GB1595267A - Azabicyclohepthenes - Google Patents
Azabicyclohepthenes Download PDFInfo
- Publication number
- GB1595267A GB1595267A GB13164/78A GB1316478A GB1595267A GB 1595267 A GB1595267 A GB 1595267A GB 13164/78 A GB13164/78 A GB 13164/78A GB 1316478 A GB1316478 A GB 1316478A GB 1595267 A GB1595267 A GB 1595267A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- azabicyclo
- hept
- ene
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000000645 desinfectant Substances 0.000 claims abstract description 3
- -1 elixir Substances 0.000 claims description 59
- 239000000243 solution Substances 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 239000004480 active ingredient Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 9
- 239000003826 tablet Substances 0.000 claims description 9
- 229920002261 Corn starch Polymers 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000008120 corn starch Substances 0.000 claims description 7
- 229940099112 cornstarch Drugs 0.000 claims description 7
- BSIMZHVOQZIAOY-UHFFFAOYSA-N 7-Oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Natural products OC(=O)C1=CCC2CC(=O)N12 BSIMZHVOQZIAOY-UHFFFAOYSA-N 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- 239000003973 paint Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 239000008223 sterile water Substances 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims description 4
- 235000020357 syrup Nutrition 0.000 claims description 4
- 239000006188 syrup Substances 0.000 claims description 4
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 3
- 229930182555 Penicillin Natural products 0.000 claims description 3
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 3
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 3
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 108010078777 Colistin Proteins 0.000 claims description 2
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 2
- 229930182566 Gentamicin Natural products 0.000 claims description 2
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 claims description 2
- 229930193140 Neomycin Natural products 0.000 claims description 2
- YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 239000003708 ampul Substances 0.000 claims description 2
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 2
- 229960003346 colistin Drugs 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 229960002518 gentamicin Drugs 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 229960000318 kanamycin Drugs 0.000 claims description 2
- 229930027917 kanamycin Natural products 0.000 claims description 2
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 claims description 2
- 229930182823 kanamycin A Natural products 0.000 claims description 2
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 claims description 2
- 229960005287 lincomycin Drugs 0.000 claims description 2
- 239000006193 liquid solution Substances 0.000 claims description 2
- 239000006210 lotion Substances 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 claims description 2
- 229960004927 neomycin Drugs 0.000 claims description 2
- 229960002950 novobiocin Drugs 0.000 claims description 2
- YJQPYGGHQPGBLI-KGSXXDOSSA-N novobiocin Chemical compound O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-N 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000003182 parenteral nutrition solution Substances 0.000 claims description 2
- 229940049954 penicillin Drugs 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 2
- 229940057838 polyethylene glycol 4000 Drugs 0.000 claims description 2
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 claims description 2
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 claims description 2
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 claims description 2
- 229960003081 probenecid Drugs 0.000 claims description 2
- 239000008227 sterile water for injection Substances 0.000 claims description 2
- 229960005322 streptomycin Drugs 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 229940100615 topical ointment Drugs 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 239000006196 drop Substances 0.000 claims 1
- 239000006194 liquid suspension Substances 0.000 claims 1
- 125000000962 organic group Chemical group 0.000 claims 1
- 229940098458 powder spray Drugs 0.000 claims 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 229940088710 antibiotic agent Drugs 0.000 abstract description 8
- 241000894006 Bacteria Species 0.000 abstract description 6
- 239000003755 preservative agent Substances 0.000 abstract description 4
- 235000019730 animal feed additive Nutrition 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 12
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- PSJNLRROOZKIHF-UHFFFAOYSA-N 3-(2-aminoethylsulfanyl)-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)C(CC)C21 PSJNLRROOZKIHF-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 101100073357 Streptomyces halstedii sch2 gene Proteins 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- OTTZHAVKAVGASB-UHFFFAOYSA-N 2-heptene Natural products CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 description 4
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 4
- LJKNRSBEKUSSIE-UHFFFAOYSA-N hept-2-ene Chemical compound [CH2]CCCC=CC LJKNRSBEKUSSIE-UHFFFAOYSA-N 0.000 description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
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- 239000007924 injection Substances 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical class CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- BOLWWJGLNPVEQA-UHFFFAOYSA-M sodium;3-[2-[bromo-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethylsulfanyl]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound [Na+].C1C(SCCN(Br)C(=O)OC(C)(C)C)=C(C([O-])=O)N2C(=O)C(CC)C21 BOLWWJGLNPVEQA-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The compound of the formula I and its pharmacologically acceptable salts are described. They can be obtained by reduction of the compound of the formula (III) in which R and R' have the meaning given in Claim 4. The compound (I) and its pharmacologically acceptable salts are effective antibiotics against Gram-positive and Gram-negative bacteria and can therefore be used as active compounds in medicaments, animal feed additives, preservatives for foodstuffs and in disinfectants. <IMAGE>
Description
(54) AZABICYCLOHEPTENES
(71) We, MERCK & CO. INC., a corporation duly organized and existing under the laws of the State. of New Jersey, United States of America, of Rahway,
New Jersey, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement:- There is a continuing need for new antibiotics. For unfortunately there is no static effectiveness of a given antibiotic because continued wide-scale usage of any such antibiotic selectively gives rise to resistant strains of pathogens. In addition, known antibiotics suffer from the disadvantages of being effective only against certain types of microorganisms. Accordingly the search for new antibiotic continues.
The invention provides 3 - (2 - aminoethylthio) - 6 - ethyl - 7 - oxo - I azabicyclo[3 2 0]hept - 2 - ene - 2 - carboxylic acid (I):-
and its pharmaceutically acceptable salts. These compounds are useful as antibiotics in animal and human therapy and in inanimate systems. The antibiotics of the present invention have been found active against a broad range of pathogens which representatively include both gram-positive bacteria such as S. aureus, Strep.
pyogenes and B. Subtilis, and gram-negative bacteria such as E. coli, Proteus morganii, Serratia and Klebsiella.
Compound I is conveniently derived from the antibiotic thienamycin (II) by removal of the 8 - hydroxyl group:
Thienamycin is disclosed and claimed in U.S. Patent No. 3,950,357.
Thienamycin and all of its stereoisomers (in pure form and as mixtures) are also obtainable by total synthesis, as described and claimed in the specification of our copending application No. 47326/77 (Serial No. 1589896). Thienamycin and its stereoisomers may serve as a starting material for the preparation of the compounds of the present invention.
In general the compounds of the present invention are prepared according to the following reaction scheme:
OR CH3CH y̆SNH2 bass ) > SCO H NH2 COOH N COOH 0 lib Ill reduction vS/\NH 2 0NCOOH o in which the radical OR of structure Ilb is easily eliminated on treatment with base to form the enelactam III which, upon reduction, yields the compound of the present invention, I. The radical OR is typically a sulfate or sulfonate.
