RU2470928C2 - Цитоскелетно-активные ингибирующие rho-киназу соединения, их композиции и применение - Google Patents
Цитоскелетно-активные ингибирующие rho-киназу соединения, их композиции и применение Download PDFInfo
- Publication number
- RU2470928C2 RU2470928C2 RU2009127798/04A RU2009127798A RU2470928C2 RU 2470928 C2 RU2470928 C2 RU 2470928C2 RU 2009127798/04 A RU2009127798/04 A RU 2009127798/04A RU 2009127798 A RU2009127798 A RU 2009127798A RU 2470928 C2 RU2470928 C2 RU 2470928C2
- Authority
- RU
- Russia
- Prior art keywords
- compound
- piperidin
- indazol
- ylamino
- methyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 278
- 239000000203 mixture Substances 0.000 title description 28
- 230000002401 inhibitory effect Effects 0.000 title description 12
- 108010041788 rho-Associated Kinases Proteins 0.000 title description 3
- 102000000568 rho-Associated Kinases Human genes 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 70
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 38
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 34
- 230000004410 intraocular pressure Effects 0.000 claims abstract description 33
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 29
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 27
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 24
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims abstract 4
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract 3
- 125000005843 halogen group Chemical group 0.000 claims abstract 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 225
- 238000000034 method Methods 0.000 claims description 115
- -1 3 - ((3- (1H-indazol-5-ylamino) piperidin-1-yl) methyl) phenoxy Chemical group 0.000 claims description 94
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 70
- 125000001424 substituent group Chemical group 0.000 claims description 65
- 229910052757 nitrogen Inorganic materials 0.000 claims description 43
- 150000002367 halogens Chemical class 0.000 claims description 36
- 125000003342 alkenyl group Chemical group 0.000 claims description 34
- 125000000304 alkynyl group Chemical group 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 208000010412 Glaucoma Diseases 0.000 claims description 22
- 230000003993 interaction Effects 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 22
- 125000002015 acyclic group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000005357 cycloalkylalkynyl group Chemical group 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 10
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 9
- 108010043137 Actomyosin Proteins 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- CPVFJCZYQSPUEE-UHFFFAOYSA-N n-[3-[[3-(1h-indazol-5-ylamino)pyrrolidin-1-yl]methyl]phenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC(CN2CC(CC2)NC=2C=C3C=NNC3=CC=2)=C1 CPVFJCZYQSPUEE-UHFFFAOYSA-N 0.000 claims description 5
- UDCBPDAHRGAKOJ-UHFFFAOYSA-N 2-[3-[[4-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]phenoxy]ethanol Chemical compound OCCOC1=CC=CC(CN2CCC(CC2)NC=2C=C3C=NNC3=CC=2)=C1 UDCBPDAHRGAKOJ-UHFFFAOYSA-N 0.000 claims description 4
- BXCXZISLTZBGJO-UHFFFAOYSA-N 2-[6-[[3-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]-2,3-dihydroindol-1-yl]ethanol Chemical compound C1=C2NN=CC2=CC(NC2CCCN(C2)CC2=CC=C3CCN(C3=C2)CCO)=C1 BXCXZISLTZBGJO-UHFFFAOYSA-N 0.000 claims description 4
- IQUZIVDCVRBBFR-GOSISDBHSA-N n-[(3r)-1-[(4-methylsulfanylphenyl)methyl]pyrrolidin-3-yl]isoquinolin-5-amine Chemical compound C1=CC(SC)=CC=C1CN1C[C@H](NC=2C3=CC=NC=C3C=CC=2)CC1 IQUZIVDCVRBBFR-GOSISDBHSA-N 0.000 claims description 4
- DPZSYTMLVCLGRU-SFHVURJKSA-N n-[(3s)-1-[(4-methylsulfanylphenyl)methyl]piperidin-3-yl]-1h-indazol-5-amine Chemical compound C1=CC(SC)=CC=C1CN1C[C@@H](NC=2C=C3C=NNC3=CC=2)CCC1 DPZSYTMLVCLGRU-SFHVURJKSA-N 0.000 claims description 4
- QQPGUHWCZXHDEH-UHFFFAOYSA-N n-[1-[(3-cyclopropylphenyl)methyl]piperidin-3-yl]-1h-indazol-5-amine Chemical compound C1CCC(NC=2C=C3C=NNC3=CC=2)CN1CC(C=1)=CC=CC=1C1CC1 QQPGUHWCZXHDEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
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- QPEIXLYASHZHRM-UHFFFAOYSA-N 2-[3-[[3-(1h-indazol-5-ylamino)pyrrolidin-1-yl]methyl]phenoxy]ethanol Chemical compound OCCOC1=CC=CC(CN2CC(CC2)NC=2C=C3C=NNC3=CC=2)=C1 QPEIXLYASHZHRM-UHFFFAOYSA-N 0.000 claims description 3
- HRCKLYFDWWYCLS-UHFFFAOYSA-N 2-[3-[[3-(isoquinolin-5-ylamino)pyrrolidin-1-yl]methyl]phenoxy]ethanol Chemical compound OCCOC1=CC=CC(CN2CC(CC2)NC=2C3=CC=NC=C3C=CC=2)=C1 HRCKLYFDWWYCLS-UHFFFAOYSA-N 0.000 claims description 3
- CIHPIJHUAGKONW-UHFFFAOYSA-N 2-[4-[[3-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]phenoxy]ethanol Chemical compound C1=CC(OCCO)=CC=C1CN1CC(NC=2C=C3C=NNC3=CC=2)CCC1 CIHPIJHUAGKONW-UHFFFAOYSA-N 0.000 claims description 3
