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US006951860B2 (12) United States Patent (10) Patent N0.: US 6,951,860 B2 Mehanna et a1. (45) Date of Patent: Oct. 4, 2005

(54) BLOCKERS 5,132,106 A 7/1992 Tuloup et a1...... 514/223.5 5,134,139 A 7/1992 Kawai et a1. . 514/211.07

Inventors: (Us); JinyungSI Mehanna, T_ Kim, Sudbury, Boston, MA 5,144,029 A 9/1992 WardAdams et 618.1.a1...... 540/610 (Us) 5,198,433 A 3/1993 Palfreyman et a1. 514/217.11 5,276,026 A 1/1994 Barrrsh et a1...... 514/212.02 (73> Assignees Messeeheseees Cellege ef Phesmeey, 2:531:33 2 511333 81315152111111: 1:: iii/552:5 Bostons MA (Us) 5,360,809 A 11/1994 Axelsson 618.1. 514/338 _ _ _ _ _ 5,387,592 A 2/1995 Bradbury et a1...... 514/312 (*) Notlcel sublectto any dlsclalmer?heterm Ofthls 5,496,815 A 3/1996 OZeki et a1...... 514/2242 patent is eXtended or adjusted under 35 5,514,693 A 5/1996 COZZl et a1...... 514/341 U.S.C. 154(1)) by 183 days. 5,607,939 A 3/1997 Kato et a1...... 514/278 5,623,051 A 4/1997 Catterall et a1...... 530/324 (21) Appl. NO.Z 09/998,623 OTHER PUBLICATIONS (22) Flled: Oct‘ 31’ 2001 Gialdi et al., Abstract to CA 56:4664g.* (65) Prior Publication Data McMurry, John, Editor of Second Edition, Organic Chem istry, 1984, pp. 742—746.* Us 200301156551“ Aug- 22, 2002 Protiva, et al. of CZ 105,590 of CA59:10010f, Nov. 15, 1962* Related US‘ Application Data Goodman & Gilman’s The Pharmacological Basis of Thera _ _ _ _ _ peutics, 9th Edition, pp. 767—774, 1996* (62) 113913175I2IIQ£fPZFP§ZatgO24€IZ§S 8/ 982’953’ ?led on Dec‘ 2’ Gialdi, et al., Chemical Abstracts, Mar. 8, 1962, 4664g, vol. ’ ' ' ’ ’ ' 56, No. 5, The American Chemical Society. (51) Int. Cl.7 ...... A61K 31/4965 Fujita, M_ et 311, “Synthesis and Ca2+ Antagonistic Activity (52) US. Cl...... 514/252.12; 514/252.13; of 2—[2—[(Aminoalkyl)oXy]—5—methoXyphenyl]—3, 514/255.03; 514/255.04; 514/613; 514/617; 4—dihydro—4—methyl—3—oXo—2H—1,4—benZo—thiaZines”, J. 514/618; 514/310; 514/255.4 Med. Chem, 1990, pp. 1898—1905, vol. 33, American (58) Field of Search ...... 514/252.12, 252.13, Chemical Society 514/255_03, 255,04, 613, 617, 618, 619 Yamamoto, K, et al., “Novel Calcium Antagonists. Synthesis and Structure—Activity Relationship Studies of BenZothia (56) References Cited zoline Derivatives”, J. Med. Chem, 1988, pp. 919—930, vol. 31, American Chemical Society. U.S. PATENT DOCUMENTS Jilek, J .; et al., “Preparation of neW antimicrobial (phenylth

4,550,116 A 10/1985 SO10 618.1...... 514/327 io)benZylamines”, Chemical Abstracts Accession No. 4,593,033 A 6/1986 Hartman et a1. 514/290 19921612134 (Abstract only). 4,596,805 A 6/1986 Jiang ...... 514/264.1 Jilek, J ., et al., “Potential antidepressasnts: 2—(methyoXy— 4,640,930 A 2/1987 Mohacsi et a1. 514/431 and hydroXyphenylthio)benZylamines as selective inhibitors 4,654,353 A 3/1987 Alker 618.1. 514/334 of 5—hydroXytryptamine re—uptake in the brain”, Chemical 4,742,069 A 5/1988 Jaunin et a1. 514/356 Abstracts Accession No. 19901458496 (Abstract only). 4,758,669 A 7/1988 Johnson et a1. . 541/263

4,791,117 A 12/1988 Press ...... 514/300 * cited by examiner 4,829,076 A 5/1989 SZilagyi et a1. . 514/356 4,847,273 A 7/1989 Jaunin et a1...... 514/347 Primary Examiner—DWayne Jones 4,918,073 A 4/1990 Riiger et a1...... 514/252.12 (74) Attorney, Agent, or Firm—Wolf, Green?eld & Sacks, 4,918,074 A 4/1990 Tsuda et a1. 514/252.12 PC 4,959,359 A 9/1990 Mohacsi et a1...... 514/211.03 4,988,713 A 1/1991 Frigerio et a1...... 514/356 (57) ABSTRACT 4,992,432 A 2/1991 Mohacsi et a1...... 514/211.03 4,994,612 A 2/1991 Jaunin et a1...... 564/88 The invention involves the identi?cation of a family of 5,017,586 A 5/1991 Schlager ...... 514/318 compounds Which block calcium channels. The compounds 5,025,010 A 6/1991 Oekonomopulos can be formulated in pharmaceutical carriers and adminis et a1...... 514/224.2 tered to subjects. The compounds are useful for treating 5,034,395 A 7/1991 Tamada et a1...... 514/277 disorders associated With calcium channel activity, such as, 5,036,098 A 7/1991 Kimura et a1...... 514/438 cardiovascular diseases, for example hypertension, conges 5,039,674 A 8/1991 Fujikura et a1. 514/217.04 tive , arrhythmia and . 5,070,088 A 12/1991 AtWal ...... 514/212.08 5,071,844 A 12/1991 Alker et a1. 514/211.11 5,106,845 A 4/1992 Carr et a1...... 514/218 4 Claims, 4 Drawing Sheets

U.S. Patent 0a. 4,2005 Sheet 2 0f 4 US 6,951,860 B2 FIG. 2 10 -0— COMP #1 5..

()~

_5~ CHARGE IN 10_ MAP (mmHgI ' _15_

-20_

-25

'30 I I l I I I T I 10 30 B0 100 130 180 270 500 DOSE IN MEG/KG FIG. 3 10 -O- COMP 2 5- +DILT.

'30 I I I I I I I I 10 30 B0 100 130 180 270 500 DOSE IN HCG/KG U.S. Patent 0a. 4,2005 Sheet 3 0f 4 US 6,951,860 B2 FIG. 4

‘30 I I I I I I I I 10 30 B0 100 130 180 270 500 DOSE IN HUG/KG

FIG. 5

-0- COMP 4 5- + DILT.

'30 I I I I I I I I 10 30 B0 100 130 180 270 500 DOSE IN MEG/KB U.S. Patent 0a. 4,2005 Sheet 4 0f 4 US 6,951,860 B2 FIG. 5

-o- COMP s s- n + 0m.

“30 I I I If T I I I 10 30 60 100 130 180 270 500 DOSE IN MCGIKG

FIG. 7 US 6,951,860 B2 1 2 CALCIUM CHANNEL BLOCKERS “4” and “5” forming an amide function With N,N dimethylaminoethyl substitution at the amide nitrogen. Sci RELATED APPLICATIONS entists at central research laboratory at Osaka, Japan, syn thesiZed a series of potent calcium channel blockers in This application is a divisional of Ser. No. 08/982,953, Which the seven membered ring of Was replaced ?led on Dec. 2, 1997, Which is now US. Pat. No. 6,541,479. With 6- and 5- membered fused-ring systems. These tWo neW FIELD OF THE INVENTION classes of calcium channel blockers, the benZothiaZine and respectively (Yamamoto, K., J. Med. Chem., This invention relates to a class of aromatic compounds v.31, p. 919—930 (1988); Fujita, M.,J. Med. Chem., v. 33, p. Which are blockers of calcium channels. The invention also 10 1898—1905 (1990)) demonstrated potent calcium channel relates to pharmaceutical compositions, methods of blocking blocking activity. Some of these compounds even demon calcium channels, kits and methods of treatment using the strated more tissue selectivity toWard calcium channels in class of compounds described herein, as Well as intermediate blood vessels. compounds useful in the preparation of the compounds. 15 SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION A neW family of calcium channel blockers, Which are Calcium channel blockers are a chemically diverse class de?ned by the structures set forth beloW, have been identi of compounds having important therapeutic value in the ?ed according to the invention. The members of the neW control of a variety of diseases including several cardiovas family of compounds constitute a neW class of calcium cular disorders, such as hypertension, angina, and cardiac channel blockers Which is not encompassed by any of the arrhythmias (Fleckenstein, Cir. Res. v. 52, (suppl. 1), three knoWn classes of calcium channel blockers, the p.13—16 (1983); Fleckenstein, Experimental Facts and dihydropyridines, the phenyl alkyl , or the benZothi Therapeutic Prospects, John Wiley, NeW York (1983); aZepines. Of the three knoWn classes the compounds of the McCall, D., Curr Pract Cara'i0l, v. 10, p. 1—11 (1985)). invention are most structurally similar to the benZothiaZ Calcium channel blockers are a heterogenous group of epine class of calcium channel blockers, Which have the that prevent or sloW the entry of calcium into cells by folloWing structural formula. regulating cellular calcium channels. (Remington, The Sci ence and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p.963 (1995)). The regu lation of calcium entry into the cells of the cardiovascular system is of paramount importance to the proper functioning of this system. Cardiac and vascular smooth muscle cells have calcium channels Within the cell membrane. Calcium in?ux through these channels initiates a process of electro mechanical coupling Which ultimately leads to muscle con traction. The ability to regulate the entry of calcium into cardiac and vascular smooth muscle cells is a poWerful therapeutic approach in the treatment of angina and hyper tension respectively. LikeWise, blocking calcium in?ux into cardiac tissues and conduction systems provides a useful Prior to the instant invention it Was believed that the fused approach to control certain types of arrhythmia. ring structure of the benZothiaZepines Was essential for the Calcium channel blockers are also believed to be useful in calcium channel blocking activity of these compounds. the treatment of other disorders in Which the regulation of Applicants, hoWever, have surprisingly discovered that com calcium plays a role in normal hemostasis. Such disorders pounds having the basic central atomic structure of the include, for example, , peripheral benZothiaZepines but lacking the fused ring structure have vascular disease, mild congestive heart failure, hypertrophic calcium channel blocking activity and actually demonstrate subaortic stenosis, protection against ischemic injury, stroke, comparable anti-hypertensive activity to traditional ben migraine, tumor resistance to anti-neoplastic drugs, ZothiaZepines such as diltiaZem. achalasia, esophageal spasms, bronchial asthma, premature In one aspect the invention is a composition of a com labor, dysmenorrhea, and enhancement of success in renal pound having the folloWing structural formula: transplantation. (Remington, The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p.963 (1995)). Wherein Ar2 is an aryl group or a heteroaryl group, Most of the currently available calcium channel blockers Wherein the heteroaryl is a ring having 5, 6, or 7 atoms, and belong to one of three major chemical groups of drugs, the Wherein at least one atom of the heteroaryl is selected from dihydropyridines, such as , the phenyl alkyl the group consisting of a sulfur, a nitrogen, and an oxygen amines, such as , and the benZothiaZepines such as atom, and Which is substituted With R1, R2, R3, R4, and R5; diltiaZem. While the structure activity relationships (SAR) Wherein Ar1 is an aryl group or a heteroaryl group, of the dihydropyridines and the phenyl alkyl amines are Well Wherein the heteroaryl is a ring having 5, 6, or 7 atoms, and de?ned and extensively studied, very limited information is Wherein at least one atom of the heteroaryl is selected from available on the SAR of benZothiaZepines such as diltiaZem. the group consisting of a sulfur, a nitrogen, and an oxygen DiltiaZem is a chiral molecule, With a seven membered atom, and Which is substituted With R6, R7, R8, R9, and R10; fused-ring system, having a thiaZepine, Which is fused With Wherein R1, R2, R3, R4, R5, R7, R8, R9, and R10 indepen a ring. The structure is further characteriZed by 65 dent of one another, are selected from the group consisting three key functional groups, a 4-methoxybenZyl substituent of —H, halogen, piperonyl, (C1—C6) alkyl, (C1—C6) alkenyl, at position “2”; an actoxy ester at position “3”; and positions (C1—C6) alkynyl, (C1—C6) alkoxy —CN, —OR‘, —SR‘, US 6,95l,860 B2 4 In another embodiment the compound has the general structural formula:

