Claims
- 1. A beta-lactam antibiotic having an .alpha.-formamido substituent on the carbon atom adjacent to the carbonyl group of the beta-lactam group and having antibacterial activity.
- 2. A compound according to claim 1 which is at least 50% pure on a w/w basis.
- 3. A compound according to claim 1 which is at least 75% pure on a w/w basis.
- 4. A compound according to claim 1 which is at least 90% pure on a w/w basis.
- 5. A compound according to claim 1 which has antibacterial activity against gram negative organisms.
- 6. A compound according to claim 1 in zwitterionic form.
- 7. A compound to claim 1 in the form of a salt.
- 8. A compound according to claim 1 in the form of an acid.
- 9. A compound according to claim 1 having the partial structure ##STR44##
- 10. A compound according to claim 1 wherein the hydrogen atoms of the --NH--CHO formamido group are cis.
- 11. A compound according to claim 1 wherein the hydrogen atoms of the --NH--CHO formamido group are trans.
- 12. A process for the preparation of a compound of claim 1 which comprises formylating a beta-lactam having an .alpha.-amino substituent on the carbon atom adjacent to the carbonyl group of the beta-lactam ring.
- 13. A pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises an antibacterially effective amount of a beta-lactam antibiotic having an .alpha.-formamido substituent on the carbon atom adjacent to the carbonyl group of the beta-lactam group having antibacterial activity, and a beta-lactamase inhibitory amount of a beta-lactamase inhibitor, in combination with a pharmaceutically acceptable carrier.
- 14. A composition according to claim 13 wherein the compound is at least 50% pure on a w/w basis.
- 15. A composition according to claim 13 wherein the compound is at least 75% pure on a w/w basis.
- 16. A composition according to claim 13 wherein the compound is at least 90% pure on a w/w basis.
- 17. A composition according to claim 13 wherein the compound has antibacterial activity against gram negative organisms.
- 18. A composition according to claim 13 wherein the compound is in zwitterionic form.
- 19. A composition according to claim 13 wherein the compound is in the form of a salt.
- 20. A composition according to claim 13 wherein the compound is in the form of an acid.
- 21. A composition according to claim 13 wherein the compound has the partial structure ##STR45##
- 22. A composition according to claim 13 wherein the hydrogen atoms of the --NH--CHO formamido group are cis.
- 23. A composition according to claim 13 wherein the hydrogen atoms of the --NH--CHO formamido group are trans.
- 24. A method of treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof an antibacterially effective amount of a beta-lactam antibiotic having an .alpha.-formamido substituent on the carbon atom adjacent to the carbonyl group of the beta-lactam group having antibacterial activity, and a beta-lactamase inhibitory amount of a beta-lactamase inhibitor, in combination with a pharmaceutically acceptable carrier.
- 25. A method according to claim 24 wherein the compound is at least 50% pure on a w/w basis.
- 26. A method according to claim 24 wherein the compound is at least 75% pure on a w/w basis.
- 27. A method according to claim 24 wherein the compound is at least 90% pure on a w/w basis.
- 28. A method according to claim 24 wherein the compound has antibacterial activity against gram negative organisms.
- 29. A method according to claim 24 wherein the compound is in zwitterionic form.
- 30. A method according to claim 24 wherein the compound is in the form of a salt.
- 31. A method according to claim 24 wherein the compound is in the form of an acid.
- 32. A method according to claim 24 wherein the compound has the partial structure ##STR46##
- 33. A method according to claim 24 wherein the hydrogen atoms of the--NH --CHO formamido group are cis.
- 34. A method according to claim 24 wherein the hydrogen atoms of the--NH --CHO formamido group are trans.
Priority Claims (8)
| Number |
Date |
Country |
Kind |
| 8123033 |
Jul 1981 |
GBX |
|
| 8123034 |
Jul 1981 |
GBX |
|
| 8136823 |
Dec 1981 |
GBX |
|
| 8136824 |
Dec 1981 |
GBX |
|
| 8207966 |
Mar 1982 |
GBX |
|
| 8209953 |
Apr 1982 |
GBX |
|
| 8209954 |
Apr 1982 |
GBX |
|
| 8215007 |
May 1982 |
GBX |
|
CROSS-REFERENCE
This is a continuation of Ser. No. 401,266, filed July 23, 1982, now U.S. Pat. No. 4,539,149.
This invention relates to a class of novel .beta.-lactam derivatives, which have antibacterial activity and are of value in the treatment of infections in humans and animals caused by a wide range of organisms, particularly Gram-negative organisms. The invention also relates to a process for the preparation of such compounds, intermediates for use in the preparation of the compounds and to pharmaceutical compositions containing the antibacterially active compounds and methods of treating bacterial infections in humans and animals utilising such compositions.
Accordingly the invention provides a class of .beta.-lactam antibiotic having an .alpha.-formamido (formamidyl) substituent on the carbon atom adjacent to the carbonyl group of the .beta.-lactam ring. The term .alpha.-formamido denotes the configuration: ##STR2##
Compounds within the present invention are those having the partial structure: ##STR3##
More particularly the present invention comprises a compound of formula (I) or a salt thereof. ##STR4## wherein R.sup.1 is hydrogen, an acyl group, in particular those found on antibacterially active penicillins or cephalosporins, or an amino-protecting group; R.sup.2 is hydrogen or a readily removable carboxyl protecting group; and Y is: ##STR5## wherein Y.sup.1 is oxygen, sulphur or --CH.sub.2 -- and Z represents hydrogen, halogen, or an organic group such as C.sub.1-4 alkoxy, --CH.sub.2 Q or --CH.dbd.CH--Q wherein Q represents hydrogen, halogen, hydroxy, mercapto, cyano, carboxy, carboxylic ester, C.sub.1-4 alkyloxy, acyloxy, aryl, a heterocyclyl group bonded via carbon, a heterocyclylthio group or a nitrogen containing heterocyclic group bonded via nitrogen.
