Macrolides with antibacterial activity

Details Macrolides with antibacterial activity Macrolides with antibacterial activity

2003-02-21

2004-05-25

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007300, C536S007400

Reexamination Certificate

active

06740642

ABSTRACT:

This invention relates to new macrolide antibiotics with improved activity and stability, to the use of such antibiotics for the treatment of infectious diseases and to compositions containing such macrolides.
The interest in macrolide antibiotics is increasing because these compounds are a very effective and safe class of agents against gram positive pathogens. Extensive spread of erythromycin A resistance among gram positive cocci isolates raised the urgent need for novel derivatives with improved activity, stability and antimicrobial spectra. The two most successful second generation agents derived from erythromycin A (1) through semisynthesis were its 6-O-methyl derivative clarithromycin (2) and the 15-membered azalide azithromycin (3) arising from a Beckman rearrangement as shown below. However, while featuring improved pharmacokinetics, none of these agents possessed a significant activity against bacterial isolates showing macrolide-lincosamide-streptogramine B (MLS B) cross resistance.
Many different semisynthetic third generation derivatives of the ketolide class of macrolide antibiotics have been described, the most potent being HMR 3647 or telithromycin (4) (EP 680967 A1 (1995); FR 2732684 A1 (1996); Bioorg. Med. Chem. Lett. (1999), 9(21), 3075-3080.) and ABT 773 (WO 9809978 (1998); J. Med. Chem. 2000, 43, 1045). However, none of these agents described thus far have been able to overcome constitutive MLS B resistance in
Staphylococcus aureus.
The invention provides new macrolide antibiotics of formula I with improved biological properties and improved stability.
wherein
R
1
is hydrogen, cyano, —S(L)
m
R
2
, —S(O)(L)
m
R
2
, or —S(O)
2
(L)
m
R
2
;
L represents —(CH
2
)
n
— or —(CH
2
)
n
Z(CH
2
)
n′
—;
m is 0 or 1;
n is 1, 2, 3, or 4;
n′ is 0, 1, 2, 3, or 4;
Z is O, S or NH;
R
2
is hydrogen, alkyl, heterocyclyl or aryl; which heterocyclyl and the aryl groups may be further substituted;
* indicates a chiral center which is in the (R) or (S) form.
and pharmaceutically acceptable acid addition salts or in vivo cleavable esters thereof.
These compounds are new and possess potent antimicrobial properties against gram positive and selected gram negative organisms. Therefore, they are useful as agents against gram positive pathogens such as staphylococci, streptococci and pneumococci as well as some gram negative strains such as
H. influenzae
and may be used in human or veterinary medicine for treatment or prevention of infections caused by susceptible organisms.
The chiral center in position 3 is preferably in the (S) whereas the center in 4 are is preferably in the (R) configuration.
As used herein the term “alkyl” refers to straight or branched chain saturated hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Such groups are for example methyl, ethyl, n-propyl, isopropyl, tertiary butyl, pentyl, hexyl, and the like.
The term “halogen” refers to chlorine, bromine or iodine.
The term “aryl” refers to 6-membered, aromatic groups with one or more nuclei from 6 to 14 carbon atoms. Examples are phenyl, naphthyl, anthryl and phenanthryl. These groups may be further substituted with, for example, phenyl, alkyl, lower alkoxy such as methoxy, ethoxy, propyloxy or n-butoxy, halogen, hydroxy, amino, alkylamino, dialkylamino or nitro.
As used herein the term “heterocyclyl” refers to an unsaturated or saturated, unsubstituted or substituted 5-, 6-, or 7-membered (mono- or bicyclic) heterocyclic ring system containing at least one hetero atom selected from the group consisting of oxygen, nitrogen, and/or sulfur. Exemplary heterocyclic substituents include, but are not limited to, for example, the following groups:
piperidinyl, morpholinyl, 2-, 3- or 4-pyridyl, pyrrolidinyl, piperazinyl, 1H-pyrazol-1-yl, 1H-[1,2,4]triazol-1-yl, 1H-imidazol-1-yl, pyrazinyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, 1H-tetrazolyl, 2H-etrazolyl; thienyl, furyl, 1H-azepinyl, tetrahydrothiophenyl, 3H-1,2,3-oxathiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadithiolyl, isoxazolyl, isothiazolyl, 4H-1,2,4-oxadiazinyl, 1,2,5-oxathiazinyl, 1,2,3,5-oxathiadiazinyl, 1,3,4-thiadiazepinyl, 1,2,5,6-oxatriazepinyl, 1,6,3,4-dioxadithiopanyl, oxazolidinyl, tetrahydrothienyl, and the like, or condensed heterocyclic ring systems such as quinolinyl, isoquinolinyl, quinazolinyl, 1H-benztriazolyl, 1H-imidazo[4,5-c]pyridinyl, 5H-imidazo[4,5-c]pyridinyl, 1H-imidazo[4,5-b]pyridin-1-yl, 3H-imidazo[4,5-b]pyridin-3-yl, 1,2,3,4-tetrahydro-isoquinolinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, 1H-benzoimidazolyl, 1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, purinyl, e.g. 9H-purin-9-yl, 6-amino-9H-purin-9-yl, and others.
The aryl or heterocyclyl groups may be further substituted by one or more substituents. Such substituents include, for example, alkyl groups such as defined above, alkoxy groups such as methoxy, ethoxy, propyloxy or butyloxy, halogen such as fluorine, chlorine, bromine or iodine, halogen substituted alkyl groups such as trifluoromethyl, trichloroethyl, nitro, amino, alkylamino, dialkylamino, alkylthio, mercapto, hydroxy, carbamoyl, a carboxyl group, an oxo group; or unsubstituted or substituted aryl as defined above; or heterocyclyl.
Especially preferred substituents for the heterocyclic groups are alkyl, alkoxy, oxo, amino, alkylamino or dialkylamino. Examples of preferred substituted heterocyclic rings are 1H-pyrimidin-2,4-dione-1-yl, 1H-pyrimidin-2,4-dione-5-methyl-1-yl, 1H-pyrimidin-4-amino-2-one-1yl, 6-amino-9H-purine-9-yl, 6-dimethylamino-9H-purine-9-yl, 3-(pyridin-3-yl)-1H-pyrazol-1-yl, 3-(pyridin-4-yl)-1H-pyrazol-1-yl, 3-(pyridin-3-yl)-1H-imidazol-1-yl, 3-(pyridin-4-yl)-1H-imidazol-1-yl, 3-(pyridin-3-yl)-1H-[1,2,4]triazol-1-yl, or 3-(pyridin-4-yl)-1H-[1,2,4]triazol-1-yl.
Preferred compounds of formula I are compounds, wherein L is —(CH
2
)
n
and n is 0, 1, 2 or 3. Further preferred are compounds of formula I, wherein R
2
is aryl or heterocyclyl, especially, wherein R
2
is phenyl, dialkoxyphenyl, 6-amino-9H-purin-9-yl or pyridinyl-1H-pyrazol-1-yl.
Especially preferred compounds of formula I are in Table 1 below:
Compound
Example
no.
R
1
no.
I-1
 1

