Condensed thienopyrimidine with inhibiting phosphodiesterase v action, method for their production and pharmaceutical composition

 

(57) Abstract:

The invention relates to novel condensed to thienopyrimidine formula I and their physiologically acceptable salts, having the effect of inhibitors of phosphodiesterase V(PDE V), and which can be used for the treatment of diseases of the cardiovascular system and for the treatment and/or therapy of disorders of potency. In the compounds of formula IR1, R2each independently of one another denotes H, OA or Hal, R1and R2together represent alkylene with 3-5 C-atoms, -O-CH2-CH2-, -CH2-O-CH2-, -O-CH2-O - or-O-CH2-CH2-O-, X denotes R4, R5or R6once substituted by substituent R7, R4denotes a linear or branched alkylene with 1-10 C-atoms, R5denotes cycloalkyl or cycloalkylation with 5-12 C-atoms, R6denotes phenyl or phenylmethyl, R7denotes COOH or cooa, And denotes alkyl with 1-6 C-atoms, and Hal denotes F, Cl, Br or I. the Invention also relates to a method for producing compounds of formula I. the Method of obtaining lies in the fact that the compound of formula II, where X has the above values, a, L denotes Cl, Br, HE, SCH3or reactive who t the above values, followed, if necessary, converting the resulting compound of the formula I one residue X in the remainder of X, for example, by hydrolysis of the ester groups to COOH groups, and/or translation of the compounds of formula I into one of its physiologically acceptable salts. 3 S. and 3 C.p. f-crystals, 1 PL.

The present invention relates to compounds of the formula I

in which

R1, R2each independently of one another denotes H, A, OA or Hal, R1and R2together represent alkylene with 3-5 C-atoms, -O-CH2-CH2-, -CH2-O-CH2-, -O-CH2-O - or-O-CH2-CH2,

X denotes one-deputizing Deputy R7, R4, R5or R6,

R4denotes a linear or branched alkylene with 1-10 C-atoms, where one or two CH2-groups may be replaced by-CH=CH-group,

R5denotes cycloalkyl or cycloalkylation with 5-12 C-atoms

R6denotes phenyl or phenylmethyl,

R7denotes COOH, cooa, CONH2, CONHA, CON (A) g or CN,

And denotes alkyl with 1-6 C-atoms and

Hal denotes F, C1, Br or I,

The basis of the invention was based on the task to obtain new compounds with valuable properties, especially those that would be suitable for the manufacture of the drugs. It has been found that the compounds of formula I and their salts along with good compatibility possess very valuable pharmacological properties. First of all, they show specific inhibition of cyclo-GMP-phosphodiesterase (PDE V).

Hintline with overwhelming cyclo-GMP-phosphodiesterase activity are described, for example, in Journ. Med. Chem. 36. page 3765 (1993) and in the same journal 37, page 2106 (1994).

The biological activity of the compounds of formula I can be confirmed using the methods described, in particular, in the international application WO 93/06104. Affinity proposed in the invention compounds to cyclo-GMP - and cyclo-AMR-phosphodiesterase identify, determining their IC50-values (concentration of inhibitor required to achieve 50% suppression of enzyme activity).

To conduct these studies can be used enzymes that produce using known methods (see, for example, W. J. Thompson and others, Biochem. 10 (1971), page 311). For experimenting you can apply a modified "group" ("batch") is possible according to the invention can be used for the treatment of diseases of the cardiovascular system, first of all, heart failure, and for the treatment and/or therapy of disorders of potency (erectile dysfunction).

The use of substituted pyrazolopyrimidinones for the treatment of impotence is described, for example, in international application WO 94/28902.

Compounds according to the invention are effective as inhibitors induced by phenylephrine contractions in the samples prepared from the cavernous bodies of hares. This biological activity can be confirmed, for example, using the method described by Holmquist (F. Holmquist) and other authors in Journ. Urol. 150, pp. 1310-1315 (1993). This inhibition of contractions is proof of the effectiveness of the proposed compounds for therapy and/or treatment of disorders of potency.

The compounds of formula I can be used as active substances in medicinal products intended for use in medicine and veterinary medicine. It is also possible, and their use as intermediate products for other active substances, with subsequent use of the latest in medicines.

The object of the invention in accordance with this are the compounds of formula I, as well as the method of obtaining compounds of the formula I according to paragraph 1, the P>X has the above values, a, L denotes C1, Br, IT, S3or a reactive esterified HE group, is subjected to the interaction with the compound of the formula III

where R1and R2have the above values, or

b) the compound of the formula I one residue X is transformed into another residue X, for example by hydrolysis of the ester groups to COOH groups, or by transformation of the COOH group in amide or cyano, and/or that the compound of formula I is transferred into one of its salts.

