Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-05-04
2003-12-02
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S009100, C514S018700, C530S317000, C530S321000, C530S330000
Reexamination Certificate
active
06656905
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a cyclic tetrapeptide compound which is useful as a medicament, to a process for producing the same and to a pharmaceutical composition comprising the same.
BACKGROUND ART
Histone deacetylases are known to play an essential role in the transcriptional machinery for regulating gene expression, and histone deacetylase inhibitors induce histone hyperacetylation and affect the gene expression. Therefore, a histone deacetylase inhibitor is useful as a therapeutical or prophylactic agent for several diseases caused by abnormal gene expression, such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), protozoal infection, or the like.
In this connection, a cyclic tetrapeptide compound that can be used as an anti-tumor agent is disclosed in JP-A-7-196686 but this publication is silent on the action against histone deacetylases and the effect against the above-mentioned various diseases.
DISCLOSURE OF INVENTION
The present invention relates to a novel cyclic tetrapeptide compound WF27082 which is useful as a medicament, to a process for producing the same and to a pharmaceutical composition comprising the same.
More particularly, it relates to a cyclic tetrapeptide compound which has a potent inhibitory effect on the activity of histone deacetylase.
The inventors of this invention also found that a histone deacetylase inhibitor, such as the WF27082, has a potent immunosuppressive effect and potent antitumor effect. Therefore, a histone deacetylase inhibitor, such as WF27082, is useful as an active ingredient of an immunosuppressant and an antitumor agent and useful as a therapeutical or prophylactic agent for an organ transplant rejection, autoimmune diseases, tumor, or the like.
Accordingly, one object of this invention is to provide a compound which has biological activities as stated above.
Another object of this invention is to provide a process for the production of WF27082 by fermentation of a WF27082-producing strain belonging to the genus Acremonium in a nutrient medium.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, the WF27082.
A yet further object of this invention is to provide a use of the histone deacetylase inhibitors, such as WF27082, for treating and preventing diseases stated above.
Thus, the present invention provides the following.
(1) A WF27082 compound of the formula:
wherein R
1
is methyl, R2is methyl or ethyl, R3 is hydrogen or methyl and R
4
is hydroxy optionally having a hydroxy-protective group,
providing that when R
3
is hydrogen, R
2
is ethyl.
(2) A WF27082 compound of (1) above, wherein R
1
is methyl, R
2
is ethyl, R
3
is methyl and R4 is hydroxy.
(3) A fungal strain belonging to the genus Acremonium, which has a deposit number FERM BP-6539 and which produces a compound having a histone deacetylase inhibitory activity.
(4) A compound having a histone deacetylase inhibitory activity, which is obtained by culturing the fungal stain of (3) above in a nutrient medium and recovering the compound from a culture broth thereof.
(5) A process for producing the WF27082 compound of (1) above, which comprises culturing, in a nutrient medium, a WF27082-producing strain belonging to the genus Acremonium and recovering the compound from a culture broth thereof.
(6) The process of (5) above, wherein the WF27082-producing strain belonging to the genus Acremonium is the fungal strain of (3).
(7) A pharmaceutical composition containing the WF27082 compound of (1) above as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
(8) A compound of (1) above for use as a medicament.
(9) A process for producing a compound having a histone deacetylase inhibitory activity, which comprises culturing, in a nutrient medium, a fungal strain belonging to the genus Acremonium, which produces a compound having a histone deacetylase inhibitory activity, and recovering said compound.
(10) A compound having a a histone deacetylase inhibitory activity, which is obtained by culturing, in a nutrient medium, a fungal strain belonging to the genus Acremonium, which produces a compound having histone deacetylase inhibitory activity, and recovering the compound from a culture broth thereof
(11) A histone deacetylase inhibitor comprising a compound of the formula (I):
wherein R
1
is methyl, R
2
is methyl or ethyl, R3 is hydrogen or methyl and R
4
is hydroxy optionally having a hydroxy-protective group.
(12) A method for inhibiting histone deacetylase, comprising using a compound (I) used in (11) above.
(13) A use of compound (I) used in (11) above for the manufacture of a medicament for inhibiting histone deacetylase.
(14) A pharmaceutical composition for treating or preventing inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections or autoimmune diseases, which comprises, as an active ingredient, a compound of the formula (1) wherein R
1
is methyl, R
2
is methyl or ethyl, R
3
is hydrogen or methyl and R
4
is hydroxy optionally having a hydroxy-protective group.
(15) A method for treating or preventing inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), or organ transplant rejections, autoimmune diseases, which comprises administering a compound (I) used in (14) above to a human being or an animal.
(16) A use of a compound (I) used in (14) above for the manufacture of a medicament for treating or preventing inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections or autoimmune diseases.
(17) A method for treating or preventing protozoal infections or tumors, which comprises administering a compound WF 27082 used in (1) above to a human being or an animal.
(18) A use of a compound WF27082 used in (1) above for the manufacture of a medicament for treating or preventing protozoal infections or tumors.
(19) A use of a histone deacetylase inhibitor as an immunosuppressant or an antitumor agent.
(20) A use of a histone deacetylase inhibitor for the manufacture of a medicament for treating or preventing organ transplant rejections, autoimmune diseases or tumors.
The compound, which has a potent inhibitory effect on the activity of histone deacetylase, can be represented by the following formula (I):
wherein R
1
is methyl, R
2
is methyl or ethyl, R
3
is hydrogen or methyl and R
4
is hydroxy optionally having a hydroxy-protective group.
Of a series of these compounds, particularly the compound of the following formula is a novel compound.
wherein R
1
is methyl, R
2
is methyl or ethyl, R
3
is hydrogen or methyl and R
4
is hydroxy optionally having a hydroxy-protective group,
providing that when R
1
is hydrogen, R
2
is ethyl.
The compound of the present invention having the formula (I), wherein R
1
is methyl, R
2
is methyl or ethyl, R3 is hydrogen or methyl and R
4
is hydroxy optionally having a hydroxy-protective group, providing that when R3 is hydrogen, R
2
is ethyl, is also referred to as WF27082.
Particulars of the above definitions and the preferred embodiments thereof are explained in detail in the following.
The term “lower” used in the specification is intended to mean 1 to 6 carbon atoms, unless otherwise indicated.
Suitable hydroxy-protective group may include:
1-(lower alkylthio)(lower)alkyl such as lower alkylthiomethyl (e.g. methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), and the like, in which the preferred one may be C
1
-C
4
alkylthiomethyl and the most preferred one may be methylthiomethyl;
trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl-di
Hino Motohiro
Mori Hiroaki
Sakamoto Kazutoshi
Takase Shigehiro
Tsurumi Yasuhisa
Fujisawa Pharmaceutical Co. Ltd.
Weber Jon P.
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