Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1997-02-21
1998-09-22
Knode, Marian C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 46, 514 47, 514 48, 514 49, 514 50, 514 51, 514261, 514 81, 514 86, 514269, 536 267, 536 268, 536 276, 536 278, 536 2781, 536 285, 536 2853, 536 41, 544264, 544242, C07H 19207, C07H 1910, C07H 1973, C07H 19173, A61K 3170
Patent
active
058114084
DESCRIPTION:
BRIEF SUMMARY
THIS APPLICATION IS A 371 OF PCT/JP95/01385, FILED JUL. 12, 1995.
TECHNICAL FIELD
The present invention relates to 2'-deoxy-2'-(substituted or unsubstituted)methylidene-4'-thionucleosides, a process for producing the same, and a use of the same.
BACKGROUND ART
With respect to the synthesis or biological activity of 4'-thionucleosides, reports have been hitherto made by the group of the Roswell Memorial Research Institute and/or Purdue University (J. Org. Chem., 36, 108-110 (1971), J. Med. Chem., 17, 535-537 (1974), J. Med. Chem., 18, 784-787 (1975), J. Org. Chem., 41, 3831-3834 (1976), Nucleic Acid Chemistry, 1, 317-323 (1978)), the group of the Southern Research Institute (J. Med. Chem., 34, 2361-2366 (1991), Nucleosides & Nucleotides, 12, 841-846 (1993)), the group of the University of Birmingham (J. Chem. Soc. Chem. Commun., 741-742 (1991), J. Med. Chem., 34, 2782-2786 (1991)), the group of Okayama University (J. Chem. Soc. Chem. Commun., 1421-1422 (1991), Nucleic Acids Symposium Series, 27, 77-78 (1992), Nucleic Acids Symposium Series, 29, 37-39 (1993), Chemistry Letters, 255-256 (1993), The Pharmaceutical Society of Japan, Proceedings of the 113th Symposium, page 82 (1993)), the group of the University of Montpellier (Nucleosides & Nucleotides, 11, 1467-1479 (1992), Nucleosides & Nucleotides, 12, 847-852 (1993)) and the like.
In addition to the above-described reports, two patent applications, Japanese Laid-Open Patent Publication No. 500666/1993 (WO 91/04033) and WO 91/16333, were made by the Southern Research Institute, and four patent applications, Japanese Laid-Open Patent Publications Nos. 506661/1992 (WO 91/01326) and 505791/1993 (WO 91/04982), Japanese Laid-Open Patent Publication No. 170760/1993 and WO 94/05687, were made by the University of Birmingham and/or The Welcome Foundation, Limited.
Furthermore, the following reports have also been made by some groups other than the above-described groups:
J. Am. Chem. Soc., 86, 5658-5663 (1964),
J. Org. Chem., 33, 189-192 (1968),
Can. J. Chem., 56, 794-802 (1978),
Nucleosides & Nucleotides, 12, 139-147 (1993),
WO 92/06993, and
WO 92/06102.
The antitumor activity of 4'-thionucleosides reported in the above-mentioned reports is not necessarily satisfactory when the clinical use of 41-thionucleosides as antineoplastic agents is taken into consideration. Therefore, there is still a need for compounds having more excellent antitumor activity.
2'-Methylidene nucleosides such as 2'-deoxy-2'-methylidenecytidine (Japanese Laid-Open Patent Publications Nos. 230699/1988 and 256698/1990) and 2'-deoxy-2'-fluoro-methylidenecytidine (Japanese Laid-Open Patent Publication No. 178272/1990) have excellent biological activity for solid cancers, so that the progress in the development thereof is now attracting attention.
We therefore made various studies in the synthesis of 4'-thionucleosides having methylidene at the 2'-position of the sugar moiety thereof. As a result, it became apparent that the methods formerly reported were applicable to the synthesis of the ribo-, ara-, or 2'- and/or 3'-deoxy-compounds of 4'-thionucleosides, but not suggestive at all for the synthesis of 4'-thionucleosides having a substituent such as methylidene at the 2'-position of the sugar moiety thereof.
