U.S. patent application number 10/770894 was filed with the patent office on 2004-08-12 for therapeutic 5-ht ligand compounds.
This patent application is currently assigned to Pharmacia & Upjohn Company. Invention is credited to McWhorter, William W. JR..
Application Number | 20040157831 10/770894 |
Document ID | / |
Family ID | 23202029 |
Filed Date | 2004-08-12 |
United States Patent
Application |
20040157831 |
Kind Code |
A1 |
McWhorter, William W. JR. |
August 12, 2004 |
Therapeutic 5-HT ligand compounds
Abstract
The present invention provides compounds of Formula (I): 1
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, and R.sup.8 have any of the values defined in the
specification, as well as pharmaceutical compositions comprising
the compounds. The invention also provides therapeutic methods as
well as processes and intermediates useful for preparing compounds
of Formula (I). The compounds are 5-HT ligands, and are useful for
treating diseases whereas modulation of 5-HT activity is
desired.
Inventors: |
McWhorter, William W. JR.;
(Parchment, MI) |
Correspondence
Address: |
FLYNN, THIEL, BOUTELL & TANIS, P.C.
2026 RAMBLING ROAD
KALAMAZOO
MI
49008-1699
US
|
Assignee: |
Pharmacia & Upjohn
Company
|
Family ID: |
23202029 |
Appl. No.: |
10/770894 |
Filed: |
February 3, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10770894 |
Feb 3, 2004 |
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10211879 |
Aug 2, 2002 |
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6720316 |
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60310331 |
Aug 6, 2001 |
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Current U.S.
Class: |
514/219 ;
514/224.5; 514/229.5; 514/249; 514/285; 540/555; 544/14; 544/343;
544/99; 546/66 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
25/28 20180101; A61P 25/00 20180101; C07D 498/16 20130101; A61P
25/22 20180101; A61P 25/24 20180101; A61P 25/18 20180101; A61P
43/00 20180101; C07D 513/16 20130101 |
Class at
Publication: |
514/219 ;
514/224.5; 514/229.5; 514/249; 540/555; 544/014; 544/099; 544/343;
546/066; 514/285 |
International
Class: |
A61K 031/551; C07D
498/04; C07D 491/04; A61K 031/542; A61K 031/538 |
Claims
What is claimed is:
1. A compound of Formula (I): 15wherein Z is --CHR.sup.9--,
--C(O)--, --O--, --S--, --S(O)--, --SO.sub.2--, --N(R.sup.9)--,
--C(O)N(R.sup.9)--, or --N(R.sup.9)C(O)--; l is 1 or 2; m is 0, 1
or 2; n is 1 or 2; R.sup.1 and R.sup.2 are each independently
hydrogen, C.sub.1-6alkyl, C.sub.3-6cycloalkyl, or
(C.sub.3-6cycloalkyl)C.sub.1-6alkyl; provided that R.sup.1 and
R.sup.2 are not both hydrogen; R.sup.3 is hydrogen or
C.sub.1-6alkyl; R.sup.4, R.sup.5, and R.sup.9 are independently
hydrogen, C.sub.1-6alkyl or arylC.sub.1-6alkylene; R.sup.6,
R.sup.7, and R.sup.8 are independently hydrogen, fluoro, chloro,
bromo, CF.sub.3, --OCF.sub.3, --N(R.sup.10).sub.2, C.sub.1-6alkyl,
C.sub.1-6alkoxy, heteroaryl or aryl; each R.sup.10 is independently
hydrogen, or --C.sub.1-6alkyl; wherein any C.sub.1-6alkyl,
C.sub.1-6alkylene, or C.sub.1-6alkoxy of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, and R.sup.10
is optionally partially unsaturated; wherein any heteroaryl or aryl
is optionally substituted with one or two substituents
independently selected from halo, --CF.sub.3, --OCF.sub.3,
C.sub.1-6alkoxy, --N(R.sup.10).sub.2, and C.sub.1-6alkyl; or a
pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R.sup.1 is hydrogen.
3. The compound of claim 1, wherein R.sup.1 is C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl)C.sub.1-6alkyl.
4. The compound of claim 1, wherein R.sup.1 is C.sub.2-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl)C.sub.1-6alkyl.
5. The compound of claim 1, wherein R.sup.1 is C.sub.3-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl)C.sub.1-6alkyl.
6. The compound of claim 1, wherein R.sup.1 is methyl, ethyl,
propyl, isopropyl, or cyclopropylmethyl.
7. The compound of claim 1, wherein R.sup.1 is ethyl, propyl,
isopropyl, or cyclopropylmethyl.
8. The compound of claim 1, wherein R.sup.1 is propyl, isopropyl,
or cyclopropylmethyl.
9. The compound of claim 1, wherein R.sup.2 is hydrogen.
10. The compound of claim 1, wherein R.sup.2 is C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl)C.sub.1-6alkyl.
11. The compound of claim 1, wherein R.sup.2 is C.sub.2-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl)C.sub.1-6alkyl.
12. The compound of claim 1, wherein R.sup.2 is C.sub.3-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl)C.sub.1-6alkyl.
13. The compound of claim 1, wherein R.sup.2 is methyl, ethyl,
propyl, isopropyl, or cyclopropylmethyl.
14. The compound of claim 1, wherein R.sup.2 is ethyl, propyl,
isopropyl, or cyclopropylmethyl.
15. The compound of claim 1, wherein R.sup.2 is propyl, isopropyl,
or cyclopropylmethyl.
16. The compound of claim 10, wherein R.sup.1 is hydrogen.
17. The compound of claim 1, wherein R.sup.1 is C.sub.2-3alkyl and
R.sup.2 is hydrogen, or C.sub.2-6alkyl.
18. The compound of claim 1, wherein R.sup.1 is hydrogen, or
C.sub.2-3alkyl; and R.sup.2 is C.sub.2-6alkyl.
19. The compound of claim 1, wherein R.sup.1 is C.sub.2-3alkyl and
R.sup.2 is C.sub.2-6alkyl.
20. The compound of claim 1, wherein R.sup.1 is ethyl or propyl and
R.sup.2 is ethyl, propyl or butyl.
21. The compound of claim 1, wherein R.sup.3 is hydrogen.
22. The compound of claim 1, wherein R.sup.3 is C.sub.1-6alkyl.
23. The compound of claim 23, wherein; and R.sup.3 is methyl,
ethyl, propyl, or butyl.
24. The compound of claim 23, wherein; and R.sup.3 is methyl or
ethyl.
25. The compound of claim 1, wherein R.sup.4 and R.sup.5 are
independently hydrogen, methyl, ethyl, propyl, butyl,
2-phenylethyl, or benzyl.
26. The compound of claim 25, wherein R.sup.4 and R.sup.5 are
independently hydrogen, methyl, ethyl, propyl, or benzyl.
