Pyrazolo[4,3-d]pyrimidine

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

 

The invention relates to compounds of formula I

in which R1, R2in each case, independently of one another represent H, A, HE, OA or Hal,

R1and R2together also represent alkylene having 3-5 C atoms, -O-CH2-CH2-, -CH2-O-CH2-, -O-CH2-O - or-O-CH2-CH2-Oh,

R3, R4in each case, independently of one another represent H or A,

X is an R5, R6or R7, monosubstituted R8,

R5represents a linear or branched alkylene having 1-10 C atoms, in which one or two CH2groups may be replaced by-CH=CH-groups, O, S or SO,

R6is cycloalkyl or cycloalkenyl having 5-12 C atoms,

R7represents phenyl or phenylmethyl,

R8represents COOH, cooa, CONH2, CONHA, CON(A)2or CN,

And is an alkyl having from 1 to 6 atoms, and

Hal represents F, Cl, Br or I,

and their physiologically acceptable salt and solvate.

Derivatives of pyrimidine is described, for example, in EP 201188 and WO 93/06104.

The invention was based on the goal of opening new compounds having valuable properties, in particular those that can be used to obtain, in addition to the state of the drugs.

It was found that the compounds of formula I and their salts have very valuable pharmacological properties, combined with good tolerability.

In particular, they show specific inhibition of cGMP phosphodiesterase (PDE V).

Quinazoline with cGMP, phosphodiesterase-inhibitory activity are described, for example, J.Med. Chem.3765 (1993) and ibid2106 (1994).

The biological activity of the compounds of formula I can be determined by methods such as described, for example, in WO 93/06104. The affinity of the compounds according to the invention with respect to cGMP and camp the phosphodiesterase determined by specifying their values IC50(concentration of inhibitor required to achieve 50% inhibition of enzymatic activity).

To conduct definitions can be applied enzymes, selected according to known methods (e.g. W.J.Thompson and others, Biochem. 1971,311). For experiments it is possible to apply the modified batch method W.J.Thompson and ..Appleman (Biochem. 1979,5228).

The connection, therefore, is suitable for treatment of disorders of the cardiovascular system, in particular, heart failure, and also for the treatment and/or therapy of disorders of potency (erectile dysfunction).

The application replaced rasolofonirina for the treatment of impotence is described, for example, in WO 94/28902.

The compounds are effective as inhibitors of phenylephrine-induced contractions in the preparations of the body cavities of rabbits. This biological activity can be demonstrated, for example, by the method described F.Holmquist and others in J.Urol.,1310-1315 (1993). Inhibition of compression shows the effectiveness of the compounds according to the invention in the treatment and/or treatment of disorders of potency.

The compounds of formula I can be used as pharmaceutical active compounds in human and veterinary medicine. They, moreover, can be used as intermediate products for other pharmaceutically active compounds.

The invention accordingly relates to compounds of the formula I and to a method for producing compounds of the formula I according to claim 1 and their salts, which is characterized by the fact that

a) compound of formula II

in which R3, R4and X have the abovementioned meanings and L represents Cl, Br, IT, S3or chemically esterified group HE is subjected to reaction with the compound of the formula III

in which R1and R2have the specified values

or

b) the compound of formula I the radical X is translated into another radical X by using, for example, hydrolysis of the ester group to COOH is the group or translation COOH group in amide or cyano

and/or the compound of formula I is transferred into one of its salts.

The solvate of the compounds of formula I should be understood as a designation of adducts of molecules of the inert solvent to compounds of the formula I, which are formed due to their mutual gravity.

The solvate represent, for example, mono - or dihydrate or alcoholate.

Above and below, the radicals R1, R2, R3, R4, R5, R5, R7, R8, X and L have the values listed in formulas I, II and III, unless expressly stated otherwise.

And represents alkyl having 1-6 atoms C.

In the above formulas, the alkyl preferably not branched and has 1, 2, 3, 4, 5 or 6 C atoms, and preferably represents methyl, ethyl or propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and n-pentyl, neopentyl, isopentyl or hexyl.