An object of the present invention is therefore to establish a novel method for synthesizing 4'-thionucleosides having methylidene at the 2'-position of the sugar moiety thereof, and, at the same time, to provide a novel and useful compound obtainable by this method.
DISCLOSURE OF THE INVENTION
We have made earnest studies in order to attain the above object, and, as a result, succeeded in obtaining 2'-deoxy-2'-(substituted or unsubstituted)methylidene-4'-thionucleosides represented by the found, and we have further confirmed that the compounds have excellent antitumor activity, thereby accomplishing the present invention.
Namely, the present invention relates to 2'-deoxy-2'-(substituted or unsubstituted)methylidene-4'-thionucleosides represented by the following ##STR2## wherein
REFERENCES:
patent: 3585189 (1971-06-01), Verheyden et al.
patent: 5026835 (1991-06-01), Ueda et al.
patent: 5047520 (1991-09-01), Matsuda et al.
patent: 5183882 (1993-02-01), Sakata et al.
patent: 5206244 (1993-04-01), Zahler et al.
patent: 5300636 (1994-04-01), Matsuda et al.
patent: 5401726 (1995-03-01), Ueda et al.
patent: 5412089 (1995-05-01), Sakata et al.
patent: 5430139 (1995-07-01), Matsuda et al.
patent: 5508393 (1996-04-01), McCarthy et al.
patent: 5591722 (1997-01-01), Montgomery et al.
patent: 5607925 (1997-03-01), Matthews et al.
patent: 5616702 (1997-04-01), Matthews et al.
patent: 5639647 (1997-06-01), Usman et al.
Yoshimura et al. (I), "A Novel Synthesis of Antineoplastic 4'-Thionucleosides Using D-Glucose as a Chiral Synthon, " 22nd Symposium on Nucleic Acid Chemistry, Nucleic Acids Symposium Series, No. 34. Oxfird University Press, Oxford, UK, originally disclosed Nov. 8-10, 1995 at Yokoyama, Japan.
Yoshimura et al. (II), "A Novel Synthesis of New Antineoplastics 2'-Deoxy-2'-substitued-4'-thiocytidines," J. Organic Chem., 61(3), 822-823 (Feb. 9, 1996).
Yoshimura et al. (III), "A Novel Synthesis of 2'-Modified-2'-deoxy-4'-thiocytidines From D-Glucose," J. Organic Chem., 62(10), 3140-3152 (May 16, 1997).
Shinji et al., "In Vitro and In Vivo Antitumor Activity of a Novel Nucleoside, 4'-Thio-2'-deoxy-2'-methylenecytidine," Biol Pharm. Bull., 19(10), 1311-1315 (1996); Chem. Abstr., 126(1), Abstr. No. 510m, p. 51 (Jan. 6, 1997); only Abstract supplied.
Takenuki et al., "Design, Synthesis and Antineoplastic Activity of 2'-Deoxy-2'-methylidenecytidine," J. Medicinal Chem., 31(6), 1063-1064 (Jun. 1988).
Lin et al., "Synthesis and Anticancer and Antiviral Activities of Various 2'- and 3'-Methylidene-Substituted Nucleoside Analogues and Crystal Structure of 2'-Deoxy-2'-methylenecytidine Hydrochloride," J. Medicinal Chem., 34(8), 2607-2615 (Aug. 1991).
Matsuda Akira
Miura Shinji
Sasaki Takuma
Satoh Hiroshi
Yoshimura Yuichi
Crane L. Eric
Knode Marian C.
Yamasa Corporation
LandOfFree
2'-deoxy-2'-(substituted or unsubstituted)methylidene-4'-thionuc does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 2'-deoxy-2'-(substituted or unsubstituted)methylidene-4'-thionuc, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2'-deoxy-2'-(substituted or unsubstituted)methylidene-4'-thionuc will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1621891