Erythromycin derivatives

Details Erythromycin derivatives Erythromycin derivatives

1999-11-02

2001-07-17

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06262030

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel erythromycin A 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 spectrum 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 Ser. No. 60/049,349, filed Jun. 11, 1997 (Yong-Jin Wu), International Application No. PCT/IB98/00741, filed May 15, 1998 (Yong-Jin Wu), U.S. patent application Ser. No. 60/046,150, filed May 9, 1997 (Yong-Jin Wu), U.S. patent application Ser. No. 60/063,676, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. application Ser. No. 60/063,161, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. application Ser. No. 60/054,866, filed Aug. 6, 1997 (Hiroko Masamune, Yong-Jin Wu, Takushi Kaneko and Paul R. McGuirk), U.S. application Ser. No. 60/049,980, filed Jun. 11, 1997 (Brian S. Bronk, Henry Cheng, E. A. Glaser, Michael A. Letavic, Takushi Kaneko and Bingwei V. Yang), U.S. application Ser. No. 60/049,348, filed Jun. 11, 1997 (Brian S. Bronk, Henry Cheng, E. A. Glaser, 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), International Application No. PCT/GB97/01819 filed Jul. 4, 1997 (Peter Francis Leadlay, James Staunton, and Jesus Cortes), U.S. application Ser. No. 60/070,343, filed Jan. 2, 1998 (Dirlam), U.S. application Ser. No. 60/070,358, filed Jan. 2, 1998 (Yong-Jin Wu) and U.S. application Ser. No. 60/097,075, filed Aug. 19, 1998 (Hengmiao Cheng, Michael A. Letavic, Carl B. Ziegler, Jason K Dutra, Brian S. Bronk), 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 a compound of the formula 1
and pharmaceutically acceptable salts thereof, wherein:
X is —O—, —NR
5
—, or (CR
5
R
6
)
g
, wherein g is 0 or 1 and wherein, when X is —NR
5
—, R
5
and R
2
are taken together to form —(CR
7
R
8
)—;
or X is taken together with R
1
to form —N═CR
7
R
8
;
or X and R
1
are taken together to form a heterocyclic ring of the formula XI
wherein in said ring of formula XI, r and p are each independently an integer ranging from 1 to 3, q is 0 or 1, and R
9
is —CH
2
—, O, S, —C(O)—, —C(S)—, —SO
2
—, —CH═CH—, —CH(OH)CH(OH)—, or —NH—; and wherein the (CH
2
)
r
and (CH
2
)
p
portions of said ring of formula XI are optionally substituted by 1 to 4 substituents and wherein each hydrogen atom of R
9
when R
9
is —CH
2
—, —CH═CH—, —CH(OH)CH(OH)—, or —NH is optionally substituted by one substituent, said optional substituents being independently selected from the group consisting of —C(O)OR
10
, —OR
10
, —C(O)R
10
, halo, nitro, cyano, 4-10 membered heterocyclic, —R
10
, —NR
10
R
11
, —NHC(O)R
10
, —NHC(O)NR
10
R
11
, C
6
-C
10
aryl, 4-10 membered heterocyclic, —S(O)
n
R
10
, and —SO
2
NR
10
R
11
, wherein n is an integer ranging from 0 to 2;
Y is R
7
or —(CR
5
R
6
)
m
R
12
, wherein m is an integer ranging from 0 to 6; and R
5
and R
6
may each independently vary when m is greater than 1;
R
1
is H, R
7
, —C(O)R
7
, —C(O)R
12
, —C(O)OR
7
, —C(O)OR
12
, or —(CR
5
R
6
)
m
R
12
, wherein integer ranging from 0 to 6;
R
2
is H or C
1
-C
12
alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of —C(O)OR
10
, —OR
10
, —C(O)R
10
, halo, nitro, cyano, 4-10 membered heterocyclic, —R
