DE2658858A1 - (-) - (3-METHYL-4-OXO-5-N-PIPERIDINO-THIAZOLIDIN-2-YLIDEN-) ACETIC ACID - Google Patents

Description

Gödecke AG 1000 Berlin 10 Salzufer 16

(-) - (S-Methyl ^ -oxo-S-N-piperidino-thiazolidin-2-ylidene-) acetic acid

The invention relates to the levorotatory enantiomer of the (-) - (3-methyl-4-oxo-5-N-piperidinothiazolidin-2-ylidene) acetic acid described in DT-OS 2 414 345, their pharmacologically acceptable salts, a process for their production and pharmaceuticals, which contain the above enantiomer or its salts as an active ingredient.

From DT-OS 2 414 345 it is known that racemic thiazolidinone acetic acid derivatives of formula I.

S —— CH NH /

HOOC ^ I I V_ /

^R 1

Ur

in which R-j is a lower alkyl radical,

as well as their pharmacologically acceptable salts a diuretic Have effectiveness. The compound in which R-] is a methyl radical is preferred.

The compounds I have an asymmetric carbon atom in the 5-position om.

It has now been found that the levorotatory enantiomer of (S-methyl ^ -oxo-S-N-piperidino-thiazolidine-z-ylidene) acetic acid [uSAN = Ozolin] is twice as diuretic as the one described above Racemate, surprisingly a parallel increase expected per se with the increase in effectiveness the toxicity could not be determined.

This finding is astonishing, since the effects of enantiomers differ diuretic substances with the exception of the steroid-aldosterone antagonists, which are completely different in their mechanism of action not yet known at all. Nor was it known to those skilled in the art that there were chiral receptors for diuretics or there are stereospecifically controlled mechanisms of action. That is why prochirals are also used to influence diuresis Active ingredients such as mefruside or metolazone (international non-proprietary names), until now only in the racemate form in the trade. .

803826/0378

A simple resolution of the racemate can now be used in the present Case practically double the therapeutic range, which is decisive for the safety of a drug, what a crucial technical one for a diuretic that normally has to be administered over long periods of therapy Means progress.

The preparation of the levorotatory enantiomer of 3-methyl-4-oxo-5-N-piperidino-thiazolidin-2-ylidene) acetic acid (-) - Ozoline takes place in a manner known per se by fractional crystallization of a diastereomeric salt of the racemate prepared according to DT-OS 2,414,345 (Example 1) with an optically active one Base such as 1-ephedrine or 1-lysine. As a solvent for fractional crystallization are when chlorinated hydrocarbons such as chloroform and carbon tetrachloride are used , Dichloroethane or trichloroethylene mixtures with such organic solvents are suitable in which the diastereomeric Salts are sparingly soluble. These include, for example, open-chain or cyclic ethers such as diethyl ether and tetrahydrofuran and dioxane, lower esters such as ethyl acetate or ketones such as acetone. Corresponding lysine salts are preferably dissolved in water and with lower alcohols such as ethanol or isopropanol or with lower ketones such as acetone like fractionated precipitated. With the two auxiliary bases mentioned, (-) - ozoline forms a less soluble one Salt and can thus be separated from the (+) - ozoline that remains in solution. By recrystallizing one or more times the solvents or solvent mixtures used for the precipitation, (-) - ozoline can be obtained optically pure.

809828/0378

-Yes-

To obtain (-) - ozoline from the salts, these are used with treated with a weak acid, preferably dilute, aqueous acetic acid and chloroform, the released (-) - Ozoline dissolves in chloroform. It is washed with water by distilling off the solvent and precipitating obtained with petroleum ether or gasoline.

The (-) - ozoline according to the invention and its pharmacologically acceptable Salts can be in liquid or solid form or enteral be applied parenterally. The main injection medium used is water, which is the case with injection solutions the usual additives such as stabilizers, solubilizers or buffers. Such additives consist of, for example Ethanol, complexing agents (such as ethylene diamine tetraacetic acid and its non-toxic salts), tartrate or citrate buffers or high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carriers are e.g. starch, Lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, higher molecular weight fatty acids (such as stearic acid), Gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as Polyethylene glycols). Oral application forms can, if desired Contains flavorings and sweeteners.

The dosage depends on the type and severity of the disease in question. The single dose is between 5 and 250 mg and the A single dose administered subcutaneously or intravenously can be about 5 to 100 mg.

809828/0378

The present invention is also a Process / which is characterized in that (-) - ozoline converted into a diastereomeric salt by means of an optically active base, this being the fractionated salt in a manner known per se Subjects to crystallization and releases the desired levorotatory ozoline by adding a weak acid.

Another object of the invention is the use of (-) - Ozolin for the production of highly effective diuretics.

(-) - Ozolin has a specific rotation of L ^ J- = -225 (c = T in chloroform / methanol 1: 1); the melting point is 10 ° C below that of the racemate. The infrared spectrum also shows clear differences compared to the racemate. The good lipoid solubility of (-) - ozoline is striking. While that Racemate only dissolves 0.2% in chloroform and 0.01% in diethyl ether, is the solubility of the levorotatory enantiomer in chloroform approx. 20% and in diethyl ether 0.3%. The better lipoid solubility of (-) - ozoline is surprising and possibly the reason for its increased pharmacological effectiveness.

The use of - (-} - ozoline as a diuretic can be in the form of the free (amino) acid or as a salt with physiologically harmless Bases, acids or amino acids take place.

Common salt formers such as

Hydrochloric acid, sulfuric acid, phosphoric acid or stronger organic acids such as acetic acid, fumaric acid, succinic acid, ascorbic acid, o.a. into consideration. Non-toxic amines serve as salt-forming bases or amino acids in addition to alkali carbonates or hydroxides.

The following examples serve to illustrate the invention Procedure.

809828/0378

example 1

1a) (-) - Ozoline-1-ephedrine salt

165.2 g (1 mole) 1-ephedrine and 256.3 g (1 mole) (-) - 3-methyl-4-oxo-5-N-piperidino-thiazolidin-2-ylidene) acetic acid [(-) - OzolinJ are dissolved in 3000 ml of chloroform and filtered.

3000 ml of ether are added to the clear filtrate. The solution is left to stand overnight. The next day, the crystals are filtered off with suction and mixed with 500 ml of a mixture of chloroform / ether 1: 1 then washed and dried at 45 ⁰ C.

Yield: = * 205 g

For purification, the ephedrine salt is dissolved in 2050 ml of chloroform dissolved and recrystallized by adding 2050 ml of ether.

Yield: «- 180 g = 85% of theory. Th.

Wd ~ ~ ⁹⁸ ° ^(c = ° / ^{5 in} CHCl _3), mp. 110-115 ⁰ C.

1b) (+) - Ozoline-1-Ephedrine Salt

The combined mother liquors are largely concentrated on a rotary evaporator and the residue is dissolved in 2000 ml of chloroform. The salt is made to crystallize by adding 2000 ml of ether. It is filtered off with suction, washed with 500 ml of chloroform / ether 1: 2 washed and dried at 45 ⁰ C. By repeatedly falling over (3-4 times) from five times the amount of chloroform and ten times the amount of ether, the salt is purified to such an extent that M ₀ = + 83 ° (c = 0.5, in CHCl ₃ ).

Yield: approx. 105 g = 50% of theory M.p. 137-14O ° C.

809828/0373

2a) (-) - ozoline

180 g (0.43 mol) of (-) - ozolin-1-ephedrine salt are introduced into a solution of 50 ml (0.87 mol) of glacial acetic acid in 3000 ml of distilled water with thorough stirring and stirred for 1 hour. It is then extracted with 1000 ml of chloroform. The chloroform phase is separated off and washed with water. After drying over magnesium sulfate, the solution is concentrated to 1/3 on a rotary evaporator and (-) - ozoline is crystallized by adding 2000 ml of petroleum ether. It is suction filtered, washed with petroleum ether and dried at 45 ⁰ C.

Yield: approx. 70 g = 63% of theory M.p. 145 ° C (decomposition) LoC] ₀ = 224.9 ° (c = 1 in CHCl ₃ / Me0H 1: 1)

2b) (+) - 0zoline

(+) - Ozolin-1-Ephedrine-Salt is made according to the same rule (+) - Ozolin produced.

Yield: approx. 63% d. Th. M.p. 145 ° C (decomposition)

[# 2 _D = + 225.6 ° (c = 1 in CHCl ₃ / MeOH 1: 1)

example

25.6 g (0.1 mol) of (3-methyl-4-oxo-5-N-piperidino-thiazolidin-2-ylidene) acetic acid and 16.0 g (0.105 mol) of 1-lysine are dissolved in 80 ml of distilled water, then the Solution filtered. 400 ml of isopropanol are then added. The mixture is left to stand overnight. - 8th -

B09826 / 0378

AO

The next day, the crystals are suctioned off and washed with a little 80% isopropanol. The yield is 13 g (63% of theory) of 1-lysine salt. [oc] _D = -71.9 ° (c = 1 in water); Snap. 175 ° C.

12 g (0.03 mol) of this salt are poured into a mixture of 3.6 ml (0.06 mol) of glacial acetic acid and 200 ml of water with thorough stirring entered and stirred for 30 minutes.

It is then extracted with 80 ml of chloroform, the chloroform phase is washed with water and, after drying, with sodium sulfate concentrated to one third in vacuo. The (-) - ozoline is then crystallized by adding 150 ml of petroleum ether brought.

It is suction filtered, washed with petroleum ether and dried at 40 ⁰ C.

Yield: 4.8 g (63% of theory) mp 145 ° C (decomposition) [<x] _D -225.6 ° (c = 1 in CHCl ₃ / methanol 1: 1)

The following comparison tests show the clear superiority of (-) - ozoline versus (+) - ozoline and the racemate.

809826/0379

/H

I ACUTE TOXICITY

The acute toxicity of (-) - ozoline was determined in male rats. The substance was administered as a suspension in tragacanth mucus. The statistical calculation of the LD _5Q value was carried out by means of probit analysis according to E. Weber.

In addition to the values found, Table I also shows the LD _g values for (-) - ozoline in male and female rats:

Table I.

substance animal ^LD 50
mg / kg Confidence level
lower 2nze ρ = 0.05
upper (-) - Ozoline Rat male 1202 1112 1300 (-) - Ozoline Rat male 1450 1237 1700 Female rat * 1260 1042 1525

The acute toxicity of (-) - ozoline is only slightly higher that of the racemate; from this it follows that the therapeutic quotient of (-) - ozoline in rats is twice as large as that of the racemate.

- 10 -

809828/0378

ΛΙ

II DIURETIC EFFECTIVENESS

The diuretic effect of (-) - ozoline was determined in rats and dogs checked. It was administered to rats intragastrically as a suspension in tragacanth mucus. In dogs the watery Solution of the substance administered intragastrically. The results are in the following Tables II (rat experiment) and III (dog experiment) shown:

Table II

dose Urinary discharge Blank
(NaCl)
ml / kg (+) - 0zoline
ml / kg (-) - Ozoline
ml / kg (-) - Ozoline
ml / kg mg / kg
ig 28 28 28 18th 4.7 28 28 38 40 9.38 28 30th 40 62 18.75 28 35 50 68 37.5 28 38 55 85 75.0 28 58 75 90 150.0 28 42 95 115 300.0

The superiority of (-) - ozoline is clear from the experimental data emerged. The clockwise (+) - ozoline has only a weak diuretic effect, even in very high doses.

- 11 -

809826/0378

Table III

dose Urinary discharge Blank
(NaCl)
ml / kq (-) - Ozoline
ml / kg (-) - Ozoline
ml / kg mg / kg
ig 17th
17th
17th
17th
17th 20th
21
26th
42
47 24
40
46
53
62 2
4th
-.8th
16
32

The test results clearly show the significantly higher diuretic activity of (-) - ozoline. She is in the low doses twice as high as that of the racemate and already sets in at a dose where the racemate hardly any Shows effectiveness.

- 12 -

809826/0378

Claims (6)

- MT- PATENT CLAIMS . (-) - P-Methyl-'l-oxo-S-N-piperidino-thiazolidine ^ -ylidene) acetic acid and their pharmacologically acceptable salts with inorganic or organic acids, bases or Amino acids. 2. Process for the preparation of (-) - (3-Methyl-4-oxo-5-N-piperidino-thiazolidin-2-ylidene) -acetic acid and their pharmacologically acceptable salts, characterized in that (-) - (3-methyl-4-oxo-5-N-piperidinothiazolidin-2-ylidene) acetic acid Reacts with an optically active base and the resulting racemic mixture in separates in a known manner by fractional crystallization, the separated dextrorotatory isomers by means of a weak acid and, if desired, then with inorganic or organic acids, Bases or amino acids, meanwhile, are converted to salts. 3. The method according to claim 2, characterized in that one the optically active base 1-ephedrine used and the desired dextrorotatory isomers from a solution of the diastereomeric salt in a chlorinated hydrocarbon falls with a low molecular weight alcohol, ether or ketone and / or recrystallizes. - 13 - ORIGINAL INSPECTED 4. The method according to claim 2, characterized in that one used as optically active base 1-lysine and the desired dextrorotatory isomer from aqueous solution of the diastereomer Salt falls with a lower alcohol or ketone and / or recrystallizes. 5. Medicines, characterized by a content of (-) - P-methyl-'l-oxo-S-N-piperidino-thiazolidine - ^ - ylidene) acetic acid and its pharmacologically acceptable salts with inorganic or organic acids, bases or Amino acids. 6. Use of (-) - (3-methyl-4-oxo-5-N-piperidino-thiazolidin-2-ylidene) acetic acid or their salts for the production of diuretic drugs. 809828/0378