1-PHENYLALKYL-4-(MERCAPTO AND CARBAMYLTHIO)ALKYL-PIPERAZINES AND -HOMOPIPERAZINES AND THEIR USE IN THE TREATMENT OF ALLERGIC DISEASES

Abstract: Compounds of the formula wherein R is hydrogen or --NH-A; A is alkyl of 1 to 8 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; or unsubstituted or mono-, di- or tri-substituted phenyl, where the substituents are each alkyl of 1 to 4 carbon atoms, halogen, trihalomethyl, alkoxy of 1 to 3 carbon atoms, carboxylic acyl of 1 to 3 carbon atoms, carboxyl, (alkoxy of 1 to 3 carbon atoms)carbonyl, nitro, cyano or di(alkyl of 1 to 3 carbon atoms)amino; R₁, R₂ and R₃, which may be identical to or different from each other, are each hydrogen, halogen, allryl of 1 to 4 carbon atoms, trihalomethyl, nitro, cyano, di(alkyl of 1 to 4 carbon atoms)amino, (alkoxy of 1 to 4 carbon atoms)carbonyl, alkoxy of 1 to 4 carbon atoms or hydroxyl; R₄ and R₅ which may be identical to or different from each other, are each hydrogen, alkyl of 1 to 4 carbon atoms or phenyl; R₆ R₇, R₈ and R₉, which may be identical to or different from each other, are each hydrogen or methyl, Y is -CH₂- or -CH₂-CH₂; j is 0 or 1; k and m are each integers of 0 to 3, their sum being no more than 6 must be 0 when j is 1; n is an integer of 2 to 4, with the proviso that n must be 3 or 4 when R₁ is hydrogen or 2-methyl, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, and R are hydrogen and j, k and m are 0 and Y is CH₂-; and non-toxic, pharmaceutically acceptable acid addition salts thereof. The compounds as well as their salts are useful for the treatment of immunological, inflammatory and allergic disorders.

Description: This invention relates to novel substituted phenylalkyl- (piperazinyl or homopiperazinyl)alkyl-thiols and -thiocarbamates and non-toxic acid addition salts thereof, to a method of preparing these compounds, to pharmaceutical compositions containing them as active ingredients, and to a method of using them as therapeutics. By virtue of their potent inhibition of mediator release in numerous cell systems, the compounds are useful for the treatment of immunological, inflammatory and allergic disorders. THE PRIOR ART Japanese Patent No. 68 13 468, abstracted in C.A. 70, 11720f (1969), discloses 2-[4-92-methylbenzyl)piperazin-1- ylzethanethiol dihydrochloride as a synthetic intermediate in the preparation of sedative and antiulcer drugs. The compound 2-(4-benzylpiperazin-1-yl)-1-methylethanethiol has a Chemical Abstract Registry Number (82627-25-6), but has not yet appeared in the literature. German Offenlegungsschrift 2,551,355 discloses 2-[4-(2aminobenzyl)piperazin-1-yl]-2-oxo-ethanethiol and 2-[4 (2-amino-3, 5-dibrotnobenzyl )piperazin-l-yl )-2-oxo-ethanethiol as antihistaminics and anticonvulsants. THE INVENTION Store particularly, the present invention relates to novel substituted phenylalkyl (piperazinyl or homopiperazinyl ) alkyl- thiols or-thiocarbamates represented by the formula EMI1.1 wherein R is hydrogen or EMI2.1 A is alkyl of 1 to 8 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; or unsubstituted or mono-, di- or tri-substituted phenyl, where the substituents are each alkyl of 1 to 4 carbon atoms, halogen, trihalomethyl, alkoxy of 1 to 3 carbon atoms, carboxylic acyl of 1 to 3 carbon atoms, carboxyl, (alkoxy of 1 to 3 carbon atoms) carbonyl, nitro, cyano or di(alkyl of 1 to 3 carbon atoms)amino; RI' R2 and R3, which may be identical to or different from each other, are each hydrogen, halogen, alkyl of 1 to 4 carbon atoms, trihalo methyl, nitro, cyano, di(alkyl of 1 to 4 carbon atoms)amino, alkoxy of 1 to 4 carbon atoms) carbonyl, alkoxy of 1 to 4 carbon atoms or hydroxyl; R4 and R5, which may be identical to or different from each other, are each hydrogen, alkyl of 1 to 4 carbon atoms or phenyl; ; R6' #7' R8 and Rg, which may be identical to or different from each other, are each hydrogen or methyl; Y is -CH2- or -CH2-CH2-; 3 is O or 1; k and m are each integers of O to 3, their sum being no more than 6 and must be O when 3 is 1; n is an integer of 2 to 4, with the proviso that n must be 3 or 4 when R1 is hydrogen or 2-methyl, R2, R3, R4, R5, R6, R7, R8,R9 and R are hydrogen and 3, k and m are 0, and Y is and non-toxic, pharmaceutically acceptable acid addition salts thereof. Specific examples of variables A, R1' R2, R3, R4 and R5 are the following: A - Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl or possible isomers thereof; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The optional substituents on the phenyl group: Methyl, ethyl, propyl, butyl or possible isomers thereof; fluorine, chlorine or bromine; trifluoro methyl or trichloromethyl; methoxy, ethoxy, propoxy, butoxy or possible isomers thereof; acetyl, propionyl or butyryl; methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; dimethylamino, N-methylethylamino, diethylamino, N-ethyl-propylamino, N-methyl-propyl amino or dipropylamino. R1, R2 and R3 - Fluorine, chlorine or bromine; methyl, ethyl, propyl, butyl or a possible isomer thereof; trifluoromethyl or trichloromethyl; dimethylamino, N-methyl-ethylamino, diethylamino, N-ethyl-propyl amino, N-methyl-propylamino or dipropylamino; methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; methoxy, ethoxy, propoxy, butoxy or possible isomers thereof. R4 and R5 - Methyl, ethyl, propyl or isopropyl. A preferred subgenus thereunder is constituted by compounds EMI3.1 wherein R is hydrogen or EMI4.1 A is alkyl of 1 to 8 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; or unsubstituted or mono-, di- or tri-substituted phenyl, where the substituents are each independently alkyl of 1 to 4 carbon atoms, halogen, trihalomethyl, alkoxy of 1 to 3 carbon atoms, carboxylic acyl of 1 to 3 carbon atoms, carboxyl, (alkoxy of 1 to 3 carbon atoms) carbonyl, nitro, cyano or di(alkyl of 1 to 3 carbon atoms)amino; ; RI is hydrogen, halogen, alkyl of 1 to 4 carbon atoms, trihalomethyl, nitro, cyano, di (alkyl of 1 to 4 carbon atoms)amino, (alkoxy of 1 to 4 carbon atoms)carbonyl, alkoxy of 1 to 4 carbon atoms or hydroxyl; R6 and R7 are each independently hydrogen or methyl; m is an integer from 0 to 3; and n is an integer of 2 to 4, with the proviso that n must be 3 or 4 when RI is hydrogen or 2-methyl, R6, R7 and R are hydrogen and m is 0; and non-toxic, pharmaceutically acceptable acid addition salts thereof. An especially preferred subgenus is constituted by compounds of the formula Ia, where R is hydrogen or EMI4.2 A is alkyl of 1 to 3 carbon atoms; cycloalkyl of 5 to 6 carbon atoms; or unsubstituted or sono-, di- - or tri-substituted phenyl, where the substituents are each independently alkyl of 1 to 4 carbon atoms, fluorine, chlorine, bromine, trifluoromethyl, methoxy, acetyl or carbethoxy; R1 is hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, trifluoromethyl or dimethyl amino; R6 and R7 are each independently hydrogen or methyl; m is an integer from 0 to 3; and n is an integer of 2 to 4, with the proviso that n must be 3 or 4 when R1 is hydrogen or 2-methyl, R6, R7 and R are hydrogen and m is O; and non-toxic, pharmaceutically acceptable acid addition salts thereof. The compounds embraced by formula I may be prepared by reacting a phenylalkyl-piperazine or -homopiperazine of the formula EMI5.1 wherein R1, R2, R3,R4, R5 R6, R7, R8, R9, j, k, m and Y have the meanings previously defined, with an alkyl halide of the formula X - (CH2)n - Z (III) wherein X and Z are identical or different halogens, and n has the meanings previously defined, to provide the alkyl halide of the formula EMI6.1 wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Y, Z, j, k, m and n have the meanings previously defined; the allyl halide IV on reaction with thiourea, followed by hydrolysis of the intermediate isothiouronium halide can provide an end product of the formula I wherein R is hydrogen, and, if desired, reacting said end product with an isocyanate of the formula A - N = C = O (V) wherein A has the meanings previously defined, to obtain an end product of the formula I wherein R is -CO-NH-A. The alkylation reaction described may be performed in a suitable solvent, such as water, dimethyl sulfoxide, dimethyl formamide, a lower alkanol of up to five carbon atoms, tetrahydrofuran or acetone, in the presence of a strong inorganic or organic base such as sodium or potassium hydroxide, a trialkylamine or pyridine and at room or elevated temperature up to the boiling point of the reaction mixture. The reaction time is temperature-dependent and may be one to several hours. The subsequent reaction of a phenylalkyl piperazinylalkyl halide of the formula IV with thiourea is carried out in the same solvents and bases as those mentioned in connection with the alkylation process; the reaction temperature may be up to the boiling point of the reaction mixture. Hydrolysis of the intermediate isothiouronium halide may be effected by the addition of water and strong inorganic base, e.g. sodium or potassium hydroxide at room or elevated temperature up to the boiling point of the reaction mixture. With this reaction free thiols of the formula I are obtained. For the preparation of an end product wherein R is -CO-NH-A, an above-mentioned thiol is reacted with an isocyanate of the formula V in the presence of a suitable inert solvent such as dioxane, tetrahydrofuran, ether, toluene or chlorinated hydrocarbons and optionally in the presence of an inorganic or organic base such as sodium or potassium carbonate, a trialkylamine or pyridine. The temperature may arise up to a reflux while the reaction time depends on the starting material and temperature used and may last from 30 minutes to several hours. The compounds embraced by formula I are basic and therefore form addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrohalic acid, especially hydrochloric or hydrobromic acid, nitric acid, sulfuric acid, o-phosphoric acid, citric acid, maleic acid, fumaric acid, propionic acid, butyric acid, acetic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or the like. The starting compounds are known or may be prepared by known methods. For example, compounds of the formula II are described in British Patent No. 480,358 and J. Am. Chem. Soc. 66, 263 (1944). Compounds of the formula IV are known, for example, from Helv. Chim. Acta 41, 1072 (1958) and Nonatshefte 87, 701 (1956). The following examples illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below. Example 1 3- (4- Benzvloiperazin-1-yl )propanethiol dihydrochioride (a) 31.5 g of l-bromo-3-chloropropane were added to a mixture of 35 g of l-benzylpiperazine, 150 ml of di methyl sulfoxide and 25 g of potassium hydroxide. The resulting mixture was stirred at room temperature for 3 hours. Water was added to the resulting solution, the reaction product was extracted with ether, dried (magnesium sulfate), and the salt was precipitated with ethereal hydrochloric acid to give 35.6 g (55X of theory) of l-ben2yl-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid. (b) 15 g of thiourea were added to a solution of 35 g of 1-benzyl-4-(3-chloropropyl)piperazine dihydrochloride, 20 g of triethylamine and 250 ml of reagent ethanol, and the mixture was refluxed for 8 hours. After the addition of a solution of 10 g of sodium hydroxide in 50 ml of water, the resulting mixture was refluxed for 4 additional hours. The ethanol was removed in vacuo, and water added to the residue which was extracted with methylene chloride, dried (sodium sulfate), and the salt was precipitated with ethereal hydrochloric acid to give 25.1 g (78% of theory) of 3-(4-benzyl-piperazinl-yl)propanethiol dihydrochloride as a white crystalline solid, M.p. 270-2730C (dec.). Example 2 N-Phenyl-S-[3-(4-benzylpiperazin-1-yl)propyl] thiocarbamate dihydrochloride monohydrate 1.6 g of phenyl isocyanate were added to a solution of 4.0 g of 3-(4-benzylpiperazin-1-yl)propqanethiol dihydrochloride and 2.6 g of triethylamine in 50 ml of methylene chloride. The mixture was refluxed for four hours, washed with water and dried (sodium sulfate). Precipitation of the salt with ethereal hydrochloric acid gave 1.2 g (20% of theory) of N-phenyl-S-[3-(4-benzylpiperazin-1-yl)propyl]thiocarbamate dihydrochloride monohydrate as a white crystalline solid, M.p. 216-2190C. Example 3 3-[4-(4-Chlorobenzyl)piperazin-1-yl]propanethiol dihydrochioride (a) Utilizing the procedure described in Example l(a), 20.0 g of 1-(4-chlorobenzyl)piperazine, 100 ml of dimethyl sulfoxide, 15.0 g of potassium hydroxide and 15.0 of l-bromo-3-chloropropane yielded 25.1 g (74% of theory) of l-(4-chlorobenzyl)-4-(3-chloro- propyl)piperazine dihydrochloride as a white crystalline solid. (b) Utilizing the procedure described in Example l(b), 6.0 g of thiourea, was reacted with 25.2 g of 1-(4 chlorobenzyl-4- (3-chloropropyl ) pip erazine dihydro chloride and 8.7 g of triethylamine in 200 ml of reagent ethanol. The hydrolysis was effected with 5.0 g of sodium hydroxide in 50 ml of water. Work-up as described above gave 16.6 g (75% of theory) of 3-[4-(4- chlorobenzyl)piperazine-1-yl]propanethiol dihydro-chloride as an off-white crystalline solid, M.p. 257-2600C. Example 4 N-Methyl-8-{3-[4-(4-chlorobenzyl)piperazin-1-yl]-propyl}thiocarbamate dihydrochloride The procedure described in Example 2 was followed, using 0.4 g of methyl isocyanate, 2.0 g of 3-[4-(4-chloro-benzyl)- piperazin-l-yllpropanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.75 g (32% of theory) of N-methyl-8[3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 240-243 C. Example 5 N-Isopropyl-S- f3- F 4- (4-chlorobenzvl )piperazin-l-vl 1propyl}thiocarbamate dihydrochloride The procedure described in Example 2 was followed, using 0.5 g of isopropyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.7 g (28% of theory) of N-isopropyl-S-{3-t4-(4-chloro- benzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 247-2500C. Example 6 N-Cyclohexyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride A mixture of 1.0 g of cyclohexyl isocyanate, 2.1 g of 3 [4-(4-chlorobenzyl)piperazin-1-yl]propanethiol and 10 ml of methylene chloride was stirred at room temperature overnight and then concentrated in vacuo. The residue crystallized upon standing. The product was recrystallized from aqueous ethanol, dissolved in ether, and the ethanol solution was dried (magnesium sulfate). The salt was then precipitated with ethereal hydrochloric acid and recrystallized twice from aqueous ethanol to give 1.2 g (30% of theory) os N-cyclohexyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thyiocarbamate dihydrochloride as a white crystalline solid, M.p. > 1650C (dec.). Example 7 N-Phenyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamte dihydrochloride The procedure described in Example 2 was followed, using 4.3 g of phenyl isocyanate, 12.7 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 7.3 g of triethylamine and 100 ml of methylene chloride, to give 9.1 g (53,' of theory) of N-phenyl-S-{3-[4-(4-chlorobenzyl)- piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. > 2300C (dec.). Example 8 N- (4-n-3utvlphenyl )-s- f3- F4- (4-chlorobenzvl )piperazin-l- vllproNeylXthiocarbamate dihvdrochloride The procedure described in Example 2 was followed, using 1.0 g of 4-n-butylphenyl isocyanate, 2.0 g of 3-(4-(4 chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.85 g (28% of theory) of N-(4-n-butylphenyl)-S-3- [4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 243 2460C. Example 9 N-(4-Fluorophenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride The procedure described in Exaiiple 2 was followed, using 0.8 g of 4-fluorophenyl isocyanate, 2.2 g of 3-[4-(4-chloro- benzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.6 g of triethylamine and 25 ii of methylene chloride, to give 1.41 g (47% of theory) of N-(4-fluorophenyl)-S-{3-[4-(4- chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 250-2520C. Example 10 N-(4-Chlorophenyl)-S{3-[4-(4-chlorobenzyl)piperazin1-yl]propyl}thiocarbamate dihydrochloride monohydrate The procedure described in Example 2 was followed, using 1.5 g of 4-chlorophenyl isocyanate, 3.5 g of 3-[4-(4-chloro- benzyl)piperazin-1-yl]propanethiol dihydrochloride, 1.2 g of trietbylainine and 50 ml of methylene chloride, to give 1.1 g (21% of theory) of N-(4-chlorophenyl)-S-{3-[4-(4- chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride monohydrate as an off-white crystalline solid, M.p. 243-2450C. Example 11 N-(3,4-Dichlorophenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride The procedure described in Example 2 was followed, using 1.6 g of 3,4-dichlorophenyl isocyanate, 3.0 g of 3-[4-(4chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.9 g of triethylamine and 50 ml of methylene chloride, to give 1.2 g (26% of theory) of N-(3,4-dichlorophenyl)-S- {3-[4-(4-chlrobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as white crystalline solid, M.p. 227-2300C. Example 12 N-(2-Methoxyphenyl)-S-{3- r4- (4-chlorobenzvl )PiPerazin-l-yl 1propyl}thiocarbamate dihydrochloride sesquihydrate The procedure described in Example 2 was followed, using 1.3 g of 2-methoxyphenyl isocyanate, 3.0 g of 3-[4-(4chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.9 g of triethylamine and 50 ml of methylene chloride, to give 0.9 g (2O of theory) of N-(2-methoxy-phenyl)-S- {3-[4-(4-chlrobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride sesquihydrate as an off-white crystalline solid, Mp. 23B-240 C. Example 13 N- (FMe.thoxyphenvl )-S- f3- r 4-(4-chlorobenzyl)piperazin-1-yl]- propyl}thiocarbamate dihydrochloride The procedure described in Example 2 was followed, using 1.3 g of 3-methoxyphenyl isocyanate, 3.0 g of 3-[4-(4chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride 0,9 g of triethylamine and 50 ml of methylene chloride, to give 1.35 g (32% of theory) of N-(3-methoxyphenyl)-S-{3- [4-(4-chlrobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as an off-white crystalline solid, Mp. 238-2400C. Example 14 N-(4-methoxyphenyl-S-{3-[4-(4-chlrobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride monohydrate The procedure described in Example 2 was followed, using 0.9 g of 4-methoxyphenyl isocyanate, 2.0 g of 3-[4-(4- chlrobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.72 g (25% of theory) of N-(4-methoxyphenyl)-S-{3-[4- (4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydro chloride moaohydrate as an off-white crystalline solid, M.p. 235-237 C. Example 15 N- (4-Acetvlphenyl )-S- C3- r4- (4-chlorobenzyl (piperazin-1-yl]- propyl}thiocarbamate dihydrochloride monohydrate The procedure described in Example 2 was followed, using 1.0 g of 4-acetylphenyl isocyanate, 2.0 g of 3-[4-(4-chloro- benzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.83 g (29% of theory) of N-(4-acetylphenyl)-S-{3-[4-(4- chlorobenzyl)piperazin-l-yl3propy3thiocarbama-te dihydrochloride monohydrate as a white crystalline solid, M.p. 235-2370C. Example 16 N-(4-Ethoxycarbonylphenyl)-S-{3-[4-(4-chlrobenzyl)piperazin1-yl]propyl}thiocarbamate dihydrochloride The procedure described in Example 2 was followed, using 1.1 g of 4-ethoxycarbonylphenyl isocyanate, 2.0 g of 3-[4 (4-chlrobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.85 g (28% of theory) of N-(4-ethoxy-carbonylphenyl)- S-{3-[4-(4-chlrobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, Mp. 231-2330C. Example 17 3-[4-(4-chlrobenzyl)piperazin-1-yl]propanethiol dihydrochloride (a) A mixture of 14.0 g of l-(4-methylbenzyl)piperazine, 8.0 g of potassium hydroxide and 125 ml of dimethyl sulfoxide was stirred for 45 minutes. 11.8 g of l-bromo-5-chloropropane were then added, and the mixture was stirred for an additional hour. Water was added, and the product was extracted with ether, and the extract was dried (sodium sulfate) and treated with etheral hydrochloric acid to give 23.3 g (94% of theory) of 1-(4-methylbenzyl)-4-(3-chloro propyl)-piperazine dihydrochloride as a white crystalline solid. (b) The procedure described in Example l(b) was followed, using 7.7 g of thiourea, 23.0 g of l-(4-methylbenzyl) 4- (3-chloropropyl )piperazine dihydrochloride, 6.5 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 6.0 g of sodium hydroxide in 40 ml of water. Work-up, as described above, gave 16.4 g (72 of theory) of 5-[4-(4-methyl- benzyl)-piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 273-2770C (dec.). Example 18 N-Phenyl-S-%{3-[4-(4-chlrobenzyl)piperazin-1-yl]propyl} thiocarbamate dihydrochloride sesquihydrate The procedure described in Example 2 was followed, using 1.4 g of phenyl isocyanate, 4.0 g of 3-[4-(4-methylbenzyl)- piperazin-l-yl)propanethiol dihydrochloride, 1.2 g of triethylamine and 50 ml of methylene chloride, to give 1.1 g (20% of theory) of N-phenyl-S-%{3-[4-(4-chlrobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride sesqui hydrate as a white crystalline solid, M.p. 255-2580C. Example 19 3-[4-(4-chlrobenzyl)-2,5-dimethylpiperazin-1-yl]propanethiol dihddrochloride (a) 22.0 g of 1-bromo-3-chloropropane were added to a mixture of 33.0 g of 4-chlorobenyl-2,5-dimethyl- piperazine, 25.0 g of potassium hydroxide and 125 ml of dimethyl sulfoxide. After stirring the solution for 3 hours at room temperature, water was added, the product was extracted with ether, and the extract was dried (magnesium sulfate) and concentrated to give 25.8 (5B% of theory) of l-(4-chlorobenzyl)-2,5- dimethyl-4-93-chloropropyl)piperazine as an oil, suitable for use in the next reaction. (b) The procedure described in Example l(b) was followed, using 12.7 g of thiourea and 26.0 g of 1-(4-chloro- benzyl)-2,5-dimethyl-4-(3-chloropropylXpiperazine in 250 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide in 50 ml of water. Work-up, as described above, gave 26.5 g (83% of theory) of 3-[4-(4-chlorobenyl)-2,5-dimethyl piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 168-171 C. Example 20 N-Phenyl-S-%{3-[4-(4-chlrobenzyl)-2,5-dimethylpiperazin-1yl] propyl}thiocarbamate dihydrochloride The procedure described in Example 2 was followed, using 1.2 g of phenyl isocyanate, 4.0 g of 1-(4-chlorobenzyl)2,5-dimethyl-4-(3-chlorophropyl)piperazine dihydrochloride, 2.0 g of triethylamine and 50 ml of methylene chloride, to give 1.1 g (22% of theory) of N-phenyl-S-{3-[4-(4- chlorobenzyl)-1,3-dimethylpiperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 215-218 C. Example 21 3-[4-(1-Phenylethyl)piperazin-1-yl]propanethiol dihydrochloride (a) The procedure described in Example 17(a) was followed, using 16.5 g of l-(l-phenylethyl) piperazine, 8.0 g of potassium hydroxide, 125 ml of dimethyl sulfoxide and 9.5 g of l-bromo-3-chloro propane. Work-up, as described above, gave 28.0 g (96% of theory) of l-(1-phenylethyl)-4-(3-chloro- propyl)piperazine