GB2040921A - Cephalosporin antibiotics - Google Patents
Cephalosporin antibiotics Download PDFInfo
- Publication number
- GB2040921A GB2040921A GB7937306A GB7937306A GB2040921A GB 2040921 A GB2040921 A GB 2040921A GB 7937306 A GB7937306 A GB 7937306A GB 7937306 A GB7937306 A GB 7937306A GB 2040921 A GB2040921 A GB 2040921A
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- United Kingdom
- Prior art keywords
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- compound
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- acid
- Prior art date
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- Granted
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- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 21
- 229940124587 cephalosporin Drugs 0.000 title abstract description 25
- 229930186147 Cephalosporin Natural products 0.000 title abstract description 24
- 150000001780 cephalosporins Chemical class 0.000 title abstract description 19
- 229940088710 antibiotic agent Drugs 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 238000002360 preparation method Methods 0.000 claims abstract description 26
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 25
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 25
- 150000002148 esters Chemical class 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 19
- 230000003115 biocidal effect Effects 0.000 claims abstract description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 10
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- -1 2 - Aminothiazol - 4 - yl Chemical group 0.000 claims description 73
- 239000002253 acid Substances 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
- 230000000903 blocking effect Effects 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 229910052705 radium Inorganic materials 0.000 claims description 12
- 229910052701 rubidium Inorganic materials 0.000 claims description 12
- 241000282414 Homo sapiens Species 0.000 claims description 7
- SXBDXXFTJVHSAF-ZCFIWIBFSA-N (6r)-5-thia-1-azabicyclo[4.2.0]oct-3-en-8-one Chemical compound S1C=CCN2C(=O)C[C@H]21 SXBDXXFTJVHSAF-ZCFIWIBFSA-N 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000012038 nucleophile Substances 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- BSPWLIZTKBIVPM-OGFXRTJISA-N COC(=O)C1=CCS[C@H]2N1C(C2)=O.CN(C)C Chemical compound COC(=O)C1=CCS[C@H]2N1C(C2)=O.CN(C)C BSPWLIZTKBIVPM-OGFXRTJISA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 38
- 230000000694 effects Effects 0.000 abstract description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 3
- 241000588921 Enterobacteriaceae Species 0.000 abstract description 2
- 241000589516 Pseudomonas Species 0.000 abstract description 2
- 235000013350 formula milk Nutrition 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- 239000000243 solution Substances 0.000 description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 150000007513 acids Chemical class 0.000 description 21
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 21
- 239000000047 product Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 229940093499 ethyl acetate Drugs 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 239000006260 foam Substances 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 238000005917 acylation reaction Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- GETQZCLCWQTVFV-UHFFFAOYSA-N anhydrous trimethylamine Natural products CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
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- 229960000583 acetic acid Drugs 0.000 description 7
- 230000010933 acylation Effects 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 6
- 238000006073 displacement reaction Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 5
- 239000012346 acetyl chloride Substances 0.000 description 5
- 125000004423 acyloxy group Chemical group 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229940126575 aminoglycoside Drugs 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- 150000003842 bromide salts Chemical class 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000006266 etherification reaction Methods 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- FZEVMBJWXHDLDB-ZCFIWIBFSA-N (6r)-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical compound S1CC=CN2C(=O)C[C@H]21 FZEVMBJWXHDLDB-ZCFIWIBFSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical class CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- QHTOIDKCEPKVCM-ZCFIWIBFSA-N cepham Chemical compound S1CCCN2C(=O)C[C@H]21 QHTOIDKCEPKVCM-ZCFIWIBFSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
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- 229960001760 dimethyl sulfoxide Drugs 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
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- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
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- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
Abstract
Cephalosporin antibiotics of general formula <IMAGE> (wherein R<a> and R<b>, which may be the same or different, each represent a C1-4 alkyl group or R<a> and R<b> together with the carbon atom to which they are attached form a C3-7 cycloalkylidene group; and R<1>, R<2> and R<3>, which may be the same or different, each represents a C1-4 alkyl group) exhibit broad spectrum antibiotic activity with unusually high activity against strains of Pseudomonas organisms as well as high activity against various members of the Enterobacteriaceae. The invention also includes the non-toxic salts and non-toxic metabolically labile esters of compounds of formula (I). Also described are compositions containing the antibiotics of the invention and processes for the preparation of the antibiotics.
Description
SPECIFICATION
Cephalosporin compounds
This invention is concerned with cephalosporin compounds possessing valuable antibiotic properties.
The cephalosporin compounds in this specification are named with reference to "cepham" after.
Amer. Chem. Soc., 1962, 84, 3400, the term "cepham" referring to the basic cepham structure with one double bond.
Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in human beings and animals, and are especially useful in the treatment of diseases caused by bacteria which are resistant to other antibiotics such as penicillin compounds, and in the treatment of penicillin-sensitive patients. In many instances it is desirable to employ a cephalosporin antibiotic which exhibits activity against both gram-positive and gram-negative microorganisms, and a significant amount of research has been directed to the development of various types of broad spectrum cephalosporin antibiotics.
Thus, for example, in our British Patent Specification No. 1,399,086, we describe a novel class of cephalosporin antibiotics containing a 7ss - (a etherified oxyimino) - acylamido group, the oxyimino group having thesyn configuration. This class of antibiotic compounds is characterised by high antibacterial activity against a range of grampositive and gram-negative organisms coupled with particularly high stability to p-lactamases produced by various gram-negative organisms.
The discovery of this class of compounds has stimulated further research in the same area in attempts to find compounds which have improved properties, for example against particular classes of organisms especially gram-negative organisms.
In our British Patent Specification No. 1,496,757, we describe cephalosporin antibiotics containing a 7p-acylamido group of the formula
(wherein R is a thienyl or furyl group; RA and RB may vary widely and may, for example, be Cl-4 alkyl groups ortogetherwith the carbon atom to which they are attached form a C37 cycloalkylidene group, and m and n are each 0 or 1 suchthatthesumofm and n is 0 or 1), the compounds being syn isomers or mixtures ofsyn and anti isomers containing at least 90% of the syn isomer. The 3-position of the cephalosporin molecule may be unsubstituted or may contain one of a wide variety of possible substituents. These compounds have been found to have particularly good activity against gramnegative organisms.
Other compounds of similar structure have been developed from these compounds in further attempts to find antibiotics having improved broad spectrum antibiotic activity and/or high activity against gram-negative organisms. Such developments have involved variations in not only the 7p- acylamido group of formula (A) but also the introduction of particular groups in the 3-position of the cephalosporin molecule.
Thus, for example, South African Patent Specification 78/1870 discloses cephalosporin antibiotics wherein the 7p-acylamido side chain is inter alia a 2-(2-amino - thiazol - 4 - yl) - 2 - (optionally substituted alkoxyimino) - acetamido group and the 3-position may be substituted, for example, by the group -CH2Y in which Y represents the residue of a nucleophile. The Specification contains, among numerous other examples, references to compounds in which the above-mentioned optionally substituted alkoxyimino group is a carboxyalkoxyimino orcarboxycycloalkoxyimino group. With regard to the 3-position, mono- and dialkylaminomethyl substituents are referred to, among numerous other possibilities. South African
Patent Specification 78/2168 discloses in broad terms sulphoxide compounds corresponding to the sulphides described in the last-mentioned Specification.
Furthermore, Belgian Patent Specification No.
836,813 describes cephalosporin compounds wherein the group R in formula (A) above may be replaced by, for example, 2-aminothiazol-4-yl, and the oxyimino group is a hydroxyimino or blocked hydroxyimino group, e.g. a methoxyimino group. In such compounds, the 3-position of the cephalosporin molecule is substituted by a methyl group which may itself be optionally substituted by any of a large number of residues of nucleophilic compounds therein described. N-Alkylaminomethyl groups are mentioned as possible substituents in the 3-position but only mono- and di-alkylaminomethyl groups are specifically identified. In the above-mentioned
Specification no antibiotic activity is ascribed to such compounds which are only mentioned as intermedi atesforthe preparation of antibiotics described in that Specification.
