Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-06
2004-03-23
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S196000
Reexamination Certificate
active
06710059
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for treating and/or preventing obesity (especially abdominal obesity), and to treating or suppressing the acquisition of abnormal insulin resistance, in susceptible warm-blooded animals including humans. The methods involve administering compounds of the general formula I below, or their pharmaceutical compositions. In other embodiments, the methods involve administering a selective estrogen receptor modulator.(“SERM”) in combination with a sex steroid precursor.
BACKGROUND OF THE RELATED ART
Obesity, a condition characterized by excessive bodily fat, is a well known risk factor for many diseases such as cardiovascular diseases, hypertension, diabetes and breast cancer. Moreover, personal appearance plays an important part in the overall well-being of most people.
Common treatments of obesity such as various diets (including food restriction diets), weight loss programs and exercise give varying degrees of success for many people. However, there remains a need for other techniques for those who experience insufficient results with prior art techniques, or for use as a supplement to prior art techniques.
Recently, some estrogen agonists/antagonists were disclosed for the treatment or prevention of obesity: Raloxifene and related compounds in European Patent Application Number EP 0 659 423 A1; estrogen agonists having a benzothiophene nucleus in European Patent Application Number EP 0 716 855 A2 ; 3,4-diphenyl chromans in International Application Number PCT/DK96/00011; naphtyl estrogen agonist/antagonist in International Application Number PCT/IB95/00286.
It was also reported that Tamoxifen, another estrogen agonist/antagonist, prevents sulpiride-induced weight gain in female rats (Baptista et al., Pharmacol., Biochem. Behav. (1997), 57(1/2), 215-222). It is also reported that Tamoxifen mimics the effect of estradiol on food intake, body weight and body composition in rats (Wade et al., American Journal of Physiology 1993, 33(6), R1219-1223.)
DHEA has also beneficial effects in the treatment and/or prevention of obesity. In aged Sprague-Dawley rats, Schwartz (in Kent, Geriatrics 37: 157-160, 1982) has observed that body weight was reduced from 600 to 550 g by DHEA without affecting food intake. Schwartz (Cancer 39: 1129-1132, 1979) observed that C3H mice given DHEA (450 mg/kg, 3 times a week) gained significantly less weight and grew older than the control animals, had less body fat and were more active. The reduction in body weight was achieved without loss of appetite or food restriction. Furthermore, DHEA could prevent weight gain in animals bred to become obese in adulthood (in Kent, Geriatrics 37: 157-160, 1982).
DHEA administration to lean Zucher rats decreased body weight gain despite increased food intake. Treated animals had smaller fat pads thus, overall, suggesting that DHEA increases food metabolism, resulting in lower weight gain and fat accumulation (Svec et al., Proc. 2nd Int. Conf. Cortisol and Anti-Cortisols, Las Vegas, Nev., USA, p. 56 abst., 1997).
Obesity was found to be improved in the Avy mutant mouse (Yen et al., Lipids 12: 409-413, 1977) and in the Zucker rat (Cleary and Zisk, Fed. Proc. 42: 536, 1983). DHEA-treated C3H mice had a younger appearance than controls (Schwartz, Cancer Res. 39: 1129-1132, 1979).
Abdominal fat has been associated with metabolic risk factors for coronary breast disease (Imbault et al. Metabolism 1999, 48 (3), 355-62; Ledoux et al. (CMAJ 1997, 157 Suppl.1; 46-53).
SUMMARY OF THE INVENTION
It is accordingly an object of the present invention to reduce adipose tissue, especially abdominal fat.
It is another object of the present invention to reduce risk of coronary heart disease, and other diseases or conditions for which obesity or excess adipose tissues are risk factors.
In one embodiment, the present invention is to provide a novel method for treating or suppressing weight gain in susceptible warm-blooded animals, including humans, said method comprising administering to a subject, in need of such treatment or suppression, a therapeutically effective amount, with or without a pharmaceutical diluent excipient or carrier, of at least one compound of the general formula I:
wherein R1 and R2 are independently selected from the group consisting of hydrogen, hydroxyl, —OM (M being selected from the group consisting of straight or branched C1-C4 alkyl, straight or branched C3-C4 alkenyl, straight or branched C3-C4 alkynyl) and a moiety convertible in vivo to hydroxyl;
wherein G is —H or —CH3; and
wherein R3 is a species selected from the group consisting of pyrrolidinyl, piperidino, morpholino, and NRaRb (Ra and Rb being independently hydrogen, straight or branched C1-C6 alkyl, straight or branched C3-C6 alkenyl, and straight or branched C3-C6 alkynyl).
In another embodiment, selective estrogen receptor modulator or pharmaceutically acceptable salt thereof is administered for reducing abdominal fat or reducing the accumulation of abdominal fat.
In another embodiment, sex steroid precursor (e.g. dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3b,17b-diol) is administered in addition to a Selective Estrogen Receptor Modulator (SERM) for the treatment of obesity or for suppressing weight gain. Human at or over fifty years of age are believed to respond well to the combination therapy, probably because precursor levels tend to undesirably decrease with age.
Thus, in that aspect, the invention provides a method for the treatment of obesity or suppression of weight gain comprising administering to a subject, in need of such suppression or treatment, a therapeutically effective amount with or without a pharmaceutical diluent or carrier, of at least one SERM and an effective amount of a at least one sex steroid precursor selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3b,17b-diol and compounds converted in vivo to any of the foregoing precursors.
In another aspect, the invention provides a method for treating or reducing the risk of developing insulin resistance comprising administering, to a subject in need of such treatment or reduction, a therapeutically effective amount of at least one SERM. In some embodiments, an effective amount of at least one sex steroid precursor selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3b,17b-diol and compounds converted in vivo to either is administered also as part of a combination therapy.
In another aspect, the invention provides a kit for the treatment of obesity having a first container which includes at least one SERM and a second container which includes at least one sex steroid precursor selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3b,17b-diol and compounds converted in vivo to either.
A pharmaceutical excipient carrier or diluent may also be provided in one or more of the containers and may include preservatives and other additives known in the art. The foregoing may also be included with any active ingredient used in any embodiment of the various inventions described herein.
As used herein, a selective estrogen receptor modulator (SERM) is a compound that either directly or through its active metabolite functions as an estrogen receptor antagonist (“antiestrogen”) in breast tissue, yet provides estrogen-like effect on body fat, on bone tissue and on serum cholesterol levels (i.e. by reducing serum cholesterol). Non-steroidal compounds that function as estrogen receptor antagonists in vitro or in human or rat breast tissue (especially if the compound acts as an antiestrogen on human breast cancer cells) is likely to function as a SERM. Non-steroidal antiestrogens we have tested and found to function as SERMs include EM-800, EM-652, EM-652.HCl (EM-01538) Raloxifene, Tamnoxifen, Idoxifene, Torimefene, LY 353381, LY 335563, GW 5638 and Droloxifene (described in more detail below). SERMs, in accordance with any embodiment of the invent
Deshaies Yves
Labrie Fernand
Marette Andre
Martel Celine
Richard Denis
Endorecherche Inc.
Ostrolenk Faber Gerb & Soffen, LLP
Seaman D. Margaret
LandOfFree
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