dihydrochloride as a white crystalline solid. (b) The procedure described in Example l(b) was followed, using 9.8 g of thiourea, 29.0 g af l-(1-phenylethyl)- 4- (3-chloropropyl )piperazine dihydrochloride, 8.3 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 6.0 g of sodium hydroxide in 40 ml of water. Work-up, as above, gave 14.5 g (51% of theory) of 3-[4-(l-phenylethyl) piperazin-l-yl]-propanethiol dihydrochloride as a white crystalline solid, M.p. 252-255 C. Example 22 N-Phenyl-S-{3-[4-(1-phenylethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride dihydrate The procedure described in Example 2 was followed, using 1.6 g of phenyl isocyanate, 4.5 g of 3-[4-(l-phenylethyl) piperazin-1-yljpropanethiol dihydrochloride, 1.3 g of triethylamine and 50 ml of methylene chloride, to give 2.1 g (38% of theory) of N-phenyl-S-{3-[4-(1-phenylethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride dibydrate as a white crystalline solid, M.p. 227-229 C. Example 23 3-(4-Phenethylpiperazin-1-yl)propanethiol dihydrochloride (a) The procedure described in Example 1(a) was followed, using 29.4 g of l-phenethyl piperazine, 25.0 g of potassium hydroxide, 100 ml of dimethyl sulfoxide and 24.0 g of l-bromo-3-chloropropane. Work-up, as described above, gave 32.6 g (64% of theory) of 1-phenethyl-4- (3-chloropropyl )piperazine dihydro chloride as an off-white crystalline solid. (b) The procedure described in Example l(b) was followed using 15.2 g of thiourea, 32.6 g of l-phenethyl-4- (3-chloropropyl)piperazine dihydrochloride, 20.0 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide in 40 ml of water. Work-up, as described above, gave 26.4 g (79% of theory) of 3-(4-phenethyl piperazin-1-yl)-propanethiol dihydrochloride as an off-white crystalline solid, M.p. 269-2720C. Example 24 N-Phenyl-S-[3-(4-phenethylpiperazin-1-yl)porpyl]-thiocarbamate dihydrochloride monohydrate The procedure described in Example 2 was followed, using 1.4 g of phenyl isocyanate, 4.0 g of 3-(4-phenethylpiperazin1-yl)propanethiol dihydrochloride, 2.4 g of triethylamine and 50 ml of methylene chloride, to give 1.9 g (35% of theory) of N-phenyl-S-[3-(4-phenethylpiperazin-1-yl)-propyl]thiocarbamate dihydrochloride monohydrate as a white crystalline solid, M.p. 272-2750C. Example 25 3- r4- (IcChlorophenethyl )Diperazin-l-vl ipropanethiol dihvdrochloride (a) The procedure described in Example 17(a) was followed, using 6.5 g of l-(4-chlorophenethyl) piperazine, 6.0 g of potassium hydroxide, 125 ml of dimethyl sulfoxide and 4.6 g of l-bromo-3-chloro- propane. Work-up, as described above, gave 6.4 g (59% of theory) of 1- (4-chlorophenethyl ) -4- (3-chloro- propyl)piperazine dihydrochloride as a white crystalline solid. (b) The procedure described in Example l(b) was followed, using 1.3 g of thiourea, 6.4 g of l-(4-chlorophen ethyl)-4-(3-chloropropyl)piperazine dihydrochloride, 1.6 g of triethylamine and 150 ml of reagent ethanol. The hydrolysis was effected with 3.5 g of sodium hydroxide and 40 ml of water. Work-up, as described above, gave 5.6 g (8gS of theory) of 3-[4-(4-chloro- phenethyl)piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 279-281 C. Example 26 N-Phenyl-S- ±2- r 4-(4-chlorophenethyl)piperazin-1-yl]- propyllthiocarbamate dihydrochloride monohydrate The procedure described in Example 2 was followed, using 1.6 g of phenyl isocyanate, 5.0 g of 3-[4-(4-chlorophenethyl)piperazine-1-yl]propanethiol dihydrochloride, 1.3 g of triethylamine and 50 ml of methylene chloride, to give 3.0 g (44% of theory) of N-phenyl-S-|5-[4-(4-chlorophen- ethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride monohydrate as a white crystalline solid, M.p. 237-239 C. Example 27 N-(4-n-Butylphenyl)-S-{3-[4-(4-chlrobenzyl)-piperazin1-yl]propyl}thiocarbamate dihydrochloride The procedure described in Example 2 was followed, using 1.4 g of 4-n-butylphenyl isocyanate, 3.0 g of 3-t4-(4- chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 0.8 g of triethylamine and 50 ml of methylene chloride, to give 1.1 g (25% of theory) of N-(4-n-butylphenyl)-S-(3-[4- (4-chlorophenyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 252-254 C. Example 28 N-(4-Methoxyphenyl-S-%{3-[4-(4-chlrobenzyl)piperazin l-yllpropyllthiocarbnmate dihydrochloride The procedure described in Example 2 was followed, using 1.7 g of 4 methoxyphenyl isocyanate, 4.0 g of 3-[4-(4chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 1.1 g of triethylamine and 50 ml of methylene chloride, to give 1.4 g (25% of theory) of N-(4-methoxyphenyl)-S-(3-[4- (4-chlorophenethyl )piperaz in- l-yl )propyli thi ocarbamate dihydrochloride as a white crystalline solid, M.p. 236-238 C, Example 29 N-(3,4,5-Trimethoxyphenyl)-S-%{3-[4-(4-chlrobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride The procedure described in Example 2 was followed, using 2.5 g of 3,4,5-trimethoxyphenyl isocyanate, 4.4 g of 3-[4- (4-chlorophenethyl)piperazin-1-yl]propanethiol dihydro chloride, 1.2 g of triethylamine and 50 ml of methylene chloride, to give 1.6 g (23% of theory) of N-(3,4,5-tri- methoxyphenyl)-S-%{3-[4-(4-chlrobenzyl)piperazin-1-yl] propyl thiocarbamate dihydrochloride as a white crystalline solid, M.p. 239-2410C. Example 30 3-[4-(4-chlrobenzyl)piperazin-1-yl]propanethiol dihydrochloride (a) The procedure described in Example 17(a) was followed, using 36.0 g of (3-phenylpropyl)piperazine, 25.0 g of potassium hydroxide, 125 ml of dimethyl sulfoxide and 28.0 g of l-bromo- 3-chloropropane, to give 46.0 g (73% of theory) of 1- (3-phenylpropyl )-4- (3-chloro- propyl)piperazine dihydrochloride. (b) The procedure described in Example 1(b) was followed, using 19.0 g of thiourea, 44.0 g of l-(3-phenyl propyl)-4-(3-chloropropyl)piperazine dihydrochloride, 25 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide in 50 ml of water. Work-up, as described above, gave 35.8 g (82% of theory) of 3-t4-(3-phenyl- propyl)piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 237-2390C. Example 31 N-Phenyl-S-%{3-[4-(4-chlrobenzyl)piperazin-1-yl] propyl}thiocarbamate dihydrochloride monohydrate The procedure described in Example 2 was followed, using 1.2 g of phenyl isocyanate, 4.0 g of 3-[4-(3-phenylpropyl)- piperazin-l-yl)propanethiol dihydrochloride, 2.2 g of triethylamine and 50 ml of methylene chloride, to give 2.1 g (41% of theory) of N-phenyl-S-t3-[4-(3-phenylpropyl)- piperazin-3-y3,]propyl)thiocarbamate dihydrochloride monohydrate as a white crystalline solid, M.p. 240-243 C. Example 32 3-[4-(4-chlrobenzyl)piperazin-1-yl] propanethiol dihydrochloride (a) The procedure described in Example 17(a) was followed, using 27.0 g of 3-(4-chlorophenyl)propyl piperazine, 22.0 g of potassium hydroxide, 250 ml of dimethyl sulfoxide and 17.7 g of l-bromo-3-chloropropane to give 22.9 g (54% of theory) of 1-[3-(4-chlorophenyl) propyl]-4-(3-chloropropyl)piperazine dihydrochloride. (b) The procedure described in Example l(b) was followed, using 7.6 g of thiourea, 22.9 g of 1-[3-(4-chloro phenyl)propyl]-4-(3-chlorophenyl)piperazine dihydro chloride. 