We have now discovered that by an appropriate selection of a small number of particular groups at the 7,3-position in combination with a trialkylammoniomethyl group at the 3-position, cephalosporin compounds having particularly advantageous activity (described in more detail below) against a wide range of commonly encountered pathogenic organisms may be obtained.
The present invention provides cephalosporin antibiotics of the general formula:
(wherein Ra and Rb, which may be the same or different, each represent a C14 alkyl group (preferably a straight chain alkyl group, i.e. a methyl, ethyl, n-propyl or n-butyl group and particularly a methyl or ethyl group) or Ra and Rb together with the carbon atom to which they are attached form a C3--7 cycloalkylidene group, preferably a C35 cycloalkylidene group; and RI, R2 and R3, which may be the same or different, each represents a C, 4 alkyl group, e.g. a methyl group) and non-toxic salts and non-toxic metabolically labile esters thereof.
The compounds according to the invention are syn isomers. Thesyn isomericform is defined by the configuration of the group
with respect to the carboxamido group. In this
Specification the syn configuration is denoted structurally as
It will be understood that since the compounds according to the invention are geometric isomers, some admixture with the corresponding anti isomer may occur.
The invention also includes within its scope the
solvates (especially the hydrates) of the compounds
of formula (I). It also includes within its scope salts of
esters of compounds of formula (I).
The compounds according to the present inven
tion may exist in tautomeric forms (for example in respect of the 2-aminothiazolyl group) and it will be
understood that such tautomeric forms, e.g. the 2-iminothiazolinyl form, are included within the scope of the invention. Moreover, the compounds of formula (I) depicted above may also exist in alternative zwitterionic forms, for example wherein the 4-carboxyl group is protonated and the carboxyl group in the 7-side chain is deprotonated. These alternative forms, as well as mixtures of zwitterionic forms, are included within the scope of the present invention.
It will also be appreciated that when Ra and Rb in the above formula represent different C1--4 alkyl groups, the carbon atom to which they are attached will comprise a centre of asymmetry. A centre of
asymmetry will also be present when R', R2 and R3 all
represent different alkyl groups. Such compounds
are diastereoisomeric and the present invention
embraces individual diastereoisomers of these
compounds as well as mixtures thereof.
The compounds according to the invention exhibit
broad spectrum antibiotic activity. Against gram
negative organisms the activity is unusually high.
This high activity extends to many,3 - lactamase
producing gram-negative strains. The compounds
also possess high stability to ss-lactamases produced
by a range of gram-negative and gram-positive
organisms.
Compounds according to the invention have been
found to exhibit unusually high activity against
strains ofPseudomonas organisms, e.g. strains of
Pseudomonas aeruginosa as well as high activity against various members of the Enterobacteriaceae (e.g. strains ofEscherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, Shigella sonnei, Enterobacter cloacae, Serratia marcescens,
Providence species, Proteus mirabilis, and especially indole-positiveProteus organisms such Proteus vulgaris and Proteus organic) and strains of Haemophilus influenzae.
The antibiotic properties of the compounds according to the invention compare very favourably with those of the aminoglycosides such as amikacin orgentamicin. In particular, this applies to their activity against strains of various Pseudomonas organisms which are not susceptible to the majority of existing commercially available antibiotic compounds. Unlike the aminoglycosides, cephalosporin antibiotics normally exhibit low toxicity in man. The use of aminoglycosides in human therapy tends to be limited or complicated by the relatively high toxicity of these antibiotics. The cephalosporin antibiotics of the present invention thus possess potentially great advantages over the aminoglycosides.
Non-toxic salt derivatives which may be formed by reaction of either or both of the carboxyl groups present in the compounds of general formula (I) include inorganic base salts such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts); amino acid salts (e.g. lysine and arginine salts); organic base salts (e.g. procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglycosamine salts). Other non-toxic salt derivatives include acid addition salts, e.g. formed with hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, formic and trifluoroacetic acids.
The salts may also be in the form of resinates formed with, for example, a polystyrene resin or cross-linked polystyrene divinylbenzene copolymer resin containing amino or quaternary amino groups or sulphonic acid groups, or with a resin containing carboxyl groups, e.g. a polyacrylic acid resin. Soluble base salts (e.g. alkali metal salts such as the sodium salt) of compounds of formula (I) may be used in therapeutic applications because of the rapid distribution of such salts in the body upon administration. Where, however, insoluble salts of compounds (I) are desired in a particular application, e.g. for use in depot preparations, such salts may be formed in conventional manner, for example with appropriate organic amines.
These and other salt derivatives such as the salts with toluene-p-sulphonic and methanesulphonic acids may be employed as intermediates in the preparation and/or purification of the present compounds of formula (I), for example in the processes described below.
Non-toxic metabolically labile ester derivatives which may be formed by esterification of either or both carboxyl groups in the parent compound of formula (I) include acyloxyalkyl esters e.g. lower alkanoyloxy-methyl or -ethyl esters such as acetoxy-methyl or ethyl or pivaloyloxymethyl esters. In addition to the above ester derivatives, the present invention includes within its scope com pounds of formula (I) in the form of other physiologically acceptable equivalents, i.e. physiologically acceptable compounds which, like the metabolically labile esters are converted in vivo into the parent antibiotic compound of formula (I).
Preferred compounds according to the present invention include those compounds of formula (I) wherein R1, R2 and R3 all represent methyl groups.
Preference is also expressed for those compounds wherein Ra and Rb both represent methyl groups or together with the carbon atom to which they are attached form a cyclobutylidene group. (6R, 7R) - 7 [(Z) - 2 - (2 - Aminothiazol - 4 - yl) - 2 - (1 - carboxycyclobut - 1 - oxyimino) acetamido] - 3 - trimethylammoniomethyl - ceph - 3 - em - 4 - carboxylate and its non-toxic salts and non-toxic metabolically labile esters are particularly preferred compounds according to the present invention. Other preferred compounds include (6R, 7R) - 7 - [(Z) - 2 - (2 - aminothiazol - 4 - yl) - 2 - (2 - carboxyprop - 2 - oxyimino) acetamido] - 3 - trimethylammoniomethyl - ceph - 3 em - 4 - carboxylate acid and its non-toxic salts and non-toxic metabolically labile esters.
Other compounds according to the present invention includes those for example wherein the groups
Ra, Rb, R1, R2 and R3 in formula (I) are as follows:-
Ra Rb R R R a) Alkyl groups -CH3 -C2H5 CH3 CH3 CH3 -C2H5 -C2H5 CH3 CH3 CH3 -CH3 -CH3 C2H5 CH3 CH3 -CH3 -C2H5 C2H5 CH3 CH3 C2H5 -C2H5 C2H5 CH3 CH3 CH3 H3 C2H5 c2H5 CH3 -CH3 -C2H5 c2H5 c2H5 CH3 -C2H5 -C2H5 | C2H5 C2H5 CH3 cH3 -CH3 2H5 c2H5 c2H5 -CH3 -C2H5 C@H5 C2H5 C2H5 -C2H5 -C2H5 C2H5 C2H5 C2H5 Ra -C-Rb R1 R2 R3 b) Cvcloalkvlidene groups cyclopropylidene -cH3 -cH3 -CH3 cyclopentylidene -CH3 -CH3 -CH3 cyclopropylidene -C2H5 -CH3 -CH3 cyclobutylidene -C2H5 -CH3 -CH3 cyclopentylidene -C2H5 -CH3 -CH3 cyclopropylidene -C2H5 -C2H5 -CH3 cyclobutylidene -C2H5 -C2H5 -CH3 cyclopentylidene -C2H5 -C2H5 -CH3 cyclopropylidene -C2H5 -C2H5 -C2H cyclobutylidene -C2H5 -C2H5 -C2H cyclopentylidene -C2H5 -C2H5 -C2H5 The compounds offormula (I) may be used for treating a variety of diseases caused by pathogenic bacteria in human beings and animals, such as respiratory tract infections and urinary tract infections.
