TWI423803B - 經環烷基胺取代之異喹啉及異喹啉酮衍生物 - Google Patents

Info

Publication number

TWI423803B

TWI423803B TW096149807A TW96149807A TWI423803B TW I423803 B TWI423803 B TW I423803B TW 096149807 A TW096149807 A TW 096149807A TW 96149807 A TW96149807 A TW 96149807A TW I423803 B TWI423803 B TW I423803B

Authority

TW

Taiwan

Prior art keywords

alkyl

isoquinolin

chloro

compound

cyclohexyloxy

Prior art date

2006-12-27

Links

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• Global Dossier
• Discuss

• VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 title description 12
• AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title description 6
• 150000002537 isoquinolines Chemical class 0.000 title 1
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 330
• 150000001875 compounds Chemical class 0.000 claims description 151
• 125000000623 heterocyclic group Chemical group 0.000 claims description 107
• -1 (C 1 -C 6 )alkyl-R' Chemical group 0.000 claims description 87
• 229910052736 halogen Inorganic materials 0.000 claims description 81
• 150000002367 halogens Chemical class 0.000 claims description 81
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 65
• 125000000217 alkyl group Chemical group 0.000 claims description 44
• 125000002947 alkylene group Chemical group 0.000 claims description 44
• 150000003839 salts Chemical class 0.000 claims description 41
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 38
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 34
• 125000004432 carbon atom Chemical group C* 0.000 claims description 31
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 29
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 26
• 229910052739 hydrogen Inorganic materials 0.000 claims description 26
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
• 229910052799 carbon Inorganic materials 0.000 claims description 24
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 21
• 125000006720 (C1-C6) alkyl (C6-C10) aryl group Chemical group 0.000 claims description 20
• 229910052757 nitrogen Inorganic materials 0.000 claims description 19
• 125000003118 aryl group Chemical group 0.000 claims description 18
• 239000001257 hydrogen Substances 0.000 claims description 18
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
• 150000001412 amines Chemical group 0.000 claims description 14
• 102000000568 rho-Associated Kinases Human genes 0.000 claims description 14
• 108010041788 rho-Associated Kinases Proteins 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 206010020772 Hypertension Diseases 0.000 claims description 11
• 239000000460 chlorine Substances 0.000 claims description 11
• 229910052801 chlorine Inorganic materials 0.000 claims description 11
• 229910052731 fluorine Inorganic materials 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 10
• 229910052717 sulfur Inorganic materials 0.000 claims description 10
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
• 239000011737 fluorine Substances 0.000 claims description 9
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
• PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical group NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 8
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
• 206010028980 Neoplasm Diseases 0.000 claims description 7
• 125000003342 alkenyl group Chemical group 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 206010012601 diabetes mellitus Diseases 0.000 claims description 7
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
• 206010019280 Heart failures Diseases 0.000 claims description 6
• 206010020880 Hypertrophy Diseases 0.000 claims description 6
• 201000010099 disease Diseases 0.000 claims description 6
• 150000002576 ketones Chemical class 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
• 230000026731 phosphorylation Effects 0.000 claims description 6
• 238000006366 phosphorylation reaction Methods 0.000 claims description 6
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
• 229920002554 vinyl polymer Polymers 0.000 claims description 6
• KIFSYDCZKXYTBM-UHFFFAOYSA-N 6-(4-amino-4-phenylcyclohexyl)oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(N)C1=CC=CC=C1 KIFSYDCZKXYTBM-UHFFFAOYSA-N 0.000 claims description 5
• 206010003210 Arteriosclerosis Diseases 0.000 claims description 5
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
• 208000006011 Stroke Diseases 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 5
• 208000011775 arteriosclerosis disease Diseases 0.000 claims description 5
• 201000011510 cancer Diseases 0.000 claims description 5
• 238000011161 development Methods 0.000 claims description 5
