Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-01-20
2002-02-05
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S535000, C514S563000, C514S532000
Reexamination Certificate
active
06344481
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to pharmaceutical compositions and methods useful in treating obesity in animals, including mammalian subjects, particularly humans and companion animals.
Hitherto, the normal method employed in treating obesity has been reduction of caloric intake, either by a reduced calorie diet or through the use of appetite suppressants (anorectic agents), or a combination of the two. In general, the use of anorectic agents alone is not entirely satisfactory since they do not remain effective for the extended time periods that are necessary to achieve weight loss or they possess undesirable side-effects, particularly central stimulatory effects.
Alternatively, certain compounds have been disclosed that are able to induce weight loss by mechanisms other than appetite suppression, e.g. through stimulation of the peripheral metabolic rate of adipose tissue. For example, U.S. Pat. Nos. 4,451,465, 4,772,631, 4977,148 and 4,999,377 disclose compounds possessing thermogenic properties at dosages causing few or no deleterious side-effects, such as cardiac stimulation. The disclosures of U.S. Pat. Nos. 4,451,465, 4,772,631, 4,977,148 and 4,999,377 are incorporated herein by reference in their entirety. It is well-known to one of ordinary skill in the art that selectivity of thermogenic effect is an important requirement for a useful therapeutic agent in the treatment of, for example, obesity and related conditions.
The present invention provides methods for treating obesity which comprise administering to an animal, including a human or companion animal, in need of such treatment an obesity-treating amount of a compound of formula (I), or a pharmaceutically acceptable salt, racemate or enantiomer thereof, shown and defined hereinbelow.
The present invention further provides pharmaceutical compositions useful in the treatment of obesity which comprise an obesity-treating amount of a compound of formula (I), or a pharmaceutically acceptable salt, racemate or enantiomer thereof and an anorectic agent.
The compounds of formula (I), the pharmaceutically acceptable salts, racemates and enantiomers thereof, methods of preparing such compounds, salts, racemates and enantiomers and pharmaceutical compositions comprising such compounds, salts, racemates and enantiomers are disclosed in U.S. Pat. Nos. 5,401,772; 5,569,674 and 5,654,468, the disclosures of which are incorporated herein by reference.
In U.S. Pat. Nos. 5,401,772; 5,569,674 and 5,654,468 there is described a series of heteroacetic acid derivatives which are claimed to be useful in the treatment of occlusive cardiovascular conditions in which, inter alia, hyperlipidemia and hyperlipoproteinemia are implicated. Such conditions may include, for example, atherosclerosis, coronary heart disease and the like.
It has been subsequently disclosed in Stephan et al., Atherosclerosis, 126, 53-63 (1996) that a representative compound of these derivatives, ethyl N-[4-[3′-[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate (CGS-26214), is devoid of both cardiovascular and thermogenic effects.
It has now been found that these heteroacetic acid derivatives, including CGS-26214, do, in fact, possess significant thermogenic properties. Accordingly, CGS-26214 and the compounds related thereto are useful in the treatment of obesity and related conditions.
SUMMARY OF THE INVENTION
This invention relates to methods for treating obesity which comprise administering to an animal, including a human or companion animal in need of such treatment, an obesity-treating amount of a compound of formula (I) or a pharmaceutically acceptable salt, racemate or enantiomer thereof, as shown and described hereinbelow. The administration of a compound of formula (I), or a pharmaceutically acceptable salt, racemate or enantiomer thereof, provides a thermogenic effect, that is thermogenesis is stimulated and, therefore, administration of the compound is of use in the treatment of obesity and conditions related thereto.
The invention is also directed to pharmaceutical compositions and methods of using such compositions in treating obesity in an animal, including a human or companion animal, which methods comprise administering to the animal in need of such treatment obesity-treating amounts of a compound of formula (I), or a pharmaceutically acceptable salt, racemate or enantiomer thereof, and an anorectic agent.
In a preferred aspect of the methods of this invention, the anorectic agent is selected from the group consisting of phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a Neuropeptide Y (hereinafter referred to as “NPY”) antagonist, a cholecystokinin-A (hereinafter referred to as “CCK-A”) agonist, a monoamine reuptake inhibitor, a sympathiomimetic agent, a serotoninergic agent, a dopamine agonist, a melanocyte-stimulating hormone receptor agonist or mimetic, a cannabinoid receptor antagonist, a melanocyte-stimulating hormone analog, a melanin concentrating hormone antagonist, the OB protein (hereinafter referred to as “leptin”), a leptin analog, a galanin antagonist and an orexin receptor antagonist. An especially preferred monoamine reuptake inhibitor is sibutramine, a preferred serotoninergic agent is dexfenfluramine or fenfluramine and a preferred dopamine agonist is bromocriptine.
The pharmaceutical compositions useful in treating obesity preferably comprise an amount of a compound of formula (I), or a pharmaceutically acceptable salt, racemate or enantiomer thereof, an anorectic agent and a pharmaceutically acceptable carrier or diluent.
The invention also relates to a kit comprising an amount of a compound of formula (I), or a pharmaceutically acceptable salt, racemate or enantiomer thereof, and a pharmaceutically acceptable carrier or diluent in a first unit dosage form, an amount of an anorectic agent and a pharmaceutically acceptable carrier or diluent in a second unit dosage form and a container.
DETAILED DESCRIPTION OF THE INVENTION
According to the instant invention, there are provided pharmaceutical compositions and methods useful for treating obesity in mammals, including humans and companion animals, which methods comprise administering to a mammal in need of such treatment an obesity-treating amount of a compound of the formula
or a pharmaceutically acceptable salt, racemate or enantiomer thereof, wherein
R is hydroxy, esterified hydroxy or etherified hydroxy;
R
1
and R
2
are, independently, halogen, trifluoromethyl or lower alkyl;
R
3
is halogen, trifluoromethyl, lower alkyl, lower alkanoyl, hydroxy-lower alkyl, aryl, aryl-lower alkyl, cycloalkyl or cycloalkyl-lower alkyl, carbocyclic arylmethyl, carbocyclic aroyl, carbocyclic arylhydroxymethyl; or
R
3
is the radical
wherein
R
8
is hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkyl or cycloalkyl-lower alkyl;
R
9
is hydroxy or acyloxy; R
10
is hydrogen or lower alkyl; or R
9
and R
10
, taken together with the carbon atom to which they are attached, form a carbonyl group;
R
4
is hydrogen, halogen, trifluoromethyl or lower alkyl;
R
5
and R
6
are, independently, hydrogen or lower alkyl or R
5
and R
6
, taken together with the carbon atom to which they are attached, form a carbonyl group;
X is O, S or —NR
7
;
R
7
is hydrogen or lower alkyl;
W is O or S and
Z is carboxyl or carboxyl derivatized as a pharmaceutically acceptable ester or amide.
Generally preferred embodiments of the pharmaceutical compositions and methods of the instant invention relate to the use of compounds of formula (I) and the pharmaceutically acceptable salts, racemates and enantiomers thereof wherein R is located at the 4′-position; R
1
and R
2
are located at the 3 and 5 positions; R
3
and R
4
are located at the 3′ and 5-positions; X is O or —NR
7
, W is O; R
4
is hydrogen and Z is carboxyl or carboxyl derivatized as a pharmaceutically acceptable ester.
A preferred embodiment of the compositions and methods of this invention relates to the use of a subgroup of compounds of formula
Cornelius Peter
Hargrove Diane M.
Morgan Bradley P.
Swick Andrew G.
Benson Gregg C.
Criares Theodore J.
Goddard Carl J.
Kim Jennifer M
Pfizer Inc.
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