RU95118170A

RU95118170A - DERIVATIVES OF HYDROXYMETHYL FOURANOUS CARBONIC ACID AND THEIR USE IN THE TREATMENT OF CARDIOVASCULAR DISEASES

Info

Publication number: RU95118170A
Application number: RU95118170/04A
Authority: RU
Inventors: Шенафингер Карл; Бон Гельмут
Original assignee: Хехст Акциенгезелльшафт
Priority date: 1993-03-06
Filing date: 1995-02-18
Publication date: 1997-09-20

Claims

1. Derivatives of hydroxymethyl furazancarboxylic acid of general formula I,

where one of the radicals R ¹ and R ² represents hydroxymethyl, and the other represents

moreover, X denotes NR ³ R ⁴ or HE or OR ⁷ ;
R ³ and R ⁴ independently of one another denote hydrogen, (C ₁ -C ₂₀ ) -alkyl, 1-phenyl- (C ₂ -C ₄ ) -alkyl, 2-phenyl- (C ₃ -C ₄ ) -alkyl, (C ₃ - C ₆ ) alkenyl, (C ₃ - C ₇ ) cycloalkyl, - (CH ₂ ) _n —NR ⁵ R ⁶ -, - (CH ₂ ) _n –OR ⁵ , - (CH ₂ ) _m - СООR ⁵ , -CH (Аlk) -СООR ⁵ , - (СН ₂ ) _m -CONR ⁵ R ⁶ , СН (Аlk) -CONR ⁵ R ⁶ ,

- (CH ₂ ) _n -NR ⁵ (COAlk), - (CH ₂ ) _n -Ar or - (CH ₂ ) _n - Het, or R ³ and R ⁴ both together with the nitrogen atom linking them form a heterocycle, which can also be substituted once or more _than once with (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₁ -C ₄ ) -alkoxy, amino group, (C ₁ -C ₄ ) -alkylamino, di ( (C ₁ - C ₄ ) -alkyl) amino group, hydroxyl group, acetoxy group, benzyl, phenethyl or Ar;
R ⁵ and R ⁶ independently of one another denote hydrogen, (C ₁ - C ₆₎ -alkyl, (C ₃ -C ₆₎ -alkenyl, (C ₃ - C ₇₎ cycloalkyl, benzyl, phenethyl or Ar;
R ⁷ means (C ₁ - C ₆ ) -alkyl, (C ₃ - C ₇ ) -cycloalkyl, benzyl, phenyl or once or repeatedly substituted by (C ₁ - C ₄ ) -alkyl, fluorine, chlorine or nitro, phenyl;
A1k means (C ₁ - C ₆ ) -alkyl;
Ar is an aryl radical with a number of C-atoms of 6 to 12, which can also be substituted once or several times by (C ₁ –C ₄ ) alkyl, (C ₁ – C ₄ ) alkoxy, amino, (C ₁ – C ₄ a) alkylamino, di ((C ₁ - C ₄ ) - alkyl) amino group, (C ₁ - C ₆ ) alkanoylamino group, sulfamoyl, fluorine, chlorine, bromine, hydroxyl group, acetoxy group, nitro group, trifluoromethyl or cyano group;
He is a heterocyclic radical with the number of heteroatoms of 1 - 3, which can also be substituted once or several times by (C ₁ - C ₄ ) alkyl, (C ₁ - C ₄ ) alkoxy, amino, (C ₁ - C ₄ ) - alkylamino, di ((C ₁ - C ₄ ) alkyl) amino group, (C ₁ - C ₆ ) alkanoylamino group, fluorine, chlorine, bromine, hydroxyl group, acetoxy group, nitro group, cyano group or Ar;
n = 0, 1, 2, 3, or 4;
m = 1, 2, 3 or 4;
p = 1, 2 or 3,
as well as their pharmacologically applicable salts.

2. Derivatives of hydroxymethyl furazancarboxylic acid of general formula I according to claim 1, characterized in that X represents NR ³ R ⁴ and one of the radicals R ³ and R ⁴ represents hydrogen, and the other radical has one of the meanings indicated in paragraph 1 , or R ³ and R ⁴ both together with the nitrogen atom linking them form a heterocycle, which can also be substituted once or several times with (C ₁ - C ₆ ) alkyl, (C ₃ - C ₇ ) cycloalkyl, (C ₁ - C ₄ ) alkoxy group, amino group, (C ₁ - C ₄ ) alkylamino group, di ((C ₁ - C ₄ ) alkyl) amino group, hydroxyl group, acetoxy group, benzo silt, fenetil or Ar.

