Thienopyrimidine, the method of production thereof, pharmaceutical preparation and method thereof

 

(57) Abstract:

The present invention relates to thienopyrimidine formula I

in which R1, R2in each case, independently of one another represent IT, or Hal; X is an R5, monosubstituted R7; R5is cycloalkyl containing 6 atoms; R7is COOH, cooa; And is an alkyl having from 1 to 6 atoms; Hal represents F, Cl, Br or I, where at least one of the radicals R1or R2is a HE, as well as their pharmaceutically acceptable salts. The compounds inhibit phosphodiesterase V and can be used to treat disorders of the cardiovascular system. Also described is a method of obtaining compounds of formula I, pharmaceutical drug-based compounds and the method of its production. 4 N. and 2 C.p. f-crystals. table 1.

The invention relates to compounds of the formula I

in which

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

X is R4, R5or R6, monosubstituted R7,

R4is unbranched or branched alkylene with 1-10 atoms, in which one or two alkylene, containing 5-12 With atoms

R6is phenyl or vinylmation,

R7is COOH, cooa, CONH2, CONHA, CON(A)2or CN,

And is alkyl having from 1 to 6 atoms

Hal represents F, Cl, Br or I,

where at least one of the radicals R1or R2HE is a,

and their pharmaceutically acceptable salts.

Derivatives of pyrimidine have been described, for example, in EP 201188 or WO 93/06104.

The basis of the invention was based on the aim to discover new compounds with valuable properties, in particular, those that can be applied for the production of medicines.

It was found that the compounds of formula I and their salts have very valuable pharmacological quality along with good tolerance.

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

Quinazoline with cGMP, phosphodiesterase-inhibitory activity, as described for example in J. Med. Chem. 36, 3765 (1993), ibid. 37, 2106 (1994).

The biological activity of the compounds of formula I can be determined by methods as described, for example, in WO 93/06104. The affinity of the compounds according to the invention with respect to cGMP and camp phosphodiesterase determine the project activity of the enzyme).

For definitions can be used enzymes isolated by known methods (e.g. W. J. Thompson and others, Biochem. 1971, 10, 311). For experiments can be used a modified “batch” method of W. J. Thompson and M. M. Appleman, Biochem. 1979, 18, 5228.

Thus, the compounds suitable for treating disorders of the cardiovascular system, in particular 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 WO 94/28902.

The compounds are effective as inhibitors phenylephrin-induced interactions drugs body cavity of rabbits. This biological effects can be demonstrated, for example, by the method described by F. Holmquist, etc. in J. Urol., 150, 1310-1315 (1993). Inhibition of contractions shows the effectiveness of the compounds according to the invention for the treatment and/or treatment of disorders of potency.

The compounds of formula I can be used as pharmaceutically active compounds in human and veterinary medicine. Additionally, they can be used as intermediates for further pharmaceutically active soede I on p. 1 and their salts, which are distinguished by the fact that

a) compound of formula II

in which

X has the specified value,

a L is CL, Br, IT, SCHs or reactive esterified HE group

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 hydrolysis of the ether group in the COOH group or conversion of COOH groups in amide or cyano

or

c) in the compound of formula I the radical R1and/or R2converted into another radical R1and/or R2the transformation of alkoxygroup in hydroxyl group,

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

Above and below, the radicals R1, R2, R3, R4, R5, R6, R7, X and L have the meanings stated for formula I, II and III, unless otherwise specifically indicated.

And represents alkyl having 1-6 With atoms.

In the above formulas, the alkyl preferably not branched and has 1, 2, 3, 4, 5 or 6 C atoms and is preferably stands, ethyl or propylene, more preferably an isopropyl

X is an R4, R5or R6radical, monosubstituted R7.

R4represents an unbranched or branched alkalinity radical having 1-10 With atoms, where alkalinity radical is preferably, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2 - or 3-methylbutanol, 1,1-, 1,2 - or 2,2-dimethylpropylene, 1-ethylpropyl, hexylene, 1-, 2-, 3 - or 4-methylpentane, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3.3-dimethylbutanol, 1 - or 2-methylpropanol, 1,1,2 - or 1,2,2-trimethylpropyl, branched or non-branched heptylene, anjilina, nonrenal or delinom.

R4is furthermore, for example, but-2-anilino or Gex-3-anilino.

Particularly preferred ethylene, propylene or butylene.

R5is cycloalkyl having 5-12 With atoms, preferably, for example, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexyldiamine or cyclohexylmethyl.