According to another embodiment of the invention we provide a process for the preparation of an antibiotic compound of general formula (I) as herein before defined or a non-toxic salt or non-toxic metabolically iabile ester thereof which comprises (A) acylating a compound of the formula
[wherein R', R2 and R3 are as defined above; B is > S or > S # 0 (a- or ss-); and the dotted line bridging the 2-, 3- and 4-positions indicates that the compound is a ceph-2-em or ceph-3-em compound] or a salt, e.g. an acid addition salt (formed with, for example, a mineral acid such as hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid or an organic acid such as methanesulphonic ortoluene-psulphonic acid) or an N-silyl derivative thereof, or a corresponding compound having a group of formula - COOR4 at the 4-position [where R4 is a hydrogen atom or a carboxyl blocking group, e.g. the residue of an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, solanol or stannanol (the said alcohol, phenol, silanol or stannanol preferably containing 1-20 carbon atoms)] and having an associated anion Such as a halide, e.g. chloride or bromide, ortrifluoroacetate anion, with an acid of formula
(wherein Ra and Rb are as hereinbefore defined; R5 represents a carboxyl blocking group, e.g. as described for R4; and R6 is an amino or protected amino group) or with an acylating agent corresponding thereto; (B) reacting a compound of formula
(wherein Ra, Rb, R6, @ B and the dotted line are as hereinbefore defined; R7 and R7a may independently represent hydrogen or a carboxyl blocking group; and Xis a replaceable residue of a nucleophile, e.g. an acyloxy group such as a dichloroacetoxy group or a halogen atom such as chlorine, bromine or iodine) or a salt thereof, with a tertiary amine of the formula
(wherein R1, R2 and R3 are as defined above); or (C) alkylating a compound of the formula
(wherein Ra, Rb, R', R2, Re, B and the dotted line are as hereinbefore defined; and R7 and R7a both represent carboxyl blocking groups) with an alkylating agent serving to form a group of formula
at the 3-position; whereafter, if necessary and/or desired in each instance, any of the following reactions, in any appropriate sequence, are carried out:
i) conversion of a A2-isomer into the desired A3 isomer, ii) reduction of a compound wherein B is > S ) 0 to form a compound wherein B is > S,
iii) conversion of a carboxyl group into a non-toxic salt or non-toxic metabolically labile ester function, and
iv) removal of any carboxyl blocking and/or
N-protecting groups.
In the above-described process (A), the starting material of formula (II) is preferably a compound wherein the dotted line represents a ceph-3-em compound.
Acylating agents which may be employed in the preparation of compounds of formula (I) include acid halides, particularly acid chlorides or bromides.
Such acylating agents may be prepared by reacting an acid (III) our a salt thereof with a halogenating agent e.g. phosphorus pentachloride, thionyl chloride or oxalyl chloride.
Acylations employing acid halides may be effected in aqueous and non-aqueous reaction media, conveniently at temperatures of from -50 to +50 C, preferably -20 to +30 C, if desired in the presence of an acid binding agent. Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as dimethylacetamide, nitriles such as acetonitrile, or mixtures of two or more such solvents. Suitable acid binding agents include tertiary amines (e.g. triethylamine or dimethylaniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate), and oxiranes such as lower 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide) which bind hydrogen halide liberated in the acylation reaction.
Acids of formula (III) may themselves be used as acylating agents in the preparation of compounds of formula (I). Acylations employing acids (III) are desirably conducted in the presence of a condensing agent, for example a carbodiimide such as N, N' dicyclohexylcarbodiimide or N - ethyl - N' - e dimethylaminopropylcarbodiimide; a carbonyl compound such as carbonyldiimidazole; or an isoxazolium salt such as N - ethyl - 5 - phenylisoxazolium perchlorate.
Acylation may also be effected with other amideforming derivatives of acids of formula (III) such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride (e.g. formed with pivalic acid or with a haloformate, such as a lower alkylhaloformate). Mixed anhydrides may also be formed with phosphorus acids (for example phosphoric or phosphorous acids), sulphuric acid or aliphatic or aromatic sulphonic acids (for example toluene -p - sulphonic acid). An activated ester may conveniently be formed in situ using, for example, 1-hydroxy-benzotriazole in the presence of a condensing agent as set out above. Alternatively, the activated ester may be preformed.
Acylation reactions involving the free acids or their above-mentioned amide-forming derivatives are desirably effected in an anhydrous reaction medium, e.g. methylene chloride, tetrahydrofuran, dimethylformamide or acetonitrile.
If desired, the above acylation reactions may be carried out in the presence of a catalyst such as 4-di-methylaminopyridine.
The acids of formula (III) and acylating agents corresponding thereto may, if desired, be prepared and employed in the form of their acid addition salts.
Thus, for example, acid chlorides may conveniently be employed as their hydrochloride salts, and acid bromides as their hydrobromide salts.
The amine compound of formula (V) may act as a nucleophileto displace a wide variety of substituents
X from the cephalosporin of formula (IV). To some extent the facility of the displacement is related to the pea of the acid HX from which the substituent is derived. Thus atoms or groups X derived from strong acids tend, in general, to be more easily displaced than atoms or groups derived from weaker acids. The facility of the displacement is also related, to some extent, to the precise identities of the alkyl groups in the compound of formula (V).
The displacement of X by the amine offormula (V) may conveniently be effected by maintaining the reactants in solution or suspension. The reaction is advantageously effected using from 1 to 20, prefer
ably 1 to 4, moles of the amine (V).
Nucleophilic displacement reactions may conveniently be carried out on those compounds of for
mula (IV) wherein the substituent X is a halogen atom or an acyloxy group for example as discussed
below.
Acyloxy groups Convenient starting materials for use in the nuc
leophilic displacement reaction with the amine of formula (V) include compounds of formula (IV) in which X is the residue of a substituted acetic acid
e.g. chloroacetic acid, dichloroacetic acid and trif
luoroacetic acid.
The substituent X may also be derived from formic
acid, a haloformic acid such as chloroformic acid, or
a carbamic acid.
When using a compound of formula (IV) in which
X represents a substituted acetoxy group, it is gen
erally desirabie that the group R7 in formula (IV) should be a hydrogen atom and that B should rep
resent > S. In this case, the reaction is advantage ously effected in an aqueous medium, preferably at a pH of 5 to 8, particularly 5.5 to 7.
The above-described process employing compounds of formula (IV) in which X is the residue of a substituted acetic acid may be carried out as described in British Patent Specification No.
1,241,657.
When using compounds of formula (IV) in which X is an acyloxy group, the reaction is conveniently effected at a temperature of -20" to +80"C, preferably 0 to +50 C.
Halogens
Compounds of formula (IV) in which X is a chlorine, bromine or iodine atom can advantageously be used as starting materials in the nucleophilic displacement reaction with the amine of formula (V). When using compounds of formula (IV) in this class, B may represent 1 S 0 and R7 may represent a carboxyl blocking group. The reaction is conveniently effected in a non-aqueous medium which preferably comprises one or more organic solvents, advantageously ethers, e.g. dioxan or tetrahydrofuran, esters, e.g. ethyl acetate, amides, e.g. formamide and N,N-dimethylformamide, and ketones, e.g. acetone. Other suitable organic solvents are described in more detail in British Patent
Specification No. 1,326,531. The reaction medium should be neither extremely acidic nor extremely basic. In the case of reactions carried out on compounds of formula (IV) in which R7 and R7" are carboxyl blocking groups the 3-trialkylammoniomethyl product will be formed as the corresponding halide salt which may, if desired, be subjected to one or more ion exchange reactions to obtain a salt having the desired anion.
