AU2007338408B2 - Substituted isoquinoline and isoquinolinone derivatives - Google Patents
Substituted isoquinoline and isoquinolinone derivatives Download PDFInfo
- Publication number
- AU2007338408B2 AU2007338408B2 AU2007338408A AU2007338408A AU2007338408B2 AU 2007338408 B2 AU2007338408 B2 AU 2007338408B2 AU 2007338408 A AU2007338408 A AU 2007338408A AU 2007338408 A AU2007338408 A AU 2007338408A AU 2007338408 B2 AU2007338408 B2 AU 2007338408B2
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- alkylene
- aryl
- heterocyclyl
- isoquinolin
- Prior art date
- 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.)
- Ceased
Links
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 title abstract description 19
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title description 20
- 150000002537 isoquinolines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 161
- -1 6-substituted isoquinoline Chemical class 0.000 claims abstract description 52
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 200
- 125000000217 alkyl group Chemical group 0.000 claims description 133
- 125000000623 heterocyclic group Chemical group 0.000 claims description 96
- 125000003118 aryl group Chemical group 0.000 claims description 94
- 229910052736 halogen Inorganic materials 0.000 claims description 88
- 150000002367 halogens Chemical class 0.000 claims description 88
- 238000000034 method Methods 0.000 claims description 78
- 150000003839 salts Chemical class 0.000 claims description 42
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- 125000002947 alkylene group Chemical group 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 18
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 206010020772 Hypertension Diseases 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 201000010260 leiomyoma Diseases 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 206010012601 diabetes mellitus Diseases 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 206010019280 Heart failures Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 208000015181 infectious disease Diseases 0.000 claims description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 238000011161 development Methods 0.000 claims description 6
- 210000004072 lung Anatomy 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 208000030507 AIDS Diseases 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 241000894006 Bacteria Species 0.000 claims description 5
- 201000006474 Brain Ischemia Diseases 0.000 claims description 5
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 5
- 208000006029 Cardiomegaly Diseases 0.000 claims description 5
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 5
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 5
- 206010030043 Ocular hypertension Diseases 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 5
- 208000017442 Retinal disease Diseases 0.000 claims description 5
- 206010038923 Retinopathy Diseases 0.000 claims description 5
- 208000007536 Thrombosis Diseases 0.000 claims description 5
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 206010008118 cerebral infarction Diseases 0.000 claims description 5
- 208000029078 coronary artery disease Diseases 0.000 claims description 5
- 230000004064 dysfunction Effects 0.000 claims description 5
- 230000002124 endocrine Effects 0.000 claims description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 5
- 201000001881 impotence Diseases 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 208000001286 intracranial vasospasm Diseases 0.000 claims description 5
- 208000017169 kidney disease Diseases 0.000 claims description 5
- 201000006370 kidney failure Diseases 0.000 claims description 5
- 230000004770 neurodegeneration Effects 0.000 claims description 5