More specifically, the 3 - (2 - aminoethylthio) - 6 - ethyl - 7 - oxo - 1
azabicyclo[3 2 0]hept - 2 - ene - 2 - carboxylic acid of the present invention, I, is
conveniently prepared by the following reaction scheme:
OH OSO2R' NHR' S I sulfonotion N COOR N COOR o O fia ILb CH3CH NHR' bose COOF; H 2 cat NHR' N COOR 0 IV debtock a NH2 -H $ COOH where R" is O- M+, M is hydrogen or any non-critical cation such as an alkali metal or organic base; or R" is alkyl or an aryl radical such as methyl or toluyl; where R is a readily removable carboxyl blocking (or protecting) group and R' is a readily removable N-blocking group. Compounds III and IV, and the corresponding compounds in which R and/or R' are/is hydrogen, are compounds in accordance with the present invention. Blocked thienamycins, IIa, are disclosed and claimed in the specification of our copending Patent Application No. 7667/77 (Serial No.
1,569,234). Preferred carboxyl-blocking groups R are benzyl and nuclearsubstituted benzyl:
where X is an inert substituent such as nitro or lower alkoxyl such as methoxy; unsubstituted benzyl is preferred. Suitable N - blocking groups, R', include bromo - t - butoxycarbonyl, chloro - t - butoxycarbonyl, bromoethoxycarbonyl, benzyloxycarbonyl and p - nitrobenzyloxycarbonyl. An especially preferred Nblocking group is bromo - t - butoxycarbonyl.
In words relative to the above reaction diagram, a suitably protected thienamycin, IIa, is converted to the corresponding sulfonate or sulfate ester, IIb, by procedures which are disclosed in the above-cited Patent Application No.
7667/77 (Serial No. 1,569,234). Typically, the intermediate compound IIb as a sulfonate is prepared by treating IIa in a solvent such as methylene chloride, THF, dioxane or CHCl3, with a sulfonating agent such as methane sulfonyl chloride or toluene sulfonyl chloride in the presence of base such as triethylamine, pyridine, 4 - dimethylaminopyridine or NaH at a temperature of from -15" to 250C for from
1 to 10 hours. Sulfate ester embodiments of intermediate compounds IIb (R" is -OOMO) are also suitable starting materials and have the following structural formula:
wherein M is hydrogen, an alkali metal cation or an organic base and R and R' are as defined above. Such sulfate esters are also disclosed and claimed in the abovecited Patent Application No. 7667/77 (Serial No. 1,569,234).
It should be noted relative to the reaction involving intermediate compounds
IIb that the groups R and R' may be, in addition to the above-named protecting groups, hydrogen. Such intermediate IIb compounds are prepared by deblocking the protected form of IIb according to conventional procedures which are described below.
It should be noted that sulfate ester compounds IIb (R" is OH) are also obtainable as natural products. Such products are disclosed in the specification of our copending Patent Application No. 5077/78 (Serial No. 1,595,234).
Relative to the above reaction diagram, the enelactam intermediate III is prepared from IIb by treating IIb with base such as NaRCO3, K2HPO4, triethylamine or 1,5 - diazabicyclo[5.4.0]undec - 5 - ene in a solvent such as methanol, TlIF or dioxane at a temperature of from -20 to 250C for 1 to 20 hours.
The 6-ethyl intermediate IV is obtained from III by reduction, preferably by treating III in a solvent such as ethanol, ethyl acetate, dioxane or benzene in the presence of a hydrogen catalyst such as PtO2, RuO2 or Pt/C, in the presence of I to 4 atmospheres of hydrogen at a temperature of from 0 to 250C for from 0.5 to 5 hours. Intermediate compound IV may be deblocked by the above-described hydrogenation procedure to obtain I or, depending upon the identity of the protecting groups R' and R, the deblocking may be accomplished by separate procedures such as hydrolysis or hydrogenation under different conditions. It should be again pointed out that deblocking may occur earlier in the scheme on intermediate compound IIb. The deblocking procedure may also be accomplished as a single step reaction in the conversion III < IV. Separate deblocking IV < I may be conducted by any of a variety of well-known procedures such as hydrolysis or hydrogenation. Preferably the carboxyl blocking group R is removed by hydrogenation in a solvent such as a.loweralkanol, for example, ethanol in the presence of a hydrogenation catalyst such as palladium, platinum or oxides thereof under 140 atmospheres of hydrogen at from 0 to 500C for from I to 10 hours. The
N- protecting group R' may also be removed by hydrogenation, but when the preferred bromo - t - butoxy carbonyl group is used the deblocking is conveniently achieved by heating a solution of IV or carboxyl-deblocked IV in a solvent such as ethanol, isopropanol or water at 25-800C for from 10 minutes to 3 hours.
The products of this invention (I) form a wide variety of pharmacologically acceptable salts with inorganic and organic bases; these include, for example,
metal salts derived from alkali metal or alkaline-earth metal hydroxides, carbonates or bicarbonates and salts derived from primary, secondary or tertiary
amines such as monoalkylamines, dialkylamines, trialkylamines, lower alkanolamines, di-loweralkanolamines, lower alkylenediamines, N,N-diaralkyl lower alkylenediamines, aralkylamines, amino substituted lower alkanols, N,N di- lower alkylamino substituted lower alkanols, amino-, polyamino- and guanidino-substituted lower alkanoic acids and nitrogen-containing heterocyclic amines. Representative examples include salts derived from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, calcium carbonate, trimethylamine, triethylamine, piperidine, morpholine, quinine, lysine, protamine, arginine, procaine, ethanolamine, morphine, benzylamine, ethylenediamine, N,N' - dibenzylethylenediamine, diethanolamine, piperazine, dimethylaminoethanol, 2 - amino - 2 - methyl - 1 propanol, theophylline and N - methylglucamine. Salts of the primary amine of I with pharmaceutically acceptable organic and inorganic acids are also contemplated. Such salts include methanesulfonate, 2 - naphthalenesulfonate, pamoate, 3 - phenyl propionate, tri - methylacetate, t - butyl acetate, p toluenesulfonate, maleate, lactate, cyclamate, fumarate, tartrate, oxalate, benzoate, acetate, succinate, citrate, glutamate, hydrochloride, hydrobromide, sulfate, phosphate, N- acetylglycinate benzenesulfonate, hexanoate, pchlorobenzenesulfonate, cyclopentanepropionate, 1,2 - ethane disulfonate, gluroheptanoate, ethanesulfonate, o - (4 - hydroxybenzoyl) - benzoate and 2 hydroxyethanesulfonate; and are prepared according to well-known procedures.
The salts can be mono- salts, such as the mono- sodium salt obtained by treating one equivalent of sodium hydroxide with one equivalent of the product (I), or mixed di-salts. Such salts may be obtained by treating one equivalent of a base having a bivalent cation, such as calcium hydroxide, with one equivalent of the 'product(l). The salts of this invention are pharmacologically acceptable nontoxic derivatives which can be used as the active ingredient in suitable unit dosage pharmaceutical forms. Also, they may be combined with other drugs to provide compositions having a broad spectrum of activity.