5.8 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide in 50 ml of water. Work-up, as described above, gave 14.1 g (65% of theory) of 3-[4-(4-chlrobenzyl)piperazin-1-yl]propane thiol dihydrochloride as a white crystalline solid, M.p. 238-242 C. Example 33 N-(4-n-Butylphenyl)-S-%{3-[4-(4-chlrobenzyl)propyl] piperazin-1-yl]propyl}thiocarbamete dihydrochloride The procedure described in Example 2 was followed, using 2.5 g of 4-n-butylphenyl isocyanate, 5.0 g of 3- 4-[3-(4 chlorophenyl)propyl]piperazin-1-yl propanethiol dihydro chloride, 1.4 g of triethylamine and 50 ml of methylene chloride, to give 2.7 g (34% of theory) of N-(4-n-butyl phenyl-S-%{3-[4-(4-chlrobenzyl)propyl]piperazin-1-yl] propyl3thiocarbamate dihydrochloride as a white crystalline solid, M.p. 270-2720C. ExamPle 34 3-[4-(4-Fluorophenyl)piperazin-1-yl]propanethiol dihydrochloride (a) The procedure described in Example l(a) was followed, using 32.8 g of l-(4-fluorobenzyl)piperazine, 30.0 g of potassium hydroxide, 100 ml of dimethyl sulfoxide and 27.0 g of 1-bromo-3-chloropropane. Work-up, as described above, gave 35.2 g (61% of theory) of l-(4- fluorobenzyl)-4-(3-chloropropyl)piperazine dihydro chloride as a white crystalline solid. (b) The procedure described in Example 1(b) was followed, using 15.2 g of thiourea, 35.2 g of l-(4-fluoro- benzyl)-4-(3-chloropropyl)piperazine dihydrochloride, 20.0 g of triethylamine and 200 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide and 50 ml of water. Work-up, as described above, gave 15.5 g (58% of theory) of 3-[4-(4-fluoro- phenyl)piperazin-1-yl]propanethiol. The salt was precipitated with ethereal hydrochloric acid to give 3-[4-(4-fluorophenyl)piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 284-2870C (dec.). Example 35 N-Phenyl-S%{3-[4-(4-fluorophenyl)piperazin-1-yl] prov1? thiocarbamate dihydrochloride 1.2 g of phenyl isocyanate was added to a solution of 2.5 g of 3-[4-(4-fluorophenyl)piperazin-1-yl]propanethiol in 75 ml of methylene chloride, and the mixture was refluxed for four hours. After the further addition of 100 ml of methylene chloride the solution was washed with water, dried (sodium sulfate) and concentrated. The salt was precipitated with etheral hydrochloric acid and recrystallized from aqueous ethanol to give 1.35 g (33% of theory) of N-phenyl-S-{3- [4- (4- fluorophenyl ) piperazin- 1-yl )propyij thioc arbamate dihydrochloride as a white crystalline solid, M.p. 250-2520C. Example 36 2-[4-(4-Chlorobenzyl)piperazin-1-yl]ethanethiol dihydrochloride (a) A mixture of 15.0 g of 1-(4-chlorobenzyl)piperazine, 14.4 g of 1-bromo-2-chlorethane and 150 ml of tetra hydrofuran was refluxed for 8 hours. The solvent was removed in vacuo, and 2N sodium hydroxide was added to the residue. The product was extracted with methylene chloride, and the extract was dried (sodium sulfate) and concentrated. The salt was precipitated with etheral hydrochloric acid to give 13.8 g (56% of theory) of 1-(4-chlorobenzyl)-4-(2 chloroethyl)piperazine dihydrochloride as a white crystalline solid. (b) The procedure described in Example l(b) was followed, using 6.1 g of thiourea, 13.8 g of l-(4-chlorobenzyl)- 4-(2-chloroethyl)piperazine dihydrochloride, 4.1 g of triethylamine and 150 ml of reagent ethanol. The hydrolysis was effected with 7.0 g of sodium hydroxide and 50 ml of water. Work-up, as described above, gave 6.7 g (62% of theory) of 2-[4-(4-chloro benzyl)piperazin-1-yl]ethanethiol dihydrochloriede as a white crystalline solid, Mp. 244-2470C. ExamPle 37 N-Phenyl-S-{2-[4-(4-chlorobenzyl)piperazin-1-yl]ethyl} thiocarbamate dihydrochloride The procedure described in Example 35 was followed, using 1.3 g of phenyl isocyanate, 3.0 g of 2-[4-(4-chlorobenzyl)- piperazin-1-yl)ethanethiol and 100 ml of methylene chloride, to give 2.2 g (43% of theory) of N-phenyl-S-{2-[4-(4-chloro- benzyl)piperazin-1-yl]ethyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 232-2360C (dec.). Example 38 N-Cyclohexyl-S-%{3-[4-(4-chlrobenzyl)piperazin-1-yl] propyl}thiocarbamate dihydrochloride The procedure described in Example 35 was followed, using 1.7 g of cyclohexyl isocyanate, 4.0 g of 3-[4-(4-chloro- phenethyl)piperazin-1-yl]propanethiol and 100 ml of methylene chloride, to give 3.8 g (58% of theory) of N-cyclohexyl-S-%{3-[4-(4-chlrobenzyl)piperazin-1-yl] propyl)thiocarbamate dihydrochloride as a white crystalline solid, M.p. 262-2670c. Example 39 N-(4-Methocyphenyl)-S-{3-[4-(4-chlorophenyl)propyl] piperazin-l-yl Ipropylthiocarbamate dihydrochloride hemihydrate The procedure described in Example 35 was followed, using 2.0 g of 4-methoxyphenyl isocyanate, 4.0 g of 3- 4-[3 (4-chlorophenyl)propyl]piperazin-1-yl propanethiol and 100 ml of methylene chloride to give 3.4 g (48% of theory) of N-(4-methoxyphenyl)-S-%{3-[4-(4-chlrobenzyl)propyl] piperazin-l-yl jpropyl)thiocarbamate dihydrochloride hemihydrate as a white crystalline solid, M.p. 240-244 C. Example 40 N-(n-Hexyl)-S-%{3-[4-(4-chlrobenzyl)piperazin-1-yl] propyl}thiocarbamate dihydrochloride The procedure described in Example 35 was followed, using 1.4 g of n-hexyl isocyanate, 3.0 g of 3-F4-(4-chlorobenzyl) psperazin-l-ylzpropanethiol and 100 ml of methylene chloride, to give 2.7 g (51% of theory) of N-(n-hexyl)-S-{3-[4-(4- chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 249-2520C (dec.). Example 41 3-{4-[4-(4-Chlorophenyl)butyl]piperazin-1-yl}propanethiol dihydrochloride (a) The procedure described in Example 1(a) was followed, using 10.0 g of 4-(4-chlorophenyl)butyl piperazine, 47.2 g of l-bromo-3-chloropropane, 150 ml of di methyl sulfoxide and 11.2 g of potassium hydroxide, to give 10.0 g (82% of theory) of 1-[4-(4-chloro- phenyl)butyl]-4-(3-chloropropyl)piperazine dihydro chloride as a white crystalline solid, M.p. 22680C. (b) The procedure described in Example l(b) was followed, using 1.0 g of thiourea, 4.0 g of 1-[4-(4-chloro phenyl)butyl]-4-(3-chloropropyl)piperazine dihydro chloride and 50 ml of reagent ethanol. The hydrolysis was effected with 4.0 g of sodium hydroxide in 50 ml of water. Work-up of the free base, as described above, followed by purification on a silica gel column (methylene chloride:methanol, 97:3), precipitation as the hydrochloride salt and recrystallization from reagent ethanol, gave (16% of theory) of 3-{4-[4-(4-chlorophenyl)butyl]- piperazin-1-yl}propanethiol dihydrochloride as a white crystalline solid, M.p. 254-259 C. Example 42 N-(n-Hexyl)-S{3-[4-[4-(4-chlorophenyl)butyl]piperazin1-yl]propyl}thiocarbamate dihydrochloride The procedure described in Example 2 was followed, using 1.0 g of n-hexyl isocyanate, 2.6 g of 3- (4-[4-(4-chloro- phenyl)butyl]piperazin-1-yl}propanethiol and 25 ml of methylene chloride, to give 1.4 g (32% of theory) of N-(n-hexyl)-S-{3-[4-(4-chlorophenyl) butyl]piperazin l-yl)propyl3thiocarbamate dihydrochloride as a white crystalline solid, M.p. 235-2450C (dec.). Example 43 3-(4-Cinnamylpiperazin-1-yl)propanethiol dihydrochloride (a) 6.0 g of cinnamyl bromide were added to a mixture of 7.4 g of 1-(3-chloropropyl)piperazine dihydro chloride hemihydrate, 6.1 g of triethylamine and 100 ml of reagent ethanol. The mixture was refluxed for 4 hours and then stirred overnight. After removal of the solvent in vacuo, water was added to the residue. The product was then extracted with ether and the extract was dried (magnesium sulfate) and concentrated. The resulting oil was chromatographed on silica gel (methylene chloride/ methanol : 9/1) and precipitated with etheral hydrochloric acid to give 7.4 g (7o of theory) of l-cinnamyl-4-(3-chloropropyl)piperazine dihydrochloride. (b) The procedure described in Example l(b) was followed, using 3.1.g of thiourea, 7.4 g of l-cinnamyl-4-(3 chloropropyl)piperazine dihydrochloride, 4.1 g of triethylamine and 100 ml of reagent ethanol. The hydrolysis was effected with 3.0 g of sodium hydroxide in 30 ml of water. Work-up, as described above, gave 3.6 g (52% of theory) of 3-(4-cinnamyl piperazin-l-yl)propanethiol dihydrochloride as a white crystalline solid, M.p. 249-252 C. Example 44 N-(n-hexyl)S-[3-(4-cinnamylpiperazin-1-yl)propyl] thioc