Above and beyond R1, R2, R3, R4, R5, R6, R7, X and L, unless otherwise indicated, have the meanings given in the interpretation of formulas I, II and III.

And denotes alkyl with 1-6 C-atoms.

In the above formulas, the alkyl is preferably unbranched, has 1, 2, 3, 4, 5 or 6 C-atoms, and preferably represents methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and n-pentyl, neopentyl, isopentyl or hexyl.

X denotes one-deputizing Deputy R7, R4, R5or R6.

R4denotes a linear or realistically how many, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, 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- or 3,3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 - or 1,2,2-trimethyl-propylene, linear or branched septilin, octiles, Nonlin or deciles.

R4also means, for example, but-2-Anilin or Gex-3-Anilin. The most preferred ethylene, propylene or butylene.

R5denotes cycloalkylation with 5-12 C-atoms, preferably, for example, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexyldiamine or cyclohexylmethyl.

R5indicates cycloalkyl, preferably with 5-7 C-atoms. Cycloalkyl represents, for example, cyclopentyl, cyclohexyl or cycloheptyl.

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

The remains of R1and R2may be identical or different and are preferably in position 3 or 4 of the phenyl ring. Each of them independently of one another denotes, for example, H, alkyl, F, Cl, Br or I, or both of them together is hydroxy or Ethylenedioxy. Preferably they represent respectively alkoxygroup, such as methoxy, ethoxy or propoxy.

The remainder R7means is preferably, for example, COOH, SOON3, SOOS2H5, CONH2, SOP(CH3)2THE N3or CN.

For inventions in General, the following applies: all residues that are repeatedly present in joints, can be identical or different, i.e., to have corresponding values independently from each other.

In accordance with this object of the invention are such compounds of formula I in which at least one of these residues has one of the above preferred values. Some preferred groups of compounds can be represented by the following subformulae Ia-Id, which fall under the formula I and in which not deciphered more residues have the meanings indicated in formula I, but there are some differences, namely:

in Ia X denotes substituted by a COOH group, sooa, CONH2, CONA2, CONHA or CN R4, phenyl or phenylmethyl,

in id R1and R2together denote alkylene with 3-5 C-atoms, -O-CH2CH2, CONA2, CONHA or CN R4, phenyl or phenylmethyl,

in Ic R1, R2each independently of one another denotes H, A, OA or Hal,

R1and R2together denote alkylene with 3-5 C-atoms, -O-CH2-CH2-, -O-CH2-O - or-O-CH2-CH2,

X denotes a substituted group COOH, cooa, CONH2, CONA2, CONHA or CN R4, phenyl or phenylmethyl,

in Id R1, R2each independently of one another denotes H, A, OA or Hal,

R1and R2together denote alkylene with 3-5 C-atoms, -O-CH2-CH2-, -O-CH2-O - or-O-CH2-CH2,

X denotes one-deputizing Deputy R7alkylen with 2-5 C-atoms, cyclohexyl, phenyl or phenylmethyl,

R7denotes COOH or cooa,

And denotes alkyl with 1-6 C-atoms

Hal denotes F, Cl, Br or I.

The compounds of formula I, as well as source materials for their production, the rest are obtained by known methods described in the literature (for example, in such fundamental publications, as Houben-Weyl, Methods der organischen Chemie, published by Georg-Thieme-Verlag, Stuttgart), a that is, when the conditions are known and suitable for carrying out the detail options.

In the compounds of formulas II or III, R1, R2, R3, R4and X have the above values, especially the values specified as preferred.

If L represents a reactive esterified HE group, the latter represents preferably alkylsulfonates with 1-6 C-atoms (preferably, methylsulfonylamino) or arylsulfonate with 6-10 C-atoms (preferably phenyl - or p-tolilsulfonil, and 2-naphthalenesulfonate).

It is preferable to obtain the compounds of formula I by the interaction of the compounds of the formula II with compounds of formula III.

The source of the substance, if necessary, may also be formed in situ, eliminating their compulsory isolation from the reaction mixture and gives the possibility of directly converting them into compounds of formula I. At the same time, the reaction can be carried out by step-wise mechanism.

Source materials of formulas II and III, in principle, known. If they are unknown, they can be obtained by known methods. For example, the compounds of formula II can be obtained by the interaction with l3from the corresponding hydroxypyrimidine that synthesize from Digene of hydroxypyrimidine carried out either by dehydrogenation of the corresponding tetrahydropyrimidine compounds, or by ordinary for obtaining derivatives of pyrimidine cyclization of derivatives of 2-aminobenzo-Hairdryer-3-carboxylic acid with aldehydes or NITRILES (see, for example, Houben-Weyl E9b/2).

Specifically, the interaction of the compounds of the formula II with compounds of the formula III is carried out in the presence of an inert solvent or in his absence at temperatures in the range of from about -20 to about +150C, preferably from 20 to 100C.