R10 R1

10

In yet another embodiment R1 1 is selected from the group consisting of —NH—CHZCHZNH2 and —NH— CH2CH2N—(CH2 Z—H and Wherein Y is S, m is 0 and n is 1—4. According to another embodiment the compound has the general structural formula: 25 Wherein each R‘ is (CH2)Z—NR“R“ and Wherein R“ is independently selected from the group consisting of (C1—C6) alkyl, (C1—C6) alkenyl, (C1—C6) alkoXy, (C1—C6) alkynyl, (C6—C20) aryl, (C6—C20) substituted aryl, (C6—C26) alkaryl, substituted (C6—C26) alkaryl, and (C5—C7) heteroaryl Wherein at least one atom of the heteroaryl is selected from the group consisting of a sulfur, a nitrogen, or an oxygen atom, Wherein the aryl and alkaryl substituents are each independently selected from the group consisting of hydrogen, halogen, (C1—C6) alkyl, (C1—C6) alkenyl, (C1—C6) 35 Wherein R15 is selected from the group consisting of alkynyl and trihalomethyl; halogen, (C1—C6) alkyl, (C1—C6) alkenyl, (C1—C6) alkynyl, and (C1—C6) alkoXy and Wherein R1—R5 are as described Wherein Z is 1—6; above. According to yet another embodiment the compound has Wherein R15 is selected from the group consisting of halogen, (C1—C6) alkyl, (C1—C6) alkenyl, (C1—C6) alkynyl, 40 the general structural formula: and (C1—C6) alkoXy; R10 R1 Wherein X is a group having the folloWing formula; R9 R2 X

R8 TH R5 R3 Wherein Y is selected from the group consisting of S, N, R7 R12 and O; and