X represents the radical R5, R6or R7, monosubstituted R7.

R3represents a linear or branched radical alkylene having 1-10 C atoms, where alkalinity radical preferably represents, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, terbutalin, pentile, 1-, 2-or 3-methylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropylene, 1-ethylpropyl, hexylen, 1-, 2-, 3 - or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- and the and 3.3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 - or 1,2,2-trimethylpropyl, linear or branched septilin, octiles, Nonlin or deciles. R5moreover represents, for example, but-2-Anilin or Gex-3-Anilin. The group of CH2in R5may preferably be substituted with oxygen. Ethylene, propylene, butylene, or CH2-O-CH2especially preferred.

R6is cycloalkylation having 5-12 C atoms, preferably, for example, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexyldiamine or cyclohexylmethyl.

R6it also represents cycloalkyl, preferably having 5-7 atoms C. Cycloalkyl represents, for example, cyclopentyl, cyclohexyl or cycloheptyl.

Hal preferably represents F, Cl or Br, and I.

The radicals R1and R2may be the same or different and are preferably in the 3 or 4 position of the phenyl ring. They represent, for example, in each case independently of one another, H, alkyl, HE, F, Cl, Br or I or together alkylene, such as, for example, propylene, butylene or pentile, moreover, ethylenoxy, methylendioxy or Ethylenedioxy. Preferably they also represent in each case alkoxy, such as, for example, methoxy, ethoxy isopropoxy.

The radical R8represents preferably, for example, COOH, cooa, such as, for example, SOON3or COOC2H5, CONH2, SOP(CH3)2The N3or CN, and in particular COOH or cooa.

The entire invention is that all radicals which occur several times, may be the same or different, i.e. are independent of each other.

Accordingly, the invention applies in particular to those compounds of formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulas Ia-If, which correspond to the formula I and in which the radicals not specified in greater detail have the meanings indicated in formula I, but in which Ia X is an R5substituted COOH, cooa, CONH2, CONA2, CONHA or CN, or represents phenyl or phenylmethyl;

in Ib R1and R2together represent alkylene having 3-5 C atoms, -O-CH2-CH2-, -O-CH2-O - or-O-CH2-CH2-O-,

X is an R5substituted COOH, cooa, CONH2, CONA2, CONHA or CN, or represents phenyl or phenylmethyl;

in Ic R1, R2in each case, independently of one another represent H, A, HE, OA and Hal

R1and R2together also represent alkylene having 3-5 C atoms, -O-CH2-CH2-, -O-CH2-O - or-O-CH2-CH2-O-,

X is an R5substituted COOH, cooa, CONH2, CONA2, CONHA or CN, or represents phenyl or phenylmethyl;

in Id R1, R2in each case, independently of one another represent H, A, HE, OA or Hal,

R1and R2together also represent alkylene having 3-5 C atoms, -O-CH2-CH2-, -O-CH2-O - or-O-CH2-CH2-O-,

X represents alkylene having 2-5 C atoms, which monogamist R8or cyclohexyl, phenyl or vinylmation,

R3represents alkyl having 1-6 C atoms,

R4represents alkyl having 1-6 C atoms,

R8represents COOH or cooa,

And is an alkyl having from 1 to 6 atoms,

Hal represents F, Cl, Br or I;

in Ie R1, R2in each case, independently of one another represent H, A, HE, OA or Hal,

R1and R2together also represent alkylene having 3-5 C atoms, -O-CH2-CH2-, -O-CH2-O - or-O-CH2-CH2-O-,

R3represents alkyl having 1-6 C atoms,

R4represents alkyl having 1-6 C atoms,

X performance is to place a -(CH 2)2-5-R8The 4-R8-cyclohexyl, 4-R8-phenyl or 4-(R8-methyl)phenyl;

If R1, R2in each case, independently of one another represent H, A, HE, OA or Hal,

R1and R2together also represent alkylene having 3-5 C atoms, -O-CH2-CH2-, -O-CH2-O - or-O-CH2-CH2-O-,

R3represents alkyl having 1-6 C atoms,

R4represents alkyl having 1-6 C atoms,

X represents - (CH2)2-5-R8in which one group of CH2may be substituted by Oh, or represents a 4-R8-cyclohexyl, 4-R8-phenyl or 4-(R8-methyl) phenyl,

R8represents COOH or cooa.