27. The compound of claim 25, wherein R.sup.4 and R.sup.5 are
independently methyl, ethyl, or benzyl.
28. The compound of claim 1, wherein R.sup.6, R.sup.7, or R.sup.8
is phenyl optionally substituted with one or two substituents
independently selected from halo, --CF.sub.3, --OCF.sub.3,
C.sub.1-6alkoxy, --N(R.sup.10).sub.2, and C.sub.1-6alkyl.
29. The compound of claim 28, wherein R.sup.6, R.sup.7, or R.sup.8
is phenyl optionally substituted with one or two substituents
independently selected from fluoro, chloro, bromo, --CF.sub.3,
--OCF.sub.3, C.sub.1-6alkoxy and --N(R.sup.10).sub.2.
30. The compound of claim 28, wherein R.sup.6, R.sup.7, or R.sup.8
is phenyl optionally substituted with one or two substituents
independently selected from fluoro, chloro, and bromo.
31. The compound of claim 28, wherein R.sup.6 is 2,4-dichlorophenyl
or 2,6-difluorophenyl.
32. The compound of claim 28, wherein R.sup.7 is 2,4-dichlorophenyl
or 2,6-difluorophenyl.
33. The compound of claim 28, wherein R.sup.8 is 2,4-dichlorophenyl
or 2,6-difluorophenyl.
34. The compound of claim 1 which is
6b-methyl-1,2,6b,7,8,9,10,10a-octahyd-
ro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole; or a pharmaceutically
acceptable salt thereof.
35. The compound of claim 1 which is
5-(2,4-dichlorophenyl)-10a-methyl-1,2-
,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole;
5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazi-
no[2,3,4-hi]pyrido[4,3-b]indole;
5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7-
,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole;
5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazin-
o[2,3,4-hi]pyrido[4,3-b]indole;
5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7-
,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole;
5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-
-b][1,4]thiazino[2,3,4-hi]indole;
5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,-
7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole;
or
5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3--
b][[1,4]thiazino[2,3,4-hi]indole; or a pharmaceutically acceptable
salt thereof.
36. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable excipient.
37. A compound of claim 1 for use in medical diagnosis or
therapy.
38. The compound of claim 37, wherein the therapy is the treatment
of a disease or disorder of the central nervous system.
39. The compound of claim 37, wherein the therapy is the treatment
of anxiety, obesity, depression, or a stress related disease.
40. The use of a compound of claim 1 to prepare a medicament for
treating or preventing a disease or disorder of the central nervous
system.
41. The use of claim 40, wherein the disease or disorder of the
central nervous system is anxiety, obesity, depression, or a stress
related disease.
42. A method for treating a disease or condition in a mammal in
need thereof wherein the 5-HT receptor is implicated and modulation
of 5-HT function is desired comprising administering a
therapeutically effective amount of a compound of claim 1 to the
mammal.
43. The method of claim 42, wherein the disease is anxiety,
obesity, depression, or a stress related disease.
44. A method for treating or preventing a disease or disorder of
the central nervous system in a mammal in need thereof comprising
administering a therapeutically effective amount of a compound of
claim 1 to the mammal.
45. A compound of Formula (II): 16wherein Z is --CHR.sup.9--,
--C(O)--, --O--, --S--, --S(O)--, --SO.sub.2--, --N(R.sup.9)--,
--C(O)N(R.sup.9)--, or --N(R.sup.9)C(O)--; l is 1 or 2; m is 0, 1
or 2; n is 1 or 2; R.sup.1 and R.sup.2 are each independently
hydrogen, C.sub.1-6alkyl, C.sub.3-6cycloalkyl, or
(C.sub.3-6cycloalkyl)C.sub.1-6alkyl; provided that R.sup.1 and
R.sup.2 are not both hydrogen; R.sup.3 is --C(O)-aryl,
--C(O)-heteroaryl, --C(O)--C.sub.1-6alkyl,
--C(O)--C.sub.1-6haloalkyl, --C(O)O--C.sub.1-6alkyl, or
--C(O)O--C.sub.1-6haloalkyl, where aryl or heteroaryl is optionally
substituted with one or two halo, --CF.sub.3, --OCF.sub.3,
C.sub.1-6alkoxy, --N(R.sup.10).sub.2, or --C.sub.1-6alkyl; R.sup.4,
R.sup.5, and R.sup.9 are independently hydrogen, C.sub.1-6alkyl or
arylC.sub.1-6alkylene; R.sup.6, R.sup.7, and R.sup.8 are
independently hydrogen, fluoro, chloro, bromo, CF.sub.3,
--OCF.sub.3, --N(R.sup.10).sub.2, C.sub.1-6alkyl, C.sub.1-6alkoxy,
heteroaryl or aryl; each R.sup.10 is independently hydrogen, or
--C.sub.1-6alkyl; wherein any C.sub.1-6alkyl, C.sub.1-6alkylene, or
C.sub.1-6alkoxy of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, and R.sup.10 is optionally
partially unsaturated; wherein any heteroaryl or aryl is optionally
substituted with one or two substituents independently selected
from halo, --CF.sub.3, --OCF.sub.3, C.sub.1-6alkoxy,
--N(R.sup.10).sub.2, and C.sub.1-6alkyl.
46. The compound of claim 45 which is tert-Butyl
6b-methyl-1,2,6b,9,10,10a-
-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate;
tert-butyl-5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydr-
o[l,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate;
tert-butyl-5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydr-
o[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(H)-carboxylate;
tert-butyl-5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro-
[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-.8(7H)-carboxylate;
tert-butyl-5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro-
[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate;
tert-butyl-5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydr-
opyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate;
tert-butyl-5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydr-
opyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate;
tert-butyl-5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro-
pyrido[4,3-b][l,4]thiazino[2,3,4-hi]indole-8(7H)-carboxlate; or
tert-butyl-5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro-
pyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole.
47. The compound of claim 46, which is tert-butyl
6b-methyl-1,2,6b,9,10,10-
a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application Serial No. 60/310331 filed on 06 Aug. 2001, under 35
USC 119(e)(i), which is incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention provides tricyclic
hexahydroazepinoindole and indoline derivatives, and more
specifically, provides compounds of Formula (I) described
hereinbelow. These compounds are 5-HT ligands, and are useful for
treating diseases wherein modulation of 5-HT activity is
desired.
BACKGROUND OF THE INVENTION
[0003] Serotonin has been implicated in a number of diseases and
conditions that originate in the central nervous system. These
include diseases and conditions related to sleeping, eating,
perceiving pain, controlling body temperature, controlling blood
pressure, depression, anxiety, schizophrenia, and other bodily
states. R. W. Fuller, Biology of Serotonergic Transmission, ed.
Neville V. Osborne, John Wiley and Sons (1982), p 221; D. J.