When using compounds of formula (IV) in which X is a halogen atom as described above, the reaction is conveniently effected at a temperature of -10 to +50 C, preferably +10 to +30"C.
In process (C) above, the 3-di-C1~4 alkylaminomethyl compound of formula (VI) is advantageously reacted with a C1-4 alkylating agent of the formula R3Y wherein R3 is as defined above and Y is a leaving group such as a halogen atom (e.g. iodine, chlorine or bromine) or a hydrocarbylsulphonate (e.g. mesylate or tosylate) group, or R3Y represents dimethyl sulphate. The alkylation reaction is preferably carried out at a temperature in the range of 0 to 60"C, advantageously 20 to 30"C. The reaction may be conveniently effected in an inert solvent such as an ether e.g. tetrahydrofuran, an amide, e.g. dimethylformamide, or a halogenated hydrocarbon, e.g. dichloromethane. Alternatively, where the alkylating agent is liquid underthe reaction conditions, this agent can itself serve as a solvent.
The compound of formula (VI) used as starting material in process (C) may be prepared for example
by reaction of a compound of formula (IV) (as defined above) with a secondary amine of formula
(wherein R' and R2 are as defined above) in an analogous manner to the nucleophilicdisplacement reaction described with respect to process (B). This reaction is preferably carried out in the presence of an acid scavenging agent. The amine itself may act as an acid scavenging agent.
The reaction product may be separated from the reaction mixture, which may contain, for example, unchanged cephalosporin starting material and other substances, by a variety of processes including recrystallisation, ionophoresis, column chromatography and use of ion-exchangers (for example by chromatography on ion-exchange resins) or mac roreticular resins.
A2-Cephalosporin ester derivatives obtained in accordance with the process of the invention may be converted into the corresponding A3-derivative by, for example, treatment of the A2-ester with a base such as pyridine ortriethylamine.
A ceph-2-em reaction product may also be oxidised to yield the corresponding ceph-3-em 1-oxide, for example by reaction with a peracid, e.g. peracetic orm-chloroperbenzoic acid; the resulting sulphoxide may, if desired, subsequently be reduced as described hereinafter to yield the corresponding ceph-3-em sulphide.
Where a compound is obtained in which B is > S 0 this may be converted to the corresponding sulphide by, for example, reduction of the corresponding acyloxysulphonium or alkoxysulphonium salt prepared in situ by reaction with e.g. acetyl chloride in the case of an acetoxysulphonium salt, reduction being effected by, for example, sodium dithionite or by iodide ion as in a solution of potassium iodide in a water-miscible solvent e.g. acetic acid, acetone, tetrahydrofuran, dioxan, dimethylformamide or dimethylacetamide. The reaction may be effected at a temperature of from -20" to +500C.
Metabolically labile ester derivatives of the compounds of formula (I) may be prepared by reacting a compound of formula (I) or a salt or protected derivative thereof with an appropriate esterifying agent such as an acyloxyalkyl halide (e.g. iodide) conveniently in an inert organic solvent such as dimethylformamide or acetone, followed, where necessary, by removal of any protecting groups.
Base salts of the compounds of formula (I) may be formed by reacting an acid of formula (I) with the appropriate base. Thus, for example, sodium or potassium salts may be prepared using the respective 2-ethyl-hexanoate or hydrogen carbonate salt.
Acid addition salts may be prepared by reacting a compound of formula (I) or a metabolically labile ester derivative thereof with the appropriate acid.
Where a compound of formula (I) is obtained as a mixture of isomers, the syn isomer may be obtained by, for example, conventio preferably used.
Acids of formula (III) (provided that Ra and Rb together with the carbon atom to which they are attached do not form a cyclopropylidene group) may be prepared by etherification of a compound of formula
(wherein Re is as herein before defined and R8 represents a carboxyl blocking group), by reaction with a compound of general formula
(wherein Ra, Rb and R5 are as hereinbefore defined and T is halogen such as chloro, bromo or iodo; sulphate; or suiphonate such as tosylate), followed by removal of the carboxyl blocking group R8. Separation of isomers may be effected either before or after such etherification. The etherification reaction is generally carried out in the presence of a base, e.g. potassium carbonate or sodium hydride, and is preferably conducted in an organic solvent, for example dimethylsulphoxide, a cyclic ether such as tetrahydrofuran or dioxan, or an N,N-disubstituted amide such as dimethylformamide. Under these conditions the configuration of the oxyimino group is substantially unchanged by the etherification reaction. The
reaction should be effected in the presence of a base
if an acid addition salt of a compound of formula (VIII) is used. The base should be used in sufficient
quantity to neutralise rapidly the acid in question.
Acids of general formula (III) may also be prepared by reaction of a compound of formula
(wherein R6 and R8 are as hereinbefore defined) with a compound of formula
(wherein Ra, Rb and RS are as defined above), fol
lowed by removal of the carboxyl blocking group Ra, and where necessary by the separation ofsyn and
anti isomers.
The last-mentioned reaction is particularly applic
able to the preparation of acids of formula (Ill) wherein Ra and Rb together with the carbon atom to
which they are attached form a cyclopropylidene
group. In this case, the relevant compounds of for
mula (Xl) may be prepared in conventional manner,
e.g. by means of the cynthesis described in Belgian
Patent Specification No. 866,422 for the preparation of t-butyl 1 -amino-oxycycloprnpan carboxylate.
The acids of formula (III) may be converted to the corresponding acid halides and anhydrides and acid addition salts by conventional methods, for example as described hereinabove.
Where X is a halogen (i.e. chlorine, bromine or iodine) atom in formula (IV), ceph-3-em starting compounds may be prepared in conventional manner, e.g. by halogenation of a 7,3-protected amino - 3 - methylceph - 3 - em - 4 - carboxylic acid ester 1,3 - oxide, removal ofthe7,3-protecting group, acylation of the resulting 7,3amino compound to form the desired 7ss-acylamido group, e.g. in an analogous manner to process (A) above, followed by reduction of the 1oxide group later in the sequence. This is described in British Patent No. 1,326,531. The corresponding ceph-2-em compounds may be prepared by the method of Dutch published Patent Application No.6,902,013 by reaction of a 3-methylceph-2-em compound with N-bromosuccinimide to yield the corresponding 3-bromomethylceph-2-em compound.
Where X in formula (IV) is an acetoxy group, such starting materials may be prepared for example by acylation of 7-aminocephalosporanic acid, e.g. in an analogous manner to process (A) above. Compounds of formula (IV) in which X represents other acyloxy groups can be prepared by acylation of the corresponding 3-hydroxymethyl compounds which may be prepared for example by hydrolysis of the appropriate 3-acetoxymethyl compounds, e.g. as described in British Patent Specifications Nos.
1,474,519 and 1,531,212.
The starting materials of formula (II) are new compounds. These compounds may be prepared in conventional manner, for example, by deprotecting a corresponding protected 7,3amino compound in conventional manner e.g. using PCC.
It should be appreciated that in some of the above transformations it may be necessary' to protect any sensitive groups in the molecule of the compound in question to avoid undesirable side reactions. For example, during any of the reaction sequences referred to above it may be necessary to protect the NH2 group of the aminothiazolyl moiety, for example by tritylation, acylation (e.g. chloroacetylation), protonation or other conventional method. The protecting group may thereafter be removed in any convenient way which does not cause breakdown of the desired compound, e.g. in the case of a trityl group by using an optionally halogenated carboxylic acid, e.g. acetic acid, formic acid, chloroacetic acid ortrifluoroacetic acid or using a mineral acid, e.g. hydrochloric acid or mixtures of such acids, preferably in the presence of a protic solvent such as water or, in the case of a chloroacetyl group, by treatment with thiourea.
