EA028364B1 - Аутотаксин-модулирующие соединения - Google Patents
Аутотаксин-модулирующие соединения Download PDFInfo
- Publication number
- EA028364B1 EA028364B1 EA201590295A EA201590295A EA028364B1 EA 028364 B1 EA028364 B1 EA 028364B1 EA 201590295 A EA201590295 A EA 201590295A EA 201590295 A EA201590295 A EA 201590295A EA 028364 B1 EA028364 B1 EA 028364B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- cis
- trifluoromethyl
- oxy
- naphthalen
- ethyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 247
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 title claims abstract description 111
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 title claims abstract description 111
- 230000000694 effects Effects 0.000 claims abstract description 23
- -1 Heptanyl Chemical group 0.000 claims description 325
- 238000000034 method Methods 0.000 claims description 183
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 145
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 134
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 129
- 125000000217 alkyl group Chemical group 0.000 claims description 92
- 150000003839 salts Chemical class 0.000 claims description 92
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 74
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 claims description 61
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 48
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 39
- 239000002253 acid Substances 0.000 claims description 37
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 37
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 36
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims description 33
- 125000004432 carbon atom Chemical group C* 0.000 claims description 30
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 29
- 201000006417 multiple sclerosis Diseases 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 241000124008 Mammalia Species 0.000 claims description 20
- 208000002193 Pain Diseases 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- DMUXSGAKEXSNGN-UHFFFAOYSA-N 2-ethyloctanoic acid Chemical compound CCCCCCC(CC)C(O)=O DMUXSGAKEXSNGN-UHFFFAOYSA-N 0.000 claims description 16
- 208000004296 neuralgia Diseases 0.000 claims description 14
- 208000021722 neuropathic pain Diseases 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- WZUBYJLFSCGSNR-UHFFFAOYSA-N 2,2-dimethylcyclobutane-1-carboxylic acid Chemical compound CC1(C)CCC1C(O)=O WZUBYJLFSCGSNR-UHFFFAOYSA-N 0.000 claims description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 208000024891 symptom Diseases 0.000 claims description 10
- 208000000094 Chronic Pain Diseases 0.000 claims description 9
- 206010065390 Inflammatory pain Diseases 0.000 claims description 9
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 9
- 208000027866 inflammatory disease Diseases 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 8
- DYWSVUBJGFTOQC-UHFFFAOYSA-N xi-2-Ethylheptanoic acid Chemical class CCCCCC(CC)C(O)=O DYWSVUBJGFTOQC-UHFFFAOYSA-N 0.000 claims description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- SZBVQLXGZWYFCQ-UHFFFAOYSA-N 9-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalene-2-carbonyl]-9-azabicyclo[3.3.1]nonane-3-carboxylic acid Chemical compound C1C(C(=O)O)CC2CCCC1N2C(=O)C(C=C1C=2C(F)(F)F)=CC=C1C=CC=2OC1CCC(C(F)(F)F)CC1 SZBVQLXGZWYFCQ-UHFFFAOYSA-N 0.000 claims description 5
- QUTQICJBWHIKGL-UHFFFAOYSA-N 9-[[8-chloro-7-(4-methylcyclohexyl)oxynaphthalen-2-yl]methyl]-9-azabicyclo[3.3.1]nonane-3-carboxylic acid Chemical compound C1CC(C)CCC1OC1=CC=C(C=CC(CN2C3CCCC2CC(C3)C(O)=O)=C2)C2=C1Cl QUTQICJBWHIKGL-UHFFFAOYSA-N 0.000 claims description 5
- MEPDPZZBXRFBRJ-YHBQERECSA-N C(C)(C)(C)[C@@H]1CC[C@H](CC1)NC=1N=CC2=CC=C(C=C2C1)C(=O)N1CCC(CC1)CC(=O)O Chemical compound C(C)(C)(C)[C@@H]1CC[C@H](CC1)NC=1N=CC2=CC=C(C=C2C1)C(=O)N1CCC(CC1)CC(=O)O MEPDPZZBXRFBRJ-YHBQERECSA-N 0.000 claims description 5
- IJPQGXROVJTEAA-VCWSNOSPSA-N C(C)(C)(C)[C@@H]1CC[C@H](CC1)NC=1N=CC2=CC=C(C=C2C1)C(=O)NC12CCC(CC1)(CC2)C(=O)O Chemical compound C(C)(C)(C)[C@@H]1CC[C@H](CC1)NC=1N=CC2=CC=C(C=C2C1)C(=O)NC12CCC(CC1)(CC2)C(=O)O IJPQGXROVJTEAA-VCWSNOSPSA-N 0.000 claims description 5
- PQIQAXYGJLEIMZ-KDURUIRLSA-N ClC=1C(=CC=C2C=CC(=CC12)CN1CCC(CC1)C(=O)O)O[C@@H]1CC[C@@H](CC1)C(F)(F)F Chemical compound ClC=1C(=CC=C2C=CC(=CC12)CN1CCC(CC1)C(=O)O)O[C@@H]1CC[C@@H](CC1)C(F)(F)F PQIQAXYGJLEIMZ-KDURUIRLSA-N 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 4
- PDZVLUXDLFYWRZ-QKUVIELKSA-N C(#N)C=1C(=CC=C2C=CC(=CC12)C(C)N1CCC(CC1)C(=O)O)O[C@@H]1CC[C@@H](CC1)C(F)(F)F Chemical compound C(#N)C=1C(=CC=C2C=CC(=CC12)C(C)N1CCC(CC1)C(=O)O)O[C@@H]1CC[C@@H](CC1)C(F)(F)F PDZVLUXDLFYWRZ-QKUVIELKSA-N 0.000 claims description 4
- PHGBDEFQUNIVAZ-DHDVMJEDSA-N C(#N)C=1C(=CC=C2C=CC(=CC12)CN1C2CC(CC1CC2)C(=O)O)O[C@@H]2CC[C@@H](CC2)CC Chemical compound C(#N)C=1C(=CC=C2C=CC(=CC12)CN1C2CC(CC1CC2)C(=O)O)O[C@@H]2CC[C@@H](CC2)CC PHGBDEFQUNIVAZ-DHDVMJEDSA-N 0.000 claims description 4
- VKHCIMALUGZBCD-CPGABTQKSA-N CC(N1C2CCC1CC(C2)C(O)=O)c1ccc2ccc(O[C@H]3CC[C@H](CC3)C(F)(F)F)c(C(F)F)c2c1 Chemical compound CC(N1C2CCC1CC(C2)C(O)=O)c1ccc2ccc(O[C@H]3CC[C@H](CC3)C(F)(F)F)c(C(F)F)c2c1 VKHCIMALUGZBCD-CPGABTQKSA-N 0.000 claims description 4
- DRNZZVUIAKJEJG-KDURUIRLSA-N FC(C=1C(=CC=C2C=CC(=CC12)CN1CCC(CC1)C(=O)O)O[C@@H]1CC[C@@H](CC1)C(F)(F)F)(F)F Chemical compound FC(C=1C(=CC=C2C=CC(=CC12)CN1CCC(CC1)C(=O)O)O[C@@H]1CC[C@@H](CC1)C(F)(F)F)(F)F DRNZZVUIAKJEJG-KDURUIRLSA-N 0.000 claims description 4
- DASZWTMGJQVNFR-BGYRXZFFSA-N OC(=O)C1CCN(Cc2ccc3ccc(O[C@H]4CC[C@H](CC4)C(F)(F)F)c(C#N)c3c2)CC1 Chemical compound OC(=O)C1CCN(Cc2ccc3ccc(O[C@H]4CC[C@H](CC4)C(F)(F)F)c(C#N)c3c2)CC1 DASZWTMGJQVNFR-BGYRXZFFSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- HNYWATKKFFNQFM-UHFFFAOYSA-N 9-[7-(4-methylcyclohexyl)oxy-8-(trifluoromethyl)naphthalene-2-carbonyl]-9-azabicyclo[3.3.1]nonane-3-carboxylic acid Chemical compound C1CC(C)CCC1OC1=CC=C(C=CC(=C2)C(=O)N3C4CCCC3CC(C4)C(O)=O)C2=C1C(F)(F)F HNYWATKKFFNQFM-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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| US12221449B2 (en) | 2019-02-01 | 2025-02-11 | Wuhan Humanwell Innovative Drug Research and Development Center Limited Company | Pyrrolopyrimidine derivative and use thereof |
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| IN2014DN09346A (https=) | 2012-06-13 | 2015-07-17 | Hoffmann La Roche | |
| MX363388B (es) * | 2012-07-27 | 2019-03-20 | Biogen Ma Inc | Agentes moduladores de autotaxina. |
| EA027809B1 (ru) | 2012-07-27 | 2017-09-29 | Биоген Айдек Ма Инк. | Соединения, которые являются s1p-модулирующими агентами и/или atx-модулирующими агентами |
| US9555050B2 (en) | 2012-07-27 | 2017-01-31 | Biogen Ma Inc. | ATX modulating agents |
| WO2014025709A1 (en) | 2012-08-06 | 2014-02-13 | Biogen Idec Ma Inc. | Compounds that are s1p modulating agents and/or atx modulating agents |
| WO2014025708A1 (en) | 2012-08-06 | 2014-02-13 | Biogen Idec Ma Inc. | Compounds that are s1p modulating agents and/or atx modulating agents |
| KR102179599B1 (ko) | 2012-09-25 | 2020-11-19 | 에프. 호프만-라 로슈 아게 | 이환형 유도체 |
| AR095079A1 (es) | 2013-03-12 | 2015-09-16 | Hoffmann La Roche | Derivados de octahidro-pirrolo[3,4-c]-pirrol y piridina-fenilo |
| CN105764905B (zh) | 2013-11-26 | 2019-06-07 | 豪夫迈·罗氏有限公司 | 新的八氢-环丁二烯并[1,2-c;3,4-c’]二吡咯-2基 |
| CN106103446B (zh) | 2014-03-26 | 2019-07-30 | 豪夫迈·罗氏有限公司 | 作为自分泌运动因子(atx)和溶血磷脂酸(lpa)生产抑制剂的二环化合物 |
| WO2015144609A1 (en) | 2014-03-26 | 2015-10-01 | F. Hoffmann-La Roche Ag | Condensed [1,4]diazepine compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors |
| GB201501870D0 (en) | 2015-02-04 | 2015-03-18 | Cancer Rec Tech Ltd | Autotaxin inhibitors |
| GB201502020D0 (en) | 2015-02-06 | 2015-03-25 | Cancer Rec Tech Ltd | Autotaxin inhibitory compounds |
| MA41898A (fr) | 2015-04-10 | 2018-02-13 | Hoffmann La Roche | Dérivés de quinazolinone bicyclique |
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