DE2606030A1 - Condensn products of erythromycyl-amine with aldehydes - antibiotic erythromycin derivs active against gram negative and gram positive bacteria - Google Patents
Condensn products of erythromycyl-amine with aldehydes - antibiotic erythromycin derivs active against gram negative and gram positive bacteriaInfo
- Publication number
- DE2606030A1 DE2606030A1 DE19762606030 DE2606030A DE2606030A1 DE 2606030 A1 DE2606030 A1 DE 2606030A1 DE 19762606030 DE19762606030 DE 19762606030 DE 2606030 A DE2606030 A DE 2606030A DE 2606030 A1 DE2606030 A1 DE 2606030A1
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- phenyl
- erythromycylamine
- group
- mercapto
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 title claims abstract description 8
- XCLJRCAJSCMIND-JCTYMORFSA-N (9S)-erythromycyclamine Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)[C@@H](N)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 XCLJRCAJSCMIND-JCTYMORFSA-N 0.000 title claims description 30
- 150000001299 aldehydes Chemical class 0.000 title claims description 10
- 229960003276 erythromycin Drugs 0.000 title abstract 2
- 241000192125 Firmicutes Species 0.000 title 1
- 230000003115 biocidal effect Effects 0.000 title 1
- -1 phenoxy, phenyl Chemical group 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 10
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims abstract description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract 2
- 239000007859 condensation product Substances 0.000 claims description 43
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 150000007524 organic acids Chemical class 0.000 claims description 13
- 235000005985 organic acids Nutrition 0.000 claims description 13
- 150000007522 mineralic acids Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- ZZWQVTBJLLXLPJ-UHFFFAOYSA-N 2-diethoxyphosphorylacetaldehyde Chemical compound CCOP(=O)(CC=O)OCC ZZWQVTBJLLXLPJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001241 acetals Chemical class 0.000 claims description 4
- NCNSBFDGXBKAKB-UHFFFAOYSA-N (methylsulfanyl)acetaldehyde Chemical compound CSCC=O NCNSBFDGXBKAKB-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- HQNDOOMQQOYEOM-UHFFFAOYSA-N 2-(4-methylphenyl)ethanethial Chemical compound CC1=CC=C(CC=S)C=C1 HQNDOOMQQOYEOM-UHFFFAOYSA-N 0.000 claims description 2
- MINDNVLLOCEDPP-UHFFFAOYSA-N 2-cyclohexylethanethial Chemical compound S=CCC1CCCCC1 MINDNVLLOCEDPP-UHFFFAOYSA-N 0.000 claims description 2
- GIDOBZXUXDNRDY-UHFFFAOYSA-N 2-hydroxy-3-oxohexanal Chemical compound CCCC(=O)C(O)C=O GIDOBZXUXDNRDY-UHFFFAOYSA-N 0.000 claims description 2
- UAMDWTCVJDBESC-UHFFFAOYSA-N 3-phenylpropanethial Chemical compound S=CCCC1=CC=CC=C1 UAMDWTCVJDBESC-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims 1
- 230000003381 solubilizing effect Effects 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 3
- 125000003545 alkoxy group Chemical group 0.000 abstract 2
- 125000004429 atom Chemical group 0.000 abstract 2
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 abstract 1
- 125000005085 alkoxycarbonylalkoxy group Chemical group 0.000 abstract 1
- 229940088710 antibiotic agent Drugs 0.000 abstract 1
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 125000004984 dialkylaminoalkoxy group Chemical group 0.000 abstract 1
- 125000002541 furyl group Chemical group 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000005113 hydroxyalkoxy group Chemical group 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- 125000004076 pyridyl group Chemical group 0.000 abstract 1
- 102220067365 rs143592561 Human genes 0.000 abstract 1
- 125000001544 thienyl group Chemical group 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000008298 dragée Substances 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 239000012166 beeswax Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- LRIFVZYCVBCSMF-UHFFFAOYSA-N ethyl 4-sulfanylidenebutanoate Chemical compound CCOC(=O)CCC=S LRIFVZYCVBCSMF-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical group CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- RAPFWIVDXSMGAP-UHFFFAOYSA-N 3-methylbutanethial Chemical compound CC(C)CC=S RAPFWIVDXSMGAP-UHFFFAOYSA-N 0.000 description 1
- UABJCXFZCYLSSK-UHFFFAOYSA-N 4,4-diethoxy-3-hydroxybutan-2-one Chemical compound CCOC(OCC)C(O)C(C)=O UABJCXFZCYLSSK-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 238000002768 Kirby-Bauer method Methods 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000721 bacterilogical effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SASYSVUEVMOWPL-NXVVXOECSA-N decyl oleate Chemical compound CCCCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC SASYSVUEVMOWPL-NXVVXOECSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
Neue Erythromycinderivate und Verfahren zu ihrer erstellungNew erythromycin derivatives and processes for their preparation
zusatz zum DBP..... (Aktenzeichen: P 25 15 075.8)) Die Erfindung betrifft neue Erythromycinderivate der allgemeinen Formeln I, Ia und Ib, ihre physiologisch verträglichen Säureadditionssalze mit anorganischen oder organischen Säuren und Verfahren zu ihrer Herstellung.Addition to the DBP ..... (file number: P 25 15 075.8)) The invention relates to new erythromycin derivatives of the general formulas I, Ia and Ib, their physiologically acceptable acid addition salts with inorganic or organic acids and processes for their preparation.
