H); 3.05 (m, 6H); 3.96 (m, 2H); 4.81 (s, 2H), 7.23- 7.76 (m, 8H).
The compounds described in Examples 41-45 were prepared from alcohol 9 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 41.
Example 41
[3-(10-trifluoromethyl-l,8-dithia-dibenzo[e,A]azulene-2-ylmethoxy)-propyl]- dimethyl-amine
To a solution of 3-dimethylaminopropylchloride hydrochloride (1.1 g, 0.007 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g) and a toluene solution of alcohol 9 (0.18 g, 0.5 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 3 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.11 g) was isolated.
1H NMR (ppm, CDC13): 2.21 (m, 2H); 2.48 (s, 6H); 2.71 (m, 2H); 3.69 (t, 2H); 4.76 (s, 2H), 7.23-7.89 (m, 8H).
Example 42
Dimethyl-[2-(10-trifluoromethyl-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)- ethylj-amine hydrochloride
By the reaction of alcohol 9 (0.18 g, 0.5 mmole) and 2-dimethylaminoethylchloride hydrochloride (1 g, 0.007 mole), an oily product was obtained, which was converted into the hydrochloride (0.1 g).
1H NMR (ppm, CDC13): 2.94 (s, 6H); 3.32 (m, 2H); 4.18 (m, 2H); 4.85 (s, 2H); 7.29- 7.70 (m, 7H); 7.93 (s, IH); 12.85 (s, IH).
Example 43
4-[2-(10-trifluoromethyl-l,8-dithia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]- morpholine
By the reaction of alcohol 9 (0.18 g, 0.5 mmole) and 4-(2-chloroethyl)-morpholine hydrochloride (1.3 g, 0.007 mole), an oily product (0.20 g) was obtained.
1H NMR (ppm, CDC13): 2.55 (m, 7H); 3.58 (m, 2H); 3.74 (m, 3H); 4.79 (s, 2H); 7.24- 7.90 (m, 8H).
Example 44 l-[2-(10-trifluoromethyl-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]- piperidin hydrochloride
By the reaction of alcohol 9 (0.18 g, 0.5 mmole) and l-(2-chloroethyl)-piperidine monohydrochloride (1.3 g, 0.007 mole), an oily product (0.18 g) was obtained, which was converted into the hydrochloride.
1H NMR (ppm, CDC13): 1.85 (m, 2H); 2.75-3.17 (m, 6H); 3.23 (m, 2H); 3.88 (m, 4H); 4.81 (s, 2H); 7.25-7.90 (m, 8H); 12.3 (s, IH).
Example 45 l-[2-(10-trifluoromethyl-l,8-dithia-dibenzo[e,Λ]azuIene-2-ylmethoxy)-ethyl]- pyrrolidine hydrochloride
By the reaction of alcohol 9 (0.18 g, 0.5 mmole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (1.2 g, 0.007 mole), an oily product (0.1 g) was obtained, which was converted into the hydrochloride.
1H NMR (ppm, CDC13): 2.01 (m, 2H); 2.75 (m, 2H); 3.10 (m, 4H); 3.99 (m, 2H), 4.17 (m, 2H); 4.83 (s, 2H); 7.26-7.91 (m, 8H); 12.3 (s, IH).
The compounds described in Examples 46-49 were prepared from alcohol 10 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 46.
Example 46
[3-(10-chloro-l,8-dithia-dibenzo[e,A]azulene-2-ylmethoxy)-propyl]-dimethyl- amine
To a solution of 3-dimethylaminopropylchloride hydrochloride (1.1 g, 0.007 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g) and a toluene solution of alcohol 10 (0.16 g, 0.48 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 3 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.17 g) was isolated.
1H NMR (ppm, CDC13): 1.91 (m, 2H); 2.36 (s, 6H); 2.56 (m, 2H), 3.69 (t, 2H); 4.74 (s, 2H); 7.2-7.7 (m, 8H).
Example 47
[2-(10-chIoro-l,8-dithia-dibenzo[e,A]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride
By the reaction of alcohol 10 (0.16 g, 0.48 mmole) and 2-dimethylaminoethylchloride hydrochloride (0.98 g, 0.0068 mole), an oily product was obtained, which was converted into the hydrochloride (0.12 g).
1H NMR (ppm, CDC13): 2.36 (s, 6H); 2.65 (m, 2H); 3.73 (m, 2H); 4.78 (s, 2H); 7.2-7.7 (m, 8H); 7.93 (s, IH).
Example 48 l-[2-(10-chloro-l,8-dithia-dibenzo[e, t]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride
By the reaction of alcohol 10 (0.16 g, 0.48 mmole) and l-(2-chloroethyl)-piperidine monohydrochloride (1.25 g, 0.0067 mole), an oily product (0.11 g) was obtained, which was converted into the hydrochloride.
1H NMR (ppm, CDC13): 1.57 (m, 2H); 2.95-3.87 (m, 10H); 4.78 (s, 2H); 7.2-7. (m, 8H).
Example 49 l-[2-(10-chloro-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-pyrrolidine
By the reaction of alcohol 10 (0.16 g, 0.48 mmole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (1.15 g, 0.0067 mole), an oily product (0.14 g) was obtained.
1H NMR (ppm, CDC13): 1.87 (m, 4H); 2.76 (m, 4H); 2.88 (m, 2H); 3.86 (m, 2H); 4.78 (s, 2H); 7.2-7.65 (m, 8H).
The compounds described in Examples 50-54 were prepared from alcohol 11 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 50.
Example 50
[3-(10-bromo-l,8-dithia-dibenzo[e,/i]azulene-2-ylmethoxy)-propyl]-dimethyl- amine hydrochloride
To a solution of 3-dimethylaminopropylchloride hydrochloride (1.18 g, 0.0074 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g) and a
toluene solution of alcohol 11 (0.2 g, 0.53 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 3 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.17 g) was isolated, which was converted into the hydrochloride.
1H NMR (ppm, CDC13): 2.23 (m, 2H); 2.81 (d, 6H); 3.17 (m, 2H); 3.74 (m, 2H), 4.75 (s, 2H); 7.21-7.81 (m, 8H); 12.3 (s, IH).
Example 51
[2-(10-bromo-l,8-dithia-dibenzo[^,/ι]azulene-2-yImethoxy)-ethyl]-dimethyl-amine hydrochloride
By the reaction of alcohol 11 (0.2 g, 0.53 mmole) and 2-dimethylaminoethylchloride hydrochloride (1.18 g, 0.0074 mole), an oily product was obtained, which was converted into the hydrochloride (0.12 g).
