SK15922001A3 - Deriváty cyklotiokarbamátu ako modulátory receptora pre progesterón - Google Patents

Info

Publication number

SK15922001A3

SK15922001A3 SK1592-2001A SK15922001A SK15922001A3 SK 15922001 A3 SK15922001 A3 SK 15922001A3 SK 15922001 A SK15922001 A SK 15922001A SK 15922001 A3 SK15922001 A3 SK 15922001A3

Authority

SK

Slovakia

Prior art keywords

substituted

alkyl

group

carbon atoms

dihydro

Prior art date

1999-05-04

Links

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• 239000002379 progesterone receptor modulator Substances 0.000 title 1
• 229940095745 sex hormone and modulator of the genital system progesterone receptor modulator Drugs 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 154
• 125000004432 carbon atom Chemical group C* 0.000 claims description 137
• 125000000217 alkyl group Chemical group 0.000 claims description 68
• 125000000623 heterocyclic group Chemical group 0.000 claims description 64
• 125000003118 aryl group Chemical group 0.000 claims description 55
• -1 and C 1 -C 6 alkyl Chemical group 0.000 claims description 53
• 229910052799 carbon Inorganic materials 0.000 claims description 52
• 229910052739 hydrogen Inorganic materials 0.000 claims description 52
• 125000003107 substituted aryl group Chemical group 0.000 claims description 47
• 229910052736 halogen Inorganic materials 0.000 claims description 46
• 150000002367 halogens Chemical class 0.000 claims description 44
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 40
• 229910052757 nitrogen Inorganic materials 0.000 claims description 37
• 125000001424 substituent group Chemical group 0.000 claims description 36
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 35
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 31
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 24
• 125000005842 heteroatom Chemical group 0.000 claims description 23
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 23
• 125000003342 alkenyl group Chemical group 0.000 claims description 22
• 125000003545 alkoxy group Chemical group 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 20
• 229910052717 sulfur Inorganic materials 0.000 claims description 19
• 125000005309 thioalkoxy group Chemical group 0.000 claims description 19
• 125000000304 alkynyl group Chemical group 0.000 claims description 18
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 18
• 229920006395 saturated elastomer Polymers 0.000 claims description 17
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 16
• 229910052760 oxygen Inorganic materials 0.000 claims description 16
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 16
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 15
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 14
• 125000004426 substituted alkynyl group Chemical group 0.000 claims description 13
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 9
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 8
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 8
• 125000001072 heteroaryl group Chemical group 0.000 claims description 8
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 7
• 238000004519 manufacturing process Methods 0.000 claims description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
• 150000001555 benzenes Chemical group 0.000 claims description 6
• 125000006697 (C1-C3) aminoalkyl group Chemical group 0.000 claims description 5
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 5
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
• 125000002252 acyl group Chemical group 0.000 claims description 4
• 125000003277 amino group Chemical group 0.000 claims description 4
• 150000001721 carbon Chemical group 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
• CUQLFUMXNAKZSH-UHFFFAOYSA-N 3-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)benzonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC=CC(C#N)=C1 CUQLFUMXNAKZSH-UHFFFAOYSA-N 0.000 claims description 3
• NAQUDAIOMWNXJF-UHFFFAOYSA-N 6-(3-fluorophenyl)-4-methyl-1,4-dihydro-3,1-benzoxazine-2-thione Chemical compound C1=C2C(C)OC(=S)NC2=CC=C1C1=CC=CC(F)=C1 NAQUDAIOMWNXJF-UHFFFAOYSA-N 0.000 claims description 3
• 201000009273 Endometriosis Diseases 0.000 claims description 3
• 210000000481 breast Anatomy 0.000 claims description 3
• 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 2