- 230000002093 peripheral effect Effects 0.000 claims description 5
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 5
- 208000037803 restenosis Diseases 0.000 claims description 5
- 208000020431 spinal cord injury Diseases 0.000 claims description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 4
- 208000020084 Bone disease Diseases 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 206010019663 Hepatic failure Diseases 0.000 claims description 4
- 206010020880 Hypertrophy Diseases 0.000 claims description 4
- 206010053159 Organ failure Diseases 0.000 claims description 4
- 208000005107 Premature Birth Diseases 0.000 claims description 4
- 206010036590 Premature baby Diseases 0.000 claims description 4
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 4
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 4
- 206010040047 Sepsis Diseases 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 4
- 210000004204 blood vessel Anatomy 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 206010061989 glomerulosclerosis Diseases 0.000 claims description 4
- 208000023589 ischemic disease Diseases 0.000 claims description 4
- 230000000302 ischemic effect Effects 0.000 claims description 4
- 210000003734 kidney Anatomy 0.000 claims description 4
- 210000004185 liver Anatomy 0.000 claims description 4
- 208000007903 liver failure Diseases 0.000 claims description 4
- 231100000835 liver failure Toxicity 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 230000008816 organ damage Effects 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 201000004240 prostatic hypertrophy Diseases 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- NWPRQFZMQIACQS-LLVKDONJSA-N 6-[(3r)-pyrrolidin-3-yl]sulfanylisoquinolin-1-amine Chemical compound C=1C=C2C(N)=NC=CC2=CC=1S[C@@H]1CCNC1 NWPRQFZMQIACQS-LLVKDONJSA-N 0.000 claims description 2
- NWPRQFZMQIACQS-NSHDSACASA-N 6-[(3s)-pyrrolidin-3-yl]sulfanylisoquinolin-1-amine Chemical compound C=1C=C2C(N)=NC=CC2=CC=1S[C@H]1CCNC1 NWPRQFZMQIACQS-NSHDSACASA-N 0.000 claims description 2
- OCQILMOPYZWUAH-UHFFFAOYSA-N 6-n-piperidin-3-ylisoquinoline-1,6-diamine Chemical compound C=1C=C2C(N)=NC=CC2=CC=1NC1CCCNC1 OCQILMOPYZWUAH-UHFFFAOYSA-N 0.000 claims description 2
- BGYOXNCYIBBOIU-UHFFFAOYSA-N 6-piperidin-3-ylsulfanylisoquinolin-1-amine Chemical compound C=1C=C2C(N)=NC=CC2=CC=1SC1CCCNC1 BGYOXNCYIBBOIU-UHFFFAOYSA-N 0.000 claims description 2
- DYVFFZLJSFMFIW-UHFFFAOYSA-N 6-piperidin-4-ylsulfanyl-2h-isoquinolin-1-one Chemical compound C=1C=C2C(=O)NC=CC2=CC=1SC1CCNCC1 DYVFFZLJSFMFIW-UHFFFAOYSA-N 0.000 claims description 2
- MGTAAZRBYFHIJN-UHFFFAOYSA-N 6-piperidin-4-ylsulfanylisoquinolin-1-amine Chemical compound C=1C=C2C(N)=NC=CC2=CC=1SC1CCNCC1 MGTAAZRBYFHIJN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 2
- 239000000969 carrier Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 17
- 102000000568 rho-Associated Kinases Human genes 0.000 abstract description 15
- 108010041788 rho-Associated Kinases Proteins 0.000 abstract description 15
- 230000026731 phosphorylation Effects 0.000 abstract description 6
- 238000006366 phosphorylation reaction Methods 0.000 abstract description 6
- 102000011131 Myosin-Light-Chain Phosphatase Human genes 0.000 abstract description 5
- 108010037801 Myosin-Light-Chain Phosphatase Proteins 0.000 abstract description 5
- 230000001404 mediated effect Effects 0.000 abstract description 5
- 230000006806 disease prevention Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 38
- 239000002904 solvent Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- 125000001424 substituent group Chemical group 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- 238000001704 evaporation Methods 0.000 description 17