R5is also cycloalkyl, preferably having 5-7 atoms. Cycloalkyl represents, for example, cyclopentyl, cyclohexyl or cycloheptyl.

Hal preferably occhialino are 3 - or 4 - position of the phenyl ring. They represent, for example, in each case independently of one another H, alkyl, alkoxy, hydroxyl, F, Cl, Br or I. Preferably they are independently from each other are Hal and hydroxyl. At least one of the radicals R1and R2is hydroxyl.

The radical R7preferably is, for example COOH, SOON3, SOOS2H5, CONH2, CON (CH3)2, CONHCH3or CN.

The entire invention is that all radicals which occur several times, can be identical or different, i.e. are independent from each other.

Accordingly, the invention relates 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 shown on subformula Ia-Id, which correspond to the formula I and in which the radicals not specified in detail, have the same meaning as in formula I, but in which

in Ia X is R4, phenyl or vinylmation, substituted by COOH, cooa, CONH2, CONA2, CONHA or CN;

in Ib R1, R2in each case, independently of one another represent CONH2, CONA2, CONHA or CN;

where at least one of the radicals R1and R2is a HE;

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

X is alkylene with 2-5 atoms, cyclohexyl, phenyl or vinylmation that monogamist R7,

R7represents COOH or cooa,

And represents alkyl with 1-6 atoms,

Hal is F, Cl, Br or I,

where at least one of the radicals R1and R2is HE;

in Id R1represents Hal

R2HE is a,

X is alkylene with 2-5 atoms, cyclohexyl, phenyl or vinylmation, monosubstituted R7,

R7represents COOH or cooa,

And is alkyl with 1-6 atoms,

Hal is F, Cl, Br or I,

And their physiologically acceptable salts.

The compounds of formula I, as well as the source materials for their production get by known methods 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 wearable is not described here in more detail.

In the compounds of the formula II or III, R1, R2, R3, R4, X and n have the abovementioned meanings, especially these preferred values.

If L is a reactive esterified HE group, it preferably is alkylsulfonate with 1-6 atoms (preferably, methylsulfonylamino) or arylsulfonate with 6-10 atoms (preferably phenyl - or p-tolilsulfonil, and additionally 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 starting materials can also be formed in place so that they are not isolated from the reaction mixture, and immediately subjected to further reactions to produce compounds of formula I.

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 be obtained, e.g. reaction with POCI3from the respective hydroxypyrimidine, which are synthesized from derivatives of thiophene and JV-substituted alkilinity esters of carboxylic acids. (Eur. J. Med. Chem. 23, 453 (1988)).

Hydroxypyrimidine derivatives of 2-aminobenzamide-3-carbocyclic acid with aldehydes or NITRILES, usual to obtain the pyrimidine derivatives (e.g., Houben Weyl E9b/2).

In particular, the reaction of the 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 .

The addition of an agent that binds acid, for example, alkali metal or alkaline-earth metals, preferably of potassium, sodium or calcium, or the addition of organic bases, such as triethylamine, dimethylamine, pyridine or quinoline, or an excess of amine may be desirable.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, Benzen, toluene or Xilin; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbontetrachloride, 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 ethylene glycol, monotropy ether (methylglycol or ethylglycol), ethylene glycol dimethyl ether (diglyme); l-formamide (DMF); NITRILES, such as dimethylsulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of the mentioned solvents.

Moreover, it is possible to translate the radical X in a compound of formula I into another radical X, i.e., the hydrolysis of ester or ceanography in the COOH group.

The group of esters can be hydrolizes, for example, using NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 .

Carbocyclic acids can be translated, for example using thionyl chloride, into the corresponding chlorides carbocyclic acids, and they can be transferred to carboxamide. Of them receive carbonitrile by removal of water by a known method.

The compounds of formula I in which R1and/or R2are OA, can be translated by known methods for the cleavage of ethers into the corresponding compounds of formula I in which R1and/or R2are hydroxyl.

The acid of formula I can be translated into the associated acid mixed with salt using a base, for example, by the reaction of equivalent quantities of acid and base in an inert solvent, such as ethanol, followed by evaporation. P is salt.

Thus, the acid of formula I can be converted to the corresponding salt of the metal or the corresponding ammonium salt using a base (e.g., the hydroxide or carbonate of sodium or potassium).

