FI67703B - Foerfarande foer framstaellning av farmakologiskt vaerdefulla (4-hydroxi-5-pyrimidinyl)-ureidobensylpenicilliner - Google Patents
Foerfarande foer framstaellning av farmakologiskt vaerdefulla (4-hydroxi-5-pyrimidinyl)-ureidobensylpenicilliner Download PDFInfo
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- FI67703B FI67703B FI800786A FI800786A FI67703B FI 67703 B FI67703 B FI 67703B FI 800786 A FI800786 A FI 800786A FI 800786 A FI800786 A FI 800786A FI 67703 B FI67703 B FI 67703B
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- Finland
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- hydroxy
- general formula
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- formula
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- 230000000144 pharmacologic effect Effects 0.000 title description 2
- -1 p-hydroxy-phenyl Chemical group 0.000 claims abstract description 56
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 7
- 150000007530 organic bases Chemical class 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 229930182555 Penicillin Natural products 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 229940049954 penicillin Drugs 0.000 claims description 36
- 239000000047 product Substances 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 19
- 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
- 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 13
- AVWRKZWQTYIKIY-UHFFFAOYSA-N ureidocarboxylic acid Natural products NC(=O)NC(O)=O AVWRKZWQTYIKIY-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 150000003230 pyrimidines Chemical class 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 239000012736 aqueous medium Substances 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 150000001540 azides Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 125000002947 alkylene group Chemical group 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 abstract 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 abstract 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 abstract 1
- 101100519284 Cercospora nicotianae PDX1 gene Proteins 0.000 abstract 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- 101100277598 Sorghum bicolor DES3 gene Proteins 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 125000002993 cycloalkylene group Chemical group 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 101150073238 sor1 gene Proteins 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 108
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 87
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- 159000000000 sodium salts Chemical class 0.000 description 36
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 35
- 238000002329 infrared spectrum Methods 0.000 description 35
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 29
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 27
- 239000007858 starting material Substances 0.000 description 27
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 16
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- 239000002585 base Substances 0.000 description 14
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
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- FKISQUDKWUHTBU-UHFFFAOYSA-N NC=1C(=NC(=NC1)NCC(C)C#N)O.NC=1C(=NC(=NC1)NCCSC)O.NC=1C(=NC(=NC1)NCCSCC)O Chemical compound NC=1C(=NC(=NC1)NCC(C)C#N)O.NC=1C(=NC(=NC1)NCCSC)O.NC=1C(=NC(=NC1)NCCSCC)O FKISQUDKWUHTBU-UHFFFAOYSA-N 0.000 description 1
- JDSLKONBGXRKRK-UHFFFAOYSA-N NC=1C(=NC(=NC1)NCCCC(=O)N)O.NC=1C(=NC(=NC1)NCCC(=O)C)O.NC=1C(=NC(=NC1)NC1CCC(CC1)O)O Chemical compound NC=1C(=NC(=NC1)NCCCC(=O)N)O.NC=1C(=NC(=NC1)NCCC(=O)C)O.NC=1C(=NC(=NC1)NC1CCC(CC1)O)O JDSLKONBGXRKRK-UHFFFAOYSA-N 0.000 description 1
- IYIOAKYXEZSFJD-UHFFFAOYSA-N NC=1C(=NC(=NC1)NCCNC(C)=O)O.NC=1C(=NC(=NC1)NCCCS(=O)(=O)N)O Chemical compound NC=1C(=NC(=NC1)NCCNC(C)=O)O.NC=1C(=NC(=NC1)NCCCS(=O)(=O)N)O IYIOAKYXEZSFJD-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- JLNTWVDSQRNWFU-UHFFFAOYSA-N OOOOOOO Chemical compound OOOOOOO JLNTWVDSQRNWFU-UHFFFAOYSA-N 0.000 description 1
- 208000005141 Otitis Diseases 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000588770 Proteus mirabilis 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
- 241000607720 Serratia Species 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 1