When used herein the term "halogen" unless otherwise defined is suitably fluorine, chlorine, bromine, and iodide, preferably chlorine and bromine.
When used herein the term "carboxylic ester" unless otherwise defined suitably includes C.sub.1-6 alkyl esters.
When used herein the term "acyloxy" unless otherwise defined suitably includes C.sub.1-6 alkylcarbonyloxy groups.
When used herein the term "aryl" unless otherwise defined suitably includes phenyl and naphthyl, preferably phenyl, optionally substituted with up to five halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo(C.sub.1-6) alkyl, hydroxy, amino, carboxy, C.sub.1-6 alkoxycarbonyl, or C.sub.1-6 alkoxycarbonyl-(C.sub.1-6)alkyl groups.
When used herein the term "heterocyclyl" unless otherwise defined suitably includes single or fused rings comprising up to four hetero atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo-(C.sub.1-6)-alkyl, hydroxy, amino, carboxy, C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkoxycarbonyl(C.sub.1-6) alkyl, aryl or oxo groups.
When used herein the terms lower means the group contains from 1 to 6 carbon atoms.
The compounds of the present invention may contain both an amino group and/or a carboxyl group and may, therefore, exist as the zwitterion or may form salts with suitable acids or bases.
The formamido group can exist in two preferred conformations, those wherein the hydrogen atoms of the --NH--CHO are, cis-- or trans--, of which the cis conformation normally predominates.
Suitably Y is --S--C(CH.sub.3).sub.2 --, --S--CH.sub.2 --, --S--CH.sub.2 --C(CH.sub.2 Q').dbd.; or --O--CH.sub.2 --C(CH.sub.2 Q').dbd., wherein Q' represents hydrogen, halogen, hydroxy, mercapto, cyano, carboxy, carboxylic ester, C.sub.1-4 alkyloxy, acyloxy or heterocyclylthio group.
Preferred values for Y in the compounds of formula (I) are --S--C(CH.sub.3).sub.2 -- and --S--CH.sub.2 --C(CH.sub.2 Q).dbd., i.e. when the compound of formula (I) is a derivative of a penicillin and cephalosporin.
A particularly preferred value for Y is --S--C(CH.sub.3).sub.2 --.
A further preferred value for Y is --S--CH.sub.2 --CZ.dbd.. wherein Z is as hereinbefore defined.
Those compounds of the formula (I) wherein R.sup.1 is a hydrogen group, or an amino-protecting group are mainly useful as intermediates in the preparation of compounds of the formula (I) wherein R.sup.1 is an acyl group, in particular those found in antibacterially active penicillins or cephalosporins.
Those compounds of the formula (I) wherein R.sup.2 is a readily removable carboxyl protecting group or a nonpharmaceutically acceptable salt are primarily useful as intermediates in the preparation of compounds of the formula (I) wherein R.sup.2 is a free carboxyl group or a pharmaceutically acceptable salt thereof. Also included within the readily removable carboxyl protecting groups R.sup.2 are pharmaceutically acceptable in vivo hydrolysable ester groups.
Since the .beta.-lactam antibiotic compounds of the present invention are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical it will readily be understood that the substantially pure form is preferred as for the .beta.-lactam antibiotic compounds. Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
Suitable amino-protecting groups R.sup.1 are those well-known in the art which may be removed under conventional conditions without disruption of the remainder of the molecule.
Examples of amino-protecting groups for R.sup.1 include benzyl optionally substituted in the phenyl ring by one or two substituents selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl, halogen or nitro; C.sub.1-4 alkoxycarbonyl, for example tert-butoxycarbonyl; benzyloxycarbonyl optionally substituted as for benzyl above; allyloxycarbonyl; trityl or trichloroethoxycarbonyl.
Suitable examples of N-protecting groups within R.sup.1 include those listed above which are removable under acid conditions optionally in the presence of a group IIb metal.
Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. Suitable ester groups of this type include those of part formula (i), (ii) and (iii): ##STR6## wherein R.sup.a is hydrogen, methyl, or phenyl, R.sup.b is C.sub.1-6 alkyl, C.sub.1-6 alkoxy or phenyl; or R.sup.a and R.sup.b together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; R.sup.c represents C.sub.1-6 alkylene optionally substitutes with a methyl or ethyl group R.sup.d and R.sup.e independently represent C.sub.1-6 alkyl; R.sup.f represents C.sub.1-6 alkyl. Examples of suitable in vivo hydrolysable ester group include for example acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, .alpha.-acetoxyethyl and .alpha.-pivaloyloxyethyl groups; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and .alpha.-ethoxycarbonyloxyethyl; dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; lactone groups such as phthalidyl and dimethoxyphthalidyl; and esters linked to a second .beta.-lactam antibiotic or to a .beta.-lactamase inhibitor.
Suitable readily removable carboxyl protecting groups for the group --CO.sub.2 R.sup.2 in formula (I) include ester derivatives of the carboxylic acid. The derivative is preferably one which may readily be cleaved.
Suitable ester-forming carboxyl-protecting groups are those which may be removed under conventional conditions. Such groups for R.sup.2 include benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or phosphorus-containing group, an oxime radical of formula --N.dbd.CHR.degree. where R.degree. is aryl or heterocyclic, or an in vivo hydrolysable ester radical such as defined above.
The carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R.sup.2 group, for example, acid--and base--catalysed hydrolysis, or by enzymically -catalysed hydrolysis, or by hydrogenolysis.
Suitable pharmaceutically acceptable salts of the carboxy group of the compound of formula (I) include metal salts e.g. aluminum, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)amine, cycloalkylamines such as dicyclohexylamine, or with procaine, dibenzylamine, N,N-dibenzylethylenediamine, 1-ephenamine, N-ethylpiperidine, N-benzyl-.beta.phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, ethylenediamine, or bases of the pyridine type such as pyridine, collidine or quinoline, or other amines which have been used to form salts with known penicillins and cephalosporins.
Other useful salts according to the present invention include the lithium and silver salt.
