Benzimidazolone histamine H3 antagonists

• US 7,220,735 B2
• Filed: 04/16/2003
• Issued: 05/22/2007
• Est. Priority Date: 04/18/2002
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Zeng, Qingbei, Aslanian, Robert G., Shih, Neng-Yang, Solomon, Daniel M., Tom, Wing C., Rosenblum, Stuart B., Berlin, Michael Y., Boyce, Christopher W., Ting, Pauline C., Mangiaracina, Pietro, Mutahi, Mwangi W., McCormick, Kevin D., Cao, Jianhua
• Primary Examiner(s): Wilson; James O.
• Assistant Examiner(s): Johnsen; Jason H.
• Application Number:
  US10/414,943
• Publication Number:
  US 20040048843A1
• Time in Patent Office: 1,497 Days
• Field of Search: 514/210.21, 544/224, 544/336, 546/184, 546/192, 546/193, 546/194
• US Class Current: 514/210.21
• 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 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Disclosed are novel compounds of the formula

wherein R¹ is benzimidazolone derivative, M¹ and M² are optionally substituted carbon or nitrogen, R² includes optionally substituted aryl or heteroaryl, and the remaining variables are as defined in the specification, and the remaining variables are as defined in the specification; also disclosed are pharmaceutical compositions comprising the compounds of formula I and methods of treating various diseases or conditions, such as allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of formula I, as well as methods of treating said diseases or conditions using the compounds of formula I in combination with an H₁ receptor antagonist.

Claims

1. A compound represented by the structural formula

2. A compound of claim 1 wherein A is a bond, a is 0, and the optional double bond is not present.

3. A compound of claim 2 wherein M² is C(R³) wherein R³ is hydrogen or halogen, b is 0;

r is 1 and p is 2.

4. A compound of claim 3 wherein Z is straight or branched C₁–

C₃ alkyl.

5. A compound of claim 4 wherein R² is a six-membered heteroaryl ring, optionally substituted with one R⁶ substituent.

6. A compound of claim 5 wherein R² is pyridyl, pyrimidyl or pyridazinyl, each optionally substituted with halogen or —

NR⁴R⁵ wherein R⁴and R⁵ are independently selected from the group consisting of H and (C₁–

C₆)alkyl, or R⁴and R⁵ together with the nitrogen to which they are attached, form a pyrrolidinyl, piperidinyl or morpholinyl ring.

7. A compound of claim 6 wherein R¹ is R-substituted benzimidazolone, wherein R is H, (C₁–

C₆)alkyl, (C₁–

C₆)alkoxy(C₁–

C₆)alkyl, R³²-aryl, R³²-heteroaryl or heterocycloalkyl(C₁–

C₆)alkyl.

8. A compound of claim 7 wherein R is H, —

CH₃, phenyl, 4-fluorophenyl, CH₃—

O—

(CH₂)₂—

,

9. A compound of claim 7 wherein R²⁵ is halogen or —

CF₃ and k is 0 or 1.

10. A compound of claim 1 selected from the group consisting of

11. A compound of claim 1 selected from the group consisting of

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

13. A method of treating nasal congestion, obesity, somnolence, narcolepsy, attention deficit hyperactivity disorder, Alzheimer'"'"'s disease or schizophrenia, comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1.

14. A pharmaceutical composition comprising an effective amount of a compound of claim 1, and an effective amount of H₁ receptor antagonist, and a pharmaceutically effective carrier.

15. A method of treating nasal congestion comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1 in combination with an effective amount of an H₁ receptor antagonist.

16. The method of claim 15 wherein said H₁ receptor antagonist is selected from the group consisting of astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine.

17. The method of claim 16 wherein said H₁ receptor antagonist is selected from the group consisting of loratadine, descarboethoxyloratadine, fexofenadine and cetirizine.

18. The method of claim 17 wherein said H₁ receptor antagonist is loratadine or descarboethoxyloratadine.