- 230000008020 evaporation Effects 0.000 description 17
- 229940093499 ethyl acetate Drugs 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- BCZPUVXMWIBIRE-UHFFFAOYSA-N 7-chloro-6-fluoroisoquinoline Chemical compound C1=NC=C2C=C(Cl)C(F)=CC2=C1 BCZPUVXMWIBIRE-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- QNNTUJSIGVWFAS-UHFFFAOYSA-N 6-bromo-2-oxidoisoquinolin-2-ium Chemical compound C1=C(Br)C=CC2=C[N+]([O-])=CC=C21 QNNTUJSIGVWFAS-UHFFFAOYSA-N 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 8
- 125000001309 chloro group Chemical group Cl* 0.000 description 8
- 239000000825 pharmaceutical preparation Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- ZTEATMVVGQUULZ-UHFFFAOYSA-N 6-bromoisoquinoline Chemical class C1=NC=CC2=CC(Br)=CC=C21 ZTEATMVVGQUULZ-UHFFFAOYSA-N 0.000 description 7
- ABZAYLFRWGIRDU-UHFFFAOYSA-N 7-bromo-6-fluoroisoquinoline Chemical compound C1=NC=C2C=C(Br)C(F)=CC2=C1 ABZAYLFRWGIRDU-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical class [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- 230000005526 G1 to G0 transition Effects 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- LIOVBCSJACUZOR-UHFFFAOYSA-N tert-butyl 4-(7-chloroisoquinolin-6-yl)sulfanylpiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1SC1=CC2=CC=NC=C2C=C1Cl LIOVBCSJACUZOR-UHFFFAOYSA-N 0.000 description 6
- 239000003039 volatile agent Substances 0.000 description 6
- MSQCQINLJMEVNJ-UHFFFAOYSA-N 1-chloroisoquinoline Chemical class C1=CC=C2C(Cl)=NC=CC2=C1 MSQCQINLJMEVNJ-UHFFFAOYSA-N 0.000 description 5
- ZDYXSEQHOVSTPA-UHFFFAOYSA-N 6-bromo-2h-isoquinolin-1-one Chemical class C1=CNC(=O)C=2C1=CC(Br)=CC=2 ZDYXSEQHOVSTPA-UHFFFAOYSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 150000003840 hydrochlorides Chemical class 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
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- 230000002829 reductive effect Effects 0.000 description 5
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- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 5
- 229940086542 triethylamine Drugs 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- BTUPJEUTBPAUHV-UHFFFAOYSA-N 6-bromo-2-[(4-methoxyphenyl)methyl]isoquinolin-1-one Chemical compound C1=CC(OC)=CC=C1CN1C(=O)C2=CC=C(Br)C=C2C=C1 BTUPJEUTBPAUHV-UHFFFAOYSA-N 0.000 description 4
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 4
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 150000001204 N-oxides Chemical class 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
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- 229960001456 adenosine triphosphate Drugs 0.000 description 4
- 125000003277 amino group Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
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- 239000000543 intermediate Substances 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 229960001866 silicon dioxide Drugs 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- USYCVFFWCMHPPG-UHFFFAOYSA-N tert-butyl 4-sulfanylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(S)CC1 USYCVFFWCMHPPG-UHFFFAOYSA-N 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- GKINUHQVRAWRQS-UHFFFAOYSA-N tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate;7-chloro-6-(pyrrolidin-3-ylmethylsulfanyl)isoquinoline Chemical compound CC(C)(C)OC(=O)N1CCC(CBr)C1.ClC1=CC2=CN=CC=C2C=C1SCC1CCNC1 GKINUHQVRAWRQS-UHFFFAOYSA-N 0.000 description 1
- WXMDYOFOMRMJTM-UHFFFAOYSA-N tert-butyl 4-(bromomethyl)piperidine-1-carboxylate;7-chloro-6-(piperidin-4-ylmethylsulfanyl)isoquinoline Chemical compound CC(C)(C)OC(=O)N1CCC(CBr)CC1.ClC1=CC2=CN=CC=C2C=C1SCC1CCNCC1 WXMDYOFOMRMJTM-UHFFFAOYSA-N 0.000 description 1
