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(12) United States Patent (10) Patent No.: US 8.470,805 B2 Chen (45) Date of Patent: Jun USOO8470805B2 (12) United States Patent (10) Patent No.: US 8.470,805 B2 Chen (45) Date of Patent: Jun. 25, 2013 (54) PROCESSES FOR PREPARING OTHER PUBLICATIONS PPERAZINUM SALTS OF KMUP AND USE THEREOF Arayne et al. Med Chem Res. (2010) 19:717-731.* Chung et al., “The xanthine derivative KMUP-1 inhibits models of pulmonary artery hypertension via increased NO and coMP-depen (75) Inventor: Ing-Jun Chen, Kaohsiung (TW) dent inhibition of RhoA, Rho kinase.' British Journal of Pharmacol (73) Assignee: Kaohsiung Medical University, ogy, (Jun. 2010) 160(4):971-986. Evans et al., Effects of HMG-CoA Reductase Inhibitors on Skeletal Kaohsiung (TW) Muscle: Are all Statins the Same?, Drug Safety (2002) 25(9):649 663. (*) Notice: Subject to any disclaimer, the term of this Hiro et al., Effects of Intensive Statin Therapy of Regression of patent is extended or adjusted under 35 coronary Atherosclerosis in Patients with Acute Coronary Syndrome: U.S.C. 154(b) by 193 days. A Multicenter Randomized Trial Evaluated by Volumetric Intravascular Ultrasound Using Pitavastatin Versus Atorvastatin (21) Appl. No.: 12/878,451 (Japan-ACSJapan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome Study), J. Am. Coll. Cardiol. (2009) (22) Filed: Sep. 9, 2010 54:293-302. Jacobson TA, “Myopathy with statin-fibrate combination therapy: (65) Prior Publication Data clinical considerations.” Nat. Rev. endocrinol. (Sep. 2009) 5(9):507 US 2011 FO136767 A1 Jun. 9, 2011 518. Lin et al., “KMUP-1 relaxes rabbit corpus cavernosum smooth muscle in vitro and in vivo: involvement of cyclic GMP and K" Related U.S. Application Data channels.” British Journal of Pharmacology (2002) 135:1159-1166. (63) Continuation of application No. 12/630.368, filed on Lipid Research Clinics Program, “The Lipid Research Clinics Coro Dec. 3, 2009. nary Primary Prevention Trial Results: Reduction in Incidence of Coronary Heart Disease.” JAMA (1984) 251(3):351-374. (30) Foreign Application Priority Data Liu et al., “cGMP-Enhancing- and O Andrenoceptor Block ade-Derived Inhibition of Rho-Kinase by KMUP-1 Provides Optimal Jan. 29, 2010 (TW) ............................... 99.102735 A Prostate Relaxation and Epithelial Cell Anti-Proliferation Efficacy.” The Prostate (2007) 67: 1397-1410. Versmissen et al., “Efficacy of statins in familial (51) Int. Cl. hypercholesterolaemia: a long term cohort study.” BMJ (Jan. 21. A6 IK3I/60 (2006.01) 2009) 338:a3041. A 6LX3L/2197 (2006.01) Wu et al., “A xanthine-based KMUP-1 with cyclic GMP enhancing CO7D 473/00 (2006.01) and K' channels opening activities in rat aortic Smooth muscle.” (52) U.S. Cl. British Journal of Pharmacology (2001) 134:265-274. USPC ....... 514/161; 514/252.16; 514/249; 544/270 (58) Field of Classification Search (Continued) USPC ...................... 544/270: 514/161,252.16, 249 Primary Examiner — Shirley V Gembeh See application file for complete search history. (74) Attorney, Agent, or Firm — Volpe and Koenig, P.C. (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS A series of monoquarternary piperazium salts including a 2,748,127 A * 5/1956 Baltzly et al. ................. 544,396 structure of a formula I or II are provided. In formula I or II, 3,703,519 A * 1 1/1972 Henderson .................... 544,403 R. R. and RX are as defined in the specification. The mono 4,198,507 A 4/1980 Barry et al. quarternary piperazium salt of KMUP or piperazine disclosed 4,231,938 A 11/1980 Monaghan et al. 4,346,227 A 8, 1982 Terahara et al. in the present invention is characterized by being presented in 4.426,383 A * 1/1984 Sugimoto et al. ........ 514,252.16 a pro-drug form and having various pharmaceutical func 4,444,784. A 4, 1984 Hoffman et al. tions. 4,739,073. A 4, 1988 Kathawala 5,006,530 A 4, 1991 Angerbauer et al. 5,159,104 A 10, 1992 Dabora et al. formula I 5,177,080 A 1/1993 Angerbauer et al. 5,260,440 A 11/1993 Hirai et al. 5,298,627 A 3, 1994 Butler et al. 6,002,021 A 12/1999 Yang et al. 6,100.407 A 8, 2000 Van Dalen et al. 6,294,680 B1 9, 2001 Vries et al. formula II 6,316,460 B1 1 1/2001 Creekmore et al. 6,979,687 B1 12, 2005 Chen 7,390,504 B2 6, 2008 Tunac 7.550.468 B2 6, 2009 Chen 2005/0209243 A1* 9, 2005 Chen ........................ 