Some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
Suitable values for Q in the compounds of the formula (I) include the acetoxy, heterocyclylthio group, and nitrogen containing heterocyclic group bonded via nitrogen.
More suitably Q and Q' represent the acetoxy or heterocyclylthio group.
The heterocyclylthio group may suitably be represented by the formula: --S--Het wherein "Het" is a five or six membered heterocyclic ring containing from 1 to 4 atoms selected from N, O, and S unsubstituted or substituted with one or two groups selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxyalkyl, C.sub.2-6 alkenyl, alkoxyalkyl, carboxyalkyl, sulphonylalkyl, carbamoylalkyl, trifluoromethyl, hydroxy, halogen, oxo, and (subst)aminoalkyl, or two substitutes may be linked to form the residue of a heterocyclic or carbocyclic ring.
Examples of the group "Het" include unsubstituted and substituted imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, triazinyl and oxadiazolyl.
Suitable groups "Het" include unsubstituted and substituted 1, 2, 3-triazolyl; 1, 2, 4-triazolyl; tetrazolyl; oxazolyl; thiazolyl; 1, 3, 4-oxadiazolyl; 1, 3, 4-thiadiazolyl, or 1, 2, 4-thiadiazolyl. Preferably the heterocyclylthio group is 1-methyl-1H-tetrazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5ylthio or 6-hydroxy-2-methyl-5-oxo-2H-1,2,4-triazin-3-ylthio.
The nitrogen containing heterocyclic group bonded via nitrogen is suitably a pyridinium group unsubstituted or substituted with one or two groups selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxyalkyl, C.sub.2-6 alkenyl, alkoxyalkyl, carboxyalkyl, sulphonylalkyl, carbamoylmethyl, carbamoyl, trifluoromethyl, hydroxy, halogen, oxo, and aminoalkyl.
From the forgoing it will be realised that preferred antibacterially active compounds of this invention can be represented by the formula (II) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: ##STR7## wherein Y is as defined with respect to formula (I); and R.sup.3 is a group such that R.sup.3 --CO--NH-- is an acylamino group, in particular that as found in antibacterially active penicillins or cephalosporins.
Suitable groups R.sup.3 CO-- for inclusion in the compounds of the formula (II) include those of the sub-formulae (a)-(e): ##STR8## wherein n is 0, 1 or 2; m is 0, 1 or 2; A.sub.1 is C.sub.1-6 alkyl, substituted C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, cyclohexenyl, cyclohexadienyl, an aromatic group, such as phenyl, substituted phenyl, thienyl, pyridyl, an optionally substituted thiazolyl group, a C.sub.1-6 alkylthio group or C.sub.1-6 alkyloxy; X is a hydrogen or halogen atom, a carboxylic acid, carboxylic ester, sulphonic acid, azido, tetrazolyl, hydroxy, acyloxy, amino, ureido, acylamino, heterocyclylamino, guanidino or acylureido group; A.sub.2 is an aromatic group such as a phenyl, a 2,6-dimethoxyphenyl, 2-alkoxy-1-naphthyl, 3-arylisoxazolyl, 3-aryl-5-methylisoxazolyl group, a substituted alkyl group, or a substituted dithietane; X.sub.1 is a CH.sub.2 OCH.sub.2, CH.sub.2 SCH.sub.2 or (CH.sub.2).sub.n group; X.sub.2 is an oxygen or sulphur atom; A.sub.3 is an aryl or heteroaryl group such as phenyl, substituted phenyl or aminothiazolyl; and A.sub.4 is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, arylamino- carbonyl, C.sub.1-6 alkylaminocarbonyl, C.sub.1-6 alkanoyl, C.sub.1-6 alkoxycarbony, C.sub.2-6 alkenyl, carboxy C.sub.1-6 alkyl, C.sub.1-6 alkylsulphonyl and di-C.sub.1-6 alkylphosphatomethyl.
More suitably A.sub.1 is C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, cyclohexenyl, cyclohexadienyl, phenyl, hydroxy-phenyl, thienyl or pyridyl group; and X is a hydrogen or halogen atom, a carboxylic acid, carboxylic ester, azido, tetrazolyl, hydroxy, acyloxy, amino, ureido, guanidino or acylureido group.
Other more suitable groups A.sub.1 include dihydroxyphenyl and diacetoxyphenyl.
Favoured groups R.sup.3 for inclusion in the compounds of the formula (II) include those of the sub-formula (f) and (g): ##STR9## wherein R.sup.4 is a phenyl, thienyl or phenoxy group; R.sup.5 is a hydrogen atom or methyl group; R.sup.6 is a phenyl, substituted phenyl, substituted thiazolyl, thienyl or cyclohexadienyl group; and R.sup.7 is a hydroxyl, carboxylic acid group or lower alkyl or phenyl, tolyl or indanyl ester thereof, amino or a substituted amino group.
Suitably the substituted phenyl group for R.sup.6 is a phenyl group substituted with up to three groups selected from C.sub.1-6 alkyl, phenyl, halogen, C.sub.1-6 alkoxy, amino, nitro, hydroxy, C.sub.1-6 alkylamido, C.sub.1-6 alkylcarbonyloxy, carboxy, C.sub.1-6 alkoxycarbonyl, halo (C.sub.1-6) alkyl, oxo (C.sub.1-6) alkyl, C.sub.1-6 alkylcarbonyl, aryloxy, aralkyloxy, arylcarbonyl, C.sub.1-6 alkylamino or di(C.sub.1-6) alkylamino.
Preferably R.sup.6 is a phenyl, p-hydroxyphenyl, thienyl or cyclohexadienyl group.
Other preferred groups R.sup.6 include 3,4-dihydroxyphenyl and 3,4-diacetoxyphenyl.
Preferably R.sup.7 is a substituted amino group.
More preferably the substituted amino group R.sup.7 is a ureido, acylamino or acylureido group.