The compounds of formula I, as well as source materials for their production in other case get on methods known in themselves, such as described in the literature (e.g., in the standard works such as Houben-Weyl, Methods der organischen Chemie [Methods of organic chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the said reactions. In this case, it is also possible to use variants which are known in themselves, but not mentioned here in more detail.

In the compounds of the formula II or III, R1, R2, R3, R4and X have the above meanings, in particular, indicated a preference for the equipment value.

If L is a chemically esterified group IT, it is a preferable alkylsulfonate having 1-6 C atoms (preferably, methylsulfonylamino), or arylsulfonate having 6-10 C atoms (preferably phenyl - or p-tolilsulfonil, moreover 2 naphthalenesulfonate).

The compounds of formula I can preferably be obtained by reaction of compounds of the formula II with compounds of formula III.

If desired, the initial substance can also be obtained in situ, so that they are not isolated from the reaction mixture, and directly subjected to further reactions to produce compounds of formula I. on the other hand, it is possible to conduct the reaction Paladino.

Typically, the source compounds of formulas II and III are known. If they are not known, they can be obtained by methods known in themselves.

The compounds of formula II can also be obtained by methods known from the literature, e.g., to form 4-amino-3-alkoxycarbonylmethyl by cyclization with NITRILES and subsequent reaction products of cyclization with phosphorus oxychloride (similar to Houben Weyl E9b/2).

In detail the reaction of compounds of the formula II with compounds of the formula III is carried out in the presence or absence of an inert solvent at temperatures between about -20 and about 150, preferably between 20 and 100.

Can is be beneficial to add an acid-binding agent, for example, a hydroxide of an alkali metal or alkaline earth metal carbonate or bicarbonate or another salt of a weak acid and alkali metals or alkaline earth metals, preferably of potassium, sodium or calcium, or the addition of organic bases, such as triethylamine, dimethylamine, pyridine or quinoline, or excess amine component.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol, onomatology or monotropy ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide", she dimethylacetamide, N is an organic or dimethylformamide (DMF); NITRILES, such as acetonitrile; sulfoxidov, such as dimethylsulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the mentioned solvents.

Then you can transfer radical is in the other radical X in a compound of formula I, e.g., by hydrolysis of its ester or cyanopropyl group COOH.

The ether groups can be gidrolizirovanny, for example, using NaOH or KOH in water, water/THF or water/dioxane at temperatures between 0 and 100.

Carboxylic acids can be translated, for example, using thionyl chloride, into the corresponding carbonylchloride, and they can be translated into carboxamide. Carbonitrile obtained from them by a known method using a dehydration.

The acid of formula I also can be converted to an acid additive salt using a base, for example, by reaction of equivalent amounts of acid and base in their inert solvent, such as ethanol, and subsequent evaporation. Suitable bases for this reaction are those which give physiologically acceptable salts. Thus, the acid of formula I can be converted to the corresponding metal salts, in particular alkali metal salts or alkaline earth metal, or into the corresponding ammonium salt using a base (e.g., the hydroxide or carbonate of sodium or potassium).

For this reaction, suitable organic bases are, in particular, those which give physiologically acceptable salts, such as, for example, ethanolamine.

