US3822267A

US3822267A - 1 substituted 4 piperazino cycloalkylthiazoles

Info

Publication number: US3822267A
Application number: US00276260A
Authority: US
Inventors: D Sorg
Original assignee: Wander AG
Current assignee: Wander AG
Priority date: 1971-08-03
Filing date: 1972-07-28
Publication date: 1974-07-02
Anticipated expiration: 1991-07-02
Also published as: FR2150715A1; GB1392007A; FR2150715B1; NL7210425A; CH556872A; AT336620B; CH570999A5; DE2237502A1; SE387949B; CH556870A; BE787059A; ATA667672A

Abstract

THE PRESENT INVENTION CONCERNS CYCLOALKYLTHIAZOLE COMPOUNDS OF THE FORMULA:

2-(4-R-PIPERAZINO-),4,5-(-CH2-(CH2)N-CH2-)-THIAZOLE

WHEREIN N IS AN INTEGER OF 1 TO 4 AND R IS HYDROGEN, ALKYL, ALKENYL, HYDROXYALKYL, ALKOXYALKYL, ALKOXYCARBONYL, ALKANOYL, ALKANOYLOXYALKYL OR BENZYL. THE COMPOUNDS EXHIBIT A STIMULATING EFFECT ON MENTAL ALERTNESS.

Description

3,822,267 1 SUBSTITUTED 4 PIPERAZINO CYCLOALKYLTHIAZOLES Dieter Sorg, Bern, Switzerland, assignor to Wander Ltd. (also known as Wander AG), Bern, Switzerland No Drawing. Filed July 28, 1972, Ser. No. 276,260

Claims priority, application Switzerland, Aug. 3, 1971,

11,373/71; June 15, 1972, 8,975/72 Int. Cl. C07d 51/70 US. Cl. 260-268 BC 14 Claims ABSTRACT OF THE DISCLOSURE I The present invention concerns cycloalkylthiazole compounds of the formula:

wherein n is an integer of l to 4 and R is hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkanoyl, alkanoyloxyalkyl or benzyl.

The compounds exhibit a stimulating effect on mental alertness.

The present invention relates to heterocyclic compounds and more specifically to cycloalkylthiazole compounds.

The present invention provides compounds of formula I, C

N IN a.

cii S wherein n is one of the integers 1, 2,3 or 4 and R is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxyalkyl of l to 4 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms, alkanoyl of 1 to 4 carbon atoms, alkanoyloxyalkyl of 2 to 6 carbon atoms or benzyl.

The present invention also provides a process for the production of a compound of formula I, which comprises (a) Reacting a reactive ester of an alcohol of formula II,

wherein R is as defined above, or

(b) Reacting a reactive ester of a compound of formula II, either as the thiocyanate or in the presence of a thiocyanate source, with a compound of formula IV,

wherein R is as defined above,

As will be readily appreciated, compounds of formula I may also be produced by interconversion from one compound of formula I to another. Thus,

"United States Patent Office 3,822,267 Patented July 2, 1974 (a') Compounds of formula I, wherein R is other than hydrogen, may be produced from the compounds of formula I, wherein R is hydrogen by substitution thereof in manner known per se.

(b') Compounds of formula I, wherein R is hydrogen, may be produced from compounds of formula I, wherein R is benzyl, alkoxycarbonyl, alkenyl, alkanoyl or methyl, by splitting off the group R and (c') Compounds of formula I, wherein R is alkanoyloxyalkyl, may be produced from the compounds of formula I, wherein R is hydroxyalkyl, by acylation thereof.

The compounds of formula I may exist either in free base or acid addition salt form. Acid addition salt forms may be produced from free base forms in manner known per se, e.g. by reaction with inorganic or organic acids, and vice versa. Examples of acids for acid addition salt formation are inorganic acids such as hydrohalic acids, sulphuric acid, nitric acid and phosphoric acid, and organic acids such as toluenesulphonic acid, acetic acid, malonic acid, succinic acid, maleic acid, malic acid and tartaric acid.