• 230000003176 fibrotic effect Effects 0.000 claims description 5
• 210000004072 lung Anatomy 0.000 claims description 5
• 230000001404 mediated effect Effects 0.000 claims description 5
• 230000002093 peripheral effect Effects 0.000 claims description 5
• 210000002307 prostate Anatomy 0.000 claims description 5
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
• RSDBMUXVVFBHFP-UHFFFAOYSA-N 6-[5-amino-5-(3-methoxypropyl)cyclooctyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CCC(CCCOC)(N)CCCC1OC(C(=C1)Cl)=CC2=C1C(=O)NC=C2 RSDBMUXVVFBHFP-UHFFFAOYSA-N 0.000 claims description 4
• 208000030507 AIDS Diseases 0.000 claims description 4
• 208000024827 Alzheimer disease Diseases 0.000 claims description 4
• 208000035143 Bacterial infection Diseases 0.000 claims description 4
• 201000006474 Brain Ischemia Diseases 0.000 claims description 4
• 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 4
• 208000006029 Cardiomegaly Diseases 0.000 claims description 4
• 208000010228 Erectile Dysfunction Diseases 0.000 claims description 4
• 206010061218 Inflammation Diseases 0.000 claims description 4
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 4
• 206010030043 Ocular hypertension Diseases 0.000 claims description 4
• 208000001132 Osteoporosis Diseases 0.000 claims description 4
• 208000001647 Renal Insufficiency Diseases 0.000 claims description 4
• 208000017442 Retinal disease Diseases 0.000 claims description 4
• 206010038923 Retinopathy Diseases 0.000 claims description 4
• 208000007536 Thrombosis Diseases 0.000 claims description 4
• SOYBTBPSATWLBZ-UHFFFAOYSA-N [4-(7-chloroisoquinolin-6-yl)oxy-1-phenylcyclohexyl]methanamine Chemical compound C1CC(OC=2C(=CC3=CN=CC=C3C=2)Cl)CCC1(CN)C1=CC=CC=C1 SOYBTBPSATWLBZ-UHFFFAOYSA-N 0.000 claims description 4
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 4
• 208000006673 asthma Diseases 0.000 claims description 4
• 208000022362 bacterial infectious disease Diseases 0.000 claims description 4
• 239000003795 chemical substances by application Substances 0.000 claims description 4
• 208000029078 coronary artery disease Diseases 0.000 claims description 4
• 210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
• 201000001881 impotence Diseases 0.000 claims description 4
• 230000004054 inflammatory process Effects 0.000 claims description 4
• 208000001286 intracranial vasospasm Diseases 0.000 claims description 4
• 201000006370 kidney failure Diseases 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 208000004296 neuralgia Diseases 0.000 claims description 4
• 230000004770 neurodegeneration Effects 0.000 claims description 4
• 208000021722 neuropathic pain Diseases 0.000 claims description 4
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 4
• 208000037803 restenosis Diseases 0.000 claims description 4
• 208000020431 spinal cord injury Diseases 0.000 claims description 4
• CONJEOHHKBJXHM-UHFFFAOYSA-N 6-[4-amino-4-(2,3-dihydroxypropyl)cyclohexyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CC(N)(CC(O)CO)CCC1OC(C(=C1)Cl)=CC2=C1C(=O)NC=C2 CONJEOHHKBJXHM-UHFFFAOYSA-N 0.000 claims description 3
• BPZATNXUWRXOFR-UHFFFAOYSA-N 6-[5-amino-5-(2,3-dihydroxypropyl)cyclooctyl]oxy-7-chloro-2h-isoquinolin-1-one Chemical compound C1CCC(N)(CC(O)CO)CCCC1OC(C(=C1)Cl)=CC2=C1C(=O)NC=C2 BPZATNXUWRXOFR-UHFFFAOYSA-N 0.000 claims description 3
• 206010002383 Angina Pectoris Diseases 0.000 claims description 3
• 208000031104 Arterial Occlusive disease Diseases 0.000 claims description 3
• 208000023275 Autoimmune disease Diseases 0.000 claims description 3
• 208000010412 Glaucoma Diseases 0.000 claims description 3
• 206010019663 Hepatic failure Diseases 0.000 claims description 3
• 206010053159 Organ failure Diseases 0.000 claims description 3
• 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 claims description 3
• 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 claims description 3
• 239000000654 additive Substances 0.000 claims description 3
• 230000004064 dysfunction Effects 0.000 claims description 3
• 230000002124 endocrine Effects 0.000 claims description 3
• 206010061989 glomerulosclerosis Diseases 0.000 claims description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
• 208000023589 ischemic disease Diseases 0.000 claims description 3
• 230000000302 ischemic effect Effects 0.000 claims description 3
• 210000003734 kidney Anatomy 0.000 claims description 3
• 208000017169 kidney disease Diseases 0.000 claims description 3
• 210000004185 liver Anatomy 0.000 claims description 3
• 208000007903 liver failure Diseases 0.000 claims description 3
• 231100000835 liver failure Toxicity 0.000 claims description 3
• 150000002825 nitriles Chemical class 0.000 claims description 3