On the other hand, the base of the formula I can be converted to an acid additive salt using an acid, for example, the reactions is th equivalent amounts of base and acid in an inert solvent, such as ethanol and subsequent evaporation. For this reaction, suitable acids are, in particular, are those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, e.g., sulfuric acid, nitric acid, hydrohalogen acid, such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, then the organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic mono - or politonalnye carboxylic, sulfonic or sulfuric acids, e.g., formic acid, acetic acid, propionic acid, Pavlova acid, diethyloxalate acid, malonic acid, succinea acid, Pimenova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultancy acid, ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, p-toluene sulfonic acid, naphtalene - and-disulfonate acid and laurylsulphate acid. Salts with physiologically unacceptable acids, e.g., the picrate, you can apply for isolation and/or purification with the joining of formula I.

The invention further relates to the use of compounds of the formula I and/or their physiologically acceptable salts for pharmaceutical preparations, in particular by non-chemical. In this case, they can be brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid media or excipients and, if necessary, together with one or more other active compounds.

The invention also relates to drugs of formula I and their physiologically acceptable salts as inhibitors of phosphodiesterase V.

The invention further relates to pharmaceutical preparations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts.

These drugs can be used as pharmaceuticals in human or veterinary medicine. Possible carriers are organic or inorganic substances which are suitable for enteral (e.g., oral) or parenteral administration or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkalophile, glycols, glyceroltrinitrate, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc and petroleum jelly. In particular, tablets, iluli, coated tablets, capsules, powders, granules, syrups, salt or drops are used for oral administration, suppositories are used for rectal application, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants are used for parenteral administration, and ointments, creams or powders are used for topical application. The new compounds can also be liofilizirovanny and received lyophilizate to apply, for example, to get injectables. These preparations can be sterilized and/or they may contain excipients, such as lubricants, preservatives, stabilizers and/or moisturizing agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavorings and/or one or more other active compounds, e.g., one or more vitamins.

The compounds of formula I and their physiologically acceptable salts can be used to control diseases in which increased level of cGMP (cyclic guanosine monophosphate) leads to the inhibition or prevention of excitation and muscle relaxation. Compounds according to the invention can in particular be used in the treatment of diseases of the cardiovascular system and for the treatment and/or therapy of disorders of potency.

In this case, as a rule, prophetic the STV preferably taken in doses of between about 1 and 500 mg, in particular, between 5 and 100 mg, per unit dosage. Daily dose is preferably between about 0.02 and 10 mg/kg of body weight. The specific dose for each patient depends, however, on various factors, for example, from the effectiveness of specific applied compound, the age, body weight, General health, sex, diet, time and schedule of admission, level of discharge, pharmaceutical combination and complexity of the particular disorder to which it is applied therapy. Preferably oral administration.

Above and below, all temperatures are in C. In the following examples, "conventional treatment" means: if necessary, water is added, the mixture is set, if necessary, depending on the composition of the final product, at a pH between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated, dried over sodium sulfate and evaporated, and the residue purified via chromatography on silica gel and/or by crystallization.

Mass spectrometry (MS): EI (ionization under the influence

electrons) M+

FAB (bombing quick

atoms) (M+H)+

Example 1

3 g of 3-[7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]methyl propionate and 1.9 g of 3-chloro-4-methoxybenzylamine ("And") in 50 ml. of dimethylformamide (DMF) is stirred at 60° C for 12 hours in the presence of potassium carbonate. After filtration the solvent is removed and the mixture is treated in the usual way. Obtain 4.6 g of 3-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]methyl propionate as a colourless oil.

The following connection get similar reactions “And”

with methyl 2-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]acetate methyl 2-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]acetate.

The following connection receive similarly, the reaction of 3,4-methylenedioxyphenethylamine with methyl 3-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]propionate, methyl 3-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]propionate.

The following connection get a similar reaction "And"

with methyl 4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]butyrate methyl 4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyrate.

The following connection receive similarly, the reaction of 3,4-methylenedioxyphenethylamine

with methyl 4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]butyrate methyl 4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-3-N-pyrazolo[4,3-d]pyrimidine-5-yl]butyrate.

The following connection get a similar reaction "And"

with methyl 5-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]valerate methyl 5-[7-(3-the loro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valerate.