1H NMR (ppm, CDC13): 2.91 (m, 6H); 3.27 (m, 2H); 4.15 (m, 2H); 4.80 (s, 2H); 7.23- 7.84 (m, 8H); 12.4 (s, IH).
Example 52 l-[2-(10-bromo-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride
By the reaction of alcohol 11 (0.2 g, 0.53 mmole) and l-(2-chloroethyl)-piperidine monohydrochloride (1.27 g, 0.0074 mole), an oily product (0.15 g) was obtained, which was converted into the hydrochloride.
1H NMR (CDC13): 1.38 (m, 2H); 1.85 (m, 2H); 2.17-2.36 ( , 2H); 2.76 (m, 2H), 3.12 (m, 2H); 3.17 (m, 2H); 4.18 (m, 2H); 4.78 (s, 2H); 7.25-7.90 (m, 8H); 12.3 (s, IH).
Example 53 l-[2-(10-bromo-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-pyrrolidine
By the reaction of alcohol 11 (0.2 g, 0.53 mmole) and l-(2-chloroethyl)-ρyrrolidine hydrochloride (1.37 g, 0.0074 mole), an oily product (0.09 g) was obtained.
1H NMR (CDC13): 1.69 (m, 4H); 2.62 (m, 4H); 2.69 (m, 2H); 3.81 (m, 2H); 4.78 (s, 2H); 7.22-7.85 (m, 8H).
Example 54
[2-(10-bromo-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-propyl]-dimethyI- amine hydrochloride
By the reaction of alcohol 11 (0.2 g, 0.53 mmole) and l-dimethylamino-2- propylchloride hydrochloride (1.18 g, 0.0074 mole), an oily product (0.12 g) was obtained, which was converted into the hydrochloride.
1H NMR (ppm, CDC13): 1.17 (d, 3H); 2.47 (s, 6H); 3.02 (m, IH); 3.68 (m, 2H); 4.77 (s, 2H); 7.1-7.85 (m, 8H).
The compounds described in Examples 55-57 were prepared from alcohol 12 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 55.
Example 55
[3-(9,ll-dimethyl-l,8-dithia-dibenzo[-?,Λ]azulene-2-yImethoxy)-propyl]-dimethyl- amine hydrochloride
To a solution of 3-dimethylaminopropylchloride hydrochloride (1.23 g, 0.0077 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g) and a toluene solution of alcohol 12 (0.18 g, 0.55 mmole) were added. The reaction mixture
was heated under vigorous stirring and reflux for 3 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product (0.13 g) was isolated, which was converted into the hydrochloride.
1H NMR (ppm, CDC13): 2.22 (m, 2H); 2.29 (s, 3H); 2.61 (s, 3H); 2.81 (s, 6H); 3.17 (m, 2H); 3.74 (m, 2H); 4.75 (s, 2H); 7.11-7.67 (m, 7H); 12.3 (s, IH).
Example 56
[2-(9,ll-dimethyl-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-dimethyl- amine hydrochloride
By the reaction of alcohol 12 (0.18 g, 0.55 mmole) and 2-dimethylaminoethylchloride hydrochloride (1.12 g, 0.0077 mole), an oily product was obtained, which was converted into the hydrochloride (0.09 g).
1H NMR (ppm, CDC13): 2.29 (s, 3H); 2.61 (s, 3H); 2.91 (m, 6H); 3.28 (m, 2H); 4.13 (m, 2H); 4.80 (s, 2H); 7.12-7.67 (m, 7H); 12.3 (s, IH).
Example 57 l-[2-(9,ll-dimethyl-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]- pyrrolidine hydrochloride
By the reaction of alcohol 12 (0.18 g, 0.55 mmole) and l-(2-chloroethyl)pyrrolidine hydrochloride (1.32 g, 0.0077 mole), an oily product (0.11 g) was obtained.
1H NMR (ppm, CDC13): 2.07 (m, 2H); 2.24 (m, 2H); 2.69 (m, 2H); 2.29 (s, 3H), 2.61 (s, 3H); 2.95 (m, 2H); 3.31 (m, 2H); 3.85 (m, 2H); 4.12 (m, 2H); 4.80 (s, 2H); 7.22- 7.85 (m, 7H); 12.5 (s, 2H).
The compounds described in Examples 58-62 were prepared from alcohol 13 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 58.
Example 58
[3-(10,ll-dichloro-l,8-dithia-dibenzo[e,Λ]azulene-2-ylmethoxy)-propyl]-dimethyl- amine hydrochloride
To a solution of 3-dimethylaminopropylchloride hydrochloride (1.5 g, 0.0095 mole) in 50%) sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g) and a toluene solution of alcohol 13 (0.2 g, 0.68 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 3 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product was isolated, which was converted into the hydrochloride (0.075 g).
1H NMR (ppm, CDC13): 2.25 (m, 2H); 2.83~(s, 6H); 3.19 (m, 2H); 3.75 (m, 2H); 4.76 (s, 2H); 7.22-7.74 (m, 7H); 12.35 (s, IH).
Example 59
[2-(10,ll-dichloro-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-dimethyl- amine hydrochloride
By the reaction of alcohol 13 (0.2 g, 0.68 mmole) and 2-dimethylaminoethylchloride hydrochloride (1.4 g, 0.0095 mole), an oily product was obtained, which was converted into the hydrochloride (0.08 g).
1H NMR (ppm, CDC13): 2.97 (s, 6H); 3.47 (m, 2H); 4.15 (m, 2H); 4.81 (s, 2H); 7.23- 7.74 (m, 7H); 12.3 (s, IH).
Example 60
4-[2-(10,ll-dichloro-l,8-dithia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]- morpholine hydrochloride
By the reaction of alcohol 13 (0.2 g, 0.68 mmole) and 4-(2-chloroethyl)-morpholine hydrochloride (1.7 g, 0.0095 mole), an oily product was obtained, which was converted into the hydrochloride (0.11 g).
1H NMR (ppm, CDC13): 3.02 (m, 2H); 3.27 (m, 2H); 3.60 (m, 2H); 3.99 (m, 2H); 4.16-4.36 (m, 4H); 4.80 (s, 2H); 7.22-7.74 (m, 7H); 12.55 (s, IH).
