Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-02
2003-01-07
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S556000
Reexamination Certificate
active
06503900
ABSTRACT:
The present invention relates to new and known [1,4]diazepino[6,7,1-jk]carbazoles and derivatives thereof, which are serotonin 5-hydroxytryptamine 2
c
(5HT
2C
) receptor agonists useful for the treatment of disorders such as obsessive-compulsive disorder, depression, anxiety, generalized anxiety disorder, schizophrenia, panic disorder, migraine, sleep disorders, such as sleep apnea, eating disorders, such as hyperphagia, obesity, epilepsy, and spinal cord injury.
BACKGROUND OF THE INVENTION
Obesity is a medical disorder characterized by an excess of body fat or adipose tissue. Comorbidities associated with obesity are Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality. As the percentage of obese individuals continues to rise both in the U.S. and abroad, obesity is expected to be a major health risk in the 21
st
Century. The serotonin 5-hydroxytryptamine (5-HT) receptor is a G-protein coupled receptor which is expressed in neurons in many regions of the human central nervous system. [Wilkinson, L. O. and Dourish, C. T. in
Serotonin Receptor Subtypes: Basic and Clinical Aspects
(ed. Peroutka, S. J.) 147-210 (Wiley-Liss, N.Y., 1991).] The 5HT
1C
receptor (formerly called the 5HT
2C
receptor) is a prominent subtype of the serotonin receptor found in the central nervous system of both rats and humans. It is expressed widely in both cortical and subcortical regions. [Julius, D. MacDermott, A. B., Axel, R. Jessell, T. M.
Science
241:558-564 (1988).] Studies in several animal species and in humans have shown that the non-selective 5HT
2C
receptor agonist, meta-chlorophenylpiperazine (MCPP) decreases food intake. [Cowen, P. J., Clifford, E. M. , Williams, C., Walsh, A. E. S., Fairburn, C. G.
Nature
376: 557 (1995).] Tecott, et a/ have demonstrated that transgenic mice lacking the 5HT
2C
receptor eat more and are heavier than Wild Type mice. [Tecott, L. H., Sun, L. M., Akana, S. F., Strack, A. M., Lowenstein, D. H., Dallman, M. F., Julius, D.
Nature
374: 542-546 (1995).] Compounds of this invention are 5HT
2C
receptor subtype selective agonists which are selective over other monoamine receptors, causes a reduction in food intake and result in a reduction in weight gain. Other therapeutic indications for 5HT
2C
agonists are obsessive compulsive disorder, depression, panic disorder, schizophrenia, sleep disorders, eating disorders, epilepsy, and spinal cord injury.
U.S. Pat. No. 3,914,250 (Oct. 21, 1975) describes 1,4-diazepino[6,5,4-jk]carbazoles as anticonvulsant agents. This invention relates to new and known 1,4-diazepino[6,5,4-jk]carbazoles and derivatives which bind to and activate 5HT
2C
receptors in the CNS and are useful for the treatment of CNS disorders which can benefit from modulation of the 5HT
2C
receptor.
DESCRIPTION OF THE INVENTION
This invention provides compounds of formula I having the structure:
wherein:
R
1
and R
2
are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluorinated alkyl of 1-6 carbon atoms, —CN, —NH—SO
2
-alkyl of 1-6 carbon atoms, —SO
2
—NH-alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, phenoyl or thiophenoyl;
R
3
, R
4
, R
5
and R
6
are independently selected from hydrogen, C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, C
1
-C
6
alkoxy or C
3
-C
6
cycloalkoxy;
R
7
is hydrogen or C
1
-C
6
alkyl;
R
8
is hydrogen or C
1
-C
6
alkyl; and
wherein the dashed line indicates an optional double bond;
or a pharmaceutically acceptable salt thereof.
In the definitions of R
1
and R
2
herein, the fluorinated alkyl and fluorinated alkoxy groups indicate the specified alkyl or alkoxy groups having any amount of fluorine substitution, including, but not limited to, groups such as —CHF
2
, —CF
3
, —C
2
F
5
, —OCF
3
, etc.
A preferred group of compounds of this invention comprises those having the formula I, above, wherein R
1
, R
2
, R
8
and R
7
are each hydrogen and R
3
, R
4
, R
5
and R
6
are as defined above, or a pharmaceutically acceptable salt thereof. Another preferred group of compounds of this invention are those of Formula I wherein R
1
, R
2
, R
5
, R
6
, R
8
and R
7
are each hydrogen and R
3
and R
4
are as defined above, or a pharmaceutically acceptable salt thereof.
The 5HT
2C
receptor agonists of this invention are useful for the treatment or prevention in mammals, preferably in humans, of disorders involving the central nervous system such as obsessive-compulsive disorder, depression, atypical depression, bipolar disorders, anxiety, generalized anxiety disorder, schizophrenia, psychoses, personality disorders, organic mental disorders, behavioral disorders associated with dementia or age-related conditions, aggressivity, drug and alcohol addiction, social phobias, sexual dysfunction, panic disorder, migraine, sleep disorders, such as sleep apnea, eating disorders, such as hyperphagia, bulimia or anorexia nervosa, obesity, epilepsy, and premenstrual tension.
This invention also includes methods of utilizing the compounds herein in treatments or preventitive regimens for treatment of central nervous system deficiencies associated with trauma, stroke, neurodegenerative diseases or toxic or infective CNS disorders including, but not limited to, encephalitis or menengitis; or cardiovascular disorders, including thrombosis; gastrointestinal disorders such as malfunction of gastrointestinal motility; and diabetes insipidus. These methods include the improvement or inhibition of further degradation of central nervous system activity during or following the malady or trauma in question. Included in these improvements are maintenance or improvement in motor and motility skills, control, coordination and strength. This invention includes methods for treating, preventing, modulating, ameliorating or improving the condition of each of these disorders in a mammal in need thereof, the methods comprising administering a therapeutically or pharmaceutically effective amount of a compound of this invention or a pharmaceutically acceptable salt thereof.
The compounds of this invention contain asymmetric carbon atoms and thus give rise to optical isomers and diastereoisomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
The term “alkyl” includes both straight- and branched-chain saturated aliphatic hydrocarbon groups and cycloalkyl groups. Halogen is defined as Cl, Br, F or I.
It will be understood that the dashed line in FIG. 1, above, indicates the optional reduction in the portion of the structure depicted.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.
Preferred compounds of this invention are those in which R
1
-R
6
are each hydrogen. Especially preferred are compounds which are enantiomerically pure stereoisomers of compounds where R is hydrogen and the indole ring is reduced or not reduced.
The compounds of this invention can be prepared according to the following scheme from commercially available starting materials or starting materials which can be prepared using literature procedures. Scheme 1 shows the preparation of a key intermediate and Scheme 2 shows the preparation of representative compound
Sabalski Joan Eileen
Sabb Annmarie Louise
Vogel Robert Lewis
Welmaker Gregory Scott
Barrett Rebecca R.
Coleman Brenda
Wyeth
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