The compounds of the present invention, I, and salts thereof are valuable antimicrobial substances which are active against various gram-positive and gramnegative pathogens. Thus, the free acid, and especially the salts thereof such as amine and metal salts, particularly the alkali metal and alkaline-earth metal salts, are useful bactericides and can be used for removing susceptible pathogens from dental and medical equipment, for separating microorganisms, and for therapeutic use in humans and animals. For this latter purpose pharmacologically acceptable salts with inorganic and organic bases such as those known in the art and used for the administration of penicillins and cephalosporins can be utilized. For example, salts such as alkali metal and alkaline-earth metal salts, and primary, secondary and tertiary amine salts can be used for this purpose. These salts can be combined with pharmaceutically acceptable liquid and solid vehicles to form suitable dosage unit forms such as pills, tablets, capsules suppositories, syrups and elixirs, which can be prepared in accordance with procedures well known in this art.
The novel compounds are valuable antibiotics active against various grampositive and gram-negative bacteria and, accordingly, find utility in human and veterinary medicine. The compounds of this invention can therefore be used as antibacterial drugs for treating infections caused by gram-positive or gram-negative bacteria, for example against Staphylococcus aureus, Escherichia coli, Klebsiella penumoniae, Bacillus subtilis, Salmonella Typhosa, Pseudomonas and Bacterium proteus. The antibacterials of the invention may further be utilized as additives to animal feedingstuffs and for preserving foodstuffs and as disinfectants. For example, they may be employed in aqueous compostions in concentrations ranging from 0. I to 100 parts of antibiotic per million parts of solution in order to destroy and inhibit the growth of harmful bacteria on medical and dental equipment and as bactericides in industrial applications, for example in waterbased paints and in the white water of paper mills to inhibit the growth of harmful bacteria.
The products of this invention may be used alone or in combination as an active ingredient in any one of a variety of pharmaceutical preparations. These antibiotics and their corresponding salts may be employed in capsule form or as tablets, powders or liquid solutions or as suspensions or elixirs. They may be administered orally, intravenously or intramuscularly.
The compositions are preferably presented in a form suitable for absorption by the gastro-intestinal tract. Tablets and capsules for oral administration may be in unit-dose presentation form, and may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica; disintegrants, for example, potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of aqueous or oily suspension, solution, emulsions, syrups or elixirs or may be presented as a dry product, for reconstitution with water or other suitable vehicles before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible oils, for example almond oil, fractionated coconut oil, oily esters, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p - hydroxybenzoates or sorbic acid. Suppositories will contain conventional suppository bases, e.g., cocoa butter or other glyceride.
Compositions for injection may be presented in unit dose form in ampoules, or in multidose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing 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.
The compositions may also be prepared in suitable forms for absorption through the mucous membranes of the nose and throat or bronchial tissues and may conveniently take the form of powder or liquid sprays or inhalants, lozenges or throat paints. For medication of the eyes or ears, the preparations may be presented as individual capsules or in liquid or semi-solid form, or may be used as drops etc. Topical applications may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints and powders.
Also, in addition to a carrier, the compositions may include other ingredients such as stabilizers, binders, antioxidants, preservatives, lubricators, suspending agents, viscosity agents or flavoring agents. In addition, there may also be included in the composition other active ingredients to provide a broader spectrum of antibiotic activity.
For veterinary medicine the composition may, for example, be formulated as an intramammary preparation in either long-acting or quick-release bases.
The dosage to be administered depends to a large extent upon the condition of the subject being treated, the weight of the host and the route and frequency of administration, the parenteral route being preferred for generalized infections and the oral route for intestinal infections. In general, a daily oral dosage consists of from 15 to 600 mg. of active ingredient per kg. of body weight of the subject in one or more applications per day. A preferred daily dosage for adult humans lies in the range of from 80 to 120 mg of active ingredient per kg. of body weight.
The compositions may be administered in several unit dosage forms, for example, in solid or liquid orally ingestible dosage forms. The compositions per unit dosage, whether liquid or solid, may contain from 0.1% to 99% of active material, the preferred range being from l0--60%. The composition will generally contain from 15 mg. to 1500 mg. of the active ingredient; however, it is usually preferable to employ a dosage in the range of from 250 mg to 1000 mg. In parenteral administration the unit dosage is usually the pure compound is a slightly acidified sterile water solution or in the form of a soluble powder intended for solution.
The following examples, in which the words "Dowex", Nujol" and "XAD" are trade marks, illustrate but do not limit the present invention.
EXAMPLE I
Preparation of N-Bromo-t-Butyloxycarbonyl Thienamycin Sodium Salt
Method A: Thienamycin (190 mg) dissolved in 15 ml. O.IM phosphate buffer and 15 ml dioxane is kept at OOC. The solution is adjusted and maintained between pH 8.5-9.0 with IN NaOH while 480 mg of bromo - t - butyl chloroformate is added to the solution during a period of 5 min. The mixture is stirred for 30 min, and then is neutralized to pH 7.0 with 1N HCI and extracted with ether. The aqueous layer is separated, concentrated to 10 ml and chromatographed on a Dowax-SOx8 (Na
Form) column (1.5"x 10"), which is eluted with H2O to give 113 mg of the desired product after lyophilization.
Method B: Thienamycin (95 mg) in 10 ml 0.1M phosphate buffer and 10 ml dioxane is kept at OOC. The pH of the solution is adjusted and maintained between 8.5-3.9 while 240 mg of bromo - t - butyl chloroformate is added. The mixture is stirred for 30 min, and then is acidified to pH 2.0 with H3PO4. The acidified solution is extracted with 2x25 ml ethyl acetate. The organic layer is separated and backextracted with 10 ml of aqueous NaNCO3 solution (solution contains 30 mg of
NaHCO3). The aqueous layer provides 30 mg of the desired product after lyophilization. NMR (60 MHz, D2O): a 1.26 (d), 1.60 (s), 2.65-3.50 (m), 3.70 (s), and 3.904.20 (m). UVmD2aOx 303 nm.
EXAMPLE 2
Preparation of N-Bromo-t-Butyloxycarbonyl thienamvcin
p-nitrobenzyl ester
The lyophilized N - bromo - t - butyloxycarbonyl thienamycin sodium salt (100 mg) is stirred at 260C with p - nitrobenzyl bromide (300 mg) in 2 ml hexamethylphosphoramide for 1 hr. The mixture is diluted with 10 ml ethyl acetate and then washed thoroughly with water. The organic layer is separated, dried over
Na2SO4 and chromatographed on two 250 u silica gel GF TLC plates using ethyl acetate as solvent (R, 0.45) to give 50 mg of the desired product. IR (CDCI3): 1777 (p lactam) and 1711 cm-' (ester); UVmEatOxH 270 nm and 322 nm; Nmr (CDCl3, 60
MHz): a 1.38 (d), 1.58 (s), 2.603.80 (m), 3.78 (s), 3.904.20 (m), 5.30 (s), 7.55 (d) and 8.30 ppm (d).
