Ethylamido fluorenes and improved method of making same

• US 5,736,578 A
• Filed: 05/10/1996
• Issued: 04/07/1998
• Est. Priority Date: 06/06/1995
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Karageorge, George N., Watson, Brett T., Yevich, Joseph P., Takaki, Katherine S., Epperson, James R., Leboulluec, Karen L.
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US08/644,510
• Time in Patent Office: 697 Days
• Field of Search: 564/189, 564/190, 564/192, 564/193, 564/194, 564/196, 564/201, 564/204, 564/209, 564/210, 564/211, 564/212, 564/213, 514/624, 514/625, 514/626, 514/627, 514/628, 514/629, 514/630
• US Class Current: 514/630
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 59/001 Acyclic or carbocyclic compounds
• CPC Class Codes: C07C 233/18 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/20 having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
• CPC Class Codes: C07C 233/60 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 235/08 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes

Abstract

Novel substituted fluorene compunds of Formula I are active as melatonergic agents: ##STR1## wherein: X=H, halogen, OH or OZ;

Z=C_1-6 alkyl; --(CH₂)_m --CF₃ (m=0-2); CD₃ ; or ##STR2## n=1 or 2; and R=C_1-6 alkyl, C_3-6 cycloalkyl, C_2-4 alkenyl, halogen substituted C_1-6 alkyl, or C_1-6 alkoxy substituted C_1-6 alkyl.

Claims

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

##STR15## wherein;

X=H, halogen, OH or OZ;

Z=C_1-6 alkyl;

--(CH₂)_m --CF₃ (m=0-2);

CD₃ or ##STR16## n=1 or 2; and

R=C_1-6 alkyl, C_3-6 cycloalkyl, C_2-4 alkenyl, halogen substituted C_1-6 alkyl, or C_1-6 alkoxy substituted C_1-6 alkyl.

2. The compound of claim 1 wherein at least one of X and ZO is methoxy.

3. The compound of claim 2 wherein R is methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, cyclobutyl or chloromethyl.

4. The compound of claim 3 selected from the group consisting of:

N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!cyclopentane carboxamide;

N- 2-(2-methoxyfluoren-9-yl) ethyl!butanamide;

N- 2-(2-methoxyfluoren-9-yl)ethyl!acetamide;

N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!butanamide;

N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!propanamide;

N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!cyclopropane carboxamide;

N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!acetamide;

N- 2-(2-ethoxy-7-methoxyfluoren-9-yl)ethyl!propanamide;

N- 2-(2-hydroxy-7-methoxyfluoren-9-yl)ethyl!propanamide;

N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!cyclobutane carboxamide; and

N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!choroacetamide.

5. The compound of claim 2 wherein R is methoxymethyl, methylvinyl, vinyl, isopropyl, or t-butyl.

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

5N- 2-(2,7-dimethoxyfluoren-9-yl)-ethyl!but-2-enamide;

N- 2-(2-methoxyfluoren-9-yl)ethyl!-2-propenamide;

N- 2-(2,7-dimethoxyfluoren-9-yI)ethyl!methoxyacetamide;

N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!-2-methyl propanamide; and

N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!-2,2-dimethyl propanamide.

7. The compound of claim 2 wherein n=2.

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

N- 3-(2,7-dimethoxyfluoren-9-yl)prop-1-yl!propanamide;

N- 3-(2,7-dimethoxyfluoren-9-yl)prop-1-yl!butanamide;

N- 3-(2,7-dimethoxyfluoren-9-yl)prop-1-yl!acetamide;

N- 3-(2,7-dimethoxyfluoren-9-yl)prop-1-yl!cyclobutane carboxamide; and

N- 3-(2,7-dimethoxyfluoren-9-yl)prop-1-yl!cyclopropane carboxamide.

9. The compound of claim 2 wherein X is F, --O(n-pentyl) or ##STR17## .

10. The compound of claim 1, N- 2-(2-methoxyfluoren-9-yl)ethyl!butanamide.

11. The compound of claim 1, N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!propanamide.

12. The compound of claim 1, N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!cyclobutane carboxamide.

13. The compound of claim 1, N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!choroacetamide.

14. The compound of claim 1, N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!butanamide.

15. The compound of claim 1, N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!acetamide.

16. The compound of claim 1, N- 2-(2,7-dimethoxyfluoren-9-yl)ethyl!cyclopropane carboxamide.

17. The compound of claim 1 wherein X is OZ and Z is CH₂ CF₃.

18. The compound of claim 1 wherein X is OZ and Z is CD₃.

19. A method of treating a sleep disorder in a mammal in need of such treatment comprising administering to said mammal an effective amount of a compound of claim 1.

20. A pharmaceutical composition for treating sleep disorders comprising an effective amount of a compound of claim 1 and a suitable amount of a pharmaceutically acceptable carrier.