It may be appropriate to supplementation acid binding agent, such as hydroxide, carbonate or bicarbonate of alkali or alkaline earth metal, or another salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium or calcium, or additives organic bases such as triethylamine, dimethylamine, pyridine or quinoline, or additives amine component in an excessive amount.

As inert solvents for these purposes are suitable among other 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, isopr, tetrahydrofuran (THF) or dioxane; a simple glycol ethers, such as onomatology or monotropy ether of ethylene glycol (methylglycol or ethylglycol), dimethyl ethers of ethylene glycol (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 these solvents.

In addition, one residue X in the compound of the formula I can be converted into another residue X, for example, gidrolizu ester or cyano to the COOH group. Ester groups can omelet, for example with NaOH or KOH in water, in a mixture of water and THF or water and dioxane at temperatures in the range from 0 to 100C.

Carboxylic acids can be converted, for example by using thionyl-chloride, into the corresponding carboxylic acid anhydrides and the last to turn in amides of carboxylic acids. Owing to ongoing known by removal of water from these amides get carbonitrile.

The acid of formula I can be translated using the Foundation of the cation in an inert solvent, such as ethanol and subsequent evaporation. For the implementation of this reaction is primarily suitable bases forming physiologically acceptable salt. Thus, in particular, the acid of formula I can be converted with bases (for example, hydroxide or carbonate of sodium or potassium) in the appropriate salt of the metal, especially in salt alkali or alkaline earth metal, or into the corresponding ammonium salt. For this reaction are suitable in the first place such organic bases, which form a physiologically acceptable salt, such as ethanolamine.

On the other hand, possible options, according to which the basis of the formula I translate using acid to the corresponding acid additive salt, for example, the interaction of equimolar amounts of base and acid in an inert solvent, such as ethanol and subsequent evaporation. For this reaction are suitable primarily acids, which form physiologically acceptable salts. Thus, in particular, can be used such inorganic acids as sulfuric acid, nitric acid, halogenation acids, such as chloride-hydrogen acid or Bioorganicheskaya acid, first of all aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalenamine dissolvability and louisanna acid. Salt also physiologically unacceptable acids, for example the picrate can be used for isolating and/or purifying compounds of formula I.

The object of the invention is further the use of compounds of the formula I and/or their physiologically acceptable salts for pharmaceutical compositions, primarily non-chemical way. While one together with at least one solid, liquid and/or semi-liquid carrier or auxiliary substance and neobyazatel sirovina form.

Another object of the invention are also drugs of formula I and their physiologically acceptable salts as inhibitors of phosphodiesterase V

The object of the invention is further pharmaceutical composition, containing in its composition at least one compound of the formula I and/or one of its physiologically acceptable salts. These compositions can be used as drugs in medicine or veterinary medicine. As carriers can use organic or inorganic substances suitable for enteral (for example oral), parenteral or local administration and not reacts with the new compounds, for example water, vegetable oils, benzyl alcohols, alkalophile, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, vaseline. For oral administration can be assigned primarily tablets, pills, coated tablets, capsules, powders, granules, syrups, medicine or drops for rectal administration is suppositories, for parenteral solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implanon lyophilizate to use, for example, for the manufacture of drugs for injection. These compositions can be sterilized and/or they may contain auxiliary substances, such as oil, preservatives, stabilizers and/or wetting, emulsifying agents, salts for regulating the osmotic pressure, buffer substances, colorants, flavorings and/or several other active substances, for example one or more vitamins.

The compounds of formula I and their physiologically acceptable salts can be used for diseases in which increased levels of cGMP (cyclo-guanosine monophosphate) contributes to the suppression or prevention of inflammatory processes and relaxation (relaxation) of the muscles. Especially now proposed in the invention compounds can also be used in the treatment of diseases of the cardiovascular system and the treatment and/or therapy of disorders of potency. When this substance is, as a rule, appoint preferably in dosages of from about 1 to 500 mg, especially from 5 to 100 mg per uniform dose. The daily dose is preferably from about 0.02 to 10 mg/kg of body weight. However, the special dose assigned to a particular patient depends on various Stoane health, sex, diet, time and method of administration, on the rate of excretion, combination of drugs and the severity of the relevant disease for which this therapy is intended. It is preferable to oral administration.

Above and beyond all temperatures are in degrees Celsius. In the examples below, the term "normal processing" we mean the following: if necessary, water is added, if necessary, depending on the structural characteristics of the final product, the pH value is set in the range of 2 to 10, extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and/or by crystallization.

Mass spectrometry (MS):EI (ionization by electron impact) M+; FAB (bombardment with accelerated atoms) (M+N)+.