3. Derivatives of hydroxymethyl furazancarboxylic acid of general formula I according to claim 1 and / or 2, wherein X is NR ³ R ⁴ and that one of the radicals R ³ and R ⁴ is hydrogen and the other is hydrogen, (C ₁ - C ₆ ) -alkyl, - (CH ₂ ) _n NR ⁵ R ⁶ , with n = 1, 2, 3 or 4, and R ⁵ and R ⁶ denote (C ₁ - C ₆ ) -alkyl, - (CH ₂ ) _n OR ⁵ , moreover, n = 2, 3 or 4, and R ⁵ denotes hydrogen or (C ₁ - C ₄ ) -alkyl, - (CH ₂ ) _n Ar, and n = 0, 1, 2, 3 or 4 and Ar denotes unsubstituted or mono- or polysubstituted phenyl, or - (CH ₂₎ _n Het, where n = 1, 2, 3 or 4 and Het denotes geterots klicheskoe ring which contains as heteroatoms 1 or 2 nitrogen or 1 nitrogen atom and 1 oxygen atom and can be mono- or multiply substituted on methyl group, or R ³ and R ⁴ are both together with the nitrogen atom linking them form a heterocycle, which also may be substituted once or repeatedly by methyl groups.

4. Derivatives of hydroxymethyl furazancarboxylic acid of general formula I according to one or more paragraphs. 1 to 3, characterized in that X represents NR ³ R ⁴ and one of the radicals R ³ and R ⁴ represents hydrogen, and the other represents hydrogen, (C ₁ -C ₆ ) -alkyl, - (CH ₂ ) _n NR ⁵ R ⁶ , moreover, n = 1, 2 or 3, and R ⁵ and R ⁶ denote (C ₁ - C ₆ ) -alkyl, - (CH ₂ ) _n Ar, and n = 1 or 2, and Ar denotes once either doubly substituted phenyl, or - (CH ₂ ) _n H t, with n = 1, 2 or 3, and H t denotes pyridyl or imidazolyl, or the radicals R ³ and R ⁴ both together form the pyrrolidine ring or piperazine ring substituted by methyl.

5. Derivatives of hydroxymethyl furazancarboxylic acid of general formula I according to claim 1, characterized in that one of the radicals R ¹ and R ⁴ is hydroxymethyl, and the other is

X is

or preferably

6. Derivatives of hydroxymethyl furazancarboxylic acid of general formula I according to one or more paragraphs. 1 to 5, characterized in that R ¹ represents hydroxymethyl.

7. Derivatives of hydroxymethyl furazancarboxylic acid of general formula I according to one or more paragraphs. 1 to 5, characterized in that R ² represents hydroxymethyl.

8. Amide 4-hydroxymethyl-2-hydroxyfurazan-3-carboxylic acid.

9. The method of obtaining derivatives of hydroxymethylfurazanecarboxylic acid of General formula I according to one or more paragraphs. 1 to 8 and their pharmacologically applicable salts, characterized in that the compound of formula II is oxidized to the compound of formula III

or formula IV or to mixtures of compounds of formulas III and IV and compounds of formulas III and / or IV with the help of the amine R ³ R ⁴ NH, where R ³ and R ⁴ have the meanings indicated in paras. 1 to 8 are transformed into compounds of the general formula I, in which one of the radicals R ¹ and R ² is —CONR ³ R ⁴ , or the compounds of formulas III and / or IV with the alcohol R ⁷ OH, where R ⁷ has the meaning specified in paragraph 1, is transformed into compounds of general formulas Ic or Id

or in a mixture of compounds of general formulas Ic and Id and under certain conditions compounds of general formulas Ic and / or Id are converted with amine R ³ R ⁴ NH into compounds of general formula I, in which one of the radicals R ¹ and R ² is -CONR ³ R ⁴ , or a compound of formula II with an amine R ³ R ⁴ NH, where R ³ and R ⁴ have the meanings indicated in paras. 1 to 8, transform into a compound of formula V

and this compound is oxidized to compounds of general formula I, in which one of the radicals R ¹ and R ² is CONR ³ R ⁴ , and under certain conditions a mixture of isomeric compounds of general formula I or a mixture of isomers of compounds of formulas III and IV, or general formulas Ic and the Id or salts of these compounds are separated using known methods, and under certain conditions, the compound of the general formula I or its salt is converted to a pharmacologically applicable salt.

10. The use of derivatives of hydroxymethylfurazanecarboxylic acid of General formula I in one or more paragraphs. 1 - 8 and their pharmacologically acceptable salts for the treatment and prevention of diseases of the cardiovascular system, especially angina pectoris (Angina pectoris), or for the treatment of erectile dysfunctions.

11. Pharmaceutical preparation, characterized in that it contains one or more hydroxymethylfurazanecarboxylic acid derivatives of general formula I according to one or more paragraphs. 1 to 8 and / or one or more of their pharmacologically applicable salts as a biologically active substance together with pharmaceutically applicable excipients and additives, and under certain conditions, one or more other pharmacological active substances.