GB1592224A - Thienamycin derivatives their production and their use as antibiotics - Google Patents
Thienamycin derivatives their production and their use as antibiotics Download PDFInfo
- Publication number
- GB1592224A GB1592224A GB17493/78A GB1749378A GB1592224A GB 1592224 A GB1592224 A GB 1592224A GB 17493/78 A GB17493/78 A GB 17493/78A GB 1749378 A GB1749378 A GB 1749378A GB 1592224 A GB1592224 A GB 1592224A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alkyl
- hydrogen
- bromine
- chlorine
- fluorine
- 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
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- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 12
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical class C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 title abstract description 19
- 229940088710 antibiotic agent Drugs 0.000 title abstract description 9
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 150000002148 esters Chemical class 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 3
- -1 dimethoxyphosphinyl Chemical group 0.000 claims description 61
- 239000000203 mixture Substances 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 20
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 239000011737 fluorine Substances 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 150000002431 hydrogen Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 238000005984 hydrogenation reaction Methods 0.000 claims description 10
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 239000005864 Sulphur Chemical group 0.000 claims description 8
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims description 8
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000005633 phthalidyl group Chemical group 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 239000003826 tablet Substances 0.000 claims description 7
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 230000003115 biocidal effect Effects 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000003973 paint Substances 0.000 claims description 6
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- 230000000844 anti-bacterial effect Effects 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 3
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
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- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 3
- 235000020357 syrup Nutrition 0.000 claims description 3
- 239000006188 syrup Substances 0.000 claims description 3
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- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 239000003708 ampul Substances 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 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
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- HVZWVEKIQMJYIK-UHFFFAOYSA-N nitryl chloride Chemical group [O-][N+](Cl)=O HVZWVEKIQMJYIK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims 1
- 229940098462 oral drops Drugs 0.000 claims 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 abstract description 19
- 238000003776 cleavage reaction Methods 0.000 abstract 1
- 230000007017 scission Effects 0.000 abstract 1
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
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- 238000010521 absorption reaction Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
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- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- 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 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 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 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
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- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
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- 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 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229960002950 novobiocin Drugs 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 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 description 1
- 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 description 1
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- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 230000002335 preservative effect Effects 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
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- 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
- 230000035484 reaction time Effects 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 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
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 235000000346 sugar Nutrition 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
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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- 238000006257 total synthesis reaction Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
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- 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 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
- C07D477/14—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 hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
-
- 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
- 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
- C07D477/02—Preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65611—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. penicillins and analogs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The therapeutically active compounds of the formula III, in which the dotted line indicates the unsaturated or saturated 2,3 bond and R' and X have the meaning given in Claim 1, as well as their pharmaceutically acceptable salts and esters, are valuable antibiotics. They can be obtained by hydrogenating cleavage and, where appropriate, by hydrogenating the double bond of thienamycin of the formula IV and its derivatives. <IMAGE>
Description
(54) THIENAMYCIN DERIVATIVES, THEIR
PRODUCTION AND THEIR USE AS
ANTIBIOTICS
(71) We, MERCK & CO. INC., a corporation organized and existing under the laws of New Jersey, United States of America, of Rahway, New Jersey,
United Sates 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. Known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms.
Moreover, there is no static effectiveness of a given antibiotic, which selectively gives rise to resistant strains of pathogens. Accordingly, the search for new antibiotics continues.
This invention is based on the discovery of 6 - ( - hydroxyethyl) - 7 -- oxo
I - azabicyclo[3 . 2 . 0]hept - 2 - ene - 2 - carboxylic acid and its pharmaceutically acceptable salts and esters, and 2,3-dihydro analogues of such compounds, which have been found useful as antibiotics, and of processes for the preparation of such compounds.
