Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-23
2002-06-11
Rotman, Alan L. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S462000
Reexamination Certificate
active
06403639
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to therapeutic agents for renal diseases or organ preservatives containing a 2,3-dihydrobenzofuran derivative as an active ingredient, as well as novel 2,3-dihydrobenzofuran derivatives.
PRIOR ART
Kidney is one of organs subjected to the most serious oxidative stress in the living body. The importance of radical injury caused by active oxygen or free radicals in the development and progress mechanism of various renal diseases such as acute renal failure, drug-induced nephropathies, glomerular nephritis, diabetic nephrosis, chronic renal failure, renal transplantation has long been pointed out. In recent years, the role of lipids in cell injury has attracted particular attention (Keane W. F., Lipids and the kidney. Kidney Int., 46:910-920, 1994; Higuchi and Sanaka, “Renal Diseases”, Antioxidants—Free radicals and bioprotection (Niki, Shimazaki and Mino, eds.) Gakkai Shuppan Center, 223-229, 1994; Aoyagi, “Therapy with Antioxidants/Scavenger, No. 3, Renal Diseases”, Therapeutics, 26:592-596, 1992). However, the effect of antioxidants, particularly lipid-peroxidation inhibitors on renal diseases has not been well explained, and any compound having a useful lipid-peroxidation inhibitory effect as a therapeutic or prophylactic agent for renal diseases or organ preservative has not been reported.
Vitamin E (&agr;-tocopherol) is a naturally occurring potent lipid-peroxidation inhibitor and its use in renal transplantation and renal ischemia models has been reported (Marubayashi, Dohi and Kawasaki, “Renal maintenance and active oxygen”, Kidney and Dialysis, 24:785-790, 1988; Takenaka M., Tatsukawa Y., Dohi K., Ezaki H., Matsukawa K., Kawasaki T., Transplantation, 32:137-141, 1981), but its effect is not sufficient. This is because it acts on only surfaces of membranes and lipid of the living body, but can not produce inhibitory effect against lipid-peroxidation in the interior of membranes and lipids (Niki E., Chem. Phys. Lipids, 44:227-253, 1987). Vitamin E is also expected to endogenously have an inhibitory effect against lipid-peroxidation on surfaces of membranes and lipid, because it endogenously occurs in a significantly large amount (Nakamura, “Absorption, Distribution and Excretion of Vitamin E”, Vitamin E—Basic and Clinical Study (Igarashi, eds.), Ishiyaku Shuppan, 33-58, 1985). However, the living body does not have a sufficient protection mechanism against lipid-peroxidation in the interior of membranes and lipids, and therefore, inhibition of lipid-peroxidation in the interior of membranes and lipids seems to have an important effect for treatment and prevention of renal diseases. The effects of use of a lipid-soluble antioxidant, probucol, in various renal disease models have been reported (Modi K. S., Schreiner G. F., Purkerson M. L., J. Lab. Clin. Med., 120:310-317, 1992; Bird J. E., Milhoan K., Wilson C. B., Young S. G., Mundy C. A., Parthasarathy S., Blantz R. C., J. Clin. Invest., 81:1630-1638, 1988; Hirano T., Mamo J. C. L., Nagano S., Sugisaki T., Nephron, 58:95-100, 1991), but such simple phenolic compounds as probucol and butylated hydroxytoluene react with lipid-peroxide radicals at a lower reactivity than &agr;-tocopherol by one or more orders of magnitude (Gotoh N., Shimizu K., Komuro E., Tsuchiya J., Noguchi N., Niki E., Biochem. Biophys. Acta, 1128:147-154, 1992; Burton G. W., Ingold K. U., J. Am. Chem. Soc., 103:6472-6477, 1981) and thus have not shown sufficient protective effect for renal functions.
Thus, a potent cytoprotective agent which inhibits lipid-peroxidation that is difficult to inhibit by Vitamin E seems to be effective for the prevention and treatment of various renal diseases and maintenance of organs.
