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(12) United States Patent (10) Patent No.: US 9.415,047 B2 Zhou Et Al

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(12) United States Patent (10) Patent No.: US 9.415,047 B2 Zhou Et Al US0094.15047B2 (12) United States Patent (10) Patent No.: US 9.415,047 B2 Zhou et al. (45) Date of Patent: Aug. 16, 2016 (54) USE OF BENZO FIVE-MEMBERED 31/4545; A61K 31/506; C07D 209/08; C07D NITROGEN HETEROCYCLIC PPERAZINE 231/56; C07D 235/08; C07D 235/14: CO7D OR PIPERDINEDERVATIVES 235/22; C07D401/06; C07D 401/12 (71) Applicants: Liaoning Emmy Biological USPC ............................................. 514/252.13, 254 Pharmaceutical Co., Ltd., Liaoning See application file for complete search history. (CN); Shenyang Emmy Pharmaceutical Research Institute (56) References Cited Co., Ltd., Liaoning (CN) U.S. PATENT DOCUMENTS (72) Inventors: Yan Zhou, Liaoning (CN): Lirong Zhang, Liaoning (CN); Jie Zhou, 3,362.956 A * 1/1968 Archer ................. CO7D 209/60 Liaoning (CN), Xin Zhou, Liaoning 544,225 3,472,854. A * 10/1969 Archer ................. CO7D 209/60 (CN) 514,906 (73) Assignees: Liaoning Emmy Biological (Continued) Pharmaceutical Co., Ltd., Liaoning (CN); Shenyang Emmy FOREIGN PATENT DOCUMENTS Pharmaceutical Research Institute Co., Ltd., Liaoning (CN) CN 1154693. A 7/1997 CN 1944404 A 4/2007 (*) Notice: Subject to any disclaimer, the term of this CN 101759693. A 6, 2010 patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS (21) Appl. No.: 14/647,408 Alessandro Boido et al., “Synthesis and pharmacological evaluation (22) PCT Fled: Nov. 25, 2013 of aryl/heteroaryl piperazinyl alkyl benzotriazoles as ligands for some serotonin and dopamine receptor subtypes.” IL FARMACO, (86) PCT NO.: PCT/CN2O13/OO1442 2001, vol. 56, pp. 263-275.* S371 (c)(1), (Continued) (2) Date: May 26, 2015 (87) PCT Pub. No.: WO2O14/07915S Primary Examiner — Kamal Saeed PCT Pub. Date: May 30, 2014 Assistant Examiner — Janet L. Coppins (74) Attorney, Agent, or Firm — Hultquist, PLLC; Steven J. (65) Prior Publication Data Hultquist US 2015/O297586 A1 Oct. 22, 2015 (30) Foreign Application Priority Data (57) ABSTRACT Nov. 26, 2012 (CN) .......................... 2012 1 0486619 This invention relates to the use of a compound informula (I) Nov. 26, 2012 (CN) .......................... 2012 1 0486967 and its salts acceptable pharmaceutically in preparation of Nov. 26, 2012 (CN) .......................... 2012 1 04871 28 vasodilative drugs: (51) Int. Cl. (I) A6 IK3I/496 (2006.01) A6 IK3 L/454 (2006.01) / x (Continued) (52) U.S. Cl. CPC ............. A6 IK3I/496 (2013.01); A61 K3I/454 R-X N-Y-N-A (2013.01); A61 K3I/4545 (2013.01); (Continued) Wherein, R. R. X, Y, A and B are defined in the invention. (58) Field of Classification Search CPC .............. A61K 31/496; A61K 31/454: A61 K 19 Claims, 11 Drawing Sheets se $3 : s $3: $.3. og re US 9.415,047 B2 Page 2 (51) Int. Cl. (56) References Cited A6 IK3I/498 (2006.01) C07D 209/08 (2006.01) U.S. PATENT DOCUMENTS CO7D 23L/56 (2006.01) 2010/0329978 A1 12/2010 McCurdy et al. CO7D 403/2 (2006.01) 2011/0306638 A1 12/2011 Li et al. CO7D 40/4 (2006.01) CO7D 405/4 (2006.01) OTHER PUBLICATIONS CO7D 413/4 (2006.01) PubMed abstract of Dabire et al., “Central 5-hydroxytyptamine A6 IK3 L/4545 (2006.01) (5-HT) receptors in blood pressure regulation.” Therapie, 1991, vol. CO7D 235/08 (2006.01) 46(6), pp. 421-429.* CO7D 40/06 (2006.01) Boido, A., et al., “Synthesis and pharmacological evaluation of aryl/ heteroaryl piperazinyl alkyl benzotriazoles as ligands for some CO7D 40/12 (2006.01) serotonin and dopamine receptor Subtypes”. “IL Farmaco'. Apr. CO7D 405/2 (2006.01) 2001, pp. 263-275, vol. 56. CO7D 413/2 (2006.01) Boido, A., et al., “Alpha1- and alpha2-adrenoreceptor antagonist C07D 417/12 (2006.01) profiles of 1- and 2-omega-(4-arylpiperazin-1-yl)alkyl-1,2,3- CO7D 417/4 (2006.01) benzotriazoles”, “Chemistry & Biodiversity, Oct. 2005, pp. 1290 1304, vol. 2. CO7D 249/8 (2006.01) Caliendo, G., et al., “Synthesis and biological activity of A6 IK3I/506 (2006.01) benzotriazole derivatives structurally related to trazodone”, “Euro C07D 235/10 (2006.01) pean Journal of Medicinal Chemistry”. Jan. 1, 1995, pp. 77-84, vol. CO7D 235/4 (2006.01) 30. C07D 235/22 (2006.01) Caliendo, G., et al., “Structureaffinity relationship studies on A6 IK 45/06 (2006.01) benzotriazole derivatives binding to 5-HT receptor subtypes”, “Euro 52) U.S. C pean Journal of Medicinal Chemistry”, 1996, pp. 207-213, vol. 31. (52) AV e. we Hoyer, D., et al., “International Union of Pharmacology classification CPC ............. A61 K3I/498 (2013.01); A61 K3I/506 of receptors for 5-hydroxytryptamine (Serotonin)”, “Pharmacologi (2013.01); A61K 45/06 (2013.01); C07D cal Reviews”, Jun. 1994, pp. 157-203, vol. 46, No. 2. 209/08 (2013.01); C07D 231/56 (2013.01); Mesangeau, C., et al., “Synthesis and pharmacological evaluation of C07D 235/08 (2013.01); C07D 235/10 indole-based sigma receptor ligands”, “European Journal of Medici nal Chemistry”, Aug. 29, 2011, pp. 5154-5161, vol. 46. (2013.01); C07D 235/14 (2013.01); C07D Mokrosz, M., et al., “Structure-activity relationship studies of CNS 235/22 (2013.01); C07D 249/18 (2013.01): agents, Part32: Effect of structural modifications in 1-arylpiperazine C07D401/06 (2013.01); C07D401/12 derivatives on alpha(1) -adrenoreceptor affinity”, “Arch. Pharm. (2013.01); C07D401/14 (2013.01); C07D (Weinheim).”. Jun. 1997, pp. 177-180, vol. 330. 403/12 (2013.01); C07D405/12 (2013.01); Co-pending Unpublished U.S. Appl. No. 147647.378, filed May 25, C07D405/14 (2013.01); C07D 413/12 2015. (2013.01); C07D 413/14 (2013.01); C07D 417/12 (2013.01); C07D 417/14 (2013.01) * cited by examiner U.S. Patent Aug. 16, 2016 Sheet 1 of 11 US 9.415,047 B2 3.SS-88 Figure i risis Figure 2 U.S. Patent Aug. 16, 2016 Sheet 2 of 11 US 9.415,047 B2 & * s M s^sk. xcoat ro X ^ S. & S S. 8 SSS- w sS s &S && & . & &&w8 sig (Niš, xi, Figare 3 & ^ Castre *akagasi -iss C Niš, trysi Figure 4 U.S. Patent Aug. 16, 2016 Sheet 3 of 11 US 9.415,047 B2 SS&S R S.S.S. S&SS. S. SSSS its C ca, sai'i. Figure 5 