NO813806L - ANALOGUE PROCEDURE FOR THE PREPARATION OF NEW PENCILLINES - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF NEW PENCILLINESInfo
- Publication number
- NO813806L NO813806L NO813806A NO813806A NO813806L NO 813806 L NO813806 L NO 813806L NO 813806 A NO813806 A NO 813806A NO 813806 A NO813806 A NO 813806A NO 813806 L NO813806 L NO 813806L
- Authority
- NO
- Norway
- Prior art keywords
- group
- hydroxy
- general formula
- ureido
- pyrimidinyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 12
- -1 hydroxy, methyl Chemical group 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 44
- 229930182555 Penicillin Natural products 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 23
- 150000002960 penicillins Chemical class 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 22
- AVWRKZWQTYIKIY-UHFFFAOYSA-N ureidocarboxylic acid Natural products NC(=O)NC(O)=O AVWRKZWQTYIKIY-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims description 13
- 229940056360 penicillin g Drugs 0.000 claims description 12
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 11
- 150000003230 pyrimidines Chemical class 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 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 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 230000000844 anti-bacterial effect Effects 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 claims 2
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 241000894006 Bacteria Species 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 229940049954 penicillin Drugs 0.000 description 12
- 238000001816 cooling Methods 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 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 description 7
- 230000000694 effects Effects 0.000 description 7
- 208000015181 infectious disease Diseases 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 241000588748 Klebsiella Species 0.000 description 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 5
- 241000589516 Pseudomonas Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 4
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 239000003960 organic solvent Substances 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
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 229960003022 amoxicillin Drugs 0.000 description 3
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 3
- 150000001448 anilines Chemical class 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229960003975 potassium Drugs 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- HGGQNXIEKPAMBB-UHFFFAOYSA-N 1-nitro-4-[(4-nitrophenyl)methylsulfonylmethyl]benzene Chemical compound C1=CC([N+](=O)[O-])=CC=C1CS(=O)(=O)CC1=CC=C([N+]([O-])=O)C=C1 HGGQNXIEKPAMBB-UHFFFAOYSA-N 0.000 description 2
- YAWXGRKOOLHJSP-UHFFFAOYSA-N 2-chloro-5-nitro-1h-pyrimidin-6-one Chemical compound [O-][N+](=O)C1=CN=C(Cl)NC1=O YAWXGRKOOLHJSP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JOOMLFKONHCLCJ-UHFFFAOYSA-N N-(trimethylsilyl)diethylamine Chemical compound CCN(CC)[Si](C)(C)C JOOMLFKONHCLCJ-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000005005 aminopyrimidines Chemical class 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 229960003623 azlocillin Drugs 0.000 description 2
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 150000003939 benzylamines Chemical class 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- LKHYFCSSVZVVNF-UHFFFAOYSA-N ethyl hexanoate;sodium Chemical compound [Na].CCCCCC(=O)OCC LKHYFCSSVZVVNF-UHFFFAOYSA-N 0.000 description 2
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000011368 organic material Substances 0.000 description 2
- 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 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
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- 238000010992 reflux Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
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- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
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- 239000000126 substance Substances 0.000 description 2
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- 150000003510 tertiary aliphatic amines Chemical class 0.000 description 2
- JETQIUPBHQNHNZ-NJBDSQKTSA-N (2s,5r,6r)-3,3-dimethyl-7-oxo-6-[[(2r)-2-phenyl-2-sulfoacetyl]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound C1([C@H](C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)S(O)(=O)=O)=CC=CC=C1 JETQIUPBHQNHNZ-NJBDSQKTSA-N 0.000 description 1
- KFIMOMYDCZFXKC-UHFFFAOYSA-N (4-methylphenyl)-oxido-sulfanylideneazanium Chemical compound CC1=CC=C([N+]([O-])=S)C=C1 KFIMOMYDCZFXKC-UHFFFAOYSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- GURKSJZOGWYTOA-UHFFFAOYSA-N 2-chloro-5-nitro-1h-pyrimidin-6-one;sodium Chemical compound [Na].[O-][N+](=O)C1=CN=C(Cl)NC1=O GURKSJZOGWYTOA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 150000005008 5-aminopyrimidines Chemical class 0.000 description 1
- 241000607534 Aeromonas Species 0.000 description 1
- 241000607528 Aeromonas hydrophila Species 0.000 description 1
- 241001112741 Bacillaceae Species 0.000 description 1
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- 241000588832 Bordetella pertussis Species 0.000 description 1
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- 241000249497 Brucellaceae Species 0.000 description 1
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- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000595586 Coryne Species 0.000 description 1
- 241000186031 Corynebacteriaceae Species 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 241000025053 Escherichia coli DSM 30083 = JCM 1649 = ATCC 11775 Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000605952 Fusobacterium necrophorum Species 0.000 description 1
- 241000605986 Fusobacterium nucleatum Species 0.000 description 1
- 241000579664 Grateloupia proteus Species 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- 241000589929 Leptospira interrogans Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 241000192017 Micrococcaceae Species 0.000 description 1
- 241000588621 Moraxella Species 0.000 description 1
- 241000588629 Moraxella lacunata Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 241000588656 Neisseriaceae Species 0.000 description 1
- 208000005141 Otitis Diseases 0.000 description 1
- 241000606860 Pasteurella Species 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
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- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000588777 Providencia rettgeri Species 0.000 description 1
- 208000032536 Pseudomonas Infections Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241000607764 Shigella dysenteriae Species 0.000 description 1
- 241000123534 Sphaerophorus Species 0.000 description 1
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- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000589886 Treponema Species 0.000 description 1
- 241000589884 Treponema pallidum Species 0.000 description 1
- 241000607598 Vibrio Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000287 alkaline earth metal oxide Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 230000000244 anti-pseudomonal effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
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- 150000001540 azides Chemical class 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229940056450 brucella abortus Drugs 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 150000001714 carbamic acid halides Chemical class 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000001271 cephalosporin group Chemical group 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 229960002457 epicillin Drugs 0.000 description 1
- RPBAFSBGYDKNRG-NJBDSQKTSA-N epicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CCC=CC1 RPBAFSBGYDKNRG-NJBDSQKTSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- LULXBAGMGMJJRW-UHFFFAOYSA-N n,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)CC(=O)N[Si](C)(C)C LULXBAGMGMJJRW-UHFFFAOYSA-N 0.000 description 1
- LARMNSCHRRUJCG-UHFFFAOYSA-N n-(2-methylsulfanyl-6-oxo-1h-pyrimidin-5-yl)benzamide Chemical compound OC1=NC(SC)=NC=C1NC(=O)C1=CC=CC=C1 LARMNSCHRRUJCG-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 239000000123 paper Substances 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229940007046 shigella dysenteriae Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 229960004932 sulbenicillin Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Denne oppfinnelse angår fremstilling av nye penicilliner med den generelle formel I This invention relates to the preparation of new penicillins of the general formula I
og deres fysiologisk forlikélige salter med uorganiske eller organiske baser, som er egnet for anvendelse i legemidler. and their physiologically compatible salts with inorganic or organic bases, which are suitable for use in pharmaceuticals.
I den ovenstående generelle formel I betyr:In the above general formula I means:
a) A en fenylgruppe oga) A a phenyl group and
R gruppen med den generelle formel IIThe R group with the general formula II
hvor n er 0 eller 1, og R1, hvis n er 0, betyr gruppene -S02-R4, -S0-R4, -S02-NH2, -S02"NH-R4eller -S02"N(R4)2, og, hvis n er 1, betyr R^de ovennevnte grupper og dessuten et hydrogen- eller fluoratom, en hydroksy-, metyl- eller metoksygruppe, idet R4i de ovenstående formler betyr en alkylgruppe med 1 til 4 karbonatomer, where n is 0 or 1, and R1, if n is 0, means the groups -SO2-R4, -SO-R4, -SO2-NH2, -SO2"NH-R4 or -SO2"N(R4)2, and, if n is 1, R^ means the above-mentioned groups and also a hydrogen or fluorine atom, a hydroxy, methyl or methoxy group, R 4 in the above formulas means an alkyl group with 1 to 4 carbon atoms,
eller R en gruppe med den generelle formel IIIor R a group of the general formula III
hvor en av resteneR2eller R3betyr en hydroksygruppe, og den annen av disse rester betyr en gruppe med formlene where one of the residues R2 or R3 means a hydroxy group, and the other of these residues means a group with the formulas
eller begge rester R2og R^ betyr gruppen -CONH2, eller or both residues R 2 and R 2 mean the group -CONH 2 , or
b) A betyr en p-hydroksyfenylgruppe ogb) A means a p-hydroxyphenyl group and
R gruppen med den generelle formel II hvor n er 0 eller 1, R the group with the general formula II where n is 0 or 1,
og R,, hvis n er 0, betyr gruppene med formlene and R,, if n is 0, means the groups with the formulas
-S02-R5, -S02-NH-R4, -S02-N(R4)2eller gruppen -S02"NH2 i metastilling, og hvis n er 1, betyr R^de ovennevnte grupper og dessuten et fluoratom, en-hydroksygruppe, en nitrogruppe, gruppen H2NC0-, gruppene -S0-CH3, -S02~CH3 eller p-H2N-S02-, eller en metyl- eller metoksygruppe, hvor R4i de ovenstående formler er som angitt ovenfor, og R,- betyr en alkylgruppe med 2 til 4 karbonatomer, eller R en gruppe med den generelle formel III hvor en av restene R2eller R^ betyr en hydroksygruppe, og den annen av disse rester betyr en gruppe med formlene -SO^-NH^, -S02-R5, -S02-NH-R4, -S02-N(R4)2 or the group -S02"NH2 in the meta position, and if n is 1, R^ means the above-mentioned groups and furthermore a fluorine atom, a-hydroxy group, a nitro group, the group H2NC0-, the groups -S0-CH3, -S02~CH3 or p-H2N-SO2-, or a methyl or methoxy group, where R4 in the above formulas is as indicated above, and R,- means an alkyl group with 2 to 4 carbon atoms, or R a group of the general formula III where one of the residues R2 or R^ means a hydroxy group, and the other of these residues means a group of the formulas -SO^-NH^,
eller begge restene R2og R^betyr or both residues R 2 and R 2 mean
gruppen -C0NH2, ellerthe group -C0NH2, or
c) A betyr en 2-tienylgruppe, en cykloheksa-1,4-dien-1-yl-gruppe, en 3,4-dihydroksyfenyl- eller en 3-klor-4-hydroksyfenylgruppe, og c) A means a 2-thienyl group, a cyclohexa-1,4-dien-1-yl group, a 3,4-dihydroxyphenyl or a 3-chloro-4-hydroxyphenyl group, and
R en gruppe med den generelle formel II hvor n er 0 eller 1, og R^betyr et fluoratom>en metyl- eller metoksygruppe eller en gruppe med formlene R a group of the general formula II where n is 0 or 1, and R^means a fluorine atom > a methyl or methoxy group or a group of the formulas
-S02-R4, -S02-NH2, -S02-NH-R4 eller -S02~N(R4)2, idet R4i disse formler er som ovenfor angitt, og R^ kan også være et hydrogenatom hvis A betyr en 2-tienyl-, 3,4-dihydroksyfenyl- eller 3-klor-4-hydroksyfenylgruppe, eller R^ kan være en hydroksygruppe eller en metylkarbonyloksygruppe hvis A betyr en 2-tienylgruppe, en cyklo- -S02-R4, -S02-NH2, -S02-NH-R4 or -S02~N(R4)2, R4 in these formulas being as indicated above, and R^ can also be a hydrogen atom if A means a 2-thienyl -, 3,4-dihydroxyphenyl or 3-chloro-4-hydroxyphenyl group, or R^ can be a hydroxy group or a methylcarbonyloxy group if A means a 2-thienyl group, a cyclo-
heksa-1,4-dien-l-ylgruppe eller en 3-klor-4-hydroksyfenylgruppe, eller hexa-1,4-dien-1-yl group or a 3-chloro-4-hydroxyphenyl group, or
R en gruppe med den generelle formel III hvor R,, betyr en hydroksygruppe og R^ en hydroksygruppe eller gruppene R a group of the general formula III where R,, means a hydroxy group and R^ a hydroxy group or groups
-CONH2, -CO-NHCH3, -SC>2-NH2, eller begge restene R2 og R^kan også samtidig bety gruppen -CONH2. Det foretrekkes slike forbindelser med den generelle formel I hvor R betyr gruppene med formlene Det har vist seg at særlig verdifulle er slike forbindelser med den generelle formel I hvor R betyr gruppen -CONH2, -CO-NHCH3, -SC>2-NH2, or both radicals R2 and R^ can also simultaneously mean the group -CONH2. Such connections with the general are preferred formula I where R denotes the groups with the formulas It has been shown that particularly valuable are such compounds of the general formula I where R denotes the group
og A en -fenyl-, 2-tienyl-, 3-klor-4-hydroksyfenyl- eller en 3,4-dihydroksy-feny1-gruppe, R gruppen and A a -phenyl-, 2-thienyl-, 3-chloro-4-hydroxyphenyl- or a 3,4-dihydroxy-phenyl group, the R group
og A en fenyl-, p-hydroksyfeny1-, 2-tienyl-, 3-klor-4-hydroksyfenyl- eller 3,4-dihydroksyfeny1, eller R gruppen and A a phenyl, p-hydroxyphenyl, 2-thienyl, 3-chloro-4-hydroxyphenyl or 3,4-dihydroxyphenyl, or the R group
og A en fenyl- eller and A a phenyl or
p-hydroksyfenylgruppe. p-hydroxyphenyl group.
