Hygromycin derivatives

Details Hygromycin derivatives Hygromycin derivatives

2000-10-20

2003-05-13

Peseley, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S023000, C536S016800, C536S018100, C536S017900

Reexamination Certificate

active

06562792

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel hygromycin 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.
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
)
hyodysentetiae
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 A derivatives of the present invention possess broad activity against both gram-negative and gram-positive bacteria and protozoa. WO 99/012941, published Sep. 14, 1999, refers to the treatment of bacterial infections by co-adminstering hygromycin and/or epihygromycin with a pyridone carboxylic acid antibacterial compound such as tosufloxacin, nalidixic acid, piromidic acid cinoxacin and/or enoxacin. Hygromycin derivatives are also described and claimed in U.S. provisional patent application Ser. No. 60/110,618 (filed Dec. 2, 1998), U.S. patent application Ser. No. 09/380,718 (filed Apr. 8, 1999), and PCT international patent application number PCT/IB99/00795 (filed May 13, 1999). The foregoing United States and PCT applications are incorporated herein by reference in their entirety.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
X is H, F, OH, or NH
2
;
Y is O or CH
2
;
Z
1
is R
3
and Z
2
is OR
13
; or Z
1
is H and Z
2
is R
3
, —NR
3
R
4
, —NR
3
C(O)R
4
or F;
or Z
1
and Z
2
are taken together to form ═O or ═NOR
3
;
W
1
is R
3
and W
2
is OR
13
; or W
1
is H and W
2
is R
3
, —NR
3
R
4
, —NR
3
C(O)R
4
, or F;
or W
1
and W
2
are taken together to form ═O or ═NOR
3
;
V is a group having the following structure
or V is R
3
OC(O)—, R
3
R
4
NC(O)— or R
3
O(R
4
)NC(O)—, in which groups R
3
and R
4
optionally can be taken together to form a 4 to 10 membered heterocyclic group which may be optionally substituted by 1 to 3 R
6
groups;
or V is a group having the following structure:
or V is a group of the structure
 where both E and Z isomers are included;
or V is a carbon-linked 4 to 10 membered heterocyclic group, which may be optionally substituted by 1 to 3 R
6
groups;
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
, or ═C(R
5
)X
1
—X
2
—R
8
, wherein:
X
1
is —CR
9
R
10
—, and X
2
is selected from —CR
9
R
10
—, —S(O)
n
— wherein n is an integer from 0 to 2, —NR
9
—, and O; where X
2
is —NR
9
—, then R
8
and R
9
may be taken together to form a 5 to 12 membered heterocyclic group, which is optionally substituted by 1 to 3 R
6
groups; or X
1
and X
2
independently or together represent a bond with the proviso that if X
1
is a bond than X
2
is either a bond or —CR
9
R
10
—;
each R
3
is independently selected from H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CR
9
R
10
)
t
(C
3
-C
10
cycloalkyl), —(CR
9
R
10
)
t
(C
6
-C
10
aryl), and —(CR
9
R
10
)
t
(4 to 10 membered heterocyclic), wherein each t is independently an integer from 0 to 5, said alkyl, alkenyl and alkynyl groups optionally contain 1 or 2 hetero moieties selected from O, —S(O)
j
— wherein j is an integer from 0 to 2, and —N(R
9
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other, and the proviso that an O atom, a S atom or a N atom are not attached directly to a triple bond or non-aromatic double bond; said cycloalkyl, aryl and heterocyclic R
3
groups are optionally fused to a benzene ring, a C
5
-C
8
cycloalkyl group, or a 4 to 10 membered heterocyclic group; the —(CR
9
R
10
)
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
6
groups, and with the proviso that R
3
must be attached through a carbon atom unless R
3
is H;
each R
4
is independently H or C
1
-C
10
alkyl;
R
5
is H or C
1
-C
6
alkyl, wherein the foregoing R
5
alkyl group is optionally substituted by 1 or 2 R
6
groups
each R
6
is independently selected from C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
10
cycloalkyl, oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —OR
7
, —C(O)R
7
, —C(O)OR
7
, —NR
9
C(O)OR
11
, —OC(O)R
7
, —NR
9
SO
2
R
11
, —SO
2
N
7
R
9
, —NR
9
C(O)R
7
, —C(O)NR
7
R
9
, —NR
7
R
9
, —S(O)
j
(CR
9
R
10
)
m
(C
6
-C
10
aryl), —S(O)
j
(C
1
-C
6
alkyl), wherein j is an integer from 0 to 2, —(CR
9
R
10
)
m
(C
6
-C
10
aryl), —O(CR
9
R
10
)
m
(C
6
-C
10
aryl), —NR
9
(CR
9
R
10
)
m
(C
6
-C
10
aryl), and —(CR
9
R
10
)
m
(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0 to 4; said alkyl, alkenyl and alkynyl groups optionally contain 1 or 2 hetero moieties selected from O, —S(O)
j
— wherein j is an integer 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, and the proviso that an O atom, a S atom or a N atom are not attached directly to a triple bond or a non-aromatic double bond; said cycloalkyl, aryl and heterocyclic R
6
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
cycloalkyl group, or a 4 to 10 membered heterocyclic group; and said alkyl, cycloalkyl, aryl and heterocyclic R groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR
9
SO
2
R
11
, —SO
2
NR
7
R
9
, —C(O)R
7
, —C(O)OR
7
, —OC(O)R
7
, —NR
9
C(O)OR
11
, —NR
9
C(O)R
7
, —C(O)NR
7
R
9
, —NR
7
R
9
, —OR
7
, C
1
-C
10
alkyl, —(CR
9
R
10
)
m
(C
6
-C
10
aryl), and —(CR
9
R
10
)
m
(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 4;
each R
7
is independently selected from H, C
1
-C
10
alkyl, C
3
-C
10
cycloalkyl, —(CR
9
R
10
)
m
(C
6
-C
10
aryl), and —(CR
9
R
10
)
m
(4 to 10 membered heterocyclic), wherein each m is independently an integer 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
9
)— with the proviso that two O atoms, two S atoms, or an O a

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