RU2001105910A

RU2001105910A - High affinity ligands for the nociceptin receptor ORL-1

Info

Publication number: RU2001105910A
Application number: RU2001105910/04A
Authority: RU
Inventors: Дин ТУЛШИАН; Джинни Д. ХО; Лайза С. СИЛЬВЕРМЭН; Джулиус Ж. МАТАСИ; Робби Л. МакЛЕОД; Джон А. ХЕЙ; Ричард В. ЧЭПМЭН; Ана БЕРКОВИЧИ; Фрэнсис М. КУСС
Original assignee: Шеринг Корпорейшн
Priority date: 1998-07-27
Filing date: 1999-07-26
Publication date: 2003-07-10

Claims

1. The compound of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein the dotted line means an optional double bond;

X ¹ is R ⁵ - (C ₁ -C ₁₂ ) alkyl, R ⁶ (C ₃ -C ₁₂ ) cycloalkyl, R ^{7 is} aryl, R ^{8 is} heteroaryl or R ¹⁰ - (C ₃ -C ₇ ) is a heterocycloalkyl group;

X ² means —CHO, —CN, —NHC (= NR ²⁶ ) NHR ^2b , —CH (= NOR ²⁶ ), —NHOR ²⁶ , R ⁷ -aryl, R ⁷ -aryl (C ₁ -C ₆ ) alkyl, R ^7- aryl (C ₁ -C ₆ ) alkenyl, R ^7- aryl (C ₁ -C ₆ ) alkynyl, - (CH ₂ ) _v OR ¹³ , - (CH ₂ ) _v COOR ²⁷ , - (CH ₂ ) _v CONR ¹⁴ R ¹⁵ , - (CH ₂ ) _v NR ²¹ R ²² or - (CH ₂ ) _v NHC (O) R ²¹ group, where v = 0, 1, 2 or 3;

or X ¹ means

and X ² is hydrogen;

or X ¹ and X ² together form a spiro group of the formula

m is 1 or 2;

n = 1, 2 or 3, provided that if n = 1, then R ¹⁶ or R ¹⁷ means C (O) R ²⁸ ;

p is 0 or 1;

Q is —CH ₂ -, —O—, —S—, —SO—, —SO ₂ - or —NR ¹⁷ -;

R ¹ , R ² , R ³ and R ^{4 are} independently selected from the group consisting of hydrogen and a (C ₁ -C ₆ ) alkyl group, or (R ¹ and R ⁴ ), or (R ² and R ³ ), or (R ¹ and R ³ ), or (R ² and R ⁴ ) together can form an alkylene bridge of 1-3 carbon atoms;

R ⁵ means from 1 to 3 substituents independently selected from the group consisting of H, R ⁷ aryl, R ⁶ - (C ₃ -C ₁₂ ) cycloalkyl, R ⁸ heteroaryl, R ¹⁰ - (C ₃ -C ₇ ) heterocycloalkyl , —NR ¹⁹ R ²⁰ , —OR ¹³ and —S (O) _0-2 R ¹³ groups;

R ⁶ means from 1 to 3 substituents independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, R ⁷ aryl, —NR ¹⁹ R ²⁰ , —OR ¹³ and —SR ¹³ groups;

R ⁷ means from 1 to 3 substituents independently selected from the group consisting of hydrogen, halide, (C ₁ -C ₆ ) alkyl, R ²⁵ -aryl, (C ₃ -C ₁₂ ) cycloalkyl, -CN, -CF ₃ , - OR ¹⁹ , - (C ₁ -C ₆ ) alkyl-OR ¹⁹ , -OCF ₃ , -NR ¹⁹ R ²⁰ , - (C _l -C ₆ ) alkyl-NR ¹⁹ R ²⁰ , -NHSO ₂ R ¹⁹ , -SO ₂ N (R ²⁶ ) ₂ , -SO ₂ R ¹⁹ , -SOR ¹⁹ , -SR ¹⁹ , -NO ₂ , -CONR ¹⁹ R ²⁰ , -NR ²⁰ COR ¹⁹ , -COR ¹⁹ , -COCF ₃ , -OCOR ¹⁹ , - OCO ₂ R ¹⁹ , -COOR ¹⁹ , - (C ₁ -C ₆ ) alkyl-NHCOOC (CH ₃ ) ₃ , - (C ₁ -C ₆ ) alkyl-NHCOCF ₃ , - (C ₁ -C ₆ ) alkyl-NHSO ₂ - (C ₁ -C ₆ ) alkyl, - (C ₁ -C ₆ ) alkyl-NHCONH- (C ₁ -C ₆ ) alkyl group or

where f = 0 - 6; or R ⁷ substituents at adjacent cyclic carbon atoms may together form a methylenedioxy or ethylenedioxy ring;

R ⁸ means from 1 to 3 substituents independently selected from the group consisting of hydrogen, halide, (C ₁ -C ₆ ) alkyl, R ²⁵ -aryl, (C ₃ -C ₁₂ ) cycloalkyl, -CN, -CF ₃ , - OR ¹⁹ , - (C ₁ -C ₆ ) alkyl-OR ¹⁹ , -OCF ₃ , -NR ¹⁹ R ²⁰ , - (C _l -C ₆ ) alkyl-NR ¹⁹ R ²⁰ , -NHSO ₂ R ¹⁹ , -SO ₂ N (R ^2b ) ₂ , —NO ₂ , —CONR ¹⁹ R ²⁰ , —NR ²⁰ COR ¹⁹ , —COR ¹⁹ , —OCOR ¹⁹ , —OCO ₂ R ¹⁹ , and —COOR ¹⁹ groups;

R ⁹ means hydrogen, (C ₁ -C ₆ ) alkyl, halide, -OR ¹⁹ , -NR ¹⁹ R ²⁰ , -NHCN, -SR ¹⁹ or - (C ₁ -C ₆ ) alkyl-NR ¹⁹ R ²⁰ group;

R ¹⁰ means H, (C ₁ -C ₆ ) alkyl, -OR ¹⁹ , - (C ₁ -C ₆ ) alkyl-OR ¹⁹ , -NR ¹⁹ R ²⁰ or - (C ₁ -C ₆ ) alkyl-NR ¹⁹ R ²⁰ group;

R ^{11 is} independently selected from the group consisting of H, R ⁵ - (C ₁ -C ₆ ) alkyl, R ⁶ - (C ₃ -C ₁₂ ) cycloalkyl, - (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl, - (C ₁ -C ₆ ) alkyl- (OR ¹⁹ , - (C ₁ -C ₆ ) alkyl-NR ¹⁹ R ²⁰ groups, and

where q and a are as defined above;

R ¹² means H, (C ₁ -C ₆ ) alkyl, halide, -NO ₂ , -CF ₃ , -OCF ₃ , -OR ¹⁹ , - (C ₁ -C ₆ ) alkyl-OR ¹⁹ , -NR ¹⁹ R ²⁰ or - (C ₁ -C ₆ ) alkyl-NR ¹⁹ R ²⁰ group;

R ¹³ is H, (C ₁ -C ₆ ) alkyl, R ^{7 is} aryl, - (C ₁ -C ₆ ) alkyl-OR ¹⁹ , - (C ₁ -C ₆ ) alkyl-NR ¹⁹ R ²⁰ or - (C ₁ -C ₆ ) alkyl-SR ¹⁹ group;

R ¹⁴ and R ^{15 are} independently selected from the group consisting of H, R ⁵ - (C ₁ -C ₆ ) alkyl, R ⁷ -aryl groups, and

where q and a are as defined above;

R ¹⁶ and R ^{17 are} independently selected from the group consisting of hydrogen, R ⁵ - (C ₁ -C ₆ ) alkyl, R ⁷ aryl, (C ₃ -C ₁₂ ) cycloalkyl, R ⁸ heteroaryl, R ⁸ heteroaryl (C ₁ -C ₆ ) alkyl, -C (O) R ²⁸ , - (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, - (C ₁ -C ₆ ) alkyl-OR ¹⁹ and - (C ₁ -C ₆ ) alkyl-SR ¹⁹ groups;

R ¹⁹ and R ^{20 are} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, aryl or aryl (C ₁ -C ₆ ) alkyl group;

R ²¹ and R ^{22 are} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₁₂ ) cycloalkyl (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) heterocycloalkyl, - (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, R ⁷ -aryl, R ⁷ -aryl (C _l -C ₆ ) alkyl, R ⁸ -heteroaryl (C _l -C _l2 ) alkanyl, - (C ₁ -C ₆ ) alkyl-OR ¹⁹ , - (C ₁ -C ₆ ) alkyl-NR ¹⁹ R ²⁰ , - (C ₁ -C ₆ ) alkyl-SR ¹⁹ , - (C _l -C ₆ ) alkyl-NR ¹⁸ - (C ₁ -C ₆ ) alkyl-O- (C ₁ -C ₆ ) alkyl and - (C _l -C ₆ ) alkyl-NR ¹⁸ - (C _l -C ₆ ) alkyl-NR ^I8 - (C ₁ -C ₆ ) alkyl groups;

R ¹⁸ is hydrogen or a (C ₁ -C ₆ ) alkyl group;

Z ¹ means R ⁵ - (C ₁ -C ₁₂ ) alkyl, R ⁷ aryl, R ⁸ heteroaryl, R ⁶ - (C ₃ -C ₁₂ ) cycloalkyl, R ¹⁰ - (C ₃ -C ₇ ) heterocycloalkyl, - CO ₂ (C ₁ -C ₆ ) alkyl, CN or –C (O) NR ¹⁹ R ²⁰ groups; Z ² means hydrogen or Z ¹ ; Z ³ means hydrogen or a (C ₁ -C ₆ ) alkyl group; or Z ¹ , Z ² and Z ³ together with the carbon atom to which they are attached form a group

or

where r = 0 - 3;

w and u = 0-3, provided that the sum of w and u = 1-3; c and d are independently 1 or 2; s = 1 to 5;

ring A is a fused R ⁷ phenyl or R ⁸ heteroaryl ring;

R ²³ means from 1 to 3 substituents independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, -OR ¹⁹ , - (C ₁ -C ₆ ) alkyl-OR ¹⁹ , -NR ¹⁹ R ²⁰ and - (C ₁ -C ₆ ) alkyl-NR ¹⁹ R ²⁰ groups;

R ²⁴ means from 1 to 3 substituents independently selected from the group consisting of R ²³ , —CF ₃ , —OCF ₃ , —NO ₂ or a halide group, or R ²⁴ substituents at adjacent cyclic carbon atoms may together form a methylenedioxy or ethylenedioxy ring;

R ²⁵ means from 1 to 3 substituents independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxyl and halide groups;

R ^{26 is} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl and R ²⁵ -C ₆ H ₄ -CH ₂ groups;

R ²⁷ means H, (C ₁ -C ₆ ) alkyl, R ⁷ -aryl (C ₁ -C ₆ ) alkyl or (C ₃ -C ₁₂ ) cycloalkyl group;

R ²⁸ means (C ₁ -C ₆ ) alkyl, - (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl, R ⁷ -aryl, R ⁷ -aryl (C ₁ -C ₆ ) alkyl, R ⁸ -heteroaryl, - (C ₁ -C ₆ ) alkyl-NR ¹⁹ R ²⁰ , - (C ₁ -C ₆ ) alkyl-OR ¹⁹ or - (C ₁ -C ₆ ) alkyl-SR ¹⁹ group;

provided that if X ¹ means

or X ¹ and X ² together mean

Z ¹ means R ^{7 is} phenyl, Z ² means not hydrogen or a (C ₁ -C ₃ ) alkyl group;

provided that if Z ¹ , Z ² and Z ³ together with the carbon atom to which they are attached form

and X ¹ and X ² together mean

R ¹¹ means non-hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) hydroxyalkyl group;

provided that if R ² and R ⁴ form an alkylene bridge, Z ¹ , Z ² and Z ³ together with the carbon atom to which they are attached do not mean

provided that if X ¹ means

and Z ¹ means R ⁶ - (C ₃ -C ₁₂ ) and cycloalkyl group, Z ² means not N.

2. The compound according to claim 1, characterized in that both Z ¹ and Z ² mean R ⁷ -aryl group.

3. The compound according to claim 1, characterized in that R ⁷ selected from the group comprising (C ₁ -C ₆ ) alkyl and halide group.

4. The compound according to claim 1, wherein X ¹ is an R ⁷ aryl group, and X ² is an OH group or —NC (O) R ²⁸ .

5. The compound according to claim 1, characterized in that X ¹ means

and X ² means hydrogen.

6. The compound according to claim 5, characterized in that R ¹² means hydrogen, and R ¹¹ means (C ₁ -C ₆ ) alkyl, - (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl, - ( C ₁ -C ₆ ) alkyl-OR ¹⁹ or - (C ₁ -C ₆ ) alkyl-NR ¹⁹ R ²⁰ group.

7. The compound according to claim 1, characterized in that X 'and X ² together form a spirocyclic group

8. The compound according to claim 7, characterized in that m = 1, R ¹⁷ means a phenyl group and R ¹¹ means - (C ₁ -C ₆ ) alkyl- (OR ¹⁹ or - (C _l -C ₆ ) alkyl-NR ¹⁹ R ²⁰ group.

9. A compound selected from the group including

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a therapeutically effective amount of an Nociceptin ORL-1 receptor agonist; therapeutic effective amount of a second drug selected from the group of antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H ₃ inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, antitussive, expectorant antagonists of NK ₁ , NK ₂ and NK ₃ tachykinin receptor and GABA _B agonists; and a pharmaceutically acceptable carrier.

12. The use of the compounds according to claim 1 for the treatment of pain, anxiety, asthma, depression or alcohol abuse.

13. The use of the ORL-1 nociceptin receptor agonist, as the only drug or in combination with a second drug intended for the treatment of cough, allergy or asthma symptoms selected from the group consisting of antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H ₃ inhibitors, agonists, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic agonists of the receptor, mast cell stabilizers, antitussives, expectorants, NK ₁ antagonists, NK ₂ and NK ₃ tachykinin receptor and onisty GABA _B, for the treatment of cough.

14. The use of a compound according to claim 1 for the manufacture of a medicament for the treatment of pain, anxiety, cough, asthma, depression and alcohol abuse.

15. The use of the ORL-1 nociceptin receptor agonist, as the only drug or in combination with a second drug intended for the treatment of cough, allergy or asthma symptoms, selected from the group consisting of antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H ₃ inhibitors, agonists, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic agonists of the receptor, mast cell stabilizers, antitussives, expectorants, NK ₁ antagonists, NK ₂ and NK ₃ tachykinin receptor and onisty GABA _B, for the manufacture of a medicament for the treatment of cough.