HRP940952A2 - Novel isoxazoline and isoxazole fibrinogen receptor antagonists - Google Patents

Info

Publication number

HRP940952A2

HRP940952A2 HR08/337,920A HRP940952A HRP940952A2 HR P940952 A2 HRP940952 A2 HR P940952A2 HR P940952 A HRP940952 A HR P940952A HR P940952 A2 HRP940952 A2 HR P940952A2

Authority

HR

Croatia

Prior art keywords

substituted

isoxazolin

aryl

alkyl

methyl

Prior art date

1993-11-24

Links

• Espacenet
• Global Dossier
• Discuss

• WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 title description 10
• CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 title description 3
• 239000002319 fibrinogen receptor antagonist Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 266
• 238000000034 method Methods 0.000 claims abstract description 104
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
• 239000003814 drug Substances 0.000 claims abstract description 18
• 230000002537 thrombolytic effect Effects 0.000 claims abstract description 15
• 230000009424 thromboembolic effect Effects 0.000 claims abstract description 12
• 229940124597 therapeutic agent Drugs 0.000 claims abstract description 10
• 229960000103 thrombolytic agent Drugs 0.000 claims abstract description 9
• -1 3H-indolyl Chemical group 0.000 claims description 312
• 125000003118 aryl group Chemical group 0.000 claims description 170
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 128
• 229920006395 saturated elastomer Polymers 0.000 claims description 74
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 66
• 125000000623 heterocyclic group Chemical group 0.000 claims description 64
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 59
• 229910052799 carbon Inorganic materials 0.000 claims description 53
• 229910052739 hydrogen Inorganic materials 0.000 claims description 50
• 125000000217 alkyl group Chemical group 0.000 claims description 49
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 49
• 229910052717 sulfur Inorganic materials 0.000 claims description 49
• 150000003839 salts Chemical class 0.000 claims description 47
• 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 46
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 46
• 229910052760 oxygen Inorganic materials 0.000 claims description 46
• 125000003386 piperidinyl group Chemical group 0.000 claims description 46
• 210000001772 blood platelet Anatomy 0.000 claims description 45
• 125000004076 pyridyl group Chemical group 0.000 claims description 45
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 41
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 39
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 39
• 125000005843 halogen group Chemical group 0.000 claims description 35
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 31
• 125000001041 indolyl group Chemical group 0.000 claims description 31
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 29
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 27
• 230000015572 biosynthetic process Effects 0.000 claims description 27
• 125000005842 heteroatom Chemical group 0.000 claims description 27
• 125000003971 isoxazolinyl group Chemical group 0.000 claims description 27
• 239000000651 prodrug Substances 0.000 claims description 26
• 229940002612 prodrug Drugs 0.000 claims description 26
• 125000004429 atom Chemical group 0.000 claims description 25
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 24
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 24
• 125000001424 substituent group Chemical group 0.000 claims description 24
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 23
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 23
• 125000002757 morpholinyl group Chemical group 0.000 claims description 23
• UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 22
• 125000002541 furyl group Chemical group 0.000 claims description 22
• 229910052736 halogen Inorganic materials 0.000 claims description 22
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 22
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 22
• 125000003545 alkoxy group Chemical group 0.000 claims description 21
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 21
• 125000001072 heteroaryl group Chemical group 0.000 claims description 21
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 21
• 125000002947 alkylene group Chemical group 0.000 claims description 20
• 150000002367 halogens Chemical class 0.000 claims description 20
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 20
• 125000000335 thiazolyl group Chemical group 0.000 claims description 20
• 125000001544 thienyl group Chemical group 0.000 claims description 20
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 19
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 19
• 150000002148 esters Chemical class 0.000 claims description 19
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• 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 15
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• 239000003146 anticoagulant agent Substances 0.000 claims description 14
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 13
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 13
• 230000002776 aggregation Effects 0.000 claims description 13
• 238000004220 aggregation Methods 0.000 claims description 13
• 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
• 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 13
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 12
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 12
• 208000035475 disorder Diseases 0.000 claims description 12
• 125000006773 (C2-C7) alkylcarbonyl group Chemical group 0.000 claims description 11
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 11
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 11
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 11
• 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 11
• 125000004926 indolenyl group Chemical group 0.000 claims description 10
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 9
• 230000002265 prevention Effects 0.000 claims description 9
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
• 125000001425 triazolyl group Chemical group 0.000 claims description 9
• XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 8
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
• 229940127219 anticoagulant drug Drugs 0.000 claims description 8
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 6
• 201000001320 Atherosclerosis Diseases 0.000 claims description 6
• 208000005189 Embolism Diseases 0.000 claims description 6
• 206010027476 Metastases Diseases 0.000 claims description 6
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
• 206010020751 Hypersensitivity Diseases 0.000 claims description 5
• 208000001132 Osteoporosis Diseases 0.000 claims description 5
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 5
• 230000007815 allergy Effects 0.000 claims description 5
• 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 5
• 208000006673 asthma Diseases 0.000 claims description 5
• 208000010125 myocardial infarction Diseases 0.000 claims description 5
• 210000000056 organ Anatomy 0.000 claims description 5
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 4
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 4
• 206010012442 Dermatitis contact Diseases 0.000 claims description 4
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
• 206010028980 Neoplasm Diseases 0.000 claims description 4
• 201000004681 Psoriasis Diseases 0.000 claims description 4
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• 206010040070 Septic Shock Diseases 0.000 claims description 4
• 229940127090 anticoagulant agent Drugs 0.000 claims description 4
• 208000010247 contact dermatitis Diseases 0.000 claims description 4
• 230000002401 inhibitory effect Effects 0.000 claims description 4
• 201000008482 osteoarthritis Diseases 0.000 claims description 4
• XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 4
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 4
• 230000036303 septic shock Effects 0.000 claims description 4
• 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 4
• 206010002388 Angina unstable Diseases 0.000 claims description 3
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• 208000007814 Unstable Angina Diseases 0.000 claims description 3
• 125000000732 arylene group Chemical group 0.000 claims description 3
• XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 3
• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 3
• 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 3
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• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 2
• 206010063837 Reperfusion injury Diseases 0.000 claims description 2
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
• GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 claims description 2
• IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims description 2
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• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 8
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
• 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims 1
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• 230000000241 respiratory effect Effects 0.000 claims 1
• 208000011580 syndromic disease Diseases 0.000 claims 1
• GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims 1
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• 150000002547 isoxazolines Chemical class 0.000 abstract description 3
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