Wherein m and n, independent of one another, are integers Wherein R12 is selected from the group consisting of of 0—5. —CO—NH—CH2CH2NH2, —CO—NH—CH2CH2N— (CH2)Z—H, and —CO —N.(CH2)2N R15.(CH2)2 and In a preferred embodiment the compound has the general Wherein R1—R5 and R7—R1O are as described above. structural formula: Preferably, Y is S, m is 0 and n is 1—4. In a more preferred embodiment m is 0 and n is 1—4. In another preferred R10 R1 embodiment Y is S, Wherein R1, R2, R3, R4, R5, R7, R8, R9, and R10, are H, and Wherein R6 is selected from the group consisting of—CO—NH—CH2CH2NH2 and substituted or unsubstituted —CO-, the substituents selected from the group consisting of —H, halogen, (C1—C6) alkyl, (C1—C6) alkenyl, (C1—C6) alkynyl, and (C1—C6) alkoXy. A pharmaceutical composition is provided according to another aspect of the invention. The pharmaceutical com position includes a pharmaceutically acceptable carrier and a compound of the invention, as described above, in an Wherein each of the R groups is as de?ned above. amount effective to inhibit calcium channels. In one embodi US 6,951,860 B2 5 6 ment the pharmaceutical composition also includes a medi aZide; BenZothiadiaZine derivatives; BenZthiaZide; BetaX cament other than the compound for the treatment of a olol Hydrochloride; Sulfate; disorder associated With calcium channel activity. Disorders Hydrochloride; Biclodil Hydrochloride; ; Biso associated With calcium channel activity include, for prolol Fumarate; Hydrochloride; ; example, cardiovascular disease, pulmonary hypertension, Bufeniode; ; ButhiaZide: CandoXatril; CandoXatri peripheral vascular disorder, migraine disorder, mania, lat; Captopril; N-Carboxyalkyl derivatives; ; epilepsy, depression, hyperuricemia, and asthma (achalasia Ceronapril; ChlorothiaZide Sodium; Chlorthalidone; asthma and bronchial asthma). In one embodiment the Cicletanine; Ciclasidomine; CilaZapril; ; Cloni medicament for the treatment of cardiovascular disease is a dine Hydrochloride; Clopamide; CyclopenthiaZide; medicament for the treatment of hypertension. In another embodiment the medicament for the treatment of cardiovas ; Cyptenamine tannates; ; Debriso cular disease is a medicament for the treatment of congestive quin Sulfate; Delapril Hydrochloride; Diapamide; DiaZoX heart failure. In yet another embodiment the medicament for ide; Dilevalol Hydrochloride; DiltiaZem Malate; Ditekiren; the treatment of cardiovascular disease is a medicament for Mesylate; Ecadotril; Enalapril Maleate; Enalap the treatment of angina. rilat; Enalkiren; EndralaZine Mesylate; EpithiaZide; Eprosa According to another aspect of the invention an interme 15 rtan; Eprosartan Mesylate; Mesylate; Fla diate in the preparation of the compounds of the invention is vodilol Maleate; Flordipine; ; Fosinopril provided. The intermediate compound has the general struc Sodium; Fosinoprilat; ; GuanabenZ Acetate; tural formula: Guanacline Sulfate; Sulfate; ; Guan cydine; Monosulfate; Guanethidine Sulfate; R1 Hydrochloride; Guanisoquin Sulfate; Sulfate; Guanoctine Hydrochloride; ; Guan R2 oXan Sulfate; GuanoXyfen Sulfate; Hydrochlo S— C H2 ride; and phthalaZines; HydralaZine PolistireX; Hydro?umethiaZide; derivatives; Indacrinone; COCl R5 R3 25 Indapamide; Indolapril Hydrochloride; ; Indoramin Hydrochloride; Hydrochloride; Ket R4 anserin; ; ; Leniquinsin; Levcro makalim; Lisinopril; Hydrochloride; Losartan Wherein R1, R2, R3, R4, and R5, independent of one Potassium; LosulaZine Hydrochloride; Mebutamate; another, are selected from the group consisting of hydrogen, Hydrochloride; ; MedroXalol halogen, nitro, alkyl, alkoXy or piperonyl. Hydrochloride; MethalthiaZide; MethyclothiaZide; Methyl A method for inhibiting calcium channel activity is pro dopa; Methyldopate Hydrochloride; Methyl 4 pyridyl vided according to another aspect of the invention. The ketone thiosemicarbarZone; ; MetolaZone; method involves the step of contacting a cell having a Fumarate; Metoprolol Succinate; Metyrosine; calcium channel With a compound of the invention, as 35 ; Maleate; MuZolimine; ; de?ned above, in an amount effective to inhibit calcium ; Ofornine; Hydrochloride; PaZoXide; channels. Hydrochloride; Perindopril Erbumine; Pempi In another aspect the invention is a method of treating a dine; ; primaperone; Protoveratrines; Raubasine; subject having a disorder associated With calcium channel Rescimetol; Rilemenidene; ; activity by administering to the subject a compound of the 40 Hydrochloride; ; Pivopril; PolythiaZide; invention, as de?ned above, in an amount effective to inhibit Hydrochloride; ; PriZidilol Hydrochloride; Qua calcium channels in the subject and a pharmaceutically ternary Ammonium Compounds; QuinaZoline derivatives; acceptable carrier. Disorders associated With calcium chan Quinapril Hydrochloride; Quinaprilat; Hydro nel activity include, for example, cardiovascular disease, chloride; Hydrochloride; Hydro pulmonary hypertension, peripheral vascular disorder, 45 chloride; Quinuclium ; Ramipril; RauWol?a Ser migraine disorder, mania, epilepsy, depression, pentina; ; Saprisartan Potassium; Saralasin hyperuricemia, and asthma (achalasia asthma and bronchial Acetate; ; ; Sul?nalol Hydro asthma). In one embodiment the subject has a cardiovascular chloride; derivatives; Tasosartan; Teludipine disease. In a preferred embodiment the cardiovascular dis Hydrochloride; Temocapril Hydrochloride; ease is selected form the group consisting of hypertension, Hydrochloride; Terlakiren; ; Tiamenidine congestive heart failure, arrhythmia, and angina. In other Hydrochloride; Ticrynafen; Tinabinol; ; Tipen embodiments the subject has a disorder selected from the tosin Hydrochloride; TrichlormethiaZide; group consisting of pulmonary hypertension, peripheral Hydrochloride; Trimethaphan Camsylate; TrimoXamine vascular disorder, migraine disorder, mania, epilepsy, Hydrochloride; Tripamide; Tyrosinase; ; Xipamide; depression, hyperuricemia, and asthma (achalasia asthma 55 Zankiren Hydrochloride; and Zofenoprilat Arginine. and bronchial asthma). In another preferred embodiment the medicament is for In one embodiment the method includes the step of treating congestive heart failure. In one embodiment the administering a medicament other than the compound for medicament for treating congestive heart failure is selected the treatment of cardiovascular disease. Preferably the medi from the group consisting of diuretics, metolaZone, cament is for treating hypertension. A medicament for , , ethacrynic acid, aldosterone treating hypertension in one embodiment is a medicament antagonists, trimterene, and . selected from the group consisting of ; In yet another preferred embodiment the medicament is y-Aminobutyric acid; Hydrochloride; Alipamide; for treating angina. In one embodiment the medicament for AlthiaZide; Amiquinsin Hydrochloride; Besy treating angina is selected from the group consisting of late; Amlodipine Maleate; ; Anaritide Acetate; 65 , , , , , AryloXypropanolamine derivatives; Maleate; Bel , , , Bufuralol, , fosdil; Bemitradine; Bendacalol Mesylate; Bendro?umethi , CaroZolol, , , US 6,951,860 B2 7 8 Maleate, DiltiaZem, Espanolol, , , FIG. 2 is a graph depicting the antihypertensive effects of , , , Isadipine, S-(4-methoxybenZyl)-N-(2-(N‘,N‘-dimethylamino)ethyl) Limaprost, , , , thiosalicylamide (an exemplary compound encompassed by , Nifedipine, , , , the family of compounds of the invention). The test com , Nitroglycerin, , , pound and a positive control (DiltiaZem) and a negative OZagrel, Penbutoolol, Pentaerythritol, Tetranitrate, , control Were administered to rats in various dosages ranging Pronethalol, , Sotaiol, , , from 10 to 500 mcg/kg and the maximal arterial blood ; Amlodipine Besylate; Amlodipine Maleate; pressure (MAP) and percent decrease in MAP Were deter Hydrochloride; Bevantolol Hydrochloride; Buto mined based on the base line blood pressure. FIG. 3 is a graph depicting the antihypertensive effects of proZine Hydrochloride; Carvedilol; CinepaZet Maleate; 10 N1-(S-(4-methoxybenZyl) thiosalicyloyl)-N4 Metoprolol Succinate; Molsidomine; Monatepil Maleate; methylpiperaZine (an exemplary compound encompassed by Primidolol; Hydrochloride; Tosifen; Verapamil the family of compounds of the invention). The experimen Hydrochloride; and Tiro?ban Hydrochloride. tal study Was carried out as described in FIG. 2. According to another preferred embodiment the medica FIG. 4 is a graph depicting the antihypertensive effects of ment is for treating arrhythmia. In one embodiment the 15 N1-(S-(4‘-methoxybenZyl) thiosalicyloyl)-N piperonylpip medicament for treating arrhythmia is selected from the eraZine (an exemplary compound encompassed by the fam group consisting of blockers such as ily of compounds of the invention). The experimental study , , , moriciZine, Was carried out as described in FIG. 2. , , , , , FIG. 5 is a graph depicting the antihypertensive effects of ?ecainide, , ; b- blockers, N1 -(S-(4-methoxybenZyl) thiosalicyloyl)-N such as propranolol, acebutolol, ; and compounds (4methoxybenZyl)piperaZine (an exemplary compound that prolong repolariZation, such as amiodarone, , encompassed by the family of compounds of the invention). sotalol. Other antiarrhythmics include Acebutol, Acecaine, The experimental study Was carried out as described in FIG. , Ajmaline, Alprenolol, Amiodarone, Amoproxan, 2. , Arotinolol, Atenolol, Bevantolol, Bretylium 25 FIG. 6 is a graph depicting the antihypertensive effects of Tosylate, Bubumolol, Bufetolol, , Bunitrolol, N1-(S-(4-methoxybenZyl)thiosalicyloyl)-N4 Bupranolol, Hydrochloride, Butobendine, (an exemplary compound encompassed by Capobenic Acid, , Carteolol, Cifenline, the family of compounds of the invention). The experimen , Gallopamil, Indenolol, , tal study Was carried out as described in FIG. 2. , Lorcainide, Meobentine, Metipranolol, FIG. 7 shoWs a kit containing the compounds of the Mexiletine, Nifenalol, Oxprenolol, , Pindolol, invention packaged in a vial and instructions for adminis Pirmenol, , Prajmaline, Pronthalol, Pyrinoline, tering the compounds. Quinidine Sulfate, Quinidine, Sotalol, , Timolol, Tocainide, Verapamil, Viquidil and . DETAILED DESCRIPTION OF THE INVENTION In one embodiment the administration is per oral. In 35 another embodiment the administration is parenteral. In The present invention provides methods and products for another embodiment the administration is intravenous. inhibiting calcium channel activity. It Was found according In yet another aspect of the invention a kit is provided. to the invention that a neW family of compounds Which have The kit includes a package housing a container containing some structural similarity to the benZothiaZaepine class of the compounds of the invention in an amount effective to 40 calcium channel blockers have calcium channel blocking inhibit calcium channels and a pharmaceutically acceptable activity. The compounds of the invention are distinct from carrier, and instructions for using the compound to treat a the benZothiaZepines because these compounds lack the subject having a calcium channel blocking disorder. fused ring structure of benZothiaZepines. Previously, it had In one embodiment the kit also includes a second con been believed that the fused ring structure of the benZothi tainer containing a medicament for the treatment of cardio 45 aZepines Was essential to their activity. Surprisingly, vascular disease. In this embodiment the instructions are for hoWever, it Was discovered according to the invention that using the compound and the medicament to treat cardiovas compounds lacking the fused ring structure actually had cular disease. The medicament for the treatment of cardio comparable calcium channel blocking activity to benZothi vascular disease in some embodiment may be selected from aZepines such as diltiaZem. the group consisting of a medicament for the treatment of Although Applicants do not Wish to be bound by a hypertension, a medicament for the treatment of congestive particular mechanism it is believed that the compounds heart failure, a medicament for the treatment of angina. according to the invention and their pharmacologically In another embodiment the kit also includes a second tolerated salts display their calcium inhibiting activity by container containing a medicament for the treatment of a in?uencing the in?ux of calcium ions into cells through migraine disorder. In this embodiment the instructions are 55 speci?c channels. The compounds prevent or sloW the entry for using the compound and the medicament to treat the of calcium into the cells by acting on allosteric sites of migraine disorder. channel proteins to cause conformational changes Which These and other aspects of the invention are described in prevent calcium passage rather than simply blocking the greater detail beloW. channels. The action of these compounds on the calcium channels can be demonstrated using many biochemical test BRIEF DESCRIPTION OF THE DRAWINGS models including the displacement of tritium-labeled dilt The present invention may be more easily and completely iaZem. In this test, membrane preparations Which contain understood When taken in conjunction With the accompa isolated calcium channels are loaded With the labeled dilt nying draWings. iaZem. After incubation With the test substance, the radio FIG. 1 illustrates the structural formulas of a reaction 65 activity released and the radioactivity remaining on the scheme for a method of synthesiZing a compound encom membrane are determined and the results are reported as an passed by the family of compounds of the invention. IC50 value. US 6,951,860 B2 10 The compounds useful according to the invention have the following general structural formula:

Wherein Ar2 is an aryl group or a heteroaryl group, Wherein the heteroaryl is a ring having 5, 6, or 7 atoms, and Wherein at least one atom of the heteroaryl is selected from the group consisting of a sulfur, a nitrogen, and an oxygen atom, and Which is substituted With R1, R2, R3, R4, and R5; 10 Wherein Ar1 is an aryl group or a heteroaryl group, Wherein R1—R1O are as described above. Wherein the heteroaryl is a ring having 5, 6, or 7 atoms, and In another illustrative embodiment of the invention the Wherein at least one atom of the heteroaryl is selected from compounds have the general structural formula: the group consisting of a sulfur, a nitrogen, and an oxygen atom, and Which is substituted With R6, R7, R8, R9, and R10; 15 R10 R1

25 Wherein R1—R5 and R7—R1O are as described above and Wherein R11 is selected from the group consisting of —NH—CH2CH2NH2, —NH—CH2CH2N—(CH2)Z—H, —N.(CH2)2N R15.(CH2)2, R‘, —OR‘, —SR‘, —NO2, —N(R‘)2, —CO—R‘, —CS—R‘, —CO—OR‘, —CS—OR‘, —CO—SR‘, —CS—SR‘, —CO—N(R‘)2, and —CS— N(R‘)2. In preferred embodiments R11 is selected from the group consisting of —NH—CH2CH2NH2 and —NH— CH2CH2N—(CH2)Z—H and Wherein Y is S, m is 0 and n is 1—4. 35 Exemplary preferred compounds are the folloWing:

1

40

Wherein each R‘ is (CH2 Z—NR“R“ and Wherein R“ is independently selected from the group consisting of (C1—C6) alkyl, (C1—C6) alkenyl, (C1—C6) alkoxy, (C1—C6) alkynyl, (C6—C20) aryl, (C6—C20) substituted aryl, (C6—C26) alkaryl, substituted (C6—C26) alkaryl, and (C5—C7) heteroaryl Wherein at least one atom of the heteroaryl is selected from the group consisting of a sulfur, a nitrogen, or an oxygen atom, Wherein the aryl and alkaryl substituents are each independently selected from the group consisting of hydrogen, halogen, (C1—C6) alkyl, (C1—C6) alkenyl, (C1—C6) alkynyl and trihalomethyl; Wherein Z is 1—6; Wherein R15 is selected from the group consisting of halogen, (C1—C6) alkyl, (C1—C6) alkenyl, (C1—C6) alkynyl, and (C1—C6) alkoxy; Wherein X is a group having the folloWing formula;

