Macrolide antibacterial compounds

Details Macrolide antibacterial compounds Macrolide antibacterial compounds

2003-02-10

2004-12-14

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06831068

ABSTRACT:

TECHNICAL FIELD
This invention is directed to compounds with antibacterial activity, processes for making the compounds and intermediates used in the processes, compositions containing the compounds, and methods for prophylaxis or treatment of bacterial infections using the compounds.
BACKGROUND OF THE INVENTION
Because the effectiveness of many drugs currently available for prophylaxis or treatment of bacterial infections is being compromised by the emergence of drug-resistant bacteria, novel antibacterial compounds would be beneficial for their therapeutic value and their contribution to the antibacterial arts.
SUMMARY OF THE INVENTION
A first embodiment of this invention, therefore, is directed to compounds, and salts, prodrugs, and salts of prodrugs thereof, having antibacterial activity, the compounds having formula (I)
in which
two of A
1
, B
1
, D
1
, and E
1
are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —CN, —OH, —SH, —C(O)H, —C(O)R
1
, —C(O)OH, —C(O)OR
1
, —C(O)NR
2
R
3
, or alkyl substituted by one, two, or three substituents independently selected from the group consisting of —CN, —OH, —SH, halo, aryl, heteroaryl, heterocyclyl, —OR
1
, —SR
1
, —C(O)H, —C(O)R
1
, —C(O)OH, —C(O)OR
1
, —CH═N—OR
1
, —OC(O)R
1
, —OC(O)OR
1
, —C(O)NR
2
R
3
, —OC(O)NR
2
R
3
, —NR
2
R
3
, —N(R
4
)C(O)H, —N(R
4
)C(O)R
1
, —N(R
4
)C(O)NR
2
R
3
, —N(R
4
)SO
2
R
1
, —OR
1
, —SR
1
, —S(O)R
1
, —SO
2
R
1
, and —SO
2
NR
2
R
3
, and the remainder are hydrogen; or
A
1
and D
1
, A
1
and E
1
, B
1
and D
1
, or B
1
and D
1
together are one- to five-membered alkylene or two to five-membered heteroalkylene, and the remainder are hydrogen; or
A
1
and B
1
together are one- to seven-membered alkylene or two- to seven-membered heteroalkylene, and D
1
and E
1
are hydrogen; or
D
1
and E
1
together are one- to seven-membered alkylene or two- to seven-membered heteroalkylene, and A
1
and B
1
are hydrogen;
X
1
is hydrogen or fluoride;
M
1
is (E)-CH═CH, (Z)-CH═CH, or C≡C;
Y
1
is arylene or heteroarylene;
L
1
is drawn from left to right and is alkylene, alkenylene, alkynylene, CH═N—O—CH
2
-(alkenylene), CH
2
N(R
5
), CH
2
N(R
5
)(CH
2
)
m
, C(O)N(R
5
), N(R
5
)C(O)N(R
6
), CH═N—N(R
5
), CH═N—N(R
5
)C(O), O, CH═N—O, CH═N—O—(CH
2
)m, C(O)N(R
5
)(CH
2
)
m
, or CH═N—O(CH
2
)
n
—O,
in which m is one, two, three, or four, and n is two, three, or four;
W
1
is hydrogen aryl, heteroaryl, or heterocyclyl;
R
1
is alkyl, aryl, heteroaryl, or heterocyclyl;
R
2
and R
3
are independently hydrogen or alkyl; or
R
2
and R
3
together are 3- to 7-membered alkylene or 3-to 7-membered heteroalkylene;
R
4
is hydrogen or alkyl;
R
5
and R
6
are independently hydrogen or alkyl; and
R
A
is hydrogen or R
P
in which R
P
is a hydroxyl protecting moiety;