On the other hand, the base of the formula I can be translated into the associated acid mixed with salt using an acid, for example, by reaction of equivalent amounts of base and acid in an inert solvent, such as ethanol, followed by evaporation. For this reaction, suitable acids are, in particular, those which give physiologically acceptable salts. Thus, there can be used inorganic acids, e.g. sulfuric acid, nitric acid, hydrohalogen acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic mono - or politonalnye carbocyclic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, Pavlova acid, diethyloxalate acid, manolova acid, succinic acid, Pimenova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic Tangolunda acid, 2-hydroxyethanesulfonic acid, Benzenesulfonic acid, p-toluensulfonate acid, naphtalene and desulfonema acid and louisanna acid. Salts with physiologically unacceptable acids, e.g. the picrate, can be used for isolation and/or purification of the compounds of formula I.

Moreover, the invention 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 regard, a suitable dose can be prepared together with at least one solid, liquid and/or semi-liquid media or excipients and, if necessary, in combination with one or more other active compound.

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

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

These drugs may be used as medicaments in human or veterinary medicine. Suitable carriers are organic or inorganic substances which eiyuuden with the new compounds, for example water, vegetable oils, benzyl alcohols, alkalophile, glycols, glyceryltrinitrate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. For oral administration suitable, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, for rectal use suppositories, for parenteral use use solutions, preferably aqueous or oil solutions, furthermore suspensions, emulsions or implants, for topical application apply creams, ointments or powders. The new compounds can also be liofilizovane, and the resulting lyophilizate be used for the production of injection preparations. These preparations can be sterilized and/or 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 for control of diseases, which increase the relaxation. Compounds according to the invention, in particular, can be used in the treatment of diseases of the cardiovascular system and for the treatment and/or therapy of disorders of potency.

In this regard, substance, usually preferably used 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, such as the effectiveness of specific applied compound, the age, body weight, General health, sex, diet, time and schedule of admission and the level of selection, pharmaceutical combination and complexity of the particular disorder to which the applied therapy. It is preferable to oral administration.

Above and below, all temperatures are in C. In the following examples, “conventional treatment” means: if necessary, add water, adjust pH, if necessary, depending on the composition of the final product, to values between 2 and 10, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated, dried over sodium sulfate and evaporated, and the residue is distilled poulsom) M+

The Belarusian library Association (fast atom bombardment) (M+N)+

Example 1

3-(4-chlorobenzamido[2,3-d]pyrimidine-2-yl)propionate methyl [obtained by cyclization of 2-amino-5,6,7,8-tetrahedralisation-3-carboxylate bromide with 3-cyanopropionic bromide, dehydrogenase with grey and subsequent chlorination with phosphorus oxychloride/dimethylamine] and 3-chloro-4-methoxybenzylamine (“a”) N-organic stirred at 110 for 5 hours. The solvent is removed, and the residue is treated in the usual way. 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]pyrimidine-2-yl]methyl propionate obtained as a colorless oil.

Subsequent receive similarly, the reaction of a with 2-(4-chlorobenzamido[2,3-d]pyrimidine-2-yl) acetate methyl 2-[4-(3-chloro-4-methoxybenzylamine)benzothieno(2,3-d]pyrimidine-2-yl]methyl acetate.

Subsequent receive similarly, reaction “AND”

4-(4-chlorobenzamido[2,3-d]pyrimidine-2-yl)methyl butyrate

4-[4-(3-chloro-4-methoxybenzylamine)benzo-thieno[2,3-d]pyrimidine-2-yl]methyl butyrate.

Subsequent receive similarly, reaction “AND”

5-(4-chlorobenzamido[2,3-d]pyrimidine-2-yl)methyl valerate

5-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]pyrimid what about[2,3-d]pyrimidine-2-yl)heptane.com bromide

7-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]pyrimidine-2-yl]heptane.com bromide.

Subsequent receive similarly, reaction “AND”

2-[4-(4-chlorobenzamido[2,3-d]pyrimidine-2-yl)cyclohex-1-yl]methyl acetate

2-{4-[4-(3-chloro-4-methoxybenzylamine)-benzothieno[2,3-d]pyrimidine-2-yl]cyclohex-1-yl}methyl acetate

Subsequent receive similarly, reaction “AND”

4-(4-chlorobenzamido[2,3-d]pyrimidine-2-yl)cyclohexanecarboxylate bromide

4-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]pyrimidine-2-yl]cyclohexanecarboxylate bromide.