The free acid of the present invention is represented by the following structural formula:
where the dotted line indicates that the compound can be 2,3-saturated or 2,3unsaturated. Preferably the compound is of formula I:
The preferred compounds of the present invention have the general formula:
where the dotted line is as defined above; R' is hydrogen; phenyl; C16 alkyl, (Cl-6 alkoxy)-(C16 alkyl); C26 alkenyl; aralkyl or nuclear-substituted aralkyl in which the alkyl residue has 1 to 3 carbon atoms, the aryl residue has 6 to 10 carbon atoms and any nuclear substituents is chlorine, fluorine, bromine, iodine, hydroxy, amino or C,~6 alkyl; C2~12 alkylthioalkyl; methanesulfonyl; dimethoxyphosphinyl;
where M# is hydrogen or an alkali metal cation; X' is oxygen or sulphur and R" is hydrogen; allyl; amino; c1-6 alkylamino; di(C1-6 alkyl)amino; C1-6 alkyl; phenylthio or nuclear substituted phenylthio in which the nuclear substitutent is
C1-6 alkyl, chlorine, fluorine, bromine or iodine; C1-6 alkoxy; C6-10 aryloxy; aralkoxy or nuclear-substituted aralkoxy in which the alkoxy residue has 1 to 3 carbon atoms and any nuclear substituent is nitro, chlorine, bromine, fluroine, iodine or C1-6 alkyl; C6-10 aryl; C2-6 alkenyl, benzyl or C1-6 haloalkyl or C1-6 perhaloalkyl where the halogen is chlorine, bromine or fluorine; X is oxygen or sulphur; R is hydrogen; benzhydryl; phthalidyl; C1-10 alkyl, phenacyl, nuclearsubstituted phenacyl in which the substitutent is chlorine, bromine, fluorine, or C1-6 alkyl; (C1-6 alkoxy)-(C1-6 alkyl); C2-12 alkanoyloxyalkyl; C1-6 haloalkyl or C1-6 perhaloalkyl in which the halogen is chlorine, bromine or fluorine; C2-6 alkenyl; aralkyl in which the alkyl residue has I to 3 carbon atoms and the aryl residue has 6 to 10 carbon atoms; heteroaralkyl in which the hetero atom is oxygen, sulphur or nitrogen; nuclear-substituted aralkyl or heteroaralkyl in which the substitutent is chlorine, fluorine, bromine, iodine or C1-6 alkyl; C1-6 alkanoyloxy; C1-6 alkoxy, heterocyclyalkyl in which the heterocycle has 4 to 10 atoms, the hetero atom is oxygen, sulphur or nitrogen and the alkyl residue comprises 1 to 6 carbon atoms; aryl or nuclear-substituted aryl having 6 to 10 ring carbon atoms and in which an nuclear substituent is hydroxy, C1-6 alkyl, chlorine, fluroine or bromine, C2-12 alkylthioalkyl;
C4-12 cycloalkylthioalkyl or (C2-10 acylthio)-(C1-6 alkyl) and the pharmaceutically acceptable salts thereof.
Particularly preferred compounds are those in which the 2(3) position is unsaturated and (a) R' is hydrogen, C16 alkyl; allyl, 2-methyl-2-propenyl, benzyl, pbromobenzyl, p-t-butylbenzyl, C2-6 alkylthioalkyl;
where R" is hydrogen, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-8 alkyl,
phenylthio, C1-6 alkoxy, phenoxy, benzyloxy, p-nitrobenzyloxy, phenyl, allyl, 2
methyl-2-propenyl, benzyl or C1-6 haloalkyl or perhaloalkyl where the halogen is
chlorine, fluorine or bromine; R is hydrogen, C1-6 alkyl, phenacyl, p
bromophenacyl, pivaloyloxymethyl, C1-6 haloalkyl, C1-6 perhaloalkyl in which the
halogen is chlorine, fluorine or bromine; C1-6 alkenyl; benzyl; benzyhydryl, p-t
butylbenzyl, p-bromobenzyl, phthalidyl, 5-indanylmethyl, phenyl, 5-indanyl, acetylthiomethyl, acetylthioethyl, pivaloylthiomethyl or C26 alkylthioalkyl and X is oxygen, or
(b) R' is hydrogen, methyl, allyl, phenyl, benzyl, methylthiomethyl, formyl, sulfo, acetyl, carbamoyl, bromoacetyl, ethoxycarbonyl or pnitrobenzyloxycarbonyl; X is oxygen; and R is hydrogen, methyl, t-butyl, phenacyl, p-bromophenacyl, pivaloyloxymethyl, 2,2,2-trichloroethyl, allyl, 3-methyl-2butenyl, 2-methyl-2-propenyl, benzyl, benzhydryl, p-t-butylbenzyl, phthalidyl, phenyl, 5-indanyl, acetylthiomethyl, acetylthioethyl, pivaloylthiomethyl or methylthiomethyl.
The compounds of the present invention are related to the recently discovered antibiotic thienamycin. Thienamycin, which is known to have the follwoing structural formula (II):
is disclosed and claimed in U.S. Patent Specification No 3,950,357. Thienamycin may serve as the starting material for the preparation of the compounds of the present invention through removal of its 3-aminoethylthio side chain.
Thienamycin and all of its isomers (in pure form and as mixtures) are also obtainable by the total synthesis disclosed and claimed in the specification of our co-pending Patent Application No. 47326/77 (Serial No. 1,589,896).
It has been found that the compounds of the present invention are broadspectrum antibiotics, which are useful in animal and human therapy and in inanimate systems. Thus, they are active against a broad range of pathogens which representatively include both gram-positive bacteria such as S. aureus, S. pyrogenes and B. subtilis, and gram-negative bacteria such as E. coli., Proteus morganfi, Klebsiella and Pseudomonas.