One suitable sub-group within the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: ##STR10## wherein Y is as defined with respect to formula (I) and R.sup.8 is phenyl, substituted phenyl, cyclohexenyl, cyclohexadienyl, or a 5- or 6-membered heterocyclic ring containing up to three hetero-atoms selected from oxygen, sulphur or nitrogen, optionally substituted with hydroxy, amino, halogen, substituted amino or C.sub.1-6 alkoxy; R.sup.9 is hydrogen or a C.sub.1-6 alkyl group and R.sup.10 is an optionally substituted 5- or 6-membered heterocyclic group containing one or two nitrogen heteroatoms; or R.sup.9 and R.sup.10 together with the nitrogen atom to which they are attached form an optionally substituted five- or six-membered heterocyclic group containing one or two nitrogen heteroatoms.
Suitably the substituted phenyl group for R.sup.8 is a phenyl group substituted with up to three groups selected from C.sub.1-6 alkyl, phenyl, halogen, C.sub.1-6 alkoxy, amino, nitro, hydroxy, C.sub.1-6 alkylamido, C.sub.1-6 alkylcarbonyloxy, carboxy, C.sub.1-6 alkoxycarbonyl, halo (C.sub.1-6) alkyl, oxo (C.sub.1-6) alkyl, C.sub.1-6 alkylcarbonyl, aryloxy, aralkyloxy, arylcarbonyl, C.sub.1-6 alkylamino or di)C.sub.1-6) alkylamino.
In formula (III), the group R.sup.8 is preferably phenyl, 4-hydroxyphenyl, 3,4-di(C.sub.1-6 alkylcarbonyloxy)phenyl, 3,4-dihydroxyphenyl, 2-thienyl, 3-thienyl or 2-amino-4-thiazolyl.
Particularly preferred groups R.sup.8 are 3,4-dihyroxyphenyl and 3,4-diacetoxyphenyl.
Suitably R.sup.9 is hydrogen.
Suitable substituents for the 5- or 6-membered heterocyclic group of R.sup.10 or R.sup.9 and R.sup.10 together include the optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group; optionally substituted phenyl, oxo; the hydroxy group optionally substituted by alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, pyrimidyl or benzyl; the optionally substituted mercapto group, the alkylsulphonyl group; the substituted imino group; or the amino group optionally substituted by an alkyl, alkenyl, cycloalkyl, phenyl, substituted phenyl or benzyl group. Alternatively two substituents on the ring may form the residue of a further carbocyclic or heterocyclic ring.
Preferred values for Y in the compounds of formula (III) are --S--C(CH.sub.3).sub.2 -- and --S--CH.sub.2 --C(CH.sub.2 Q).dbd., wherein Q is as hereinbefore defined i.e. when the compound of formula (III) are derivatives of a penicillin and cephalosporin.
The carbon atom marked * in formulae herein is asymmetric so that the compounds may exist as two optically active diastereoisomers. In general that prepared from the D-side chain exhibits the highest antibacterial activity and accordingly the D compound or the DL mixtures are preferred, with the D compound being particularly preferred.
Preferred compounds within formula (III) are the penicillin derivatives of formula (IV) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: ##STR11## wherein R.sup.11 is phenyl, substituted phenyl, cyclohexenyl, cylohexadienyl, or a 5- or 6-membered heterocyclic ring containing up to three heteroatoms selected from oxygen, sulphur or nitrogen, optionally substituted with hydroxy, amino, halogen or C.sub.1-6 alkoxy; R.sup.12 is hydrogen or C.sub.1-6 alkyl and R.sup.13 is an optionally substituted five- or six-membered heterocyclic group containing one or two nitrogen heteroatoms; or R.sup.12 and R.sup.13 together with the nitrogen atom to which they are attached form an optionally substituted five- or six-membered heterocyclic group containing one or two nitrogen heteroatoms.
In formula (IV) the group R.sup.11 is preferably phenyl, 4-hydroxyphenyl, 2-thienyl, 3-thienyl, 2-amino-4-thiazolyl, 3,4-dihydroxyphenyl or 3,4-diacetoxyphenyl.
Particularly preferred groups R.sup.11 include 3,4-dihydroxyphenyl and 3,4-diacetoxyphenyl.
Suitable substituents for the five- or six-membered heterocyclic group of R.sup.13 or R.sup.12 and R.sup.13 together include the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, optionally substituted phenyl, oxo, the hydroxy group optionally substituted by alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, pyrimidyl or benzyl, the optionally substituted mercapto group, the alkylsulphonyl group, the substituted imino group, or the amino group optionally substituted by an alkyl, alkenyl, cycloalkyl, phenyl, substituted phenyl or benzyl group. Alternatively two substituents on the ring may form the residue of a further carbocyclic or heterocyclic ring.
Preferably R.sup.12 is hydrogen.
One particularly preferred sub-group within the present invention provides a compound of formula (V) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: ##STR12## wherein R.sup.8 and Y are as defined with respect to formula (III) and R.sup.14 represents hydrogen, C.sub.1-6 alkyl, substituted alkyl, aryl, or aralkyl; R.sup.15 and R.sup.16 are the same or different and represent hydrogen, C.sub.1-6 alkyl, substituted alkyl, halogen, amino, hydroxy or C.sub.1-6 alkoxy or R.sup.15 and R.sup.16 form the residue of 5- or 6-membered carbocyclic or heterocyclic ring.
Suitable values for Y in the compounds of formula (V) are --S--C(CH.sub.3).sub.2 -- and --S--CH.sub.2 --C(CH.sub.2 Q).dbd. wherein Q is as hereinbefore defined.
Preferably Y in the compounds of formula (V) is --S--C(CH.sub.3).sub.2 -- or --S--CH.sub.2 --C(CH.sub.2 Q').dbd. wherein Q' is as hereinbefore defined. Preferred compounds within formula (V) are the penicillin derivatives of formula (VI) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: ##STR13## wherein R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are as hereinbefore defined.
Suitable C.sub.1-6 alkyl groups R.sup.14, R.sup.15 and R.sup.16 in formula (V) and formula (VI) include methyl, ethyl, n- and iso-propyl, n, sex-, iso- and tert-butyl. Preferably R.sup.14 is ethyl. Preferably R.sup.15 and R.sup.16 are hydrogen.
