OA12134A - Novel substituted pyrazoloÄ4-3-eÜdiazepines, pharmaceutical compositions containing them, use as medicinal products and processes for preparing them. - Google Patents

Info

Publication number

OA12134A

OA12134A OA1200200203A OA1200200203A OA12134A OA 12134 A OA12134 A OA 12134A OA 1200200203 A OA1200200203 A OA 1200200203A OA 1200200203 A OA1200200203 A OA 1200200203A OA 12134 A OA12134 A OA 12134A

Authority

OA

OAPI

Prior art keywords

diazepin

pyrazolo

dihydro

ethyl

ppm

Prior art date

2000-01-05

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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 5
• 238000000034 method Methods 0.000 title abstract description 49
• 230000008569 process Effects 0.000 title abstract description 7
• 229940126601 medicinal product Drugs 0.000 title abstract description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 190
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 206
• 125000004432 carbon atom Chemical group C* 0.000 claims description 202
• -1 methoxy, hydroxyl Chemical group 0.000 claims description 165
• 229910052757 nitrogen Inorganic materials 0.000 claims description 111
• 229910052760 oxygen Inorganic materials 0.000 claims description 90
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 87
• 125000005842 heteroatom Chemical group 0.000 claims description 80
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 74
• 239000001301 oxygen Substances 0.000 claims description 74
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 73
• 125000000217 alkyl group Chemical group 0.000 claims description 65
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 60
• 239000005864 Sulphur Substances 0.000 claims description 59
• 125000003118 aryl group Chemical group 0.000 claims description 48
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 45
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 45
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 41
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 34
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
• 125000004429 atom Chemical group 0.000 claims description 30
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 26
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
• 125000003342 alkenyl group Chemical group 0.000 claims description 23
• 238000006243 chemical reaction Methods 0.000 claims description 23
• 229910052717 sulfur Inorganic materials 0.000 claims description 22
• 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 21
• 229910052799 carbon Inorganic materials 0.000 claims description 20
• 229910052736 halogen Inorganic materials 0.000 claims description 20
• 150000002367 halogens Chemical class 0.000 claims description 20
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
• UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 15
• 229910052739 hydrogen Inorganic materials 0.000 claims description 14
• 239000001257 hydrogen Substances 0.000 claims description 12
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
• IADSMOLIAFCBCX-UHFFFAOYSA-N 3-cyclohexyl-1-propyl-5-pyridin-4-yl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1=2N=C(C=3C=CN=CC=3)CNC(=O)C=2N(CCC)N=C1C1CCCCC1 IADSMOLIAFCBCX-UHFFFAOYSA-N 0.000 claims description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 9