Penicillinforbindelsene med den generelle formel IThe penicillin compounds of the general formula I
kan foreligge i to tautomere former (nemlig av laktim- og av laktam-typen). Det er særlig avhengig av det aktuelle oppløsningsmiddel og arten av substituenten R, hvilken av de to former I eller I' som dominerer: can exist in two tautomeric forms (namely lactim- and lactam-type). It is particularly dependent on the relevant solvent and the nature of the substituent R, which of the two forms I or I' predominates:
Det vil forstås at de innledningsvis angitte forbindelser med formel I alltid omfatter begge tautomerer. It will be understood that the initially indicated compounds of formula I always include both tautomers.
Forbindelsene med den generelle formel I kan med hensyn til chiralitetssenteret C foreligge i begge de mulige R- og S-konfigurasjoner, og også som en blanding av disse to konfigurasjoner. Særlig foretrekkes slike forbindelser som har D=R-konfigurasjon.' With respect to the chirality center C, the compounds of the general formula I can exist in both the possible R and S configurations, and also as a mixture of these two configurations. Particular preference is given to such compounds which have a D=R configuration.'
De nye halvsyntetiske penicilliner med den generelle formel I oppviser et bredt virkningsspektrum mot gram-positive og gram-negative bakterier og har en meget god forlikelighet i The new semi-synthetic penicillins with the general formula I show a broad spectrum of action against gram-positive and gram-negative bacteria and have a very good compatibility in
mennesker.human beings.
Som kjent hemmer penicillin-antibiotika veksten av forskjellige gram-positive og gram-negative bakterier. Det er videre kjent at bare få penicilliner har god virkning mot viktige gram-negative skadelige bakterier, som særlig opptrer i hospitaler, så som Pseudomonas og Klebsiélla. I løpet av de senere år har.det imidlertid stadig vært en økende opptreden av infeksjoner som forårsakes av disse bakterier, særlig Pseudomonas-arter. Penicillin-derivater så som carbenicillin (US-patent 3.142.673), sulbenicillin (US-patent 3.660.379) As is known, penicillin antibiotics inhibit the growth of various gram-positive and gram-negative bacteria. It is also known that only a few penicillins have a good effect against important gram-negative harmful bacteria, which particularly occur in hospitals, such as Pseudomonas and Klebsiella. In recent years, however, there has been an increasing occurrence of infections caused by these bacteria, particularly Pseudomonas species. Penicillin derivatives such as carbenicillin (US patent 3,142,673), sulbenicillin (US patent 3,660,379)
og ticarcillin (US-patent 3.282.926) beskrives riktignok som antipseudomonale antibiotika, men oppviser både in vitro og in vivo bare en måtelig virkning. En viktig videreutvikling er acylerte derivater av cc-amino-benzyl-penicilliner, f.eks. ampicillin og amoxycillin. Fra disse klasser forbindelser som i de senere år har vært intenst bearbeidet, har man nylig funnet frem til azlocillin = 6-(D-a-[(2-okso-imidazolidin-l-yl)-karbonylamino]-4-fenylacetamido)-penicillansyre-natriumsalt (f.eks. belgisk patent-767 647) som et annet antipseudomonas-penicillin. For en vellykket behandling må imidlertid dette penicillin administreres i store doser. Dessuten er dets virkning mot Klebsiélla og E.coli-arter bare måtelig. Det har således foreligget et ytterligere behov for å finne frem til nye penicilliner som har en forsterket virkning mot bakterier så som Psudomonas resp. Klebsiélla og E. coli. and ticarcillin (US patent 3,282,926) are indeed described as antipseudomonal antibiotics, but both in vitro and in vivo show only a moderate effect. An important further development is acylated derivatives of cc-amino-benzyl penicillins, e.g. ampicillin and amoxycillin. From these classes of compounds, which in recent years have been intensively processed, azlocillin = 6-(D-a-[(2-oxo-imidazolidin-l-yl)-carbonylamino]-4-phenylacetamido)-penicillanic acid has recently been found sodium salt (eg, Belgian patent-767,647) as another antipseudomonas penicillin. However, for a successful treatment, this penicillin must be administered in large doses. Moreover, its activity against Klebsiella and E.coli species is only moderate. There has thus been a further need to find new penicillins that have an enhanced effect against bacteria such as Psudomonas resp. Klebsiella and E. coli.
Mens det som nevnt er forsket intenst med hensyn til acylderivater av a-amino-benzylpenicilliner og fremdeles forskes, er det kjent lite med hensyn til derivater hvor en heterocyklisk gruppe er forbundet over en ureido-bro (NHCNH-) While, as mentioned, acyl derivatives of α-amino-benzylpenicillins have been intensively researched and are still being researched, little is known about derivatives where a heterocyclic group is connected via a ureido bridge (NHCNH-)
til a-benzylkarbonatomet i a-aminobenzylpenicilliner.to the α-benzyl carbon atom in α-aminobenzylpenicillins.
Riktignok er det i tysk off.skrift 2.450.668 og 2.535.655 og US-patent 4.031.230 beskrevet hydroksypyridylureido-benzyl-penicilliner med den generelle formel IV: Admittedly, hydroxypyridylureido-benzyl penicillins with the general formula IV are described in German official documents 2,450,668 and 2,535,655 and US patent 4,031,230:
Disse forbindelser er imidlertid med hensyn til sin antibakterielle aktivitet tydelig underlegne i forhold til forbindelsene ifølge den ålment tilgjengelige europeiske patent-ansøkning 79 .100 468.2 , som adskiller seg fra forbindelsene som fremstilles ifølge oppfinnelsen, bare ved andre betydninger av resten R og ved andre kombinasjoner av restene A og R. These compounds, however, with regard to their antibacterial activity are clearly inferior to the compounds according to the widely available European patent application 79 100 468.2, which differ from the compounds produced according to the invention, only by other meanings of the residue R and by other combinations of the residues A and R.
De nye forbindelser fremstilt ifølge oppfinnelsen har imidlertid bedre aktiviteter sammenlignet med forbindelsene ifølge denne europeiske patentansøkning overfor skadelige mikroorganismer, særlig bakterier, så som E. coli, Pseudomonas og Klebsiélla. However, the new compounds produced according to the invention have better activities compared to the compounds according to this European patent application against harmful microorganisms, especially bacteria, such as E. coli, Pseudomonas and Klebsiella.
Forbindelsene med den generelle formel I kan fremstilles som følger: 1) Ved omsetning av en forbindelse med den generelle formel V The compounds with the general formula I can be prepared as follows: 1) By reacting a compound with the general formula formula V
hvor A er som ovenfor angitt, med et pyrimidinderivat med den generelle formel VI where A is as indicated above, with a pyrimidine derivative of the general formula VI
hvor R er som ovenfor angitt, og B betyr gruppen -NCO eller et reaktivt derivat av gruppen NHCOOH, som f.eks.'gruppene -NHC0C1, -NHCOBr eller where R is as indicated above, and B means the group -NCO or a reactive derivative of the group NHCOOH, such as, for example, the groups -NHC0C1, -NHCOBr or
idet gruppen NHC0C1 er særlig foretrukket. Det kan også anvendes blandinger av slike pyrimidinderivater med den generelle formel VI hvor B dels har den ene og dels den annen av de ovennevnte betydninger, f.eks. gruppene the group NHC0Cl being particularly preferred. It is also possible to use mixtures of such pyrimidine derivatives with the general formula VI where B partly has one and partly the other of the above meanings, e.g. the groups
samtidig ved siden av hverandre. simultaneously next to each other.
Utgangsforbindelsene med den generelle formel V kanThe starting compounds of the general formula V can
anvendes i form av sine uorganiske eller organiske salter,used in the form of their inorganic or organic salts,
f.eks. som trietylammoniumsalt eller natriumsalt. Omsetningen kan utføres i passende blandinger av vann og slike organiske oppløsningsmidler som er blandbare med vann, f.eks. ketoner så som aceton, cykliske etere, så som tetrahydrofuran eller dioksan, nitriler så som acetonitril, formamider så som dimetylformamid, dimetylsulfoksyd eller alkoholer så som isopropanol eller i heksametapol. Herunder holder man reaksjonsblandingens pH-verdi ved tilsetning av baser eller ved anvendelse av buffer-oppløsninger i et pH-område fra ca. 2,0 til 9,0, fortrinnsvis mellom pH 6,5 og 8,0. Det er imidlertid også mulig å gjennom-føre omsetningen i vannfrie, organiske oppløsningsmidler, f.eks. halogenerte hydrokarboner så som kloroform eller metylenklorid, under tilsetning av baser, fortrinnsvis trietylamin, dietylamin eller N-etylpiperidin. e.g. such as triethylammonium salt or sodium salt. The reaction can be carried out in suitable mixtures of water and such organic solvents as are miscible with water, e.g. ketones such as acetone, cyclic ethers such as tetrahydrofuran or dioxane, nitriles such as acetonitrile, formamides such as dimethylformamide, dimethyl sulfoxide or alcohols such as isopropanol or in hexametapol. Below this, the pH value of the reaction mixture is kept by adding bases or by using buffer solutions in a pH range from approx. 2.0 to 9.0, preferably between pH 6.5 and 8.0. However, it is also possible to carry out the reaction in anhydrous, organic solvents, e.g. halogenated hydrocarbons such as chloroform or methylene chloride, with the addition of bases, preferably triethylamine, diethylamine or N-ethylpiperidine.