- 108010021119 Trichosanthin Proteins 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000287 alkaline earth metal oxide Inorganic materials 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- ZGUNAGUHMKGQNY-UHFFFAOYSA-N alpha-phenylglycine Chemical compound OC(=O)C(N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-UHFFFAOYSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960003311 ampicillin trihydrate Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 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
- FCPVYOBCFFNJFS-LQDWTQKMSA-M benzylpenicillin sodium Chemical compound [Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 FCPVYOBCFFNJFS-LQDWTQKMSA-M 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical class [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 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
- 235000012255 calcium oxide Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001714 carbamic acid halides Chemical class 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- OUVDSJRBIAHMFT-UHFFFAOYSA-N carbamoylcarbamoyl n-carbamoylcarbamate Chemical compound NC(=O)NC(=O)OC(=O)NC(N)=O OUVDSJRBIAHMFT-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000001271 cephalosporin group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 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
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 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
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- UANIHYVTNQLZIY-UHFFFAOYSA-N ethyl 2-[(5-amino-6-oxo-1H-pyrimidin-2-yl)amino]acetate Chemical compound CCOC(=O)CNC1=NC=C(N)C(=O)N1 UANIHYVTNQLZIY-UHFFFAOYSA-N 0.000 description 1
- LKHYFCSSVZVVNF-UHFFFAOYSA-N ethyl hexanoate;sodium Chemical compound [Na].CCCCCC(=O)OCC LKHYFCSSVZVVNF-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- SIGPWCVHTYIKME-UHFFFAOYSA-N hexamethanol Chemical compound OC.OC.OC.OC.OC.OC SIGPWCVHTYIKME-UHFFFAOYSA-N 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
- 238000000338 in vitro Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical class [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 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
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 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
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003142 primary aromatic amines Chemical class 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- FVLAYJRLBLHIPV-UHFFFAOYSA-N pyrimidin-5-amine Chemical compound NC1=CN=CN=C1 FVLAYJRLBLHIPV-UHFFFAOYSA-N 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000012927 reference suspension Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 150000003336 secondary aromatic amines Chemical class 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000015424 sodium Nutrition 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
- 229910000030 sodium bicarbonate Inorganic materials 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
- UDWXLZLRRVQONG-UHFFFAOYSA-M sodium hexanoate Chemical compound [Na+].CCCCCC([O-])=O UDWXLZLRRVQONG-UHFFFAOYSA-M 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
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003510 tertiary aliphatic amines Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000003513 tertiary aromatic amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000004684 trihydrates Chemical class 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
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 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)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Claims (3)
1 J-N -1 θ' *COOH (III) där A avser detsamma som ovan, omsätts i ett lösningsmedel vid en temperatur mellan -10°C - rumstemperatur med ett pyrimidinderivat med den allmänna formeln (IV) 45 67703 B — OH f IΓ (IV) N<Y^N R där R avser detsanuna som ovan och B avser qruppen -NCO eller gruppens -NHCOOH reaktiva derivat, eller b) ureidokarboxylsyran enligt den allmänna formeln (V) * A-CH-COOH \ NH CO NH A^oh (V) R där A och R avser detsanuna som förut, eller dess salt eller reaktiva derivat bringas att reagera med 6-aminopenicillansyran enligt formeln (VI) S CH3 ν-Ί—r ^ I CH3 "-\ COOH (VI) eller med dess oorganiska eller organiska salter eller reaktiva 46 6770 3 derivator och möjligt därefter hydrolyseras eller katalytiskt hydro-genolyseras den sä här erhällna produkten till penicillin enligt den allmänna formeln (I) eller (I') och/eller om önskas därefter den erhällna penicillinen enligt den allmänna formeln (I) eller (I1) transformeras till sitt salt medelst oorganiska eller organiska baser.
