Piperazino derivatives as neurokinin antagonists

• US 5,798,359 A
• Filed: 05/25/1995
• Issued: 08/25/1998
• 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: Shih, Neng-Yang, Chen, Xiao, Blythin, David J., Shue, Ho-Jane, Piwinski, John
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US08/451,113
• Time in Patent Office: 1,188 Days
• Field of Search: 544/360, 544/359, 544/372, 514/255, 514/210, 514/212, 540/481, 540/597
• US Class Current: 514/252.12
• 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:

##STR271## wherein each R₁ is independently selected from the group consisting of ##STR272## provided R_a is not H in ##STR273## and each R₂, and R₃ is independently selected from the group consisting of ##STR274## 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 ##STR275## moiety, and no more than one R_c'"'"' is other than H in the ##STR276## moiety;

R₄ is ##STR277## n is 0to 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 ##STR278## p₁ and p₂ are each independently 1 to 4 with the proviso that p₁ and p₂ added together are 2 to 6;

each t is 0 to 4;

each u is independently 0 to 2;

R₅ is selected from the group consisting of ##STR279## wherein R_a is not H when R₅ is ##STR280## and with the proviso that when R₅ is C₃ -C₆ alkenyl or C₃ -C₆ alkynyl, the double or triple bond cannot be directly attached to nitrogen;

R₆ is selected from the group consisting of H, C₁ -C₆ alkyl, ##STR281## 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 according to claim 1 wherein one of R₁, R₂, and R₃ in the ##STR282## moiety of formula I is H.

3. A compound according to claim 1 wherein two of R₁, R₂, and R₃ in the ##STR283## moiety of formula I is H.

4. A compound according to claim 1 wherein all of R_c or all of R_c'"'"' are H.

5. A compound according to claim 1 wherein R₄ is phenyl or ##STR284## wherein each R₁ is independently ##STR285## and where R_a is not H in ##STR286## and each R₂, and R₃ can be independently ##STR287## each R_a and R_b is independently selected from the group consisting of H, C₁ -C₆ alkyl, CF₃, C₂ F₅, phenyl, and benzyl.

6. A compound according to claim 1 wherein R₅ is ##STR288##

7. A compound according to claim 1 wherein R₆ is ##STR289##

8. A composition comprising a neurokinin antagonistic effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier material.

9. A compound according to claim 1, wherein n is 0 to 3.

10. A method for for inducing neurokinin antagonism which comprises administering a neurokinin antagonistic effective amount of a compound according to claim 1 to a mammal in need thereof.

11. A method for treating chronic airway diseases selected from the group consisting of asthma and allergies;

inflammatory diseases selected from the group consisting of inflammatory bowel disease, psoriasis, fibrositos, osteoarthritis, and rheumatoid arthritis;

migraine;

central nervous system disorders selected from the group consisting of depression, psychosis, dementia, and Alzheimer'"'"'s disease;

Down'"'"'s syndrome;

neuropathy;

multiple sclerosis;

ophthalmic disorders;

conjunctivitis;

auto immune disorders;

graft rejection;

systemic lupus erythematosus;

GI disorders selected from the group consisting of Crohn'"'"'s disease and ulcerative colitis;

disorders of bladder function;

circulatory disorders such as angina;

Raynaud'"'"'s disease;

coughing and pain comprising administering an effective amount of a compound of claim 1 to a mammal in need of such treatment.

12. A compound selected from the group consisting of ##STR290## a compound selected from the group consisting of ##STR291## wherein Ar is phenyl or 3,4-dichlorophenyl ##STR292## or a pharmaceutically acceptable salt thereof.