SE415352B - PROCEDURE FOR PREPARING TIAZOLIDINO DERIVATIVES - Google Patents

Description

7503380-3 2 It is known that 3-methyl analogs of compound, which are unsubstantiated situated in the 5-position and having a free carboxy group, can be prepared by careful saponification of the corresponding ethyl ester. Try to in this way to prepare compounds of general formula I, which exhibits a basic substituent in the 5-position, ioke has been successful and resulted in each case in isomerization or degradation of the ring system. This was expected as these simultaneously exhibits the structure of cyclic enaminocarbonyl compounds. chain, S-S, N-acetalor and thioaminals. Reaction bone nomenclature and the sensitivity of such groups in alkaline and acidic environments is known from ' the literature; Liebigs Ann. D. Chemistry, Zêâ (1969), 66-65.

It has now been found that the acid-catalyzed alkyl-oxygen cleavage is possible when an ester of the general formula ïrW _ (II) R 2 OOC-CH = C C = O ' * \ '/ f IN 111 wherein R 1 is as defined and R 2 is an alkyl group having 2-6 carbon atoms, are treated at a temperature between -5 and + 25 ° C with an approx 40-50% solution of hydrogen bromide in acetic acid, after which the free amino acid (I) after elimination of the acidic mixture is isolated and that it is obtained the acid may be reacted with a physiologically compatible base formation of the corresponding salt. The solution range is mainly limited only by the solubility of HBr in the acid. Although acetic acid is most suitable, For example, lower alkyl acids having 1 to 5 carbon atoms can be used, such as propionic acid 'or butyric acid.

Under these conditions, R 2 is carefully cleaved in the form of a Alken or alkyl bromide.-Despite the high acid concentration, more neither isomerization nor degradation, nor the expected one the decarboxylation of the formed free acid.

The groups R1 are straight chain or branched alkyl groups with up to kol carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl groups.

The pharmacologically acceptable salts may be alkali metal. the metal salts, in particular the potassium salts, as well as the alkaline earth metal the salts. These can be prepared by reacting the free amino acids. the acids (I) with the metal hydroxides or carbonates in question.

The alkyl oxygen cleavage according to the invention is carried out in a In such a way that the compounds of the general formula (II) at a 75033-80-3 temperature of between -5 and + 5oC is reduced in a ÜOÉ-like solution of bromine hydrogen in glacial acetic acid and the cleavage of the alkyl group is initiated by slowly heating the reaction mixture at room temperature, i.e. about 15-2500. After full turnover, what orfordrur about 1-70 hours, the acid mixture is removed in vacuo and the residue it is digested with water. The free amino acids (I) can then be folded at pn 6 and isolated.

For thermodynamic reasons, they are intended according to the invention the acids primarily HÜOC / N-H1-trans configuration with respect to the exocyclic double bond ("Z" configuration).

If the free acids are then converted to their potassium salts, For example, the compounds (I) may be precipitated in an equimolar amount of aqueous solution of potassium bicarbonate or potassium carbonate, which contains 1-15% of a lower alcohol, at a temperature of about # 0-6000, leaving the salt isolated by drying, preferably freeze-drying.

Compounds of formula (II), used as starting materials, are known or can be prepared in a manner analogous to that used was prepared for the preparation of the known compounds by reacting the compounds described in U.S. Pat. No. 3,072,653 with piperidine.

The compounds of formula I exhibit valuable pharmacological properties activities, in particular diuretic activity, and is distinguished by a - interesting spectrum of activity not previously known in associated with diuretic compounds. Furthermore, it enables outstanding the solubility in water of the alkali metal salts in a physiological optimal pH value a wide range of uses, especially at therapy of acute pulmonary and cerebral edema and in the treatment of acute cessation in renal function; it is also possible to increase blood flow through with BO-SO%, without reducing the filtration rate, while known diuretics do not significantly affect blood flow through the kidney. rarna. Furthermore, known diuretics, in contrast to the present one, reduce compounds, the filtration rate.

As dog experiments have shown, the present in contrast to commercially available diuretics, hardly the excretion of potassium by experimentally arranged experimentally diures. The new associations also show a remarkably low toxicity and, in addition to their diuretic effect, they also exhibit a disorderly antihypertensive effect. One has also been observed regulatory effect on body temperature.