Boullin, Serotonin in Mental Abnormalities 1, John Wiley and Sons
(1978), p. 316; J. Barchas, et al., Serotonin and Behavior,
Academic Press, New York, N.Y. (1973). Serotonin also plays an
important role in peripheral systems, such as the gastrointestinal
system, where it has been found to mediate a variety of
contractile, secretory, and electrophysiologic effects.
[0004] As a result of the broad distribution of serotonin within
the body, there is a tremendous interest in drugs that affect
serotonergic systems. In particular, receptor-specific agonists and
antagonists are of interest for the treatment of a wide range of
disorders, including anxiety, depression, hypertension, migraine,
obesity, compulsive disorders, schizophrenia, autism,
neurodegenerative disorders (e.g. Alzheimer's disease,
Parkinsonism, and Huntington's chorea), and chemotherapy-induced
vomiting. M. D. Gershon, et al., The Peripheral Actions of
5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al., Journal of
Cardiovascular Pharmacology, 15:Supplement 7 (1990).
[0005] The major classes of serotonin receptors (5-HT.sub.1-7)
contain fourteen to eighteen separate receptors that have been
formally classified. See Glennon, et al., Neuroscience and
Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol.
Rev. 1994, 46, 157-203. Recently discovered information regarding
subtype identity, distribution, structure, and function suggests
that it is possible to identify novel, subtype specific agents,
having improved therapeutic profiles (e.g. fewer side effects).
[0006] For example, the 5-HT.sub.2 family of receptors is comprised
of 5-HT.sub.2A, 5-HT.sub.2B, and 5-HT.sub.2C subtypes, which have
been grouped together on the basis of primary structure, secondary
messenger system, and operational profile. All three subtypes are
G-protein coupled, activate phospholipase C as a principal
transduction mechanism, and contain a seven-transmembrane domain
structure. There are distinct differences in the distribution of
the three 5-HT.sub.2 subtypes. The 5-HT.sub.2B and 5-HT.sub.2A
receptors are widely distributed in the periphery, while the
5-HT.sub.2C receptor has been found only in the central nervous
system, being highly expressed in many regions of the human brain.
See G. Baxter, et al. Trends in Pharmacol. Sci. 1995, 16,
105-110.
[0007] Subtype 5-HT.sub.2A has been associated with effects
including vasoconstriction, platelet aggregation, and
bronchoconstriction, while subtype 5-HT.sub.2C has been associated
with diseases that include depression, anxiety, obsessive
compulsive disorder, panic disorders, phobias, psychiatric
syndromes, and obesity. Very little is known about the
pharmacological role of the 5-HT.sub.2B receptor. See F. Jenck, et
al., Exp. Opin. Invest. Drugs, 1998, 7, 1587-1599; M. Bos, et al.,
J. Med. Chem., 1997, 40, 2762-2769; J. R. Martin, et al., The
Journal of Pharmacology and Experimental Therapeutics, 1998, 286,
913-924; S. M. Bromidge, et al., J. Med. Chem., 1998, 41 1598-1612;
G. A. Kennett, IDrugs, 1998, 1, 4, 456-470; and A. Dekeyne, et al.,
Neuropharmacology, 1999, 38, 415-423.
[0008] International Patent Applications WO 00/77001, WO 00/77002,
and WO 00/77010 disclose tetracyclic compounds that are reported to
possess activity as serotonin agonists and antagonists.
[0009] U.S. Pat. No. 4,438,120 discloses polycyclic compounds that
are reported to possess tranquilizer activity.
[0010] U.S. Pat. No. 4,219,550 discloses tetracyclic compounds that
are reported to possess tranquilizer and antidepressant
properties.
[0011] There is currently a need for pharmaceutical agents that are
useful to treat diseases and conditions that are associated with
5-HT receptors.
SUMMARY OF THE INVENTION
[0012] In accordance with the present invention, novel compounds
which demonstrate useful biological activity, and particularly
activity as 5-HT receptor ligands, are provided. Thus, the present
invention provides a compound of Formula (I): 2
[0013] wherein Z is --CHR.sup.9--, --C(O)--, --O--, --S--,
--S(O)--, --SO.sub.2--, --N(R.sup.9)--, --C(O)N(R.sup.9)--, or
--N(R.sup.9)C(O)--;
[0014] 1 is 1 or 2;
[0015] m is 0, 1 or 2;
[0016] n is 1 or 2;
[0017] R.sup.1 is hydrogen, C.sub.1-6alkyl, C.sub.3-6cycloalkyl, or
(C.sub.3-6cycloalkyl)C.sub.1-6alkyl; and R.sup.2 is hydrogen,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl, or
(C.sub.3-6cycloalkyl)C.sub.1-6alk- yl; provided that R.sup.1 and
R.sup.2 are not both hydrogen;
[0018] R.sup.3 is hydrogen or C.sub.1-6alkyl;
[0019] R.sup.4, R.sup.5 and R.sup.9 are independently hydrogen,
C.sub.1-6alkyl or arylC.sub.1-6alkylene;
[0020] R.sup.6, R.sup.7, and R.sup.8 are independently hydrogen,
fluoro, chloro, bromo, CF.sub.3, --OCF.sub.3, --N(R.sup.10).sub.2,
C.sub.1-6alkyl, C.sub.1-6alkoxy, heteroaryl or aryl; and
[0021] each R.sup.10 is independently hydrogen, or
--C.sub.1-6alkyl;
[0022] wherein any C.sub.1-6alkyl, C.sub.1-6alkylene, or
C.sub.1-6alkoxy of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, and R.sup.10 is optionally
partially unsaturated; and
[0023] wherein any heteroaryl or aryl is optionally substituted
with one or two halo, --CF.sub.3, --OCF.sub.3, C.sub.1-6alkoxy,
--N(R.sup.10).sub.2, or --C.sub.1-6alkyl;
[0024] or a pharmaceutically acceptable salt thereof.