The benzyl ester is obtained as above except an equivalent amount of benzyl bromide is substituted for the p - nitrobenzyl bromide of Example 2.
EXAMPLE 3
Preparation of N-Benzyloxycarbonyl thienamycin benzyl ester
Thienamycin (214 mg, 0.79 mmol) is dissolved in ice-cold, deionized H2O (22 ml) and the solution is stirred with ice-bath cooling; NaHCO3 (995 mg, 11.85 mmol) is added all at once and stirring is continued for 5 mins. Dioxane (17.6 ml) is then added and the solution is stirred 5 more minutes. An ice-cold solution of benzyl chloroformate (242 mg, 1.42 mmol) in TMF (5 ml) is then added in 5 equal portions over 16 mins. After stirring for 15 more minutes in the cold, the reaction mixture is layered with ice-cold diethylether (Et2O) (40 ml) and acidified to pH 6.8 with cold 5% aqueous H3PO4. The layers are separated and the aqueous portion is extracted with more cold Et2O (2x30 ml). The aqueous phase is layered with ice-cold ethyl acetate (EtOAc, 35 ml) and the mixture is stirred rapidly with ice-bath cooling while the pH is brought to 2.4 with cold 10% aqueous H3PO4. The layers are separated and the aqueous portion extracted with more cold EtOAc (15 ml). The combined EtOAc solution is washed with ice-cold brine (20 ml) dried with Na2SO4 in the cold, and filtered. This solution contains N- benzyloxycarbonyl thienamycin.
Ice-cold, ethereal phenyldiazomethane (15 ml of a 0.25 M solution) is added to the EtOAc solution and the resulting solution is left in a refrigerator for one hour.
The solvents are evaporated in vacuo and the residue is twice diluted with EtOAc and stripped in vacuo to remove dioxane. The residue is dissolved in EtOAc (5 ml) and the solution slowly diluted with Et2O (5 ml). After storing in a refrigerator overnight, the mixture is filtered to remove the precipitate. This material is washed with cold Et2O and dried in vacuo to yield N - benzyloxycarbonyl thienamycin benzyl ester (160 mg) as an off-white solid.
The mother liquors and washings are combined and evaporated in vacuo. The residue is triturated with hexane (3x50 ml), dissolved in EtOAc, and passed through a sintered glass funnel containing silica gel (2 g). The silica gel pad is washed with more EtOAc. The combined EtOAc eluant is evaporated in vacuo to about 1 ml, diluted with Et2O to 5 ml., and left in a refrigerator for two days. The precipitate is collected, washed with cold Et2O and dried in vacuo to yield additional N benzyloxycarbonyl thienamycin benzyl ester (48 mg) as. white flakes.
The first crop of product has: mp 125126 (micro hot stage); ir (CH2CI2) 3608, 3424, 1780, 1720, 1514, 1332, 1206, and 1137 cm-', uv (dioxane)317 (E 11,800) nm; nmr (CDCl3) a 1.34 (d, 3, CH3), 2.70--3.55 (m, 7, CH2, SCH2, INCH2, H6) 4.16 (m, 2, H5, H8), 5.10 (s, 2, NCO2CH2), 5.29 (ABq, 2, CO2CH2), and 7.32 (m, 10, ArH).
EXAMPLE 4
N-Benzyloxycarbonyl thienamycin benzyl ester
Thienamycin (798 mg, 2.93 mmol) is dissolved in ice-cold H2O (200 ml) and the resulting solution is stirred with ice-bath cooling. Solid NaRCO3 (2.462 g, 29.3 mmol) is added in one portion and, after a few minutes, dioxane (200 ml) is added.
The resulting mixture is stirred in the cold for 3 mins and then treated dropwise over 10 minutes with a solution of benzyl chloroformate (750 mg, 4.4 mmol) in anhydrous dioxane (12 ml). After stirring an additional 10 minutes in the cold, the reaction mixture is extracted with ice-cold Et2O (2x 120 ml). The aqueous portion is layered with cold EtOAc (100 ml) and vigorously stirred while acidifying to pH 2.3 with cold 1M H2SO4. The layers are separated and the aqueous phase is extracted with additional cold EtOAc (2x30 ml). The combined EtOAc solution is washed with ice-cold brine (50 ml) and then extracted with ice-cold 0.05 N LiOH (58.6 ml).
The aqueous LiOH extract is rotary evaporated in vacuo to remove EtOAc and then lyophilized to provide crude N - benzyloxycarbonyl thienamycin lithium salt (1.0 g) as a light-yellow solid.
A sample of the above lithium carboxylate (864 mg) is suspended in anhydrous hexamethylphosphoramide (HMPA) (15.7 ml) and treated with benzyl bromide (1.15 ml). The resulting mixture is stirred under N2 at 250C. for 2 hrs, then diluted with EtOAc (350 ml) and washed with H2O (2x300 ml), 5% NaHCO3 (150 ml), H2O (2x 150 ml) and brine (150 ml). The EtOAc solution is dried with MgSO4, filtered and evaporated in vacuo to a gummy residue. This material is triturated with hexane (5x 10 ml) to remove excess of benzyl bromide and dried in vacuo to a light-yellow solid (817 mg). The crude product is dissolved in warm EtOAc (15 ml) and diluted with Et2O (15 ml). The resulting solution is seeded and left in a freezer overnight.
The precipitate is collected, washed with cold Et2O, and dried in vacuo to yield N benzyloxycarbonyl thienamycin benzyl ester (405 mg) as an off-white solid.
The mother liquors and washings are evaporated in vacuo to an oily residue which is dissolved in warm EtOAc (-5 ml) and diluted with Et2O (~10 ml). The solution is left in a freezer for several days to yield a second crop of product (106 mg) as a yellow solid.
EXAMPLE 5
N-Benzyloxycarbonyl O-methanesulfonyl thienamycin benzyl ester
N- Benzyloxycarbonyl thienamycin benzyl ester (tu mg, u.I mmol) Is dissolved in anhydrous CH2Cl2 (3.0 ml) and the solution is stirred with ice-bath cooling under a N2 atmosphere. Triethylamine (Et3N) (27.9 l, 0.2 mmol) is added to the solution followed by dropwise addition over 5 mins of a solution of methanesulfonyl chloride (17.2 mg, 0.15 mmol) in CH2C12 (0.4 ml). The resulting solution is stirred in the cold for 90 mins, then diluted with ice-cold CH2C12 (10 ml), washed with cold H2O (5 ml), cold 0.1M pH 3 phosphate buffer (2 ml) and cold 2%
NaHCO3 (5 ml), dried with MgSO4, and filtered. Evaporation of the solvent in vacuo affords N - benzyloxycarbonyl 0 - methanesulfonyl thienamycin benzyl ester (57 mg) as a pale-yellow oil: nmr (CDCl3) 1.56 (d, 3, CHCH3), 2.82-3.52 (m, 7, CH2 SCHIZ, NCH2, H6), 3.00 (s, 3, CH3SO2), 4.28 (d oft, 1, H5), 5.08 (d of q, 1, H8), 5.09 (s, 2, NCO2CM2, 5.26 (ABq, 2, CO2CM2, and 7.32 (m, 10, ArH).
