13-methyl erythromycin derivatives

Details 13-methyl erythromycin derivatives 13-methyl erythromycin derivatives

2003-05-19

2004-08-17

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S007200, C536S007300

Reexamination Certificate

active

06777543

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel macrolide compounds that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to methods of preparing the novel compounds and pharmaceutical compositions containing the novel compounds. In addition, the present invention includes methods of treating bacterial and protozoal infections through the administration of the novel compounds to mammals, fish and birds requiring such treatment.
Although some 13-methyl erythromycins (also known as 15-norerythromycins) have been reported previously (Kibwage et al.,
J. Antibiotics
, vol. 40, pp. 1-6, (1987); Weber & McAlpine, U.S. Pat. No. 5,141,926), these have been confined to 15-norerythromycin C and 6-deoxy-15-norerythromycins B and D. Moreover, not only have these 15-norerythromycins been found as extremely minor components co-expressed with high levels of “natural” erythromycins (13-ethyl erythromycins), but the 13-methyl counterparts (15-norerythromycins A and B) to the most desirable and biologically-active “natural” erythromycins (erythromycin A and B) have never previously been isolated.
Chemical modification of “natural” erythromycins has proven to be an extremely effective means for enhancing the bioefficacy of the “natural” molecules. Thus, one would expect chemical modification of novel erythromycins to similarly produce compounds with desirable and enhanced bioefficacies. International Patent Application WO 98/01546, PUBLISHED Jan. 15, 1998, filed Jul. 4, 1997, describes in general terms the production of novel polyketides through recombinant DNA technologies. The use of these technologies to generate novel erythromycins, many of which have starter units different from the propionate starter unit characteristic of the “natural” erythromycins, is described in pending International Patent Application WO 98/01571, PUBLISHED Jan. 15, 1998, filed Jul. 4, 1997. Chemical modification of these novel erythromycins is also described in co-pending International Patent Applications WO 99/35156, PUBLISHED Jul. 15, 1999, filed Dec. 21, 1998, and WO 99/35157, published Jul. 15, 1999.
Macrolide antibiotics are known to be useful in the treatment of a broad spectrum of bacterial and protozoal infections in mammals (including humans), fish and birds. Various derivatives of erythromycin A that are useful as antibiotic agents are referred to in U.S. patent application serial No. 60/049,349, filed Jun. 11, 1997; U.S. patent application serial No. 60/046,150, filed May 9, 1997; U.S. patent application serial No. 60/063,676, filed Oct. 29, 1997; U.S. patent application serial No. 60/087,798, filed Jun. 3, 1998; U.S. patent application serial No. 60/054,866, filed Aug. 6, 1997; U.S. patent application serial No. 60/063,161, filed Oct. 29, 1997; U.S. patent application serial No. 60/117,342, filed Jan. 27, 1999; U.S. patent application serial No. 60/130,809, filed Apr. 23, 1999; U.S. patent application serial No. 60/130,912, filed Apr. 23, 1999; and U.S. patent application serial No. 60/130,913, filed Apr. 23, 1999. Each of the foregoing U.S. patent applications is incorporated herein by reference in its entirety. Like other macrolide antibiotics, the novel erythromycin derivatives of the present invention possess activity against infections caused by various gram-positive and gram-negative bacteria as well as protozoa, as described below.
SUMMARY OF THE INVENTION
