Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-31
2003-02-04
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254090, C514S323000, C514S365000, C514S394000, C514S411000, C544S142000, C544S372000, C546S200000, C548S205000, C548S305100, C548S444000
Reexamination Certificate
active
06514968
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides aminoalkoxy carbazole derivatives, and more specifically, provides compounds of formula (I) described herein below. These compounds are 5-HT ligands, and are useful for treating diseases wherein modulation of 5-HT activity is desired.
BACKGROUND OF THE INVENTION
Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which 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, 221 (1982); D. J. Boullin, Serotonin in Mental Abnormalities 1:316 (1978); J. Barchas, et al., Serotonin and Behavior, (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.
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).
The major classes of serotonin receptors (5-HT
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).
For example, the 5-HT
6
receptor was identified in 1993 (Monsma et al. Mol. Pharmacol. 1993, 43, 320-327 and Ruat, M. et al. Biochem.
Biophys. Res. Com.
1993, 193, 269-276). Several antidepressants and atypical antipsychotics bind to the 5-HT
6
receptor with high affinity and this binding may be a factor in their profile of activities (Roth et al.
J. Pharm. Exp. Therapeut.
1994, 268, 1403-1410; Sleight et al.
Exp. Opin. Ther. Patents
1998, 8, 1217-1224; Bourson et al.
Brit. J. Pharm.
1998, 125, 1562-1566; Boess et al.
Mol. Pharmacol.
1998, 54, 577-583; Sleight et al.
Brit. J. Pharmacol.
1998, 124, 556-562). In addition, the 5-HT6 receptor has been linked to generalized stress and anxiety states (Yoshioka et al.
Life Sciences
1998, 17/18, 1473-1477). Together these studies and observations suggest that compounds that antagonize the 5-HT receptor will be useful in treating disorders of the central nervous system.
Compounds of the present invention are 5-HT ligands (e.g. receptor-specific agonists or antagonists). Thus they are useful for treating diseases wherein modulation of 5-HT activity is desired. Specifically, the compounds of this invention are useful in the treatment of psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, schizoaffective disorder, delusional disorder, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, a stress related disease such as anxiety, migraine headache, drug addiction, convulsive disorders, personality disorders, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, sleep disorders, disorders of the gastrointestinal or cardiovascular system (e.g., stress incontinence), neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, 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, 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 specific developmental disorder, agitation disorder, selective serotonin reuptake inhibition (SSRI) “poop out” syndrome or a Tic disorder (e.g., Tourette's syndrome). More specifically, the compounds of this invention are useful to treat psychotic, affective, vegetative, and psychomotor symptoms of schizophrenia or the extrapyramidal motor side effects of an antipsychotic drug. This last action will allow higher doses of antipsychotics to be used and thus greater antipsychotic efficacy to be obtained as a result of a reduction in side effects. The compounds of this invention are also useful in the modulation of eating behavior and thus are useful in treating excess weight and associated morbidity and mortality.
INFORMATION DISCLOSURE
International Publication No. WO95/03296 discloses carbazole and dibenzofuran hapten compounds.
Abstract of International Publication No. WO/9747601 discloses new heterocyclic compounds useful for treating schizophrenia.
European Patent Application EP 839806 discloses tricyclic compounds useful for inhibiting sPLA2 mediated release of fatty acids for conditions such as septic shock.
U.S. Pat. No. 5,668,167 discloses carbazole derivatives useful for treating microbial infections.
U.S. Pat. No. 4,503,067 discloses carbazolyl-(4)-oxypropanolamine compounds useful for treating cardiac diseases.
U.S. Pat. No. 3,932,424 discloses carbazoles useful as antiviral agents.
U.S. Pat. No. 3,896,145 discloses carbazoles useful as antiinflammatory, analgesic, and anti-rheumatic agents.
U.S. Pat. No. 3,759,948 discloses tricyclic carboxylic acid and ester derivatives useful as anti-inflammatory, anti-pyretic and analgesic agents.
DE 4330175 discloses beta carbolines useful for treating Parkinson's disease, Alzheimer's disease, senile dementia, epilepsy, schizophrenia, migraine etc.
Abstract of Japanese Patent No. 06228095 discloses carbazole derivatives useful for treating ischaemic encephalopathy.
Abstract of French Patent No. 2516512 discloses pyrido-indole derivatives useful for treating cardiac rhythm diseases.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I
wherein
R
1
is
(a) H,
(b) halo, or
(c) C
1-6
alkyl;
R
2
is
(a) H,
(b) halo,
(c) —OH,
(d) —CN,
(e) —CF
3
,
(f) —O(C
1-6
)alkyl,
(g) C
1-6
alkyl,
(h) C
3-6
cycloalkyl,
(i) —NR
5
R
6
,
(j) —CONR
5
R
6
,
(k) —SO
2
NR
5
R
6
,
(l) —COOR
7
,
(m) —OCF
3
, or
(n) phenyl, optionally substituted with halo, OH, O(C
1-4
) alkyl, or C
1-6
alkyl; each R
3
is independently
(a) H,
(b) C
1-6
alkyl, or
(c) C
3-6
cycloalkyl;
R
4
is
(a) aryl, or
(b) heteroaryl;
R
5
and R
6
are independently
(a) H,
(b) C
1-6
alkyl, or
(c) C
3-6
cycloalkyl;
R
7
is
(a) H,
(b) C
1-6
alkyl, or
(c) (C
1-3
alkyl)-
Engelmann John H.
Pharmacia & Upjohn Company
Wright Sonya N.
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