Process (a) of the invention may be effected as follows:

A compound of formula II may be reacted with a. compound of formula III either in an inert solvent or without solvent. If a solvent is used, it is preferable to use an alcohol, conveniently in aqueous form, such as methanol, ethanol or isopropanol, a ketone such as acetone, an ether such as dioxane, an aromatic solvent such as benzene, toluene or xylene, an amide such as dimethyl formamide'or dimethyl sulphoxide. The reaction may conveniently be effected at a temperature between room temperature and 140 C., preferably between 70 and 120 C., or, in the absence of a solvent, at a temperature between 70 and 120 C.

The compounds of formula III may be reacted either in free base or acid addition salt form.

Suitable reactive esters of alcohols of formula II for the above reaction are, for example, a hydrohalic acid ester, especially hydrobromic or hydrochloric acid ester, or toluene sulphonic acid ester. The use of these esters directly yields the corresponding acid addition salts of the compounds of formula I. However, when it is desired to obtain the compounds of formula I in free base form, an acid-binding agent, e.g. triethylamine, may be added to the reaction mixture.

Process (b) of the invention may be effected as follows:

The alcohol of formula II may be employed in the form of the thiocyanate thereof, or when employed in any other reactive ester form, a thiocyanate source should be employed. The thiocyanate source may be provided by effecting the reaction in the presence of thiocyanic acid or in the presence of a thiocyanate salt, e.g. an alkali metal thiocyanate, such as potassium thiocyanate, or ammonium thiocyanate. Alternatively, one convenient way of providing a thiocyanate source is by employing the compound of formula IV in thiocyanate acid addition salt form.

To provide the thiocyanate of the alcohol of formula II, or the thiocyanic acid addition salt form of the compound of formula IV, the compound of formula II or formula IV, as the case may be, may be reacted with thiocyanate acid or a thiocyanate, e.g. an alkali metal thiocyanate such as potassium thiocyanate or ammonium thiocyanate, in an inert solvent, e.g. ethanol, aqueous ethanol or dioxane, at a temperature between room temperature and 120 C., preferably between 70 and C. The subsequent reaction between the thiocyanate ester of the alcohol of formula II and the compound of formula IV, or between a reactive ester of the alcohol of formula I I andthe thiocyanic acid addition salt of the compound of formula IV, as the case may be, or alternatively, the reaction between a reactive ester of an alcohol of formula II and the compound of formula IV in the presence of thiocyanic acid or a thiocyanate salt, may be effected under similar conditions to those hereinbefore described for the reaction in accordance with process (a).

Interconversion of compounds of formula I, in accordance with processes (a'), (b') and (c), may be effected as follows, viz:

In accordance with process (a'), a reactive ester of a compound of formula V,

R'OH V wherein R has all the significances of R other than hydrogen,

e.g. a hydrohalic acid ester or sulphonic acid ester, may be reacted with a compound of formula I, wherein R is hydrogen. The reaction may be effected in the presence of an inert solvent such as an alcohol, e.g. ethanol, benzene, toluene, dioxane or pyridine, or alternatively in the absence of a solvent, at a temperature between room temperature and 120 C., preferably between 50 and 80 C. The presence of an acid-binding agent, e.g. 1,8-bis- (dimethylamino)naphthalene, in this reaction is convenient.

Alternatively the group R may be introduced into a compound of formula I, wherein R is hydrogen by reactive alkylation, i.e. by reaction with the aldehyde analogue of the compound of formula V, either with simultaneous reduction with hydrogen in the presence of a catalyst, e.g. platinum oxide, at room temperature, or in the presence of a reducing agent such as formic acid. The latter reaction is conveniently effected by dissolving the unsubstituted compound in 90% formic acid and heating to a temperature between 50 and 150 C., preferably at the boil, with the corresponding aldehyde for 5 to 20 hours.

The introduction of a hydroxyalkyl group may be effected by reacting the unsubstituted compound with an alkylene oxide, the reaction conveniently being effected in an organic solvent, e.g. an alcohol such as methanol, at a temperature of 0 C. to room temperature.

In accordance with process (b'), the removal of a benzyl group may, for example, be effected by hydrogenolysis. Hydrogenolysis is preferably effected by dissolving the starting material in an alcohol, e.g. ethanol, or in ethyl acetate, and hydrogenating with hydrogen, at normal pressure, in the presence of a noble metal catalyst, preferably platinum oxide or palladium charcoal, at a temperature between room temperature and 50 C. When R denotes a benzyl, methyl or alkenyl group, the removal of these groups may be effected by reacting the starting material with cyanogen bromide or with a chloroformic acid ester, e.g. the ethyl or benzyl ester, and converting the resulting reaction product hydrolytically or hydrogenolytically into the secondary amine.

