Patent GB-1464551-A (GB)
Title: Alpha-substituted amino-phenylacetamido penicillanic acid and cephalosporanic acid derivatives methods for their preparation and their use
IPC: C07D499/64
Filed: 1973-02-08
Abstract: 1464551 α - (Substituted amino) - phenylacetamido - penam and cepham derivatives GIST-BROCADES NV 7 Feb 1974 [8 Feb 1973] 6267/73 Headings C2C and C2P Novel Compounds I  in which W represents a group II or III  in which U is an imido group or a group OE (where E is H, a salt-forming cation or an esterforming group and U is H, halo, an azido group, a hydroxy group, an amino group, a carbamoyloxy group, a cyano group, an acetoxy group, a lutidinyl, picolinyl or pyridyl group; or a group -S-Q (wherein Q represents an optionally substituted (C 2-6 )-alkenyl, benzyl, thienyl, furyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, isoxazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, imidazolyl, benzoxazolyl, triazolopyridyl or purinyl group)], and Y represents (A) a group wherein X and R are the same or different and each represents an oxygen or sulphur atom, and Z<SP>1</SP> and Z<SP>2</SP> are the same or different and each represents a C 1-6  alkoxy group, a C 1-6  alkylthio group, an optionally substituted phenoxy group, an optionally substituted benzyloxy group, a mono-C 1-6  alkylamino, mono-C 5-8  cycloalkylamino, di-C 1-6  alkylamino, monophenylamino, mono(mono-nuclear heterocyclyl)amino, C 1-6  alkoxy-carbonyl-hydrazino, or a C 1-6  alkanoyl hydrazino group, an optionally substituted C 1-6  alkyl group, an optionally substituted phenyl group, a hydroxy group or a group OM, wherein M represents a salt-forming cation, or Z<SP>1</SP> and Z<SP>2</SP> form together with the phosphorus atom to which they are attached an optionally unsaturated 5 to 7 membered heterocyclic ring, optionally substituted by at most four C 1-6  alkyl groups, (B) a group wherein Z<SP>3</SP> represents a C 1-6  alkyl, C 1-6  alkoxy, di-C 1-6  alkylamino, phenyl or hydroxy group, and Z<SP>4</SP> represents a C 1-6  alkoxy, C 1-6  alkylthio, phenoxy, mono-C 1-6  alkylamino, mono-C 5-8  cycloalkylamino, di-C 1-6  alkylamino, mono-phenyl amino, or mono(mono-nuclear heterocyclyl)- amino group; (C) a group -CO-NH-SO 2 -Z<SP>5</SP> in which Z<SP>5</SP> is NR<SP>1</SP>R<SP>2</SP> (wherein R<SP>1</SP> represents a hydrogen atom or a C 1-6  alkyl group, and R<SP>2</SP> represents a hydrogen atom, a C 1-6  alkyl group optionally substituted by an optionally esterified carboxy group, a phenyl radical, a C 5-8  cycloalkyl radical, an optionally substituted mono-nuclear heterocyclic residue containing 5 to 7 atoms in the ring and containing one or more hetero-atoms selected from oxygen, sulphur and nitrogen, or R<SP>2</SP> represents an amino group optionally substituted by a C 1-6  alkyl, phenyl or C 1-6  alkoxycarbonyl group, or R 2  represents a phenyl group, or an oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, thiazolyl or pyridyl group optionally carrying one or more C 1-6  alkyl substituents, or R<SP>1</SP> and R<SP>2</SP> together with the nitrogen atom to which they are attached represent a mononuclear heterocyclic nucleus containing 5 or 6 atoms in the ring and optionally having besides the nitrogen atom additional hetero atom(s) selected from oxygen, nitrogen and sulphur, or Z<SP>5</SP> represents a group -X-R<SP>3</SP>, wherein X is as hereinbefore defined and R<SP>3</SP> represents a C 1-6  alkyl group, or Z<SP>5</SP> represents a hydroxy group or a group -OM, wherein M is as hereinbefore defined; (D) a group wherein Z<SP>6</SP> represents a hydrogen atom, a group -CO-R<SP>4</SP> in which R<SP>4</SP> represents a C 1-6  alkoxy, phenoxy, C 1-6  alkylthio or arylthio group or R<SP>4</SP> represents an optionally substituted amino group -NR<SP>1</SP>R<SP>2</SP>, in which R<SP>1</SP> and R<SP>2</SP> are as hereinbefore defined, or (E) a group wherein R<SP>5</SP> and R<SP>6</SP> are the same or different and each represents a C 1-6  alkyl, phenyl or C 5-8  cycloalkyl group and R<SP>7</SP> represents a hydrogen atom, a C 1-6  alkyl, C 5-8  cycloalkyl or phenyl group, or one of the symbols R<SP>5</SP> and R<SP>6</SP> together with R<SP>7</SP> and the "-C-N-" group represent a mononuclear heterocyclic nucleus containing 5, 6 or 7 atoms in the ring, and the other symbol represents a C 1-6  alkyl, phenyl or C 5-8  cycloalkyl group, or R<SP>5</SP> and R<SP>6</SP> together with the nitrogen atom to which they are attached represent a mononuclear heterocyclic nucleus containing 5 or 6 atoms in the ring, and R<SP>7</SP> is as hereinbefore defined are prepared by reacting a compound X in which # is H, an alkali metal or a silyl group and W<SP>1</SP> is a Group XI or XII wherein U<SP>1</SP> represents an imido group or a group -OE<SP>1</SP>, in which E<SP>1</SP> represents an esterforming protecting group, which can be removed after the reaction by hydrolysis, hydrogenation or a substitution reaction using a basic or nucleophilic reagent and V<SP>1</SP> has the same significance as above for the symbol V, with the proviso that groups within the definition of V which may react under the reaction conditions have been protected by methods known per se, with a cornpound, (A1) of formula in an inert organic solvent at temperatures within the range of from - 30 to 30 C., or (A2) of the formula [wherein Z<SP>1</SP> represents a (lower)alkyl, (lower)- alkoxy, di(lower)alkylamino, phenyl or hydroxy group] in an inert organic solvent at temperatures below 0 C., followed by reacting a compound so obtained with a compound of the formula [wherein Z<SP>21</SP> represents a (lower)alkoxy, (lower)- alkylthio, phenoxy, mono(lower)alkylamino, mono - cycloalkylamino, di(lower)alkylamino, mono-phenylamino, or mono(mono-nuclear heterocyclyl)amino group] at temperatures below 25 C., optionally in the presence of an acidbinding agent or (B1) of the formula in an inert organic solvent at temperatures below 35 C., optionally in the presence of an acid-  binding agent or (C1) of formula  in an inert organic solvent at temperatures below 0 C., followed by reacting the compound so  obtained with a compound of the formula  2<SP>5</SP>-H at a temperature below 25 C. optionally  in the presence of an acid-binding agent or (D1) of the formula [wherein K represents a group -NH-Z<SP>6</SP>] in an inert organic solvent at temperatures below 35 C., optionally in the presence of an acidbinding agent or (E1) of Formula XIX wherein K represents a group in an inert organic solvent at temperatures below 35C., optionally in the presence of an acid-binding agent, removing any protecting groups present, and optionally converting by methods known per se a group within the definition of V into another group within the definition of V and optionally converting by methods known per se a penicillanic or cephalosporanic acid derivative thus obtained into a pharmaceutically acceptable salt or ester thereof. Compounds I have antibacterial activity and form with a carrier or excipient a pharmaceutical composition which may be administered topically orally or parenterally. They are also used in disinfecting compositions in association with a carrier for application by washing or spraying.