Tricyclic erythromycin derivatives

Details Tricyclic erythromycin derivatives Tricyclic erythromycin derivatives

1997-01-07

2001-08-14

Berch, Mark L. (Department: 1624)

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

Organic compounds

Carbohydrates or derivatives

C536S007200, C536S007300

Reexamination Certificate

active

06274715

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 tricyclic erythromycin 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),
(E)

Erythromycin
R
a
R
b
A
—OH
—CH
3
B
—H
—CH
3
C
—OH
—H
D
—H
—H
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 Grarn-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.
SUMMARY OF THE INVENTION
The present invention provides a novel class of antibacterial tricyclic erythromycin compounds which possess antibacterial activity.
In one aspect of the present invention are disclosed novel tricyclic erytliromycin compounds selected from the group having the formulas:
as well as the pharmaceutically acceptable salts and esters thereof. In formulas (I)-(IV) above,
A, B, D and E are independently selected from the group consisting of:
(a) hydrogen;
(b) C
1
-C
6
-alkyl, as defined below, optionally substituted with one or more substituents selected from the group consisting of:
(i) atyl;
(ii) substituted-aryl;
(iii) heteroaryl;
(iv) substituted-heteroaryl;
(v) heterocycloalkyl;
(vi) hydroxy;
(vii) C
1
-C
6
-alkoxy;
(viii) halogen consisting of Br, Cl, F or I; and
(ix) NR
3
R
4
, where R
3
and R
4
are independently selected from hydrogen and C
1
-C
6
-alkyl, or R
3
and R
4
are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function consisting of —O—, —NH—, —N(C
1
-C
6
-alkyl-)-, —N(aryl-C
1
-C
6
-alkyl-)-, —N(substituted-aryl-C
1
-C
6
-alkyl-)-, —N(heteroaryl-C
1
-C
6
-akyl-)-, —N(substituted-heteroaryl-C
1
-C
6
-alkyl-)-, —S— or —S(O)
n
—, wherein n is 1 or 2;
(c) C
3
-C
7
-cycloalkyl;
(d) atyl;
(e) substituted-aryl;
(f) heteoaryl;
(g) substituted-heteroaryl;
(h) heterocycloalkyl; and
(i) a group selected from option (b) above further substituted with —M—R
5
, wherein M is selected from the group consisting of:
(aa) —C(O)—NH—;
(bb) —NH—C(O)—;
(cc) —NH—
(dd) —N(CH
3
)—
(ee) —O—
(ff) —S(O)
n
—, wherein n is 0, 1 or 2;
(gg) —C(═NH)—NH—;
(hh) —C(O)—O—;
(ii) —O—C(O)—;
(jj) —O—C(O)—NH—;
(kk) —NH—C(O)—O—; and
(ll) —NH—C(O)—NH—;
and R
5
is selected from the group consisting of:
(aaa) C
1
-C
6
-alkyl, optionally substituted with a substituent selected from the group consisting of:
(i) aryl;
(ii) substituted-aryl;
(iii) heteroaryl; and
(iv) substituted-heteroaryl;
(bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl;
(eee) substituted-heteroaryl; and
(fff) heterocycloalkyl; or
any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function consisting of:
—O—,
—NH—,
—N(C
1
-C
6
-alkyl-)-,
—N(aryl-C
1
-C
6
-alkyl-)-,
—N(substituted-aryl-C
1
-C
6
-alkyl-)-,
—N(heteroaryl-C
1
-C
6
-alkyl-),
—N(substituted-heteroaryl-C
1
-C
6
-alkyl-)-,
—S— or —S(O)
n
—, wherein n is 1 or 2;
—C(O)—NH—;
—C(O)—NR
5
—, wherein R
5
is as described above;
—NH—C(O)—;
—NR
5
—C(O)—, wherein R
5
is as described above; and
—C(═NH)—NH—;
R
1
is selected from the group consisting of:
(a) hydrogen;
(b) hydroxy;
(c) —O—C
1
-C
3
-alkyl;
(d) —O—C
3
-C
5
-cycloalkyl;
(e) —O—C
1
-C
3
-alkyl-C
3
-C
5
-cycloalkyl;
(f) —O—C(O)—C
1
-C
3
-alkyl;
(g) —O—C(O)—OC
