HRP20150726T1 - Supstituirani izokinolini i izokinolinoni kao inhibitori rho kinaze - Google Patents
Supstituirani izokinolini i izokinolinoni kao inhibitori rho kinaze Download PDFInfo
- Publication number
- HRP20150726T1 HRP20150726T1 HRP20150726TT HRP20150726T HRP20150726T1 HR P20150726 T1 HRP20150726 T1 HR P20150726T1 HR P20150726T T HRP20150726T T HR P20150726TT HR P20150726 T HRP20150726 T HR P20150726T HR P20150726 T1 HRP20150726 T1 HR P20150726T1
- Authority
- HR
- Croatia
- Prior art keywords
- phenyl
- isoquinolin
- amino
- chloro
- cyclohexyloxy
- Prior art date
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- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 title 1
- 150000002537 isoquinolines Chemical class 0.000 title 1
- 239000003590 rho kinase inhibitor Substances 0.000 title 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 67
- 150000001875 compounds Chemical class 0.000 claims 45
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 20
- 125000001072 heteroaryl group Chemical group 0.000 claims 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 17
- 229910052736 halogen Inorganic materials 0.000 claims 16
- 150000002367 halogens Chemical class 0.000 claims 16
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 14
- 150000003839 salts Chemical class 0.000 claims 13
- 125000004432 carbon atom Chemical group C* 0.000 claims 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims 7
- 125000002947 alkylene group Chemical group 0.000 claims 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 6
- 229910052799 carbon Inorganic materials 0.000 claims 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 4
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims 4
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 4
- 201000010260 leiomyoma Diseases 0.000 claims 4
- -1 O-phenyl Chemical group 0.000 claims 3
- 210000004204 blood vessel Anatomy 0.000 claims 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 3
- 230000002265 prevention Effects 0.000 claims 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 2
- 208000010228 Erectile Dysfunction Diseases 0.000 claims 2
- 206010019663 Hepatic failure Diseases 0.000 claims 2
- 206010020772 Hypertension Diseases 0.000 claims 2
- 206010020880 Hypertrophy Diseases 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 208000002193 Pain Diseases 0.000 claims 2
- 208000001647 Renal Insufficiency Diseases 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 2
- 206010012601 diabetes mellitus Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 208000035475 disorder Diseases 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 230000004064 dysfunction Effects 0.000 claims 2
- 201000001881 impotence Diseases 0.000 claims 2
- 208000001286 intracranial vasospasm Diseases 0.000 claims 2
- 208000017169 kidney disease Diseases 0.000 claims 2
- 201000006370 kidney failure Diseases 0.000 claims 2
- 210000004185 liver Anatomy 0.000 claims 2
- 208000007903 liver failure Diseases 0.000 claims 2
- 231100000835 liver failure Toxicity 0.000 claims 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims 2
- 208000037803 restenosis Diseases 0.000 claims 2
- 208000020431 spinal cord injury Diseases 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
- GTXPCQSOJFSFDA-UHFFFAOYSA-N 6-[3-(1-aminopropyl)-3-(4-fluorophenyl)cyclobutyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1C(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CC1(C(N)CC)C1=CC=C(F)C=C1 GTXPCQSOJFSFDA-UHFFFAOYSA-N 0.000 claims 1
- OFMUARFXQFXAJD-UHFFFAOYSA-N 6-[3-(1-aminopropyl)-3-(4-fluorophenyl)cyclopentyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CC1(C(N)CC)C1=CC=C(F)C=C1 OFMUARFXQFXAJD-UHFFFAOYSA-N 0.000 claims 1
- WRUOESUYDCICAH-UHFFFAOYSA-N 6-[4-(1-amino-1-cyclopentylethyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1C(N)(C)C1CCCC1 WRUOESUYDCICAH-UHFFFAOYSA-N 0.000 claims 1
- HIGFRQRMUXCTFB-UHFFFAOYSA-N 6-[4-(1-amino-1-cyclopropylethyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1C(N)(C)C1CC1 HIGFRQRMUXCTFB-UHFFFAOYSA-N 0.000 claims 1
- BMQMXAQHQBQTQJ-UHFFFAOYSA-N 6-[4-(1-amino-1-phenylethyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1C(N)(C)C1=CC=CC=C1 BMQMXAQHQBQTQJ-UHFFFAOYSA-N 0.000 claims 1
- AXIQQRNMXJFFET-UHFFFAOYSA-N 6-[4-(1-amino-2-methylpropyl)-4-(4-fluorophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)C(C)C)C1=CC=C(F)C=C1 AXIQQRNMXJFFET-UHFFFAOYSA-N 0.000 claims 1