Wherein Y is selected from the group consisting of S, N, and O; and Wherein m and n, independent of one another, are integers of 0—5. 65 In one illustrative embodiment of the invention the com pounds have the general structural formula:

US 6,951,860 B2

10

25

The nomenclature used herein is based on I.U.P.A.C. nomenclature. Throughout this disclosure, the following terms, unless otherWise indicated, shall be understood to have the following meanings: The term “alkyl” as used in the present description 40 alone—or in combination—denotes straight-chain and branched, saturated aliphatic hydrocarbon residues. Pre ferred alkyl groups have no more than about 12 carbon atoms and may be methyl, ethyl and structural of propyl, butyl, pentyl, heXyl, heptyl, octyl, nonyl, decyl, 45 undecyl and dodecyl. “LoWer alkyl” means an alkyl group as above, having 1 to about 6 carbon atoms. Examples of loWer alkyl-groups are methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, tert butyl, n-pentyl, isopentyl and neopentyl. The term “alkoXy” denotes an alkyl radical group Which is attached to the remainder of the molecule by oXygen. The term “C2—C6-alkenyl” denotes straight-chain and branched hydrocarbon groups With 2—6 carbon atoms in Which at least one carbon-carbon triple bond is unsaturated 55 such as allyl, butenyl and the like. The term “C2—C6-alkynyl” denotes straight-chain and branched hydrocarbon groups With 2—6 carbon atoms in Which at least one carbon-carbon triple bond is present such as propargyl and the like. The term “halogen” denotes the four halogen atoms ?uorine, chlorine, bromine and iodine. The term “aryl” denotes a mono-aromatic hydrocarbon residue With up to 10 carbon atoms in an aromatic ring 65 structure. The term “heteroaryl group” embraces 5-, 6 and 7-membered mono- heterocycles Which include at least one US 6,951,860 B2 17 18 atom selected from the group consisting of sulfur, oxygen, the pure isomers and all possible diastereoisomeric mixtures and nitrogen and Which are optionally mono-, di- or tri and racemates, as Well as the separation of these diastere substituted by halogen, phenyl, C1—C6-alkyl, C3—C6 oisomeric mixtures Which can be carried out according to alkenyl, C3—C6-alkynyl, C1—C6-alkoxy. knoWn methods. These mixtures of diastereomers can be In one aspect of the invention the compounds are present fractionated into the components by conventional methods, in a pharmaceutical preparation. The pharmaceutical prepa for example selective crystalliZation from suitable solvents rations of the invention include pharmaceutically-acceptable of chromatography on silica gel or aluminum oxide. Cus amounts and pharmaceutically-acceptable compositions. tomary methods can be used to fractionate the racemates Such preparations may routinely contain salts, buffering into the individual enantiomers, for example by salt forma tion With optically active acids, such as camphorsulfonic agents, preservatives, compatible carriers, and optionally 10 acid or dibenZoyltartaric acid, and selective crystalliZation, other therapeutic agents. When used in medicine, the salts or by derivatiZation With suitable optically active reagents, should be pharmaceutically acceptable, but non separation of the diastereomeric derivatives and cleavage pharmaceutically acceptable salts may conveniently be used again. The compounds also include solvated and unsolvated to prepare pharmaceutically-acceptable salts thereof and are forms. not excluded from the scope of the invention. Such phar 15 The foregoing compounds are derived from commercially macologically and pharmaceutically-acceptable salts available products or are synthesiZed de novo using routine include, but are not limited to, those prepared from the chemical synthetic procedures knoWn to those of ordinary folloWing acids: hydrochloric, hydrobromic, sulfuric, nitric, skill in the art. Several examples of chemical synthesis phosphoric, maleic, acetic, salicylic, citric, formic, malonic, methods are presented in the Examples beloW. succinic, hydriodic, tartaric, lactic, fumaric, oxalic, and the An exemplary scheme for synthesiZing tWo compounds of like. Also, pharmaceutically-acceptable salts can be pre the invention is presented in FIG. 1. Thiosalicylic acid pared as alkaline metal or alkaline earth salts, such as (molecule 1) is alloWed to interact With substituted-benZyl sodium, potassium or calcium salts. As used herein, a (molecule 2) to produce S-(substituted-benZyl)thiosalicylic composition of the compounds described above includes acid (molecule 3). The S-(substituted-benZyl)thiosalicylic salts thereof. 25 acid (molecule 3) is then mixed With sulfonyl chloride The compounds of the invention may be combined, (molecule 4) to produce S-(substituted-benZyl)thiosalicyloyl optionally, With a pharmaceutically-acceptable carrier. The chloride (molecule 5). N1-(S-(substituted-benZyl) term “pharmaceutically-acceptable carrier” as used herein thiosalicyloyl)-N4- (molecule 6) can means one or more compatible solid or liquid ?ller, diluents be prepared by interacting the S-(substituted-benZyl) or encapsulating substances Which are suitable for admin thiosalicyloyl chloride With N4-substituted piperaZine istration into a human or other animal. The term “carrier” (molecule 8). S-benZyl-N-aminoethylthiosalicylamide denotes an organic or inorganic ingredient, natural or (molecule 7) can be prepared from the S-(substituted synthetic, With Which the active ingredient is combined to benZyl)thiosalicyloyl chloride by the addition of N,N facilitate the application. The components of the pharma dimethyl (molecule 9). ceutical compositions also are capable of being co-mingled 35 The invention also encompasses a composition of inter With the molecules of the present invention, and With each mediate compound S-(substituted-benZyl)thiosalicyloyl other, in a manner such that there is no interaction Which chloride, having the folloWing general structural formula: Would substantially impair the desired pharmaceutical effi cacy. R1 The pharmaceutical compositions may contain suitable 40 buffering agents, including: acetic acid in a salt; citric acid R2 S— C in a salt; boric acid in a salt; and phosphoric acid in a salt. H2 The pharmaceutical compositions also may contain, optionally, suitable preservatives, such as: benZalkonium COCl R5 R3 chloride; ; parabens and thimerosal. 45 Pharmaceutical compositions of the invention may be R4 formulated for various administration modes. Carrier for mulations suitable for oral, subcutaneous, intravenous, Wherein R1, R2, R3, R4, and R5, independent of one intramuscular, etc. Administrations are described in more another, are selected from the group consisting of hydrogen, detail beloW and also can be found in Remington, The halogen, nitro, alkyl, alkoxy or piperonyl constitutes another Science and Practice of Pharmacy, Nineteenth Edition, aspect of the invention. The intermediate compound is Mack Publishing Company, Eaton, Pa. (1995) Which is useful for preparing the calcium channel blocking com hereby incorporated by reference. pounds of the invention. The pharmaceutical compositions may conveniently be The compounds according to the invention, are useful presented in unit dosage form and may be prepared by any 55 Whenever it is desirable to inhibit calcium channel activity of the methods Well-knoWn in the art of pharmacy. All in a cell having a calcium channel. It is particularly useful methods include the step of bringing the compounds of the for inhibiting calcium channel activity in situ, and desirably invention into association With a carrier Which constitutes in a subject having a disorder associated With calcium one or more accessory ingredients. In general, the compo channel activity. By de?nition, the Word “in-situ” encom sitions are prepared by uniformly and intimately bringing passes and includes the terms “in-vivo”, “ex-vivo” and the compounds into association With a liquid carrier, a ?nely “in-vitro”. divided solid carrier, or both, and then, if necessary, shaping The invention includes a method for inhibiting calcium the product. channel activity by contacting a cell having a calcium The compounds of the invention contain at least one channel With a compound of the invention, in an amount asymmetric carbon atom and can therefore exist as enanti 65 effective to inhibit calcium channels. “Inhibiting calcium omers or diastereomers. The present invention embraces all channels” as used herein refers to the prevention or sloWing possible stereoisomers of the compounds of the invention, of calcium entry into a cell through cellular calcium chan US 6,951,860 B2 19 20 nels. An amount of the compound of the invention Which is vascular system of the subject. It is desirable to reduce the effective to inhibit calcium channels is that amount suf?cient risk in these subjects of developing congestive heart failure. to sloW the entry of calcium into a cell by at least 25% as A “subject having arrhythmia” is a subject Who has a assessed by any in vitro assay used in the art. More prefer disorder involving a variation from the normal rhythm of the ably the amount effective to inhibit calcium channels is that heart beat. Arrhythmia may arise as a result of altered amount suf?cient to sloW the entry of calcium into a cell by normal automaticity of impulse generation, abnormal gen at least 50%. An exemplary in vitro assay for assessing the eration of impulses, and abnormalities of impulse conduc rate of calcium entry into a cell is provided in Example 2 tion. A“subj ect at risk of developing arrhythmia” is a subject beloW. Who has a propensity of developing arrhythmia because of Methods for treating a subject in order to inhibit calcium certain factors affecting the cardiovascular system of the channel activity of the subject are encompassed by the subject. Factors Which in?uence the development of arrhyth invention. The compounds of the invention in a pharmaceu mia include but are not limited to acute infections, such as tically acceptable carrier are administered to the subject in viral myocarditis, acute rheumatic fever, Lyme disease, and an amount effective to inhibit calcium channels in the degenerative diseases, as a result of interruption of the blood subject. 