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- KQPWWQHXOJMBMB-UHFFFAOYSA-N tert-butyl 4-[(7-chloroisoquinolin-6-yl)amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1NC1=CC2=CC=NC=C2C=C1Cl KQPWWQHXOJMBMB-UHFFFAOYSA-N 0.000 description 1
- MXNOFWNKIBEEDL-UHFFFAOYSA-N tert-butyl 4-[isoquinolin-6-yl(methyl)amino]piperidine-1-carboxylate Chemical compound C=1C=C2C=NC=CC2=CC=1N(C)C1CCN(C(=O)OC(C)(C)C)CC1 MXNOFWNKIBEEDL-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
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- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
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- C07D401/00—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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| EP06026896.8 | 2006-12-27 | ||
| EP06026896 | 2006-12-27 | ||
| PCT/EP2007/011165 WO2008077552A1 (en) | 2006-12-27 | 2007-12-19 | Substituted isoquinoline and isoquinolinone derivatives |
Publications (2)
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| AU2007338408A1 AU2007338408A1 (en) | 2008-07-03 |
| AU2007338408B2 true AU2007338408B2 (en) | 2012-07-26 |
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| AU2007338408A Ceased AU2007338408B2 (en) | 2006-12-27 | 2007-12-19 | Substituted isoquinoline and isoquinolinone derivatives |
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| US7470787B2 (en) | 2005-07-11 | 2008-12-30 | Aerie Pharmaceuticals, Inc. | Isoquinoline compounds |
| EP2526948A1 (en) | 2006-09-20 | 2012-11-28 | Aerie Pharmaceuticals, Inc. | RHO kinase inhibitors |
| US8455513B2 (en) | 2007-01-10 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
| US8455514B2 (en) | 2008-01-17 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-and 7-amino isoquinoline compounds and methods for making and using the same |
| US8541449B2 (en) * | 2008-06-24 | 2013-09-24 | Sanofi | Substituted isoquinolines and isoquinolinones as Rho kinase inhibitors |
| 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 |
| EP2317849A4 (en) * | 2008-06-26 | 2011-11-02 | Inspire Pharmaceuticals Inc | PROCESS FOR THE TREATMENT OF LUNG DISEASES WITH RHO KINASE INHIBITOR COMPOUNDS |
| US8410147B2 (en) | 2008-06-26 | 2013-04-02 | Inspire Pharmaceuticals, Inc. | Method for treating diseases associated with alterations in cellular integrity using Rho kinase inhibitor compounds |
| US8450344B2 (en) | 2008-07-25 | 2013-05-28 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
| ES2834451T3 (es) | 2009-05-01 | 2021-06-17 | Aerie Pharmaceuticals Inc | Inhibidores de mecanismo doble para el tratamiento de enfermedades |
| CN110396085B (zh) | 2013-03-15 | 2024-11-15 | 爱尔康公司 | 联合治疗 |
| US10351535B2 (en) * | 2013-12-20 | 2019-07-16 | Esteve Pharmaceuticals, S.A. | Piperazine derivatives having multimodal activity against pain |
| FR3017868A1 (fr) | 2014-02-21 | 2015-08-28 | Servier Lab | Derives d'isoquinoleine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| CN105085478B (zh) * | 2014-04-28 | 2019-04-12 | 南京明德新药研发股份有限公司 | 异喹啉磺胺衍生物及其药物组合物和制药用途 |
| RU2017107558A (ru) | 2014-09-15 | 2018-10-18 | Руджен Холдингс (Кайман) Лимитед | Производные пирролопиримидина в качестве антагонистов nmda-рецептора nr2b |
| WO2016126869A1 (en) | 2015-02-04 | 2016-08-11 | Rugen Holdings (Cayman) Limited | 3,3-difluoro-piperidine derivatives as nr2b nmda receptor antagonists |
| MX380424B (es) | 2015-06-01 | 2025-03-12 | Rugen Holdings Cayman Ltd | Compuestos heterociclicos de 3,3-difluorpiperidina carbamato como antagonistas del receptor de n-metil-d-aspartato (nmda) nr2b. |
| CN105237474B (zh) * | 2015-09-30 | 2017-08-29 | 沈阳药科大学 | 6‑羟基‑7‑芳甲酰基喹啉酮类化合物的制备及其应用 |
| US9643927B1 (en) | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
| WO2017086941A1 (en) | 2015-11-17 | 2017-05-26 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
| CN109640966A (zh) | 2016-08-31 | 2019-04-16 | 爱瑞制药公司 | 眼用组合物 |