arbamate djlwdrochloride The procedure described in Example 2 was followed, using 0.4 g of n-hexyl isocyanate, 1.0 g of 3-(4-cinnemyl-piperazin- l-yl)propanethiol dihydrochloride, 0.6 g of triethylamine and 50 ml of methylene chloride, to give 0.44 g (31% of theory) of N-(n-hexyl)-S-[3-(4-cinnamylpiperazin-1-yl]propyl]thiocarbamate dihydrochloride as a white crystalline solid, M/p. 251-253 C. Example 45 3-[4-(4-chlorobenzyl)homopiperazin-1-yl]propanethiol (a) 15.7 g of l-broino-3-chloropropane were added to a cooled solution of 15.0 g of 1-(4-chlorobenzyl)homo piperazine and 12.0 g of potassium hydroxide in 50 ml of dimethyl sulfoxide. The mixture was stirred at 5-10 C for one hour, and then an additional 30 minutes at room temperature. After the addition of ice water, the product was extracted with ether, and the extract was dried (magnesium sulfate) and concentrated in vacuo. Final purification was effected on a silicia gel column (methylene chloride: methanol, 9:1), and the solvent was removed in vacuo to give 8.4 g (42g of theory) of l-(4-chlorobenzyl) 4-(3-chloropropyl)-homopiperazine as an oil. (b) 4.1 g of thiourea were added to a mixture of 8.0 g of 1-(4-chlorobenzyl)-4-(3-chloropropyl)homopiperazine and 100 ml of reagent ethanol. The mixture was refluxed for 6 hours and then stirred overnight at room temperature. A solution of 5.0 g of sodium hydroxide in 30 ml of water was added, and the resulting solution was refluxed for 4 hours. The ethanol was removed in vacuo, and water was added to the residue. The product was extracted with methylene chloride, and the extract was dried (sodium sulfate) and concentrated to give 3.1 g (39% of theory) of 3-[4-(4-chlorobenzl)homo- piperazin-l-ylgpropanethiol as a yellow oil. Example 46 N-(n-Hexyl)-S-{3-[4-(4-chlorophenyl) butyl]piperazin1-yl]propyl}thiocarbamate dihydrochloride The procedure described in Example 2 was followed, using 1.3 g of n-hexyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)- homopiperazin-l-ylgpropanethiol and 75 ml of methylene chloride, to give 1.3 g (33% of theory) of N-(n-hexyl)-s- a-[4-(4-chlorobenzyl)homopiperazin-1-ylapropyl}thio- carbamate dihydrochloride as a tan powder, M.p. 183-1870C. Example 47 N-(t-Butyl)-S-{3-[4-(4-chlorophenyl) butyl]piperazin-1-yl]propyl}thiocarbamate dihydrochloride sesquihydrate The procedure described in Example 2 was followed, using 0.8 g of t-butyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 1.6 g of triethylamine and 75 ml of methylene chloride, to give 2.2 g (60% of theory) of N-(t-butyl)-S-±3-[4-(4-chloro- benzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride sesquihydrate as a white crystalline solid, M.p. 246-2480C. The compounds of the present invention,that is, those embraced by formula I above and their non-toxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, they exhibit potent ihhibittion of mediator release in numerous cell systems of warm-blooded animals such as rats, guinea pigs and humans, and are therefore useful for the treatment of allergic diseases such as allergic asthma, rhinitis, con3unctivitis, hay fever, urticaria, food allergies and the like. Moreover, it has been realized that also compounds described in the above-mentioned Japanese Patent No. 6813468 and excluded, therefore, from formula I above, namely compounds wherein n is 2, when R is hydrogen and h is 2-methyl, may exhibit similar pharmacological activity. Neither this nor any pharmacological activity, however, is mentioned in the Japanese patent. The new compounds inhibit, at a concentration of as low as 1 pool, the release of histamine and other mediators of anaphylaxis from granule containing cells like human basophils and mast cells, measured according to the following method: Mediator release from mast cells and basophils has been implicated in many allergic and inflammatory disorders. The activity of compounds in inhibiting the non-cytoxic exocytosis of such mediators can be evaluated in in vitro models such as the inhibition of mediator release from isolated cellular systems induced by antigen-antibody interaction. We include here data obtained in examples of such models to illustrate the biological activity of the novel compounds and the broad scope of their activity. This information is provided in the following table. The cellular systems cited therein are as follows: RPMC: Rat peritoneal mast cell preparation GPBL: Guinea pig leukocytes2 HBL: Human basophil-enriched leukocytes3 A comparison with the activities of the clinical standards theophylline and disodium cromoglycate (DSCG) in these systems is also provided. Compounds Mediator Release Inhibition IC50 (uM)* RPMC GPBL HBL 1-Cyclohexy-S-{3-[4-(4- 3 10 3 hlorobenzyl)piperazin-1-yl] ropyl}thiocarbamate dihydro chloride 3-[4-(4-Chlorophenethyl)- 6 5 5 piperazin-1-yl]propanethiol dihydrochloride N-(4-Methoxyphenyl)-S-{3-[4- 6 40 3 (4-chlorophenethyl)piperazin l-yl ipropyij thiocarbamate dihydrochloride N-(4-n-Butylphenyl)-S-{3-[4- 5 10 4 [3-(4-chlorophenyl)propyl]piperazin-1-yl]propyl}thiocarbamate dihydrochloride Theophylline > 1000 200 400 DSCG > 1000 * Concentration of the compounds required in the cellular reaction mixture to inhibit 50% of the release of the pharmacological mediators from the target cells. 1 Y. Morita and R.P. Siraganian, J. Immunol. 127, 1339 (1981). 2 M.A. Lett-Brown, D.O. Thueson and J.A. Grant, Int. Arch. Allergy Appl. Immunol. 64, 241 (1981). 3 R.P. Siraganian and W. Hook in "Manual of Clinical I m lnology", 2nd Edition, N.R. Rose and H. Friedman, ed., pp. 808, Washington, D.C. (1980). For pharmaceutical purposes the compounds of the present invention are administered to warm-blooded animals topically, perorally, parenterally or by the respiratory route as active ingredients in customary pharmaceutical compositions, that is, compositions constisting essentially of an inert pharmaceutical carrier and an effective amount of the active ingredient. The oral and the topical route are preferred. When they are to be administered by the oral route the compounds of the present invention may be compounded in the form of syrups, tablets, capsules, pills and the like. Preferably, the compositions are in unit dosage form, or in a form in which the patient can administer to himself a single dose. When the composition is in the form of a tablet, powder or lozenge, any pharmaceutical carrier suitable for formulating solid compositions may be used. Examples of such carriers are various starches, lactose, glucose, sucrose, cellulose, dicalcium phosphate, and chalk. The composition may also be in the form of an ingestible capsule (for example, of gelatin) containing the compound; or in the form of a syrup, a liquid solution or a suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerin, saline, water, propylene glycol, sorbitol solution which may be compounded with flavoring or coloring agents to form syrups. The compounds of this invention may also be administered by other than the oral route. In accordance with routine pharmaceutical procedure, the composition may be formulated, for example, for rectal administration as a suppository or for presentation in an inJectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, such as sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids, which may contain bacteriostatic agents, antioxidants, preservatives, buffers, or other solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose forms such as ampules or disposable injection devices, or in multi-dose vials such as a bottle from which the appropriate dose may be withdrawn, or