The new compounds of formula I as well as their pharmacological commercially acceptable salts may be administered enterally or parenterally, 7503380-3 Ä which is not the case with the esters, in admixture with liquid or conventional solid pharmaceutical diluents or carriers.

As the injection, it is particularly convenient to use water, containing the conventional additives for solution for injection, for example stabilizers, solubiliserin o agents ooh / or buffer average. Compositions suitable for oral administration may optionally contain seasoning and / or sweetening agents.

The dosage depends on the nature and severity of the disease intended for treatment. The individual oral dose is between 10 and 500 mg and the subcutaneous or intravenous administered individual dose may be between 5 and 200 mg.

The invention is further illustrated by the following examples, wherein the stated temperatures refer to degrees Celsius. K _ åšemgel. ' 3-Methyl-4-oxo-5N-Biperidino-thiazolidine-2-ylidene-acetic acid readers' i In 55 g of butyl-3-methyl-M-oxo-5N-piperidine-thiazolidin-2-ylidone acetate is lowered at a temperature between -3 and 00 in 100 ml of 100% solution of hydrogen bromide in acetic acid. The reaction mixture is heated for a long time. and to 200 and stored for 1.5 hours at this temperature. Then most of the hydrogen bromide / acetic acid phase is removed under jet vacuum at a bath temperature of 25-40 °. The residue is digested with , 0.5 liters of water and the pH is adjusted to 6.0 with sodium bicarbonate.

Foaming can be inhibited by the addition of ether. The solid product filtered off with suction and dried in vacuo over anhydrous calcium chloride. rid. Any remaining starting material can be easily separated by dissolving in cold 2N sodium carbonate solution, filtering and In acidification of film area with dilute acetic acid. 25 g are obtained (56 92) 3-Methyl-α-oxo-5N-piperidino-thiazolidin-2-ylidene-acetic acid, which melts while probing at 163.90 after recrystallization from methanol or ethanol. 7 c111116N2O3s (molecular weight 256.32) _} _ Calculated: c 51.514 H 6.29 N10, 93 s 12.51 so runner: c 51.67 H 6.12 N1o, 77 is12.3lr <ß Butyl-3-methyl-4-oxo-SN-piperidino-thiazolidin-2-ylidene acetate, used as starting material, is prepared as follows: 141 g of ethyl tert-butyl cyanoacetate (b.p. 600 / 1.5 mm Hg; = 1, 1: 18o) and 1201111 ethylthioglycolate are dissolved in 1 liter of the solution, mixed with 110 ml of triethylamine and stirred for 72 hours at room temperature. 20 fi, lucky. The majority of the solvent is distilled off in vacuo and the solid the substance is separated, separated and washed with a small amount 7503380-3 benzene on a suction filter. After air drying you get ijh g (79 É) tert-butyl-α-oxo-thiazolidin-2-ylidene acetate, which after recrystallization sation from isopropanol melts at 177, ÜÖ. 63.5 g of tert-butyl---oxo-thiazolidin-2-ylidone-acetate and 1 potassium carbonate is suspended in 250 ml of methanol. The reaction mixture heated to reflux temperature and mixed dropwise with a solvent 37.8 g of dimethyl sulphate in 50 ml of methanol. After one hour, the reaction is taken. The solvent is removed in vacuo and the residue is removed. in 0.5 liters of water. The crude tert-butyl-3-methyl-β-oxo-thiazole The lidin-2-ylidene acetate is taken up in ether and the ether phase is dried and dunstas. The residue is recrystallized from cyclohexane. 56 g are obtained (82 E) tert-butyl- (3-methyl-Ä-oxo-thiazolidin-2-ylidene) -acetate, which melts at 77, h °. _ 36.8 g of tert-butyl 3-methyl-oxo-thiazolidin-2-ylidene-acetate dissolved in 700 ml of anhydrous carbon tetrachloride. Under reflux conditions first add 0.3 g of azo-bis-isosobutyranitrile and then below a period of 10 minutes 29 g of N-bromosuccinimide. After 20 minutes reflux heating, the reaction mixture and the filtrate are filtered evaporate to dryness in vacuo. The oily residue is taken up in 0.5 liters of benzene, cooled to +50 and mixed in several portions with 32 ml piperidine. After several hours of storage at room temperature the piperidine hydrobromide formed and the filtrate are separated. evaporate in vacuo. After adding 50 ml of isopropanol, the mixture is cooled. The precipitated tert-butyl-3-methyl---oxo-5N-piperidino- -thiazolidin-2-ylidene acetate is recrystallized from isopropanol. Out- the yield is 21.5 g (38% over two steps) and the product melts at 1540. c15H2¿N2o3s (moiekyivikz 312, h1) Calculated: C 57.66 H 7.7h N 8.97 s 10.26% Found: C 57.56 H 7.80 N 9.15 s 10.3% Eeäieel.E = 100 g of ethyl 3-methyl-α-oxo-SN-piperidinothiazolidin-2-ylidene acetate is reduced with stirring at 0 DEG in 200 ml of 40% solution of hydrogen bromide in acetic acid. The vessel, -containing the reaction mixture, closed with a Bunsen valve (to avoid overpressure of ethylene) and the reaction mixture Stir with a magnetic stirrer under 65 ' hours at room temperature. The reaction mixture is worked up on i variant A specified method. 7.0 g (53%) of 3-methyl-α-oxo-5N- -piperidine-thiazolidin-2-ylidene-acetic acid, which during decomposition melts at 163.9 °.

EëemBâl.â- β-Glium-Bzmethyl-β-β-5-N-piperidino-thiazolidin-2-ylidene acetate 5.1 g (0.02 mol) of 3-methyl-4-oxo-SN-piperidino-thiazolidine-2- 7503380-3 -ylidene acetic acid is transferred to a paste with 10% ethanol and finish with 50 mg of 4? -íg potassium bicarbonate solution in water. Among- The mixture is heated briefly on a water bath to 500, until the gas outlet the development is completed and a complete solution is obtained. Among- the mixture is cooled to 15-20 ° and water is removed in a rotary evaporator. tare at 0.05 mm Hg under freeze-drying conditions. The rest of the crystallized from isopropanol. 3.5 g (59.3 E) of potassium -3-methyl-4-oxo-N-piperidino-thiazolidin-2-ylidene acetate in the form of (colorless crystals, which sönaeraeias at 150 ”. §§S¶asl_2- ' 3-Ethyl-α-oxo-SN-piperidino-thiazolidin-2-ylidene-acetic acid 50 g of ethyl β-ethyl-h-oxo-sn-piperidino-thiazolidin-2-zylamino-p -acetate is reacted and worked up analogously to the experiment according to examples 1) 12.5 g (28%) of 3-ethyl-4-oxo-5N-piperiaino-thiazolamine are obtained. -3-ylidene-acetic acid, which melts after recrystallization from methanol .rid 1ÅS °. The melting takes place during decarboxylation and is somewhat amusing the heating speed unit.) .c12H18N2O3s (molecular weight 270.35) Calculated: C 53.31 H 6.71 N 10.36 s 11.86% runner; c 53, h1 H 6.59 N 10.19 s 11.72 å The following compounds are prepared in an analogous manner: 3-propyl-α-oxo-SN-piperidino-thiazolidin-2-ylidene-acetic acid, m.p. 1450; 3-n-butyl-4-oxo-5N-piperidino-thiazolidin-2-ylidene-acetic acid, m.p. 130- 14 ° C. i 9 ïâšalneli- 20 g of ethyl 3-methyl-h-oxo-5N-piperidino-thiazolion-2-ylidene- acetate is reduced with stirring at 0 DEG-5 DEG in 50 ml of 40% solution of hydrogen bromide in propionic acid. The solution is processed according to Example 1, iant B; reaction time 72 hours. yield 7.0 g (39%). melting point 163 ° (decomposition). K '§Uze2el_ä- 20'g ethyl-3-methyl-Ä-oxo-SN-piperidino-thiazolidone-2-ylidene acetate is reduced while stirring at 0 DEG-50 DEG C. in 50 ml of a 40% strength solution hydrogen bromide in butyric acid. The solution is worked on in Example 1, variant B, amgimet mode, reaction time 70 hours. Yield 6.9 g (39 á). molten point (decomposition) 163416Ä °.