The reaction of the starting material with cyanogen bromide is preferably effected by heating the reaction components in an inert solvent, such as benzene, toluene or dioxane, to a temperature between 80 and 120 C., preferably to the boil. The reaction of the starting material with the chloroformic acid ester may be effected either in the absence of an inert solvent or in an inert solvent such as benzene, at a temperature between 70 and 120 0, preferably at the boil. This reaction yields compounds containing a cyano or a carbalkoxy group. These groups may subsequently be removed hydrolytically or hydrogenolytically.

Hydrogenolysis to the secondary amine is effected under the conditions indicated above. Hydrolysis may, for example, be effected by heating the reaction product with an aqueous mineral acid, preferably hydrochloric acid, preferably to the boil.

The subsequent removal of an alkanoyl or alkoxycarbonyl group is likewise effected hydrolytically, whereby the conditions indicated above may be used.

The hydrohalic acid esters of alcohols of formula II, used as starting materials in processes (a) and (b), are

either known or may be produced in known manner, e.g. be reacting a ketone of formula VI,

C 2 O A Ca VI wherein n is as defined above,

with a halogen or a halogenation agent, such as N-bromosuccinimide or sulphuryl chloride. It is not essential that the hydrohalic acid esters of an alcohol of formula II be isolated before the subsequent reaction with the thiourea derivative of formula III.

Other esters, e.g. toluenesulphonic acid esters, of an alcohol of formula II may, for example, be obtained by reacting the corresponding hydrohalic acid ester with a salt, preferably the sodium salt, of the corresponding acid.

The thiourea derivatives of formula III, required as starting materials in process (a), are known or may be produced in known manner, e.g. by heating piperazine or a piperazine derivative of formula IV with ammonium thiocyanate in concentrated aqueous solution, to a temperature between and C., for several hours.

The piperazine derivatives of formula IV are known or may be produced in known manner.

The compounds of formula I obtained in accordance with the processes described above, may be isolated in known manner, e.g. by extraction, precipitation or acid addition salt formation, and may be subsequently purified in known manner, e.g. by recrystallization.

The compounds of formula I are useful because they possess pharmacological activity in animals.

More particularly, the compounds are useful as psychostimulating agents, especially for increasing mental alertness or awareness as indicated by a stimulating eflfect on the mental alertness of mice when administered orally at a dose of from 0.5 to 20 mg./kg. animal body weight. The effect is observed by a mode of behaviour such as a continuous shaking of the head, characteristic of compounds with a strong psychoactive effect. Every five minutes, each animal is under observation over a period of two minutes to ascertain whether shaking of the head occurs.

For the abovementioned use, the dose to be administered will naturally vary depending on the compound used, the mode of administration and the condition to be treated. However, in general, satisfactory results are obtained when administered at a daily dose of from 0.15 to 20 mg./kg. animal body weight, which may be administered in divided doses 2 to 5 times a day, or in retard form. For the larger mammals, the total daily dosage is in the range of from about 10 mg. to about 200 mg., and dosage forms suitable for oral administration comprise from about 2 mg. to about 200 mg. of the compound admixed with a solid or liquid pharmaceutical carrier or diluent.

Examples of pharmaceutical carriers and diluents are lactose, maize, starch, talc and magnesium stearate.

The preferred class of compounds of formula I are those wheerin R is alkyl of 1 to 4 carbon atoms or hydroxyalkyl of 1 to 4 carbon atoms.

Free base and pharmaceutically acceptable acid addition salt forms of the compounds of formtla I have the same type of activity.

Examples of forms of pharmaceutical compositions for oral administration are tablets, granulates, capsules or dragees, and an example for parenteral administration is an injectable solution.

An example of a tablet composition is as follows:

20 mg. of 2-(4-methyl-l-piperazinyl)-5,6-dihydro-4H- cyclopentathiazole,

70 mg. of maize starch,

5 mg. of talc, and

0.1 mg. of magnesium stearate.