The present invention relates to novel derivatives of erythromycin that are useful as antibacterial and antiprotozoal agents in mammals (including humans), fish and birds. In particular, the compounds of the present invention include novel 13-methyl erythromycin derivatives prepared by chemical modification of 13-methyl erythromycins, which have been produced by direct fermentation. The invention further relates to methods for preparing the claimed compounds, pharmaceutical compositions containing such compounds and methods of treatment with such compounds and compositions.
In particular, the present invention relates to compounds of formula 1 :
and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
A is H or halogen;
X is selected from —C(O)—, —CH(NR
8
R
9
)—, —CHR
8
NR
9
—, —NR
9
CHR
8
—, —C(═NR
8
)— and —C(═N—OR
8
)—, wherein the first dash of each of the foregoing X groups is attached to the C-10 carbon of the compound of formula 1 and the last dash of each group is attached to the C-8 carbon of the compound of formula 1;
Y is selected from CH
2
, C(O), CHF, CF
2
, C═C(R
a
R
b
), CHSR
7
, CHR
7
, C═S, —C(═NR
8
)—, —C(═N—OR
8
), CH(OR
8
), CH(OC(O)R
8
), CH(OC(O)Ar), CH(OC(O)NR
8
R
9
), CH(O(CR
a
R
b
)
n
Ar), CH(OC(O)(CR
a
R
b
)
n
Ar), CH(OC(O)(CR
a
R
b
)
n
NR
8
(CR
a
R
b
)
n
Ar), CH(OC(O)NR
8
NR
8
R
9
), CH(OC(O)NR
8
(CR
a
R
b
)
n
NR
8
(CR
a
R
b
)
n
Ar), CH(OC(O)NR
8
NR
8
(CR
a
R
b
)
n
NR
8
(CR
a
R
b
)
n
Ar), —CH(NR
8
R
9
)—, CH(NR
8
C(O)R
8
), CH(NR
8
C(O)NR
8
R
9
), CH(NR
8
C(O)OR
8
), CH(S(CR
a
R
b
)
n
Ar), —CH(NH(CR
a
R
b
)
n
NR
8
(CR
a
R
b
)
n
Ar) and CH(NH(CR
a
R
b
)
n
Ar), wherein n is an integer ranging from 0 to 10;
or Y has the following structure:
R
1
and R
2
can be taken separately or together;
when taken separately, R
1
is independently selected from OR
8
, OC(O)R
8
, OC(O)NR
8
R
9
, NR
8
R
9
, NR
8
C(O)R
8
, NR
8
C(O)NR
8
R
9
, O(CR
a
R
b
)
n
Ar, S(CR
a
R
b
)
n
Ar and N(CR
a
R
b
)
n
Ar, wherein n is an integer ranging from 0 to 10;
when taken separately, R
2
is independently selected from OR
8
, O-mesyl, O-tosyl, OC(O)R
8
, OC(O)NR
8
R
9
, NR
8
R
9
, NR
8
C(O)R
8
, NR
8
C(O)NR
8
R
9
, O(CR
a
R
b
)
n
Ar, S(CR
a
R
b
)
n
Ar and NH(CR
a
R
b
)
n
Ar, wherein n is an integer ranging from 0 to 10;
each of R
a
and R
b
is independently selected from H, halo and a C
1
-C
6
alkyl;
R
a
and R
b
together with the carbon to which they are attached can form a 3- to 10-membered cyclic or heterocyclic diradical, wherein one or two carbons of said diradical are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)
2
—, a—N(C
1
-C
6
)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
(CR
a
R
b
)
n
is alkylene, wherein n is an integer ranging from 0 to 10, uninterrupted or interrupted by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)
2
—, a —N(C
1
-C
6
)alkyl- and —C(O)— and optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
when taken together, R
1
and R
2
taken with the intervening atoms form an additional ring having one of the following structures:
B
1
is selected from O, (CR
aa
R
bb
)
m
, SO
2
, O and NR
7
, wherein m is 0 or 1;
Z is selected from (CR
aa
R
bb
)
m
, C(O), C(NR
aa
), P—OR
aa
, P(O)OR
aa
, P(O)NR
aa
R
bb
, Si(R
c
R
d
), SO, SO
2
, (CR
aa
R
bb
)
m
CO and CO(CR
aa
R
bb
)
m
, wherein m is 1 or 2;
R
c
and R
d
are independently selected from a C
1
-C
8
alkyl, a C
6
-C
10
aryl and a C
4
-C
10
heterocyclic;
R
aa
and R
bb
are independently selected from H and a C
1
-C
6
alkyl;
R
aa
and R
bb
together with the carbon to which they are attached can form a 3- to 10-membered cyclic or heterocyclic diradical, wherein one or two carbons of said diradical are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)
2
—, a —N(C
1
-C
6
)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
when B
1
is NR
7
, B
1
and R
6
together with the nitrogen to which they are attached can form a 3- to 10-membered ring wherein one or two carbons of said ring are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)
2
—, a —N(C
1
-C
6
) alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
when B
1
is NR
7
, B
1
and R
6
together with the nitrogen to which they are attached can form —N═C(R
7
)(R
a

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