2″-deoxy hygromycin derivatives

Details 2″-deoxy hygromycin derivatives 2″-deoxy hygromycin derivatives

1999-09-07

2002-01-29

Solola, Taofiq A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S338000, C514S465000, C544S109000, C546S283700, C549S435000

Reexamination Certificate

active

06342497

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel 2″-deoxy hygromycin A derivatives that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment.
The compounds of the present invention may be derived from hygromycin A. Hygromycin A is a fermentation-derived natural product first isolated from
Streptomyces hygroscopicus
in 1953. As an antibiotic, hygromycin A possesses activity against human pathogens and is reported to possess potent in vitro activity against
Serpulina
(Treponema)
hyodysentenae
which causes swine dysentery. Several references refer to semisynthetic modifications of hygromycin A, including the following: derivatization of the 5″ ketone of hygromycin A to the 2,4-dinitrophenylhydrazone is referred to in K. Isono et al.,
J. Antibiotics
1957, 10, 21, and R. L. Mann and D. O. Woolf,
J. Amer Chem. Soc.
1957, 79, 120. K. Isono et al., ibid., also refer to the thiosemicarbazone at 5″; reduction of the 5″ ketone of hygromycin A to the 5′ alcohol is referred to in R. L. Mann and D. O. Woolf, ibid., as well as in S. J. Hecker et al.,
Bioorg. Med. Chem. Lett.
1992, 2, 533 and S. J. Hecker et al.,
Bioorg. Med. Chem. Lett.
1993, 3, 295; furanose analogues are referred to in B. H. Jaynes et al.,
Bioorg. Med. Chem Lett.
1993, 3, 1531, and B. H. Jaynes et al.,
J. Antibiot.
1992, 45, 1705; aromatic ring analogues are referred to in S. J. Hecker et al.,
Bioorg. Med. Chem. Lett.
1993, 3, 289, and C. B. Cooper et al.,
Bioorg. Med. Chem. Lett.
1997, 7, 1747; enamide analogues are referred to in S. J. Hecker et al.,
Bioorg. Med. Chem. Lett.
1992, 2, 533; aminocyclitol analogues are referred to in S. J. Hecker et al.,
Bioorg. Med. Chem. Lett.
1992, 2, 1015, and in S. J. Hecker et al.,
Bioorg. Med. Chem. Lett.
1992, 2, 1043. The hygromycin derivatives of the present invention possess activity against both gram-negative and gram-positive bacteria and protozoa.
United States provisional patent application No. 60/084058, filed May 4, 1998, entitled “Hygromycin A Derivatives”, (No. 60/084,058), with named inventors K. E. Brighty, R. G. Linde II, M. R. Jefson, E. L. McCormick and S. S. Guhan, also refers to hygromycin A analogues and is incorporated herein by reference in its entirety.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
and to pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
R
1
is H and R
2
is —NR
3
R
4
, —NR
4
C(O)R
3
, —OC(O)NR
3
R
4
or —OR
3
;
or R
1
and R
2
are taken together to form ═O, ═N—OR
3
, ═CR
4
R
3
, ═CR
4
C(O)R
3
, ═CR
4
C(O)OR
3
, or ═CR
4
C(O)NR
3
R
4
;
each R
3
is independently selected from H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, —(CH
2
)
t
(C
3
-C
10
cycloalkyl), —(CH
2
)
t
(C
6
-C
10
aryl), and —(CH
2
),(4-10 membered heterocyclic), wherein t is an integer ranging from 0 to 5, said alkyl group optionally contains 1 or 2 hetero moieties selected from O, —S(O)
j
— wherein j is an integer ranging from 0 to 2, and —N(R
7
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said cycloalkyl, aryl and heterocyclic R
3
groups are optionally fused to a benzene ring, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; the —(CH
2
)
t
— moieties of the foregoing R
3
groups optionally include a carbon-carbon double or triple bond where t is an integer between 2 and 5; and the foregoing R
