OA11450A - N-Ä(substituted five-membered di-or triaza diunsaturated ring)carbonylÜ guanidine derivatives for the treatment of ischemia. - Google Patents

Info

Publication number

OA11450A

OA11450A OA1200000223A OA1200000223A OA11450A OA 11450 A OA11450 A OA 11450A OA 1200000223 A OA1200000223 A OA 1200000223A OA 1200000223 A OA1200000223 A OA 1200000223A OA 11450 A OA11450 A OA 11450A

Authority

OA

OAPI

Prior art keywords

mono

compound

alkyl

pharmaceutically acceptable

optionally

Prior art date

1998-02-27

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• 208000028867 ischemia Diseases 0.000 title claims abstract description 30
• 150000002357 guanidines Chemical class 0.000 title description 4
• 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 title 1
• 230000000451 tissue damage Effects 0.000 claims abstract description 30
• 231100000827 tissue damage Toxicity 0.000 claims abstract description 30
• 239000003112 inhibitor Substances 0.000 claims abstract description 24
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
• 150000001875 compounds Chemical class 0.000 claims description 603
• 125000000217 alkyl group Chemical group 0.000 claims description 292
• -1 benzodioxanyl Chemical group 0.000 claims description 259
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 221
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 151
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 129
• 125000003545 alkoxy group Chemical group 0.000 claims description 128
• 229910052757 nitrogen Inorganic materials 0.000 claims description 117
• 125000003282 alkyl amino group Chemical group 0.000 claims description 112
• 125000004414 alkyl thio group Chemical group 0.000 claims description 110
• 150000003839 salts Chemical class 0.000 claims description 108
• 229940002612 prodrug Drugs 0.000 claims description 95
• 239000000651 prodrug Substances 0.000 claims description 95
• 229920006395 saturated elastomer Polymers 0.000 claims description 93
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 89
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 88
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 86
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 83
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 82
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 81
• 239000000203 mixture Substances 0.000 claims description 81
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 81
• 125000001153 fluoro group Chemical group F* 0.000 claims description 80
• 229910052760 oxygen Inorganic materials 0.000 claims description 80
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 79
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 79
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 79
• 239000001301 oxygen Substances 0.000 claims description 79
• CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 77
• SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 77
• 235000019000 fluorine Nutrition 0.000 claims description 77
• 229960004198 guanidine Drugs 0.000 claims description 77
• 229910052717 sulfur Inorganic materials 0.000 claims description 75
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 74
• 239000011593 sulfur Substances 0.000 claims description 74
• 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 72
• 125000005843 halogen group Chemical group 0.000 claims description 69
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 67
• 125000005842 heteroatom Chemical group 0.000 claims description 66
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 61
• 125000004423 acyloxy group Chemical group 0.000 claims description 60
• 125000001424 substituent group Chemical group 0.000 claims description 58
• 210000001519 tissue Anatomy 0.000 claims description 57
• 229910052799 carbon Inorganic materials 0.000 claims description 56
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 55
• 125000002619 bicyclic group Chemical group 0.000 claims description 53
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 50
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 49
• FUQOTYRCMBZFOL-UHFFFAOYSA-N 5-chloro-1H-indole-2-carboxylic acid Chemical group ClC1=CC=C2NC(C(=O)O)=CC2=C1 FUQOTYRCMBZFOL-UHFFFAOYSA-N 0.000 claims description 47
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
• 241000124008 Mammalia Species 0.000 claims description 40
• 239000002253 acid Substances 0.000 claims description 39
• 230000000694 effects Effects 0.000 claims description 37
• 239000003937 drug carrier Substances 0.000 claims description 35
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
• 239000003288 aldose reductase inhibitor Substances 0.000 claims description 29
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 26
• 230000006378 damage Effects 0.000 claims description 24