Videre kan omsetningen utføres i en sammensetning av vann og et ikke-vannblandbart oppløsningsmiddel så som etere, f.eks. dietyleter, halogenerte hydrokarboner, f.eks. kloroform eller metylenklorid, karbondisulfid, ketoner, f.eks. isobutylmetyl-keton, estere, f.eks. eddiksyreetylester, aromatiske oppløsnings-midler, f.eks. benzen, idet det'er hensiktsmessig å omrøre kraftig og å holde pH-verdien i et område på ca. pH 2,0 til 9,0, fortrinnsvis mellom 6,5 og 8,0, ved basetilsetning eller ved anvendelse av-bufferoppløsninger. Man kan også utføre omsetningen i bare vann i nærvær av en organisk eller uorganisk base eller under tilsetning av bufferstoffer. Furthermore, the reaction can be carried out in a composition of water and a non-water-miscible solvent such as ethers, e.g. diethyl ether, halogenated hydrocarbons, e.g. chloroform or methylene chloride, carbon disulphide, ketones, e.g. isobutyl methyl ketone, esters, e.g. acetic acid ethyl ester, aromatic solvents, e.g. benzene, as it is appropriate to stir vigorously and to keep the pH value in a range of approx. pH 2.0 to 9.0, preferably between 6.5 and 8.0, by base addition or by using buffer solutions. One can also carry out the reaction in just water in the presence of an organic or inorganic base or with the addition of buffer substances.
Hvis man som utgangsmaterialer for fremgangsmåtenIf one as starting materials for the procedure
anvender silylderivatene av forbindelsene med den generelle formel V (f.eks. mono- eller di-trimetylsilyl-derivatene) og omsetter dem med forbindelser med den generelle formel VI, arbeider man vanligvis hensiktsmessig i vann- og hydroksylgruppe-frie oppløsningsmidler, f.eks. i halogenerte hydrokarboner så som metylenklorid eller kloroform, benzen, tetrahydrofuran, aceton eller dimetylformamid osv. Tilsetning av baser er her ikke nødvendig, men kan i enkelte tilfeller være fordelaktig for å forbedre utbyttet og renheten av produktene. Som eventuelt tilsatte baser anvendes hensiktsmessig tertiære alifatiske eller aromatiske aminer så som pyridin eller trietylamin, eller sekundære aminer som på grunn av sterisk hindring er vanskelige å acylere, så som dicykloheksylamin. use the silyl derivatives of the compounds of the general formula V (e.g. the mono- or di-trimethylsilyl derivatives) and react them with compounds of the general formula VI, one usually conveniently works in water- and hydroxyl group-free solvents, e.g. . in halogenated hydrocarbons such as methylene chloride or chloroform, benzene, tetrahydrofuran, acetone or dimethylformamide, etc. The addition of bases is not necessary here, but can in some cases be beneficial to improve the yield and purity of the products. Tertiary aliphatic or aromatic amines such as pyridine or triethylamine, or secondary amines which are difficult to acylate due to steric hindrance, such as dicyclohexylamine, are suitably used as optionally added bases.
Istedenfor silylestrene kan også alle andre karboksyl-derivater av a-amino-benzylpenicilliner, som er kjent i forbindelse med fremstilling av halvsyntetiske penicilliner, anvendes. Typiske eksempler er tritylestrene, p-nitrobenzy1-estrene eller fenacylestrene. I tilknytning til omsetningene kan disse derivater omdannes til de nye penicilliner ved kjente metoder. Mengden av de anvendte baser fastlegges f.eks. på grunnlag av en bestemt pH-verdi som skal opprettholdes. Når en pH-måling og -innstilling ikke foretas eller ikke er mulig eller praktisk på grunn av utilstrekkelige mengder av vann i fortynningsmidlet, anvendes for de ikke-silylerte forbindelser med den generelle formel IV fortrinnsvis 1,0 til 2,0 molekvivalenter base. Ved anvendelse av silylerte forbindelser, benytter man fortrinnsvis opptil en molekvivalent base. Instead of the silyl esters, all other carboxyl derivatives of α-amino-benzylpenicillins, which are known in connection with the production of semi-synthetic penicillins, can also be used. Typical examples are the trityl esters, the p-nitrobenzyl esters or the phenacyl esters. In connection with sales, these derivatives can be converted into the new penicillins by known methods. The quantity of the bases used is determined, e.g. on the basis of a specific pH value to be maintained. When a pH measurement and adjustment is not carried out or is not possible or practical due to insufficient amounts of water in the diluent, preferably 1.0 to 2.0 molar equivalents of base are used for the non-silylated compounds of the general formula IV. When using silylated compounds, preferably up to one molar equivalent of base is used.
Som baser kan prinsipielt anvendes alle de organiske og uorganiske baser som vanligvis anvendes i den organiske kjemi, så som alkali- og jordalkalihydroksyder, jordalkalioksyder, alkali- og jordalkalikarbonater og -hydrogenkarbonater, ammoniakk, primære, sekundære og tertiære alifatiske og aromatiske aminer og heterocykliske baser. F.eks. kan nevnes natrium-, kalium- og kalsiumhydroksyd, kalsiumoksyd, natrium-og kaliumkarbonat, natrium- og kaliumhydrogenkarbonat, etylamin, metyletylamin, trietylamin, hydroksyetylamin, anilin, pyridin og piperidin. Ved anvendelse av de silylerte utgangsmaterialer .må man imidlertid ta hensyn til de ovennevnte begrensninger med hensyn til arten av baser. As bases, all the organic and inorganic bases that are usually used in organic chemistry can be used, such as alkali and alkaline earth hydroxides, alkaline earth oxides, alkali and alkaline earth carbonates and hydrogen carbonates, ammonia, primary, secondary and tertiary aliphatic and aromatic amines and heterocyclic bases . E.g. mention may be made of sodium, potassium and calcium hydroxide, calcium oxide, sodium and potassium carbonate, sodium and potassium hydrogen carbonate, ethylamine, methylethylamine, triethylamine, hydroxyethylamine, aniline, pyridine and piperidine. When using the silylated starting materials, however, one must take into account the above-mentioned limitations with regard to the nature of the bases.
Som buffersystemer kan man anvende alle vanlige buffer-blandinger, f.eks. fos fatbuffere, citratbuffere og tris-(hydroksymetyl)-amino-metan-buffere. All common buffer mixtures can be used as buffer systems, e.g. phos fat buffers, citrate buffers and tris-(hydroxymethyl)-amino-methane buffers.
Reaksjonstemperaturene kan varieres innenfor et stort område. Vanligvis arbeider man mellom ca. -20 og ca. +50°C, fortrinnsvis mellom 0 og +20°C. The reaction temperatures can be varied within a large range. Usually you work between approx. -20 and approx. +50°C, preferably between 0 and +20°C.
Reaksjonskomponentene med de generelle formler.IV og V kan uten videre omsettes med hverandre i ekvimolare mengder. Det kan imidlertid i enkelte tilfeller være hensiktsmessig å anvende den ene av de to reaksjonskomponenter i overskudd for dermed å lette rensningen av sluttproduktet eller for å heve utbyttet. The reaction components with the general formulas IV and V can be readily reacted with each other in equimolar amounts. However, in some cases it may be appropriate to use one of the two reaction components in excess in order to facilitate the purification of the final product or to increase the yield.
2) Ved omsetning av ureidokarboksylsyrer med den generelle formel VII 2) When reacting ureidocarboxylic acids with the general formula VII
hvor A og R har de ovenfor angitte betydninger, deres salter eller reaktive derivater, med 6-amino-penicillansyre med formel VIII where A and R have the meanings given above, their salts or reactive derivatives, with 6-amino-penicillanic acid of formula VIII
eller dens uorganiske eller organiske salter eller derivater som lett kan overføres til 6-aminopenicillansyre. Det derved or its inorganic or organic salts or derivatives which can be readily converted to 6-aminopenicillanic acid. That thereby
dannede reaksjonsprodukt kan eventuelt derefter hydrolyseres eller katalytisk hydrogene-l<y>seres til et penicillin med den generelle formel I. formed reaction product can optionally then be hydrolyzed or catalytically hydrogenated to a penicillin with the general formula I.
Som reaktive derivater av ureidokarboksylsyrene med den generelle formel VII kan f.eks. anvendes deres syreanhydrider så som de som kan avledes av klormaursyreestere, f.eks. klormaursyreety1- eller -isobutylester, eller deres reaktive estere, så som p-nitrofenylestrene eller N-hydroksy-succinimid-estrene, eller deres reaktive amider så som N-karbonylimidazol, og også deres syrehalogenider så som det tilsvarende syreklorid, eller deres syreazider. Prinsipielt kan imidlertid alle sammenkoblingsmetoder anvendes, slik som kjent fra Ø-laktam-kjemien. As reactive derivatives of the ureidocarboxylic acids with the general formula VII, e.g. are used their acid anhydrides such as those that can be derived from chloroformate esters, e.g. chloroformate ethyl or isobutyl ester, or their reactive esters, such as the p-nitrophenyl esters or the N-hydroxy-succinimide esters, or their reactive amides such as N-carbonylimidazole, and also their acid halides such as the corresponding acid chloride, or their acid azides. In principle, however, all coupling methods can be used, as is known from Ø-lactam chemistry.
6-aminopenicillansyren anvendes fordelaktig i form avThe 6-aminopenicillanic acid is advantageously used in the form of
et av sine derivater. Som derivater er det her f.eks. tale om: dens trimetylsilylester, tritylester, p-nitrobenzylester, fenacylester eller dens 0,N-bis-trimetylsilylderivat. Disse derivater omsettes fortrinnsvis i et aprotisk oppløsningsmiddel så som metylenklorid eller tetrahydrofuran. Man kan også anvende 6-aminopenicillansyren i form av dens salter, f.eks. dens trietylammoniumsalt, og man benytter her f.eks. metylenklorid eller et protisk oppløsningsmiddel eller et vandig medium eller et vandig-organisk oppløsningsmiddel, så som tetrahydrofuran-vann-blandinger. one of its derivatives. As derivatives, there are e.g. namely: its trimethylsilyl ester, trityl ester, p-nitrobenzyl ester, phenacyl ester or its 0,N-bis-trimethylsilyl derivative. These derivatives are preferably reacted in an aprotic solvent such as methylene chloride or tetrahydrofuran. One can also use the 6-aminopenicillanic acid in the form of its salts, e.g. its triethylammonium salt, and one uses here e.g. methylene chloride or a protic solvent or an aqueous medium or an aqueous-organic solvent such as tetrahydrofuran-water mixtures.