Example 1

Methyl ester of 3-(4-chlorobenzamido- [2,3-d] -pyrimidine-2-yl)propionic acid [obtained by cyclization of methyl ester 2-amino-5,6,7,8-tetrahedralisation-3-carboxylic acid by the action of methyl ester 3-cyanopropionic acid, Daydreamin (compound "a") N-organic stirred for 5 hours at 110C. Then the solvent is removed and conduct regular processing. The result is the methyl ester of 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl]propionic acid as colorless oil.

In a similar way by the interaction of the compounds And methyl ether of 2-(4-chlorobenzamido- [2,3-d]-pyrimidine-2-yl) acetic acid to obtain methyl ester of 2-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] acetic acid.

In a similar way interaction of 3,4-methylenedioxyphenethylamine with methyl ether 3-(4-chlorobenzamido-[2,3-d]-pyrimidine-2-yl)propionic acid get methyl ester 3-[4-(3,4-methylendioxy-benzylamino)benzothieno-[2,3-d]-pyrimidine-2-yl] propionic acid.

In a similar way interaction connection "And" methyl ester, 4-(4-chlorobenzamido-[2,3-d]-pyrimidine-2-yl)butyric acid get methyl ester 4- [4-(3-chloro-4-methoxybenzylamine)benzothieno- [2,3-d] -pyrimidine-2-yl] butyric acid.

In a similar way interaction of 3,4-methylenedioxyphenethylamine with methyl ester of 4-(4-chlorobenzamido-[2,3-d]-pyrimidine-2-yl)butyric acid get methyl ester 4- [4-(3,4-methylenedioxybenzyl)benzothieno-[2,3-d]-pyrimidine-2-yl] butyric kislotnimi-2-yl)valerianic acid get methyl ester 5-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] valerianic acid.

In a similar way interaction of 3,4-methylenedioxyphenethylamine with methyl ester of 5-(4-chlorobenzamido- [2,3-d]-pyrimidine-2-yl) valerianic acid get methyl ester 5-[4-(3,4-methylendioxy-benzylamino)benzothieno-[2,3-d]-pyrimidine-2-yl] valerianic acid.

In a similar way by the interaction of the compounds And methyl ether 7-(4-chlorobenzamido-[2,3-d]-pyrimidine-2-yl) heptane acid get methyl ester of 7-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] heptane acid.

In a similar way interaction of 3,4-methylenedioxyphenethylamine with methyl ether 7-(4-chlorobenzamido-[2,3-d]-pyrimidine-2-yl) heptane acid get methyl ester of 7-[4-(3,4-methylenedioxyphenethylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] heptane acid.

In a similar way by the interaction of the compounds And methyl ether 2- [4-(4-chlorobenzamido-[2,3-d]-pyrimidine-2-yl) cyclohexyl-1-yl] acetic acid get methyl ester 2-{4-[4-(3-chloro-4-methoxybenzyl)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexyl-1-yl} acetic acid.

In a similar way interaction of 3,4-methylenedioxyphenethylamine with methyl ester 2-[4-(4-chlorobenzamido-[2,3-d]-pyrimidine-2-yl)cyclohexyl-1-yl] acetic Kisil} acetic acid.

In a similar way interaction benzylamine

with methyl ether 3-(4-chlorobenzamido-[2,3-d]-pyrimidine-2-yl)propionic acid get methyl ester 3-(4-benzylaminopurine-[2,3-d] -pyrimidine-2-yl)propionic acid;

with methyl ester of 4-(4-chlorobenzamido- [2,3-d]-pyrimidine-2-yl) butyric acid get methyl ester of 4-(4-benzylaminopurine-[2,3-d]-pyrimidine-2-yl) butyric acid;

with methyl ester of 5-(4-chlorobenzamido-[2,3-d]-pyrimidine-2-yl)valerianic acid get methyl ester 5-(4-benzylaminopurine-[2,3-d]-pyrimidine-2-yl)valerianic acid.

In a similar way interaction connection "And" methyl ester, 4-(4-chlorobenzamido- [2,3-d]-pyrimidine-2-yl)cyclohexanecarboxylic acid get methyl ester 4-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl]cyclohexanecarboxylic acid, and interaction with 3,4-methylenedioxyaniline get methyl ester 4- [4- (3,4-methylenedioxyphenethylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexanecarbonyl acid.

Example 2

Methyl ester of 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno- [2,3-d]-pyrimidine-2-yl] propionic acid are dissolved in monopetalum ether of ethylene glycol is chlormethine. Adding petroleum ether, to obtain 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno- [2,3-d]-pyrimidine-2-yl] propionic acid with tPLS.

The precipitated crystals are dissolved in isopropanol, stirred into ethanolamine and after crystallization receive 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] propionic acid, ethanolamine salt.

