UA73525C2 - Compounds for the treatment of ischemia - Google Patents

Info

Publication number

UA73525C2

UA73525C2 UA2002032515A UA2002032515A UA73525C2 UA 73525 C2 UA73525 C2 UA 73525C2 UA 2002032515 A UA2002032515 A UA 2002032515A UA 2002032515 A UA2002032515 A UA 2002032515A UA 73525 C2 UA73525 C2 UA 73525C2

Authority

UA

Ukraine

Prior art keywords

alkyl

carbonylguanidine

pyrazole

compound

mono

Prior art date

1999-09-30

Links

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• Global Dossier
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• 208000028867 ischemia Diseases 0.000 title claims abstract description 36
• 150000001875 compounds Chemical class 0.000 title claims description 490
• 238000011282 treatment Methods 0.000 title claims description 24
• 238000000034 method Methods 0.000 claims abstract description 124
• 239000000203 mixture Substances 0.000 claims abstract description 105
• 206010021143 Hypoxia Diseases 0.000 claims abstract description 35
• 230000000451 tissue damage Effects 0.000 claims abstract description 24
• 231100000827 tissue damage Toxicity 0.000 claims abstract description 24
• 230000007954 hypoxia Effects 0.000 claims abstract description 20
• 125000000217 alkyl group Chemical group 0.000 claims description 232
• MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 196
• -1 oxy, methylene Chemical group 0.000 claims description 176
• 150000003839 salts Chemical class 0.000 claims description 111
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 110
• 229920006395 saturated elastomer Polymers 0.000 claims description 109
• 229910052757 nitrogen Inorganic materials 0.000 claims description 95
• 229940002612 prodrug Drugs 0.000 claims description 93
• 239000000651 prodrug Substances 0.000 claims description 93
• 125000003545 alkoxy group Chemical group 0.000 claims description 84
• 229910052760 oxygen Inorganic materials 0.000 claims description 65
• 239000003112 inhibitor Substances 0.000 claims description 64
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 56
• 239000001301 oxygen Substances 0.000 claims description 56
• 210000001519 tissue Anatomy 0.000 claims description 55
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 49
• 125000005842 heteroatom Chemical group 0.000 claims description 49
• 229910052717 sulfur Inorganic materials 0.000 claims description 49
• 239000011593 sulfur Substances 0.000 claims description 49
• 239000002904 solvent Substances 0.000 claims description 44
• 125000005843 halogen group Chemical group 0.000 claims description 42
• 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 40
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 39
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 39
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
• 241000124008 Mammalia Species 0.000 claims description 33
• 210000002216 heart Anatomy 0.000 claims description 33
• 125000004429 atom Chemical group 0.000 claims description 31
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 31
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
• 125000003282 alkyl amino group Chemical group 0.000 claims description 29
• 229910052799 carbon Inorganic materials 0.000 claims description 26
• 125000003386 piperidinyl group Chemical group 0.000 claims description 25
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
• 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 23
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 22
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 125000005699 methyleneoxy group Chemical group [H]C([H])([*:1])O[*:2] 0.000 claims description 22
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 21
• 125000002619 bicyclic group Chemical group 0.000 claims description 21
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 21
• 125000002541 furyl group Chemical group 0.000 claims description 20
• 125000006413 ring segment Chemical group 0.000 claims description 20
• OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 19
• 239000003795 chemical substances by application Substances 0.000 claims description 19
• 125000002757 morpholinyl group Chemical group 0.000 claims description 19
• 239000002552 dosage form Substances 0.000 claims description 18
• 125000004076 pyridyl group Chemical group 0.000 claims description 18
• 125000000335 thiazolyl group Chemical group 0.000 claims description 18
• 125000002971 oxazolyl group Chemical group 0.000 claims description 17
• 239000003937 drug carrier Substances 0.000 claims description 16
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims description 16
