GB1582716A - 2-amino-cyclopent-1-ene-1-thiocarboxylic acid-disulphides and a process for the preparation thereof - Google Patents

Abstract

Novel N-substituted 2-amino-cyclopent-1-ene-1-dithiocarboxylic acids of the general formula <IMAGE> in which R denotes an unsubstituted straight or branched alkyl group having 5 or 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, which is substituted by alkoxy groups having 1 to 4 carbon atoms, or by hydroxyl, carboxyl and/or amino groups, an alkenyl group having 2 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl group, are prepared by reacting 2-amino-cyclopent-1-ene-1-dithiocarboxylic acid with amines of the general formula NH2-R. The novel compounds have a dopamine- beta -hydroxylase-inhibiting effect.

Description

(54) 2-AMINO-CYCLOPENT-1-ENE-1-THIOCARBOXYLIC ACID DISULFIDES AND A PROCESS FOR THE PREPARATION THEREOF (71) We, RICHTER GEDEON VEGYESZETI GYAR RT., a Hungarian body corporate, of 21 Gyomroi ut, Budapest X, Hungary, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to new 2-amino-cyclopent-1-ene-1- thiocarboxylic aciddisulfides and pharmaceutical compositions containing the same, furthermore to a process for the preparation thereof.

The novel compounds according to the invention correspond to the general formula (I),

wherein R represents a C16 alkyl group having optionally a C14 alkoxy, hydroxy, carboxy and/or amino substituent, a C24 alkenyl group or a C, cycloalkyl group.

These compounds exert dopaminess-hydroxvlase inhibiting effects and, according to a further feature of the invention, there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (I) in association with a pharmaceutical adjuvant and/or auxiliary agent.

As is known, substances influencing nervous functions exert their activities almost exclusively on the stimulus transfer processes. These processes are in general known and thus it is possible to prepare compounds by which such processes can be influenced in a more or less controlled manner. The intervention into elementary nervous processes involves, however, not only the influencing of the nervous system itself, but also the influencing of processes under the control of the nervous system. The efforts made in this respect in the last few years also encompass the research work performed in connection with dopamine-,ss-hydroxylase and compounds inhibiting its effects.

Dopamine-p-hydroxylase catalyzes the conversion of dopamine into noradrenaline, which is the last enzymatic step in the biosynthesis of noradrenaline. The normal level of noradrenaline, a substance playing a significant role in the transport processes of symphatic nervous stimuli, is an essential factor of the normal nervous functions and of the normal functions of processes under the control of the nervous system.

Substances with dopamine-p-hydroxylase inhibiting effects enable one to influence the noradrenergic functions. This fact is of great importance in both research work and therapy, since, in the field of research work, the consequences of the partial or total extinction of noradrenergic funcions can be examined by decreasing the noradrenaline level with dopamine-p-hydroxylase inhibitors, and, in the field of therapy, the hyperfunction of the noradrenergic system can be compensated with dopamine ,ss-hydroxylase inhibitors. Thus it has recently been found that dopamine-,B-hydroxylase inhibitors can be applied in therapy of hypertension and Parkinsonism.

As is known, benzyloxyamine and benzylhydrazine exert dopamine-ss-hydroxylase inhibiting effects (van der Schoot et al.: Advances in Drug Research, Vol. 2, p. 47, Harper and Simmons; Nikodijevic et aL: J. Pharm. Exp. Ther. 140, 224/1963/).

These compounds, however, exert their activities for a short period and thus they are not applied in therapy. Disulfiram and diethyl dithiocarbamate, the reduction metabolite of the former compound (Goldstein et al.: Life Sci. 3, 769/1964/), as well as several N,N-disubstituted dithiocarbamates (Maj et al.: Eur. J. Pharmacol. 9, 183/1970/; Lippman et al.: Arch. Int. Pharmacodyn. Ther. 189, 348/1971/) are substances known to exert strong dopamine-j-hydroxylase inhibiting effects. 2,2 Dipyridyl proved to be also effective under in vitro conditions (Green: Biochim.