- VLBSXPHPOKRVKU-UHFFFAOYSA-N 6-[4-(1-amino-2-methylpropyl)-4-phenylcyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)C(C)C)C1=CC=CC=C1 VLBSXPHPOKRVKU-UHFFFAOYSA-N 0.000 claims 1
- CRLHBHUZBNCEPQ-UHFFFAOYSA-N 6-[4-(1-amino-3-methylbutyl)-4-phenylcyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CC(C)C)C1=CC=CC=C1 CRLHBHUZBNCEPQ-UHFFFAOYSA-N 0.000 claims 1
- AFRBTAMJGMAFRQ-UHFFFAOYSA-N 6-[4-(1-aminobutyl)-4-(4-fluorophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CCC)C1=CC=C(F)C=C1 AFRBTAMJGMAFRQ-UHFFFAOYSA-N 0.000 claims 1
- LLVCLJWQMUWYEL-UHFFFAOYSA-N 6-[4-(1-aminobutyl)-4-phenylcyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CCC)C1=CC=CC=C1 LLVCLJWQMUWYEL-UHFFFAOYSA-N 0.000 claims 1
- YTKRMQWTMAPYTG-UHFFFAOYSA-N 6-[4-(1-aminocyclopropyl)-4-(2-fluorophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C=1C(=CC=CC=1)F)C1(N)CC1 YTKRMQWTMAPYTG-UHFFFAOYSA-N 0.000 claims 1
- WZPPAUUBOALZLD-UHFFFAOYSA-N 6-[4-(1-aminocyclopropyl)-4-phenylcyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C=1C=CC=CC=1)C1(N)CC1 WZPPAUUBOALZLD-UHFFFAOYSA-N 0.000 claims 1
- OGAQSGVXNLVFBF-UHFFFAOYSA-N 6-[4-(1-aminoethyl)-4-(4-fluorophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)C)C1=CC=C(F)C=C1 OGAQSGVXNLVFBF-UHFFFAOYSA-N 0.000 claims 1
- CIKIGJOBVDDYLZ-UHFFFAOYSA-N 6-[4-(1-aminoethyl)-4-phenylcyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)C)C1=CC=CC=C1 CIKIGJOBVDDYLZ-UHFFFAOYSA-N 0.000 claims 1
- CPGHMTMPNOTZCW-UHFFFAOYSA-N 6-[4-(1-aminopropyl)-4-(2-bromophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CC)C1=CC=CC=C1Br CPGHMTMPNOTZCW-UHFFFAOYSA-N 0.000 claims 1
- ZFUKABWRJSABMY-UHFFFAOYSA-N 6-[4-(1-aminopropyl)-4-(2-chlorophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CC)C1=CC=CC=C1Cl ZFUKABWRJSABMY-UHFFFAOYSA-N 0.000 claims 1
- PNDWHPADZWZCDY-UHFFFAOYSA-N 6-[4-(1-aminopropyl)-4-(2-fluorophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CC)C1=CC=CC=C1F PNDWHPADZWZCDY-UHFFFAOYSA-N 0.000 claims 1
- NJIJMCLSKFYTRP-UHFFFAOYSA-N 6-[4-(1-aminopropyl)-4-(3-bromophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CC)C1=CC=CC(Br)=C1 NJIJMCLSKFYTRP-UHFFFAOYSA-N 0.000 claims 1
- VRZUOBHJGVHYRT-UHFFFAOYSA-N 6-[4-(1-aminopropyl)-4-(4-bromophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CC)C1=CC=C(Br)C=C1 VRZUOBHJGVHYRT-UHFFFAOYSA-N 0.000 claims 1
- XQWHDEGAXVGHOG-UHFFFAOYSA-N 6-[4-(1-aminopropyl)-4-(4-fluorophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CC)C1=CC=C(F)C=C1 XQWHDEGAXVGHOG-UHFFFAOYSA-N 0.000 claims 1
- XJBLGOARPOJWHH-UHFFFAOYSA-N 6-[4-(1-aminopropyl)-4-[4-(trifluoromethyl)phenyl]cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CC)C1=CC=C(C(F)(F)F)C=C1 XJBLGOARPOJWHH-UHFFFAOYSA-N 0.000 claims 1
- MRJGIWUVSRIJSD-UHFFFAOYSA-N 6-[4-(1-aminopropyl)-4-phenylcyclohexyl]oxy-4-bromo-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=C(Br)C=3C=2)Cl)CCC1(C(N)CC)C1=CC=CC=C1 MRJGIWUVSRIJSD-UHFFFAOYSA-N 0.000 claims 1
- SPWUEWHNIVIJRQ-UHFFFAOYSA-N 6-[4-(1-aminopropyl)-4-phenylcyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(N)CC)C1=CC=CC=C1 SPWUEWHNIVIJRQ-UHFFFAOYSA-N 0.000 claims 1
- GYPNUOWBUNRRNV-UHFFFAOYSA-N 6-[4-(1-aminopropyl)-4-phenylcyclohexyl]oxy-7-methyl-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)C)CCC1(C(N)CC)C1=CC=CC=C1 GYPNUOWBUNRRNV-UHFFFAOYSA-N 0.000 claims 1
- MUEXALMEAAAYCS-UHFFFAOYSA-N 6-[4-(1-aminopropyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(C(N)CC)CCC1OC(C(=C1)Cl)=CC2=C1C(=O)NC=C2 MUEXALMEAAAYCS-UHFFFAOYSA-N 0.000 claims 1
- BFZLHUZSEOGNEP-UHFFFAOYSA-N 6-[4-(2-aminopentan-2-yl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(C(C)(N)CCC)CCC1OC(C(=C1)Cl)=CC2=C1C(=O)NC=C2 BFZLHUZSEOGNEP-UHFFFAOYSA-N 0.000 claims 1
- KKPBMLYYYNNEBE-UHFFFAOYSA-N 6-[4-(2-aminopropan-2-yl)-4-(4-fluorophenyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(C)(N)C)C1=CC=C(F)C=C1 KKPBMLYYYNNEBE-UHFFFAOYSA-N 0.000 claims 1
- AZSSAHPYYZHSLO-UHFFFAOYSA-N 6-[4-(2-aminopropan-2-yl)-4-phenylcyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C(C)(N)C)C1=CC=CC=C1 AZSSAHPYYZHSLO-UHFFFAOYSA-N 0.000 claims 1
- JIFURUPEHVTVTI-UHFFFAOYSA-N 6-[4-(3-aminopentan-3-yl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(C(N)(CC)CC)CCC1OC(C(=C1)Cl)=CC2=C1C(=O)NC=C2 JIFURUPEHVTVTI-UHFFFAOYSA-N 0.000 claims 1
- PPHYHKQOKOHXMK-FXMMLYEBSA-N 6-[4-[(r)-amino-(4-fluorophenyl)methyl]cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1([C@@H](C2CCC(CC2)OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)N)=CC=C(F)C=C1 PPHYHKQOKOHXMK-FXMMLYEBSA-N 0.000 claims 1
