New sulfur-containing derivatives with amide bond, the method of production thereof, their use as medicines and pharmaceutical compositions

 

The invention can be used in medicine, in particular as medicaments having inhibitory action on endotelinzawisimogo enzyme. The invention relates to products of formula (I)where n= 0 or 1; R1is, in particular, phenyl or biphenyl, optionally substituted, in particular, benzyloxy-, dioxolan or halogen; R2in particular, hydrogen or stands, substituted, in particular, indolium, phenylthio or phenyl, optionally substituted; a is carboxy, tetrazolyl or substituted alkyl, as well as all the salts and isomers of the products of formula (I). The invention can be used in the treatment of diseases caused by abnormally high amounts of endothelin. 5 C. and 4 h.p. f-crystals, 1 table.

Description text in facsimile form (see graphic part). Tn

Claims

1. Pharmaceutical composition having inhibitory effect on endotelinzawisimogo enzyme containing as active principle a compound of formula (I)where n is an integer of 0 or 1; R1is a phenyl or biphenyl, promom halogen; R2is a hydrogen atom or stands, substituted phenyl, phenylthio or indolium and, if necessary, the second phenyl, where the radicals phenyl, phenylthio and indolyl may be substituted by one or more radicals chosen from halogen atoms, hydroxyl, optionally protected, alkoxyl, linear or branched, containing not more than 4 carbon atoms, cyano-, carboxy-radical, free, turned into salt, esterified or laminirovannogo, benzyloxy-, teinila, naphthyl and phenyl, the latter three radicals may be substituted by one or more radicals, selected from halogen atoms, hydroxyl optionally protected, alkoxyl, linear or branched, containing not more than 4 carbon atoms, cyano-, carboxy-radical, free, turned into salt, esterified or laminirovannogo; And is a carboxy radical, free, turned into salt, esterified or laminirovannyy, tetrazolium, free or converted into a salt, or alkyl containing not more than 10 carbon atoms and substituted by a radical selected from carboxyethyl, free, turned into salt, esterified or laminirovannogo, Radik the sludge, naphthyl, teinila, indolyl and pyridyl, and these radicals are optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, optionally protected, alkoxyl, linear or branched, containing not more than 4 carbon atoms, cyano -, and free, turned into salt, esterified or laminirovannogo carboxy radical;represent a possible asymmetric centers in the compounds of formula (I),
moreover, the above compounds of formula (I) are presented in all possible isomer, racemic, enantiomeric or diastereoisomeric forms, as well as their additive salts with inorganic and organic acids or with inorganic and organic bases, with the exception of Tirana.

2. The composition according to p. 1, where in formula (I), n is an integer of 0 or 1; R1is a phenyl or biphenyl, optionally substituted or bromine atom or benzyloxy radicals, or dioxolan and, if necessary, by a halogen atom; R2is a hydrogen atom or stands, substituted phenyl, phenylthio or indolium and, if necessary, the second phenyl radical, where the radicals phenyl, fertilissima, linear or branched, containing not more than 4 carbon atoms, benzyloxy, teinila, naphthyl and phenyl, which itself can be substituted by hydroxyl, optionally protected or alkoxyl, linear or branched, containing not more than 4 carbon atoms; a is a carboxy radical, free, turned into salt esterified or laminirovannyy, tetrazolium, free or converted into a salt, or alkyl containing not more than 8 carbon atoms and substituted by a radical selected from carboxy radical, free, turned into salt, esterified or laminirovannogo, hydroxyl, optionally substituted, alkoxy radical containing not more than 4 carbon atoms, and phenoxy-radical, and the above compounds of formula (I) are presented in all possible isomer, racemic, enantiomeric or diastereoisomeric forms, as well as their additive salts with inorganic and organic acids or with inorganic and organic bases.

3. Composition under item 1 or 2, where in the formula (I) n= 1; R1is a phenyl or biphenyl, optionally substituted or bromine atom or benzyloxy radicals, or dioxolan and, if necessary, the atom halog is benzyloxy radicals, or two phenyl radicals, or a radical of phenylthio or phenyl, which itself can be substituted by tanila, naphthyl or phenyl, which itself can be substituted by hydroxyl, optionally protected, alkoxy radicals containing not more than 4 carbon atoms, or benzyloxy radicals; a is a carboxy radical, free, turned into salt, esterified or laminirovannyy, or alkyl containing not more than 8 carbon atoms and substituted phenoxy-radical, and the above compounds of formula (I) are presented in all possible isomer, racemic, enantiomeric or diastereoisomeric forms, as well as their additive salts with inorganic and organic acids or with inorganic and organic bases.

4. The composition according to p. 1, where the compound of formula (I) is a compound selected from the group of: N-[3-(3-bromophenyl)-2-(mercaptomethyl)-1-oxopropyl] -L-Tryptophan, N-[3-((1,1'-biphenyl)-3-yl)-2-(mercaptomethyl)-1-oxopropyl] -L-Tryptophan, (R, S) N-[3-(4-bromophenyl)-2-(mercaptomethyl)-1-oxopropyl] -L-Tryptophan, (R, S) N-[3-((1,1'-biphenyl)-4-yl)-2-(mercaptomethyl)-1-oxopropyl] -L-Tryptophan, (S) N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl] -4-(2-thienyl)-L-Phenylalanine, (S) N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl] -4-(1-naftilamin] -L-Phenylalanine, (S, S) - N-(2-((1,1'-biphenyl)-4-yl)-1-(1H-tetrazol-5-yl)-ethyl)-alpha-(mercaptomethyl)-benzoylpropionic, (R) and (S) - N-[3-(3-bromophenyl)-2-(mercaptomethyl)-1-oxopropyl] -4-(2-thienyl)-L-Phenylalanine (isomer a and b), N-[3-(3-bromophenyl)-2-(mercaptomethyl)-1-oxopropyl] -7-(phenylmethoxy)-Tryptophan, as well as their additive salts with inorganic and organic acids or with inorganic and organic bases.

