| PATENT ASSIGNEE'S COUNTRY | Japan |
| UPDATE | 09.99 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 28.09.99 |
| PATENT TITLE |
Pharmaceutical agents containing methotrexate derivative |
| PATENT ABSTRACT |
Compounds represented by the general formula: ##STR1## (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, the general formula NHCOR.sub.5, the general formula CONR.sub.6 R.sub.7, PO.sub.3 H.sub.2 or SO.sub.3 H; and n is an integer of 1-4) or salts therof are useful as therapeutic agents of autoimmune diseases such as systemic lupus erythematosus and nephritic diseases such as glomerulonephritis. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 25.09.97 |
| PATENT CT FILE DATE | 26.03.96 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | 03.10.96 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
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). Primary Examiner: Henly, III; Raymond Attorney, Agent or Firm: Browdy and Neimark |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
I claim: 1. A method for the treatment of an autoimmune disease selected from the group consisting of systemic lupus erythematosus, autoimmune nephritis and glomerulonephritis, in a patient in need of said treatment, comprising administering to said patient an amount effective for said treatment of a composition comprising as active ingredient a compound of formula (I): ##STR6## where R.sub.1 is 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 formula COOR.sub.4, where R.sub.4 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms, or the formula NHCOR.sub.5, where R5 is an optionally substituted phenyl group, or the 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, and a pharmaceutical excipient. 2. The method of claim 1 wherein said patient is one whose autoimmune disease is systemic lupus erythematosus. 3. The method of claim 1 wherein said patient is one whose autoimmune disease is autoimmune nephritis. 4. The method of claim 1 wherein said patient is one whose autoimmune disease is glomerulonephritis. 5. The method of claim 1 wherein said patient is one whose autoimmune disease is lupus nephritis. 6. A method for the treatment of an autoimmune disease selected from the group consisting of systemic lupus erythematosus, autoimmune nephritis and glomerulonephritis, in a patient in need of said treatment, comprising administering to said patient an amount effective for said treatment of a compound of formula (II): ##STR7## 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. |
| PATENT DESCRIPTION |
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 proliferation of human lymphocytes, rat and human keratinocytes and mouse cancer cells (P388, colon 26) and suggests the utility of the compounds as therapeutic agents for rheumatoid arthritis, psoriasis and cancers on the basis of the experimental results. In addition, International Publication WO 94/14810 discloses data showing that compounds represented by the general formula (II) have an inhibitory effect on the proliferation of synovial cells derived from rheumatoid arthritis patients, thus suggesting the utility of the compounds as antirheumatics. However, no report has yet been made showing that compounds represented by the general formula (I) are effective against diseases such as systemic lupus erythematosus and glomerulonephritis. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the suppressive effect of various drugs on urinary protein excretion from MRL/lpr mice; FIG. 2 is a graph showing the prolongation of the survival of MRL/lpr mice by various drugs; FIG. 3 is a graph showing the suppressive effect of various drugs on urinary protein excretion from NZB/WF1 mice; FIG. 4 is a graph showing the prolongation of the survival of NZB/WF1 mice by various drugs; and FIG. 5 is a graph showing the suppressive effect of various drugs on the elevation of BUN in NZB/WF1 mice. BEST EMBODIMENT FOR CARRYING OUT THE INVENTION The pharmaceutical agents of the invention are useful in the treatment of autoimmune diseases such as systemic lupus erythematosus and autoimmune glomerulonephritis. The agents are particularly useful in the treatment of lupus nephritis. The pharmaceutical agents of the invention are also useful in the treatment of nephritis, in particular, glomerulonephritis. Examples of glomerulonephritis include not only lupus nephritis but also nephritis caused by polyarteritis nodosa, nephritis caused by Schonlein-Henoch purpura, nephritis caused by Weigner's granulomatosis and Goodpasture's syndrome. The "lower alkyl group" as used in the invention refers to straight- or branch-chained alkyl groups having 1-6 carbon atoms unless otherwise specified by carbon number, and preferred examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl groups, etc. The "substituent" refers to lower alkyl, hydroxyl, amino, halogeno, cyano, lower alkyloxy, mercapto, acyl, acyloxy, phenyl, carboxyl, lower alkyloxycarbonyl groups, etc., and preferred examples include carboxyl, lower alkyloxycarbonyl groups, etc. The "carboxyalkyl group" refers to lower alkyl group substituted by one or more carboxyl groups and preferred examples include lower alkyl groups substituted by one carboxyl group, more preferred examples including a 3-carboxypropyl group. Preferred examples of the lower alkylsulfonyl group include a methanesulfonyl group, etc. The compounds of the invention may be used in the form of salts obtainable by conventional methods. Usable salts include: inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodies, sulfates and phosphates; organic acid salts such as succinates, malonates, acetates, maleates, fumarates, citrates, gluconates, mandelates, benzoates, salicylates, methanesulfonates, benzenesulfonates and p-toluenesulfonates; and metal salts such as sodium, potassium and magnesium salts; inorganic and organic acid salts are preferred, with hydrobromides and methanesulfonates being particularly preferred. Compounds preferred for use as therapeutic agents of the invention are those described in the Examples of International Publications WO 92/03436 and WO 94/14810 and the most preferred compounds are those described in the Examples of International Publication WO 94/14810. Pharmaceutical agents containing the compounds of the invention can be administered either perorally or parenterally, with peroral administration being particularly preferred. The dose varies with the type of the disease to be treated, the body weight of the patient, symptoms and the like, and the usual dose ranges from 0.01 to 100 mg/day/person. The pharmaceutical agents containing the compounds of the invention can take various dosage forms including solutions (e.g. injections), tablets, capsules and powders. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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