Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-16
2003-12-23
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S271000, C549S272000
Reexamination Certificate
active
06667338
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 9-amino erythromycin derivatives which are antibacterial agents, compositions containing the compounds, methods for making the compounds, synthetic intermediates employed in the processes, and methods for the treatment of bacterial infections.
BACKGROUND OF THE INVENTION
Macrolide antibacterial agents are widely used to treat and prevent bacterial infections. However, the discovery of bacterial strains having resistance or insufficient susceptibility to macrolide antibacterial agents has spurred the development of compounds with modified or improved profiles of antibiotic activity. One such class of compounds are 9-amino erythromycin derivatives. 9-Amino erythromycin derivatives are macrolide antibacterial agents with a core ring structurally similar to the erythronolide A or B ring except for the presence of a substituted or unsubstituted nitrogen moiety at the 9-position. U.S. Pat. No. 6,025,350 discloses the preparation of C-4″-substituted 9-amino erythromycin derivatives. PCT application WO 99/21866, published May 6, 1999 discloses 9-aminoketolides.
The clinical application of macrolide antibiotics such as erythromycin is limited, due in part to their instability at lower pH, that is, low acid stability. Under acidic conditions, such as, for example, in the gut, intramolecular cyclization occurs as the 6-hydroxyl attacks the 9-keto group, leading to intermediates which lack significant antibacterial activity (J. Majer,
Antimicrob. Agents Chemother
., 19, 628-633 (1981); K. Tsuji,
J. Chrom
., 158, 337-348 (1978); G. S. Duthu,
J. Liq. Chrom
., 7, 1023-1032 (1984)). The presence of the amino group at the 9-position would improve acid stability in this novel series of compounds.
Thus, novel 9-amino erythromycin derivatives which display improved profiles of antibacterial activity would represent a useful contribution to the art.
SUMMARY OF THE INVENTION
In its principle embodiment, therefore, the present invention provides 9-amino erythromycin derivatives of formula (I)
and formula (II)
or therapeutically acceptable salts or prodrugs thereof, wherein
R
1
is selected from hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, and (heterocycle)alkynyl,
provided that R
1
is not hydrogen in compounds of formula (II);
R
2
and R
3
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkanoyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxycarbonyl, cycloalkyloyl, cycloalkylsulfonyl, cycloalkylaminocarbonyl, cycloalkylthiocarbonyl, aryl, arylalkyl, aroyl, aryloxycarbonyl, arylsulfonyl, alkylaminocarbonyl, alkylthiocarbonyl, arylaminocarbonyl, arylthiocarbonyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, (heterocycle)carbonyl, (heterocycle)aminocarbonyl, (heterocycle)oxycarbonyl, (heterocycle)thiocarbonyl, (heterocycle)sulfonyl, hydroxyl, and a nitrogen protecting group; or
R
1
and R
2
together are selected from —C(O)—, —CH
2
CH═CHCH
2
—, alkylene, —CH
2
C(O)—, and —C(O)CH
2
—, wherein for —CH
2
C(O)— and —C(O)CH
2
—, each group is drawn with its left end attached to the nitrogen and its right end attached to the oxygen; or
R
2
and R
3
taken together with the nitrogen atom to which they are attached form a heterocycle;
R
4
and R
5
are hydrogen; or
R
3
and R
4
together are selected from —C(O)—, —CH
2
CH═CHCH
2
—, alkylene, —CH(R
7
)—, —(CH
2
)
m
C(O)—, and —C(O)(CH
2
)
m
—, wherein m is an integer ranging from 1 to 4, and wherein for —(CH
2
)
m
C(O)— and —C(O)(CH
2
)
m
—, each group is drawn with its left end attached to the nitrogen and its right end attached to the oxygen; or
R
4
and R
5
together are selected from —CH(R
7
)— and —C(O)—;
R
6
is selected from hydrogen, alkanoyl, alkyl, aryl, carboxamido, and (heterocycle)carbonyl;
R
7
is selected from hydrogen, alkyl, alkenyl, aryl, arylalkyl, (heterocycle)alkyl and cycloalkyl; and
R
p
is selected from hydrogen, trimethylsilyl, arylalkyl, aroyl, and alkanoyl.
In another embodiment, the present invention provides pharmaceutical compositions which comprise a therapeutically effective amount of a compound of formula (I) or a compound of formula (II), or therapeutically acceptable salts or prodrugs thereof, in combination with a therapeutically acceptable carrier.
In yet another embodiment, the present invention provides a method of treating bacterial infections in a host mammal in recognized need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a compound of formula (II), or therapeutically acceptable salts or prodrugs thereof.
In still yet another embodiment of the present invention are provided methods for the preparation of compounds of formula (I) and compounds of formula (II).
DETAILED DESCRIPTION OF THE INVENTION
It is understood that the following detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.
In one embodiment of the present invention are compounds having formula (I)
or therapeutically acceptable salts or prodrugs thereof, wherein
R
1
is selected from hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, and (heterocycle)alkynyl;
R
2
and R
3
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkanoyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxycarbonyl, cycloalkyloyl, cycloalkylsulfonyl, cycloalkylaminocarbonyl, cycloalkylthiocarbonyl, aryl, arylalkyl, aroyl, aryloxycarbonyl, arylsulfonyl, alkylaminocarbonyl, alkylthiocarbonyl, arylaminocarbonyl, arylthiocarbonyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, (heterocycle)carbonyl, (heterocycle)aminocarbonyl, (heterocycle)oxycarbonyl, (heterocycle)thiocarbonyl, (heterocycle)sulfonyl, hydroxyl, and a nitrogen protecting group; or
R
1
and R
2
together are selected from —C(O)—, —CH
2
CH═CHCH
2
—, alkylene, —CH
2
C(O)—, and —C(O)CH
2
—, wherein for —CH
2
C(O)— and —C(O)CH
2
—, each group is drawn with its left end attached to the nitrogen and its right end attached to the oxygen; or
R
2
and R
3
taken together with the nitrogen atom to which they are attached form a heterocycle;
R
4
and R
5
are hydrogen; or
R
3
and R
4
together are selected from —C(O)—, —CH
2
CH═CHCH
2
—, alkylene, —CH(R
7
)—, —(CH
2
)
m
C(O)—, and —C(O)(CH
2
)
m
—, wherein m is an integer ranging from 1 to 4, and wherein for —(CH
2
)
m
C(O)— and —C(O)(CH
2
)
m
—, each group is drawn with its left end attached to the nitrogen and its right end attached to the oxygen; or
R
4
and R
5
together are selected from —CH(R
7
)— and —C(O)—;
R
6
is selected from hydrogen, alkanoyl, alkyl, aryl, carboxamido, and (heterocycle)carbonyl;
R
7
is selected from hydrogen, alkyl, alkenyl, aryl, arylalkyl, (heterocycle)alkyl and cycloalkyl; and
R
p
is selected from hydrogen, trimethylsilyl, arylalkyl, aroyl, and alkanoyl.
The 9-amino group is the key feature of this molecular series, thus providing desirable physicochemical properties. Accordingly, the 9-amino group of the compounds of formula (I) can be unsubstituted or substituted in various ways, such substituents including, but not limited to, a nitrogen protecting group, alkanoyl, arylalkyl, (heterocycle)alkyl, alkyl, alkoxy, and the like.
In a preferred embodiment of the compounds of formula (I) of the present inventio
Djuric Stevan W.
Ma Zhenkun
Phan Ly Tam
Zhang Suoming
Abbott Laboratories
Donner B. Coregory
Owens Amelia
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