Ureidokarboksylsyrene, deres salter eller deres reaktive derivater omsettes med 6-aminopenicillansyren eller dens derivater i et oppløsningsmiddel ved temperaturer mellom -40 og • +40°C, eventuelt i nærvær av en base. Hvis f.eks. et anhydrid av ureidokarboksylsyren, f.eks. anhydridet med etylklorformiat, omsettes med et derivat av 6-aminopenicillansyre, foretas omsetningen under avkjøling, f.eks. ved -10 til +10°C i nærvær av et tertiært amin så som trietylamin eller N>N-dimetylanilin, The ureidocarboxylic acids, their salts or their reactive derivatives are reacted with the 6-aminopenicillanic acid or its derivatives in a solvent at temperatures between -40 and • +40°C, possibly in the presence of a base. If e.g. an anhydride of the ureidocarboxylic acid, e.g. the anhydride with ethyl chloroformate, is reacted with a derivative of 6-aminopenicillanic acid, the reaction is carried out while cooling, e.g. at -10 to +10°C in the presence of a tertiary amine such as triethylamine or N>N-dimethylaniline,
i et oppløsningsmiddel så som aceton, tetrahydrofuran, dimetylformamid, kloroform, diklormetan, heksametapol eller i en blanding av disse oppløsningsmidler. Hvis man f.eks. omsetter en N-hydroksysuccinimidester av ureidokarboksylsyren med 6-amino-penicillansyren, foretas omsetningen fortrinnsvis ved 0 til 20°C i nærvær av en base så som trietylamin, i et oppløsningsmiddel så som dimetylformamid, diklormetan, dioksan eller i en blanding in a solvent such as acetone, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, hexametapol or in a mixture of these solvents. If you e.g. reacts an N-hydroxysuccinimide ester of the ureidocarboxylic acid with the 6-amino-penicillanic acid, the reaction is preferably carried out at 0 to 20°C in the presence of a base such as triethylamine, in a solvent such as dimethylformamide, dichloromethane, dioxane or in a mixture
av slike oppløsningsmidler.of such solvents.
Omsetningen av en ureidokarboksylsyre med den generelle formel VII selv eller dens salter med 6-amino-penicillansyren eller med dens salter foretas fordelaktig i nærvær av et kondensasjonsmiddel, f.eks. i nærvær av N,N<1->dicykloheksy1-karbpdiimid. The reaction of a ureidocarboxylic acid of the general formula VII itself or its salts with 6-amino-penicillanic acid or with its salts is advantageously carried out in the presence of a condensing agent, e.g. in the presence of N,N<1->dicyclohexy1-carbpdiimide.
Hvis det anvendes et derivat av 6-aminopenicillansyren, f.eks. en av dens ovennevnte estere, får man alt efter reaksjons-betingelsene eventuelt et reaksjonsprodukt som f.eks. ennu inneholder esterfunksjonen. Et slikt reaksjonsprodukt kan imidlertid lett overføres til penicillinet med den generelle formel I. Hvis f.eks. karboksylgruppen i 6-aminopenicillansyren foreligger i form av sin silylester, kan den efter omsetningen likeledes foreligge i form av sin silylester i det oppnådde penicillin med den generelle formel I. I dette tilfelle av-hydrolyseres denne silylestergruppe efter den egentlige omsetning, hvorved man får forbindelsen med den generelle formel I. I andre tilfeller, f.eks. når det foreligger en p-nitrobenzylester, avspaltes denne p-nitrobenzylestergruppe efter den egentlige omsetning, hvorved man får penicilliner med den generelle formel I. If a derivative of 6-aminopenicillanic acid is used, e.g. one of its above-mentioned esters, depending on the reaction conditions, a reaction product such as e.g. still contains the ester function. However, such a reaction product can easily be transferred to the penicillin with the general formula I. If, for example, the carboxyl group in the 6-aminopenicillanic acid is present in the form of its silyl ester, after the reaction it can also be present in the form of its silyl ester in the obtained penicillin with the general formula I. In this case, this silyl ester group is de-hydrolyzed after the actual reaction, whereby the compound is obtained with the general formula I. In other cases, e.g. when a p-nitrobenzyl ester is present, this p-nitrobenzyl ester group is split off after the actual reaction, whereby penicillins with the general formula I are obtained.
Opparbeidelsen av reaksjonsblandingen oppnådd ved begge fremgangsmåter efter fullført omsetning foretas i henhold til metoder som er vanlige for 3-laktam-antibiotika, og det samme gjelder for isolering og rensning av sluttproduktene, f.eks. The processing of the reaction mixture obtained by both methods after completion of the reaction is carried out according to methods that are common for 3-lactam antibiotics, and the same applies to the isolation and purification of the end products, e.g.
for frigjøring av syren fra dens salter og overføring av den frie syre til andre salter ved hjelp av uorganiske eller organiske baser. For fremstilling av kalium- eller natrium-saltene er det særlig hensiktsmessig å felle disse salter fra en alkoholisk-eterisk oppløsning av den frie syre ved tilsetning av kalium- eller natrium-2-etylheksanoat. for the liberation of the acid from its salts and the transfer of the free acid to other salts by means of inorganic or organic bases. For the preparation of the potassium or sodium salts, it is particularly appropriate to precipitate these salts from an alcoholic-etheric solution of the free acid by adding potassium or sodium 2-ethylhexanoate.
De som utgangsmaterialer anvendte forbindelser med den generelle formel V er kjent fra litteraturen, se f.eks. The compounds of the general formula V used as starting materials are known from the literature, see e.g.
E. H. Flynn, Cephalosporines and Penicillines, Academic Press, New York og London (1972). E. H. Flynn, Cephalosporines and Penicillines, Academic Press, New York and London (1972).
Utgangsmaterialene med den generelle formel VI kan f.eks. fremstilles ved omsetning av de passende 5-aminopyrimidiner med den generelle formel IX The starting materials with the general formula VI can e.g. are prepared by reacting the appropriate 5-aminopyrimidines of the general formula IX
hvor R er som ovenfor angitt, med fosgen. Denne omsetning foretas fortrinnsvis i et ikke-hydroksylgruppe-holdig opp-løsningsmiddel så som tetrahydrofuran, metylenklorid, kloroform, dimetoksyetan eller heksametapol, ved temperaturer mellom -40 og +60°C, fortrinnsvis mellom -10 og +20°C. Det anbefales da å binde det dannede hydrogenklorid ved hjelp av ekvimolare mengder av en inert, organisk base så som trietylamin eller pyridin. Som oppløsningsmiddel kan også pyridin anvendes i overskudd. Hvis de aktuelle aminopyrimidiner med den generelle formel IX skulle være tungtløselige i et av de nevnte oppløsningsmidler, kan fosgeneringen også foretas i heterogen fase. Videre kan aminopyrimidinene med den generelle formel IX ved behandling med et silyleringsmiddel så som heksametyldisilazan eller trimetylklorsilan/trietylamin eller N,O-bistrimetylsilylacetamid, overføres til et vanligvis i de nevnte oppløsningsmidler meget lettløselig, enkelt- eller, i henhold til de tilstedeværende utskiftbare hydrogenatomer, fler-silylert aminopyridin, som derefter reagerer med fosgen til de tilsvarende forbindelser med den generelle formel VI. Alt efter arten av oppløsningsmiddel, temperaturen, mengden og arten av den anvendte base, dannes enten overveiende det tilsvarende isocyanat eller karbaminsyrehalogenid eller en blanding av disse to forbindelser. Alt efter reaksjons-betingelsene kan forbindelsen med den generelle formel VI også delvis eller helt foreligge som et med isocyanatene isomert dihydro-oksazolo-pyrimidin med den generelle formel Via where R is as above, with phosgene. This reaction is preferably carried out in a non-hydroxyl group-containing solvent such as tetrahydrofuran, methylene chloride, chloroform, dimethoxyethane or hexametapol, at temperatures between -40 and +60°C, preferably between -10 and +20°C. It is then recommended to bind the formed hydrogen chloride using equimolar amounts of an inert, organic base such as triethylamine or pyridine. As a solvent, pyridine can also be used in excess. If the relevant aminopyrimidines with the general formula IX should be poorly soluble in one of the mentioned solvents, the phosgenation can also be carried out in a heterogeneous phase. Furthermore, the aminopyrimidines of the general formula IX can, by treatment with a silylating agent such as hexamethyldisilazane or trimethylchlorosilane/triethylamine or N,O-bistrimethylsilylacetamide, be transferred to a usually in the mentioned solvents very easily soluble, single or, according to the exchangeable hydrogen atoms present, polysilylated aminopyridine, which then reacts with phosgene to give the corresponding compounds of the general formula VI. Depending on the nature of the solvent, the temperature, the amount and the nature of the base used, either predominantly the corresponding isocyanate or carbamic acid halide or a mixture of these two compounds is formed. Depending on the reaction conditions, the compound with the general formula VI can also partially or completely exist as a dihydro-oxazolo-pyrimidine with the general formula Via isomeric with the isocyanates
eller ved foregående silylering alt efter arten av substituenten R, som en enkelt- eller fler-silylert analog. or by preceding silylation, depending on the nature of the substituent R, as a single- or multi-silylated analogue.
De ved fosgenering dannede utgangsforbindelser med den generelle formel VI resp. blandinger derav er vanligvis godt oppløselige i de ovennevnte oppløsningsmidler og kan efter fjernelse av overskudd av fosgen, uten ytterligere rensning omsettes direkte med de passende penicillinderivater med den generelle formel V. The starting compounds with the general formula VI or mixtures thereof are usually well soluble in the above-mentioned solvents and, after removal of excess phosgene, can be reacted directly with the appropriate penicillin derivatives of the general formula V without further purification.
Det er imidlertid også mulig å isolere mellomproduktet med den generelle formel Via, eventuelt desilylere det med et protisk oppløsningsmiddel, f.eks. vann eller metanol, However, it is also possible to isolate the intermediate with the general formula Via, optionally desilylate it with a protic solvent, e.g. water or methanol,
rense det på grunnlag av dets løselighetsegenskaper og omsette det på den ovenfor beskrevne måte. purify it on the basis of its solubility properties and react it in the manner described above.
Fremstillingen av de 2-substituerte 5-amino-4-hydroksy-pyrimidiner med den generelle formel IX er, i den utstrekning de ikke allerede er beskrevet i den ålment tilgjengelige europeiske patentansøkning 7 9 100 468.2, nærmere beskrevet i de følgende eksempler. Særlig egnet er omsetningen av 2-klor-4-hydroksy-5-nitro-pyrimidin med aniliner eller benzylaminer i vandig oppløsning, idet nitrogruppen derefter reduseres ved kjente metoder, eller omsetning av 5-benzoylamino-4-hydroksy-2-metylmerkaptopyrimidin med de passende aniliner eller benzylaminer i smelte eller i et høytkokende oppløsningsmiddel som f.eks. sulfolan. The preparation of the 2-substituted 5-amino-4-hydroxy-pyrimidines of the general formula IX is, to the extent that they are not already described in the generally available European patent application 7 9 100 468.2, described in more detail in the following examples. Particularly suitable is the reaction of 2-chloro-4-hydroxy-5-nitro-pyrimidine with anilines or benzylamines in aqueous solution, the nitro group being then reduced by known methods, or reaction of 5-benzoylamino-4-hydroxy-2-methylmercaptopyrimidine with the suitable anilines or benzylamines in melt or in a high-boiling solvent such as sulfolane.
