4-(allumination)-2,4-dihydropyrazol-3-ones, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts. The compounds are selective inhibitors with GMP specific phosphodiesterase. Part of the invention are also the YERAZ, (cGMP, RDE), containing as active substance a compound of the formula I or one of its salts. The invention also relates to 4-(4,5-dihydro-3-methyl-5-oxo-4- (2-(2-propenyloxy) anilinomethylene)-1-H-pyrazole-1-yl)-benzoic acid. 4 S. and 2 C.p. f-crystals, 1 PL.

The invention relates to derivatives2the pyrazolinone-5 the General formula I:

< / BR>
where

R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, phenyl, unsubstituted or substituted once to three-fold amino, acyl, halogen, nitro, CN, AO, carboxyla, sulfonium, AND-O-CO -,-CO-NH-, AND-CO-PA-, carbamoyl, N-allylcarbamate, N,N-dialkylammonium (with 1-6 C-atoms in the alkyl part), AND-O-CO-NH-, AND-O-CO-PA-, SO2NR4R5(R4and R5can represent H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, S, O, which may be substituted (a) (a-CO-NH-SO2- AND-CO-PA-SO2-, A-SO2-NH -,-SO2-PA-, (A-SO2-)2N-, tetrazolium or fosforom; or pyridyl;

R2denotes alkyl with 1-5 C-atoms, alkoxycarbonylmethyl, hydroxyalkyl, hydroxyarylalkyl;

R3denotes hydrogen, alkyl with 1-5 C-atoms with param alkyl, aminoalkanoic, aminoalkyl, carbarnoyl, SO2NR4R5(R4and R5represent H, alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, S, O, which may be substituted);

And denotes alkyl with 1-6 C-atoms, straight or branched chain, substituted by fluorine or chlorine, alkyl with 1-6 C-atoms, straight or branched chain, and to their physiologically acceptable salts.

Part of the invention are also methods of obtaining these compounds, but especially their use as selective inhibitors G specific phosphodiesterase (cGMP, RDE) and thus as pharmaceutically active compounds.

These partially known for other purposes, and effective as of cGMP RDE inhibitors compounds can be applied in various fields of medicine. In particular they can be used for the treatment of diseases of the cardiovascular system, heart failure, arteriosclerosis and other diseases caused by impaired function of the coronary vessels of the heart.

From the literature it is known a large number of compounds that have an inhibitory effect on G RD-esterase.

So, in hibitory RDE, which can be used to treat diseases of the coronary vessels of the heart in heart failure or heart failure. However, this patent does not specify any examples of these compounds, nor particularly effective RDE-inhibitors, in particular, for cGMP, RDE.

In WO-A1-93/06104 described substituted pyrazolo [-4,3]-pyrimidine-7-ons with superior as opposed opened in the aforementioned patent to the class of compounds personality inhibitors regarding cGMP RD-esterase compared with camp RD-esterases. However, this patent does not take into account the selectivity of these compounds against other phosphodiesterase I, II and III.

However, simultaneously inhibiting activity of the compounds on the other phosphodiesterase is of great importance, because while the inhibitory effect on other esterase except G-phosphodiesterase (V) may be a whole range of unwanted side effects when they are used as medicines.

Therefore, the objective of this invention to provide compounds which have a particularly pronounced inhibitory activity on cGMP-phosphodiesterase (V), but at the same time on the other phosphodiesterase not Okakarara explained by inhibition RD-esterase I-IV, not found.

At the same time the task of this invention is to develop a method by which the compounds can be obtained with high yields and with high pureness.

It was found that to solve this problem of the compounds of formula (I)

< / BR>
where

R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, phenyl, unsubstituted or substituted once to three-fold amino, acyl, halogen, nitro, SP, AO, carboxyla, sulfonium, AND-O-CO -,-CO-NH-, A-CO-NA-, carbamoyl, N-allylcarbamate, N,N-dialkylammonium (with 1-6 C-atoms in the alkyl part), AND-O-CO-NH-, A-O-CO -, NA-, SO2NR4R5(R4and R5can represent H or alkyl with 1-6 C-atoms, or R4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, S, O, which may be substituted through (a) (a-CO-NH-SO2- AND-CO-PA-SO2- ,- SO2-NH -,-SO2-PA-AND-SO2-)2N-, tetrazolium or fosforom phenyl; or pyridyl,

R2denotes alkyl with 1-5 C-atoms, alkoxycarbonylmethyl, hydroxyalkyl, hydroxyarylalkyl;

R3denotes H, alkyl with 1-5 C-atoms, straight or branched chain is alkanolamine, aminoalkyl, carbarnoyl, SO2NR4R5(R4and R5represent H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, S, O, which may be substituted by a);

And denotes alkyl with 1-6 C-atoms, straight or branched chain, substituted by fluorine or chlorine, alkyl with 1-6 C-atoms, straight or branched chain, or their salts.

Further, the subject invention are new compounds of General formula (1), where

R1may designate, in addition, also phenyl, unsubstituted or substituted once to three times by halogen, nitro, cyano, carboxyla or amino, and

R2denotes hydroxyalkyl and

R3denotes H, alkyl with 1-5 C-atoms, straight or branched-chain alkoxy with 1-5 C-atoms, straight or branched chain, substituted by fluorine or chlorine, alkyl-, or their salts.

Preferred compounds of General formula (I), where

R1have the above meanings and R2denotes H5WITH2-O-CO-CH2and

R3denotes aminoalkanoic, alkanolamine, carbarnoyl, SO2NR4R5(R4and R5denote H or alkyl with 1-6 C-atoms Il is et to be replaced by a);

or their salts.

In particular, the subject invention are the following compounds:

methyl ester of N-3(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-carbamino acid;

4-((2-ethoxyaniline)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-N-ethylbenzylamine;

complex ethyl ester 2-(1-4-(N,N-diethylcarbamoyl)-phenyl)-4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-4-(N,N-diethylcarbamoyl)-phenyl)-4-((2-ethoxyaniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-acetamidophenyl)-4-((2-ethyl-aniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1-(4-triftoratsetofenona)-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-ethoxycarbonylphenyl)-4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(4-((2-ethylaminomethyl)-4,5 - dihydro-1-(4-methanesulfonamido)-5-oxo-1H-pyrazole-3-yl)-acetic acid;

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-5H-pyrazole-1-yl)-phenyl)-ndimethylacetamide;

N, N-IER is iminomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide;

4-(2-ethoxyaniline)-2,4-dihydro-5-methyl-2-(4-(4-morpholinylcarbonyl)-phenyl)-3H-pyrazole-3-one;

4-(2-ethylaminomethyl)-2,4-dihydro-5-methyl-2-(4-(4-methyl-1-piperazinylcarbonyl)-phenyl)-3H-pyrazole-3-one;

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-methanesulfonamide;

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-triptorelin;

N-(4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl) phenyl)-N-methylsulfonylmethane;

N, N-diethyl-4-(4,5-dihydro-4-(2-ethoxyaniline)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide;