The compounds obtained according to the invention have marked take pharmaceutical advantages in comparison with the known ethyl 3-methyl- The 4-oxo-5-piperidino-A2'a-thiazolidine acetate, described in the article kansxa patent specification 3.o72.653. I _ L Compounds prepared according to the invention may be administered 7soszao-3 by injection and can therefore be used in medical crises, such as in acute pulmonary and cerebral edema. The present compounds have stronger effect than the thiazolidine acetate after intragastric and intravenous administration administration. Compounds obtained according to the invention have little effect on potassium excretion, even to a lesser extent than that of the the part available to the furosemide, which is known to have little effect on potassium excretion.

The following examples illustrate the improved activities of present compounds in comparison with prior art compounds.

Ethozoline consists of ethyl 3-methyl-H-oxo-5-piperidino-A2'a-thiazolidine acetate and 3282 of 3-methyl-4-oxo-SN-piperidino-thiazolidine -? §¿G @ gg¿_§- acetic acid.

Qigïåâ m fi fommmmm fi 1. Try intragastric administration m3 fi * ÛÛ'ÜH N fl äwl = Experiments were performed on 5 anesthetized beagles with nn weight of 15-22 kg, which was trained to lie on a table without being fixed.

The animals were not episiotomized. A rubber catheter was inserted into the bladder, excreted urine was collected separately for each animal and the volume measured at 30 minute intervals. When a constant urine flow is achieved arrived, the test substances were administered with a gastric tube. Diuretics diluted with physiological saline so that a constant volume of 25 mg / kg maintained- Three animals received the test substances and two turned as controls. Dalläàsta administered the diuretic dose was 1.56 mg / kg. Dosages were increased by a factor of 2 up to 50 mg / kg.

Result: '_ Table 1: Comparison between the maximum achieved effects of Etozolin and 3282 on diuresis in conscious beings dogs after intragastric administration Substance Éos ml / animal / min.

Ina / kg rcozoline 25.0 and 7.8 3282 _ i 25.0 10.9 As shown in Table I, the maximum diuretic is achieved the effect of both substances after 25.0 mg / kg. An increase in dose does not cause any further increase in urine secretion. The maxi- However, the malt achieved effect of 3282 is much higher than that of Etozolin. 2. Try intravenous administration âleäesü Experiments were performed on female dogs and bitches of mixed breeds, anesthetized 7503380-3 1 with pentobarbital. Body weight ranges between 9 and 11 kg. Efter_lapar- The proximal portion of the ureters was cannulated and the urine was cannulated. excreted by each kidney was recovered at intervals of 10 minutes.

Arterial and venous pressure were recorded throughout the experiment. In the 1.5 ml / kg per minute a tempered physiological cell was infused. solution for 1; 5 hours- After a constant urine flow is reached, diuretics were injected into the femoral vein. The starting dose was 2.0 mg / kg, which was increased by a factor of 2 up to 6ü, 0 mg / kg.VTyå animals were used for each dosage level: As shown in Figs. 1 and 2, there is a rectilinear assembly. band between dose and response after administration of 3282 (r = = 0.8799). After 32.0 mg / kg, urine excretion is increased to 16 ml / minute _and animals. Dosage dependence is less significant Ethanol (r = 0.5SS3); which substance is far less active: after administration of 32.0 mg / kg increases urine flow by only 2.25 ml / minute and animals. 7503380-z 415 352 wxxwz mon ww zA.woo Nm m fl .æ. v. N ß OO ° V '-; oo ° c -OO'Z -O0'I . fl o fl vdh fi ww fi wë fl m wm fl w> ßH # G fl hmvmw Hd fifl ä fl @Um> m fi mQ mø fi mwhä fl w m fl Nwmm> d fl dMHm> nH n fl _H5mwh OO¿u & Û.N | OO.v OO.w OO.w uU0.0H -uO.NH -oo. «H 1UO.wa wo.w ~ u0.0N iOO.NN | uO.vN uvïwz won Emon 10 1sozzao ~ z -oo-v ma hrs...

