FI69065C - FRUIT PROCESSING OF PHARMACOLOGICAL PROPERTIES OF 3- (1-CARBOXY-ALCOXY) -PYRAZOLE DERIVATIVES - Google Patents

Description

γβί .... ADVERTISEMENT 69065

JSäf® l J '* UTLÄGGNINGSSKRIFT

<45) Patent ccJ.Ji-1'i (51) Kv.lk//lnt.CI.4 C 07 D 231/20 FINLAND —FINLAND (21) Patent application - Patentansfiknlng 780791 (22) HakemiipSIvä - Ansöknlngsdag 13.03 · 78 ( Fl) (23) Primer - Gildghetsdag 13.03 * 78 (41) Become public - Bllvit offendlg 1 5.09 · 78

National Board of Patents and Registration of Finland NlhtSvikslpanon and Hearing Publication—

Patent- och registerstyrelsen '' Ansökan utlagd och utl.skriften publlcerad 30.08.85 (32) (33) (31) Privilege claimed - Begärd prloritet 1 4.03.77 1A.03.77 German Democratic Republic-Democratic Republic of Germany (DD) 197819, 197820 (71) VEB Berlin-Chemie, Glienicker Weg 125-127, 1199 Berlin, German Democratic Republic of Germany (DD) (72) Helmut Dorn, Berlin, Rudiger Ozegowski, Berlin, German Democratic Republic of Germany (DD) (7A) Oy Borenius & Co Ab (5A) Process for the preparation of pharmacologically valuable 3 '(1-carboxyalkoxy) pyrazole derivatives For the preparation of pharmacologically valuable pharmacologically active compounds 3- (1-carboxy-α1-coxy) -pyrazole derivatives

The present invention relates to a process for the preparation of new pharmacologically valuable 3- (1-carboxyalkoxy) -pyrazole derivatives of the general formula

R'v / H

Me V *] ° V I / \ (1), C — C — O CH 2 —Ph

/ I

HO k in which R1 represents chlorine or methyl and R2 represents straight-chain or branched -C4-alkyl, and for the preparation of their salts with physiologically tolerable inorganic or organic bases.

These new compounds strongly lower serum cholesterol / 4-lipoprotein and triglyceride levels, so they can be used to treat high blood fats. Since increased blood serum fat content is an essential risk factor for the development of coronary heart disease and arteriosclerosis in general, the compounds of general formula (I) are particularly suitable as cardiovascular drugs for the treatment of arteriosclerosis and the prevention of myocardial infarction.

In addition, the new compounds are characterized by their fairly good anti-inflammatory effect.

DD Patent 118 638 discloses a process for the preparation of 3- (1-carboxyalkoxy) pyrazole derivatives having an alkyl group or a phenyl group having 1 to 3 carbon atoms in the 5-position of the compounds. These compounds have been proposed for use in the treatment of hyperlipidemia. however, it has been found that their pharmacological and therapeutic properties are not sufficient for medical use.

According to the invention, the novel compounds are prepared by reacting the 3-hydroxy-pyrazole derivatives of the general formula II with the β-pyrazolinone (3) derivatives of the general formula III and the Δ4-pyrazolinone (3) derivatives of the general formula III.

VT

A’A (III) o n ’c% —λ

B

mixtures of tautomers in which the formulas have the same meaning as defined above are reacted in a manner known per se with either alcohols of the general formula IV li 69065

Me I (IV)

Z, C — C — OH

R * wherein R 2 is as defined above and Z is Cl, Br or J, or per mole of the mixture of tautomers (II / III) with at least 1 mole of the carbonyl compound of the general formula V

Me I (V) c = o! R * in which R2 is as defined above, and at least 1 mole of trihalomethane per mole of tautomer mixture (II / III)

Z3CH

wherein Z is as defined above, optionally with the addition of a catalytic amount of alkali metal iodide, and the addition of 4 to 6 moles of alkali metal hydroxide, alcoholate, hydride or amide in a polar-aprotic solvent, after which the compounds are, if desired, made physiologically tolerable in a manner known per se. .