- PPHYHKQOKOHXMK-KDDGLUCOSA-N 6-[4-[(s)-amino-(4-fluorophenyl)methyl]cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1([C@H](C2CCC(CC2)OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)N)=CC=C(F)C=C1 PPHYHKQOKOHXMK-KDDGLUCOSA-N 0.000 claims 1
- MKPRTRXVCIGXIN-UHFFFAOYSA-N 6-[4-[1-amino-1-(4-fluorophenyl)ethyl]cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1C(N)(C)C1=CC=C(F)C=C1 MKPRTRXVCIGXIN-UHFFFAOYSA-N 0.000 claims 1
- UOGOEUPLBFPATJ-UHFFFAOYSA-N 6-[4-[1-amino-1-(4-methoxyphenyl)ethyl]cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1=CC(OC)=CC=C1C(C)(N)C1CCC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CC1 UOGOEUPLBFPATJ-UHFFFAOYSA-N 0.000 claims 1
- SZTLVAWLUPKYPD-UHFFFAOYSA-N 6-[4-[amino(cyclopropyl)methyl]cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1C(N)C1CC1 SZTLVAWLUPKYPD-UHFFFAOYSA-N 0.000 claims 1
- BMRPPZOLASKMNX-UHFFFAOYSA-N 6-[4-[amino(phenyl)methyl]-4-phenylcyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(C=1C=CC=CC=1)C(N)C1=CC=CC=C1 BMRPPZOLASKMNX-UHFFFAOYSA-N 0.000 claims 1
- YUEHJLLLJGFLIX-UHFFFAOYSA-N 6-[4-[amino(phenyl)methyl]cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1C(N)C1=CC=CC=C1 YUEHJLLLJGFLIX-UHFFFAOYSA-N 0.000 claims 1
- PPHYHKQOKOHXMK-UHFFFAOYSA-N 6-[4-[amino-(4-fluorophenyl)methyl]cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1C(N)C1=CC=C(F)C=C1 PPHYHKQOKOHXMK-UHFFFAOYSA-N 0.000 claims 1
- YURKZQQODXBHTG-UHFFFAOYSA-N 6-[4-[amino-(4-methoxyphenyl)methyl]cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1=CC(OC)=CC=C1C(N)C1CCC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CC1 YURKZQQODXBHTG-UHFFFAOYSA-N 0.000 claims 1
- OTFMTKRGAFUSGP-UHFFFAOYSA-N 6-[4-[amino-(4-methylphenyl)methyl]cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1=CC(C)=CC=C1C(N)C1CCC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CC1 OTFMTKRGAFUSGP-UHFFFAOYSA-N 0.000 claims 1
- CYVRLWCXEBEXLQ-PYOCLPCOSA-N 6-[[(1r,2r,4r)-2-(1-aminopropyl)-2-phenyl-5-bicyclo[2.2.1]heptanyl]oxy]-7-chloro-2h-isoquinolin-1-one Chemical compound C1([C@]2(C(N)CC)[C@]3([H])C[C@@](C(C3)OC=3C(=CC=4C(=O)NC=CC=4C=3)Cl)(C2)[H])=CC=CC=C1 CYVRLWCXEBEXLQ-PYOCLPCOSA-N 0.000 claims 1
- CYVRLWCXEBEXLQ-QQCBBXHASA-N 6-[[(1s,2s,4s)-2-(1-aminopropyl)-2-phenyl-5-bicyclo[2.2.1]heptanyl]oxy]-7-chloro-2h-isoquinolin-1-one Chemical compound C1([C@@]2(C(N)CC)[C@@]3([H])C[C@](C(C3)OC=3C(=CC=4C(=O)NC=CC=4C=3)Cl)(C2)[H])=CC=CC=C1 CYVRLWCXEBEXLQ-QQCBBXHASA-N 0.000 claims 1
- FNJVATRBVCJICC-UHFFFAOYSA-N 6-n-[4-(1-aminopropyl)-4-(4-methoxyphenyl)cyclohexyl]isoquinoline-1,6-diamine Chemical compound C1CC(NC=2C=C3C=CN=C(N)C3=CC=2)CCC1(C(N)CC)C1=CC=C(OC)C=C1 FNJVATRBVCJICC-UHFFFAOYSA-N 0.000 claims 1
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- 230000004054 inflammatory process Effects 0.000 claims 1
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- 230000000302 ischemic effect Effects 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- 150000002632 lipids Chemical class 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 claims 1
- RBMLFOQLFNJMOC-UHFFFAOYSA-N n-[4-(1-aminopropyl)-4-(4-methoxyphenyl)cyclohexyl]isoquinolin-6-amine Chemical compound C1CC(NC=2C=C3C=CN=CC3=CC=2)CCC1(C(N)CC)C1=CC=C(OC)C=C1 RBMLFOQLFNJMOC-UHFFFAOYSA-N 0.000 claims 1
- 230000004770 neurodegeneration Effects 0.000 claims 1
- 210000000056 organ Anatomy 0.000 claims 1
- 230000008816 organ damage Effects 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 208000030613 peripheral artery disease Diseases 0.000 claims 1
- 210000005259 peripheral blood Anatomy 0.000 claims 1
- 239000011886 peripheral blood Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 210000000130 stem cell Anatomy 0.000 claims 1
- 208000037804 stenosis Diseases 0.000 claims 1
- 230000036262 stenosis Effects 0.000 claims 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
Classifications
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Claims (45)
1. Spoj s formulom (I)
[image]
naznačen time da
R1 je H, OH ili NH2;
R3 je H, halogen, CN, (C1-C6)alkil, OH, NH2, ili NHR';
R4 je H, halogen, hidroksi, CN, (C1-C6)alkil, R', ili (C1-C6)alkilen-R';
R5 je H, halogen, CN, (C1-C6)alkil, ili R';
R7 je H, halogen, CN, (C1-C6)alkil, O-(C1-C6)alkil, R', ili SO2-NH2;
R8 je H, halogen ili (C1-C6)alkil;
R9 je OH, halogen, (C1-C6)alkil, C(O)OH, C(O)NH2, ili O-CH3, pri čemu je (C1-C6)alkil nesupstituiran ili supstituiran.