Ureidokarboksylsyrene med den generelle formel VII kan lett oppnås ved omsetning av pyrimidinderivater med den generelle formel VI med glycinderivater med den generelle formel X hvor A er som ovenfor angitt. Omsetningen skjer ved temperaturer mellom -20 og +40°C, fortrinnsvis mellom 0 og +20°C, The ureidocarboxylic acids of the general formula VII can be easily obtained by reacting pyrimidine derivatives of the general formula VI with glycine derivatives of the general formula X where A is as indicated above. The turnover takes place at temperatures between -20 and +40°C, preferably between 0 and +20°C,
i et oppløsningsmiddel. Som oppløsningsmidler kan her f.eks. anvendes blandinger av vann og organiske oppløsningsmidler som er blandbare med vann, f.eks. aceton, tetrahydrofuran, dioksan, acetonitril, dimetylformamid, etanol eller dimetylsulfoksyd. Eventuelt er det nødvendig å anvende et hydrogen-halogenid-bindende middel, og egnede slike midler er f.eks. trialkylaminer så som trietylamin, eller uorganiske baser så som fortynnet natronlut. in a solvent. As solvents, e.g. mixtures of water and organic solvents which are miscible with water are used, e.g. acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, ethanol or dimethylsulfoxide. If necessary, it is necessary to use a hydrogen-halide binding agent, and suitable such agents are e.g. trialkylamines such as triethylamine, or inorganic bases such as dilute caustic soda.
Det er funnet at forbindelsene med den generelle formel I er i besittelse av verdifulle farmakologiske egenskaper med god forlikelighet. De nye virkestoffer kan således anvendes til forebyggelse og kjemoterapi av lokale og systemiske infeksjoner i menneske- og dyre-medisinen. Som sykdommer som kan forhindres resp. helbredes ved hjelp av de nye forbindelser, kan f.eks. nevnes slike i luftveiene, munnhulen og urinveiene. Forbindelsene virker særlig mot faryngitt, pneumonia, peritonitt, pyelonefritt, otitt, cystitt, endokarditt, bronkitt, artritt og vanlige systemiske infeksjoner. Videre kan disse forbindelser anvendes som stoffer for konservering av uorganiske eller organiske materialer, særlig av organiske materialer så som polymerer, smøremidler, farver, fibere, lær, papir og tre såvel som levnetsmidler. It has been found that the compounds of the general formula I possess valuable pharmacological properties with good compatibility. The new active substances can thus be used for prevention and chemotherapy of local and systemic infections in human and animal medicine. As diseases that can be prevented or can be healed with the help of the new compounds, e.g. those in the respiratory tract, oral cavity and urinary tract are mentioned. The compounds are particularly effective against pharyngitis, pneumonia, peritonitis, pyelonephritis, otitis, cystitis, endocarditis, bronchitis, arthritis and common systemic infections. Furthermore, these compounds can be used as substances for the preservation of inorganic or organic materials, in particular of organic materials such as polymers, lubricants, paints, fibres, leather, paper and wood as well as foodstuffs.
Dette muliggjøres ved at forbindelsene med den generelle formel I både in vit ro. og in vivo virker meget sterkt mot skadelige mikroorganismer, særlig mot grampositive og gram-negative bakterier og bakterielignende mikroorganismer, og de utmerker seg særlig ved et bredt virkningsspektrum. Dessuten viser forbindelsene med den generelle formel I efter parenteral administrering høye speil i vev, serum, organer og i urinen. This is made possible by the fact that the compounds of the general formula I both in vit ro. and in vivo works very strongly against harmful microorganisms, especially against gram-positive and gram-negative bacteria and bacteria-like microorganisms, and they are particularly distinguished by a broad spectrum of effects. Moreover, after parenteral administration, the compounds of the general formula I show high levels in tissues, serum, organs and in the urine.
I den følgende tabell 1 er angitt typiske, særligIn the following table 1, typical ones are indicated, in particular
aktive penicilliner fremstilt ifølge oppfinnelsen. De nevnte penicilliner kan fremstilles i henhold til fremgangsmåtene 1 eller 2. Det er her tale om forbindelser med den generelle formel I hvor A og R er definert som følger: active penicillins produced according to the invention. The aforementioned penicillins can be prepared according to methods 1 or 2. These are compounds of the general formula I where A and R are defined as follows:
Med disse penicillinderivater kan man f.eks. behandle og/eller forhindre lokale og/eller systemiske sykdommer som forårsakes av de følgende mikroorganismer eller av blandinger av disse: Micrococcaceae, så som Staphylokokker; With these penicillin derivatives, one can e.g. treat and/or prevent local and/or systemic diseases caused by the following microorganisms or by mixtures thereof: Micrococcaceae, such as Staphylococci;
Lactobacteriaceae, så som Streptokokker; Lactobacteriaceae, such as Streptococci;
Neisseriaceae, så som Neisserier; Neisseriaceae, such as Neisseries;
Corynebacteriaceae, så som Coryne-bakterier; Corynebacteriaceae, such as Coryne bacteria;
Enterobacteriaceae, så som Escherichiae-bakterier av Coli-gruppen, Klebsiella-bakterier, f.eks. K. pneumoniae; Enterobacteriaceae, such as Escherichiae bacteria of the Coli group, Klebsiella bacteria, e.g. K. pneumoniae;
Proteae-bakterier av Proteus-gruppen, f.eks. Proteus vulgaris; Salmonella-bakterier, f.eks. S. thyphimurium; Proteae bacteria of the Proteus group, e.g. Proteus vulgaris; Salmonella bacteria, e.g. S. thyphimurium;
Shigella-bakterier, f.eks. Shigella dysenteriae; Shigella bacteria, e.g. Shigella dysenteriae;
Pseudomonas-bakterier, f.eks. Pseudomonas aeruginosa; Aeromonas-bakterier, f.eks. Aeromonas lique faciens, Pseudomonas bacteria, e.g. Pseudomonas aeruginosa; Aeromonas bacteria, e.g. Aeromonas lique faciens,
Spirillaceae, så som Vibrio-bakterier, f.eks. Vibrio cholerae; Parvobacteriaceae eller Brucellaceae, så som Pasteurella-bakterier; Brucella-bakterier, f.eks. Brucella abortus; Haemophilus-bakterier, f.eks. Haemophilus influenzae; Bordatella-bakterier, f.eks. Bordetella pertussis; Spirillaceae, such as Vibrio bacteria, e.g. Vibrio cholerae; Parvobacteriaceae or Brucellaceae, such as Pasteurella bacteria; Brucella bacteria, e.g. Brucella abortus; Haemophilus bacteria, e.g. Haemophilus influenzae; Bordatella bacteria, e.g. Bordetella pertussis;
Moraxella-bakterier, f.eks. Moraxella lacunata; Moraxella bacteria, e.g. Moraxella lacunata;
Bacteroidaceae, så som Bacteroides-bakterier; Bacteroidaceae, such as Bacteroides bacteria;
Fusiforme-bakterier, f.eks. Fusobacterium fusiforme; Sphaerophorus-bakterier, f.eks. Sphaerophorus necrophorus; Bacillaceae, så som aerobe sporedannere, f.eks. Bacillus anthracis; anaerobe sporedanner-Chlostridier, f.eks. Chlostridium perfringens; Spirochaetaceae, så som Borrelia-bakterier; Fusiform bacteria, e.g. Fusobacterium fusiforme; Sphaerophorus bacteria, e.g. Sphaerophorus necrophorus; Bacillaceae, such as aerobic spore formers, e.g. Bacillus anthracis; anaerobic spore formers-Chlostridia, e.g. Clostridium perfringens; Spirochaetaceae, such as Borrelia bacteria;
Treponema-bakterier, f.eks. Treponema pallidum; Treponema bacteria, e.g. Treponema pallidum;
Leptospira-bakterier, sp som Leptospira interrogans.Leptospira bacteria, sp such as Leptospira interrogans.
Den ovenstående liste over mikroorganismer er kunThe above list of microorganisms is only
eksempler og skal ikke representere noen begrensning.examples and shall not represent any limitation.
Virkningen av penicillinene fremstilt ifølge oppfinnelsenThe action of the penicillins prepared according to the invention
kan f.eks. demonstreres ved følgende undersøkelser:can e.g. is demonstrated by the following investigations:
1. In vitro forsøk1. In vitro experiments
For undersøkelsene ble metoden med rekkefortynningsprøveFor the investigations, the method was a serial dilution test
1 mikrotitersystem anvendt. Undersøkelsen av forbindelsene med hensyn til bakteriostase ble foretatt i flytende medium. Bakteristase-virkningen ble undersøkt ved følgende konsentrasjoner: >64, 64, 32, 16, 8, 4, 2, 1, 0,5, 0,25, 0,125, 0,05, 0,03, 0,015 og 0,007Mg/ml. Det ble benyttet et næringsmedium med følgende sammensetning: 1 microtiter system used. The examination of the compounds with regard to bacteriostasis was carried out in liquid medium. The bacteriostasis effect was investigated at the following concentrations: >64, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.05, 0.03, 0.015 and 0.007Mg/ml . A nutrient medium with the following composition was used:
10 g pepton, i g kjøttekstrakt-oksoid, 3 g natriumklorid,10 g peptone, i g meat extract oxoid, 3 g sodium chloride,
2 g sek.natriumfosfat fortynnes med destillert vann til 1000 ml (pH 7,2-7,4). Bare ved undersøkelse mot Streptokokker ble 1% glukose tilsatt. Primærkulturenes alder var ca. 20 timer. Innstillingen av bakteriesuspensjonen ble foretatt på et fotometer (ifølge "Eppendorf") (reagensglass-diameter 14 mm, filter 546 nm) på grunnlag av uklarheten i en bariumsulfat-sammenligningssuspensjon som ble oppnådd med en bariumsulfat-oppslemning fremstilt ved at 3,0 ml l%ig bariumkloridoppløsning ble satt til 97 ml l%ig svovelsyre. Efter innstillingen ble Streptococcus Aronsen i forholdet 1:15 og de øvrige prøve-bakterier i forholdet 1:1500 fortynnet videre med en koksalt-oppløsning. 16 mg av prøveforbindelsen ble innveiet i 10 ml målekolber og fortynnet med oppløsningsmidlet til merket. Den videre fortynningsrekke ble foretatt med destillert vann eller det passende oppløsningsmiddel. 2 g sec. sodium phosphate is diluted with distilled water to 1000 ml (pH 7.2-7.4). Only when testing against Streptococci was 1% glucose added. The age of the primary cultures was approx. 20 hours. The setting of the bacterial suspension was made on a photometer (according to "Eppendorf") (tube diameter 14 mm, filter 546 nm) on the basis of the turbidity of a barium sulfate comparison suspension obtained with a barium sulfate slurry prepared by adding 3.0 ml l % barium chloride solution was added to 97 ml of 1% sulfuric acid. After the setting, Streptococcus Aronsen in a ratio of 1:15 and the other test bacteria in a ratio of 1:1500 were further diluted with a sodium chloride solution. 16 mg of the test compound was weighed into 10 ml volumetric flasks and diluted with the solvent to the mark. The further dilution series was made with distilled water or the appropriate solvent.
Fordypningene i mikrotiterplåtene ble fylit med 0,2 ml næringsmedium, 0,01 ml av den ønskede fortynning av prøve-forbindelsen og 1 dråpe bakteriesuspensjon (0,01 ml) og dyrket i 18 til 20 timer ved 37°C. En oppløsningsmiddelkontroll ble alltid tatt med. The wells in the microtiter plates were filled with 0.2 ml of nutrient medium, 0.01 ml of the desired dilution of the test compound and 1 drop of bacterial suspension (0.01 ml) and cultured for 18 to 20 hours at 37°C. A solvent control was always included.