[0025] In another aspect, the present invention also provides:
[0026] a pharmaceutical composition comprising a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient (the composition preferably
comprises a therapeutically effective amount of the compound or
salt),
[0027] a method for treating a disease or condition in a mammal
(e.g. a human) in need thereof wherein a 5-HT receptor is
implicated and modulation of a 5-HT function is desired comprising
administering a therapeutically effective amount of a compound of
Formula (I), or a pharmaceutically acceptable salt thereof to the
mammal,
[0028] a method for treating or preventing a disease or disorder of
the central nervous system in a mammal in need thereof comprising
administering a therapeutically effective amount of a compound of
Formula (I), or a pharmaceutically acceptable salt thereof to the
mammal,
[0029] a compound of Formula (I) or a pharmaceutically acceptable
salt thereof for use in medical diagnosis or therapy (e.g. the
treatment or prevention of 5-HT related disease such as anxiety,
obesity, depression, or a stress related disease),
[0030] the use of a compound of Formula (I), or a pharmaceutically
acceptable salt thereof to prepare a medicament useful for treating
or preventing a disease or disorder of the central nervous system
in a mammal in need thereof, and
[0031] a method for modulating 5-HT receptor function, comprising
administering an effective modulatory amount of a compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
[0032] The invention also provides novel intermediates of Formula
II and processes disclosed herein that are useful for preparing
compounds of Formula (I): 3
[0033] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, l, m, and n, have the definitions of
formula I and R.sup.3 is --C(O)-aryl, --C(O)-heteroaryl,
--C(O)--C.sub.1-6alkyl, --C(O)--C.sub.1-6haloalkyl,
--C(O)O--C.sub.1-6alkyl, or --C(O)O--C.sub.1-6haloalkyl, where aryl
or heteroaryl is optionally substituted with one or two halo,
--CF.sub.3, --OCF.sub.3, C.sub.1-6alkoxy, --N(R.sup.10).sub.2, or
--C.sub.1-6alkyl.
DETAILED DESCRIPTION OF THE INVENTION
[0034] The compounds of the invention are useful for treating or
preventing diseases or disorders of the central nervous system.
Specific diseases or disorders of the central nervous system for
which a compound of Formula (I) may have activity include, but are
not limited to: obesity, depression, schizophrenia,
schizophreniform disorder, schizoaffective disorder, delusional
disorder, a stress related disease (e.g. general anxiety disorder),
panic disorder, a phobia, obsessive compulsive disorder,
post-traumatic-stress syndrome, immune system depression, a stress
induced problem with the urinary, gastrointestinal or
cardiovascular system (e.g., stress incontinence),
neurodegenerative disorders, autism, chemotherapy-induced vomiting,
hypertension, migraine, headaches, cluster headaches, sexual
dysfunction in a mammal (e.g. a human), addictive disorder and
withdrawal syndrome, an adjustment disorder, an age-associated
learning and mental disorder, anorexia nervosa, apathy, an
attention-deficit disorder due to general medical conditions,
attention-deficit hyperactivity disorder, behavioral disturbance
(including agitation in conditions associated with diminished
cognition (e.g., dementia, mental retardation or delirium)),
bipolar disorder, bulimia nervosa, chronic fatigue syndrome,
conduct disorder, cyclothymic disorder, dysthymic disorder,
fibromyalgia and other somatoform disorders, generalized anxiety
disorder, an inhalation disorder, an intoxication disorder,
movement disorder (e.g., Huntington's disease or Tardive
Dyskinesia), oppositional defiant disorder, peripheral neuropathy,
post-traumatic stress disorder, premenstrual dysphoric disorder, a
psychotic disorder (brief and long duration disorders, psychotic
disorder due to medical condition, psychotic disorder NOS), mood
disorder (major depressive or bipolar disorder with psychotic
features) seasonal affective disorder, a sleep disorder, a specific
development disorder, agitation disorder, selective serotonin
reuptake inhibition (SSRI) "poop out" syndrome or a Tic disorder
(e.g., Tourette's syndrome).
[0035] The following definitions are used, unless otherwise
described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy,
etc. denote both straight and branched groups; but reference to an
individual radical such as "propyl" embraces only the straight
chain radical, a branched chain isomer such as "isopropyl" being
specifically referred to. Alkylene denotes a divalent straight or
branched alkyl (e.g. ethylene --CH.sub.2CH.sub.2--). When alkyl or
alkylene can be partially unsaturated, the alkyl chain may comprise
one or more (e.g. 1, 2, 3, or 4) double or triple bonds in the
chain.
[0036] Aryl denotes a phenyl radical or an ortho-fused bicyclic
carbocyclic radical having about nine to ten ring atoms in which at
least one ring is aromatic. Heteroaryl denotes a radical of a
monocyclic aromatic ring containing five or six ring atoms
consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected
from the group consisting of non-peroxide oxygen, sulfur, and N(X)
wherein X is absent or is H, O, C.sub.1-8alkyl, phenyl or benzyl,
as well as a radical of an ortho-fused bicyclic heterocycle of
about eight to ten ring atoms derived therefrom, particularly a
benz-derivative or one derived by fusing a propylene, trimethylene,
or tetramethylene diradical thereto.
[0037] It will be appreciated by those skilled in the art that
compounds of the invention having a chiral center may exist in and
be isolated in optically active and racemic forms. Some compounds
may exhibit polymorphism. It is to be understood that the present
invention encompasses any racemic, optically-active, polymorphic,
tautomeric, or stereoisomeric form, or mixture thereof, of a
compound of the invention, which possesses the useful properties
described herein, it being well known in the art how to prepare
optically active forms (for example, by resolution of the racemic
form by recrystallization techniques, by synthesis from
optically-active starting materials, by chiral synthesis, or by
chromatographic separation using a chiral stationary phase) and how
to determine 5-HT activity using the standard tests which are well
known in the art.
[0038] The carbon atom content of various hydrocarbon-containing
moieties is indicated by a prefix designating the minimum and
maximum number of carbon atoms in the moiety, i.e., the prefix
C.sub.i-j indicates a moiety of the integer "i" to the integer "j"
carbon atoms, inclusive. Thus, for example, C.sub.1-8alkyl refers
to alkyl of one to eight carbon atoms, inclusive.
[0039] The compounds of the present invention are generally named
according to the IUPAC or CAS nomenclature system. Abbreviations
which are well known to one of ordinary skill in the art may be
used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h"
for hour or hours and "rt" for room temperature).
[0040] Specific and preferred values listed below for radicals,
substituents, and ranges, are for illustration only; they do not
exclude other defined values or other values within defined ranges
for the radicals and substituents.
[0041] Specifically, C.sub.1-6alkyl can be methyl, ethyl, propyl,
isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
C.sub.1-6alkoxy can be methoxy, ethoxy, propoxy, isopropoxy,
butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be
furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl,
thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl,
pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide),
indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its
N-oxide).
[0042] A specific value for Z is --CHR.sup.9--, --C(O)--, --O--,
--S--, --S(O)--, --SO.sub.2--, or --N(R.sup.9)--.
[0043] A specific value for Z is --CHR.sup.9--, --C(O)--, --S--, or
--O--.
[0044] A specific value for Z is --O--.
[0045] A specific value for R.sup.1 is hydrogen.
[0046] A specific value for R.sup.1 is C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl)C.sub.1-6alkyl.
[0047] A specific value for R.sup.1 is C.sub.2-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl)C.sub.1-6alkyl.
[0048] A specific value for R.sup.1 is C.sub.3-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl)C.sub.1-6alkyl.
[0049] A specific value for R.sup.1 is methyl, ethyl, propyl,
isopropyl, or cyclopropylmethyl.
