IE41805B1 - Thiazolidinone-acetic acid derivatives - Google Patents

Abstract

The present invention is concerned with new thiazolidinone-acetic acid derivatives and with the preparation thereof.

Description

The present invention is concerned with new thiazolidinone-acetic acid derivatives and with the preparation thereof.

The new thiazolidinone-acetic acid derivatives according to the present invention are compounds of the general formula:- wherein is an alkyl radical containing up to 4 carbon atoms; and the pharmacologically compatible salts thereof.

United States Patent Specifications Nos. 3,182,603 and 3,072,653, as well as Liebigs Annalen der Chemie, 665. 150— 165/1963, describe certain substituted 2-methylene-thiazolidin4-ones which have an analgesic, sedative and anti-inflammatory action. Some halogen-substituted compounds of. this type are also known to possess a certain gall-stimulating and diuretic action. These previously known biologically-active compounds differ from the compounds’of the present invention by the absence of a free carboxyl group.

It is known that 3~methyl analogues of compounds unsubstituted in the 5-position and having a free carboxyl group can be prepared by the gentle saponification of the corresponding ethyl esters. Attempts to prepare, in this manner, compounds of general formula (I), which possess a basic substituent in the 5-position, were unsuccessful and, in every case, resulted in an isomerisation or a destruction of the ring system. This was expected since these compounds simultaneously have the structure of cyclic enamine carbonyl compounds, of ketene-S,N-acetals and of thio-aminals. The reactivity and sensitivity of such groupings to alkaline and acidic influences is known from the literature (see Liebigs ! Ann. d. Chemie, 725. 66—68/1969).

We have now found that acid-catalysed alkyl oxygen splitting is possible when an ester of the general formula :- wherein Rj has the same meaning as above and R2 is an alkyl radical containing 2 to 6 carbon atoms, is treated at a temperature below ambient temperature with an approximately 40 to 5θ$ solution of hydrogen bromide in an aliphatic carboxylic acid containing up to 5 carbon atoms and the free amine acid (I), after removal of the acid mixture, is isolated. The range of the acid solution is mainly limited by the solubility of hydrogen bromide in the carboxylic acid.

Acetic acid is preferred but other aliphatic carboxylic - 3 41805 acids containing ap to 5 carbons, such as propionic acid or butyric acid, may also be used.

Under these conditions, the alkyl radical is gently split off as an alkene or an alkyl bromide. In spite of the high acid concentration, neither isomerisation, nor destruction, nor the expected decarboxylation of the free acid formed takes place.

The radicals are straight-chained or branched alkyl radicals containing up to 4 carbon atoms, i.e. methyl, ethyl, n-propyl, isopropyl> n-butyl, isobutyl and tert.ybutyl radicals.

The pharmacologically compatible salts are preferably the alkali metal salts, especially the potassium salts, as well as the alkaline earth metal salts. These can be prepa15 red by reacting the free amino acids (X) with appropriate metal hydroxides or carbonates.

The alkyl-oxygen splitting according to the present invention can be carried out by introducing the compounds of general formula (II), at a temperature of -5°C. to +5°C., into a 40% solution of hydrogen bromide in an aliphatic carboxylic acid containing up to 5 carbon atoms and preferably in glacial acetic acid, splitting off the alkyl radical being initiated by slowly warming the reaction mixture to ambient temperature, i.e. to 15—25°C. After completion of the reaction, which usually takes about 1 to 72 hours, the acid mixture is removed in a vacuum and the residue is digested with water. The free amino acids (I) can then be precipitated otit at pH 6 and isolated.

For thermodynamic reasons, the acids of the present invention preferably have the HOOC/N—trans-configuration - 4 41805 with regard to the exocyclic double bond (Z-configuration).

If the free acids are subsequently to be converted to their pharmacologically compatible salts, for example their potassium salts, then the compounds (I) can be introduced into an equimolar amount of an aqueous solution of an appropriate bicarbonate or carbonate solution, which contains 1—15# of an alcohol containing up to 4 carbon atoms, at a temperature of about 40—60°C., whereafter the salt isolated by drying and preferably by freeze-drying.

The compounds of general formula (II) used as startf ing materials are known or can be prepared in a manner analogous to that used for the preparation of the known compounds, for example, by reacting the compounds described in U.S. Patent Specification No. 3,072,653 with N-bromosuccinimide and then with piperidine.