N, N-diethyl-4-(4,5-dihydro-4-(2-methoxyaniline)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide;

3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzosulfimide;

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzosulfimide;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-nitrophenyl)-5-oxo-1H-pyrazole-3-yl)-acetic acid;

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzoic acid;

4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-N-hexylbenzene;

4-(4-(2-atilano the-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzamide;

4-(2-ethylaminomethyl)-2,4-dihydro-5-propyl-2-(4-pyridyl)-3H-pyrazole-3-one;

N, N-diethyl-4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzamide;

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-N-hexylbenzene;

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzamide;

4-(2-ethylaminomethyl)-2,4-dihydro-5-propyl-2-(4-(1H-tetrazol-5-yl)-phenyl)-3H-pyrazole-3-one;

4-(2-ethylaminomethyl)-2,4-dihydro-5-methyl-2-(3-(1H-tetrazol-5-yl)-phenyl)-3H-pyrazole-3-one;

4-(4,5-dihydro-3-methyl-5-oxo-4-(2-cryptomaterial)-1H-pyrazole-1-yl)-benzoic acid;

4-(4-(2-ethylaminomethyl)-3-ethoxycarbonylmethyl-4,5 - dihydro-5-oxo-1H-pyrazole-1-yl)benzoic acid;

4-(4,5-dihydro-3-methyl-5-oxo-4-(2-(2-propenyloxy)-anilinomethylene)-1H-pyrazole-1-yl)-benzoic acid;

4-(4,5-dihydro-3-methyl-5-oxo-4-(2-proportionalisation)-1H-pyrazole-1-yl)-benzoic acid;

4-(4,5-dihydro-4-(2-isopropylaminomethyl)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid;

3-(4-(2-ethylenediaminetetramethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide;

complex ethyl ester 2-(1-(4-methoxycarbonylaminophenyl)-4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1H-ilen)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-(N,N-diethylcarbamoyl)-phenyl)-4-(2-ethoxyaniline)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-acetamidophenyl)-4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-1-(4-triftoratsetofenona)-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-methoxycarbonylaminophenyl)-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-methanesulfonamido)-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-acetamidophenyl)-4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-methoxycarbonylaminophenyl)-5-oxo-1H-pyrazole-3-yl)-acetic acid;

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-phenyl)-methanesulfonamide;

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-phenyl)-ndimethylacetamide;

methyl ester of N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-phenyl)-carbamino acid;

complex is acid;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(3-methanesulfonamido)-5-oxo-1H-pyrazole-3-yl)-acetic acid;

and their physiologically not causing fears of salt.

The subject of the invention are, in particular, the medicinal product of General formula (I),

where

R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, phenyl, unsubstituted or substituted once to three-fold amino, acyl, halogen, nitro, SP, AO, carboxyla, sulfonium, AND-O-CO-, A-CO-NH-, AND-CO-PA-, carbamoyl, N-allylcarbamate, N,N-dialkylammonium (with 1-6 C-atoms in the alkyl part), AND-O-CO-NH-, AND-O-CO-PA-, SO2R4R5(R4and R5can represent H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, S, O, which may be substituted by a), A-CO-NH-SO2-, A-CO-NA-SO2- ,- SO2-NH-, A-SO2-NA, (A-SO2-)2N-, tetrazolium or fosforom; or pyridyl;

R2denotes alkyl with 1-5 C-atoms, alkoxycarbonylmethyl, hydroxyalkyl, hydroxyarylalkyl;

R3denotes H, alkyl with 1-5 C-atoms, straight or branched-chain alkoxy with 1-5 C-atoms, straight or RAR>R5(R4and R5denote H, alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, S, O, which may be substituted through A) and their physiologically acceptable salts.

Use of drugs as selective inhibitors of cGMP-specific phosphodiesterase is also part of the invention, and special developments of the invention are the use of compounds of General formula (I) and/or a corresponding physiologically acceptable salts, or the above-mentioned drugs for the manufacture of formulations of medicines for the treatment of diseases, in particular cardiovascular system and heart failure, as well as pharmaceutical compositions that contain at least one of the aforementioned compounds of formula (I) and/or at least one of their physiological salts, or related medicines.

The subject invention are also pharmaceutical compositions containing as active substance at least one compound of formula (I), where the residues R1, R2and R3have the above values, and/or, at IU is passed, liquid or semi-liquid carrier or auxiliary substance.

Pharmaceutical compositions can also contain drugs with inhibitory action.

Part of the invention is also a method for obtaining compounds of the above formula (I) with above defined substituents R1, R2and R3or relevant inhibitors, characterized in that compounds of General formula II

< / BR>
where R1and R2have the above values, make relevant, giving the formaldehyde compounds, such as triazine, or with suitable trialkylaluminium, in particular triethylorthoformate, in compounds of General formula

< / BR>
where X denotes amino -, or-O-alkyl-group with 1-6 C-atoms in the alkyl), and, if necessary, in situ transform with the corresponding aniline derivatives of the formula III

< / BR>
where R3may have specified values, or their salts, optionally in a suitable solvent, into compounds of the formula I, and/or the fact that the compound of the formula I one or more residues R transform in one or more other residues R.

The compounds of formula (I) for the most part with other substituents known the unity of formula 1 can also be used as selective inhibitors of c-GMP-specific phosphodiesterase and in particular, for the treatment of diseases of the cardiovascular system and heart failure.

Particularly advantageous for the use of compounds according to the invention as pharmaceutically active substances is very specific braking G-phosphodiesterase (V), while for the phosphodiesterase RDE I, II, III and IV can be measured braking, which is more than 10,000 times smaller, i.e., unworthy of mention braking. In accordance with the application of specifically acting compounds as medicines do not experience any side effects, which usually occur due to inhibition of other phosphodiesterase.

The compounds of formula II, as well as their original substance can be obtained well-known specialist of numerous publications or slightly modified methods. Corresponding methods are also described in European patent EP-B1-0 274 642 or in the fundamental works as Houben-Weul, "Methods of organic chemistry", publisher George-Tim, Stuttgart, known or specified in the overview guide "Pyrazolones, pyrazolidone and derivatives", Wiley, R. H., Wiley, P.; Interscience Publishers, Jonh Wiley & Sons (1964) literature or described in the following articles: Ringel, C. , Mayer, R., J. Prakt. Ch, . , Chem. Pharm. Bull. (CPBTAL), 29 (1) (1981), 244 and on the following pages; Wilson, J. D., Pulmer, T. D., Dasher, Z. P., Beam, C. F. J. Heterocucl. Chem. 17 (2) (1980) 389-391; Neunhoefer, H., Koehler. Y., Deger, H.-J.; Ziebigs Ann. Chem. (1985), 1, 78-89 Ege, S., Adams, A. D., Yess, E. J., Ragone, K. S., Kober, B. J., J. Chem. Soc. Perkin Trans. (1983) 2, 325-321; Pathak, R. B., Bahel, S. C., J. Indian Chem. Soc. 57 (1980) 1108-1111; Ali, M. I., El-Morsy, M. M. S. , H. Hammouda, A., Sharaf, M. F., Egypt J. Chem. 22 (1979) 179-188; Mcevoy F. J., J. D. Albright, J. Org. Chem. 44 (1979) 4597-4603.

