Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-28
2001-10-30
Berch, Mark L (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S265000, C548S326500
Reexamination Certificate
active
06310070
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel purine derivatives or pharmaceutically acceptable salts thereof and their application as medicines. The medicine comprising a purine derivative or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient is useful as a nephritis curative medicine, particularly as a medicine for improving proteinuria due to glomerulo nephritis and preventing aggravation of nephritis. Due to these curative effects, the medicine is expected to improve the quality of life for nephritis patients and to deter or avoid the introduction of dialysis to those patients.
BACKGROUND OF THE INVENTION
Presently, with the exception of certain kidney diseases, a causitive therapy vital for the treatment of chronic nephritis has not yet been realized. Most medical treatments currently applied to nephritis therefore aim at relaxation of symptoms and retardation or prevention of progression of the disease. A drug therapy, as well as confinement of daily behavior and dietetics, is the major treatment of chronic nephritis. As a drug therapy, an oral steroid drug is used as the primarily chosen medicine, in addition to conventional anti-platelet drugs. A cocktail treatment, in which four types of drugs (i.e. an immunosuppressive drug, a blood coagulation inhibitor and steroid, an immunosuppressive drug, an anti-platelet drug and blood coagulation inhibitor) simultaneously administered, is applied to the treatment of refractory nephritis and rapidly progressive glomerulo nephritis which are difficult to be cured by conventional drugs (Kidney and Dialysis, 34, 555 (1994)).
On the other hand, efforts for establishing new drugs and methods of treatment for nephritis have been undertaken in recent years. These efforts have matured into the development of an angiotensin converting enzyme inhibitor for the treatment of chronic nephritis or nephrotic syndrome (Nephrol. Dial. Transplant., 6, 936 (1993)) and the development of a novel immunosuppressive drug called cyclosporin which is used for the treatment of refractory nephrotic syndrome (Brit. Med. J., 295, 1165 (1987)), for example. Other drugs in which the introduction of is under study include, a thromboxanes synthetic enzyme inhibitor (Clin. Neph., 30, 276 (1988)), a platelet activating factor antagonist medicine (Kidney Int., 31, 1248 (1987)), various growth stimulating factors such as transforming growth factory-&bgr;, and cytokines as well as their receptor inhibitors (Nature, 346, 371 (1990)). In addition, LDL apheresis has been applied to the treatment of focal sclerosing glomerulonephritis which presents concomitant with hyper lipemia, and found to be effective for the improvement of proteinuria and retardation of kidney function disorder. (Kidney and Dialysis, 34, 555 (1994)).
Although these various methods of treatment have been proven to exhibit certain clinical effects, a medicine effective for the treatment of nephritis without any adverse side effects has yet to be discovered. Establishment of an effective treatment method for nephritis is essential not only to retard introduction of dialysis to a nephritis patient and improve the quality of life for the patient, but also to improve treatment economy. For these reasons, the development of a medicine which can be effectively applied to the treatment of nephritis has been pursued. The present inventors have also proposed and filed an application for a patent relating to the use of purine derivatives exhibiting an anti-inflammation function as an agent for the treatment of nephritis (Japanese Patent Application Laid-open No. 316158/1995). However, development of a novel and more effective drug for the treatment of nephritis has long been anticipated.
DISCLOSURE OF THE INVENTION
The present invention has been accomplished in order to overcome the problems described above. Specifically, an object of the present invention is to provide a novel compound exhibiting a depression effect on an inflammation which is peculiar to nephritis and a pharmaceutical composition for the treatment of nephritis which comprises this novel compound as an active ingredient. The present inventors have undertaken extensive studies to develop a novel compound effective for suppressing inflammatory disease and have found novel purine compounds and their derivatives, and evaluated their biological activities to discover that these compounds possess a certain biological activity effective for the treatment of nephritis. This finding has led to the completion of the present invention.
Accordingly, an object of the present invention is to provide purine derivatives of the following general formula (I),
wherein R
1
is a hydrocarbon group having 17 or less carbon atoms or a group in which one or more CH
2
g roups in the hydrocarbon group which do not directly bind with the carbon atom at 2 position of the purine ring are replaced by carbonyl groups, sulfonyl groups, O, or S and/or in which one or more CH groups in the hydrocarbon group which do not directly bind with the carbon atom at 2 position of the purine ring are replaced by N, C-halogen, or C—C≡N; and R
2
is a hydrocarbon group having 16 or less carbon atoms or a group in which one or more CH
2
groups in the hydrocarbon group which do not directly bind with the methylene group on the nitrogen atom at 7 position of the purine ring are replaced by carbonyl groups, sulfonyl groups, O, or S and/or in which one or more CH groups in the hydrocarbon group which do not directly bind with the methylene group on the nitrogen atom at 7 position of the purine ring are replaced by N, C-halogen, or C—C≡N, or pharmaceutically acceptable salts thereof. Another object of the present invention is to provide a pharmaceutical composition for the treatment of nephritis comprising said purine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
As depicted in the test examples hereinafter, the pharmaceutical composition for the treatment of nephritis of the present invention exhibits a pharmacological action to relax and retard the pathology caused by primary nephritis of various types which include an acute inflammatory reaction, immunoreaction, and various kidney function disorders due to blood vessel operative substances, as well as secondary nephritis caused by diabetic mellitus and hypertension.
The novel purine derivatives of the present invention will now be described in detail. The purine ring skeleton of the purine derivative possesses a 7-methylhypoxanthine(6-oxo-7-methylpurine) skeleton which is a tautomerism structure of 7-methylpurin-6-ol, with the 2 position being replaced by substituent R
1
— and the 7 position by substituent R
2
—SH
2
—, respectively. The novel purine derivatives are described as hypoxanthine derivatives, although these compounds possess both hypoxanthine(6-oxopurine) and purine-6-ol(6-hydroxypurine) which are mutually tautomeric. In addition, in the above-mentioned general formula (I) there is a hypoxanthine (6-oxopurine) skeleton wherein the hydrogen atom on the nitrogen atom of 1 position transfers onto the nitrogen atom at 3 position. These structures are also in the relationship of tautomerism and included in the present invention.
Given as examples of pharmaceutically acceptable salts of the purine derivatives of the present invention are salts of a pharmaceutically acceptable acid such as hydrochloride, sulfate, acetate, hydrobromate, phosphate, succinate, maleate, fumarate, citrate, gluconate, methanesulfonate, and p-toluenesulfonate, and salts of a pharmaceutically acceptable cation such as sodium salt, potassium salt, and calcium salt. The pharmaceutically acceptable salts of the purine derivative can be prepared by recrystallization, or the like, of a mixture of the purine derivative and a corresponding acid or base.
The groups R
1
and R
2
which characterize the purine derivatives of the present invention will now be described in more detail. The groups R
1
and R
2
are respectively selected from a hydrocarbon group or
Isobe Yoshiaki
Kisanuki Sumitsugu
Matsuda Yoshikazu
Matsui Junko
Yokoyama Akihisa
Berch Mark L
Japan Energy Corporation
Testa Hurwitz & Thibeault LLP
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