1 COOH NH rV N γΝΗ R dSr A är en fenyl- eller 4-hydroxifenylgrupp, och R är en grupp med formeln 44 67703 NH - Z - X där Z Mr en eventuellt med en eller tvM metylgrupper substituerad alkylengrupp med totalt 1-4 kolatomer eller en med en hydroxigrupp som substituenten X substituerad cyklohexylgrupp, och X Mr en cyanogrupp, hydroxigrupp, merkaptogrupp, aminokarbonyl- eller aminosulfonylgrupp eller en grupp med den allmänna formeln /Rl -COR,, -COOR,, -N \ *2 -NHCORlf -OR1, -OCORji, -SRlf -SORjl eller -S02R^, varvid i dessa formler R-^ avser en rakkedjad eller förgrenad alkylgrupp med 1-4 kolatomer och R2 Mr en vMteatom eller en alkylgrupp med 1-4 kolatomer, varvid i en grupp med formeln /Ri -N , eller -OR,, R, kan ocksM avse en fenylgrupp, och deras Nr2 fysiologiskt IMmpliga salter med oorganiska eller organiska baser, kännetecknat därav, att a) en förening med den allmänna formeln (III) A-CH-CONH -3 iH, *
1. Förfarande för framställning av farmakologiskt värdefulla (4-hydroxi-5-FYri!Tlidinyl)-ureidobensylpenicilliner med formeln (I) * ^S^/CH3 A-CH-CONH-1-S ch3 NH I co ^- N X I O COOH NH Sr°‘ N γΝ R eller deras tautomerer med formeln (I') * S / 3 A-CH-CONH -S NH I 3 I X- n - CO of
2. Förfarande enligt patentkravet la, kännetecknat därav, att användes pyrimidindorivaten enligt patentkravets la allmänna formel (IV), där B avser gruppen -NCO eller där B avser gruppens -NHCOOH reaktiva derivat, eller i det sista fallet denna pyrimidinderivats blandning med nägon annan pyrimidinderivat enligt den allmänna formeln (IV), där B avser gruppen -NCO, och reaktionen utförs varken medan det finns med oorgansikt eller organiskt salt av föreningen enligt den allmänna formeln (III) i blandningar av vatten och med vatten blandande organiska lösningsmedel eller i organiska lösningsmedel eller i blandning av vatten och med vatten oblandande organiska lösningsmedel vid pH-värdet mellan 2,0 - 9,0 i som lösningsmedel fungerande vatten under närvaro av en bas eller buffertlösning eller medan det finns med silylderivat av föreningen enligt den allmänna formeln (III) eller karboxylderivat, i lösningsmedel inte innehällande vatten och hydroxylgrupper, möjligt genom att öka baser.
3. Förfarande enligt patentkravet lb, kännetecknat därav, att som reaktiva derivator av ureidokarboxylsyror enligt den allmänna formeln (V) användes deras syraanhydrider, deras reaktiva ester eller amider, deras syrahalogenider eller syraazider och att 6-aminopenicillansyran enligt formeln (VI) bringas att reagera som silylester, tritylester, p-nitrobensylester, fenacyl-ester och Ο,Ν-bis-trimetylsilylderivat i aprotiskt lösningsmedel, i formen av salt emellertid i protiskt lösninsmedel, i metylenklorid eller i vattenhaltigt medium eller i vattenorganiskhaltigt lösningsmedel vid temperaturer mellan -40 - +40°C, möjligt under nävarvo av en bas och/eller ett kondenseringsmedel och, medan den slutliga produkten ännu avser ester, därefter estergruppen hydrolyseras eller hydroqenolyseras. II
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2910190 | 1979-03-15 | ||
| DE19792910190 DE2910190A1 (de) | 1979-03-15 | 1979-03-15 | Neue penicilline, ihre salze, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI800786A7 FI800786A7 (fi) | 1980-09-16 |
| FI67703B true FI67703B (fi) | 1985-01-31 |
| FI67703C FI67703C (fi) | 1985-05-10 |
Family
ID=6065482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI800786A FI67703C (fi) | 1979-03-15 | 1980-03-13 | Foerfarande foer framstaellning av farmakologiskt vaerdefulla (4-hydroxi-5-pyrimidinyl)-ureidobensylpenicilliner |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4289775A (sv) |
| EP (1) | EP0016374B1 (sv) |
| JP (1) | JPS55124789A (sv) |
