Substituted oximes, hydrazones and olefins useful as neurokinin antagonists

• US 5,688,960 A
• Filed: 10/31/1996
• Issued: 11/18/1997
• Est. Priority Date: 05/02/1995
• Status: Expired due to Term

• Current Assignee: Schering Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Shankar, Bandarpalle B.
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US08/742,013
• Time in Patent Office: 383 Days
• Field of Search: 546/202, 514/324
• US Class Current: 546/202
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/52 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 211/76 attached in position 2 or 6
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 333/22 Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Compound represented by the structural formula ##STR1## or a pharmaceutically acceptable salt thereof, wherein: a is 0, 1, 2 or 3;

b, d and e are independently 0, 1 or 2;

R is H, C_1-6 alkyl, --OH or C₂ -C₆ hydroxyalkyl;

A is an optionally substituted oxime, hydrazone or olefin;

X is a bond, --C(O)--, --O--, --NR⁶ --, --S(O)_e --, --N(R⁶)C(O)--, --C(O)N(R⁶)-- --OC(O)NR⁶ --, --OC(═S)NR⁶ --, --N(R⁶)C(═S)O--, --C(═NOR¹)--, --S(O)₂ N(R⁶)--, --N(R⁶)S(O)₂ --, --N(R⁶)C(O)O-- or --OC(O)--;

T is H, phthalimidyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyl or bridged cycloalkyl;

Q is heteroaryl;

R^6a, R^7a, R^8a, R^9a, R⁶ and R⁷ are H, C_1-6 alkyl, C₂ -C₆ hydroxyalkyl, C₁ -C₆ alkoxy-C₁ -C₆ alkyl, phenyl or benzyl; or R⁶ and R⁷, together with the nitrogen to which they are attached, form a ring;

R^9a is R⁶ or --OR⁶ ;

Z is morpholinyl, optionally N-substituted piperazinyl, optionally substituted ##STR2## or substituted ##STR3## g is 0-3 and h is 1-4, provided the sum of h and g is 1-7; wherein aryl, heterocycloalkyl, heteroaryl, cycloalkyl and bridged cycloalkyl groups are optionally substituted; methods of treating asthma, cough, bronchospasm, imflammatory diseases, and gastrointestinal disorders with said compounds, and pharmaceutical compositions comprising said compounds are disclosed.

Claims

1. A compound represented by the structural formula ##STR128## or a pharmaceutically acceptable salt thereof, wherein:

a is 0, 1, 2 or 3;

b and d are independently 0, 1 or 2;

R is H, C_1-6 alkyl, --OR⁶ or C₂ -C₆ hydroxyalkyl;

A is ═

N--OR¹, ═

N--N(R²)(R³), ═

C(R¹¹)(R¹²) or ═

NR²⁵ ;

X is a bond, --C(O)--, --O--, --NR⁶ --, --S(O)_e --, --N(R⁶)C(O)--, --C(O)N(R⁶)-- --OC(O)NR⁶ --, --OC(═

S)NR⁶ --, --N(R⁶)C(═

S)O--, --C(═

NOR¹)--, --S(O)₂ N(R⁶)--, --N(R⁶)S(O)₂ --, --N(R⁶)C(O)O-- or --OC(O)--, provided that when d is 0, X is a bond, --C(O)--, --NR⁶ --, --C(O)N(R⁶)--, --N(R⁶)C(O)--, --OC(O)NR⁶ --, --C(═

NOR¹)--, --N(R⁶)C(═

S)O--, --OC(═

S)NR⁶ --, --N(R⁶)S(O)₂ -- or --N(R⁶)C(O)O--;

provided that when A is ═

C(R¹¹)(R¹²) and d is 0, X is not --NR⁶ -- or --N(R⁶)C(O)--; and

provided that when A is ═

NR²⁵, d is 0 and X is --NR⁶ -- or --N(R⁶)C(O)--;

T is H, R⁴ -aryl, R⁴ -heterocycloalkyl, R⁴ -heteroaryl, phthalimidyl, R⁴ -cycloalkyl or R¹⁰ -bridged cycloalkyl;