Biophys. Acta 81, 394/1964/). Bis (1 -methyl-4-homopiperazinyl-thiocarbonyl ) -disulfide is one of the most potent dopamine-fi-hydroxylase inhibitors under in vivo conditions (Florvall et al.: Acta Pharmaceut. Sulcica 7, 7/1970/). Aromatic and alkyl thiourea derivatives exert long-lasting dopamine-P-hydroxylase inhibiting effects (Johnson et al.: J. Pharm. Exptl. Ther. 171, 80/1970/).

Of the microbial substances fusaric acid (5-butyl-picolinic acid) and its derivatives (Hidaka et al.: Molac, Pharmacol. 9, 172/1973), oosponol (Umezawa et al.: J. Antibiotics 25, 239/1972/) and dopastine (Iinuma et awl.: J. Agr. Biol. Chem. 38, 2107/1974/) are known to exert strong dopamine-,B-hydroxylase inhibiting effects.

Subsequent examinations have shown that some of the known and commercially available drugs, such as hydralazine, methimazol and amphetamine, also possess dopamine-ss-hydroxylase inhibiting effects.

Most of rhe above compounds have, however, the disadvantage that although they possess dopamine-,B-hydroxylase inhibiting effects, they are rather toxic in prolonged treatments, thus they can be applied in therapy only in a restricted manner, if at all.

The new compounds according to the invention possess strong dopamine-P- hydroxylase inhibiting effects and are less toxic than the known compounds with similar activities. Consequently the new compounds can be applied to great advantage in therapy.

The dopamine-,ss-hydroxylase inhibiting effects of the new compounds according to the invention were examined by the following tests: The tests were performed on male Wister rats weighing 150 to 200 g. The dopamine-ss-hydroxylase inhibiting effects of the compounds were evaluated by determining the change in noradrenaline, dopamine and adrenaline levels of the cerebrum, heart, spleen and adrenol gland. The serotonine and 5-hydroxy-indolylacetic acid levels of the cerebrum were also determined. The measurements were performed as follows: The animals were decaptitated, the cerebrum, heart, spleen and adrenal gland were removed quickly and the organs were frozen by placing them onto a metal sheet cooled with drice ice. The frozen organs were stored for a maximum of one night at --20"C.

Determination of the adrenaline content of adrenal gland.

The adrenal glands were freed from fat and homogenized in 3.0 ml of ice-cold 0.4 N perchloric acid. The homogenized mixtures were centrifuged for 10 minutes at 00C at a speed of 3200 r.p.m. using a Janetzky K40 type centrifuge, 0.05 ml samples were taken from the supematant and the adrenaline level was determined directly by the method of Laverty et al. (Anal. Biochem. 22, 269/1968/).

Determination of the noradrenaline content of heart and spleen.

The organs were weighed in the frozen state and then homogenized in 5.0 ml of 0.4 N perchloric acid containing 0.05% of EDTA-Naa and 0.1% of Na,S,O,. The homogenized mixtures were centrifuged as described above for the treatment of the adrenal gland, the supernatants were decanted, and the pH was adjusted to 8.0 + 0.1 with a 0.1 molar tris buffer containing 20 g/l of NaOH and 25 g/l of EDTA-Na2.