The following connection get a similar reaction 3.4 methylenedioxyphenethylamine

with methyl 5-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]valerate methyl 5-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo [4,3-d]pyrimidine-5-yl]valerate.

The following connection get a similar reaction "And"

with methyl 7- [7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]heptanoate methyl 7-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d] pyrimidine-5-yl]heptanoate.

The following connection receive similarly, the reaction of 3,4-methylenedioxyphenethylamine

with methyl 7-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]heptanoate methyl 7-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]heptanoate.

The following connection get a similar reaction "And"

with methyl 2-[4-(7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl-)cyclohex-1-yl]acetate methyl 2-{4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexyl-1-yl}acetate.

The following connection receive similarly, the reaction of 3,4-methylenedioxyphenethylamine

With methyl 2-[4-(7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohex-1-yl]acetate methyl 2-{4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexyl-1-yl}acetate.

The following compounds of the floor is given similarly by the reaction of benzylamine

with methyl 3-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]propionate, methyl 3-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]propionate; methyl 4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]butyrate

methyl 4-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyrate; methyl 5-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]valerate methyl 5-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valerate.

The following connection get a similar reaction "And"

with methyl 4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]-cyclohexanecarboxylate methyl 4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexanecarboxylate and the following connections receive similarly, the reaction of 3,4-methylenedioxyphenethylamine methyl 4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexanecarboxylate.

Example 2

4.3 g of methyl 3-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]propionate was dissolved in 30 ml of tetrahydrofuran (THF) and, after addition of 10 ml of 10% NaOH, stirred at 60° C for 8 hours. After addition of 10% Hcl deposited crystals are separated and recrystallized from methanol. Obtain 3.7 g of 3-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]about the Ionova acid, TPL 178° .

Using evaporation with an equivalent amount of a methanol solution of potassium hydroxide receive the sodium salt of the acid in the form of amorphous powder.

Similarly, of the esters mentioned in Example 1, receive connections

2-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]acetic acid,

3-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]propionic acid,

4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid, TPL 152° ;

4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid, TPL 172° ;

5-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid, TPL 159° ;

5-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid, ethanolamine salt, TPL 160° ;

7-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]heptane acid,

7-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]heptane acid,

2-{4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexyl-1-yl}acetic acid,

2-{4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]p is rimidine-5-yl]cyclohexyl-1-yl}acetic acid,

3-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]propionic acid,

4-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]butyric acid,

5-[7-benzylamino-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]valeric acid, TPL 185° ;

4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexanecarbonyl acid,

4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexanecarbonyl acid.

Similarly receive connections

5-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid, salt cyclohexylamine, TPL 148°;

4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-ethyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid, TPL 176°;

4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-ethyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid, TPL 187° ,

4-[7-(3-chloro-4-methoxybenzylamine)-1-ethyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid, TPL 206° ;

4-[7-(3,4-methylenedioxybenzyl)-1-ethyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid, TPL 177° ;

4-[7-benzylamino-1-methyl-3-ethyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]butyric acid, TPL 208° ;

4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid, TPL 250° ;/p>

4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-methyl-1H-pyrazolo [4,3-d]pyrimidine-5-yl]butyric acid, TPL 225° ;

4-[7-benzylamino-1-methyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid, TPL 201° ;

5-[7-(4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid, TPL 160° ;

5-[7-(3-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid, TPL 141° ;

5-[7-(4-chlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid, TPL 148° ;

5-[7-(3-chlorobenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid, TPL 151° .

Example 3

A mixture of 1.8 g of methyl 4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d]pyrimidine-5-yl]phenylcarbamate ("In") and 1.5 g of 3-chloro-4-methoxybenzylamine in 20 ml of N-methylpyrrolidone heated at 110° C for 4 hours. After cooling, it is treated in the usual way. Obtain 2.2 g of methyl 4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-5-yl]benzoate.

Analogously to Example 2 from 1.2 g of ester obtain 1.0 g

4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]benzoic acid, ethanolamine salt, TPL 139° .

Analogously to Example 1 from "In" and 3,4-methylenedioxyphenethylamine get

methyl 4-[7-(3,4-methylenedioxybenzyl)-1-IU the Il-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]benzoate, and from it by hydrolysis of ester

4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]benzoic acid.

Similarly receive connections

4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]phenylacetic acid, salt of glucamine, TPL 114° and

4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo [4,3-d]pyrimidine-5-yl]phenylacetic acid.

Example 4

1 equivalent of 3-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]propionic acid and 1.2 equivalents of thionyl chloride is stirred in dichloromethane for 2 hours. The solvent is removed and receive 3-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo [4,3-d]pyrimidine-5-yl]propionyl chloride. The product is transferred in aqueous ammonia, stirred for 1 hour and after conventional treatment has obtained 3-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidine-5-yl]propionamide.

Example 5

1 equivalent of DMF and 1 equivalent of oxalicacid dissolved in acetonitrile at 0. Then add 1 equivalent of 3-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]propionamide. The mixture is stirred for 1 hour. After the usual processing gain 3-[7-(3-chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-3-N-pyrazolo[4,3-d]-pyrimidine-5-yl]propio itril.

Example 6

Analogously to Examples 1, 2 and 3 by means of the reaction of the corresponding derivatives of chloropyrimidine with 3,4-ethylenedioxythiophene get carboxylic acid, shown below:

4-[7-(3,4-ethylenedioxythiophene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid,

3-[7-(3,4-ethylenedioxythiophene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]propionic acid,

5-[7-(3,4-ethylenedioxythiophene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid,

7-[7-(3,4-ethylenedioxythiophene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]heptane acid,

2-{4-[7-(3,4-ethylenedioxythiophene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexyl-1-yl}acetic acid,

4-[7-(3,4-ethylenedioxythiophene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexanecarbonyl acid,

4-[7-(3,4-ethylenedioxythiophene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]benzoic acid,

4-[7-(3,4-ethylenedioxythiophene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]benzoic acid,

4-[7-(3,4-ethylenedioxythiophene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]phenylacetic acid.

Similarly, reaction with 3,4-dichlorophenylamino receive connections below:

4-[7-(3,4-dichlorophenylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid, TPL 209° ,

3-[7-(3,4-dichlorophenylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]propionic acid,

5-[7-(3,4-dichlorophenylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid,

7-[7-(3,4-dichlorophenylamino)-1 - methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]heptane acid,

2-{4-[7-(3,4-dichlorophenylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexyl-1-yl}acetic acid,

4-[7-(3,4-dichlorophenylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexanecarbonyl acid,

4-[7-(3,4-dichlorophenylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]benzoic acid,

4-[7-(3,4-dichlorophenylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]phenylacetic acid,

Similarly, reaction with 3-chloro-4-ethoxybenzylidene receive connections below:

4-[7-(3-chloro-4-ethoxybenzylidene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid,

3-[7-(3-chloro-4-ethoxybenzylidene)-1-methyl-3-propyl-1H-pyrazolo [4,3-d]pyrimidine-5-yl]propionic acid,

5-[7-(3-chloro-4-ethoxybenzylidene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid,

7-[7-(3-chloro-4-ethoxybenzylidene)-1-methyl-3-propyl-1H-pyrazolo [4,3-d]pyrimidine-5-yl]heptane acid,

2-{4-[7-(3-chloro-4-ethoxybenzylidene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexyl-1-yl}acetic acid,

4-[7-(chloro-4-ethoxybenzylidene)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexanecarbonyl acid,

4-[7-(3-chloro-4-ethoxybenzylidene)-1-methyl-3-propyl-1H-pyrazolo [4,3-d]pyrimidine-5-yl]benzoic acid,

4-[7-(3-chloro-4-ethoxybenzylidene)-1-methyl-3-propyl-1H-pyrazolo [4,3-d]pyrimidine-5-yl]phenylacetic acid,