As such compounds, 4,6-di-t-butyl-2,3-dihydrobenzofuran derivatives were found to show a potent cytoprotective effect on kidney-derived cells (JP 10-72458A/98, WO97/9701729), but no report has shown that 2,3-dihydrobenzofuran derivatives having no or only one t-butyl group show such an effect.
DISCLOSURE OF THE INVENTION
As a result of extensive research to solve the above problems, we found that 2,3-dihydrobenzofuran derivatives having specific substituents show a potent cytoprotective effect on kidney-derived cells, and thus accomplished the present invention.
Accordingly, the present invention provides therapeutic agents for renal diseases containing a compound of general formula (1):
wherein
R
1
represents a hydrogen atom or an acyl group,
R
2
, R
3
and R
4
, which may be identical or different, each represents a hydrogen atom, a lower alkyl group or a lower alkenyl group, and
R
5
and R
6
, which may be identical or different, each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted aryl group, or
R
5
and R
6
combine to form a cycloalkyl group or a saturated heterocyclic group containing one or more oxygen atoms, sulfur atoms or alkyl-substituted nitrogen atoms,
provided that R
2
and R
3
can not simultaneously represent a t-butyl group, or an optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also provides organ preservatives containing a compound of the above general formula (1) or an optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also provides compounds of general formula (1):
wherein
R
1
represents a hydrogen atom or an optionally substituted acyl group,
R
2
, R
3
and R
4
, which may be identical or different, each represents a hydrogen atom, a lower alkyl group or a lower alkenyl group, provided that any one of R
2
and R
3
represents a t-butyl group but both of R
2
and R
3
can not represent a t-butyl group, and
R
5
and R
6
, which may be identical or different, each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group or an optionally substituted aryl group, or
R
5
and R
6
combine to form a cycloalkyl group or a saturated heterocyclic group containing one or more oxygen atoms, sulfur atoms or alkyl-substituted nitrogen atoms,
provided that the following cases are excluded where:
R
4
represents a 2-propenyl group;
three or more of R
2
, R
3
, R
4
, R
5
and R
6
simultaneously represent a hydrogen atom;
R
2
and R
4
simultaneously represent a hydrogen atom and R
5
and R
6
simultaneously represent a methyl group; and
R
3
, R
4
, R
5
and R
6
simultaneously represent a methyl group,
or optically active isomers or pharmaceutically acceptable salts thereof.
In one aspect, compounds of the above general formula (1) are represented by general formula (2):
wherein R
4
represents a hydrogen atom or a t-butyl group, and R
1
, R
3
, R
5
and R
6
have the same meanings as defined above.
In another aspect, compounds of the above general formula (1) are represented by general formula (3):
wherein R
1
, R
2
, R
5
and R
6
have the same meanings as defined above, provided that the total carbon number of R
2
, R
5
and R
6
is at least 3.
The present invention also provides compounds of general formula (1):
wherein
R
1
represents a hydrogen atom or an optionally substituted acyl group,
R
2
and R
4
simultaneously represent a t-butyl group, and
R
3
, R
5
and R
6
simultaneously represent a hydrogen atom,
or optically active isomers or pharmaceutically acceptable salts thereof.
The present invention also provides compounds of general formula (1):
wherein
R
1
represents a hydrogen atom or an optionally substituted acyl group,
R
2
, R
3
and R
4
, which may be identical or different, each represents a hydrogen atom, a lower alkyl group or a lower alkenyl group, provided that any of R
2
and R
3
can not represent a t-butyl group, and
R
5
and R
6
, which may be identical or different, each represents an optionally substituted alkyl group containing 1 to 10 carbon atoms, an optionally substituted alkenyl group containing 2
Cynshi Osamu
Ishikawa Akira
Kato Yoshiaki
Takashima Yoshiaki
Tamura Kunio
Browdy and Neimark , P.L.L.C.
Chugai Seiyaku Kabushiki Kaisha
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