The compounds of general formula (I) possess valuable pharmacological activities, especially a diuretic activity, and are characterised by an interesting spectrum of activity not previously known for diuretic compounds. Furthermore, the outstanding water-solubility of the alkali metal salts at a physiologically optimum pH value permits a wide field of use, especially in the therapy of acute lung and brain oedema and in the treatment of acute kidney failure; it is also possible to increase the flow of blood through the kidneys by 30—5θ$, without reducing the filtration rate, whereas previously known diuretics do not substantially influence the flow of blood through the kidneys. Furthermore, the known diuretics, in contradistinction to the compounds of the present invention, reduce the filtration rate.

As animal experiments on dogs have shown, the com5 pounds according to the present invention, in contradistinction to the commercially available diuretics, in the case of experimentally equally adjusted diuretics, scarcely influence the excretion of potassium. Furthermore, the new compounds (I) have a remarkably low toxicity and, in addition to their diuretic action, also exhibit an outstanding anti-hypertensive effect. In addition, a regulatory effect on the body temperature has been observed.

The new compounds of general formula (X) according to the present invention, as well as their pharmacologicallycompatible salts, can be administered ertterally or parenterally, which the corresponding esters cannot, in admixture with liquid or solid pharmaceutical diluents or carriers.

As injection medium, it is particularly preferred to use water which contains the conventional additives for injection solutions, for example stabilising agents, solubilising agents and/or buffers. Compositions suitable for oral administration can, if desired, contain flavouring and/or sweetening agents.

The dosage depends upon the nature and severity of the disease to be treated. The individual oral dose is usually between 10 and 500 mg. and the subcutaneously or .intraveneously administered individual dose can be between about 5 to 200 mg.

The following Examples are given for the purpose of illustrating the present invention:Example 1. 3-Methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene-acetic acid Variant A: g. tert.-Butyl 3 - methyl - 4 - oxo - 5 - piperidino - thiazolidin - 2 - ylidene - acetate are introduced, at -6.41805 -3 to 0°C., into 100 cc. of a 40% solution of hydrogen bromide in acetic acid. The reaction mixture is slowly warmed to 20°C. and then left at this temperature for 1.5 hours. Subsequently, the greater part of the hydrogen bromide-acetic acid phase is removed under waterpump vacuum at a bath temperature of 25—40°C. The residue is digested with 0.5 liter water and the pH adjusted to 6.0 with sodium bicarbonate. Foaming can be inhibited by the addition of ether. The solid product is filtered off with suction and dried in a vacuum over anhydrous calcium chloride. Any remaining starting material can easily be separated by dissolving in cold 2 N aqueous sodium carbonate solution, filtering and acidifying the filtrate with dilute acetic acid. There are obtained 25 g. (56% of theory) 3 - methyl - 4 - oxo - 5 - piperidinothiazolidin - 2 - ylidene - acetic acid which melts, with decomposition at 163.9°C., after recrystallisation from methanol or ethanol.

Analysis; CUH16N2°3S (MiW· 256-32) calc.: C 51-54%; H 6.29%; N 10.93%; S 12.51% found: C 51.67%; H 6.12%; N 10.77%; S 12.34% The tert.-butyl 3 - methyl - 4 - oxo - 5 - piperidino - thiazolidin - 2 - ylidene - acetate used as starting material is prepared as follows: 141 g. ethyl tert.-butyl-cyanoacetate (b.p. 6O°C./1.5 20 mm.Hg.; η 1.4180) and 120 cc. ethyl thioglycolate are dissolved in 1 liter benzene, mixed with 140 cc, triethylamine and stirred for 72 hours at ambient temperature. The bulk of the solvent is then distilled off in a vacuum and the solid residue is separated and washed with a little benzene on a - 7 41805 suction filter. There are obtained, after air drying, 134 g. (79# of theory) tert.-butyl 4 - oxo - thiazolidin - 2ylidene - acetate which, after recrystallisation from isopropanol, melts at 177.4°C. 63.5 g. tert.-butyl 4 - oxo - thiazolidin - 2 - ylidene - acetate and 41.4 g. potassium carbonate are suspended in 250 cc. methanol. The reaction mixture is heated to reflux temperature and mixed dropwise with a solution of 37.8 g. dimethyl sulphate in 50 cc. methanol. After an hour, the reaction is finished. The solvent is removed in a vacuum and the residue is introduced into 0.5 litre water. The crude tert.-butyl 3 - methyl - 4 - oxo - thiazolidin- 2 - ylideneacetate is taken up in ether and the ethereal phase is then dried and evaporated and the residue is recrystallised from cyclohexane. There are obtained 56 g. (82# of theory) tert.butyl 3 - methyl - 4 - oxo - thiazolidin - 2- ylidene-acetate, which melts at 77.4°C. 36.8 g. tert.-butyl 3 - methyl - 4 - oxo - thiazolidin2 - ylidene - acetate are dissolved in 700 cc. anhydrous carbon tetrachloride. Under reflux conditions, there is first introduced 0.3 g. azo - bis'- - -isobutyrie acid nitrile and then, within a period of 10 minutes, 29 g. N - bromosuccinimide. After boiling under reflux for 20 minutes, the reaction mixture is filtered and the filtrate is evapora25 ted to dryness in a vacuum. The oily residue is taken up in 0.5 litre benzene, cooled to +5°C. and mixed in several portions with 32 cc. piperidine. After standing for several hours at ambient temperature, the piperidine hydrobromide formed is separated off and the filtrate evaporated in a vacuum. After the addition of 50 cc. isopropanol, the mix8 ture is cooled to 0°C. The precipitated tert. - butyl 3inethyl - 4 oxo- 5 - piperidino - thiazolidin - 2 - ylidene - acetate is recrystallised from isopropanol. The yield is 21.5 S· (38% of theory over 2 stages) and the product melts at 154°C.

Analysis: C15H14N2°3S (M'W· 312.41) calc.: C 57.66%; H 7.74%; N 8.97%; S 10.26% found: C 57.56%; H 7.80%; N 9.15%; S 10.33% Variant B: 100 g Ethyl 3 - methyl - 4 - oxo - 5 - piperidinothiazolidin - 2 - ylidene - acetate are introduced, while stirring at 0°C., into 200 ce. of a 40% solution of hydrogen bromide in acetic acid. The vessel containing the reaction mixture is closed with a Bunsen valve (in order to avoid an ι overpressure of ethylene) and the reaction mixture is stirred with a magnetic stirrer for 65 hours at ambient temperature. The reaction mixture is then worked up in the manner described in Variant A. There are obtained 47*0 g. (53% of theory) 3methyl - 4 - oxo - 5 - piperidino - thiazolidin - 2 - ylideneacetic acid which melts, with decomposition, at 163.9°C.

Example 2.

Potassium 3 - methyl - 4 - oxo - 5 - piperidino - thiazolidin2 - ylidene - acetate .1 g. (0,02 mol) 3 - methyl - 4 - oxo - 5 - piperidino - thiazolidin - 2 - ylidene - acetic acid are pasted with 10% ethanol and digested with 50 ml. of a 4% aqueous solution of potassium bicarbonate. The reaction mixture is briefly heated on a water-bath to 50°C. until the evolution of gas ceases and complete solution is obtained. The reaction mixture is then cooled to 15—20°C. and water is removed in a rotary evaporator at 0.05 mm.Hg. pressure under freeze drying conditions. The residue is recrystallised from isopropanol. There are obtained 3.5 g. (59*3% of theory) of potassium 3 - methyl - 4 - oxo - 5 - piperidino - thiazolidin5 2 - ylidene - acetate in the form of colourless crystals which decompose at 150°C.

Example 3· - Ethyl - 4 - oxo - 5 - piperidino - thiazolidin - 2ylidene - acetic acid 50' g. ethyl 3 - ethyl - 4 - oxo - 5 - piperidinothiazolidin - 2 - ylidene - acetate are reacted and worked up in a manner analogous to that described in Example 1.

There are obtained 12.5 g. (28# of theory) 3 - ethyl - 4oxo - 5 - piperidino - thiazolidin - 2 - ylidene - acetic acid which, after recrystallisation from methanol, melts at 148°C. (Melting takes place with decarboxylation and is somewhat dependent upon the rate of heating up).

Analysis: C12H18°3S (M-W· 270-35) calcs: C 53-31%; H 6.71%; N 10.36%; S 11.86% found: C 53-41%; H 6.59%; N 10.19%; S 11.72% Tho following compounds are prepared in an analogous manner: - propyl - 4 - oxo - 5 - piperidino - thiazolidin25 2 - ylidene - acetic acid; - n - butyl - 4 - oxo - 5 - piperidino - thiazolidin - ylidene - acetic acid; and - isobutyl - 4 - oxo - 5 - piperidino - thiazolidin2 - ylidene - acetic acid.

Example 4· - Methyl - 4 - oxo - 5 - piperidino - thiazolidin - 2ylidene - acetic acid g. Ethyl 3 - methyl - 4 - oxo - 5 - piperidino5 thiazolidin - 2 - ylidene - acetate are introduced, while stirring at 0—5°C.} into 50 cc. of a 40$ solution of hydrogen bromide in propionic acid. The reaction mixture is worked up as described in Example 1. Variant B, the reaction Lime being 72 hours. There are obtained 7.0 g (39$ of theory) 3 - methyl - 4 - oxo - 5 - piperidino - thiazolidin2 - ylidene- acetic acid; m.p. 163°C. (decomp.).

Example 5.

- Methyl - 4 - oxo - 5 - piperidino -» thiazolidin - 2ylidene - acetic acid g. ethyl 3-methyl-4-oxo-5-piperidino - thiazolidin2 - ylidene - acetate are introduced, while stirring at 0—5°C., into 50 cc. of a 40$ solution of hydrogen bromide in butyric acid. The reaction mixture is worked up as described in Example 1, Variant B, the reaction time being 70 hours.

There are obtained 6.9 g. (39$ of theory) 3 - methyl - 4oxo - 5 - piperidino - thiazolidin - 2 - ylidene - acetic acid; m.p. I63—164°C. (decomp.).

The compounds of the present invention exhibit marked pharmaceutical advantages when compared with ethyl 3 - methyl2 ct 4 - oxo - 5 - piperidino - Δ ’ - thiazolidine acetate known from U.S. Patent Specification No. 3,072,653.

The compounds of the present invention can be administered by injection and can, therefore, be used in medical emergencies, such as acute lung and brain oedema. The com30 pounds of the present invention are more potent than the above-mentioned known thiazolidine acetate after intragastric and intravenous administration. The compounds of the present invention have little effect on potassium excretion and even less than that of the commerically available Furosemide, which is known to have little effect on potassium excretion.

The following Examples illustrate the improved activities of the compounds of the present invention, when compared with previously known compounds (Etozolin is ethyl 3 - methyl4 - oxo - 5 - piperidino - Δ ’ - thiazolidine acetate and 3282 is 3 -* Methyl - 4 - oxo - 5 - piperidino - thiazolidin2 - ylidene acetic acid):Example 6.

Diuresis 1. Experiments by intragastric administration.

Method: Experiments were carried out in 5 unanaesthetised adult female Beagle dogs, weighing 15 to 22 kg., which were trained to lie on a table without fixation. The animals were not episiotomised. A rubber catheter was introduced into the bladder and excreted urine was collected separately for each animal, the volume being measured at 30 minute intervals. After a constant urine flow was achieved, the test substances were administered by a stomach tube. The diuretics were diluted with saline solution so that a constant volume of 25 ml./kg. was reached. Three animals received the test substances and two served as controls. The lowest dose of the diuretics administered was 1.56 mg./kg. Dosages were increased by a factor of 2 up to 50 mg./kg.

Resu I t.s: Tab]e 1: Comparison oi the maximal achievable effects of Etozolin and 3282 on the diuresis of conscious dogs after intragastric administration.

Test substance Dose mg./kg. ml·/animal/ min. Etozolin 25.0 7.8 3282 25.0 10.9 As can be seen from Table 1, the maximal diuretic effect of both substances is reached after 25.0 mg,/kg. An increase of the dose does not result in a further increase of urine excretion. The maximal achievable effect of 3282 is, however, far higher than that of Etozolin. 2. Experiments by intravenous administration.

Method; Experiments were performed in male and female mongrel dogs, anaesthetised with pentsbaribital. The body weight was between 9 and 11 kg. After laparotomy, the proximal part of the ureters was canulated and the urine excreted by each kidney collected at intervals of 10 minutes. Arterial and venous pressure were recorded throughout the experiment. Initially, 1.5 ml./kg. min. of a warm saline solution were infused for 1.5 hours. After a constant urine flow was reached, the diuretics were injected into the femoral vein. The initial dose was 2,0 mg./kg., which was increased by a factor of 2 up to 64.Ο mg./kg. Two animals were used for each dosage level.

As is shown by Figures 1 and 2 of the accompanying drawings, there is a linear dosage dependent effect after the administration of 3282 (r = 0.8799). Following 32.0 mg./kg., the urine excretion is increased to 16 ml./minute - 13 41805 per animal. The dosage dependency is less significant in the case of Etozolin (r = 0.5583), this substance being far less active: following the administration of 32.0 mg./kg., urine flow is only increased to 2.25 ml./minute per animal.

Example 7.

Influence on potassium excretion Method: A total of 19 clearance experiments in 8 female dogs and 1 male dog, weighing from 17 to 25 kg., were carried out. Animals were anaesthetised with 30.0 mg./kg. pentabarbitol intravenously.

At the beginning of the experiment, one litre saline solution was infused within the course of one hour. Xn the urine which was collected by using a bladder catheter, in addition to other parameters, the potassium and sodium concentrations were determined by flame photometry.

Results: The two lines shown in each of Figures 3 and 4 of the ι accompanying drawings bound all the results of the clearance experiments with 3282 which could.be used for statistical evaluation. From these lines, it is obvious that, with higher amounts of sodium excreted, potassium excretion is increased much more with Furosemide than with 3282.

Example 8.

Acute Toxicity.

The acute toxicity of 3282 is very favourable. In experiments on rats, in which 3282 was Injected into the tail vein, no deaths were observed up to dosages of 1,000 mg./kg. (higher dosages were not used). Thus, the intravenous toxicity of 3282 is by far more favourable than that of Etoxolin, the - 14 41805 of' Etozolin in rats being 56.6 mg./kg. .i.v. (confidence limits: 45·9—69.5 mg./kg.).

In experiments on mice, in which 3282 was administered intragastrically as an aqueous solution,none of the animals died up to dosages of 2,250 mg./kg. within 48 hours.

Claims (15)

1. Thiazolidinone-acetic acid derivatives of the general formula:HOOC-CH = C lO -Cl·-] I c=o 5 wherein is an alkyl radical containing up to 4 carbon atoms and the physiologically-compatible salts thereof.

2. 3 - Methyl - 4 - oxo - 5 - piperidino - thiazolidin 2 - ylidene - acetic acid.

3. Potassium 3 - methyl - 4 - oxo - 5 - piperidino10 thiazolidin - 2 - ylidene - acetate.

4. 3 - Ethyl - 4 - oxo - 5 - piperidino - thiazolidin2 - ylidene - acetic acid.

5. 3 - Propyl - 4 - oxo - 5 - piperidino - thiazolidin 2 - ylidene - acetic acid. 15

6. 3 - n - Butyl - 4 - oxo - 5 - piperidino thiazolidin - 2 - ylidene - acetic acid,

7. 3 - Isobutyl - 4 - oxo - 5 - piperidino - thiazolidin - 2 - ylidene - acetic acid.

8. A process for the preparation of compounds Of 20 the general formula given in claim 1, wherein a compound of the general formulajH Ί S -C—N r 2 ooc-ch C G=0 \/ Ν' I Ri - 16 41805 in which R^ has the same meaning as in claim 1 and R 2 is an alkyl radical containing 2 to 6 carbon atoms, is treated at a temperature below ambient temperature with an approximately 40 to 50% solution of hydrogen bromide in an aliphatic carboxy]ic acid containing up to 5 carbon atoms, whereafter Lhe acid mixture is removed and the desired amino aci.d is isolated,

9. A process according to claim 8, wherein the treatment Ls carried out at a temperature of -5°C. to +25°C.

10. A process according to claim 8 or Q, wherein the residue obtained after removal of the acid mixture is digested with watei· and adjusted to a pH of 6 to precipitate out the desired acid.

11. A process according to any of claims 8 to 10, wherein the aliphatic carboxylic acid used is acetic acid, propionic acid or butyric acid.

12. A process according to any of claims 8 to 11, wherein the acid obtained is reacted with a physiologically compatible base to give the corresponding salt.

13. A process for the preparation of compounds according to claim 1, substantially as hereinbefore described and exemplified.

14. Compounds according to claim 1, whenever prepared by the process according to any of claims 8 to 13.

15. Pharmaceutical compositions, comprising at least one compound according to claim 1, in admixture with a solid or liquid pharmaceutical diluent or carrier.