The compounds of the formula I are conveniently prepared by the hydrogenation of thienamycin (II, above) according to the following reaction:
where each of R2 and R3, independently of the other, is hydrogen or acyl.
Preferably R2 is hydrogen. A salt, ester or amide of the starting material may be used instead to produce the salt, ester or amide of Compound I. Preferably this starting material is of formula:
where R' is H or acyl and R, R' and X are as defined above.
Preferably, the starting material is an N-acylated thienamycin derivative in which the acyl residue comprises an aromatic ring, such as N-phenoxyacetyl thienamycin:
Such N-acylated thienamycin compounds, in which the acyl residue comprises an aromatic ring, are preferred in the preparation of the compounds of the present invention since it is convenient to isolate the desired product after hydrogenolysis by chromatographic resolution of the reaction mixture on a polystyrene resin, which has an affinity for the aromatic nucleus carried by the cleaved cysteaminyl side chain but little or no affinity for the decysteaminyl thienamycin derivatives of the present invention.
Suitable catalysts for the above hydrogenation reaction include the platinum metals such as palladium, platinum and rhodium, oxides thereof, and Raney nickel.
Preferably, as mentioned above, the thienamycin substrate is an N-acylated thienamycin derivative in which the acyl residue comprises an aromatic ring.
Preferably, the hydrogenation reaction is conducted in a hydrogenation flask in which the thienamycin substrate to be reduced is dissolved in water or an aqueous mixture of water and a polar organic solvent such as dioxane, tetrahydrofuran or dimethylformamide (DMF). The unsaturated compound is obtained in essentially quantitative yield on hydrogenation as described above at from 0 to 500C, under from 1 to 2 atmospheres of hydrogen for from 0.5 to 3 hours. The 2,3-dihydro compound is obtained by hydrogenation as described above at from 0 to 700 at from 1 to 10 atmospheres of hydrogen for from 3 to 10 hours.
As mentioned above, the desired product of the above hydrogenation scheme is separated from its starting material and from the cysteaminyl residue by chromatographic separation on a polystyrene resin such as XAD-2 resin (obtained from the Rohm & Haas Company). Typically, the separation procedure is conducted by charging the reaction volume onto a column of XAD-2 resin, followed by elution with water. Identification of the desired fractions is made by monitoring labelled fractions by ultra-violet absorption and high-pressure liquid chromatography, HPLC (Waters Associates). Because of the affinity for the XAD2 resin for the aromatic acyl moiety, the separation of the products of the present invention is easily effected from the starting material and from by-products of the hydrogenolysis. Typically, evaluation of the fractions off the XAD-2 resin is carried out by injecting a sample portion (1 ,ul) of the fraction in question into the HPLC system which is equipped with 254 nm uv detector and 2 ft.xl/8 inch i.d. column packed with C,8 Bondapak reverse phase absorbent (supplied by Waters
Associates). The column is eluted with 10 /" tetrahydrofuran (THF) aqueous solution at a flow rate of 0.5 mVmin.
As already mentioned, the compounds of the present invention are valuable antibiotics active against various gram-positive and gram negative bacteria and accordingly they find utility in human and veterinary medicine and in inanimate systems. 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, Kiebsiella pneumoniae, Bacillus subtilis, Salmonella typhosa, Pseudomonas and Bacterium proteus. The antibacterial compounds of the invention may further be utilized as additives to animal feedstuffs, for preserving foodstuffs and as disinfectants. For example, they may be used in aqueous compositions in concentrations ranging from 0.1 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 the active ingredient in any one of a variety of pharmaceutical preparations. They may be used in capsule form or as tablets, powders or liquid solutions or as suspensions or elixirs. They may be administered orally, intraveneously 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 well known methods. 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, gl;cose/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 glycerides.
Compositions for injection may be presented in unit dose form in ampoules, or in multidose containers with an added preservative. The compositions may Sake such forms as suspensions, solutions and 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, in liquid or semi-solid form, or may be used as drops. Topical applications may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, or 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 flavouring agents. In addition, there may also be included in the composition other active ingredients to provide a broader spectrum or 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 and the weight of the host, 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 1060 /^ The compositions will generally contain from 15 mg. to 1500 mg. of the active ingredient; however, in general, a preferable dosage is in the range of from 250 mg. to 1000 mg. In parenteral administration the unit dosage is usually the pure compound in a slightly acidified sterile aqueous solution or in the form of a soluble powder intended for solution.
The following examples further illustrate the present invention.