Similarly receive the following connections:

4-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] butyric acid, tPL225C;

5-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] valeric acid, tPL210C;

4-[4-(3,4-methylenedioxyphenethylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] butyric acid hydrochloride, tPL245C.

In a similar way from the esters mentioned in example 1 are given the following carboxylic acids:

2-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] acetic acid,

3-[4-(3,4-methylenedioxyphenethylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] propionic acid,

5-[4-(3,4-methylenedioxyphenethylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] valeric acid,

7-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-PYRANOVA acid

2-{4-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexyl-1-yl} acetic acid,

2-{4-[4-(3,4-methylenedioxyphenethylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexyl-1-yl} acetic acid,

3-(4-benzylaminopurine- [2,3-d] -pyrimidine-2-yl)propionic acid,

4-(4-benzylaminopurine-[2,3-d]-pyrimidine-2-yl) butyric acid,

5-(4-benzylaminopurine-[2,3-d]-pyrimidine-2-yl) valeric acid,

4-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexanecarbonyl acid

4-[4-(3,4-methylenedioxyphenethylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexanecarbonyl acid.

Example 3

A mixture of 1.5 g of methyl ester of 4-(4-chlorobenzamido)- [2,3-d]-pyrimidine-2-yl)phenylcarbinol acid (compound B) obtained by dehydrogenation of the corresponding 5,6,7,8-tetrahydrothieno- [2,3-d] -pyrimidine compounds of sulfur and subsequent chlorination with phosphoroxychloride/dimethylamine, and 1.5 g of 3-chloro-4-methoxybenzylamine in 20 ml of N-methylpyrrolidone heated for 4 hours to 110C. After cooling, conduct normal processing. The result is 2.6 g of methyl ester of 4-[4-(3-chloro-4-methoxybenzylamine)-[1]bettiga ether obtain 1.0 g of 4-[4-(3-chloro-4-methoxybenzylamine) - [1] benzothieno- [2,3-d] -pyrimidine-2-yl]benzoic acid, ethanolamine salt with tPL189-190C.

Analogously to example 1 from compound B and 3,4-methylenedioxyphenethylamine get methyl ester 4-[4-(3,4-methylenedioxyphenethylamine)-[1] benzothieno-[2,3-d]-pyrimidine-2-yl] benzoic acid or ester by hydrolysis receive 4- [4-(3,4-methylenedioxyphenethylamine)-[1] benzothieno-[2,3-d]-pyrimidine-2-yl] benzoic acid, sodium salt with tPL>260C.

Similarly receive connections

4-[4-(3-chloro-4-methoxybenzylamine)-[1]benzothieno-[2,3-d]-pyrimidine-2-yl]phenylacetic acid, ethanolamine salt with tPL202C and

4-[4-(3,4-methylenedioxyphenethylamine)-[1]benzothieno-[2,3-d]-pyrimidine-2-yl]phenylacetic acid.

Example 4

1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] propionic acid and 1.2 equivalent of thionyl chloride is stirred for 2 hours in dichloromethane. Then the solvent is removed and the result is the acid chloride of 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]-pyrimidine-2-yl] propionic acid. Next he was transferred to aqueous ammonia, stirred for one hour and after the usual processing receive amide 3-[4-(3-chlorine is ivalent DMF and 1 equivalent of oxalicacid dissolved at 0 ° C in acetonitrile. Then add 1 equivalent of the amide 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d] -pyrimidine-2-yl] propionic acid. Further stirred for one hour and after the usual processing gain 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno- [2,3-d]-pyrimidine-2-yl] propionitrile.

Example 6

Analogously to examples 1, 2 and 3 by the interaction of the corresponding derivatives of chloropyrimidine with 3,4-ethylenedioxythiophene get the following carboxylic acids:

4-[4-(3,4-ethylenedioxythiophene)benzothieno-[2,3-d]-pyrimidine-2-yl] butyric acid,

3-[4-(3,4-ethylenedioxythiophene)benzothieno-[2,3-d]-pyrimidine-2-yl] propionic acid,

5-[4-(3,4-ethylenedioxythiophene)benzothieno-[2,3-d]-pyrimidine-2-yl] valeric acid,

7-[4-(3,4-ethylenedioxythiophene)benzothieno-[2,3-d]-pyrimidine-2-yl] heptane acid,

2-{4- [4-(3,4-ethylenedioxythiophene)benzothieno-[2,3-d]-pyrimidine-2-yl]cyclohexyl-1-yl} acetic acid,

4-[4- (3,4-ethylenedioxythiophene)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexane acid,

4-[4-(3,4-atlantooccipital)- [1]benzothieno-[2,3-d]-pyrimidine-2-yl]benzoic acid decomposition at 220-230C,

4-[4-(3,4-atlantooccipital) -[1]bessiliem receive the following connections:

4-[4-(3,4-dichloraniline)benzothieno-[2,3-d]-pyrimidine-2-yl] butyric acid,

3-[4-(3,4-dichloraniline)benzothieno-[2,3-d]-pyrimidine-2-yl] propionic acid,

5-[4-(3,4-dichloraniline)benzothieno-[2,3-d]-pyrimidine-2-yl] valeric acid,

7-[4-(3,4-dichloraniline)benzothieno-[2,3-d]-pyrimidine-2-yl] heptane acid,

2-{4-[4-(3,4-dichloraniline)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexyl-1-yl] acetic acid,

4-[4- (3,4-dichloraniline)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexanecarbonyl acid

4-[4-(3,4-dichloraniline)-[1] benzothieno-[2,3-d]-pyrimidine-2-yl] benzoic acid,

4-[4-(3,4-dichloraniline)-[1] benzothieno-[2,3-d]-pyrimidine-2-yl] phenylacetic acid.

In a similar way interaction C3-chloro-4-ethoxybenzylidene receive the following connections:

4- [4-(3-chloro-4-ethoxybenzylidene)benzothieno-[2,3-d]-pyrimidine-2-yl] butyric acid,

3-[4-(3-chloro-4-ethoxybenzylidene) benzothieno-[2,3-d]-pyrimidine-2-yl] propionic acid,

5-[4-(3-chloro-4-ethoxybenzylidene)benzothieno-[2,3-d]-pyrimidine-2-yl] valeric acid,

7-[4-(3-chloro-4-ethoxybenzylidene)benzothieno-[2,3-d]-pyrimidine-2-yl] heptane acid,

4-[4-(3-chloro-4-ethoxybenzylidene)benzothieno- [2,3-d]-pyrimidine-2-yl] cyclohexanecarbonyl acid

4-[4- (3-chloro-4-ethoxybenzylidene)-[1] benzothieno- [2,3-d]-pyrimidine-2-yl] benzoic acid, tPL185-187C;

4-[4-(3-chloro-4-ethoxybenzylidene)-[1] benzothieno-[2,3-d]-pyrimidine-2-yl]phenylacetic acid.

Similar by interaction with 3-chloro-4-isopropoxyaniline receive the following connections:

4-[4-(3-chloro-4-isopropoxyaniline)benzothieno-[2,3-d]-pyrimidine-2-yl] butyric acid,

3-[4-(3-chloro-4-isopropoxyaniline)benzothieno-[2,3-d]-pyrimidine-2-yl] propionic acid,

5-[4-(3-chloro-4-isopropoxyaniline)benzothieno-[2,3-d]-pyrimidine-2-yl] valeric acid,

7-[4-(3-chloro-4-isopropoxyaniline)benzothieno-[2,3-d]-pyrimidine-2-yl] heptane acid,

2-{4-[4-(3-chloro-4-isopropoxyaniline)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexyl-1-yl} acetic acid,

4- [4-(3-chloro-4-isopropoxyaniline)benzothieno-[2,3-d]-pyrimidine-2-yl] cyclohexanecarbonyl acid

4- [4-(3-chloro-4-isopropoxyaniline) - [1] benzothieno-[2,3-d] -pyrimidine-2-yl] benzoic acid, tPL240-241C,

4- [4- (3-chloro-4-isopropoxyaniline) - [1] benticheskih composition and technology of their preparation in the appropriate dosage forms.

Example: Vials for injection solutions

A solution of 100 g of the active substance of the formula I and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water using 2 N. hydrochloric acid set at pH 6.5, sterile filtered, filled flask, lyophilized in sterile sterile conditions and sealed. Each vial contains 5 mg of active substance.

Example B: Suppositories

First prepare a mixture of 20 g of the active substance of the formula I, 100 g of soya lecithin and 1400 g of cocoa butter, the mixture is then melted, poured into molds and allowed to harden. 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 NaH2RHO4·2H2O, 28,48 g PA2NRA4·N2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. Then set to pH 6.8, adjusted to a volume of 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

When observing aseptic conditions prepare a mixture of 500 mg of the active substance of the formula I with 99.5 g of petroleum jelly.

Example D: Pill

Prigotovit the Arata magnesium, which then tabletirujut by the conventional methods in such a way that each tablet contains 10 mg of active substance.

Example E: Bean

Analogously to example D is pressed tablets, which then according to standard technology is covered by a shell of sucrose, potato starch, talc, tragant and dye.

Example G: Capsule

2 kg of active substance of the formula I according to standard technology to produce capsules with terrorisation coating in such a way that each capsule contains 20 mg of active substance.

Example 3: Ampoules

A solution of 1 kg of active substance of the formula I in 60 l of double-distilled water is sterile filtered, dispensed into ampoules under sterile conditions lyophilized sealed and sterile. Each ampoule contains 10 mg of active substance.

