6-O-carbamate ketolide derivatives

Details 6-O-carbamate ketolide derivatives 6-O-carbamate ketolide derivatives

2000-05-24

2002-07-16

Riley, Jezia (Department: 1637)

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

Organic compounds

Carbohydrates or derivatives

C536S007400, C536S124000, C536S125000, C514S029000

Reexamination Certificate

active

06420535

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel macrolide compound or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, to 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.
BACKGROUND OF THE INVENTION
Erythromycins A, B, C and D, represented by formula (I),
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. 5,444,051 and U.S. Pat. No. 5,770,579 disclose 6-O-substituted-3-oxoerythromycin derivatives in which the substituents are selected from alkyl, —CONH
2
, —CONHC(O)alkyl and —CONHSO
2
alkyl. PCT application WO 97/10251, published Mar. 20, 1997, discloses 6-O-methyl 3-descladinose erythromycin derivatives.
European Patent Application 0216169, published Apr. 1, 1987, discloses erythromycin A 6-carbamate derivatives.
European Patent Application 596802, published May 11, 1994, discloses bicyclic 6-O-methyl-3-oxoerythromycin A derivatives.
PCT application WO 92/09614, published Jun. 11, 1992, discloses tricyclic 6-O-methylerythromycin A derivatives.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to a compound represented by a formula selected from the group consisting of:
a compound of the formula
a compound of the formula
a compound of the formula
a compound of the formula
a compound of the formula
a compound of the formula
a compound of the formula
a compound of the formula
a compound of the formula
or a pharmaceutically acceptable salt, solvate, ester, or prodrugs thereof, wherein:
R
p
is hydrogen or a hydroxy protecting group;
A is —O— or —NH—;
M is either absent or selected from the group consisting of:
(a) —(CH
2
)
l
— where l is 1 to 5,
(b) —(CH
2
)
m
—CH═CH— where m is 0 to 3,
(c) —(CH
2
)
n
—C≡C— where n is 0 to 3;
R
1
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 independently selected from the group consisting of:
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl, and
(iv) substituted heteroaryl;
R is selected from the group consisting of:
(a) aryl,
(b) substituted aryl,
(c) heteroaryl,
(d) substituted heteroaryl, and
(e) Ar
1
—Ar
2
wherein Ar
1
and Ar
2
are independently selected from the group consisting of:
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl, and
(iv) substituted heteroaryl;
X is selected from the group consisting of:
(a) O
(b) N—OH
(c) N—O—U—R
3
wherein U is selected from the group consisting of:
(i) —C(O)—
(ii) —C
1
-C
6
alkyl,
(iii) —C
1
-C
6
alkenyl, and
(iv) —C
1
-C
6
alkynyl,
and R
3
is selected from the group consisting of:
(i) hydrogen,
(ii) aryl,
(iii) substituted aryl,
(iv) heteroaryl,
(v) substituted heteroaryl, and
(vi) Ar
1
—Ar
2
wherein Ar
1
and Ar
2
are independently selected from the group consisting of:
(1) aryl,
(2) substituted aryl,
(3) heteroaryl, and
(4) substituted heteroaryl;
W is selected from the group consisting of
(a) —NH—(CH
2
)
p
— wherein p is 0 to 5,
(b) —(CH
2
)
q
— wherein q is 0 to 5,
(c) —O—(CH
2
)
r
— wherein r is 0 to 5,
(d) —NH—C
1
-C
6
alkenyl-,
(e) —C
1
-C
6
alkenyl-,
(f) —O—C
1
-C
6
alkenyl-,
(g) —NH-C
1
-C
6
alkynyl-,
(h) —C
1
-C
6
alkynyl-, and
(i) —O-C
1
-C
6
alkynyl-,
R
4
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 independently selected from the group consisting of:
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl, and
(iv) substituted heteroaryl; and
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
1
or —L—M—R
2
, wherein M, R
1
, and R
2
are as defined above, and 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) —C(O)O—;
(9) —OC(O)—;
(10) —OC(O)NH—;
(11) —NHC(O)O—; and
(12) —NHC(O)NH—; 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
, R
a
R
c
, R
a
R
d
, R
b
R
c
, R
b
R
d
or R
c
R
d
taken together with the atom or atoms to which they are attached 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-)—; —N(substituted heteroaryl-C
1
-C
6
alkyl-)—; —S(O)
x
—, wherein x is 0, 1, or 2; —C(O)—NH—; —NH—C(O)—; —C(O)—NR
12
—; and —NR
12
—C(O)—; wherein R
12
is hydrogen, C
1
-C
3
alkyl, C
1
-C
3
alkyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
In another aspect, the invention relates to a process for preparing a compound of formula I, II, II-A, III, IV, IV-A, V, VI, and VI-A, as defined above, comprising the steps of:
(a) reacting a compound having a formula:
 wherein V is selected from the group consisting of:
(i) O,
(ii) N—O—(CH
2
)
s
—R
x
, wherein s is 0 to 5 and R
x
is selected from the group consisting of:
(1) hydrogen,
(2) alkyl,
(3) substituted alkyl,
(4) aryl,
(5) substituted aryl,
(6) heteroaryl, and
(7) substituted heteroaryl,
(iii) N—O—C(O)—(CH
2
)
s
—R
x
, wherein s and R
x
is as defined above,
(iv) N—O—C(R
y
)(R
z
)—O—R
x
, wherein R
x
is as defined above, and R
y
and R
z
are independently selected from the group consisting of:
(1) hydrogen,
(2) unsubstituted C
1
-C
12
-alkyl,
(3) C
1
-C
12
-alkyl substituted with aryl, and
(4) C
1
-C
12
-alkyl substituted with substituted aryl,
or R
y
and R
z
taken together with the carbon to which each is attached form a C
3
-C
12
-cycloalkyl ring; and R
p
and R
p2
are as defined above;
with either (i) an isocyanate reagent of the formula O═C═N—M—R
1
, O═C═N—M—R
2
, O═C═N—C(O)—M—R
1
, O═C═N—C(O)—M—R
2
, O═C═N—S(O)
2
—M—R
1
, or O═C═N—S(O)
2
—M—R
2
, wherein M, R
1
, and R
2
are as defined above, or (ii) an activated isocyanate derivative followed by an alkylation with a compound of the formula X
1
—M—R
1
or X
1
—M—R
2
, wherein M, R
1
, and R
2
are as defined above, and X
1
is a halide or a leaving group, and optionally removing the activating group;
(b) carrying out one or more of the following steps in any suitable order:
(i) removing any hydroxy protecting group that may be present;
(ii) removing a protecting group on the C9-oxime;
(iii) converting the C9-oxime into a keto moiety;
(iv) removing the cladinose sugar and oxidizing the resulting hydroxy group;
(v) converting the 11,12-diol into an 11,12-carbonate;
(vi) converting the 11,12-diol into an 11,12-carbamate optionally substituted on the nitrogen atom; and
(vi) preparing a tricyclic imine derivative from the 11,12-carbamate.
In a preferred process, the 11,12-carbonate is prepared by treating the compound of the formula:
wherein R is selected from the group consisting of —M—R
1
, —M—R
2
, —C(O)—M—R
1
, —C(O)—M—R
2
, —S(O)
2
—M—R
1
,

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