Pirazino indole derivatives

Details Pirazino indole derivatives Pirazino indole derivatives

2001-10-09

2004-10-05

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S344000

Reexamination Certificate

active

06800627

ABSTRACT:

The present invention relates to pyrazinoindole derivatives, to pharmaceutical compositions containing them and to their medicinal use. The active compounds of the present invention are useful in treating obesity and other disorders.
It has been recognised that obesity is a disease process influenced by environmental factors in which the traditional weight loss methods of dieting and exercise need to be supplemented by therapeutic products (S. Parker, “Obesity: Trends and Treatments”,
Scrip Reports
, PJB Publications Ltd, 1996).
Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m
2
). Thus, the units of BMI are kg/m
2
and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m
2
, and obesity as a BMI greater than 30 kg/m
2
. There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.
As the BMI increases there is an increased risk of death from a variety of causes that is independent of other risk factors. The most common diseases with obesity are cardiovascular disease particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.
Compounds marketed as anti-obesity agents include Orlistat (Reductil®) and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a high incidence of unpleasant (though relatively harmless) side-effects such as diarrhoea. Sibutramine (a mixed 5-HT
oradrenaline reuptake inhibitor) can increase blood pressure and heart rate in some patients. The serotonin release/reuptake inhibitors fenfluramine (Pondimin®) and dexfenfluramine (Redux™) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.
The non-selective 5-HT
2C
receptor agonists/partial agonists m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFMPP) have been shown to reduce food intake in rats (G. A. Kennett and G. Curzon,
Psychopharmacol
., 1988, 98, 93-100, G. A. Kennett, C. T. Dourish and G. Curzon,
Eur. J. Pharmacol
., 1987, 141, 429-453) and to accelerate the appearance of the behavioural satiety sequence (S. J. Kitchener and C. T. Dourish,
Psychopharmacol
., 1994, 113, 369-377). Recent findings from studies with mCPP in normal human volunteers and obese subjects have also shown decreases in food intake. Thus, a single injection of mCPP decreased food intake in female volunteers (A. E. S. Walsh et al.,
Psychopharmacol
., 1994, 116, 120-122) and decreased the appetite and body weight of obese male and female subject during subchronic treatment for a 14 day period (P. A. Sargeant et al.,
Psychopharmacol
., 1997, 113, 309-312). The anorectic action of mCPP is absent in 5-HT
2C
receptor knockout mutant mice (L. H. Tecott et al.,
Nature
, 1995, 374, 542-546) and is antagonised by the 5-HT
2C
receptor antagonist SB-242084 in rats (G. A. Kennett et al.,
Neuropharmacol
., 1997, 36, 609-620). It seems therefore that mCPP decreases food intake via an agonist action at the 5-HT
2C
receptor. However, although both mCPP and TFMPP exhibit high affinity for the 5-HT
2C
receptor they are both non-selective, having appreciable activity at other 5-HT receptors (G. A. Kennett,
Curr. Opin. Invest. Drugs
, 1993, 2, 317-362).
The preparation of pyrazino[1,2-a]indoles as serotonergic agents, useful as antidepressants and anxiolytics, is disclosed in PCT application WO 9612721. The compounds of this invention are reported to possess high affinity for the serotonergic 5-HT
1A
receptor. Substituted pyrazino[1,2-a]indoles are used as intermediates in the preparation of heterocyclyl O-substituted alcoholamines as fibrinogen receptor antagonist products as disclosed in PCT application WO 9800401. Pyrazino[1,2-a]indole derivatives are also reported in the preparation of 3-piperazinomethylpyrrolo[2,3-b]pyridines as dopamine D4 receptor antagonists as disclosed in U.S. Pat. No. 5,576,319 and WO 9420497. 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole and 3-ethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole are disclosed in
Med. Chem. Res
., 1993, 3, 240-248 and their 5-HT
1A
and 5-HT
2
binding affinity reported. The 5-HT
1A
and 5-HT
2
binding affinity for 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole is reported to be the same as that observed for 1-phenylpiperazine and demonstrates an approximate ten fold selectivity for 5-HT
1A
receptors.
It is an object of this invention to provide selective, directly acting 5-HT
2
receptor ligands for use in therapy and particularly for use as anti-obesity agents. It is a further object of this invention to provide directly acting ligands selective for 5-HT
2B
and/or 5-HT
2C
receptors, for use in therapy and particularly for use as anti-obesity agents. It is a further object of this invention to provide selective, directly acting 5-HT
2C
receptor ligands, preferably 5-HT
2C
receptor agonists, for use in therapy and particularly for use as anti-obesity agents.
According to the present invention there is provided a chemical compound of formula (I):
wherein:
R
1
to R
3
are independently selected from hydrogen and lower alkyl;
X
1
is selected from N and C—R
4
;
X
2
is selected from N and C—R
5
;
X
3
is selected from N and C—R
6
;
X
4
is selected from N and C—R
7
;
R
4
, R
5
and R
7
are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy, alkoyl aryloyl, alkylthio, arylthio, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, dialkylamino, nitro, cyano, carboalkoxy, carboaryloxy and carboxy; and
R
6
is selected from hydrogen, halogen, alkyl, aryl, aryloxy, alkylthio, arylthio, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, dialkylamino and cyano;
with the proviso that R
4
to R
7
are not all selected as hydrogen, and pharmaceutically acceptable salts and addition compounds and prodrugs thereof.
As used herein, the term “alkyl” means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted. Where cyclic, the alkyl group is preferably C
3
to C
12
, more preferably C
5
to C
10
, more preferably C
5
to C
7
. Where acyclic, the alkyl group is preferably C
1
to C
10
, more preferably C
1
to C
6
, more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and isopentyl), more preferably methyl. It will be appreciated therefore that the term “alkyl” as used herein includes alkyl (branched or unbranched), substituted alkyl (branched or unbranched), alkenyl (branched or unbranched), substituted alkenyl (branched or unbranched), alkynyl (branched or unbranched), substituted alkynyl (branched or unbranched), cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkynyl and substituted cycloalkynyl.
As used herein, the term “lower alkyl” means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical wherein said cyclic lower alkyl group is C
5
, C
6
or C
7
, and wherein said acyclic lower alkyl group is C
1

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