Example 61 l-[2-(10,ll-dichIoro-l,8-dithia-dibenzo[e,Λ]azu!ene-2-ylmethoxy)-ethyl]- piperidine hydrochloride
By the reaction of alcohol 13 (0.2 g, 0.68 mmole) and l-(2-chloroethyl)-piperidine monohydrochloride (1.7 g, 0.0095 mole), an oily product was obtained, which was converted into the hydrochloride (0.045 g).
1H NMR (ppm, CDC13): 1.42 (m, 2H); 1.87 (m, 2H); 2.23-2.37 (m, 2H); 2.78 (m, 2H); 3.22 (m, 2H); 3.65 (m, 2H); 4.19 (m, 2H); 4.79 (s, 2H); 7.22-7.74 (m, 7H); 12.1 (s, IH).
Example 62 l-[2-(10,ll-dichloro-l,8-dithia-dibenzo[^,/ ]azulene-2-ylmethoxy)-ethyl]- pyrrolidine hydrochloride
By the reaction of alcohol 13 (0.2 g, 0.68 mmole) and l-(2-chloroethyl)-pyrrolidine hydrochloride (1.62 g, 0.0095 mole), an oily product was obtained, which was converted into the hydrochloride (0.09 g).
1H NMR (ppm, CDC13): 2.02-2.25 (m, 4H); 2.94 (m, 2H); 3.32 (m, 2H); 3.88 (m, 2H); 4.15 (m, 2H); 4.81 (s, 2H); 7.22-7.73 (m, 7H); 12.4 (s, IH).
The compounds described in Examples 63-64 were prepared from alcohol 14 and the corresponding chloroalkyldialkylamine hydrochloride according to the process described in Example 63.
Example 63
[3-(9-chloro-ll-fluoro-l,8-dithia-dibenzo[e, (]azulene-2-ylmethoxy)-propyl]- dimethyl-amine hydrochloride
To a solution of 3-dimethylaminopropylchloride hydrochloride (1.22 g, 0.0077 mole) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride (0.15 g) and a toluene solution of alcohol 14 (0.19 g, 0.55 mmole) were added. The reaction mixture was heated under vigorous stirring and reflux for 3 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product was isolated, which was converted into the hydrochloride (0.095 g).
1H NMR (ppm, CDC13): 2.24 (m, 2H); 2.82 (s, 6H); 3.18 (m, 2H); 3.74 (m, 2H); 4.77 (s, 2H); 7.11-7.73 (m, 7H); 12.35 (s, IH).
Example 64
[2-(9-chloro-ll-fluoro-l,8-dithia-dibenzo[^,/ι]azulene-2-ylmethoxy)-ethyl]- dimethyl-amine hydrochloride
By the reaction of alcohol 14 (0.19 g, 0.55 mmole) and 2-dimethylaminoethylchloride hydrochloride (1.12 g, 0.0077 mole), an oily product was obtained, which was converted into the hydrochloride (0.07 g).
1H NMR (ppm, CDC13): 2.97 (m, 6H); 3.37 (m, 2H), 4.2 (m, 2H); 4.87 (s, 2H); 7.08- 7.79 (m, 7H); 12.5 (s, IH).
Example B Preparation of aldehydes
To a dichloromethane solution of alcohol (0.002 mole/15 ml) (Table 1) dipyridine chrome (VI) oxide (pyridyl-dichromate, PDC, 0.003 mole) was added. The reaction mixture was stirred at room temperature within a period of 3 to 18 hours. To the reaction mixture diethyl ether (20 ml) was added and the diluted reaction mixture was purified on a florisil column. The obtained product was additionally purified on a silica gel column.
According to the process of Example B, starting from appropriate alcohols (Table 1, compounds 4 and 3) there were obtained dibenzoazulene derivatives, wherein Ri, R3, R , R5, R , R7, R8 and R9 = H, Rι0 = CHO and R2, R3, R4 and X have the meanings shown in Table 2.
Table 2
The following compounds described in Examples 65-68 were prepared from aldehydes disclosed in Table 2 and the corresponding phosphorous-ylides according to the process described in Example 65.
Example 65
3-(ll-fluoro-8-oxa-l-thia-dibenzo[e, ι]azulene-2-yι)-acrylic acid methyl ester
To a solution of aldehyde 15 (0.07 g, 0.0024 mole) in toluene (10 ml), ylide III (methyl(triphenyl)phosphoranylide acetate) (0.08 g, 0.0024 mole) was added. The reaction mixture was stirred under reflux for 4 hours and then it was cooled to room temperature, evaporated to dryness and extracted with ethyl acetate. After purification by column chromatography a crystalline product (0.03 g) was isolated.
1H NMR (ppm, CDC13): 3.82 (s, 3H); 6.31 (d, IH, J=15.67 Hz); 7.01-7.07 (m, 2H); 7.12-7.17 (m, IH); 7.21-7.46 (m, 4H); 7.48 (s, IH); 7.80 (d, IH, J=15.69 Hz).
Example 66
3-(ll-chloro-8-oxa-l-thia-dibenzo[e,/ι]azulene-2-yl)-acryIic acid methyl ester
To a solution of aldehyde 16 (0.15 g, 0.48 mmole) in tetrahydrofuran (20 ml), ylide III (0.24 g, 0.72 mmole) was added. The reaction mixture was stirred under reflux for 4 hours and then it was cooled to room temperature, evaporated to dryness and extracted with ethyl acetate. After purification by column chromatography a crystalline product (0.08 g) was isolated.
1H NMR (ppm, CDC13): 3.82 (s, 3H); 6.30 (d, IH, J-15.68 Hz); 7.08-7.57 (m, 8H); 7.80 (d, IH, J=15.68 Hz).
Example 67 4-(ll-fluoro-8-oxa-l-thia-dibenzo[e,/ι]azulene-2-yl)-but-3-ene-2-one
To a solution of aldehyde 15 (0.14 g, 0.47 mmole) in toluene (10 ml), ylide IV (acetylmethylentriphenylphosphoran) (0.15 g, 0.47 mmole) was added. The reaction mixture was stirred under reflux for 4 hours and then it was cooled to room temperature, evaporated to dryness and extracted with ethyl acetate. After purification by column chromatography a crystalline product (0.08 g) was isolated.