R6 je odsutan
ili je jedan (C1-C4)alkilen vezan na cikloalkilni prsten, u kojem (C1-C4)alkilen tvori drugu vezu na različit ugljikov atom cikloalkilnog prstena tako da tvori biciklički prstenasti sustav s formulom,
[image]
[image]
[image]
ili, ako m i s su 2, m je 3 i s je 1, ili m je 4 i s je 0,
R6 je CH2-CH-(CH2)2 koji je vezan s jednim CH2 na cikloalkilni prsten i druga dva CH2 su vezana na različite ugljikove atome cikloalkilnog prstena; te
ako m je 3 i s je 3,
R6 su dvije metilenske skupine vezane na različite ugljikove atome cikloalkilnog prstena, pri čemu metilenske skupine ili CH2-CH-(CH2)2 skupina su vezane na ugljikove atome cikloalkilnog prstena tako da oni tvore adamantanski sustav s formulom
[image]
pri čemu L se može vezati na bilo koji sekundarni ili tercijarni ugljikov atom i
pri čemu je biciklički prstenski sustav ili adamantanski sustav nesupstituiran ili proizvoljno supstituiran s R9;
R10 je
H, fenil, O-fenil, ili (C5-C6)heteroaril,
pri čemu fenil ili (C5-C6)heteroaril je nesupstituiran ili supstituiran;
R11 je
H,
(C1-C6)alkil,
(C1-C6)alkilen-R',
(C3-C8)cikloalkil,
(C5-C10)heteroaril,
(C3-C8)heterocikloalkil,
(C6-C10)aril;
ili R11 i R12 zajedno s atomom ugljika na koji su vezani tvore (C3-C8)cikloalkilni ili (C3-C8)-heterocikloalkilni prsten;
R12 je
(C1-C6)alkil,
(C3-C8)cikloalkil,
(C5-C10)heteroaril,
(C3-C8)heterocikloalkil, ili
(C6-C10)aril;
ili R12 je H, uz uvjet da r = 2 i drugi R12 nije H;
ili R11 i R12 zajedno s atomom ugljika na koji su vezani tvore (C3-C8)cikloalkilni ili (C3-C8)-heterocikloalkilni prsten;
R13 i R14 su neovisno jedan od drugoga
H,
R',
(C1-C6)alkil,
(C1-C6)alkilen-R',
(C1-C6)alkilen-O-(C1-C6)alkil,
(C1-C6)alkilen-O-R',
C(O)(C1-C6)alkil,
C(O)R', ili
C(O)(C1-C6)alkilen-R'
C(O)N[(C1-C6)alkil]2,
pri čemu R', (C1-C6)alkil, ili (C1-C6)alkilen su nesupstituirani ili supstituirani, ili
R13 i R14, zajedno sa N-atomom na koji su vezani, tvore nesupstituirani ili supstituirani (C3-C8) heterocikloalkilni prsten,
n je 0, 1, 2, 3 ili 4;
m je 1, 2, 3 ili 4;
s je 0, 1, 2, ili 3;
r je 1 ili 2;
L je O, S, ili NH;
R' je
(C3-C8)cikloalkil,
(C5-C10)heteroaril,
(C3-C8)heterocikloalkil,
(C6-C10)aril;
pri čemu u ostatcima R3 do R14 alkil ili alkilen je nesupstituiran ili proizvoljno supstituiran jednom ili više puta s OH, OCH3, C(O)OH, C(O)OCH3, NH2, NHCH3, N(CH3)2, C(O)NH2, C(O)NHCH3 ili C(O)N(CH3)2;
pri čemu u ostatcima R3 do R14 cikloalkil ili heterocikloalkil je nesupstituiran ili proizvoljno supstituiran jednom ili više puta s (C1-C6)alkil, halogen, OH, OCH3, C(O)OH, C(O)OCH3, NH2, NHCH3, N(CH3)2, C(O)NH2, C(O)NHCH3 ili
C(O)N(CH3)2;
pri čemu u ostatcima R3 do R14 alkil ili alkilen je nesupstituiran ili proizvoljno supstituiran jednom ili više puta s halogenom;
pri čemu u ostatcima R3 do R14 (C6-C10)aril i (C5-C10)heteroaril su nesupstituirani ili proizvoljno supstituirani jednom ili više puta sa skupinom koja je neovisno odabrana od skupine koju čine halogen, OH, NO2, N3, CN, C(O)-(C1-C6)alkil, C(O)-(C6-C10)aril, COOH, COO(C1-C6)alkil, CONH2, CONH(C1-C6)alkil, CON[(C1-C6)alkil]2, (C3-C8)cikloalkil, (C1-C6)alkil, (C1 -C6)alkilen-NH(C1-C6)alkil, (C1-C6)alkilen-N[(C1-C6)alkil]2, (C2-C6)alkenil, (C2-C6)alkinil, O-(C1-C6)alkil, O-C(O)-(C1-C6)alkil, PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkil, SO2N[(C1-C6)alkil]2, S-(C1-C6)alkil; SO-(C1-C6)alkil, SO2-(C1-C6)alkil SO2-N=CH-N[(C1-C6)alkil]2, SF5,
C(NH)(NH2), NH2, NH-(C1-C6)alkil, N[(C1-C6)alkil]2, NH-C(O)-(C1-C6)alkil, NH-C(O)O-(C1-C6)alkil, NH-SO2-(C1-C6)alkil, NH-SO2-(C6-C10)aril, NH-SO2-(C5-C10)heteroaril, NH-SO2-(C3-C8)heterocikloalkil, N(C1-C6)alkil-C(O)-(C1-C6)alkil, N(C1-C6)alkil-C(O)O-(C1-C6)alkil, N(C1-C6)alkil-C(O)-NH-(C1-C6)alkil], (C6-C10)aril, (C1-C6)alkilen-(C6-C10)aril, O-(C6-C10)aril, O-(C1-C6)alkilen-(C6-C10)aril, (C5-C10)heteroaril, (C3-C8)heterocikloalkil, (C1-C6)alkilen-(C5-C10)heteroaril, (C1-C6)alkilen-(C3-C8)heterocikloalkil, O-(C1-C6)alkilen-(C5-C10)heteroaril, O-(C1-C6)alkilen-(C3-C8)heterocikloalkil,
pri čemu navedeni (C6-C10)aril, (C5-C10)heteroaril, (C3-C8)heterocikloalkil ili (C3-C8)cikloalkil može biti supstituiran jednom ili do tri puta sa skupinom koja je neovisno odabrana iz skupine koju čine halogen, OH, NO2, CN, O-(C1-C6)alkil, (C1-C6)alkil, NH2, NH(C1-C6)alkil, N[(C1-C6)alkil]2, SO2CH3, COOH, C(O)O-(C1-C6)alkil, CONH2, (C1-C6)alkilen-O-(C1-C6)alkil, (C1-C6)alkilen-O-(C6-C10)aril, ili O-(C1-C6)alkilen-(C6-C10)aril; ili
pri čemu (C6-C10)aril je susjedno supstituiran sa O-(C1-C4)alkilen-O skupinom pri čemu 5-8-člani prsten se tvori zajedno s atomima ugljika na koje su vezani atomi kisika; i
pri čemu arilni supstituenti za (C6-C10)aril, (C5-C10)heteroaril, (C3-C8)heterocikloalkil ili (C3-C8)cikloalkil skupine ne mogu biti dalje supstituirani sa skupinom koja sadrži aril, heteroaril, heterocikloalkil, ili (C3-C8)cikloalkil;
njihovi stereoizomerni i/ili tautomerni oblici i/ili njihove farmaceutski prihvatljive soli.
