4,5 or 6-Alkylaminoalkyl-2-Alkyl-4,5,6,7-Tetrahydro Benzo[d]thiazoles

This invention relates to amino benzothiazole derivatives.

Applicant has previously disclosed in French Pat. No. FR 7731891 aminobenzothiazole derivatives which have an useful activity on the central nervous system.

This invention relates to new amino benzothiazole derivatives which could be prepared only via an entirely different synthetic route and which, additionally, are applicable in a different therapeutic area.

Thus, this invention relates to compounds having the general formula (I): ##STR2## in which: R is hydrogen or C.sub.1-6 alkyl, and R' is hydrogen or C.sub.1-6 alkyl,

and their pharmaceutically acceptable acid addition salts.

The addition salts may typically be those formed with hydrochloric, hydrobromic, sulfuric acids and the pharmaceutically acceptable organic acids.

A process for the preparation of the compounds of the formula (I), comprises:

(a) reacting a bromo keto-ester of the formula (II): ##STR3## in which R" is C.sub.1-2 alkyl, with a thioamide of the formula ##STR4## in which R is as previously defined, to give an ester of the formula (III): ##STR5##

(b) reducing the ester of the formula (III) with lithium aluminum hydride to an alcohol of the formula (IV): ##STR6##

(c) converting the alcohol of the formula (IV), with p-toluenesulfonyl chloride, to the corresponding tosylate of the formula (V): ##STR7##

(d) reacting the tosylate of the formula (V) with an amine of the formula R'-NH.sub.2 in which R' is as previously defined, to give an amine of the formula (I), and, if desired,

(e) converting the amine of the formula (I) to a pharmaceutically acceptable acid addition salt.

Some of the bromo esters (II) used as starting materials are known compounds:

2-bromo-6-ethoxycarbonyl-cyclohexanone (J. E. BRENNER, J. Org. Chem., 1961, 26, 22),

2-bromo-4-ethoxycarbonyl-cyclohexanone (L. BERGER and co-workers, German Pat. No. 2,214,501, Oct. 5, 1971, Chem. Abstr. 1973, 78, 29609b).

The other bromo keto-esters of the formula (II) are prepared in an analogous manner.

The reaction with a thioamide may be effected within a solvent such as an alcohol (ethanol, isopropanol) or dimethylformamide, at room temperature in the case of low molecular weight thioamides (R=H, CH.sub.3) or with mild heating in the case of higher thioamides (40.degree.-60.degree. C.).

The resulting benzothiazole (III) may be isolated, after evaporating off the solvent, due to its slightly basic character (dissolution in aqueous acidic medium).

Step (b), comprising reducing ester (III) to an alcohol (IV) with lithium aluminum hydride, may be effected within ether or tetrahydrofuran, at room temperature (or preferably at a low temperature <0.degree. C. in the case of the derivatives in which R=H).

The alcohols (IV) may be isolated and purified according to usual techniques (distillation, crystallization), or directly converted to tosylates (V) with p-toluenesulfonyl chloride, in the presence of a tertiary base such as pyridine.

The tosylates (V) may be purified by crystallization or may be used crude for the reaction with amine R'NH.sub.2. For this latter reaction, excess primary amine R'NH.sub.2 is advantageously used within a solvent such as methanol or ethanol, in an autoclave and at a temperature of about 100.degree. C.

The resulting amines (I) are obtained by evaporating off the solvent and are distilled under reduced pressure. These are strong bases, which are fairly readily converted to the carbonates on exposure to the air.

They are advantageously converted to salts, such as the hydrochlorides, by addition of a slight deficiency of anhydrous acid, within an inert solvent such as ether.

The following non-limiting Examples illustrate the present invention.

4-Aminomethyl-4,5,6,7-tetrahydro-benzo[d]thiazole and its hydrochloride (I, R=R'=H; substitution at 4-position)

(1) 4-Ethoxycarbonyl-4,5,6,7-tetrahydro-benzo[d]thiazole (III)

90 g (0.36 mole) 2-bromo-6-ethoxycarbonyl-cyclohexanone (II) are dissolved in 300 ml anhydrous ethanol containing 22 g (0.36 mole) thioformamide. After 60 hrs at room temperature and evaporation of the solvent, the residue is taken up into isopropyl oxide and extracted repeatedly with 2 N HCl. The acidic solution is made alkaline and the resulting oil is extracted with ether and is then distilled (b.p..sub.0.1 =100)104.degree. C.). Yield=31%.

(2) 4-Hydroxymethyl-4,5,6,7-tetrahydro-benzo[d]thiazole (IV)

To a solution of 1.14 g (30 mmoles) of AlLiH.sub.4 in 50 ml anhydrous tetrahydrofuran, cooled to -20.degree. C. and maintained at that temperature, are slowly added 6.66 g (30 mmoles) of the above derivative (III) dissolved in 30 ml anhydrous THF. After 30 minutes at -20.degree. C., excess AlLiH.sub.4 is destroyed by addition of isopropanol at -20.degree. C. followed by 5 ml saturated aqueous sodium chloride, and is then stirred for 2 hrs. The resulting precipitate is filtered off and washed with ethyl acetate; the filtrate is evaporated and the oily residue is taken up in the hot with hexane; product (IV) crystallizes on cooling. Yield: 70%. M.p.=74.degree.-75.degree. C.

(3) 4-Tosyloxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (V)

9.95 g (52 mmoles) p-toluenesulfonyl chloride are added portionwise to a mixture of 8 g (47 mmoles) of the above derivative (IV) and 15 g anhydrous pyridine, while maintaining the temperature at 10.degree. C. After stirring for 24 hrs at room temperature, the mixture is hydrolyzed and is then extracted with ethyl acetate. The combined organic phases are washed with water, dried and evaporated. The residual oil crystallizes slowly. The product is recristallyzed from boiling isopropyl oxide, on cooling. Yield: 72%. M.p.=64.degree.-65.degree. C.

(4) 4-Aminomethyl-4,5,6,7-tetrahydrobenzo[d]thiazole and its hydrochloride (I, R=R'=H)

A solution of 26 g (80 mmoles) of the above derivative (V) in 40 ml methanol is heated with 180 g ammonia, in an autoclave, for 5 hrs at 90.degree. C. After evaporation of the solvent and addition of 3.8 g (96 mmoles) sodium hydroxide dissolved in 25 ml water, the resulting amine is extracted repeatedly with ether, dried and distilled. B.p..sub.0.1 =97.degree.-100.degree. C. Yield=54%.

The amine (I, R=R'=H) is converted to the hydrochloride by addition of a slight deficiency of anhydrous HCl to a solution of the base in ether. Yield: 98%. M.p.=210.degree. C.

4-(N-Methylaminomethyl)-4,5,6,7-tetrahydro-benzo[d]thiazole and its hydrochloride (I, R=H; R'=CH.sub.3 ; substitution at 4-position)

30.4 g (93 mmoles) of derivative (V) described in Example 1 are stirred for 60 hrs at room temperature with a solution of 150 g methylamine in 150 ml water. The mixture is homogeneous after 48 hrs. The solution is evaporated to dryness; the residue is taken up into excess 2 N sodium hydroxide and extracted with methylene chloride. The oily residue obtained after evaporation of the solvent is distilled. B.p..sub.0.2 =96.degree.-99.degree. C. Yield: 80%.

The amine is converted to the hydrochloride by addition of a slight deficiency of anhydrous HCl, in ether. Yield:88%. M.p.=120.degree. C. (dec.).

2-Methyl-4-aminomethyl-4,5,6,7-tetrahydro-benzo[d]thiazole and its hydrochloride (I, R=CH.sub.3 ; R'=H; 4-substitution)

(1) 2-Methyl-4-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[d]thiazole (III)

This compound is prepared by action of thioacetamide on 2-bromo-6-carbethoxy-cyclohexanone (II), according to the process described in Example 1. B.p..sub.0.1 =102.degree.-105.degree. C.

(2) 2-Methyl-4-hydroxymethyl-4,5,6,7-tetrahydrobenzo[d]-thiazole (IV)

The compound is prepared by reduction of above derivative (III) with AlLiH.sub.4, according to the process described in Example 1. B.p..sub.0.4 =102.degree.-106.degree. C. Yield: 82%.

(3) 2-Methyl-4-tosyloxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (V)

This compound is prepared by action of p-toluenesulfonyl chloride on above alcohol (IV), according to the process of Example 1. M.p.=97.degree.-98.degree. C. Yield: 89%.

(4) 2-Methyl-4-aminomethyl-4,5,6,7-tetrahydrobenzo[d]thiazole and its hydrochloride (I; R=CH.sub.3 ; R'=H)

The compound is prepared by action of ammonia on the above tosylate (V), according to the process described in Example 1. B.p..sub.0.1 =76.degree.-78.degree. C. Yield: 75%. (the base is rapidly carbonated in air).

The amine is converted to the hydrochloride with anhydrous HCl, in ether. M.p.=140.degree. C. (dec.). Yield: 90%.

2-Methyl-4-(N-methylaminomethyl)-4,5,6,7-tetrahydro-benzo[d]thiazole and its hydrochloride (I; R=R'=CH.sub.3 ; 4-substitution)

This compound is prepared from tosylate (V) described in Example 3, by action of a large excess of methylamine dissolved in methanol, at 130.degree. C. in an autoclave. The amine is isolated according to the usual procedure, described in the preceding Examples. B.P..sub.0.5 =98.degree.-102.degree. C. Yield: 38%.

The amine is converted to the hydrochloride with a slight deficiency of anhydrous HCl, dissolved in ether. M.p.=144.degree. C. (dec.). Yield: 75%.

5-(N-Methylaminomethyl)-4,5,6,7-tetrahydro-benzo[d]thiazole and its hydrochloride (I; R=H; R'=CH.sub.3 ; 5-substitution)

(1) 5-Methoxycarbonyl-4,5,6,7-tetrahydro-benzo[d]thiazole (III)

The compound is prepared by action of thioformamide on 2-bromo-5-methylcarbonyl cyclohexanone, as described in Example 1. B.p. 0.4=110.degree.-120.degree. C. Yield: 35.5%.

(2) 5-Hydroxymethyl-4,5,6,7-tetrahydro-benzo[d]thiazole (IV)

The compound is prepared by reduction of compound (III) obtained above with AlLiH.sub.4, as described in Example 1. B.p..sub.0.6 =138.degree.-144.degree. C. Yield=81%.

(3) 5-Tosyloxymethyl-4,5,6,7-tetrahydro-benzo[d]thiazole (V)

The compound is prepared from above derivative (IV) according to the procedure of Example 1. M.p.=87.degree.-88.degree. C. Yield: 70%.

(4) 5-(N-methylaminomethyl)-4,5,6,7-tetrahydrobenzo[d]-thiazole and its hydrochloride (I; R=H; R'=CH.sub.3)

The compound is prepared by action of methylamine dissolved in ethanol, on the above tosylate (IV), in an autoclave at 100.degree. C. B.p..sub.0.5 =115.degree.-120.degree. C. Yield: 82%.

Hydrochloride: M.p.=201.degree.-202.degree. C. Yield: 82%.

2-Methyl-5-(N-methylaminomethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole and its hydrochloride (I; R=R'=CH.sub.3 ; substitution at 5-position)

(1) 2-Methyl-5-ethoxycarbonyl-4,5,6,7-tetrahydro-benzo[d]thiazole (III)

The compound is prepared by action of thioacetamide on 2-bromo-5-ethoxycarbonyl cyclohexanone (II), as described in Example 1. B.P..sub.0.4 =116.degree.-120.degree. C.

(2) 2-Methyl-5-hydroxymethyl-4,5,6,7-tetrahydro-benzo[d]-thiazole (IV)

The compound is prepared by reduction of the above derivative (III) with AlLiH.sub.4, according to the procedure described in Example 1. B.p..sub.0.5 =120.degree.-140.degree. C.

The crude product is purified by crystallization from carbon tetrachloride. M.p.=52.degree.-55.degree. C.

(3) 2-Methyl-5-tosyloxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (V)

The compound is prepared by action of p-toluenesulfonyl chloride on the above alcohol (IV), according to the procedure described in Example 1. M.p.=105.degree.-106.degree. C. Yield: 74%.

(4) 2-Methyl-5-(N-methylaminomethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole (I; R=R'=CH.sub.3)

The compound is prepared by action of methylamine on the above tosylate (V) dissolved in methanol, in an autoclave at 100.degree. C. B.P..sub.0.5 =100.degree.-110.degree. C. Yield: 75%.

The amine is converted to the hydrochloride according to the procedure described in Example 1. M.p.=248.degree.-250.degree. C. (dec.). Yield: 80%.

2-Methyl-6-(N-methylaminomethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole and its hydrochloride (I; R=R'=CH.sub.3 ; substitution at 6-position)

(1) 2-Methyl-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[d]thiazole (III)

The compound is prepared by action of thioacetamide on 2-bromo-4-ethoxycarbonyl-cyclohexanone according to the procedure described in Example 1. B.p..sub.0.3 =110.degree.-120.degree. C. Yield: 30%.

(2) 2-Methyl-6-hydroxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (IV)

The compound is prepared by reduction of the above derivative (III) according to the procedure described in Example 1. B.p..sub.0.4 =145.degree.-155.degree. C. M.p.=101.degree.-102.degree. C. Yield:70%.

(3) 2-Methyl-6-tosyloxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (V)

The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV) according to the procedure described in Example 1. M.p.=70.degree.-71.degree. C. Yield: 71%.

(4) 2-Methyl-6-(N-methylaminomethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole and its hydrochloride (I; R=R'=CH.sub.3)

The compound is prepared by action of methylamine dissolved in methanol, on the above tosylate (V), in an autoclave at 100.degree. C. B.p..sub.0.3 =105.degree.-115.degree. C. Yield: 83%.

The base is converted to the hydrochloride with a slight deficiency of HCl in anhydrous ether. M.p.=176.degree.-178.degree. C. Yield: 93%.

6-Aminomethyl-4,5,6,7-tetrahydro-benzo[d]thiazole and its hydrochloride (I; R=R'=H; 6-substitution)

(1) 6-Ethoxycarbonyl-4,5,6,7-tetrahydro-benzo[d]thiazole (III)

The compound is obtained by action of thioformamide on 2-bromo-4-ethoxycarbonyl-cyclohexanone, according to the procedure described in Example 1. B.p..sub.0.2 =105.degree.-115.degree. C. Yield: 27%.

(2) 6-Hydroxymethyl-4,5,6,7-tetrahydro-benzo[d]thiazole (IV)

The compound is prepared by reduction of the above derivative (III) according to the procedure described in Example 1. B.p..sub.1 =140.degree.-150.degree. C. Yield: 66%.

(3) 6-Tosyloxymethyl-4,5,6,7-tetrahydro-benzo[d]thiazole (V)

The compound is prepared from the above derivative (IV) according to the procedure described in Example 1. M.p.=90.degree.-91.degree. C. Yield: 64%.

(4) 6-Aminomethyl-4,5,6,7-tetrahydro-benzo[d]thiazole (I; R=R'=H)

The compound is prepared by action of ammonia on the above tosylate (V), in methanol, in an autoclave at 100.degree. C. B.p..sub.0.5 =100.degree.-106.degree. C. Yield: 42%.

Hydrochloride: M.p.=218.degree.-219.degree. C. Yield: 95%.

2-Ethyl-6-(N-ethylaminomethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole and its hydrochloride (I; R=R'=C.sub.2 H.sub.5 ; substitution at 6-position)

(1) 6-Ethoxycarbonyl-4,5,6,7-tetrahydro-benzo[d]thiazole (III)

The compound is prepared by action of thiopropionamide on 2-bromo-4-ethoxycarbonyl cyclohexanone within dimethyl formamide at room temperature. B.p..sub.0.2 =112.degree.-118.degree. C. Yield: 42%.

(2) 2-Ethyl-6-hydroxymethyl-4,5,6,7-tetrahydro-benzo[d]thiazole (IV)

The compound is prepared by reduction of the above derivative (III) with AlLiH.sub.4 within ether, at room temperature. B.p..sub.0.5 =142.degree.-144.degree. C. Yield: 86%.

(3) 2-Ethyl-6-tosyloxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (V)

The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. M.p.=54.degree.-56.degree. C. Yield: 65%.

(4) 2-Ethyl-6-(N-ethylaminomethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole and its hydrochloride (I; R=R'=C.sub.2 H.sub.5)

The compound is prepared by action of ethylamine in methanol solution on the above tosylate (V), in an autoclave at 90.degree. C. B.p..sub.0.1 =106.degree.-109.degree. C. Yield: 71%.

Hydrochloride: M.p.=187.degree. C. Yield: 100%.

6-(N-n-Propylaminomethyl)-4,5,6,7-tetrahydro-benzo[d]thiazole and its hydrochloride (I; R=H; R'=nC.sub.3 H.sub.7 ; substitution at 6-position)

The compound is prepared from the tosylate (V) described in Example 8, by action of a methanol solution of n-propylamine, in an autoclave at 90.degree. C. B.p..sub.0.05 =96.degree.-100.degree. C. Yield: 61%.

The base is converted to the hydrochloride with HCl dissolved in anhydrous ether. M.p.=166.degree. C. Yield: 87%.

2-n-Butyl-4-(N-methylaminomethyl)-4,5,6,7-tetrahydro-benzo[d]thiazole and its hydrochloride (I; R=nC.sub.4 H.sub.9 ; R'=CH.sub.3 ; substitution at 4-position)

(1) 2-n-Butyl-4-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[d]thiazole (III)

The compound is obtained by action of thiovaleramide on 2-bromo-6-ethoxycarbonyl-cyclohexanone according to the procedure described in Example 1. B.p..sub.0.5 =116.degree.-128.degree. C. Yield: 28%.

(2) 2-n-Butyl-4-hydroxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (IV)

The compound is prepared by reduction of the above derivative (III), with AlLiH.sub.4 in ether at room temperature. B.p..sub.0.6 =130.degree.-132.degree. C. Yield: 48%.

(3) 2-n-Butyl-4-tosyloxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (V)

The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. The product is an undistillable oil which is used crude for the subsequent reactions.

(4) 2-n-Butyl-4-(N-methylaminomethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole and its hydrochloride (I; R=nC.sub.4 H.sub.9 ; R'=CH.sub.3)

The compound is prepared by action of methylamine in methanol solution on the above tosylate (V), in an autoclave at 90.degree. C. B.p..sub.0.5 =118.degree.-120.degree. C. Yield: 74%.

The base is converted to the hydrochloride with HCl in anhydrous ether. M.p.=128.degree. C. Yield: 70%.

(1) 2-n-Butyl-5-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[d]thiazole (III)

The compound is obtained by action of thiovaleramide on 2-bromo-5-ethoxycarbonyl-cyclohexanone within dimethyl formamide at room temperature. B.p..sub.0.5 =140.degree.-142.degree. C. Yield: 56%.

(2) 2-n-Butyl-5-hydroxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (IV)

The compound is prepared by reduction of the above derivative (III) with AlLiH.sub.4 in ether at room temperature. B.p..sub.0.15 =138.degree.-142.degree. C. Yield: 89%.

(3) 2-n-Butyl-5-tosyloxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (V)

The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. It is obtained as an undistillable oil which is used crude for the subsequent reactions.

(4) 2-n-Butyl-5-(N-methylaminomethyl)-4,5,6,7-benzo[d]thiazole and its hydrochloride (I; R=nC.sub.4 H.sub.9 ; R'=CH.sub.3)

The compound is obtained by action of methylamine in methanol solution on the above tosylate (V), in an autoclave at 90.degree. C. B.p.=122.degree.-124.degree. C. Yield: 72%.

The base is converted to the hydrochloride with HCl in anhydrous ethanol. M.p.=169.degree.-171.degree. C. Yield: 100%.

2-Isopropyl-5-(N-methylaminomethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole and its hydrochloride (I; R=iC.sub.3 H.sub.7 ; R'=CH.sub.3 ; substitution at 5-position)

(1) 2-Isopropyl-5-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[d]thiazole (III)

The compound is obtained by action of thio-isobutyramide on 2-bromo-6-ethoxycarbonyl-cyclohexanone within dimethylformamide, at room temperature. B.p..sub.0.05 =109.degree.-111.degree. C. Yield: 50%.

(2) 2-Isopropyl-5-hydroxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (IV)

The compound is prepared by reduction of the above derivative (III) with AlLiH.sub.4 in ether at room temperature. B.p..sub.0.1 =122.degree.-126.degree. C. Yield: 83%.

(3) 2-Isopropyl-5-tosyloxymethyl-4,5,6,7-tetrahydrobenzo[d]thiazole (V)

The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. M.p.=82.degree.-83.degree. C. Yield: 71%

(4) 2-Isopropyl-5-(N-methylaminomethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole and its hydrochloride (I; R=iC.sub.3 H.sub.7 ; R'=CH.sub.3)

The compound is prepared by action of methylamine in methanol solution on the above tosylate (V), in an autoclave at 90.degree. C. B.p.=108.degree.-109.degree. C. Yield: 85%.

The base is converted to the hydrochloride with HCl in anhydrous ether. M.p.=177.degree. C. Yield: 98%.

Other Examples of compounds of the formula (I) prepared in an analogous manner are tabulated in following Table I.

The compounds of the formula (I) and their pharmaceutically acceptable acid addition salts possess useful pharmacological properties, particularly on the cardiovascular system. Thus, they have an effect, which is substantial with some of them, on the increase of the blood rate of flow for the perfusion of the limbs.

This activity on the cardiovascular system was demonstrated by means of a conventional test in dogs comprising determining the rate of flow of the femoral arteries. Thus, with some of the compounds, there was noted an increase of the arterial rate of flow from as low a dosage as 0.1-0.5 mg/kg i.v.

In addition, in the case of an acute occlusion of the femoral artery, there was noted a marked decrease of the resistance of the collateral arteries with the compounds of Examples 6 and 11, without substantially affecting the systemic blood pressure, nor the tissue perfusion pressure.

Most of the compounds, of the formula (I) have low toxicity, as is apparent from following Table II in which are given the LD.sub.50 per os and i.p. in mice.

The compounds of the formula (I) and their pharmaceutically acceptable acid addition salts are therapeutically useful in the treatment of circulatory insufficiencies of different origins.

In that respect, the compounds of Examples 6 and 11 appear to be particularly useful.

The compounds may be administered to humans by the oral, rectal or parenteral routes, as the free base or in salt form, in aqueous solution or as solutions in other pharmaceutically acceptable solvents, as suspensions or in crystalline form. The different formulations may contain 10-500 mg active ingredient per unit dose and the daily dosage regimen in humans may vary from 20 mg to 2 g depending on the therapeutic applications contemplated.