2-amino-benzoxazinone derivatives for the treatment of obesity

Details 2-amino-benzoxazinone derivatives for the treatment of obesity 2-amino-benzoxazinone derivatives for the treatment of obesity

2001-07-06

2003-12-02

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S092000

Reexamination Certificate

active

06656934

ABSTRACT:

The present invention provides known and novel compounds, their use in the inhibition of an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality (in vivo, as the enzyme naturally occurs), their use in medicine, and particularly in the prevention and/or treatment of obesity or an obesity-related disorder. Also provided are methods for the prevention and/or treatment of obesity or an obesity-related disorder and for promoting/aiding non-medical weight loss and the use of the compounds in the manufacture of a medicament for the aforementioned indications. In respect of novel compounds the invention also provides processes for their manufacture, compositions containing them, and methods for manufacturing such compositions.
In the last 20 years, there has been an increasing trend in obesity in the populations of the developed world. The increased incidence of obesity is due in part to the ready availability of food in numerous retail outlets and westernised diets that have high saturated fat and lower fibre contents such that the food is energy dense. The lifestyle of the populations of the developed world has also become more sedentary with the increased mechanisation of society and the steady reduction of manual labour intensive industries. There now exists an energy imbalance between the energy intake from calorie dense foods and the reduced energy expenditure required for a sedentary lifestyle. Some of the excess energy intake is stored as fat in the adipose tissue, the accumulation of which over a period of time results in obesity and can be a significant contributory factor to other diseases and disorders.
Obesity is now recognised by the medical profession as a metabolic disease. In the USA, it is estimated that 25% of the adult population is considered clinically obese (Body Mass Index>30). Obesity can be a debilitating condition which reduces the quality of life and increases the risk of related disorders such as diabetes, cardiovascular disease and hypertension. It has been estimated that $45 billion of US healthcare costs, or 8% per annum of total healthcare spend, is as a direct result of obesity. The traditional approaches to long term weight management such as diet and exercise have proved ineffective alone to control the spread of obesity. Today, more than ever, there is considerable interest in developing safe, effective drugs for the treatment of obesity.
Pharmacological approaches to the treatment of obesity have focused on either developing drugs that increase energy expenditure or drugs that reduce energy intake. One approach to the reduction of energy intake is to reduce the body's ability to digest and absorb food, in particular fat. The key enzymes involved in the digestion of fat are hydrolytic enzymes. The most significant of the fat degrading enzymes are lipases, primarily, but not exclusively pancreatic lipase that is secreted by the pancreas into the gut lumen. The lipase inhibitor lipstatin has formed the basis of the anti-obesity drug, orlistat. Orlistat is the subject of published European Patent Application No. EP129748, which relates to compounds of formula:
where A is —(CH
2
)
5
— or:
and their use in inhibiting pancreatic lipase and treating hyperlipaemia and obesity. Orlistat has as its major active moiety a beta-lactone group that reacts to form an ester with the side chain hydroxyl group of serine 152 within the active site of pancreatic lipase. Even if orlistat provides an effective method for treating obesity, there remains a need to provide alternative drugs and methods for use in the control and treatment of obesity, obesity-related disorders and non-medical weight loss. Inhibitors of enzymes involved in the degradation of fat are provided here and shown to be effective in the prevention and/or treatment of obesity, obesity-related disease and/or cosmetic weight loss.
U.S. Pat. No. 4,657,893 (Syntex) describes a broad class of 2-amino-4H-3,1-benzoxazin-4-ones of the formula:
wherein R
1
is hydrogen or lower alkyl, R
2
and R
3
are each independently hydrogen, halo, lower alkyl, hydroxy, lower alkoxy, lower thioalkyl, —NO
2
, —N(R
1
)
2
, —NR
1
COR
1
, —NHCON(R
1
)
2
or NHCOOR
1
; and X is inter alia—NHR where R is lower alkyl, lower alkenyl, lower alkynyl, optionally substituted lower cycloalkyl or optionally substituted phenyl lower alkyl. The compounds are said to be useful as serine protease inhibitors and to treat physiologic conditions and disease states known to involve serine proteases, or as contraceptives. The specification describes various conditions and diseases involving enzymatic pathways, including inflammation, arthritis, tumor cell metastasis, pulmonary emphysema, mucocutaneous lymph node syndrome, adult respiratory distress syndrome and pancreatitis. It is also suggested that the compounds may have antiparasitic, anticoagulant and/or antiviral activity. Similar compounds are also described by Krantz et al in
J. Med. Chem.
1990 33:464-479.
2-Amino-4H-3,1-benzoxazin-4-ones as inhibitors of serine protease are also described by Hays et al in
J. Med. Chem.
1998 41:1060-1067. This paper describes inter alia 2-(substituted phenyl)amino benzoxazinones, where the phenyl substituents include halogen, methyl, SMe, and OCF
3
, as well as certain 2-(heterocyclic)amino benzoxazinones. Some of these compounds are also described in U.S. Pat. No. 5,652,237 (Warner Lambert).
German OLS 2315303 (Bayer AG) describes the preparation of compounds of the formula
where R is an alkyl or aryl residue which may be substituted by nitro, halogen, alkyl, alkoxy or an aryl group, and R′ and R″ are each independently hydrogen, halogen, nitro, optionally substituted alkyl, cycloalkyl, aralkyl, aryl, alkoxy or aryloxy groups. The only values of R exemplified are nitrophenyl and mono- and di-chlorophenyl. The compounds are said to be useful as intermediates for pharmaceuticals and plant protection agents.
We have now found that a particular class of benzoxazinone compounds has activity as lipase inhibitors
Accordingly, a first aspect of the invention provides a compound comprising formula (I)
or a pharmaceutically acceptable salt, ester, amide or prodrug therof; in the manufacture of a medicament for the treatment of conditions which require the inhibition of an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality; wherein in formula (I):
A is a 6 membered aromatic or hetero-aromatic ring;
R
1
is a branched or unbranched alkyl (optionally interrupted by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or a substituted derivative therof wherein the substituents are one or more independently chosen from the group consisting of halogen, alkyl, halosubstituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy, cyano, nitro, —C(O)R
4
, —CO
2
R
4
, —SOR
4
, —SO
2
R
4
, —NR
6
R
7
, —OR
6
, —SR
6
, —C(O)CX
1
X
2
NR
6
R
7
, —C(O)NR
4
R
5
, —C(O)N(OR
5
)R
6
, —NR
6
C(O)R
4
, —CR
6
(NH
2
)CO
2
R
6
, —NHCX
1
X
2
CO
2
R
6
, —N(OH)C(O)NR
6
R
7
, —N(OH)C(O)R
4
, —NHC(O)NR
6
R
7
, —C(O)NHNR
6
R
7
, —C(O)N(OR
5
)R
6
, or a lipid or steroid (natural or synthetic), with the proviso that any hetero atom substituent in R
1
and/or R
2
must be separated from the exocyclic nitrogen atom by at least two carbon atoms (preferably saturated); and
R
2
is hydrogen or is a group as defined above for R
1
;
and where:
R
4
is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl, reduced heteroarylalkyl, —OR
6
, —NHCX
1
X
2
CO
2
R
6
or —NR
6
R
7
;
R
5
is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl;
R
6
and R
7
are independently selected from hydrogen, alkyl, alkenyl, alkynyl,

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