Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1994-07-12
2003-05-06
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S260000
Reexamination Certificate
active
06559149
ABSTRACT:
This application is a 371 of PCT /JP93/00096, filed Jan. 27, 1993.
1. Technical Field
This invention relates to novel methotrexate derivatives, more particularly to novel methotrexate derivatives that are useful as antirheumatic agents.
2. Background Art
Methotrexate had long been used as a therapeutic agent for leukemia but ever since Gubner et al. reported its effectiveness in the treatment of rheumatoid arthritis (RA) and psoriasis in 1951, methotrexate has been used as a therapeutic agent for RA in both Europe and the United States of America. Fairly recently, detailed investigations were conducted on the method of administration and dose of methotrexate to reveal that low-dose methotrexate therapy causes fairly less side effects and yet exhibit excellent efficacy. However, the administration of methotrexate causes various side effects that cannot be ignored, such as hepatopathy and pulmonary fibrosis and, hence, a strong need exists for the advent of drugs that cause lesser side effects without compromise in their efficacy.
The present inventors conducted intensive studies in search for methotrexate derivatives that exceed methotrexate in efficacy as a rheumatism treating agent. The present invention has been accomplished on the basis of these studies.
DISCLOSURE OF THE INVENTION
The present invention provides methotrexate derivatives that are represented by the following general formula (II):
{where W is a group represented by the general formula:
[where R
1
is a lower alkyl group having 1-4 carbon atoms; R
2
is a lower alkyl group having 1-4 carbon atoms or a trifluoromethyl group; R
3
is a hydrogen atom, a lower alkyl group having 1-4 carbon atoms or a trifluoromethyl group; R
4
is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; R
5
is a group represented by the general formula COOR
6
(where R
6
is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms) or a group represented by the formula SO
3
H; and n is an integer of 1-4], or the general formula:
[where R
7
is a lower alkyl group having 1-4 carbon atoms; R
8
is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; R
6
is a group represented by the general formula COOR
10
(where R
10
is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms) or a group represented by the formula SO
3
H; and m is an integer of 1-4], or the general formula:
[where R
11
is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; R
12
is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; R
13
is a group represented by the general formula COOR
14
(where R
14
is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms) or a group represented by the formula SO
3
H; and l is an integer of 1-4], or the general formula:
[where R
15
is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; R
16
is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; and k is an integer of 2 or 3].
The present invention also relates to the use of these compounds as antirheumatics. The antirheumatics of the present invention include a known compound, namely, 3′-methylaminopterin (see Cancer Research, Vol. 20, No. 10, 698-733, 1960); however, the use of this compound as an antirheumatic agent has not been known.
REFERENCES:
patent: 4490529 (1984-12-01), Rosowsky
patent: 5354753 (1994-10-01), Ohi et al.
patent: 0048000 (1982-03-01), None
patent: 5-132485 (1993-05-01), None
patent: 5-339268 (1993-12-01), None
patent: 6-16670 (1994-01-01), None
patent: 92-03436 (1992-03-01), None
patent: 93-15077 (1993-08-01), None
Worth et al. Jour. Med. Chem vol. 21 pp331-7 (1978).*
Venditti et al. Cancer Research, vol. 20 No. 10 pp. 698-733, (1960).*
Broughton et al., Chemical Abstracts, vol. 115:247448, 1991.*
Chabner et al.,Polyglutamation of Methotrexate, The Journal of Clinical Investigation, Inc., vol. 76, pp. 907-912, Sep. 1985.
Montgomery et al.,Analogues of Methotrexate, Journal of Medicinal Chemistry, vol. 22, No. 7, pp. 862-868 Jan 15, 1979.
Rosowsky et al.,Methotrexate Analogues. 26. Inhibition of Dihydrofolate Reductase and Folylpolyglutamate Synthetase Activity and in Vitro Tumor Cell Growth by Methotrexate and Aminopterin Analogues Containing a Basic Amino Acid Side Chain,Journal of the Medical Chemistry, vol. 29, pp. 655-660, 1986.
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 the Medical Chemistry, vol. 27, pp. 600-604, 1984.
Rosowsky et al.,Methotrexate Analogues. 33. N&dgr;-Acyl-N&agr;-(4-amino-4-deoxypteroyl)-L-ornithine Derivatives: Synthesis and in Vitro Antitumor Activity, Journal of the Medical Chemistry, vol. 31, pp. 1332-1337, 1988.
Rosowsky et al.,Methotrexate Analogues. 28. Synthesis and Biological Evaluation of New y-Monoamides of Aminopterin and Methotrexate,Journal of the Medical Chemistry, vol. 29, pp. 1703-1709, 1986.
Piper et al.,10-Propargylaminopterin and Alkyl Homologues of Methotrexates as Inhibitors of Folate Metabolism, Journal of the Medical Chemistry, vol. 25, pp. 877-880, 1982.
Rosowsky et al.,Methotrexate Analogues. 20. Replacement of Glutamate by Longer-Chain Amino Diacids: Effects on Dihydrofolate Reductase Inhibition, Cytotoxicity, and Vivo Antitumor Activity, Journal of the Medical Chemistry, vol. 26, pp. 1719-1724, 1983.
Piper et al.,Studies on Analogues of Classical Antifolates Bearing the Naphthoyl Group in Place of Benzoyl in the Side Chain, Journal of the Medical Chemistry, vol. 36, pp. 4161-4171, 1993.
Galivan et al,y-Fluoromethotrexate: Synthesis and biological activity of a potent inhibitor of dihydrofolate reductase with greatly diminished ability to form poly-y-glutamates, Proc. Natl. Acad. Sci. USA, vol. 82, pp. 2598-2602, May 1985.
Degraw et al.,Synthesis and Antifolate Properties of 9-Alkyl-10-deazaminopterins, Journal of the Medical Chemistry, vol. 33, pp. 212-215, 1990.
Abraham et al.,Folate Analogues. 33. Synthesis of Folate and Antifolate Poly-y-glutamates by[(9-Fluorenylmethoxy)oxy]carbonyl Chemistry and Biological Evaluation of Certain Methotrexate Polyglutamate Polylysine Conjugates as Inhibitors of the Growth of H35 Hepatoma Cells, Journal of Medical Chemistry, vol. 33, pp. 711-717, 1990.
Cosulich et al,Analogs of Pteroylglutamic Acid. IX. Derivatives with Substituents on the Benzene Ring, Journal of the American Chemical Society, vol. 75, No. 19, Oct. 5, 1953.
Kato Nobuaki
Kuroki Toshio
Maruyama Noriaki
Matsuoka Hiroharu
Nakagomi Kazuya
Chugai Seiyaku Kabushiki Kaisha
Raymond Richard L.
LandOfFree
Methotrexate derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methotrexate derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methotrexate derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3068382