2. Spoj s formulom (I) prema zahtjevu 1, pri čemu R1 je H i naznačen time da ima formulu (II)
[image]
3. Spoj s formulom (I) prema zahtjevu 1, pri čemu R1 je OH i naznačen time da ima formulu (IIIa)
[image]
ili formulu (IIIb)
[image]
4. Spoj prema zahtjevu 1, naznačen time da R1 je NH2.
5. Spoj prema jednom od zahtjeva od 1 do 4, naznačen time da R3 je H, halogen, (C1-C6)alkil, ili NHR', pri čemu (C1-C6)alkil i R' su nesupstituirani ili supstituirani.
6. Spoj prema jednom od zahtjeva od 1 do 5, naznačen time da R3 je H.
7. Spoj prema jednom od zahtjeva od 1 do 6, naznačen time da R4 je H, halogen, (C1-C6)alkil ili (C1-C2)alkilen-fenil, pri čemu (C1-C6)alkil ili fenil su nesupstituirani ili supstituirani.
8. Spoj prema jednom od zahtjeva od 1 do 7, naznačen time da R4 je H ili halogen.
9. Spoj prema jednom od zahtjeva od 1 do 8, naznačen time da R5 je H, halogen, (C1-C6)alkil, (C6-C10)aril, (C3-C8)cikloalkil ili (C5-C10)heteroaril, pri čemu (C1-C6)alkil, (C6-C10)aril, (C3-C8)cikloalkil ili (C5-C10)heteroaril su nesupstituirani ili supstituirani.
10. Spoj prema jednom od zahtjeva od 1 do 9, naznačen time da R5 je H.
11. Spoj prema jednom od zahtjeva od 1 do 10, naznačen time da R7 je H, halogen, (C1-C6)alkil, O-(C1-C6)alkil, ili R', pri čemu (C1-C6)alkil ili R' su nesupstituirani ili supstituirani.
12. Spoj prema jednom od zahtjeva od 1 do 11, naznačen time da R7 je H, metil ili kloro.
13. Spoj prema jednom od zahtjeva od 1 do 12, naznačen time da R8 je H.
14. Spoj prema jednom od zahtjeva od 1 do 13, naznačen time da R9 je nesupstituiran ili supstituiran (C1-C6)alkil.
15. Spoj prema bilo kojem od zahtjeva 1 do 14, naznačen time da R10 je H ili fenil proizvoljno supstituiran s (C1-C6)alkil, F, Cl, Br, OMe ili CF3.
16. Spoj prema bilo kojem od zahtjeva 1 do 15, naznačen time da R10 je H.
17. Spoj prema bilo kojem od zahtjeva 1 do 16, naznačen time da R11 je H ili metil.
18. Spoj prema bilo kojem od zahtjeva 1 do 17, naznačen time da R12 je
(C1-C6)alkil, pri čemu proizvoljno jedan ili više vodika su supstituirani s fluoro;
(C3-C8)cikloalkil,
(C5-C6)heteroaril, ili
(C6-C10)aril,
pri čemu (C3-C8)cikloalkil, (C5-C6)heteroaril ili (C6-C10)aril su nesupstituirani ili supstituirani.
19. Spoj prema bilo kojem od zahtjeva 1 do 18, naznačen time da R12 je metil, etil, propil, izopropil, ciklopropil, trifluorometil, tiazolil ili fenil nesupstituiran ili supstituiran s (C1-C4)alkilom ili halogenom.
20. Spoj prema bilo kojem od zahtjeva 1 do 18, naznačen time da R11 i R12 tvore supstituiran ili nesupstituiran (C3-C8)cikloalkilni prsten.
21. Spoj prema jednom od zahtjeva od 1 do 20, naznačen time da R13 i R14 su neovisno jedan od drugoga
H,
(C1-C6)alkil,
(C3-C8)cikloalkil,
(C1-C4)alkilen-(C3-C8)cikloalkil,
(C1-C4)alkilen-(C5-C10)heteroaril,
(C1-C4)alkilen-(C3-C8)heterocikloalkil,
C1-C4)alkilen-(C6-C10)aril,
(C1-C6)alkilen-O-(C1-C6)alkil,
C(O)(C1-C6)alkil, ili
R13 i R14, zajedno sa N-atomom na koji su vezani, tvore (C3-C8) heterocikloalkil skupinu,
pri čemu (C1-C6)alkil, (C3-C8)cikloalkil, (C1-C4)alkilen, C5-C10)heteroaril, (C3-C8)heterocikloalkil, ili (C6-C10)aril su nesupstituirani ili supstituirani.
22. Spoj prema bilo kojem od zahtjeva 1 do 21, naznačen time da
R13 je H ili (C1-C6)alkil; i
R14 je
H,
(C1-C6)alkil,
(C3-C8)cikloalkil,
(C1-C4)alkilen-(C3-C8)cikloalkil,
(C1-C4)alkilen-(C5-C10)heteroaril,
(C1-C4)alkilen-(C3-C8)heterocikloalkil,
(C1-C4)alkilen-(C6-C10)aril, ili
(C1-C4)alkilen-O-(C1-C6)alkil,
pri čemu (C1-C6)alkil, (C3-C8)cikloalkil, (C1-C4)alkilen, (C5-C10)heteroaril, (C3-C8)heterocikloalkil, ili (C6-C10)aril su nesupstituirani ili supstituirani.
23. Spoj prema bilo kojem od zahtjeva 1 do 22, naznačen time da
R13 je H, (C1-C6)alkil i
R14 je H, (C1-C6)alkil ili (C3-C8)cikloalkil,
pri čemu (C1-C6)alkil ili (C3-C8)cikloalkil su nesupstituirani ili supstituirani.
