6,11-4-carbon bridged erythromycin derivatives

Details 6,11-4-carbon bridged erythromycin derivatives 6,11-4-carbon bridged erythromycin derivatives

2002-07-25

2004-06-22

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007300, C536S007400

Reexamination Certificate

active

06753318

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel semisynthetic macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to 6,11-4-carbon bridged erythromcyin derivatives, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
BACKGROUND OF THE INVENTION
Erythromycins A through D, represented by formula (E) as illustrated below,
are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterials, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
Kashimura et al. have disclosed 6-O-methylerythromycin derivatives having a tricyclic basic nuclear structure in European Application 559896, published Nov. 11, 1991. Also, Asaka et al. have disclosed 5-O-desoaminylerythronolide derivatives containing a tricyclic carbamate structure in PCT Application WO 93/21200, published Apr. 22, 1992.
Recently erythromycin derivatives containing a variety of substituents at the 6-O position have been disclosed in U.S. Pat. Nos. 5,866,549 and 6,075,011 as well as PCT Application WO00/78773. Furthermore, Ma, Or et. al. have described erythromycin derivatives with aryl groups tethered to the C-6 position in
J. Med Chem.,
44, pp 4137-4156 (2001). U.S. Pat. No. 6,046,171 and PCT application WO 99/21864, published May 6, 1999, disclose certain 6,11-bridged erythromycin derivatives.
SUMMARY OF THE INVENTION
The present invention provides a novel class of C6-C11 bridged macrolide compounds that possess antibacterial activity.
In one embodiment, the compounds of the present invention are represented by formula I, as illustrated below or their pharmaceutically acceptable salts, esters and prodrugs::
wherein
W is selected from the group consisting of:
(a) —CH
2
—C(A)═C(B)—CH
2
—;
 wherein,
A and B are independently selected from the group consisting of:
(i) hydrogen;
(ii) deuterium;
(iii) halogen;
(iv) R
1
, wherein R
1
is selected from the group consisting of:
 a. C
1
-C
6
alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
 b. C
2
-C
6
alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
 c. C
2
-C
6
alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
(v) R
2
, wherein R
2
is selected from the group consisting of:
 a. aryl;
 b. heteroaryl;
 c. substituted aryl; and
 d. substituted heteroaryl;
(vi) —(C
1
-C
3
-alkyl)-M—(C
1
-C
3
-alkyl)-R
2
, wherein M═—O—, —NH—, —N(CH
3
)—, —NHC(O)—, —S(O)
n
—, wherein n=0, 1 or 2, and R
2
is as previously defined;
(vii) —(C
1
-C
3
-alkyl)-M—R
2
, wherein M and R
2
are as previously defined;
(viii) —C(O)—J—R
3
, wherein J is absent, O or S, and R
3
is H, R
1
or R
2
, where R
1
and R
2
are as previously defined; and
(ix) —C(O)—NR
11
R
12
, wherein R
11
and R
12
are each independently selected from the group consisting of:
 a. hydrogen;
 b. C
1
-C
6
-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
 c. C
2
-C
6
-alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
 d. C
2
-C
6
-alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
 e. R
11
and R
12
taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain one or more heterofunctions selected from the group consisting of: —O—, —NH—, —N(C
1
-C
6
-alkyl)-, —N(R
2
)—, —S(O)
n
—, wherein n and R
2
are as previously defined;
(b) —CH
2
—CH(A)—C(B)═CH—, wherein A and B are as previously defined;
(c) —CH
2
—CH(E)—CH(G)—CH
2
—;
 wherein E and G are independently selected from the group consisting of:
(i) A, wherein A is as previously defined;
(ii) —OH;
(iii) —OR
p
, wherein R
p
is a hydroxy protecting group;
(iv) —O—R
9
, wherein R
9
is R
1
or R
2
, and wherein R
1
and R
2
are as previously defined;
(v) —S(O)
n
R
9
, wherein n and R
9
are as previously defined;
(vi) —NHC(O)R
3
, wherein R
3
is as previously defined;
(vii) —NHC(O)NR
11
R
3
, wherein R
11
and R
3
are as previously defined;
(viii) —NHS(O)
2
R
9
, wherein R
9
is as previously defined;
(ix) —NHR
13
, wherein R
13
is an amino protecting group; and
(x) —NR
11
R
12
, wherein R
11
and R
12
are as previously defined;
(d)
 wherein:
(i) —Q— is selected from the group consisting of: —O—; —O—C(O)—CH(R
7
)—; —N(R
7
)—; —O—C(O)—N(R
7
)—; —O—C(O)—O—; —N(R
7
)—N═N—; —C(R
7
)═N—O—; and CH(R
7
)—N(R
8
)—O—; wherein R
7
and R
8
are independently selected from R
3
, wherein R
3
is as previously defined; or
(ii) —Q— taken together with the two carbon atoms it is attached to is selected from the group consisting of:
a. cycloalkylene;
b. cycloalkenylene; and
c. heterocycloalkylene; and
(e) —CH
2
—C(R
4
)(R
5
)—CH
2
—CH
2
—;
 wherein R
4
and R
5
taken together with the carbon atom to which they are attached are selected from the group consisting of:
(i) C═O;
(ii) C(OR
1
)
2
, wherein R
1
is as previously defined;
(iii) C(SR
1
)
2
, wherein R
1
is as previously defined;
(iv) C[—O(CH
2
)
m
]
2
, wherein m is 2 or 3;
(v) C[—S(CH
2
)
m
]
2
, wherein m is as previously defined,
(vi) C═CHR
3
, wherein R
3
is as previously defined;
(vii) C═N—O—R
3
, wherein R
3
is as previously defined;
(viii) C═NNHR
3
, wherein R
3
is as previously defined;
(ix) C═NNHC(O)R
3
, wherein R
3
is as previously defined;
(x) C═NNHC(O)NR
11
R
3
, wherein R
11
and R
3
are as previously defined;
(xi) C═NNHS(O)
2
R
9
, wherein R
9
is as previously defined;
(xii) C═NNHR
13
, wherein R
13
is as previously defined; and
(xiii) C═NR
9
, wherein R
9
is as previously defined;
X and Y are:
(a) independently selected from the group consisting of:
(i) hydrogen;
(ii) deuterium;
(iii) —OH;
(iv) OR
p
, wherein R
p
is as previously defined; and
(v) —NR
14
R
15
, wherein R
14
and R
15
are each independently selected from the group consisting of:
a. hydrogen;
b. C
1
-C
12
alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and
c. R
14
and R
15
, taken together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl ring optionally substituted with one or more hetero atoms selected from the group consisting of O, S and N; or
(b) taken together with the carbon atom to which they are attached are selected from the group consisting of:
(i) C═O;
(ii) C═NR
3
, wherein R
3
is as previously defined;
(iii) C═NC(O)R
3
, wherein R
3
is as previously defined;
(iv) C═N—OR
6
, wherein R
6
is selected from the group consisting of:
a.

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