T É .Z Z I. W w. f .e n .. w m, W W O O O _ ß .v _ _ _ _ .- .fl o fl aßnum flflfi ävß mw fl w> dR ¥ flfi møßwm Hd flflflfl 0flfi> wUmQ mo: mwußwø wm.cw fi0 N0 »u bd nm ¥ Hm> fl H n m Hdm fi h XVW / EUPP / NIW / ÉW __...- --......, ._> ...... ~. - .- ._ vsossso-se 11 Exemgel Z.

Effect on potassium excretion Method.

A total of 19 cleaning trials were performed on dogs, 8 bitches and 1 male dog with a weight of 1? -25 kg. The animals were anesthetized intravenously 30.0 mg / kg pentobarbital. A _ At the beginning of the experiment, 1 liter of physiological saline was infused. under one hour. In the urine recovered using a bladder catheter was determined in addition to other parameters also potassium and sodium concentrations by flame photometry.

Results: The two lines in Fig. 3 and Ä delimit all the purification experiment with 3282 that could be used for statistical evaluation »Med using these two lines, it is found that with higher amounts of Decomposed sodium increases potassium excretion far more with furosemide than with 3282 .i I 0.200- uguof 3: Relationship - c l- 33282 " .hno 0 U o. ___- ... f; "o. I f fifififi" 'n " c- '4 mfzv *' I c .o .V, n '. _ . O o o f, 'u u "n v ° u - _. p g .. 'u 0, , n o 'Å I * p _ , -. '° ". ° íuà-J-e fi rrwvw n-uncmnwn fi f-ø: - _ 1 .ø * n-ßw I 'I sodium excretion (ENaf) after 3282.

KV ~ - _. __ _ mv <= 1 / mf fi¿. e íwxrosaznxfi íï-p-n-Au-w 0.500 «1,000 1,500 _ 2,000 2 ' a.o_oo 0 fïN-w e between renal potassium excretion and z-'enal 'Û fi- OU- a-oqop 1,500 2,090 - - .. e gxg-H. 'fm renal sodium excretion (ENa-r) after furosemide. 2: 5 00 aíooo 5§a + . ' lïöåhålianfuie between: anal 'kaiiumemetiou fi> (E¿ +)' een 7503380-3 13 Exemgel 8.

Acute toxicity The acute toxicity of 3282 is extremely favorable.

In rat experiments, 3282 injected into the tail vein, no killed animals were observed at doses up to 1000 mg / kg (higher doses were not used). The intravenous toxicity The density of 3282 is thus significantly more favorable than that of Etozolin. LD50 for Etozolin in rats is 56.6 mg / kg intravenously (confidence limits) 45.9 ~ 69.5 Ing / ke) - In mouse experiments, 3282 were administered intragastrically as an aqueous solution, none of the animals died up to a dosage of 2,250 mg / kg within # 8 hours.

Claims (5)

7503380-3 É 14. 'ha PATENTKRÅV I 1. Process for the preparation of compounds of the general formula ln S "" "* 'CH ~ N l 1 | ii ¿HOOC-CE = CC = O» I § * \' / 'e _ e I H1' and salts thereof, wherein R1 is alkyl of 1-4 carbon atoms, characterized in that a compound of the general formula .H. I fc ~ N> I g -II RZOOC- '= QC = O * \ wherein R 1 has the indicated meaning and R 2 is alkyl of 2-6 carbon atoms, is treated at a temperature between -5 and + 25 ° C with a 40-50% solution of hydrogen bromide in a carboxylic acid. with 1 to 5 carbon atoms, after which the acid mixture is removed and the desired compound of formula I is isolated and the acid obtained is optionally reacted with a physiologically compatible base to form the corresponding salt. 2. A process according to claim 1, characterized in that the residue obtained after elimination of the acid mixture is digested with water and adjusted to pH 6 to precipitate the desired acid. _ _ 3. A process according to claim 1, characterized in that the organic acid is acetic acid. l. _ 4. A process according to claim 1, characterized in that the organic acid is propionic acid. 5. A process according to claim 1, characterized in that the organic acid is butyric acid. PUBLICATIONS MADE: