Swainsonine derivatives and methods for preparing the same

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C546S183000, C546S014000, C546S015000

Reexamination Certificate

active

06262065

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to derivatives of swainsonine, which are useful as anticancer agents and as glycosidase inhibitors. The present invention also relates to methods of preparing such derivatives and intermediates useful for preparing said derivatives.
2. Discussion of the Background
The indolizidine alkaloid (−)-swainsonine is of long standing interest due to its diverse biological activity. For the isolation from the fungus
Rhizoctonia leguminicola
, see:
(a) Guengerich, F. P. et al,
J. Am. Chem
. Soc., vol. 95, p. 2055 (1973).
(b) Schneider, J. J. et al.
Tetrahedron
, vol. 39, pp. 29-32 (1983).
(c) Hino, M. et al,
J. Antibiot
., vol. 35, pp. 926-935 (1985).
(d) Patrick, M. S. et al,
Biotechnol. Lett
., vol. 17, pp. 433-438 (1995).
For the isolation from the legume
Swainsona canescens
, see:
(e) Colegate, S. M. et al,
Aust. J. Chem
., vol. 32, pp. 2257-64 (1979).
For the isolation from the locoweed
Astragalus lentiginosus
, see:
(f) Molyneux, R. J.,
Science
, vol. 216, pp. 190-191 (1982).
For the isolation from Weir vine, see:
(g) Molyneux, R. J.,
J. Nat. Prod
., vol. 58, pp. 878-886 (1995).
For a review of the synthesis and biological activity of swainsonine and other glycosidase inhibitors, see:
Nishimura. Y. In
Studies in Natural Products Chemistry
; Atta-ur-Rahmaii, Ed.; Elsevier: Amsterdam, vol. 10; pp. 495-583 (1992).
(−)-Swainsonine may be considered an azasugar analog of mannose, and is indeed a potent inhibitor of many mannosidases including the glycoprotein processing enzyme mannosidase II (see: Elbein, A. D.,
Ann. Rev. Biochem
., vol. 56, pp. 497-534 (1987); Cenci Di Bello, I. et al,
Biochem. J
., vol. 259. pp. 855-861 (1989); Winchester, B. et al;
Glycbiology
, vol. 2, pp. 199-210 (1992); and Kaushal G. P. et al,
Methods in Enzymology
, vol. 230, pp. 316-329 (1994)). Swainsonine is the first glycoprotein-processing inhibitor to be selected for clinical testing as an anticancer drug (see: Goss, P. E. et al
Clin. Cancer Res
., vol. 1, pp. 935-944 (1995); and Das, P. C. et al,
Oncol. Res
., vol. 7, pp. 425-433 (1995)).
A great deal of effort has been expended on developing synthetic routes to swainsonine. See e.g.,
(a) Suami, T. et al,
Chem. Lett
., pp. 513-516 (1984).
(b) Ali, M. H. et al,
J. Chem. Soc., Chem. Commun.,
447-448 (1984).
(c) Fleet, G. W. J. et al,
Tetrahedron Lett
., vol. 25, pp. 1853-1856 (1984).
(d) Yasuda, N. et al,
Chem. Lett
., pp. 1201-1204(1984).
(e) Adams, C. E. et al,
J. Org. Chem
., vol. 50, pp. 420-422 (1985).
(f) Suami, T.,
Carbohydr. Res
., vol. 136, pp. 67-75 (1985).
(g) Ali, M. H. et al,
Carbohydr. Res
., vol. 136, pp. 225-240 (1985).
(h) Setoi, H. et al,
J. Org. Chem
., vol. 50, pp. 3948-3950 (1985).
(i) Ikota, N. et al,
Chem. Pharm. Bull
., vol. 35, pp. 2140-25143 (1987).
(j) Ikota, N., et al,
Heterocycles
, vol. 26, p. 2368 (1987).
(k) Bashyal, B. P. et al,
Tetrahedron
, vol. 43, p. 3083 (1987).
(l) Dener, J. M. et al,
J. Org. Chem
., vol. 53, pp. 6022-6030 (1988).
(m) Carpenter, N. M. et al,
Tetrahedron Lett
., vol. 30, pp. 7261-7264 (1989).
(n) Bennett, R. B. et al,
J. Am. Chem. Soc
., vol. 111, pp. 2580-2582 (1989).
(o) Pearson, W. H. et al,
Tetrahedron Lett
., vol. 31, p. 7571(1990).
(p) Miller, S. A.,
J. Am. Chem. Soc
., vol. 112, pp. 8100-8112 (1990).
(q) Ikota, N. et al,
Chem. Pharm. Bull
., vol. 38, p. 2712 (1990).
(r) Fleet, G. W. J., U.S. Pat. No. 5,023,340 (1991).
(s) Naruse, M. et al,
J. Org. Chem
., vol. 59, pp. 1358-1604 (1994).
(t) Hunt, J. A. et al,
Tetrahedron Lett
., vol. 36, pp. 501-504 (1995).
(u) Kang, S. H. et al.
Tetrahedron Lett
., vol. 36, pp. 5049-5052 (1995).
For a synthesis of the non-natural (+)-enantiomer of swainsonine, see:
(v) Oishi. T. et al,
Synlett
., pp. 404-406 (1995).
For formal syntheses, see:
(w) Gonzalez, F. B. et al,
Bull. Chem. Soc. Jpn
., vol. 65. pp. 567-574 (1992).
(x) Honda, T., et al.
J. Chem. Soc., Perkin Trans
., vol. 1, pp. 2091-2101 (1994).
(y) Angermann, J. et al,
Sylett
, pp. 1014-1016 (1995).
(z) Zhou, W.-S. et al,
Tetrahedron Lett
., vol. 36, pp. 1291-1294 (1995).
(aa) Zhou, W.-S. et al,
J. Chem. Soc. Perkin Trans
., vol. 1, pp. 2599-2604 (1995).
However, there is still a need for other compounds which exhibit similar anticancer and glycosidase inhibition properties as swainsonine.
Thus, there remains a need for compounds which exhibit anticancer activity. There also remains a need for compounds which inhibit glycosidase enzymes. There also remains a need for intermediates and methods useful for preparing such compounds.
SUMMARY OF THE INVENTION
Accordingly, it is one object of the present invention to provide novel compounds which are useful as anticancer agents.
It is another object of the present invention to provide novel compounds which are useful as glycosidase inhibitors.
It is another object of the present invention to provide novel intermediates useful for preparing such compounds.
It is another object of the present invention to provide a method for preparing such compounds.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors discovery that compounds of the formula (I):
where:
R is:
straight chain C
1-22
-alkyl;
branched C
3-22
-alkyl;
C
3-8
-cycloalkyl;
C
3-8
-cycloalkyl substituted with straight chain C
1-22
-alkyl;
C
3-8
-cycloalkyl substituted with branched C
3-22
-alkyl;
a group of the formula
 wherein:
X′=O, S, NH, NR
1
(R
1
is C
1-22
-alkyl), or NAr;
m=0-5;
n=0-5; and
m+n≧2;
—(CH
2
)
n′
Ar (n′=1 to 22);
—(CH
2
)
n′
G (n′=1 to 22);
—Ar; and
—G;
wherein Ar is:
 where
n″=2 to 5;
X′=NH, NR
1
(R
1
is C
1-22
-alkyl), NAr, O, or S and each carbon atom may be substituted with halogen, C
1-22
-alkyl, C
6-10
-aryl, or G;
wherein G is:
F, Cl, Br, I,
—OH, —OR
1
, —OCHO, —OCOR
1
, —OCO
2
R
1
, —OCONH
2
, —OCONHR
1
, OCONR
1
R
1
, OCOSR
1
, —ONH
2
, —ONHR
1
, —ONR
1
R
1
;
—N
3
, —NO
2
, —NH
2
, —NHR
1
, —NR
1
R
1
, —NHOH, —NR
1
OH, —NHOR
1
, —NR
1
OR
1
, —NHNH
2
, —NR
1
NH
2
, —NHNHR
1
, —NR
1
NHR
1
, —NHNR
1
R
1
, —NR
1
NR
1
R
1
, —NHC(═O)H, —NR
1
(C═O)H, —NH(C═O)R
1
, —NR
1
(C═O)R
2
, —NH(C═O)OR
1
, —NR
1
(C═O)OR
2
, —NH(C═O)NH
2
, —NH(C═O)NHR
1
, —NH(C═O)NR
1
R
1
, —NR
1
(C═O)NH
2
, —NR
1
(C═O)NHR
2
, —NR
1
(C═O)NR
2
R
3
, —NH(C═NH)NH
2
, —NR
1
(C═NH)NH
2
, —NH(C═NH)NHR
1
, —NR
1
(C═NH)NHR
2
, —NH(C═NH)R
1
R
2
, —NR
1
(C═NH)NR
2
R
3
, —NH(C═NR
1
)NHR
2
, —NR
1
(C═NR
1
)NHR
3
, —NH(C═NR
1
)NR
2
R
3
, —NR
1
(C═NR
2
)NR
3
R
4
,
—SH, SR
1
, —S(C═O)R, —S(C═O)OR
1
, —S(O)R
1
, —SO
2
R
1
, —SO
3
R
1
, —SO
3
H,
—SeR
1
,
—CN, —CHO, —COR
1
, —CHNOH, —CHNOR
1
, —CR
1
NOH, —CR
1
NHOR
2
, —CN, —CO
2
H, —CO
2
R
1
, —CONH
2
, —CONHR
1
, —CONR
1
R
2
, —CSNH
2
, —CSNHR
1
, —CSNR
1
R
2
, —C(NH)OR
1
, —C(NR)OR
1
, —C(NH)SR
1
, —C(NR)SR
1
, —(NH)NH
2
, —C(NR
1
)NH
2
, —C(NH)NR
1
R
2
, —C(NR)R
1
R
2
, —C(NR
1
)NHR
2
, —CONHOH, —CONR
1
OH, —CONHOR
1
, —CONR
1
OR
2
, —CONHNH
2
, —CONR
1
NH
2
, —CONHNR
1
R
1
, —CONR
1
NHR
2
, -or CONR
1
NR
2
R
3
,
(wherein R
1
, R
2
, and R
3
are each independently C
1-22
-alkyl);
each R
1
, independently of the other, is H, acetyl, benzyl, methoxymethyl, tosyl, mesyl, trifluoromesyl, tri(C
1-4
alkyl)silyl, di(C
1-4
alkyl)phenylsilyl, diphenyl(C
1-4
alkyl)silyl, or triphenylsilyl, or both R together form an alkylidene protecting group;
R″ is H, acetyl, benzyl, methoxymethyl, tosyl, mesyl, trifluoromesyl, tri(C
1-4
alkyl)silyl, di(C
1-4
alkylsilyl)phenylsilyl, diphenyl(C
1-4
alkyl)silyl, or triphenylsilyl;
X is H, Cl, Br, or R
4
(where R
4
is C
1-22
-alkyl);
Y is H, Cl, Br, or —CHR
2
OH, —CR
2
R
3
OH, —CH
2
CHR
2
OH, —CH
2
CR
2
R
3
OH, —SR
2
, —SeR
2
, —OH, —NH
2
, —R
5
(where R
2
, R
3
, and R
5
are independently of each other C
1-22
-alkyl);
or X and Y together form a covalent bond;
A and A′ are both H or

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