Example 2

3-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]pyrimidine-2-yl]methyl propionate dissolved in monopetalum ether of ethylene glycol and stirred at 100 for 5 hours after addition of 32% NaOH. After addition of 20% Hcl, the mixture is extracted with dichloromethane. The addition of petroleum ether to obtain 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]-pyrimidine-2-yl]propionic acid, so pl. 218 .

Precipitated precipitated crystals are dissolved in isopropanol and treated with ethanolamine. After crystallization receive 3-[4-(3-chloro-4-methoxybenzylamine)-benzothieno[2,3-d]pyrimidine-2-yl]propionic acid ethanolamine salt.

5-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]pyrimidine-2-yl]valeric acid, so pl. 210 ; salt ethanolamine, so pl. 141 , get similarly.

Carboxylic acids listed below, receive the similarly of the esters listed in Example 1:

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

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

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

4-[4-(3-chloro-4-methoxybenzylamine)benzothieno-[2,3-d]pyrimidine-2-yl]cyclohexanecarboxylic acid, ethanolamine salt, so pl. 167 .

Example 3

A mixture of 1.5 g of 4-(4-chlorobenzamido[2,3-d]pyrimidine-2-yl)phenolcarboxylic bromide (“B”) obtained by dehydrogenating corresponding connection 5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine with grey, and subsequent chlorination with phosphorus oxychloride/dimethylamine, and 1.5 g of 3-chloro-4-methoxybenzylamine in 20 ml of N-methylpyrrolidone heated to 110 (for 4 hours. After cooling, the mixture is treated in the usual way. Obtain 2.6 g of 4-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]pyrimidine-2-yl]benzoate is pyrimidine-2-yl]benzoic acid, salt ethanolamine, so pl. 189-190°, 1.2 G. of ester.

The compound 4-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]pyrimidine-2-yl]phenylacetic acid, ethanolamine salt, so pl. 130 receive the same.

Example 4

1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]pyrimidine-2-yl]propionic acid and 1.2 equivalents of thionyl chloride is stirred in dichloromethane for 2 hours. The solvent is removed and receive 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]-pyrimidine-2-yl]propionyl chloride. The mixture is transferred into aqueous ammonia, stirred for 1 hour and, after conventional treatment, receive 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]pyrimidin-2-yl]propionamide.

Example 5

1 equivalent of DMF and 1 equivalent of oxalicacid dissolved in acetonitrile at 0 . Then add 1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamine)-benzothieno[2,3-d]pyrimidine-2-yl]propionamide. The mixture was then stirred for one hour. After the usual processing gain 3-[4-(3-chloro-4-methoxybenzylamine)benzothieno[2,3-d]pyrimidine-2-yl]propionitrile.

Example 6

The compounds obtained in Examples 1-5, can be translated into the corresponding hydroxyl compounds, and using the thieno[2,3-d]pyrimidine-2-yl]propionate,

methyl 2-[4-(3-chloro-4-hydroxybenzylidene)benzothieno[2,3-d]pyrimidine-2-yl]acetate

methyl 4-[4-(3-chloro-4-hydroxybenzylidene)benzothieno[2,3-d]pyrimidine-2-yl]butyrate,

methyl 5-[4-(3-chloro-4-hydroxybenzylidene)benzothieno[2,3-d]pyrimidine-2-yl]valerate,

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

methyl 2-{4-[4-(3-chloro-4-hydroxybenzylidene)-benzothieno[2,3-d]pyrimidine-2-yl]cyclohex-1-yl}acetate

methyl 4-[4-(3-chloro-4-hydroxybenzylidene)benzothieno[2,3-d]pyrimidine-2-yl]cyclohexanecarboxylate,

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

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

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

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

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

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

4-[4-(3-chloro-4-hydroxybenzylidene)benzothieno-[2,3-d]pyrimidine-2-yl]cyclohexanecarboxylic acid,

3-[4-(3-chloro-4-hydroxybenzylidene)benzothieno-[2,3-d]pyrimidine-2-yl]propionamide,

3-[4-(3-chloro-4-hydroxybenzylidene)benzothieno-[2,3-d]pyrimidine-2-yl]propionitrile,

get that way.

