Phenyl-alkyl-imidazoles

• US 6,034,251 A
• Filed: 11/05/1998
• Issued: 03/07/2000
• Est. Priority Date: 11/07/1997
• Status: Expired due to Fees

• Current Assignee: Schering Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Aslanian, Robert G., McCormick, Kevin D., Piwinski, John J.
• Primary Examiner(s): Higel, Floyd D.
• Application Number:
  US09/185,972
• Time in Patent Office: 488 Days
• Field of Search: 548/338.1, 548/341.1, 548/341.5, 548/342.1, 514/399, 514/400
• US Class Current: 548/338.1
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Abstract

Disclosed are novel phenyl-alkyl-imidazoles of the formula ##STR1## wherein R¹, R⁷, m, n, p, q, X, Y, Z, R and R¹⁵ are as defined in the specification.

Also disclosed are pharmaceutical compositions comprising the compounds of formula I.

Further disclosed are methods of treating allergy, inflammation, hypotension, glaucoma, sleeping disorders, states of hyper and hypo motility of the gastrointestinal tract, hypo and hyperactivity of the central nervous system, Alzheimer'"'"'s, schizophrenia, obesity and migraines by administering compounds of formula I.

Also disclosed are methods for treatment of upper airway allergic responses comprising administering a compound, or salt or solvate thereof, of formula I in combination or admixture with a histamine H₁ receptor antagonist.

Claims

1. A compound of the formula:

##STR55## or a pharmaceutically acceptable salt or solvate thereof, wherein;

the double bond (a) is of the E or Z, configuration;

each R¹ is independently selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, phenyl and benzyl;

each R⁷ is independently selected from the group consisting of hydrogen, lower alkyl, halogen, trihalomethyl, NR¹⁰ R¹¹, or a group OR¹⁰, whereby R¹⁰ and R¹¹ are independently selected from hydrogen, lower alkyl or trihalomethyl;

X is --CONR⁵ --;

--SO₂ --, --S--;

--CO--;

--COO--;

--CN(OR⁵)NR⁵ --;

--C(NR⁵)NR⁵ --;

--SONR⁵ --;

--SO₂ NR⁵ -- and, provided p is not zero, X is also --O--;

--NR⁵ --;

--NR⁵ CONR⁵ --;

--OCONR⁵ --;

--O--CO-- or --NR⁵ CO--;

Y is C₁ -C₃ -alkyl, unsubstituted or substituted at any carbon atom of the group by one substituent R⁵ ;

Z is C(R¹)₂ ;

wherein no more than two R¹ groups are other than hydrogen;

n is 1 or 2;

m is 0 or 1;

p is 0 or 1;

q is 0 or 1;

R is selected from;

(1) C₃ to C₇ cycloalkyl,

(2) heterocyclic groups,

(3) aryl,

(4) heteroaryl,

(5) substituted C₃ to C₇ cycloalkyl having 1-3 substituents independently selected from the group consisting of lower alkyl trihalomethyl and NR¹⁰ R¹¹, wherein R¹⁰ and R¹¹ are independently selected from hydrogen, lower alkyl or trihalomethyl,

(6) substituted heterocyclic having 1-3 substituents independently selected from the group consisting of lower alkyl trihalomethyl and NR¹⁰ R¹¹, wherein R¹⁰ and R¹¹ as defined above, said substituents being bound to carbon atoms in the ring such that the total number of substituents in the ring is 1 to 3; and

wherein the heterocyclic ring contains nitrogen atoms, said nitrogen atoms are unsubstituted or substituted with lower alkyl;

(7) substituted aryl having 1-3 substituents independently selected from the group consisting of lower alkyl, halogen, trihalomethyl, CN, NO₂, OR¹⁰ or NR¹⁰ R¹¹, wherein R¹⁰ and R¹¹ as defined above,

(8) substituted heteroaryl having 1-3 substituents independently selected from the group consisting of lower alkyl, halogen, trihalomethyl, CN, NO₂, OR¹⁰ or NR¹⁰ R¹¹, wherein R¹⁰ and R¹¹ are as defined above; and

each R⁵ independently represents hydrogen, lower alkyl or poly-halo-loweralkyl.