1
-C
3
-alkyl; and
(h) —O—C(O)—NH—C
1
-C
3
-alkyl;
R
2
is hydrogen or a hydroxy-protecting group, as defined below; and
Z is hydroxy or protected-hydroxy;
with the provisos that when the compound is of Formulas (I), (II) or (III) then A, B, D, and E may not all be hydrogen, D and E may not be C
1
-C
3
-alkyl when A and B are hydrogen, nor may one of D and E be hydrogen and the other be C
1
-C
3
-alkyl when A and B are hydrogen.
In another aspect of the present invention are disclosed pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier and treatment of bacterial infections with such compositions. Suitable carriers and methods of formulation are also disclosed. The compounds and compositions of the present invention have antibacterial activity.
In a furter aspect of the present invention are provided processes for the preparation of tricyclic macrolide derivatives of Formulas (I), (II), (III) and (IV) above.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention are compounds selected from the group having Formula (I) above, wherein A, B, D, E, and R
1
-R
5
are as described above.
In a second embodiment of the present invention are compounds selected from the group having Formula (II) above, wherein A, B, D, E, R
1
-R
5
and Z are as described above.
In another embodiment of the present invention are compounds selected from the group having Formula (III) above, wherein A, B, D, E, and R
1
-R
5
are as described above.
In yet another embodiment of the present invention are compounds selected from the group having Formula (IV) above, wherein A, B, D, E, and R
1
-R
5
are as described above.
In one preferred embodiment of the present invention are compounds of Formula (III) above wherein R
1
is hydrogen, hydroxy or methoxy, R
2
is hydrogen, and A, B, D, E and R
1
-R
5
are as described above.
In another preferred embodiment of the present invention are compounds of Formula (III) above wherein R
1
is hydrogen or methoxy, R
2
is hydrogen, and any three of the A, B, D and E groups are hydrogen and the other group is selected from a singly substituted C
1
-C
6
-alkyl group comprised of —(CH
2
)
m
R
6
where m=1, 2, 3 or 4 and R
6
is:
(a) aryl;
(b) substituted-aryl;
(c) heteroaryl;
(d) substituted-heteroaryl;
(e) heterocycloalkyl;
(f) hydroxy;
(g) C
1
-C
6
-alkoxy
(h) NR
3
R
4
, where R
3
and R
4
are independently selected from hydrogen and C
1
-C
6
-alkyl, or R
3
and R
4
are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function consisting of —O—, —NH—, —N(C
1
-C
6
-alkyl-)-, —N(aryl-C
1
-C
6
-alkyl-)-, —N(substituted-aryl-C
1
-C
6
-alkyl-)-, —N(heteroaryl-C
1
-C
6
-alkyl-)-, —N(substituted-heteroaryl-C
1
-C
6
-alkyl-)-, —S— or —S(O)
n
—, wherein n is 1 or 2;
(i) halogen consisting of Br, Cl, F or I;
(j) C
1
-C
3
alkyl; or
(k) —(CH
2
)
r
—M—(CH
2
)
s
—R
7
wherein r=0, 1 or 2; s=0, 1 or 2 and M is
(aa) —C(O)—NH—;
(bb) —NH—C(O)—;
(cc) —NH—
(dd) —N(CH
3
)—
(ee) —O—
(ff) —S(O)
n
—, wherein n is 0, 1 or 2;
(gg) —C(═NH)—NH—;
(hh) —C(O)—O—;
(ii) —O—C(O)—;
(jj) —O—C(O)—NH—;
(kk) —NH—C(O)—O—; and
(ii) —NH—C(O)—NH—;
and R
7
is selected from the group consisting of:
(aaa) C
1
-C
3
-alkyl,
(bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl; and
(eee) substituted-heteroaryl.
In yet another preferred embodiment of the present invention are com

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