Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-15
2003-04-15
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212060, C514S214020, C514S214030, C514S286000, C514S288000, C540S472000, C540S556000, C546S063000, C548S421000, C548S424000, C548S425000
Reexamination Certificate
active
06548493
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to certain novel compounds represented by structural Formula (I)
or pharmaceutically acceptable salt forms thereof, wherein R
1
, R
5
, R
6a
, R
6b
, R
7
, R
8
, R
9
, X, b, k, m, and n, and the dashed lines are described herein. The invention is also concerned with pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders. The compounds of this invention are serotonin agonists and antagonists and are useful in the control or prevention of central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.
BACKGROUND OF THE INVENTION
There exists a substantial correlation for the relationship between 5-HT2 receptor modulation and a variety of diseases and therapies. To date, three subtypes of the 5-HT2 receptor class have been identified, 5-HT2A, 5-HT2B, and 5-HT2C. Prior to the early 1990's the 5-HT2C and 5-HT2A receptors were referred to as 5-HT1C and 5-HT2, respectively.
The agonism or antagonism of 5-HT2 receptors, either selectively or nonselectively, has been associated with the treatment of various central nervous system (CNS) disorders. Ligands possessing affinity for the 5-HT2 receptors have been shown to have numerous physiological and behavioral effects (Trends in Pharmacological Sciences, 11, 181, 1990). In the recent past the contribution of serotonergic activity to the mode of action of antidepressant drugs has been well documented. Compounds that increase the overall basal tone of serotonin in the CNS have been successfully developed as antidepressants. The serotonin selective reuptake inhibitors (SSRI) function by increasing the amount of serotonin present in the nerve synapse. These breakthrough treatments, however, are not without side effects and suffer from delayed onset of action (Leonard, J. Clin. Psychiatry, 54(suppl), 3, 1993). Due to the mechanism of action of the SSRIs, they effect the activity of a number of serotonin receptor subtypes. This non-specific modulation of the serotonin family of receptors most likely plays a significant role in the side effect profile. In addition, these compounds often have a high affinity for a number of the serotonin receptors as well as a multitude of other monoamine neurotransmitters and nuisance receptors. Removing some of the receptor cross reactivity would allow for the examination and possible development of potent therapeutic ligands with an improved side effect profile.
There is ample evidence to support the role of selective 5-HT2 receptor ligands in a number of disease therapies. Modulation of 5-HT2 receptors has been associated with the treatment of schizophrenia and psychoses (Ugedo, L., et.al., Psychopharmacology, 98, 45, 1989). Mood, behavior and hallucinogenesis can be affected by 5-HT2 receptors in the limbic system and cerebral cortex. 5-HT2 receptor modulation in the hypothalamus can influence appetite, thermoregulation, sleep, sexual behavior, motor activity, and neuroendocrine function (Hartig, P., et.al., Annals New York Academy of Science, 149, 159). There is also evidence indicating that 5-HT2 receptors mediate hypoactivity, effect feeding in rats, and mediate penile erections (Pyschopharmacology, 101, 57, 1990).
Compounds exhibiting selectivity for the 5-HT2B receptor are useful in treating conditions such as tachygastria, hypermotility associated with irritable bowel disorder, constipation, dyspepsia, and other peripherally mediated conditions.
5-HT2A antagonists have been shown to be effective in the treatment of schizophrenia, anxiety, depression, and migraines (Koek, W., Neuroscience and Behavioral reviews, 16, 95, 1996). Aside from the beneficial antipsychotic effects, classical neuroleptic are frequently responsible for eliciting acute extrapyramidal side effects and neuroendocrine disturbances. These compounds generally possess significant dopamine D2 receptor affinity (as well as other nuisance receptor affinity) which frequently is associated with extra pyramidal symptoms and tardive dyskinesia, thus detracting from their efficacy as front line treatments in schizophrenia and related disorders. Compounds possessing a more favorable selectivity profile would represent a possible improvement for the treatment of CNS disorders.
U.S. Pat. Nos. 3,914,421; 4,013,652; 4,115,577; 4,183,936; and 4,238,607 disclose pyridopyrrolobenzheterocycles of formula:
where X is O, S, S (═O) or SO
2
; n is 0 or 1; R
1
is various carbon substituents, and Z is a monosubstituent of H, methyl, or chloro.
U.S. Pat. No. 4,219,550 discloses pyridopyrrolobenzheterocycles of formula:
where X is O or S; R
1
is C
1-4
alkyl or cyclopropyl; R
2
is H, CH
3
, OCH
3
, Cl, Br, F, or CF
3
; and (A) is —CH
2
—, —CH(CH
3
)—, or —CH
2
CH
2
—.
SUMMARY OF THE INVENTION
One object of the present invention is to provide novel compounds which are useful as agonists or antagonists of 5-HT2 receptors, more specifically 5-HT2A and 5-HT2C receptors, or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep and sexual disorders, migraine and other conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof. More specifically, the present invention provides a method for treating obesity anxiety, depression, or schizophrenia.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of Formula (I):
or pharmaceutically acceptable salt or prodrug forms thereof, wherein R
1
, R
5
, R
6a
, R
6b
, R
7
, R
8
, R
9
, X, b, k, m, and n are defined below, are effective agonists or antagonists of 5-HT2 receptors.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Thus, in a first embodiment, the present invention provides a novel compound of Formula (I):
or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein:
b is a single bond or a double bond;
X is —CHR
10
—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)
2
—, —NR
10A
—, —C(═O) NR
10A
—, or —NR
10A
C (═O)—;
R
1
is selected from
H,
C(═O)R
2
,
C(═O)OR
2
,
C
1-8
alkyl,
C
2-8
alkenyl,
C
2-8
alkynyl,
C
3-7
cycloalkyl,
C
1-6
alkyl substituted with Z,
C
2-6
alkenyl substituted with Z,
C
2-6
alkynyl substituted with Z,
C
3-6
cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C
1-3
alkyl substituted with Y,
C
2-3
alkenyl substituted with Y,
C
2-3
alkynyl substituted with Y,
C
1-6
alkyl substituted with 0-2 R
2
,
C
2-6
alkenyl substituted with 0-2 R
2
,
C
2-6
alkynyl substituted with 0-2 R
2
,
aryl substituted with 0-2 R
2
, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0-2 R
2
;
Y is selected from
C
3-6
cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered h
Calvello Emilie J. B.
Chen Wenting
Deng Wei
Lee Taekyu
McClung Christopher D.
Bristol-Myers Squibb Pharma Company
Kifle Bruck
Larsen Scott K.
O'Brien Maureen P.
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