Following the above procedure, N - bromo - t - butyloxycarbonyl 0 methanesulfonyl thienamycin p - nitrobenzyl ester is obtained when the N benzyloxycarbonyl thienamycin benzyl ester is replaced by an equivalent amount of N - bromo - t - butyloxycarbonyl thienamycin p - nitrobenzyl ester.
EXAMPLE 6 B enzyl 6-ethylidene-3-(2-benzyloxycarbonylaminoethyl)-thio-7- oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
Powdered NaHCO3 (12.9 mg, 0.154 mmol) is added to a solution of N benzyloxycarbonyl 0 - methanesulfonyl thienamycin benzyl ester (44 mg, 0.077 mmol) in anhydrous methanol and the resulting mixture is stirred at 25"C. for 100 mins. The mixture is diluted with CH2C12 (15 ml) washed with H2O (3x5 ml), dried over MgSO4, filtered, and evaporated in vacuo to an oil (33 mg). This material is purified by tIc on a 250 x20x20 cm silica gel GF plate, using 3:1 EtOAc-CHC13 as developing solvent. The major UV visible band is removed and eluted with EtOAc to give an oil (24 mg). This material is rechromatographed as described to provide benzyl 6 - ethylidene - 3 - (2 - benzyloxycarbonylaminoethyl) - thio - 7 - oxo 1 - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylate (16 mg) as a pale-yellow oil: irCMCl3)36f0, 1779, 1715, 1508, 1330, 1271, 1178,and and 1121 cm-';nmr(CDCI3)8 1.80 (d, 3, CH3), 2.6-3.6 (m, 6, CH2, SCH2, NCH;), 4.68 (d oft, 1, H5), 5.07 (s, 2, NCO2CM2, 5.28 (s, 2, CO2CM2, 6.36 (d of q, 1, =CH), and 7.3 (m, 10, ArH); uv (MeOH) 306 (E 6500) nm; mass spectrum m/e 478 (M+), 410, 343, 269, and 210.
Following the above procedure, p - nitrobenzyl 6 - ethylidene - 3 - (2 bromo - t - butyloxycarbonylaminoethyl)thio - 7 - oxo - I azabicyclo[3.2.0]hept - 2- ene - 2- carboxylate is obtained when the N benzyloxycarbonyl 0 - methanesulfonyl thienamycin benzyl ester of Example 6 is replaced by an equivalent amount of N - bromo - t - butyloxycarbonyl 0 methanesulfonyl thienamycin p - nitrobenzyl ester from Example 5.
EXAMPLE 7
B enzyl 6-ethyl-3-(2-benzyloxycarbonylaminoethyl)thio-7
oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
A mixture of benzyl 6 - ethylidene - 3 - (2 - benzyloxycarbonylaminoethyl)thio - 7 - oxo - I - azabicyclo[3.2.0]hept - 2 ene - 2 - carboxylate (4 mg) as an oil: ir (CHCI3) 3470, 1776,1715,1505,1325, 1276, 1230 and 1125 cm-t, nmr (CDCl3) a 1.01 (t, 3, CH2CH), 1.77 (m, 2CH2, CM), 2.8- 3.6 (m, 7, CH2, SCH2, NCH2, H6), 4.19 (d of t, H5), 5.09 (s, 2, NCO3CM2()) 5.27 (ABq, 2, CO2CH2), and 7.32 (m, 10, ArH); uv (MeOH) 316 nm; mass spectrum m/e 480 (M+), 410.
Following the above procedures, p - nitrobenzyl 6 - ethyl - 3 - [2 - (bromo t - butoxycarbonylamino)thio - 7 - oxo - I - azabicyclo[3.2.0]hept - 2 - ene - 2 carboxylate is obtained when the benzyl 6 - ethylidene - 3 - (2 benzyloxycarbonylaminoethyl)thio - 7 - oxo - 1 - azabicyclo[3.2.0]hept - 2ene - 2 - carboxylate of Example 7 is replaced by an equivalent amount of p nitrobenzyl 6 - ethylidene - 3 - (2 - bromo - t - butyloxycarbonylaminoethyl) thio - 7 - oxo - I - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylate.
EXAMPLE 8
6-Ethylidene-3-(2-aminoethyl)thio-7-oxo- 1 -azabicyclo [3.2.01- hept-2-ene-2-carboxylate
Benzyl 6 - ethylidene - 3 - (2 - benzyloxycarbonylaminoethyl)thio - 7 oxo - 1 - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylate (10 mg) is dissolved in
EtOH (4 ml) and treated with 0.1M pH 7 phosphate buffer (2 ml) and 10% Pd/C (20 mg). The mixture is hydrogenated at atmospheric pressure at 250 C, for 1 hr, and then filtered. The filtrate is concentrated in vacuo to 2 ml and extracted with
EtOAc. The aqueous portion is chromatographed on a Dowex-SOx4 (sodium form) ion-exchange column, using deionized H2O as eluting solvent. The desired fractions are combined and lyophilized to afford 6 - ethylidene - 3 - (2 aminoethyl)thio - 7 - oxo - 1 - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylate.
EXAMPLE 9
6-Ethyl-3-(2-aminoethyl)thio-7-oxo- 1 -azabicyclo[3 .2.0{- hept-2-ene-2-carboxylic acid
A mixture of benzyl 6 - ethyl - 3 - (2 - benzyloxycarbonylaminoethyl)
thio - 7 - oxo - 1 - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylate (10 mg) and
10% Pd/C (20 mg) in 1:1 dioxane-H2O (4 ml) is hydrogenated at 40 psi for I hr. The
mixture is filtered to remove the catalyst which is washed with more H2O (4 ml).
The combined filtrate and washings are concentrated in vacuo to 2 ml and loaded onto a column of 200400 mesh Dowex-SOx4 (Na form) ion-exchange resin. The column is eluted with deionized 1120. The appropriate fractions are pooled and
lyophilized to provide 6 - ethyl - 3 - (2 - aminoethyl)thio - 7 - oxo - 1 - azabicyclo[3.2.0]hept - 2 - -ene - 2 - carboxylic acid.