24. Spoj prema bilo kojem od zahtjeva 1 do 23, naznačen time da R13 i R14 su H.
25. Spoj prema jednom od zahtjeva od 1 do 24, naznačen time da R6 je odsutan.
26. Spoj prema jednom od zahtjeva od 1 do 25, naznačen time da m je 2 i s je 2
27. Spoj prema jednom od zahtjeva od 1 do 26, naznačen time da m je 3 i s je 1.
28. Spoj prema jednom od zahtjeva od 1 do 27, naznačen time da n je 0, 1, ili 2.
29. Spoj prema jednom od zahtjeva od 1 do 28, naznačen time da n je 0.
30. Spoj prema jednom od zahtjeva od 1 do 29, naznačen time da r je 1.
31. Spoj prema jednom od zahtjeva od 1 do 30, naznačen time da L je S.
32. Spoj prema jednom od zahtjeva od 1 do 31, naznačen time da L je NH.
33. Spoj prema jednom od zahtjeva od 1 do 32, naznačen time da L je O.
34. Spoj prema zahtjevu 1 naznačen time da je odabran iz skupine koja sadrži
6-[4-(1-amino-propil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-ciklopropil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-{[4-(1-aminopropil)-4-fenilcikloheksil]oksi}-7-kloroizokinolin-1(2H)-on,
6-[4-(1-amino-butil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-butil)-4-(4-fluoro-fenil)-ciklo-heksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-propil)-4-(4-bromo-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-propil)-4-(2-bromo-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-propil)-4-(4-trifluorometil-fenil)-ciklo-heksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-propil)-4-(2-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-propil)-4-(2-kloro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-propil)-4-fenil-cikloheksiloksi]-7-metil-2H-izokinolin-1-on,
6-[4-(1-amino-etil)-4-(4-fluoro-fenil)-ciklo-heksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-2-metil-propil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-3-metil-butil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(amino-fenil-metil)-4-fenil-ciklo-heksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-1-metil-etil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-ciklopropil)-4-(2-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-etil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-1-metil-etil)-4-fenil-ciklo-heksiloksi]-7-kloro-2H-izokinolin-1-on,
6-(4-[amino(ciklopropil)metil]-4-fenil-cikloheksil}oksi)-7-kloroizokinolin-1(2H)-on,
6-[4-(1-amino-propil)-4-(4-izopropil-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-propil)-4-(3-metoksi)-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-propil)-4-(3-bromo-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-2-metil-propil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on, ili
6-[4-(1-amino-propil)-4-fenil-cikloheksiloksi]-4-bromo-7-kloro-2H-izokinolin-1-on,
njihovi stereoizomerni i/ili tautomerni oblici i/ili njihove farmaceutski prihvatljive soli.
35. Spoj prema zahtjevu 1 naznačen time da je odabran iz skupine koja sadrži
cis-6-[4-(1-amino-propil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(1-amino-propil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-ciklopropil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-{[4-(1-amino-propil)-4-fenilcikloheksil]oksi}-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(1-amino-propil)-4-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-butil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(1-amino-butil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-butil)-4-(4-fluoro-fenil)-ciklo-heksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(1-amino-butil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-Amin-propil)-4-(4-bromo-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(2-bromo-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on
cis-6-[4-(1-amino-propil)-4-(4-trifluorometil-fenil)-ciklo-heksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(2-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(2-kloro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-fenil-cikloheksiloksi]-7-metil-2H-izokinolin-1-on,
cis-6-[4-(1-amino-etil)-4-(4-fluoro-fenil)-ciklo-heksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(1-amino-etil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3-bromo-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(1-amino-propil)-4-(3-bromo-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3-metoksi)-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(1-amino-propil)-4-(3-metoksi-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(amino-fenil-metil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(1-amino-2-metil-propil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(1-amino-3-metil-butil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(amino-fenil-metil)-4-fenil-ciklo-heksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-(1-amino-1-metil-etil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-ciklopropil)-4-(2-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-etil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-1-metil-etil)-4-fenil-ciklo-heksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-(4-[amino(ciklopropil)metil]-4-fenil-ciklo-heksil}oksi)-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(4-izopropil-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-2-metil-propil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on, i
cis-6-[4-(1-amino-propil)-4-fenil-cikloheksiloksi]-4-bromo-7-kloro-2H-izokinolin-1-on,
njihovi stereoizomerni i/ili tautomerni oblici i/ili njihove farmaceutski prihvatljive soli.
36. Spoj prema zahtjevu 1 naznačen time da je odabran iz skupine koja sadrži
trans-6-[4-((S)-amino-fenil-metil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
trans-6-[4-((R)-amino-fenil-metil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-((S)-1-amino-propil)-4-fluoro-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-((R)-1-amino-propil)-4-fluoro-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-((S)-amino-ciklopropil-metil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-((R)-amino-ciklopropil-metil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-((R)-amino-ciklopropil-metil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-((S)-amino-ciklopropil-metil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-((S)-1-amino-etil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-((R)-1-amino-etil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-{4-[(S)-amino-(4-fluoro-fenil)-metil]-cikloheksiloksi}-7-kloro-2H-izokinolin-1-on,
6-{4-[(R)-amino-(4-fluoro-fenil)-metil]-cikloheksiloksi}-7-kloro-2H-izokinolin-1-on,
cis-6-[4-((R)-1-amino-propil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on, i
cis-6-[4-((S)-1-amino-propil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on, njihovi tautomerni oblici i/ili njihove farmaceutski prihvatljive soli.