• 210000000056 organ Anatomy 0.000 claims description 3
• 230000008816 organ damage Effects 0.000 claims description 3
• KHXBQZITYUJRMU-UHFFFAOYSA-N 6-[(1-amino-4-bicyclo[2.2.2]octanyl)oxy]-7-chloro-2h-isoquinolin-1-one Chemical compound C1=CNC(=O)C(C=C2Cl)=C1C=C2OC1(CC2)CCC2(N)CC1 KHXBQZITYUJRMU-UHFFFAOYSA-N 0.000 claims description 2
• XCNFSJZIYIUKAZ-CPWXYTRJSA-N 6-[[(1r,5r)-2-amino-6-bicyclo[3.3.1]nonanyl]oxy]-7-chloro-2h-isoquinolin-1-one Chemical compound C1=CNC(=O)C(C=C2Cl)=C1C=C2OC1CC[C@@]2([H])C(N)CC[C@]1([H])C2 XCNFSJZIYIUKAZ-CPWXYTRJSA-N 0.000 claims description 2
• VPSYCISPBILXNB-UHFFFAOYSA-N 7-chloro-6-[4-cyclopropyl-4-(ethylamino)cyclohexyl]oxy-2h-isoquinolin-1-one Chemical compound C1CC(OC=2C(=CC=3C(=O)NC=CC=3C=2)Cl)CCC1(NCC)C1CC1 VPSYCISPBILXNB-UHFFFAOYSA-N 0.000 claims description 2
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
• 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
• 208000002249 Diabetes Complications Diseases 0.000 claims description 2
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 2
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 2
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 2
• 150000001924 cycloalkanes Chemical class 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 150000001335 aliphatic alkanes Chemical class 0.000 claims 3
• 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims 2
• UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 2
• 208000031226 Hyperlipidaemia Diseases 0.000 claims 1
• 102000008934 Muscle Proteins Human genes 0.000 claims 1
• 108010074084 Muscle Proteins Proteins 0.000 claims 1
• 208000006399 Premature Obstetric Labor Diseases 0.000 claims 1
• 206010036600 Premature labour Diseases 0.000 claims 1
• 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims 1
• 239000000835 fiber Substances 0.000 claims 1
• 208000026440 premature labor Diseases 0.000 claims 1
• 150000003254 radicals Chemical group 0.000 claims 1
• 238000000034 method Methods 0.000 description 134
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 98
• 239000000203 mixture Substances 0.000 description 98
• 238000001514 detection method Methods 0.000 description 94
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
• 239000000243 solution Substances 0.000 description 72
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
• 238000006243 chemical reaction Methods 0.000 description 53
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
• 235000019439 ethyl acetate Nutrition 0.000 description 39
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 37
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 36
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
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• 239000011541 reaction mixture Substances 0.000 description 26
• 239000000047 product Substances 0.000 description 25
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 24
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
• 230000015572 biosynthetic process Effects 0.000 description 24
• 238000003786 synthesis reaction Methods 0.000 description 23
• 239000012043 crude product Substances 0.000 description 22
• PTKVNYJGJSGOCB-UHFFFAOYSA-N 7-chloro-6-fluoro-2-[(4-methoxyphenyl)methyl]isoquinolin-1-one Chemical compound C1=CC(OC)=CC=C1CN1C(=O)C2=CC(Cl)=C(F)C=C2C=C1 PTKVNYJGJSGOCB-UHFFFAOYSA-N 0.000 description 20
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
• 239000002585 base Substances 0.000 description 20
• 238000003756 stirring Methods 0.000 description 20
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 19
• 125000001424 substituent group Chemical group 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 18
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• 239000010410 layer Substances 0.000 description 16
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• 150000001721 carbon Chemical group 0.000 description 15
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• 230000003068 static effect Effects 0.000 description 14
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• 239000012074 organic phase Substances 0.000 description 12
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
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• USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 10
• 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 10
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• CUUMQWIQWBZTOL-UHFFFAOYSA-N 6-fluoro-2-[(4-methoxyphenyl)methyl]isoquinolin-1-one Chemical compound C1=CC(OC)=CC=C1CN1C(=O)C2=CC=C(F)C=C2C=C1 CUUMQWIQWBZTOL-UHFFFAOYSA-N 0.000 description 6
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