In the following stages of the reaction of compounds of formula II turn further into the compounds of the invention of formula I which may exist as geometric isomers or mixtures of isomers of different composition. This can be done or through an intermediate stage, in which the 4-position pyrazolinone ring substituted methylene group, and the subsequent transformation from a derivative of aniline, or substitution can be made directly through the appropriate aniline derivative. The choices you get depends on the chemical properties of the Vice-pyrazolinone.

Some of the obtained compounds of formula I may exist in tautomeric equilibrium:

< / BR>
However, it is always about the use of compounds of formula I, although meant as pure compounds and their mixtures with different amounts of tautomeric or isomeric soy is eaten compounds of General formula IIA

< / BR>
where R1and R2have the above meanings and X may denote the amino - or alkoxygroup, with the corresponding aniline derivatives of the formula III

< / BR>
where R3may have the above values.

This transformation is carried out if necessary in the presence of a suitable diluent at temperatures from 0 to 120oWith, especially at elevated temperatures.

The compounds of formula IIA can be obtained by transformation of suitable compounds of General formula II

< / BR>
with the giver formaldehyde groups from the group of triazine, dimethylformamide, dimethylformamidine, chemical gold, acid chloride formic acid, formamide or alkyl derivatives of formamide with 1-6 C-atoms in the alkyl or from a group of trialkylaluminium, in particular triethylorthoformate. If necessary, the transformation is carried out in a suitable, do not interfere with the subsequent application of a diluent, such as, for example, glacial acetic acid, and possibly in the presence of a catalyst. The compounds of formula IIA can be identified as intermediate products. But you can also turn them on directly by the reaction in the location with the corresponding amines of the formula III in connection is, what if the compounds of formula II are sensitive substituents that react mainly when turning with the giver formaldehyde compounds or conversion of aniline derivative of formula III. In these cases, mainly corresponding aryl-isocyanate turn in a known manner in the presence of a base, especially butyl or metallice, with a corresponding compound of formula II.

Compounds of General formula II are usually obtained by transformation of a-ketoesters or 1,3-dicarbonyl compounds of General formula IV

< / BR>
where R2can have the above meanings, with hydrazines of General formula V

< / BR>
or their salts, as for example, their hydrochloride, hydrosulfate, gidroksilnami, in particular, if necessary in the presence of a suitable diluent, which does not interfere with further use of the reaction product, such as ethanol, and, if necessary, in the presence of a suitable catalyst, such as toluenesulfonic acid, at temperatures between 0 and 120oC.

Used 1,3-dicarbonyl compounds of the formula IV are known compounds of organic chemistry, and they are either available commercially or synthesized well-known is known compounds or they can be obtained well-known specialist methods (see e.g. , Houben-Weyl, methods of organic chemistry, volume X 2, page 203, publisher Tim Stuttgart, 1967).

As mentioned above, the compounds of the present invention exhibit a selectivity above average as inhibitors for G RD-esterase. Therefore, under the influence of these inhibitors, the concentration of cGMP in the body increases. This manifests itself in a favorable increase in the inhibition of platelet aggregation, increased activity of granulocytes, braking spasm of the blood vessels and increasing vasodilator activity, as well as in enhancing the effect of relaxing factor-induced endothelium. In accordance with this connection is used to treat various diseases, including various manifestations of hypertension, heart failure of various causes atherosclerosis, the effects of the narrowing of the blood vessels, for example, stroke, bronchitis, chronic or allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by disorders of peristalsis of the digestive system.

The biological activity of the compounds of the present invention were determined by the methods described, for example, in international application WO-A1-93/06104.

Thus, the chemical with the inhibition required to achieve 50% inhibition of enzyme activity). For the implementation of the determination by the known methods used selected enzymes (e.g. by W. J. Thompson and others; Biochem., 1971, 10, 311). For the implementation of the experiments used a modified batch-method of W. J. Thompson and M. M. Appleman (Biochem., 18, 5228).

The results of these experiments show that the compounds according to the General formula I are effective and selective inhibitors for cGMP-phosphodiesterase. This applies in particular to such compounds of General formula I, in which R2denotes the residue is methyl, propyl, hydroxycarbonylmethyl and alkoxycarbonylmethyl, and R1means benzoic acid, benzosulfimide, N-methyl - or N, N'-dialkylphosphinate, acylaminoalkyl, N,N-diethylbenzamide or amides of benzoic acid.

Compounds of General formula I, the substituents methyl - or propyl - as R2and benzoic acid, benzamide, N-hexylbenzene or N,N-diethylbenzamide, benzosulfimide or acidaminophilum as R1are especially pronounced inhibiting platelet aggregation effect.

Therefore, compounds of General formula I and their physiologically acceptable salts can be used for the auxiliary substance and, if it is desired, with one or more other active substances form a suitable dosage form. Obtained in this way forms that can be used as drugs in medicine or veterinary medicine. As substances-media use of organic or inorganic substances which are suitable for intestinal (e.g., oral or rectal) or parenteral administration or for use in the form of sprays for inhalation, and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, acetate of glycerol and other glycerides of fatty acids, gelatin, soy lecithin, carbohydrates as lactose or starch, magnesium stearate, talc or cellulose. For oral administration are, in particular, tablets, coated tablets, capsules, syrups, juices or drops, are of special interest lacquer tablets and capsules resistant to gastric juice coatings or shells. For rectal use suppositories, for parenteral use, solutions, mainly oily or aqueous solutions, then suspensions, emulsions or implants. For appointment as sprays for inhalation can be working gas (e.g., perchloroethane). It is reasonable to apply the active ingredient in micronized form, and can be one or more additional physiologically tolerated solvents, e.g. the ethanol. Solutions for inhalation can be entered using conventional inhalers. Active substances, which are claimed according to the invention can also be lyophilized and the resulting products lyophilization is used for example for the manufacture of drugs for injection. These forms can be sterilized and/or they may contain auxiliary substances, such as preservatives, stabilizers and/or substances with a high surface activity, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and/or aromatic substances. They can, if desired, also contain one or more other active substances, for example one or more vitamins, one or more diuretics, one or more anti-inflammatory drugs.

Compounds according to the invention according to formula I, as a rule, by analogy with other known, commercially available drugs, but especially similar to the one described in U.S. patent 4 880 804 SOA unit dosage. Daily dosage is predominantly between about 0.1 and 50 mg/kg, especially between 1 and 10 mg/kg of body weight. However, the specific dose for each patient depends on various factors such as the efficiency of the applied compound, the age, body weight, General health, nutrition, time and mode of appointment, from the rate of release from combinations of medicinal substances and the severity of the respective disease, which is directed therapy. Prefer oral administration.

Below are examples that serve to illustrate the invention but do not limit the invention to these examples.

In the following examples, "conventional processing" means add, if required, water, establish, if required, depending on the structure of the final product, the pH is between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and/or crystallization.