15 supply to the sinus node. It is desirable to reduce the risk in The terms “treating” and “treatment” as used herein refer these subjects of developing arrhythmia. to the treatment of a disorder in a subject, particularly a The term “angina” as used herein refers to either variant human, and include: preventing the disorder from occur angina or exertional angina as those terms are de?ned in the ring in a subject Which may be predisposed to the disorder Seventh edition of Goodman and Gilman’s, The Pharma but has not yet been diagnosed as having it; (ii) inhibiting the cological Basis of Therapeutics. A “subject having angina” disorder, i.e., arresting or sloWing its development; and/or is a subject having ischemic heart disease Which is mani (iii) relieving the disorder, i.e. causing regression of the fested by sudden, severe, pressing substernal pain that often disorder. radiates to the left shoulder and along the left arm. The compounds of the invention are preferably useful for Pulmonary hypertension is a disease characteriZed by treating a subject having a disorder associated With calcium 25 increased pulmonary arterial pressure and pulmonary vas channel activity. A “disorder associated With calcium chan cular resistance of the vessels, as Well as vascular remod nel activity” as used herein is a physiological malfunction eling Which leads to narroWed lumens of the vessels. Pul arising from cellular damage and/or cellular death caused by monary hypertension can be primary, i.e. of unknoWn or excessive levels of intracellular calcium ions. Such disorders unidenti?able cause, or can be secondary to a knoWn cause include, for example, but are not limited to cardiovascular such as hypoxia or congenital heart shunts. The term “pri disease, pulmonary hypertension, peripheral vascular mary pulmonary hypertension” generally refers to a condi disorder, migraine disorder, mania, epilepsy, depression, tion in Which there is elevated arterial pressures in the small hyperuricemia, and asthma (achalasia asthma and bronchial pulmonary arteries. Pulmonary hypertension generally asthma). See, e.g., Harrisons, Principles of Internal Medi occurs independently of and is unrelated to systemic hyper cine (McGraW Hill, Inc., NeW York) for a more detailed 35 tension. In vitro studies have concluded that changes in description of each of these conditions. Ca++ concentrations may be involved in pulmonary tissue The term “subject” as used herein, is intended to mean damage associated With pulmonary hypertension. Farruck et humans, primates, horses, coWs, sWine, goats, sheep, dogs, al.,Am. Rev. Respir'. Dis., v. 145, No. 6, p. 1389—97 (1992). and cats. A subject having pulmonary hypertension as used herein is A “cardiovascular disease” as used herein is a disease of 40 a subject having a right ventricular systolic or a pulmonary the heart and/or blood vessels caused by high levels of artery systolic pressure, at rest, of at least 20 mmHg. calcium ions Within the cardiac tissue. Preferably the car Pulmonary hypertension is measured using conventional diovascular disease is selected form the group consisting of procedures Well-knoWn to those of ordinary skill in the art. hypertension, congestive heart failure, arrhythmia, and A subject at risk of developing pulmonary hypertension angina. 45 may be treated prophylactically to reduce the risk of pul A “subject having hypertension” is a subject Who has a monary hypertension. Asubject With an abnormally elevated disorder involving elevated arterial pressure. A “subject at risk of pulmonary hypertension is a subject With chronic risk of developing hypertension” is a subject Who has a exposure to hypoxic conditions, a subject With sustained propensity of developing hypertension because of certain , a subject With multiple pulmonary emboli, factors affecting the cardiovascular system of the subject. a subject With cardiomegaly and/or a subject With a family Factors Which in?uence the development of hypertension history of pulmonary hypertension. include but are not limited to exposure to environmental “Peripheral vascular disorder” is a disorder caused by factors such as high salt intake, occupation, and ; as segmental lesions arising from stenosis or occlusion of large Well as obesity and heredity. It is desirable to reduce the risk and medium siZe blood vessels, and most often occurs in the in these subjects of developing hypertension. Reducing the 55 upper extremities. risk of hypertension includes a sloWing of the progression A “migraine disorder” as used herein is a disorder Which toWards hypertension or preventing the development of involves complex periodic attacks of vascular headache. hypertension. Vascular headache is generally temporal or unilateral in A “subject having congestive heart failure” is a subject onset. Migraines are generally familial and often are trig Who has a disorder involving a clinical syndrome of diverse gered by factors such as diet, alcohol, chocolate, coffee, etiologies linked by the common denominator of impaired exposure to sunlight, exercise, tension, or the use of oral heart pumping in Which the heart cannot pump blood contraceptives, or physiological changes such as occur dur commensurate With the requirements of the metaboliZing ing the menstrual cycle. No one biochemical mechanism has tissues, or can do so only from an elevated ?lling pressure. been identi?ed yet Which appears to be responsible for A “subject at risk of developing congestive heart failure” is 65 causing migraines. The predominate belief expressed in the a subject Who has a propensity of developing congestive literature is that of extracranial vessels causes heart failure because of certain factors affecting the cardio migraine. Many treatment efforts, therefore, have aimed at US 6,951,860 B2 21 22 methods of causing vasoconstriction. More recently, evi doses in the range of 0.1 to 100 milligrams/kg body Weight, dence has shown that activation of prejunctional 5-HT1 in one or several administrations per day, Will yield the heteroreceptors on primary afferent trigeminovascular desired results. The dose for intravenous and intramuscular ?bers, by drugs such as and , administration generally ranges betWeen 1 to 300 mg, and alleviate migraine pain, suggesting a neuronal pathogenesis preferably 5 to 150 mg, a day. In the event that the response as opposed to a vascular one. in a subject is insufficient at such doses, even higher doses Mania, often seen in conjunction With depression in the (or effective higher doses by a different, more localiZed bipolar disorder of manic-depressive illness, is characteriZed delivery route) may be employed to the extent that patient by a display of symptoms such as euphoria, increased tolerance permits. In the event that loWer doses are suf?cient psycho-motor activity, rapid speech, ?ight of ideas, 10 to improve disorders associated With calcium channel decreased need for sleep, distractability, grandiosity and activity, loWer doses may be employed. Multiple doses per poor judgment. day are contemplated to achieve appropriate systemic levels Epilepsy is a disorder characteriZed by chronic recurrent of compounds. In one embodiment a maximal dose is paroxysmal changes in neurologic function Which is caused administered ?rst, folloWed by submaximal dosages. by abnormalities in the electrical activity of the brain. 15 Optionally, the compounds of the invention are adminis Epilepsy may arise as a result of neurologic injury, anoxia or tered to the subject in combination With a method for ischemia before or during birth, a structural brain lesion, treating a disorder associated With calcium channel activity. other systemic medical diseases, such as hypoglycemia, The method for treating the disorder associated With calcium hypocalcemia, hypomagnesemia, and infections, or genet channel activity may be a surgical method, a method involv ics. 20 ing a therapy (e. g., a pharmaceutical, gene therapy, etc.) Depression also knoWn as major depressive disorder is a or a combination of the foregoing. Drug therapies Which are mood disorder of unknoWn cause. Genetic factor, neu useful for treating the disorder include but are not limited to rotransmitter dysregulation, environmental factors, brain antihypertensives, anti-anginal drugs, anti-arrhythmia drugs, environmental interactions and biological rhythms have all drugs for the treatment of congestive heart failure, anti been suggested potential contributors to the cause of depres 25 migraine drugs, anti-epileptic drugs, , anti sion. asthmatics, drugs for the treatment of hyperuricemia, and Hyperuricemia as used herein is a disorder characteriZed drugs for the treatment of peripheral vascular disorder. by excessive plasma or serum concentrations of urate. Antihypertensives include but are not limited to Ajmaline; Ordinarily a subject having concentrations of urate in the g-Aminobutyric acid; AlfuZosin Hydrochloride; Alipamide; plasma of greater than 420 mmol/L (7.0 mg/dL) is said to 30 AlthiaZide; Amiquinsin Hydrochloride; Amlodipine Besy have clinical hyperuricemia. Hyperuricemia may result from late; Amlodipine Maleate; Amosulalol; Anaritide Acetate; either an increases urate production (often caused by high Aryloxypropanolamine derivatives; Atiprosin Maleate; Bel levels of exogenous purines in the diet or increases in fosdil; Bemitradine; Bendacalol Mesylate; Bendro?umethi endogenous production), decreased uric acid (e.g., aZide; BenZothiadiaZine derivatives; BenZthiaZide; Betax decreased glomerular ?ltration, decreased tubular secretion, 35 olol Hydrochloride; Bethanidine Sulfate; Bevantolol or enhanced tubular reabsorption) or a combination of the Hydrochloride; Biclodil Hydrochloride; Bisoprolol; Biso tWo. prolol Fumarate; Bucindolol Hydrochloride; Bupicomide; Asthma is a disease of the airWays Which is characteriZed Bufeniode; Bufuralol; ButhiaZide: Candoxatril; Candoxatri by increased responsiveness of the tracheobronchial tissue to lat; Captopril; N-Carboxyalkyl derivatives; Carvedilol; resulting in narroWing of the air passages. 