Similarly, reaction with 3-chloro-4-isopropoxyaniline receive connections below

4-[7-(3-chloro-4-isopropoxyaniline)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid,

3-[7-(3-chloro-4-isopropoxyaniline)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]propionic acid,

5-[7-(3-chloro-4-isopropoxyaniline)-1-methyl-3-propyl-3-N-pyrazolo[4,3-d]pyrimidine-5-yl]valeric acid,

7-[7-(3-chloro-4-isopropoxyaniline)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]heptane acid,

2-{4-[7-(3-chloro-4-isopropoxyaniline)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexyl-1-yl)acetic acid,

4-[7-(3-chloro-4-isopropoxyaniline)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]cyclohexanecarbonyl acid,

4-[7-(3-chloro-4-isopropoxyaniline)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]benzoic acid,

4-[7-(3-chloro-4-isopropoxyaniline)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]phenylacetic acid.

Example 7

Analogously to Examples 1 and 2 receive the connection

[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimid is n-5-ylethoxy]acetic acid, salt ethanolamine, TPL 138° .

The examples below relate to pharmaceutical products.

Example: Capsule injection

A solution of 100 g of the active compounds of formula I and 5 g of hydrogenphosphate disodium set at pH 6.5 in 3 l of double-distilled water using 2N hydrochloric acid, sterile filtered, making capsules for injection, lyophilizer under sterile conditions and sealed under sterile conditions. Each injection capsule contains 5 mg of active ingredient.

Example: Suppositories

A mixture of 20 g of active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allow to cool. Each suppository contains 20 mg of the active ingredient.

Example: Solution

The solution obtained from 1 g of the active compounds of formula I, 9,38 g NaH2PO4·2H2O, 28,48 g Na2HPO4·N2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. pH is adjusted to 6.8, and the solution is brought to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

500 mg of the active compounds of formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: Tablets

A mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 to the talc and 0.1 kg of magnesium stearate is pressed in the usual way, receiving the tablets such that each tablet contains 10 mg of active ingredient.

Example F: coated Tablets

Tablets are pressed analogously to Example E and are then coated with usual coating consisting of sucrose, potato starch, talc, tragakant and dye.

Example G: Capsules

2 kg of active compound of the formula I is introduced into hard gelatin capsules in the usual way, so that each capsule contained 20 mg of the active ingredient.

Example N: Ampoules

A solution of 1 kg of active compound of the formula I in 60 l of double-distilled water is sterilized by filtration, making capsules, lyophilizer under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Example I: Spray for inhalation

14 g of the active compounds of formula I are dissolved in 10 l of isotonic NaCl solution bring in commercially available containers with dispenser with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (about 0.1 ml) corresponds to a dose of approximately 0,14 mg

1. The compounds of formula I

in which R1, R2each independently of one another denotes H, HE, OA or Hal, or R1and R2together represent-O-CH2-O - or-O-CH2- sub> 2-O-;

R3, R4designate A;

X denotes one-deputizing the radical R8, R5or R7;

R5denotes a linear or branched alkylene with 1-10 C-atoms, where one or two CH2-groups can be replaced by O;

R7denotes phenyl or phenylmethyl;

R8denotes COOH, cooa, CONH2, CONHA, CON(A)2or CN;

And denotes alkyl with 1-6 C-atoms and

Hal denotes F, Cl, Br or I,

and their physiologically acceptable salt or solvate.

2. The compounds of formula I according to claim 1:

(a) 5-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]pentane acid;

(b) 4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]benzoic acid;

(C) 4-[7-(3,4-methylenedioxybenzyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]butyric acid;

(g) 5-[7-(benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl]pentane acid;

(d) [7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylethoxy]acetic acid,

and their physiologically acceptable salt and solvate.