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 16
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 16
• 238000001356 surgical procedure Methods 0.000 claims description 16
• 101100419015 Hordeum vulgare RPS27 gene Proteins 0.000 claims description 15
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 15
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 15
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 15
• 230000001225 therapeutic effect Effects 0.000 claims description 15
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 15
• 125000004414 alkyl thio group Chemical group 0.000 claims description 14
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 14
• 125000004193 piperazinyl group Chemical group 0.000 claims description 14
• 239000012190 activator Substances 0.000 claims description 13
• 239000003085 diluting agent Substances 0.000 claims description 13
• 125000001153 fluoro group Chemical group F* 0.000 claims description 13
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
• 239000002327 cardiovascular agent Substances 0.000 claims description 12
• 229940125692 cardiovascular agent Drugs 0.000 claims description 12
• 210000004185 liver Anatomy 0.000 claims description 12
• 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 11
• 229960005305 adenosine Drugs 0.000 claims description 11
• 210000004556 brain Anatomy 0.000 claims description 11
• WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 10
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 10
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 10
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
• 102000005962 receptors Human genes 0.000 claims description 10
• 108020003175 receptors Proteins 0.000 claims description 10
• 125000001544 thienyl group Chemical group 0.000 claims description 10
• 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 9
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 9
• 125000005605 benzo group Chemical group 0.000 claims description 9
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 9
• 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 8
• 125000002393 azetidinyl group Chemical group 0.000 claims description 8
• 125000001041 indolyl group Chemical group 0.000 claims description 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
• 102000048186 Endothelin-converting enzyme 1 Human genes 0.000 claims description 6
• 108030001679 Endothelin-converting enzyme 1 Proteins 0.000 claims description 6
• 102000001253 Protein Kinase Human genes 0.000 claims description 6
• 239000011575 calcium Substances 0.000 claims description 6
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 6
• 125000001475 halogen functional group Chemical group 0.000 claims description 6
• 108060006633 protein kinase Proteins 0.000 claims description 6
• 239000003379 purinergic P1 receptor agonist Substances 0.000 claims description 6
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
• 239000005557 antagonist Substances 0.000 claims description 5
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 5
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 5
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 5
• 125000001624 naphthyl group Chemical group 0.000 claims description 5
• 230000003647 oxidation Effects 0.000 claims description 5
• 238000007254 oxidation reaction Methods 0.000 claims description 5
• 239000001103 potassium chloride Substances 0.000 claims description 5
• 235000011164 potassium chloride Nutrition 0.000 claims description 5
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
• 230000002537 thrombolytic effect Effects 0.000 claims description 5
• 239000005541 ACE inhibitor Substances 0.000 claims description 4
• BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 4
• 229940123208 Biguanide Drugs 0.000 claims description 4
• 229940127291 Calcium channel antagonist Drugs 0.000 claims description 4
• GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 4
• 229960001138 acetylsalicylic acid Drugs 0.000 claims description 4
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 4
• 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 4
• 150000004283 biguanides Chemical class 0.000 claims description 4
• 239000000480 calcium channel blocker Substances 0.000 claims description 4
• 229960002896 clonidine Drugs 0.000 claims description 4
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
• IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 claims description 4
• 229960002768 dipyridamole Drugs 0.000 claims description 4
• 239000002934 diuretic Substances 0.000 claims description 4
• 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 4
