C12 modified erythromycin macrolides and ketolides having...

Details C12 modified erythromycin macrolides and ketolides having... C12 modified erythromycin macrolides and ketolides having...

2002-07-03

2004-06-29

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007300, C536S007400

Reexamination Certificate

active

06756359

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel semi-synthetic macrolides and ketolides having antibacterial activity, to pharmaceutical compositions comprising these compounds, and to a medical method of treatment. More particularly, this invention concerns to C12 modified erythromycin macrolides and ketolide derivatives, compositions containing these compounds, methods of producing the compounds and methods of treating bacterial infections.
BACKGROUND OF THE INVENTION
Erythromycins A through D, represented by formula (I):
(I)

Erythromycin
R
1
R
2
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 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. For example, the compound 6-OMe erythromycin A, or clarithromycin, has found widespread use. However, even this compound is beginning to lose its effectiveness and other erythromycin derivatives having improved activity are needed. Other 6-O-substituted erythromycin compounds have also been proposed for this purpose. For example, PCT application WO 92/09614, published Jun. 11, 1992, discloses tricyclic 6-O-methylerythromycin A derivatives. U.S. Pat. No. 5,444,051 discloses 6-O-substituted-3-oxoerythromycin A 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 596802, published May 11, 1994, discloses bicyclic 6-O-methyl-3-oxoerythromycin A derivatives.
More recently, a class of 3-O ketolide erythromycin derivatives have been disclosed in U.S. Pat. Nos. 6,147,197 and 5,635,485. Representative lead compounds in this class include, for example ABT-773 disclosed in U.S. Pat. No. 6,147,197 and telithromycin disclosed in U.S. Pat. No. 5,635,485. The structures of these compounds are as follows:
Other modifications that have shown promise include modifications at C2, including, for example, those shown in U.S. Pat. No. 6,124,269 and International Application Publication No. WO 00/69875, the disclosures of which are incorporated herein by reference.
Despite much activity in designing 14-membered macrolide derivatives, few examples of modifications at C12 exist, especially with regards to the C12-C21 bond. U.S. Pat. No. 4,857,641 (Hauske) discloses that when the C9-C11 erythromycin positions are protected as cyclic thiocarbonates, the C12 OH can be selectively activated and eliminated over the C6 OH to give an exocyclic double bond, and the thiocarbonate protecting group can then be removed reductively with NaBH. Stereoselective dihydroxylation is disclosed as the sole olefin modification. U.S. Pat. No. 5,217,960 (Lartey), discloses that the above C12 exocyclic alkene formation of Hauske can also be effected with a protected amino group at C9 and a formate ester at C11. However, elimination at C6 did occur, suggesting that the C9 amino substituent does not provide as great a steric impediment to C6 OH activation as does the Hauske C9 thiocarbonate. The desired C12 olefin could be separated and isolated, and is disclosed as participating in stereoselective epoxidation, dihydroxylation, and hydroboration reactions, wherein all reagents attack the same face of the olefin (top face if the macrolide is drawn as shown above). Of these products, only the epoxide is disclosed as being derivatized by ring opening with alkyl amines. (Ring opening with other nucleophiles is suggested, but only generally, and no specific examples are given). It should be noted that the C12 modified compounds of Hauske and Lartey exhibit minimal antibacterial activity.
Efficient strategies for synthetic modifications involving the C12-C21 bond rely, in part, on the ability to selectively differentiate between the aglycon alcohols of erythromycin A. The differentiation appears to be dependent upon the identity of the C9 substituent, although the order and degree of selectivity can be difficult to predict. For example, the reactivity of the aglycon alcohols generally decrease when comparing C11 to C6 to C12. However as seen in the Hauske and Lartey examples above, the C12 OH can become more reactive than the C6 OH if the C9 ketone is modified in a particular manner. Alternatively when the C9 ketone is functionalized as various oximes (see U.S. Pat. No. 6,147,195), the C6 OH can be selectively alkylated over both C12 and C11. Finally, it has been shown that when erythromycin A is treated with NaBH
4
to form a bis-erythromycin A borate ester followed by alkylation with MeI, selective methylation occurs at C12 over both C11 and C6 (JOC, 1999, p. 2107).
SUMMARY OF THE INVENTION
The present invention provides novel 14 membered macrolide and ketolide antibiotics containing C12 modifications, useful common intermediates for introducing C12 modifications, methods for their synthesis, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.
In one embodiment, the present invention provides compounds of the following formula (II):
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein
A. V is —OCOR
x
, carbonyl, or a cladinose moiety of the formula:
 wherein R
x
is H, alkyl, —O-alkyl, —N(H)-alkyl, or —N(alkyl)
2
;
B. either Y and Z taken together define a group X, wherein X is selected from the group consisting of
(1) ═O,
(2) ═N—OH,
(3) ═N—O—R
1
where R
1
is selected from the group consisting of
(a) C
1
-C
12
-alkyl,
(b) C
1
-C
12
-alkyl substituted with alkoxy,
(c) C
1
-C
12
-alkyl substituted with aryl,
(d) C
1
-C
12
-alkyl substituted with substituted aryl,
(e) C
1
-C
12
-alkyl substituted with heteroaryl,
(f) C
1
-C
12
-alkyl substituted with substituted heteroaryl,
(g) C
3
-C
12
-cycloalkyl, and
(h) —Si—(R
2
)(R
3
)(R
4
) wherein R
2
, R
3
, R
4
are each independently selected from C
1
-C
12
-alkyl and aryl; and
(4) ═N—O—C(R
5
)(R
6
)—O—R
1
wherein R
1
is as previously defined and R
5
and R
6
are each independently selected from the group consisting of
(a) hydrogen,
(b) C
1
-C
12
-alkyl,
(c) C
1
-C
12
-alkyl substituted with aryl,
(d) C
1
-C
12
-alkyl substituted with substituted aryl,
(e) C
1
-C
12
-alkyl substituted with heteroaryl, and
(f) C
1
-C
12
-alkyl substituted with substituted heteroaryl;
or R
5
and R
6
taken together with the atoms to which they are attached form a C
3
-C
12
-cycloalkyl ring; or
Y and Z are ═N— when taken together with T to form a moiety of the structure:
 or
one of Y and Z is hydrogen and the other is selected from a group consisting of
(1) hydroxy,
(2) protected hydroxy, and
(3) NR
7
R
8
wherein R
7
and R
8
are independently selected from hydrogen and alkyl, subsituted alkyl, or R
7
and R
8
are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH, —N(C
1
-C
6
-alkyl)-, —N(aryl)-, —N(aryl-C
1
-C
6
-alkyl-)-, —N(substituted-aryl-C
1
-C
6
-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C
1
-C
6
-alkyl-)-, —N(substituted-heteroaryl-C
1
-C
6
-alkyl-)-, and —S— or S(O)
n
— wherein n is 1 or 2;
C. T is selected from the group consisting of —O—Rg, —O—, —NH—, N(W—Rf)—, and —CH(W—Rf)—, wherein
(1) W is absent or is selecte

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