RU2002119010A

RU2002119010A - ADAMANTANE DERIVATIVES

Info

Publication number: RU2002119010A
Application number: RU2002119010/04A
Authority: RU
Inventors: Лилиан АЛЬКАРА (GB); Лилиан АЛЬКАРА; Мойа КЭФФРИ (GB); Мойа КЭФФРИ; Марк ФЕРБЕР (GB); Марк Фербер; Тимоти ЛУКЕР (GB); Тимоти Лукер; Майкл МОРТИМОР (GB); Майкл МОРТИМОР; Остен ПИММ (GB); Остен ПИММ; Филлип ТОРН (GB); Филлип ТОРН; Пол ВИЛЛИС (GB); Пол ВИЛЛИС
Original assignee: Астразенека Аб (Se); Астразенека Аб
Priority date: 1999-12-17
Filing date: 2000-12-12
Publication date: 2004-01-10
Also published as: RU2272025C2

Claims

1. The compound of General formula

where D represents CH ₂ or CH ₂ CH ₂ ;

E represents C (O) NH or NHC (O);

R ¹ and R ² each independently represent hydrogen, halogen, amino, nitro, C ₁ -C ₆ alkyl or trifluoromethyl, wherein R ¹ and R ² cannot simultaneously mean hydrogen;

R ³ represents a group of the formula

R ⁴ represents a C ₁ -C ₆ alkyl group;

X represents an oxygen or sulfur atom or a group NR ¹³ , SO or SO ₂ ;

R ⁵ represents hydrogen or R ⁵ represents C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl, each of which may optionally be substituted with at least one substituent selected from halogen, hydroxyl, (di) –C ₁ - C ₆ -alkylamino, -YR ⁶ ,

and a 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaromatic ring may be optionally substituted with at least one substituent selected from halogen, hydroxyl and C ₁ -C ₆ alkyl ;

Y represents an oxygen or sulfur atom or a group of NH, SO or SO ₂ ;

R ⁶ represents a —R ⁷ Z group, where R ⁷ represents a C ₂ -C ₆ alkyl group and Z represents —OH, —CO ₂ H, —NR ⁸ R ⁹ , —C (O) NR ¹⁰ R ^11, or -N (R ¹² ) C (O) -C ₁ -C ₆ alkyl group and, in the case when Y represents an oxygen or sulfur atom or an NH group, R ⁶ additionally represents hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, -C (O) NR ¹⁴ R ¹⁵ , -CH ₂ OC (O) R ¹⁶ , -CH ₂ OS (O) OR ¹⁷ or -C (O) OCH ₂ OR ¹⁸ ;

R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group;

R ¹³ represents hydrogen, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cyaloalkylmethyl or R ¹³ represents a C ₁ -C ₆ alkyl group optionally substituted with at least one substituent selected from hydroxyl and C ₁ -C ₆ alkoxy ;

R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ each independently represent a C ₁ -C ₆ alkyl group;

with the proviso that when E is C (O) NH, X is O, NH or N (C ₁ -C ₆ alkyl), then R ^{5 is} not a hydrogen atom or an unsubstituted C ₁ -C ₆ alkyl group;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound according to claim 1, where D represents CH ₂ .

3. The compound according to claim 1 or 2, where E represents NHC (O).

4. The compound according to any one of claims 1 to 3, where R ¹ and R ² each independently represent a hydrogen atom, chlorine or bromine, or amino, nitro, C ₁ -C ₃ alkyl or trifluoromethyl group.

5. The compound according to any one of the preceding paragraphs, where X represents an oxygen atom or a group NR ¹³ .

6. The compound according to claim 5, where R ¹³ represents hydrogen, - (CH ₂ ) ₂ OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl or cyclohexylmethyl.

7. The compound according to any one of the preceding paragraphs, where R ⁵ represents a C ₁ -C ₆ alkyl group substituted with one substituent -YR ⁶ .

8. The compound according to any one of the preceding paragraphs, where Y represents an oxygen or sulfur atom or an NH group.