In the following non-limitative Examples all temperatures are indicated in degrees Centigrade. The vacuum employed is 8 to 20 mm. of Hg, unless indicated otherwise.

EXAMPLE 1 2-( l-Methyl-l-piperazinyl)-5,6,7,8-tetrahydro- 4H-cycloheptathiazole [Process (a)] 5.7 g. of 2-bromocycloheptanone and 4.8 g. of 4-methyl- 1-piperazinyl-thiocarboxamide are heated on a steam bath (approx. 100) in 20 cc. of ethanol for four hours. After concentrating by evaporation in a vacuum, the residue is dissolved in water, a 4 N aqueous sodium hydroxide solution is added, and the basic 2-(4-methyl-1-piperazinyl)- 5,6,7,8 tetrahydrd 4H cycloheptathiazole is taken up in ether. After concentrating the ethereal solution, the base crystallizes and has a M.P. of 73-74 (recrystallized from ether/petroleum ether). Treatment of this base with hydrochloric acid in ethanol yields the dihydrochloride having a M.P. of 245-247.

EXAMPLE 2 2- (4-Methyl-1-piperazinyl) -5,6-dihydro-4H- cyclopentathiazole [Process (a)] Proceeding in a manner analogous to that described in Example 1, but using an equivalent amount of Z-bromocyclopentanone in place of Z-bromocycloheptanone, 2-(4- methyl 1 piperazinyl) 5,6 dihydro 4H cyclopentathiazole is obtained as base having a M.P. of 65 (recrystallized from ether/petroleum ether). The dihydrochloride has a M.P. of 240 (recrystallized from ethanol).

EXAMPLE 3 2- [4- (Z-Hydroxyethyl) -1-piperazinyl] -tetrahydro-4H- cycloheptathiazole [Process (a)] Proceeding in a manner analogous to that described in Example 1, but using an equivalent amount of 4-(2- hydroxyethyl)-1-piperazinyl-thiocarboxamide in place of 4-methyl 1 piperazinyl-thiocarboxamide, 2-[4-(2-hydroxyethyl) 1 piperazinyl] 5,6,7,8 tetrahydro-4H- cycloheptathiazole is obtained as base having a M.P. of 103-1035 (recrystallized from ether/petroleum ether). The dihydrochloride has a M.P. of 215 (indefinite) (recrystallized from ethanol/ethyl acetate).

EXAMPLE 4 2 (4-Benbyl-l-piperazinyl -5,6,7,8-tetrahydro-4H- cycloheptathiazole [Process (a) 1 Proceeding in a manner analogous to that described in Example 1, but using an equivalent amount of 4- benzyl-l-piperazinyl-thiocarboxamide in place of 4-methyl-l-piperazinyl-thiocarboxamide, 2 (4-'benzyl-lpiperazinyl) 5,'6,7,8 tetrahydro-4H-cycloheptathiazole is obtained as base having a M.P. of 98-99 (recrystallized from ether/petroleum ether). The dihydrochloride has an indefinite M.P. from 215 (recrystallized from ethanol/ethyl acetate.

EXAMPLE 5 2- (4-Methyll-piperazinyl) -4,5 6,7-tetrahydrocyclohexathiazole [Process (a)] 5.3 g. of 2-bromocyclohexanone are mixed with 4.8 g. of 4-methyl-1-piperazinyl-thiocarboxamide, and the mixture is heated in an oil bath for 3 hours. Temperature: 130. The reaction cake is subsequently dissolved in Water, an aqueous 4 N sodium hydroxide solution is added, and the product which precipitates is taken up in ether. After the addition of hydrochloric acid in etha- 1101, the dihydrochloride of 2- (4-methyl-l-piperazinyl)-4, 5,6,7-tetrahydro-cyclohexathiazole, having a decomposition point of 215-220 (recrystallized from ethanol), crystallizes.

6 EXAMPLE 6 2-(4-Methyl-1-piperazinyl)-4,5,6,7,8,9-hexahydrocyclooctathiazole [Process (a)] Proceeding in a manner analogous to that described in Example 5, but using an equivalent amount of 2-bromocyclooctanone in place of 2-bromocyclohexanone, 2-(4- methyl 1 piperazinyl)-4,5,6,7,8,9-hexahydro-cyclooctathiazole is obtained as dihydrochloride having a M.P. of 206-208 (recrystallized from ethanol).