Avlesningen ble foretatt makroskopisk, slik at man fikk den aktuelle grensekonsentrasjon (= laveste, ennu bakterio-statisk virksomme konsentrasjon). The reading was carried out macroscopically, so that the relevant limit concentration (= lowest, still bacteriostatically effective concentration) was obtained.
Som prøveorganismer ble benyttet:The following organisms were used as test organisms:
Staphylococcus aureus SG 511, Escherichia coli ATCC 11 775, Pseudomonas aeruginosa Hamburgensis og Walter, Serratia marcescens ATCC 13 880, Klebsiélla pneumoniae ATCC 10 031 og BC 6, Proteus mirabilis Hamburgensis, Proteus rettgeri BC 7 og Enterobacter cloacae ATCC 13 047. Staphylococcus aureus SG 511, Escherichia coli ATCC 11 775, Pseudomonas aeruginosa Hamburgensis and Walter, Serratia marcescens ATCC 13 880, Klebsiélla pneumoniae ATCC 10 031 and BC 6, Proteus mirabilis Hamburgensis, Proteus rettgeri BC 7 and Enterobacter cloacae ATCC 13 047.
I den følgende tabell 2 er angitt de fundne minimale hemmende konsentrasjoner (MHK) for typiske representanter for de nye forbindelser, hvor nummereringen svarer til den som er benyttet i tabell 1. In the following table 2, the minimum inhibitory concentrations (MIC) found for typical representatives of the new compounds are indicated, where the numbering corresponds to that used in table 1.
En rekke av de nye forbindelser ble undersøkt in vivo A number of the new compounds were investigated in vivo
ved eksperimentelle infeksjoner på mus. Man anvendte som patogene bakterier E. coli ATCC 11775 og Pseudomonas aeruginosa Walter. Det ble fremkalt en intraperitoneal infeksjon med in experimental infections of mice. E. coli ATCC 11775 and Pseudomonas aeruginosa Walter were used as pathogenic bacteria. An intraperitoneal infection was induced with
0,2 ml av en 5% mucin-suspensjon av bakteriene. Dette svarer til ca. 2 x 10 6 E. coli bakterier, resp. 8 x 10 5 Pseudomonas-bakterier pr. mus. Hunnmus av stammen NMRI ble oppdelt i grupper på hver 10 dyr, to grupper ble ubehandlet, og de øvrige grupper ble behandlet subkutant med forskjellige doser av de aktuelle nye penicilliner for å bestemme ED^q (dose hvor 0.2 ml of a 5% mucin suspension of the bacteria. This corresponds to approx. 2 x 10 6 E. coli bacteria, resp. 8 x 10 5 Pseudomonas bacteria per mouse. Female mice of the strain NMRI were divided into groups of 10 animals each, two groups were left untreated, and the other groups were treated subcutaneously with different doses of the relevant new penicillins to determine the ED^q (dose where
,50% av dyrene overlevde). Ved E. coli infeksjonen ble behandling ,|Eoretatt en gang. Ved Pseudomonas-infeksjonen ble behandling foretatt tre ganger. .50% of the animals survived). In the case of the E. coli infection, treatment was taken once. In the case of the Pseudomonas infection, treatment was carried out three times.
Observasjonstiden utgjorde i begge tilfeller 7 dager. Resultatene fra disse forsøk med representative penicilliner fremstilt ifølge oppfinnelsen er angitt i tabell 3. The observation period was 7 days in both cases. The results from these experiments with representative penicillins produced according to the invention are given in table 3.
Som sammenligningsforbindelser tjente de kjente penicilliner med den generelle formel As comparison compounds, the known penicillins with the general formula served
med with
R = H : Azlocillin = A R = H : Azlocillin = A
R = S02CH3 : Mezlocillin = B R = SO 2 CH 3 : Mezlocillin = B
videre further
D-a-[(4-hydroksy-3-pyridyl)-ureido]-benzylpenicillin-natrium D-α-[(4-hydroxy-3-pyridyl)-ureido]-benzylpenicillin sodium
(se tysk off.skrift 2.450.668) = C (see German official document 2.450.668) = C
og and
piperacillin (T 1220) = D piperacillin (T 1220) = D
Den akutte toksisitet ble bestemt ved peroral og subkutan administrering av forbindelsene ifølge tabell 1 til hvite laboratoriemus i stigende doser. The acute toxicity was determined by peroral and subcutaneous administration of the compounds according to Table 1 to white laboratory mice in increasing doses.
LD,-Q er den dose som medfører at 50% av dyrene dør i løpet av 8 dager efter administreringen. Samtlige forbindelser viser ved oral administrering en LD^^på over 4 g/kg, ved subkutan administrering en LD5q på over 3 g/kg, dvs. ved 3 g/kg døde ingen dyr, og forbindelsene er dermed i praksis ugiftige. LD,-Q is the dose which causes 50% of the animals to die within 8 days of administration. All compounds show an LD^^ of over 4 g/kg when administered orally, and an LD5q of over 3 g/kg when administered subcutaneously, i.e. at 3 g/kg no animals died, and the compounds are thus practically non-toxic.
De angitte verdier viser at representative penicilliner fremstilt ifølge oppfinnelsen, på grunn av sitt brede anti-biotiske spektrum, sin høye antibakterielle aktivitet, sin lave toksisitet og sitt høye serumspeil efter subkutan og oral administrering, er verdifulle antibiotika. The stated values show that representative penicillins produced according to the invention, due to their broad antibiotic spectrum, their high antibacterial activity, their low toxicity and their high serum level after subcutaneous and oral administration, are valuable antibiotics.
De nye forbindelser kan innføres i farmasøytiske preparater for behandling av infeksjonssykdommer både hos mennesker og dyr. The new compounds can be introduced into pharmaceutical preparations for the treatment of infectious diseases in both humans and animals.
Som foretrukne farmasøytiske preparater kan nevnes As preferred pharmaceutical preparations can be mentioned
tabletter, dragéer, kapsler, granulater, stikkpiller, opp-løsninger, suspensjoner, emulsjoner, salver, geleer, kremer, puddere og spray-preparater. Fordelaktig administreres virkestoffet eller en blanding av forskjellige virkestoffer med den generelle formel I i human- eller veterinær-medisinen, i en dosering mellom 5 og 500, fortrinnsvis 10-200 mg/kg kroppsvekt pr. 24 timer, eventuelt i form av flere enkeltadministreringer. En enkelt administrering inneholder virkestoffet eller virke-stoffene i mengder på fortrinnsvis ca. 1 til ca. 100, spesielt 5 til 60 mg/kg kroppsvekt. Det kan imidlertid være nødvendig å avvike fra nevnte doseringer, og særlig avhengig av arten og kroppsvekten hos individet som skal behandles, arten og graden av sykdommen, arten av preparatet og administreringsformen for legemidlet, og dessuten det tidsrom resp. intervall i løpet av hvilket administreringen skjer. Således kan det i enkelte tilfeller være tilstrekkelig å anvende mindre enn den ovenfor angitte mengde virkestoff, mens det i andre tilfeller er nød-vendig med mer enn den angitte virkestoffmengde. Fastleggelse av den til enhver tid nødvendige optimale dosering og administrerings form for virkestoffet kan lett foretas av enhver fagmann på grunnlag av hans fagkunnskap. tablets, dragees, capsules, granules, suppositories, solutions, suspensions, emulsions, ointments, gels, creams, powders and spray preparations. Advantageously, the active ingredient or a mixture of different active ingredients with the general formula I is administered in human or veterinary medicine, in a dosage between 5 and 500, preferably 10-200 mg/kg body weight per 24 hours, possibly in the form of several individual administrations. A single administration contains the active ingredient or active ingredients in quantities of preferably approx. 1 to approx. 100, especially 5 to 60 mg/kg body weight. However, it may be necessary to deviate from the aforementioned dosages, and in particular depending on the nature and body weight of the individual to be treated, the nature and degree of the disease, the nature of the preparation and the form of administration of the medicine, and also the time period or interval during which the administration takes place. Thus, in some cases it may be sufficient to use less than the amount of active substance indicated above, while in other cases it is necessary to use more than the indicated amount of active substance. Determining the optimal dosage and form of administration required at all times for the active substance can easily be carried out by any professional on the basis of his professional knowledge.
Ved parenteral administrering foretrekkes det å oppløseFor parenteral administration, it is preferred to dissolve
den nye penicillinforbindelse i et ugiftig, flytende medium for injeksjonsformål og å injisere oppløsningen intramuskulært, intravenøst eller subkutant. the new penicillin compound in a non-toxic liquid medium for injection purposes and to inject the solution intramuscularly, intravenously or subcutaneously.
Det er også mulig å oppløse den nye penicillinforbindelseIt is also possible to dissolve the new penicillin compound
i et ugiftig, flytende medium eller i et salvegrunnlag eller blande den med dette og å påføre oppløsningen eller blandingen direkte på det skadede sted. Forbindelsene kan også anvendes som stikkpiller efter blanding med et grunnlag for stikkpiller eller efter oppløsning deri. in a non-toxic, liquid medium or in an ointment base or mixing it with this and applying the solution or mixture directly to the damaged area. The compounds can also be used as suppositories after mixing with a base for suppositories or after dissolution therein.
Eksempler på ugiftige, flytende medier som kan anvendesExamples of non-toxic, liquid media that can be used
for fremstilling av injiserbare preparater som inneholder penicillinforbindelsen som virkestoff, er sterilisert, avionisert vann, fysiologisk koksaltoppløsning, glukoseoppløsning for injeksjon, Ringers oppløsning eller aminosyreoppløsning for injeksjon. for the manufacture of injectable preparations containing the penicillin compound as active ingredient, are sterilized, deionized water, physiological saline solution, glucose solution for injection, Ringer's solution or amino acid solution for injection.
Penicillinforbindelsen kan også oppløses i andre injiserbare preparater og administreres parenteralt. The penicillin compound can also be dissolved in other injectable preparations and administered parenterally.
For oral administrering anvendes de nye penicillinforbindelser i form av et farmasøytisk preparat som inneholder forbindelsen(e), eventuelt blandet med farmasøytisk forlikelige bærere, f.eks. For oral administration, the new penicillin compounds are used in the form of a pharmaceutical preparation containing the compound(s), possibly mixed with pharmaceutically compatible carriers, e.g.
et organisk eller uorganisk, fast eller flytende hjelpestoff, som er egnet for oral administrering.. Eventuelt kan disse preparater også inneholde hjelpestoffer, stabilisatorer og andre vanlig anvendte tilsetningsstoffer. an organic or inorganic, solid or liquid excipient, which is suitable for oral administration. Optionally, these preparations may also contain excipients, stabilizers and other commonly used additives.
Når det gjelder anvendelse som f6r-tilsetningsmidler, kan de nye forbindelser anvendes i vanlige konsentrasjoner og til-beredninger sammen med for-stoffet resp. forstoff-preparater eller med drikkevannet. Derved kan en inveksjon av gram-negative eller gram-positive bakterier forhindres, forbedres og/eller helbredes, og likeledes kan man oppnå en forbedring av vekten og en forbedring av forutnyttelsen. When it comes to use as precursor additives, the new compounds can be used in normal concentrations and preparations together with the precursor or precursor preparations or with the drinking water. Thereby, an infection by gram-negative or gram-positive bacteria can be prevented, improved and/or cured, and likewise an improvement in weight and an improvement in utilization can be achieved.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere (angivelsene av Rf-verdier gjelder for systemet n-butanol-vann-iseddik = 60:25:15, Si02~plate). The following examples shall serve to illustrate the invention further (the indications of Rf values apply to the system n-butanol-water-glacial vinegar = 60:25:15, SiO2~plate).