9. The compound of claim 8, in which R ⁶ represents - (CH ₂ ) ₂ OH, - (CH ₂ ) ₃ OH, hydrogen, methyl, isopropyl, methylcarbonyl or tert-butylcarbonyl.

10. The compound of formula (I), its pharmaceutically acceptable salt or MES according to claim 1, selected from the group including:

2-chloro-5 dihydrochloride - [[2- (2-hydroxyethylamino) ethylamino] methyl] -N (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5 - [[2- (2-hydroxyethoxy) ethylamino] methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5 - [(3-hydroxy-2,2-dimethylpropylamino) methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5 - [(5-hydroxypentylamino) methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5 - [[2 - [(2-hydroxyethylthio) ethylamino] methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(2-hydroxyethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide acetate;

2-chloro-5- [3 - [(3-hydroxypropyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide hydrochloride;

2-chloro-5- [3- (methylamino) propyl] -N- acetate (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide acetate;

2-chloro-5- [3 - [(1-methylethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide hydrochloride;

5- [3 - [(2-amino-2-methylpropyl) amino] propyl] -2-chloro-N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide dihydrochloride;

2-chloro-5- [3 - [(4-hydroxybutyl) amino] propyl] -N- (tricyclo [3.3.1. I ³ ' ⁷ ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(2-hydroxy-2-methylpropyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide acetate;

2-chloro-5- [3 - [[2- (methylamino) ethyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide dihydrochloride;

(S) -2-chloro-5- [3 - [(2-hydroxypropyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide hydrochloride;

(R) -2-chloro-5- [3 - [(2-hydroxypropyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide hydrochloride;

(R) -2-chloro-5- [3 - [(2-hydroxy-1-methylethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide hydrochloride;

2-chloro-5- [3 - [[2-hydroxy-1- (hydroxymethyl) -1-methylethyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

5- [3 - [[2- (acetylamino) ethyl] amino] propyl] 2-chloro-N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide hydrochloride;

2-chloro-5- [3 - [[2- (diethylamino) ethyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide dihydrochloride;

2-chloro-5- [3 - [(3-methoxypropyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide hydrochloride;

2-chloro-5- [3 - [(3-hydroxy-3-methylbutyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide hydrochloride;

2-chloro-5- [3 - [(2-methoxyethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide hydrochloride;

2-chloro-5 - [[3- (methylamino) propoxy] methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5 - [[2 - [(2-hydroxyethyl) amino] ethoxy] methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide salt;

acetic acid salt of 2-chloro-5 - [[2 - [(3-hydroxypropyl) amino] ethoxy] methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5 - [[[3 - [(1-methylethyl) amino] propyl] amino] methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-l-ylmethyl) benzamide;

5 - [[(3-aminopropyl) amino] methyl] -2-chloro-N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5 - [[[2 - [(1-methylethyl) amino] ethyl] amino] methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

trifluoroacetic acid salt of 2,2-dimethylpropyl ether 3- [[3- [4-chloro-3 - [[(tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) amino] carbonyl] phenyl] propyl] amino] propanoic acid;

5 (2-aminoethyl) -2-chloro-N (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(2-hydroxyethyl) pentylamino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- (methyl-2-propenylamino) propyl] -N- (tricyclo [3.3. 1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [[2- (dimethylamino) ethyl] methylamino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

5- [3- (butylethylamino) propyl] -2-chloro-N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5 [3 (methylpentylamino) propyl] –N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [[2- (diethylamino) ethyl] ethylamino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(2-hydroxyethyl) methylamino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- (dipropylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(2-hydroxyethyl) (1-methylethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

5- [3- [butyl (2-hydroxyethyl) amino] propyl] -2-chloro-N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl benzamide;

2-chloro-5- [3- (diethylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- (dimethylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