37. Spoj prema zahtjevu 1 naznačen time da je odabran iz skupine koja sadrži
cis-6-[4-(1-amino-propil)-4-piridin-2-il-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(2,4-difluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(4-fluoro-2-metil-fenil)cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3,5-difluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3,4-difluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-o-tolil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(2-trifluorometoksi-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(4-fluoro-3-metoksi-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3-ethoksi-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3-metoksi-4-metil-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3,4-difluoro-fenil)-cikloheksiloksi]-7-metil-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3,5-difluoro-fenil)-cikloheksiloksi]-7-fluoro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3,4-difluoro-fenil)-cikloheksiloksi]-7-fluoro-5-metil-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3,5-difluoro-fenil)-cikloheksiloksi]-7-metoksi-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(2-metoksi-fenil)-cikloheksiloksi]-7-kloro-2H izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(4-trifluoro-metoksi-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-1-metil-etil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3,5-difluoro-fenil)-cikloheksiloksi]-4-benzil-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3,5-difluoro-fenil)-cikloheksiloksi]-5-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3,5-difluoro-fenil)-cikloheksiloksi]-5,7-dimetil-2H-izokinolin-1-on,
cis-6-[4-(amino-ciklopropil-metil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3-trifluorometil-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3-trifluorometoksi-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3-trifluorometoksi-fenil)-cikloheksiloksi]-7-metil-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-(3-trifluorometil-fenil)-cikloheksiloksi]-7-metil-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-fenil-cikloheksiloksi]-7-fluoro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-fenil-cikloheksiloksi]-7-fluoro-5-metil-2H-izokinolin-1-on,
cis-6-[4-(1-amino-propil)-4-fenil-cikloheksiloksi]-4-benzil-7-kloro-2H-izokinolin-1-on,
cis-4-[1-(1-amino-propil)-4-(7-kloro-1-okso-1,2-dihidro-izokinolin-6-iloksi)-cikloheksil]-benzonitril,
cis-3-[1-(1-amino-propil)-4-(7-kloro-1-okso-1,2-dihidro-izokinolin-6-iloksi)-cikloheksil]benzonitril,
6-[cis-4-(1-amino-propil)-4-(3-methanesulfonil-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[(1S,4S,5S)-5-(1-amino-propil)-5-fenil-biciklo[2.2.1]hept-2-iloksi]-7-kloro-2H-izokinolin-1-on,
6-[(1R,4R,5R)-5-(1-amino-propil)-5-fenil-biciklo[2.2.1]hept-2-iloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-benzilamino-propil)-4-fenil-cikloheksiloksi]-7-metil-2H-izokinolin-1-on,
cis-6-[4-(1-dietilamino-propil)-4-fenil-cikloheksiloksi]-7-metil-2H-izokinolin-1-on,
cis-7-metil-6-[4-(1-propilamino-propil)-4-(3-trifluorometil-fenil)-cikloheksiloksi]-2H-izokinolin-1-on,
cis-6-[4-(1-kenzilamino-propil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-7-Kloro-6-[4-(1-isobutilamino-propil)-4-fenil-cikloheksiloksi]-2H-izokinolin-1-on,
cis-6-[4-(1-kutilamino-propil)-4-fenil-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-7-kloro-6-{4-[1-(ciklopropilmetil-amino)-propil]-4-fenil-cikloheksiloksi}-2H-izokinolin-1-on,
cis-6-[4-(2-amino-propil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(2-amino-butil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-2-fluoro-etil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
cis-6-[4-(1-amino-3-metoksi-propil)-4-(4-fluoro-fenil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-[3-(1-amino-propil)-3-(4-fluoro-fenil)-ciklobutiloksi]-7-kloro-2H-izokinolin-1-on, i
6-[3-(1-amino-propil)-3-(4-fluoro-fenil)-ciklopentiloksi]-7-kloro-2H-izokinolin-1-on,
i njihovi stereoizomerni i/ili tautomerni oblici i/ili njihove farmaceutski prihvatljive soli.
38. Spoj prema zahtjevu 1 naznačen time da je odabran iz skupine koja sadrži
cis-1-[4-(7-kloro-izokinolin-6-iloksi)-1-(3,4-difluoro-fenil)-cikloheksil]-propilamin,
cis-1-[4-(7-bromo-izokinolin-6-iloksi)-1-(3,4-difluoro-fenil)-cikloheksil]-propilamin,
cis-1-[1-(3,5-difluoro-fenil)-4-(5,7-dimetil-izokinolin-6-iloksi)-cikloheksil]-propilamin,
cis-1-[1-(3,5-difluoro-fenil)-4-(7-fluoro-5-metil-izokinolin-6-iloksi)-cikloheksil]-propilamin,
cis-1-[1-(3,4-difluoro-fenil)-4-(7-fluoro-izokinolin-6-iloksi)-cikloheksil]-propilamin,
cis-1-[4-(7-kloro-izokinolin-6-iloksi)-1-(3,5-difluoro-fenil)-cikloheksil]-propilamin,
cis-1-[4-(5-kloro-izokinolin-6-iloksi)-1-(3,5-difluoro-fenil)-cikloheksil]-propilamin,
cis-1-[4-(7-kloro-izokinolin-6-iloksi)-1-fenil-cikloheksil]-propilamin,
cis-1-[4-(5,7-dimetil-izokinolin-6-iloksi)-1-fenil-cikloheksil]-propilamin,
cis-1-[4-(7-fluoro-izokinolin-6-iloksi)-1-fenil-cikloheksil]-propilamin,
cis-1-[4-(5-kloro-izokinolin-6-iloksi)-1-fenil-cikloheksil]-propilamin,
cis-1-[4-(7-fluoro-5-metil-izokinolin-6-iloksi)-1-fenil-cikloheksil]-propilamin,
cis-1-[4-(7-bromo-izokinolin-6-iloksi)-1-fenil-cikloheksil]-propilamin,
cis-1-[4-(7-metil-izokinolin-6-iloksi)-1-fenil-cikloheksil]-propilamin,
cis-6-[4-(1-amino-propil)-4-fenil-cikloheksiloksi]-7-kloro-izokinolin-1-ilamin,
[4-(1-amino-propil)-4-(4-metoksi-fenil)-cikloheksil]-izokinolin-6-il-amin, i
1-amino-[4-(1-amino-propil)-4-(4-metoksi-fenil)-cikloheksil]-izokinolin-6-il-amin,
i njihovi stereoizomerni i/ili tautomerni oblici i/ili njihove farmaceutski prihvatljive soli.
39. Spoj prema zahtjevu 1 naznačen time da je odabran iz skupine koja sadrži
6-[4-(1-amino-1-fenil-etil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
6-{4-[amino-(4-metoksi-fenil)-metil]-cikloheksiloksi}-7-kloro-2H-izokinolin-1-on,
6-{4-[amino-(4-fluoro-fenil)-metil]-cikloheksiloksi}-7-kloro-2H-izokinolin-1-on,
6-[4-(amino-p-tolil-metil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on, ili
6-[4-(amino-fenil-metil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
i njihovi stereoizomerni i/ili tautomerni oblici i/ili njihove farmaceutski prihvatljive soli.