Carboxyl blocking groups used in the preparation of compounds of formula (I) or in the preparation of necessary starting materials are desirably groups which may readily be split off at a suitable stage in the reaction sequence, conveniently at the last stage.
It may, however, be convenient in some instances to employ non-toxic metabolically labile carboxyl blocking groups such as acyloxy-methyl or-ethyl groups (e.g. acetoxy-methyl or ethyl or pivaloyloxymethyl) and retain these in the final product to give an appropriate ester derivative of a compound of formula (I).
Suitable carboxyl blocking groups are well known in the art, a list of representative blocked carboxyl groups being included in British Patent No.
1,399,086. Preferred blocked carboxyl groups include aryl lower alkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups such as t-butoxycarbonyl; and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. Carboxyl blocking group(s) may subsequently be removed by any of the appropriate methods disclosed in the literature; thus, for example, acid or base catalysed hydrolysis is applicable in many cases, as are enzymically-catalysed hydrolyses.
The following Examples illustrate the invention.
All temperatures are in 'Petrol' means petroleum ether (b.p.40-60 ).
Preparation 1
Ethyl (Z)-2 - (2 - aminothiazol - 4 - yl)-2- (hydrox- yimino) acetate
To a stirred and ice-cooled solution of ethyl acetoacetate (292 g) in glacial acetic acid (296 ml) was added a solution of sodium nitrite (180 g) in water (400 ml) at such a rate that the reaction temperature was maintained below 1000. Stirring and cooling were continued for about 30 min., when a solution of potassium chloride (160 g) in water (800 ml) was added. The resulting mixture was stirred for one hour. The lower oily phase was separated and the aqueous phase was extracted with diethyl ether.
The extract was combined with the oil, washed successively with water and saturated brine, dried, and evaporated. The residual oil, which solidified on standing, was washed with petrol and dried in vacuo over potassium hydroxide, giving ethyl (Z) 2 (hydroxyimino) - 3 - oxobutyrate (309 g).
A stirred and ice-cooled solution of ethyl (Z) - 2 (hydroxyimino) - 3 - oxobutyrate (150 g) in dichloromethane (400 ml) was treated dropwise with sulphuryl chloride (140 g). The resulting solution was kept at room temperature for 3 days, then evaporated. The residue was dissolved in diethyl ether, washed with water until the washings were almost neutral, dried, and evaporated. The residual oil (177 g) was dissolved in ethanol (500 ml) and dimethylaniline (77 ml) and thiourea (42 g) was added with stirring. After two hours, the mixture was filtered and the residue washed with ethanol and dried to give the title compound (73 g); m.p. 188" (decomp.).
Preparation 2
Ethyl (Z) - 2 - hydroxyimino - 2 - (2 - tritylaminothiazol - 4- yl) - acetate, hydrochloride
Trityl chloride (16.75 g) was added portionwise over 2 hours to a stirred and cooled (-30 ) solution of the product of Preparation 1 (12.91 g) and triethylamine (8.4 ml) in dimethylformamide (28 ml).
The mixture was allowed to warm to 150 over one hour, stirred for a further 2 hours and then partitioned between water (500 ml) and ethyl acetate (500 ml). The organic phase was separated, washed with water (2 x 500 ml) and then shaken with 1N HCI (500 ml). The precipitate was collected, washed successively with water (100 ml), ethyl acetate (200 ml) and ether (200 ml) and dried in vacuo to provide the title compound as a white solid (16.4 g); m.p. 184 to 186 (decomp.).
Preparation 3
Ethyl (Z)-2- (2- t-butoxycarbonylprop - 2 - oxyimino) -2- (2- tritylaminothiazol - 4 - yl) acetate
Potassium carbonate (34.6 g) and t-butyl
2-bromo-2-methylpropionate (24.5 g) were added to
a stirred solution under nitrogen of the product of
Preparation 2 (49.4 g) in dimethylsulphoxide (200 ml)
and the mixture was stirred at room temperature for
6 hours. The mixture was poured into water (2 1), stirred for 10 mins., and filtered. The solid was
washed with water and dissolved in ethyl acetate
(600 ml). The solution was washed successively with
water, 2N hydrochloric acid, water, and saturated
brine, dried, and evaporated. The residue was
recrystallised from petrol to give the title compound (34g),m.p. 123.5 to 1250.
Preparation 4 rZ) - 2 - (2-t-Butoxycarbonylprop -2 - oxyimino)-2- (2- trityl - aminothiazol - 4 - yl) acetic acid
The product of Preparation 3 (2 g) was dissolved in methanol (20 ml) and 2N sodium hydroxide (3.3 ml) was added. The mixture was refluxed for 1.5 hours and then concentrated. The residue was taken up in
a mixture of water (50 ml), 2N hydrochloric acid (7
ml), and ethyl acetate (50 ml). The organic phase was
separated, and the aqueous phase extracted with
ethyl acetate. The organic solutions were combined,
washed successively with water and saturated brine,
dried and evaporated. The residue was recrystallised
from a mixture of carbon tetrachloride and petrol to
give the title compound (1 g), m.p. 152 to 156 (decomp.).
Preparation 5
Ethyl (Z)-2- (2 - tritylaminothiazol - 4 - yl)-2- (1 - butoxy - carbonylcyclobut - 1- oxyimino) acetate The product of Preparation 2 (55.8 g) was stirred
under nitrogen in dimethylsulphoxide (400 ml) with
potassium carbonate (finely ground, 31.2 g) at room temperature. After 30 minutes,t-butyl 1-bromocyclobutanecarboxylate (29.2 g) was added.
After 8 hours further potassium carbonate (31.2 g) was added. More potassium carbonate (6 x 16 g portions) was added during the next three days and furthert-butyl 1-bromocyclobutanecarboxylate (3.45
g) was added after 3 days. After4 days in all, the
mixture was poured into ice-water (ca. 3 litres) and the solid was collected by filtration and washed well
with water and petrol. The solid was dissolved in
ethyl acetate and the solution washed with brine
(twice), dried with magnesium sulphate and evapo
rated to a foam. This foam was dissolved in ethyl
acetate-petrol (1 :2) and filtered through silica gel
(500 g). Evaporation gave the title compound (60 g)
as a yellow foam, vmax (CHBr3) 3400 (NH) and 1730 cm-1 (ester).
Preparation 6 (Z) - 2 - (1- t - Butoxycarbonylcyclobut - 1- oxyimino) - 2 (2- trityl - aminothiazol - 4 - yl) acetic acid
A mixture of the product of Preparation 5 (3.2 g) and potassium carbonate (1.65 g) was refluxed in methanol (180 ml) and water (20 ml) for 9 hours and the mixture was cooled to room temperature. The mixture was concentrated and the residue partitioned between ethyl acetate and water, to which was added 2N HCI (12.2 ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried and evaporated to give the title compound (2.3 g); Amax (ethanol) 265 nm (E1cm1%243).
Example I a) Diphenylmethyl (1S, 6R, 7R) - 3 - Bromomethyl -7 [(Z) - 2 - (2 - t - butoxycarbonylprop - 2 - oxyimino) - 2 - (2 - tritylaminothiazol - 4 - yl) acetamido] ceph - 3 em -4 - carboxylate, I-Oxide
A solution of the product of Preparation 4 (0.526 g) in dry tetrahydrofuran (6 ml) was treated successively with 1-hydroxybenztriazole monohydrate (0.141 g) and N,N' - dicyclohexylcarbodiimide (0.198 g) in tetrahydrofuran (4 ml). The developing suspension was stirred for 30 minutes at 23 and then filtered. A solution of diphenyl - methyl (IS, 6R, 7R) - 7 - amino - 3 - bromomethylceph - 3 - em - 4 - carboxy late, 1-oxide (0.427 g) in dichloromethane (260 ml) was treated at 23 with the above filtrate. The solution was stirred for 18 hours at 20 to 25 , evaporated to dryness, then the residue was dissolved in dich
loromethane and washed successively with satu
rated aqueous sodium bicarbonate, water and brine, then dried and evaporated in vacuo to a foam (1.01 9).
