Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2003-04-08
2004-11-30
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007300, C536S007400
Reexamination Certificate
active
06825171
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to novel erythromycin derivatives that are useful as antibacterial agents and antiprotozoa agents and for other applications (e.g., anticancer, atherosclerosis, gastric motility reduction, etc.) 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 infections and protozoa infections and in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment.
Macrolide antibiotics are known to be useful in the treatment of a broad sprectrum of bacterial infections and protozoa infections in mammals, fish and birds. Such antibiotics include various derivatives of erythromycin A such as azithromycin which is commercially available and is referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359, both of which are incorporated herein by reference in their entirety. Additional macrolides are referred to in U.S. patent application serial No. 60/049349, filed Jun. 11, 1997 (Yong-Jin Wu), U.S. patent application serial No. 60/046150, filed May 9, 1997 (Yong-Jin Wu), U.S. patent application serial No. 60/063,676, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. application serial No. 60/063,161, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. application serial No. 60/054,866, filed Aug. 6, 1997 (Hiroko Masamune, Yong-Jin Wu, Takushi Kaneko and Paul R. McGuirk), U.S. application serial No. 60/049,348, filed Jun. 11, 1997 (Brian S. Bronk, Michael A. Letavic, Takushi Kaneko and Bingwei V. Yang), International Application No. PCT/GB97/01810 filed Jul. 4, 1997 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey), and International Application No. PCT/GB97/01819 filed Jul. 4, 1997 (Peter Francis Leadlay, James Staunton, and Jesus Cortes), all of which are incorporated herein by reference in their entirety. Like azithromycin and other macrolide antibiotics, the novel macrolide compounds of the present invention possess potent activity against various bacterial infections and protozoa infections as described below.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C
3
-C
8
alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C
5
-C
8
cycloalkyl group wherein the alkyl group is an alpha-branched C
2
-C
5
alkyl group; a C
3
-C
8
cycloalkyl or C
5
-C
8
cycloalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C
1
-C
4
alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C
1
-C
4
alkyl groups or halo atoms;
or R is phenyl which may be optionally substituted with at least one substituent selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy and C
1
-C
4
alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano;
or R may be with a formula (a) as shown below
wherein X
1
is O, S or —CH
2
—, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a+b+c+d≦5;
or R is CH
2
R
24
, wherein R
24
is H, C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C
3
-C
8
cycloalkyl or C
5
-C
8
cycloalkenyl either or which may be optionally substituted by methyl or one or more C
1
-C
4
alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C
1
-C
4
alkyl groups or halo atoms; or a group of the formula SR
23
wherein R
23
is C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C
1
-C
4
alkyl groups or halo atoms; and
R
4
is H or acyl of an organic acid of up to 18 carbon atoms.
The present invention further relates to compounds of the formula
A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein:
R is an alpha-branched C
3
-C
8
alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups; a C
5
-C
8
cycloalkylalkyl group wherein the alkyl group is an alpha-branched C
2
-C
5
alkyl group; a C
3
-C
8
cycloalkyl or C
5
-C
8
cycloalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C
1
-C
4
alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C
1
-C
4
alkyl groups or halo atoms;
or R is phenyl which may be optionally substituted with at least one substituent selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy and C
1
-C
4
alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano; or R may be with a formula (a) as shown below
wherein X
1
is O, S or —CH
2
—, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a+b+c+d≦5;
X is —(CR
5
R
8
)
g
— or —NR
5
—, wherein g is 0 or 1;
wherein when X is —NR
5
—, X and R
3
optionally may be taken together to form —N═CR
7
R
8
,
or when X is —NR
5
—, X and R
3
optionally may be taken together to form a heterocyclic of the formula
wherein n is selected from an integer ranging from 1 to 3, p is selected from an integer ranging from 1 to 3, q is 0 or 1, and R
9
is selected from CH
2
, O, S, C═O, C═S, SO
2
, —CH═CH—, —CH(OH)CH(OH)—, and NH;
or when X is —NR
5
—, X and R
3
together form a heterocyclic as defined above having substituents selected from the group consisting of —C(O)OR
10
, —OR
10
, C
1
-C
10
alkanoyl, halo, nitro, cyano, R
10
, 4-10 membered heterocyclic, C
6
-C
10
aryl, —C(O)NR
10
R
12
, —NHC(O)R
10
, —NHC(O)NR
10
R
11
, —NR
10
R
11
, —SR
10
, —S(O)R
10
, —SO
2
R
10
and —SO
2
NR
10
R
11
;
or R is CH
2
R
24
, wherein R
24
is H, C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms; or a C
3
-C
8
cycloalkyl or C
5
-C
8
cycloalkenyl either or which may be optionally substituted by methyl or one or more C
1
-C
4
alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C
1
-C
4
alkyl groups or halo atoms; or a group of the formula SR
23
wherein R
23
is C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C
1
-C
4
alkyl groups or halo atoms;
R
10
and R
11
are each independently selected from H, C
1
-C
10
alkyl;
or R
3
is selected from H, C(═O)Z, C(═O)OZ, (CR
5
R
6
)
m
Z, C(═O)R
7
, C(═O)OR
7
, (CR
5
R
6
)
m
R
7
, wherein m is an integer ranging fro
Benson Gregg C.
Forman Frank W.
Peselev Elli
Pfizer Inc.
Richardson Peter C.
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