A further preferred subgroup of compounds within the present invention are the compounds of formula )VII) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: ##STR14## wherein R.sup.3 is as hereinbefore defined; Y.sup.1 is oxygen or sulphur; and Q.sup.2 represents acetyloxy, a group -SHet, wherein Het is as hereinbefore defined, or Q.sup.2 represents a subgroup of formula (h): ##STR15## wherein R.sup.q and R.sup.p may be the same or different and each represents hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxyalkyl, C.sub.1-6 alkenyl, alkoxyalkyl, carboxyalkyl, sulphonylalkyl, carbamoylalkyl, carbamoyl, trifluoromethyl, hydroxy, halogen, and aminoalkyl.
Suitable values of R.sup.3 CO- within formula (VII) are those of formulae (a) to (g) as hereinbefore defined with reference to formula (II).
Suitable groups `Het` within formula (VII) include substituted and unsubstituted 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; oxazolyl; thiazolyl; 1,3,4-oxadiazolyl; 1,2,4-triazinyl; 1,3,4-thiadiazolyl or 1,2,4-thiadiazolyl. Preferably the groups `SHet` is 1-methyl-1H-tetrazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, 1carboxymethyl-1H-tetrazol-5-ylthio or 6-hydroxy-2-methyl-5-oxo-2H-1,2,4-triazin-3ylthio.
Suitably R.sup.q represents hydrogen.
Suitably R.sup.p represents hydrogen, sulphonylalkyl or carbamoyl, preferably the substituent R.sup.p is in the 4-position.
Suitably Y.sup.1 is sulphur.
Suitably Y.sup.1 is oxygen.
Preferably R.sup.3 within the formula (VII) is a subgroup of formula (j): ##STR16## wherein R.sup.8, R.sup.14, R.sup.15 and R.sup.16 are as hereinbefore defined with reference to formula (V).
Specific compounds within this invention include the following and pharmaceutically acceptable salts and in-vivo hydrolysable esters thereof:
Of those compounds listed above particularly preferred compounds are the following and pharmaceutically acceptable salts and in-vivo hydrolysable esters thereof:
The antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine according to techniques and procedures per se known in the art with reference to other antibiotics, and the invention therefore includes within its scope a pharmaceutical composition comprising an antibiotic compound according to the present invention such as, for example a compound of formula (II) above together with a pharmaceutically acceptable carrier or excipient.
The compositions may be formulated for administration by any suitable route, such as oral or parenteral, or by topical application. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polycinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine, tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example nethyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
Suppositories will contain conventional suppository base, e.g. cocoa-butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use, Parenteral suspensions are prepared insubstantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99.5% by weight active agent, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions are in unit dosage form, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 100 to 10,000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration.
The antibiotic compound according to the present invention may be the sole therapeutic agent in the compositions of the invention or is present in combination with other antibiotics and.or .beta.-lactamase inhibitory agents.
Advantageously the compositions also comprise a compound of formula (VIII) or a pharmaceutically acceptable salt or ester thereof: ##STR17## wherein A is hydroxyl, substituted hydroxyl, thiol, substituted thio, amino, mono- or di-hydrocarbyl substituted amino, or mono- or di-acylamino.
A further advantageous composition comprises an antibacterially effective amount of an antibiotic compound according to the invention together with a .beta.-lactamse inhibitory amount of a .beta.-lactamase inhibitor of formula (IX) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: ##STR18## and a pharmaceutically acceptable carrier or excipient.
Further suitable .beta.-lactamase inhibitors include .beta.-bromopenicillanic acid and salts and in vivo hydrolysable esters and .beta.-iodopenicillanic acid and salts and in vivo hydrolysable esters thereof.
Such composition of this invention which include .beta.-lactamase inhibitory amount of a .beta.-pactamase inhibitor are formulated in a conventional manner using techniques and procedures per se known in the art.
The present invention also includes a method of treating bacterial infections in humans and animals which comprises the administration of a therapeutically effective amount of an antibiotic compound of this invention.
The antibiotic compounds of the present invention are active against a broad range of gram positive and gram negative bacteria, in particular they are useful for treatment of respiratory tract and urinary tract infections in humans and mastitis in cattle. A particular advantage of the antibacterially active compounds of this invention is their stability to .beta.-lactamase enzymes and they are therefore effective against .beta.-lactamase producing organisms.
In another aspect the present invention provides a process for the preparation of a compound of the present invention which process comprises formylating a .beta.-lactam having an 60 -amino substituent on the carbon atom adjacent to the carbonyl group of the .beta.-lactam ring.
The present invention further provides a process for the preparation of a compound of formula (I) which process comprises formylating a compound of formula (X): ##STR19## where any reactive groups may be protected; R.sup.17 is an amino protecting group or an acyl group as found in antibacterially active penicillins and cephalosporins and wherein any reactive groups may be protected; and R.sup.18 is a readily removable carboxy protecting group; and thereafter, if necessary, carrying out one or more of the following steps:
Suitable formylating agents include mixed anhydrides such as formic acetic anhydride. The reaction may suitably be carried out in a temperature in the range -50.degree. C. to 30.degree. C. in aprotic solvent such as, for example, dichloromethane, chloroform, dimethylformamide, tetrahydrofuran, hexamethylphosphoramide, or dimethylsulphoxide, in the presence of a tertiary base. A preferred tertiary base employed in the reaction is a base of the pyridine type, such as pyridine, lutidine or picoline.
A process for preparing compounds within formula (X) is disclosed in U.S. Pat. No. 3.962,214 and in U.K. Pat. No. 1348984.
