6-O-alkyl-2-nor-2-substituted ketolide derivatives

Details 6-O-alkyl-2-nor-2-substituted ketolide derivatives 6-O-alkyl-2-nor-2-substituted ketolide derivatives

2000-11-30

2003-05-27

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007400

Reexamination Certificate

active

06569836

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel macrolide compound or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof; a composition comprising the compound and a suitable carrier; a method of preparing the compound; and a method of treatment and prevention of infections in a mammal comprising administering the compound.
BACKGROUND OF THE INVENTION
Erythromycins A, B, C and D, represented by the formula below,

Erythromycin
R′
R″
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 antibacterial agents, 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.
U.S. Pat. No. 4,874,748 describes a 2-norerythromycin D derivative, which were produced in a strain
Streptomyces erythreus
12693-240 transformed by pNJI bearing DNA from
Streptomyces antibioticus
. The potential of using genetic engineering techniques to produce novel members of the commercially important class of antibiotics, the macrolides, was demonstrated by James B. McAlpine et al.,
Journal of Antibiotics
, XL(8) 1115-1122 (1987). These processes provide structurally determined 2-norerythromycin derivatives, however the antibacterial activities of 2-norerythromycins A, B, C and D can be somewhat disappointing.
PCT Publication No. WO 99/21871, published on May 6, 1999, describes the 2-position of a 3,9-diketo-6—O-substituted tricyclic imine or carbamate can be substituted with a halogen. The C-2 carbon of the 2-substituted 3,9-diketo-6—O-substituted tricyclic imine or carbamate is substituted with a methyl and a halogen atom selected from fluorine, chlorine, bromine or iodine.
Copending U.S. patent application Ser. No. 09/312,517, filed May 14, 1999, discloses C-2 modified erythromycin derivatives wherein the C-2 carbon of a 6—O-substituted ketolide derivative has been substituted with methyl and a substituent selected from substituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl.
U.S. Pat. Nos. 5,561,118; 5,770,579 and 5,444,051 describe erythromycin derivatives having C-2 substitution with methyl and a substituent selected from hydrogen, alkyl and alkylamine.
SUMMARY OF THE INVENTION
The invention relates to a new class of macrolide compounds having antibacterial activity. Novel modifications of the C2-position of compounds of the invention provide a new class of 6—O-alkyl-2-nor-2-substituted ketolide derivatives. The compounds can be prepared via C2-derivatization of a 2-norerythromycin fermentation product or the 2-methyl group of an erythromycin derivative can be removed by new methods and further derivatized to afford the desired C2-derivatization. Pharmaceutical compositions and a method of treatment are also described herein.
In one aspect, therefore, the present invention relates to compounds selected from the group consisting of:
or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, wherein:
R
p
is hydrogen or a hydroxy protecting group;
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:
(i) hydroxy;
(ii) —CH═O;
(iii) aryl;
(iv) substituted aryl;
(v) heteroaryl;
(vi) substituted heteroaryl;
(vii) Ar
1
-Ar
2
, wherein Ar
1
and Ar
2
are independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
(viii) —NR′R″, wherein R′ and R″ are independently selected from the group consisting of hydrogen and C
1
-C
6
alkyl, or wherein R′ and R″ are taken with nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function selected from the group 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-)—, and —N(substituted heteroaryl-C
1
-C
6
-alkyl-)—;
(b) C
1
-C
6
-alkenyl;
(c) C
1
-C
6
-alkenyl-R
2
;
(d) C
1
-C
6
-alkynyl; and
(e) C
1
-C
6
-alkynyl-R
2
;
R
2
is selected from the group consisting of:
(a) hydrogen;
(b) aryl;
(c) substituted aryl;
(d) heteroaryl;
(e) substituted heteroaryl; and
(f) Ar
1
-Ar
2
, wherein Ar
1
and Ar
2
are as defined above;
R
3
is selected from the group consisting of:
(a) hydrogen;
(b) OH;
(c) F, Cl, Br or I;
(d) C
1
-alkyl substituted with one or more substituents selected from the group consisting of:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) —NR′R″, wherein R′ and R″ as defined above; and
(vi) —OR
5
, wherein R
5
is hydrogen or C
1
-C
6
alkyl optionally substituted with one or more substituents selected from the group consisting of:
(1) aryl;
(2) substituted aryl;
(3) heteroaryl; and
(4) substituted heteroaryl;
(vii) —OC(O)R
5
, wherein R
5
is as defined above;
(e) C
2
-C
6
alkyl optionally substituted with one or more substituents selected from the group consisting of:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) —NR′R″, wherein R′ and R″ as defined above;
(vi) —OR
5
, wherein R
5
is as defined above; and
(vii) —OC(O)R
5
, wherein R
5
is as defined above;
(f) C
1
-C
6
-alkenyl;
(g) C
1
-C
6
-alkenyl-R
2
, wherein R
2
is as defined above;
(h) C
1
-C
6
-alkynyl;
(i) C—C
6
-alkynyl-R
2
, wherein R
2
is as defined above;
(j) —OR
5
, wherein R
5
is as defined above;
(k) —OC(O)R
5
, wherein R
5
is as defined above;
(l) —CH
2
SO
2
NHR
5
, wherein R
5
is as defined above;
(m) —CH
2
S(O)
x
R
5
, wherein x is 0,1 or 2, and R
5
is as defined above; and
(n) —CH
2
NHR
5
, wherein R
5
is as defined above;
R
4
is selected from the group consisting of:
(a) hydrogen;
(b) OH;
(c) NH
2
;
(d) NHR
5
, wherein R
5
as defined above;
(e) PhSe;
(f) F, Cl, Br or I,
or R
3
and R
4
taken together with the atoms to which each is attached forms a 3- to 6-membered aromatic or non-aromatic ring optionally containing a heteroatom, wherein the non-aromatic ring optionally contains one to two double bonds or R
3
and R
4
taken together form a ═CH
2
(exocyclic methylene), —CH
2
O— (epoxide) or ═O (oxo);
R
a
, R
b
, R
c
and R
d
are 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:
(i) —L—M—R
6
, wherein
L is either absent or selected from the group consisting of:
(1) —C(O)NH—;
(2) —NHC(O)—;
(3) —NH—;
(4) —N(CH
3
)—;
(5) —O—;
(6) —S(O)
x
—, wherein x is 0, 1, or 2;
(7) —C(═NH)NH—;
(8) —NHC(═NH)—;
(9) —C(O)O—;
(10) —OC(O)—;
(11) —OC(O)NH—;
(12) —NHC(O)O—; and
(13) —NHC(O)NH—;
M is either absent or selected from the group consisting of:
(1) —(CH
2
)
1
—, wherein 1 is 1 to 5,
(2) —(CH
2
)
m
—CH═CH—, wherein m is 0 to 3,
(3) —(CH
2
)
n
—C≡C— wherein n is 0 to 3;
R
6
is selected from the group consisting of:
(1) hydrogen,
(2) aryl,
(3) substituted aryl,
(4) heteroaryl,
(5) substituted heteroaryl, and
(6) Ar
1
-Ar
2
, wherein Ar
1
and Ar
2
are independently selected from the group consisting of:
(a) aryl,
(b) substituted aryl,
(c) heteroaryl, and
(d) substituted heteroaryl; and
(ii) halogen;
(c) C
3
-C
7
cycloalkyl;
(d) heterocycloalkyl; and
(e) substituted heterocycloalkyl;
or any one pair of substituents selected from the group consisting of R
a
R
b

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