Example 7

Analogously to Example 1 by reaction of 0.01 mol of methyl 4-(4-chlorobenzamido[2,3-d]pyrimidine-2-yl)cyclohexanecarboxylate with 0.02 mol of 3-chloro-4-hydroxybenzylidene in 40 ml of 1-methyl-2-pyrrolidone, after conventional treatment, get

methyl 4-[4-(3-chloro-4-hydroxybenzylidene)benzothieno[2,3-d]pyrimidine-2-yl]cyclohexanecarboxylate

Connection

methyl 4-[4-(3-methoxy-4-hydroxybenzylidene)benzothieno[2,3-d]pyrimidine-2-yl]cyclohexanecarboxylate and

methyl 4-[4-(4-hydroxybenzylidene)benzothieno-[2,3-d]pyrimidine-2-yl]cyclohexanecarboxylate

get likewise.

The hydrolysis of esters, analogously to Example 2, of which receive connections

4-[4-(3-chloro-4-hydroxybenzylidene)benzothieno[2,3-d]pyrimidine-2-yl]cyclohexanecarboxylic acid, ethanolamine salt, so pl. 200-202 ;

4-[4-(3-methoxy-4-hydroxybenzylidene)benzothieno-[2,3-]pyrimidine-2-yl]cyclohexanecarboxylic acid,

4-[4-(4-hydroxybenzylidene)benzothieno(2,3-d]-pyrimidine-2-yl]cyclohexanecarboxylate crimein-2-yl]butyric acid,

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

2-[4-(3-methoxy-4-hydroxybenzylidene)benzothieno-[2,3-d]pyrimidine-2-yl]acetic acid,

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

2-(4-[4-(3-methoxy-4-hydroxybenzylidene)benzothieno[2,3-d]pyrimidine-2-yl]cyclohex-1-yl}acetic acid,

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

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

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

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

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

3-{4-(4-(4-hydroxybenzylidene)benzothieno[2,3-d]-pyrimidine-2-yl]cyclohex-1-yl}propionic acid,

get likewise.

The following examples relate to pharmaceutical preparations.

Example: ampoules for injection

A solution of 100 g of the active compounds of formula I and 5 g of hydrogenphosphate disodium brought to a pH in 3 l of double-distilled water using 2N hydrochloric to the Eski sealed. Each ampoule for injection contains 5 mg of active compound.

Example: Suppositories

A mixture of 20 g of the active compounds of formula I is dissolved 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 active compound.

Example: Solution

A solution is prepared from 1 g of the active compounds of formula I, 9,38 g NaH2PO42H2O, 28,48 g Na2HPO4N2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The solution is brought to pH 6.8, the volume was adjusted 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: Pill

A mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of sodium stearate is pressed in the usual manner to obtain tablets so that each tablet contained 10 mg of active compound.

Example F: coated Tablets

Analogously to Example E tablets are pressed and then coated with usual coating of sucrose, potato starch is in hard gelatin capsules in the usual way, so that each capsule contains 20 mg of active compound.

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, Packed in ampoules, lyophilizer under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound.

Example I: Spray for inhalation

14 g of the active compounds of formula I are dissolved in 10 l of isotonic NaCl solution and the solution is filled in a commercially available spray containers with a pump mechanism. The solution can be sprayed into the mouth or nose. One dose spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg

Test solubility; Inhibition of PDE V

The tests were carried out in the measurement of solubility by shaking the flask.

1. Thienopyrimidine formula I

in which R1, R2in each case, independently of one another represent IT, or Hal;

X is R5, monosubstituted R7;

R5is cycloalkyl containing 6 C-atoms;

R7is COOH, cooa;

And is alkyl having from 1 to 6 C-atoms;

Hal break IT,

as well as physiologically acceptable salts.

2. The compound of formula I under item 1: (e)4-[4-(3-chloro-4-hydroxybenzylidene)benzothieno-[2,3-d]-pyrimidine-2-yl]cyclohexanecarboxylic acid,

as well as its physiologically acceptable salt.

3. The method of obtaining compounds of formula I on p. 1 and their salts, which consists in the fact that a) compound of formula II

in which X has the specified value.

L is CL, Br,

subjected to reaction with the compound of the formula III

in which R1and R2have the specified values,

b) the compound of formula I the radical X is translated into another radical X by hydrolysis of the ether group in the COOH group and/or a compound of formula I is transferred into one of its salts.

4. Method for the production of pharmaceutical preparations, characterized in that the compound of formula I under item 1 and/or one of its physiologically acceptable salts is dosed in the form of a suitable dose together with at least one solid, liquid or semi-liquid media or excipients.

5. Pharmaceutical drug that has comparable activity against inhibition of PDE, characterized in that it contains at least one compound of formula I under item 1 and/or one of the e is suitable as inhibitors of phosphodiesterase V.

 

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