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(12) United States Patent (10) Patent No.: US 9,493,432 B2 Fieldhouse Et Al

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(12) United States Patent (10) Patent No.: US 9,493,432 B2 Fieldhouse Et Al USOO949.3432B2 (12) United States Patent (10) Patent No.: US 9,493,432 B2 Fieldhouse et al. (45) Date of Patent: Nov. 15, 2016 (54) CYCLOPENTYLBENZAMIDE DERVATIVES C07D 417/12: C07D 277/64; C07D 403/12: AND THEIR USE FOR THE TREATMENT OF C07D 215/12: C07D 513/04 PSYCHOTIC AND COGNITIVE DISORDERS See application file for complete search history. (71) Applicant: Takeda Pharmaceutical Company Limited, Osaka (JP) (56) References Cited U.S. PATENT DOCUMENTS (72) Inventors: Charlotte Fieldhouse, Cambridge (GB); Angela Glen, Cambridge (GB); 6,548,539 B1 4/2003 Pikul et al. John Stephen Robinson, Cambridge 2010/0222366 A1* 9/2010 Santella ............... CO7D 211/52 (GB); Tatsuhiko Fujimoto, Fujisawa 514,255.05 (JP) FOREIGN PATENT DOCUMENTS (73) Assignee: Takeda Pharmaceuticals Company EP 2653469 A1 10, 2013 Limited, Osaka (JP) WO 9606098 A1 2, 1996 WO 97.23466 A1 7/1997 WO 97.30998 A1 8, 1997 (*) Notice: Subject to any disclaimer, the term of this WO 98.51671 A 11, 1998 patent is extended or adjusted under 35 WO 99.03859 A1 1, 1999 U.S.C. 154(b) by 0 days. WO 99.05.134 A1 2, 1999 WO 99.27783. A 6, 1999 WO OOf 42044 A1 T 2000 (21) Appl. No.: 15/029,356 WO O1,29034 A1 4/2001 WO 01,36417 A1 5, 2001 (22) PCT Fed: Oct. 14, 2014 WO 01,60821 A1 8, 2001 WO 02/08212 A1 2, 2002 (86) PCT No.: WO 02/094794 A1 11 2002 WO 02/096912 A1 12/2002 S 371 (c)(1), WO O3,087102 A1 10, 2003 (2) Date: Apr. 14, 2016 WO O3,087103 A1 10, 2003 (Continued) (87) PCT Pub. No.: WO2O1S/OSS994 PCT Pub. Date: Apr. 23, 2015 OTHER PUBLICATIONS Prior Publication Data International Preliminary Report on Patentability, issued in connec (65) tion with International Application No. PCT/GB2014/053079 on US 2016/0222O3O A1 Aug. 4, 2016 Apr. 19, 2016, 7 pages. (Continued) (30) Foreign Application Priority Data Oct. 15, 2013 (GB) ................................... 1318222.5 Primary Examiner — Matthew Coughlin (51) Int. C. (74) Attorney, Agent, or Firm — Barnes & Thornburg C07D 277/82 (2006.01) LLP: Scott D. Rothenberger CO7D 24I/44 (2006.01) CO7D 40/12 (2006.01) (57) ABSTRACT CO7D 263/58 (2006.01) CO7D 413/12 (2006.01) The present invention provides compounds of formula (I) CO7D 417/4 (2006.01) and pharmaceutically acceptable salts thereof, wherein n, L. C07D 417/12 (2006.01) X, R. R. R', R and R their preparation, pharmaceutical C07D 277/64 (2006.01) compositions containing them and their use in therapy. CO7D 403/2 (2006.01) C07D 215/12 (2006.01) (I) CO7D 53/04 (2006.01) X (52) U.S. C. CPC ........... C07D 277/82 (2013.01); C07D 215/12 Ra Rb 5’ (2013.01); C07D 241/44 (2013.01); C07D 263/58 (2013.01); C07D 277/64 (2013.01); R NL N C07D 401/12 (2013.01); C07D 403/12 R2 N (2013.01); C07D 413/12 (2013.01); C07D 417/12 (2013.01); C07D 417/14 (2013.01); uj (R), C07D 513/04 (2013.01) (58) Field of Classification Search CPC C07D 277/82: C07D 241/44; C07D 401/12: C07D 263/58; C07D 413/12: C07D 417/14: 15 Claims, No Drawings US 9,493.432 B2 Page 2 (56) References Cited Coleman et al., “Orexin receptor antagonists: a review of promising compounds patented since 2006”. Expert Opinion on Therapeutic Patents, Informa Healthcare, GB, vol. 20, No. 3, Mar. 1, 2010, 18 FOREIGN PATENT DOCUMENTS pageS. Hess, H. M.; Brown, H. C., Synthesis of 3-cyclopenten-1-one and WO O3,087104 A1 10, 2003 3-cyclopenten-1-ol. J. Org Chem., 1967, 32, 4138-4139. WO O3O99276 A1 12/2003 WO 2004/O1661.6 A1 2, 2004 Brookes, P.; Milne, D. J.; Murphy, P. J.; Spolaore, B., Epoxide WO 2004/O16617 A1 2, 2004 rearrangements using dilithiated amino alcohols as chiral bases, WO 2004/O19947 A1 3, 2004 Tetrahedron 2002, 58, 4675-4680. WO 20080O8517 A2 1, 2008 Guan, Y.; Grenn, M. A.; Bergstrom, D. E. Stereocontrolled Syn WO 2009003993 A1 1, 2009 thesis of (1R,3R.4S)- and (1S,3R.4S)-3,4-diaminocyclopentanols, WO 2009080533 A1 T 2009 Synlett 1999, 4, 426-428. WO 2012O81692 A1 6, 2012 Sakurai et al., “Orexins and Orexin Receptors: A Family of Hypo WO 2O1505.5994 A1 4/2015 thalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior, Cell, 1998, 92, 573. De Lecea et al., “The hypocretins: Hypothalamus-specific peptides OTHER PUBLICATIONS with neuroexcitatory activity”. Proc. Nat. Acad. Sci., 1998, 95, 322. Chemelli et al., “Narcolepsy in orexin Knockout Mice: Molecular Search Report issued by the United Kingdom Intellectual Property Genetics of Sleep Regulation”. Cell, 1999, 98, 437. Office for Application No. GB1318222.5, Apr. 14, 2014, 4 pages. Harris et al., “Arousal and reward: a dichotomy in orexin function'. International Search Report and Written Opinion, International Trends Neurosci., 2006, 29, 571. Application No. PCT/GB2014/053079, mailed Nov. 19, 2014, 10 pageS. * cited by examiner US 9,493,432 B2 1. 2 CYCLOPENTYLBENZAMIDE DERVATIVES L represents CH, O, NH or N(CH): AND THEIR USE FOR THE TREATMENT OF R" represents a hydrogen atom or a C-C alkyl or C-C, PSYCHOTIC AND COGNITIVE DSORDERS haloalkyl group; R" represents a hydrogen atom or a C-C alkyl or C-C, CROSS-REFERENCE TO RELATED haloalkyl group; X represents CF, CHR, O or NC(O)R’: APPLICATIONS R represents a hydrogen atom or a C-C alkyl group; This application is a 35 U.S.C. S371 (b) National Stage n is 0 or an integer 1, 2, 3, 4 or 5: Application of International Application No. PCT/GB2014/ each R independently represents halogen, hydroxyl, 10 cyano, C-C alkyl, C-C haloalkyl, C-C hydroxy 053079, filed Oct. 14, 2014, and published as alkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, WO2015055994 on Apr. 23, 2015, which claims priority C-C alkylcarbonyloxy, C-C alkoxycarbonyl, from GB 1318222.5, filed Oct. 15, 2013, the contents of NR'R'', CONR'R'', C-C cycloalkyl, C-C, which are hereby incorporated in their entirety by reference. cycloalkyloxy, C-C cycloalkylmethyl or a 5- to The present invention relates to amide derivatives, pro 15 6-membered heteroaryl group, the heteroaryl group cesses for their preparation, pharmaceutical compositions being optionally substituted by at least one substituent containing them and their use in therapy, particularly in the Selected from C-C alkyl, C-C alkoxy and C-C, treatment or prevention of conditions having an association haloalkoxy; with the orexin sub-type 1 receptor. R" and Reach independently represent a hydrogen atom The orexin peptides (orexin A and orexin B, OXA and or a C-C alkyl or C-C cycloalkyl group, or R and OxB), also known as hypocretins, were discovered in 1998 R may together with the nitrogen atom to which they by two groups (Sakurai et al., Cell, 1998, 92, 573 and De are attached form a 4- to 7-membered saturated het Lecea et al., Proc. Nat. Acad. Sci., 1998, 95, 322). These erocyclic ring optionally Substituted by at least one neuropeptides are both derived from the common precursor Substituent selected from halogen and hydroxyl; pre-pro-orexin and are produced in the lateral hypothalamus. 25 Rand Reach independently represent a hydrogen atom OXA is a 33 amino acid residue which has similar potency or a C-C alkyl or C-C cycloalkyl group, or R and at both the Ox1R (orexin 1 receptors) and OX2R (orexin 2 R" may together with the nitrogen atom to which they receptors) whereas OxB is made up of 28 amino acids and are attached form a 4- to 7-membered saturated het binds selectively to the Ox2R. erocyclic ring optionally Substituted by at least one Orexin receptors are believed to be implicated in both 30 Substituent selected from halogen and hydroxyl; feeding behavior (Sakurai et al., Cell, 1998, 92, 573) and R represents a hydrogen or halogen atom or a hydroxyl also in regulating sleep architecture (Chemelli et al., Cell, group; 1999, 98,437). More recently, it has been shown that orexin R represents a C-C alkyl, C-C alkoxy, benzyloxy, receptors are implicated in arousal, reward, learning and Co-Co aryl, or heteroaryl group; memory (Harris et al., Trends Neurosci., 2006, 29. 571). 35 R'' and R' each independently represent a hydrogen WO 2003/099276 describes a broad class of compounds, atom or a C-C alkyl or C-C cycloalkyl group, or R' including certain amides, which are useful as factor Xa and R' may together with the nitrogen atom to which inhibitors for treating thromboembolic disorders. In addi they are attached form a 4- to 7-membered saturated tion, U.S. Pat. No. 6,548,539 describes certain amide deriva heterocyclic ring optionally Substituted by at least one tives for use in treating cancer. 40 Substituent selected from halogen and hydroxyl; and We have now discovered a class of compounds that are R'' and R' each independently represent a hydrogen orexin receptor antagonists which, in general, show selec atom or a C-C alkyl or C-C cycloalkyl group, or R' tivity for the orexin 1 receptor over the orexin 2 receptor. and R' may together with the nitrogen atom to which In accordance with the present invention, there is there they are attached form a 4- to 7-membered saturated fore provided a compound of formula (I) 45 heterocyclic ring optionally Substituted by at least one Substituent selected from halogen and hydroxyl; or a pharmaceutically acceptable salt thereof.
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