Pyrazole[3,4-d]pyrimidines having anticonvulsant and anti-allergic/asthma action methods for their production (options) and pharmaceutical composition

 

(57) Abstract:

The invention relates to new pyrazole[3,4-d]pyrimidines having anticonvulsant and anti-allergic/asthma action methods for their preparation (options) and pharmaceutical compositions based on them. Pyrazole[3,4-d]pyrimidines correspond to the General formula 1 or its tautomer, where X is oxygen, sulfur, - halogen, C1-4-alkyl, C1-4-alkoxygroup or trifluoromethyl, m= 1 or 2. Methods for obtaining compounds of General formula 1 are in the cyclization of compounds of formula 2 with formamide or in the interaction of compounds of formula 1 where X is oxygen, with paternity phosphorus or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide. The pharmaceutical composition comprises one or more compounds of formula 1 and one or more physiologically-tolerated excipients and/or carriers. 4 C. and 4 h.p. f-crystals, 4 PL.

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The invention relates to pyrazole[3,4-d] pyrimidine-4(5H)-Onam and pyrazole[3,4-d] pyrimidine-4(5H)-thiones and their tautomers, having in position 2 benzyl Deputy, to a method for their production and their use as pharmaceuticals, in particular for the treatment of various forms of epilepsy the ical dermatitis.

The adenosine receptor is set as a target for influence on disorders of various body systems (e.g., Central nervous system, respiratory tract and other). Pyrazole[3,4-d]pyrimidines are of interest from a pharmacological point of view, as compounds structurally similar to adenine.

2-Benzyltoluene pyrazole[3,4-d] pyrimidine-4(5H)-thiones and their tautomers unknown.

Pyrazole[3,4-d]pyrimidine-4(5H)-ones and their tautomers, containing in position 2 substituted benzyl Deputy, is also unknown.

Hitherto only described 2-benzylphenol[3,4-d]pyrimidine-4(5H)-he [R. böhm (R. Bhm, Pharmacie 1986, 41, 430); Eisenacher, success and BEM (Th. Eisencher, R. Pech, R. Bhm, Pharmazie 1991, 46, 747)]. This compound was obtained by cyclization of ethyl ester of 3-amino-1-benzylphenol-4-carboxylic acid using formamide. 2-benzyltoluene esters of 3-aminopyrazole-4-carboxylic acid can be obtained by benzylidene esters of 3-aminopyrazole-4-carboxylic acid [Senda, Hirota, young (S. Senda, K. Hirota, G.-N. Yang, Chem. Pharm. Bull. 1972, 20(2), 391)].

Mention any assumptions about the specific pharmacological action of 2-benzylphenol[3,4-d]pyrimidine-4(5H)-it is unknown.

The disadvantages of the known pretiosum the sicnosti and idiosyncrasy; on the other hand, these tools are ineffective for certain forms of epilepsy.

Various forms of allergic/asthmatic diseases, for example bronchial asthma, are also not amenable to treatment with medicines.

Thus, the present invention is the task of creating connections with favorable pharmacological properties, suitable as pharmaceuticals, in particular for the treatment of epilepsy and various allergic/asthmatic diseases.

In accordance with the present invention, such new compounds are 2-ar(alkyl)-pyrazole[3,4-d] pyrimidine-4(5H)-ones and 2-ar(alkyl)-pyrazole[3,4-d]pyrimidine-4(5H)-thiones General formula 1

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or tautomers, in which X is oxygen or sulfur,

Y is halogen, C1-C4-alkyl, C1-C4-alkoxygroup or trifluoromethyl.

Examples of compounds of General formula 1 are:

(1) 2-(2-terbisil)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

(2) 2-(2-Chlorobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

(3) 2-(2-bromobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

(4) 2-(2-iodobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

(5) 2-(2-trifloromethyl)-pyrazole[3,4-d]pyrimidin-4(5H)-he;

(8) 2-(2,6-diferensial)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

(9) 2-(2-chloro-6-terbisil)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

(10) 2-(2,6-dichlorobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

(11) 2-(2,4-dichlorobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

(12) 2-(4-methoxybenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

(15) 2-(2-Chlorobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-tion;

(16) 2-(2-bromobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-tion;

(17) 2-(2-iodobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-tion;

(18) 2-(2-trifloromethyl)-pyrazole[3,4-d]pyrimidine-4(5H)-tion;

(19) 2-(2,6-diferensial)-pyrazole[3,4-d]pyrimidine-4(5H)-tion.

The method of obtaining compounds of General formula 1 and their tautomers, in which X represents oxygen, based on the cyclization of compounds of General formula 2 with wavelengths

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where Z is hydroxyl, alkoxygroup or amino group;

Y is halogen, C1-C4-alkyl, C1-C4-alkoxygroup or trifluoromethyl.

The method of obtaining compounds of formula 1 and their tautomers, in which X represents sulfur, based on the substitution in the compounds of formula 1 and their tautomers group, X represents oxygen, sulfur using paternostro phosphorus or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide.

aminopyrazole-4-carboxylic acid. By alkylation of these products respectively replaced by halodendron in conditions of phase transfer receive the compounds of formula 2.

Compounds in accordance with the present invention are suitable for the preparation of pharmaceutical compositions and medicines.

Accordingly, the present invention features a pharmaceutical composition having anticonvulsant and antiallergic/Antiasthmatic activity containing the active substance given in one or more of the above compounds in combination with one or more physiologically tolerated excipients and/or carriers and, if necessary, with diluent.

Drugs can be introduced, for example, parenterally (e.g. intravenously, intramuscularly, subcutaneously), local (through the nose, by inhalation or orally.

The dosage form can prepare well-known in the pharmaceutical practice methods.

Compounds in accordance with the present invention have a strong anticonvulsant and, accordingly, antiallergic/Antiasthmatic effect.

rdEd., Raven Press, New York, 1989). The results are presented in table 1. For oral administration obtained similar results.

For example, for compound 2 (2-(2-Chlorobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-one) in rats in the sample at the maximum electroshock effective dose (ED50) was 32 mg/kg (oral), and neurotoxic dose (NT50) exceeded 250 mg/kg of Compound 15 (2-(2-Chlorobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-tion) also has a strong anticonvulsant effect in a wider therapeutic range (in rats by oral administration ED50=12 mg/kg, NT50>460 mg/kg).

2. Anti-allergic/asthma efficiency

Antiasthmatic action of the compounds in accordance with the present invention were tested in vivo in male Guinea pigs after oral administration, it was determined the inhibition of migration of eosinophilic granulocytes in the lung.

Guinea pigs male line Dunkin Hartley Shoe weighing 200-250 g were sensitized by subcutaneous injection of egg albumin (10 mg+1 mg aluminum hydroxide) and re-sensitised two weeks. A week after the second sensitization aigning for 20-30 seconds. After 24 hours the animals under urethane anesthesia produced bronchoalveolar lavage (BAP) in two portions of the salt solution, 5 ml each. The wash fluid was collected and centrifuged at 400g for 10 minutes the Precipitate suspended in 1 ml of saline solution. Counting eosinophilic granulocytes produced by a microscopic method in the Neubauer chamber. For staining used set for trial on eosinophils type Becton Dickinson (5877). In this set for selective staining of eosinophils applicable Floxin Century, the Count of eosinophils produced in the wash liquid after BAP each animal and counted the number of eosinophils in the millions for each animal. The subjects of the substance is administered orally 2 hours before the provoking allergen.

The percentage inhibition of eosinophils in animals treated with the test substance was calculated by the following formula:

% inhibition=(a-C)-(b-C)/(a-C)100,

where a is the number of eosinophils in animals of the provoked group not treated with the test substance;

In the number of eosinophils in animals of the provoked group treated with the test substance;

With the number of eosinophils in animals of n is Noah asthma migration of eosinophilic granulocytes in the lungs by 74%.

Compounds in accordance with the present invention suitable for the treatment of, for example, bronchial asthma, rhinoconjunctivitis and atopic dermatitis.

Compounds in accordance with the present invention are specific link subtype AND3adenosine receptor.

Receptor antagonists AND3adenosine can by blocking these receptors to inhibit the secretion of mediators. Recently it was shown that receptor antagonists AND3adenosine also inhibit the reduction of the intracellular concentration of camp in eosinophilic granulocytes and thereby to suppress the release of cytokines and other mediators from these cells (Jacobson et al., 1995). Thus it is possible, on the one hand, to mitigate the unpleasant acute symptoms, greatly affecting quality of life, and on the other hand, to suppress the underlying inflammatory disease processes.

Values FORipresented in table 2 show that the compounds in accordance with the present invention bind to the receptors, and the data on selectivity (columns 3 and 4) indicate that binding occurs selectively. It is possible that this new mechanism linking helps Biologicheskie and do not limit the scope of protection.

General method of preparing compounds of formula 1 and their tautomers, where X is oxygen, according to table 3 (examples 1-13)

To 40 ml of formamide was added 30 mmol of compounds of formula 2 and heated at a temperature in the range of 100oWith up to 200oC for 8-16 hours. After cooling, the precipitated precipitated crude product is filtered off with suction and recrystallized from an appropriate solvent, such as ethanol or dimethylformamide.

General method of preparing compounds of formula 1 and their tautomers, where X is sulfur, according to table 4 (examples 14-20)

Methods AND

To 100 ml of pyridine was added 20 mmol of the compound of formula 1 in which X is oxygen, and 80 mmol paternostro phosphorus and heated at a temperature in the range of 80oWith up to 115oC for 4-8 hours. After cooling, the precipitated precipitated crude product is purified by recrystallization from a suitable solvent, e.g. ethanol.

Method IN

To 100 ml of xylene was added 10 mmol of the compound of formula 1 in which X is oxygen, and 20 mmol of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide and heated for 8-24 hours. After cooling, the precipitated precipitated crude product is separated by filtration and PTS is and shows the composition of four tracks, relevant to the present invention, where the active principle is proposed by the present invention the connection.

Example 1, mg:

Active start - 200-250

Monohydrate lactose - 300-375

Microcrystalline cellulose - 50

Hydroxypropylcellulose - 50

Magnesium stearate - 10-20

Composition 2, mg:

Active start - 200-250

Swelling corn starch - 300-400

Sodium salt of cross-linked carboxymethylcellulose - 50

Stearylamine acid - 10-20

Highly dispersed silicon dioxide - 10-20

The hypromellose - 10-20

Macrogol- 10-20

Composition 3, mg:

Active start - 200-250

Lactose - 300-400

Talc - 50

Microcrystalline cellulose - 10-20

Corn starch - 10-20

Eudragit- 10-20

Macrogol- 10-20

Composition 4, mg:

Active start - 200-250

Sodium salt carboxymethylamino starch - 300-400

Powdered cellulose is 10-20

Microcrystalline cellulose - 10-20

Copolymer of polyvinylpyrrolidone (Copolyvidon) - 10-20

Macrogol- 10-20

Monohydrate lactose - 10-20

Magnesium stearate - 10-20

Poly(O-2-hydroxypropyl, methyl)C is sulfur;

Y is halogen, C1-C4-alkyl, C1-C4-alkoxygroup or trifluoromethyl;

m = 1 or 2.

2. Connection on p. 1, characterized in that it is a

2-(2-terbisil)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(2-Chlorobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(2-bromobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(2-iodobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(2-trifloromethyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(2-methylbenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(3-trifloromethyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(2,6-diferensial)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(2-chloro-6-terbisil)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(2,6-dichlorobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(2,4-dichlorobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(4-methoxybenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-he;

2-(2-Chlorobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-tion;

2-(2-bromobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-tion;

2-(2-iodobenzyl)-pyrazole[3,4-d]pyrimidine-4(5H)-tion;

2-(2-trifloromethyl)-pyrazole[3,4-d]pyrimidine-4(5H)-tion;

2-(2,6-diferensial)-pyrazole[3,4-d]pyrimidine-4(5H)-tion.

3. Connection on p. 1 or 2 for the preparation of drugs for the treatment of epilepsy.

4. Connection on p. 1 or p. 2 for the preparation of medicinal denene General formula 1

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or tautomer,

where X is oxygen;

Y is halogen, C1-C4-alkyl, C1-C4-alkoxygroup or trifluoromethyl;

m = 1 or 2

characterized in that the compound of formula 2

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where Z is hydroxyl, alkoxygroup or amino group;

Y is halogen, C1-C4-alkyl, C1-C4-alkoxygroup or trifluoromethyl;

m = 1 or 2

subjected to cyclization with formamide.

6. The method of obtaining compounds of General formula 1

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or tautomer,

where X is sulfur;

Y is halogen, C1-C4-alkyl, C1-C4-alkoxygroup or trifluoromethyl;

m = 1 or 2

characterized in that the compound of General formula 1

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or tautomer,

where X is oxygen;

Y is halogen, C1-C4-alkyl, C1-C4-alkoxygroup or trifluoromethyl;

m = 1 or 2

enter into reaction with paternity phosphorus or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide.

7. Pharmaceutical composition having anticonvulsant and antiallergic/Antiasthmatic activity containing the active substance in combination with one or more physiologically tolerated supporting aetsa one or more pyrazole[3,4-d]pyrimidines under item 1.

8. The pharmaceutical composition according to p. 7, characterized in that the active substance is one or more pyrazole[3,4-d]pyrimidines according to p. 2.

 

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