1H NMR (ppm, CDC13): 2.35 (s, 3H); 6.60 (d, IH, J=15.85 Hz); 7.02-7.08 (m, 2H); 7.14-7.17 (m, IH); 7.22-7.48 (m, 4H); 7.52 (s, IH); 7.65 (d, IH, J=15.86 Hz).
Example 68 4-(ll-chloro-8-oxa-l-thia-dibenzo[e,/ι]azulene-2-yl)-but-3-ene-2-one
To a solution of aldehyde 16 (0.15 g, 0.48 mmole) in tetrahydrofuran (10 ml), ylide IV (0.15 g, 0.47 mmole) was added. The reaction mixture was stirred under reflux for 4 hours and then it was cooled to room temperature, evaporated to dryness and extracted with ethyl acetate. After purification by column chromatography a crystalline product (0.08 g) was isolated.
1H NMR (ppm, CDC13): 2.39 (s, 3H); 6.61 (d, IH, J 5.87 Hz); 7.01-7.60 (m, 8H); 7.65 (d, lH, J=15.86 Hz).
Example 69 3-(ll-fluoro-8-oxa-l-thia-dibenzo[e,/ι]azulene-2-yl)-acrylic acid
The hydrolysis of the ester prepared as described in Example 65 (0.03 g, 0.085 mmole) was performed with 2 M KOH (reflux, 2 to 5 hours) and by acidifying the reaction mixture with concentrated HCl. The obtained crystalline product was filtered off and washed with water (0.02 g).
1H NMR (ppm, CDC13): 6.3 (d, IH); 7.02-7.09 (m, 2H); 7.12-7.17 (m, IH); 7.22-7.48 (m, 4H); 7.53 (s, IH); 7.9 (d, IH).
Example 70
3-(l l-fluoro-8-oxa-l-thia-dibenzo [e,h] azulene-2-yl)-propionic acid
To an ethanol solution (10 ml) of the acid prepared in Example 66, 5% Pd/C (5 mg) moistened with water (50%) was added. The reaction mixture was stirred at room
temperature in hydrogen atmosphere at the pressure of 300 kPa. After the filtration of the catalyst and the evaporation of the solvent a product was obtained, which was purified by column chromatography on a silica gel column.
1H NMR (CDC13): 2.83 (t, 2H); 3.23 (t, 2H); 6.93-7.45 (m, 7H).
Claims (24)
1. Dibenzoazulene derivatives, their pharmacologically acceptable salts and solvates represented by formula I
characterized in that
X can represent CH2 or a heteroatom such as O, S, S^O), S(=0)2 or NRi3, wherein Rι3 means hydrogen, Cι.6 alkyl, Cι-6 alkylcarbonyl, arylcarbonyl, Cι-6 alkylsulfonyl or arylsulfonyl and Ri, R2, R3, R4, R5, R^, R7, Rg, R9 independently from each other represent substituents, which can be hydrogen, halogens (fluorine, chlorine or bromine); or C1-C7 alkyls, alkenyls, aryls or heteroaryls; or can represent different groups: halomethyl, hydroxy, C1-C7 alkoxy or aryloxy, C1-C7 alkylthio or arylthio, Ci- C7 alkylsulfonyl, ciano, amino, mono- and di-C C7 substituted amines, derivatives of carboxylic group (C1-C7 carboxylic acids and their anhydrides, C1-C7 unsubstituted, mono-, di-substituted amides, C1-C7 alkyl or aryl esters), C C7 derivatives of carbonyl group (C1-C7 alkyl or aryl carbonyls), and Rι0 can represent substituents such as: C2- C15 alkyls, C2-Cι5 alkenyls, C2-Cι5 alkinyls, aryls or heteroaryls, C1-C15 haloalkyls, Ci- C15 hydroxyalkyls, C1-C15 alkyloxy, C1-C15 alkylthio, C3-Cι5 alkylcarbonyls, C2-Cι5 alkylcarboxylic acid, C2-Cι5 alkylsters, C1-C15 alkylsulfonyls, C1-C15 alkylarylsulfonyls, arysulfonyls and C1-C15 alkylamines represented by the general formula -(CH2)n-A wherein n means 1-15, and one or more methylene groups that can be substituted with an oxygen or sulfur atom, and
A represents a five- or six-membered, saturated or unsaturated ring with one, two or three heteroatoms, or wherein Rn and Rι independently from each other represent hydrogen, Cι-C7 alkyl, alkenyl, alkinyl, aryl or heteroaryl, or a heterocycle with 1-3 heteroatoms.
2. A compound and salt according to claim 1, characterized in that X represents -S- or -0-.
3. A compound and salt according to claim 2, characterized in that Rι0 represents -CH20(CH2)n-A.
4. A compound and salt according to claim 3, characterized in that A represents morpholine-4-yl.
5. A compound and salt according to claim 3, characterized in that A represents piperidine-1-yl.
6. A compound and salt according to claim 3, characterized in that A represents pyrrolidine-1-yl.
7. A compound and salt according to claim 3, characterized in that A represents
8. A compound and salt according to claim 7, characterized in that Rn and Ru simultaneously represent -CH3 or -CH2CH3.
9. A compound and salt according to claim 2, characterized in that R10 represents -CF OH.
10. A compound and salt according to claim 2, characterized in that Rι0 represents -CHO.
11. A compound and salt according to claim 2, characterized in that Rio represents -CH=CH(CH2)nCOORι3, wherein n can be from 0 to 12 and RJ3 has a meaning as previously defined.
12. A compound and salt according to claim 2, characterized in that R10 represents -(CH2)nCOORι3, wherein n can be from 0 to 13 and Rι3 has a meaning as previously defined.
13. A compound and salt according to claim 11, characterized in that n is 0 and Rι3 is -H or -CH3.
14. A compound and salt according to claims 2-9, characterized in that R2 is F, Cl, Br or -CH3.
15. A compound and salt according to claims 2-9, characterized in that R3 is F, Cl, Br, -CF3 or -CH3.
16. A compound and salt according to claims 2-9, characterized in that R4 is F, Cl or -CH3.
17. Process for the preparation of dibenzoazulene derivatives represented by the formula (ii), wherein all radicals and symbols have the meanings as defined in claim 9, characterized in that a hydride reduction of an ester of the formula (i), wherein all radicals and symbols have the previously defined meanings, is performed in suitable nonpolar solvents (preferably aliphatic ethers) at a temperature from 0 to 60°C within a period of 1 to 5 hours, whereupon an isolation and purification ofthe thus obtained alcohol compounds by recrystallization or column chromatography can be performed.