I-2
 2

I-3
 3

I-4
 4

I-5
CH
3
S—
 5

I-6
 6

I-7
 7

I-8
 8

I-9
 9

I-10
10

I-11
11

I-12
12

I-13
13

I-14
14

I-15
15

I-16
16

I-17
17

I-18
18

I-19
19

I-20
20

I-21
21

I-22
22

I-23
CN
23

I-24
24

I-25
H
25

I-26
26

I-27
27

I-28
28

I-29
29

I-30
30

I-31
31

I-32
32

I-33
33

I-34
34

I-35
35

I-36
36

I-37
37

I-38
38

I-39
39
If desired, compounds of formula I can be converted into a pharmaceutically acceptable acid addition salt. The salt formation is effected at room temperature with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, trifluoroacetates, maleates, succinates, methanesulphonates, p-toluenesulphonates and the like are examples of such salts.
Further the compounds can be converted into in vivo cleavable esters, for example into esters with the 2′-hydroxy group of the sugar moiety, such esters are e.g. acetates, pivaloyl esters, tartrates, maleates, succinates, and the like. These esters can be prepared according to methods known in the art, for example by reaction with an appropriate anhydride.
The compounds of the present invention and their pharmaceutically acceptable acid addition salts or in vivo cleavable esters thereof are useful as antibacterial therapeutics. Compounds of formula I possess excellent antibacterial activity against selected pathogenic bacteria such as strains of
Staphylococcus aureus
and
Streptococcus pneumoniae
. They can thus be used as medicaments for the treatment of infectious diseases especially of infectious diseases caused by staphylococci, such a

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