3
groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 5 R
5
groups;
each R
4
is independently H or C
1
-C
10
alkyl;
each R
5
is independently selected from C
1
-C
10
alkyl, C
3
-C
10
cycloalkyl, halo, cyano, nitro, trifluoromethyl, diifluoromethoxy, trifluoromethoxy, azido, —OR
6
, —C(O)R
6
, —C(O)OR
6
, —NR
7
C(O)OR
9
, —OC(O)R
6
, —NR
7
SO
2
R
9
, —SO
2
NR
6
R
7
, —NR
7
C(O)R
6
, —C(O)NR
6
R
7
, —NR
6
R
7
, —S(O)
j
(CH
2
)
m
(C
6
-C
10
aryl), —S(O)
j
(C
1
-C
6
alkyl), wherein j is an integer from 0 to 2, —(CH
2
)
m
(C
6
-C
10
aryl), —O(CH
2
)
m
(C
6
-C
10
aryl), —NR
7
(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4; said alkyl group optionally contains 1 or 2 hetero moieties selected from O, —S(O)
j
— wherein j is an integer ranging from 0 to 2, and —N(R
7
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said cycloalkyl, aryl and heterocyclic R
5
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, cycloalkyl, aryl and heterocyclic R
5
groups are optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, difluoromethoxy, trifluoromethyl, trifluoromethoxy, azido, —NR
7
SO
2
R
9
, —SO
2
NR
6
R
7
, —C(O)R
6
, —C(O)OR
6
, —OC(O)R
6
, —NR
7
C(O)OR
9
, —NR
7
C(O)R
6
, —C(O)NR
6
R
7
, —NR
6
R
7
, —OR
6
, C
1
-C
10
alkyl, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4;
each R
6
is independently selected from H, C
1
-C
10
alkyl, C
3
-C
10
cycloalkyl, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, —S(O)
j
— wherein j is an integer ranging from 0 to 2, and —N(R
7
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said cycloalkyl, aryl and heterocyclic R
6
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R
6
substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, difluoromethoxy, trifluoromethyl, trifluoromethoxy, azido, —C(O)R
7
, —C(O)OR
7
, —OC(O)R
7
, —NR
7
C(O)R
8
, —C(O)NR
7
R
8
, —NR
7
R
8
, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
each R
7
and R
8
is independently H or C
1
-C
6
alkyl; and,
R
9
is selected from the substituents provided in the definition of R
6
except H.
Preferred compounds of formula 1 include those wherein R
1
and R
2
are taken together to form ═N—OR
3
, and R
3
is C
1
-C
4
alkyl, C
2
-C
4
alkenyl, —(CH
2
)
t
(C
6
-C
10
aryl) or —(CH
2
)
t
(4-10 membered heterocyclic), wherein t is an integer ranging from 0 to 3, the heterocyclic group is optionally fused to a benzene ring, the aryl group is optionally fused to a 5 or 6 membered heterocyclic group, and the foregoing R
3
groups, including said optionally fused moieties, are optionally substituted by 1 to 5 substituents independently selected from nitro, halo, C
1
-C
3
alkoxy, C
1
-C
4
alkyl, trifluoromethyl, acetamido, tert-butoxycarbonylamino, tert-butoxycarbonylaminomethyl, tert-butoxycarbonyl, —NR
6
R
7
, phenyl, cyclohexyl, carboxy, aminomethyl, difluoromethoxy, trifluoromethoxy, cyano, piperidinyl, morpholino, phenoxy, and phenylthio.
Other preferred compounds of formula 1 include those wherein R
1
and R
2
are taken together to form ═N—OR
3
, and R
3
is —(CH
2
)
t
(C
6
C
10
aryl) or —(CH
2
)
t
(4-10 membered heterocyclic), wherein t is an integer ranging from 0 to 3, the heterocyclic group is optionally fused to a benzene ring, the aryl group is optionally fused to a 5 or 6 membered heterocyclic group, and the foregoing R
3
groups, including said optionally fused moieties, are optionally substituted by 1 to 5 substituents independently selected from nitro, halo, C
1
-C
3
alkoxy, C
1
-C
4
alkyl, difluoromethoxy, trifluoromethyl, acetamido, tert-b

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