2. The compound of claim 1 wherein both R⁷ are hydrogen.

3. The compound of claim 2 wherein n is 1.

4. The compound of claim 3 wherein R¹ is hydrogen and R is selected from:

(1) phenyl substituted by one or two substitutents selected from;

lower alkyl, halogen, trihalomethyl, CN, NO₂, OR¹⁰ or NR¹⁰ R¹¹, wherein R¹⁰ and R¹¹ as defined above, or (2) pyridyl substituted by one or two substitutents selected from;

lower alkyl, halogen, trihalomethyl, CN, NO₂, OR¹⁰ or NR¹⁰ R¹¹, wherein R¹⁰ and R¹¹ as defined above.

5. The compound of claim 4 wherein R represents phenyl substituted by or pyridyl substituted by one or two substituents selected from:

halogen, methoxy, CF₃, CN or OCF₃.

6. The compound of claim 5 wherein said substituent is chlorine or fluorine.

7. The compound of claim 5 wherein R is (1) mono-substituted phenyl wherein said substituent is in the 3- or the 4-position or (2) a di-substituted phenyl wherein the two substituents are the same and are in the 3,5-positions.

8. The compound of claim 7 wherein X is --CONR⁵.

9. The compound of claim 8 wherein m is 0.

10. The compound of claim 9 wherein (1) p is 0 and (2) q is 0 or 1, wherein when q is 1, then Y represents --CHR⁵ CHR⁵ -- wherein one R⁵ is hydrogen.

11. The compound of claim 10 wherein said substituent is chlorine or fluorine.

12. The compound of claim 1 selected from:

##STR56##

13. The compound of claim 12 wherein R is (1) mono-substituted phenyl wherein said substituent is in the 3- or the 4-position or (2) a di-substituted phenyl wherein the two substituents are the same and are in the 3,5-positions.

14. The compound of claim 7 having the formula wherein R is selected from (1) phenyl, (2) 4-Cl-phenyl, (3) 3,5-dimethyl-phenyl, (4) 3-F-phenyl, (5) 4-F-phenyl, (6) 3-methoxy-phenyl or (7) 3-CN-phenyl.

15. The compound of claim 7 having the formula ##STR57## wherein m is 0 or 1 and R is selected from (1) phenyl, (2) 4-chlorophenyl, (3) 3,5-dimethylphenyl, (4) 3-fluorophenyl, (5) 4-fluorophenyl, (6) 3-methoxyphenyl or (7) 3-cyanophenyl.

16. The compound of claim 7 wherein X is selected from --NH--, --SO₂ --, --O-- or --SO₂ NH--.

17. The compound of claim 16 wherein the substituent is chlorine or fluorine.

18. The compound of claim 16 wherein R is (1) phenyl, (2) phenyl substituted in the 3- or 4-position by Cl, F, CN or OCH₃, or (3) phenyl substituted in the 3- and 5-positions by Cl, F, CF₃, CH₃, OCH₃ or OCF₃.

19. The compound of claim 18 wherein (1) m is 0 or 1, (2) p is 1 and (3) q is 0 or 1, wherein when q is 1 then Y represents --CH₂ CH₂ --.

20. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier or excipient.

21. A method of treating allergy, inflammation, cardiovascular disease, hypotension, glaucoma, sleeping disorders, diseases of the GI-tract, states of hyper and hypo motility of the gastrointestinal tract, or disturbances of the central nervous system, hypo and hyperactivity of the central nervous system, Alzheimer'"'"'s, schizophrenia, obesity and migraines, comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable acid addition salt or solvate thereof, to a patient in need of such treatment.

22. A method for treatment of upper airway allergic responses comprising administering to a patient in need of such treatment a compound, or a salt or solvate thereof, of claim 1 in combination or admixture with a histamine H₁ receptor antagonist.

23. The method of claim 22 wherein said H₁ antagonist is selected from:

loratadine, descarboethoxyloratadine, fexofenadine, cetirizine.

24. The method of claim 23 wherein said H₁ antagonist is selected from:

loratadine or descarboethoxyloratadine.