5. Composition according to any one of paragraphs. 1-4, intended for the treatment of diseases such as hypertension caused by endothelin, vasospasm, the consequences of a brain hemorrhage, renal failure, myocardial infarction, heart failure, and also in the prevention of post-angioplasticheskih restenosis, cardio sclerosis and fibrosis of blood vessels.

6. The method of obtaining compounds of formula (I), characterized in that the compound of formula (II)

subjected to the reaction of interaction with the compound of the formula (III)
R'1-CH2-Hal1(III)
where Hal1is a chlorine atom or iodine;
R'1matter specified in paragraph 1 for R1where possible reactive functions are optionally protected,
obtaining the compounds of formula (IV)

receiving the compounds of formula (V)

where R'1has the above value, which is subjected to the reactions of elimination and saponification with obtaining the compounds of formula (VI)

where R'1shall have the meaning given above for R1;
which is subjected to the reaction of interaction with the compound of the formula (Xlla)

where W is alkyl or phenyl,
obtaining the compounds of formula (VII)

where R'1and W have the above values,
which is, or is subjected to the reaction of interaction, in the presence of a blending agent with the compound of the formula (VIII)

where R'2has the above meaning;
And' has the meaning specified in paragraph 1 And, where possible reactive functions are optionally protected,
obtaining the compounds of formula (IX)

where R'1, R'2W and A' have the above values,
or is exposed to chlorination agent with obtaining the appropriate acid chloride, which is injected into the reaction interaction with the compound of the above formula (VIII) to obtain the product of the above f is subject to any order, to obtain products of formula (I) or, if necessary, of one of its derivatives: reaction of saponification of essential functions to acid; the reaction for the conversion of Sinopoli in acidic or tetrazolyl function; the conversion of alkoxyphenyl in hydroxypoly; the esterification reaction, the salt formation or amination acid function; reactions release tylenol group of radical

the reaction of removing the protective groups, which can carry the reaction; the reaction of formation of the corresponding salts with inorganic or organic acids or bases, the resulting products of formula (I) are all possible isomer, racemic, enantiomeric and diastereoisomeric form.

7. The method of obtaining compounds of formula (I), characterized in that the compound of formula (X)

where R'1has the above value, diasterous in the presence of a halogenation agent to obtain compounds of formula (XI)

where R'1has the above value,
Hal is a halogen atom, which is introduced into the reaction interaction with thioacetate formula (XIIb)

where W and R'1have the above values,
which is injected into the reaction interaction with the product of the above formula (VIII) with a compound of formula (XIV)

where R'1, R'2And' and W have the above values,
the compound obtained of the formula (XIV) is subjected to one or more of the following reactions carried out in any order, to obtain products of formula (I) or, if necessary, of one of its derivatives: reaction of saponification of essential functions to acid; the reaction for the conversion of Sinopoli in acidic or teratology function; the conversion of alkoxy function in the hydroxy function; the esterification reaction, the salt formation or amination acid function; reactions release tylenol group of radical

the reaction of removing the protective groups, which can carry the reaction; the reaction of formation of the corresponding salts with inorganic or organic acids or bases,
the resulting products of formula (I) are all possible isomer, racemic, enantiomeric and diastereoisomeric form.

8. Compounds: N-[3-(3 is Tofan, (R, S) N-[3-(4-bromophenyl)-2-(mercaptomethyl)-1-oxopropyl] -L-Tryptophan, (R, S) N-[3-((1,1'-biphenyl)-4-yl)-2-(mercaptomethyl)-1-oxopropyl] -L-Tryptophan, (S) N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl] -4-(2-thienyl)-L-Phenylalanine, (S) N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl] -4-(1-naphthyl)-L-Phenylalanine, (S) - 4-phenyl-N-[(2-mercaptomethyl)-1-oxo-3-phenylpropyl] -L-Phenylalanine, (S, S) - N-(2-((1,1'-biphenyl)-4-yl)-1-(1H-tetrazol-5-yl)-ethyl)-alpha-(mercaptomethyl)-benzoylpropionic, (R) and (S) - N-[3-(3-bromophenyl)-2-(mercaptomethyl)-1-oxopropyl] -4-(2-thienyl)-L-Phenylalanine (isomer a and b), N-[3-(3-bromophenyl)-2-(mercaptomethyl)-1-oxopropyl] -7-(phenylmethoxy)-Tryptophan,
as well as their additive salts with pharmaceutically acceptable inorganic and organic acids or with inorganic and organic bases.

9. The use of the compounds of formula (I):

where n is an integer of 0 or 1;
R1is phenyl;
R2is a hydrogen atom;
And - alkyl containing up to 10 carbon atoms or carboxylation, free or esterified with a lower alcohol,
or their salts as inhibitors endotelinzawisimogo enzyme.

 

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< / BR>
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