Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-26
2003-10-21
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S063000, C514S450000, C546S281700, C549S214000, C549S270000
Reexamination Certificate
active
06635662
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel radicicol derivatives or pharmacologically acceptable salts thereof which show tyrosine kinase inhibition activity and have antitumor or immunosuppression effects.
BACKGROUND ART
It is known that microbial metabolite radicicol represented by the following formula (B) has an antifungal effect and an anticancer effect [
Nature,
171, 344 (1953);
Neoplasma,
24, 21 (1977) ], an immunosuppression effect (Japanese Published Unexamined Patent Application No. 298764/94), or morphology normalization effect of ras or mos canceration cells [
Oncogene,
11, 161 (1995)].
Furthermore, it is known that radicicol derivatives in which the phenolic hydroxyl group is modified with various acyl groups have an antitumor effect (Japanese Published Unexamined Patent Application No. 226991/92). In addition, it is disclosed that radicicol derivatives in which the phenolic hydroxyl group is modified with an acyl group or an alkyl group show an angiogenesis inhibition effect (Japanese Published Unexamined Patent Application No. 279279/94) or an interleukin 1 production inhibition effect (Japanese Published Unexamined Patent Application No. 40893/96) Recently, oxime derivatives of dienone of a radicicol derivative showing antitumor action and immunosuppression action have been published (WO 96/33989: published on Oct. 31, 1996), and antitumor radicicol derivatives represented by the following formula (B′) have also been published (Japanese Published Unexamined Patent Application 202781/97: published on Aug. 5, 1997).
(In the formula, R
1p
and R
2p
represent a hydrogen atom or an acyl group; and X
p
represents a halogen atom, a hydroxyl group or a lower alkoxy group.)
Additionally, it is known that ansamycins antibiotics, geldanamycin, represented by formula (C) [
The Journal of Antibiotics,
23, 442 (1970)] has tyrosine kinase inhibition activity and antitumor effects [for example,
Cancer Research,
52, 1721 (1992) and
Cancer Research,
54, 2724 (1994)]. It is shown that these effects are expressed by the inhibition of the activation of a tyrosine kinase, such as Src, ErbB-2, Lck or the like, and a serine/threonine kinase Raf-1, through the formation of a complex of geldanamycin with a molecular chaperone Hsp (heat shock/stress protein) 90 by binding to Hsp90 [for example,
Proceedings of the National Academy of Sciences
of the U.S.A, 91, 8324 (1994) and
The Journal of Biological Chemistry,
270, 24585 (1995)]. Consequently, drugs capable of acting upon Hsp90 are also included in tyrosine kinase inhibitors and useful not only as antitumor agents but also for the prevention and treatment of various diseases such as osteoporosis, immune diseases, and the like.
Tyrosine kinase is an enzyme which uses ATP as a phosphate donor and catalyzes transfer of its &ggr;-phosphate group to the hydroxyl group of a specified tyrosine residue of a substrate protein, thereby taking an important role in the control mechanism of intracellular signal transduction. Various tyrosine kinase families are known. Tyrosine kinase activities, such as Src in colon cancer, ErbB-2 in breast cancer and gastric cancer, Abl in leukemia, and the like, increase. Disordered increase in the tyrosine kinase activity causes abnormal differentiation and proliferation of cells. Consequently, specific inhibitors of tyrosine kinase are useful in preventing and treating various diseases, including as antitumor agents.
Lck is a tyrosine kinase which is activated when T lymphocytes are activated by antigen stimulation, and an inhibitor of this enzyme is useful as an immunosuppressant. Also, it is known that Src relates to bone resorption in osteoclast, and an inhibitor of this tyrosine kinase is useful as a bone resorption inhibitor for the treatment of osteoporosis. Additionally, inhibitors of receptor type tyrosine kinases of various growth factors, such as FGF-R (epidermal growth factor receptor), FGF-R (fibroblast growth factor receptor), PDGF-R (platelet-derived growth factor receptor), and the like, are useful as a solid cancer growth inhibitor, an angiogenesis inhibitor, a vascular smooth muscle growth inhibitor, and the like.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide novel radicicol derivatives or pharmacologically acceptable salts thereof which show tyrosine kinase inhibition activity and have antitumor or immunosuppression effects.
The present invention can provide radicicol derivatives represented by the following formula (I) or pharmacologically acceptable salts thereof:
wherein R
1
and R
2
are the same or different, and each represents hydrogen, alkanoyl, alkenoyl, tert-butyldiphenylsilyl or tert-butyldimethylsilyl;
R
3
represents:
Y—R
5
{wherein Y represents substituted or unsubstituted alkylene; and R
5
represents CONR
6
R
7
(wherein R
6
represents hydrogen, hydroxyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, or NR
8
R
9
(wherein R
8
and R
9
are the same or different, and each represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted alkanoyl, substituted or unsubstituted aroyl, carbonyl bound to a substituted or unsubstituted heterocyclic ring, or substituted or unsubstituted arylcarbamoyl), or is combined together with R
7
and adjoining N to represent a substituted or unsubstituted heterocyclic group; and R
7
is combined together with R
6
and adjoining N to represent a substituted or unsubstituted heterocyclic group, or represents hydroxyl, substituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, or NR
10
R
11
(wherein R
10
and R
11
have the same meaning as R
8
and R
9
defined above, respectively)), CO
2
R
12
(wherein R
12
represents substituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group), substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridonyl, substituted or unsubstituted pyrrolidonyl, substituted or unsubstituted uracilyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted morpholino, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted thiomorpholino, or substituted or unsubstituted dioxolanyl},
COR
13
(wherein R
13
represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted aryl, substituted or unsubstituted lower alkoxy, or NR
14
R
15
(wherein R
14
and R
15
are the same or different, and each represents hydrogen, substituted or unsubstituted-lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted pyridyl, or R
14
and R
15
are combined together with adjoining N to represent a substituted or unsubstituted heterocyclic group)), or
substituted or unsubstituted aryl;
X represents halogen, or is combined together with R
4
to represent a single bond; and
R
4
is combined together with X to represent a single bond, or represents hydrogen, alkanoyl, alkenoyl, or —SO—Z {wherein Z represents formula (A):
wherein R
1A
and R
2
Akinaga Shiro
Akiyama Tadakazu
Amishiro Nobuyoshi
Ino Yoji
Miyata Mayumi
Kyowa Hakko Kogyo Co. Ltd.
McKane Joseph K.
Sackey Ebenezer
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