40. Spoj prema zahtjevu 1 naznačen time da je odabran iz skupine koja sadrži
6-{4-[1-amino-1-(4-fluoro-fenil)-etil]-cikloheksiloksi}-7-kloro-2H-izokinolin-1-on,
6-{4-[1-amino-1-(4-metoksi-fenil)-etil]-cikloheksiloksi}-7-kloro-2H-izokinolin-1-on,
6-{4-[1-amino-1-ciklopentil-etil]-cikloheksiloksi}-7-kloro-2H-izokinolin-1-on,
6-{4-[1-amino-1-etil-propil]-cikloheksiloksi}-7-kloro-2H-izokinolin-1-on,
6-{4-[1-amino-1-ciklopropil-etil]-cikloheksiloksi}-7-kloro-2H-izokinolin-1-on,
6-{4-[1-amino-1-n-propil-etil]-cikloheksiloksi}-7-kloro-2H-izokinolin-1-on,
6-[4-(1-amino-propil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on, i
6-[4-(amino-ciklopropil-metil)-cikloheksiloksi]-7-kloro-2H-izokinolin-1-on,
i njihovi stereoizomerni i/ili tautomerni oblici i/ili njihove farmaceutski prihvatljive soli.
41. Spoj s formulom (I) i/ili njegova farmaceutski prihvatljiva sol prema jednom od zahtjeva 1 do 41 naznačen time da je za uporabu kao lijek.
42. Spoj s formulom (I) i/ili njegova farmaceutski prihvatljiva sol prema jednom od zahtjeva 1 do 40 naznačen time da je za uporabu za liječenje i/ili sprječavanje hipertenzije, plućne hipertenzije, očne hipertenzije, retinopatije, glaukoma, poremećaja perifernog krvotoka, bolesti perifernih arterija (PAOD), koronarne bolesti srca, angine pektoris, hipertrofije srca, zatajenja srca, ishemijskih bolesti, ishemijskog zatajenja organa (krajnjeg oštećenja organa), fibroidnih pluća, fibroidne jetre, zatajenja jetre, nefropatije, zatajenja bubrega, fibroze bubrega, glomeruloskleroze bubrega, hipertrofije organa, astme, kronične opstruktivne plućne bolesti (KOPB), sindroma respiratornog distresa kod odraslih, trombotičnih poremećaja, kapi, cerebralnog vazospazma, cerebralne ishemije, boli, degeneracije neurona, ozljede leđne moždine, Alzheimerove bolesti, prijevremenog poroda, erektilne disfunkcije, endokrinih disfunkcija, arterioskleroze, hipertrofije prostate, dijabetesa i komplikacija kod dijabetesa, metaboličkog sindroma, restenoze krvnih žila, ateroskleroze, upale, autoimunih bolesti, AIDS-a, osteopatije, infekcije probavnog sustava s bakterijama, sepse ili razvoja i napredovanja raka.
43. Spoj s formulom (I) i/ili njegova farmaceutski prihvatljiva sol prema jednom od zahtjeva 1 do 40 naznačen time da je za uporabu za liječenje i/ili sprječavanje hipertenzije, plućne hipertenzije, fibroidne jetre, zatajenja jetre, nefropatije, zatajenja bubrega, kronične opstruktivne plućne bolesti (KOPB), cerebralnog vazospazma, boli, ozljede leđne moždine, erektilne disfunkcije, restenoze krvnih žila, ili razvoja i napredovanja raka.
44. Spoj s formulom (I) i/ili njegova farmaceutski prihvatljiva sol prema jednom od zahtjeva 1 do 40 naznačen time da je za uporabu kod ljekovitih pristupa povezanih s matičnim stanicama ili kod liječenja induciranim pluripotentnim matičnim stanicama, za poboljšanje prepoznavanja ili kod liječenja ili prevencije depresije, epilepsije, fibroidnog srca, papilarne nekroze bubrega, tubulo-intersticijske disfunkcije, multiple skleroze, stenoze krvnih žila ili lipidnih poremećaja.
45. Lijek naznačen time da sadrži djelotvornu količinu barem jednog spoja s formulom (I) i/ili njegove farmaceutski prihvatljive soli prema jednom od zahtjeva 1 do 40, farmaceutski prihvatljive pomoćne tvari i nosače, te gdje je to prikladno, dodatne aditive i/ili druge aktivne sastojke.
Applications Claiming Priority (4)
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|---|---|---|---|
| EP08290606 | 2008-06-24 | ||
| US15314909P | 2009-02-17 | 2009-02-17 | |
| PCT/EP2009/004421 WO2009156100A1 (en) | 2008-06-24 | 2009-06-19 | Substituted isoquinolines and isoquinolinones as rho kinase inhibitors |
| EP20090768949 EP2303846B1 (en) | 2008-06-24 | 2009-06-19 | Substituted isoquinolines and isoquinolinones as rho kinase inhibitors |
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| HRP20150726TT HRP20150726T1 (hr) | 2008-06-24 | 2015-07-03 | Supstituirani izokinolini i izokinolinoni kao inhibitori rho kinaze |
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| US (1) | US8541449B2 (hr) |
| EP (1) | EP2303846B1 (hr) |
| JP (1) | JP5713893B2 (hr) |
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| EP2809659A1 (en) | 2012-02-03 | 2014-12-10 | Basf Se | Fungicidal pyrimidine compounds |
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| WO2013113776A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
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| FR3017868A1 (fr) | 2014-02-21 | 2015-08-28 | Servier Lab | Derives d'isoquinoleine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| WO2016180918A1 (en) | 2015-05-12 | 2016-11-17 | Platod | Combination of pharmacological and microfluidic features for improved platelets production |
| EP3640242B1 (en) | 2017-06-16 | 2023-04-19 | Hitgen Ltd. | Rock-inhibiting compound and uses thereof |
| CN109810174B (zh) * | 2017-11-21 | 2021-01-01 | 首都医科大学 | 异喹啉-3-甲酰-TARGD(aa)aa,其制备,抗静脉血栓活性和应用 |
| CN110317169B (zh) * | 2018-03-29 | 2022-06-03 | 复旦大学 | 一种1-取代异喹啉酮化合物及其制备方法 |
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