Indoline derivatives and method of treating obesity

Details Indoline derivatives and method of treating obesity Indoline derivatives and method of treating obesity

2001-10-15

2002-11-12

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S449000

Reexamination Certificate

active

06479534

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to indoline derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions comprising them and to their medicinal use. The active compounds of the present invention are useful in treating obesity, diabetes and other disorders.
BACKGROUND OF THE INVENTION
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 (XENICAL®) 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-chlorphenylpiperazine (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 subjects 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 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-aminoethyl pyrazole derivatives bind to 5-HT
2C
receptors and may be used in the treatment of obesity. WO-A-98/30548 discloses aminoalkylindazole compounds as 5-HT
2C
-agonists for the treatment of CNS diseases and appetite regulation disorders. Substituted 1,2,3,4-tetrahydrocarbazoles have been reported as synthetic trypanocides in J. Med. Chem., 1970, 13, 327 and J. Med. Chem., 1973, 16, 1411. 9-(2-Dialkylaminopropyl)-1,2,3,4-tetrahydrocarbazoles have been disclosed in U.S. Pat. Nos. 2,687,414 and 2,541,211. 7-Substituted-9-(2-dialkylaminoethyl)-1,2,3,4-tetrahydrocarbazoles have been disclosed in DE 930,988. The pharmacological effects of 2,3-polymethyleneindoles have been described in J. Med. Chem., 1964, 69, 2910. Derivatives of polynuclear indoles have been described as antidepressants in J. Med. Chem., 1964, 7,625. Amino-substituted penthienoindoles with pharmacological properties are disclosed in U.S. Pat. No. 3,142,678. 1,2,3,4-Tetrahydrocyclopent[b]indoles are disclosed in FR 2,242,983 and DE 2,438,413. 4-(3-Aminobutyl)-1,2,3,4- tetrahydrocyclopent[b]indole has been described in Khim. Geterotskikl. Soedin, 1970, 6, 371.
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.
It is a further object of this invention to provide compounds of formula (I) which are useful in the treatment and/or prevention of disorders involving elevated plasma blood glucose, particularly diabetes mellitus, Type II or non-insulin dependent diabetes mellitus (NIDDM); Type I or insulin dependent diabetes mellitus (IDDM); and Type III or malnutrition-related diabetes. The diabetes may be diabetes secondary to pancreatic disease; or diabetes related to steroid use.
SUMMARY OF THE INVENTION
The compounds of formula (I) are selective agonists of 5-HT
2
receptors and are useful for the treatment of obesity and diabetes. The compounds of formula (I) are also useful in the treatment and/or prevention of the sequelae of hyperglycaemia; in the treatment and/or prevention of diabetic complications; and in the treatment of insulin dependence.
Compounds according to the invention are those of formula (I)
wherein
R
1
and R
2
are independently selected from hydrogen, alkyl, alkenyl, alkinyl, and cycloalkyl;
R
3
is alkyl, alkenyl, alkinyl, or cycloalkyl;
R
4
, R
5
, R
6
and R
7
are independently selected from hydrogen, alkyl, alkenyl, alkinyl, cycloalkyl, halogen, haloalkyl, hydroxy, aryl, amino, mono- and dialkylamino, alkoxy, cycloalkylloxy, aryloxy, heteroaryloxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, nitro, cyano, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heteroaryl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and carboxyl;
the ring A represents a 5 or 6 membered partially unsaturated or saturated carbocyclic or saturated or partially unsaturated heterocyclic ring, wherein the two atoms of the indoline ring to which ring A is fused form a saturated C—C single bond; and
pharmaceutically acceptable salts, esters and/or addition compounds thereof.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the invention is directed to compounds of formula (I):
wherein
R
1
and R
2
are independently selected from hydrogen, alkyl, alkenyl, alkinyl, and cycloalkyl;
R
3
is alkyl, alkenyl, alkinyl, or cycloalkyl;
R
4
, R
5
, R
6
and R
7
are independently selected from hydrog

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