18. Process for the preparation of dibenzoazulenes represented by the formula (iii), wherein all radicals and symbols have the meanings as defined in claim 10, characterized in that alcohols of general formula I, wherein all radicals and symbols have the meanings as defined in claim 9, are subjected to an oxidation with pyridinyl- dichromate or pyridinyl-chlorochromate, the reaction in dichloromethane being performed at room temperature within a period of 1 to 2 hours, whereupon an isolation and purification of the thus obtained aldehyde compounds can be perfonned by column chromatography.
19. A process for the preparation of a compound ofthe general formula I, wherein all radicals and symbols have the meanings as defined in claim 3, characterized in that an alcohol ofthe formula (ii), wherein all radicals and symbols have meanings as defined in claim 9, is reacted with a compound ofthe formula II
Cl-(CH2)n-A II
wherein symbols n and A have meanings as previously defined, the reaction being perfonned at a temperature from 20 to 100°C within a period of 1 to 24 hours under the conditions of phase-transfer catalysis in a two-phase alkaline medium (preferably 50% NaOH-toluene) and in the presence of a phase-transfer catalyst (preferably benzyl-triethyl-ammonium-chloride, benzyl-triethyl-ammonium-bromide, cetyl- trimethyl-bromide), and after the treatment of the reaction mixture the obtained product is isolated by recrystallization or chromatography on a silica gel column.
20. A process for the preparation of a compound of a formula I, wherein all radicals and symbols have the meanings as defined in claim 11, characterized in that an aldehyde of a general formula (iii), wherein all radicals and symbols have the meanings as defined in claim 10, is reacted with a triphenylphosphorous reagent ofthe formula III
Ph3P+CH-(CH)2)nCOOCH3 III
the reaction being performed in a suitable dry solvent at reflux temperature of the solvent within a period of 1 to 24 hours, and after the treatment ofthe reaction mixture the obtained ester is isolated, purified by recrystallization or chromatography on silica gel column and hydrolyzed by refluxing in 20% KOH for a period of 3 hours and then the product is isolated by acidifying with HCl and filtration.
21. A process for the preparation of a compound ofthe general formula I, wherein all radicals and symbols have the meanings as defined in claim 1, characterized in that an aldehyde ofthe general formula I, wherein all radicals and symbols have the meanings as defined in claim 10, is reacted with a triphenylphosphorous reagent of the formula IV
Ph3P+CH-(CH)2)nCOCH3 IV
the reaction being performed in a suitable dry solvent at reflux temperature of the solvent within a period of 1 to 24 hours, and after the treatment ofthe reaction mixture the obtained methyl ketone is isolated and purified by recrystallization or chromatography on a silica gel column.
22. A process for the preparation of a compound ofthe general formula I, wherein all radicals and symbols have meanings as defined in claim 12, characterized in that an alkene compound defined in claim 11, wherein all radicals and symbols have the meanings as defined in claim 11, is subjected to catalytic hydrogenation in the presence of a catalyst that may be paladium on active charcoal, rhodium or platinum (IV) oxide in a suitable organic solvent under a hydrogen pressure of 100 kPa to 300 kPa within a period of 2 to 6 hours and then the product is purified by chromatography on a silica gel column.
23. Compounds: dimethyl-[3-(8-oxa-l-thia-dibenzo[e,A]azulene-2-ylmethoxy)-propyl]-amine hydrochloride, dimethyl- [2-(8-oxa- 1 -thia-dibenzo[e, /z]azulene-2-ylmethoxy)-ethyl]-amine hydrochloride,
4-[2-(8-oxa-l-thia-dibenzo[e, z]azulene-2-ylmethoxy)-ethyl]-mo holine hydrochloride,
1 - [2-(8-oxa- 1 -thia-dibenzo [e, h] azulene-2-y lmethoxy)-ethy 1] -piperidine hydrochloride,
1 - [2-(8-oxa- 1 -thia-dibenzo [e, h] azulene-2-y lmethoxy)-ethy l]-pyrrolidine hydrochloride,
[3-(9-chloro-8-oxa- 1 -thia-dibenzo [e, /ϊ]azulene-2-yhnethoxy)-propyl]-dimethyl-amine,
[2-(9-chloro- 8-oxa- 1 -thia-dibenzo [e, h] azulene-2-y lmethoxy)-ethy 1] -dimethy 1-amine,
4-[2-(9-chloro-8-oxa-l-thia-dibenzo[e, z]azulene-2-ylmethoxy)-ethyl]-morpholine, l-[2-(9-chloro-8-oxa-l-thia-dibenzo[e,/?]azulene-2-ylmethoxy)-ethyl]-piperidine, l-[2-(9-chloro-8-oxa-l-thia-dibenzo[e,Λ]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,
[3-(l l-chloro-8-oxa-l-thia-dibenzo[e,A]azulene-2-ylmethoxy)-propyl]-dimethyl- amine,
[2-( 11 -chloro- 8-oxa- 1 -thia-dibenzo[e, h] azulene-2-y lmethoxy)-ethy 1] -dimethy 1-amine,
4-[2-(l l-chloro-8-oxa-l-thia-dibenzo[e,A]azulene-2-ylmethoxy)-ethyl]-morpholine, l-[2-(l l-chloro-8-oxa-l-thia-dibenzo[e, z]azulene-2-ylmethoxy)-ethyl]-piperidine,
1 - [2-( 11 -chloro- 8-oxa- 1 -thia-dibenzo [e, h] azulene-2-y lmethoxy)-ethy l]-pyrrolidine,
[3 -( 11 -fluoro- 8-oxa- 1 -thia-dibenzo [e, h] azulene-2-y lmethoxy)-propy l]-dimethyl-amine hydrochloride,
[2-(l l-fluoro-8-oxa-l-thia-dibenzo[e,t7]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,