[0050] A specific value for R.sup.1 is ethyl, propyl, isopropyl, or
cyclopropylmethyl.
[0051] A specific value for R.sup.1 is propyl, isopropyl, or
cyclopropylmethyl.
[0052] A specific value for R.sup.1 is ethyl or propyl.
[0053] A specific value for R.sup.1 is C.sub.2-3alkyl.
[0054] A specific value for R.sup.2 is hydrogen.
[0055] A specific value for R.sup.2 is C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl)C.sub.1-6alkyl.
[0056] A specific value for R.sup.2 is C.sub.2-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl) C.sub.1-6alkyl.
[0057] A specific value for R.sup.2 is C.sub.3-6alkyl,
C.sub.3-6cycloalkyl, or (C.sub.3-6cycloalkyl) C.sub.1-6alkyl.
[0058] A specific value for R.sup.2 is methyl, ethyl, propyl,
isopropyl, or cyclopropylmethyl.
[0059] A specific value for R is ethyl, propyl, isopropyl, or
cyclopropylmethyl.
[0060] A specific value for R.sup.2 is propyl, isopropyl, or
cyclopropylmethyl.
[0061] A specific value for R.sup.2 is ethyl, propyl or butyl.
[0062] A specific value for R.sup.2 is arylC.sub.1-8alkylene.
[0063] A specific value for R.sup.2 is C.sub.2-6alkyl.
[0064] A specific compound of Formula (I) is a compound wherein
R.sup.1 is hydrogen, and wherein R.sup.2has any of the specific or
preferred valued described herein.
[0065] A specific value for R.sup.3 is hydrogen.
[0066] A specific value for R.sup.3 is C.sub.1-6alkyl.
[0067] A specific value for R.sup.3 is methyl, ethyl, propyl or
butyl.
[0068] A more specific value for R.sup.3 is methyl or ethyl.
[0069] A specific value for R.sup.4 is hydrogen, methyl, ethyl,
propyl, butyl, 2-phenylethyl or benzyl.
[0070] A specific value for R.sup.4 is hydrogen, methyl, ethyl,
propyl or benzyl.
[0071] A specific value for R.sup.4 is methyl, ethyl or benzyl.
[0072] A specific value for R.sup.5 is hydrogen, methyl, ethyl,
propyl, butyl, 2-phenylethyl or benzyl.
[0073] A specific value for R.sup.5 is hydrogen, methyl, ethyl,
propyl or benzyl.
[0074] A specific value for R.sup.5 is methyl, ethyl or benzyl.
[0075] A specific value for R.sup.6, R.sup.7, or R.sup.8 is phenyl
optionally substituted with one or two substituents independently
selected from fluoro, chloro, bromo, --CF.sub.3, --OCF.sub.3,
C.sub.1-6alkoxy, --N(R.sup.10).sub.2, and C.sub.1-6alkyl.
[0076] A specific value for R.sup.6 is phenyl optionally
substituted with one or two substituents independently selected
from fluoro, chloro, bromo, --CF.sub.3,--OCF.sub.3,
C.sub.1-6alkoxy, --N(R.sup.10).sub.2, and C.sub.1-6alkyl.
[0077] A specific value for R.sup.7 is phenyl optionally
substituted with one or two substituents independently selected
from fluoro, chloro, bromo, --CF.sub.3, --OCF.sub.3,
C.sub.1-6alkoxy, --N(R.sup.10).sub.2, and C.sub.1-6alkyl.
[0078] A specific value for R.sup.8 is phenyl optionally
substituted with one or two substituents independently selected
from fluoro, chloro, bromo, --CF.sub.3, --OCF.sub.3,
C.sub.1-6alkoxy, --N(R.sup.10).sub.2, and C.sub.1-6alkyl.
[0079] A specific value for R.sup.6is 2,4-dichlorophenyl or
2,6-difluorophenyl.
[0080] A specific value for R.sup.7 is 2,4-dichlorophenyl or
2,6-difluorophenyl.
[0081] A specific value for R.sup.8 is 2,4-dichlorophenyl or
2,6-difluorophenyl.
[0082] Another aspect of the present invention is where R.sup.1 is
H, and R.sup.2 is alkyl. Another aspect of the present invention is
where R.sup.1 is alkyl, and R.sup.2 is H. Another aspect of the
present invention is where each R.sup.1 and R.sup.2 are alkyl.
[0083] Specifically, the invention also provides a method for
treating or preventing anxiety, obesity, depression, schizophrenia,
a stress related disease (e.g. general anxiety disorder), panic
disorder, a phobia, obsessive compulsive disorder,
post-traumatic-stress syndrome, immune system depression, a stress
induced problem with the gastrointestinal or cardiovascular system,
or sexual dysfunction in a mammal (e.g. a human) in need thereof
comprising administering a therapeutically effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof to the mammal.
[0084] Specifically, the invention also provides a method of
treating or preventing anxiety, obesity, depression, or a stress
related disease, comprising administering to a mammal (e.g. a
human) in need of such treatment, a therapeutically effective
amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof.
[0085] Specifically, the invention also provides the use of a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof to prepare a medicament for treating or preventing anxiety,
obesity, depression, schizophrenia, a stress related disease (e.g.
general anxiety disorder), panic disorder, a phobia, obsessive
compulsive disorder, post-traumatic-stress syndrome, immune system
depression, a stress induced problem with the gastrointestinal or
cardiovascular system, or sexual dysfunction in a mammal (e.g. a
human) in need thereof.
[0086] Specifically, the invention also provides the use of a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof to prepare a medicament for treating or preventing anxiety,
obesity, depression, or a stress related disease in a mammal (e.g.
a human) in need thereof.
[0087] The invention also provides a method for preparing a
compound of Formula (I) wherein R.sup.3 is hydrogen comprising
deprotecting a corresponding compound of Formula (I) wherein
R.sup.3 is a suitable nitrogen protecting group.
[0088] Compounds of the invention can generally be prepared using
the synthetic methods illustrated in Scheme 1. Starting materials
can be prepared by procedures described herein or by procedures
that would be well known to one of ordinary skill in organic
chemistry. The variables used in the Scheme are as defined below or
as in the claims.