Example: Inhalation spray

14 g of the active substance of the formula I are dissolved in 10 l of isotonic NaCl solution and then the solution is poured into a conventional, commercially available cartridges, equipped with a pumping device. The solution can be applied to inhalation mouth and nose. Issued from cans for one pressing portion (approximately 0.1 ml) corresponds to the dose pharmacologically activity against inhibition phosphodiesterase V

Tests were conducted in accordance with the methodology described P. Hamet and others (1983) “Rapid activation of od cAMP phosphodiesterase in platelets of rats”. Can. J. Biochem. Cell Biol. 61: 1158-65.

The following table lists the tested compounds, the values of their pharmacological activity IC50the melting point (MP) or mass spectrometry (EI-M+for these compounds, as well as examples,which describe the synthesis of these compounds.

Metric values IC50(concentration in mmol/l; that is, 50% inhibition of phosphodiesterase V) were obtained for the following compounds of the formula I

1. Condensed thienopyrimidine formula I

in which R1, R2each independently of one another denotes H, OA or Hal;

R1and R2together represent alkylene with 3-5 C-atoms, -O-CH2-CH2-,

-CH2-O-CH2-, -O-CH2-O - or-O-CH2-CH2-O-;

X denotes R4, R5or R6once substituted by substituent R7;

R4denotes a linear or branched alkylene with 1-10 C-atoms;

R5means cyclol>denotes COOH or cooa;

And denotes alkyl with 1-6 C-atoms;

Hal denotes F, Cl, Br or I,

and their physiologically acceptable salts.

2. The compounds of formula I on p. 1:

(a) 3-[4-(3-chloro-4-methoxybenzylamine)benzo[4,5]thieno[2,3-d]pyrimidine-2-yl]propionic acid;

(b) 4-[4-(3,4-methylenedioxyphenethylamine)benzo[4,5]thieno[2,3-d]pyrimidine-2-yl] butyric acid;

(C) 7-[4-(3,4-methylenedioxyphenethylamine)benzo[4,5]thieno-[2,3-d]pyrimidine-2-yl]heptane acid;

(g) 7-[4-(3-chloro-4-methoxybenzylamine)benzo[4,5]thieno[2,3-d]pyrimidine-2-yl] heptane acid;

(e) 5-[4-(3-chloro-4-methoxybenzylamine)benzo[4,5]thieno[2,3-d]pyrimidine-2-yl] valeric acid;

(e) 2-{4-[4-(3-chloro-4-methoxybenzylamine)benzo[4,5]thieno[2,3-d]pyrimidine-2-yl]cyclohexyl-1 - yl}acetic acid;

(W) 4-[4-(3,4-methylenedioxyphenethylamine)benzo[4,5]thieno[2,3-d]pyrimidine-2-yl] cyclohexanecarbonyl acid;

(C) 4-[4-(3,4-methylenedioxyphenethylamine)benzo[4,5]thieno[2,3-d]pyrimidine-2-yl] benzoic acid;

(or) 4-[4-(3,4-methylenedioxyphenethylamine)benzo[4,5]thieno[2,3-d]pyrimidine-2-yl] phenylacetic acid;

(K) 4-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]pyrimidine-2-yl] cyclohe compounds of formula I on p. 1, and also their salts, characterized in that the compound of formula II

where X has the above values, a, L denotes CL, Br, HE, SCH3or a reactive esterified HE group, is subjected to the interaction with the compound of the formula III

where R1and R2have the above values, followed, if necessary, converting the resulting compound of the formula I one residue X in the remainder of X, for example, by hydrolysis of the ester groups to COOH groups, and/or translation of the compounds of formula I into one of its physiologically acceptable salts.

4. Pharmaceutical composition having inhibitory activity against phosphodiesterase V, characterized in that it contains at least one compound of formula I under item 1 and/or one of its physiologically acceptable salts.

5. The pharmaceutical composition according to p. 5, characterized in that it contains at least one compound of formula I under item 1 and/or one of its physiologically acceptable salts in an amount of 1-500 mg per dose.

6. The compounds of formula I on p. 1 and their physiologically acceptable salts, having the effect of inhibitors of phosphodiesterase V.