As described in more detail, the procedure is as follows: To a mixture of 1 mole of the tautomer mixture of general formulas (II) and (III) and 0.4 to 3.2 l of a polar aprotic solvent, e.g. acetone, methyl ethyl ketone, a cyclic ketone with 5 to 7 carbon atoms, acetonitrile, dioxane or tetrahydrofuran, preferably 0.6 to 1.3 l of acetone or dioxane, 4 to 6 moles of alkali metal hydroxide, alcoholate, hydride or amide, preferably 4 , 0 to 4.2 moles of sodium hydroxide or potassium hydroxide, with mechanical stirring at 5 to 45 ° C, in particular at 15 to 25 ° C. To this mixture is added, with stirring and possibly simultaneously cooling with water, a solution of 1.0 to 1.03 moles, suitably 1.01 to 1.05 moles of the alcohol of general formula (IV) in 50 to 500 ml. , suitably in 50 to 160 ml of the solvent used for the above mixture, the temperature of the slightly exothermic reaction being maintained at 15 to 70 ° C, suitably at 15 to 35 ° C. The reaction mixture is then boiled with mechanical stirring and redistillation at 60 to 150 ° C, suitably 70 to 110 ° C, until the thin layer chromatogram (silica gel G, eluting with ethanol, n- or i-propanol), development of iodine) it is no longer possible to detect any tautomer mixture. The reaction time is 2 .. .60 hours. The solvent is then removed by distillation, possibly under reduced pressure. The remaining salt is dissolved in water and the pH of the solution is adjusted to 4.0 to 6.5 by adding an acid to give a 3- (1-carboxyalkoxy) -pyrazole derivative of the general formula (I) wherein R1. R4 is as defined above and R1 is OH, precipitates crystalline or amorphous. The precipitated product is treated with an aqueous solution of 1.0 to 3.0 moles, suitably 1.2 to 2.0 moles of acidic alkyl carbonate, whereby the carboxylic acid of general formula (I) (R 1 = OH) is dissolved as an alkali salt. It is also possible to dissolve the precipitated product in a solvent which is immiscible with water, e.g. methylene chloride, chloroform, trichlorethylene or acetic acid ester, and to shake the solution thus obtained in the aqueous acidic alkali carbonate solution described above. When the pH of the acidic aqueous solution is adjusted to 2.5 to 6.0, the 0-selective carboxylic acid of general formula (I) precipitates in 85 to 100% yields, calculated on the tautomer mixture used. This carboxylic acid can be recrystallized at a loss of 4 to 10%, suitably from benzene, toluene, xylene, lower alcohols, an aqueous alcohol mixture or water.

Another embodiment of the 0-selective substitution of tautomer mixtures (II and III) is based on the fact that 1 mole of the tautomer mixture and 4 to 6 moles, suitably 4.0 to 4.2 moles of the early hydroxide, alcoholate, hydride or amide, suitably 4.0 to 4.2 moles of sodium hydroxide or potassium hydroxide, as a solution of one of the above-mentioned solvents, are mixed, the ketone solvents of general formula (V), e.g. acetone, methyl ethyl ketone, cyclopentanone and cyclohexanone simultaneously acting as reaction components, and must be present at least 1 mole of compound (V) per mole of tautomer mixture (IIa III). When non-ketone solvents are used, e.g. dioxane and tetrahydrofuran, 1.0 to 1.5 moles, suitably 1.0 to 1.1 moles of the ketone of general formula (V) are added to the reaction mixture. 1.0 to 2.5 moles, suitably 1.2 to 1.4 moles of trihalomethane, suitably chloroform, are then added to the mixture described above, and the reaction mixture is then boiled with mechanical stirring and refluxing for about 0.5 moles. ... 15 hours at 20 to 150 ° C, suitably 20 to .80 ° C, until no more starting material can be detected in the thin layer chromatogram. Further work-up is carried out as described above.