• 229910052721 tungsten Inorganic materials 0.000 claims description 9
• 238000004519 manufacturing process Methods 0.000 claims description 8
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 7
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 7
• SPZQULGHYXNVQH-UHFFFAOYSA-N 3-tert-butyl-1-ethyl-5-(4-methylphenyl)-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CC)N=C(C(C)(C)C)C=2N=C1C1=CC=C(C)C=C1 SPZQULGHYXNVQH-UHFFFAOYSA-N 0.000 claims description 7
• 239000003112 inhibitor Substances 0.000 claims description 7
• YTAUWOYFZUDJRA-UHFFFAOYSA-N (3-tert-butyl-1-ethyl-5-phenyl-6h-pyrazolo[4,3-e][1,4]diazepin-8-yl)cyanamide Chemical compound C1NC(=NC#N)C=2N(CC)N=C(C(C)(C)C)C=2N=C1C1=CC=CC=C1 YTAUWOYFZUDJRA-UHFFFAOYSA-N 0.000 claims description 6
• YXASLZMHNCLGRP-UHFFFAOYSA-N 1-ethyl-5-phenyl-3-propan-2-yl-6,7-dihydropyrazolo[4,3-e][1,4]diazepine-8-thione Chemical compound C1NC(=S)C=2N(CC)N=C(C(C)C)C=2N=C1C1=CC=CC=C1 YXASLZMHNCLGRP-UHFFFAOYSA-N 0.000 claims description 6
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 6
• OVUPYHJKVBHLMW-UHFFFAOYSA-N 3-butan-2-yl-1-ethyl-5-pyridin-4-yl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound CCC(C)C1=NN(CC)C(C(NC2)=O)=C1N=C2C1=CC=NC=C1 OVUPYHJKVBHLMW-UHFFFAOYSA-N 0.000 claims description 6
• FMDWGNQQWFTIQP-UHFFFAOYSA-N 3-tert-butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CC)N=C(C(C)(C)C)C=2N=C1C1=CC=C(O)C=C1 FMDWGNQQWFTIQP-UHFFFAOYSA-N 0.000 claims description 6
• JTOMRCCCZBWBJL-UHFFFAOYSA-N 4-(8-oxo-3-propan-2-yl-1-propyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile Chemical compound C1NC(=O)C=2N(CCC)N=C(C(C)C)C=2N=C1C1=CC=C(C#N)C=C1 JTOMRCCCZBWBJL-UHFFFAOYSA-N 0.000 claims description 6
• DPCZJJQUOLGDOQ-UHFFFAOYSA-N 5-tert-butyl-3-propan-2-yl-1-propyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound N1=C(C(C)(C)C)CNC(=O)C2=C1C(C(C)C)=NN2CCC DPCZJJQUOLGDOQ-UHFFFAOYSA-N 0.000 claims description 6
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 6
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 6
• 108700012920 TNF Proteins 0.000 claims description 6
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
• 238000007363 ring formation reaction Methods 0.000 claims description 6
• 125000001424 substituent group Chemical group 0.000 claims description 6
• IHUDPRHRAGKBGU-UHFFFAOYSA-N (1-ethyl-3-methyl-5-phenyl-6h-pyrazolo[4,3-e][1,4]diazepin-8-yl)cyanamide Chemical compound C1N=C(NC#N)C=2N(CC)N=C(C)C=2N=C1C1=CC=CC=C1 IHUDPRHRAGKBGU-UHFFFAOYSA-N 0.000 claims description 5
• GNLWACUIBIYKAA-UHFFFAOYSA-N 3-(cyclohexylmethyl)-1-ethyl-5-pyridin-4-yl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1=2N=C(C=3C=CN=CC=3)CNC(=O)C=2N(CC)N=C1CC1CCCCC1 GNLWACUIBIYKAA-UHFFFAOYSA-N 0.000 claims description 5
• 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 5
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 5
• FMUVIVRWEJMDAH-UHFFFAOYSA-N 3-tert-butyl-1-ethyl-5-phenyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepine-8-thione Chemical compound C1NC(=S)C=2N(CC)N=C(C(C)(C)C)C=2N=C1C1=CC=CC=C1 FMUVIVRWEJMDAH-UHFFFAOYSA-N 0.000 claims description 5
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