10
, —NR
10
R
11
, —NHC(O)R
10
, —NHC(O)NR
10
R
11
, C
6
-C
10
aryl, 4-10 membered heterocyclic, —S(O)
n
R
10
, and —SO
2
NR
10
R
11
, wherein n is an integer ranging from 0 to 2;
each R
3
is independently selected from H, —C(O)R
12
or C
1
-C
18
alkanoyl, wherein in the alkyl portion of said alkanoyl one or two carbons optionally may be replaced by a heteroatom selected from O, S and N;
each R
5
and R
6
is independently H, halo, or C
1
-C
10
alkyl and R
5
and R
6
may each independently vary when m is greater than 1;
each R
7
and R
8
is independently selected from H and C
1
-C
18
alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of —C(O)OR
10
, —OR
10
, —C(O)R
10
, halo, nitro, cyano, 4-10 membered heterocyclic, —R
10
, —NR
10
R
11
, —NHC(O)R
10
, —NHC(O)NR
10
R
11
, C
6
-C
10
aryl, 4-10 membered heterocyclic, —S(O)nR10 and —SO
2
NR
10
R
11
, wherein n is an integer ranging from 0 to 2;
each R
10
and R
11
is independently H or C
1
-C
10
alkyl; and,
R
12
is a 4-10 membered heterocycyl or C
6
-C
10
aryl, wherein said heterocycyl and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of —C(O)OR
10
, —OR
10
, —C(O)R
10
, halo, nitro, cyano, 4-10 membered heterocyclic, —R
10
, —NR
10
R
11
, —NHC(O)R
10
, —NHC(O)NR
10
R
11
, C
6
-C
10
aryl, 4-10 membered heterocyclic, —S(O)
n
R
10
, and —SO
2
NR
10
OR
11
, wherein n is an integer ranging from 0 to 2.
This invention further relates to a compound of the formula 2
and pharmaceutically acceptable salts thereof, wherein:
X is —O—, —NR
5
—, or (CR
5
R
6
)
g
, wherein g is 0 or 1 and wherein, when X is —NR
5
—, R
5
R
2
are taken together to form —(CR
7
R
8
)—;
or X is taken together with R
1
to form —N═CR
7
R
8
;
or X and R
1
are taken together to form a heterocyclic ring of the formula XI
wherein in said ring of formula XI, r and p are each independently an integer ranging from 1 to 3, q is 0 or 1, and R
9
is —CH
2
—, O, S, —C(O)—, —C(S)—, —SO
2
—, —CH═CH—, —CH(OH)CH(OH)—, or —NH—; and wherein the (CH
2
)
r
and (CH
2
)
p
portions of said ring of formula XI are optionally substituted by 1 to 4 substituents and wherein each hydrogen atom of R
9
when R
9
is —CH
2
—, —CH═CH—, —CH(OH)CH(OH)—, or —NH is optionally substituted by one substituent, said optional substituents being indepently selected from the group consisting of —C(O)OR
10
, —OR
10
, —C(O)R
10
, halo, nitro, cyano, 4-10 membered heterocyclic, —R
10
, —NR
10
R
11
, —NHC(O)R
10
, —NHC(O)NR
10
R
11
, C
6
-C
10
aryl, 4-10 membered heterocyclic, —S(O)
n
R
10
, and —SO
2
NR
10
R
11
, wherein n is an integer ranging from 0 to 2;
R
1
is H, R
7
, —C(O)R
7
, —C(O)R
12
, —C(O)OR
7
, —C(O)OR
12
, or —(CR
5
R
6
)
m
R
12
, wherein m is an interger ranging from 0 to 6;
R
2
is H or C
1
-C
12
alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of —C(O)OR
10
, —OR
10
, —C(O)R
10
, halo, nitro, cyano, 4-10 membered heterocyclic, —R
10
, —NR
10
R
11
, —NHC(O)R
10
, —NHC(O)NR
10
R
11
, C
6
-C
10
aryl, 4-10 membered heterocyclic, —S(O)
n
R
10
, and —SO
2
NR
10
R
11
, wherein n is an integer ranging from 0 to 2;
each R
3
and R
4
is independently selected from H, —C(O)R
12
or C
1
-C
18
alkanoyl, wherein in the alkyl portion of said a

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