5- [3- (butylmethylamino) propyl] -2-chloro-N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(2-hydroxyethyl) propylamino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- [ethyl (2-hydroxyethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- (dibutylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- (ethylpropylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- [methyl (1-methylethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [[3- (dimethylamino) propyl] methylamino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- [cyclohexyl (2-hydroxyethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-l-ylmethyl) benzamide;

2-chloro-5- [3- (cyclohexylmethylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- (cyclohexylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [[1- (hydroxymethyl) -2,2-dimethylpropyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- (cyclopropylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [[2- (dimethylamino) ethyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(3-hydroxy-2,2-dimethylpropyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(1,1-dimethylethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [[3- (dimethylamino) propyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- (cyclopentylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -5- [3 - [(1,2,2-trimethylpropyl) amino] propyl] benzamide;

5- [3- (butylamino) propyl] -2-chloro-N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [[1- (hydroxymethyl) -2-methylpropyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(1-methylpropyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [[2- (methylthio) ethyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(2-hydroxy-1,1-dimethylethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(cyclohexylmethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- (2-propenylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(2-fluoroethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [(2-methoxy-1-methylethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3- [3- (methylamino) propoxy] propyl] -N-tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide dihydrochloride;

5 - [[[(1-aminocyclopropyl) methyl] (2-hydroxyethyl) amino] methyl] -2-chloro-N (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

5 - [[(2-hydroxyethyl) [2- (methylamino) ethyl] amino] methyl] -2-methyl-N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide;

2-chloro-5- [3 - [[2- (1-methyl-1H-imidazol-4-yl) ethyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl )benzamide;

2-chloro-5- [3 - [[2- (lH-imidazol-4-yl) ethyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) benzamide; and

2-chloro-5- [3 - [[3- (1H-imidazol-1-yl) propyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-l-ylmethyl) benzamide.

11. The method of obtaining the compounds of formula (I) according to claim 1, which consists in the fact that (a) when X represents an oxygen or sulfur atom or a group NR ¹³ , a compound of general formula

where L ¹ represents a leaving group and D, E, R ¹ , R ² and R ⁴ have the meanings indicated in formula (I), are reacted with a compound of the general formula

where X 'represents an oxygen or sulfur atom or a group NR ¹³ and R ⁵ has the meanings indicated in formula (I), optionally in the presence of an acceptable silver salt; (b) when X is SO or SO ₂ , the corresponding compound of formula (I) in which X is a sulfur atom is reacted with a suitable oxidizing agent; or

(c) when X is a group NR ¹³ , a compound of general formula

where R ²⁰ represents a bond or a C ₁ -C ₅ alkyl group and D, E, R ¹ and R ² have the meanings indicated in formula (I), are reacted with a compound of the general formula

where R ⁵ and R ¹³ have the meanings indicated in formula (I) in the presence of a reducing agent; and after performing steps (a), (b) or (c), the resulting compound of formula (I) is optionally converted to a pharmaceutically acceptable salt or solvate thereof.

12. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 10, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

13. A method for producing a pharmaceutical composition according to claim 12, which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 10 with a pharmaceutically acceptable adjuvant, diluent or carrier.

14. The compound of formula (I) or its pharmaceutically acceptable salt or solvate according to any one of claims 1 to 10, intended for use in therapy.

15. The compound of formula (I) or its pharmaceutically acceptable salt or solvate according to any one of claims 1 to 10, intended for the treatment of rheumatoid arthritis.

16. The compound of formula (I) or its pharmaceutically acceptable salt or solvate according to any one of claims 1 to 10, intended for the treatment of chronic obstructive pulmonary disease.

17. The use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 10 in the manufacture of a medicament for use in therapy, for example, for the treatment of rheumatoid arthritis or chronic obstructive pulmonary disease.

18. A method of suppressing immunity, which comprises administering to a subject in need of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 10.

19. The method of suppressing immunity according to p. 18 in the treatment of rheumatoid arthritis.

20. A method for treating chronic obstructive pulmonary disease, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 10.