Med "ampicillin" menes det a-aminobenzylpenicillin, med "amoxycillin" menes det a-amino-p-hydroksy-benzylpenicillin og med "epicillin" menes det a-amino-a-(1,4-cykloheksadien-1-yl)-metylpenicillin som har D=R-konfigurasjon i sidekjeden. By "ampicillin" is meant α-aminobenzylpenicillin, by "amoxycillin" is meant α-amino-p-hydroxy-benzylpenicillin and by "epicillin" is meant α-amino-α-(1,4-cyclohexadien-1-yl)- methylpenicillin which has D=R configuration in the side chain.
I. Fremstilling av utgangsforbindelseneI. Preparation of the starting compounds
Eksempel AExample A
5- amino- 4- hydroksy- 2- p- metylsulfonylanilino- pyrimidin5- amino- 4- hydroxy- 2- p- methylsulfonyl anilino- pyrimidine
3,2 g (0,019 mol) 4-metyltio-nitrobenzen oppløses i 20 ml maursyre og tilsettes 0,05 mol hydrogenperoksyd som 30%ig opp-løsning ved romtemperatur. Derved oppvarmes oppløsningen. Dissolve 3.2 g (0.019 mol) of 4-methylthio-nitrobenzene in 20 ml of formic acid and add 0.05 mol of hydrogen peroxide as a 30% solution at room temperature. The solution is thereby heated.
Efter 1 times henstand ved romtemperatur foretas felning med isvann, bunnfallet avsuges og tørres ved 50°C i vakuum. Man får 2,9 g (76,2% av det teoretiske) p-nitrofenylmetylsulfon. After standing for 1 hour at room temperature, precipitation is carried out with ice water, the precipitate is suctioned off and dried at 50°C in a vacuum. 2.9 g (76.2% of the theoretical) of p-nitrophenylmethylsulfone are obtained.
3,42 g (0,017 mol) p-nitrofenyl-metyl-sulfon oppløses i 100 ml metanol og hydrogeneres i nærvær av 1 g Raney-nikkel ved 50°C og 5 bar. Oppløsningen filtreres fra katalysatoren og inndampes til tørrhet. Residuet oppløses i 40 ml dioksan og tilsettes en oppløsning av 3,77 g (0,0175 mol) 2-klor-4-hydroksy-5-nitro-pyrimidin-natriumsalt • lf^O i 120 ml vann. Oppløsningen oppvarmes på dampbad i 3 timer. Efter avkjøling avsuges det utfelte bunnfall, vaskes med vann og tørres ved 50°C i vakuum. 3.42 g (0.017 mol) of p-nitrophenyl-methyl-sulfone are dissolved in 100 ml of methanol and hydrogenated in the presence of 1 g of Raney nickel at 50°C and 5 bar. The solution is filtered from the catalyst and evaporated to dryness. The residue is dissolved in 40 ml of dioxane and a solution of 3.77 g (0.0175 mol) of 2-chloro-4-hydroxy-5-nitro-pyrimidine sodium salt • lf^O in 120 ml of water is added. The solution is heated on a steam bath for 3 hours. After cooling, the deposited precipitate is suctioned off, washed with water and dried at 50°C in a vacuum.
Utbytte: 3,1 g (58,7% av det teoretiske) 4-hydroksy-2-p-mety1-sulfonylanilino-5-nitropyrimidin. Yield: 3.1 g (58.7% of theory) 4-hydroxy-2-p-methyl-sulfonylanilino-5-nitropyrimidine.
3,3 g (0,01063 mol) 4-hydroksy-2-p-metylsulfonylanilino-5-nitropyrimidin oppløses i 50 ml vann under oppvarmning ved tilsetning av 6 ml konsentrert ammoniakk. Under omrøring tilsettes 7,83 g (0,045 mol) natriumditionitt alt på en gang. Derefter omrøres i ytterligere 15 minutter ved 60°C. Efter avkjøling avsuges det dannede bunnfall, vaskes med vann og tørres ved 50°C i vakuum. 3.3 g (0.01063 mol) of 4-hydroxy-2-p-methylsulfonyl anilino-5-nitropyrimidine are dissolved in 50 ml of water while heating by adding 6 ml of concentrated ammonia. While stirring, 7.83 g (0.045 mol) of sodium dithionite are added all at once. Then stir for a further 15 minutes at 60°C. After cooling, the formed precipitate is suctioned off, washed with water and dried at 50°C in a vacuum.
Utbytte: 2,4 g (80,6% av det teoretiske) 5-amino-4-hydroksy-2-p-metylsulfonylanilino-pyrimidin. Yield: 2.4 g (80.6% of theory) 5-amino-4-hydroxy-2-p-methylsulfonyl anilino-pyrimidine.
NMR-spektrum (DMSO + CD30D) signaler ved ppm: 3,15 (s, 3H),NMR spectrum (DMSO + CD30D) signals at ppm: 3.15 (s, 3H),
7,2 (s, 1H), 7,8 (bred s, 4H).7.2 (s, 1H), 7.8 (broad s, 4H).
Eksempel b Example b
5- amino- 4- hydroksy- 2- p- metylsulfinylanilino- pyrimidin5- amino- 4- hydroxy- 2- p- methylsulfinyl anilino- pyrimidine
3,8 g (0,014 mol) 4-hydroksy-2-p-metyltio-anilino-5-nitro-, pyrimidin oppslemmes i 50 ml iseddik, tilsettes 2,3 g (0,02 mol) 30%ig hydrogenperoksyd og oppvarmes under omrøring i 10 minutter på dampbad. Efter avkjøling avsuges det dannede bunnfall og tørres i vakuum. 3.8 g (0.014 mol) of 4-hydroxy-2-p-methylthio-anilino-5-nitro-pyrimidine are suspended in 50 ml of glacial acetic acid, 2.3 g (0.02 mol) of 30% hydrogen peroxide are added and heated under stirring for 10 minutes on a steam bath. After cooling, the formed precipitate is suctioned off and dried in a vacuum.
Utbytte: 2,2 8 g (55% av det teoretiske) 4-hydroksy-2-p-mety1-sulfinylanilino-5-nitro-pyrimidin. Yield: 2.28 g (55% of theory) 4-hydroxy-2-p-methyl-sulfinylanilinino-5-nitro-pyrimidine.
2,1 g (0,0079 mol) 4-hydroksy-2-p-metylsulfinylanilino-5-nitropyrimidin oppslemmes i 60 ml vann og oppløses ved tilsetning av 7 ml konsentrert ammoniakk og oppvarmning. 8 g natriumditionitt tilsettes på en gang, og oppløsningen oppvarmes i 20 minutter på dampbad. Efter avkjøling bringes oppløsningen til pH 7 med iseddik og får stå i flere timer i kjøleskap. 2.1 g (0.0079 mol) of 4-hydroxy-2-p-methylsulfinylanilinino-5-nitropyrimidine are suspended in 60 ml of water and dissolved by adding 7 ml of concentrated ammonia and heating. 8 g of sodium dithionite are added at once, and the solution is heated for 20 minutes on a steam bath. After cooling, the solution is brought to pH 7 with glacial acetic acid and allowed to stand for several hours in a refrigerator.
Efter avsugningen renses råproduktet ved kromatografi over en silikagelkolonne (elueringsmiddel kloroform/metanol 5:1). Utbytte: 0,8 g (38,2% av det teoretiske). After extraction, the crude product is purified by chromatography over a silica gel column (eluent chloroform/methanol 5:1). Yield: 0.8 g (38.2% of the theoretical).
NMR-spektrum (DMSO + CD30D) signaler ved ppm: 2,75 (s, 3H), 7,15 (s, 1H), 7,7 (q, 4H). NMR spectrum (DMSO + CD 3 OD) signals at ppm: 2.75 (s, 3H), 7.15 (s, 1H), 7.7 (q, 4H).
Ved å gå ut fra det passende substituerte anilin og 4-hydroksy-2-p-metyltio-anilino-5-nitro-pyrimidin resp. 2-klor-4-hydroksy-5-nitropyrimidin og påfølgende reduksjon ble pyrimidinene angitt i den følgende tabell syntetisert på analog måte. Starting from the suitably substituted aniline and 4-hydroxy-2-p-methylthio-anilino-5-nitro-pyrimidine resp. 2-chloro-4-hydroxy-5-nitropyrimidine and subsequent reduction, the pyrimidines indicated in the following table were synthesized in an analogous manner.
Pyrimidiner med den generelle formelPyrimidines of the general formula
Pyrimidiner med den generelle formel Pyrimidines of the general formula
Pyrimidiner med den generelle formelI Pyrimidines of the general formula I
Eksempel C Example C
D- L- g-[ 3-( 4- hydroksy- 2- p- metylaminosulfonYlanilino- 5- pyrimidinyl)-ureido]- tienyleddiksyre D- L- g-[ 3-( 4- hydroxy- 2- p- methylaminosulfonYlanilino- 5- pyrimidinyl)-ureido]- thienylacetic acid
2,95 g (0,01 mol) 5-amino-2-p-metylaminosulfonylanilino-4-hydroksy-pyrimidin oppvarmes under tilbakeløpskjøling i 30 minutter i 100 ml tørr tetrahydrofuran sammen med 6 g trimetylsilyldietylamin. Derefter inndampes til tørrhet i vakuum, og det faste produkt oppløses i 60 ml tørr tetrahydrofuran under nitrogen. Denne oppløsning settes under isavkjøling dråpevis til 1,05 g fosgen, oppløst i 50 ml tetrahydrofuran. 2.95 g (0.01 mol) of 5-amino-2-p-methylaminosulfonyl anilino-4-hydroxy-pyrimidine are heated under reflux for 30 minutes in 100 ml of dry tetrahydrofuran together with 6 g of trimethylsilyldiethylamine. It is then evaporated to dryness in vacuo, and the solid product is dissolved in 60 ml of dry tetrahydrofuran under nitrogen. This solution is added dropwise under ice-cooling to 1.05 g of phosgene, dissolved in 50 ml of tetrahydrofuran.
Man omrører videre i 5 minutter ved romtemperatur og inndamper til ca. halvt volum i vakuum. Denne oppløsning settes under isavkjøling dråpevis til 1,57 g (0,01 mol) D,L-tienylglycin, You continue to stir for 5 minutes at room temperature and evaporate to approx. half volume in vacuum. This solution is added dropwise under ice-cooling to 1.57 g (0.01 mol) D,L-thienylglycine,
som ble oppløst med IN natronlut i en blanding av 50 ml tetrahydrofuran og 20 ml vann. Ved slutten av tilsetningen innstilles pH-verdien på 8,0. Man omrører videre i 1 time ved romtemperatur, avdriver tetrahydrofuranet i vakuum, tilsetter noe vann og utrister to ganger med etylacétat ved pH 7,0. which was dissolved with 1N caustic soda in a mixture of 50 ml of tetrahydrofuran and 20 ml of water. At the end of the addition, the pH value is set to 8.0. The mixture is stirred for 1 hour at room temperature, the tetrahydrofuran is evaporated in vacuo, some water is added and the mixture is decanted twice with ethyl acetate at pH 7.0.