Compounds of the formula (X) may be prepared by the reaction of a corresponding compound of the formula (XI): ##STR20## wherein Y, R.sup.17 and R.sup.18 are as hereinbefore defined, and R.sup.19 is C.sub.1-6 alkyl, aryl or benzyl; with anhydrous ammonia, an ammonium salt or an amine of the formula (XII):
Suitable examples of the alkyl group for R.sup.19 include C.sub.1-6 alkyl groups such as methyl, ethyl, n-, or iso-propyl, and n-, sec-; iso-, or tert-butyl groups.
A preferred alkyl group for R.sup.19 is methyl.
Suitable examples of the aryl group R.sup.19 include phenyl, optionally substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, or nitro. Preferred aryl groups for R.sup.19 include phenyl, o-, m- or p-methylphenyl, o-, m- or p-nitrophenyl, in particular p-methylphenyl.
Suitable solvents in which the reaction may be performed include for example, diethylether, tetrahydrofuran, dimethylformamide, methanol and hexamethylphosphoramide. The reactions are generally carried out under an inert atmosphere and at moderate to low temperatures i.e. in the range -100.degree. C. to 30.degree. C. The course of the reaction may be followed by conventional methods such as thin layer chromatography and terminated when an optimum quantity of product is present in the reaction mixture.
The preferred metal ion for use in the above process is the mercuric ion, aptly in the form of mercuric acetate.
Alternatively compounds of the formula (X) may be prepared by the reaction of a corresponding compound of the formula (XIII): ##STR21## wherein R.sup.17, R.sup.18 and R.sup.19 are as hereinbefore defined; Hal is chloro or bromo, with anhydrous ammonia, an ammonium salt or an amine of formula (XII) as hereinbefore defined and thereafter if necessary removing any protecting group to form the compound of formula (X). The compounds of the formula (XIII) may be prepared by the reaction of a compound of the formula (XI) as hereinbefore defined, with a halogenating agent such as chlorine or bromine in an inert solvent, for example dichloromethane, at a depressed temperature such as -80.degree. C. to -30.degree. C.
A further method of preparation of the compounds of the formula (X) comprises the reaction of a compound of the formula (XIV): ##STR22## wherein R.sup.17, R.sup.18 and R.sup.19 are as hereinbefore defined; with anhydrous ammonia, an ammonium salt or an amine of the formula (XII) as hereinbefore defined and thereafter if necessary removing any protecting group to form the compound of the formula (X).
Suitably such a reaction is performed at a non-extreme temperature for example 0.degree. C.-60.degree. C., normally 10.degree. C.-40.degree. C. and preferably ambient. The reaction is conveniently performed in an aprotic solvent such as tetrahydrofuran or dioxan.
It will be appreciated that the processes for preparation of a compound of formula (X) described hereinbefore proceed via an imine intermediate; other processes proceeding via such an intermediate are also included herein.
The compounds of the formula (XIV) may be prepared by the oxidation of a compound of the formula (XI) as hereinbefore defined. Such oxidation may conveniently performed in conventional manner, for example using a per-acid such as peracetic acid or m-chloroperbenzoic acid, suitably at an ambient or depressed temperature. Suitable solvents for such a sulphoxidation include ethylacetate, chloroform, dichloromethane, dioxan and tetrahydrofuran.
Examples of suitable protecting groups for the group R.sup.20 include those known in the art as being cleavable to provide the --NH--. Mention may be made of silyl groups such as trimethylsilyl, tertiarybutyldimethylsilyl, and tri-isopropylsilyl. A preferred protecting group is (p-methoxymethoxy)phenyl which is removable by cerium ammonium nitrate. Other protecting groups of interest include those cleavable by methanolysis such as --C(CO.sub.2 R).dbd.0 (This moiety may be derived from groups of the type --C(CO.sub.2 R).dbd.C(CH.sub.3).sub.2). Further suitable protecting groups include 4-nitrobenzyl and 2,4-dimethoxybenzyl which is removable with potassium persulphate.
The oxidation of a compound of the formula (XI) which contains sulphur atoms in addition to that shown in the formula may oxidise the additional sulphur atoms and accordingly it may be necessary to reduce the thus formed sulphoxide or sulphone to the corresponding sulphide.
Preferably Y in the compound of formula (XIII) is --0--CH.sub.2 -CZ.dbd. wherein Z is as hereinbefore defined.
The starting material for the above processes i.e. compound of formula (XI) above may be prepared by acylation or protection, under conventional conditions of the compound (XV): ##STR23## wherein R.sup.18, R.sup.19 and Y are as defined hereinbefore.
Compounds of the formula (XV) may be prepared by methods known or analogous to those known for the preparation of .alpha.-substituted-thio cephalosporins and 6.alpha.-substituted-thio penicillins.
Compounds of formula (XV) may suitably be prepared form a Schiff's base derivative as outlined in Scheme 1. ##STR24##
The compound of formula (XV) is prepared by reacting the amino compound (A) with an aldehyde of formula Ar--CHO wherein Ar is an aryl group to form the Schiff base (B). The Schiff base (B) is reacted with a base to form an anion which is treated with a thiosulphonate of formula:
Compounds of formula (XV) may also be prepared by reacting a thiooxime compound of formula (XVI): ##STR25## wherein R.sup.18 and R.sup.19 are as defined hereinbefore above with a tri(alkyl)phosphine or tri(aryl)phosphine, followed by treatment with an acid catalyst such as silica gel. The process is as described in U.S. Pat. No. 119,778 and in J. Amer. Chem. Soc., 1980, 102, 1690.
Compounds within formula (XV) and (XVI) may also be prepared by the process disclosed in U.S. Pat. No. 3,962,214 or an appropriate modification thereof.