 

Same patents:

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

The invention relates to new thienopyrimidine formula I, their pharmaceutically acceptable salts, having the effect of inhibitors of phosphodiesterase V, which can be used to combat diseases of the cardiovascular system and for the treatment and/or therapy of disorders, to pharmaceutical compositions in a form suitable for the treatment

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The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

< / BR>
where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

< / BR>
is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

The invention relates to new thienopyrimidine General formula I or their physiologically acceptable salts, having the properties of an inhibitor of phosphodiesterase V, which can be used in the pharmaceutical industry for the treatment of diseases of the cardiovascular system, in particular heart failure, and for treatment of violations of a potentiality

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to new thienopyrimidine, as well as their physiologically acceptable salts with inhibitory activity against phosphodiesterase V (PDE V), which can be used to combat diseases of the cardiovascular system and for the treatment and/or therapy of disorders of potency

The invention relates to thiophene derivative of the formula I, in which Ra and Rb may be the same or different and mean hydrogen, alkyl, acyl, alkenyl, phenyl, or Ra and Rb together may form a benzene ring or cyclohexanone ring, its pharmaceutically acceptable salts and hydrates

The invention relates to the class of heterocyclic metallocenes and containing catalytic systems, as well as the method of polymerization joining the polymerized monomers using a given catalytic system, and these heterocyclic metallocene correspond to the formula (I), YjRiZjjMeQkP1,

where Y represents a coordinating group containing the Central radical with six-electrons, directly coordinating IU, which condensed one or more rings containing at least one atom that is not carbon atom and is selected from S; R" represents a divalent bridging communication between the groups Y and Z; Z is a coordinating group having the same meaning as Y; Me represents a transition metal of group 3, 4, 5, 6; Q is halogen or linear or branched C1-C6-alkyl; R represents a counterion; i=0 or 1; j=1-3; jj=0-2; k=1-3 and 1= 0-2

The invention relates to new tricyclic pyrazole derivative or its pharmaceutically acceptable salt

The invention relates to vysokomernoa tritium 2-methyl-4-(4-methyl-1-piperazinil)-10H-thieno[2,3-b] [1,5] benzodiazepine, which can be used

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

The invention relates to new sulfadimethoxine bellrowan five-membered cyclic compounds of General formula I

< / BR>
where R(1), R(2) mean N; R(3) means R(10b)-CnH2nwhere n=0, 1; R(10b) means methyl; R(4) means R(13)-CrH2rwhere r=0, 1, 2, 3, 4, 5, 6; R(13) means methyl, nitrogen-containing aromatic 6-membered heterocycle; R(5), R(6) R(7) R(8) independently of one another denote H, F, Cl, Br, I, -NO2, -Y-CsH2s-R(18); Y represents-O-; s=1, 2, 3, 4, 5, 6; R(18)=H, methyl; X is-CR(22)R(23)-, -SO2- where R(22) R(23) means H or methyl, and their physiologically acceptable salts

The invention relates to new N-sulfonylpiperidinylmethylene derivative of the formula I

< / BR>
where n = 1; R1means1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, C1-C6haloalkyl or a group NR11R12where R11and R12each independently from one another mean H, C1-C6alkyl; R2means N; R3means1-C6alkyl; R4, R5, R6and R7have the same or different values and each independently from one another mean H, C1-C4alkyl; R8means C1-C6alkyl; a represents C1-C6alkylen; means phenyl, optionally substituted by 1-3 substituents, which may be the same or different and selected from the group comprising C1-C8alkyl, C1-C8haloalkyl,1-C8alkoxy, C1-C8haloalkoxy, C2-C8alkanoyl, halogen, C1-C8alkoxycarbonyl, nitro; or naphthyl or thienyl

The invention relates to new derivatives of 2-aminopyridine F.-ly (1) where denotes unsubstituted or substituted phenyl, pyridyl, thienyl, thiazolyl, hinely, cinoxacin-2-yl or Antonelliana derivatives; D is unsubstituted or substituted phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, hinely, triazolyl, oxazolyl, isoxazolyl or Antonelliana derivatives, provided that C and D are not simultaneously have the following values: S - phenyl, and D is phenyl, S - phenyl, and D - pyridyl, With - pyridyl and D - phenyl, - pyridyl and D - pyridyl; R1- R4- hydrogen, NO2or NH2

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to N-substituted aminotetralin formula 1

< / BR>
where R1independently selected from the group consisting of hydrogen; hydroxy; halogen; C1-8-alkoxy; substituted C1-8-alkoxy, where the Deputy is a halogen; n is 0-2; Y is methylene; m is 0-3;1means hydrogen;2means hydrogen; R2selected from the group consisting of hydrogen; hydroxy; C1-6-alkyl, C1-6-alkenyl; phenyl; substituted phenyl where the Deputy is chosen from halogen, C1-6-alkyl, C1-6-alkoxy, trifter-C1-6-alkyl, nitro; naphthyl and pyridyl; L is chosen from the group consisting of C1-8-alkylene; C1-4-alkylen-C3-7-cycloalkyl-C1-4-alkylene; C1-4-alkylen-aryl-C1-4-alkylene; R3selected from phenyl; substituted phenyl where the Deputy is chosen from halogen, nitro, C1-8-alkoxy, trifloromethyl and amino-C1-8-alkyl; naphthyl; and tanila and their enantiomers, diastereoisomers and pharmaceutically acceptable salts

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction
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