Indoline derivatives as 5-HT2B and or 5-HTC receptor ligands

Details Indoline derivatives as 5-HT2B and or 5-HTC receptor ligands Indoline derivatives as 5-HT2B and or 5-HTC receptor ligands

2001-03-01

2002-04-30

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S483000

Reexamination Certificate

active

06380238

ABSTRACT:

The present invention relates to indoline derivatives, to processes and intermediates for their preparation, 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 releaser/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, 96, 93-100; G. A. Kennett, C. T. Dourish and G. Cuzon,
Eur. J. Pharmacol.,
1987, 141, 429-435) 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 dose 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 subjects during subchronic treatment for a 14 day period (P. A. Sargeant et al.,
Psychopharmacol.,
1997, 133, 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.
Other compounds which have been proposed as 5-HT
2C
receptor agonists for use in the treatment of obesity include the substituted 1-aminoethyl indoles disclosed in EP-A-0655440. CA-2132887 and CA-2153937 disclose that tricyclic 1-aminoethylpyrrole derivatives and tricyclic 1-aminoethylpyrazole derivatives bind to 5-HT
2C
receptors and may be used in the treatment of obesity. WO-A-98130548 discloses aminoalkylindazole compounds as 5-HT
2C
agonists for the treatment of CNS diseases and appetite regulation disorders.
It is an object of this invention to provide selective, directly acting 5HT
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 for use in therapy a chemical compound of formula (I):
wherein:
R
1
to R
3
are independently selected from hydrogen and alkyl;
R
4
to R
7
are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxyl, alkylsulfonyl, arylsulfoxyl, arylsulfonyl, amino, monoalkylamino, dialkylamino, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylanrinocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, arninocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino, wherein at least one of R
4
to R
7
is a substituent group other than hydrogen, and pharmaceutically acceptable salts 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. Where cyclic, the alkyl group is preferably C
3
to C
12
, more preferably C
5
to C
10
, more preferably C
5
, C
6
or 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) or butyl (n-butyl, isobutyl or tertiary-butyl), more preferably methyl.
As used herein, the term “lower alkyl” means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
As used herein, the term “aryl” means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably one, heteroatom, such as pyridyl, pyrrolyl, faranyl and thienyl.
As used herein the term “heterocyclyl” means a saturated 4, 5, 6 or 7-membered ring preferably a 5 or 6-membered ring) containing 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) selected from O, S and N (preferably from O and N).
The alkyl, aryl and heterocyclyl groups may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include:
carbon-containing groups such as
alkyl,
aryl,
arylalkyl (e.g. substituted and unsubstituted phenyl, substituted
and unsubstituted benzyl);
halogen atoms and halogen-containing groups such as
haloalkyl
(e.g. trifluoromethyl);
oxygen-containing groups such as
alcohols
(e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl),
ethers
(e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl),
aldehydes
(e.g. carboxaldehyde),
ketones
(e.g. alkylcarbonyl, alkylcarbonylalkyl,
arylcarbonyl, arylalkylcarbonyl,
arylcarbonylalkyl),
acids
(e.g. carboxy, carboxyalkyl),
acid derivatives
(e.g. alkoxycarbonyl, alkoxycarbonylalkyl,
such as esters
alkylcarbonyloxy, alkylcarbonyloxyalkyl),
amides
(e.g. aminocarbonyl, mono- or di-
alkylaminocarbonyl, aminocarbonylalkyl, mono-
or di-alkylaminocarbonylalkyl,
arylaminocarbonyl),
carbamates
(e.g. alkoxycarbonylamino,
aryloxycarbonylamino, aminocarbonyloxy, mono-
or di-alkylaminocarbonyloxy,
arylaminocarbonyloxy)
and ureas
(e.g. mono- or di-alkylaminocarbony

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