100 mg of prepared Altos (Anton et al J. Pharm. Ther. 138, 360/1962/) were added to the samples, and the mixtures obtained were shaken mechanically for 20 minutes. Thereafter the Al2O., was washed with 2 X 10 ml of distilled water, and noradrenaline was eluted with 1.0 ml of 0.5 N perchloric acid. 0.5 ml samples of the eluate were applied for the determination of noradrenaline. Noradrenaline was determined according to the method of Shellenberger et al. (Anal. Biochem. 39, 356/ 1971/), with the following modifications of the basic procedure: 0.5 ml of 0.1 molar Na-K-phosphate buffer, containing 9 g/l of EDTA-Na2, were added to 0.5 ml of the eluate, and the catacholamines (noradrenaline in the examination of heart and spleen and noradrenaline and dopamine in the examination of the cerebrum) were oxidized with 0.1 ml of a 0.1 N iodine solution in 5% potassium iodide. After exactly 2 minutes oxidation was stopped by adding 0.25 ml of a 2.5% sodium sulfite solution in 4.4 N aqueous sodium hydroxide to the mixture. 2 minutes after the introduction of the alkaline sulfite solution 0.2 ml of concentrated acetic acid were added to the samples, upon which the pH decreased to 4.4 to 4.5. Thereafter the samples were placed for 5 minutes into a drying oven heated to 100"C, and then the samples were cooled with ice water. The fluorescence of noradrenaline was measured with an OPTON spectrophotometer at wavelengths of 380 nm (excitation) and 490 nm (emission).

Determination of the noradrenaline, dopamine, serotonine and 5-hydroxy-indolylacetic acid contents of brain.

The brains were homogenized in 10 parts by volume of 0.4 N perchloric acid.

The homogenized mixture was stored at--20"C overnight, thereafter it was thawed and centrifuged as described above. A sample of the homogenized mixture corresponding to 0.5 g of brain was removed, the pH of the sample was adjusted to 8.0+0.1 with 0.1 molar tris-buffer of the above composition, and the sample was processed as described above for the determination of the noradrenaline content of heart and spleen, with the difference that 1.5 mol of 0.05 N perchloric acid were applied as eluting agent. 0.5 ml of the eluate were applied to determine the the noradrenaline and dopamine contents. The measurement was performed as described above, with the difference that samples of 0.5 ml were applied for the recording of the fluorescence of noradrenaline. The residue was placed for 50 minutes into a drying oven heated to 100"C, thereafter the sample was cooled with ice water, and the fluorescence of dopamine was recorded at wavelengths of 325 nm (excitation) and 380 nm (emission).

In a further test series the serotonine and 5-hydroxy-indolylacetic acid contents were also determined, beside the determination of the noradrenaline and dopamine content, from the same sample. In this instance the brains were homogenized in 10 ml of 75% ethanol, 0.2 ml of EDTA-Na2 and 5% of ascorbic acid were added to the homogenized mixtures, and the homogenized mixtures were maintained at --200C overnight. The mixtures were then centrifuged as described above, and 5.0 ml samples of the supernatant were removed. The samples were diluted with equal volumes of distilled water, and poured onto ion exchange columns of 0.5 X 1.5 cm dimensions, filled with buffered "Amberlite" [registered Trade Mark] CG-30 (200 to 400 mesh). The columns were washed with 5 ml of distilled water followed by 1.0 ml of 0.2 N hydrochloric acid, and the first eluate and the aqueous washings were collected for the determination of 5-hydoxy-indolylacetic acid. Elution was continued with a further 1.2 ml of 0.2 N hydrochloric acid in order to remove noradrenaline, dopamine and serotonine. Samples of 0.3 ml were used for the determinations Noradrenaline and dopamine were determined by the method of Shellenberger, modified as described above, whereas serotonine was determined by the method of Curzon et al. (Brit. J. Pharmacol. 39, 653/1970/). The basic method was modified as follows: A 0.5% solution of ortho-phthal (di)aldehyde in absolute ethanol was diluted with 10 N hydrochloric acid to 50-fold of its original volume, and 0.6 ml of the resulting 0.01% ortho-phthal(di)aldehyde solution were added immediately to 0.5 ml of the serotonine-containing sample. The sample was placed into a hot water bath for 10 minutes, thereafter cooled with tap water, and the fluorescence was recorded at wavelengths of 360 nm (excitation) and 490 nm (emission).