3. Method of producing compounds of the formula I according to claim 1 and their salts, characterized in that the compound of formula II

p num="259"> in which R3, R4and X have the meanings indicated in claim 1;

L denotes S, Br, IT, S3or a reactive esterified HE group

subjected to interaction with the compound of the formula III

in which R1and R2have the above values,

followed if necessary by hydrolysis of the compounds of the formula I, in which X represents an ester group to the corresponding carboxylic acid, which optionally further transformyour in amide or cyano, and/or the compound of formula I translate it into one of its salts.

4. A method of obtaining a pharmaceutical composition having inhibitory activity against phosphodiesterase V, characterized in that the compounds of formula I according to claim 1 and/or one (one) of its physiologically acceptable salts and solvate together with at least one solid, liquid or semi-liquid carrier or auxiliary substance are prepared in an appropriate dosage form.

5. Pharmaceutical composition having inhibitory activity against phosphodiesterase V and designed to combat diseases of the cardiovascular system and/or for the treatment of disorders, characterized in that it contains in its the m part, at least one compound of formula I according to claim 1 and/or one (one) of its physiologically acceptable salts and solvate.

6. The compounds of formula I according to claim 1 and their physiologically acceptable salt and solvate to fight with diseases of the cardiovascular system and for the treatment and/or therapy of disorders of potency.

7. The compounds of formula I according to claim 1 and their physiologically acceptable salt and solvate as inhibitors of phosphodiesterase V.



 

Same patents:

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to imidazole derivative of the formula (I)

or its pharmaceutically acceptable salt

The invention relates to organic chemistry and can find application in medicine

The invention relates to heterocyclic compounds with substituted phenyl group of formula Ior its pharmaceutically acceptable salt, in which R1represents a C1-C6alkyl; R2represents a C1-C6alkyl; R3represents H or halogen andrepresents a substituted heterocycle, as defined in paragraph 1 of the claims; and X represents NH or O

The invention relates to organic chemistry and can find application in medicine

The invention relates to an improved process for the preparation of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-she formulas (I) and its pharmaceutically acceptable salts by the interaction of the compounds of formula (II), where R1and R2means hydrogen or R1means hydrogen and R2means methyl, with a mixture of formic acid and formaldehyde in the presence of tetrabutylammonium bromide, and the ratio of tetrabutylammonium bromide to the original compound is from 1:60 to 1:130, preferably 1:100

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes substituted benzoylcyclohexanediones of the general formula (I):

wherein m = 0 or 1; n = 0 or 1; A means a single bond or alkanediyl (alkylene) with 1-4 carbon atoms; R1 means hydrogen atom or unsubstituted alkyl with from 1 to 6 carbon atoms; R2 means methyl; R3 means hydrogen atom, nitro-, cyano-group, halogen atom, alkyl with from 1 to 4 carbon atoms substituted with halogen atom, alkoxy-group with from 1 to 4 carbon atoms or alkyl sulfonyl with from 1 to 4 carbon atoms; R4 means nitro-group, halogen atom, unsubstituted alkyl with from 1 to 4 carbon atoms of that substituted with halogen atom; Z means heterocycle, and herbicide agent based on thereof. Also, invention describes substituted derivatives of benzoic acid of the general formula (III):

wherein values n, A, R3, R4 and Z are given above. These compounds represent the parent substances used for preparing compound of the formula (I). Compounds of the formula (I) elicit high and selective herbicide activity.

EFFECT: valuable properties of compounds.

7 cl, 8 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of piperazinylalkylthiopyrimidine of the formula (I): wherein R1 represents hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkanoyl or di-(C1-C4-alkyl)-amino-(C1-C4-alkyl); R2 means hydrogen atom or benzyl substituted with 1-3 substitutes taken among the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy-group, di-(C1-C4-alkyl)-amino-group, hydroxyl group and halogen atom; n = 2, 3 or 4, and to its pharmaceutically acceptable acid addition salt. Also, invention describes a method for preparing compounds and pharmaceutical composition based on thereof. Compounds are useful for treatment of diseases arising as result of the central nervous system injury.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

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