• DCBOJAHTRJNPIJ-UHFFFAOYSA-N 2-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)thiophene-3-carbonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C=1SC=CC=1C#N DCBOJAHTRJNPIJ-UHFFFAOYSA-N 0.000 claims description 2
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• SHWQSMSSKKIGRW-UHFFFAOYSA-N 3-(2-sulfanylidenespiro[1h-3,1-benzoxazine-4,1'-cyclohexane]-6-yl)benzonitrile Chemical compound O1C(=S)NC2=CC=C(C=3C=C(C=CC=3)C#N)C=C2C21CCCCC2 SHWQSMSSKKIGRW-UHFFFAOYSA-N 0.000 claims description 2
• JWRMZXFZQZVKSD-UHFFFAOYSA-N 3-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC(F)=CC(C#N)=C1 JWRMZXFZQZVKSD-UHFFFAOYSA-N 0.000 claims description 2
• NGXWFLCNLTYJKI-UHFFFAOYSA-N 3-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)-5-methylbenzonitrile Chemical compound CC1=CC(C#N)=CC(C=2C=C3C(C)(C)OC(=S)NC3=CC=2)=C1 NGXWFLCNLTYJKI-UHFFFAOYSA-N 0.000 claims description 2
• RILXTHFMVLBOPN-UHFFFAOYSA-N 3-(8-bromo-4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=C(Br)C=C1C1=CC(F)=CC(C#N)=C1 RILXTHFMVLBOPN-UHFFFAOYSA-N 0.000 claims description 2
• XURBBVPMTVGZEP-UHFFFAOYSA-N 3-fluoro-5-(2-sulfanylidenespiro[1h-3,1-benzoxazine-4,1'-cyclohexane]-6-yl)benzonitrile Chemical compound FC1=CC(C#N)=CC(C=2C=C3C4(CCCCC4)OC(=S)NC3=CC=2)=C1 XURBBVPMTVGZEP-UHFFFAOYSA-N 0.000 claims description 2
• YLRADUODZWLKHG-UHFFFAOYSA-N 3-fluoro-5-(8-fluoro-4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)benzonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=C(F)C=C1C1=CC(F)=CC(C#N)=C1 YLRADUODZWLKHG-UHFFFAOYSA-N 0.000 claims description 2
• YXZAVJPXYUAVKV-UHFFFAOYSA-N 4-(2-sulfanylidenespiro[1h-3,1-benzoxazine-4,1'-cyclohexane]-6-yl)thiophene-2-carbonitrile Chemical compound O1C(=S)NC2=CC=C(C=3C=C(SC=3)C#N)C=C2C21CCCCC2 YXZAVJPXYUAVKV-UHFFFAOYSA-N 0.000 claims description 2
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
• UKMZDGICTYHTEO-UHFFFAOYSA-N 4-methyl-5-(2-sulfanylidenespiro[1h-3,1-benzoxazine-4,1'-cyclohexane]-6-yl)thiophene-2-carbonitrile Chemical compound C1=C(C#N)SC(C=2C=C3C4(CCCCC4)OC(=S)NC3=CC=2)=C1C UKMZDGICTYHTEO-UHFFFAOYSA-N 0.000 claims description 2
• KBUBDEWGNXRLKX-UHFFFAOYSA-N 5-(2-sulfanylidenespiro[1h-3,1-benzoxazine-4,1'-cyclohexane]-6-yl)thiophene-2-carbonitrile Chemical compound O1C(=S)NC2=CC=C(C=3SC(=CC=3)C#N)C=C2C21CCCCC2 KBUBDEWGNXRLKX-UHFFFAOYSA-N 0.000 claims description 2
• MQYRSOFJNHXZHN-UHFFFAOYSA-N 5-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)-1-ethylpyrrole-2-carbonitrile Chemical compound CCN1C(C#N)=CC=C1C1=CC=C(NC(=S)OC2(C)C)C2=C1 MQYRSOFJNHXZHN-UHFFFAOYSA-N 0.000 claims description 2
• HYELXXFFGVQXLM-UHFFFAOYSA-N 5-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)-1h-pyrrole-2-carbonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC=C(C#N)N1 HYELXXFFGVQXLM-UHFFFAOYSA-N 0.000 claims description 2
• BCDNJBDJBGOTIA-UHFFFAOYSA-N 5-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)-1h-pyrrole-2-carbothioamide Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC=C(C(N)=S)N1 BCDNJBDJBGOTIA-UHFFFAOYSA-N 0.000 claims description 2
• JXEZBFHBHFDRCM-UHFFFAOYSA-N 5-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)-4-methylthiophene-2-carbonitrile Chemical compound C1=C(C#N)SC(C=2C=C3C(C)(C)OC(=S)NC3=CC=2)=C1C JXEZBFHBHFDRCM-UHFFFAOYSA-N 0.000 claims description 2
• YULOLNRYBCOJDS-UHFFFAOYSA-N 5-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)-4-propylthiophene-2-carbonitrile Chemical compound C1=C(C#N)SC(C=2C=C3C(C)(C)OC(=S)NC3=CC=2)=C1CCC YULOLNRYBCOJDS-UHFFFAOYSA-N 0.000 claims description 2
• NUQMIQUEODQESK-UHFFFAOYSA-N 5-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)furan-2-carbonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC=C(C#N)O1 NUQMIQUEODQESK-UHFFFAOYSA-N 0.000 claims description 2
• XSBJYXLVQYKJTL-UHFFFAOYSA-N 5-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)thiophene-2-carbonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC=C(C#N)S1 XSBJYXLVQYKJTL-UHFFFAOYSA-N 0.000 claims description 2
• IBEVIFARERDACQ-UHFFFAOYSA-N 5-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)thiophene-3-carbonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC(C#N)=CS1 IBEVIFARERDACQ-UHFFFAOYSA-N 0.000 claims description 2
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
• WYHOTGLZCWQZME-UHFFFAOYSA-N 6-(3-bromophenyl)-4,4-dimethyl-1h-3,1-benzoxazine-2-thione Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC=CC(Br)=C1 WYHOTGLZCWQZME-UHFFFAOYSA-N 0.000 claims description 2