EXAMPLE 1
Sodium 6-(a-Hydroxyethyl)-7-oxo- 1 -azabicyclo[3 .2. 0]hept- 2-ene-2-carboxylate from hydrogenolysis of N-phenoxyacetyl
thienamycin sodium salt
Step A. Preparation of N-phenoxyacetyl thienamycin sodium salt
To a 250-ml flask containing thienamycin (190 mg.) is added 30 ml. of water, 0.6 g of sodium bicarbonate and 30 ml. of dioxane. While the mixture is stirred and kept at OOC, phenoxyacetyl chloride (170 mg.) is added dropwise to the flask during a period of 10 minutes. The solution is stirred for an additional 10 minutes and then acidified with 30 /n phosphoric acid to pH 4.5. The acidified solution is quickly extracted with 50 ml. of ether to remove excess of reagent and its hydrolysis product, phenoxyacetic acid. The aqueous layer so obtained is further acidified with 30 jO phosphoric acid to pH 2.0, and extracted with 50 ml of ethylacetate. The organic layer which contains the free acid of N-phenoxyacetyl thienamycin is separated and back-extracted with 30 ml of aqueous solution containing 60 mg. of sodium bicarbonate. The aqueous layer is free-dried to yield 120 mg. of Nphenoxyacetyl thienamycin sodium salt. Electrophoresis (0.5 M, pH 7.0, phosphate, buffer, 2KV for 20 min): single bioactive zone which moves 45 mm toward anode. UV: 43 302 nm.
Step B. Preparation of Sodium 6-(a-Hydroxyethyl)-7-oxo-l- azabicyclo[3 .2. 0]hept-2-ene-2-carboxylate
To a 250-ml. hydrogenation flask containing 1.4 g of palladium oxide and 5 ml. of water is added 73 mg. of N-phenoxyacetyl thienamycin sodium salt in 27 ml. of water. The mixture is stirred under 1 atm. hydrogen at 250 C. for 3 hours; whereupon the catalyst is removed by filtration. The filtrate is concentrated to 5 ml. and charged to a 80 ml. XAD-2 resin column. The column is eluted with water in 3- ml. fractions, which are monitored by uv absorption. The fractions containing the title compound are identified, combined and freeze-dried to give 12 mg. of sodium 6 - (a - hydroxyethyl) - 7 - oxo - 1 - azabicyclo[3 .2. 0]hept - 2 - ene 2 - carboxylate. Electrophoresis (0.5 M pH 7.0 phosphate buffer, 2 kv for 20 min): single bioactive zone which moves 70 mm toward anode. UV: 2aOx 265 nm. 100
MHZ NMR (D2O): 1.29 (d), 2.86 (m), 3.39 (q), 4.24 (quintet), 4.26 (dt) and 6.27 ppm (q). The antibacterial activity of this compound is inhibited by p-lactamase.
EXAMPLE 2
Sodium 6-(a-Hydroxyethyl)-7-oxo- 1 -azabicyclo[3 .2. 0]heptane-2-carboxylate
from hydrogenolysis of N-phenoxyacetyl thienamycin sodium salt
The reaction described in Example 1, Step B, is repeated except that the reaction time is extended to 6 hours. Fractionation of the reaction mixture by the
XAD-2 column on elution with water gives sixty 3-ml. fractions. Fractions No. 15 to No. 60, which are detected by uv absorption, are combined and identified to be the unsaturated product of Example 1. Fractions No. 1 to No. 14, which show no uv absorption are bio-assayed on MB-108 plates to show that the activity starts at fraction No. 6, peaks at fraction No. 9 and diminishes at fraction No. 13. The antibacterial activity of these fractions is inhibited by p-lactamase. Fractions No. 9 to No. 13 are evaporated to dryness to provide 0.5 mg. of the title compound.
EXAMPLE 3
Sodium 6-(α-Hydroxyethyl)-7-oxo-1-azabicyclo[3. 2. 0]hept
2-ene-2-carboxylate from hydrogenolysis of thienamycin
sodium salt
Following the procedure of Example 1, Step B, except that the Nphenoxyacetyl thienamycin is replaced by an equivalent amount of thienamycin, there is obtained the title compound, which is isolated from the reaction mixture by preparative thin-layer chromatography using 20% methanol in water as the eluting solvent on silica gel plates (silica gel GF, Analtech Inc.)
EXAMPLE 4
Preparation of Benzyl 6-(a-Hydroxyethyl)-7-oxo- 1 - azabicyclo[3 .2. 0]-hept-2-ene-2-carboxylate (II)
Sodium 6 - (a - hydroxyethyl) - 7 - oxo - I - azabicyclo[3 .2.0] - hept - 2 ene - 2 - carboxylate (I) (5 mg.) is stirred with benzylbromide (0.2 ml.) in hexamethylphosphoramide (0.5 ml.) at 250C for 30 min. To the mixture is added 5 ml. of ethyl acetate. After the mixture has been thoroughly washed with water, the organic layer is separated, dried over sodium sulfate and concentrated to 0.2 ml.
