Muscarine agonists

• US 5,718,912 A
• Filed: 10/28/1996
• Issued: 02/17/1998
• Est. Priority Date: 10/28/1996
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Thomspon, Wayne J., Mallorga, Pierre, Bell, Ian M., Munson, Peter M., Ransom, Richard W., Sugrue, Michael F.
• Primary Examiner(s): Schofer, Joseph L.
• Assistant Examiner(s): FAULKNER, DIEDRA SARRAE
• Application Number:
  US08/736,705
• Time in Patent Office: 477 Days
• Field of Search: 514/318, 514/323, 546/199, 546/194, 546/193, 544/333
• US Class Current: 424/427
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond

Abstract

This invention is concerned with novel 1- cycloalkylpioeridin-4-yl!-2H benzimidazolones, their compositions and method of use. The novel compounds are selective muscarinic agonists of the m2 subtype with low activity at the m3 subtype. The compounds are effective for the treatment of glaucoma with fewer side effects than the pilocarpine therapy.

Claims

1. A compound of structural formula I ##STR3## or pharmaceutically acceptable salts thereof, or diastereomers, enantiomers or mixtures thereof;

wherein;

R₁ -R₄ are independently H, alkyl, halo, alkoxy, OH, HOCH2--, aryl, 3-pyridyl, 5-pyrimidinyl, amino, dialkylamino, alkene, thioalkyl, or alkylamino;

X is C;

A is alkyl, alkoxy, carboxyalkyl, alkoxyamino, alkylamino, dialkylamino, dialkoxyamino, carboxylic acid, ═

O, hydroxy, C═

O, N, or does not exist;

E is H, alkyl, alkylamino, dialkylamino, aryl, heteroaryl, heterocycle, alkoxy, alkoxyaryl, alkoxyheteraryl, carbonyl heterocycle, alkoxyhetercycle, or does not exist; and

Y is H, alkyl, halo, alkylamino, alkoxyamino, alkoxy, dialkylamino, or amino.

2. The compound of claim 1 wherein R₁ -R₄ are independently H, alkyl, or halo;

A is alkyl, alkoxyamino, N, C═

O, ═

O, or carboxyalkyl;

E is H, alkyl, aryl, heteroaryl, heterocycle, alkylamino, or dialkylamino; and

Y is H, alkyl, or halo.

6. A method of treating ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a compound of claim 1.

7. A method of treating ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a compound of claim 1, known to be selective for m2 receptors, but less active at m3 receptors.

10. A method of preventing ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a compound of claim 1.

11. A method of preventing ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a compound of claim 1, known to be selective for m2 receptors, but less active at m3 receptors.

14. A composition useful for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of claim 1.

15. A composition useful for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of claim 1, known to be selective for m2 receptors, but less active at m3 receptors.

18. A composition useful for the prevention of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of claim 1.

19. A composition useful for the prevention of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of claim 1, known to be selective for m2 receptors, but less active at m3 receptors.

3. The compound:

1,3-dihydro-1-{1- 4-oxo-cyclohex-1-yl!piperidin-4-yl}-2H-benzimidazol -2-one;

5-methyl-1,3-dihydro-1-{1- 4-oxo-cyclohex-1-yl!piperidin-4-yl}-2H-benzimidazol-2-one;

5-chloro-1,3-dihydro-1-{1- 4-oxo-cyclohex-1-yl!piperidin-4-yl}-2H-benzimidazol-2-one;

5-fluoro-1,3-dihydro-1-{1- 4-oxo-cyclohex-1-yl!piperidin-4-yl}-2H-benzimidazol-2-one;

1,3-dihydro-1-{1- 2-fluoro-4-oxo-cyclohex-1-yl!piperidin-4-yl}-2H-benzimidazol-2-one;

1,3-dihydro-1-{1- 2-oxo-1,3-dioxolan-5-yl!piperidin-4-yl}-2H-benzimidazol-2-one;

1,3-dihydro-1-{1- 2(1H)-oxo-tetrahydropyrimidin-5-yl!piperidin-4-yl}-2H-benzimidazol-2-one; and

1,3-dihydro-1-{1- 1,3-dimethyl-2(1H)-oxo-tetrahydropyrimidin-5-yl!piperidin-4-yl}-2H-benzimidazol-2-one.

4. A method of treating ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a muscarinic agonist.

5. A method of treating ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a muscarinic agonist known to be selective for m2 receptors, but less active at m3 receptors.

8. A method of preventing ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a muscarinic agonist.

9. A method of preventing ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a muscarinic agonist known to be selective for m2 receptors, but less active at m3 receptors.

12. A composition useful for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a muscarinic agonist.

13. A composition useful for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a muscarinic agonist, known to be selective for m2 receptors, but less active at m3 receptors.

16. A composition useful for the prevention of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a muscarinic agonist.

17. A composition useful for the prevention of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a muscarinic agonist, known to be selective for m2 receptors, but less active at m3 receptors.