as a solid form or concentrate which can be used to prepare an injectable formulation. The compounds of this invention may also suitable be presented for administration via tne respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In sich a case the particles of active compounds suitably have diameters of less than 20 microns, preferably less than 10 microns. ltere appropriate, small amounts of other antiallergics, anti-asthmatic and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, metaproterenol, salbutamol, phenylephrine, fenoterol, and ephedrine; xanthine derivatives such as theophylline and aminophylline; and corticosteroids such as prednisolone and adrenal stimulants such as ACZH may be included. The compounds of this invention may also be presented as an ointment, cream, lotion, gel, aerosol, or solution for topical application to the skin, nose, or eye. Topical solution for the nose and the eye may contain, in addition to the compounds of this invention, suitable buffers, toxicity adjusters, microbial preservatives, antioxidants and viscosity-impairing agents in an aqueous vehicle. Examples of agents used to increase viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrroli- done, polysorbates or glycerin. Microbial preservatives added may include benzalkonium chloride, thimerosal, chlorobutanol or phenylethyl alcohol. Topical preparations for the eye may also be presented as ointments in a suitable inert base consisting of mineral oil, petrolatum, polyethylene glycols or lanolin derivatives, along with microbial preservatives. In addition to these dosage forms, a skin paint can also be formulated for application to the skin. In any of the foregoing formulations, a suitable dosage unit may contain from 0.005 to 500 mg of the active ingredient The effective dose of a compound of this invention depends on the particular compound employed, the condition of the patient, and on the frequency and route of administration, but in general is in the range of from 0.0001 mg/kg to 10 mg/kg, inclusive, of the patient's body weight. In the preferred topical administration, a 0.001 to 0.5%, preferably a 0.01 to 0.1% solution is provided for. As is common practice, the composition will usually be accompanied by written or printed directions for use in the medical treatment concerned, in this case as an antiallergic agent for the prophylaxis and treatment of for example, asthma, hayfever, rhinitis or allergic eczema. The following example illustrates the preparation and properties of compositions of this invention. For the preparation of pharmaceutical compositions, the compounds of the formula I are mixed in the usual way with appropriate pharmaceutical carrier substances and aroma, flavoring and coloring materials and formed, for example, into tablets or capsules or, with the addition of appropriate adjutants, suspended or dissolved in water or in an oil, for example corn oil. The compounds of the formula I can be administered orally and parenterally in liquid or solid form. As inJection medium, it is preferred to use water which contains the stabilizing agents, solubilizing agents and/or buffers conventionally used for injection solutions. Additives of this type include, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complex formers (such as EDTA), antioxidants (such as sodium bisulfite, sodium metabisulfite or ascorbic acid), high molecular weight polymers (such as liquid polyethylene oxides) for viscosity regulation, and polyethylene derivatives of sorbitol anhydrides. Preservatives may also be added if necessary, such as benzoic acid, methyl or propyl paraben, benzalkonium chloride and other quaternary ammonium compounds. Solid carrier material which can be used include, for example, starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silica, dibasic calcium phosphate, and high molecular weight polymers (such as polyethylene glycol). Compositions suitable for oral administration can, if desired, contain flavoring and/or sweetening agents. For topical administration, the compounds of the present invention can also be used in the form of powders or ointments, for which purpose they are mixed with, for example, powdered, physiologically compatible diluents or conventional ointment bases. The following examples illustrate a few pharmaceutical dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of using the invention. The parts are parts by weight unless otherwise specified. Example 48 Tablets The tablet composition is compounded from the following ingredients: N-Phenyl-S-{3-[4-(4-chlorophenyl) piperazin-1-yl]propyl}thio carbamate dihydrochloride 0.010 parts Stearic acid 0.010 Dextrose 1.890 " Total 1.910 parts Preparation: The ingredients are admixed in conventional manner, and the mixture is compressed into 1.91 gm-tablets, each of which is an oral dosage unit composition containing 10 mg of the active ingredient. Example 49 Ointment The ointment composition is compounded from the following ingredients: 3-[4-(4-Chlorophenethyl)piperazin 1-yljpropanethiol dihydrochloride 2.000 parts Fuming hydrochloric acid 0.011 Sodium pyrosulfite 0.050 " Mixture (1:1) of cetyl alcohol and stearyl alcohol 20.000 " White vaseline 5.000 Synthetic bergamot oil 0.075 1? Distilled water q.s.ad 100.000 " Preparation: The ingredients are uniformly blended in conventional manner into an ointment, 100 gm of which contain 2.0 gm of the active ingredient. Example 50 Inhalation aerosol The aerosol composition is compounded from the following ingredients: N-Cyclohexyl-S-3-[4-(4-chloro- benzyl)piperazin-1-yl]propyl}thio carbamate dihydrochloride 1.00 parts Soybean lecithin 0.20 " Propellant gas mixture (Freon 11, 12 and 14) q.s.ad 100.00 II Preparation: The ingredients are compounded in conventional manner and the composition is filled into aerosol containers equipped with a metering valve which releases 0.5 to 2.0 mg of active ingredient per actuation of the valve. Example 51 Hypodermio solution The solution is compounded from the following ingredients: N-(4-Methoxyphenyl)-S-{3-[4-(4 chlorophenethyl)piperazin-l- yl]propyl}thiocarbamate dihydro chloride 5.0 parts Sodium pyrosulfite 1.0 " Sodium salt of FDTA 0.5 " Sodium chloride 8.5 n Double-distilled water q.s.ad 1000.0 n Preparation: The individual ingredients are dissolved in a sufficient amount of double-distilled water, the solution is diluted to the indicated concentration with additional doubledistilled water, the resulting solution is filtered until free from suspended particles, and the filtrate is filled under aseptic conditions into 1 ml-ampules which are subsequently sterilized and sealed. Each ampule contains 5 mg of the active ingredient. Example 52 Topical solution (ophthalmic or nasal) The solution is compounded from the following ingredients: N-(4-n-Butylphenyl)-S-{3-[4-[3 (4-chlorophenyl0propyl]-piperazin 1-ylipropyl thiocarbamate dihydro chloride 0.020 parts Disodium hydrogen phosphate 0.758 " Dihydrogen sodium phosphate 0.184 " Sodium chloride 0.365 parts Polyvinyl alcohol 3.500 I1 Benzalkonium chloride 0.010 " Distilled water q.s.ad 100.000 " Preparation: The ingredients are dissolved in conventional manner to form an aqueous solution. The solution is appropriately filtered, with the ophthalmic solution requiring sterile filtration. Each ml of the solution contains 0,2 mg of the active ingredient. Any one of the other compounds embraced by formula I or a non-toxic salt thereof may be substituted for the particular active ingredient in examples 48 through 52. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredient may be varied to meet particular requirements. While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