EXAMPLE 10
Preparation of Sodium 6-ethyl-3-[2-(bromo-t-butoxycarbonylamino)- ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
p-Nitrobenzyl 6 - ethyl - 3 - [2 - (bromo - t butoxycarbonylamino)ethylthio] - 7 - oxo - 1 - azabicyclo[3.2.0]hept - 2 - ene 2 - carboxylate (20 mg) is dissolved in 4 ml. ethanol. To the solution is added 2 ml pH 8.0, 0. IM phosphate buffer and 60 mg of 10% Pd/C. The mixture is stirred under 1 atm of H2 at 250C for 75 min, and then filtered from the catalyst. The filtrate is neutralized to pH 7.0 with 2.5 N HCI, concentrated to 3 ml and briefly extracted with 5 ml ether. The aqueous solution so obtained contains sodium 6 - ethyl - 3 [2 - (bromo - t - butoxycarbonylamino)ethylthio] - 7 - oxo - I azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylate.
EXAMPLE 11
Preparation of 6-ethyl-3-(2-aminoethyl)thio-7-oxo-1-azabicyclo[3.2.0]-
hept-2-ene-2-carboxylic acid
The solution obtained in the previous example which contains sodium 6 ethyl - 3 - [2 - (bromo - t - butoxycarbonylamino)ethylthio] - 7 - oxo - I azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylate, is heated at 665"C for I hr.
The mixture is chromatographed on a Dowex-SOx8 (Na form) ion-exchange column which is eluted with water to give the desired 6 - ethyl - 3 - (2 aminoethyl)thio - 7 - oxo - 1 - azabicyclo[3.2.0] - hept - 2 - ene - 2 - carboxylic acid.
EXAMPLE 12
N-(p-nitrobenzyloxycarbonyl)thienamycin p-nitrobenzyl ester
Thienamycin (140 mg, 0.51 mmol) is dissolved in ice-cold H2O (35 ml) and the solution is treated with NaHCO3 (428 mg, 5.1 mmol). Dioxane (35 ml) is then added with stirring and ice-bath cooling. After 3 mins, a solution of p - nitrobenzyl chloroformate (165 mg, 0.765 mmol) in dioxane (2 ml) is added dropwise over 2 mins. The resulting mixture is stirred in the cold for 10 mins and then extracted with ice-cold Et2O (2x20 ml). The aqueous phase is sepated, layered with ice-cold
EtOAc (35 ml), and acidified to pH 2.3 with 1M H2SO4 while vigorously stirring in an ice-bath. The layers are separated and the aqueous portion extracted with more cold EtOAc (2x5 ml). The combined EtOAc extracts are washed with ice-cold brine and then extracted thoroughly with 0.05 N aq LiOH (10 ml). The LiOH extract is rotary evaporated to remove EtOAc and then lyophilized to provide crude N-(p - nitrobenzyloxycarbonyl)thienamycin lithium salt (288 mg) as a yellow solid.
A portion of the crude lithium carboxylate (250 mg) and p - nitrobenzyl bromide (373 mg, 1.73 mmol) in anhydrous HMPA (2.65 ml) are stirred at room temperature for 105 mins. The mixture is diluted with EtOAc (60 ml), washed with H2O (2xS0 ml), 5% NaHCO3 (25 ml), H2O (2x25 ml), and brine (25 ml), dried with
MgSO4, filtered, and evaporated i.v. to a yellow solid (423 mg). This material is triturated with Et2O to remove excess p - nitrobenzyl bromide and the remaining crystals are filtered off and dried i.v. to yield N - (p - nitrobenzyloxycarbonyl)thienamycin p - nitrobenzyl ester (126 mg) as a yellow solid: mp 163.5--165"; ir (Nujol mull) 1773 and 1690 cm-'; nmr (DMSO-d6) a 1.15 (d, 3, CH3), 2.8-3.6 (m, 7, CH2, SCH2, NCH2, H6), 4.0 (m, 2, H5, H8), 5.22 (s, 2, NCO2CH2Ar), 5.40 (ABq, 2, CO2CH2Ar), 7.70 (m, ArH), 8.27 (m, ArH).
EXAMPLE 13
N-(p-nitrobenzyloxycarbonyl) O-methanesulfonyl thienamycin
p-nitrobenzyl ester
To an ice-cold, stirring solution of N - - (p - nitrobenzyloxycarbonyl) thienamycin p - nitrobenzyl ester (186 mg, 0.32 mmol) in anhydrous tetrahydrofuran (THF) (9.5
ml) is added Et3N (89 ,ul, 0.64 mmol) and, dropwise over 2 mins, a solution of
methanesulfonyl chloride (55 mg, 0.48 mmol) in T11F (1.0 ml). The resulting
mixture is stirred in the cold and under N2 for 90 mins, and then diluted with ice
cold CH2C12 (50 ml). The solution is washed with cold H2O (20 ml), cold 0. I M pH 3
phosphate buffer (20 ml), and cold 5% NaHCO3 (20 ml), dried with MgSO4, filtered,
and evaporated in vacuo to a yellow foam. This material is triturated with anhydrous
Et2O to provide N - (p - nitrobenzyloxycarbonyl) 0 - methanesulfonyl thienamycinp - nitrobenzyl ester (192 mg) as apale-yellow solid: mp 131133 ; ir (CH2CI2) 1786, 1727, 1522, and 1350 cm-l; nmr (DMSO-d6) 1.42 (d, 3, CH3), 2.5
3.4 (m, 7, CH2, SCH2, INCH2, H6), 3.25 (s, 3, CH3SO2), 3.93 (m, 1, H5), 5.03 (m, 1,
H8), 5.20 (s, 2, NCO2CH2Ar), 5.43 (m, 2, CO2CH2Ar), 7.63 (m, ArH), and 8.25 (m, ArH); mass spectrum m/e 664 (M+), 578, 500, 415, 372, 304.
Anal., calculated for C2,H28N4O,2S2: C, 48.79, ~ H, 4.25; N, 8.43; S, 9.65.
Found: C, 49.i9; Hit.36: N, 8.09; S, 9.61.
EXAMPLE 14
p-Nitrobenzyl 6-ethylidene-3-[2-(p-nitrobenzyloxycarbonylamino)ethylthio]- 7-oxo- 1 -azabicyclo [3.2.0] hept-2-ene-2-carboxylate
A solution of N - (p - nitrobenzyloxycarbonyl) 0 - methanesulfonyl
thienamycin p - nitrobenzyl ester (50 mg, 0.075 mmol) in anhydrous dioxane (0.75 ml) is treated with anhydrous MeOH (2.5 ml) and NaHOC3 (12.6 mg, 0.15 mmol).
The resulting mixture is stirred at room temperature for 17 hours. The precipitate is
filtered off, washed with several portions of H2O, and dried in vacuo to yield p nitrobenzyl 6 - ethylidene - 3 - [2 - (p - nitrobenzyloxycarbonylamino)ethylthio] - 7 - oxo - 1 - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylate (32 mg) as a white solid: mp 160--161b; ir (CH2CI2) 1779, 1730, 1524, and 1351 cm-'; nmr (DMSO-d6) a 1.86 (d, 3, CH3), 2.8-3.8 (m, 6, CH2, SCH2, Cm2); 4.85 (ml, H5), 5.22 (s, 2, NCO2CH2Ar), 5.42 (Abq, 2, CO2CH2Ar), 6.44 (m, 1, =CH), 7.68 (m, ArH), and 8.25 (m, ArH); mass spectrum m/e 500 (M+ -68), 415, 304, 256, 239, 223, 209.
