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(12) United States Patent (10) Patent No.: US 8,980,887 B2 Yang Et Al

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(12) United States Patent (10) Patent No.: US 8,980,887 B2 Yang Et Al US00898O887B2 (12) United States Patent (10) Patent No.: US 8,980,887 B2 Yang et al. (45) Date of Patent: Mar. 17, 2015 (54) 2-ARYL Trapanietal, J. Med. Chem. 2005, 48,292-305.* IMIDAZO 1.2-APYRIDINE-3-ACETAMIDE Supplementary European Search Report dated Oct. 23, 2013 PCT/ DERIVATIVES, PREPARATION METHODS CN2011075500 in corresponding application. AND USES THEREOF S. Paul, et al., "Zinc Medicated Friedel-Crafts Acylation in Solvent Free Conditions Under Microwave Irradiation' Synthesis 2003, No. 18, pp. 2877-2881. (75) Inventors: Rifang Yang, Beijing (CN); Yunfeng Li, G. Trapani, et al., Structure-Activity Relationships and Effects on Beijing (CN); Yongzhen Li, Beijing Neuroactive Steroid Synthesis in a Series of 2-Phenylimidazo[1,2-C. (CN); Nan Zhao, Beijing (CN); Pyridineacetamide Peripheral Benzodiazepine Receptors Ligands, Liuhong Yun, Beijing (CN), Juanjuan Journal of Medicinal Chemistry, 2005, vol. 48, No. 1. Published Dec. Qin, Beijing (CN); Zhongyao Feng, 13, 2004, pp. 292-305. Beijing (CN); Youzhi Zhang, Beijing Papadopoulos V. et al., “Translocator protein (18kDa): new nomen (CN) clature for the peripheral-type benzodiazepine receptor based on its structure and molecular function.” Trends in Pharmacological Sci (73) Assignees: Institute of Pharmacology, Beijing ence, vol. 27, No. 8, p. 402-409 (2006). (CN); Toxicology Academy of Military Scarf A.M. et al., “The translocator protein (18 kDa): central nervous Medical Sciences P.L.A., China, system disease and drug design.” Journal of Medicinal Chemistry, Beijing (CN) vol. 52, No. 3, p. 581-592 (2009). Li Y. et al., Synthesis and anxiolytic effects of 2-aryl imidazo[1,2-a (*) Notice: Subject to any disclaimer, the term of this pyridine-3-acetamide derivatives, Journal of International Pharma patent is extended or adjusted under 35 ceutical Research, vol. 37, No. 4, p. 292-301 (2010). U.S.C. 154(b) by 0 days. James M.L. et al., “Development of ligands for the peripheral benzodiapene receptor.” Current Medicinal Chemistry, vol. 13, No. (21) Appl. No.: 13/805,967 17, p. 1991-2001 (2006). Samanta S. et al. “Search for Structural Requirements of 2-Phenylimidazo 1.2-Opyridineacetamide Analogs to Improve (22) PCT Filed: Jun. 9, 2011 Affinity and Selectivity towards Central and/or Peripheral Benzodiazepine Receptors.” Internet Electronic Journal of Molecu (86). PCT No.: PCT/CN2011/075500 lar Design, vol. 6, issue 7, p. 183-189 (2007). S371 (c)(1), Taliani S. et al. “Translocator protein ligands as promising therapeu (2), (4) Date: Apr. 18, 2013 tic tools for anxiety disorders.” Current Medicinal Chemistry, vol. 16, No. 26, p. 3359-3380 (2009). Rupprecht R. et al. “Translocator protein (18 kD) as target for (87) PCT Pub. No.: WO2011/160548 anxiolytics without benzodiazepine-like side effects.” Science vol. PCT Pub. Date: Dec. 29, 2011 325, p. 490-495 (2009). (Continued) (65) Prior Publication Data US 2013/02O3754 A1 Aug. 8, 2013 Primary Examiner — Wu-Cheng Winston Shen Assistant Examiner — Jean Cornet (30) Foreign Application Priority Data (74) Attorney, Agent, or Firm — Brinks Gilson & Lione Jun. 25, 2010 (CN) .......................... 2010 1 0209752 (57) ABSTRACT (51) Int. Cl. Disclosed are 2-arylimidazol-2-alpyridine-3-acetamide A 6LX3/535 (2006.01) derivatives represented by formula I, their tautomer, racemate CO7D 47L/04 (2006.01) or optical isomer, their pharmaceutically acceptable salt, or (52) U.S. Cl. their solvates, wherein R', R, R and Rare defined as in the CPC .................................... C07D 471/04 (2013.01) specification. Preparation methods of said compounds and USPC ........ 514/233.2: 514/300; 435/375; 54.6/121: use of said compounds in treating and/or preventing central 544f127 nervous system disease associated with TSPO functional dis (58) Field of Classification Search order USPC ................ 514/233.2, 300; 435/375; 54.6/121: 544f127 See application file for complete search history. (56) References Cited FOREIGN PATENT DOCUMENTS CN 1858.050 A 11, 2006 CN 101.336242 A 12/2008 WO WO99,51594 10, 1999 WO WO 2008022396 A1 * 2/2008 OTHER PUBLICATIONS STN Accession No. 2006: 1186013 CAPLUS, 2006.