The antibacterially active compounds of formula (II) as hereinbefore defined may suitably be prepared by reacting a compound of formula (XVII): ##STR26## wherein the amino group is optionally substituted with a group which permits acylation to take place and R.sup.2 is as hereinbefore defined with reference to formula (I) above, with an N-acylating derivative of an acid of formula (XVIII):
Suitable groups which permit acylation to take place and which are optionally present on the amino group of the starting material of the formula (XVII) include N-silyl, N-stannyl and N-phosphorus groups, for example trialkylsilyl groups such as trimethylsilyl, trialkyltin groups such as tri-n-butyltin, groups of formula --P.R.sup.a R.sup.b wherein R.sup.a is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, R.sup.b is the same as R.sup.a or is halogen or R.sup.a and R.sup.b together form a ring; suitable such phosphorus groups being --P(OC.sub.2 H.sub.5).sub.2, --P(C.sub.2 H.sub.5).sub.2, ##STR27##
The carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R.sup.2 group, for example, acid--and base--catalysed hydrolysis, or by enzymically--catalysed hydrolysis, or by hydrogenolysis.
Suitable carboxyl-protecting derivatives for the group --CO.sub.2 R.sup.2 in formula (XVII) include salts and ester derivatives of the carboxylic acid as described hereinbefore with reference to formula (I).
A reactive N-acylating derivative of the acid (XVIII) is employed in the above process. The choice of reactive derivative will of course be influenced by the chemical nature of the substituents of the acid.
Suitable N-acylating derivatives include an acid halide, preferably the acid chloride or bromide. Acylation with an acid halide may be affected in the presence of an acid binding agent for example, tertiary amine (such as triethylamine, pyridine or dimethylaniline), an inorganic base (such as calcium carbonate or sodium bicarbonate) or an oxirane, which binds hydrogen halide liberated in the acylation reaction. The oxirane is preferably a (C.sub.1-6)-1,2-alkylene oxide - such as ethylene oxide or propylene oxide. The acylation reaction using an acid halide may be carried out at a temperature in the range -50.degree. C. to +50.degree. C., preferably -20.degree. C., to +20.degree. C., in aqueous or non-aqueous media such as water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Alternatively, the reaction may be carried out in an unstable emulsion of water-immiscible solvent, especially an aliphatic ester or ketone, such as methyl isobutyl ketone or butyl acetate.
The acid halide may be prepared by reacting the acid (XVIII) or a salt thereof with a halogenating (e.g. chlorinating or brominating) agent such as phosphorus pentachloride, thionyl chloride or oxolyl chloride.
Alternatively, the N-acylating derivative of the acid (XVIII) may be a symmetrical or mixed anhydride. Suitable mixed anhydrides are alkoxyformic anhydrides, or anhydrides with, for example, carbonic acid monoesters, trimethyl acetic acid, thioacetic acid, diphenylacetic acid, benzoic acid, phosphorus acids (such as phosphoric or phosphorous acids) or aliphatic or aromatic sulphonic acids (such as p-toluenesulphonic acid). When a symmetrical anhydride is employed, the reaction may be carried out in the presence of 2,6-lutidine as catalyst.
Alternatively N-acylating derivatives of acid (XVIII) are the acid azide, or activated esters such as esters with 2-mercaptopyridine, cyanomethanol, p-nitrophenol, 2,4-dinitrophenol, thiophenol, halophenols, including pentachlorophenol, monomethoxyphenol, N-hydroxy succinimide, or 8-hydroxyquinoline; or amides such as N-acylsaccharins, N-acylthiazolidin-2-thione or N-acylphthalimides; or an alkylidene iminoester prepared by reaction of the acid (XVIII) with an oxime.
Other reactive N-acylating derivatives of the acid (XVIII) include the reactive intermediates formed by reaction in situ with a condensing agent such as a carbodiimide, for example, N,N'-diethyl-, dipropyl- or diisopropylcarbodiimide, N,N'-di-cyclohexylcarbodiimide, or N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide; a suitable carbonyl compound, for example, N,N'-carbonyldiimidazole or N,N'-carbonylditriazole; an isoxazolinium salt, for example, N-ethyl-5-phenylisoxazolinium-3-sulphonate or N-t-butyl-5-methylisoxazolinium perchlorate; or an N-alkoxycarbonyl 2-alkoxy-1,2-dihydroquinoline, such as N-ethoxycarbonyl 2-ethoxy-1,2-dihydroquinoline. Other condensing agents include Lewis acids (for example BBr.sub.3 --C.sub.6 H.sub.6); or a phosphoric acid condensing agent such as diethylphosphorylcyanide. The condensation reaction is preferably carried out in an organic reaction medium, for example, methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan or tetrahydrofuran.
Aptly the acid of formula (XVIII) is an acid of formula (XIX): ##STR28## wherein R.sup.8, R.sup.9 and R.sup.10 are as hereinbefore defined; thereby affording a compound of formula (III) as hereinbefore defined.
Aptly Y in formula (XVII) is --S--C(CH.sub.3).sub.2 -- and the acid of formula (XVIII) is an acid of formula (XX): ##STR29## wherein R.sup.11, R.sup.12 and R.sup.13 are as hereinbefore defined; thereby affording a compound of formula (IV) as hereinbefore defined.
The compounds of formula (III) may also suitably be prepared by reacting a compound of formula (XXI): ##STR30## wherein R.sup.2, R.sup.8 and Y are as hereinbefore defined and the .alpha.-amino group is optionally substituted with a group which permits acylation to take place, and any reactive groups may be protected with an N-acylating derivative of an acid of formula (XXII): ##STR31## wherein R.sup.9 and R.sup.10 are as hereinbefore defined and wherein any reactive groups may be protected; and thereafter, if necessary, carrying out one or more of the following steps:
The compounds of formula (IV) as hereinbefore defined are aptly prepared by reacting a compound of formula (XXIII): ##STR32## wherein the .alpha.-amino group is optionally substituted with a group which permits acylation to take place and any reactive groups may be protected, and R.sup.2 and R.sup.11 are as hereinbefore defined with an N-acylating derivative of an acid of formula (XXIV): ##STR33## wherein R.sup.12 and R.sup.13 are as defined with respect to formula (IV) above and any reactive groups may be protected; and thereafter, if necessary, carrying out one or more of the following steps:
The compounds of formula (XXI) herein which are inter alia intermediates for the compounds of formula (III) as hereinbefore defined may be prepared by reacting a compound of formula (XVII) with an N-acylating derivative of an acid of formula (XXV): ##STR34## wherein R.sup.21 is an amino-protecting group and thereafter removing protecting group R.sup.21.
