Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-16
2004-03-16
Goldberg, Jerome D. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06706714
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to derivatives of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2,-a]quinoxalin-5(6H) ones which are serotonin 5-hydroxytryptamine 2
C
(5HT
2C
) receptor agonists useful for the treatment of disorders such as obsessive-compulsive disorder, depression, anxiety, schizophrenia, migraine, sleep disorders, eating disorders, obesity, type II diabetes, and epilepsy.
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, New York, 1991).] The 5HT
2C
receptor (formerly called the 5HT
1C
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 al 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., Jullus, 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, and epilepsy.
U.S. Pat. Nos. 4,032,639; 4,089,958; and 4,203,987 describe 2,3,4,4a-Tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6)-ones and derivatives thereof as antihypertensive agents. In contrast, compounds of this invention bind to and activate the 5HT
2C
receptors in the CNS and are useful for the treatment of CNS disorders.
Indian J. Chem. 17B, 244-245 (1979) discloses 3-Substituted 2,3,4,4a,5,6-Hexahydro-1(H)-pyrazino[1,2-a]quinoxalines which exhibit no anorexigenic or stimulant activity at 60 mg/kg i.p. dose. Weak CNS depressant activity and significant hypotensive activity in anaesthetized animals. Tachyphylaxis was observed.
DESCRIPTION OF THE INVENTION
This invention provides compounds of formula I having the structure
wherein
R is hydrogen or alkyl of 1-6 carbon atoms;
R′ is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl;
R
1
, R
2
, R
3
, and R
4
are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, —CN, alkyl sulfonamide 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, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl;
X is CR
5
R
6
or a carbonyl group;
R
5
and R
6
are each, independently, hydrogen or alkyl of 1-6 carbon atoms;
or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R
1
, R
2
, R
3
, or R
4
are not hydrogen;
which are 5HT
2C
receptor agonists useful for the treatment of disorders involving the central nervous system such as obsessive-compulsive disorder, depression, anxiety, panic disorder, schizophrenia and schizophrenic disorders, migraine, sleep disorders, eating disorders, obesity, type II diabetes, and epilepsy.
This invention provides methods for treatment, inhibition or alleviation of symptoms of schizophrenic disorders in a mammal in need of such treatment. These methods include those for the schizophrenic disorders known in the art, including those defined by the American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III, 1980), its revision DSM-III-R (1987) or the DSM-IV (1996). These methods include those for schizophrenia, schizophreniform syndromes, or schizoaffective disorders. Also included are related psychotic syndromes referred to as brief reactive psychoses, as well as borderline or latent schizophrenia and simple schizophrenia, which are also referred to as borderline or schizotypal personality disorders. Additional methods include late onset schizophrenia-like syndromes, such as the involutional paraphrenias, which are also known as paranoid disorder or atypical psychosis.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may 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. The term “aroyl” is defined as an aryl ether, where aryl is defined as an aromatic system of 6-14 carbon atoms, which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. Preferred aryl groups include phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl groups. Halogen is defined as Cl, Br, F, and I.
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 at least one of R
1
, R
2
, R
3
, or R
4
are not hydrogen, and the non-hydrogen substituents of R
1
, R
2
, R
3
, and R
4
are halogen or trifluoromethyl.
Preferred enantiomerically pure compounds of formulas IA and IB are provided as follows:
wherein R, R
1
, R
2
, R
3
, and R
4
are as described above.
The compounds of this invention can be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention.
In Scheme 1, the symbol Cbz represents a carbobenzyloxy group and Y stands for chlorine, fluorine, or bromine. A solution of 4-carbobenzyloxypiperazine-2-carboxylic acid (I) is allowed to react with a substituted ortho-nitrohalobenzene (II) to give a 4-carbobenzyloxy-1-(
o
-nitro-substituted-phenyl)-piperazine-2-carboxylic acid (III). The reaction is carried out in an inert organic solvent, such as dimethylsulfoxide, in the presence of a base, such as triethylamine, at a temperature above ambient temperature, such as 50-150° C.
The intermediate (III) is cyclized by a process involving reduction of the nitro group to an amino group, preferably by reaction of a metal, such as iron, in an acid, such as acetic acid, followed by heating at elevat
Nelson James Albert
Sabb Annmarie Louise
Welmaker Gregory Scott
Goldberg Jerome D.
Hild Kimberly R.
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