Compounds of general formula (I) in which R1 represents a chlorine atom can also be prepared by reacting 3- (1-carboxyalkoxy) -pyrazole derivatives of general formula (I) in which R1 represents a hydrogen atom according to the invention in an inert solvent, e.g. chlorinated hydrocarbon, dialkyl ether, tetrahydrofuran, dioxane, acetic acid or water, with a chlorinating agent, e.g. chlorine, sulfuryl chloride, tert-butyl hypochlorite, N-chloramide, optionally adding hydrogen chloride, e.g. , alkaline earth carbonate or acidic alkali carbonate, and a radical scavenger is added in a catalytic amount, suitably <*, Ä. '-azoisobutyric acid dinitrile or dimethyl ester.

In this case, the procedure is as follows:

According to the invention, a mixture of 1 mole of a 3- (1-carboxyalkoxy) pyrazole derivative of the general formula (I) in which R * represents hydrogen and an inert solvent, e.g. a chlorinated hydrocarbon, a dialkyl ether, tetrahydrofuran, dioxane is added , acetic acid or water, suitably tetrachlorohydrocarbon or methylene chloride, to which 0.5 to 0.8 moles of anhydrous calcium, potassium or sodium carbonate are optionally added, e.g. 0.95 to 1.5 moles of acidic potassium or sodium carbonate and suitably 0.02 to 0.0001 moles of oi, o <.'-azobutyric acid dinitrile or dimethyl ester as radical generator, followed by the addition of a chlorinating agent, suitably 0 , 95 to 1.5 moles, as such or dissolved in an inert solvent, with mechanical stirring at -5 to 80 ° C, suitably at 0 to 35 ° C. The reaction time is 10 to 180 minutes, during which the progress of the reaction is monitored by thin-layer chromatography, suitably using small plates of size 69065 (silica gel G, 3: 2 by volume ethanol / carbon tetrachloride as eluent, and iodine as developer). The solvent is then removed by distillation. The residue contains 80-100% of a 4-chloro-substituted 3- (1-carboxyalkoxy) -pyrazole derivative of the formula (I).

According to the invention, the derivative obtained can be purified by dissolving it in an aqueous solution of alkali hydroxide or alkali carbonate and shaking this solution together with a suitable water-immiscible solvent, e.g. with an acetic acid ester, and / or by treatment with activated carbon, after which the compound of general formula (I) is precipitated by acidifying the reaction mixture. The compounds of general formula (I) can also be purified according to the invention by dissolving the crude compound of general formula (I) in an organic solvent, suitably a halogenated hydrocarbon, and pouring the solution suitably through a column containing silica gel.

The process according to the invention gives 4-chloro-substituted compounds of the general formula (1) in yields of 80 to 96% of the theoretically calculated amounts.

The resulting carboxylic acids of the general formula (I) can be converted into their salts by means of physiologically tolerable inorganic or organic bases.

The novel compounds of the general formula (I) or their salts can be used as medicaments as such or in admixture with solid, liquid or semi-liquid carriers. Suitable carriers are inert organic or inorganic substances, e.g. water, isotonic aqueous solutions, polyethylene glycols, gelatin, milk sugar, cellulose or starch and their derivatives, talc, magnesium stearate.

Excipients, for example preservatives, stabilizers and wetting agents, flavoring or perfuming agents, may be added to the pharmaceutical preparations. In addition, these preparations may also contain one or more other active ingredients, e.g. β-adrenolytically active substances or nicotinic acid derivatives. Tablets, capsules, syrups or I! May be used for intraperitoneal administration. 7 69065 dragees, in which case the latter can also be made into multilayer dragnes. The daily dosage of the new compounds of the general formula (I) is in the range 10 mg to 1 mg / kg of body weight.

The following examples further illustrate the invention.

Example 1

With vigorous stirring and cooling the reaction vessel, a solution of 8.22 g of 9.2 g (44 moles) of 1-benzyl-4-chloro-3-hydroxypyrazole, 100 ml of acetone and 7.05 g of sodium hydroxide is added. (44 moles) 1,1,1-trichloro-t-butanol · 0.5 H2O

In 50 ml of acetone. After stirring for about 40 hours, the solvent is removed by distillation. The residue is dissolved in water, the aqueous solution is washed twice ... three times with 8 ml of acetic acid ester each time, and the pH of the aqueous phase is adjusted to 4 to 5 with mineral acid. The crude 1-benzyl-3- (1-carboxy-1-methylethoxy) -4-chloropyrazole obtained is recrystallized from toluene. Melting point 125.5-126 ° C (from toluene). Yield 7.7 g (59% of theory)