Suitable amino protecting groups R.sup.21 include those disclosed hereinbefore with reference to group R.sup.1, with alkoxycarbonyl groups such as, for example, 4-nitrobenzyloxycarbonyl and trichloroethyloxycarbonyl being particularly preferred.
The compounds of formula (XXIII) herein which are inter alia intermediates for the compounds of formula (IV) as hereinbefore defined may be prepared by reacting a compound of formula (XXVI): ##STR35## wherein R.sup.2 is as defined hereinbefore with an N-acylating derivative of an acid of formula (XXVII): ##STR36## wherein R.sup.11 is as defined hereinbefore and any reactive groups therein may be protected and R.sup.21 is an amino-protecting group as hereinbefore defined; and thereafter removing protecting group R.sup.21.
The antibacterially active compounds of formula (II) as hereinbefore defined may also suitably be prepared by formylating a compound of formula (XXVIII): ##STR37## wherein R.sup.3, R.sup.18 and Y are as hereinbefore defined and wherein any reactive groups may be protected and thereafter, if necessary, carrying out one or more of the following steps:
When Y in formula (XXVIII) is --S--C(CH.sub.3).sub.2 -- and R.sup.3 is a group of formula (XXIX): ##STR38## wherein R.sup.11, R.sup.12 and R.sup.13 are as hereinbefore defined the process affords a compound of formula (IV) as hereinbefore defined.
The intermediate compound of formula (XVII) as hereinbefore defined may suitably be prepared by formylating a compound of formula (XXX): ##STR39## wherein R.sup.18, R.sup.21 and Y are as hereinbefore defined and thereafter removing the protecting group R.sup.21 and if necessary, converting a group R.sup.18 to a group R.sup.2.
Suitable formylating agents and reaction conditions are as hereinbefore defined.
When Y in the compound of formula (XXX) is --S--C(CH.sub.3).sub.2 -- the process produces the compound of formula (XXVI) herein.
The sub-group of compounds within the present invention of formula (XXXI): ##STR40## wherein Y.sup.1 and `Het` are as defined hereinbefore with reference to formula (VII) and R.sup.1 and R.sup.2 are as defined hereinbefore with reference to formula (X) may suitably be prepared by reacting a compound of formula (XXXII): ##STR41## wherein Y.sup.1, R.sup.1 and R.sup.2 are as defined hereinbefore and wherein any reactive groups may be protected and R.sup.22 is a leaving group; with a thiol of formula:
Suitable leaving groups R.sup.22 include halogen such as iodide or bromide or an acyloxy groups such as, for example the acetyloxy group.
The thiol HetSh may be reacted as the free compound or a salt with an alkali metal such as sodium or potassium. This reaction is desirably conducted in a solvent. For example, use can be made of water, or organic solvents inert to the starting compounds, such as dimethylformamide, dimethylacetamide, dioxane, acetone, alcohol, 1,2-dichloroethane, acetonitrile, dimethylsulfoxide or tetrahydrofuran, or mixtures thereof. The reaction temperature and time depend, among other factors, upon the starting compounds and solvent to be employed but generally the reaction is carried out at a selected temperature within the range of 0.degree. C. to 100.degree. C. for a selected time of a few hours to several days. The reaction is desirably conducted between pH 3 and 7. To prevent oxidation of the thio compounds it is advantageous to carry out the reaction in an inert gaseous atmosphere, e.g. nitrogen gas.
The subgroup of compounds within the present invention of formula (XXXIII): ##STR42## wherein R.sup.1, R.sup.2, R.sup.p, R.sup.q and Y.sup.1 are as defined hereinbefore may suitably be prepared by reacting a compound of formula (XXXII) as hereinbefore defined with the appropriately substituted pyridine.
Suitably the reaction with the pyridine is carried out in a polar solvent such as water, and in the presence of a catalyst such as an alkali metal thiocyanate or an alkali metal halide such as, for example sodium iodide.
From the foregoing it will be appreciated that the compounds of (XVII) and protected derivatives thereof are valuable intermediates and form another preferred aspect of the present invention.
Particularly preferred compounds within formula (XVII) are the zwitteronic compounds of formula (XXXIV) or a salt thereof: ##STR43## wherein Y is as defined hereinbefore.
Suitably Y is formulae (XVII) and (XXXIV) is --S--C(CH.sub.3).sub.2 --, --S--CH.sub.2 --, --S--CH.sub.2 --C(CH.sub.2 Q').dbd.or --O--CH.sub.2 --C(CH.sub.2 Q').dbd., wherein Q' is as hereinbefore defined.
Preferred values for Y in the compounds of formulae (XVII) and (XXXIV) are --S--C(CH.sub.3).sub.2 -- and --S--CH.sub.2 --C(CH.sub.2 Q).dbd., i.e. when the compounds are derivatives of the penicillin and cephalosporin nucleus.
A particularly preferred value for Y in formulae (XVII) and (XXXIV) is --S--C(CH.sub.3).sub.2 --.
Specific compounds within formula (XVII) include the following or a salt thereof:
The antibiotic compounds of the present invention are active against a wide range of gram negative and gram positive organisms including E.coli such as, for example ESS, JT4, JT425 and NCTC 10418; Pseudomonas Spp. such as Ps.aeruginosa for example 10662 and Dalgleish; Serratia marcescens US32; Klebsiella aerogenes A; Enterobacter cloacae N1; P.mirabilis such as, for example C977 and 889; P.morganii; P.rettgeri; B.subtilis; Staph aureus such as, for example Oxford and Russell; N.catarrhalis 1502; Strep faecalis I; .beta.-Haemolytic Strep CN10. The MIC data included in the following examples is representative of the activity of the compounds of the present invention.
US Referenced Citations (5)
Continuations (1)
|
Number |
Date |
Country |
| Parent |
401266 |
Jul 1982 |
|
Patent Grant
4877783