514,252.16 2008.0312249 A1 12, 2008 Chen FOREIGN PATENT DOCUMENTS TW 200848044 1, 2006 WO 9513283 5, 1995 12 Claims, 5 Drawing Sheets US 8,470.805 B2 Page 2 OTHER PUBLICATIONS Soluble Guanylate Cyclase and Protein Kinase G.” Mol Pharmacol Wu et al., “KMUP-1, a xanthine derivative, induces relaxation of (2006)70:977-985. Wu et al., “KMUP-1 activates BK channels in basilar artery guinea-pig isolated trachea: the role of the epithelium, cyclic myocytes via cyclic nucleotide-dependent protein kinases. British nucleotides and K" channels.” British Journal of Pharmacology Journal of Pharmacology (2005) 146:862-871. (2004) 142: 1105-1114. Van Straten et al., “Analysis of Organic Acids in Aqueous Samples.” Wu et al., “Inhibition of Proinflammatory Tumor Necrosis Factor-o- Agilent Technologies (2004). Induced Inducible Nitric-Oxide Synthase by Xanthaine-based 7-2- Taiwanese Office Action, Taiwanese Application No. 099102735. 4-(2-Chlorobenzene)piperazinylethyl-1,3-dimethylxanthine filed Jan. 29, 2010. (KUMP-1) and 7-2-4-(4-Nitrobenzene)piperazinylethyl-1,3- dimethylxanthine (KUMP-3) in Rat Trachea: The involvement of * cited by examiner U.S. Patent Jun. 25, 2013 Sheet 1 of 5 US 8,470,805 B2 Fig. 1 (a)KMUP-1 HCl (1) -- Na O (c) manufacturing KMUP-1-statin complex compound U.S. Patent Jun. 25, 2013 Sheet 2 of 5 US 8,470,805 B2 Fig. 2A KMUP-1 HC-N O f H H, H Cl 9 | -Rosuvastatinic acid (8) -Pitavastatinic acid (9) U.S. Patent Jun. 25, 2013 Sheet 3 of 5 US 8,470,805 B2 Fig. 2B F O Cels'-- OH OH O -Altorvastatinic acid (10) non-steroid anti-inflammatory (NSAIDs) carboxylic acids 9 . O 'o. O Orr . HN O 2 , -N O N O N Y-NH, )-N o N M \- N CHO C -Methotrexate(11) -Indomethacin(12) anti-diabetic carboxylic acids ( H S N & )KX-9O O -Repaglinide (13) -Nateglinide(14) U.S. Patent Jun. 25, 2013 Sheet 4 of 5 US 8,470,805 B2 Fig. 2C anti-asthmatic carboxylic acids - Gemfibrozil (17) -Fibric acid (18) O O -o-Yo, -y-polyglutamic acid (22) U.S. Patent Jun. 25, 2013 Sheet 5 of 5 US 8,470,805 B2 Q CH, N O NNNN.Y. C-N N NO Y' w 2 KMUP-3 HCl (22) KMUP-2 HCl (23) US 8,470,805 B2 1. PROCESSES FOR PREPARING PPERAZINUM SALTS OF KMUP AND USE (I) THEREOF FIELD OF THE INVENTION The present invention relates to the complex compounds and their preparation thereofused as the pro-drugs of differ or formula ent pharmaceutical functions. Particularly, the present inven 10 tion first relates to the preparation of quarternary piperazium salts of KMUP compounds and the anti-hypercholester (II) olemia activity of KMUP-1 as well as pleitropic effects of O KMUP-associated piperazinium salts. 15 --. BACKGROUND OF THE INVENTION Ra-N N-R1 Statins, which have a general structure of is provided, wherein R may be a hydrogen, or a benzene ring O OH OH having a Substituting group being a halogen atom, an amino group, a nitro group, a C1-C5 alkyl group or a C1-C5 alkoxy ---> Xb group; R is one of a hydrogen and a Xanthine group Substi 25 tuted with a Substituting group being selected from a group consisting of a halogen atom, an amino group, a nitro group. wherein Xb represents the remained structure part of the a C1-C5 alkyl group and a C1-C5 alkoxy group; RX contains open-lactone statins, are currently the therapeutically effec a carboxylic group which donated from a group consisting of tive drugs available for reducing the concentration of the 30 a mineral acid, an organic acid, a statin, a fibric acid deriva low-density lipoprotein (LDL) particle having the risk of tive, a member of non-steroid anti-inflammatory drugs cardiovascular disease existing in the bloodstream of (NSAIDs), an anti-diabetic drug and an anti-asthmatic drug; patients. A high concentration of LDL in the bloodstream has RX may bean anion of the above-mentioned groups carrying been linked to the formation of coronary lesions and would a negative charge. obstruct the blood flow and cause thrombosis. To date, statins 35 have been used in the treatments of hypercholesterolemia The above-mentioned halogen refers to fluorine, chlorine, (Versmissen J, et al., Efficacy of statins in familial hypercho bromine and iodine. lesterolaemia: a long term cohort study. BMJ. 2009 Jan 21; According to the present invention, a compound of formula 338:a3041), hyper-lipoproteinemia, atherosclerosis (Hiro, T., (I) where R and Rare hydrogen refers to a piperazine salt. et al., Effect of Intensive Statin Therapy on Regression of 40 Nevertheless, formula (I) may represent as formula Coronary Atherosclerosis in Patients With Acute Coronary Syndrome. J Am Coll Cardiol, 2009: 54:293-302), benigh prostate hyperplasia (BPH) and osteoporosis by decreasing (IA) osteoclast formation. In contrast, KMUP-1 is the first exposed as a new non-statin 3-hydroxy-3-methylglutaryl-co 45 Ra-N" N-R1 enzyme A (HMG-CoA) inhibitor in this invention, compared to previous invention described in patent U.S. Pat. No. 7.550, RX 468 B2 (2009). U.S.
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