• 229940118148 Aldose reductase inhibitor Drugs 0.000 claims description 23
• 239000003981 vehicle Substances 0.000 claims description 22
• 239000003795 chemical substances by application Substances 0.000 claims description 21
• 239000003085 diluting agent Substances 0.000 claims description 21
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 20
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 20
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 18
• 230000002107 myocardial effect Effects 0.000 claims description 18
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 18
• 230000001225 therapeutic effect Effects 0.000 claims description 18
• 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 16
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 16
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 16
• 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 15
• 239000002552 dosage form Substances 0.000 claims description 15
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 15
• 238000001356 surgical procedure Methods 0.000 claims description 15
• ROJNYKZWTOHRNU-UHFFFAOYSA-N 2-chloro-4,5-difluoro-n-[[2-methoxy-5-(methylcarbamoylamino)phenyl]carbamoyl]benzamide Chemical compound CNC(=O)NC1=CC=C(OC)C(NC(=O)NC(=O)C=2C(=CC(F)=C(F)C=2)Cl)=C1 ROJNYKZWTOHRNU-UHFFFAOYSA-N 0.000 claims description 14
• 238000007675 cardiac surgery Methods 0.000 claims description 14
• 238000004519 manufacturing process Methods 0.000 claims description 14
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 14
• 125000000623 heterocyclic group Chemical group 0.000 claims description 13
• 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 12
• 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 12
• 210000004556 brain Anatomy 0.000 claims description 12
• 210000000056 organ Anatomy 0.000 claims description 12
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 11
• 125000001041 indolyl group Chemical group 0.000 claims description 11
• 210000004185 liver Anatomy 0.000 claims description 11
• 229920002527 Glycogen Polymers 0.000 claims description 10
• WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 10
• 230000000747 cardiac effect Effects 0.000 claims description 10
• 239000002327 cardiovascular agent Substances 0.000 claims description 10
• 229940125692 cardiovascular agent Drugs 0.000 claims description 10
• MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 claims description 10
• 229940096919 glycogen Drugs 0.000 claims description 10
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 10
• 125000006709 (C5-C7) cycloalkenyl group Chemical group 0.000 claims description 9
• 208000027418 Wounds and injury Diseases 0.000 claims description 9
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
• 208000014674 injury Diseases 0.000 claims description 9
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 8
• 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 8
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
• 150000002148 esters Chemical class 0.000 claims description 8
• 239000008024 pharmaceutical diluent Substances 0.000 claims description 8
• 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 7
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
• 210000005003 heart tissue Anatomy 0.000 claims description 7
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000001624 naphthyl group Chemical group 0.000 claims description 7
• 239000003379 purinergic P1 receptor agonist Substances 0.000 claims description 7
• 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 6
• 229960005305 adenosine Drugs 0.000 claims description 6
• 125000003118 aryl group Chemical group 0.000 claims description 6
• 125000005874 benzothiadiazolyl group Chemical group 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 125000002950 monocyclic group Chemical group 0.000 claims description 6
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 5
• RIIVBOIBIOLLPO-UHFFFAOYSA-N 2-phthalazin-1-ylacetic acid Chemical group C1=CC=C2C(CC(=O)O)=NN=CC2=C1 RIIVBOIBIOLLPO-UHFFFAOYSA-N 0.000 claims description 5
• 239000005541 ACE inhibitor Substances 0.000 claims description 5
• BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 5
• 229940127291 Calcium channel antagonist Drugs 0.000 claims description 5
• GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 5
• 229960001138 acetylsalicylic acid Drugs 0.000 claims description 5
• 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 5
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
• 239000002876 beta blocker Substances 0.000 claims description 5
• 229940097320 beta blocking agent Drugs 0.000 claims description 5
• 239000000480 calcium channel blocker Substances 0.000 claims description 5
• 229960002896 clonidine Drugs 0.000 claims description 5
• 239000002934 diuretic Substances 0.000 claims description 5
