Beta-lactam antibiotics, their preparation and use

Claim 2

A compound of the formula (II): or a salt or ester thereof wherein R 3 is a hydrogen atom or is an organic group bonded via a carbon atom to the carbapenem ring, n is zero or one, X is a saturated or unsaturated hydrocarbon radical optionally substituted by bromo or chloro, and R 4 is a C 1-6 alkyl, C 2-6 alkenyl, C 1-10 aralkyl or aryl group, any of such groups R 4 being optionally substituted.

Claim 3

A compound as claimed in claim 1 wherein R 3 is a hydrogen atom or is a group of the sub-formula i): wherein R 5 is a hydrogen atom or sulphonato-oxy or salt or ester thereof, hydroxy, C l-4 alkoxy, OCOR 8 or OCO 2 R 8 group wherein R 8 is a C l-4 alkyl, phenyl or optionally substituted benzyl group; R 6 is a hydrogen atom or C l-4 alkyl group: and R 7 is a hydrogen atom or C 1-4 alkyl group: and X is C l-6 alkanediyl, C 2-6 alkenediyl optionally substituted by bromo or chloro, or C 3-8 cycloalkanediyl. 3. A compound as claimed in claim 1 or 2 of the formula (III): or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof wherein: A) R 3 is a hydrogen atom or is a group of the sub-formula a): wherein R 5 is a hydrogen atom or a hydroxy, C 1-4 alkox y, OCOR8 or OCO 2 R 8 group wherein R 8 is a C 1 -4 alkyl, phenyl, benzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, C l-3 alkobenzyl or nitrobenzyl group; R 6 is a hydrogen atom or C 1-4 alkyl group; R 7 is a hydrogen atom or C 1-4 alkyl group; X 1 is a group of the sub-formula (b) or (c): wherein n is zero or 1; R 9 is a hydrogen atom or C 1-4 alkyl group; R 10 is a hydrogen atom or C 1-4 alkyl group; and R 4 is a C 1-6 alkyl, C 2-6 alkenyl, C 1-10 aralkyl or aryl group, any of such groups R 4 being optionally substituted: or B) R 3 is a CH 3 CH(OH)-group, R 4 is a methyl group,and X 1 is a group of the sub-formula (d) or (e); wherein Y is a bromine or chlorine atom: C) R 3 is a CH 3 CH(OSO 3 H)- group or methyl or ethyl ester thereof; R 4 is a methyl group; and X 1 is a group of the sub-formula (f) or (g): wherein n is zero or 1; and Z is a hydrogen, chlorine or bromine atom: or D) R 3 is a CH 3 CH(OSO 3 H)-group or methyl or ethyl ester thereof; R 4 is a C 1-6 alkyl, C 2-6 alkenyl, C 1-10 aralkyl or aryl group, any of such R 4 groups being optionally substituted; and X 1 is a group -S-CH2-CH2-: or E) R 3 is a CH 3 CH(OSO 3 H)-group or a methyl or ethyl ester thereof; R 4 is an ethyl group; and X is a group -S-CH=CH-: or F) R 3 is a CH 3 CH(SR o )-group wherein R o is a C 1-6 alkyl, C 2-6 alkenyl, C 1-10 aralkyl, or aryl group; R 4 is a methyl group; and X is a group -S-CH 2 CH 2 - or group of the sub-formula h): wherein n is zero or 1: with the proviso that when R 3 is a CH 3 CH(OS0 3 H)-group or methyl or ethyl ester thereof the C-5 and C-6 protons are cis.

Claim 4

A compound as claimed in any of claims 1-3 wherein the group -S(O) n -X- is of the sub-formula -SCH 2 CH 2 -.

Claim 5

A compound as claimed in any of claims 1-3 wherein the group -S(O) n -X- is of the sub-formula -SCH=CH-.

Claim 6

A compound as claimed in any of claims 1 to 5 wherein R 4 is methyl.

Claim 7

A compound as claimed in claim 1 of the formula (IV), (V), (VI) or (VII): or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.

Claim 8

A compound as claimed in claim 7 wherein the methyl substituent of the tetrazolyl is replaced by an aminomethyl substituent.

Claim 9

A compound as claimed in any of claims 1 to 7 in the form of an alkali metal salt.

Claim 10

A compound as claimed in claim 1 selected from: (5R, 6R)-6-[(lS)-l-Hydroxyethyl]-3-[2-(5-methyltetrazol-1-yl)ethylthio]-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid, Mono Sodium Salt of (5R, 6R)-6-[(lS)-1-Hydroxysulphonyloxyethyl]-3-[2-(5-methyltetrazol-l-yl)ethylthio]-7-oxo-l-azabicyclo [3.2.0]hept-2-ene-2-,carboxylic acid, (5R, 6S)-3-[2-(5-Methyltetrazol-1-yl)ethylthio]-6-[(1S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0.]hept-2-ene-2-carboxylic acid, Sodium (5R,6R)-3-[(E)2-(5-Methyltetrazol-1-yl)ethenylthio]-6-[sodium(1S)-1-sulphonatooxyethyl]-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate, Sodium (5R, 6R)-3-[2-(5-Methyltetrazol-1-yl)ethylthio]-6-[sodium(1S)-1-sulphonatooxyethyl]-7-oxo-lazabicyclo [3.2.0]hept-2-ene-2-carboxylate, Sodium (5R, 6R)-6-[(1S)-1-Hydroxyethyl]-3-[2-(5-methyltetrazol-1-yl)ethylthio]-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate, sodium (5RS, 6SR)-6-[(1RS)-1-Hydroxyethyl]-1-[2-(5-methyltetrazol-1-yl) ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, Sodium (5R, 6R)-6-[(lS)-1-Hydroxyethyl]-3-[(E)-2-(5-methyltetrazol-1-yl)ethenylthio]-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate, Phthalidyl (5R, 6R)-6-[(1S)-1-Hydroxyethyl]-3-[2-(5-methyltetrazol-1-yl)ethyl thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and (SRS, 6SR)-3-[2-(5-aminomethyl tetrazol-1-yl)ethylthio]-6-[1(R S)-1-hydroxyethyl thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and sodium (5RS,6RS)-6-[(1RS-1-hydroxyethyl]-3-[(Z)-2-(5-methyltetrazol-1-yl)ethenylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

Claim 11

A pharmaceutical composition which comprises a compound as claimed in any of claims 1 to 9 and a pharmaceutically acceptable carrier.

Claim 12

A process for the preparation of a compound of the formula (III) or a pharmaceutically acceptable compound salt or ester which comprises the reaction of azide ion with a compound of the formula (X): Wherein R 13 and R 14 are respectively either groups R 3 and R 4 wherein R 3 and R 4 are as defined in Claim 3, o . r R 13 and R 14 are groups that on chemical cleavage afford groups R 3 and R 4 ; X 1 is as defined in Claim 3; R a is a hydrogen atom or a carboxy-blocking group; and T is a bromine or chlorine atom; and thereafter if necessary performing one or more of the following steps: i) removing any carboxy-blocking group R a , ii) converting the product into a pharmaceutically acceptable salt or ester, iii) oxidising the sulphur atom to afford a compound wherein n is one, iv) converting any group R 13 to R 3 and any group R 14 to R 4 .