EXAMPLE 15
6-Ethyl-3-(2-aminoethyl)thio-7-oxo- 1 -azabicyclo[3 .2.0] - hept-2-ene-2-carboxylic acid
A mixture of p-nitrobenzyl 6 - ethylidene - 3 - [2 - (p nitrobenzyloxycarbonylamino)ethylthio] - 7 - oxo - I - azabicyclo[3.2.0]hept 2 - ene - 2 - carboxylate (37 mg), PtO2 (40 mg), THF (4 ml) and EtOH (2 ml) is hydrogenated at 50 psi and 25"C., for 2.5 hrs. The catalyst is filtered off and washed thoroughly with 0.1M pH 7 phosphate buffer (5 ml). The combined filtrate and washings are concentrated in vacuo to remove most of the organic solvents. The aqueous residue is chromatographed on a column of Dowex-SOx4 (Na form) ionexchange resin: the product being eluted with deionized H2O. The appropriate fractions are combined and lyophilized to afford 6 - ethyl - 3 - (2 aminoethyl)thio - 7 - oxo - I - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylic acid.
EXAMPLE 16
O-Sulfo-Thienamycin
To a solution of 50 mg of N - (p - nitrobenzyloxycarbonyl) thienamycin p nitrobenzyl ester in 0.5 ml of pyridine is added 20 mg of pyridine sulfuric anhydride.
The mixture is allowed to react at 250 for 4 hours then the excess of pyridine is removed under reduced pressure. The residue is stirred with 20 ml each of methylene chloride and 0.1% sodium bicarbonate solution for 30 minutes then the aqueous layer is separated and freeze dried. The solid residue containing 0 - sulfo
N - (p - nitrobenzyloxycarbonyl)thienamycin p - nitrobenzyl ester, sodium salt is dissolved in 20 ml of 1:1 aqueous dioxane and hydrogenated for four hours in the presence of 5.0 mg of platinum oxide catalyst at 40 PSIG. The catalyst is filtered and the filtrate is extracted twice with ethyl acetate. The aqueous layer is concentrated to 5 ml and chromatographed on 40 ml of XAD-2 resin. The column is eluted with water and the fraction containing O-sulfo thienamycin sodium salt is recovered and freeze dried.
EXAMPLE 17
Preparation of Pharmaceutical Compositions
One such unit dosage form consists in mixing 120 mg 3 - (2 - aminoethylthio) - 6 - ethyl - 7 - oxo - I - azabicyclo[3.2.0] - hept - 2 - ene - 2 carboxylic acid with 20 mg. of lactose and 5 mg. of magnesium stearate and placing the 145 mg mixture into a No. 3 gelatin capsule. Similarly, by employing more of the active ingredient and less lactone, other dosage forms can be put up in No. 3 gelatin capsules and should it be necessary to mix more than 145 mg of ingredients together, larger capsules such as compressed tablets and pills can also be prepared.
The following examples are illustrative of the preparation of pharmaceutical formulations:
Tablet Per Tablet
3 - (aminoethylthio) - 6 - ethyl - 7 - oxo - I
azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylic acid 125 mg.
Cornstarch, U.S.P. 6 mg.
Dicalcium Phosphate 192 mg.
Lactose, U.S.P. 190 mg.
The active ingredient is blended with the dicalcium phosphate, lactose and about half of the cornstarch. The mixture is then granulated with 15% cornstarch paste (6 mg.) and rough-screened. It is dried at 450C. and screened again through
No. 16 screens (U.S. standard). The balance of the cornstarch and the magnesium stearate is added and the mixture is compressed into tablets, approximately 0.5 inch in diameter each weighing 800 mg.
Parenteral Solution
Ampoule: 3 - (2 - aminoethylthio)- 6 - ethyl - 7 - oxo - 1 azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylic
acid 500 mg.
diluent: sterile water for injection 2 ml.
Opthalmic Solution
3 - (2 - aminoethylthio)- 6 - ethyl - 7 - oxo - 1 azabicyclo[3.2.0] hept - 2 - ene - 2 - carboxylic acid 100 mg.
Hydroxypropylmethyl cellulose 5 mg.
Sterile Water I ml.
Optic Solution
3 - (2 - aminoethylthio)- 6 - ethyl - 7 - oxo - 1 azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylic acid 100 mg.
Benzalkonium Chloride 0.1 mg.
Sterile Water I ml.
Topical Ointment 3 - (2 - arninoethylthio) - 6 - ethyl - 7 - oxo - 1 - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylic acid 100 mg.
Polyethylene Glycol 4000 U.S.P. 400 mg.
Polyethylene Glycol 400 U.S.P. 1.0 gram
The active ingredient in the above formulations may be administered alone or in combination with other biologically active ingredients as, for example, with other antibacterial agents such as lincomycin, a penicillin, streptomycin, novobiocin, gentamicin, neomycin, colistin and kanamycin, or with the other therapeutic agents such as probenecid.
WHAT WE CLAIM IS:
1. A compound having the structural formula:
and its pharmaceutically acceptable salts.
2. A compound having the structural formula:
wherein each of R' and R is hydrogen or an easily removable protecting group.
3. A compound according to Claim 2 where R' and R are both hydrogen.
4. A compound having the structural formula:
where R' and R are hydrogen (R' and R are not both hydrogen at the same time) or an easily removable protecting group.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (17)
- **WARNING** start of CLMS field may overlap end of DESC **.The active ingredient is blended with the dicalcium phosphate, lactose and about half of the cornstarch. The mixture is then granulated with 15% cornstarch paste (6 mg.) and rough-screened. It is dried at 450C. and screened again through No. 16 screens (U.S. standard). The balance of the cornstarch and the magnesium stearate is added and the mixture is compressed into tablets, approximately 0.5 inch in diameter each weighing 800 mg.Parenteral Solution Ampoule: 3 - (2 - aminoethylthio)- 6 - ethyl - 7 - oxo - 1 azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylic acid 500 mg.diluent: sterile water for injection 2 ml.Opthalmic Solution3 - (2 - aminoethylthio)- 6 - ethyl - 7 - oxo - 1 azabicyclo[3.2.0] hept - 2 - ene - 2 - carboxylic acid 100 mg.Hydroxypropylmethyl cellulose 5 mg.Sterile Water I ml.Optic Solution3 - (2 - aminoethylthio)- 6 - ethyl - 7 - oxo - 1 azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylic acid 100 mg.Benzalkonium Chloride 0.1 mg.Sterile Water I ml.Topical Ointment 3 - (2 - arninoethylthio) - 6 - ethyl - 7 - oxo - 1 - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylic acid 100 mg.Polyethylene Glycol 4000 U.S.P. 400 mg.Polyethylene Glycol 400 U.S.P. 1.0 gram The active ingredient in the above formulations may be administered alone or in combination with other biologically active ingredients as, for example, with other antibacterial agents such as lincomycin, a penicillin, streptomycin, novobiocin, gentamicin, neomycin, colistin and kanamycin, or with the other therapeutic agents such as probenecid.WHAT WE CLAIM IS: 1. A compound having the structural formula:and its pharmaceutically acceptable salts.