4-[2-(l l-fluoro-8-oxa-l-thia-dibenzo[e, t]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride, l-[2-(l l-fluoro-8-oxa-l-thia-dibenzo[e,A]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride, l-[2-(l l-fluoro-8-oxa-l-thia-dibenzo[e, t]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,
[3-(l,8-dithia-dibenzo[e, 2]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,
[2-(l,8-dithia-dibenzo[e, z]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,
4-[2-(l,8-dithia-dibenzo[e, 2]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride, l-[2-(l,8-dithia-dibenzo[e,/z]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride, l-[2-(l,8-dithia-dibenzo[e, t]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,
[3 -( 11 -fluoro- 1 ,8-dithia-dibenzo[e, /z]azulene-2-ylmethoxy)-propy l]-dimethy 1-amine hydrochloride,
[2-(l l-fluoro-l,8-dithia-dibenzo[e, z]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,
4-[2-(l l-fluoro-l,8-dithia-dibenzo[e,/7]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,
1 - [2-( 11 -fluoro- 1 , 8-dithia-dibenzo [e, z]azulene-2-y lmethoxy)-ethy 1] -piperidine hydrochloride,
1 - [2-( 11 -fluoro- 1 , 8-dithia-dibenzo [e, h] azulene-2-y lmethoxy)-ethy l]-pyrrolidine hydrochloride,
[3-(l l-chloro-l,8-dithia-dibenzo[e,A]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,
[2-( 11 -chloro- 1 , 8-dithia-dibenzo [e, h] azulene-2-y lmethoxy)-ethy 1] -dimethy 1-amine hydrochloride,
4-[2-(l 1 -chloro- 1 ,8-dithia-dibenzo[e, / zulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,
1 -[2-( 11 -chloro- 1 ,8-dithia-dibenzo[e, /z]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,
1 - [2-( 11 -chloro- 1 , 8-dithia-dibenzo[e, h] azulene-2-y lmethoxy)-ethy l]-pyrrolidine hydrochloride, [3-(l l-bromo-l,8-dithia-dibenzo[e, 2]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,
[2-(l l-bromo-l,8-dithia-dibenzo[e, ϊ]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride,
4-[2-(ll-bromo-l,8-dithia-dibenzo[e, z]azulene-2-ylmethoxy)-ethyl]-morpholine, l-[2-(l l-bromo-l,8-dithia-dibenzo[e,/ι]azulene-2-ylmethoxy)-ethyl]-piperidine, l-[2-(l l-bromo-l,8-dithia-dibenzo[e, z]azulene-2-ylmethoxy)-ethyl]-pyrrolidine,
[3 -( 10-trifluoromethyl- 1 ,8-dithia-dibenzo[e, zjazulene-2-ylmethoxy)-propyl]-dimethyl- amine, dimethyl- [2-( 10-trifluoromethyl- 1 , 8-dithia-dibenzo [e, A]azulene-2-ylmethoxy)-ethyιj- amine hydrochloride,
4-[2-(10-trifluoromethyl-l,8-dithia-dibenzo[e, 2]azulene-2-ylmethoxy)-ethyl]- morpholine, l-[2-(10-trifluoromethyl-l,8-dithia-dibenzo[e, t]azulene-2-ylmethoxy)-ethyl]- piperidine hydrochloride,
1 - [2-( 10-trifluoromethyl- 1 , 8-dithia-dibenzo[e, /t]azulene-2-ylmethoxy)-ethyl] - pyrrolidine hydrochloride,
[3-(10-chloro-l,8-dithia-dibenzo[e,A]azulene-2-ylmethoxy)-propyl]-dimethyl-amine,
[2-(10-chloro-l,8-dithia-dibenzo[e,A]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine hydrochloride, l-[2-(10-chloro-l,8-dithia-dibenzo[e,A]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,
1 - [2-( 10-chloro- 1 , 8-dithia-dibenzo [e, h] azulene-2-y lmethoxy)-ethy 1] -pyrrolidine,
[3 -( 10-bromo- 1 , 8-dithia-dibenzo[e, h] azulene-2-y lmethoxy)-ρropyl] -dimethy 1-amine hydrochloride,
[2-( 10-bromo- 1 ,8-dithia-dibenzo[e, A]azulene-2-ylmethoxy)-ethyl]-dimethy 1-amine hydrochloride,
1 - [2-( 10-bromo- 1 , 8-dithia-dibenzo[e, h] azulene-2-y lmethoxy)-ethy 1] -piperidine hydrochloride,
1 - [2-( 10-bromo- 1 , 8-dithia-dibenzo [e, h] azulene-2-y lmethoxy)-ethy 1] -pyrrolidine, [2-(10-bromo-l,8-dithia-dibenzo[e, z]azulene-2-ylmethoxy)-propyl]-dimethyl-amine hydrochloride,
[3-(9, 11 -dimethyl- 1 , 8-dithia-dibenzo [e, A]azulene-2-ylmethoxy)-propyl]-dimethyl- amine hydrochloride,
[2-(9, 11 -dimethyl- 1 , 8-dithia-dibenzo[e, Λ]azulene-2-ylmethoxy)-ethyl]-dimethy 1-amine hydrochloride,
1 - [2-(9, 11 -dimethyl- 1 , 8-dithia-dibenzo[e, h] azulene-2-y lmethoxy)-ethy 1] -pyrrolidine hydrochloride,
[3 -( 10, 11 -dichloro- 1 , 8-dithia-dibenzo [e, /z]azulene-2-y lmethoxy)-propy 1] -dimethy 1- amine hydrochloride,
[2-( 10, 11 -dichloro- 1 ,8-dithia-dibenzo[e, Λ]azulene-2-ylmethoxy)-ethyl]-dimethyl- amine hydrochloride,
4-[2-(10,ll-dichloro-l,8-dithia-dibenzo[e, z]azulene-2-ylmethoxy)-ethyl]-morpholine hydrochloride,
1 -[2-( 10,11 -dichloro- 1 ,8-dithia-dibenzo[e, t]azulene-2-ylmethoxy)-ethyl]-piperidine hydrochloride,
1 - [2-( 10,11 -dichloro- 1 , 8-dithia-dibenzo [e, A]azulene-2-ylmethoxy)-ethyl]-pyrrolidine hydrochloride,
[3 -(9-chloro- 11 -fluoro- 1 , 8-dithia-dibenzo[e, h] azulene-2-y lmethoxy)-propy 1] - dimethyl-amine hydrochloride,
[2-(9-chloro- 11 -fluoro- 1 , 8-dithia-dibenzo[e, h] azulene-2-y lmethoxy)-ethy 1] -dimethy 1- amine hydrochloride,
3-(l l-fluoro-8-oxa-l-thia-dibenzo[e, t]azulene-2-yl)-acrylic acid methyl ester,
3-(l l-chloro-8-oxa-l-thia-dibenzo[e,A]azulene-2-yl)-acrylic acid methyl ester,
4-(l l-fluoro-8-oxa-l-thia-dibenzo[e,A]azulene-2-yl)-but-3-ene-2-one,
4-(l l-chloro-8-oxa-l-thia-dibenzo[e,A]azulene-2-yl)-but-3-ene-2-one,
3-(l l-fluoro-8-oxa-l-thia-dibenzo[e, t]azulene-2-yl)-acrylic acid,
3-(l l-fluoro-8-oxa-l-thia-dibenzo[e,A]azulene-2-yl)-propionic acid.
