RU2001122114A

RU2001122114A - 4- (heterocyclylsulfonamido) -5-methoxy-6- (2-methoxyphenoxy) -2-phenyl- or pyridylpyrimidines as endothelin receptor antagonists

Info

Publication number: RU2001122114A
Application number: RU2001122114/04A
Authority: RU
Inventors: Фолькер БРЕУ; Филипп КОАССОЛО; Рольф ХУБЕР; Вернер НЭДАР; Анри РАМЮЗ; Себастьен РУКС; Ханс Петер Вессель
Original assignee: Ф.Хоффманн-Ля Рош Аг
Priority date: 1999-01-18
Filing date: 2000-01-10
Publication date: 2003-06-20

Claims

1. The compound of formula (I)

in which R ¹ is pyridyl, pyrrolyl, imidazolyl, thiazolyl, thiazolinyl or oxazolyl, optionally substituted with halogen, (ness.) alkyl, hydroxy (ness.) alkyl or (ness.) alkenyl;

R ² is R ²¹ , —YR ^22, or heterocyclyl, wherein heterocyclyl may optionally be substituted with one, two, or three substituents independently selected from the group consisting of hydroxy, (ness.) Alkenyl, amino, (ness.) Alkanoylamino, (ness.) alkoxycarbonylamino, (ness.) alkyl or hydroxy (ness.) alkyl;

R ²¹ is cyano, hydroxy lower alkyl, carboxy, —C (O) NR ^a R ^b , - (CH ₂ ) _1-4 NHR ^c , - (CH ₂ ) _1-4 NHC (O) NH (CH ₂ ) _0-3 CH ₃ , amidino, hydroxyamidino, (ness.) Alkoxycarbonyl or hydroxy (ness.) Alkoxy-carbonyl;

R ²² is hydrogen, (ness.) Alkanoyl, carboxy (ness.) Alkyl, (ness.) Alkoxycarbonyl, (ness.) Alkoxycarbonyl- (ness.) Alkyl, carbamoyl (ness.) Alkyl, di (ness.) Alkylcarbamoyl- (ness.) alkyl, allyl, (ness.) alkyl or hydroxy (ness.) alkyl;

R ^a is hydrogen or lower alkyl optionally substituted with hydroxy or lower alkoxy;

R ^b is hydrogen or lower alkyl;

R ^c is hydrogen, acetyl or lower alkylsulfonyl;

X is —CH— or —N—;

Y is —O—, —NH—;

and its pharmaceutically acceptable salts and esters.

2. The compound according to claim 1, in which R ¹ is pyridyl or thiazolyl, optionally substituted with halogen, (ness.) Alkyl, hydroxy (ness.) Alkyl or (ness.) Alkenyl.

3. The compound according to claim 1, in which R ¹ denotes pyridyl or thiazolyl, optionally substituted by (ness.) Alkyl or (ness.) Alkenyl.

4. The compound according to any one of claims 1 to 3, in which R ²¹ denotes cyano, hydroxy (ness.) Alkyl, carboxy, (ness.) Alkoxycarbonyl, -CCONR ^a R ^b , -CH ₂ NHR ^c , amidino, hydroxyamidino or —CH ₂ NHC (O) NHCH ₂ CH ₃ , where R ^a , R ^b and R ^c are as defined in claim 1.

5. The compound according to any one of claims 1 to 3, in which R ²¹ denotes cyano, carboxy, carbamoyl, (ness.) Alkoxycarbonyl, hydroxy (ness.) Alkyl, acetylaminomethyl or methylsulfonylaminomethyl.

6. The compound according to any one of claims 1 to 5, in which R ² denotes R ²¹ , -YR ²² or heterocyclyl selected from the range including 2-pyrimidinyl, 2-imidazolyl, [1,2,4] oxadiazole-3- sludge, 2-oxazolyl or 2-thiazolyl optionally substituted with one, two or three substituents independently selected from the group consisting of (ness.) alkyl, hydroxy (ness.) alkyl, (ness.) alkenyl, (ness. ) alkoxycarbonylamino, (ness.) alkanoylamino, hydroxy or amino.

7. The compound according to any one of claims 1 to 5, in which R ² denotes R ²¹ , -YR ²² or heterocyclyl selected from the range including 2-pyrimidinyl, 2-imidazolyl or [1,2,4] oxadiazole-3- sludge optionally substituted with lower alkyl, isopropenyl, tert-butoxycarbonylamino, formylamino, acetylamino, hydroxy, amino or hydroxymethyl.

8. The compound according to any one of claims 1 to 7, in which R ²² denotes hydrogen, (ness.) Alkyl, carboxymethyl, (ness.) Alkoxycarbonyl- (ness.) Alkyl, carbamoylmethyl, dimethylcarbamoylmethyl, hydroxy (ness.) Alkyl or acetyl.