[0089] The secondary amino group of a suitably substituted
4-piperidone hydrochloride, monohydrate I-1 [J Hamon, F Espaze, J
Vignon, J-M Kamenka, Eur. J. Med. Chem. 34 125-35 (1999)] is
protected with an electron withdrawing protecting group, such as,
for example, a trifluoroacetyl group, in the presence of a base,
such as pyridine, in an appropriate solvent, such as
CH.sub.2Cl.sub.2, at room temperature to yield I-2. A G M Barrett,
J C A Lana, J. Chem. Soc., Chem. Com. 471 (1978). The N-protected
4-piperidone I-2 is reacted with a substituted hydrazine
hydrochloride I-3 in an appropriate solvent, such as 2-propanol, at
reflux to yield an intermediate N-alkylindolinine salt, which is in
turn reacted with an appropriate nucleophile, such as hydride,
derived from a reducing agent, such as NaBH.sub.4, or a Grignard
reagent, to yield indoline I-4. See for example A. Ebnoether, et
al., Helv. Chim. Acta 52 629-38 (1969). The protecting group of the
amino nitrogen is removed under appropriate conditions, such as,
for example, treatment with a basic reagent, such as NaOH, in an
appropriate solvent, such as 1:1 THF:H.sub.2O, at room temperature.
The amino nitrogen is reprotected with a protecting group, such as,
for example, a tert-butoxy carbonyl group, in the presence of a
base, such as, for example, NaOH, in an appropriate solvent, such
as, for example, 1:1 THF:H.sub.2O to yield indoline I-5. Depending
upon the nature of amino nitrogen protecting group, it may be
unnecessary to carry out this protecting group (I4.fwdarw.I5)
exchange. Indoline I-5 is halogenated with a halogenating agent,
such as bromine, in an appropriate solvent, such as chloroform, to
yield the halogenated indoline I-6. [See for example, the procedure
in WO 0077010 A2] Indoline I-6 is coupled with an appropriate aryl
boronic acid in the presence of an appropriate catalyst, such as
dichlorobis(triphenylphosphine)-palladiu- m(II), and an appropriate
base, such as 2N Na.sub.2CO.sub.3, in an appropriate solvent, such
as benzene, to yield indoline I-7. N Miyaura, A Suzuki, Chem. Rev.
95 2457-83 (1995). Other types of coupling reactions, such as the
Stille reaction, may also be used to bring about formation of this
aryl-aryl bond. The protecting group on the amino nitrogen of
indoline I-7 is removed by treatment with an appropriate acid, such
as trifluoroacetic acid, in an appropriate solvent, such as
CH.sub.2Cl.sub.2, to yield amine I-8. 4
[0090] A substituted hydrazine hydrochloride II-1 and a
.gamma.-ketocarboxylic acid II-2 in an appropriate solvent, such as
2-propanol, at reflux are reacted to yield indole II-3 (Scheme 2).
M W Bullock, S W Fox, J. Am. Chem. Soc.73 5155-7 (1951). The indole
II-3 is treated with an oxidant, such as singlet oxygen, followed
by a mild reducing reagent, such as dimethyl sulfide, to prepare
rearrangement product II-4, which is in turn treated with a base,
such as 10% KOH in MeOH, to provide ketoacid II-5. M Ihara, K
Noguchi, K Fukumoto, T Kamatani, Tetrahedron 41 2109-14 (1985).
Ketoacid II-5 is condensed with an appropriate amine to yield amide
II-6. A Couture, E Deniau, P Woisel, P Grandclaudon, J F
Carpentier, Tetrahedron Lett. 37 3697-3700 (1996). Amide II-6 is
converted to olefin II-7 by means of an intramolecular Wittig
reaction and II-7 is in turn reduced by means of an appropriate
reagent, such as H.sub.2, Pd/C, to yield amide II-8. Amide II-8 is
treated with a suitable reducing agent, such as LAH, to yield amine
II-9. The benzyl protecting group of amine II-9 is removed under
suitable conditions, such as H.sub.2, Pd/C, and the resulting
secondary amine is protected with an appropriate protecting group,
such as the Boc group, under appropriate conditions, such as
(Boc).sub.2O, 1N KOH, EtOAc, to yield indoline II-10. II-10 is
converted to II-12 by essentially the same procedure as is
previously described for the conversion of I-5 to I-8. 5
[0091] In cases where compounds are sufficiently basic or acidic to
form stable nontoxic acid or base salts, administration of the
compounds as salts may be appropriate. Examples of pharmaceutically
acceptable salts are organic acid addition salts formed with acids
which form a physiological acceptable anion, for example, tosylate,
methanesulfonate, acetate, citrate, malonate, tartarate, succinate,
benzoate, ascorbate, .alpha.-ketoglutarate, and
.alpha.-glycerophosphate. Suitable inorganic salts may also be
formed, including hydrochloride, sulfate, nitrate, bicarbonate, and
carbonate salts.
[0092] Pharmaceutically acceptable salts may be obtained using
standard procedures well known in the art, for example by reacting
a sufficiently basic compound such as an amine with a suitable acid
affording a physiologically acceptable anion. Alkali metal (for
example, sodium, potassium or lithium) or alkaline earth metal (for
example calcium) salts of carboxylic acids can also be made.
[0093] Compounds of the present invention can conveniently be
administered in a pharmaceutical composition containing the
compound in combination with a suitable excipient. Such
pharmaceutical compositions can be prepared by methods and contain
excipients which are well known in the art. A generally recognized
compendium of such methods and ingredients is Remington's
Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th Ed.,
1975). The compounds and compositions of the present invention can
be administered parenterally (for example, by intravenous,
intraperitoneal or intramuscular injection), topically, orally, or
rectally.
[0094] For oral therapeutic administration, the active compound may
be combined with one or more excipients and used in the form of
ingestible tablets, buccal tablets, troches, capsules, elixirs,
suspensions, syrups, wafers, and the like. Such compositions and
preparations should contain at least 0.1% of active compound. The
percentage of the compositions and preparations may, of course, be
varied and may conveniently be between about 2 to about 60% of the
weight of a given unit dosage form. The amount of active compound
in such therapeutically useful compositions is such that an
effective dosage level will be obtained.
[0095] The tablets, troches, pills, capsules, and the like may also
contain the following: binders such as gum tragacanth, acacia, corn
starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, fructose, lactose or aspartame or
a flavoring agent such as peppermint, oil of wintergreen, or cherry
flavoring may be added. When the unit dosage form is a capsule, it
may contain, in addition to materials of the above type, a liquid
carrier, such as a vegetable oil or a polyethylene glycol. Various
other materials may be present as coatings or to otherwise modify
the physical form of the solid unit dosage form. For instance,
tablets, pills, or capsules may be coated with gelatin, wax,
shellac or sugar and the like. A syrup or elixir may contain the
active compound, sucrose or fructose as a sweetening agent, methyl
and propylparabens as preservatives, a dye and flavoring such as
cherry or orange flavor. Of course, any material used in preparing
any unit dosage form should be pharmaceutically acceptable and
substantially non-toxic in the amounts employed. In addition, the
active compound may be incorporated into sustained-release
preparations and devices.
[0096] The compounds or compositions can also be administered
intravenously or intraperitoneally by infusion or injection.
