HU176023B - Process for producing meso-ionic degehydro derivatives of 1,7-dihydro-1-substituted-3h-pyrasolo-square bracket-4,3-e-square bracket closed-1,2,4-triazolo-square bracket-4,3-c-square bracket closed-pyrimidine-3-thiones and 3-thionones - Google Patents

Abstract

New pyrazolo[4,3e]1,2,4-triazolo [4,3-c]pyrimidine derivatives which have the formula <IMAGE> wherein R1 is hydrogen, C1-7alkyl, phenyl-C1-7alkyl, cycloalkyl or hydroxy- C1-7alkyl; R2 is hydrogen or C1-7 alkyl; R3 is C1-7alkyl, cycloalkyl or hydroxy-C1-7alkyl; and X is sulfur or oxygen, are useful as anti- inflammatory agents.

Description

The present invention relates to a process for the preparation of 1,7-dihydro-1-substituted-3H-pyrazolo [4,3-e] 1,2,4-triazolo [4,3-c] pyrimidin-3-thione and -3-one for the preparation of meso-ionic didehydro derivatives of general formula (I). The compounds are new.

United States Patent 4,053,474 discloses 10 groups of 3-mercapto-7H-pyrazolo [4,3-e] -1,2,4-triazolo [4,3-c] pyrimidines which have a and / or unsubstituted or substituted at the 9-position with lower alkyl groups and derivatives having different substituents on the 3-sulfur atom. These compounds are prepared by one of two methods of sequential treatment of 1- and / or 3-unsubstituted or substituted 4-halopyrazolo [3,4-d] pyrimidines with hydrazine and 1,1-thiocarbonyldiimidazole. These compounds are of Formula A wherein R ₁ and R ₂ are hydrogen or lower alkyl, R 3 is hydrogen, a salt-forming ion, -C (lower) alkyl, lower alkyl or substituted lower alkyl, wherein lower alkyl

The substituents of O 1 are hydroxy, cyano, phenfl, -C- (short 30

OR _s R

(IIC) alkyl, -C-R4, -N1 or -CON \

RER "group, wherein _R5 and Re are independently hydrogen or lower alkyl, or R ₅ and R _o heterocyclic radical such as pyrrolidino, piperidino, morpholino or piperazinyl radical form R4-lower alkyl or phenyl, with the nitrogen atom, and R ₇ and R _g are independently hydrogen or lower alkyl group having.

It has been found that when the above unsubstituted or substituted 4-halopyrazolo [3,4-d] pyrimidines are treated with monosubstituted hydrazine instead of hydrazine followed by 1,1-thiocarbonyldiimidazole, a 1,7-dihydro-1-substituted The meso-ionic didehydro derivative of -3H-pyrazolo [4,3-e] 1,2,4-triazolo [4,3-c] pyrimidine-3-thione is obtained, the desired meso-ionic form wherein the sulfur atom negative and nitrogen is positively charged and the substituent of the original hydrazine reagent is now in the 1-position. The same meso-ionic derivative can be prepared by using carbon disulfide instead of 1,1-thiocarbonyldiimidazole. Similarly, analogous oxygen-containing products can be prepared by using 1,1-quinonyldiimidazole instead of 1,1-thiocarbonyldiimidazole.

The present invention thus relates to a process for the preparation of 1,7-dihydro-1-substituted 3H-pyrazolo [4,3-e] 1,2,4-triazolo [4,3-c] pyrimidin-3-thione or -3-one. for the preparation of meso-ionic didehydro derivatives of the general formula wherein

R 1 is C 1-5 alkyl,

R _{2 is} hydrogen,

R _{3 is C} 1-6 alkyl, and X is sulfur or oxygen.

Preferred compounds are those compounds of formula I wherein R 1 and R _{3 are C} 1-4 alkyl, R _{2 is} hydrogen, and X is primarily sulfur.

According to the present invention, the compound of formula I is prepared from a 4-halopyrazolo [3,4-d] pyrimidine of formula II wherein halo, preferably ld, R ₁ and R ₂ are as defined above, by reacting this compound in an alcohol such as ethanol or propanol, preferably at room temperature, with a substituted hydrazine of formula III wherein R _{3 is} as defined above, and the resulting intermediate of formula IV in an inert organic reaction medium such as dimethylformamide, ethyl acetate, diethylene glycol dimethyl ether or the like; higher, e.g. At 80 ° C

With thiocarbonyldiimidazole or carbon disulfide. This gives compounds of formula I wherein X is sulfur. As a reagent

Using 1,1-carbonyldiimidazole, the product of formula I is obtained wherein X is oxygen.

Starting materials can be prepared according to U.S. Patents 4,053,474, 3,720,674, 3,732,225 and 3,873,556 and J. Org. Chem., 21, 1240 (1956).

The novel compounds of the present invention have anti-inflammatory activity and can be used, for example, as anti-inflammatory agents to reduce local inflammatory conditions. They may be edemaous or may result from the proliferation of connective tissue in various mammalian species such as rats, dogs, and the like. The compounds are administered orally at ca. 1-100 mg / kg / day, preferably

In doses of 3-20 mg / kg / day, as a single dose or in divided doses, according to the instructions of the "Mouse Active Arthus Assay". The active ingredient is prepared in the form of tablets, capsules, solutions or suspensions, each containing up to 500 mg of a didehydro derivative of the Formula I, or mixtures thereof, in dosage units. The active ingredient is admixed with physiologically acceptable solvents, carriers, binders, preservatives, stabilizers, flavorings, as is customary in the pharmaceutical art. Alternatively, topical formulations may be used which have a concentration of ca. They contain from 0.01% to 3% by weight of the active ingredient in a conventional lotion, cream or ointment.

An exemplary embodiment of the process of the present invention is illustrated by the examples which serve as a model for the preparation of similar compounds using appropriately substituted other reagents. In the examples, the temperature values are given in ° C.

Example 1

Meso-ionic didehydro derivative of 1,7-dihydro-1,7-dimethyl-3H-pyrazolo [4,3-e] 1,2,4-triazolo [1,3-c] pyrimidine-3-thione

A) 1-Methyl-4-carbethoxy-5-aminopyrazole

320 g of ethyl ethoxymethylene-ethyl acetate are dissolved in 2 liters of absolute ethanol and 87 g of methyl hydrazine are added dropwise with stirring, while the temperature rises to 35 °. The reaction mixture was refluxed for 12 hours, then the solvent was distilled off and the solid residue was recrystallized from a little methanol. 162 g (95.8%) of 1-methyl-4-carbethoxy-5-aminopyrazole are obtained, m.p. 92-93 ° C.

B) 5 - [(Ethoxymethylene) amino] -1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

84.6 g of l-methyl-4-carbethoxy-5-aminopyrazole and

74.1 g of triethyl ortho-formic acid is heated until the ethanol is cleaved off. The oily residue is distilled in an oil pump vacuum. This gives 5 - [(ethoxymethylene) amino] -1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, m.p. 98-102 ° C, melting point 32-34 °. Yield 87%.

C) 1-Methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one

57.2 g of ethyl 5 - [(ethoxymethylene) amino] -1-methyl-1H-pyrazole-4-carboxylic acid are dissolved in 200 ml of ethanol, 4.4 g of ammonia are added and the reaction mixture is autoclaved for 60 hours at 60 ° C. we. The mixture was cooled, filtered and the remaining 1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one crystallized from dimethylformamide. M.p. 289-290 ° C. Yield: 31 g (80.7%).

D) 1-Methyl-4-chloropyrazolo [3,4-d] pyrimidin-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one is added to 300 ml of phosphorus oxychloride, and refluxing the mixture. The excess phosphorus oxychloride was distilled off and the semi-solid residue was extracted with boiling benzene (3 x 100 mL). The benzene extracts are combined, the extract is concentrated to half its volume and added to light petroleum. The mixture was left in the refrigerator for 12 hours, the precipitated 1-methyl-4-chloropyrazolo [3,4-d] pyrimidine was filtered off with suction and recrystallized from cyclohexane to give 54 g (60.5%) of a white crystalline product, m.p. -96 °.

E) 1-Methyl-4- (1-methylhydrazino) pyrazolo [3,4-d] pyrimidine 1-Methyl-4-chloropyrazolo [3,4-d] pyrimidine was dissolved in 1 L of n-propanol. 45 g of methyl hydrazine were added dropwise at room temperature and stirred for 35 hours. The reaction mixture is then filtered and the remaining 1-methyl-4- (1-methylhydrazino) pyrazolo [3,4-d] pyrimidine is added and recrystallized twice from dimethylformamide with activated carbon. 67.2 g (84%) of a white crystalline product are obtained, m.p.

F) Meso-ionic didehydro derivative of 1,7-dihydro-1,7-dimethyl-3H-pyrazolo [4,3-e] 1,2,4-triazolo [4,3-c] pyrimidine-3-thione g l Methyl 4- (1-methylhydrazino) pyrazolo [3,4-d] pyrimidine was dissolved in 100 ml of dimethylformamide and 30 g of 1,1-thiocarbonyldiimidazole dissolved in 20 ml of dimethylformamide was added simultaneously. The reaction mixture was stirred at room temperature for 12 hours. The precipitate which formed was collected by suction and crystallized from dimethylformamide together with the residue obtained by evaporation of the filtrate by the addition of activated carbon. 29 g (75.4%) of 1,7-dihydro-1,7-dimethyl-3H-pyrazolo [4,3-e] 1,2,4-triazolo [4,3-c] pyrimidine-3-thione meso yielding an ionic didehydro derivative in the form of yellowish felt-like crystals. The product has a melting point > 270 °.

Example 2 1,7-Dihydro-1-methyl-7-isopropyl-3H-pyrazolo [4,3-e] 1,2,4-triazolo [4,3-c] pyrimidine-3-thio meso-didehydro from

A) 1-Isopropyl-4-carbethoxy-5-aminopyrazole

Example 1A, but using isopropyl hydrazine instead of methylhydrazine to give 1-isopropyl-4-carbethoxy-5-aminopyrazole, b.p. 123-127 at 0.05 mm.

B) 5 - [(Ethoxymethylene) amino] 14 isopropyl

H-pyrazole-4-carboxylic acid ethyl ester

Using the above product obtained in A in Example 1 Part B, the ethyl ester of 5 - [(ethoxymethylene) amino] -1-isopropyl-1H-pyrazole-4-carboxylic acid having a boiling point of 0.01 mm at 98-103

C) 1-Isopropyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one

The product from Part B was used in Example 1C to give 1-isopropyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one, m.p. 193 °.

D) 4-Chloro-1-isopropylpyrazolo [3,4-d] pyrimidine

The product of Part C was used in Example 1, Method D, to give the title compound

4-chloro-1-isopropylpyrazolo [3,4-d] pyrimidine, m.p. 47-49 ° C.

E) 1-Isopropyl-4- (1-methylhydrazino) pyrazolo [3,4-d] pyrimidine

The product prepared according to Part D was used in Example 1E) to give 1-z opr op 114- (1-methylhydrazino) pyrazolo [3,4-d] pyrimidine, m.p. 105-108 °.

F) 1,7-Dihydro-1-methyl-7-isopropyl-3H-pyrazolo [4,3-e] 1,2,4-triazolo [4,3-c] pyrimidine-3-thio meso-didehydro from

The product prepared according to Part E was used in Example 1, Method F to give the title compound

1.7-Dihydro-1-methyl-7-isopropyl-3H-pyrazolo [4,3-e] -

The meso-ionic didehydro derivative of 1,2,4-triazolo [4,3-c] pyrimidine-3-thione, m.p. 290-292 °.

Example 3

Butyl-1,7-dihydro-7-methyl-3H-pyrazolo [4,3-e]

Meso-ionic didehydro derivative of 1,2,4-triazolo [4,3-c] pyrimidine-3-thione

A) 4- (1-Butylhydrazino) -1-methyl-1H-pyrazolo [3,4-d] pyrimidine

In Example 1, Method E, methylhydrazine is substituted with butylhydrazine to give 4- (1-butylhydrazino) -1-methyl-1H-pyrazolo [3,4-d] pyrimidine, m.p. 68-72 ° C.

B) 1-Butyl-1,7-dihydro-7-methyl-3H-pyrazole

- Meso-ionic didehydro derivative of [4,3-e] 1,2,4-triazolo [4,3-c] pyrimidine-3

The product from Part A was used in Example 1, F to give 1-butyl-1,7-dihydro-7-methyl-3H-pyrazolo [4,3-e] 1,2,4-triazolo [a] The meso-ionic didehydro derivative of 4,3-c] pyrimidine-3-thione, m.p. 272-275 °.

Example 4

Meso-didehydro derivative of 1.7-dihydro-1-isopropyl-7-methyl-3H-pyrazolo [4,3-e] 1,2,4-triazolo [4,3-c] pyrimidine-3-thione

A) 4- (1-Isopropylhydrazino) 4-methyl-1 H-pyrazolo [3,4-d] pyrimidine

In Example 1, Method E, methylhydrazine is replaced by isopropylhydrazine to give 4- (1-isopropylhydrazino) -1-methyl-1H-pyrazolo [3,4-d] pyrimidine, m.p. 57 °.

B) Meso-ionic didehydro derivative of 1,7-dihydro-1-isopropyl-7-methyl-3H-pyrazolo [4,3-e] 1,2,4-triazolo [4,3-c] pyrimidine-3-thione

The product prepared according to Part A was used in Example F, Example 1 to give the title compound

1,7-Dihydro-1-isopropyl-7-methyl-3H-pyrazolo [4,3-ej-

The 1,2,4-triazolo [43-c] pyrimidine-3-thione is a ionic didehydro derivative with a melting point of 316-317 °.

Example ^{5 5}

1,7 * Dihydro-1,7-dimethyl-3H-pyrazole {4,3-e]

1.2.4 Meso-ionic didehydro derivative of triazolo (43-c) pyrimidine-3-thione

A) 1-Methyl-4- (1-methylhydrazino) -pyrazolo [3,4-d] pyrimidine

Dissolve 1.7 g of methyl hydrazine in 30 ml of ethanol and add 3.3 g of 4-chloro-1-methyl-pyrazolo (3,4-d) pyrimidine in portions, reflux for 30 minutes and refrigerate. After stirring overnight, the mixture was filtered and the product recrystallized from 1-methyl-4- (1-methylhydrazino) pyrazolo [3,4-d] pyrimidine from ethanol-methanol. The product had a melting point of 213-215 °.

B) 1,7-Dihydro-l, 7-dimethyl-3H-pyrazolo [4,3-e] l, _l 2 4-triazolo (43-c] pyrimidine-3-thione meso-ionic didehydro derivative 25

Dissolve 0.5 g of the product of Part A in 10 ml of dimethylformamide and add 0.22 g of carbon disulphide dropwise. The reaction mixture was then heated at 80 ° for 2 hours. The

The meso-ionic didehydro derivative of 1,7-dihydro-1,7-dimethyl-3H-pyrazolo [43-e] 1,2,4-triazolo [4,3-c] pyrimidine-3-thione crystallizes until the reaction is complete. The reaction mixture was cooled and filtered to give 35 g of product, m.p. 300 °.

Example 6

1.7-Dihydro-1,7-dimethyl-3H-pyrazolo [4,3-e]

1.2.4-Meso-ionic didehydro derivative of triazolo (43-c) pyrimidin-3-one

1.7 g of 1-methyl-4- (1-methylhydrazino) -pyrazolo [3,4-d] -45-pyrimidine and 1.62 g of 1,1-carbonyldiimidazole in 20 ml of dimethylformamide at 80 ° stir for minutes. The mesonic ionic didehydro derivative of the product, 1,7-dihydro-1,7-dimethyl-3H-pyrazolo [4,3-e] 1,2,4-triazolo [43-c] pyrimidin-3-one The product was recrystallized from dimethylformamide, m.p. 303-306 DEG C. Yield: 1.6 g.

Claims (6)

Patent claims: 55 A process for the preparation of 1,7-dihydro-1-substituted-3H-pyrazolo [43-e] 1,2,4-triazolo [4,3-c] pyrimidine-3-thione and -3-one meso for the preparation of ionic didehydro derivatives - 60 R 1 is C 1-5 alkyl, R _{2 is} hydrogen, R _{3 is C} 1-6 alkyl and X represents an oxygen or sulfur atom, characterized in that a compound of the formula II, in which R 1 and R _{2 is} as defined above and a halogen atom is reacted with a hydrazine of formula III, wherein R _{3 is} as defined above, and the resulting intermediate of formula IV is obtained. (a) for the preparation of compounds of the formula I in which X is oxygen; With 1,1-carbonyldiimidazole, or b) reacting a compound of formula I wherein X is sulfur with 1,1-thiocarbonyldiimidazole or carbon disulfide. Process for variant b) according to claim 1, which is 1,7-dihydro-1,7-dimethyl-3H-pyrazolo [4,3-e] 1,2,4-triado [4,3-c] pyrimidine For the preparation of the meso-ionic didehydro derivative of -3 · -thion by reacting 1-methyl-4-chloropyrazolo [3,4-d] pyrimidine with methylhydrazine, the resulting 1-methyl4- (1-methylhydrazino) pyrazolo [ 3,4-d] pyrimidine is reacted with 1,1-thiocarbonyldiimidazole or carbon disulfide. The process of process variant b) according to claim 1, is carried out on 1,7-dihydro-1-methyl-7-isopropyl-3H-pyrazolo [4,3-e] 1,2,4-triazolo [43-c} The pyrimidine -3-thio meso-ionic didehydro derivative is prepared by reacting 4-chloro-1-isopropylpyrazolo [3,4-d] pyrimidine with methylhydrazine followed by 1-isopropyl-4- (1-methylhydrazino) - pyrazolo [3,4-d] pyrimidine is reacted with 1,1-thiocarbonyldiimidazole. The process of process variant b) according to claim 1, which is carried out on 1-butyl-1,7-dihydro-7-methyl-3H-pyrazolo [4,3-e] 1,2,4-triazole [4]. 3-cis pyrimidine-3-thione meso-ionic didehydro derivative by reacting 4-chloro-1-methylpyrazolo [3,4-d] pyrimidine with butylhydrazine followed by 4- (1-butyl) -hydrazino-1-methyl-1H-pyrazolo [3,4-d] pyrimidine is reacted with 1,1-thiocarbonyldiimidazole. The process of process variant b) according to claim 1, which is carried out on 1,7-dihydro-1-isopropyl-7 · methyl-3H-pyrazolo [4,3-e] 1,2,4 · triazolo [4,3-c]. A process for preparing the meso-ionic didehydro derivative of pyridine midin-3-thione by reacting 1-chloro-4-methylpyrazolo [3,4-d] pyrimidine with isopropyhydrazine to give 4- (1-isopropylhydrazino) -1-methyl -1H-pyrazolo [3,4-d] pyrimidine is reacted with 1,1-thiocarbonyldiimidazole The process of embodiment (a) according to claim 1, which is 1,7-dihydro-1,7-dimethyl-3H-pyrazolo [43-e] 1,2,4-triazolo [4,3-c] pyrimidine-3. -one is prepared by reacting 4-ldoro-1-methylpyrazolo [3,4-d] pyrimidine with methylhydrazine followed by 1-methyl-4- (1-methylhydrazino) pyrazolo [3 4-d] piriniidint With 1,1-carbonyldiimidazole.