RU2001135801A

RU2001135801A - Beta2-adrenergic agonists

Info

Publication number: RU2001135801A
Application number: RU2001135801/04A
Authority: RU
Inventors: Бернар КЕНЮ; Айан Брюс; Алек Робин ФЭРХЭРСТ; Дейвид Битти
Original assignee: Новартис Аг
Priority date: 1999-06-04
Filing date: 2000-06-02
Publication date: 2003-08-27

Claims

1. The compound of the formula

in free form or in the form of a salt or solvate,

where Ar is a group of the formula

R ¹ is hydrogen, hydroxy or alkoxy,

R ² and R ³ each independently of one another is hydrogen or alkyl,

R ⁴ , R ⁵ , R ⁶ and R ^{7 are} each independently hydrogen, halogen, cyano, hydroxy, alkoxy, aryl, alkyl, alkyl, substituted with one or more halogen atoms or one or more hydroxy or alkoxy groups, alkyl, comprising one or more heteroatoms, alkenyl, trialkylsilyl, carboxy, alkoxycarbonyl or –CONR ¹¹ R ¹² , where R ¹¹ and R ^{12 are} each independently hydrogen or alkyl, or R ⁴ and R ⁵ , R ⁵ and R ⁶ , or R ⁶ and R ⁷ together with the carbon atoms to which they are attached represent a carbocyclic or heterocyclic ring. some ring;

R ⁸ is halogen, —OR ¹³ , —CH ₂ OR ¹³ or —NHR ¹³ , where R ¹³ is hydrogen, alkyl, alkyl containing one or more heteroatoms, —COR ¹⁴ , where R ¹⁴ is hydrogen, —N (R ¹⁵ ) R ¹⁶ , alkyl or alkyl, including one or more heteroatoms, or aryl and R ¹⁵ and R ^16, each independently of one another, are hydrogen, alkyl or alkyl, including one or more heteroatoms, or R ¹³ is —C (= NH) R ¹⁷ , —SOR ^17, or —SO ₂ R ¹⁷ , wherein R ¹⁷ is alkyl or alkyl including one or more heteroatoms;

R ⁹ is hydrogen, or R ⁸ is —NHR ¹⁸ , where —NHR ¹⁸ and R ⁹ together with the carbon atoms to which they are attached represent a 5 or 6 membered heterocycle,

R ¹⁰ is —OR ¹⁹ or —NHR ¹⁹ , where R ¹⁹ is hydrogen, alkyl, alkyl containing one or more heteroatoms, or —COR ²⁰ , where R ²⁰ is —N (R ²¹ ) R ²² , alkyl or alkyl, including one or more heteroatoms, or aryl, and R ²¹ and R ²² each independently of one another is hydrogen, alkyl or alkyl, including one or more heteroatoms,

X is halogen or halomethyl or alkyl,

Y is carbon or nitrogen,

n = 1 or 2,

p = 0 when Y is nitrogen, or 1 when Y is carbon,

q and r each is 0 or 1, the sum q + r = 1 or 2; and

the carbon atom marked with an asterisk * is in the R or S configuration, or a mixture thereof, if R ¹ is hydroxy or alkoxy.

2. The compound of claim 1, wherein Ar is a group of formula II in which Y is a carbon atom, R ⁸ is —NHR ¹⁸ and —NHR ¹⁸ and R ⁹ together are a group of formula —NH — CO — R ²³ -, wherein R ²³ is an alkylene, alkenylene or alkyleneoxy group, a group of the formula —NH — SO ₂ —R ²⁴ , where R ²⁴ is an alkyleneoxy group, a group of the formula —NH — R ²⁵ (COOR ²⁶ ) -, where R ²⁵ is alkylene or alkenylene and R ²⁶ is alkyl, or a group of the formula —NH — CO — NH or —NH — CO — S—, R ¹⁰ is —OR ¹⁹ , where R ¹⁹ is as defined in claim 1, X is alkyl, p = 1, q = 1 and r = 0 or 1.

3. The compound according to claim 2, in which Ar represents a group of formula III, IV, V, VI or VII:

in which R ²⁹ , R ³⁰ and R ³¹ each independently of one another is hydrogen or C ₁ -C ₄ alkyl

in which Z is —O—, —NH or —S—.

