Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-01-27
2002-08-27
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S550000, C554S077000, C554S085000, C554S088000, C554S218000, C560S147000, C560S149000, C560S155000, C560S179000, C562S899000
Reexamination Certificate
active
06441036
ABSTRACT:
The present invention relates to novel fatty acid analogous which can be used for the treatment and/or prevention of obesity, fatty liver and hypertension. Further, the invention relates to a nutritional composition comprising such fatty acid analogues, and a method for reducing the total weight, or the amount of adipose tissue in an animal. The invention also relates to a method for improving the quality of product such as meat, milk and eggs.
BACKGROUND OF THE INVENTION
Hyperlipidemia and obesity afflict an increasing proportion of the population in Western societies and are associated with the development of serious conditions such as atherosclerosis, hypertension, fatty liver and insulin resistance. These conditions may eventually lead to the clinical manifestations of coronary heart diseases (CD) and non-insulin dependent diabetes mellitus (NIDDM).
Treatment with modified fatty acids represent a new way to treat these diseases.
EP 345.038 describes the use of non-&bgr;-oxidizable fatty acid analogues for the treatment of hyperlipidaemic conditions and for reducing the concentration of cholesterol and triglycerides in the blood of mammals.
PCT/NO95/00195 describes alkyl-S—CH
2
COOR and alkyl-Se—CH
2
COOR for the inhibition of the oxidative modification OF ldl.
It has now been found that the analogues described in the prior art publication mentioned above, i.e. non-&bgr;-oxidizable fatty acids substituted with Sulphur or Selenium in the 3-position have broader area of applications.
Further, we have now synthesized and characterized novel fatty acid analogues which impose an effect on obesity, hypertension and fatty liver.
In feeding experiments with the fatty acid analogues in accordance with the present invention, the results show that these compounds lower the adipose tissue mass and body weight, and are thus potent drugs for the treatment of obesity and overweight.
Further, we have shown that the fatty acid analogues are potent antidiabetic compounds, with a profound effect on the levels of glucose and insulin.
Further, the compounds have been proved to have an favourable effect on restenosis, and exhibit good anti-oxidative properties.
Obesity
Obesity is a chronic disease that is highly prevalent in modern society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, reproductive disorders such as polycystic ovarian disease, dermatological disorders such as infections, varicose veins, Acanthosis nigricans, and eczema, exercise intolerance, diabetes mellitus, insulin resistance, hyper-tension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injury, thromboembolic disease, cancer, and coronary heart disease.
Existing therapies for obesity include standard diets and exercise, very low calorie diets, behavioral therapy, pharmacotherapy involving appetite suppressants, thermogenic drugs, food absorption inhibitors, mechanical devices such as jaw wiring, waist cords and balloons, and surgery. Caloric restriction as a treatment for obesity causes catabolism of body protein stores and produces negative nitrogen balance.
Considering the high prevalence of obesity in our society and the serious consequences associated therewith as discussed above, any therapeutic drug potentially useful in reducing weight of obese persons could have a profound beneficial effect on their health. There is a need in the art for a drug that will reduce total body weight of obese subjects toward their ideal body weight without significant adverse side effects, and which also will help the obese subject to maintain the reduced weight level.
It is therefore an object of the present invention to provide a treatment regimen that is useful in returning the body weight of obese subjects toward a normal, ideal body weight.
It is another object to provide a therapy for obesity that results in maintenance of the lowered body weight for an extended period of time. Further, is is an object to reduce or inhibit the weight gain normally induced by fat rich diets.
It is yet another object to prevent obesity and, once treatment has begun, to arrest progression or prevent the onset of diseases that are the consequence of, or secondary to, the obesity, such as hypertension and fatty liver. These and other objects will be apparent to those of ordinary skill in the art.
The obesity herein may be due to any cause, whether genetic or environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, Type II diabetics, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity.
Hypertension
Increased blood pressure is a common condition in the developed countries of the world where, in very broad terms, the population eat too much and do not take sufficient exercise. Hypertension can have a variety of uncomfortable and dangerous side effects and it is seen as a major risk factor in relation to coronary heart disease. Hypertension can be associated with specific causes such as kidney disease or adrenal tumours but in most instances it is not. Obesity is regarded as a risk factor in relation to hypertension and a first line strategy in relation to obese hypertensive patients is to suggest weight reduction. It is therefore reasonable to anticipate that the present compounds, e.g. TTA and TSA which can have an effect on obesity, will reduce hypertension.
Specific ailments attributable to hypertension include heart failure, myocardial infarction, rupture or thrombus of the blood vessels in the brain, and kidney damage.
It is therefore an object of the present invention to provide a treatment regimen that is useful in lowering the blood pressure.
Fatty liver
The mechanism of production of fatty hepatosis is not entirely clear, but appears to be a combinaticn of several factors, such as sparing action of ethanol oxidation on utilization of liver triacylglycerols, excessive mobilization of triacylglycerols from adipose tissue to the liver caused in part by action of ethanol in triggering release of hormones, and failure to synthesize sufficient lipoprotein for transport of triacylglycerols because of alterations of amino acid availability.
Fatty cirrhosis is characterized by the liver cells being infiltrated with fat (triacylglycerols). The infiltration usually being due to alcohol ingestion.
The explanation for the ethanol induced increase in hepatic deposition of fat is still not very well understood. However, most investigators believe that ethanol inhibits hepatic fatty acid oxidation which secondarily causes fatty acids to be stored as triacylglycerol.
Fatty liver as a concomitant of the ingestion of high fat diets, alcohols or chlorinated hydrocarbons is a well-known phenomenon. Chronic intake of ethanol results in, among other things, hepatic injury to the accumulation of triglycerides and eventually, cirrhosis.
It is thus an object of the present invention to provide a treatment regimen that is useful in lowering the concentration of triacylglycerols in the liver. It is anticipated that such a regimen will provide an inhibiting effect on the development of a fatty liver condition, and also be suited as a method for the treatment of the manifested disease.
The compounds of the present invention both activates the &bgr;-oxidation, and also reduces the concentration of triglycerieds in the liver.
Mechanisms of action
Minor modifications of natural fatty acids, sulphur, selenium or oxygen replacing one or more of carbons in the fatty acid backbone. The compounds defined by the formula I have properties which give them a unique combination of biological effects.
Tetradecylthioacetic acid (TTA) is most thoroughly studied and we have shown several beneficial effects in various test animals.
The studies have shown that TTA has properties very similar to natural fatty acid
Carr Deborah D.
Reed & Associates
Thia Medica AS
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