CA2938344C - Derives de 5-benzylisoquinoleine pour le traitement de maladies cardiovasculaires - Google Patents
Derives de 5-benzylisoquinoleine pour le traitement de maladies cardiovasculaires Download PDFInfo
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- CA2938344C CA2938344C CA2938344A CA2938344A CA2938344C CA 2938344 C CA2938344 C CA 2938344C CA 2938344 A CA2938344 A CA 2938344A CA 2938344 A CA2938344 A CA 2938344A CA 2938344 C CA2938344 C CA 2938344C
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- 238000011282 treatment Methods 0.000 title claims abstract description 36
- 208000024172 Cardiovascular disease Diseases 0.000 title description 2
- 150000005520 5-benzylisoquinolines Chemical class 0.000 title 1
- 230000004913 activation Effects 0.000 claims abstract description 9
- 239000011435 rock Substances 0.000 claims abstract description 9
- 230000002265 prevention Effects 0.000 claims abstract description 8
- 230000026731 phosphorylation Effects 0.000 claims abstract description 7
- 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 7
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 claims abstract description 6
- 101150111584 RHOA gene Proteins 0.000 claims abstract description 6
- 230000007170 pathology Effects 0.000 claims abstract description 5
- 230000037361 pathway Effects 0.000 claims abstract description 4
- 238000005859 coupling reaction Methods 0.000 claims description 114
- 230000003287 optical effect Effects 0.000 claims description 114
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 110
- -1 5 - ({5 - [(1R) -1-aminoethyl] -3,4-dihydro-2H-chromen-8-yl} carbonyl) isoquinolin Chemical compound 0.000 claims description 97
- 150000001875 compounds Chemical class 0.000 claims description 97
- 239000002253 acid Substances 0.000 claims description 77
- 150000003839 salts Chemical class 0.000 claims description 73
- 150000004677 hydrates Chemical class 0.000 claims description 61
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 48
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 47
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 41
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 33
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000004429 atom Chemical group 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 15
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- 238000006722 reduction reaction Methods 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 210000002216 heart Anatomy 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 208000010412 Glaucoma Diseases 0.000 claims description 7
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 6
- TWASBYPJZBHZQJ-UHFFFAOYSA-N 1-methylcyclopentan-1-amine Chemical compound CC1(N)CCCC1 TWASBYPJZBHZQJ-UHFFFAOYSA-N 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 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
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 claims description 5
- IPBPLHNLRKRLPJ-UHFFFAOYSA-N oxan-4-ylmethanamine Chemical compound NCC1CCOCC1 IPBPLHNLRKRLPJ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 206010016654 Fibrosis Diseases 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 230000004761 fibrosis Effects 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 239000010948 rhodium Substances 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- DYIUGUJFYHGQBI-UHFFFAOYSA-N 1-[3,5-difluoro-4-(isoquinolin-5-ylmethyl)phenyl]ethanamine Chemical compound FC=1C=C(C=C(C=1CC1=C2C=CN=CC2=CC=C1)F)C(C)N DYIUGUJFYHGQBI-UHFFFAOYSA-N 0.000 claims description 3