This foam was purified by chromatography on
preparative silica plates using toluene: ethyl acetate: acetic acid = 190:50:2.5 as eluant. The purified product was isolated as a foam which was dissolved in ethyl acetate (5 ml) and precipitated from petrol (200 ml) to give the title compound (0.69 g) as a colourless powder; Amax (EtOH) 268 nm (E1cm1% 182) with an inflection at 242 nm
E1cm1%230), vmax (Nujol) 3375 (NH), 1805 ( -lactam),
1730 (CO2R) and 1688 and 1515 cm' (CONH).
b) Diphenylmethyl (1S, 6R, 7R)- 7-[(z) -2- (2 - butoxycarbonyl - prop - 2 - oxyimino) - 2 - (2 tritylaminothiazol - 4 - yl) - acetamido] - 3 trimethylammoniomethylceph -3- em -4- carboxy- late, I-Oxide, Bromide Salt
The product of stage a) (0.154 g), alumina-dried
tetrahydrofuran (0.3 ml) and anhydrous
trimethylamine in drytetrahydrofuran (0.155 g of
trimethylamine in 1 ml of solution) (0.065 ml) were
stirred at 24 for 1 hour. The reaction mixture was
added dropwise to well-stirred ether (220 ml) and the
resulting suspension was stirred vigorously for 10
minutes. The solid was filtered off, washed with ether and dried in vacuo to give the title compound (0.131 g) m.p. 158 to 178 (decomp.); [α]D21 + 11 (c 0.53, CHCl3). c) Diphenylmethyl 66R, 7R) - 7 - [(Z) - 2 - (2 - t t-Butox- ycarbonyl-prop -2-oxyimino)-2- (2- tritylaminothiazol - 4 - yl) acetamido] - 3 trimethylammoniomethylceph - 3 - em - 4 - carboxy- late, lodide Salt
The product of stage b) (1.87 g) and acetone (4.7 ml) were stirred at-10 as a solution. Dry, powdered potassium iodide (1.14 g) was added and the mixture was stirred at-10 for 2 minutes. Dry, powdered potassium iodide (1.14 g) followed by acetyl chloride (0.25 ml) were added and the vigorously stirred mixture was allowed to warm to 0 over 20 minutes. The mixture was stirred at 0 to +2 for 1 hour. The mixture was added dropwise to a stirred solution of sodium metabisulphite (0.850 g) in water (47 ml).
The resulting solid was filtered off, washed with water and dried in vacuo over phosphorus pentoxide to give a solid (1.939 g). The above procedure was repeated using the solid (1.87 g), acetone (4.7 ml), dry powdered potassium iodide (1.14 g), acetyl chloride (0.25 ml) and a reaction time at 0 to +2 of 25 minutes. This gave the title compound (1.951 g) as a solid, m.p. 142 to 1760; [a]2J-160 (c 0.38, CHCI3). d)Diphenylmethyl(SR, 7R)- 7-[(Z)-2. (2-t- Butoxycarbonyl - prop - 2- oxyimino) -2- (2 - tritylaminothiazol - 4- yl) - acetamido] -3- trimethylammoniomethylceph - 3- em -4- carhoxy- late, Trifluoroacetate Salt
The product of stage c) (1.826 g) was dissolved in acetone : ethanol = 9:1 and chromaiographed on "Deacidite" FF SRA 62 ion exchange resin (strong anion exchange resin) trifluornacetate form. The column was eluted with the above solvent mixture.
A forerun of 20 mi was discarded and the next 250 ml were evaporated in vacuo immediately to give the title compound (1.595 g) as a red-brown foam. e) (6R, 7R) - 7 - [(Z) - 2 - (2 - Aminothiazol - 4 - yl) - 2 (2 - carboxy - prop - 2 - oxyimino)acetamido] - 3 trimethylammoniomethylceph - 3 - em - 4 - carboxylate
The product of stage d) (1.37 g), anisole (1.37 ml) and trifiuoroacetic acid (5.5 ml) were swirled together at 250 for 1 minutes, when a solution was formed, and then for a further 1 minute. The volatile material was evaporated off and the residue was - azeotroped with toluene (twice). The gum was dissolved in acetone (10 ml) and precipitated into petrol
(500 ml). The brown solid was filtered off, washed with petroleum ether and dissolved in acetone. The solution was evaporated to a foam (1.117 g).
The foam (1.117 g), anisole (0.25 ml) and trif
luoroacetic acid (5 ml) were swirled together at 28 for 5 minutes. The volatile material was removed
and the residue was azeotroped with toluene (twice).
The resulting brown oil was precipitated with acetone (10 ml) and 40 to 60 petroleum ether (500 ml) to give a solid (1.066 g).
The solid (0.2 g) was dissolved in trifluoroacetic acid : water = 1:1(2 ml) and the solution was stirred at 28 for 30 minutes. The mixture was evaporated to dryness and the resulting gum was dissolved in water (10 ml). The cloudy solution was filtered, the residue was washed with water (10 ml, 5 ml) and the filtrate was freeze-dried to give a foam, (0.17 g). The foam was triturated with ether, the solid obtained was filtered rapidly and dried in vacuo to give the title compound (0.1489) as a solid associated with 1.8 moles of trifluoroacetic acid; [α]D22 + 120 (c 0.3; EtOH : H2O = 1:1); Ainf(pH6 buffer) 230 nm (E 17,000), A inf 260 nm (E 10,200).
Example 2 a) Diphenylmethyl (15, 6R, 7R) - 3 - Bromomethyl -7 [(Z) - 2 - (1 - t - butoxycarbonylcyclobut - 1 oxyimino) - 2- (2- tritylamino - thiazol -4 - yl) acetamido] - ceph -3- em - 4 - carboxylate, 1 Oxide
A stirred solution of the product of Preparation 6 (1.167 g) in tetrahydrofuran (15 ml) was treated successively with 1-hydroxybenztriazole hydrate (0.337 g) and N,N'-dicyclohexylcarbodiimide (0.495 g) for 30 minutes at 22 .