24. Use of compounds according to claims 1 to 16 as inhibitors of production of cytokines or inflammation mediators in the treatment or prophylaxis of any pathological condition or disease induced by excessive unregulated production of cytokines or inflammation mediators, whereat non-toxic doses of suitable pharmaceutical preparations can be administered orally, parenterally or topically.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HR20000310A HRP20000310A2 (en) | 2000-05-17 | 2000-05-17 | New dibenzoazulene compounds as tumor necrosis factor inhibitors |
| HRP20000310A | 2000-05-17 | ||
| PCT/HR2001/000027 WO2001087890A1 (en) | 2000-05-17 | 2001-05-16 | Thienodibenzoazulene compounds as tumor necrosis factor inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2001256560A1 true AU2001256560A1 (en) | 2002-02-14 |
| AU2001256560B2 AU2001256560B2 (en) | 2005-10-06 |
Family
ID=10947110
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU5656001A Pending AU5656001A (en) | 2000-05-17 | 2001-05-16 | Thienodibenzoazulene compounds as tumor necrosis factor inhibitors |
| AU2001256560A Ceased AU2001256560B2 (en) | 2000-05-17 | 2001-05-16 | Thienodibenzoazulene compounds as tumor necrosis factor inhibitors |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU5656001A Pending AU5656001A (en) | 2000-05-17 | 2001-05-16 | Thienodibenzoazulene compounds as tumor necrosis factor inhibitors |
Country Status (36)
| Country | Link |
|---|---|
| US (2) | US6897211B2 (en) |
| EP (1) | EP1284977B1 (en) |
| JP (1) | JP2003533528A (en) |
| KR (1) | KR100823064B1 (en) |
| CN (1) | CN1194976C (en) |
| AR (1) | AR030562A1 (en) |
| AT (1) | ATE434619T1 (en) |
| AU (2) | AU5656001A (en) |
| BG (1) | BG65967B1 (en) |
| BR (1) | BR0111202A (en) |
| CA (1) | CA2409090C (en) |
| CR (1) | CR6860A (en) |
| CY (1) | CY1109328T1 (en) |
| CZ (1) | CZ301770B6 (en) |
| DE (1) | DE60139070D1 (en) |
| DK (1) | DK1284977T3 (en) |
| DZ (1) | DZ3357A1 (en) |
| EA (1) | EA006069B1 (en) |
| EE (1) | EE200200636A (en) |
| ES (1) | ES2328335T3 (en) |
| GE (1) | GEP20043304B (en) |
| HR (1) | HRP20000310A2 (en) |
| HU (1) | HUP0302295A3 (en) |
| IL (1) | IL152809A0 (en) |
| IS (1) | IS6621A (en) |
| MA (1) | MA27125A1 (en) |
| MX (1) | MXPA02011269A (en) |
| NO (1) | NO20025510L (en) |
| NZ (1) | NZ522553A (en) |
| PL (1) | PL204849B1 (en) |
| PT (1) | PT1284977E (en) |
| RS (1) | RS50893B (en) |
| SI (1) | SI1284977T1 (en) |
| SK (1) | SK17702002A3 (en) |
| WO (1) | WO2001087890A1 (en) |
| ZA (1) | ZA200209180B (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HRP20020305A8 (en) | 2002-04-10 | 2009-03-31 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | 2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
| HRP20020304B1 (en) * | 2002-04-10 | 2008-04-30 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | 1-oxa-3-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the production thereof |
| HRP20020303B8 (en) | 2002-04-10 | 2009-03-31 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | Benzonaphthoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
| HRP20020441A2 (en) * | 2002-05-21 | 2003-12-31 | Pliva D D | 1-oxa-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediate for preparation thereof |
| HRP20020440B1 (en) | 2002-05-21 | 2008-02-29 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | 1-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof |
| HRP20020452A2 (en) | 2002-05-23 | 2004-02-29 | Pliva D D | 1,2-diaza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof |
| HRP20020451A2 (en) * | 2002-05-23 | 2003-12-31 | Pliva D D | 1-tia-3-aza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof |
| HRP20020453A2 (en) | 2002-05-23 | 2003-12-31 | Pliva D D | 1,3-diaza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediate for preparation thereof |
| HRP20030160A2 (en) * | 2003-03-06 | 2005-04-30 | Pliva-Istra�iva�ki institut d.o.o. | 1-thiadibenzoazulene derivatives and biological action thereof |
| HRP20030324A2 (en) | 2003-04-24 | 2005-02-28 | Pliva-Istra�iva�ki institut d.o.o. | Compounds of antiinflammatory effect |
| EP1706394B1 (en) * | 2003-11-12 | 2014-12-17 | Dr. Reddy's Laboratories, Inc. | Preparation of escitalopram |
| HRP20030955A2 (en) * | 2003-11-21 | 2005-08-31 | Pliva-Istra�iva�ki institut d.o.o. | USE OF 1-OXADIBENZO[e,h]AZULENES FOR THE MANUFACTURE OF PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT AND PREVENTION OF CENTRAL NERVOUS SYSTEM DISEASES AND DISORDERS |
| HRP20030954A2 (en) * | 2003-11-21 | 2005-08-31 | Pliva D.D. | USE OF 1-AZA-DIBENZO[e,h]AZULENES FOR THE MANUFACTURENT AND PREVENTION OF CENTRAL NERVOUS SYSTEM DISEASES AND DISORDERS |
| HRP20040104A2 (en) * | 2004-01-30 | 2005-10-31 | Pliva-Istra�iva�ki institut d.o.o. | Use of benzonaphthoazulenes for the manufacture of pharmaceutical formulations for the treatment and prevention of central nervous system diseases and disorders |
| CA2585711A1 (en) | 2004-10-27 | 2006-05-04 | Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. | Conjugates with anti-inflammatory activity |
| EP1824820A2 (en) * | 2004-12-07 | 2007-08-29 | Janssen Pharmaceutica N.V. | Substituted tetracyclic tetrahydrofuran,pyrrolidine and tetrahydrothiophene derivatives |