Example 2

18.8 g (0.1 mol) of 1-benzyl-4-methyl-3-hydroxypyrazole, 16.0 g (0.4 mol) of sodium hydroxide and 130 ml of acetone are mixed thoroughly. A solution of 19.55 g (0.1 mol) of 1,1,1-trichloro-t-butanol · H 2 O in 45 ml of acetone is then added dropwise to the reaction mixture under cooling, and the reaction mixture is boiled for about 60 hours with stirring and applying redistillation. The solvent is then removed by distillation, the residue is dissolved in water and the solution is acidified with mineral acid to pH 4 to 5 to give crude 1'-benzyl-3- (1-carboxy-1-methylethoxy) -4-> ethylpyrazole. precipitates. The precipitate is washed with water and then treated with 210 ml of aqueous acidic potassium or sodium carbonate solution, clarified with 100 mg of activated carbon, filtered and acidified with mineral acid to pH 5. Melting point 115 ° C (from toluene). Yield 26 g (95% of theory).

69065

Example 3

To a solution of 6.55 g (25.1 moles) of 1-benzyl-3- (1-carboxy-1-methylethoxy) pyrazole in 75 ml of methylene chloride is added 4.1 mg (0.0025 moles) of ct, o ('- azoisobutyric acid-dinitrile), and the reaction mixture is cooled to 0-3 ° C. With stirring, a solution of 3.38 g ( 25.1 moles) of sulfuryl chloride in 14 ml of methylene chloride and stirred for a further 15 minutes, the solvent is removed by distillation and the residue is recrystallized from toluene with a little addition of activated carbon to give 6.78 g of 1-benzyl-3- (1-carboxy-1 -methyl-ethoxy) -4-chloro-pyrazole (92% of theory), m.p. 125.5-126 ° C.

Example 4

A mixture of 18.82 g (0.1 mol) of 1-benzyl-3-hydroxy-4-methyl-pyrazole, 150 ml of methyl ethyl ketone and 17.9 g of 1-benzyl-3-hydroxy-4-pyrazole is heated to 45-50 ° C with mechanical stirring. of chloroform. During the hour, 24 g of sodium hydroxide are added with constant stirring, keeping the temperature of the mixture in the range from 50 to 60 ° C. The unreacted methyl ethyl ketone is then removed by distillation under reduced pressure at a bath temperature of 50 [deg.] C., the residue is taken up in 300 g of water and neutralized with concentrated hydrochloric acid. The crude acid is separated from the precipitated, suction-filtered and water-washed product by treatment with a solution of 8.4 g of sodium bicarbonate in 200 ml of water, separation of the sodium bicarbonate solution from the insoluble portion, purification with activated carbon, filtration and acidification with hydrochloric acid until pH value 4 ... 5. The precipitated product is washed with water, dried and recrystallized twice from carbon tetrachloride. 19.8 g (69% of theory) of 1-benzyl-3- (1-carboxy-1-methylpropoxy) -4-methylpyrazole with a melting point of 86-87 ° C are thus obtained.

Pharmacological experiments

In order to demonstrate the valuable therapeutic properties of the novel compounds of formula (I), they were compared with the close compounds known from DD patent publication 118,638.

li 69065 9

The results presented in the following Comparative Table show the antisclerotic effect of the new compounds and show the serum lipid lowering and antithrombotic effect of the compounds and their toxicity. In all these areas, the compounds confirmed according to the invention have a surprisingly good effect with low toxicity, which suggests their usefulness as therapeutic agents.

It should be further noted that the effect of the combination being a serum-lipid lowering effect combined with protection against thromboembolism is both surprising and hitherto unknown.

comparison Table

Compounds 1, 2 and 5 are compounds according to the application, compounds 3, 4 and 6 are compounds according to DD-118 638.

4-position in the 5-position & -lipoprotein ± - Serum-LD, 0 Antitranal sub-existing sub- nlen and triglycolesterolytic tituent tituent serIe-reduced / gg / Kg effect.