9. The compound according to any one of claims 1 to 7, in which R ²² denotes hydrogen, (ness.) Alkyl, (ness.) Alkoxycarbonyl- (ness.) Alkyl or hydroxy (ness.) Alkyl.

10. The compound according to claim 1, selected from a series including

4- [4-methoxy-5- (2-methoxyphenoxy) -6- (5-methylpyridin-2-sulfonylamino) pyrimidin-2-yl] pyridin-2-carboxylic acid,

4- [4-methoxy-5- (2-methoxyphenoxy) -6- (5-methylpyridin-2-sulfonylamino) pyrimidin-2-yl] pyridin-2-carboxylic acid methyl ester,

[2- (2-Hydroxymethylpyridin-4-yl) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] 5-methylpyridin-2-sulfonic acid amide,

4- [4-methoxy-5- (2-methoxyphenoxy) -6- (5-methylpyridin-2-sulfonylamino) pyrimidin-2-yl] pyridin-2-carboxylic acid ethyl ester,

4- [4- (5-Isopropylpyridin-2-sulfonylamino) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-2-yl] pyridin-2-carboxylic acid methyl ester,

N-hydroxy-4- [4-methoxy-5- (2-methoxyphenoxy) -6- (5-methylpyridin-2-sulfonylamino) pyrimidin-2-yl] pyridin-2-carboxamidine,

{6-methoxy-5- (2-methoxyphenoxy) -2- [2- (5-methyl [1,2,4] oxadiazol-3-yl) pyridin-4-yl] pyrimidin-4-yl} amide 5- methylpyridin-2-sulfonic acid,

[2- [2- (Methanesulfonylaminomethyl) pyridin-4-yl] -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] 5-methylpyridin-2-sulfonic acid amide,

[2- [2- (Methanesulfonylaminomethyl) pyridin-4-yl] -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] 5-isopropylpyridin-2-sulfonic acid amide,

{6-methoxy-5- (2-methoxyphenoxy) -2- [2- (5-methyl [1,2,4] oxadiazol-3-yl) pyridin-4-yl} pyrimidin-4-yl] amide 5- isopropylpyridin-2-sulfonic acid,

[2- (2-Cyanopyridin-4-yl) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] 5-methylpyridin-2-sulfonic acid amide,

[2- (3-Hydroxyphenyl) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] 5-methylpyridin-2-sulfonic acid amide,

[2- [3- (2-Hydroxyethoxy) phenyl] -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] amide 5-methylpyridin-2-sulfonic acid and

[2- [2- (2-Hydroxyethoxy) pyridin-4-yl] -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] 5-isopropylpyridin-2-sulfonic acid amide,

[2- (2-Hydroxypyridin-4-yl) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] 5-methylpyridin-2-sulfonic acid amide,

{3- [4-methoxy-5- (2-methoxyphenoxy) -6- (5-methylpyridin-2-sulfonylamino) pyrimidin-2-yl] phenoxy} acetic acid ethyl ester,

[2- (2-Hydroxymethylpyridin-4-yl) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] 5-isopropylpyridin-2-sulfonic acid amide,

N- {4- [4- (5-Isopropylpyridin-2-sulfonylamino) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-2-yl] pyridin-2-ylmethyl} acetamide,

4- [4- (5-isopropylpyridin-2-sulfonylamino) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-2-yl] pyridin-2-carboxylic acid,

4- [4- (5-Isopropylpyridin-2-sulfonylamino) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-2-yl] pyridin-2-carboxylic acid isopropyl ester,

4- [4- (5-Isopropylpyridin-2-sulfonylamino) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-2-yl] pyridin-2-carboxylic acid ethyl ester,

[2- [2- (2-Hydroxyethoxy) pyridin-4-yl] -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] 5-methylthiazole-2-sulfonic acid amide,

4- [4- (5-Isopropylpyridin-2-sulfonylamino) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-2-yl] pyridin-2-carboxylic acid amide,

N-hydroxy-4- [4- (5-isopropylpyridin-2-sulfonylamino) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-2-yl] pyridin-2-carboxamidine,

3- [4-methoxy-5- (2-methoxyphenoxy) -6- (5-methylpyridin-2-sulfonylamino) pyrimidin-2-yl] phenyl ester of acetic acid,

4- [4- (5-Isopropylpyridin-2-sulfonylamino) -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-2-yl] pyridin-2-carboxylic acid methyl ester and

4- [4-methoxy-5- (2-methoxyphenoxy) -6- (5-methylpyridin-2-sulfonylamino) pyrimidin-2-yl] pyridin-2-carboxylic acid 1-acetoxyethyl ester.

11. The compound according to claim 1, selected from the group including:

[2- [3- (2-Hydroxyethoxy) phenyl] -6-methoxy-5- (2-methoxyphenoxy) pyrimidin-4-yl] 5-methylpyridin-2-sulfonic acid amide,

4- [4-methoxy-5- (2-methoxyphenoxy-6- (5-methylpyridin-2-sulfonylamino) pyrimidin-2-yl] pyridin-2-carboxylic acid methyl ester,

{6-methoxy-5- (2-methoxyphenoxy) -2- [2- (5-methyl [1,2,4] oxadiazol-3-yl) pyridin-4-yl] pyrimidin-4-yl} amide 5- methylpyridin-2-sulfonic acid and

12. The compound according to claim 1, selected from the group including:

13. A pharmaceutical composition comprising a compound according to any one of claims 1-12, and a pharmaceutically acceptable carrier and / or adjuvant.

14. The pharmaceutical composition according to item 13, further comprising any active substances selected from antihypertensive drugs, antiarrhythmic drugs, anti-angina pectoris, antithrombotic agents and lipid lowering agents, as well as antioxidants.

15. The use of the compounds according to any one of claims 1 to 12 for the preparation of medicines intended for the treatment or prevention of diseases associated with abnormal vascular tone and endothelial dysfunction.

16. A method for the prevention and / or therapeutic treatment of diseases associated with abnormal vascular tone and endothelial dysfunction, comprising administering a compound according to any one of claims 1-12 to a person or animal.

17. A method of producing compounds according to any one of claims 1 to 12, comprising

a) the interaction of the compounds of formula (II)

where R ¹ has the meanings indicated in claim 1,

with trialkylsilyl cyanide and trialkylamine to give a compound of formula (Ia)

where R ¹ has the meanings indicated in claim 1; or

b) the interaction of the compounds of formula (III)

in which R ¹ has the meanings indicated in claim 1,

with sodium methylate in methanol to give the corresponding imino ester intermediate, optionally followed by treatment with a base such as NaH to give the compound of the above formula (Ia), wherein R ¹ is as defined in claim 1; or

c) the interactions indicated for stage a) or b), followed by the conversion of a compound of formula (Ia) into a compound of formula (I), in which R ² is the radical R ²¹ , where R ²¹ has the meanings indicated in claim 1; or

d) converting a compound of formula (I) in which X is as defined in claim 1, R ² is a moiety of R ²¹ , where R ²¹ is hydroxyamidino, to a compound of formula (I) in which R ² is optionally substituted [1 , 2,4] oxadiazole, by ring closure using an acceptable structural element containing a carbon atom in position 1, and / or its corresponding activated forms; or

d) the interaction of the compounds of formula (II)

in which R ¹ has the meanings indicated in claim 1,

with the corresponding functionalized (bearing certain functional groups) alcohol, using tosyl chloride as a reagent in the presence of a base, to obtain a compound of formula (I) in which R ² is —YR ²² and R ¹ and R ²² are as defined in claim 1 ; or

e) the interaction of the compounds of formula

in which R ² has the meanings indicated in claim 1,

with a sulfonamide of the formula (VI)

in which R ¹ has the meanings indicated in claim 1,

in an acceptable solvent in the presence of an acceptable base followed by treatment with methanol to give a compound of formula (Id)

in which R ¹ and R ² have the meanings indicated in claim 1; or

g) the interaction according to the above stage e), where R ² denotes cyano and R ¹ has the meanings indicated in claim 1, followed by further conversion of the product into a compound of formula (Id), in which R ² denotes heterocyclyl or fragment -YR ²¹ ; or

h) the interaction according to the above stage e), where R ¹ has the meanings indicated in claim 1, and

(I) R ² is cyano, followed by further conversion of the product to a compound of formula (Id), in which R ² is heterocyclyl or a fragment of R ²¹ ; or

(II) R ² is YH, followed by further conversion of the product to a compound of formula (Id), in which R ² is —YR ²² ; or i) the conversion of a compound of formula (Id)

in which R ¹ has the meanings indicated in claim 1, and

(I) R ² is (ness.) Alkoxycarbonyl- (ness.) Alkyl, to a compound of formula (Id) in which R ² is carboxy (ness.) Alkyl, or hydroxy (ness.) Alkyl; or

(II) R ² is carboxy (lower) alkyl, to a compound of formula (Id) in which R ² is di (lower) alkylcarbamoyl- (lower) alkyl, or

(III) R ² is hydroxy or amino, in a compound of formula (Id) in which R ² is a —Y- (lower) alkanoyl or —Y- (lower) alkoxycarbonyl moiety.

18. Compounds according to any one of claims 1 to 12, obtained by the method according to 17.

19. Compounds according to any one of claims 1 to 12, intended for the treatment of diseases associated with abnormal vascular tone and endothelial dysfunction.

20. New compounds, processes and methods, as well as the use of such compounds mainly as described above.