Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-06-15
1998-03-17
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544 52, A61K 3154, C07D27916
Patent
active
057286922
DESCRIPTION:
BRIEF SUMMARY
THIS IS A 371 OF PCT/JP 93/01867 FILED DEC. 24, 1993.
TECHNICAL FIELD
This invention relates to a novel methotrexate derivative, and, more specifically, to a novel methotrexate derivative useful as an antirheumatic agent.
TECHNICAL BACKGROUND
Hitherto, methotrexate has been used for many years as a treating agent for leukemia, but, since Gubner et al reported in 1951 the effectiveness by using aminopterin for rheumatoid arthritis (RA) and psoriasis, an attention has been drawn to aminopterin as a treating agent for RA and it has mainly been used in Europe and U.S.A. In relatively recent years, the method of use and the dosage thereof have been studied in more detail, and it becomes apparent that the treatment at a low dose of methotrexate exhibits low side effects and excellent effectiveness. However, since side effects such as hepatic disorders and lung fibrosis caused by administration of methotrexate is not negligible, development of a drug having less side effects and yet having excellent effects is desired.
Hitherto, methotrexate derivatives in which an alkyl group other than a methyl group has been introduced into N.sup.10, for example, having the following formula: ##STR2## (J. Med. Chem., 22, 862 (1979) and having the following formula: ##STR3## (J. Med. Chem., 25, 877 (1982) have been known, but none of these compounds showed a satisfactory activity.
The present inventors made extensive studies for developing compounds having a good balance between a pharmacological effect as an antirheumatic agent and side effects in the above type of methotrexate derivatives, and as a result completed the present invention.
DISCLOSURE OF THE INVENTION
The present invention relates to a methotrexate derivative represented by the following general formula (I): ##STR4## wherein R.sub.1 and R.sub.2 may be the same or different and each represents a hydrogen atom or a lower alkyl group having from 1 to 4 carbon atoms, and a salt thereof. Further, the present invention provides an antirheumatic agent containing at least one of these compounds as an effective ingredient.
BRIEF DESCRIPTION OF DRAWING
FIG. 1 shows a percent cell propagation at each of the concentrations of the test drugs.
BEST MODE FOR WORKING THE INVENTION
The compounds according to the present invention are described as a general formula in broad concept in WO 92/3436, but are novel compounds, none of which has been actually produced and have not been disclosed in literature references. These compounds are synthesized, for example, in the following manner: ##STR5## wherein R.sub.1 and R.sub.2 may be the same or different and each represents a hydrogen atom or a lower alkyl group having from 1 to 4 carbon atom, A represents a protective group, and X represents a halogen atom.
The reaction for obtaining a compound of the general formula (3) from a compound of the general formula (1) and a compound of the general formula (2) is performed by an amido-bond forming reaction generally used. For example, the compound of the general formula (1) is suspended in an acid halogenating agent such as thionyl chloride and oxalyl chloride and stirred in the presence of a catalytic amount of dimethylformamide, etc. at room temperature to obtain an acid halide which is then dissolved in a solvent such as dichloromethane and added to an aqueous solution of the compound of the general formula (2) under ice cooling or water cooling, followed by stirring at room temperature in the presence of an inorganic salt such as potassium carbonate, sodium hydroxide and sodium bicarbonate.
Examples of the protective group represented by A in the formula include a protective group for an amino group such as an acyl group, and preferably, a carbobenzoxy group, a tosyl group and an acetyl group. The compound of the general formula (1) can be obtained, for example, by the method described in International Publication WO 92/3436.
The compound of the general formula (3) is de-protected by the usual method thereby converting into the compound of the general formula (4). For ex
REFERENCES:
Marpat Abstract of WO/92/3436 (Mar. 5, 1992) Ohi et al. (Abstract #117:48228).
Ohi Nobuhiro
Suzuki Hiroshi
Chugai Seiyaku Kabushiki Kaisha
Henley III Raymond
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