Antibiotic compounds

Details Antibiotic compounds Antibiotic compounds

2001-02-13

2003-02-18

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S414000, C514S210050, C514S210090, C514S210110

Reexamination Certificate

active

06521612

ABSTRACT:

The present invention relates to carbapenems and in particular to such compounds containing a carboxy substituted phenyl group. This invention further relates to processes for their preparation, to intermediates in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
The compounds of this invention are antibiotics and can be used in the treatment of any disease that is conventionally treated with antibiotics for example in the treatment of bacterial infection in mammals including humans.
Carbapenems were first isolated from fermentation media in 1974 and were found to have broad spectrum antibacterial activity. Since this discovery substantial investigations have been made into new carbapenem derivatives and many hundreds of patents and scientific papers have been published.
The first, and so far the only, carbapenem to be commercially marketed is imipenem (N-formimidoyl thienamycin). This compound has a broad spectrum of antibacterial activity.
The present invention provides compounds with a broad spectrum of antibacterial activity including against both Gram positive and negative, aerobic and anaerobic bacteria. They exhibit good stability to beta-lactamases. In addition representative compounds of this invention exhibit a very favourable duration of action.
The carbapenem derivatives referred to herein are named in accordance with the generally accepted semi-systematic nomenclature:
Accordingly the present invention provides a compound of the formula (I):
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:
R
1
is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;
R
2
is hydrogen or C
1-4
alkyl;
R
3
is hydrogen or C
1-4
alkyl;
R
4
and R
5
are the same or different and are selected from hydrogen, halo, cyano, C
1-4
alkyl, nitro, hydroxy, carboxy, C
1-4
alkoxy, C
1-4
alkoxycarbonyl, aminosulphonyl, C
1-4
alkylaminosulphonyl, di-C
1-4
-alkylaminosulphonyl, carbamoyl, C
1-4
alkylcarbamoyl, di-C
1-4
alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C
1-4
alkylamino, di-C
1-4
alkylamino, C
1-4
alkanoylamino, C
1-4
alkanoyl(N—C
1-4
alkyl)amino, C
1-4
alkanesulphonamido and C
1-4
alkylS(O)
n
— wherein n is zero, one or two:
with the proviso that there is no hydroxy or carboxy substituent in a position ortho to the link to —NR
3
—.
Alkyl when used herein includes straight chain and branched chain substituents for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
Preferably R
1
is 1-hydroxyethyl.
R
2
is hydrogen or C
1-4
alkyl for example methyl, ethyl, n-propyl, isopropyl or n-butyl. Preferably R
2
is hydrogen or methyl and in particular R
2
is methyl.
R
3
is hydrogen or C
1-4
alkyl for example methyl, ethyl, n-propyl, isopropyl or n-butyl. Preferably R
3
is hydrogen.
R
4
and R
5
are the same or different and are selected from hydrogen; halo for example fluoro, bromo or chloro; cyano; C
1-4
alkyl for example methyl, ethyl, n-propyl, isopropyl or n-butyl; nitro; hydroxy; carboxy; C
1-4
alkoxy for example methoxy or ethoxy; C
1-4
alkoxycarbonyl for example methoxycarbonyl, ethoxycarbonyl and n-propoxycarbonyl; aminosulphonyl; C
1-4
alkylaminosulphonyl for example methylaminosulphonyl and ethylaminosulphonyl; di-C
1-4
alkylaminosulphonyl for example di-methylaminosulphonyl, methylethylaminosulphonyl and di-ethylaminosulphonyl; carbamoyl; C
1-4
alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; di-C
1-4
alkylcarbamoyl for example dimethylcarbamoyl or diethylcarbamoyl; trifluoromethyl; sulphonic acid; amino; C
1-4
alkylamino for example methylamino or ethylamino; di-C
1-4
alkylamino for example dimethylamino or diethylamino; C
1-4
alkanoylamino for example acetamido or propionamido; C
1-4
alkanoyl(N—C
1-4
alkyl)amino for example N-methylacetamido; C
1-4
alkanesulphonamido for example methanesulphonamido; and C
1-4
alkylS(O)
n
— for example methylthio, methylsulphinyl or methylsulphonyl.
In a particular aspect a suitable class of compounds is that in which R
4
and R
5
are the same or different and are selected from hydrogen, fluoro, chloro, hydroxy, carboxy, cyano, nitro, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, trifluoromethyl, sulphonic acid, methylsulphinyl, methylsulphonyl, methanesulphonamido or acetamido.
R
4
and R
5
may both be other than hydrogen but, in general, it is particularly preferred that at least one of R
4
and R
5
is hydrogen.
Particularly preferred compounds are those in which R
4
is hydrogen, carboxy, fluoro, chloro, methyl, methoxy, cyano, sulphonic acid or methoxycarbonyl and R
5
is hydrogen.
The present invention covers all epimeric, diastereoisomeric and tautomeric forms of the compounds of the formula (I) wherein the absolute stereochemistry at the 5-position is as illustrated in formula (I). When a bond is represented by a wedge, this indicates that in three dimensions the bond would be coming out of the paper and when a bond is hatched, this indicates that in three dimensions the bond would be going back into the paper. The compounds of the formula (I) have a number of other stereocentres, namely: within the group R
1
(when R
1
is 1-hydroxyethyl or 1-fluoroethyl); at the 6-position; at the 1-position (when R
2
is C
1-4
alkyl); and at the 2′ and 4′ positions in the pyrrolidine ring:
Preferred compounds are those in which the beta-lactam ring protons are in trans configuration with respect to one another. When R
1
is 1-hydroxyethyl or 1-fluoroethyl it is preferred that the 8-substituent has the R-configuration. Thus a preferred class of compounds is that of the formula (III):
and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof, wherein R
2
, R
3
, R
4
and R
5
are as hereinbefore defined.
When R
2
is C
1-4
alkyl for example methyl it is preferred that the compound is in the form of the 1R configuration.
Preferred compounds are those in which the pyrrolidine ring has the following absolute stereochemistry at the 2′- and 4′-positions:
A preferred class of compounds of the present invention is that of the formula (IV):
and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof wherein R
3
, R
4
, and R
5
are as defined hereinbefore in formula (I).
Particularly preferred compounds within the formula (IV) are those wherein R
3
is hydrogen and R
4
and R
5
are the same or different and are selected from hydrogen, fluoro, chloro, hydroxy, carboxy, cyano, nitro, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, methanesulphonyl, trifluoromethyl, sulphonic acid, methylsulphinyl, methanesulphonamido or acetamido.
Especially preferred compounds within the formula (IV) are those wherein R
3
and R
5
are both hydrogen and R
4
is hydrogen, carboxy, fluoro, chloro, methyl, methoxy, cyano, sulphonic acid or methoxycarbonyl.
Suitable pharmaceutically acceptable salts include acid addition salts such as hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. For the avoidance of doubt there may be one, two or three salt-forming cations dependent on the number of carboxylic acid functions and the valency of said cations.
Preferred pharmaceutically acceptable salts are sodium and potassium salts. However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically acceptable or not.
In vivo hydrolysable esters are those pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering, eg. intravenously to

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