DK142873B - Analogous process for preparing 5-phenyl-thiazolidin-4-one derivatives. - Google Patents

Description

(11) PUBLICATION 142873 DENMARK (bi) int.ci.3 c 07 o 277/34 (21) Note 5075/75 (22) Filed on 11 · HOV. 1975 (24) Race day 1 1. NOV. 1 975 (44) The application submitted and the petition published on 1 6 · fsb «1 9o1

DIRECTORATE OF

PATENT AND TRADE MARKET (30) Priority book from the (71) WARNER-LAMBERT COMPANY, 201 Tabor Road, Morria Plalna, New Jersey 07950, US.

(72) Inventor: Manfred Franz Reinhold Herrmann, 7811 St. Peter, 25 Wolfaweg, DE: Gerhard £ atz ± nger, 7809 Denzlingen, Im Mattenbuehl 7, DE.

(74) Plenipotentiary:

The engineering company Budde, Schou & Co.

(54) Analogous release procedure for the preparation of 5-phenyl-thiazolidin-4-one derivatives.

The present invention relates to an analogous process for the preparation of novel pharmacologically active 5-phenyl-thiazolidin-4-one derivatives which are particularly useful in the treatment of hepatic dysfunction.

It is known that certain substituted 2-methylene-thiazolidine-4-ones have analgesic, sedative and anti-inflammatory effects, as described in U.S. Patent Nos. 3,182,063 and 3,072,653 and Liebigs Annalen der Chemie, 665, 150-165 (1963). Furthermore, it is known that some of these compounds have some choleretic and diuretic effect. The compounds of this invention differ from the known compounds in that they are substituted at the 5-position with a phenyl group.

2 142873

The introduction of this group and the modification of the substituents have surprisingly been found to lead to compounds which are valuable pharmaceuticals with excellent hepatoprotective and curative anti-hepatotoxic effects, and which, especially with prolonged treatment, exhibit no undesirable choleretic or other side effect. Thus, the compounds of this invention are particularly useful for long-term liver therapy.

The 5-phenyl-thiazolidin-4-ones disclosed herein have the general formula 0 ΐ ~ 0 1 "In im R-O-C-CH = CC = 0 1 '\ N / έ2 1 2 where R is C1-6 alkyl, R is C1-6 alkyl or C-aralkyl, and R3 is C1 _g-alkyl or Cyg-aralkyl or a basic group of the formula / r4 - (CH ~) -N ς 2 m \ r5 x _ K28 (n> R-0-C-CH = CC = 0 R2 1 2 where R and R have the meanings given above and X is a hydrogen atom or an alkali metal atom, is reacted with a compound of general formula V - R 3 (III) 3 where V represents a reaction capable ester group and R is as above 3 for and when R in the compound formed is a basic group, the compound is optionally converted into an acid addition salt thereof.

The reactive ester groups V may be, for example, halides or sulfates.

The process is usually carried out by dissolving a 2a suitable 3-alkyl-5-phenyl-4-oxo - [beta] -thiazolidine acetic acid ester in a lower aliphatic alcohol, e.g. ethanol or tert-butanol, after which, depending on the reactivity of the radical to be introduced, either directly reacted with compounds of formula (III) in the presence of an acid binder or converted by an alkali metal alcoholate into the corresponding alcohol to the intermediate alkali metal salt which is then reacted with a compound of formula (III). The reaction is preferably carried out at a temperature of 60-100 ° C and is usually completed after 1-5 hours.

The starting material of the general formula (II) may be prepared by reacting a compound of the general formula o-CH - SH (IV) CO - OR 4 wherein R 4 represents a C 1-6 alkyl group, with a nitrile of the general formula NC - CH 2 - CO - 0 - R1 (V) wherein R1 has the meaning given above, in the presence of a basic catalyst to form a compound of the general formula 4 (II) - 'ίνϊ)

R-O-C-CH = C C = 0 K

H

wherein R 1 is as defined above, which is then alkylated or benzylated in the more acidic 3-position with appropriate reactive esters, e.g. alkyl or benzyl halides, after which the compound is either converted to the 5-alkali metal salt in a suitable alkaline medium or reacted in an inert medium with a free halogen, preferably bromine.

As inert solvents, chlorinated hydrocarbons, e.g. carbon tetrachloride. The bromination can be carried out directly with free bromine or with N-bromosuccinimide. The reaction time is usually approx. 1- approx. 2 hours at temperatures between approx.

50 and 80 ° C. The compounds of the general formula (VI) are also novel compounds.

2

The introduction of the group R can be carried out at a temperature between approx. 60 and 100 ° C and is usually carried out in a polar solvent e.g. ethanol or isopropanol, by adding a molar amount or excess of an acid acceptor, e.g. pyridine, triethylamine or potassium carbonate. The reaction time is approx. 1-5 hours.

The cyclo condensation of the compounds of formula (IV) and (V) is carried out analogously to the process described in the specification of U.S. Patent Nos. 3,182,063 and 3,072,653.

When the compounds of formula (I) contain a basic amino group, pharmacologically acceptable salts can be prepared in the usual manner, e.g. by neutralizing the free base with pharmacologically acceptable inorganic or organic acids.

The compounds of general formula (I) and their salts may be administered enterally or parenterally in admixture with conventional solid or liquid pharmaceutical diluents or carriers. As an injection medium, it is preferred to use water containing the additives usual for injection solutions, e.g. stabilizers, solubilizers or buffers. Compositions for oral administration may contain flavorings and / or sweeteners.

The dosage of the compounds of this invention depends on the nature and severity of the disease. The individual oral dose is usually of the order of approx. 50 to 500 mg.

The process according to the invention is explained in more detail in the following examples.

5 142873

Example 1 O n

Ethyl 3-methyl-5-ethyl-5-phenyl-4-oxo-A '-thlazolidine acetate

A solution of sodium tert-butyrate is prepared by dissolving 1/2 g (0/05 mol) of sodium shavings in 150 ml of anhydrous boiling tert-butanol.

2 Q

To this solution is added 14 g of ethyl 3-methyl-5-phenyl-4-oxo-A '' -thiazolidine acetate and then a solution of 20 ml of ethyl iodide in 100 ml of anhydrous ethanol is added. After refluxing for 45 minutes, a yellow solution is formed. After an additional 45 minutes, all solvent is evaporated in vacuo and the residue is partitioned between 0.5 liters of water and 100 ml of ether. The ether phase is dried and distilled, and the resulting residue is distilled. At a boiling point of 200 ° C / 1 mm Hg, ethyl 3-methyl-5-ethyl-5-phenyl-4-9 R-oxo-A '-thiazolidine acetate is obtained as a high viscous yellow oil.

IR spectrum: 1712 cm -1 (s, lactam ring), 1688 cm (s, α, β-unsaturated -1 -1 -1 ester), 1570 cm (CH = C), 1180 cm (s, C-0 asymmetry) , 1040 cm 2 (m, C-0 symmetry), 795 cm 2 (m, HC =), 695 cm 2 (m, phenyl).

Analysis for C ^ gHH gNO ^S (mol. Weight 305.39): C *H% N% S%

Calculated 62.93 6.27 4.58 10.50

Found 62.70 6.29 4.75 10.29

The compounds used as starting materials are prepared as follows:

To a solution of 10.6 g (0.1 mole) of triethylamine in 210 ml of anhydrous benzene was quickly added a mixture of 11.9 g (0.1 mole) of ethyl cyanoacetate and 18.2 g (0.1 mole) of methyl -a-mercaptophenyl acetate, after which the reaction mixture is stirred for 18 hours at room temperature.

Part of the reaction product gradually precipitates in the form of plate-shaped crystals which are isolated. The reaction mixture is evaporated to dryness in vacuo and the residue together with the precipitated product is recrystallized from benzene. 14.6 g (55.5% of theory) of ethyl 5- 2-o-phenyl-4-oxo-A '-thiazolidine acetate are obtained, m.p. 177-178 ° C.

2 Q

n-Butyl-5-phenyl-4-oxo-A '-thiazolidine acetate is prepared in an analogous manner. From 0.1 mole of the reactants 21.0 g (72% of theory) of the product is obtained, which after recrystallization from acetate-water melts at 137 ° C.

9 rt 15.8 g (0.06 mol) of ethyl 5-phenyl-4-oxo-A '-thiazolidine acetate are dissolved in 240 ml of 96% ethanol and stirred gently with reflux with 9.1 g ( 0.66 mol) of powdered potassium carbonate. With continued external heating, 7.6 g (0.06 mol) of dimethyl sulfate is added dropwise. Then the reaction mixture is heated at reflux for 1 hour, then it is heated to ca. 0.5 liters of hot water. The separated product is filtered off and dried and then recrystallized from cyclohexane. 12.0 g (72% of theory) of ethyl 3-methyl-5-phenyl-4-oxo-A 2'a-thiazolidine acetate are obtained, m.p. 112-114 ° C.

2 ex n-Butyl-3-methyl-5-phenyl-4-oxo-β-thiazolidine acetate is prepared in an analogous manner. Using 0.035 mol of the reactants, 8.0 g (74.8% of theory) of the product is obtained, which after recrystallization from ligroin melts at 98 ° C.

For example, using diethyl sulfate is obtained. analogously 2 ex n-butyl-3-ethyl-5-phenyl-4-oxo-β-thiazolidine acetate. When 0.06 mole of the reactants is used, the yield is 12.1 g (63.3% of theory). After recrystallization of a mixture of ether and petroleum ether (1: 1), the product has a melting point of 84 ° C.

Example 2 2 ct

Ethyl 5-phenyl-3,5-dibenzyl-4-oxo-A '-thiazolidine acetate 10.5 g (0.04 mole) of ethyl 5-phenyl-4-oxo-A2'a-thiazolidine acetate dissolve in 180 ml of anhydrous ethanol and mix with 12.14 g (0.088 mol) of anhydrous powdered potassium carbonate. Then, the reaction mixture is boiled with stirring. Benzyl chloride (10.08 g (0.08 mol)) is gradually added and the reaction mixture is then heated under reflux for 2 hours. The still hot reaction mixture is poured into 0.5 liters of hot water and the separated product is isolated and taken up in a mixture of benzene and ethyl acetate (1: 1). After removal of the solvent mixture, the residue is digested with ether and recrystallized from ethanol. 8 g (42.4% of theory) of ethyl 5-phenyl-3,5-dibenzyl-4-oxo-A2'a-thiazolidine acetate are obtained, m.p. 154-156 ° C. Analysis for C27H25NO3S (mole weight 443.57): C%

Calculated 72.81 5.70 3.36 7.37

Found 73.10 5.69 3.16 7.73

Example 3 2 <x

Ethyl 3-methyl-5-phenyl-5-benzyl-4-oxo-A '-thiazolidine acetate 8.31 g (0.03 mol) ethyl 3-methyl-5-phenyl-4-oxo-A2' α-thiazolidine acetate and 4.56 g (0.033 mol) of anhydrous, powdered potassium carbonate are added to 120 ml of anhydrous ethanol. The reaction mixture is heated at reflux and 3.78 g (0.03 mole) of benzyl chloride is added dropwise over 1.5 hours. Then half of the solvent is distilled off and the residue is digested with hot water. Then, extract with ethyl acetate / and the residue of this extract is stirred for a few hours with cyclohexane. After recrystallization from petroleum ether, 6.0 g (54.5% of theory) of ethyl 3-methyl-5-phenyl-5-benzyl-4-oxo-β-α-thiazolidine acetate is obtained, m.p. . 105-107 ° C.

Analysis for C ^ HH NONO₂S (mole weight 367.47): C% H% N% S%

Calculated 68.63 5.76 3.82 8.73

Found 68.63 5.57 3.93 9.01

Example 4

2 BEERS

Ethyl 3-methyl-5-phenyl-5- (2-diethylaminoethyl) -4-oxo-β-thiazolidine-acetate

Analogous to the procedure described in Example 3, 2 cc of ethyl 3-methyl-5-phenyl-4-oxo-A '-thiazolidine acetate is reacted with diethyl aminoethyl chloride. After introducing the reaction mixture into hot water, extract with ethyl acetate. This extract is then shaken with 2N hydrochloric acid. The hydrochloric acid phase is made alkaline with 1 N aqueous sodium hydroxide solution and the crude base which is separated is taken up in ether. The ether solution is evaporated, the residue dissolved in isopropanol and the product precipitated by the addition of oxalic acid. The oxalate is isolated and recrystallized from isopropanol. Using 0.025 moles of the starting materials, 3.5 g (27% of theory) of ethyl 3- 3- α -methyl-5-phenyl-5- (2-diethylaminoethyl) -4-oxo-β thiazolidine acetate, m.p. 126-128 ° C.

Analysis for C 22 H 30 N 2 O 7 S (° xalate) (mole weight 466.56): C% H% N% S%

Calculated 56.64 6.49 6.00 6.87

Found 56.53 6.27 6.04 6.58

Pharmacological comparison trials Acute toxicity

The acute toxicity of the thiazolidones is tested on male mice (NMRI) with a body weight of 21-26 g. Before the start of the experiment, the animals are fasted for 24 hours with access to water ad libitum. 4 mice are used in each dose group. The dose is increased by a factor of 2. The test compounds are suspended in 1% tragacanth mucus and administered intragastric by a gastric tube. The amount of liquid administered is 0.2 ml / 10 g body weight. The animals are kept under observation for a total of 7 days. As standard substance is used silymarin, which is a mixture of three isomers, sllybin, silydiamine and silychristine produced in and isolated from the fruit of Silybum marianum belonging to the species Carduus marianus L. The main component is silybin, 2- [2,3-dihydro-2 ( 4-hydroxy-3-methoxy-phenyl - 3-hydroxymethyl) -1,4-benzodioxin-6-yl] -2,3-dihydro-3,5,7-trihydroxy - 4H-l-benzopyran-4-one, known antihepatotoxic principle, see Merck Index, 9 ed. (1976) page 1103, and having a LD 2 Q value of 5: 1600 in the above sample, whereas the 2 µ compound prepared in Example 1 is ethyl 3-methyl-5-ethyl-5-phenyl-4-oxo- β-thiazolidine acetate has very low acute toxicity with an LD

1600 mg / kg.

Investigation of the anti-heptatotoxic effect of thiazolidones on rats with liver damage induced by carbon tetrachloride. In this trial, the anesthetic period of rats with liver damage induced by carbon tetrachloride after administration of sodium hexobarbital was determined with and without treatment with the thiazolidones. Silymarin is used as a standard substance as it is representative of the known compounds with anti-hepatotoxic action.

The anesthetic period after incorporation of sodium hexobarbital is essentially determined by the rate of metabolism of this compound in the liver. In the case of animals with liver damage caused by carbon tetrachloride, the hexobarbital anesthetic period is extended due to the effect on the liver enzyme system which degrades foreign substances of radicals formed from carbon tetrachloride. These may be part of an exchange with the enzyme system and block its degradation of barbiturate, cf. T.C. Butler, J. Pharmacol, exp. Therap., 311, 134/1961,. T.F.Slater, Nature, 36, 209/1966 and R-O. Recknagel, Pharmacol. Rev., 19, 145/1967.

Therefore, the determination of the period of anesthesia in animals with liver damage caused by carbon tetrachloride gives an indication of the functional state of the liver, cf. T. Balazs and H.C. Grice, Toxicol, app. Pharmacol., 5, 387/1963 and R. Megirian, J. Pharmacol, exp. Therap., 144, 331/1964. This method can be used to determine substances with heptatoprotective properties as they counteract the prolongation of the anesthetic period by liver damage caused by carbon tetrachloride.

Method.

As experimental animals, male rats (SIV 50) with a body weight of 110-160 g are used. They are given standard feed and have free access to water.

Each experimental group comprises 10-12 animals. In each case, the treatment with thiazolido and silymarin takes place over a total of 4 days, the substances being administered daily suspended in tragacanth mucus (2 ml / 100 g), where the administration is made intragastric by means of a gastric probe. . On the second day of treatment, carbon tetrachloride is administered and on the fourth day of treatment the anesthetic period is determined. The animals in two control groups, one given carbon tetrachloride and the other not, are administered at the same time a daily dose of 2 ml / kg tragacanth mucus. Prior to administration of the carbon tetrachloride, the animals are fasted for 16 hours. The carbon tetrachloride is administered as a 1:50 dilution in sesame oil (1 ml of the dilution per 100 g body weight). The animals in the control group without liver damage due to carbon tetrachloride are administered at the time the other animals are administered the carbon tetrachloride, only sesame oil in the above amount.

To determine the anesthetic period, 70 mg / kg of freshly prepared sodium hexobarbital solution (1 ml / 100 g) is injected into the tail vein of the animals over 1 minute. The criterion for the anesthetic period is the time for the completion of the hexobarbital injection up to the recovery of position and standard reflexes. During the anesthetic period, normal body temperature is maintained by heat lamps.

From the individual results of each study group, the average value is calculated with the corresponding standard deviations. In order to determine the effect of the thiazolidones and the effect of silymarin on the anesthetic period of the animals with liver damage induced by carbon tetrachloride, the difference between the average anesthetic period for the control group with the carbon tetrachloride ether, and the control group without the carbon tetrachloride anadrachloride anadrachloride liver damage is added. the control group without liver damage is calculated as a percentage thereof. The so-called Student's test is used to study the difference between individual study groups too significantly. The results of the comparison experiments are given in the following table.

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The table shows that liver damage in rats induced by carbon tetrachloride leads to a marked extension of the anesthetic period compared with control animals without carbon tetrachloride liver damage. The statistical calculation in all experiments yields a highly significant difference (p = <0.001) between two control study groups.

The thiazolidone tested by intragastric administration for 4 days produced a clear reduction of the anesthetic period in rats with carbon tetrachloride liver damage compared with the results of the corresponding control group with non-treatment liver damage.

This anti-hepatotoxic effect of the thiazolidones is highly significant, as shown in the last column of the table. In contrast, silymarin tested at doses of 100 and 200 mg / kg does not reduce the anesthetic period in animals with carbon tetrachloride liver damage. The anesthetic period of carbon tetrachloride liver-damaged animals treated with silymarin even shows a slight, albeit not significant, percentage increase compared to untreated animals with liver damage.

Since the acute toxicity test for the thiazolidones gives an LD 2 value of 1600 mg / kg, and since the anti-hepatotoxic effect of the carbon tetrachloride test is obtained at substantially lower doses than with silymarin, the compounds of the invention provide a very good therapeutic spectrum.