The desired product (3.0 mg) is isolated by TLC, silica gel GF plates (Rf 0.31, 20% ethylacetate/chloroform). The product shows ir absorption at 1780 cms (p-lactam), uv absorption at 276 nm, mass spectrum at m/e 287 (molecular ion) and nmr resonance at 3.18 ppm (q, J=3.0 and 6.0 Hz); which data are consistent with the assigned structure (II, R=CH2-C6H6).
EXAMPLE 5
Preparation of Benzyl 6-(a-Acetoxyethyl)-7-oxo- 1 - azabicyclo[3 .2. 0]-hept-2-ene-2-carboxylate (II)
Benzyl 6-(α-Hydroxyethyl)-7-oxo-1-azabicyclo[3. 2. 0]hept-2-ene-2carboxylate (I) (18 mg) is dissolved in 1 ml of pyridine (Py) and 0.2 ml of acetic anhydride (Ac2O). The mixture is stirred at 250C. for 3 hours and then evaporated to dryness to give an oily residue. The residue is dissolved in 0.2 ml. chlorofdrm and chromatographed on two 20x20 cm 250 , silica gel TLC plates (Rf 0.56, 20 /, ethylacetate/chloroform) to give 4 mg. of the desired product (II) which shows nmr (CDCl3, 60 MHZ) resonances at 2.02 (s, OAc), 6.48 (t, vinyl proton) and 7.40 ppm (m, aromatic protons) and ir (CHCl3) carbonyl vibrations at 1780 (p-lactam) and 1740 cm-t (esters).
EXAMPLE 6
Preparation of sodium 6-(a-Acetoxyethyl)-7-oxo-1- azabicyclo[3 .2. 0]-hept-2-ene-2-carboxylate (II)
Benzyl 6 - (a - Acetoxyethyl) - 7 - oxo - 1 - azabicyclo[3 .2.0] - hept - 2 ene - 2 - carboxylate (I) (4 mg.) is dissolved in 2 ml. of dioxane and 2 ml. of phosphate buffer (0.1 M, pH 7.0). The mixture is stirred at 250C. under 1 atm of hydrogen in the presence of 10% Pd/C catalyst (10 mg.) for 10 min. The mixture is then filtered from the catalyst and extracted with 5x2 ml. ether. The aqueous layer is separated and freeze-dried to give 1 mg. of the title compound which is biologically active against Staphylococcus. The product shows uv absorption at 268 nm and HPLC retention time of 6.5 min as compared to that of 3.2 min for its 6-(a- hydroxy) analogue (2 ft.xl/8 1/8 in. C,8 Bondapak column eluted with 10% THF aqueous solution at a flow rate of 0.5 ml./min).
EXAMPLE 7
Following the procedure of Example 4 except that there is substituted for the benzylbromide of Example 4 an equivalent amount of bromomethylpivalate, 1 bromo - 3 - methyl - 2 - butene, 1 - chloro - 2 - methylpropene, p-t-butylbenzyl bromide and 3-bromophthalide, there are obtained respectively, the following esters:
R
pivaloyloxymethyl,
3-methyl-2-butene- 1 -yl,
2-methyl-2-propene- 1 -yl,
p-t-butyl benzyl, and
phthalidyl.
EXAMPLE 8
Following the procedure of Example 5 except that there is substituted for the acetic anhydride/pyridine of Example 6 an equivalent amount of ethyl chloroformate in the presence of an equivalent amount of triethylamine in the solvent methylene chloride; methyl iodide in the presence of an equivalent amount of lithium diisopropylamide in the solvent dimethylformamide; methanesulfonyl chloride in the presence of an equivalent amount of triethylamine in the solvent methylene chloride and dimethylphosphorochloridate in the presence of an equivalent amount of triethylamine in the solvent methylene chloride, respectively, there are obtained the following (O-R'): O-ethoxycarbonyl-, O-methyl-, O- methanesulfonyl-, and O-dimethoxyphosphinyl derivatives of benzyl 6 - (a hydroxyethyl) - 7 - oxo - 1 - azabicyclo[3 .2.0] - hept - 2 - ene - 2 carboxylate.
EXAMPLE 9
Following the procedure of Example 6 except that there is substituted, for benzyl 6 - (a - Acetoxyethyl) - 7 - oxo - 1 - azabicyclo[3 .2.0] - hept - 2 - ene 2 - carboxylate, an equivalent amount of O-ethoxycarbonyl, O-methyl, and 0 dimethxyphosphinyl derivatives of benzyl 6 - (a - Hydroxyethyl) - 7 - oxo - 1 azabicyclo[3 .2.0] - hept - 2 - ene - 2 - carboxylate, there are obtained, respectively, the following compounds: O-ethyloxycarbonyl, O-methyl and 0dimethoxyphosphinyl derivatives of sodium 6 - (a - hydroxyethyl) - 7 - oxo - 1 azabicyclo[3.2. - - hept - 2 - ene - 2 - carboxylate.
