Benzodioxa alkylene ethers as melatonergic agents

• US 5,981,571 A
• Filed: 10/09/1998
• Issued: 11/09/1999
• Est. Priority Date: 12/10/1996
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Parker, Michael F., Mattson, Ronald J., Johnson, Graham, Keavy, Daniel J., Yevich, Joseph P., Takaki, Katherine S., Catt, John D.
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US09/169,784
• Time in Patent Office: 396 Days
• Field of Search: 549/350, 549/362, 549/441, 514/450, 514/452, 514/466
• US Class Current: 514/450
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 307/79 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 311/58 other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 313/08 condensed with one six-membered ring
• CPC Class Codes: C07D 317/58 Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 321/10 condensed with carbocyclic rings or ring systems
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

Novel derivatives of benzodioxa alkylene ethers are provided which are useful as melatonergic agents.

Claims

1. A compound of Formula I or a pharmaceutically acceptable solvate thereof having the Formula:

##STR28## wherein Q¹ and Q² each are independently hydrogen or halogen;

X is oxygen;

Y is (CH₂)_n, with n=1-4;

Z is oxygen;

R is hydrogen, halogen or C_1-4 alkyl in both cases;

m is 1 or2;

R¹ is C_1-6 alkyl, C_3-6 cycloalkyl, C_1-3 haloalkyl, C_1-6 alkylamino, C_2-6 alkenyl, C_1-4 alkoxy(C_1-4)alkyl, C_1-4 alkylthio(C_1-4)alkyl or C_1-4 trifluoromethylalkyl; and

R² is hydrogen or C_1-4 alkyl.

2. The compound of claim 1 wherein Q¹ and Q² are independently hydrogen or iodo and m is 1.

3. The compound of claim 2 wherein R¹ is C_1-6 alkyl, C_3-4 cycloalkyl, C_1-3 haloalkyl, C_2-3 alkenyl, C_1-2 alkoxy(C_1-2)alkyl or C_1-2 trifluoromethylalkyl and R² is hydrogen.

4. The compound of claim 3 wherein X is oxygen, Y is (CH₂)n in which n is 1or 2 and Z is oxygen.

5. The compound of claim 4, selected from the group consisting of:

(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl]acetamide;

(-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl]acetamide;

(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl]propanamide;

(-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl] propanamide;

(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl]butanamide;

(-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl] butanamide;

(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl]cyclopropane carboxamide;

(-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl] cyclopropane carboxamide;

(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl]-2-methylpropanamide;

(-)-(trans)-N-[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl]-2-methylpropanamide;

(-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]propanamide;

(-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]acetamide;

(-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]cyclopropanecarboxamide;

(-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]butanamide;

(+)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]propenamide;

(-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]trifluoroacetamide;

(-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl) cycloprop-1-yl]methyl]-3,3,3-trifluoropropanamide;

(+)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]propanamide;

(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]-methyl]acetamide;

(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]-methyl]propanamide;

(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]-methyl]butanamide;

(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]-2-methylpropanamide; and

(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]-methyl]cyclopropane carboxamide.

6. The compound of claim 5, selected from the group consisting of:

(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl]acetamide;

(-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl]acetamide;

(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl]propanamide;

and (-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cycloprop-1-yl]methyl] propanamide.

7. The compound of claim 5, selected from the group consisting of:

(-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]propanamide;

(-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]acetamide;

(-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]cyclopropanecarboxamide; and

(-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cycloprop-1-yl]methyl]butanamide.

8. A method of treating sleep disorders in a patient in need of such treatment comprising administering to said patient a therapeutic amount of a compound of claim 1.

9. A composition useful for treating sleep disorders comprising a therapeutic amount of a compound of claim 1 and a suitable amount of a pharmaceutically acceptable carrier.

10. A method of treating circadian rhythm-related disorders in a patient in need of such treatment comprising administering to said patient a therapeutic amount of a compound of claim 1.

11. A composition useful for treating circadian rhythm-related disorders comprising a therapeutic amount of a compound of claim 1 and a suitable amount of a pharmaceutically acceptable carrier.