ES2878054T3 - Espiroheptanil hidantoínas como inhibidores de ROCK - Google Patents

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Publication number

ES2878054T3

ES2878054T3 ES18752653T ES18752653T ES2878054T3 ES 2878054 T3 ES2878054 T3 ES 2878054T3 ES 18752653 T ES18752653 T ES 18752653T ES 18752653 T ES18752653 T ES 18752653T ES 2878054 T3 ES2878054 T3 ES 2878054T3

Authority

ES

Spain

Prior art keywords

alkyl

heptan

heterocycle

carbocycle

oxy

Prior art date

2017-07-12

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 239000011435 rock Substances 0.000 title description 42
• 239000003112 inhibitor Substances 0.000 title description 12
• 150000001469 hydantoins Chemical class 0.000 title description 9
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 442
• 150000001875 compounds Chemical class 0.000 claims abstract description 146
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 118
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 106
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 67
• 150000002367 halogens Chemical class 0.000 claims abstract description 66
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 61
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 59
• 150000003839 salts Chemical class 0.000 claims abstract description 55
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 48
• 125000000304 alkynyl group Chemical group 0.000 claims abstract description 48
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 47
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 45
• 239000012453 solvate Substances 0.000 claims abstract description 41
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 37
• 101100495911 Arabidopsis thaliana CHR10 gene Proteins 0.000 claims abstract description 35
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 28
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 25
• 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 14
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 12
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims abstract description 12
• 150000001721 carbon Chemical group 0.000 claims abstract description 12
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 10
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 8
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 8
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 8
• 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 7
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 5
• 229910052701 rubidium Inorganic materials 0.000 claims abstract description 5
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract 5
• -1 carbocycle Chemical group 0.000 claims description 154
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 95
• 235000005152 nicotinamide Nutrition 0.000 claims description 70
• 239000011570 nicotinamide Substances 0.000 claims description 70
• 125000003003 spiro group Chemical group 0.000 claims description 55
• 229910052739 hydrogen Inorganic materials 0.000 claims description 46
• 229910052717 sulfur Inorganic materials 0.000 claims description 38
• 238000011282 treatment Methods 0.000 claims description 28
• 229960003966 nicotinamide Drugs 0.000 claims description 24
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
• 229910004013 NO 2 Inorganic materials 0.000 claims description 20
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 19
• 239000008194 pharmaceutical composition Substances 0.000 claims description 17
• 201000010099 disease Diseases 0.000 claims description 14
• 230000000694 effects Effects 0.000 claims description 14
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 12
• 239000003937 drug carrier Substances 0.000 claims description 12
• 229940079593 drug Drugs 0.000 claims description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
• 108010041788 rho-Associated Kinases Proteins 0.000 claims description 9
• 102000000568 rho-Associated Kinases Human genes 0.000 claims description 9
• 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 8
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• 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 7
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• 208000035475 disorder Diseases 0.000 claims description 7
• 238000011321 prophylaxis Methods 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 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• 206010019280 Heart failures Diseases 0.000 claims description 5
• 230000001594 aberrant effect Effects 0.000 claims description 5
• XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 claims description 5
• 206010002383 Angina Pectoris Diseases 0.000 claims description 4
• 201000001320 Atherosclerosis Diseases 0.000 claims description 4
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 230000003176 fibrotic effect Effects 0.000 claims description 4
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
• 208000029078 coronary artery disease Diseases 0.000 claims description 3
• 208000027866 inflammatory disease Diseases 0.000 claims description 3
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
• 206010061216 Infarction Diseases 0.000 claims description 2
• 125000005843 halogen group Chemical group 0.000 claims description 2
• 230000007574 infarction Effects 0.000 claims description 2
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
• YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims 6
• DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims 6
• 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims 3
• 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims 2
• 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims 2
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 2
• 125000004282 imidazolidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])N([H])C1([H])* 0.000 claims 2
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 2
• 125000006516 2-(benzyloxy)ethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
• 125000000134 2-(methylsulfanyl)ethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])[*] 0.000 claims 1
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 1
• 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims 1
• 125000005916 2-methylpentyl group Chemical group 0.000 claims 1
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims 1
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
• 208000023275 Autoimmune disease Diseases 0.000 claims 1
• NRBZGXSYLFWLJH-PSWASXTPSA-N C(C1=CC=CC=C1)[C@H]1NC(N(C1=O)C1CC2(CC(C2)OC2=NC=CC=C2C(=O)N)C1)=O Chemical compound C(C1=CC=CC=C1)[C@H]1NC(N(C1=O)C1CC2(CC(C2)OC2=NC=CC=C2C(=O)N)C1)=O NRBZGXSYLFWLJH-PSWASXTPSA-N 0.000 claims 1
• GIILBOOEKVDWPQ-UHFFFAOYSA-N NC(=O)C1=C(OC2CC3(C2)CC(C3)N2C(=O)CN(C2=O)C2=CC=CC=C2)N=CC=C1 Chemical compound NC(=O)C1=C(OC2CC3(C2)CC(C3)N2C(=O)CN(C2=O)C2=CC=CC=C2)N=CC=C1 GIILBOOEKVDWPQ-UHFFFAOYSA-N 0.000 claims 1
• VIQMCVQBGKFAQN-UHFFFAOYSA-N NC(=O)C1=C(OC2CC3(C2)CC(C3)N2C(=O)CN(CC3=CC=CC=C3)C2=O)N=CC=C1 Chemical compound NC(=O)C1=C(OC2CC3(C2)CC(C3)N2C(=O)CN(CC3=CC=CC=C3)C2=O)N=CC=C1 VIQMCVQBGKFAQN-UHFFFAOYSA-N 0.000 claims 1
• 208000031481 Pathologic Constriction Diseases 0.000 claims 1
• 208000018262 Peripheral vascular disease Diseases 0.000 claims 1
• 206010047163 Vasospasm Diseases 0.000 claims 1
• 230000000747 cardiac effect Effects 0.000 claims 1
• 208000026106 cerebrovascular disease Diseases 0.000 claims 1
• 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims 1
• 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 1
• 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims 1
• 210000004072 lung Anatomy 0.000 claims 1
• 210000003205 muscle Anatomy 0.000 claims 1
• 230000002981 neuropathic effect Effects 0.000 claims 1
• FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims 1
• 230000000771 oncological effect Effects 0.000 claims 1
• 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
• 208000037804 stenosis Diseases 0.000 claims 1
• 230000036262 stenosis Effects 0.000 claims 1
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 55
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 16
• 125000004429 atom Chemical group 0.000 abstract description 13
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 6
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract description 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 2
• 229910006074 SO2NH2 Inorganic materials 0.000 abstract 2
• XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 abstract 1
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 abstract 1
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract 1
• 108010081348 HRT1 protein Hairy Proteins 0.000 abstract 1
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 abstract 1
• JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract 1
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 abstract 1
• 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 abstract 1
• 235000019256 formaldehyde Nutrition 0.000 abstract 1
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