Solutions of the active compound or its salts can be prepared in
water, optionally mixed with a nontoxic surfactant. Dispersions can
also be prepared in glycerol, liquid polyethylene glycols,
triacetin, and mixtures thereof and in oils. Under ordinary
conditions of storage and use, these preparations contain a
preservative to prevent the growth of microorganisms.
[0097] Pharmaceutical dosage forms suitable for injection or
infusion can include sterile aqueous solutions or dispersions or
sterile powders comprising the active ingredient which are adapted
for the extemporaneous preparation of sterile injectable or
infusible solutions or dispersions, optionally encapsulated in
liposomes. In all cases, the ultimate dosage form should be
sterile, fluid and stable under the conditions of manufacture and
storage. The liquid carrier or vehicle can be a solvent or liquid
dispersion medium comprising, for example, water, ethanol, a polyol
(for example, glycerol, propylene glycol, liquid polyethylene
glycols, and the like), vegetable oils, nontoxic glyceryl esters,
and suitable mixtures thereof. The proper fluidity can be
maintained, for example, by the formation of liposomes, by the
maintenance of the required particle size in the case of
dispersions or by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many cases, it will be preferable to include isotonic agents, for
example, sugars, buffers or sodium chloride. Prolonged absorption
of the injectable compositions can be brought about by the use in
the compositions of agents delaying absorption, for example,
aluminum monostearate and gelatin.
[0098] Sterile injectable solutions can be prepared by
incorporating the active compound in the required amount in the
appropriate solvent with various of the other ingredients
enumerated above, as required, followed by filter sterilization. In
the case of sterile powders for the preparation of sterile
injectable solutions, the preferred methods of preparation are
vacuum drying and the freeze drying techniques, which yield a
powder of the active ingredient plus any additional desired
ingredient present in the previously sterile-filtered
solutions.
[0099] For topical administration, the present compounds may be
applied in pure form, i.e., when they are liquids. However, it will
generally be desirable to administer them to the skin as
compositions or formulations, in combination with a
dermatologically acceptable carrier, which may be a solid or a
liquid.
[0100] Useful solid carriers include finely divided solids such as
talc, clay, microcrystalline cellulose, silica, alumina and the
like. Useful liquid carriers include water, alcohols or glycols or
water-alcohol/glycol blends, in which the present compounds can be
dissolved or dispersed at effective levels, optionally with the aid
of non-toxic surfactants. Adjuvants such as fragrances and
additional antimicrobial agents can be added to optimize the
properties for a given use. The resultant liquid compositions can
be applied from absorbent pads, used to impregnate bandages and
other dressings, or sprayed onto the affected area using pump-type
or aerosol sprayers. Thickeners such as synthetic polymers, fatty
acids, fatty acid salts and esters, fatty alcohols, modified
celluloses or modified mineral materials can also be employed with
liquid carriers to form spreadable pastes, gels, ointments, soaps,
and the like, for application directly to the skin of the user.
[0101] Useful dosages of the compounds of Formula (I) can be
determined by comparing their in vitro activity, and in vivo
activity in animal models. Methods for the extrapolation of
effective dosages in mice, and other animals, to humans are known
to the art; for example, see U.S. Pat. No. 4,938,949.
[0102] The compound is conveniently administered in unit dosage
form; for example, containing about 0.05 mg to about 500 mg,
conveniently about 0.1 mg to about 250 mg, most conveniently, about
1 mg to about 150 mg of active ingredient per unit dosage form. The
desired dose may conveniently be presented in a single dose or as
divided doses administered at appropriate intervals, for example,
as two, three, four or more sub-doses per day. The sub-dose itself
may be further divided, e.g., into a number of discrete loosely
spaced administrations.
[0103] The compositions can conveniently be administered orally,
sublingually, transdermally, or parenterally at dose levels of
about 0.01 to about 150 mg/kg, preferably about 0.1 to about 50
mg/kg, and more preferably about 0.1 to about 10 mg/kg of mammal
body weight.
[0104] For parenteral administration the compounds are presented in
aqueous solution in a concentration of from about 0.1 to about 10%,
more preferably about 0.1 to about 7%. The solution may contain
other ingredients, such as emulsifiers, antioxidants or
buffers.
[0105] The exact regimen for administration of the compounds and
compositions disclosed herein will necessarily be dependent upon
the needs of the individual subject being treated, the type of
treatment and, of course, the judgment of the attending
practitioner.
[0106] The ability of a compound of the invention to act as a 5-HT
receptor agonist or antagonist can also be determined using in
vitro and in vivo assays that are known in the art. The invention
provides compounds of Formula (I) that act as either agonists or as
antagonists of one or more 5-HT receptor subtypes. The compounds of
the invention are 5-HT ligands, which typically displace >50% of
a radiolabeled test ligand from one or more 5-HT receptor subtype
at a concentration of 1 .mu.M. The procedures used for testing such
displacement are well known and would be readily available to one
skilled in the art. For example, see L. W. Fitzgerald et al., Mol.
Pharmacol, 2000, 57, 1, 75-81; and D. B. Wainscott, et al., J.
Pharmacol Exp Ther, 1996, 276, 2, 720-727.
DESCRIPTION OF PREFERRED EMBODIMENTS
Preparation 1:
Preparation of 1-Trifluoroacetyl-3-methylpiperidin-4-one
[0107] 3-Methyl-4-piperidone hydrochloride (1.00 g, 6.68 mmol) was
suspended in CH.sub.2Cl.sub.2 (50 mL) and stirred at room
temperature under N.sub.2. Pyridine (1.35 mL, 16.7 mmol) was added
to the reaction mixture followed by trifluoroacetic anhydride (1.13
mL, 8.02 mmol). The reaction mixture was stirred at room
temperature for 1.5 hours. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (50 mL) and washed with 5% aqueous NaHCO.sub.3
(1.times.25 mL), 10% citric acid (1.times.25 mL) and water
(1.times.25 mL). The organic phase was dried over Na.sub.2SO.sub.4,
filtered and concentrated to yield
1-trifluoroacetyl-3-methylpiperidin-4-one (1.33 g) in 95% yield. MS
(ESI+) for C.sub.8H.sub.10F.sub.3NO.sub.2 m/z 210.1
(M+H).sup.+.
Preparation 2:
Preparation of
8-Trifluoroacetyl-6b-methyl-1,2,6b,7,8,9,10,10a-octahydro[1-
,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole
[0108] 2,3-Dihydro-4H-1,4-benzoxazin-4-amine hydrochloride (0.0830
g, 0.444 mmol) and 1-trifluoroacetyl-3-methylpiperidin-4-one
(0.0929 g, 0.444 mmol) were combined in 2-propanol (3.75 mL) and
stirred at reflux for 3.75 hours under N.sub.2. The reaction
mixture was cooled to room temperature, NaBH.sub.4 (0.0523 g, 1.38
mmol) was added and the reaction mixture was refluxed for 1 hour
under N.sub.2. The cooled reaction mixture was quenched with
CH.sub.3OH (2 mL) and partitioned between CH.sub.2Cl.sub.2 and
H.sub.2O. The layers were separated and the aqueous layer was
extracted with CH.sub.2Cl.sub.2. The combined CH.sub.2Cl.sub.2
extracts were washed with H.sub.2O, dried over Na.sub.2SO.sub.4,
filtered and concentrated to yield crude
8-trifluoroacetyl-6b-methyl-1,2,6b,7,8,9,-
10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (0.130
g). MS (ESI+) for C.sub.16H.sub.17F.sub.3N.sub.2O.sub.2 m/z 327.0
(M+H).sup.+.