Den vandige fase innstilles derefter på pH 2,7 med 2N saltsyre. Det utfelte produkt avsuges og tørres. The aqueous phase is then adjusted to pH 2.7 with 2N hydrochloric acid. The precipitated product is suctioned off and dried.
Utbytte: 3,3 g (69%) .Yield: 3.3 g (69%) .
IR-spektrum: 3300, 1660, 1555 cm<-1>. IR spectrum: 3300, 1660, 1555 cm<-1>.
NMR-spektrum (DMSO + CD30D) signaler ved ppm:NMR spectrum (DMSO + CD30D) signals at ppm:
2,45 (s, 3H), 5,50 (s, 1H), 7,05 (m, 2H), 7,40 (m, 1H), 7,80 2.45 (s, 3H), 5.50 (s, 1H), 7.05 (m, 2H), 7.40 (m, 1H), 7.80
(q, 4H), 8,35 (s, 1H). (q, 4H), 8.35 (s, 1H).
Analogt ble følgende ureidokarboksylsyrer syntetisert: a) ureidokarboksylsyrer med den generelle formel b) ureidokarboksylsyrer med den generelle formel c) ureidokarboksylsyrer med den generelle formel Analogously, the following ureidocarboxylic acids were synthesized: a) ureidocarboxylic acids with the general formula b) ureidocarboxylic acids with the general formula c) ureidocarboxylic acids with the general formula
II Fremstilling av sluttproduktene II Production of the final products
Eksempel 1 Example 1
D- a-[ 3-( 4- hydroksy- 2- p- metylaminosulfonylanilino- 5- pyrimidinyl)-ureido]- p- hydroksy- benzylpenicillin- natrium D- a-[ 3-( 4- hydroxy- 2- p- methylaminosulfonyl anilino- 5- pyrimidinyl)-ureido]- p- hydroxy- benzylpenicillin- sodium
1,47 g (0,005 mol) 5-amino-4-hydroksy-2-p-metylaminosulfonylanilino-pyrimidin oppslemmes i 50 ml tørr tetrahydrofuran og oppvarmes under tilbakeløpskjøling sammen med 4 g trimetylsilyldietylamin til fullstendig oppløsning (10 til '30 minutter). Oppløsningen inndampes til tørrhet i vakuum, opptas igjen i 50 ml tetrahydrofuran og settes dråpevis under isavkjøling til en oppløsning av 530 mg fosgen i 35 ml tørr tetrahydrofuran. Man omrører videre i 10 minutter ved romtemperatur og inndamper derefter i vakuum til ca. halvt volum. 1.47 g (0.005 mol) of 5-amino-4-hydroxy-2-p-methylaminosulfonyl anilino-pyrimidine is suspended in 50 ml of dry tetrahydrofuran and heated under reflux together with 4 g of trimethylsilyldiethylamine until complete dissolution (10 to 30 minutes). The solution is evaporated to dryness in vacuo, taken up again in 50 ml of tetrahydrofuran and added dropwise under ice-cooling to a solution of 530 mg of phosgene in 35 ml of dry tetrahydrofuran. Stirring is continued for 10 minutes at room temperature and then evaporated in a vacuum to approx. half volume.
Man suspenderer 2,1 g (0,005 mol) amoxicillin i en opp-løsningsmiddelblanding av 40 ml tetrahydrofuran og 10 ml vann. Under isavkjøling setter man trietylamin til oppløsningen. 2.1 g (0.005 mol) of amoxicillin are suspended in a solvent mixture of 40 ml of tetrahydrofuran and 10 ml of water. Under ice-cooling, triethylamine is added to the solution.
Til denne oppløsning settes dråpevis den ovenfor fremstilte oppløsning, idet pH-verdien holdes på ca. 7,0 ved tilsetning av trietylamin. Man omrører videre i 1 time i isbad, lar blandingen komme til romtemperatur, tilsetter 20 ml vann og fjerner tetrahydrofuranet i vakuum. Den vandige fase utristes en gang med etylacetat ved pH 7,0 og innstilles på pH 2,8 med IN saltsyre under isavkjøling. Det utfelte penicillin avsuges The solution prepared above is added dropwise to this solution, keeping the pH value at approx. 7.0 when triethylamine is added. The mixture is stirred for 1 hour in an ice bath, the mixture is allowed to come to room temperature, 20 ml of water is added and the tetrahydrofuran is removed in vacuo. The aqueous phase is decanted once with ethyl acetate at pH 7.0 and adjusted to pH 2.8 with 1N hydrochloric acid under ice cooling. The precipitated penicillin is suctioned off
og tørres i vakuum.and dried in a vacuum.
Ved tilsetning av den beregnede mengde natrium-etylheksanoat i metanol fremstilles natriumsaltet og utfelles med eter. Utbytte: 2,16 g (62%); By adding the calculated amount of sodium ethyl hexanoate in methanol, the sodium salt is prepared and precipitated with ether. Yield: 2.16 g (62%);
IR-spektrum: 1765, 1650, 1610 cm"<1>; IR spectrum: 1765, 1650, 1610 cm"<1>;
NMR-spektrum (DMSO + CD30D) signaler ved ppm: 1,55 (d, 6H),NMR spectrum (DMSO + CD30D) signals at ppm: 1.55 (d, 6H),
2,55 (s, 3H), 4,05 (s, 1H), 5,45 (d + s, 3H), 6,75 (d, 2H), 2.55 (s, 3H), 4.05 (s, 1H), 5.45 (d + s, 3H), 6.75 (d, 2H),
7,30 (d, 2H), 7,85 (q, 4H), 8,35 (s, 1H). 7.30 (d, 2H), 7.85 (q, 4H), 8.35 (s, 1H).
Ved denne fremgangsmåte ble penicillinene med den følgende formel syntetisert: By this method, the penicillins with the following formula were synthesized:
Eksempel 50 Example 50
D, L- g-[ 3-( 2- p- aminosulfonylanilino- 4- hydroksy- 5- pyrimidinyl)-ureido]- 2- tienylmety1- penicillin- natrium D, L- g-[ 3-( 2- p- aminosulfonyl anilino- 4- hydroxy- 5- pyrimidinyl)-ureido]- 2- thienylmethy1-penicillin- sodium
En oppløsning av 2,3 g (5 mmol) D,L-a-[3-(2-p-aminosulfonylanilino-4-hydroksy-5-pyrimidinyl)-ureido]-tienyl-eddiksyre i 50 ml dimetylformamid og 25 ml metylenklorid tilsettes 0,52 g (5,1 mmol) N-metylmorfolin og avkjøles til -20 til 25°C. Til blandingen settes 0,54 g (5 mmol) klormaursyre-etylester oppløst i 20 ml metylenklorid, og blandingen omrøres i 45 minutter ved -20°C (Oppløsning A). Add 0 .52 g (5.1 mmol) of N-methylmorpholine and cooled to -20 to 25°C. To the mixture is added 0.54 g (5 mmol) chloroformic acid ethyl ester dissolved in 20 ml of methylene chloride, and the mixture is stirred for 45 minutes at -20°C (Solution A).
Til en suspensjon av 1,1 g (5 mmol) 6-aminopenicillansyreTo a suspension of 1.1 g (5 mmol) 6-aminopenicillanic acid
i 50 ml metylenklorid settes dråpevis 3,1 g (30 mmol) trietylamin, derefter omrøres i 1-2 timer ved romtemperatur inntil oppløsning er oppnådd, og endelig avkjøles til -20°C (oppløsning B). 3.1 g (30 mmol) of triethylamine are added dropwise to 50 ml of methylene chloride, then stirred for 1-2 hours at room temperature until a solution is obtained, and finally cooled to -20°C (solution B).
Man setter oppløsning B til oppløsning A, mens temperaturen holdes ved -20°C, og lar reaksjonsblandingen reagere videre i 45 minutter ved -20°C og 2 timer ved romtemperatur. Solution B is added to solution A, while the temperature is kept at -20°C, and the reaction mixture is allowed to react further for 45 minutes at -20°C and 2 hours at room temperature.
Derefter tilsettes 150 ml vann, den vandige fases pH-verdi innstilles på 7,2, det organiske skikt fraskilles, og vann-fasen ekstraheres 3 ganger med etylacetat. Etylacetat-ekstrakten kastes. Man dekker den vandige fase med et lag av etylacetat og innstiller dens pH på 3,0 ved tilsetning av 2N saltsyre. Det organiske skikt fraskilles, tørres med natriumsulfat og inndampes. Man oppløser det oppnådde penicillin i metanol og utfeller natriumsaltet ved tilsetning av en ekvimolar mengde natrium-etylheksanoat. 150 ml of water are then added, the pH value of the aqueous phase is adjusted to 7.2, the organic layer is separated, and the aqueous phase is extracted 3 times with ethyl acetate. The ethyl acetate extract is discarded. The aqueous phase is covered with a layer of ethyl acetate and its pH is adjusted to 3.0 by adding 2N hydrochloric acid. The organic layer is separated, dried with sodium sulphate and evaporated. The penicillin obtained is dissolved in methanol and the sodium salt is precipitated by adding an equimolar amount of sodium ethyl hexanoate.
Utbytte: 2.9 g (84% av det teoretiske),Yield: 2.9 g (84% of the theoretical),
IR-spektrum: 1760, 1655, 1600 cm"<1>, IR spectrum: 1760, 1655, 1600 cm"<1>,
NMR-spektrum (DMSO + CD30D) signaler ved ppm:NMR spectrum (DMSO + CD30D) signals at ppm:
1,55 (d, 6H), 4,0 (s, 1H), 5,45 (m, 3H), 7,1 (m, 2H), 7,45 1.55 (d, 6H), 4.0 (s, 1H), 5.45 (m, 3H), 7.1 (m, 2H), 7.45
(m, 1H), 7,85 (q, 4H), 8,35 (s, 1H). (m, 1H), 7.85 (q, 4H), 8.35 (s, 1H).
I henhold til fremgangsmåten i eksempel 50 ble følgende penicilliner syntetisert: a) med formel b) med formelen c) med formelen According to the procedure in example 50, the following penicillins were synthesized: a) with the formula b) with the formula c) with the formula
Forbindelsene med den generelle formel I og I' kan inn-arbeides i de vanlige farmasøytiske anvendelsesformer så The compounds with the general formula I and I' can be incorporated into the usual pharmaceutical application forms as
som tabletter, dragéer, kapsler eller ampuller. Enkeltdosen utgjør for voksne vanligvis mellom 50 og 1000 mg, fortrinnsvis 100 til 500 mg, og den daglige dose utgjør mellom 100 og 4000 mg, fortrinnsvis 250 til 2000 mg. as tablets, dragées, capsules or ampoules. The single dose for adults is usually between 50 and 1000 mg, preferably 100 to 500 mg, and the daily dose is between 100 and 4000 mg, preferably 250 to 2000 mg.
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DE3042440A1 (en) | 1982-06-24 |
IL64245A0 (en) | 1982-02-28 |
ES8304993A1 (en) | 1983-03-16 |
AU7735481A (en) | 1982-05-20 |
JPS57109793A (en) | 1982-07-08 |
ZA817745B (en) | 1983-07-27 |
EP0051773A1 (en) | 1982-05-19 |
ES513341A0 (en) | 1983-03-16 |
DD201904A5 (en) | 1983-08-17 |
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