EXAMPLE 10
Preparation of Pharmaceutical Compositions
One unit dosage form is prepared by mixing 120 mg. of pivaloyloxymethyl 6 (a - hydroxyethyl) - 7 - oxo - 1 - azabicyclo[3 .2. 0]hept - 2 - ene - 2 carboxylate 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 using more of the active ingredient and less lactose, 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 and compressed tablets and pills can also be prepared.
The following examples are illustrative of the preparation of pharmaceutical formulations:
Tablet Per Tablet
Pivaloyloxymethyl 6 - (a - hydroxyethyl) - 7 - oxo 1- - azabicyclo[3 . 2. 0]hept - 2 - ene - 2 - carboxylate 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 a 15 /" cornstarch paste (6 mg.) and rough-screened. It is dried at 45cm. and screened again through
No. 16 (U.S. Standard) screens. 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:
Sodium 6 - (a - hydroxyethyl)- 7 - oxo - 1 - azabicyclo[3 .2. 0]hept - 2 - ene - 2 - carboxylate 500 mg.
Diluent: Serile Water for Injection 2 cc.
Opthalmic Solution
Sodium 6 - (a - hydroxyethyl) - 7 - oxo - I azabicyclo[3 .2. 0]hept - 2 - ene - 2 - carboxylate 100 mg.
Hydroxypropylmethyl Cellulose 5 mg.
Sterile Water to I ml.
Otic Solution
Sodium 6 - (a - hydroxyethyl)- 7 - oxo - 1 - azabicyclo[3 .2. 0]hept - 2 - ene - 2 - carboxylate 100 mg.
Benzalkonium Chloride 0.1 mg.
Sterile Water to 1 ml.
Topical Ointment
Pivaloyloxymethyl 6 - (a - hydroxyethyl) - 7 - oxo 1 - azabicyclo[3 .2. 0]hept - 2 - ene - 2
carboxylate 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 other therapeutic agents such as probenecid.
Claims (18)
1. A compound having the structure:
where the dotted line indicates that the compound can be 2,3-saturated or 2,3unsaturated, and the pharmaceutically acceptable salt, and ester derivatives thereof.
2. A compound according to claim 1 having the structure:
3. A compound having the structure:
where the dotted line is as defined in claim 1; R is hydrogen; phenyl; C,~fi alkyl, (C-6 alkoxy)-(C1-6 alkyl); C26 alkenyl; aralkyl or nuclear-substituted aralkyl in which the alkyl residue has 1 to 3 carbon atoms, the-aryl residue has 6 to 10 carbon atoms and any nuclear substituent is chlorine, fluorine, bromine, iodine, hydroxy, amino or C1-6 alkyl; C2-12 alkylthioalkyl; methanesulfonyl; dimethoxyphosphinyl;
where M# is hydrogen or an alkali metal cation; X' is oxygen or sulphur and R" is hydrogen; allyl; amino; C1-6 alkylamino; di-(C1-6 alkyl) amino, C1-5 alkyl, phenylthio or nuclear-substituted phenylthio in which the nuclear substituent is
C1-6 alkyl, chlorine, fluorine, bromine or iodine; C1-6 alkoxy; C6-10 aryloxy; aralkoxy or nuclear-substituted aralkoxy in which the alkoxy residue has 1 to 3 carbon atoms and any nuclear substituent is nitro, chlorine, bromine, fluorine, iodine or C1-6 alkyl; C6-10 aryl; C26 alkenyl having 2 to 6 carbon atoms, benzyl or
C1-6 haloalkyl or C1-6 perhaloalkyl where the halogen is chlorine, bromine, or fluorine; X is oxygen or sulphur; R is hydrogen, benzhydryl, phthalidyl, C1-10 alkyl, phenacyl, nuclear-substituted phenacyl in which the substituent is chlorine, bromine, fluorine or C1-6 alkyl; (C1-6 alkoxy)-(C1-6 alkyl); C2-12 alkanoyloxyalkyl;
C1-6 haloalkyl or C1-6 perhaloalkyl in which the halogen is chlorine, bromine, or fluorine; C26 alkenyl; aralkyl in which the alkyl residue has 1 to 3 carbon atoms and the aryl residue has 6 to 10 carbon atoms heteroaralkyl in which the hetero atom is oxygen, sulphur or nitrogen; nuclear-substituted'aralkyl or heteroaralkyl in which the substituent is chlorine, fluorine, bromine, iodine or C1-6 alkyl; C16 alkanoyloxy; C16 alkoxy; heterocyclylalkyl in which the heterocycle has 4 to 10 atoms, the hetero atom is oxygen, sulphur or nitrogen and the alkyl residue comprises 1 to 6 carbon atoms; aryl or nuclear-substituted aryl having 6 to 10 ring carbon atoms and in which any nuclear-substituent is hydroxy, C16 alkyl, chlorine, fluorine, or bromine; 2-12 alkylthioalkyl; C4~,2 cycloalkylthioalkyl or (C2~,0 acylthio)-(C1-6 alkyl) and the pharmaceutically acceptable salts thereof.
4. A compound according to claim 3 which has the following structural formula:
in which R', R and X are as defined in claim 3.
5. A compound according to claim 4 in which R' is hydrogen, C16 alkyl, allyl, 2-methyl-2-propenyl, benzyl, p-bromobenzyl, p-t-butylbenzyl, C28 alkylthioalkyl;
where R" is hydrogen, amino, C16 alkylamino, di(C,~6 alkyl) amino, C16 alkyl, phenylthio, C1-6 alkoxy, phenoxy, benzyloxy, p-nitrobenzyloxy, phenyl, allyl, 2
methyl-2-propenyl benzyl or C1-6 haloalkyl or perhaloalkyl where the halogen is chlorine, fluorine or bromine; R is hydrogen, C1-6 alkyl, phenacyl, p
bromophenacyl, pivaloyloxymethyl, C1-6 haloalkyl or C1-6 perhaloalkyl in which
the halogen is chlorine, fluorine or bromine; C26 alkenyl; benzyl, benzhydryl, p-t
butylbenzyl, p-bromobenzyl, phthalidyl, 5-indanylmethyl, phenyl, 5-indanyl,
acetylthiomethyl, acetylthioethyl, pivaloylthiomethyl or C26 alkylthioalkyl and X
is oxygen.
6. A compound according to claim 4 in which R' is hydrogen, methyl allyl,
phenyl, benzyl, methylthiomethyl, formyl, sulfo, acetyl, carbamoyl, bromoacetyl,
ethoxycarbonyl or p-nitrobenzyloxycarbonyl; X is oxygen; and R is hydrogen,
methyl, t-butyl, phenacyl, p-bromophenacyl; pivaloyloxymethyl, 2,2,2
trichloroethyl, allyl 3-methyl-2-butenyl, 2-methyl-2-propenyl, benzyl, benzhydryl,
p-t-butylbenzyl, phthalidyl, phenyl, 5-indanyl, acetylthiomethyl,. acetylthioethyl,
pivaloylthiomethyl or methylthiomethyl.
7. A method of preparing a compound according to claim 1 comprising the
hydrogenation of a compound having the structural formula:
where each of R2 and R3, independently of the other, is hydrogen or acyl or a corresponding salt or ester thereof.
8. A method for preparing a compound according to claim 3 comprising hydrogenation of a compound having the structural formula:
where R1 is H or acyl and R, R' and X are as defined in claim 3.
9. An antibiotic pharmaceutical composition comprising a compound according to claim 3 and a pharmceutical carrier therefor.
10. An antibiotic pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical carrier therefor.
11. An antibacterial composition containing as active ingredient a compound as claimed in claim 1 or 3 and a diluent or carrier.
12. A composition as claimed in claim 11 in which the diluent is water and the concentration of active ingredient is 0..1 to 100 ppm.
13. A composition as claimed in claim 11 in the form of a water-based paint or paper-mill white water.
14. A human or animal food containing as an additive a compound as claimed in claim I or 3
15. A composition as claimed in claim 9 or 10 in the form of a capsule, tablet, powder, liquid solution, suspension, emulsion, elixir, syrup, dry product for reconstitution with water or other vehicle, suppository, ampoule of sterile liquid, powder or liquid spray or inhalant, throat paint, lozenge, aural or oral drops, ointment, cream, lotion, topical paint or intramammary veterinary preparation.
16. A composition as claimed in claim 9 or 10 substantially as hereinbefore described in any one of the separate embodiments of Example 10.
17. A method of preparing a compound as claimed in claim 1 or 3, substantially as hereinbefore described in any one of Examples I to 9.