5-Hydroxy-indolylacetic acid was determined from the mixture of the first eluate and the aqueous washings. 10 ml of distilled water and 0.2 ml of concentrated hydrochloric acid were added to the mixture, and the sample was poured onto a 0.8 X 4.0 cm column filled with Sephadex G-10. The column was washed with 15 ml of 0.1 N hydrochloric acid followed by 1.8 to 2.0 ml of 0.02 N aqueous ammonia, and then 5-hydroxy-indolylacetic acid was eluted with a further 2.0 ml of aqueous ammonia.

0.5 ml samples were used in the measurements, and the determination was performed according to the method of Korf et al. (Biochem. Pharmacol. 20, 659/1971/).

The test results are summarized in Table I. In the tests disulfiram, 2,2-dipyridyl, bis (1 methyl-4-homopiperazinyl-thiocarbonyl) -disulfide, sodium diethyldithiocarb amate and N-phenyl-N'-(2-thiazolyl)-thiourea were applied as reference substances.

The values indicated in Table 1 are the percentages in relation to the amine levels of the controls measured in the same tests (+ standard error). The statistical calculations were performed on a TPA/i type computer, using Student's t test.

The meanings of the abbreviations used in Table 1 are as follows: NA: noradrenaline DA: dopamine SE: serotonine 5-HIAA: 5-hydroxy-indolylacetic acid AD: adrenaline Comp.: compound Adm.: method of administration Dos.: dosage, mg/kg Time: period of treatment, hours a: 0.01 # p@ < 0.05 b: 0.001 @ < p < 0.01 d: p 1 < 0.001 M-1: 2- (N-butyl) -amino-cyclopent-1 -ene-thiocarboxylic acid-disulfide M-2: 2- (N-methoxyethyl) amino-cyclopent-1-ene-thiocarboxylic acid-disulfide M-3: 2- (N-cyclohexyl) -amino-cyclopent- 1-ene-thiocarboxylic acid-disulfide M-4: 2- (N-ethyl)-amino-cyclopent-1-ene-thiocarboxylic acid-disulfide M-5: 2- ( N-allyl) -amino-cyclopent- 1-ene-thiocarboxylic acid-disulfide DS: disulfiram [bis-diethylthiocarbamoyl)-disulfide] DDC-Na: sodium diethyldithiocarbamate 2,2-D: 2,2,-pyridyl FLA-63: bis!(1-methyl-4-homopiperazinyl)-thiocarbonyl-disulfide U- 14624: N-phenyl-N'- (2-thiazolyl)-thiourea n = number of animals.

TABLE 1 Amine levels [percentage in relation to the controls] Brain Heart Spleen Adrenal gland Comp. Adm. dos. Time n NA DA SE 5-HIAA NA NA AD M-1 i.p. 100 4 17 80.1 # 4.3a 118.3 # 5.7a - - 91.5 # 5.2 - 81.0 # 8.5a i.p. 200 4 6 70.9 # 5.2c 94.2 # 7.5 97.6 # 5.6@ 127.8 # 8.3a 108.5 # 9.4 114.5 # 28.2 91.7 # 4.3 i.p. 200 8 6 81.6 # 7.3 91.0 # 12.7 97.3 # 11.3 126.4 # 7.1 91.7 # 4.6 96.4 # 23.1 87.7 # 4.2 M-2 i.p. 100 4 6 41.9 # 2.7c 131.5 # 8.9b 113.3 # 2.8a 108.3 # 9.6 91.8 # 5.9 81.4 # 10.8 77.5 # 6.3a i.p. 200 4 6 39.6 # 4.9c 134.6 # 4.0c 112.8 # 5.6 150.9 # 15.4c 91.7 # 9.2 69.9 # 16.9 96.3 # 6.7 i.p. 200 8 6 28.5 # 1.4c 120.6 # 5.8a 106.0 # 7.5 161.4 # 10.0c 75.7 # 3.7a 61.9 # 9.9 97.0 # 7.9 p.o. 500 4 5 73.6 # 2.8a 114.5 # 2.4b 102.7 # 5.3 95.4 # 6.0 86.3 # 10.1 103.1 # 18.9 96.3 # 6.0 p.o. 500 8 5 51.2 # 2.8c 111.0 # 4.0 90.9 # 6.7 105.9 # 4.9 74.0 # 8.4a 101.0 # 14.3 88.1 # 5.1 M-3 i.p. 200 4 6 64.6 # 1.8c 124.2 # 4.0a 104.5 # 7.6 142.8 # 8.0c 94.7 # 6.8 83.2 # 8.9 109.0 # 2.3 i.p. 200 8 6 76.9 # 2.2c 116.2 # 3.3b 105.3 # 4.5 177.5 # 10.8c 89.5 # 3.0 68.7 # 6.7 105.6 # 3.3 M-4 i.p. 100 4 5 41.8 # 2.3c 99.0 # 5.22 106.7 # 2.2 - 92.9 # 3.3 64.1 # 7.6 123.4 # 4.6 i.p. 200 4 6 34.4 # 2.6c 134.9 # 5.4c 112.5 # 5.2 155.0 # 8.5c 97.8 # 8.8 85.0 # 10.8 97.3 # 4.1 i.p. 200 8 6 34.2 # 3.5c 121.7 # 6.1 103.9 # 7.4 195.4 # 4.8c 81.3 # 5.7 86.5 # 23.5 79.0 3.9c p.o. 500 4 5 83.9 # 4.8a 106.7 # 3.4 117.5 # 4.6b - 82.4 # 82. 125.4 # 12.4 121.4 # 13.7 p.o. 500 8 5 73.7 # 4.7a 92.6 # 4.0 91.2 # 0.9b - 97.5 # 5.6 64.6 # 12.4 107.5 # 8.9 M-5 i.p. 200 4 6 50.5 # 5.2c 123.6 # 8.1a 112.7 # 8.0 117.1 # 6.5 100.0 # 3.9 66.1 # 18.1 93.3 # 8.0 i.p. 200 8 6 64.5 # 4.4c 104.7 # 5.7 108.0 # 8.0 125.7 # 10.5 91.8 # 3.7 88.5 # 33.9 69.8 # 6.8a DS i.p. 200 4 22.5c 111 122 - 98 - 52c 400 4 24.1c 112 117 - 102 - 66c DDC-Na i.p. 400 64.1c 120 - 2,2-D i.p. 37.5 4 79.5b 116 - - 104 100 80a 75 4 41.2@ 95 100 58b - 63b FLA-63 i.p. 50 4 24.6 118 124b 134b 96 58c 43c U-14624 i.p. 200 4 31.6 121 137b 174c 106 111 72b The data of Table I clearly demonstrate that the new compounds according to the invention considerably decrease the noradrenaline level in the brain. Depending on the dosage, the method of administration and the duration of treatment, the extent of decrease is 50 to 70%. At the same time a considerable (20 to 30%) increase in dopamine level can also be observed. The increase of serotonine level is less significant, the 5-hydroxy-indolylacetic acid level increases, however, occasionally by 50 to 90%.

The noradrenaline levels of heart and spleen, and the adrenaline level of adrenal gland decrease as well, these decreases are, however, not always significant even for compounds strongly decreasing the cerebral noradrenaline level. This phenomenon can be attributed presumably to the fact that the catecholamine turn overs of these organs are slow, furthermore that adrenal gland possesses a relatively large depot of catecholamines (noradrenaline and adrenaline), and the missing nor adrenaline contents of spleen and heart are quickly supplemented by circulation.

A unequivocal decrease of catecholamine level cannot be observed in these organs with known dopamine- -hydroxylase inhibitors, either.

The toxicity data of the compounds according to the invention are listed in Table 2.