• 229930182470 glycoside Natural products 0.000 claims description 4
• 150000002338 glycosides Chemical class 0.000 claims description 4
• 210000000936 intestine Anatomy 0.000 claims description 4
• 210000003734 kidney Anatomy 0.000 claims description 4
• 210000004072 lung Anatomy 0.000 claims description 4
• XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 4
• 229960003105 metformin Drugs 0.000 claims description 4
• 230000036961 partial effect Effects 0.000 claims description 4
• 239000008024 pharmaceutical diluent Substances 0.000 claims description 4
• 239000008063 pharmaceutical solvent Substances 0.000 claims description 4
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
• 229960002816 potassium chloride Drugs 0.000 claims description 4
• IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 claims description 4
• 229960001289 prazosin Drugs 0.000 claims description 4
• 210000002027 skeletal muscle Anatomy 0.000 claims description 4
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 3
• JVGJINYQXKIBDT-UHFFFAOYSA-N 1-(2-bromophenyl)-5-cyclopropyl-n-(diaminomethylidene)pyrazole-4-carboxamide Chemical compound NC(=N)NC(=O)C=1C=NN(C=2C(=CC=CC=2)Br)C=1C1CC1 JVGJINYQXKIBDT-UHFFFAOYSA-N 0.000 claims description 3
• ZJQFENWMXOATQM-UHFFFAOYSA-N 1-(2-chloro-4-methylsulfonylphenyl)-5-cyclopropyl-n-(diaminomethylidene)pyrazole-4-carboxamide Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1N1C(C2CC2)=C(C(=O)NC(N)=N)C=N1 ZJQFENWMXOATQM-UHFFFAOYSA-N 0.000 claims description 3
• DZXZXYVVTHIODU-UHFFFAOYSA-N 1-(2-chloro-5-methoxyphenyl)-5-cyclopropyl-n-(diaminomethylidene)pyrazole-4-carboxamide Chemical compound COC1=CC=C(Cl)C(N2C(=C(C(=O)NC(N)=N)C=N2)C2CC2)=C1 DZXZXYVVTHIODU-UHFFFAOYSA-N 0.000 claims description 3
• KTMBRLHJWLVWJN-UHFFFAOYSA-N 1-(2-chloro-5-methylsulfonylphenyl)-5-cyclopropyl-n-(diaminomethylidene)pyrazole-4-carboxamide Chemical compound CS(=O)(=O)C1=CC=C(Cl)C(N2C(=C(C(=O)NC(N)=N)C=N2)C2CC2)=C1 KTMBRLHJWLVWJN-UHFFFAOYSA-N 0.000 claims description 3
• OBARLXYWADULRB-UHFFFAOYSA-N 1-(2-chlorophenyl)-5-cyclopropyl-n-(diaminomethylidene)pyrazole-4-carboxamide Chemical compound NC(=N)NC(=O)C=1C=NN(C=2C(=CC=CC=2)Cl)C=1C1CC1 OBARLXYWADULRB-UHFFFAOYSA-N 0.000 claims description 3
• IRQHMLZBZSIPCM-UHFFFAOYSA-N 1-(2-chlorophenyl)-n-(diaminomethylidene)-5-methylpyrazole-4-carboxamide Chemical compound CC1=C(C(=O)NC(N)=N)C=NN1C1=CC=CC=C1Cl IRQHMLZBZSIPCM-UHFFFAOYSA-N 0.000 claims description 3
• AWDVOIVMYCOEGE-UHFFFAOYSA-N 1-(3-chloro-2h-indazol-5-yl)-n-(diaminomethylidene)-5-ethylpyrazole-4-carboxamide Chemical compound CCC1=C(C(=O)NC(N)=N)C=NN1C1=CC=C(NN=C2Cl)C2=C1 AWDVOIVMYCOEGE-UHFFFAOYSA-N 0.000 claims description 3
• PJRZFTYVWGASFT-UHFFFAOYSA-N 1-(3h-benzimidazol-5-yl)-n-(diaminomethylidene)-5-ethylpyrazole-4-carboxamide Chemical compound CCC1=C(C(=O)NC(N)=N)C=NN1C1=CC=C(N=CN2)C2=C1 PJRZFTYVWGASFT-UHFFFAOYSA-N 0.000 claims description 3
• XRJAKWJGDAHTMH-UHFFFAOYSA-N 1-(5-carbamoyl-2-chlorophenyl)-5-cyclopropyl-n-(diaminomethylidene)pyrazole-4-carboxamide Chemical compound NC(=N)NC(=O)C=1C=NN(C=2C(=CC=C(C=2)C(N)=O)Cl)C=1C1CC1 XRJAKWJGDAHTMH-UHFFFAOYSA-N 0.000 claims description 3
• XLMUCHBVEFPSRM-UHFFFAOYSA-N 1-(8-bromoquinolin-5-yl)-5-cyclopropyl-n-(diaminomethylidene)pyrazole-4-carboxamide Chemical compound NC(=N)NC(=O)C=1C=NN(C=2C3=CC=CN=C3C(Br)=CC=2)C=1C1CC1 XLMUCHBVEFPSRM-UHFFFAOYSA-N 0.000 claims description 3
• RQGPHRVFYWHLQW-UHFFFAOYSA-N 1-[2-chloro-5-(dimethylsulfamoyl)phenyl]-5-cyclopropyl-n-(diaminomethylidene)pyrazole-4-carboxamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C(N2C(=C(C(=O)NC(N)=N)C=N2)C2CC2)=C1 RQGPHRVFYWHLQW-UHFFFAOYSA-N 0.000 claims description 3
• 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 claims description 3
• NGHMKLRBKIPQRY-UHFFFAOYSA-N 5-butyl-n-(diaminomethylidene)-1-quinolin-5-ylpyrazole-4-carboxamide Chemical compound CCCCC1=C(C(=O)NC(N)=N)C=NN1C1=CC=CC2=NC=CC=C12 NGHMKLRBKIPQRY-UHFFFAOYSA-N 0.000 claims description 3
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• DJEYTYIFAGYQSJ-UHFFFAOYSA-N 5-cyclopropyl-n-(diaminomethylidene)-1-[4-fluoro-2-(trifluoromethyl)phenyl]pyrazole-4-carboxamide Chemical compound NC(=N)NC(=O)C=1C=NN(C=2C(=CC(F)=CC=2)C(F)(F)F)C=1C1CC1 DJEYTYIFAGYQSJ-UHFFFAOYSA-N 0.000 claims description 3
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• ILFGQIXDWBVCFS-UHFFFAOYSA-N n-(diaminomethylidene)-5-propan-2-yl-1-quinolin-5-ylpyrazole-4-carboxamide Chemical compound CC(C)C1=C(C(=O)NC(N)=N)C=NN1C1=CC=CC2=NC=CC=C12 ILFGQIXDWBVCFS-UHFFFAOYSA-N 0.000 claims description 3
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