40 Ceronapril; ChlorothiaZide Sodium; Chlorthalidone; Asthma attacks are triggered by allergens, pharmacologic Cicletanine; Ciclasidomine; CilaZapril; Clonidine; Cloni stimuli, environment and air pollution, occupational factors, dine Hydrochloride; Clopamide; CyclopenthiaZide; infections, exercise and emotional stress. CyclothiaZide; Cyptenamine tannates; Darodipine; Debriso The compounds of the invention are administered in quin Sulfate; Delapril Hydrochloride; Diapamide; DiaZox effective amounts. In general an effective amount is that 45 ide; Dilevalol Hydrochloride; DiltiaZem Malate; Ditekiren; amount sufficient to produce a medically desirable result DoxaZosin Mesylate; Ecadotril; Enalapril Maleate; Enalap (eg an antihypertensive amount, anti-anginal amount, anti rilat; Enalkiren; EndralaZine Mesylate; EpithiaZide; Eprosa manic amount, etc.). Effective amounts Will depend, of rtan; Eprosartan Mesylate; Fenoldopam Mesylate; Fla course, on the particular condition being treated; the severity vodilol Maleate; Flordipine; Flosequinan; Fosinopril of the condition, individual patient parameters including Sodium; Fosinoprilat; GuanabenZ; GuanabenZ Acetate; age, physical condition, siZe and Weight, the duration of the Guanacline Sulfate; Guanadrel Sulfate; GuanaZodine; Guan treatment, the nature of the concurrent therapy (if any), the cydine; Guanethidine Monosulfate; Guanethidine Sulfate; speci?c route of administration and like factors Within the Guanfacine Hydrochloride; Guanisoquin Sulfate; Guanoclor knoWledge and expertise of the health practitioner. These Sulfate; Guanoctine Hydrochloride; GuanoxabenZ; Guan factors are Well knoWn to those of ordinary skill in the art 55 oxan Sulfate; Guanoxyfen Sulfate; HydralaZine Hydrochlo and can be addressed With no more than routine experimen ride; HydraZines and phthalaZines; HydralaZine Polistirex; tation. For example, an amount effective for treating hyper Hydro?umethiaZide; ImidaZole derivatives; Indacrinone; tension Would be an amount suf?cient to reduce the arterial Indapamide; Indolapril Hydrochloride; Indoramin; blood pressure so as to achieve a diastolic pressure of Indoramin Hydrochloride; Indorenate Hydrochloride; Ket approximately 82 mmHg or less and a systolic pressure of 60 anserin; Labetalol; Lacidipine; Leniquinsin; Levcro approximately 130 mmHg or less. It Will be understood that makalim; Lisinopril; Lofexidine Hydrochloride; Losartan the compounds of the invention can be used to treat hyper Potassium; LosulaZine Hydrochloride; Mebutamate; tension prophylactically in subjects at risk of developing Mecamylamine Hydrochloride; Medroxalol; Medroxalol hypertension as Well as in subjects having hypertension. Hydrochloride; MethalthiaZide; MethyclothiaZide; Methyl Generally, systemic doses of active compounds Will be 65 dopa; Methyldopate Hydrochloride; Methyl 4 pyridyl from about 0.01 milligrams/kg body Weight per day to 10 ketone thiosemicarbarZone; Metipranolol; MetolaZone; milligrams/kg body Weight per day. It is expected that oral Metoprolol Fumarate; Metoprolol Succinate; Metyrosine; US 6,951,860 B2 23 24 MinoXidil; Monatepil Maleate; MuZolimine; Nebivolol; segide; Hydrochloride; OXetorpne; PeXotyline; Nitrendipine; Ofornine; Pargyline Hydrochloride; PaZoXide; Maleate; Sumatriptan Succinate; and Pelanserin Hydrochloride; Perindopril Erbumine; Pempi Maleate. dine; PiperoXan; primaperone; Protoveratrines; Raubasine; Anti-epileptic drugs include but are not limited to Fel Rescimetol; Rilemenidene; Pronethalol; PhenoXybenZamine bamate; ; and Tolgabide. Hydrochloride; Pinacidil; Pivopril; PolythiaZide; PraZosin Antidepressants include but are not limited to Hydrochloride; Primidolol; PriZidilol Hydrochloride; Qua , , , ternary Ammonium Compounds; QuinaZoline derivatives; Dimetracrine, , N-Oside, Quinapril Hydrochloride; Quinaprilat; QuinaZosin Hydro , NoXiptilin, , ; chloride; Quinelorane Hydrochloride; Quinpirole Hydro Adra?nil, , Deanol, Deanol Aceglumate, Deanol chloride; Quinuclium Bromide; Ramipril; RauWol?a Ser AcetamidobenZoate, , , pentina; Reserpine; Saprisartan Potassium; Saralasin , , , Hematoporphyrin, Acetate; Sodium Nitroprusside; Sotalol; Sul?nalol Hydro Hypercinin, , , chloride; Sulfonamide derivatives; Tasosartan; Teludipine OXa?oZane, , Pyrisuccideanol, Rubidium Hydrochloride; Temocapril Hydrochloride; TeraZosin 15 Chloride, , , , , Hydrochloride; Terlakiren; Tiamenidine; Tiamenidine , L- and Zimeldine Hydrochloride; Ticrynafen; Tinabinol; TiodaZosin; Tipen Hydrochloride; ; AdinaZolam Mesylate; Alapro tosin Hydrochloride; TrichlormethiaZide; TrimaZosin clate; Aletamine Hydrochloride; Hydrochloride; Hydrochloride; Trimethaphan Camsylate; TrimoXamine Hydrochloride; ; Hydrochloride; Tripamide; Tyrosinase; Urapidil; Xipamide; Maleate; AZaloXan Fumarate; ; Zankiren Hydrochloride; and Zofenoprilat Arginine. Hydrochloride; Bipenamol Hydrochloride; Anti-anginal drugs include but are not limited to Hydrochloride; Butacetin; Hydrochloride; Car Acebutolol, Alprenolol. Amiodarone, Arotinolol, Atenolol, oXaZone; CartaZolate; ; Hydrochlo Bepridil, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, ride; Mesylate; ClodaZon Hydrochloride; Clo Bupranolol, CaroZolol, Carteolol, Celiprolol, CinepaZet 25 mipramine Hydrochloride; Fumarate; Cyclindole; Maleate, DiltiaZem, Espanolol, Felodipine, Gallopamil, Hydrochloride; Cyprolidol Hydrochloride; Imolamine, Indenolol, Isosorbide Dinitrate, Isadipine, CyproXimide; Tosylate; Hydrochlo Limaprost, Mepindolol, Molsidomine, Nadolol, ride; DaZadrol Maleate; DaZepinil Hydrochloride; Nicardipine, Nifedipine, Nifenalol, Nilvadipine, Nipradilol, Hydrochloride; DeXamisole; DeXimafen; Nisoldipine, Nitroglycerin, OXprenolol, OXyfedrine, DibenZepin Hydrochloride; DioXadrol Hydrochloride; OZagrel, Penbutoolol, Pentaerythritol, Tetranitrate, Pindolol, Dothiepin Hydrochloride; Hydrochloride; DuloX Pronethalol, Propranolol, Sotaiol, Terodiline, Timolol, etine Hydrochloride; Maleate; Encyprate; Eto Toliprolol; Amlodipine Besylate; Amlodipine Maleate; peridone Hydrochloride; Fantridone Hydrochloride; Fenme BetaXolol Hydrochloride; Bevantolol Hydrochloride; Buto toZole Hydrochloride; ; proZine Hydrochloride; Carvedilol; CinepaZet Maleate; 35 Fumarate; Hydrochloride; ; FluoXet Metoprolol Succinate; Molsidomine; Monatepil Maleate; ine Hydrochloride; Hydrochloride; GamfeXine; Primidolol; RanolaZine Hydrochloride; Tosifen; Verapamil GuanoXyfen Sulfate; Imafen Hydrochloride; Hydrochloride; and Tiro?ban Hydrochloride. Hydrochloride; Imipramine Hydrochloride; Anti-arrhythmia drugs include but are not limited to Hydrochloride; Hydrochloride; ; Iso sodium channel blockers such as quinidine, procainamide, 40 carboXaZid; Ketipramine Fumarate; Hydro disopyramide, moriciZine, lidocaine, meXiletine, phenytoin, chloride; ; ; Maprotiline Hydrochlo tocainide, encainide, ?ecainide, propafenone, indecainide; ride; Hydrochloride; Hydrochloride; b-adrenergic blockers, such as propranolol, acebutolol, Hydrochloride; ; ; esmolol; and compounds that prolong repolariZation, such as Modaline Sulfate; Napactadine Hydrochloride; NapameZole amiodarone, bretylium, sotalol. Other antiarrhythmics 45 Hydrochloride; Hydrochloride; ; include Acebutol, Acecaine, Adenosine, Ajmaline, Nitrafudam Hydrochloride; Maleate; Nortrip Alprenolol, Amiodarone, AmoproXan, Aprindine, tyline Hydrochloride; Phosphate; Arotinolol, Atenolol, Bevantolol, Bretylium Tosylate, Hydrochloride; Hydrochloride; ; Bubumolol, Bufetolol, Bunaftine, Bunitrolol, Bupranolol, ; Sulfate; Hydrochlo Butidrine Hydrochloride, Butobendine, Capobenic Acid, ride; PiZotyline; Pride?ne Hydrochloride; Hydro CaraZolol, Carteolol, Cifenline, Cloranolol, Gallopamil, chloride; Hydrochloride; Maleate; Indenolol, Ipratropium Bromide, Lorajmine, Lorcainide, Rolicyprine; Hydrochloride; Hydro Meobentine, Metipranolol, MeXiletine, Nifenalol, chloride; Hydrochloride; ; ; OXprenolol, Penbutolol, Pindolol, Pirmenol, Practolol, Hydrochloride; Fumarate; Tan Prajmaline, Pronthalol, Pyrinoline, Quinidine Sulfate, 55 damine Hydrochloride; ThiaZesim Hydrochloride; ThoZali Quinidine, Sotalol, Talinolol, Timolol, Tocainide, none; TomoXetine Hydrochloride; Hydrochlo Verapamil, Viquidil and Xibenolol. ride; TrebenZomine Hydrochloride; ; Drugs for the treatment of congestive heart failure include Trimipramine Maleate; Hydrochloride; ViloX but are not limited to thiaZide diuretics, metolaZone, aZine Hydrochloride; Zimeldine Hydrochloride; and furosemide, bumetanide, ethacrynic acid, aldosterone Zometapine. antagonists, trimterene, and amiloride. Anti-asthmatics include but are not limited to Ablukast; Anti-migraine drugs include but are not limited to Ali Ablukast Sodium; Hydrochloride; Bunaprolast; liropride; ; propanolol; ; Cinalukast; Cromitrile Sodium; Cromolyn Sodium; antidepressants; like-drugs; ; Enofelast; IsamoXole; Fumarate; Levcromakalim; ergot alkaloids; ; stadol; Mesylate; 65 LodoXamide Ethyl; LodoXamide Tromethamine; Mon ; Ergocorninine; ; Ergot; Ergota telukast Sodium; OntaZolast; OXarbaZole; ; Pir mine; FlumedroXone acetate; FonaZine; ; Methy iprost; Piriprost Potassium; ; Pobilukast Edamine; US 6,951,860 B2 25 26 QuaZolast; Repirinast; Ritolukast; Sulukast; TetraZolast Cachets are a capsule like container having a drug encap Meglumine; Tiaramide Hydrochloride; Tibenelast Sodium; sulated in a shell. The drug is placed into the tWo halves of Tomelukast; Tranilast; Verlukast; Verofylline; Zarirlukast. the shell and the edges of the tWo halves are sealed to Drugs for the treatment of hyperuricemia include but are produce a the sealed capsule like container. not limited to allopurinol and uricosuric agents. Dragees are a coated form of tablet. The dragee core is Drugs for the treatment of peripheral vascular disorder coated With ?avoring solution such as concentrated sugar include but are not limited to heparin, pentoxifylline, throm solutions Which may optionally contain gum arabic, talc, bolytic drugs, and vasodilators. polyvinyl, pyrrolidone, carbopol, gel, polyethylene glycol, The