| US11000526B2 (en) | 2016-11-22 | 2021-05-11 | Rugen Holdings (Cayman) Limited | Treatment of autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders |
| KR20190135027A (ko) | 2017-03-31 | 2019-12-05 | 에어리 파마슈티컬즈, 인코포레이티드 | 아릴 시클로프로필-아미노-이소퀴놀리닐 아미드 화합물 |
| CA3112391A1 (en) | 2018-09-14 | 2020-03-19 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
| CN109180586B (zh) * | 2018-10-10 | 2022-03-08 | 成都理工大学 | 作为Rho激酶抑制剂的六氢氮杂卓-4-基氧基苯甲酰胺类化合物 |
| WO2020092528A1 (en) | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity |
| ES2979163T3 (es) | 2018-10-31 | 2024-09-24 | Gilead Sciences Inc | Compuestos de 6-azabenzimidazol sustituidos como inhibidores de HPK1 |
| EP3972695A1 (en) | 2019-05-23 | 2022-03-30 | Gilead Sciences, Inc. | Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors |
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| WO2007065916A1 (en) * | 2005-12-08 | 2007-06-14 | N.V. Organon | Isoquinoline derivatives |
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| DK2102164T3 (da) | 2006-12-27 | 2011-03-21 | Sanofi Aventis | Cycloalkylaminsubstituerede isochinolin- og isochinolinonderivater |
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2007
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- 2007-12-19 RU RU2009128693/04A patent/RU2009128693A/ru not_active Application Discontinuation
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- 2007-12-19 JP JP2009543373A patent/JP5405315B2/ja not_active Expired - Fee Related
- 2007-12-19 MY MYPI20092505A patent/MY155279A/en unknown
- 2007-12-19 WO PCT/EP2007/011165 patent/WO2008077552A1/en not_active Ceased
- 2007-12-19 CN CN200780048282.0A patent/CN101573353B/zh not_active Expired - Fee Related
- 2007-12-19 CA CA2673918A patent/CA2673918C/en not_active Expired - Fee Related
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2009
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- 2009-05-22 ZA ZA200903552A patent/ZA200903552B/xx unknown
- 2009-06-16 CO CO09062102A patent/CO6210826A2/es not_active Application Discontinuation
- 2009-06-18 US US12/487,455 patent/US8748614B2/en not_active Expired - Fee Related
- 2009-06-23 SV SV2009003312A patent/SV2009003312A/es unknown
- 2009-06-24 IL IL199537A patent/IL199537A/en not_active IP Right Cessation
- 2009-06-24 MA MA32037A patent/MA31022B1/fr unknown
- 2009-06-25 TN TNP2009000268A patent/TN2009000268A1/fr unknown
- 2009-06-25 NO NO20092424A patent/NO20092424L/no not_active Application Discontinuation
- 2009-06-26 EC EC2009009470A patent/ECSP099470A/es unknown
- 2009-06-26 DO DO2009000162A patent/DOP2009000162A/es unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007065916A1 (en) * | 2005-12-08 | 2007-06-14 | N.V. Organon | Isoquinoline derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008077552A1 (en) | 2008-07-03 |
| US8748614B2 (en) | 2014-06-10 |
| AU2007338408A1 (en) | 2008-07-03 |
| CA2673918C (en) | 2015-02-17 |
| IL199537A0 (en) | 2010-03-28 |
| SV2009003312A (es) | 2010-02-05 |
| KR20090094338A (ko) | 2009-09-04 |
| NO20092424L (no) | 2009-09-18 |
| MX2009006517A (es) | 2009-06-26 |
| US20100105650A1 (en) | 2010-04-29 |
| RU2009128693A (ru) | 2011-02-10 |
| CR10814A (es) | 2009-08-12 |
| CA2673918A1 (en) | 2008-07-03 |
| JP2010514717A (ja) | 2010-05-06 |
| CN101573353A (zh) | 2009-11-04 |
| CO6210826A2 (es) | 2010-10-20 |
| MA31022B1 (fr) | 2009-12-01 |
| MY155279A (en) | 2015-09-30 |
| BRPI0720986A2 (pt) | 2014-03-11 |
| DOP2009000162A (es) | 2009-07-31 |
| TN2009000268A1 (en) | 2010-10-18 |
| JP5405315B2 (ja) | 2014-02-05 |
| ZA200903552B (en) | 2010-04-28 |
| ECSP099470A (es) | 2009-07-31 |
| IL199537A (en) | 2013-11-28 |
| CN101573353B (zh) | 2014-08-06 |
| EP2114920A1 (en) | 2009-11-11 |
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