Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-02-12
1994-10-11
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544 57, 544 584, 544 586, 544 61, 544105, 544243, 544260, A61K 31505, C07D47508
Patent
active
053547535
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a methotrexate derivative, more specifically to a novel methotrexate derivative available as an antirheumatic agent, psoriasis curing agent and carcinostatic agent.
2. Prior art
Methotrexate has been known as a curing agent of leukemia, and Gubner et al. reported its effectiveness for rheumatoid arthritis (RA) or psoriasis in 1951 and it has been used until then as a curing agent of RA in Europe and the United States. Relatively recently, detailed investigations about method of use and dose have been carried out, and it has been clarified that methotrexate therapy in a low dose develops excellent effectivity with a relatively limited side effects. However, side effects such as hepatopathy or fibroid lung caused by the administration of methotrexate cannot be ignored so that a drug having fewer side effects and increased effectiveness has earnestly been desired.
As methotrexate derivatives to which an alkyl group other than methyl group is introduced at N.sup.10, there have been known for example, the following formula: ##STR2## (J. Med. Chem., 22, p. 862 (1979)) or the formula: ##STR3## (j. Med. Chem. 25, p. 877 (1982)), and the like, however, they did not necessarily show sufficient activity.
SUMMARY OF THE INVENTION
The present invention is to provide a novel methotrexate derivative represented by the following formula (I): ##STR4## wherein R.sup.1 represents one 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.sup.2 represents hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a benzyl group; n represents an integer of 1 to 4; R.sup.3 represents a group represented by the formula: COOR.sup.4 (where R.sup.4 represents hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms), NHCOR.sup.5 (where R.sup.5 represents a phenyl group which may be substituted), CONR.sup.6 R.sup.7 (where R.sup.6 represents hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms; R.sup.7 represents a lower alkyl group having 1 to 4 carbon atoms, a phenyl group or a carboxylalkyl group each of which may be substituted or a lower alkylsulfonyl group), PO.sub.3 H.sub.2 or SO.sub.3 H,
The compound of the present invention has an excellent antirheumatic function, psoriasis curing function and carcinostatic function and is also characterised in having a lower toxicity than that of the conventional methotrexate.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 to 3 show amounts (ratio) of 3H-UdR to be uptake at a respective concentration of drugs to be tested.
FIG. 4 shows "rat keratinocyte growth inhibitions function" and FIG. 5 shows "human keratinocyte growth inhibition function", respectively. Absorbances at respective concentrations of drugs to be tested are shown based on an absorbance when no drug is added as 100%.
FIG. 6 shows "growth inhibition function of P388 cell" and FIG. 7 shows "growth inhibition function of colon 26". Absorbances at respective concentrations of drugs to be tested are shown based on an absorbance when no drug is added as 100%.
FIG. 8 shown weight changes in rats when methotrexate or the compound of the present invention is administered, FIG. 9 shows change in number of white blood cells (WBC) and red blood cells (RBC), and FIG. 10 shows changes in liver function and TG content in liver.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compounds of the present invention are each novel and have not yet been described in any of references and may be synthesized, for example, as follows:
Method A
##STR5##
Method C
When R.sub.3 in the formula (I) represents the formula: ##STR6## carbon atoms, ##STR7## above, R' represents hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, A.sup.1 and A.sup.2 each represents a protective group and X represents a halogen atom.
In Method A, the reaction for obtaining the compound of the formula (2) from the compound of the formula (1) is carried out by suspending the compound of the formula (1)
REFERENCES:
J. Het. Chem. 20, 807, 1983.
J. A. Montgomery et al., "Analogues of Methotrexate", Journal of Medicinal Chemistry, 1979, vol. 22, No. 7 pp. 862-868.
J. R. Piper et al., "Synthesis of .alpha. and .gamma. substituted amides, peptides, and esters of methotrexate and their evaluation as inhibitors of folate metabolism", Journal of Medicinal Chemistry, 1982, 25, No 2. pp. 182-187.
A. Rosowsky et al., "Methotrexate Analogues. 33. N .delta.-Acyl-N .alpha.-(4-amino-deoxypetroyl)-L-ornithine Derivatives: Synthesis and in Vitro Antitumor Activity", Journal of Medicinal Chemistry, 1988, 31, No. 7, pp. 1332-1337.
R. J. Kempton et al., "Lysine and Ornithine Analogues of Methotrexate as Inhibitors of Dihydrofolate Reductase," Journal of Medicinal Chemistry, 1982, vol. 25, No. 4, pp. 475-477.
J. R. Piper et al., "10-Propargylaminopterin and Alkyl Homologues of Methotrexate as Inhibitors of Folate Metabolism", Journal of Medicinal Chemistry, 1982, vol. 25, No. 7, pp. 877-880.
J. R. Piper et al., "A Synthetic Approach to Poly (-glutamyl) Conjugates of Methotrexate", Journal of Medicinal Chemistry, 1983, vol. 26, No. 2, pp. 291-296.
A. Rosowsky et al., "Methotrexate Analogues. 20. Replacement of Glutamate by Longer Chain Amino Diacids: Effects on Dihydrofolate Reductase Inhibition, Cytotoxicity, and in Vivo Anti Antitumor activity", Journal of Medicinal Chemistry, vol. 26, No. 12, pp. 1719-1725, 1983.
A. Rosowsky et al., "Methotrexate Analogues, 19. Replacement of the Glutamate Side Chain in Classical Antifolates by L-Homocysteic Acid and L-Cysteic Acid: Effect on Enzyme Inhibition and Antitumor Activity." Journal of Medicinal Chemistry, vol.: 27, No. 5 pp. 600-604, 1989.
A. Rosowsky et al. "Methotrexate Analogues. 26. Inhibition of Dihydrofolate Reductase and Folypolyglutamate Synthetase Activity and in Vitro Tumor Cell Growth by Methotrexate and Aminopterin Analogues Containing a Basic Amino Acid Side Chain", Journal of Medicinal Chemistry, 1986, vol. 29, No. 5.
Methotrexate Analogues. 32. Chain Extension, .alpha.-Carboxyl Deletion, and -Carboxyl Replacement by Sulfonate and Phosphonate: "Effect on Enzyme Binding and Cell.varies.Growth Inhibition", Journal of Medicinal Chemistry, 1988 vol. 31, No. 7 pp. 1326-1331.
D. F. Worth et al. "Folate Antagonists. 10. Synthesis and Antimalarial Effects of 6-[[(Aryl and aralkyl) amino]methyl]-2,4-pteridinediamines and -pteridinediamine 8-Oxides", Journal of Medicinal Chemistry, 1978, vol. 21, No. 4 pp. 331-337.
Akamatsu Ken-ichi
Kato Nobuaki
Matsuoka Hiroharu
Mihara Masahiko
Miyamoto Katushito
Chugai Seiyaku Kabushiki Kaisha
Gupta Y. N.
Shah Mukund J.
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