Filtration afforded a solution of the activated ester which was added to a solution of diphenylmethyl (15, 6R, 7R) - 7 - amino - 3 - bromomethylceph - 3 - em - 4 - carboxylate 1-oxide (0.95 g) in dichloromethane (550 ml). The solution was stirred for 16 hours then evaporated to dryness. A solution of the residue in dichloromethane was washed successively with aqueous sodium bicarbonate, and brine, and then dried and evaporated to a foam (2.2 g) which was purified by preparative thin-layer chromatography (using toluene : ethyl acetate: acetic acid = 40:10:1 for development) to give the title compound (1.4 g) with Amax (EtOH) 266 nm (E1cm1% 192) and an inflection at 242.5 nm (E1cm1%224), #max (Nujol) 3360 (NH), 1805 ( -lactam), 1730 (CO3R) and 1689 and 1520 cm-' (CONH). b) Diphenylmethyl (1S, 6R, 7R) - 7 - [(Z) - 2 - (1
Butoxycarbonyl - cyclobut - 1- oxyimino) - 2- (2- tritylaminothiazol - 4 - yl) - acetamido] - 3 trimethylammoniomethylceph -3- em -4- carboxy- late, 1-Oxide, Bromide Salt
The product of stage a) (1.2 g), alumina-dried tetrahydrofuran (2.5 ml) and anhydrous trimethylamine in dry tetrahydrofuran [0.49 ml of a solution of trimethylamine (0.155 g) in tetrahydrofuran (1 ml)] were stirred at 24 for 30 minutes. The reaction mixture was added dropwise to stirred ether (900 ml) and the resulting suspension was stirred vigorously for 10 minutes. The solid was filtered off, washed with ether and dried in vacuo to give the title compound (1.16 g), m.p. 156 to 1700 (decomp); [a]22 + 6 (c 0.48, CHC13). c) Diphenylmethyl (6R, 7R) - 7 - [(Z) - 2 - (1 - t - Butoxycarbonyl - cyclobut - 1 - oxyimino) - 2 - (2- tritylaminothiazol - 4- yl) - acetamido] -3- trimethylammoniomethylceph -3- em -4- carboxy- late, lodide Salt
The product of stage b) (1.05 g) and acetone (2.6 ml) were stirred as a solution at-10 . Dry, powdered potassium iodide (0.625 g) was added and the mixture was stirred at -10 for 2 minutes. Further dry, powdered potassium iodide (0.625 g) was added followed by acetyl chloride (0.14 ml). The stirred mixture was allowed to warm to 0 and it was stirred at 0 to +20 for a hour. The mixture was added dropwise to a stirred solution of sodium metabisulphite (0.465 g) in water (26 ml). The resulting solid was filtered off, washed with water and dried in vacuo over phosphorus pentoxideto give a solid (1.072 g). The above procedure was repeated using the solid (1.072 g), acetone (2.6 ml), dry, powdered potassium iodide (0.625 g), and acetyl chloride (0.14 ml) to give the title compound (1.131 g) as a solid, m.p. 133 to 1700 (decomp) [a]D-33 (c 0.6, CHCI3). d) (6R, 7R) - 7 - [(Z) - 2 - (2 - Aminothiazol - 4 - yl) - 2 (1 - carboxy - cyclobut - 1 - oxyimino)acetamido] - 3 trimethylammoniomethyl - ceph - 3 - em - 4 - carboxylate
The product of stage c) (0.2 g) was wetted with anisole (0.2 ml) and trifluoroacetic acid (0.8 ml) was added. An immediate precipitate was formed and the suspension was swirled for 2 minutes atca 23 when the precipitate became gummy. The mixture was evaporated to dryness and the residue was triturated with ether to give a solid which was wetted with anisole (0.035 ml) and trifluoroacetic acid (4 ml) was added. A very fine precipitate formed and the suspension was swirled at 23 for 15 minutes. The mixture was evaporated to a gum which was triturated with ether to give the title compound (0.091 g) as a solid, associated with 1 mole of trifluoroacetic acid and 0.4 mole of hydrogen iodide, [α]D22 + 45 (c 0.22, ethanol:water=1:1), # inf (pH 6 buffer) 257.5 nm (E1 c/rn 240), A inf 296 nm (E1cm1% 115).
Example 3 a) Diphenylmethyl (15, 6R, 7R)- 7- [(z)-2- (1 - Butoxycarbonyl - cyclobut - 1- oxyimino) - 2 - (2- tritylaminothiazol - 4 - yl) - acetamido] - 3 dimethylaminomethylceph - 3 - em - 4 - carboxylate, 1-Oxide
The product of Example 2(a) (0.52 g) in dry tetrahydrofuran (2 ml) was treated with a solution of dimethylamine in ethanol (33% w/w; 0.20 ml). After
15 minutes at 219 the mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was extracted with more ethyl acetate (25 ml) and the total organic solution was washed
with water (2 x 50 ml) and dried (Na2SO4) and evapo
rated to a foam (0.498 g). The crude product was
purified by preparative thin-layer chromatography
on silica-gel plates (2mm thick) eluted with ethyl ace
tate. The main band, Rf 0.4 yielded a foam (0.331 g)
which was dissolved in ethyl acetate (2 ml) and
added slowly to stirred petrol (50 ml). The precipitate
was filtered off and washed with petrol and dried in
vacuo to give the title compound (0.224 g) as a solid, [α]D-21 (c 0.87%, CHC13), Ajnf(EtOH) 245 nm (E1 cm1% 225), 260 (E1 cm1% 305 nm (E1 cm1%57). b)D/phenylmethyl(1S, 6R, 7R)- 7- [(z)-2- (1 - Butoxycarbonyl - cyclobut - 1 - oxyimino) - 2 - (2 tritylaminothiazol -4- yl) - acetamido] -3- trimethylammoniomethylceph -3- em -4- carboxy- late, oxide, lodide Salt
The product from stage (a) (0.201 g) was dissolved
in iodomethane (1 ml) and the solution was left to stand at 21 for 1 hours. Diethyl ether (20 ml) was added, and the precipitate was triturated and then filtered off and washed with ether and dried in vacuo to give the title compound (0.199 g) as a solid,[a]D + lox (c 0.87%, CHCI3), Ajnf(EtOH) 260 nm
(E1 cm1% 160), 265 nm (E1 cm1% 154) and 305 nm (E1 cm1%64)
with a Amax at 394 nm (E1cm1%43).
Example 4
a) Diphenylmethyl (1S, 6R, 7R) - 7 - Formamido - 3 - trimethylammoniomethylceph -3- em -4- carboxy- late, 1-oxide, Bromide Salt
A solution of diphenylmethyl (1S, 6R, 7R) - 3
bromomethyl - 7 - formamidoceph - 3 - em - 4 - car boxylate, 1-oxide (1.01 g) in dry N,N
dimethylformamide (3 ml) was treated with a solu
tion (0.8 ml) of anhydrous trimethylamine in tet
rahydrofuran (0.155 g of trimethylamine per ml of
solution) and the solution was stirred at 21 for 15
minutes. Ether (10 ml) was added and the supernat
ant solution was discarded. Trituration of the oily
residue with ether (ca. 15 ml) gave a precipitate
which was filtered off, washed with ether and dried rapidly vacuo to give the title compound (1.002 g)
as a solid m.p. 1400 to 1500 (with decomp), #max(Nujol) ca. 3400 (NH), 1798 ( -lactam), 1680 (C=0
of HCONH), 1732 (CO2R), and 1035cm-1 (sulphox
ide).
b) Diphenylmethyl) (1S, 6R, 7T) - 7 - Amino - 3 trimethylammoniomethylceph -3- em -4- carboxy- late, 1-Oxide, Hydrochloride and Bromide Salts
A mixture of the product of stage (a) (0.562 g) in
methanol (5 ml) was stirred at 0 and treated, drop
wise, with phosphoryl chloride (0.28 ml) over 10
minutes. The mixture was stirred at 0 for 2 hours to
precipitate a buff solid. Ether (15 ml) was added to
the stirred mixture then the precipitate was filtered
off and washed successively with either and ethyl
acetate and dried in vacuo to give the title compound
(0.479 g) as a solid, #max(EtOH) 280 nm
(E1 cm% 11 cal carriers or excipients.
The antibiotic compounds according to the invention may be formulated for injection and may be presented in unit dose form in ampoules, or in multi-dose containers, if necessary with an added preservative. The compositions may also take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
If desired, such powder formulations may contain an appropriate non-toxic base in order to improve the water-solubility of the active ingredient and/or to ensure that when the powder is reconstituted with water, the pH of the resulting aqueous formulation is physiologically acceptable. Alternatively, the base may be present in the water with which the powder is reconstituted. The base may be, for example, an inorganic base such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base such as lysine or lysine acetate.
The antibiotic compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
For medication of the eyes or ears, the preparations may be formulated as individual capsules, in liquid or semi-solid form, or may be used as drops.
Compositions for veterinary medicine may, for example, be formulated as intramammary preparations in either long acting or quick-release bases.
The compositions may containing from 0.1% upwards, e.g. 0.1-99%, of the active material, depending on the method of administration. When the compositions comprise dosage units, each unit should preferably contain 50-1500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 500 to 6000 mg per day, depending on the route and frequency of administration. For example, in adult human treatment 1000 to 3000 mg per day administered intravenously or intrumuscularly should normally suffice. In treating Pseudomonas infections higher daily doses may be required.
The antibiotic compounds according to the invention may be administered in combination with other therapeutic agents such as antibiotics, for example penicillins or other cephalosporins.