4. The compound according to claim 1, in which Ar is a group of formula II in which Y is carbon, R ⁸ is —CH ₂ OR ¹³ , where R ¹³ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy —C ₁ -C ₄ alkyl, R ⁹ is hydrogen, R ¹⁰ is —OR ¹⁹ , where R ¹⁹ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl or R ¹⁰ is —NHR ¹⁹ , where R ¹⁹ is hydrogen, C ₁ -C ₄ alkyl, or —COR ²⁰ , where R ²⁰ is C ₁ -C ₄ alkyl, C ₆ -C ₁₀ aryl, or –N (R ²¹ ) R ²² , where R ²¹ and R ²² each independently of one another is hydrogen or C ₁ -C ₄ alkyl, p and q are each 1 and r = 0; or a group of formula II in which Y is nitrogen, R ⁸ is —CH ₂ OR ¹³ , where R ¹³ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, R ¹⁰ is -OR ¹⁹ , where R ¹⁹ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, p and r = 0 and q = 1, wherein Ar is preferably a group of formula XII, XIII or XIV

5. The compound according to claim 1, in which Ar is a group of formula II in which Y is carbon, R ⁸ is —NHR ¹³ , where R ¹³ is hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkyl, including 1-3 heteroatoms, -COR ¹⁴ , where R ¹⁴ is hydrogen, C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ alkyl, including 1-3 heteroatoms, or R ¹³ is —C (= NH) R ¹⁷ , -SOR ¹⁷ or —SO ₂ R ¹⁷ , where R ¹⁷ is C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ alkyl including 1 to 3 heteroatoms, R ⁹ is hydrogen, R ¹⁰ is —OR ¹⁸ , where R ¹⁸ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, p and q are each 1 and r = 0, with Ar preferred stands for group of formula XV

6. The compound according to any one of the preceding paragraphs, in which R ⁴ and R ⁷ are the same and each is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy and either R ⁵ and R ⁶ are the same and each is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, or R ⁵ and R ⁶ together are - (CH ₂ ) _s - or -O (CH ₂ ) _t O-, where s = 3 or 4 and t = 1 or 2.

7. The compound according to claim 1, in which Ar represents a group of formula III, IV or V according to claim 3, formula XII according to claim 4 or formula XV according to claim 5, R ¹ is hydroxy, R ² and R ³ are hydrogen and R ⁴ and R ⁷ are the same and each is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy and either R ⁵ and R ⁶ are the same and each is hydrogen, C ₁ -C ₄ alkyl, C ₁ - C ₄ alkoxy or C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, or R ⁵ and R ⁶ together are - (CH ₂ ) ₄ or —O (CH ₂ ) ₂ O—, in free or salt form or solvate.

8. The compound according to any one of the preceding paragraphs, in which R ¹ denotes hydroxy or alkoxy, and the carbon atom in formula I, indicated by an asterisk *, is in the R-configuration.

9. The compound of the formula

in free form or in the form of a salt or solvate,

(A) where Ar is a group of the formula

wherein R ²⁹ , R ³⁰ and R ^{31 are} each H, R ¹ is OH, R ² and R ^{3 are} each H;

(I) n = 1 and R ⁴ and R ^{7 are} each CH ₃ O— and R ⁵ and R ^{6 are} each H; or

(II) n = 1 and R ⁴ and R ^{7 are} each H and each R ⁵ and R ⁶ is CH ₃ CH ₂ -; or

(III) n = 1 and R ⁴ and R ⁷ each represents H and R ⁵ and R ⁶ each represents CH ₃ -; or

(IV) n = 1 and R ⁴ and R ⁷ each represents CH ₃ CH ₂ - and R ⁵ and R ⁶ each represents H; or

(V) n = 1 and R ⁴ and R ^{7 are} each H and R ⁵ and R ⁶ together are - (CH ₂ ) ₄ -; or

(VI) n = 1 and R ⁴ and R ^{7 are} each H and R ⁵ and R ⁶ together are —O (CH ₂ ) ₂ O—; or

(VII) n = 1 and R ⁴ and R ⁷ each represents H and R ⁵ and R ⁶ each represents CH ₃ (CH ₂ ) ₃ -; or

(VIII) n = 1 and R ⁴ and R ⁷ each represents H and R ⁵ and R ⁶ each represents CH ₃ (CH ₂ ) ₂ -; or

(IX) n = 2, R ⁴ , R ⁵ , R ⁶ and R ^{7 are} each H; or

(X) n = 1 and R ⁴ and R ⁷ each represents H and R ⁵ and R ⁶ each represents CH ₃ OCH ₂ -; or

(B) where Ar is a group of the formula

in which R ¹³ is H, R ¹ is OH, R ² and R ^{3 are} each H, R ⁴ and R ^{7 are} each H and R ⁵ and R ^{6 are} each H and n = 1; or

(B) is a compound selected from the range including

8-hydroxy-5- [1-hydroxy-2- (indan-2-ylamino) ethyl] -1H-quinolin-2-one,

5- [2- (5,6-dimethoxyindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one,

5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-3-methyl-1H-quinolin-2-one,

5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-methoxymethoxy-6-methyl-1H-quinolin-2-one,

5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-6-methyl-1H-quinolin-2-one,

8-hydroxy-5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -3,4-dihydro-1H-quinolin-2-one,

N- {2-hydroxy-5 - [(R) -1-hydroxy-2- (2,5,6-trimethylindan-2-ylamino) ethyl] phenyl} formamide,

5 - [(R) -2- (5,6-diethyl-2-methylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one,

(S) -5- [2- (4,7-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one hydrochloride,

5 - [(R) -1-hydroxy-2- (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-one hydrochloride,

(R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one maleate,

(R) -5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one hydrochloride,

N- {5 - [(R) -2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -2-hydroxy phenyl} formamide,

4 - [(R) -2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -2-dimethylaminophenol hydrochloride,

4 - [(R) -2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -2-methylaminophenol hydrochloride,

N- {5- [2- (5,6-diethylindan-2-ylamino) -1-hydroxyethyl] -2-hydroxyphenyl} methane sulfonamide hydrochloride,

(R) -8-hydroxy-5 - [(S) -1-hydroxy-2- (4,5,6,7-tetramethylindan-2-ylamino) ethyl] -1H-quinolin-2-one,

8-hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2-ylamino) ethyl] -1H-quinolin-2-one,

5- [2- (5,6-diethylindan-2-ylamino) ethyl] -8-hydroxy-1H-quinolin-2-one,

8-hydroxy-5 - [(R) 1-hydroxy-2- (2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalene-2-ylamino) ethyl] - 1H-quinolin-2-one,

5 - [(S) -2- (2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] naphthalen-2-ylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinoline- 2-he

N- {2-hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2-ylamino) ethyl] phenyl} methanesulfonamide,

{2-hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2-ylamino) ethyl] phenyl} ethanesulfonic acid amide,

{2-hydroxy-5 - [(R) -1-hydroxy-2- (2-methylindan-2-ylamino) ethyl] phenyl} propan-1-sulfonic acid amide,

N- {5- [2- (2-ethylindan-2-ylamino) -1-hydroxyethyl] -2-hydroxyphenyl} methanesulfonamide or

N- {2-hydroxy-5 - [(R) -1-hydroxy-2- (2,5,6-trimethylindan-2-ylamino) ethyl] phenyl} methanesulfonamide.

10. The compound according to claim 1 in combination with a steroid, dopamine receptor agonist or anticholinergic or antimuscarinic agent.

11. A pharmaceutical composition comprising a compound according to any one of the preceding paragraphs, optionally in combination with a pharmaceutically acceptable carrier.

12. The use of a compound according to any one of claims 1 to 10 for the preparation of a medicament for the treatment of a condition that can be prevented or alleviated by activation of the β2-adrenergic receptor.

13. The use of compounds according to any one of claims 1 to 10 for the preparation of a medicinal product intended for the treatment of obstructive or inflammatory diseases of the respiratory tract.

14. The method of obtaining the compounds of formula I in free form or in the form of a salt or solvate, namely, that:

(a) to obtain a compound wherein R ¹ is hydroxy, or (I) a compound of the formula is reacted

with a compound of the formula

where Ar ¹ denotes Ar, as defined in claim 1, or its protected form, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n have the meanings specified in claim 1, and R ³² denotes hydrogen or an amino protecting group,

or (II) restore the compound of the formula

where Ar ¹ denotes Ar, as defined in claim 1, or its protected form; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the meanings indicated in claim 1,

with the conversion of the indicated keto group to the group —CH (OH) -; or

(b) to obtain a compound where R ¹ is hydrogen, the corresponding compound of formula I is reduced where R ¹ is hydroxy; or

(c) to obtain a compound of the formula I, where R ¹ is alkoxy, or (I) O-alkylation of the corresponding compound of the formula I, where R ¹ is hydroxy, or (II) reacts the corresponding compound containing a leaving group instead of R ¹ with an alcohol of formula R ¹ H, where R ¹ is alkoxy, and optionally converting the resulting compound of formula I in protected form into the corresponding compound in unprotected form, and the resulting compound of formula I in free form or in salt or lvata.

15. The compound of formula XVII

where R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined in claim 1, wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are groups such that the benzene ring to which they attached, is symmetrically substituted;

R ³² is hydrogen or an amino protecting group, with the exception of compounds where R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{32 are} each hydrogen, where R ⁴ and R ⁷ are methyl or methoxy when R ⁵ , R ⁶ and R ³² each is hydrogen, and where R ⁴ , R ⁷ and R ³² are hydrogen, when R ⁵ and R ^{6 are} each hydroxy, fluoro or chloro.