TABLE 2 Method of Compound Animal administration LDso mg/kg M-2 mice i.p. > 1500 M-3 mice i.p. > 1000 M-4 mice i.p. 1000-1500 M-5 mice i.p. > 1000 FLA-63 mice i.p. 150 212-D mice i.p. 280 rats i.p. A1150 Hydralazine mice i.p. 83 DS rats p.o. 8600 + 370 rabbits p.o. 1800 + 130 Dopastine mice i.p. 250 -- 500 i.p. 460 p.o. 750 Fusaric acid mice p.o. 230 + 25 Chlorofusaric acid mice p.o. 470+85 Oosponol mice i.p. 40 p.o. 280 u-14624 mice i.p. w680 p.o. > 1000 The data of Table 2 indicates that the LDso values of the new compounds according to the invention are very favourable, thus these compounds can be adminis tered for prolonged periods.

The new disulfide compounds of the general formula (I) can, for example, be prepared, according to the invention, by oxidizing a corresponding 2-amino-cyclopent l-ene-1-dithiocarboxylic acids of formula (II), wherein R is as defined above.

Oxidation is performed with an oxidizing agent capable of forming disulfides, such as, for example, hydrogen peroxide or potassium permanganate According to a preferred method of the invention the starting dithiocarboxylic acid is dissolved or supended in a suitable solvent or diluent, the mixture is rendered alkaline, and then the disulfide is oxidized by adding an acid and hydrogen peroxide to the mixture.

As solvent or diluent preferably water is applied. The reaction mixture is rendered alkaline preferably by adding an alkali metal hydroxide, such as e.g. sodium hydroxide thereto.

The acid applied is preferably a mineral acid, such as e.g. sulfuric acid.

The starting substances are partly known (J. Org. Chem. 37, 1727/1972/).

The preparation of the starting substances not hitherto known is described in our co-pending Application No. 54172/77 (Serial No. 1582403) of even date herewith.

The invention is elucidated in detail by the aid of the following not-limiting Examples.

Example 1.

2- (N-Allyl) \ -amino-cyclopent- 1 -ene-] -thiocarboxylic acid-disulfide.

6.0 g (0.015 moles) of sodium hydroxide are added, as a 10% aqueous solution, to a suspension of 2.98 g (0.015 moles) of 2-(N-allyl)-amino-cyclopent-1-ene-1- dithiocarboxylic acid in 30 ml of water. The mixture obtained is shaken for about 10 minutes. A solution is prepared from 3 ml of water, 0.9 g (0.0075 moles) of concentrated sulfuric acid and 0.9 g (0.0075 moles + 10%) of 30% hydrogen peroxide, and this solution is added in portions, at 200C, to the above alkaline mixture. The resultant mixture is shaken for a further 3 hours and thereafter the precipitate obtained is filtered off, washed with water and dried under an I.R. lamp.

The title compound, melting at 140-1410C, is obtained with a yield of 84.4%.

Analysis: Calculated: S: 32.3% N: 7.08% Found: S: 31.84% N: 6.80% Example 2.

2-(N-Ethyl) -amino-cyclopent-1-ene-1-thiocarboxylic acid-disulphite.

12.0 g (0.03 moles) of sodium hydroxide are added, as a 10% aqueous solution, to a suspension of 5.6 g (0.03 moles) of 2-(N-ethyl)-amino-cyclopent-1-ene-1 dithiocarboxylic acid in 60 ml of water. The mixture obtained is shaken for some minutes. A solution is prepared from 8 ml of water, 1.65 g (0.016 moles) of concentrated sulfuric acid and 1.86 g of 30% hydrogen peroxide, and this solution is added in portions, at about 200 C, to the alkaline solution obtained above. The mixture thus formed is shaken for an additional 3 hours and thereafter the solids are filtered off, washed with water and dried under an I.R. lamp. The crude product is dissolved in a 1:3 mixture of chloroform and benzene. The resultant solution is decolourized with activated carbon, filtered, and the filtrate is stored in a refrigerator overnight.

