Hygromycin A derivatives

Details Hygromycin A derivatives Hygromycin A derivatives

1999-12-02

2001-06-12

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S023000, C536S016800, C536S017900, C536S018100

Reexamination Certificate

active

06245745

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel 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.
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
)
hyodysenteriae
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. Hygromycin A derivatives are also described and claimed in U.S. provisional patent application Nos. 60/084,042 (filed May 4, 1998) and 60/084,058 (filed May 4, 1998), both of which U.S. provisional applications are incorporated herein by reference in their entirety.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
and to pharmaceutically acceptable salts and solvates thereof wherein:
each X
1
is selected from —CR
6
R
7
—, —S(O)
n
— wherein n is 0 to 2, —NR
6
— and a bond and X
2
is selected from —CR
6
R
7
—, —S(O)
n
— wherein n is 0 to 2, —NR
6
—, O, and a bond, except that (a) if either X
1
or X
2
is S, or S(O) then the other moiety (X
1
or X
2
) is —CR
6
R
7
— or a bond; (b) if either X
1
or X
2
is SO
2
then the other moiety (X
1
or X
2
) is —NR
6
—, —CR
6
R
7
— or a bond; (c) if X
1
is —NR
6
—, then X
2
is selected from SO
2
and —C(O)—; and (d) if X
2
is O than X
1
must be —CR
6
R
7
—;
R
1
is H or OH;
R
2
is H, C
1
-C
6
alkyl, or halo, wherein the foregoing R
2
alkyl group is optionally substituted by 1 or 2 R
4
groups;
or where X
2
is —NR
6
—, then R
3
and X
2
may be taken together to form a 5 to 12 membered ring, wherein said ring is saturated or partially unsaturated with up to 3 carbon-carbon double bonds, the carbon atoms of said ring are optionally subsituted by 1 to 3 R
4
groups, and the ring optionally contains up to 2 additional hetero moieties (in addition to the X
2
moiety which is —NR
6
—) selected from O, S(O)
j
wherein j is an integer from 0 to 2, and —NR
6
—, with the proviso that two O atoms, two S atoms, an O and S atom, an N and O atom, and an N and S atom are not attached directly to each other;
each R
3
is independently selected from H, C
1
-C
10
alkyl, —(CR
6
R
7
)
t
(C
6
-C
10
aryl), —(CR
6
R
7
)
t
(4-10 membered heterocyclic), —C(O)(CR
6
R
7
)
t
(C
6
-C
10
aryl), —C(O)(CR
6
R
7
)
t
(4-10 membered heterocyclic), —C(O)NR
6
(CR
6
R
7
)
t
(C
6
-C
10
aryl), and —C(O)NR
6
(CR
6
R
7
)
t
(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 —NR
6
— with the proviso that two O atoms, two S atoms, an O and S atom, an N and O atom, and an N and S atom are not attached directly to each other; the —(CR
6
R
7
)
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 heterocyclic and aryl moieties of the foregoing R
3
groups are optionally substituted by 1 to 5 R
4
groups;
each R
4
is independently selected from C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxy, C
1
-C
6
alkoxy, —C(O)R
5
, —C(O)OR
5
, —NR
6
C(O)OR
8
, —OC(O)R
5
, —NR
6
SO
2
R
8
, —SO
2
NR
5
R
6
, —NR
6
C(O)R
5
, —C(O)NR
5
R
6
, —NR
5
R
6
, —S(O)
j
(CR
6
R
7
)
m
(C
6
-C
10
aryl), —S(O)
j
(C
1
-C
6
alkyl), —(CR
6
R
7
)
m
(C
6
-C
10
aryl), —O(CR
6
R
7
)
m
(C
6
-C
10
aryl), —NR
6
(CR
6
R
7
)
m
(C
6
-C
10
aryl), —(CR
6
R
7
)
m
(4-10 membered heterocyclic), —C(O)(CR
6
R
7
)
m
(C
6
-C
10
aryl), and —C(O)(CR
6
R
7
)
m
(4-10 membered heterocyclic), wherein m is an integer from 0 to 4; j is an integer from 0 to 2, and said alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R
4
groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR
6
SO
2
R
8
, —SO
2
NR
5
R
6
, —C(O)R
5
, —C(O)OR
5
, —OC(O)R
5
, —NR
6
C(O)OR
8
, —NR
6
C(O)R
5
, —C(O)NR
5
R
6
, —NR
5
R
6
, —OR
5
, C
1
-C
10
alkyl, —(CR
6
R
7
)
m
(C
6
-C
10
aryl), and —(CR
6
R
7
)
m
(4-10 membered heterocyclic), wherein m is an integer from 0 to 4;
each R
5
is independently selected from H, C
1
-C
10
alkyl, —(CR
6
R
7
)
m
(C
6
-C
10
aryl), and —(CR
6
R
7
)
m
(4-10 membered heterocyclic), wherein m is an integer from 0 to 4, and the foregoing R
5
substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R
6
, —C(O)OR
6
, —OC(O)R
6
, —NR
6
C(O)R
7
, —C(O)NR
6
R
7
, —NR
6
R
7
, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
each R
6
and R
7
is independently H, —C(O)(C
1
-C
6
alkyl), C
1
-C
6
alkyl or fluoro; and,
R
8
is selected from the substituents provided in the definition of R
5
except R
8
is not H.
Specific embodiments of said compounds of formula 1 include those wherein X
1
is —CH
2
— and X
2
is O.
Other specific embodiments of said compounds of formula 1 include those wherein X
1
is —CH
2
—, X
2
is O, and R
3
is —(CR
6
R
7
)
t
(C
6
-C
10
aryl) wherein t is as defined above, R
6
and R
7
are both H, and said aryl group is optionally substituted by 1 to 4 R
4
groups. In a more specific embodiment, said aryl group is a phenyl group optionally substituted by 1 to 4 R
4
groups.
Other specific embodiments of said compounds of formula 1 include those wherein X
1
is —CH
2
—, X
2
is O, and R
3
is —(CR
6
R
7
)
t
(4-10 membered heterocyclic), wherein t is as defined above, R
6
and R
7
are both H, and said heterocyclic group is optionally substituted by 1 to 4 R
4
groups. In a more specific embodiment, said heterocyclic group is a pyridyl group or benzothiazolyl group optionally substituted by 1 to 4 R
4
groups.
Other specific embodiments of said compounds of formula 1 include those wherein X
1
is —CH
2
—, X
2
is O, and R
3
is —C(O)(CR
6
R
7
)
t
(C
6
-C
10
aryl) wherein t is as defined above, R
6
and R
7
are both H, and said aryl group is optionally substituted by 1 to 4 R
4
groups. In a more specific embodiment, said aryl group is a phenyl group optionally substituted by 1 to 4 R
4
groups.
Other specific embodiments of said compounds of formula 1 include th

Affiliated with

Also associated with

Rating

Hygromycin A derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Hygromycin A derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hygromycin A derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2522877