EXAMPLE 7 2-[4-(2-Hydroethyl)-1-piperazinyl]-5,6,7,8-tetrahydro- 4H-cycloheptathiazole [Process (b)] 3.04 g. of ammonium thiocyanate are added to 5.2 g. of 1-(2-hydr0xyethyl)piperazine in 20 cc. of ethanol, and the mixture is heated to the boil on a water bath (bath temperature until ammonia evolution stops (approx. half an hour). After the addition of 9.55 g. of 2-bromocycloheptanone, the reaction mixture is diluted with 10 cc. of ethanol and is heated at the same bath temperature for a further 12 hours. The mixture is subsequently concentrated by evaporation in a vacuum and the residue is dissolved in a small amount of dilute hydrochloric acid. The resulting mixture is extracted twice with ether. The aqueous phase is rendered alkaline with a concentrated caustic soda solution and is exhaustively extracted with ether. Upon concentrating the dried ether solution, the base of 2-[4-(2-hydroxyethyl)-1-piperazinyl]-5,6,7,8-tetrahydro-4H-cycloheptathiazole, having a M.P. of 103, crystallizes.

EXAMPLE 8 2-(4-Methyl-l-piperazinyl)-5,6,7,8tetrahydro4H- cycloheptathiazole [Process (b)] Proceeding in a manner analogous to that described in Example 7, but using an equivalent amount of lmethylpiperazine in place of 1-(2-hydroxyethyl)-piperazine, 2 (4-methyl-l-piperazinyl)-5,6,7,8-tetrahydro-4H- cycloheptathiazole, having a M.P. of 73, is obtained.

EXAMPLE 9 2- [-4-(2-Methoxyethyl)-l-piperazinyl]-5,6,7,8-tetrahydro- 4H-cycloheptathiazole [Process (b)] 6.4 g. of Z-bromocycloheptanone and 3.25 g. of potassium thiocyanate are heated on a steam bath (100") in 30 cc. of ethanol and 5 cc. of water for 1 /2 hours. After the addition of 4.8 g. of 1-(2-methoxyethyl) piperazine in 15 cc. of ethanol, the mixture is heated to 100 for a further 15 hours. After concentrating by evaporation in a vacuum, the residue is taken up in a small amount of Water and is extracted twice with ether. After drying the ether solution, the dihydrochloride of 2-[4-(2-methoxyethyl)-1-piperazinyl]-5,6,7,8-tetrahydro 4H cycloheptathiazole is precipitated in crystalline form by passing hydrogen chloride gas through the solution. After recrystallization from absolute ethanol, the dihydrochloride has a M.P. of 203-205.

EXAMPLE 10 2-(4-Methyl-1-piperazinyl)-5,6,7,8-tetrahydro-4H- cycloheptathiazole [Process (b) Proceeding in a manner analogous to that described in Example 9, but using an equivalent amount of l-methylpiperazine in place of 1-(2-methoxyethyl)piperazine, 2- (4-methyl-1-piperazinyl) 5,-6,7,8 tetrahydro-4H-cycloheptathiazole dihydrochloride, having a M.P. of 246, is obtained.

EXAMPLE 11 2- [4- (2-Hydroxyethyl l-piperazinyl] -,5,6,7,8-tetrahydro-4H-cycloheptathiazole [Process (b)] Proceeding in a manner analogous to that described in Example 9, but using an equivalent amount of l-(2-hy- 7 droxyethyl) piperazine in place of l-(2-methoxy-ethyl)- piperazine, 2- [4-(2-hydroxyethyl)-1-piperazinyl] 5,6,7,8- tetrahydro-4H-cycloheptathiazole dihydrochloride, having a M.P. of 212-215 (indefinite), is obtained.