The following formulation illustrates how a compound according to the invention may be made up into a pharmaceutical composition.
Formulation -- For Injection
Formula Per Vial (6R, 7R)-7-[(2)-2-(2- (2-Aminothiazol-4-yl)-2-(1 carboxycyclo - but - 1 - oxyimino) - acetamido] - 3 trimethylammoniomethyl - ceph - 3 - em - 4 - carboxylate 500 mg
Sodium Carbonate, anhydrous 49 mg
Method
Blend the sterile cephalosporin antibiotic with sterile sodium carbonate under aseptic conditions.
Fill aseptically into glass vials under a blanket of sterile nitrogen. Close the vials using rubber discs, or plugs, held in position by aluminium overseals, thereby preventing gaseous exchange or ingress of microorganisms. Reconstitute the product by dissolving in Water for Injections or other suitable sterile vehicle shortly before administration.
CLAIMS
1. Cephalosporin antibiotics of general formula
(wherein Ra and Rb, which may be the same or different, each represent a C14 alkyl group or Ra and Rb together with the carbon atom to which they are attached form a C3~, cycloalkylidene group; and R',
R2 and R3, which may be the same or different, each represents a C,-4 alkyl group) and non-toxic salts and non-toxic metabolically labile esters thereof.
Claims (1)
- 2. Compounds as claimed in claim 1 wherein at least one of Ra and Rb represents a methyl or ethyl group.3. Compounds as claimed in claim 1 wherein Ra and Rb together with the carbon atom to which they are attached form a C- cycloalkylidene group.4. Compounds as claimed in any of the preceding claims wherein R1, R2 and R3 all represent methyl groups.5. (6R, 7R) - 7 -[(z) - 2 - (2 - Aminothiazol - 4 - yl) 2- (2- carboxyprop -2 - oxyimino) - acetamido] - 3 trimethylammonia - methyl - ceph - 3 - em - 4 - carboxylate.6. The non-toxic salts of the compound of claim 5.7. (6R, 7R) - 7 - [(z) - 2 - (2 - Aminothiazol - 4 - yl) 2 - (1 - carboxycyclobut- 1 - oxyimino) - acetamido] 3 - trimethylammonio - methyl - ceph - 3 - em - 4 carboxylate.8. The non-toxic salts of the compound of claim 7.9. A process for the preparation of an antibiotic compound of general formula (I) as defined in claim 1 or a non-toxic salt or non-toxic metabolically labile ester thereof which comprises (A) acylating a compound of formula(wherein R', R2 and R3 are as defined in claim 1; B is > S or > S o0 and the dotted line bridging the 2-3- and 4-positions indicates that the compound is a ceph-2-em or ceph-3-em compound), or a salt or N-silyl derivative thereof or a corresponding compound having a group of formula -COOR4 at the 4-position (where R4 is a hydrogen atom or a carboxyl blocking group) and having an associated anion AO with an acid of formula(wherein Ra and Rb are as defined in claim 1; R5 represents a carboxyl blocking group; and Re is an amino or protected amino group) or with an acylating agent corresponding thereto; (B) reacting a compound of formula(wherein Ra, Rb, Re, B and the dotted line are as hereinbefore defined; R7 and R7a may independently represent hydrogen or a carboxyl blocking group; and X is a replaceable residue of a nucleophile) or a salt thereof with a tertiary amine of the formula(wherein R', R2 and R3 are as defined above); or (C) alkylating a compound of formula(wherein Ra, Rb, R1, R2, Re, B and the dotted lines are as hereinbefore defined; and R7 and R7" both represent carboxyl blocking groups with an alkylating agent serving to form a group of formula(wherein R', R2 and R3 are as defined above) at the 3-position; whereafter if necessary and/or desired in each instance, any of the following reactions, in any appropriate sequence, are carried out: i) conversion of a A2-isomer into the desired A3 isomer, ii) reduction of a compound wherein B is > S ~0 to form a compound wherein B is > S, iii) conversion of a carboxyl group into a non-toxic salt or non-toxic metabolically labile ester function, and iv) removal of any carboxyl blocking and/or N-protecting groups.10. A pharmaceutical composition for use in human or veterinary medicine comprising an antibiotic compound as claimed in any of claims 1 to 8 in association with a pharmaceutical carrier or excipient.
Applications Claiming Priority (2)
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GB7842163 | 1978-10-27 |
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Cited By (1)
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GB2117770A (en) * | 1982-03-29 | 1983-10-19 | Bristol Myers Co | Cephalosporin derivatives |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GR78245B (en) * | 1980-09-12 | 1984-09-26 | Ciba Geigy Ag | |
CA1213882A (en) * | 1982-03-04 | 1986-11-12 | Jun Okumura | Cephalosporins |
US4486586A (en) * | 1983-02-10 | 1984-12-04 | Bristol-Myers Company | Cephalosporin derivatives |
DE3409431A1 (en) * | 1983-10-08 | 1985-04-18 | Hoechst Ag, 6230 Frankfurt | CEPHALOSPORINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
DE3404906A1 (en) * | 1984-02-11 | 1985-08-14 | Bayer Ag, 5090 Leverkusen | 1-OXADETHIACEPHALOSPORINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
-
1979
- 1979-10-26 NL NL7907881A patent/NL7907881A/en not_active Application Discontinuation
- 1979-10-26 ES ES485435A patent/ES485435A1/en not_active Expired
- 1979-10-26 ES ES485434A patent/ES485434A1/en not_active Expired
- 1979-10-26 ES ES485433A patent/ES485433A1/en not_active Expired
- 1979-10-26 SE SE7908895A patent/SE7908895L/en not_active Application Discontinuation
- 1979-10-26 IT IT50681/79A patent/IT1164746B/en active
- 1979-10-26 CA CA338,568A patent/CA1131618A/en not_active Expired
- 1979-10-26 NZ NZ191936A patent/NZ191936A/en unknown
- 1979-10-26 IE IE2069/79A patent/IE49099B1/en unknown
- 1979-10-26 DK DK452579A patent/DK452579A/en not_active Application Discontinuation
- 1979-10-26 GB GB7937306A patent/GB2040921B/en not_active Expired
- 1979-10-26 DE DE19792943437 patent/DE2943437A1/en not_active Withdrawn
- 1979-10-26 CH CH964479A patent/CH644867A5/en not_active IP Right Cessation
- 1979-10-26 FR FR7926640A patent/FR2439787A1/en active Granted
- 1979-10-29 AT AT0698179A patent/AT367765B/en not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2117770A (en) * | 1982-03-29 | 1983-10-19 | Bristol Myers Co | Cephalosporin derivatives |
US4457929A (en) * | 1982-03-29 | 1984-07-03 | Bristol-Myers Company | 3-Quaternary ammonium methyl)-substituted cephalosporin derivatives |
Also Published As
Publication number | Publication date |
---|---|
GB2040921B (en) | 1982-12-22 |
IE49099B1 (en) | 1985-07-24 |
ES485433A1 (en) | 1980-07-01 |
CH644867A5 (en) | 1984-08-31 |
FR2439787A1 (en) | 1980-05-23 |
AT367765B (en) | 1982-07-26 |
DE2943437A1 (en) | 1980-05-08 |
NL7907881A (en) | 1980-04-29 |
ATA698179A (en) | 1981-12-15 |
FR2439787B1 (en) | 1983-04-29 |
DK452579A (en) | 1980-04-28 |
ES485435A1 (en) | 1980-07-01 |
IT1164746B (en) | 1987-04-15 |
SE7908895L (en) | 1980-04-28 |
CA1131618A (en) | 1982-09-14 |
ES485434A1 (en) | 1980-07-01 |
IT7950681A0 (en) | 1979-10-26 |
NZ191936A (en) | 1982-09-07 |
IE792069L (en) | 1980-04-27 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |