IE46100B1 - Clavulanic acid ethers - Google Patents
Clavulanic acid ethersInfo
- Publication number
- IE46100B1 IE46100B1 IE2448/77A IE244877A IE46100B1 IE 46100 B1 IE46100 B1 IE 46100B1 IE 2448/77 A IE2448/77 A IE 2448/77A IE 244877 A IE244877 A IE 244877A IE 46100 B1 IE46100 B1 IE 46100B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- ester
- salt
- formula
- composition
- Prior art date
Links
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 229960003324 clavulanic acid Drugs 0.000 title claims abstract description 6
- -1 Clavulanic acid ethers Chemical class 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 150000002148 esters Chemical class 0.000 claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 229930182555 Penicillin Natural products 0.000 claims abstract description 18
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 229930186147 Cephalosporin Natural products 0.000 claims abstract description 10
- 229940124587 cephalosporin Drugs 0.000 claims abstract description 10
- 150000001780 cephalosporins Chemical class 0.000 claims abstract description 10
- 238000007327 hydrogenolysis reaction Methods 0.000 claims abstract description 7
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 29
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims description 18
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 17
- 239000011734 sodium Chemical class 0.000 claims description 17
- 229910052708 sodium Inorganic materials 0.000 claims description 17
- 229960003022 amoxicillin Drugs 0.000 claims description 16
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 14
- 229910052744 lithium Inorganic materials 0.000 claims description 13
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 12
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 229940049954 penicillin Drugs 0.000 claims description 8
- 229960000723 ampicillin Drugs 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000011591 potassium Chemical class 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000011575 calcium Chemical class 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 238000006266 etherification reaction Methods 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 239000011777 magnesium Chemical class 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- 241000972349 Ocoa Species 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 229960003311 ampicillin trihydrate Drugs 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 159000000001 potassium salts Chemical class 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 3
- 238000007257 deesterification reaction Methods 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 150000002641 lithium Chemical class 0.000 claims 1
- 229910003002 lithium salt Inorganic materials 0.000 claims 1
- 159000000002 lithium salts Chemical class 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 150000002960 penicillins Chemical class 0.000 abstract description 10
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 230000002195 synergetic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- AZUFHGGGPUUXKI-FLFDDASRSA-N benzyl (2r,3z,5r)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound O=C([C@@H]1N2C(=O)C[C@H]2O\C1=C/CO)OCC1=CC=CC=C1 AZUFHGGGPUUXKI-FLFDDASRSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- 230000036765 blood level Effects 0.000 description 4
- 229940090805 clavulanate Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000003973 alkyl amines Chemical class 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NOTFZGFABLVTIG-UHFFFAOYSA-N Cyclohexylethyl acetate Chemical compound CC(=O)OCCC1CCCCC1 NOTFZGFABLVTIG-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 229930195708 Penicillin V Natural products 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 2
- 229960003669 carbenicillin Drugs 0.000 description 2
- 229950004030 cefaloglycin Drugs 0.000 description 2
- FUBBGQLTSCSAON-PBFPGSCMSA-N cefaloglycin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)COC(=O)C)C(O)=O)=CC=CC=C1 FUBBGQLTSCSAON-PBFPGSCMSA-N 0.000 description 2
- 229960002588 cefradine Drugs 0.000 description 2
- 229940106164 cephalexin Drugs 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- HGBLNBBNRORJKI-WCABBAIRSA-N cyclacillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C1(N)CCCCC1 HGBLNBBNRORJKI-WCABBAIRSA-N 0.000 description 2
- 229960004244 cyclacillin Drugs 0.000 description 2
- 150000008049 diazo compounds Chemical class 0.000 description 2
- RPBAFSBGYDKNRG-NJBDSQKTSA-N epicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CCC=CC1 RPBAFSBGYDKNRG-NJBDSQKTSA-N 0.000 description 2
- 229960002457 epicillin Drugs 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 235000019371 penicillin G benzathine Nutrition 0.000 description 2
- 229940056360 penicillin g Drugs 0.000 description 2
- 229940056367 penicillin v Drugs 0.000 description 2
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229960003672 propicillin Drugs 0.000 description 2
- HOCWPKXKMNXINF-XQERAMJGSA-N propicillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(CC)OC1=CC=CC=C1 HOCWPKXKMNXINF-XQERAMJGSA-N 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 2
- 229960004659 ticarcillin Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- UQLLWWBDSUHNEB-CZUORRHYSA-N Cefaprin Chemical class N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CSC1=CC=NC=C1 UQLLWWBDSUHNEB-CZUORRHYSA-N 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000599862 Homo sapiens Intercellular adhesion molecule 3 Proteins 0.000 description 1
- 102100037871 Intercellular adhesion molecule 3 Human genes 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000005864 Sulphur Chemical group 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940048479 ampicillin 250 mg Drugs 0.000 description 1
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- ZYFYTWZIMOACBS-UHFFFAOYSA-N butan-1-ol;ethanol;hydrate Chemical compound O.CCO.CCCCO ZYFYTWZIMOACBS-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960003972 cefacetrile Drugs 0.000 description 1
- RRYMAQUWDLIUPV-BXKDBHETSA-N cefacetrile Chemical class S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC#N)[C@@H]12 RRYMAQUWDLIUPV-BXKDBHETSA-N 0.000 description 1
- 229960003866 cefaloridine Drugs 0.000 description 1
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical class O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical class CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960004350 cefapirin Drugs 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical class S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical class [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- JWMLCCRPDOIBAV-UHFFFAOYSA-N chloro(methylsulfanyl)methane Chemical compound CSCCl JWMLCCRPDOIBAV-UHFFFAOYSA-N 0.000 description 1
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960003884 hetacillin Drugs 0.000 description 1
- DXVUYOAEDJXBPY-NFFDBFGFSA-N hetacillin Chemical compound C1([C@@H]2C(=O)N(C(N2)(C)C)[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 DXVUYOAEDJXBPY-NFFDBFGFSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229960003806 metampicillin Drugs 0.000 description 1
- FZECHKJQHUVANE-MCYUEQNJSA-N metampicillin Chemical compound C1([C@@H](N=C)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 FZECHKJQHUVANE-MCYUEQNJSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Esters of compounds of the formula I, in which X and R<1> to R<3> have the meanings given in Claim 1, are obtained by reacting an ester of clavulanic acid with a compound of the formula V, in which Y is a readily displaceable radical. The corresponding free carboxylic acids, or their salts, are obtained by cleaving the esters by hydrolysis or hydrogenolysis. The compounds increase the antibacterial effect of penicillins and cephalosporins. They can be used in synergistic drug preparations.
Description
The present invention relates to new ethers of clavulanio acid, to pharmaceutical compositions containing them and to a process for their preparation.
In Belgian Patent No. 847045 it was disclosed that 5 ethers of clavulanio acid could be prepared by the reaction of a corresponding ester of clavulanio acid with an etherifying agent such as a diazo compound. It has now been found that certain classes of ethers can be prepared in good yield by a -facile reaction. These new ethers, which enhance the anti-bacterial effectiveness of penicillins and cephalosporins, form part of this invention.
Accordingly, the present invention provides the compounds of the formula (I): and salts and esters thereof wherein X is an oxygen or sulphur 15 atom.
When used herein the term lower means that the group contains not more than 6 carbon atoms and more suitably not more than 4 carbon atoms. - 2 The preferred value for X is the oxygen atom.
Thus certain favoured compounds of this invention are those of the formula (II): and salts and ethers thereof wherein R is as defined in relation to formula (I).
Suitable values for R include the methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl groups; more suitable values for R are the methyl, ethyl, and propyl groups; and especially suitable values for R are the methyl and ethyl groups, and a preferred value far R is the methyl group.
The compounds of the formula (I) are suitably in the form of a salt such as the lithium, sodium, potassium,calcium, >4,6100 magnesium, ammonium or substituted ammonium salt such as the methylamine, dimethylamine, trimethylamine, pyrrolidine, or other such lower alkylamine, di-lower alkylamine, tri-lower alkylamine or heterocyclic amine salts.
Particularly suitable salts include the lithium, sodium, potassium and calcium salts.
Preferred salts include the lithium, sodium and potassium salts.
Suitable esters of the compounds of the formula (II) include those of the formulae (III) and (IV): wherein X and R are as defined in relation to formula (I) and A1 is an alkyl group of 1-8 carbon atoms optionally 4 4 substituted by halogen or a group of the formula OA , OCOA , 4 4 SA or S02A wherein A is a hydrocarbon qroup of up to 6 carbon 2 toms; A is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halogen or by a group A3 or OA3 where A3 is an alkyl group of up to carbon atoms; and A3 is a phenyl group optionally 5 substituted by halogen or by a group A or OA where A is an alkyl group. - 4 4 6 10 6 Particularly suitable values for the O-Ci^-XR1 moieties in the compounds of this invention include those of the following sub-formulae (a) and (b): -O-CH2OCH3 (a) -O-CH2OC2H5 (b) A preferred value for the OCH2-XR'1' moiety in the compounds of this invention is that of the preceding sub-formula (a). Thus compounds of this invention worthy of mention include 9-0-methoxymethylclavulanic acid; lithium 9-0-methoxymethylciavulanate; sodium 9-0-methoxymethylclavulanate; potassium 9-O-methyoxymethylclavulanate; calcium 9-0-methoxymethylclavulanate; magnesium 9-0-methoxymethylclavulanate; and other salts of 9-0-methoxymethylclavulanic acid such as those with ammonia or with pharmaceutically acceptable amines.
It is believed that the organisms most readily treated by the compounds of this invention are Staphylococcus, Proteus, Klebsiella and Escherichia coli. Particularly good blood levels are achieved after oral administration of the compounds. - 5 46100 The present invention also provides pharmaceutical compositions which comprise a compound of the formula (I) as hereinbefore defined or a salt or ester thereof and a pharmaceutically acceptable carrier.
Most suitably the compound of the formula (I) in the composition of. this invention will be in the form of a pharmaceutically acceptable salt or in-vivo hydrolysable ester.
Preferably the compound of the formula (I) in the composition of this invention will be a pharmaceutically acceptable salt of a compound of the formula (II).
The composition of this invention may be presented orally or parenterally or in other convenient form. Generally the composition will he adapted for oral administration to humans or for administration by injection to humans.
Veterinary compositions may also be prepared.
Normally the composition of this invention will be in unit dosage form containing from about 20 mg to 250 mg, for example about 50 or 100 mg, of the active ingredient.
Such compositions will usually be administered from 20 2 to 6 times daily, for example 3 or 4 times daily,so that the daily dose is from about 60 · mg to 1000 mg, more usually from about 200 mg to about 1000 mg.
Desirably the composition of this invention will also comprise a penicillin or cephalosporin. Most suitably the ratio of compound of this invention to penicillin or 61 0 0 cephalosporin is from 1:10 to 10:1, more usually 2:1 to 1:5, for example 1:1 to 1:3(by weight).
Suitable penicillins and cephalosporins for inclusion in such compositions include those named in Belgian Specification No. 827926.
Particularly suitable penicillins for inclusion in the compositions of this invention include ampicillin, amoxycillin and their pro-drugs such as their in-vivo hydrolysafcls esters.
Preferred penicillins for inclusion in the compositions of this invention include ampicillin trihydrate and amoxycillin trihydrate, particularly amoxycillin trihvdrate. Other preferred penicillins include the pharmaceutically acceptable salts of amoxycillin.
Penicillins suitable for inclusion in orally administrable compositions of this invention include benzylpenicillin, phenoxymethylpenicillin, propicillin, amoxycillin, ampicillin, epicillin, cyclacillin and their salts and in-vivo hydrolysable esters and aldehyde and ketone adducts of those penicillins containing a 6-a-aminoacylamido side chain and their salts. Suitable penicillin in-vivo hydrolysable esters include the acetoxymethyl, pivaloyloxymethyl, os-ethoxycarbonyloxyethyl and phthalidyl esters of ampicillin or amoxycillin or the phenyl, tolyl and indanyl α-esters of carbenicillin and ticarcillin and salts thereof.
Suitable aldehyde and ketone adducts of penicillins containing a 6-ct-aminoacylamido side chain include the formaldehyde and acetone adducts metampicillin and hetacillin and their salts. Suitable penicillins for inclusion in injectably or infusably administrable compositions include the acceptable salts of benzylpenicillin, phenoxymethylpenicillin, carbenicillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin and cyclacillin.
Cephalosporins suitable for inclusion in orally administrable compositions of this invention Include cephalexin, cephradine, cephaloglycine and their salts and in-vivo hydrolysable esters and aldehyde and ketone adducts of those cephalosporins containing a 7-a-aminoacylamido side chain and their salts. Suitable cephalosporins for inclusion in the injectable or infusable compositions of this invention include the salts of cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole, cephapirin, cephradine and cephaloglycine. 610 0 In a further aspect the present invention provides a process for the preparation of a compound of the formula (I) or a salt or ester thereof which comprises the reaction of an ester of clavulanic acid with a compound of the formula (V); Y -CH2 - XR (V) wherein X, and R^ are as defined in relation to formula (I) and Y is a readily displaceable atom or group; ana thereafter, if desired,converting the thus produced ester into the free acid or a salt or other ester thereof.
Suitable values for Y include I, Br, Cl, , OSC^Cli^CH, or other similar atoms or groups readily displaced by a nucleophile.
Particularly suitable moieties Y include bromine and chlorine atoms.
The etherification reaction will normally be effected in the presence of a base of low nucleophilicity such as 2, 4, 6-collidine, potassium carbonate, sodium bicarbonate or 2,6-lutidine.
The etherification will normally take place at a non-extreme temperature such as -20° to 30°C, for example about 0° to 20°C.
The solvent used for the reaction may comprise dichloromethane, chloroform, dimethylformamide or tetrahydrofuran.
In another process aspect this invention also provides a process for the preparation of a compound of .the formula (I) or a salt or ester thereof which process comprises the reaction of an ester of clavulanic acid with a compound of the formula (VI) : R5 - 0 - CH2 - OR (VI) wherein R is as defined in relation to formula (I) and R is a tertiary alkyl group of 4 - 6 carbon atoms; and thereafter if desired converting the thus produced ester into the free acid or a salt or other ester thereof.
A particularly suitable group R3 is the t-butyl group.
Most suitably the reaction utilizes an excess of the compound of the formula (VI). Generally at least 1 molar excess and preferably 2-5 molar excess of the compound of the formula (VI) is employed. If the compound of the formula (vi) utilized is a volatile liquid it may be used as a solvent.
The present invention also provides a process for the preparation of the compounds of the formula (I) or a salt thereof which process comprises the de-esterification of a corresponding ester of a compound of the formula (I). 4 6 lOO Such de-esterification processes may involve hydrolysis or hydrogenolysis. Thus, for example an ester may be subjected to mild base hydrolysis to yield a salt of the compound of the formula (I) or alternatively a hydrogenolysable ester may be catalytically hydrogenated to yield the free acid or, if a base is present or added latex· j. a salt» More specifically a lower alkyl ester such as a methyl ester may be hydrolysed at pH 7-10 by the slow addition of equivalent of base or a benzyl, methoxybenzyi, nitrobenzyl or like ester may be hydrogenated in the presence of a transition metal catalyst such as palladium on charcoal optionally in the presence of a base such as NaHCOy Na2CO3, KHCOj, K2CO3, Li2CO3 or the like.
This invention also provides a process for the preparation of esters of the compounds of the formula (1) which process comprises the esterification of the compound of the formula (I) or a salt thereof.
Thus a compound of the formula (I) may be reacted with a diazo compound or a salt of the compound of the formula (I) may be reacted with a reactive halocompound or the like.
The following Examples illustrate the invention: Benzyl 9-0-methoxymethylclavulanate Example 1 ch2oh (e 1) ch2och2och3 C00CHoC,H, '2k.n2c6n5 (e 2) \ C00CHoCcH, '2cn2u6n5 Benzyl clavulanate (e 1) (2.89 g, 0.01 mole), chlorodimethyl ether (1.6 ml, 1.7 g) and 2, 4, 6-collidine (1.3 ml) were dissolved in dichloromethane (20 ml) at 5°C with stirring. After 1 hr at 10° tic showed that the benzyl clavulanate had disappeared almost completely. Water (50 ml) was added and the mixture shaken and separated (aqueous solution was strongly acidic) 3% aqueous sodium bicarbonate solution (50 ml) was added to the dichloromethane layer.
The organic phase was separated, dried (Na2SO4), filtered, treated with silica (5 g), filtered, evaporated to low volume and subjected to column chromatography on silica gel using ethyl acetate and cyclohexane as eluents. The product was isolated as a pale yellow oil (1 g). „ (film) 1803, 1753, 1700 cm-1(C=C); 6(CDC13) 3.01 (1H, bd, J 17 Hz 6-8-CH) 3.33 (3H, s, OCH3) 3.50 (1H, dd, J 3 and 17 Hz, 6-ot-CH) 4.14 (2H, bd, J 7Hz, CHCHjO) 4.57 (3H, s, CH-jO) 4.86 (1H, bdt, J 7 and 1.5 Hz, CH=) 5.10 (1H, d, J 1.5) Hz) 5.69 (lH, bd, J 3 Hz, 5-CH) 7.36 6(5H, s, CgHg) 6 i u ο Lithium 9-0-methoxymethylclavulanate Example 2 CH2OCH2OCH3 (e3) H CH2OCH2OCH3 Benzyl o-methoxymethylclavulanate (e2) (0.7 g) in tetrahydrofuran (7 ml) containing water (0.5 ml) was hydrogenated over 10% palladised charcoal (0.2 g) for 1 hr. to yield a solution of (e3). The catalyst was removed by filtration, and the filtrate added to water (10 ml), neutralised with 1 M lithium hydroxide solution to pH 7.0, and evaporated to dryness, to give colourless crystals, which were triturated with acetone, filtered, washed with ether and air-dried, to yield 0.45 g of the title compound (e4). vmax (Nujol mull) 1785, 1705, 1617 cm 1; 6D2O) 2.98 (IH, d, J 17Hz, Sg-CH), 3.43 (IH, dd, J 17 and 3Hz, 6a-CH), 4.07 (2H, d, J 8Hz, 9-¾) , ~4.5 (under HOD, OCH2O), 4.79 (IH, t, J 8Hz, 8-CH=), 4.83 (IH, s, 3-CH), .61 (IH, d, J 3Hz, 5-CH).
Nujol is a registered trade mark.
Example 3 Benzyl 9-0-ethoxymethylclavulanate ,CHo0CH20C2H5 (el) o .co2ch2c6h5 (e5) A mixture of benzyl clavulanate (el) (5.78 g), 2,4,6-collidine (5.8 ml) and chloromethyl-ethyl ether (3.7 ml) in dichloromethane (100 ml) was stirred at room temperature for 2 h. The reaction mixture was then washed with aqueous hydrochloric acid (2M, 100 ml), dried over anhydrous sodium carbonate - magnes.ium sulphate, and evaporated to dryness to give an oil which was chromatographed over silica gel (50 g).
Elution of the column with cyclohexane-ethyl acetate gave the title compound (e5) (6.15 g) as an oil, [a]2° + 45.2° (c, 1.0; CHC1,) , v (CHC1,) 1810, 1755, 1705, 1310, 1190, and 1030 cm-1, 5(CDC13) 7.28 (5Hs, ArH) 5.61 (1H, d, J = 2.5 Hz, 5-CH), 5.13 (2H, s, -CH2Ar), .03 (IH, broad s , 3-CH), 4.78 (IH, broad t, J = 8Hz, 8-CH), 4.56 (2H, s , -OCH2O-), 4.09 (2H, broad d, J 8Hz, 9-¾) , 3.52 (2H, g, J = 7.5 Hz. - OCHjCHg), 3.41 (IH, dd, J = 17Hz, J = 2.5Hz, 6a-CH), 2.99 (IH, d, J = 17Hz, 68—CH) , and 1.18 (3H, t, J = 7.5Hz, OCH2CH3) (Found: C, 62.2; H, 6.15; N, 3.8%.
C18H21NO6 retIu^res cr 62.25; H, 6.1; N, 4.05%).
Example 4 Lithium 9-0-ethoxymethylclavulanate A solution of benzyl 9-0-ethoxymethylclavulanate (e5) (5.95 g) in tetrahydrofuran (80ml) and water (2 drops) was hydrogenated at room temperature and pressure in the presence of 10% palladium-charcoal (3.35%) for O.5h.
The mixture was then filtered, the filtrate diluted with water (250ml) and neutralised to pK 7.2 with aqueous lithium hydroxide (1M). The mixture was then evaporated to dryness and the residue, after trituestioB. with ether, afforded the title compound (e6) (4.4 g), [a]20 + 34.8° (c,1.0; H20), vmaj£ (KBr) 1780, 1700, 1620, 1320 and 1030 cm1' (CD20) 5·™Χ(1Η, d, J = 2.5 Hz, 5-CH), 4.90 (lH,s , 3-CH), 4.88 (IH, broad t, J = 8 Hz, 8 - CH) , 4.68 (2H, s, -OCH2O-), 4.17 (2H, d, J = 8Hz, 9-CH2), 3.58 (2H, q, J = 8HZ, -OCH2CH3), 3.52 (IH, dd, J = H2, J' = 2.5Hz, 6a-CH), 3.04 (IH, d, J = 17Hz, Sg-CH), and 1.13 (3H, t, J = 8Hz,-OCH2CH3).
Example 5 Benzyl 9-O-methylthiomethylclavulanate (el)-} '3 (e8) A solution of benzyl clavulanate (el) (2.89 g, 0.1 mole) and 2, 4, 6-collidine (2 ml, 0.015 mole) in dimethoxyethane (10 ml) was added to a mixture of sodium iodide (1.5 g) and chloromethyl methyl sulphide (0.97 g, 0.01 mole) in 1,25 dimethoxyethane (20 ml) at 0°C under Argon. The mixture was stirred at 50°C for 3 h. and then at room temperature for 66 h. This was then poured into ice-water (40 ml) and extracted with ethyl acetate (3 x 40 ml). The organic extract was washed with dilute hydrochloric acid (5M, 100 ml), brine (100 ml), dried and evaporated to give an oil which was chromatographed over silica gel (30 g). Elution of the column with cyclohexane-ethyl acetate afforded benzyl 9-0-methylthiomethylclavulanate (e8) (0.4 g) as a colourless oil, θ° + 38.3° (c, 2.0; CHC13), (liquid film) 1805, 1750, 1695, 1300, 1180, and 1035 cm1, δ (CDC13) 7. 28 (5H, s, ArH), 5.61 (1H, d, J = 2.5Hz, 5-CH), 5.12 (2H, s, -GH2Ar), 5.03 (1H, s, 3-CH), 4,75 (lH, broad t, J = 8HZ, 8-CH, 4.49 (2H, s, -OCH2SMe), 4.10 (2H, d, J = 9-¾) , 3.42 (1H, dd, J = 17Hz, J' = 2.5Hz, 6 17Hz, 6β-CH) , and 2.09 (3H, s, -8¾) , m/e (relative intensity) 301.0968 (25, M+-MeSH), 288.0849 (10, M+-C2H5S),' 272.0903 (5,M+-C2H50S), 230 (30, M+-C2H5OS-C2H5OS-C2H20), and 91 (100). 4 610 0 Example 6 Lithium 9-0-methylthiomethylclavulanate I-f °\r~ och2sch3 (e8) -J— CO-Li (e9) A mixture of benzyl 9-0-methylthiomethylclavulanate (0.35 g), tetrahydrofuran (15 ml), and water (15 ml) was titrated to constant pH at pH 10 with lithium hydroxide solution (1M) in a pH-stat at 24°C. The addition of lithium hydroxide was stopped after 2 h. The solution was than concentrated in vacuo to 10 ml and then diluted with water (10 ml). This aqueous mixture was extracted with ethyl acetate (2 x 20 ml) and then evaporated to dryness. The residue was purified by column chromatography over cellulose (10 g). Elution of the column with butanol-water-ethanol (5:5:1, top phase) gave lithium 9-O-methylthiomethylclavulanate (e9) (0.04 g), u (Nujol) 1780, 1695, 1620, 1300, and 1020 cm-1, ό (D20) 5.80 (IH, d, J = 2.5Hz, 5-CH), 5.05 (IH, s, 3-CH), 4.97 (IH, broad t, J = 8Hz, 8-CH), 4.73 (2H, s, -OCHjSMe), 4.27 (2H, d, J = 8Hz, 9-¾), 3.63 (IH, dd, j = 18Hz, J' = 2.5Hz, 6a-CH), 3.14 (IH, d, J = 18Hz, 68-CH), and 2.19 (3H, s, -SCH3).
Example 7 Sodium 9-0-methoxymethylclavulanate £-Methoxybenzyl (J-methoxymethylclavulanate (e7) (5.0 g) was dissolved in ethanol (60 ml) in a pressure bottle.
Sodium bicarbonate (1.39 g) in water (8 ml) was added.
The bottle was purged with nitrogen and 10% palladium on charcoal catalyst (0.75 g, Johnston-Mathey Type 76/L) was added. The mixture was then hydrogenated at 25 psi for one hour. Thin layer chromatography (E. Merck gel, ethyl acetate/chloroform 50/50) (E.Marck is a registered trade mark) showed the hydrogenolysis to be conplete and the mixture was filtered through Celite (Oalite is a registered trade mark), and the Cfelite was washed with water(lQml). The filtrate was evaporated, using a rotary evaporator, to a gum. The gum was dissolved in acetone (10ml) and to this solution 1 was added, with vigorous shaking, dry diethyl ether (900 ml). This gave a fine white precipitate. The suspension was chilled at 4°C for two hours and then filtered. The solid was washed with ether (2 x 100 ml) and immediately dried in a low vacuum desiccator to yield the title compound (e21) as a hydroscopic pale yellow powder (2.1 g). 610 0 Example 8 Compositions: The following may be prepared in conventional manner utilizing dry ingredients under a dry atmosphere: a. Tablets of the following composition may be prepared: Sodium 9-0-methoxymethylclavulanate 150 mg Anhydrous ampicillin 300 mg Microcrystalline cellulose 600 mg Magnesium stearate 15 mg b. Capsules of the following compositions may be prepared: Sodium 9-O-methoxymethylcalvulanate 250 mg Magnesium stearate 2.5 mg Sodium starch glycollate 5.0 mg c. The following may be sealed into ampoules for reconstitution in sterile water for immediate injection: Sodium 9-0-methoxymethylclavulanate 50 mg Sodium ampicillin 250 mg _ 19 Example 9 Pharmacology; Using conventional methods the following results were obtained: a. Compound of Example 7 MIC (pg/ml) of Ampicillin Cone11 Inhibitor (yg/ml) Staph. Russell Prot. C 889 Kleb E 70 E, coli JT 39 20 - 1.0 - 5 - 2.0 1.6 4 1 0.3 - 1.6 125 0 125 > 2000 1000 > 2000 b. Compound of Example 4 MIC (pg/ml) of Ampicillin Cone11 Inhibitor (pg/ml) Staph. Russell Kleb E 70 Proteus C 889 E. coli JT 39 E. coli JT 410 20 - y " 5 0.04 <3.12 t (3.12 1.0 2.0 125 1 o.e 15.6 4.0 - 0 250 o o . . > 2000 1000 250 4 6 10 0 e. Blood Levels obtained with Sodium Methoxymethyl clavulanate The following blood levels were found after subcutaneous administration to mice at a dose of 10 mg/kg? the result for sodium clavulanate is included for comparison: Time (mins) 20 30 45 60 pg/ml sodium ether 3.1 3.4 1,3 0.8 pg/ml sodium clavulanate 4.2 2.2 0.8 0.5 The following blood levels were found after oral administration to mice at a dose of 20 mg/kg? the result for sodium clavulanate is included for comparison: Time (mins) 15 30 45 60 pg/ml sodium ether 10.8 7.4 2.1 1.4 15 pg/ml sodium clavulanate 3.5 2.6 1.5 0.6 f. Curative effect of Sodium 9-Q-Methoxymethylclavulanate and Amoxycillin The following CD5Q values were obtained in intraperitoneal Escherichia coli JT 39 infections. The test materials were administered either by sub-cutaneous administration 1 and 5 hours post infection or by oral administration 1, 3 and 5 hours post infection: Test Material CD50 (m9/k9) of Amoxycillin (Sub-cutaneous Dosing) 2.5 mg/kg Sodium 9-O-Methoxymethyl- 6.8 clavulanate + Amoxycillin 2.5 mg/kg Sodium Clavulanate 14 + Amoxycillin mg/kg Sodium 9-0-Methoxymethyl- 23.4 clavulanate + Amoxycillin mg/kg Sodium Clavulanate 40 + Amoxycillin Test Material CDso x 3) of Amoxycillin (Oral Dosing) mg/kg Sodium 9-O-Methoxymethyl- 11 clavulanate + Amoxycillin mg/kg Sodium Clavulanate 9 + Amoxycillin 610 0 Example 10 9-0-methoxymethylclavulanlc acid (eh) C02H CHo0CHo0CH, IE ¢- p To a solution of lithium 9-0-methoxymethylclavulanate (O.h3g) in water (25ml), covered with ethyl acetate (50ml) and stirred, was added Amberlite IR 120 (H+form) strong acid ion exchanae resin until the pH of the aqueous layer was <2.0 (about 20ml wet resin). The mixture was filtered,and the filtrate separated. The aqueous layer was extracted with 3x 30ml portions of io ethyl acetate. The ethyl acetate extracts were combined, dried quickly over molecular sieve (3A,30g), filtered and evaporated to an oil in a rotary evaporator under reduced pressure, to yield 0.3g of the title material.I.r.(film): tA max 2500 - 3600 (very broad), 1805, 1750, 1695cm"1.
Amberlite is a registered Trade Mark.
Claims (55)
1. CLAIMS :1. A compound of the formula (1): V co 2 h or a salt or ester thereof wherein X is an oxygen or sulphur atom and R 1 is a lower alkyl group.
2. A compound as claimed in claim 1 wherein X is an oxygen atom.
3. A compound as claimed in eitherof claims 1 or 2 wherein κ is a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl group.
4. A compound as claimed in either of claims 1 or 2 wherein R 1 is a methyl, ethyl, n-propyl or iso-propyl group.
5. A compound as claimed in either of claims 1 or 2 wherein R 1, is a methyl group.
6. A compound as claimed in either of claims 1 or 2. wherein R 1 is an ethyl group.
7. A compound as claimed in claim 1 wherein OCH^XR 1 is och 2 och 3 .
8. A compound as claimed in claim wherein OCE^XR 1 is 0CH 2 0C 2 Hg.
9. A compound as claimed in any of claims 1 - 8 in the fonn of the acid.
10. A compound as claimed in any of claims 1 - 8 in the form of a salt. 4 01 Ο Ο
11. A compound in any of claims l-β in the form of a lithium, sodium, potassium, calcium, magnesium, ammonium or substituted ammonium salt. 12. A compound as claimed in any of claims 1 - i- . in the form of a lithium salt. 13. A compound as claimed in any of claims 1 -8 in the form of a sodium salt. 14. A compound as claimed in any of claims 1 -S in the form of a potassium salt. 10 15. A compound as claimed in any of claims 1 - θ which is an ester wherein the ester moiety is of the sub-formula (c) or (d): CC^A 1 (c) co 2 cha 2 a 3 (d) wherein A 3- is an alkyl group of 1-8 carbon atoms optionally 4 4 1J substituted by halogen or a group of the formula OA , OCOA , 4 4 4 SA or SO 2 A wherein A is a hydrocarbon atom, an alkyi group of up to 4 carbon atoms or a phenyl group optionally substituted by halogen or by a group A 3 or OA 3 where A 3 3 . is an alkyl group of up to 6 carbon atoms; and A is a 20 phenyl group optionally substituted by halogen or by a group 5 5 5 A or OA where A is an alkyl group.
12. 15. A compound as claimed in any of claims 1-8 which is a hydrolysable ester.
13. 17. A compound as claimed in any of claims 1-8 which is 25 a hydrogenolysable ester.
14. 18. A compound as claimed in claim 16 wherein the ester is the methyl ester.
15. 19. A compound as claimed in claim 17 wherein the ester is the benzyl ester. 30
16. 20 „ A compound as claimed in claim 17 wherein the ester is a methoxybonzyl ester.
17. 21. A compound as claimed in claim 17 wherein the ester is a nitrobenzyl ester.
18. 22. A pharmaceutical composition which comprises a compound as claimed in any of claims 1-21 and a pharmaceutically acceptable carrier.
19. 23. A composition as claimed in claim 22 which comprises a pharmaceutically acceptable salt of a compound as claimed in any of claims 1 - 8.
20. 24. A compositions as claimed in claim 23 wherein the salt is as claimed in claim 14.
21. 25. A composition as claimed in claim 23 wherein the salt is as claimed in claim 24.
22. 26. A composition as claimed in any of claims 22 - 25 in unit dosage form which contains from 20 to 250 mg of a compound as claimed in any of claims 1 - 21.
23. 27. A composition as claimed in any of claims 22 - 26 which also comprises a penicillin.
24. 28. A composition as claimed in any of claims 22 - 26 which also comprises a cephalosporin.
25. 29. A composition as claimed in claims 27 or 28 wherein the weight ratio of a compound as claimed in any of claims 1 - 21 to a penicillin or a cephalosporin is 1:10 to 10:1.
26. 30. A composition as claimed in claim 29 wherein the ratio is 2:1 to 1:5.
27. 31. A composition as claimed in claim 29 wherein the ratio is 1:1 to 1:3.
28. 32. A composition as claimed in any of claims 27 or 29 - 31 wherein the penicillin is ampicillin, amoxycillin or a pro-drug therefor.
29. 33. A composition as claimed in any of claims 27 or 29 - 31 wherein the penicillin is ampicillin trihydrate. 4 610 0
30. 34. A composition as claimed in any of claims 27 or 29 - 31 wherein the penicillin is amoxycillin trihydrate.
31. 35. A process for the preparation of a compound of the formula (I) as defined in claim 1 or a salt or ester thereof which process comprises the reaction of an ester of clavulanic acid with a compound of the formula (V): Y-CH -X-R 1 (V) wherein X, and R?- are as defined in claim I and Y is a readily dispaceable group: and thereafter, if desired, converting the thus produced ester into the free acid or salt or other ester thereof.
32. 36. A process as claimed in claim 35 wherein Y is I, Br, Cl, OSO 2 CH 3 or OSO 2 C g H 4 CH 3 .
33. 37. A process as claimed in claim 35 wherein v is Br or Cl.
34. 38. A process as claimed in any of claims 35 - 37 wherein the etherification step is carried, out in the presence of a base of low nucleophilicity.
35. 39. A process as claimed in any of claims 35 - 38 wherein the etherification step is carried out at -20°C to 30°C.
36. 40. A process as claimed in any of claims 35 - 39 adapted to the preparation of an ester.
37. 41. A process for the preparation of a compound of the formula (I) as defined in claim 1 or a salt or ester thereof which process comprises the reaction of an ester of clavulanic acid with a compound of the formula (VI): R 5 -O-CH 2 -OR 1 (VI) 1 5 wherein R is as defined in claim 1 and R is a tertiary alkyl group of 4 - 6 carbon atoms: and thereafter if desired converting the thus formed ester into the free acid or a salt or other ester thereof. β ο jl υ υ
38. 42. A process as claimed in claim 41 wherein R is a tert-butyl group.
39. 43. A process for the preparation of a compound of the formula (X) as defined in claim 1 or a salt thereof which process comprises the de-esterification of a corresponding ester of a compound of the formula (I).
40. 44. A process as claimed in claim 43 for the preparation of a salt of the compound of the formula (I) which process comprises the mild base hydrolysis of an ester of the compound of the formula (I).
41. 45. A process as claimed in claim 44 wherein the ester is the methyl ester.
42. 46. A process as claimed in claim 43 wherein the deesterification is effected by hydrogenolysis.
43. 47. A process as claimed in claim 46 wherein the hydrogenolysis is of a benzyl ester.
44. 48. A process as claimed in claim 46 wherein the hydrogenolysis is of a methoxybenzyl ester.
45. 49. A process as claimed in claim 46 wherein the hydrogenolysis is of a nitrobenzyl ester.
46. 50. Benzyl 9-0-methoxymethylclavulanate.
47. 51. Lithium 9-0-methoxymethylclavulanate
48. 52. Benzyl 9-0-ethoxymethylclavulanate.
49. 53. Lithium 9-0-ethoxymethylCLavulanate.
50. 54. Benzyl 9-0-methylthiomethylclavulanate.
51. 55. Lithium 9-0-methylthiomethylclavulanate.
52. 56. 9-0-Methoxymethylclavulanic acid.
53. 57. Sodium 9-0-methoxymethylclavulanate.
54. 58. Potassium 9-0-methoxymethylclavulanate.
55. 59. Calcium 9-0-methoxymethylclavulanate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE2947/81A IE46101B1 (en) | 1976-12-03 | 1977-12-02 | Clavulanic acid ethers |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB50444/76A GB1595176A (en) | 1976-12-03 | 1976-12-03 | Clavulanic acid ethers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE46100L IE46100L (en) | 1978-06-03 |
| IE46100B1 true IE46100B1 (en) | 1983-02-23 |
Family
ID=10455915
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2448/77A IE46100B1 (en) | 1976-12-03 | 1977-12-02 | Clavulanic acid ethers |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5392796A (en) |
| AU (1) | AU515916B2 (en) |
| BE (1) | BE861325A (en) |
| CH (1) | CH637395A5 (en) |
| DE (1) | DE2752701A1 (en) |
| DK (1) | DK540177A (en) |
| FR (2) | FR2372837A1 (en) |
| GB (1) | GB1595176A (en) |
| IE (1) | IE46100B1 (en) |
| NL (1) | NL7713220A (en) |
| SE (1) | SE7713710L (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2004541B (en) * | 1977-09-16 | 1982-05-12 | Beecham Group Ltd | Ethers of clavulanic acid a process for their preparation and pharmaceutical compositions containing them |
| EP0002370B1 (en) * | 1977-12-02 | 1983-05-11 | Beecham Group Plc | A process for the preparation of ether derivatives of clavulanic acid |
| EP0080284A1 (en) * | 1981-11-25 | 1983-06-01 | Beecham Group Plc | Derivatives of clavulanic acid, processes for their preparation and their use |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE44295B1 (en) * | 1975-10-13 | 1981-10-07 | Beecham Group Ltd | Clavulanic acid derivatives |
| GB1573503A (en) * | 1975-12-17 | 1980-08-28 | Glaxo Lab Ltd | Clavulanic acid derivatives |
-
1976
- 1976-12-03 GB GB50444/76A patent/GB1595176A/en not_active Expired
-
1977
- 1977-11-25 DE DE19772752701 patent/DE2752701A1/en not_active Withdrawn
- 1977-11-29 BE BE183035A patent/BE861325A/en not_active IP Right Cessation
- 1977-11-30 FR FR7736053A patent/FR2372837A1/en active Granted
- 1977-11-30 NL NL7713220A patent/NL7713220A/en not_active Application Discontinuation
- 1977-12-02 CH CH1479277A patent/CH637395A5/en not_active IP Right Cessation
- 1977-12-02 IE IE2448/77A patent/IE46100B1/en unknown
- 1977-12-02 JP JP14560177A patent/JPS5392796A/en active Pending
- 1977-12-02 AU AU31189/77A patent/AU515916B2/en not_active Expired
- 1977-12-02 SE SE7713710A patent/SE7713710L/en unknown
- 1977-12-02 DK DK540177A patent/DK540177A/en not_active Application Discontinuation
-
1979
- 1979-01-30 FR FR7902279A patent/FR2411194A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| CH637395A5 (en) | 1983-07-29 |
| FR2411194B1 (en) | 1982-02-26 |
| DE2752701A1 (en) | 1978-06-08 |
| FR2372837A1 (en) | 1978-06-30 |
| NL7713220A (en) | 1978-06-06 |
| GB1595176A (en) | 1981-08-12 |
| IE46100L (en) | 1978-06-03 |
| BE861325A (en) | 1978-05-29 |
| JPS5392796A (en) | 1978-08-15 |
| FR2372837B1 (en) | 1980-07-25 |
| FR2411194A1 (en) | 1979-07-06 |
| DK540177A (en) | 1978-06-04 |
| AU515916B2 (en) | 1981-05-07 |
| AU3118977A (en) | 1979-06-07 |
| SE7713710L (en) | 1978-06-04 |
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