in which, for the foregoing,
each aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, and heterocycloalkylene is unsubstituted or substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halo, —CN, —OH, —SH, —NH
2
, —NO
2
, ═O, —CF
3
, —CH
2
CF
3
, —CF
2
CF
3
, —OCF
3
, —OCH
2
CF
3
, —OCF
2
CF
3
, —OR
30
, —SR
30
, —S(O)R
35
, —SO
2
R
35
, —C(O)H, —C(O)R
35
, —C(O)OH, —C(O)OR
35
, —NH(R
35
), —N(R
35
)(R
36
), —C(O)NH
2
, —C(O)NH(R
35
), —C(O)N(R
35
)(R
36
), —OC(O)R
35
, —OC(O)OR
35
, —OC(O)NH
2
, —OC(O)NH(R
35
), —OC(O)N(R
35
)(R
36
), —NHC(O)H, —NHC(O)R
35
, —NHC(O)OR
35
, —NHC(O)NH
2
, —NHC(O)NH(R
35
), —NHC(O)N(R
35
)(R
36
), —SO
2
NH
2
, —SO
2
NH(R
35
), —SO
2
N(R
35
)(R
36
), R
40
, and alkyl substituted with one or two substituents independently selected from the group consisting of halo, —CN, —OH, —SH, ═O, —OR
30
, —SR
30
, —C(O)OH, —C(O)OR
35
, —NH
2
, —NH(R
35
), —N(R
35
)(R
36
), —C(O)NH
2
, —C(O)NH(R
35
), —C(O)N(R
35
)(R
36
), —OC(O)R
35
, —OC(O)NH
2
, —OC(O)NH(R
35
), —OC(O)N(R
35
)(R
36
), —SO
2
NH
2
, —SO
2
NH(R
35
), —SO
2
N(R
35
)(R
36
) and R
40
;
R
30
is alkyl or alkyl substituted with a substituent selected from the group consisting of halo and —OR
45
;
R
35
and R
36
are independently selected alkyl;
R
40
is phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolidinyl, inidazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halo, —CN, —OH, —SH, —NO
2
, ═O, —CF
3
, —CH
2
CF
3
, —CF
2
CF
3
, —OCF
3
, —OCH
2
CF
3
, —OCF
2
CF
3
, —OR
45
, —SR
45
, —S(O)R
50
, —SO
2
R
50
, —C(O)H, —C(O)R
50
, —C(O)OH, —C(O)OR
50
, —NH
2
, —NH(R
50
), —N(R
50
)(R
51
), —C(O)NH
2
, —C(O)NH(R
50
), —C(O)N(R
50
)(R
51
), —OC(O)R
50
, —OC(O)OR
50
, —OC(O)NH
2
, —OC(O)NH(R
50
), —OC(O)N(R
50
)(R
51
), —NHC(O)H, —NHC(O)R
50
, —NHC(O)OR
50
, —NHC(O)NH
2
, —NHC(O)NH(R
50
), —NHC(O)N(R
50
)(R
51
), —SO
2
NH
2
, SO
2
NH(R
50
), and —SO
2
N(R
50
)(R
51
);
R
45
is alkyl; and
R
50
and R
51
are independently selected alkyl.
A second embodiment of this invention is directed to processes for making the compounds of the first embodiment.
A third embodiment of this invention is directed to intermediates which are useful in the second embodiment.
A fourth embodiment of this invention is directed to compositions comprising a therapeutically effective amount of a compound of the first embodiment.
A fifth embodiment of this invention is directed to methods for prophylaxis or treatment of bacterial infections in a fish or a mammal comprising administering thereto a therapeutically effective amount of a compound of the first embodiment.
In a preferred fifth embodiment of this invention, the beneficiary of prophylaxis or treatment of bacterial infections is a mammal.
In a more preferred fifth embodiment of this invention, the beneficiary of prophylaxis or treatment of bacterial infections is a human.


REFERENCES:
patent: 6075133 (2000-06-01), Or et al.
patent: 6498146 (2002-12-01), Wu

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