• JGZLNKUOAMAIAG-UHFFFAOYSA-N 6-(3-chloro-5-fluorophenyl)-4,4-dimethyl-1h-3,1-benzoxazine-2-thione Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC(F)=CC(Cl)=C1 JGZLNKUOAMAIAG-UHFFFAOYSA-N 0.000 claims description 2
• UMQGDADSFKJZKD-UHFFFAOYSA-N 6-(3-methoxyphenyl)-4,4-dimethyl-1h-3,1-benzoxazine-2-thione Chemical compound COC1=CC=CC(C=2C=C3C(C)(C)OC(=S)NC3=CC=2)=C1 UMQGDADSFKJZKD-UHFFFAOYSA-N 0.000 claims description 2
• 208000026310 Breast neoplasm Diseases 0.000 claims description 2
• 206010046798 Uterine leiomyoma Diseases 0.000 claims description 2
• 230000000740 bleeding effect Effects 0.000 claims description 2
• 210000001072 colon Anatomy 0.000 claims description 2
• 238000002657 hormone replacement therapy Methods 0.000 claims description 2
• LAQPNDIUHRHNCV-UHFFFAOYSA-N isophthalonitrile Chemical compound N#CC1=CC=CC(C#N)=C1 LAQPNDIUHRHNCV-UHFFFAOYSA-N 0.000 claims description 2
• 201000010260 leiomyoma Diseases 0.000 claims description 2
• 230000002611 ovarian Effects 0.000 claims description 2
• 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 2
• 239000003814 drug Substances 0.000 claims 4
• 125000004429 atom Chemical group 0.000 claims 3
• 125000005843 halogen group Chemical group 0.000 claims 2
• WGSXKYXKAARAKD-UHFFFAOYSA-N 1-fluoro-3-isocyanato-5-(trifluoromethyl)benzene Chemical group FC1=CC(N=C=O)=CC(C(F)(F)F)=C1 WGSXKYXKAARAKD-UHFFFAOYSA-N 0.000 claims 1
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 1
• RBQGHCLXAHBLNH-UHFFFAOYSA-N 3-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)-1-methylpyrrole-2-carbonitrile Chemical compound CN1C=CC(C=2C=C3C(C)(C)OC(=S)NC3=CC=2)=C1C#N RBQGHCLXAHBLNH-UHFFFAOYSA-N 0.000 claims 1
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 1
• DCXHYBSZULGYNI-UHFFFAOYSA-N 4,4-dimethyl-1h-3,1-benzoxazine-2-thione Chemical compound C1=CC=C2C(C)(C)OC(=S)NC2=C1 DCXHYBSZULGYNI-UHFFFAOYSA-N 0.000 claims 1
• UCEMKOZZXFXATD-UHFFFAOYSA-N 4-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)thiophene-2-carbonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CSC(C#N)=C1 UCEMKOZZXFXATD-UHFFFAOYSA-N 0.000 claims 1
• JSOJTUILYANJMW-UHFFFAOYSA-N 4-benzyl-6-(3-chlorophenyl)-4-methyl-1h-3,1-benzoxazine-2-thione Chemical compound O1C(=S)NC2=CC=C(C=3C=C(Cl)C=CC=3)C=C2C1(C)CC1=CC=CC=C1 JSOJTUILYANJMW-UHFFFAOYSA-N 0.000 claims 1
• QLNYJNLJIJPEAO-UHFFFAOYSA-N 5-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)-2-fluorobenzonitrile Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC=C(F)C(C#N)=C1 QLNYJNLJIJPEAO-UHFFFAOYSA-N 0.000 claims 1
• KTBKDGMHHINKLK-UHFFFAOYSA-N 6-(3,5-difluorophenyl)-4,4-dimethyl-1h-3,1-benzoxazine-2-thione Chemical compound C1=C2C(C)(C)OC(=S)NC2=CC=C1C1=CC(F)=CC(F)=C1 KTBKDGMHHINKLK-UHFFFAOYSA-N 0.000 claims 1
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• 206010009944 Colon cancer Diseases 0.000 claims 1
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• 206010060862 Prostate cancer Diseases 0.000 claims 1
• 208000009956 adenocarcinoma Diseases 0.000 claims 1
• 239000003433 contraceptive agent Substances 0.000 claims 1
• 230000002254 contraceptive effect Effects 0.000 claims 1
• 230000002357 endometrial effect Effects 0.000 claims 1
• 201000001514 prostate carcinoma Diseases 0.000 claims 1
• JHWNSFIRRIBDRF-UHFFFAOYSA-N tert-butyl 2-cyano-5-(4,4-dimethyl-2-sulfanylidene-1h-3,1-benzoxazin-6-yl)pyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(C#N)=CC=C1C1=CC=C(NC(=S)OC2(C)C)C2=C1 JHWNSFIRRIBDRF-UHFFFAOYSA-N 0.000 claims 1
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• 238000005160 1H NMR spectroscopy Methods 0.000 description 115
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 85
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• 239000000243 solution Substances 0.000 description 48
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• 239000002904 solvent Substances 0.000 description 38
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
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• 238000003818 flash chromatography Methods 0.000 description 23
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• 229910052786 argon Inorganic materials 0.000 description 16
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• 238000004364 calculation method Methods 0.000 description 16
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• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 13
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• 239000002585 base Substances 0.000 description 12
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