All temperatures above and below specified in theoC.

Examples:

1 (a) 5-methyl-2-(4-nitrophenyl)-2,4-dihydro-pirut in 30 ml of ethanol and 45 minutes when the phlegm. The mixture is slightly thickened in a vacuum. Then sucked off the precipitated crystals.

Yield: 1.20 g of 5-methyl-2-(4-nitrophenyl)-2,4-dihydro-pyrazole-3-one (64% of theory).

Melting point: 223oC.

1B), 4-(2-ethylenediaminetetra)-5-methyl-2-(4-nitrophenyl)-2,4-dihydro-pyrazole-3-one

(single-stage reaction: addition of formamide and aniline).

1 g of 5-methyl-2-(4-nitrophenyl)-2,4-dihydro-pyrazole-3-one, 190 mg of 1,3,5-triazine and 0.74 ml of 2-ethylaniline heated in 50 ml of ethanol for 4 days with phlegm. The solvent is evaporated in vacuo and the obtained crude reaction product is purified by chromatography on silica gel with a mixture of solvents consisting of dichloromethane and methanol at a mixing ratio of 93:3 as solvent.

Output: 1,33 g of 4-(2-ethylenediaminetetra)-5-methyl-2-(4-nitrophenyl)-2,4-dihydro-pyrazole-3-one (83% of theory).

Melting point: 220oC.

1C) 3-methyl-4-aminomethyl-1-phenyl-4,5-dihydro-pyrazole-5-he (inclusion of formamide).

To a suspension 52,3 g (0,3 mol) 3-methyl-1-phenyl-2-pyrazolin-5-it in 800 ml of ethanol are added under stirring 8,11 g (0.1 mol) of 1,3,5-triazine and boil one hour in the phlegm. Then the solution is evaporated to a smaller volume. This saiden the ethene-1-phenyl-4,5-dihydropyrazol-5-he chromatography on silica gel using a solvent mixture of dichloromethane/acetone in a ratio of 4:1 as solvent.

The process of evaporation of the mother liquor obtain 36 g of the resin from which emit in the same way by chromatography 14.1 g of dimeric compound (melting point: 180,6oC). Produce recrystallization from acetone.

1d) 3-methyl-4-(2-propositionalization)-1-phenyl-4,5-dihydro-pyrazole-5-he

(accession aniline)

2 g of 3-methyl-4-aminomethyl-1-phenyl-4,5-dihydro-pyrazole-5-she and 1.6 g of salt 2 propoxyimino-triperoxonane acid contribute to ethanol and boiled for 1.5 hours with phlegm. The reaction solution is thickened. Then the reaction product is separated by chromatography on silica gel with a mixture of solvents from methylethylketone/hexane 4:1 as the solvent and recrystallized from a mixture of methylethylketone/hexane.

Yield: 1.5 g of 3-methyl-4-(2-propositionalization)-1-phenyl-4,5-dihydro-pyrazole-5-it (45.5% of theory).

Not detect any dimeric product.

1E) 4-(2-methoxyphenylacetyl)-5-methyl-2-phenyl-2,4-dihydropyrazol-3-one

2 g of 5-methyl-2-phenyl-2,4-dihydro-pyrazole-3-she, 188 ml of triethylorthoformate and 1.29 ml of o-anisidine heated with 5 ml of glacial acetic acid up to 70oWith 2 hours under stirring. The reaction mixture is cooled and stirred with 10 ml of methanol. Besieged sieges is ethyl-2-phenyl-2,4-dihydro-pyrazole-3-one (31% of theory).

Melting point: 143oC.

2A), 4-(4,5-dihydro-4-(2-ethylaminomethyl)-3-methyl-5-oxo-1H-pyrazole-1-yl)-N-hexyl-benzamide

(additional education derived substituent in position 1).

0.5 g (1,43 mmol) of 4-(4,5-dihydro-4-(2-ethylaminomethyl)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid and to 0.19 ml (1,43 mmol) hexylamine and 20 ml of dimethylformamide are mixed with each other at room temperature in a reaction flask and stirred for about 5 minutes. Then add successively 0.27 g (1,43 mmol) of N-(3-dimethylaminopropyl)-N'-l 0,19 g (1,43 mmol) 1-hydroxy-benzotriazole and 0.18 ml (1,43 mmol) N-methylmorpholine and stirred for 3 hours at room temperature. The end of the reaction is determined by thin layer chromatography (CH2Cl2/Meon 9:1 (ninhydrin-opryskivatel). Then the reaction mixture absorb into 200 ml of water (no sediment), twice extracted with simple ethyl ester, United dried ether phase over sodium sulfate, then filtered, evaporated simple ether in a vacuum, and thus obtained residue recycle chromatography (column: silica gel Si6Oh, solvent: a simple methylbutanoyl ether).

Yield: 250 mg of 4-(4,5-dihydro-4-(2-ethylaniline the ethene)-4,5-dihydro-3-methyl-1-(3-(1H-tetrazol-5-yl)-phenyl)-1H-pyrazole-5-he

(additional education derived substituent in position 1)

200 mg (0.6 mmol) of 3-(4,5-dihydro-4-(2-ethylaminomethyl)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzonitrile, 480 mg (2.4 mmol) of the azide trimacinolone and 20 ml of toluene mixed together and heated with stirring for two days when the phlegm. After this time the reaction chromatography can detect even a small amount of the intermediate product. Processing is as follows: the precipitate, which formed during the reaction, is sucked off. In this case we are talking about a product that is contaminated only by Sn salts. Therefore, the product is purified by chromatography (column: silica gel Si6O solvent: CH2Cl2/Meon 9:1).

Yield: 100 mg of 4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-1-(3-(1H-tetrazol-5-yl)-phenyl-1H-pyrazole-5-he (45.5% of theory).

In particular, other than those mentioned in the examples get 1 and 2 connections on the described methods, the application of triazine or trimethylphosphate received the following derivatives of pyrazole-3-one of General formula I:

3. From 4-(4-morpholinyl)-sulfonylhydrazide and ethylacetoacetate

5-methyl-2-(4-(4-morpholinyl)-sulfanilyl)-2,4-dihydro-pyrazole-3-one

and from 2-ethylaniline,

4-(2-ptx2">

4. From the phenyl-3-ndimethylacetamide and ethylacetoacetate

N-(3-(-4,5-dihydro-3-methyl-5-oxo-5H-pyrazole-1-yl)-phenyl)-ndimethylacetamide),

and from 2-ethylaniline,

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-5H-pyrazole-1-yl)-phenyl)-ndimethylacetamide, so pl. 263oC.

5. Of N,N-diethyl-4-hydrazinonicotinamide and ethylacetoacetate,

N, N-diethyl-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide,

and from 2-ethylaniline,

N, N-diethyl-4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide, so pl.: 194oC.

6. Of N-ethyl-4-hydrazinonicotinamide and ethylacetoacetate,

N-ethyl-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide,

and from 2-ethylaniline,

N-ethyl-4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide, so pl.: 260oC.

7. From 4-(4-morpholinyl)-sulfonylhydrazide and ethylacetoacetate,

5-methyl-2-(4-(4-morpholinyl)-sulfanilyl)-2,4-dihydro-pyrazole-3-one,

and from 2-butoxyaniline,

4-(2-butoxyaniline)-2,4-dihydro-5-methyl-2-(4-(4-morpholinylcarbonyl)-phenyl)-3H-pyrazole-3-one, so pl.: 171oC.

8. From 4-(4-morpholinyl)sulfonylhydrazide and ethylacetoacetate,

5-methyl-2-(4-(�)-2,4-dihydro-5-methyl-2-(4-(4-morpholinylcarbonyl)-phenyl)-3H-pyrazole-3-one, so pl.: 265oC.

9. From 4-(4-methylpiperazine)-sulfonylhydrazide and ethylacetoacetate,

5-methyl-2-(4-(4-methylpiperazine)-sulfanilyl)-2,4-dihydro-pyrazole-3-one,

and from 2-ethylaniline,

4-(2-ethylaminomethyl)-2,4-dihydro-5-methyl-2-(4-(4-methyl-1-piperazinylcarbonyl)-phenyl)-3H-pyrazole-3-one, so pl.: 254oC.

10A) 2-(3-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one

(hydrogenation Deputy)

A solution consisting of 15 g of 5-methyl-2-(3-nitrophenyl)-2,4-dihydro-pyrazole-3-one in 400 ml of methanol, hydronaut in the presence of 10 g of Raney Nickel. The catalyst is filtered off and the obtained after concentration of the solution in vacuo, the residue is recrystallized from isopropanol.

Yield: 8.0 g of 2-(3-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one (62% of theory).

Melting point: 265oC.

Similarly obtained from the corresponding nitro compounds:

2-(4-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one (amorphous),

2-(2-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one (amorphous).

10B) Reaction of the amino group of the N-substituent of pyrazole

A solution of 4.0 g of 2-(3-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one in 30 ml of dichloromethane and 2 ml of pyridine is mixed with ice cooling and stirring with 2.2 ml met the Oh and water, dried and concentrated in vacuo.

From the obtained N-(3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-methanesulfonamide and 2-ethylaniline get:

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-methanesulfonamide, so pl.: 192oC.

11. The reaction of the amino group of the N-substituent of pyrazole with complex methyl ether of Harborview acid or acid chloride of methansulfonate

A solution of 4.0 g of 2-(3-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one in 30 ml of dichloromethane and 2 ml of pyridine is mixed with ice cooling and stirring with 2.2 ml complicated methyl ether of Harborview acid and stirred for 2 hours. Then the solution was washed with diluted hydrochloric acid and water, dried and concentrated in vacuo.

Output: 4.2V g complex methyl ester of N-(3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl-carbamino acid (76% of theory), oil.

Further transformation of 2-ethylaniline get methyl ester N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl-carbamino acid, so pl.: 229oC.

Similarly obtained from:

2-(4-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one and acid chloride of methansulfonate,

methyl ester of N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-carbamino acid.

12. N-(4-phenyl-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-ndimethylacetamide

(the reaction of the amino group of the N-substituent of the pyrazole derivative of acetic acid)

to 1.9 g of 2-(4-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one in 40 ml of tetrahydrofuran is mixed under ice cooling and stirring with 1.0 ml of acetanhydride and additionally stirred for 2 hours. The solution was concentrated in vacuo and the residue is treated in the usual way.

Yield: 1.5 g of N-(4-phenyl-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-ndimethylacetamide (65% of theory), oil.

Similarly obtained from 2-(4-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one and triftoratsetata.

N-(4-phenyl-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-triptorelin;

from 2-(3-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one and triftoratsetata,

N-(3-phenyl-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-triptorelin;

from 2-(3-AMINOPHENYL)-5-methyl-2,4-dihydro-pyrazole-3-one and acetanhydride,

N-(3-phenyl-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-ndimethylacetamide;

5-methyl-2-(4-AMINOPHENYL)-2,4-dihydro-pyrazole-3-one (produced in analogy with example 10) and acetanhydride,

N-(4-phenyl-(4,5-is)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-acetamide", she so pl.: 230oC.

13. 5-methyl-2-(4-AMINOPHENYL)-2,4-dihydro-pyrazole-3-one and methanesulfonanilide (transformation occurs for example receiving 11, and methanesulfonanilide used in the respective molar quantity)

N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-methylsulfonylmethane, and 2-ethylaniline.

N-(4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5 - oxo-1H-pyrazole-1-yl)-phenyl)-N-methylsulfonylmethane, so pl.: 268oC.

14. 5-methyl-2-(2-AMINOPHENYL)-2,4-dihydro-pyrazole-3-one and methanesulfonanilide (transformation occurs for example receiving 11).

N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-methanesulfonamide,

and from 2-ethylaniline

N-(2-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-methanesulfonamide, so pl.: 231oC.

15. 5-methyl-2-(3-AMINOPHENYL)-2,4-dihydro-pyrazole-3-one and triftoratsetata (transformation occurs in example 12)

N-(3-phenyl-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-5-yl))-triptorelin, and 2-ethylaniline

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-5-yl)-phenyl)-triptorelin, so pl.: 240oC.

16. Of N,N-diethyl-4-hydrazine the ID, and from 2-ethoxyaniline

N, N-diethyl-4-(4,5-dihydro-4-(2-ethoxyaniline)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide, so pl.: 170oC.

17. Of N,N-diethyl-4-hydrazinonicotinamide and ethyl acetate

N, N-diethyl-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide, and 2-methoxyaniline

N, N-diethyl-4-(4,5-dihydro-4-(2-methoxyaniline)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide, so pl.: 191oC.

18. Of N-ethyl-4-hydrazinonicotinamide and ethylacetoacetate

N-ethyl-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide, and 2-ethoxyaniline

4-((2-ethoxyaniline)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-N-ethylbenzylamine, so PL: 238oC.

19. 5-methyl-2-(4-AMINOPHENYL)-2,4-dihydro-pyrazole-3-she and complex ethyl ether of Harborview acid (for example, receiving 11).

Complex ethyl ester of N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl-carbamino acid, and 2-methoxyaniline.

Complex ethyl ester of N-(4-(4,5-dihydro-4-(2-methoxyaniline)-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-carbamino acid, so pl.: 212oC.

20. 5-methyl-2-(4-AMINOPHENYL)-2,4-dihydro-pyrazole-3-she propionitrile (on the Lin.

N-(4-(4-(2-ethoxyaniline)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-propionamide, so pl.: 208oC.

21. From 4-(1-piperidyl)-sulfonylhydrazide and ethylacetoacetate

5-methyl-2-(4-(1-piperidinylcarbonyl)-phenyl)-3H-pyrazole-3-one and 2-ethoxyaniline,

4-(2-ethoxyaniline)-2,4-dihydro-5-methyl-2-(4-(1-piperidinylcarbonyl)-phenyl)-3H-pyrazole-3-one, so pl.: 252oC.

22. From N-tert.-butyl-4-hydrazinonicotinamide and ethylbutylamine

N-tert. -butyl-4-(4,5-dihydro-3-propyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide and 2-ethoxyaniline

N-tert. -butyl-4-(4-(2-ethoxyaniline)-4,5-dihydro-3-propyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide, so pl.: 254oC.

23. N-acetyl-4-(4-(2-ethoxyaniline)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide

(education derived N-substituent of pyrazole derived by condensation of aniline).

In a solution of 1.0 g of 4-(4-(2-amoxicillinonline)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide and 0.9 g of dimethylaminopyridine in 30 ml of pyridine is buried under ice cooling to 0.17 ml acetanhydride and additionally stirred for 10 hours. Obtained after concentration in vacuo the residue is mixed with razbavlen-(2-ethoxyaniline)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide.

(42.5% of theory).

Melting point: 282oC.

24. 4-hydrazinonicotinamide and ethylacetoacetate

4-(4,5-dihydro-3-methyl-5-oxo-2H-pyrazole-1-yl)-benzosulfimide, and 2-ethoxyaniline

4-(4-(2-ethoxyaniline)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide, so pl.: 241oC.

25. From phenylhydrazine and complex methyl ester 5-hydroxy-3-oxo-pentanol acid

5-(2-hydroxyethyl)-2-phenyl-2,4-dihydro-pyrazole-3-one and 2-ethylaniline,

4-(2-ethylaminomethyl)-2,4-dihydro-5-(2-hydroxyethyl)-2-phenyl-1H-pyrazole-3-one.

26. 4-methoxyphenylhydrazine and ethylbutylamine 2,4-dihydro-2-(4-methoxybenzyl)-5-propyl-3H-pyrazole-3-one and 2-ethylaniline

4-(2-ethylaminomethyl)-2,4-dihydro-2-(4-methoxybenzyl)-5-propyl-3H-pyrazole-3-one, oil.

27. 2-propoxybenzaldehyde and ethylbutylamine

2,4-dihydro-2-(2-propoxyphenyl)-5-propyl-3H-pyrazole-3-one and 2-ethylaniline

4-(2-ethylaminomethyl)-2,4-dihydro-2-(2-propoxyphenyl)-5-propyl-3H-pyrazole-3-one, so pl.: 75,2oC.

28. 4-brompheniramine and ethylbutylamine

2-(4-bromophenyl)-2,4-dihydro-5-propyl-3H-pyrazole-3-one and 2-ethylaniline

2-(4-bromophenyl)-4-(2-ethylaminomethyl)-is the

2,4-dihydro-2-(4-nitrophenyl)-5-propyl-3H-pyrazole-3-one and 2-ethylaniline,

4-(2-ethylaminomethyl)-2,4-dihydro-2-(4-nitrophenyl)-5-propyl-3H-pyrazole-3-one, so pl.: 211oC.

30. 3-hydrazinobenzothiazole and ethylbutylamine

3-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzosulfimide and 2-ethylaniline,

3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzosulfimide, so pl.: 258,6oC.

31. 4-hydrazinobenzothiazole and ethylbutylamine

4-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzosulfimide and 2-ethylaniline

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzosulfimide, so pl.: 205,2oC.

32. 4-nitrophenylhydrazine and diethyl-3-oxoglutarate complex ethyl ester of 2-(4,5-dihydro-1-(4-nitrophenyl)-5-oxo-lH-pyrazole-3-yl)-acetic acid, and 2-ethylaniline

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-nitrophenyl)-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl.: 224,5oC.

33. 4-hydrazinobenzene acid and ethylacetoacetate

4-(4,5-dihydro-5-oxo-3-methyl-1H-pyrazole-1-yl)-benzoic acid and 2-ethylaniline

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-ATA

2,4-dihydro-2-(2-pyridyl)-5-propyl-3H-pyrazole-3-one and 2-ethylaniline

4-(2-ethylaminomethyl)-2,4-dihydro-2-(2-pyridyl)-5-propyl-3H-pyrazole-3-one, so pl.: 151oC.

35. 2-pyridyldithio and ethylacetoacetate

2,4-dihydro-5-methyl-2-(2-pyridyl)-3H-pyrazole-3-one and 2-ethylaniline,

4-(2-ethylaminomethyl)-2,4-dihydro-5-methyl-2-(2-pyridyl)-3H-pyrazole-3-one, so pl.: 182,9oC.

36. 4-hydrazinobenzene acid and ethylbutylamine

4-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzoic acid and 2-ethylaniline

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzoic acid, so pl.: 254,5oC.

37. From 4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid and hexylamine

4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-N-hexylbenzene, so pl.: 62,1oC.

38. From 4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid and aqueous ammonia

4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzamid, so pl.: 225,2oC.

39. From 4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid and aqueous solution of N,N-diethylam the P CLASS="ptx2">

40. 4-pyridyldithio and ethylbutylamine 2,4-dihydro-5-propyl-2-(4-pyridyl)-3H-pyrazole-3-one and 2-ethylaniline

4-(2-ethylaminomethyl)-2,4-dihydro-5-propyl-2-(4-pyridyl)-3H-pyrazole-3-one, so pl.: 159,2oC.

41. 4-chlorophenylhydrazone and ethylacetoacetate 2-(4-chlorophenyl)-2,4-dihydro-5-methyl-3H-pyrazole-3-one and 2-ethylaniline

2-(4-chlorophenyl)-4-(2-ethylaminomethyl)-2,4-dihydro-5-methyl-3H-pyrazole-3-one.

42. From 4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzoic acid and an aqueous solution of diethylamine

N, N-diethyl-4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzamid, so pl.: 123oC.

43. From 4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzoic acid and hexylamine

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-N-hexylbenzene, so pl.: 46,7oC.

44. From 4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzoic acid and aqueous ammonia

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzamid, so pl.: 170oC.

45. 4-hydrazinobenzothiazole and ethylbutylamine

4-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzene.: 196,7oC.

46. Of N,N-diethyl-3-hydrazino-4-methoxybenzenesulfonamide and ethylbutylamine

N, N-diethyl-3-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-4-methoxybenzenesulfonamide and 2-ethylaniline

N, N-diethyl-3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-4-methoxybenzenesulfonamide, oil.

47. 3-hydrazinobenzothiazole and ethylacetoacetate

3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzonitrile and 2-ethylaniline

3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzonitrile, so pl.: 210,8oC.

48. Of N-hexyl-3-hydrazino-4-propoxybenzaldehyde and ethylacetoacetate

3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-methyl)-N-hexyl-4-propoxybenzaldehyde and 2-ethylaniline

3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl-methyl)-N-hexyl-4-propoxybenzaldehyde resin.

49. 2-hydrazinobenzene acid and ethylbutylamine

2-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzoic acid and 2-ethylaniline

2-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzoic acid, so pl.: 126,9oC.

50. From 4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-nil)-3H-pyrazole-3-one, so pl.: 248,5oC.

51. 3-pyridylketone and ethylbutylamine

2,4-dihydro-5-propyl-2-(3-pyridyl)-3H-pyrazole-3-one and 2-ethylaniline

4-(2-ethylaminomethyl)-2,4-dihydro-5-propyl-2-(3-pyridyl)-3H-pyrazole-3-one, so pl.: 143,9oC.

52. From 3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzonitrile and azide trimacinolone

4-(2-ethylaminomethyl)-2,4-dihydro-5-methyl-2-(3-(1H-tetrazol-5-yl)-phenyl)-3H-pyrazole-3-one, so pl.: 261,6oC.

53. From hydrazinobenzene acid and ethylacetoacetate

4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid and 2-triptorelin

4-(4,5-dihydro-3-methyl-5-oxo-4-(2-cryptomaterial)-1H-pyrazole-1-yl)-benzoic acid, so pl.: 289,4oC.

54. From the p-hydrazinobenzene acid and diethyl-3-oxoglutarate

4-(3-ethoxycarbonylmethyl-4,5-dihydro-5-oxo-1H-pyrazole-1-yl)-benzoic acid and 2-ethylaniline

4-(4-(2-ethylaminomethyl)-3-ethoxycarbonylmethyl-4,5-dihydro-5-oxo-1H-pyrazole-1-yl)-benzoic acid, so pl.: 246oC.

55. From p-hydrazinobenzene acid and ethylacetoacetate

4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid and 2-(2-propenyloxy)aniline

4-(4,5-dihydro-3-IU is. the C p-hydrazinobenzene acid and ethylacetoacetate

4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid and 2-propoxyimino

4-(4,5-dihydro-3-methyl-5-oxo-4-(2-proportionalisation)-1H-pyrazole-1-yl)-benzoic acid, so pl.: 259,6oC.

57. From p-hydrazinobenzene acid and ethylacetoacetate

4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid and 2-methoxyaniline,

4-(4,5-dihydro-4-(2-methoxyaniline)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid, so pl.: >300oC.

58. From p-hydrazinobenzene acid and ethylacetoacetate

4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid and 2-isopropylaniline

4-(4,5-dihydro-4-(2-isopropylaminomethyl)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid, so pl.: 269,5oS. 59.

59. From commercially available 3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide and 2-ethylaniline

3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide, so pl.: 229,2oC.

60. From complex ethyl ester 2-(1-(4-AMINOPHENYL)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid and triftoratsetata and subsequent transformation with ethylaniline

complex ethyl E. 197oC.

61. From complex ethyl ester 2-(1-(4-AMINOPHENYL)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid and

difficult methyl ether of Harborview acid and subsequent conversion with 2 ethylaniline,

complex ethyl ester 2-(1-(4-methoxycarbonylaminophenyl)-4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl. : 145oC.

62. From complex ethyl ester of 2-(4,5-dihydro-1-(4-AMINOPHENYL)-5-oxo-1H-pyrazole-3-yl)-acetic acid and acid chloride of methansulfonate and the subsequent transformation of 2-ethylaniline,

complex ethyl ester 2-(4-((2-ethylaminomethyl)-4,5-dihydro-1-(4-methanesulfonamido)-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl. : 165oC.

63. From complex ethyl ester of 2-(4,5-dihydro-1-(4-AMINOPHENYL) 5-oxo-1H-pyrazole-3-yl)-acetic acid and acid chloride of acetic acid and subsequent conversion with 2 ethylaniline

complex ethyl ester 2-(1-(4-acetamidophenyl)-4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl.: 197oC.

In the same way received:

Complex ethyl ester 2-(1-(4-(N,N-diethylcarbamoyl)-phenyl)-4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-uksosn the ilen)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl.: 127oC;

complex ethyl ester 2-(1-(4-acetamidophenyl)-4-(2-ethylaniline-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl.: 194oC;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-1-(4-triptoreline-phenyl)-1H-pyrazole-3-yl)-acetic acid, so pl. : 197oC;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-methoxycarbonylaminophenyl)-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl.: 144oC;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-methanesulfonamido)-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl. : 165oC;

complex ethyl ester 2-(1-(4-acetamidophenyl)-4-(2-ethylaniline-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl.: 168oC;

2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-methoxycarbonylaminophenyl)-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl.: 181oC.

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-phenyl)-methanesulfonamide, so pl.: 214oC;

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-phenyl)-ndimethylacetamide, so pl.: 181oC;

methyl ester of N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-phenyl)-to the 3-triptoreline-phenyl)-1H-pyrazole-1-yl)-acetic acid, so pl. : 190oC;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(3-methanesulfonamido)-5-oxo-1H-pyrazole-3-yl)-acetic acid, so pl. : 174oC.

The following examples relate to pharmaceutical finished forms:

Example: glass vials for injection

A solution of 100 g of the active substance of the formula I and 5 g of acid dinatriumfosfaatti in 3 l of double distilled water was adjusted using 2 N. hydrochloric acid to pH 6.5, sterile filtered, filled into vials for injection under sterile conditions is subjected to lyophilization, sterile closed. Each vial for injection contains 5 mg of active substance.

Example: candles

Melt a mixture of 20 g of the active substance of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and cooled. Each suppository contains 20 mg of active substance.

Example: solution

Prepare a solution of 1 g of the active substance of the formula I, 9,38 g Pan2RHO42H2Oh, 28,48 g PA2NRA4N2O and 0.1 g of chloride benzalkone in 940 ml of double distilled water. Set the pH value of 6.8, the complement to 1 l and sterilized by irradiation. This solution can be applied in the form of eye practical conditions.

Example E: tablets

A mixture of 1 kg of active substance of formula 1, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is formed in the usual manner into tablets, so that each tablet contained 10 mg of active substance.

Example F: bean

Analogously to example E is pressed tablets, then the usual way is applied a coating of sucrose, potato starch, talc, tragant and dye.

Example G: capsules

2 kg of active substance of the formula I is administered in capsules of hard gelatin, so that each capsule contained 20 mg of the active substance.

Example N: ampoules

A solution of 1 kg of active substance of the formula I in 60 l of double distilled water is sterile filtered, filled into ampoules under sterile conditions is subjected to lyophilization, sterile closed. Each ampoule contains 10 mg of active substance.

PHARMACOLOGICAL DATA

Studied biological activity of some typical compounds of General formula (I) shown in the table:

< / BR>
The compounds of formula (I), where n=1 is marked with * in the rest of the compounds with n=0. Compounds in which R1-phenyl-(CH)2n-group is replaced by pyridyloxy group, pomace the em benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, phenyl, unsubstituted or substituted once to three times by amino, acyl, halogen, a nitro-group, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium with 1-6 C-atoms in the alkyl part, A-CO-NH-, AND-O-CO-NH-, AND-O-CO-NA, SO2NR4R5, (R4and R5denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N or O, which may be substituted),-CO-NH-SO2- ,- SO2NH -,-SO2-)2N or tetrazolyl; or pyridyl;

R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl;

R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3,

And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3except 5-methyl-2-phenyl-4-(o-trilaminate)-2,4-dihydropyrazol-3-it,

or their salts.