| US20080096830A1 (en) * | 2005-01-13 | 2008-04-24 | Mladen Mercep | Anti-Inflammatory Macrolide Conjugates |
| PT2026651E (en) | 2006-03-08 | 2013-06-04 | Cortria Corp | Combination therapy with non-selective cox inhibitors to prevent cox-related gastric injuries |
| US8389482B2 (en) | 2007-01-30 | 2013-03-05 | New York University | Short peptides useful for treatment of ischemia/reperfusion injury and other tissue damage conditions associated with nitric oxide and its reactive species |
| WO2008096755A1 (en) * | 2007-02-07 | 2008-08-14 | Nippon Suisan Kaisha, Ltd. | Vanilloid receptor (vr1) inhibitor and use thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3711489A (en) * | 1971-03-31 | 1973-01-16 | Pfizer | Certain 8,9-dihydro(3,4,7,8)cycloocta(1,2-d)imidazoles |
| JPS53116385A (en) * | 1977-03-19 | 1978-10-11 | Hokuriku Pharmaceutical | Pyrazin derivative and method for its production |
| US4198421A (en) * | 1978-11-30 | 1980-04-15 | E. I. Du Pont De Nemours And Company | Antiinflammatory 2-substituted-dibenzo[2,3:6,7]oxepino[4,5-d]imidazoles |
| CZ288865B6 (en) * | 1996-04-12 | 2001-09-12 | Janssen Pharmaceutica N. V. | Substituted tetracyclic derivatives of tetrahydrofuran, process of their preparation, composition containing these derivatives and use of these derivatives as a medicament |
| GB9713368D0 (en) * | 1997-06-25 | 1997-08-27 | Weston Medical Ltd | Flame control |
| EP0887339A1 (en) * | 1997-06-27 | 1998-12-30 | Roche Diagnostics GmbH | Azulene derivatives and medicaments containing them |
-
2000
- 2000-05-17 HR HR20000310A patent/HRP20000310A2/en not_active Application Discontinuation
-
2001
- 2001-05-16 HU HU0302295A patent/HUP0302295A3/en unknown
- 2001-05-16 CZ CZ20024090A patent/CZ301770B6/en not_active IP Right Cessation
- 2001-05-16 IL IL15280901A patent/IL152809A0/en unknown
- 2001-05-16 RS YUP-841/02A patent/RS50893B/en unknown
- 2001-05-16 DZ DZ013357A patent/DZ3357A1/en active
- 2001-05-16 PL PL365054A patent/PL204849B1/en not_active IP Right Cessation
- 2001-05-16 PT PT01929882T patent/PT1284977E/en unknown
- 2001-05-16 EP EP01929882A patent/EP1284977B1/en not_active Expired - Lifetime
- 2001-05-16 DE DE60139070T patent/DE60139070D1/en not_active Expired - Lifetime
- 2001-05-16 EA EA200201223A patent/EA006069B1/en not_active IP Right Cessation
- 2001-05-16 AT AT01929882T patent/ATE434619T1/en not_active IP Right Cessation
- 2001-05-16 MX MXPA02011269A patent/MXPA02011269A/en active IP Right Grant
- 2001-05-16 CA CA2409090A patent/CA2409090C/en not_active Expired - Fee Related
- 2001-05-16 DK DK01929882T patent/DK1284977T3/en active
- 2001-05-16 JP JP2001584284A patent/JP2003533528A/en active Pending
- 2001-05-16 AU AU5656001A patent/AU5656001A/en active Pending
- 2001-05-16 WO PCT/HR2001/000027 patent/WO2001087890A1/en active IP Right Grant
- 2001-05-16 CN CNB018115896A patent/CN1194976C/en not_active Expired - Fee Related
- 2001-05-16 AU AU2001256560A patent/AU2001256560B2/en not_active Ceased
- 2001-05-16 ES ES01929882T patent/ES2328335T3/en not_active Expired - Lifetime
- 2001-05-16 BR BR0111202-3A patent/BR0111202A/en not_active Application Discontinuation
- 2001-05-16 EE EEP200200636A patent/EE200200636A/en unknown
- 2001-05-16 SK SK1770-2002A patent/SK17702002A3/en unknown
- 2001-05-16 NZ NZ522553A patent/NZ522553A/en unknown
- 2001-05-16 KR KR1020027015567A patent/KR100823064B1/en not_active Expired - Fee Related
- 2001-05-16 SI SI200130930T patent/SI1284977T1/en unknown
- 2001-05-16 GE GE5019A patent/GEP20043304B/en unknown
- 2001-05-17 AR ARP010102339A patent/AR030562A1/en active IP Right Grant
-
2002
- 2002-11-11 MA MA26901A patent/MA27125A1/en unknown
- 2002-11-12 ZA ZA200209180A patent/ZA200209180B/en unknown
- 2002-11-14 IS IS6621A patent/IS6621A/en unknown
- 2002-11-15 NO NO20025510A patent/NO20025510L/en not_active Application Discontinuation
- 2002-11-18 US US10/298,217 patent/US6897211B2/en not_active Expired - Fee Related
- 2002-12-17 BG BG107399A patent/BG65967B1/en unknown
- 2002-12-17 CR CR6860A patent/CR6860A/en not_active Application Discontinuation
-
2005
- 2005-03-25 US US11/090,743 patent/US20050171091A1/en not_active Abandoned
-
2009
- 2009-08-20 CY CY20091100888T patent/CY1109328T1/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2409090C (en) | Thienodibenzoazulene compounds as tumor necrosis factor inhibitors | |
| AU2001256560A1 (en) | Thienodibenzoazulene compounds as tumor necrosis factor inhibitors | |
| EP1506202B1 (en) | 1-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof | |
| EP1509528B1 (en) | 1,3-diaza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof | |
| EP1492795B1 (en) | 1- or 3-thia-benzonaphthoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof | |
| EP1509530B1 (en) | 2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof | |
| US20050148577A1 (en) | 1-oxa-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof | |
| EP1603921B1 (en) | Thiadibenzoazulene derivatives for the treatment of inflammatory diseases | |
| EP1587807B1 (en) | 1,2-diaza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof | |
| KR20050016336A (en) | 2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |