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Substituted Cyclopentanes, Tetrahydrofuranes and Pyrrolidines As Orexin Receptor Antagonists
| Content Provider | The Lens |
|---|---|
| Abstract | The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, Formula (I) wherein L, X, R a , R b , R 1 , R 2 and R 3 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. |
| Related Links | https://www.lens.org/lens/patent/013-400-011-366-53X/frontpage |
| Language | English |
| Publisher Date | 2017-10-17 |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Patent |
| Jurisdiction | United States of America |
| Date Applied | 2015-02-19 |
| Agent | Barnes & Thornburg Llp Scott D. Rothenberger |
| Applicant | Takeda Pharmaceuticals Co |
| Application No. | 201515120002 |
| Claim | A compound of formula wherein R 1 represents an 8- to 10-membered fused bicyclic heteroaromatic group optionally substituted by at least one substituent independently selected from halogen, cyano, hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkoxycarbonylamino, C 1 -C 3 haloalkoxy, —NR 4 R 5 , C 3 -C 6 cycloalkylamino, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkylcarbonylamino, sulphonamido, C 1 -C 3 alkylsulphonyl, C 1 -C 3 alkylsulphonylamino and —C(O)NR 6 R 7 ; L represents a bond, CH 2 , O, NH or N(CH 3 ); R a represents a hydrogen atom or a C 1 -C 3 alkyl or C 1 -C 3 haloalkyl group; R b represents a hydrogen atom or a C 1 -C 3 alkyl or C 1 -C 3 haloalkyl group; X represents CF 2 , CHR 8 ; R 2 represents a hydrogen atom or a C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group; R 3 represents a 5- or 6-membered monocyclic heteroaromatic group optionally substituted by at least one substituent independently selected from halogen, hydroxyl, cyano, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 alkenyl, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkoxycarbonyl, —NR 10 R 11 , —C(O)NR 12 R 13 , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkylmethyl or a 5- or 6-membered heteroaryl group, the heteroaryl group being optionally substituted by at least one substituent independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy; R 4 and R 5 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 4 and R 5 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen, hydroxyl and C 1 -C 3 alkoxy; R 6 and R 7 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 6 and R 7 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen and hydroxyl; R 8 represents a hydrogen or halogen atom or a hydroxyl group; R 10 and R 11 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 10 and R 11 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen, hydroxyl and C 1 -C 3 alkoxy; and R 12 and R 13 each independently represent a hydrogen atom or a C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl group, or R 12 and R 13 may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen and hydroxyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 1 , wherein R 1 represents a 9- or 10-membered fused bicyclic heteroaromatic group containing one or two ring heteroatoms independently selected from nitrogen, oxygen and sulphur, the heteroaromatic group being optionally substituted by one or more halogen atoms. A compound according to claim 1 , wherein R 1 represents a 9- or 10-membered fused bicyclic heteroaromatic group selected from quinoxalinyl, benzothiazolyl, benzoxazolyl, quinolinyl and quinazolinyl, all optionally substituted as claimed in claim 1 . A compound according to claim 1 , wherein X represents CH 2 . A compound according to claim 1 , wherein L represents NH. A compound according to claim 1 , wherein R 2 represents a hydrogen atom or methyl group. A compound according to claim 1 , wherein R 3 represents a 5- or 6-membered monocyclic heteroaromatic group selected from pyridinyl, pyrimidinyl and pyrazinyl, all optionally substituted as claimed in claim 1 . A compound according to claim 1 , wherein R 3 is optionally substituted by at least one substituent independently selected from fluorine, chlorine, bromine, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, —NR 10 R 11 , or a 5- or 6-membered heteroaryl group, the heteroaryl group being optionally substituted by one or two substituents independently selected from C 1 -C 2 alkyl, C 1 -C 2 alkoxy and C 1 -C 2 haloalkoxy. A compound according to claim 1 , wherein R 3 is optionally substituted by at least one 5- or 6-membered heteroaryl group selected from triazolyl, pyrazolyl, oxadiazolyl, pyrimidinyl and imidazolyl, all optionally substituted by one or two substituents independently selected from C 1 -C 2 alky A compound of formula (I) as claimed in claim 1 selected from the group consisting of: 3-Bromo-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino] cyclopentyl]-pyridine-2-carboxamide; 6-Bromo-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino] cyclopentyl]-3-methoxypyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-methoxypyridine-2-carboxamide; 3-Chloro-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino] cyclopentyl]-pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-methoxy-N-methylpyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzoxazol-2-yl)amino]cyclopentyl]-3-methoxypyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-(propan-2-yloxy)pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-methoxy-6-methylpyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-(1H-pyrazol-1-yl)pyridine-2-carboxamide; 3-Fluoro-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-(piperidin-1-yl)pyridine-2-carboxamide; 3-(Azetidin-1-yl)-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-(pyrrolidin-1-yl)pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide; 3-Methoxy-N-[(1S,2S)-2-[(quinoxalin-2-yl)amino]cyclopentyl]pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-methoxy-6-(trifluoromethyl)pyridine-2-carboxamide; 3-Ethoxy-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-(trifluoromethoxy)pyridine-2-carboxamide; 3-(Difluoromethoxy)-N-[(1S,2S)-2-[(6-fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Chloro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Chloro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-(difluoromethoxy)pyridine-2-carboxamide; 3-(Difluoromethoxy)-N-[(1S,2S)-2-[(6-fluoro-1,3-benzoxazol-2-yl)amino]cyclopentyl]pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Fluoro-1,3-benzothiazol-2-yl)amino]cyclopentyl]-3-(1H-1,2,3-triazol-1-yl)pyridine-2-carboxamide; N-[(1S,2S)-2-[(6-Chloro-1,3-benzoxazol-2-yl)amino]cyclopentyl]-3-(difluoromethoxy)pyridine-2-carboxamide; 3-Ethoxy-6-methyl-N-[2-(quinolin-2-ylmethyl)cyclopentyl]pyridine-2-carboxamide; 3-Ethoxy-6-methyl-N-[2-(quinolin-2-ylmethyl)cyclopentyl]pyridine-2-carboxamide; enantiomers thereof and pharmaceutically acceptable salts of any of the foregoing. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 , in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents. A composition according to claim 11 , wherein the one or more other therapeutic agents are selected from carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone and lithium. |
| CPC Classification | Preparations For Medical; Dental Or Toiletry Purposes HETEROCYCLIC COMPOUNDS Specific Therapeutic Activity Of Chemical Compounds Or Medicinal Preparations |
| Examiner | Yong Chong |
| Extended Family | 169-977-115-842-311 031-675-948-647-213 112-478-261-017-964 187-211-992-994-644 044-280-398-976-981 129-071-231-033-317 155-331-855-488-791 117-292-316-091-35X 078-467-025-447-976 088-551-252-853-688 076-867-267-080-775 097-131-826-682-730 060-873-682-416-432 047-644-456-152-512 080-156-173-622-629 120-427-076-637-256 168-040-882-456-228 010-068-805-266-88X 108-273-063-000-121 146-712-013-199-718 173-632-743-856-942 023-323-092-762-521 028-033-627-576-554 013-400-011-366-53X 112-230-602-232-699 166-614-958-452-221 |
| Patent ID | 9790220 |
| Inventor/Author | Fieldhouse Charlotte Glen Angela Fujimoto Tatsuhiko Robinson John Stephen |
| IPC | A61K31/015 A61K31/16 A61K31/4439 A61K31/4545 A61K31/4709 A61K31/498 C07D401/12 C07D413/12 C07D417/12 C07D417/14 |
| Status | Inactive |
| Owner | Takeda Pharmaceutical Company Limited |
| Simple Family | 169-977-115-842-311 031-675-948-647-213 112-478-261-017-964 187-211-992-994-644 044-280-398-976-981 129-071-231-033-317 155-331-855-488-791 117-292-316-091-35X 078-467-025-447-976 088-551-252-853-688 076-867-267-080-775 097-131-826-682-730 060-873-682-416-432 047-644-456-152-512 080-156-173-622-629 120-427-076-637-256 168-040-882-456-228 010-068-805-266-88X 108-273-063-000-121 146-712-013-199-718 173-632-743-856-942 023-323-092-762-521 028-033-627-576-554 013-400-011-366-53X 112-230-602-232-699 166-614-958-452-221 |
| CPC (with Group) | A61K31/015 A61K31/16 A61K31/4439 A61K31/4545 A61K31/4709 A61K31/498 C07D401/12 C07D413/12 C07D417/12 C07D417/14 A61P25/04 A61P25/18 A61P25/22 A61P25/28 A61P25/30 A61P43/00 A61K31/428 A61K45/06 |
| Issuing Authority | United States Patent and Trademark Office (USPTO) |
| Kind | Patent/New European patent specification (amended specification after opposition procedure) |
