Piperazino derivatives as neurokinin antagonists

• US 5,719,156 A
• Filed: 05/02/1995
• Issued: 02/17/1998
• 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: Piwinski, John, Shih, Neng-Yang, Chen, Xiao, Blythin, David J., Shue, Ho-Jane
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US08/432,739
• Time in Patent Office: 1,022 Days
• Field of Search: 544/349, 544/359, 514/249, 514/255, 514/221, 514/218, 514/215, 514/183, 540/473, 540/567, 540/575, 540/593
• US Class Current: 514/252.13
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems

Abstract

The invention relates to compounds of the formulas ##STR1## wherein Z, R_c, y, x, l₁, l₂, l₃, u, R₄,R_c'"'"', n, R₁, R₂, and R₃, are as described herein. These compounds are neurokinin antagonists. These compounds are useful in the treatment of chronic airway diseases such as asthma.

Claims

1. A compound of the formula:

##STR209## wherein each R₁ is independently ##STR210## and where R_a is not H in ##STR211## and each R₂, and R₃ is independently ##STR212## each R_a and R_b is independently selected from the group consisting of H, C₁ -C₆ alkyl, CF₃, C₂ F₅, phenyl, and benzyl;

each R_c and R_c'"'"' is selected from the group consisting of H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, unsubstituted or substituted phenyl, and unsubstituted or substituted benzyl, with the proviso that no more than one R_c is other than H in the ##STR213## moiety, and no more than one R_c'"'"' is other than H in the ##STR214## moiety;

##STR215## n is 0 to 5;

l₃ is 2,

x is 0, and y is 2 to 4;

or x is 1, and y is 0 to 3;

Z is ##STR216## m₂ is 0 to 2;

n₂ is 1 to 2;

each t is 0 to 4;

each u is independently 0 to 2; and

R₉ is selected from the group consisting of ##STR217## wherein R_a is not H, when R₉ is ##STR218## and wherein substituted means 1 to 3 substituents independently selected from the group consisting of H, C₁ -C₆ alkyl, CF₃, C₂ F₅, OH, OC₁ -C₆ alkyl, Cl, Br, I and F;

or a pharmaceutically acceptable salt thereof.

2. A compound of the formula:

##STR219## wherein each R₁ is independently ##STR220## and where R_a is not H in ##STR221## and each R₂, and R₃ is independently ##STR222## each R_a and R_b is independently selected from the group consisting of H, C₁ -C₆ alkyl, CF₃, C₂ F₅, phenyl, and benzyl;

each R_c and R_c'"'"' is selected from the group consisting of H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, unsubstituted or substituted phenyl, and unsubstituted or substituted benzyl, with the proviso that no more than one R_c is other than H in the ##STR223## moiety, and no more than one R_c'"'"' is other than H in the ##STR224## moiety;

R₄ is ##STR225## n is 0 to 5;

13 is 2,

x is 0, and y is 2 to 4;

or x is 1, and y is 0 to 3;

Z is ##STR226## m₂ is 0 to 2;

n₂ is 1 to 2;

each t is 0 to 4;

each u is independently 0 to 2; and

R₉ is selected from the group consisting of ##STR227## wherein R_a is not H, when R₉ is ##STR228## and wherein substituted means 1 to 3 substituents independently selected from the group consisting of H, C₁ -C₆ alkyl, CF₃, C₂ F₅, OH, OC₁ -C₆ alkyl, Cl, Br, I and F;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 wherein all of R_c or all of R_c'"'"' are H.

4. A compound according to claim 2 wherein u is 0, n is 1 and x is 1.

5. A compound according to claim 4 wherein one of R₁, R₂, and R₃ in ##STR229## moiety of formula I is H.

6. A compound according to claim 2 having the formula ##STR230## wherein R₄ is phenyl or ##STR231##

7. A compound according to claim 6 wherein m₂ is 0 and n₂ is 1.

8. A compound according to claim 2, wherein n is 0 to 2.

10. A composition comprising a neurokinin antagonistic effective amount of a compound according to claim 2 and a pharmaceutically acceptable carrier material.

11. A method for inducing neurokinin antagonism which comprises administering a neurokinin antagonistic effective amount of a compound according to claim 2 to a mammal in need thereof.

12. A method for treating asthma or bronchospasm comprising administering to a mammal in need of such treatment a neurokinin antagonistic effective amount of a compound of claim 2.

9. A compound selected from the group consisting of ##STR232## wherein Z is ##STR233## or a pharmaceutically acceptable salt thereof;

and ##STR234## wherein Z is ##STR235## or a pharmaceutically acceptable salt thereof.