Q is R⁵ -heteroaryl;

R¹ is H, C_1-6 alkyl, --(C(R⁶)(R⁷))_n --G, --G², --(C(R⁶)(R⁷))_p --M-- (C(R¹³)(R¹⁴))_n --(C(R⁸)(R⁹))_u --G, --C(O)N(R⁶)--(C(R¹³)(R¹⁴))_n --(C(R⁸)(R⁹))_u --G or --(C(R⁶)(R⁷))_p --M--(R⁴ -heteroaryl);

R² and R³ are independently selected from the group consisting of H, C_1-6 alkyl, --CN, --(C(R⁶)(R⁷))_n --G, --G², --C(O)--(C(R⁸)(R⁹))_n --G and --S(O)_e R¹³ ;

or R² and R³, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of --O--, --S-- and --N(R¹⁹)--;

R⁴ and R⁵ are independently 1-3 substituents independently selected from the group consisting of H, halogeno, --OR⁶, --OC(O)R⁶, --OC(O)N(R⁶)(R⁷), --N(R⁶)(R⁷), C_1-6 alkyl, --CF₃, --C₂ F₅, --COR⁶, --CO₂ R⁶, --CON(R⁶)(R⁷), --S(O)_e R¹³, --CN, --OCF₃, --NR⁶ CO₂ R¹⁶, --NR⁶ COR⁷, --NR⁸ CON(R⁶)(R⁷), R¹⁵ -phenyl, R¹⁵ -benzyl, NO₂, --N(R⁶)S(O)₂ R¹³ or --S(O)₂ N(R⁶)(R⁷);

or adjacent R⁴ substituents or adjacent R⁵ substituents can form a --O--CH₂ --O-- group; and

R⁴ can also be R¹⁵ -heteroaryl;

R⁶, R⁷, R⁸, R^6a, R^7a, R^8a, R¹³ and R¹⁴ are independently selected from the group consisting of H, C_1-6 alkyl, C₂ -C₆ hydroxyalkyl, C₁ -C₆ alkoxy-C₁ -C₆ alkyl, R¹⁵ -phenyl, and R¹⁵ -benzyl;

or R⁶ and R⁷, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of --O--, --S-- and --N(R¹⁹)--;

R⁹ and R^9a are independently selected from the group consisting of R⁶ and --OR⁶

R¹⁰ and R^10a are independently selected from the group consisting of H and C_1-6 alkyl;

R¹¹ and R¹² are independently selected from the group consisting of H, C₁ -C₆ alkyl, --CO₂ R⁶, --OR⁶, --C(O)N(R⁶)(R⁷), C₁ -C₆ hydroxyalkyl, --(CH₂)_r --OC(O)R⁶, --(CH₂)_r --OC(O)CH═

CH₂, --(CH₂)_r --O(CH₂)_s --CO₂ R⁶, --(CH₂)_r --O--(CH₂)_s --C(O)N(R⁶)(R⁷) and --(CH₂)_r --N(R⁶)(R⁷);

R¹⁵ is 1 to 3 substituents independently selected from the group consisting of H, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ alkylthio, halogeno, --CF₃, --C₂ F₅, --COR¹⁰, --CO₂ R¹⁰, --C(O)N(R¹⁰)₂, --S(O)_e R^10a, --CN, --N(R¹⁰)COR¹⁰, --N(R¹⁰)CON(R¹⁰)₂ and --NO₂ ;

R¹⁶ is C_1-6 alkyl, R¹⁵ -phenyl or R¹⁵ -benzyl;

R¹⁹ is H, C₁ -C₆ alkyl, --C(O)N(R¹⁰)₂, --CO₂ R¹⁰, --(C(R⁸)(R⁹))_f --CO₂ R¹⁰ or --(C(R⁸)(R⁹))_u --C(O)N(R¹⁰)₂ ;

f, n, p, r and s are independently 1-6;

u is 0-6;

G is selected from the group consisting of H, R⁴ -aryl, R⁴ -heterocycloalkyl, R⁴ -heteroaryl, R⁴ -cycloalkyl, --OR⁶, --N(R⁶)(R⁷), --COR⁶, --CO₂ R⁶, --CON(R⁷)(R⁹), --S(O)_e R¹³, --NR⁶ CO₂ R¹⁶, --NR⁶ COR⁷, --NR⁸ CON(R⁶)(R⁷), --N(R⁶)S(O)₂ R¹³, --S(O)₂ N(R⁶)(R⁷), --OC(O)R⁶, --OC(O)N(R⁶)(R⁷), --C(═

NOR⁸)N(R⁶)(R⁷), --C(═

NR²⁵)N(R⁶)(R⁷), --N(R⁸)C(═

NR²⁵)N(R⁶)(R⁷), --CN, --C(O)N(R⁶)OR⁷, and --C(O)N(R⁹)--(R⁴ -heteroaryl), provided that when n is 1 and u is 0, or when R⁹ is --OR⁶, G is not --OH or --N(R⁶)(R⁷);

M is selected from the group consisting of a double bond, --O--, --N(R⁶)--, --C(O)--, --C(R⁶)(OR⁷)--, --C(R⁸)(N(R⁶)(R⁷))--, --C(═

NOR⁶)N(R⁷)--, --C(N(R⁶)(R⁷))═

NO--, --C(═

NR²⁵)N(R⁶)--, --C(O)N(R⁹)--, --N(R⁹)C(O)--, --C(═

S)N(R⁹)--, --N(R⁹)C(═

S)-- and --N(R⁶)C(O)N(R⁷)--, provided that when n is 1, G is not OH or --NH(R⁶); and

when p is 2-6, M can also be --N(R⁶)C(═

NR²⁵)N(R⁷)-- or --OC(O)N(R⁶)--;

G² is R⁴ -aryl, R⁴ -heterocycloalkyl, R⁴ -heteroaryl, R⁴ -cycloalkyl, --COR⁶, --CO₂ R¹⁶, --S(O)₂ N(R⁶)(R⁷) or --CON(R⁶)(R⁷);

e is 0, 1 or 2, provided that when e is 1 or 2, R¹³ and R^10a are not H;

R²⁵ is H, C₁ -C₆ alkyl, --CN, R¹⁵ -phenyl or R¹⁵ -benzyl;

Z is ##STR129## or morpholinyl;

g and j are independently 0-3;

h and k are independently 1-4, provided the sum of h and g is 1-7;

J is two hydrogen atoms, ═

O, ═

S, ═

NR⁹ or ═

NOR¹ ;

L and L¹ are independently selected from the group consisting of H, C₁ -C₆ alkyl, C₁ -C₆ alkenyl, --CH₂ -cycloalkyl, R¹⁵ -benzyl, R¹⁵ -heteroaryl, --C(O)R⁶, --(CH₂)_m --OR⁶, --(CH₂)_m --N(R⁶)(R⁷), --(CH₂)_m --C(O)--OR⁶ and --(CH₂)_m --C(O)N(R⁶)(R⁷);

m is 0 to 4, provided that when j is 0, m is 1-4;

R²⁶ and R²⁷ are independently selected from the group consisting of H, C₁ -C₆ alkyl, R⁴ -aryl and R⁴ -heteroaryl;

or R²⁶ is H, C₁ -C₆ alkyl, R⁴ -aryl or R⁴ -heteroaryl, and R²⁷ is --C(O)R⁶, --C(O)--N(R⁶)(R⁷), --C(O)(R⁴ -aryl), --C(O)(R⁴ -heteroaryl), --SO₂ R¹³ or --SO₂ --(R⁴ -aryl);

R²⁸ is H, --(C(R⁶)(R¹⁹))_t --G, --(C(R⁶)(R⁷))_v --G² or --NO₂ ;

t and v are 0, 1, 2 or 3, provided that when j is 0, t is 1, 2 or 3;

R²⁹ is H, C₁ -C₆ alkyl, --C(R¹⁰)₂ S(O)_e R⁶, R⁴ -phenyl or R⁴ -heteroaryl;

R³⁰ is H, C₁ -C₆ alkyl, R⁴ -cycloalkyl, --(C(R¹⁰)₂)_w --(R⁴ -phenyl), --(C(R¹⁰)₂)_w --(R⁴ -heteroaryl), --C(O)R⁶, --C(O)OR⁶, --C(O)N(R⁶)(R⁷), ##STR130## w is 0, 1, 2, or 3;

V is ═

O, ═

S or ═

NR⁶ ; and

q is 0-4.

2. A compound of claim 1 wherein X is --O--, --C(O)--, a bond, --NR⁶ --, --S(O)_e --, --N(R⁶)C(O)--, --C(O)NR⁶, --OC(O)NR⁶ -- or --C(═

NOR¹)--.

3. A compound of claim 1 wherein T is R⁴ -aryl, R⁴ -heteroaryl, R⁴ -cycloalkyl or R¹⁰ -bridged cycloalkyl.

4. A compound of claim 1 wherein Q is R⁵ -heteroaryl wherein R⁵ is H.

5. A compound of claim 1 wherein R^6a, R^7a, R^8a and R^9a are independently selected from the group consisting of H, hydroxyalkyl and alkoxyalkyl.

6. A compound of claim 1 wherein Z is ##STR131##

7. A compound of claim 1 wherein X is --O--, --C(O)--, a bond, --NR⁶ --, --S(O)_e --, --N(R⁶)C(O)--, --C(O)NR⁶, --OC(O)NR⁶ -- or --C(═

NOR¹)--;

T is R⁴ -aryl, R⁴ -heteroaryl, R⁴ -cycloalkyl or R¹⁰ -bridged cycloalkyl;

R^6a, R^7a, R^8a and R^9a are independently selected from the group consisting of H, hydroxyalkyl and alkoxyalkyl; and

Z is ##STR132##

8. A compound of claim 1 wherein A is ═

N--OR¹.

9. A compound of claim 1 wherein A is ═

N--N(R²)(R³).

10. A compound of claim 1 wherein A is ═

C(R¹¹)(R¹²).

11. A compound of claim 1 wherein A is ═

NR²⁵.

12. A compound of claim 7 wherein A is ═

N--OR¹.

13. A compound of claim 12 wherein X is --O--, --NR⁶ --, --N(R⁶)C(O)-- or --C(O)NR⁶ --.

14. A compound of claim 12 wherein T is R⁴ -aryl.

15. A compound of claim 12 wherein Q is benzothienyl.

16. A compound of claim 12 wherein R^6a, R^7a, R^8a and R^9a are each H.

17. A compound of claim 12 wherein Z is ##STR133##

18. A compound of claim 1 wherein Q is benzothienyl, T is R⁴ -aryl, R is H, a is 1, A is ═

NOR¹, ##STR134## is --CH₂ --O--CH₂, --CH₂ --N(R⁶)C(O)--, --CH₂ NR⁶ CH₂ -- or CH₂ C(O)NR⁶ --, and Z is ##STR135##

19. A compound of claim 18 wherein T is R⁴ -phenyl and ##STR136## is --CH₂ --O--CH₂ or --CH₂ --N(R⁶)C(O)--.

20. A compound of claim 18 wherein R¹ is H, alkyl, --(CH₂)_n --G, --(CH₂)_p --M--(CH₂)_n --G or --C(O)N(R⁶)(R⁷), wherein M is --O-- or --C(O)N(R⁹)-- and G is --CO₂ R⁶, --OR⁶, --C(O)N(R⁶)(R⁹), --C(═

NOR⁸)N(R⁶)(R⁷), --C(O)N(R⁹)(R⁴ -heteroaryl) or R⁴ -heteroaryl.

21. A compound of claim 1 selected from:

##STR137##

22. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

23. A method of treating asthma, cough, bronchospasm, central nervous system diseases, inflammatory diseases and gastrointestinal disorders comprising administering an effective amount of a compound of claim 1 to a mammal in need of such treatment.