above-described drug therapies are Well knoWn to and/or titanium dioxide, lacquer solutions, and suitable those of ordinary skill in the art and are administered by 10 organic solvents or solvent mixtures. The dragee coatings modes knoW to those of skill in the art. The combined drug therapies are administered in amounts Which are effective to may also contain dyestuffs or pigments. achieve the physiological goals (to improve the disorder, Compositions suitable for rectal administration include e.g., reduce hypertension), in combination With the com suppository bases and retention enemas Which include for pounds of the invention. Thus, it is contemplated that the example, natural or hardened oils, Waxes, fats, semi-liquid drug therapies may be administered in amounts Which are 15 polyols and the like. not capable of improving the disorder When the drug thera Compositions suitable for parenteral administration con pies are administered alone but Which are capable of veniently comprise a sterile aqueous preparation of the improving the disorder When administered in combination compounds of the invention, Which is preferably isotonic With the compounds of the invention. With the blood of the recipient. This aqueous preparation When administered the compounds of the invention are 20 may be formulated according to knoWn methods using administered Wither per se or in pharmaceutically acceptable suitable dispersing or Wetting agents and suspending agents. carriers using a variety of administration routes. The par The sterile injectable preparation also may be a sterile ticular mode selected Will depend of course, upon the injectable solution or suspension in a non-toxic parenterally particular drug selected, the severity of the condition being acceptable diluent or solvent, for example, as a solution in treated and the dosage required for therapeutic ef?cacy. The 25 1,3- diol. Among the acceptable vehicles and solvents methods of the invention, generally speaking, may be prac that may be employed are Water, Ringer’s solution, and ticed using any mode of administration that is medically isotonic sodium chloride solution. In addition, sterile, ?xed acceptable, meaning any mode that produces effective levels oils are conventionally employed as a solvent or suspending of the active compounds Without causing clinically unac medium. For this purpose any bland ?xed oil may be ceptable adverse effects. Such modes of administration 30 employed including synthetic mono- or di-glycerides. In include oral, rectal, topical, nasal, bronchial, interdermal, or parenteral routes. The term “parenteral” includes addition, fatty acids such as oleic acid may be used in the subcutaneous, intravenous, intramuscular, or infusion. Intra preparation of injectables. venous or intramuscular routes are not particularly suitable Compositions suitable for buccal administration may take for long-term therapy and prophylaxis. They could, the form of tablets, loZenges, etc. hoWever, be preferred in emergency situations. Oral admin 35 Topical formulations include the drug of interest in a istration Will be preferred for prophylactic treatment because cream, lotion, gel, transdermal patch or poWdered form. of the convenience to the patient as Well as the dosing Optionally the topical formulations may include permeation schedule. enhancers that are useful for enhancing the uptake of the Compositions suitable for oral administration may be drug through the skin. Permeation enhancers are Well knoWn presented as discrete units, such as capsules, tablets, 40 in the art and are commercially available. loZenges, pills, liquids, cachets, dragees, gels, lactose maiZe Compositions suitable for nasal or bronchial administra starch or derivatives thereof, talc, stearic acid, or its salts and tion include emulsions for aerosol delivery. In general an the like each containing a predetermined amount of the aerosol is a ?nely dispersed mist, foam, or semisolid mate active compounds. Other compositions include suspensions rial Which is delivered to the nose or mouth as a spray in aqueous liquids or non-aqueous liquids such as a syrup, 45 poWered by a lique?ed or compressed gas or a pump. elixir or an emulsion. Aerosols sprays may be delivered in a pressuriZed pack or Atablet is a solid pharmaceutical dosage form containing nebuliZer With the use of a propellant, such as ?uorocarbon a drug substance prepared either by compression or molding propellants (e.g., dichlorodi?uoromethane, methods. The tablet may optionally include suitable trichloro?uoromethane, dichlorotetra?uoroethane), hydro diluents, additives, or excipients. Tablets may be of any carbon propellants or compressed gases such as nitrogen, shape or siZe Which can be orally ingested. For instance, , and carbon dioxide. The aerosol may be tablets may be discoid, round, oval, oblong, cylindrical, or housed in any suitable type of container, such as tin-plated triangular. steel, aluminum, and glass. Many aerosol containers also A gelatin capsule is a solid dosage form having a drug include valves for emitting the aerosol, actuators and meters. substance enclosed either in a hard or soft soluble container 55 Other delivery systems can include time-release, delayed or shell made of a suitable form of gelatin. The hard gelatin release or sustained release delivery systems. Such systems capsule Which is also referred to as the dry-?lled capsule can avoid repeated administrations of the compounds consists of tWo sections, one of Which slips ver the other to described above, increasing convenience to the subject and completely surround the drug formulation. Soft gelatin the physician. Many types of release delivery systems are capsules include glycerin, sorbitol or a similar polyol for 60 available and knoWn to those of ordinary skill in the art. produce a soft globular gelatin shell Which can be ?lled With They include polymer base systems such as poly(lactide a drug. glycolide), copolyoxalates, polycaprolactones, Lozenges also knoWn as pastilles or troches are generally polyesteramides, polyorthoesters, polyhydroxybutyric acid, discoid shaped solid materials Which contain the drug and and polyanhydrides. Microcapsules of the foregoing poly the a suitably ?avored base. LoZenges are placed in the oral 65 mers containing drugs are described in, for example, US. cavity and alloWed to sloWly dissolve in order to deliver the Pat. No. 5,075,109. Delivery systems also include non drug. polymer systems that are: lipids including sterols such as US 6,951,860 B2 27 28 , cholesterol esters and fatty acids or neutral fats Perkin-Elmer 1420 Ratio Recording infrared spectropho such as mono- di- and tri-glycerides; hydrogel release sys tometer and Nicolet Impact 410 FT-IR spectrophotometer. H tems; sylastic systems; peptide based systems; Wax coatings; NMR spectra Were recorded on a Varian T-60 NMR spec compressed tablets using conventional binders and excipi trometer With tetramethylsilane (TMS) as an internal stan ents; partially fused implants; and the like. Speci?c dard; the values of chemical shift(s) are given in parts per examples include, but are not limited to: (a) erosional systems in Which the compound of the invention is con millionProgress (ppm) of the reactionand coupling Was monitored constants by (J) TLC in onhertZ silica gel tained in a form Within a matrix such as those described in plate (Whatman, PE SIL G/UV). US. Pat. Nos. 4,452,775, 4,667,014, 4,748,034 and 5,239, S-(4-MethoxybenZyl)thiosalicylic acid. Thiosalicylic acid 660 and (b) difusional systems in Which an active compo 10 15.419 g(0.1 M) Was dissolved in 150 mL of dimethylfor nent permeates at a controlled rate from a polymer such as mamide (DMF) and 41.463 g(0.3M) of K2CO3, Was added described in US. Pat. Nos. 3,832,253, and 3,854,480. In to the mixture With stirring. To the above solution, addition, pump-based hardWare delivery systems can be 4-methoxybenZyl chloride 15.661 g(0.1M) Was added and used, some of Which are adapted for implantation. the mixture Was re?uxed for 10 hours. The solution then Was Use of a long-term sustained release implant may be 15 cooled to room temperature and 150 mL of Water Was added particularly suitable for treatment of chronic conditions. and the mixture Was acidi?ed With 3M HCl. The precipitated Long-term release, are used herein, means that the implant material Was collected by gravity ?ltration and Washed With is constructed and arranged to delivery therapeutic levels of to give 27.364 g(99.7%) of White poWder With a the active compounds for at least 30 days, and preferably 60 melting point of 225—227° C. and the folloWing speci?ca days. Long-term sustained release implants are Well-knoWn 20 tions: to those of ordinary skill in the art and include some of the IR(KBr)3200—2500 cm_1, 1673 cm_1, 1510 cm_1, 1234 release systems described above. cm_1, 1027 cm_1. The invention also includes kits. The compounds of the invention can be placed in a vial and be incorporated into a kit to be used in the treatment of a disorder associated With 25 calcium channel activity. In certain embodiments, a medi 1-(4-MethoxybenZyl) piperaZine. A solution of 1.077 cament for the treatment of cardiovascular disease can also (12.5 mM) of piperaZine in 20 mL of absolute Was be placed in a vial and included in the same kit. In other prepared in a 125-mL of Erlenmeyer ?ask, and Was Warmed embodiments other medicaments for treating a subject hav in a bath at 65° C. 1.988 g(12.5 mM) of piperaZine dihy drochloride hydrate Was dissolved in the solution, by sWirl ing a calcium channel blocking disorder can also be placed 30 in a vial and included in the same kit. The kits can include ing. Under continuous heat at 65° C. 1.958(12.5 mM) of instructions or other printed material on hoW to administer 4-methoxybenZyl chloride Was added With vigorous stirring, the compounds. In certain other embodiments the medica for ?ve minutes. The separation of White needles com ments for treating a subject having a calcium channel menced almost immediately. After the solution had been stirred for an additional 25 minutes at 65° C., it Was cooled, blocking disorder can be part of a kit that does not include 35 the compounds of the invention, but includes instructions or and kept in an ice bath for about 30 minutes. The crystals of other printed material on hoW to combine the medicament piperaZine dihydrochloride hydrate Were collected by suc With the compounds of the invention. tion ?ltration, Washed With three 5 mL portions of ice-cold A kit embodying features of the present invention, gen absolute ethanol, then dried. Recovery of the dihydrochlo ride Was 1.748 g(88%). Filtrate from this solution Was erally designated by the numeral 2, is illustrated in FIG. 7. 