• 239000001103 potassium chloride Substances 0.000 claims description 5
• 235000011164 potassium chloride Nutrition 0.000 claims description 5
• 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 5
• 229960001289 prazosin Drugs 0.000 claims description 5
• 210000002027 skeletal muscle Anatomy 0.000 claims description 5
• 230000002537 thrombolytic effect Effects 0.000 claims description 5
• 238000002054 transplantation Methods 0.000 claims description 5
• 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 4
• 125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 claims description 4
• 239000002593 adenosine A3 receptor agonist Substances 0.000 claims description 4
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[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
• 210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
• 229930182470 glycoside Natural products 0.000 claims description 4
• 150000002338 glycosides Chemical class 0.000 claims description 4
• 210000003734 kidney Anatomy 0.000 claims description 4
• 210000004072 lung Anatomy 0.000 claims description 4
• 229960002816 potassium chloride Drugs 0.000 claims description 4
• 210000001525 retina Anatomy 0.000 claims description 4
• 210000000952 spleen Anatomy 0.000 claims description 4
• 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 claims description 3
• NWYHYJVRSBVTGC-UHFFFAOYSA-N 5-ethyl-1-quinolin-5-ylpyrazole-4-carboxylic acid Chemical compound CCC1=C(C(O)=O)C=NN1C1=CC=CC2=NC=CC=C12 NWYHYJVRSBVTGC-UHFFFAOYSA-N 0.000 claims description 3
• HDPFDIUJHFATNN-UHFFFAOYSA-N 5-methyl-1-naphthalen-1-ylpyrazole-4-carboxylic acid Chemical compound CC1=C(C(O)=O)C=NN1C1=CC=CC2=CC=CC=C12 HDPFDIUJHFATNN-UHFFFAOYSA-N 0.000 claims description 3
• ZEDQLIICZORELY-UHFFFAOYSA-N 5-methyl-1-quinolin-6-ylpyrazole-4-carboxylic acid Chemical compound CC1=C(C(O)=O)C=NN1C1=CC=C(N=CC=C2)C2=C1 ZEDQLIICZORELY-UHFFFAOYSA-N 0.000 claims description 3
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
• 230000000968 intestinal effect Effects 0.000 claims description 3
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• 210000001032 spinal nerve Anatomy 0.000 claims description 3
• YDCGVASFVACWKF-NRFANRHFSA-N 5-chloro-1h-indole-2-carboxylic acid [1-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1yl)-2-oxoethyl]amide Chemical compound C1CC(O)CCN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=C(F)C=C1 YDCGVASFVACWKF-NRFANRHFSA-N 0.000 claims description 2
• CNAUCBNUTUGRDC-UHFFFAOYSA-N 5-cyclopropyl-1-[2-(trifluoromethyl)phenyl]pyrazole-4-carboxylic acid Chemical compound OC(=O)C=1C=NN(C=2C(=CC=CC=2)C(F)(F)F)C=1C1CC1 CNAUCBNUTUGRDC-UHFFFAOYSA-N 0.000 claims description 2
• GDXBRVCQGGKXJY-UHFFFAOYSA-N 5-cyclopropyl-n-(diaminomethylidene)-1-quinolin-5-ylpyrazole-4-carboxamide Chemical compound NC(N)=NC(=O)C=1C=NN(C=2C3=CC=CN=C3C=CC=2)C=1C1CC1 GDXBRVCQGGKXJY-UHFFFAOYSA-N 0.000 claims description 2
• LFOAPSAWYUILCY-UHFFFAOYSA-N 5-cyclopropyl-n-(diaminomethylidene)-1-quinolin-8-ylpyrazole-4-carboxamide Chemical compound NC(=N)NC(=O)C=1C=NN(C=2C3=NC=CC=C3C=CC=2)C=1C1CC1 LFOAPSAWYUILCY-UHFFFAOYSA-N 0.000 claims description 2
• 229940122294 Phosphorylase inhibitor Drugs 0.000 claims description 2
• SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 2
• 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
• 125000004537 indazol-5-yl group Chemical group N1N=CC2=CC(=CC=C12)* 0.000 claims description 2
• YUZRJRZCWFSHBF-UHFFFAOYSA-N n-(diaminomethylidene)-5-propyl-1-quinolin-6-ylpyrazole-4-carboxamide Chemical compound CCCC1=C(C(=O)NC(N)=N)C=NN1C1=CC=C(N=CC=C2)C2=C1 YUZRJRZCWFSHBF-UHFFFAOYSA-N 0.000 claims description 2
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• 229910002651 NO3 Inorganic materials 0.000 claims 3
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• WAAVFJWSRFFSSW-BETUJISGSA-N 5-chloro-n-[2-[(3s,4r)-3,4-dihydroxypyrrolidin-1-yl]-2-oxoethyl]-1h-indole-2-carboxamide Chemical compound C1[C@@H](O)[C@@H](O)CN1C(=O)CNC(=O)C1=CC2=CC(Cl)=CC=C2N1 WAAVFJWSRFFSSW-BETUJISGSA-N 0.000 claims 2
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• ZHHBBKBQTKYXIS-UHFFFAOYSA-N n-(diaminomethylidene)-2-methyl-5-phenylpyrazole-3-carboxamide Chemical compound C1=C(C(=O)NC(N)=N)N(C)N=C1C1=CC=CC=C1 ZHHBBKBQTKYXIS-UHFFFAOYSA-N 0.000 claims 1
• IAPMTJLFQONPMP-UHFFFAOYSA-N n-(diaminomethylidene)-5-ethyl-1-(2-methyl-3h-benzimidazol-5-yl)pyrazole-4-carboxamide Chemical compound CCC1=C(C(=O)NC(N)=N)C=NN1C1=CC=C(N=C(C)N2)C2=C1 IAPMTJLFQONPMP-UHFFFAOYSA-N 0.000 claims 1
• WZNARTSEKZYYQH-UHFFFAOYSA-N n-(diaminomethylidene)-5-ethyl-1-quinolin-6-ylpyrazole-4-carboxamide Chemical compound CCC1=C(C(=O)NC(N)=N)C=NN1C1=CC=C(N=CC=C2)C2=C1 WZNARTSEKZYYQH-UHFFFAOYSA-N 0.000 claims 1
• 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 1
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