- GCWJCJSCGSLPQM-UHFFFAOYSA-N 2-[5-[[3-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]-2-methylphenoxy]ethanol Chemical compound C1=C(OCCO)C(C)=CC=C1CN1CC(NC=2C=C3C=NNC3=CC=2)CCC1 GCWJCJSCGSLPQM-UHFFFAOYSA-N 0.000 claims description 3
- QBXDKOPEYCIHQK-UHFFFAOYSA-N 2-[5-[[3-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]indol-1-yl]acetic acid Chemical compound C1=C2NN=CC2=CC(NC2CCCN(C2)CC=2C=C3C=CN(C3=CC=2)CC(=O)O)=C1 QBXDKOPEYCIHQK-UHFFFAOYSA-N 0.000 claims description 3
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- XEQSNPVXRPAPMJ-NRFANRHFSA-N 2-[6-[[(3s)-3-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]indol-1-yl]ethanol Chemical compound C1=C2NN=CC2=CC(N[C@H]2CCCN(C2)CC2=CC=C3C=CN(C3=C2)CCO)=C1 XEQSNPVXRPAPMJ-NRFANRHFSA-N 0.000 claims description 3
- IGNAVGHLKLQNRU-UHFFFAOYSA-N 2-[6-[[3-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]indol-1-yl]acetic acid Chemical compound C1=C2NN=CC2=CC(NC2CCCN(C2)CC2=CC=C3C=CN(C3=C2)CC(=O)O)=C1 IGNAVGHLKLQNRU-UHFFFAOYSA-N 0.000 claims description 3
- XEQSNPVXRPAPMJ-UHFFFAOYSA-N 2-[6-[[3-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]indol-1-yl]ethanol Chemical compound C1=C2NN=CC2=CC(NC2CCCN(C2)CC2=CC=C3C=CN(C3=C2)CCO)=C1 XEQSNPVXRPAPMJ-UHFFFAOYSA-N 0.000 claims description 3
- HFFGJIJZKRLHOZ-UHFFFAOYSA-N 2-ethynyl-5-[[3-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]phenol Chemical compound C1=C(C#C)C(O)=CC(CN2CC(CCC2)NC=2C=C3C=NNC3=CC=2)=C1 HFFGJIJZKRLHOZ-UHFFFAOYSA-N 0.000 claims description 3
- LWKUYNWGILHOCX-UHFFFAOYSA-N 3-[3-[[3-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]phenoxy]propan-1-ol Chemical compound OCCCOC1=CC=CC(CN2CC(CCC2)NC=2C=C3C=NNC3=CC=2)=C1 LWKUYNWGILHOCX-UHFFFAOYSA-N 0.000 claims description 3
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- YCNQEIDRNDLZLW-UHFFFAOYSA-N ethyl 2-[3-[[3-(1h-indazol-5-ylamino)piperidin-1-yl]methyl]phenoxy]acetate Chemical compound CCOC(=O)COC1=CC=CC(CN2CC(CCC2)NC=2C=C3C=NNC3=CC=2)=C1 YCNQEIDRNDLZLW-UHFFFAOYSA-N 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
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Classifications
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—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
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C07D401/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/007—Methods or devices for eye surgery
- A61F9/00781—Apparatus for modifying intraocular pressure, e.g. for glaucoma treatment
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
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- General Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Ophthalmology & Optometry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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Applications Claiming Priority (5)
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| US87055506P | 2006-12-18 | 2006-12-18 | |
| US60/870,555 | 2006-12-18 | ||
| US11/958,214 US8071779B2 (en) | 2006-12-18 | 2007-12-17 | Cytoskeletal active rho kinase inhibitor compounds, composition and use |
| US11/958,214 | 2007-12-17 | ||
| PCT/US2007/087973 WO2008077057A2 (en) | 2006-12-18 | 2007-12-18 | Cytoskeletal active rho kinase inhibitor compounds, composition and use |
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| RU (1) | RU2470928C2 (enExample) |
| WO (1) | WO2008077057A2 (enExample) |
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2007
- 2007-12-17 US US11/958,214 patent/US8071779B2/en active Active
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- 2007-12-18 BR BRPI0720457-4A patent/BRPI0720457A2/pt not_active IP Right Cessation
- 2007-12-18 JP JP2009541644A patent/JP5511385B2/ja not_active Expired - Fee Related
- 2007-12-18 MX MX2009006493A patent/MX2009006493A/es unknown
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- 2007-12-18 RU RU2009127798/04A patent/RU2470928C2/ru not_active IP Right Cessation
- 2007-12-18 WO PCT/US2007/087973 patent/WO2008077057A2/en not_active Ceased
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| WO2001056988A1 (en) * | 2000-02-01 | 2001-08-09 | Kirin Beer Kabushiki Kaisha | Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same |
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| US8604218B2 (en) | 2013-12-10 |
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| BRPI0720457A2 (pt) | 2014-01-14 |
| AU2007333715A1 (en) | 2008-06-26 |
| CA2672825A1 (en) | 2008-06-26 |
| CN103254172A (zh) | 2013-08-21 |
| KR20090091767A (ko) | 2009-08-28 |
| US20120046275A1 (en) | 2012-02-23 |
| CN101583361A (zh) | 2009-11-18 |
| MX2009006493A (es) | 2009-09-10 |
| EP2099457A4 (en) | 2011-08-17 |
| US8071779B2 (en) | 2011-12-06 |
| AU2007333715B2 (en) | 2013-01-10 |
| US20080214614A1 (en) | 2008-09-04 |
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