| AT (1) | ATE731T1 (sv) |
| AU (1) | AU536154B2 (sv) |
| CA (1) | CA1138434A (sv) |
| DE (2) | DE2910190A1 (sv) |
| DK (1) | DK110480A (sv) |
| ES (2) | ES8103097A1 (sv) |
| FI (1) | FI67703C (sv) |
| GR (1) | GR74000B (sv) |
| IL (1) | IL59614A (sv) |
| NO (1) | NO800755L (sv) |
| NZ (1) | NZ193127A (sv) |
| PH (1) | PH15821A (sv) |
| PT (1) | PT70956B (sv) |
| ZA (1) | ZA801499B (sv) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3042440A1 (de) * | 1980-11-11 | 1982-06-24 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue penicilline, ihre salze, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| EP0053693A1 (de) * | 1980-12-05 | 1982-06-16 | Dr. Karl Thomae GmbH | Neue Penicilline, ihre Salze, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1040166A (en) * | 1964-07-29 | 1966-08-24 | Beecham Group Ltd | Penicillins |
| US3308023A (en) * | 1964-08-20 | 1967-03-07 | American Home Prod | Therapeutic compositions containing 6-[d-2-(d-2-amino-2-phenylacetamido)-2-phenylacetamido]penicillanic acid |
| FR2288521A1 (fr) * | 1974-10-25 | 1976-05-21 | Merck Patent Gmbh | Nouvelles penicillines et procede pour leur preparation |
| US4038271A (en) * | 1976-11-08 | 1977-07-26 | E. R. Squibb & Sons, Inc. | [[[(2,4-Dioxo-1-imidazolidinyl)amino]-carbonyl]amino]acetylpenicillin derivatives |
| ES477520A1 (es) * | 1978-02-25 | 1979-06-01 | Thomae Gmbh Dr K | Procedimiento para la preparacion de nuevas penicilinas. |
-
1979
- 1979-03-15 DE DE19792910190 patent/DE2910190A1/de not_active Withdrawn
-
1980
- 1980-02-14 ES ES488573A patent/ES8103097A1/es not_active Expired
- 1980-02-20 GR GR61244A patent/GR74000B/el unknown
- 1980-03-05 AT AT80101107T patent/ATE731T1/de not_active IP Right Cessation
- 1980-03-05 EP EP80101107A patent/EP0016374B1/de not_active Expired
- 1980-03-05 DE DE8080101107T patent/DE3060217D1/de not_active Expired
- 1980-03-13 FI FI800786A patent/FI67703C/fi not_active IP Right Cessation
- 1980-03-13 JP JP3212680A patent/JPS55124789A/ja active Pending
- 1980-03-14 IL IL59614A patent/IL59614A/xx unknown
- 1980-03-14 DK DK110480A patent/DK110480A/da not_active Application Discontinuation
- 1980-03-14 CA CA000347735A patent/CA1138434A/en not_active Expired
- 1980-03-14 NO NO800755A patent/NO800755L/no unknown
- 1980-03-14 PT PT70956A patent/PT70956B/pt unknown
- 1980-03-14 ZA ZA00801499A patent/ZA801499B/xx unknown
- 1980-03-14 AU AU56450/80A patent/AU536154B2/en not_active Ceased
- 1980-03-14 NZ NZ193127A patent/NZ193127A/xx unknown
- 1980-05-14 US US06/149,839 patent/US4289775A/en not_active Expired - Lifetime
- 1980-05-29 PH PH24084A patent/PH15821A/en unknown
- 1980-10-08 ES ES495716A patent/ES495716A0/es active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| DK110480A (da) | 1980-09-16 |
| GR74000B (sv) | 1984-06-06 |
| ES488573A0 (es) | 1981-02-16 |
| ES8103097A1 (es) | 1981-02-16 |
| PT70956A (de) | 1980-04-01 |
| NZ193127A (en) | 1982-09-07 |
| PT70956B (de) | 1981-06-25 |
| EP0016374A1 (de) | 1980-10-01 |
| IL59614A0 (en) | 1980-06-30 |
| FI800786A7 (fi) | 1980-09-16 |
| US4289775A (en) | 1981-09-15 |
| ES8106529A1 (es) | 1981-06-16 |
| JPS55124789A (en) | 1980-09-26 |
| PH15821A (en) | 1983-04-08 |
| CA1138434A (en) | 1982-12-28 |
| IL59614A (en) | 1983-02-23 |
| AU5645080A (en) | 1980-09-18 |
| ZA801499B (en) | 1981-11-25 |
| NO800755L (no) | 1980-09-16 |
| DE2910190A1 (de) | 1980-10-02 |
| ES495716A0 (es) | 1981-06-16 |
| DE3060217D1 (en) | 1982-04-01 |
| ATE731T1 (de) | 1982-03-15 |
| AU536154B2 (en) | 1984-04-19 |
| EP0016374B1 (de) | 1982-03-03 |
| FI67703C (fi) | 1985-05-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM | Patent lapsed |
Owner name: DR. KARL THOMAE GESELLSCHAFT MIT |