2. Connection on p. 1, selected from the group consisting of

methyl ester of 3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-carbamino acid;

4 the initial ester 2-(1-(4-(N, N-diethylcarbamoyl)-phenyl)-4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-(N, N-diethylcarbamoyl)-phenyl)-4-((2-ethoxyaniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-acetamidophenyl)-4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1-(4-triftoratsetofenona)-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-ethoxycarbonylphenyl)-4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(4-((2-ethylaminomethyl)-4,5-dihydro-1-(4-methanesulfonamido)-5-oxo-1H-pyrazole-3-yl)-acetic acid;

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-5H-pyrazole-1-yl)-phenyl)-ndimethylacetamide;

N, N-diethyl-4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide;

N-ethyl-4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide;

4-(2-ethoxyaniline)-2,4-dihydro-5-methyl-2-(4-(4-morpholinylcarbonyl)-phenyl)-3H-pyrazole-3-one;

4-(2-ethylaminomethyl)-2,4-dihydro-5-methyl-2-(4-(4-methyl-1-Pieper is phenyl)-methanesulfonamide;

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl)-triptorelin;

N-(4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-phenyl-N-methylsulfonylmethane;

N, N-diethyl-4-(4,5-dihydro-4-(2-ethoxyaniline)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide;

N, N-diethyl-4-(4,5-dihydro-4-(2-methoxyaniline)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide;

3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzosulfimide;

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzosulfimide;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-nitrophenyl)-5-oxo-1H-pyrazole-3-yl)acetic acid;

4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzoic acid;

4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-N-hexylbenzene;

4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzamide;

N, N-diethyl-4-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzamide;

4-(2-ethylaminomethyl)-2,4-dihydro-5-propyl-2-(4-pyridyl)-3H-pyrazole-3-one;

N, N-diethyl-4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-Piras>4-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-benzamide;

4-(2-ethylaminomethyl)-2,4-dihydro-5-propyl-2-(4-(1H-tetrazol-5-yl)-phenyl)-3H-pyrazole-3-one;

4-(2-ethylaminomethyl)-2,4-dihydro-5-methyl-2-(3-(1H-tetrazol-5-yl)-phenyl)-3H-pyrazole-3-one;

4-(4,5-dihydro-3-methyl-5-oxo-4-(2-cryptomaterial)-1H-pyrazole-1-yl)-benzoic acid;

4-(4-(2-ethylaminomethyl)-3-ethoxycarbonylmethyl-4,5-dihydro-5-oxo-1H-pyrazole-1-yl)-benzoic acid;

4-(4,5-dihydro-3-methyl-5-oxo-4-(2-proportionalisation)-1H-pyrazole-1-yl)-benzoic acid;

4-(4,5-dihydro-4-(2-isopropylaminomethyl)-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzoic acid;

3-(4-(2-ethylaminomethyl)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-yl)-benzosulfimide;

complex ethyl ester 2-(1-(4-methoxycarbonylaminophenyl)-4-((2-ethylaniline)-methylene)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)acetic acid;

complex ethyl ester 2-(1-(4-(N, N-diethylcarbamoyl)phenyl)-4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-(N, N-diethylcarbamoyl)-phenyl-4-(2-ethoxyaniline)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-acetamidophenyl)-4-(2-ethylaminomethyl-5-oxo-1-(4-triftoratsetofenona)-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-methoxycarbonylaminophenyl)-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-methanesulfonamido)-5-oxo-1H-pyrazole-3-yl)-acetic acid;

complex ethyl ester 2-(1-(4-acetamidophenyl)-4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-1H-pyrazole-3-yl)-acetic acid;

2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(4-methoxycarbonylaminophenyl)-5-oxo-1H-pyrazole-3-yl)-acetic acid;

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-phenyl)-methanesulfonamide;

N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-ndimethylacetamide;

methyl ester of N-(3-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-1-yl)-phenyl)-carbamino acid;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-5-oxo-1-(3-triftoratsetofenona)-1H-pyrazole-1-yl)-acetic acid;

complex ethyl ester 2-(4-(2-ethylaminomethyl)-4,5-dihydro-1-(3-methanesulfonamido)-5-oxo-1H-pyrazole-3-yl)-acetic acid.

3. The compounds of formula I on p. 1 as selective inhibitors with GMP specific phosphodiesterase.

4. 4-(4,5-dihydro-3 composition, inhibiting GMP specific phosphodiesterase, containing as active substance at least one compound of formula I under item 1 and/or one of their salts in an effective amount along at least one solid, liquid or semi-liquid carrier or auxiliary substance.

6. The method of obtaining 4-(allumination)-2,4-dihydropyrazol-3-ones by PP. 1 and 2, characterized in that compounds of General formula

< / BR>
where R1and R2have the values listed in paragraph 1, make with the appropriate connections, giving formaldehyde, such as triazine, or with suitable trialkylaluminium, in particular, triethylorthoformate, in compounds of General formula

< / BR>
where X denotes amino -, or-O-alkyl group with 1-6 C-atoms in the alkyl, and, if necessary, in situ, make with the appropriate aniline derivatives of the formula

< / BR>
where R3matter specified in paragraph 1, or their salts to the compounds of formula I.

 

Same patents:

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new derivatives of carboxylic acids of General formula I containing heterocyclic ring

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

< / BR>
in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

< / BR>
in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

< / BR>
in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

< / BR>
in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

< / BR>
in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

< / BR>
in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

< / BR>
in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

< / BR>
in radical

< / BR>
p) conversion of the acid function in function

< / BR>
q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them

The invention relates to new pyrimidine compounds or their salts with pharmaceutically acceptable acids and pharmaceutical compositions based on them

The invention relates to derivatives of N-sulfanilimide formula I, where R1and R2denote hydrogen, halogen, C1-4alkyl, C1-4alkoxycarbonyl or phenyl which can be substituted one to three times, equal or different residues from the group comprising halogen, C1-4alkyl, trifluoromethyl; R3- halogen, cyano, trifluoromethyl; R4- 4-isoxazolyl, pyrazolyl, which may be substituted with halogen, C1-4the alkyl, amino group, cycloalkyl, as well as their acid-salt additive

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts

The invention relates to new Amida condensed terracarbon acid of General formula I, where G is Q(C)k-W-(C)m-Z, Q is phenyl, 2-, 3-, 4-pyridyl, which may be substituted; T is halogen, hydrogen, hydroxyl, amino, C1-C6alkoxy; W is-O-, -N-, -S-, CR7R8where R7and R8the same or different and represent H, C1-C6alkyl; X is hydrogen; Z is hydroxyl, C1-C6alkoxy, C3-C7cycloalkylation, NH2and other, NR9COR10where R9and R10the same or different represent H, C1-C6alkyl, etc

The invention relates to new sulfonamide of General formula I, where R1-R8A and B have the meanings indicated in the formula, which are inhibitors of endothelin and can be used for the treatment of diseases associated with the activity of endothelin, such as high blood pressure, as well as to pharmaceutical compositions based on

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded
Up!