w xAtiodipite Los Cat, (ii. Figure 6 U.S. Patent Aug. 16, 2016 Sheet 4 of 11 US 9.415,047 B2 s six is Figure 7 xx-xxx-xxxx U.S. Patent Aug. 16, 2016 Sheet 6 of 11 US 9.415,047 B2 is retiri * - Doxazosia .x. it's - 8:-3 Ariadipiae 3-...".8wsWSS-3 s SS **t E. Figure id U.S. Patent Aug. 16, 2016 Sheet 8 of 11 US 9.415,047 B2 Figare 7 S. ". x - Six ...S. -ieg Croit, Figure i8 U.S. Patent Aug. 16, 2016 Sheet 10 of 11 US 9.415,047 B2 wCasarai &ioxazisit M 88:& S. -iss , rai. Figure 2 *Citri s& -8S s SSS & -log C ca, noit. Figare 22 U.S. Patent Aug. 16, 2016 Sheet 11 of 11 US 9.415,047 B2 Mew stro w Artiedipiae Figure 23 !”? -log C (5-HT, moll-1 Figare 24 US 9,415,047 B2 1. 2 USE OF BENZO FIVE-MEMBERED (C-C alkyl), alkyl parts in the above said groups are substi NITROGEN HETEROCYCLIC PPERAZINE tuted by anyone or more halogen atoms. OR PIPERDINEDERVATIVES A, B and X respectively indicate CH or N. R indicates H. halogen, CN, C-C alkyl, C-C alkoxyl, CROSS-REFERENCE TO RELATED 5 CHO, CO(C-C alkyl). COO(C-C alkyl), COOH, NO, APPLICATIONS NH, NH(C-C alkyl), N(C-C alkyl), SH, S(C-C alkyl). —S(O) (C-C alkyl). —S(O)H or —S(O)(C-C alkyl). This application is a U.S. national phase under the provi alkyl parts in the above said groups are substituted by anyone sions of 35 U.S.C. S371 of International Patent Application or more halogenatoms. If R indicates poly Substituted group, No. PCT/CN13/01442 filed Nov. 25, 2013, which in turn 10 claims priority of Chinese Patent Application No. R is independently chosen from halogen, CN, C-C alkyl, 201210487128.6 filed Nov. 26, 2012, Chinese Patent Appli C-C alkoxyl, CHO, CO(C-C alkyl). COO(C-C alkyl). cation No. 201210486967.6 filed Nov. 26, 2012, and Chinese COOH, NO, NH, NH(C-C alkyl), N(C-C alkyl), SH, Patent Application No. 2012.10486619.9 filed Nov. 26, 2012. S(C-C alkyl). —S(O) (C-C alkyl). —S(O)H or —S(O) The disclosures of Such international patent application and 15 (C-C alkyl), alkyl parts in the above said groups are substi Chinese priority patent applications are hereby incorporated tuted by anyone or more halogen atoms. herein by reference in their respective entireties, for all pur Y indicates Saturated or unsaturated Straight or branched poses. hydrocarbon chain composed of 1-8 carbonatoms substituted by anyone or more halogen atoms, in which anyone or more FIELD OF THE INVENTION 2O carbonatoms are Substituted by hetero atoms Such as oxygen, Sulfur or nitrogen. The present invention relates to use of benzo five-mem bered nitrogen heterocyclic piperazine or piperidine deriva ILLUSTRATION BY ACCOMPANYING tives in preparation of vasodilative drugs. FIGURES 25 BACKGROUND OF THE INVENTION FIG. 1 illustrates the accumulated concentration effect curve of vasodilative effects of compound II-2 (10-10' Currently there are various categories of vasodilative drugs mol-L") versus vasoconstrictive effects of adrenaline (10 available in clinical field, e.g., C. receptor blockers, including mol-L") on excised blood vessels from rabbits.
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