Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-03
2002-03-05
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S410000, C514S422000, C514S443000, C514S448000
Reexamination Certificate
active
06353003
ABSTRACT:
FIELD OF THE INVENTION
The present invention deals with the disciplines of medicinal chemistry, cardiovascular physiology, and pharmacology. Specifically, the present invention is related to decreasing known risk factors of cardiovascular disease and other related symptoms associated with increased levels of homocysteine and C-reactive protein by administering certain 2-aryl-3-aroylbenzo[b]thiophenes.
BACKGROUND OF THE INVENTION
Cardiovascular disease is a major cause of death in the United States and a major source of morbidity, medical cost, and economic loss to millions of people. Two of the most common and destructive aspects of cardiovascular disease are the appearance of atherosclerosis and thrombolitic events.
In recent years, a great deal of progress has been achieved in the treatment of cardiovascular disease. This progress has been possible not only because of the advancement of therapeutic intervention in the disease mechanisms, but also through the early identification of patients at risk of developing the disease. Indeed, patient risk identification and early treatment are important features of modern medical practice. Over the last twenty years, a variety of factors and clinical parameters have been identified which correlate with either the current state or the future probability of developing cardiovascular disease. Such risk factors may include measurable biochemical or physiological parameters, e.g., serum cholesterol, HDL, LDL, fibrin levels, etc., or behavioral of life-style patterns, such as obesity, smoking, etc. (For further information see: “Cardiovascular risk factors in the elderly”, Kannel W.,
Coronary Artery Disease
, 8:565-575, 1997 and references cited therein.) Risk factors most germane to the present invention are levels of homocysteine and C-reactive protein.
The intrinsic relationship between a measurable parameter or risk factor and the disease state is not always clear. In other words, it is not always clear whether the risk factor itself is causative or contributory to the disease or is instead an ancillary reflection that is indicative of the disease. Thus, a therapeutic modality, which effects a risk factor, may be directly modifying a pathological mechanism of the disease and its future course, or may be indirectly benefiting some contributory process related to the disease.
Additionally, many risk factors associated with cardiovascular disease are involved in other pathological states in either a causative or indicative role. Therefore, improvement in a particular risk factor in cardiovascular disease may have other beneficial effects in other diseases related to that risk factor. For example, several conditions are known to be associated with abnormally high homocysteine levels, including genetic defect, menopause, hypercholesterolemia, smoking, hypertension, renal failure, and deficiencies in vitamins B
6
, B
12
, and folic acid.
Of particular interest to the methods of the present invention is the reduction of cardiovascular risk factors associated with abnormally high levels of homocysteine and C-reactive protein. It has been shown in a number of clinical studies that high levels of homocysteine in the blood are positively linked with cardiovascular disease. Furthermore, in patients suffering from genetic abnormalities which cause an increase in homocysteine (homocysteinuria), there is a great increase of early onset cardiovascular disease and other pathological conditions, inter alia, occular pathologies, skeletal and peridontal abnormalities, central nervous system irregularities, etc.
Homocysteine is also an intermediate found in the biochemical pathway related to the synthesis of the amino acids glutathione, methionine, and cysteine. Abnormally high levels of homocysteine is indicative of a metabolic disorder in the biochemical synthesis of these amino acids and is, thus, predictive of disease states associated with abnormally low levels of these amino acids. For example, glutathione has known bio-protective anti-oxidant properties such as the cyto-protection of monocytes and macrophages from oxidized low density lipoproteins (LDL). The oxidative action of oxidized LDL's on monocytes and macrophages is thought to be a pathological mechanism in atherosclerotic arterial damage.
C-reactive protein is produced by the liver in response to cytokine production. Cytokines are produced as part of an inflammatory response in the body. Thus, C-reactive protein levels are a marker of systemic inflammatory activity. Chronic inflammation is thought to be one of the underlying and sustaining pathologies in cardiovascular disease.
At menopause, with the loss of estrogen, women's prevalence of cardiovascular disease increases. Also, the risk factors of cardiovascular disease increase, especially lipid (cholesterol and triglyceride), homocysteine, and C-reactive protein levels. Today, the most common method of preventing cardiovascular disease in post-menopausal women is Hormone Replacement Therapy (HRT). However, many women do not comply with this therapy because of the unpleasant side-effects, such as bloating, resumption of mensus, breast tenderness, fear of uterine and breast cancer, etc. Additionally, while HRT does lower cholesterol and homocysteine levels, HRT raises C-reactive protein levels. A new therapeutic agent which lowers these risk factors would be beneficial.
SUMMARY OF THE INVENTION
The present invention provides methods for decreasing levels of homocysteine and C-reactive protein in humans comprising administering to a human in need thereof an effective amount of a compound of formula I:
or a pharmaceutical salt or solvate thereof; wherein:
R
1
and R
3
are independently hydrogen, methyl, benzoyl, substituted benzoyl, or C(O)-(C
1
-C
6
alkyl);
R
2
is selected from the group pyrolidin-1-yl, piperidin-1-yl, and hexamethyleneimin-1-yl; where the R
2
group is optionally the N-oxide.
Further, the present invention relates to a method for inhibiting conditions or detrimental effects caused by an excess of homocysteine and/or C-reactive protein comprising administering to a human in need thereof, an effective amount of a compound of formula I, or a pharmaceutical salt or solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to the discovery that a select group of 2-aryl-3-aroylbenzo[b]thiophenes, i.e., the compounds of formula I, are useful for lowering the levels of homocysteine and C-reactive protein.
As used herein, the term “effective amount” means an amount of a compound of formula I which is capable of decreasing levels of homocysteine and/or C-reactive protein and/or inhibiting conditions or detrimental effects caused by an excess of homocysteine and/or C-reactive protein.
The term “estrogen deficient” refers to a condition, either naturally occurring or clinically induced, where a woman can not produce sufficient estrogenic hormones to maintain estrogen dependent functions, e.g., menses, homeostasis of bone mass, neuronal function, cardiovascular condition, etc. Such estrogen deficient situations arise from, but are not limited to, menopause and surgical or chemical ovarectomy, including its functional equivalent, e.g., medication with GnRH agonists or antagonists, ICI 182780, and the like.
The term “inhibiting” in the context of inhibiting conditions or detrimental effects caused by an excess of homocysteine and/or C-reactive protein includes its generally accepted meaning, i.e., prohibiting, restraining, alleviating, ameliorating, slowing, stopping, or reversing the progression or severity of an increase of homocysteine and/or C-reactive protein and the pathological sequelae, i.e., symptoms, resulting from that event.
General terms used in the description of compounds herein described bear their usual meanings. For example, “C
1
-C
6
alkyl” refers to straight, branched, or cyclic aliphatic chains of 1 to 6 carbon atoms including methyl, ethyl, propyl, iso-propyl, cyclopropyl, n-butyl, pentyl, hexyl and the like.
The term “substituted benzoyl” refers to b
Boudreaux William R.
Delacroix-Muirheid C.
Eli Lilly and Company
Jones Dwayne C.
Sales James J.
LandOfFree
Method for reducing levels of homocysteine and C-reactive... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for reducing levels of homocysteine and C-reactive..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for reducing levels of homocysteine and C-reactive... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2859693