Preparation 3:
Preparation of tert-Butyl
6b-methyl-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[-
2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate
[0109]
8-Trifluoroacetyl-6b-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazi-
no[2,3,4-hi]pyrido[4,3-b]indole and NaOH (0.209 g, 5.23 mmol) were
dissolved in a mixture of THF (5 mL) and H.sub.2O (5 mL). The
resulting mixture was stirred vigorously for 4 hours. Di-tert-butyl
dicarbonate (0.463 g, 2.12 mmol) was added in two separate portions
and the reaction mixture was stirred at room temperature for 40
hours. The reaction mixture was concentrated and the residue was
partitioned between EtOAc (25 mL) and H.sub.2O (25 mL). The layers
were separated and the aqueous layer was extracted with EtOAc (25
mL). The combined organic layers were washed with brine (15 mL),
dried over MgSO.sub.4, filtered and concentrated to yield a crude
product (0.168 g), which was purified by chromatography (SiO.sub.2
20 g, eluted with 1:1 heptane:Et.sub.2O) tert-butyl
6b-methyl-1,2,6b,9,10,10a-hexahydro[1,4]-oxazino[2,3,4-hi]pyri-
do[4,3-b]indole-8(7H)-carboxylate (0.0841 g) in 57% overall yield
from 2,3-dihydro-4H-1,4-benzoxazin-4-amine hydrochloride and
1-trifluoroacetyl-3-methylpiperidin-4-one. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 1.35(s, 3 H), 1.49(s, 9 H), 1.81-1.89(m,1 H),
1.93-1.98(m, 1 H), 2.70(ddd, J=11,10,3.3 Hz, 1 H), 2.80-3.06(br m,
1 H), 2.94(br s, 1 H), 3.11-3.22(br m, 1 H),
3.41(ddd,J=11.0,2.2,2.2 Hz, 1 H), 3.70-3.87(br m, 1 H), 3.90(br d,
J=10.9 Hz, 1 H), 4.41(ddd,J=11,10,2.3 Hz, 1 H), 4.45(ddd,J=11,3,2
Hz, 1 H), 6.56(dd,J=5,4 Hz, 1 H), 6.66(d,J=5 Hz, 1 H), 6.66(d,J=4
Hz, 1 H); MS (ESI+) for C.sub.19H.sub.26N.sub.2O.sub- .3 m/z 331.0
(M+H).sup.+.
[0110] Using synthetic procedures similar to those described
herein, the following compounds of Formula (II) can also be
prepared.
[0111] tert-Butyl
6b-methyl-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi-
]pyrido[4,3-b]indole-8(7H)-carboxylate;
[0112]
tert-butyl-5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-oc-
tahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate;
[0113]
tert-butyl-5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-oc-
tahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(H)-carboxylate;
[0114]
tert-butyl-5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-oct-
ahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate;
[0115]
tert-butyl-5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-oct-
ahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate;
[0116]
tert-butyl-5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-oc-
tahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate;
[0117]
tert-butyl-5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-oc-
tahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate;
[0118]
tert-butyl-5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-oct-
ahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxlate;
or
[0119]
tert-butyl-5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-oct-
ahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole.
EXAMPLE 1
Preparation of
6b-Methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-h-
i]pyrido[4,3-b]indole
[0120] 6
[0121] tert-Butyl
6b-methyl-1,2,6b,9,10,10a-hexahydro[1,4]-oxazino[2,3,4-h-
i]pyrido[4,3-b]indole-8(7H)-carboxylate (0.0711 g, 0.215 mmol) was
dissolved in CH.sub.2Cl.sub.2 (2 mL). Trifluoroacetic acid (0.50
mL, 0.46 mmol) was added and the reaction mixture was stirred in a
sealed reaction vessel for 4 hours at room temperature. The
reaction mixture was cooled in an ice bath and 1N aqueous NaOH (15
mL) was added and the resulting mixture was extracted with
CH.sub.2Cl.sub.2 (2.times.25 mL) and 25:1
CH.sub.2Cl.sub.2:CH.sub.3OH (1.times.26 mL). The combined organic
extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated to yield a crude product (0.0464 g), which was
purified by chromatography (SiO.sub.2 10 g, eluted with 90:10:1
CH.sub.2Cl.sub.2:CH.sub.3OH:concentr- ated aqueous NH.sub.4OH) to
yield 6b-methyl-1,2,6b,7,8,9,10,10a-octahydro[-
1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (0.0453 g) in 91% yield.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.42 (s, 3 H), 1.78-1.87
(m, 1 H), 1.90-1.96 (m, 1 H), 2.68 (ddd, J=10.8, 9.5, 3.5 Hz, 1 H),
2.71 (d, J=13.3 Hz, 1H), 2.74 (d, J=13.3 Hz, 1 H), 2.81-2.94 (m, 3
H) 3.40 (ddd, J=11.0, 2.1, 2.1 Hz, 1 H), 4.37-4.47 (m,2H), 6.53
(dd, J=7.5, 1.7 Hz, 1 H), 6.59-6.65 (m, 2 H); 1.96 (m, 1 H MS
(ESI+) for C.sub.14H.sub.18N.sub.2O m/z 231.1 (M+H).sup.+.
[0122] Using synthetic procedures similar to those described
herein, the following compounds of Formula (I) can also be
prepared.
5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazin-
o[2,3,4-hi]pyrido[4,3-b]indole
[0123] 7
5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazin-
o[2,3,4-hi]pyrido[4,3-b]indole
[0124] 8
5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino-
[2,3,4-hi]pyrido[4,3-b]indole
[0125] 9
5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino-
[2,3,4-hi]pyrido[4,3-b]indole
[0126] 10
5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3--
b][1,4]thiazino[2,3,4-hi]indole
[0127] 11
5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3--
b][1,4]thiazino[2,3,4-hi]indole
[0128] 12
5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b-
][1,4]thiazino[2,3,4-hi]indole
[0129] 13
5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b-
][1,4]thiazino[2,3,4-hi]indole
[0130] 14
[0131] The invention has been described with reference to various
specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications may be
made while remaining within the spirit and scope of the
invention.
* * * * *