* 19 Claims, 6 Drawing Sheets US 8,980,887 B2 Page 2 (56) References Cited G. Trapani, et al., “Synthesis and Binding Affinity of 2-Phenylimidazo (1.2- a pyridine Derivatives for both Central and OTHER PUBLICATIONS Peripheral Benzodiazepine Receptors. A New Series of High-Affin ity and Selective Ligands for the Peripheral Type'. J. Med. Chem. Kita A. et al., “Lack of tolerance to anxiolysis and withdrawal symp- 1997, vol. 40, pp. 3109-31 18. toms in mice repeatedly treated with AC-5216, a selective TSPO Y. Sumalatha, et al., “Synthesis and Spectral Characterization of ligand.” Progress in Neuro-Psychopharmacology and Biological Process-Related Substances to the Hypnotic Agent Zolpidem'. Psychiatry, vol. 33, p. 1040-1045 (2009). ARKATUSA, Inc., ARKIVOC-2009 (vii), pp. 143-149. Notification of Reexamination of Chinese Application No. 201010209752.0. With English translation. * cited by examiner U.S. Patent Mar. 17, 2015 Sheet 1 of 6 US 8,980,887 B2 Fig. 1 sfiu?ssouogouequun.N (uæquunu) 11"(mg/kg) Fig. 2 U.S. Patent Mar. 17, 2015 Sheet 2 of 6 US 8,980,887 B2 DW 30 0.1 0.3 DMI (mg/kg) 8# (mg/kg) Fig. 3 100 5 O O O 0.1 0.1 YL-IPA 08(mg/kg) O 3 O 3 PK11195(mg/kg) Fig. 4 U.S. Patent Mar. 17, 2015 Sheet 3 of 6 US 8,980,887 B2 Fig. 5 U.S. Patent US 8,980,887 B2 30 O O O Fig. 6 U.S. Patent Mar. 17, 2015 Sheet 6 of 6 US 8,980,887 B2 0.6 re Eg St 0.4 E --- - s Ee E - Ee . E. 0.0 E DW ? 3 10 YL-IPAO8(mg/kg) Fig. 9 3 al 5 E. E 2 E C at 1 E O - 2 e E O OW 3. 10 YL-PAO8(mg/kg) Fig. 10 US 8,980,887 B2 1. 2 2-ARYL called as mitochondrial benzodiazepine receptor (MBR). The IMIDAZO 1.2-APYRIDINE-3-ACETAMIDE whole structure of the receptor complex comprises a translo DERIVATIVES, PREPARATION METHODS cator protein 18 KDa (TSPO) located at mitochondrial outer AND USES THEREOF membrane, and TSPO as the minimum functional unit of PBR/MBR can combine with pharmaceutical ligand and cho CROSS-REFERENCE TO RELATED lesterol and exert important functions (Trends PharmacolSci, APPLICATIONS 2006, 27(8): 402-409; J Med Chem, 2009, 52(3): 581-592). TSPO has potential value in treatment of anxiety. After The present application is a S371 national stage application TSPO combines with corresponding ligand, it can promote of PCT International Application No. PCT/CN2011/075500, 10 the entrance of cholesterol into mitochondria, and stimulate filed Jun. 9, 2011, which application claims a right of priority biosynthesis of neurosteroids, while neurosteroids can act on to Chinese Patent Application No. 201010209752.0, filed GABA-A receptor and produce anxiolytic effects, but do not Jun. 25, 2010, both of which are incorporated herein by produce apparent side effects. reference in their entirety. At present, TSPO ligands are very widely studied, and it 15 has been reported that many compounds exert good activity in TECHNICAL FIELD vivo and in vitro, and TSPO ligands having relatively high affinity and selectivity are reported as well. According to their The present invention belongs to medical chemical field, chemical structure, there are mainly benzodiazepines (e.g., and relates to 2-arylimidazol-2-alpyridine-3-acetamide 4'-chlorodiazepam (Ro5-4864), isoquinoline amides, ben derivatives, their preparation methods and uses. The present Zothiazepines, benzoxazepines, indole acetamides (e.g., invention further relates to a pharmaceutical composition FGIN), imidazopyridine acetamides, aryloxyaniline deriva comprising a compound of Formula I, its tautomer, its race tives, pyrazolopyrimidine acetamides, 3-indolyloxamides, mic or optical isomer, its pharmaceutically acceptable salt, or 2-arylpyrimidine derivatives, and 2-aryl-8-oxypurine deriva its Solvate, a method for treatment and/or prophylaxis of a tives. These ligands have roughly same basic structure, and central nervous system disease associated with TSPO func 25 can be concluded as: containing one hydrogen bond donator tional disorder, and a method for combating cell apoptosis in (81, usually amide), two lipophilic areas (PAR and FRA) on Vivo or in vitro, combating a tumor, inflammatory immuno mother ring backbone, and another lipophilic area (LA) bind regulation, neuroprotection, or regulating TSPO activity. ing to receptor via allosterism (Curr Med Chem, 2006, 13(17): 1991-2001. Curr Med Chem, 2009, 16(26): 3359 Formula I 30 3380.). In corresponding animal models and clinical studies, some of the selective TSPO ligands had been showed potential values in creating new drugs with TSPO as target. For example, PK1 1195, a TSPO/PBR selective antagonist, has 35 been widely used in finding new types of TSPO ligands and activity comparison as a tool drug. In addition, Emapunil (AC-5216, XBD173) has high selectivity and affinity, less side effects, no remarkable withdrawal symptoms and drug withdraw rebounding symptoms, and thus enters phase II 40 clinical research (Science 2009, 325, 490-195; Prog Neuro BACKGROUND ART Psychoph, 2009, 33, 1040-1045.). However, most of these compounds have poor pharmacokinetics, low bioavailability, Anxiety disorder has main symptoms such as panic, uneasy difficulty in penetrating blood brain barrier. Hence, it is still and repeated anxieties, and patients under mental disorder needed to find better TSPO ligands. state cannot exert normal living ability and effectively work, 45 and long-term of diseases may grievously influence patients CONTENTS OF THE INVENTION health and daily life, and even may induce more serious consequences such as Suicide. In addition, the later phase of One aspect of the present invention relates to a compound anxiety is usually accompanied with depression symptoms.
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