The crystals thus obtained are filtered off, washed with benzene and dried in air. The title compound, melting at 150-1520C, is obtained with a yield of 30%.

Analysis: Calculated: S: 34.4% N: 7.53% Found: S: 34.1% N: 7.45 /O Example 3.

2-(N-Methoxyethyl ) -amino-1-cyclopent-1-ene- 1-thiocarboxylic acid-disulfide.

5.0 g (0.0125 moles) of sodium hydroxide are added in portions, as a 10% aqueous solution, to a suspension of 2.7 g (0.0125 moles) of 2-(N-methoxyethyl)amino-1-cyclopent-1-ene-dithiocarboxylic acid in 27 ml of water at a temperature of about 200 C. The mixture obtained is shaken for some minutes. A solution is prepared from 3 ml of water, 0.66 g (0.0067 moles) of concentrated sulfuric acid and 0.77 g (0.0067 moles) of 30% hydrogen peroxide, and this solution is added to the above obtained alkaline mixture. The resultant mixture is shaken for 3 hours and then allowed to stand overnight. The solids are filtered off, washed with water and dried under an I.R. lamp. The title compound, melting at 132-1390C with decomposition, is obtained with a yield of 48.2%.

Analysis: Calculated: S: 29.65% N: 6.48% Found: S: 29.18% N: 6*39% Example 4.

2- (N-Cyclohexyl) -amino-cyclopent-1-ene-1-thiocarboxylic acid-disulfide.

6.0 g (0.015 moles) of sodium hydroxide are added, as a 10% aqueous solution, to a suspension of 3.6 g (0.015 moles) of 2-(N-cyclohexyl)-amino-cyclopent-1-ene-1dichlocarboxylic acid in 40 ml of water. The mixture obtained is shaken for 10 minutes. A solution is prepared from 5 ml of water, 0.8 g of concentrated sulfuric acid and 0.9 g of 30% hydrogen peroxide, and this solution is added at about 20 C to the above obtained alkaline mixture. The resultant mixture is shaken for 4 hours and the solids are filtered off, washed with water, and dried under an I.R. lamp The title compound, melting at 148-1520C, is obtained with a yield of 64.6%.

Claims (11)

Analysis: Calculated: S: 26.55% N: 5.83 /c Found: S: 23.67% N: 5.3 /c WHAT WE CLAIM IS:-

1. Compounds of general formula (I),

wherein R represents a C1-6 alkyl group having optionally a C1-4 alkoxy, hydroxy, carboxy and/or amino substituent, a C2-@ alkenyl group or a C2-8 cycloalkyl group.

2. 2-(N-Butvl) -amino-cyclopent-1-ene-thiocarboxylic acid-disulfide.

3. 2-(N-Methoxyethyl)-amino-cyclopent-1-ene-thiocarboxylic acid-disulfide.

4. 2-(N-Cyclohexyl)-amino-cyclopent-1-ene-thiocarboxylic acid-disulfide.

5. 2-(N-Ethyl)-amino-cyclopent-1-ene-thiocarboxylic acid disulfide.

6. 2- (N-Allyl) -amino-cyclopent-1-ene-thiocarboxylic acid-disulfide.

7. A pharmaceutical composition comprising, as active ingredient, at least one compound of formula (I) as defined in claim 1 in association with a pharmaceutical adjuvant and/or auxiliary agent.

8. A process for the preparation of a compound of general formula (I) as defined in claim 1 which comprises ses oxidizing of a compound of general formula (I) as (II),

(wherein R is as defined in claim 1) whereby the desired compound of formula (I) is obtained.

9. A process as claimed inn claim 8 substantially as hereinbefore described.

10. A process as claimed in claim 8 substantially as hereinbefore described with reference to the Examples.

11. Compounds of general formula (I) as defined in claim 1 whenever prepared by a process as claimed in any one of claims 8 to 10.