Claims: WE CLAIM: 1. A compound of the formula EMI40.1 wherein R is hydrogen or EMI40.2 A is alkyl of 1 to 8 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; or unsubstituted or mono-, di- or tri-substituted phenyl, where the substituents are each independently alkyl of 1 to 4 carbon atoms, halogen, trihalomethyl, alkoxy of 1 to 3 carbon atoms, carboxylic acyl of 1 to 3 carbon atoms, carboxyl, (alkoxy of 1 to 3 carbon atoms)carbonyl, nitro, cyano or di(alkyl of I to 3 carbon atoms)amino; R1, R2 and R3 are each independently hydrogen, halogen, alkyl of 1 to 4 carbon atoms, tri halomethyl, nitro, cyano, di(alkyl of 1 to 4 carbon atoms)amino, (alkoxy of 1 to 4 carbon atoms) carbonyl, alkoxy of 1 to 4 carbon atoms or hydroxyl; ; R4 and R5 are each independently hydrogen, alkyl of 1 to 4 carbon atoms or phenyl; R6, R7r R8 and R9 are each independently hydrogen or methyl; Y is -CH2- or -CH2-CH2-; 3 is O or 1; k and m are each integers of O to 3, their sum being no more than 6 and must be 0 when 3 is 1; and n is an integer of 2 to 4, with the proviso that n must be 3 or 4 when R1 is hydrogen or 2-methyl, R2, R3 R4, R5, R6' 7 % R9 and R are hydrogen and j, k and m are 0 and Y is -CH2-; or a non-toxic, pharmaceutically acceptable acid addition salt thereof. 2. A compound of claim 1 which is of the formula EMI41.1 wherein R is hydrogen or EMI41.2 A is alkyl of 1 to 8 carbon atoms; cycloallvl of 3 to 7 carbon atoms; or unsubstituted or mono-, di- or tri-substituted phenyl, where the substituents are each independently alkyl of 1 to 4 carbon atoms, halogen, trihalomethyl, alkoxy of 1 to 3 carbon atoms, carboxylic acyl of 1 to 3 carbon atoms, carboxyl, (alkoxy of 1 to 3 carbon atoms)carbonyl, nitro, cyano or di(alkyl of 1 to 3 carbon atoms)amino; R1 is hydrogen, halogen, alkyl of 1 to 4 carbon atoms, trihalomethyl, nitro, cyano, di(alkyl of 1 to 4 carbon atoms)amino, (alkoxy of 1 to 4 carbon atoms)carbonyl, alkoxy of 1 to 4 carbon atoms or hydroxyl; R6 and R7 are each independently hydrogen or methyl; m is an integer from 0 to 3; and n is an integer of 2 to 4, with the proviso that n must be 3 or 4 when R1 is hydrogen or 2-methyl, R6, R7 and R are hydrogen and m is O; or a non-toxic, pharinaceutically acceptable acid addition salt thereof. 3. A compound of claim 2, where R is hydrogen or EMI42.1 A is alkyl of 1 to 3 carbon atoms; cycloalkyl of 5 to 6 carbon atoms; or unsubstituted or mono-, di- or tri-substituted phenyl, where the substituents are each independently alkyl of 1 to 4 carbon atoms, fluorine, chlorine, bromine, trifluoromethyl, methoxy, acetyl or carbethoxy; R1 is hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, trifluoromethyl or dimethylamino; R6 and R7 are each independently hydrogen or methyl; m is an integer from O to 3; and n is an integer of 2 to 4, with the proviso that n must be 3 or 4 when R1 is hydrogen or 2-methyl, R6, R7 and R are hydrogen and m is 0; or a non-toxic, pharmaceutically acceptable acid addition salt thereof. 4. The compound of claim 1 which is N-cyolohexyl-S-{3-[4- (4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride. 5. The compound of claim 1 which is 3-[4-(4-chlorophenethyl) piperazin-l-yl)propanethiol dihydrochloride. 6. The compound of claim 1 which is N-(4-methoxyphenyl)-S {3-[4-(4-chlorophenethyl)piperazin-1-yl]propyl}thio carbamate dihydrochloride. 7. The compound of claim 1 which is N-(4-n-butylphenyl)-S {3-[4-[3-(4-chlorophenyl)propyl]piperrazin-1-yl]propyl} thiocarbamate dihydrochloride. 8. The compound of claim 1 which is 3-[4-(4-chlorobenzyl) piperazin-l-yl ]propanethiol dihydrochloride. 9. The compound of claim 1 which is N-phenyl-S-f3-[4-(4- chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydro chloride. 10. The compound of claim 1 which is 2-[4-(4-chlorobenzyl) piperazin-l-yl)ethanethiol dihydrochloride. 11. The compound of claim 1 which is N-(4-fluorophenyl)-S- (3- [4- (4-chlorobenzyl )piperazin-l-yl )propyljthiocarbamate dihydrochloride. 12. The compound of claim 1 which is N-(3,4,5-trimethoxy- phenyl)-S-{3-[4-(4-chlorophenyl)piperazin-1-yl] propyl}thiocarbamate dihydrochloride. 13. The compound of claim 1 which is N-phenyl-S-(2-[4-(4- chlorobanzyl)piperazin-1-yl]ethyl}thiocarbamate dihydro chloride. 14. The compound of claim 1 which is N-cyclohexyl-S-{3-[4- (4-chlorophenethyl )piperazin-l-yl )propylj thiocarbamate dihydrochloride. 15. The compound of claim 1 which is N-(4-methoxyphenyl)-S- {3-[4-[3-(4-chlrphenyl)propyl]piperazin-1-yl]propyl} thi oc arbamate dihydrochloride hemihydrate. 16. The compound of claim 1 which is N-(n-hexyl)-S-t3-[4- (4-chlorobenzyl)homopiperazin-1-ylZpropyl}thiocarbAmAte dihydrochloride. 17. An immunological, antiallergic or antiinflammatory composition consisting essentially of an inert pharma ceutical carrier and an effective immunological, anti allergic or antiinflammatory amount of a compound of claim 1. 18. The method of treating immunological, allergic or inflammatory reactions in a warm-blooded animal in need thereof, which comprises perorally, parenterally, topically or by inhalation administering to said animal an effective immunological, antiallergic or anti inflammatory amount of a compound of claim 1. 19. The method of preparing a compound of the formula EMI44.1 wherein R is hydrogen or EMI44.2 A is alkyl of 1 to 8 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; or unsubstituted or mono-, di- or tri substituted phenyl, where the substituents are each independently alkyl of 1 to 4 carbon atoms, halogen, trihalomethyl, alkoxy of 1 to 3 carbon atoms, carboxylic acyl of 1 to 3 carbon atoms, carbdxyl, (alkoxy of 1 to 3 carbon atoms)carbonyl, nitro, cyano or di(alkyl of 1 to 3 carbon atoms)amino; R1, R2 and R3 are each independently hydrogen, halogen, alkyl of 1 to 4 carbon atoms, tri halomethyl, nitro, cyano, di(alkyl of 1 to 4 carbon atoms)amino, (alkoxy of 1 to 4 carbon atoms)carbonyl, alkoxy of 1 to 4 carbon atoms or hydroxyl; ; R4 and R5 are each independently hydrogen, alkyl of 1 to 4 carbon atoms or phenyl; R6, R7, R8 and R9 are each independently hydrogen or methyl; Y is -CH2- or -CH2-CH2-; j is O or 1; k and m are each integers of O to 3, their sum being no more than 6 and must be 0 when j is 1; and n is an integer of 2 to 4, with the proviso that n must be 3 or 4 when R1 is hydrogen or -methyl, R2, R3, R4, R5, R6, R7, R8, R9 and R are hydrogen and j, k and m are O and Y is -CH2-; which comprises reacting a compound of the formula EMI45.1 wherein R1, R2, R3, R4 R5, R6, R7, R8, R9, j, k, m and Y have the meanings previously defined, with an alkyl halide of the formula X - (CH2)n - Z wherein X and Z are identical or different halogens, and n has the meanings previously defined, reacting the alkyl halide of the formula EMI46.1 wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Y, z, j, k, m and n have the meanings previously defined, thus obtained with thiourea, subjecting the resulting intermediate isothiouronium halide to hydrolysis to obtain an end product of the formula I wherein R is hydrogen, and reacting said end product with an isocyanate of the formula A-N=C=0 wherein A has the meanings previously defined, to obtain an end product of the formula I wherein R is -CO-NH-A.

Inventors: BARSUMIAN, EDWARD L., DR., DEVLIN, JOHN P., DR., HARGRAVE, KARL D., DR
Applicants: BOEHRINGER INGELHEIM LTD.
Application year: 1984
Main classification: C07D295
IPC codes: A61P29, A61K31, C07D243, A61P37, C07D241, C07D295