40 Kit 2 is comprised of the folloWing major elements: pack evaporated to dryness at reduced pressure, and crude 1-(4 aging 4, a dosage form 6, a dosage form 10 and instructions methoxybenZyl)-4-piperaZinium chloride remained as a resi 8. Packaging 4 can be a box-like structure for holding due. dosage form 6, a dosage form 10 and instructions 8. Indi In order to remove any piperaZine dihydrochloride, the viduals skilled in the art can readily modify packaging 4 to 45 material Was heated in about 20 ml of absolute ethanol to suit individual needs. produce crystals Which Were rapidly ?ltered. Concentration Dosage form 6 comprises compounds of the invention in of the ?ltrate folloWed by cooling produced 2.629 g(87%) of an effective amount for for treating a subject having a 1-(4-methoxybenZyl)-4-piperaZinium chloride in the form of calcium channel blocking disorder. Dosage form 10 com a White crystal having a melting point of 154—157° C. A prises a medicament for treating a subject having a calcium solution of this salt in 20 ml of Water Was made alkaline channel blocking disorder, such as a medicament for the (pH>12) With about 20 ml of 5N sodium hydroxide solution, treatment of cardiovascular disease. extracted With CH2Cl2 and then dried over MgSO4 for 30 The invention Will be more fully understood by reference minutes. Filtration, folloWed by solvent evaporation at to the folloWing examples. These examples, hoWever, are reduced pressure, produced a White solid Which Was crys merely intended to illustrate the embodiments of the inven 55 talliZed from petroleum ether to give (1.393 g, 54%) of the tion and are not to be construed to limit the scope of the product having a melting point of 99—101° C. and the invention. folloWing speci?cations: IR(KBr) 3392 cm_1, 2943 cm_1, 1509 cm_1, 1301 cm_1, EXAMPLES 1034 cm_1, 991 cm_1. Example 1 60 Synthesis of the Compounds of the Invention 1-(4-NitrobenZyl)piperaZine hydrochloride. A solution of 1.077 (12.5 mM) of piperaZine Was prepared in 20 mL of 1. Preparation of Intermediate Compounds Useful in the absolute ethanol in a 125-mL of Erlenmeyer ?ask. The Synthesis of the Compounds of the Invention: 65 solution Was Warmed in a bath at 65° C. and 1.988 g(12.5 Melting points Were determined using MEL-TENP appa mM) of piperaZine dihydrochloride hydrate Was dissolved in ratus and are uncorrected. IR spectra Were taken With the solution, by sWirling. Under continuous heat at 65° C., US 6,951,860 B2 29 30 1.988 g(12.5 mM) of 4-nitrobenZyl chloride Was added With this salt Was prepared in 15 mL of Water and Was mixed With vigorous stirring, for ?ve minutes. The separation of White about 40 mL of 5 N sodium hydroxide solution. The product needles commenced almost immediately. The solution Was Was extracted With CH2Cl2 and dried over MgSO4 for 30 stirred for an additional 25 minutes at 65° C., and kept in an minute. The product Was then ?ltered and the solvent ice bath for about 30 minutes. The crystals of piperaZine evaporated at reduced pressure to give the dihydrochloride hydrate Were collected by suction ?ltration, 1-(4—ChlorobenZyl) piperaZine (2.627 g, 50%). NMR Washed With three 5 mL portions of ice-cold absolute (CDCl3)2.4(s,1H), 2.5—83(m, 4H), 3.0—3.38(m, 4H), 3.45(s, ethanol and then dried. Approximately 4.456 g(224%) of the 2H),7.5—7.8(m, 4H). dihydrochloride Was recovered. Filtrate from this solution 2. Preparation of S-(4-methoxybenZyl)-N-(2-(N‘,N‘ Was evaporated to dryness at reduced pressure and crude 10 dimethylamino)ethyl) thiosalicylamide 1-(4-NitrobenZyl)-4-piperaZinium chloride Was left as a resi The compound S-(4-methoxybenZyl)-N-(2-(N‘,N‘ due. dimethylamino)ethyl) thiosalicylamide (compound 1) Was prepared by adding 0.02M(823 mg) of the precursor S-(4 In order to remove any piperaZine dihydrochloride, the methoxybenZyl) thiosalicylic acid to 10 mL of SOCl2, and material Was heated in about 20 mL of absolute ethanol to re?uxing for 2 hours folloWed by removal of the excess produce crystals Which Were rapidly ?ltered. Concentration 15 SOCl2 under reduced pressure. N,N-dimethyl ethylenedi of the ?ltrate folloWed by cooling produced 0.840 g(26%) of (6 mM, 528 mg) Was dissolved in 10 mL of ice cold 1—4-NitrobenZyl)-4-piperaZinium chloride in the form of a benZene. The acid chloride suspended in benZene Was then White crystal having a melting point of 209—212° C. sloWly added to the amine solution. The mixture Was stirred IR(KBr) 3513 cm_1, 2930 cm_1, 1514 cm_1, 1350 cm_1, overnight at room temperature. Water (20 mL) Was added 1100 cm_1, 743 cm_1. 20 the next day, folloWed by separation of the aqueous layer. The remaining organic layer Was Washed With 10% NaOH NMR(CDCl3) 2.60—2.95(m, 4H), 3.0—3.36(m,$H), 3.60 solution and the aqueous layer Was again removed. The (s,2H), 7.4—7.2 (m,4H). aqueous layers Were combined and extracted tWice With 10 1-(4-FluorobenZyl) piperaZine hydrochloride. A solution mL of (CHCl3.) The CHCl3. extracts Were of 2.154 g(25 mM) of piperaZine in 25 mL of absolute 25 combined With the benZene layer and dried over anhydrous ethanol, Was Warmed in a bath at 65° C. PiperaZine dihy MgSO4. Solvents Were removed under reduced pressure. drochloride hydrate (3.9765 g(25 mM)) Was dissolved in the The remaining oily product Was dissolved in methanol (100 solution, by sWirling. In the bath at 65° C. 3.6145 g(25 mM) mL), then 600 mL of distilled Water Were added and the of 4-?uorobenZyl chloride Was added to the solution With mixture Was stirred for 24 hours. The separated crystals Were vigorous stirring. The separation of White needles com 30 collected With gravity ?ltration and Washed With distilled menced almost immediately. After the solution had been Water, folloWed by petroleum ether to give 279 mg (27%) of stirred for an additional 25 minutes at 65° C., it Was cooled, pale yelloW crystals having a melting point of 83—84.5° C. and the unstirred solution Was kept in an ice bath for about and the folloWing speci?cations: 30 minutes. The crystals of piperaZine dihydrochloride IR(KBr)3322 cm_1, 3257 cm_1, 2943 cm_1, 1633 cm_1, hydrate Were collected by suction ?ltration, Washed With 35 1511 cm_1, 1029 cm_1. three 5 mL portions of ice-cold absolute ethanol, and then dried. Approximately 3.989 g (100.3%) of the dihydrochlo ride Was recovered. Filtrate from this solution Was evapo A summary of the elemental analysis of each of com rated to dryness at reduced pressure and crude 1-(4 pounds 1—5 is presented in Table I beloW. methoxybenZyl)-4-piperaZinium chloride Was left as a 40 3. Preparation of N1-(S-(4-methoxybenZyl) residue. For removal of any piperaZine dihydrochloride, the thiosalicyloyl)-N4-methylpiperaZine chloride may be crystalliZed after rapidly ?ltering a hot The compound N1-(S-(4-methoxybenZyl) thiosalicyloyl) solution in about 20 mL of absolute ethanol. Concentration N4-methylpiperaZine (compound 2) Was prepared in a man of the ?ltrate folloWed by cooling gave 5.248 g(91%) of ner similar to that described above for S-(4-methoxybenZyl) 1-(4-?uorobenZyl)-4-piperaZinium chloride. 45 N-(2-(N‘,N‘-dimethylamino)ethyl) thiosalicylamide. After 1-(4—ChlorobenZyl) piperaZine. A solution of 2.154 g(25 preparing the S-benZylthiosalicyloyl chloride from 0.02M mM) of piperaZine in 25 mL of absolute ethanol Was (5.487 g) of S-(4-methoxybenZyl)thiosalicylic acid and 20 Warmed in a bath at 65° C. and 3.9765 g(25 mM) of mL of SOCl2, the mixture Was suspended in Warm benZene piperaZine dihydrochloride hydrate Was dissolved in the (30 mL) and Was sloWly added to a 20 mL cold solution of solution by sWirling. Then 4.026 g(25 mM) of 4.007 g (0.04M) 1-methylpiperaZine in benZene. The mix 4-chlorobenZyl chloride Was added to the solution With ture Was stirred overnight at room temperature. The next day vigorous stirring,. The separation of White needles com 40 mL of Water Were added, the aqueous layer Was menced almost immediately. After the solution had been separated, and extracted tWice With 15 mL CH2Cl2. The stirred for an additional 25 minutes at 65° C., it Was cooled, extracts Were combined With the benZene layer, Washed With and the unstirred solution Was kept in an ice bath for about 55 10% NaOH solution and dried over anhydrous MgSO4. 30 minutes. The crystals of piperaZine dihydrochloride Removal of the solvents under reduced pressure left an oily hydrate Were collected by suction ?ltration, Washed With product Which Was dissolved in petroleum ether (10 ml). A three 5 mL portions of ice-cold absolute ethanol, and then precipitate separated out upon cooling in an ice bath. The dried. Approximately 4.023 g(101.2%) of the dihydrochlo separated solid Was collected by suction ?ltration and ride Was recovered. Filtrate from this solution Was evapo 60 Washed With petroleum ether to give 3.372 g (47%) of the rated to dryness at reduced pressure, crude 1-(4 product in the form of White crystals and having a melting methoxybenZyl)-4-piperaZinium chloride Was left as a point of 77—78° C. and the folloWing speci?cations: residue. For removal of any piperaZine dihydrochloride, the IR(KBR) 2943 cm-1 1633 cm_1, 1512 cm_1, 1440 cm_1, chloride may be crystalliZed after rapidly ?ltering a hot 1251 cm_1, 1001 cm_1. solution in about 20 mL of absolute ethanol. Concentration 65 NMR (CDCl)2.25(s,3H), 2.2—2.5(m,4H), 2.97—3.25(m, of the ?ltrate folloWed by cooling gave 6.447 g(104%) of 2H), 3.68(s,3H), 3.6—3.85(m,2H), 4.0(s,2H), 6.6—7.25(m, 10(4-?uorobenZyl)-4-piperaZinium chloride. A solution of 8H).