- 2. A compound having the structural formula:wherein each of R' and R is hydrogen or an easily removable protecting group.
- 3. A compound according to Claim 2 where R' and R are both hydrogen.
- 4. A compound having the structural formula:where R' and R are hydrogen (R' and R are not both hydrogen at the same time) or an easily removable protecting group.
- 5. A process for preparing a compound according to Claim I comprisingtreating a compound of the formula:with a reducing agent; where R and R' are as defined in Claim 2.
- 6. A process for preparing a compound according to Claim 2 comprising treating a compound of the formula:with base; wherein the residue OR" is an easily eliminable group and R' and R are as defined in Claim 2.
- 7. The process of Claim 6 where R" is sulfo or an organo sulfonyl group.
- 8. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutical carrier.
- 9. A pharmaceutical composition comprising, in unitary dosage form, a therapeutically effective amount of a compound according to Claim 1 and a pharmaceutical carrier.
- 10. An animal or human food containing as an antibacterial agent a compound as claimed in Claim 1.
- 11. Waterbased paint containing as an antibacterial agent a compound as claimed in Claim 1.
- 12. White water of a paper mill containing as an antibacterial agent a compound as claimed in Claim 1.
- 13. A disinfectant in which the active antibacterial agent is a compound as claimed in Claim 1.
- 14. A composition as claimed in Claim 8 in the form of a tablet, capsule, powder, liquid suspension or solution, elixir, syrup, emulsion, water-dispersible composition, suppository, injectable liquid, liquid or powder spray or inhalent, lozenge, throat paint, ophthalmic or aural drops, ointment, cream, lotion, topically administrable paint, or intramammary veterinary preparation.
- 15. A composition as claimed in Claim 8 substantially as hereinbefore described with reference to any one of the embodiments of Example 17.
- 16. A process that produces a compound as claimed in any one of Claims I to 4 substantially as hereinbefore described with reference to any appropriate foregoing Example.
- 17. A compound as claimed in Claim 1, 2 or 4, when prepared by a process substantially as hereinbefore described with reference to any appropriate foregoing Example or an obvious chemical equivalent of such a process.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US78581177A | 1977-04-08 | 1977-04-08 | |
US86123077A | 1977-12-16 | 1977-12-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1595267A true GB1595267A (en) | 1981-08-12 |
Family
ID=27120448
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB13164/78A Expired GB1595267A (en) | 1977-04-08 | 1978-04-04 | Azabicyclohepthenes |
Country Status (11)
Country | Link |
---|---|
JP (1) | JPS53127491A (en) |
CH (1) | CH640236A5 (en) |
DE (1) | DE2815157A1 (en) |
DK (1) | DK123578A (en) |
FR (1) | FR2386545A1 (en) |
GB (1) | GB1595267A (en) |
IE (1) | IE47043B1 (en) |
IT (1) | IT1102456B (en) |
LU (1) | LU79403A1 (en) |
NL (1) | NL7802826A (en) |
SE (1) | SE7803173L (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GR62185B (en) * | 1977-03-31 | 1979-03-02 | Panlabs Inc | Preparation process of an antibiotic ps-5 and its derivatives with inhibitory activity of b-lactamase |
JPS5473788A (en) * | 1977-11-17 | 1979-06-13 | Sanraku Inc | Antibiotic n-desacetyl ps-5 |
EP0005349A1 (en) * | 1978-05-06 | 1979-11-14 | Beecham Group Plc | Alkylcarbapenems, their preparation, use in pharmaceutical compositions and intermediates |
JPS5572191A (en) * | 1978-11-22 | 1980-05-30 | Sanraku Inc | Antibiotic n-desacetyl ps-5 |
JPS55136282A (en) * | 1979-04-06 | 1980-10-23 | Shionogi & Co Ltd | Novel antibiotic pa-31088-4 |
US4235922A (en) * | 1979-06-15 | 1980-11-25 | Merck & Co., Inc. | 3-(2-Aminoethylthio)-6-ethyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid |
EP0055990B1 (en) * | 1979-08-10 | 1986-06-11 | Beecham Group Plc | Beta-lactam antibiotics, their preparation and use |
JPS5683489A (en) * | 1979-12-12 | 1981-07-08 | Shionogi & Co Ltd | New antibiotic pa-39504-x1 and it preparation |
JPS5764693A (en) * | 1980-10-07 | 1982-04-19 | Kowa Co | Novel carbapenem compound and its preparation |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3950357A (en) * | 1974-11-25 | 1976-04-13 | Merck & Co., Inc. | Antibiotics |
-
1978
- 1978-03-15 NL NL7802826A patent/NL7802826A/en not_active Application Discontinuation
- 1978-03-20 SE SE7803173A patent/SE7803173L/en unknown
- 1978-03-20 DK DK123578A patent/DK123578A/en unknown
- 1978-03-30 IE IE631/78A patent/IE47043B1/en unknown
- 1978-04-04 GB GB13164/78A patent/GB1595267A/en not_active Expired
- 1978-04-05 IT IT48747/78A patent/IT1102456B/en active
- 1978-04-06 FR FR7810238A patent/FR2386545A1/en active Granted
- 1978-04-07 DE DE19782815157 patent/DE2815157A1/en not_active Ceased
- 1978-04-07 JP JP4045678A patent/JPS53127491A/en active Pending
- 1978-04-07 CH CH379278A patent/CH640236A5/en not_active IP Right Cessation
- 1978-04-10 LU LU79403A patent/LU79403A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
CH640236A5 (en) | 1983-12-30 |
IT1102456B (en) | 1985-10-07 |
IE47043B1 (en) | 1983-12-14 |
IE780631L (en) | 1978-10-08 |
DK123578A (en) | 1978-10-09 |
SE7803173L (en) | 1978-10-09 |
DE2815157A1 (en) | 1978-10-19 |
LU79403A1 (en) | 1978-11-27 |
NL7802826A (en) | 1978-10-10 |
FR2386545A1 (en) | 1978-11-03 |
JPS53127491A (en) | 1978-11-07 |
IT7848747A0 (en) | 1978-04-05 |
FR2386545B1 (en) | 1980-08-01 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed [section 19, patents act 1949] | ||
PCNP | Patent ceased through non-payment of renewal fee |