• XTBFTFBYVPRMAO-UHFFFAOYSA-N 5-(4-aminophenyl)-1-ethyl-3-propan-2-yl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CC)N=C(C(C)C)C=2N=C1C1=CC=C(N)C=C1 XTBFTFBYVPRMAO-UHFFFAOYSA-N 0.000 claims description 5
• HYLDHXVOHZISTR-UHFFFAOYSA-N 5-(4-hydroxyphenyl)-3-propan-2-yl-1-propyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CCC)N=C(C(C)C)C=2N=C1C1=CC=C(O)C=C1 HYLDHXVOHZISTR-UHFFFAOYSA-N 0.000 claims description 5
• 241001061127 Thione Species 0.000 claims description 5
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 5
• 150000001721 carbon Chemical group 0.000 claims description 5
• 201000010099 disease Diseases 0.000 claims description 5
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
• 230000037390 scarring Effects 0.000 claims description 5
• YPRBAEYFBIYTLT-UHFFFAOYSA-N (1-ethyl-5-phenyl-3-propan-2-yl-6h-pyrazolo[4,3-e][1,4]diazepin-8-yl)cyanamide Chemical compound C1NC(=NC#N)C=2N(CC)N=C(C(C)C)C=2N=C1C1=CC=CC=C1 YPRBAEYFBIYTLT-UHFFFAOYSA-N 0.000 claims description 4
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
• ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 4
• 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 4
• FAWYZPDABNVXQY-UHFFFAOYSA-N 3-butan-2-yl-1-ethyl-5-phenyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound CCC(C)C1=NN(CC)C(C(NC2)=O)=C1N=C2C1=CC=CC=C1 FAWYZPDABNVXQY-UHFFFAOYSA-N 0.000 claims description 4
• FZKOUTKAKUPEED-UHFFFAOYSA-N 3-butan-2-yl-1-propyl-5-pyridin-4-yl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CCC)N=C(C(C)CC)C=2N=C1C1=CC=NC=C1 FZKOUTKAKUPEED-UHFFFAOYSA-N 0.000 claims description 4
• BZDVLDVHUYAPON-UHFFFAOYSA-N 3-butyl-1-ethyl-5-phenyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound CCCCC1=NN(CC)C(C(NC2)=O)=C1N=C2C1=CC=CC=C1 BZDVLDVHUYAPON-UHFFFAOYSA-N 0.000 claims description 4
• ONUXVZFUVBOSGE-UHFFFAOYSA-N 3-cyclohexyl-1-ethyl-5-pyridin-4-yl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1=2N=C(C=3C=CN=CC=3)CNC(=O)C=2N(CC)N=C1C1CCCCC1 ONUXVZFUVBOSGE-UHFFFAOYSA-N 0.000 claims description 4
• WTBXEFXUGDEOHG-UHFFFAOYSA-N 3-tert-butyl-1-ethyl-5-phenyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CC)N=C(C(C)(C)C)C=2N=C1C1=CC=CC=C1 WTBXEFXUGDEOHG-UHFFFAOYSA-N 0.000 claims description 4
• BZQVAGJLHAWIQO-UHFFFAOYSA-N 5-(4-aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CC)N=C(C(C)(C)C)C=2N=C1C1=CC=C(N)C=C1 BZQVAGJLHAWIQO-UHFFFAOYSA-N 0.000 claims description 4
• RWDKSZKUTHRKKA-UHFFFAOYSA-N 5-(4-methylphenyl)-3-propan-2-yl-1-propyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepine-8-thione Chemical compound C1NC(=S)C=2N(CCC)N=C(C(C)C)C=2N=C1C1=CC=C(C)C=C1 RWDKSZKUTHRKKA-UHFFFAOYSA-N 0.000 claims description 4
• VLBWSWIXZFSVBY-UHFFFAOYSA-N 5-tert-butyl-1-ethyl-3-propan-2-yl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound N1=C(C(C)(C)C)CNC(=O)C2=C1C(C(C)C)=NN2CC VLBWSWIXZFSVBY-UHFFFAOYSA-N 0.000 claims description 4
• 206010003645 Atopy Diseases 0.000 claims description 4
• KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 4
• 206010020751 Hypersensitivity Diseases 0.000 claims description 4
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
• 206010040070 Septic Shock Diseases 0.000 claims description 4
• 208000006673 asthma Diseases 0.000 claims description 4
• 229910052731 fluorine Inorganic materials 0.000 claims description 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
• 150000002829 nitrogen Chemical group 0.000 claims description 4
• 230000036303 septic shock Effects 0.000 claims description 4
• 125000001544 thienyl group Chemical group 0.000 claims description 4
• IKHHVDTUIGOGBF-UHFFFAOYSA-N 1-(cyclopropylmethyl)-3-methyl-5-phenyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound N1=C(C=2C=CC=CC=2)CNC(=O)C2=C1C(C)=NN2CC1CC1 IKHHVDTUIGOGBF-UHFFFAOYSA-N 0.000 claims description 3
• SOBJIQWCXGZDBE-UHFFFAOYSA-N 1-ethyl-5-(4-methylphenyl)-3-propan-2-yl-6,7-dihydropyrazolo[4,3-e][1,4]diazepine-8-thione Chemical compound C1NC(=S)C=2N(CC)N=C(C(C)C)C=2N=C1C1=CC=C(C)C=C1 SOBJIQWCXGZDBE-UHFFFAOYSA-N 0.000 claims description 3
• HHSSTYLSMCSOHC-UHFFFAOYSA-N 1-ethyl-5-phenyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CC)N=CC=2N=C1C1=CC=CC=C1 HHSSTYLSMCSOHC-UHFFFAOYSA-N 0.000 claims description 3
• OETSJRZSRPIUJQ-UHFFFAOYSA-N 3,5-ditert-butyl-1-ethyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound N1=C(C(C)(C)C)CNC(=O)C2=C1C(C(C)(C)C)=NN2CC OETSJRZSRPIUJQ-UHFFFAOYSA-N 0.000 claims description 3
• DNYRTYORKRGOOU-UHFFFAOYSA-N 3,5-ditert-butyl-1-propyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepine-8-thione Chemical compound N1=C(C(C)(C)C)CNC(=S)C2=C1C(C(C)(C)C)=NN2CCC DNYRTYORKRGOOU-UHFFFAOYSA-N 0.000 claims description 3
• LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 3
• QQXMCVGWMFZOQA-UHFFFAOYSA-N 3-(cyclohexylmethyl)-1-ethyl-5-phenyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1=2N=C(C=3C=CC=CC=3)CNC(=O)C=2N(CC)N=C1CC1CCCCC1 QQXMCVGWMFZOQA-UHFFFAOYSA-N 0.000 claims description 3
• XNWWIPMMEIJLHO-UHFFFAOYSA-N 3-butyl-1-ethyl-5-phenyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepine-8-thione Chemical compound CCCCC1=NN(CC)C(C(NC2)=S)=C1N=C2C1=CC=CC=C1 XNWWIPMMEIJLHO-UHFFFAOYSA-N 0.000 claims description 3
• HJKDWOPWRFRYKL-UHFFFAOYSA-N 3-tert-butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CCC)N=C(C(C)(C)C)C=2N=C1C1=CC=C(OC)C=C1 HJKDWOPWRFRYKL-UHFFFAOYSA-N 0.000 claims description 3
• WDZKEWAQIYYMFP-UHFFFAOYSA-N 3-tert-butyl-5-(4-methylphenyl)-1-propyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CCC)N=C(C(C)(C)C)C=2N=C1C1=CC=C(C)C=C1 WDZKEWAQIYYMFP-UHFFFAOYSA-N 0.000 claims description 3
• GDXLUSSAJYVVIV-UHFFFAOYSA-N 4-(1-ethyl-8-oxo-3-propan-2-yl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile Chemical compound C1NC(=O)C=2N(CC)N=C(C(C)C)C=2N=C1C1=CC=C(C#N)C=C1 GDXLUSSAJYVVIV-UHFFFAOYSA-N 0.000 claims description 3
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• FKYYBIZGZWYBFQ-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-1-ethyl-3-methyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CC)N=C(C)C=2N=C1C=1SC=CC=1Cl FKYYBIZGZWYBFQ-UHFFFAOYSA-N 0.000 claims description 3
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• UEKCOHNJLIIPIH-UHFFFAOYSA-N 5-(4-methylphenyl)-3-propan-2-yl-1-propyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CCC)N=C(C(C)C)C=2N=C1C1=CC=C(C)C=C1 UEKCOHNJLIIPIH-UHFFFAOYSA-N 0.000 claims description 3
• JZSUNPRKXXPGGV-UHFFFAOYSA-N 5-cyclohexyl-1-ethyl-3-methyl-6,7-dihydropyrazolo[4,3-e][1,4]diazepin-8-one Chemical compound C1NC(=O)C=2N(CC)N=C(C)C=2N=C1C1CCCCC1 JZSUNPRKXXPGGV-UHFFFAOYSA-N 0.000 claims description 3
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