US 5,856,321 A · Antibiotic compounds

Abstract

The present invention relates to carbapenems and provides a compound of the formula (I): ##STR1## or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein: R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl; R.sup.2 is hydrogen or C.sub.1-4 alkyl; R.sup.3 is hydrogen or C.sub.1-4 alkyl; R.sup.4 and R.sup.5 are the same or different and are selected from hydrogen, halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, aminosulphonyl, C.sub.1-4 alkylaminosulphonyl, di-C.sub.1-4 -alkylaminosulphonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N--C.sub.1-4 alkyl)amino, C.sub.1-4 alkanesulphonamido and C.sub.1-4 alkylS(O).sub.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.sup.3 --. Processes for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them.

Claims37

Dependent claims

A process for preparing a compound of the formula (I) ##STR17## or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:

R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;
R.sup.2 is hydrogen or C.sub.1-4 alkyl;
R.sup.3 is hydrogen or C.sub.1-4 alkyl;
R.sup.4 and R.sup.5 are the same or different and are selected from hydrogen, halo, cyano, C.sub.14 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, aminosulphonyl, C.sub.1-4 alkylaminosulphonyl, di-C.sub.1-4 -alkylaminosulphonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N--C.sub.1-4 alkyl)amino, C.sub.1-4 alkanesulphonamido and --S(O).sub.n C.sub.1-4 alkyl and 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.sup.3 -- which process comprises:
reacting a compound of formula (VI) with a compound of formula (VII):
##STR18## wherein R.sup.2, R.sup.4, and R.sup.5 are as defined above, R.sup.4 and R.sup.5 optionally being protected --COOR.sup.6 and --COOR.sup.7 are carboxy or protected carboxy;
R.sup.8 is a group R.sup.3 as defined above, or an amino protecting group;
R.sup.9 is hydrogen or an amino protecting group;
and R.sup.10 is a group R.sup.1, as defined above, protected 1-hydroxyethyl or protected hydroxymethyl;
and L is a leaving group;
and wherein any functional group is optionally protected and thereinafter optionally:
(i) removing any protecting groups;
(ii) forming a pharmaceutically acceptable salt;
and
(iii) esterifying hydroxy and carboxy groups to form an in vivo hydrolysable ester.

13 more elements

A process for preparing a compound of the formula (I) ##STR19## or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:

R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;
R.sup.2 is hydrogen or C.sub.1-4 alkyl;
R.sup.3 is hydrogen or C.sub.1-4 alkyl;
R.sup.4 and R.sup.5 are the same or different and are selected from hydrogen, halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, aminosulphonyl, C.sub.1-4 alkylaminosulphonyl, di-C.sub.1-4 -alkylaminosulphonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N--C.sub.1-4 alkyl)amino, C.sub.1-4 alkanesulphonamido and --S(O).sub.n C.sub.1-4 alkyl and 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.sup.3 --, which process comprises:
cyclising a compound of the formula (VIII):
##STR20## wherein R.sup.2, R.sup.4, and R.sup.5 are as defined above, R.sup.4 and R.sup.5 optionally being protected;
--COOR.sup.6 and --COOR.sup.7 are carboxy or protected carboxy;
R.sup.8 is a group R.sup.3 as defined above, or an amino protecting group;
R.sup.9 is hydrogen or an amino protecting group;
and R.sup.10 is a group R.sup.1, as defined above, protected 1-hydroxyethyl or protected hydroxymethyl;
R.sup.11 -R.sup.13 are independently selected from C.sub.1-6 alkoxy, aryloxy, di-C.sub.1-6 alkylamino and diarylamino or any two of R.sup.11 -R.sup.13 represents o-phenylenedioxy;
or one of R.sup.11 -R.sup.13 is C.sub.1-4 alkyl, allyl, benzyl or phenyl and the other two values are independently selected from C.sub.1-4 alkyl, trifluoromethyl or phenyl, wherein any phenyl group is optionally substituted with C.sub.1-3 alkyl or C.sub.1-3 alkoxy;
and wherein any functional group is optionally protected and thereinafter optionally:
(i) removing any protecting groups;
(ii) forming a pharmaceutically acceptable salt;
and
(iii) esterifying hydroxy and carboxy groups to form an in vivo hydrolysable ester.

15 more elements

Dependencies are inferred from the claim text.

Antibiotic compounds

Life of this patent

Antibiotic compounds

Life of this patent

Abstract

Claims37