No R1 R2 R3 (Wistar- Eloon rat) jSnud 1 Cl Me H e) 5 a) 8 a) 7 80 g) ______8 c) _______ 2 Me Me H d) e) 5 8 a) 7 80 f) 57.7 b) 23.4 b) _____8 C) ______ 3 Cl Me Me 11 17 a) 3.5 50 g) 36.7 b) 15.2 b) _____14 c) _____ 4 Cl Me Ph 31.7 ^ 13.3 b) 3, 2 40 g) 5 Me Et H® * 4 7 a ^ 8.3 90 f) 63.6 b) 25.9 b) _____6 C * _____ 6 Me Et Me 9 12 a * 3.9 60 g) _____38, 9 b) 15.6 b) __ * \ _ r Π HO c — C — 0 / ^ N / NnCH, Ph 10 69065 a) In the serum of WISTAR rats, "Fructose model" (5 days after dosing, from the fourth day 10 % fructose as drinking liquid); ED20 (mg / kg) b) in the serum of normal lipemic WISTAR rats, two p.o. after dosing 1.10 ~ 4 mol / kg in two days (% compared to controls, n = 10) c) Reduction of triglycerides in the "Fructose model" as in a); ED20 (mg / kg) f) 2 and 5 hours i.v. After ADP injection.

g) 2 hours i.v. After ADP injection.

d) This new compound with a combination of R1 = methyl (4-position) and R3 = hydrogen (5-position) increases the p.o. in mini-LEWE pigs. after dosing very significantly HDL cholesterol by lowering total cholesterol.

e) These new compounds with a combination of R1 = Cl or methyl (in the 4-position) and R3 = hydrogen (in the 5-position) have shown very low toxicity. After a daily dose of 150 mg / kg (6-month test, Mini-LEWE pigs weighing 40 to 60 kg), no toxic effects were observed.

The antithrombotic effect shown in the table is calculated from the number of live mice (%, n = 10) in a single rapid 400 mg / kg ADP i.v. after the injection. Animals were given once p.o. 12 hours before ADP injection. 1.10 μmol / kg of test compound. All untreated control animals died after 2 to 3 minutes (acute thromboembolism).

it

Claims (1)

A process for the preparation of pharmacologically valuable 3- (1-carboxyalkoxy) -pyrazole derivatives of the general formula. wherein R1 represents chlorine or methyl and R1 represents straight-chain or branched-C1-4-alkyl, and for the preparation of their salts with physiologically tolerable inorganic or organic bases, characterized in that that the R 1 / H nf (II) AvKv HO N CH, -Ph of the 3-hydroxy-pyrazole derivatives of the general formula II and the R 1, H „XX (III) O of the Δ4 -pyrazolinone (3) derivatives of the general formula III NhT NCH 2 -PH H tautomeric mixtures in which R 1 · is as defined above are reacted in a manner known per se with either alcohols of the general formula IV Me tt-C-OH (iv) R * in which R 2 is as defined above as defined, and z is Cl, Br or J, or per mole of tautomer mixture (II / III) with at least 1 mole of a carbonyl compound of general formula V 69065 Me c = o I (V) RJ wherein R 2 is as defined above, and t per mole of the automeric mixture (II / III) with at least 1 mole of trihalomethane Z3CH wherein Z is as defined above, optionally adding a catalytic amount of alkali metal iodide, and adding 4 to 6 moles of alkali metal hydroxide, alcoholate, hydride or amide polar in an aprotic solvent, after which, if desired, the compounds are converted into their physiologically tolerable salts in a manner known per se. For the preparation of a pharmacologically active compound, 3- (1-carboxyalkoxy) -pyrazole compounds with all the formulas or (i) ^ C-C-O // N / NNCH1-Ph / I HO and the active formula R1 are chlorine or methyl and R2 is enriched or substituted with C4-alkyl, but also with a physiological mixture of organic or organic bases, which can be treated with a 3-hydroxypyrazole mixture with all the compounds of formula II% _ / H s (II )) 1 i -N \ HO ^ VCHj — Ph li