EXAMPLE 12 2-( l-Piperazinyl -5,6,7, 8-tetrahydro-4H-cycloheptathiazole [Interconversion of compounds of formula I] 30 g. of 2-(4-benzyl-l-piperazinyl)-5,6,7,8-tetrahydro- 4H-cycloheptathiazole and 13.6 g. of cyanogen bromide are heated in an oil bath (90) for 18 hours in 280 cc. of absolute benzene. The reaction solution is subsequently extracted with 1000 cc. of 5 N hydrochloric acid, and after the addition of 100 cc. of concentrated hydrochloric acid, the aqueous solution is heated in an oil bath (120-l40) for 26 hours. After concentrating in a vacuum to k, of the original volume, the reaction mixture is made alkaline with a concentrated aqueous sodium hydroxide solution and is extracted with ether. After concentrating the ethereal solution, 2-(l-piperazinyl)-5,6,7,8-tetrahydro-4H cycloheptathiazole, having a M.P. of 70-73 crystallizes. Treatment with hydrochloric acid in ethanol yields the dihydrochloride, having a M.P. of 185 (indefinite) (recrystallized from ethanol/ ethyl acetate).

EXAMPLE l3 3-(4 Allyl-l-piperazinyl) 5,6,7,8, tetrahydro 4H- cycloheptathiazole [Interconversion of compounds of formula I] 2.4 g. of 2-(l-piperazinyl)-5,6,7,8-tetrahydro-4H-cycloheptathiazole, 1.4 g. of allyl bromide and 2.14 g. of 1,8- bis-(dimethylamino)naphthalene are heated in an oil bath (90) for 10 hours in 30 cc. of ethanol. After concentrating by evaporation in a vacuum, the crystalline residue is extracted twice with ether. The ethereal solution is subsequently concentrated, whereby 2-(4-allyl-l-piperazinyl)- 5,6,7,8-tetrahydro-4H-cyclohepthathiazole, having a M.P. of 59-61 crystallizes (recrystallized from hexane). Treatment with hydrochloric acid in ethanol yields the dihydrochloride having a M.P. of 196200 (recrystallized from ethanol/ ether) EXAMPLE 14 2-[4-(2 Hydroxyethyl) 1 piperazinyl] 5,6,7,8 tetrahydro-4H-cycloheptathiazole [Interconversion of compounds of formula I] 2.6 g. of ethylene oxide are passed into a solution of 4.75 g. of 2-(l-piperazinyl)-5,6,7,8-tetrahydro-4H-cycloheptathiazole in 20-cc. of methanol at while stirring. The solution is stirred at 0 for hours and subsequently at room temperature for hours. The reaction solution is subsequently concentrated by evaporation in a vacuum, the residue is taken up in ether, the ethereal solution is filtered, and the dihydrochloride of 2-[4-(2-hydroxyethyl)- l-piperazinyl]-5,6,7,8-tetrahydro-4H cycloheptathiazole, having a M.P. of 212-215 (recrystallized from ethanol/ ethyl acetate), is precipitated in crystalline form with hydrogen chloride gas.

EXAMPLE 2-(4-Acetyl 1 piperazinyl)-5,6,7,8-tetrahydro-4H-cycloheptathiazole [Interconversion of compounds of formula I] 2.0 g. of 2-(1-piperazinyl)-5,6,7,8-tetrahydro-4H-cycloheptathiazole are heated to 90 in 15 cc. of acetic anhyride for 3 hours. After decomposing the excess acetic andride for 3 hours. After decomposing the excess acetic an aqueous 2 N sodium hydroxide solution and is extracted with chloroform. The basic 2-(4-acetyl-1-piperazinyl)-5,- 6,7,8-tetrahydro-4H-cycloheptathiazole crystallizes upon concentrating the chloroform solution. M.P. 114-115".

8 EXAMPLE 16 2-(4-Ethoxycarbonyl 1 piperazinyl)-5,6,7,8-tetrahydro- 4H-cycloheptathiazole [Interconversion of compounds of formula I] 2.4 g. of 2-(l-piperazinyl)-5,6,7,8-tetrahydro-4H-cycloheptathiazole and 1.1 g. of 1,8-bis-(dimethylamino)naphthalene are dissolved in 50 cc. of ether, and a solution of 1.1 g. of chloroformic acid ethyl ester in 10 cc. of ether is added at +1 to +3 After allowing the reaction solution to stand at 20 for 1 hour, extraction is effected with water. The ethereal solution is concentrated by evaporation, whereby 2-(4-ethoxycarbonyl-l-piperazinyl)-5,6,7,8- tetrahydro-4H-cycloheptathiazole, having a M.P. of 98- 100", is obtained in crystalline form. Treatment with bydrochloric acid in ethanol yields the monohydrochloride having a M.P. of 163-165 (decomp.) (recrystallized from ethanol/ ether) EXAMPLE 17 2-[4-(2-Acetoxyethyl) 1 piperazinyl]-5,6,7,8-tetrahydro-4H-cycloheptathiazole [Interconversion of compounds of formula I] 3 g. of 2-[4-(2-hydroxethyl)-1-piperazinyl]-5,6,7,8-tetrahydro-4H-cycloheptathiazole and 1.2 g. of acetic anhydride are heated to 5060 in 5 cc. of benzene for 20 hours. After concentrating by evaporation in a vacuum, 2-[4-(2-acetoxyethyl)-1-piperazinyl] 5,6,7,8-tetrahydro- 4-H-cycloheptathiazole is obtained as crystalline product. M.P. 48-50 (recrystallized from ethyl acetate).

EXAMPLE 18 2-(4-Allyl-l-piperazinyl)-5,6,7,8-tetrahydro-4H- cycloheptathiazole [Process (b)] Proceeding in a manner analogous to that described in Example 7, but using an equivalent amount of l-allylpiperazine in place of 1-(2-hydroxyethyl) piperazine, 2- (4 allyl-l-piperazinyl)-5,6,7,8-tetrahydro-4H-cyclol1eptathiazole is obtained. The dihydrochloride of this compound has a M.P. of 196-200 (recrystallized from ethanol/ ether) EXAMPLE 19 2-(4-Allyl-l-piperazinyl)-5,6,7,8-tetrahydro-4H- cycloheptathiazole [Process (a)] wherein n is one of the integers l, 2, 3 or 4 and R is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms, alkanoyl of 1 to 4 carbon atoms, alkanoyloxyalkyl of 2 to 6 carbon atoms or benzyl,

in free base or pharmaceutically acceptable acid addition salt form.

2. A compound of Claim 1, wherein R is alkyl of l to 4 carbon atoms or hydroxyalkyl of 1 to 4 carbon atoms.

3. The compound of Claim 1, which is 2-(4-methyll-piperazinyl)-5,6,7,8-tetrahydro-4H-cycloheptathiazole.

4. The compound of Claim 1, which is 2-(4-methyl-1- piperazinyl)-5,6-dihydro-4H-cyc1opentathiazole.

5. The compound of Claim 2, which is 3- [4-(2-hydroxyethyl)-1-piperazinyl]-5,6,7,8-tetrahydro 4H cycloheptathiazole.

6. The compound of Claim 1, which is 2-(4-benzyl-1- piperazinyl)-5,6,7,8-tetrahydro-4H-cycloheptathiazole.

7. The compound of Claim 1, which is 2-(4-methyl-1- piperazinyl) -4,5,6,7-tetrahydro-cyclohexathiazole.

8. The compound of Claim 1, which is 2-(4-methyl-1- piperazinyl)-4,5,6,7,8,9-hexahydro-cyclooctathiazole.

9. The compound of Claim 1, which is 2-[4-(2-methoxyethyl)-l-piperazinyl]-S,6,7,8-tetrahydro 4H cycloheptathiazole.

10. The compound of Claim 1, which is 2-(1-piperazinyl -5 6,7,8-tetrahydro-4H-cycloheptathiazole.

11. The compound of Claim 1, which is 3-(4-a1lyl-1- piperazinyl -5 ,6,7,8-tetrahydro-4H-cyclohept athiazole.

12. The compound of Claim 1, which is 2-(4-acety1-1- piperazinyl)-5,6,7,8-tetrahydro-4H-cycloheptathiazole.

5 heptathiazole.

References Cited UNITED STATES PATENTS 2,877,231 3/1959 De Stevens 260268 BC 3,489,757 1/1970 Koppe 260268 BC 3,694,449 9/1972 Wei 260268 BC OTHER REFERENCES Himizu et al.: Chem. Abstr., Vol. 72, C01. 790300 (1970).

DONALD G. DAUS, Primary Examiner US. Cl. X.R.

20 260268 R, 268 BC, 586 R; 424-250