18. A compound according to claim I or 3 when prepared by a method as claimed in claim 7, 8 or 17.
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE7805032A SE7805032L (en) | 1978-05-03 | 1978-05-02 | CARBOXYLIC ACIDS AND DERIVATIVES THEREOF |
GB17493/78A GB1592224A (en) | 1978-05-03 | 1978-05-03 | Thienamycin derivatives their production and their use as antibiotics |
DE19782820055 DE2820055A1 (en) | 1978-05-03 | 1978-05-08 | 6- (ALPHA-HYDROXYAETHYL) -7-OXO-1- AZABICYCLO SQUARE CLAMP ON 3.2.0 SQUARE BRACKET FOR HEPT-2-EN- (AND HEPTANE) -2-CARBONIC ACID AND ITS DERIVATIVES |
NL7804976A NL7804976A (en) | 1978-05-03 | 1978-05-09 | 6- (ALFA-HYDROXYETHYL) -7-OXO-1-AZABICYCLO-3.2.0-HEPT- -2-EEN-2-CARBONIC ACID, METHOD FOR THE PREPARATION THEREOF AND PROCESS FOR THE PREPARATION OF A PHARMACY PREPARATION WITH USE OF THIS COMPOUND AND PREPARATION THEREOF. |
FR7814597A FR2426054A1 (en) | 1978-05-03 | 1978-05-17 | 6- (A-HYDROXYETHYL) -7-OXO-1-AZABICYCLO (3.2.0.) HEPT-2-ENE (AND HEPTANE) -2-CARBOXYLIC ACID AND ITS DERIVATIVES USEFUL AS A MEDICINAL PRODUCT |
CH535478A CH638522A5 (en) | 1978-05-03 | 1978-05-17 | Therapeutically active 6-(alpha-hydroxyethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivatives, and processes for their preparation |
LU79677A LU79677A1 (en) | 1978-05-03 | 1978-05-18 | PREPARATION OF 6- (A-HYDROXYETHYL) -7-OXO-1-AZABICYCLO (3,2, O) HEPT-2-ENE-2-CARBOXYLIC ACID AND DERIVATIVES WITH ANTIBIOTIC ACTIVITY |
JP5901878A JPS54151996A (en) | 1978-05-03 | 1978-05-19 | 66*alphaahydroxyethyl**77oxoo11azabicyclo *3*2*0*heptoo22ene *and heptane**22carboxylic acid and its derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB17493/78A GB1592224A (en) | 1978-05-03 | 1978-05-03 | Thienamycin derivatives their production and their use as antibiotics |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1592224A true GB1592224A (en) | 1981-07-01 |
Family
ID=10096140
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB17493/78A Expired GB1592224A (en) | 1978-05-03 | 1978-05-03 | Thienamycin derivatives their production and their use as antibiotics |
Country Status (8)
Country | Link |
---|---|
JP (1) | JPS54151996A (en) |
CH (1) | CH638522A5 (en) |
DE (1) | DE2820055A1 (en) |
FR (1) | FR2426054A1 (en) |
GB (1) | GB1592224A (en) |
LU (1) | LU79677A1 (en) |
NL (1) | NL7804976A (en) |
SE (1) | SE7805032L (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2966497D1 (en) * | 1978-10-24 | 1984-01-26 | Merck & Co Inc | 6-, 1- and 2-substituted-1-carbapen-2-em-3-carboxylic acids, processes for the preparation of such compounds and pharmaceutical composition comprising such compounds |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3950357A (en) * | 1974-11-25 | 1976-04-13 | Merck & Co., Inc. | Antibiotics |
DE2811514A1 (en) * | 1977-03-19 | 1978-09-21 | Beecham Group Ltd | ESTER OF 7-OXO-1-AZABICYCLO SQUARE CLAMP ON 3.2.0 SQUARE CLAMP FOR HEPT-2-EN-2-CARBONIC ACID AND ITS DERIVATIVES, METHOD FOR PRODUCING THESE COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS |
EP0002564B1 (en) * | 1977-11-12 | 1984-06-20 | Beecham Group Plc | Derivatives of 7-oxo-1-azabicyclo(3.2.0)-hept-2-ene-2-carboxylic acid, their preparation, pharmaceutical compositions containing them and intermediates |
-
1978
- 1978-05-02 SE SE7805032A patent/SE7805032L/en not_active Application Discontinuation
- 1978-05-03 GB GB17493/78A patent/GB1592224A/en not_active Expired
- 1978-05-08 DE DE19782820055 patent/DE2820055A1/en not_active Ceased
- 1978-05-09 NL NL7804976A patent/NL7804976A/en not_active Application Discontinuation
- 1978-05-17 FR FR7814597A patent/FR2426054A1/en active Granted
- 1978-05-17 CH CH535478A patent/CH638522A5/en not_active IP Right Cessation
- 1978-05-18 LU LU79677A patent/LU79677A1/en unknown
- 1978-05-19 JP JP5901878A patent/JPS54151996A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
CH638522A5 (en) | 1983-09-30 |
NL7804976A (en) | 1979-11-13 |
FR2426054B1 (en) | 1980-11-07 |
JPS54151996A (en) | 1979-11-29 |
FR2426054A1 (en) | 1979-12-14 |
SE7805032L (en) | 1979-11-03 |
LU79677A1 (en) | 1979-02-02 |
DE2820055A1 (en) | 1979-11-22 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed | ||
PCNP | Patent ceased through non-payment of renewal fee |