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 3
- 206010002383 Angina Pectoris Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 3
- 206010072877 Intestinal fibrosis Diseases 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 208000007474 aortic aneurysm Diseases 0.000 claims description 3
- 210000001367 artery Anatomy 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 201000001881 impotence Diseases 0.000 claims description 3
- 208000001286 intracranial vasospasm Diseases 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 3
- 208000037905 systemic hypertension Diseases 0.000 claims description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- LGDWLHZEGZDFKO-UHFFFAOYSA-N 5-[4-(1-amino-2-cyclohexylethyl)-2,6-difluorobenzoyl]-2H-isoquinolin-1-one Chemical compound NC(CC1CCCCC1)C1=CC(=C(C(=O)C2=C3C=CNC(C3=CC=C2)=O)C(=C1)F)F LGDWLHZEGZDFKO-UHFFFAOYSA-N 0.000 claims description 2
- 201000006474 Brain Ischemia Diseases 0.000 claims description 2
- GYXFWMWDEACEHA-UHFFFAOYSA-N CC(C1=CC(F)=C(C2=CC3=CC=CC=C3C(O)=N2)C(F)=C1)N Chemical compound CC(C1=CC(F)=C(C2=CC3=CC=CC=C3C(O)=N2)C(F)=C1)N GYXFWMWDEACEHA-UHFFFAOYSA-N 0.000 claims description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 2
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010022489 Insulin Resistance Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 claims description 2
- MZQREGYHCORZLY-UHFFFAOYSA-N [4-(1-aminoethyl)-2,6-difluorophenyl]-isoquinolin-5-ylmethanone Chemical compound NC(C)C1=CC(=C(C(=C1)F)C(=O)C1=C2C=CN=CC2=CC=C1)F MZQREGYHCORZLY-UHFFFAOYSA-N 0.000 claims description 2
- JQFABIADGHVJOR-UHFFFAOYSA-N [4-(2-aminopropan-2-yl)-2,6-difluorophenyl]-isoquinolin-5-ylmethanone Chemical compound NC(C)(C)C1=CC(=C(C(=C1)F)C(=O)C1=C2C=CN=CC2=CC=C1)F JQFABIADGHVJOR-UHFFFAOYSA-N 0.000 claims description 2
- 238000002399 angioplasty Methods 0.000 claims description 2
- 206010008118 cerebral infarction Diseases 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
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- 201000001421 hyperglycemia Diseases 0.000 claims description 2
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- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 230000002093 peripheral effect Effects 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
- 230000009885 systemic effect Effects 0.000 claims description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 2
- QFRGLNMYAGDIGJ-UHFFFAOYSA-N 5-(2,6-difluoro-4-piperidin-2-ylbenzoyl)-2H-isoquinolin-1-one Chemical compound FC1=C(C(=O)C2=C3C=CNC(C3=CC=C2)=O)C(=CC(=C1)C1NCCCC1)F QFRGLNMYAGDIGJ-UHFFFAOYSA-N 0.000 claims 1
- HALMAQKIBIWCIX-CQSZACIVSA-N 5-[(3R)-3-amino-4,6-difluoro-2,3-dihydro-1H-indene-5-carbonyl]-2H-isoquinolin-1-one Chemical compound N[C@@H]1CCC2=CC(=C(C(=C12)F)C(=O)C1=C2C=CNC(C2=CC=C1)=O)F HALMAQKIBIWCIX-CQSZACIVSA-N 0.000 claims 1
- VSHUNRKWZUXTEZ-UHFFFAOYSA-N 5-[4-(1-aminoethyl)-2-fluoro-3-methoxybenzoyl]-2H-isoquinolin-1-one Chemical compound NC(C)C1=C(C(=C(C(=O)C2=C3C=CNC(C3=CC=C2)=O)C=C1)F)OC VSHUNRKWZUXTEZ-UHFFFAOYSA-N 0.000 claims 1
- FBSSVAIINOQLST-UHFFFAOYSA-N 5-[4-(2-aminopropan-2-yl)-2,6-difluorobenzoyl]-2H-isoquinolin-1-one Chemical compound NC(C)(C)C1=CC(=C(C(=O)C2=C3C=CNC(C3=CC=C2)=O)C(=C1)F)F FBSSVAIINOQLST-UHFFFAOYSA-N 0.000 claims 1
- DUXHWHVGNPCVDY-GFCCVEGCSA-N 5-[4-[(1R)-1-aminoethyl]-2-methylbenzoyl]-2H-isoquinolin-1-one Chemical compound N[C@H](C)C1=CC(=C(C(=O)C2=C3C=CNC(C3=CC=C2)=O)C=C1)C DUXHWHVGNPCVDY-GFCCVEGCSA-N 0.000 claims 1
- IGGBAFJWZHYCGF-LLVKDONJSA-N 5-[8-[(1R)-1-aminoethyl]-2,3-dihydro-1,4-benzodioxine-5-carbonyl]-2H-isoquinolin-1-one Chemical compound N[C@H](C)C1=CC=C(C2=C1OCCO2)C(=O)C1=C2C=CNC(C2=CC=C1)=O IGGBAFJWZHYCGF-LLVKDONJSA-N 0.000 claims 1
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- MZQREGYHCORZLY-SNVBAGLBSA-N [4-[(1R)-1-aminoethyl]-2,6-difluorophenyl]-isoquinolin-5-ylmethanone Chemical compound N[C@H](C)C1=CC(=C(C(=C1)F)C(=O)C1=C2C=CN=CC2=CC=C1)F MZQREGYHCORZLY-SNVBAGLBSA-N 0.000 claims 1
- YOQPTORFJXGRNM-APDXDRDNSA-N [4-[(1S)-1-aminoethyl]-2,6-difluorophenyl]-isoquinolin-5-ylmethanol Chemical compound N[C@@H](C)C1=CC(=C(C(=C1)F)C(O)C1=C2C=CN=CC2=CC=C1)F YOQPTORFJXGRNM-APDXDRDNSA-N 0.000 claims 1
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- 230000015572 biosynthetic process Effects 0.000 abstract description 26
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- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 1045
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 881
- 238000005481 NMR spectroscopy Methods 0.000 description 204
- 239000000243 solution Substances 0.000 description 179
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 169
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- 239000000203 mixture Substances 0.000 description 125
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- ILRSABOCKMOFGW-UHFFFAOYSA-N isoquinoline-5-carbaldehyde Chemical compound N1=CC=C2C(C=O)=CC=CC2=C1 ILRSABOCKMOFGW-UHFFFAOYSA-N 0.000 description 18
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 15
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- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1451389A FR3017868A1 (fr) | 2014-02-21 | 2014-02-21 | Derives d'isoquinoleine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR1451389 | 2014-02-21 | ||
| PCT/FR2015/050415 WO2015124877A1 (fr) | 2014-02-21 | 2015-02-20 | Dérivés de 5-benzylisoquinoléine pour le traitement de maladies cardiovasculaires |
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| CA2938344A1 CA2938344A1 (fr) | 2015-08-27 |
| CA2938344C true CA2938344C (fr) | 2018-07-03 |
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| CA2938344A Active CA2938344C (fr) | 2014-02-21 | 2015-02-20 | Derives de 5-benzylisoquinoleine pour le traitement de maladies cardiovasculaires |
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| US10640496B2 (en) * | 2016-06-17 | 2020-05-05 | Daewoong Pharmaceutical Co., Ltd. | Method for producing diphenylmethane derivative |
| US12338238B2 (en) | 2018-06-07 | 2025-06-24 | Disarm Therapeutics, Inc. | Inhibitors of SARM1 |
| JP2021529830A (ja) * | 2018-07-02 | 2021-11-04 | エコール・ポリテクニーク・フェデラル・ドゥ・ローザンヌ（ウペエフエル）Ｅｃｏｌｅ Ｐｏｌｙｔｅｃｈｎｉｑｕｅ Ｆｅｄｅｒａｌｅ ｄｅ Ｌａｕｓａｎｎｅ （ＥＰＦＬ） | ラクテート増強化合物及びその使用 |
| US11248004B2 (en) | 2018-11-06 | 2022-02-15 | Cervello Therapeutics, Llc. | Substituted isoquinolines as rock kinase inhibitors |
| ES2991902T3 (es) | 2018-11-06 | 2024-12-05 | Cervello Therapeutics LLC | Inhibidores de la cinasa rock |
| BR112021017354A2 (pt) | 2019-03-01 | 2021-11-16 | Beijing Tide Pharmaceutical Co Ltd | Método para o tratamento de doença hepática adiposa e/ou esteatoepatite |
| JP7699820B2 (ja) | 2019-03-22 | 2025-06-30 | サニオナ エー／エス | 新規カリウムチャネル阻害剤 |
| EP4051680B1 (en) | 2019-10-30 | 2025-09-03 | Biogen MA Inc. | Condensed bi-heterocycles as inhibiting agents for bruton's tyrosine kinase |
| CN115974647B (zh) * | 2022-12-05 | 2024-09-03 | 江苏宏邦化工科技有限公司 | 以四氢-4-甲基-2-苯基-2h-吡喃-4-醇为原料制备苯乐戊醇的方法 |
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| EP0187371B1 (en) | 1984-12-27 | 1991-06-19 | Asahi Kasei Kogyo Kabushiki Kaisha | Substituted isoquinolinesulfonyl compounds |
| JPH07277979A (ja) * | 1994-04-12 | 1995-10-24 | Asahi Chem Ind Co Ltd | 過粘性症候群治療または予防剤 |
| ATE506967T1 (de) | 1999-04-27 | 2011-05-15 | Mitsubishi Tanabe Pharma Corp | Arzneimittel zur präventiven oder therapeutische behandlung von lebererkrankungen |
| BR0113170A (pt) * | 2000-08-11 | 2004-01-06 | Purdue Research Foundation | Processo para a preparação de dinapsolina |
| AU2002326823B2 (en) * | 2001-09-06 | 2005-12-15 | Merck Sharp & Dohme Corp. | 17beta-hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases |
| EP1470121B1 (en) * | 2002-01-23 | 2012-07-11 | Bayer HealthCare LLC | Pyrimidine derivatives as rho-kinase inhibitors |
| JP2007008816A (ja) | 2003-10-15 | 2007-01-18 | Ube Ind Ltd | 新規イソキノリン誘導体 |
| RS51139B (sr) * | 2005-06-28 | 2010-10-31 | Sanofi-Aventis | Derivati izohinolina kao inhibitori rho-kinaze |
| MX2008001053A (es) | 2005-07-26 | 2008-03-19 | Sanofi Aventis | Derivados de isoquinolona sustituidos con piperidinilo en calidad de inhibidores de rho-quinasa. |
| PT1912949E (pt) | 2005-07-26 | 2011-11-23 | Sanofi Sa | Derivados de ciclo-hexilamina isoquinolona como inibidores da rho-cinase |
| US7867999B1 (en) * | 2005-12-22 | 2011-01-11 | Alcon Research, Ltd. | Hydroxyamino- and amino-substituted pyridine analogs for treating rho kinase-mediated diseases and conditions |
| US7893088B2 (en) * | 2006-08-18 | 2011-02-22 | N.V. Organon | 6-substituted isoquinoline derivatives |
| DK2102164T3 (da) | 2006-12-27 | 2011-03-21 | Sanofi Aventis | Cycloalkylaminsubstituerede isochinolin- og isochinolinonderivater |
| MX2009005862A (es) * | 2006-12-27 | 2009-06-17 | Sanofi Aventis | Nuevos derivados de isoquinolina e isoquinolinona sustituidos. |
| KR20090094338A (ko) | 2006-12-27 | 2009-09-04 | 사노피-아벤티스 | 치환된 이소퀴놀린 및 이소퀴놀리논 유도체 |
| JP5421783B2 (ja) | 2006-12-27 | 2014-02-19 | サノフイ | Ｒｈｏキナーゼ阻害剤としての置換イソキノロン及びイソキノリノン誘導体 |
| MX2009005964A (es) | 2006-12-27 | 2009-06-15 | Sanofi Aventis | Derivados de isoquinolina sustituidos con cicloalquilamina. |
| ES2364511T3 (es) | 2006-12-27 | 2011-09-05 | Sanofi | Derivados de isoquinolona e isoquinolinona sustituidos con cicloalquilamina. |
| TW200845988A (en) * | 2007-04-05 | 2008-12-01 | Astrazeneca Ab | New compounds and their uses 707 |
| BRPI0914330A2 (pt) | 2008-06-24 | 2019-09-24 | Sanofi Aventis | derivados de isoquinolina e isoquinolinona substituídos bl-e policíclicos |
| PL2313374T3 (pl) | 2008-06-24 | 2014-03-31 | Sanofi Sa | 6-podstawione izochinoliny i izochinolinony |
| US8541449B2 (en) | 2008-06-24 | 2013-09-24 | Sanofi | Substituted isoquinolines and isoquinolinones as Rho kinase inhibitors |
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2014
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