Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-09-25
1999-09-28
Henly, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31505
Patent
active
059589280
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to pharmaceutical agents containing methotrexate derivatives. More specifically, the invention relates to pharmaceutical agents containing methotrexate derivatives effective against autoimmune diseases (e.g. systemic lupus erythematosus) and glomerulonephritis.
BACKGROUND ART
Methotrexate (MTX) is an antifolate and is used for the treatment of acute leukemia, malignant lymphoma and other diseases. It is also known as an immunosuppressive drug and is primarily used for preventing acute graft-versus-host reactions in bone marrow transplantation. Furthermore, administration of low doses of MTX is known to be effective for the treatment of rheumatoid arthritis.
However, MTX causes comparatively severe side effects such as hepatotoxicity and fibrosis in lungs, which are often problematic in its clinical use. Consequently, development of drugs are desired that have strong efficacy and minimal side effects.
DISCLOSURE OF INVENTION
An object of the invention is to provide therapeutic agents for autoimmune diseases (e.g. systemic lupus erythematosus) and glomerulonephritis that are excellent in terms of balance of efficacy and side effects.
As a result of intensive studies conducted to attain the above-stated object, the present inventors found that compounds represented by the general formula (I): ##STR2## where R.sub.1 is one member selected from the group consisting of CH.sub.2, CH.sub.2 CH.sub.2, CH.sub.2 O, CH.sub.2 S and CH.sub.2 SO; R.sub.2 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms or a benzyl group; R.sub.3 is a group represented by the general formula COOR.sub.4 (where R.sub.4 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms) or the general formula NHCOR.sub.5 (where R.sub.5 is an optionally substituted phenyl group) or the general formula CONR.sub.6 R.sub.7 (where R.sub.6 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms, and R.sub.7 is a lower alkyl group having 1-4 carbon atoms or an optionally substituted phenyl group or a carboxyalkyl group or a lower alkylsulfonyl group) or a group represented by PO.sub.3 H.sub.2 or SO.sub.3 H; n is an integer of 1-4, or salts thereof are useful as therapeutic agents for autoimmune diseases (e.g. systemic lupus erythematosus) and glomerulonephritis. The present invention has been accomplished on the basis of this finding.
Thus, the present invention relates to a therapeutic agent for autoimmune diseases (e.g. systemic lupus erythematosus) and glomerulonephritis which contains a compound represented by the general formula (I): ##STR3## where R.sub.1 is one member of the group consisting of CH.sub.2, CH.sub.2 CH.sub.2, CH.sub.2 O, CH.sub.2 S and CH.sub.2 SO; R.sub.2 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms or a benzyl group; R.sub.3 is a group represented by the general formula COOR.sub.4 (where R.sub.4 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms) or the general formula NHCOR.sub.5 (where R.sub.5 is an optionally substituted phenyl group) or the general formula CONR.sub.6 R.sub.7 (where R.sub.6 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms, and R.sub.7 is a lower alkyl group having 1-4 carbon atoms or an optionally substituted phenyl group or a carboxyalkyl group or a lower alkylsulfonyl group) or a group represented by PO.sub.3 H.sub.2 or SO.sub.3 H; n is an integer of 1-4, or a salt thereof as an active ingredient.
The invention also relates to a therapeutic agent for autoimmune diseases (e.g. systemic lupus erythematosus) and glomerulonephritis which contains a compound represented by the general formula (II): ##STR4## where R.sub.8 and R.sub.9 which may be the same or different represent a hydrogen atom or a lower alkyl group having 1-4 carbon atoms, or a salt thereof as an active ingredient.
The compounds of the invention which are represented by the general formula (I) are described in International Publication WO 92/03436, which discloses data showing the ability of the compounds to suppress the
REFERENCES:
patent: 5354753 (1994-10-01), Ohi et al.
patent: 5728692 (1998-03-01), Ohi et al.
Mihara, M. et al., "Effect of Methotrexate Treatment on the Onset of Autoimmune Kidney Disease in Lupus Mice," Chem. Pharm. Bull., 40-8:2177-2181 (1992).
Segal, R. et al., "Methotrexate Treatment in Murine Experimental Systemic Lupus Erythematosus (SLE); Clinical Benefits Associated with Cytokine Manipulation," Clin. Exp. Immunol., 101:66-72 (1995).
Rothenberg, R. J. et al., "The Use of Methotrexate in Steriod-Resistant Systemic Lupus Erythematosus," Arthritis and Rheumatism, 31-5:612-615 (1988).
LeBlanc, B. A. E. W., et al., "Methotrexate in Systemic Lupus Erythmatosus," The Journal of Rheumatology, 21:836-838 (1994).
Wilson, K., et al., "A 2 Year, Open End Trail of Methotrexate in Systemic Lupus Erythematosus," The Journal of Rheumatology, 21:1674-1677 (1994).
Baggott, J. E. "Long-term Treatment of the MRL/lpr Mouse With Methotrexate and 10-Deazaaminofterin," Agents Actions, 35:104-111 (1992).
Chugai Seiyaku Kabushiki Kaisha
Henly, III Raymond
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