In den obigen allgemeinen Formeln I, Ia und Ib bedeutet R die Mercaptogruppe, die Phenylmercaptogruppe, die gegebenenfalls durch Methyl-, Methoxy-, Athoxy-, Isopropoxy- oder Propoxygruppen substituiert sein kann, eine Phenylalkylmercaptogruppe mit 1 bis 3 Kohlenstoffatomen im Alkylenteil, eine geradkettige oder verzweigte Alkylmercaptogruppe mit 1 bis 5 Kohlenstoffatomen, die Cyclohexylmercaptogruppe, eine Hydroxyalkylmercapto-, Dialkylaminoalkylmercapto-, Alkoxycarbonylalkylmercapto- oder eine Cyanoalkylmercaptogruppe mit jeweils 1 bis 3 Kohlenstoffatomen im Alkylen-und Alkylteil, einen Acyloxyrest der allgemeinen Formel in der R1 eine geradkettige oder verzweigte Alkylgruppe mit 1 bis 5 Kohlenstoffatomen, die Benzyl- oder Phenylgruppe bedeutet, den N-Phenylcarbamoylrest, einen Carboxamidomethyloxyrest der allgemeinen Formel in der R2 und R3, die gleich oder voneinander verschieden sein können, die Methyl-, Athyl-, Propyl- oder Tso propylgruppe bedeuten, oder eine Dialkylphosphonogruppe der allgemeinen Formel in der R4 eine geradkettige oder verzweigte Alkylgruppe mit 1 bis 5 Kohlenstoffatomen darstellt, Die Verbindungen der allgemeinen Formel I, Ia und Ib lassen sich wie folgt herstellen: Durch Umsetzung von Erythromycylamin der Formel II, mit Aldehyden der allgemeinen Formel III, in der R wie oben angegeben definiert ist.In the above general formulas I, Ia and Ib, R denotes the mercapto group, the phenyl mercapto group which may optionally be substituted by methyl, methoxy, ethoxy, isopropoxy or propoxy groups, a phenylalkyl mercapto group with 1 to 3 carbon atoms in the alkylene part, a straight-chain one or branched alkyl mercapto group with 1 to 5 carbon atoms, the cyclohexyl mercapto group, a hydroxyalkyl mercapto, dialkylaminoalkyl mercapto, alkoxycarbonylalkyl mercapto or a cyanoalkyl mercapto group with in each case 1 to 3 carbon atoms in the alkylene and alkyl part, an acyloxy radical of the general formula in which R1 is a straight-chain or branched alkyl group with 1 to 5 carbon atoms, the benzyl or phenyl group, the N-phenylcarbamoyl radical, a carboxamidomethyloxy radical of the general formula in which R2 and R3, which can be the same or different from one another, represent the methyl, ethyl, propyl or tisopropyl group, or a dialkylphosphono group of the general formula in which R4 represents a straight-chain or branched alkyl group with 1 to 5 carbon atoms, the compounds of the general formula I, Ia and Ib can be prepared as follows: By reacting erythromycylamine of the formula II, with aldehydes of the general formula III, in which R is defined as given above.
Die Umsetzung wird vorzugsweise in einem Lösungs- oder Suspensionsmittel bei Temperaturen zwischesl 0° und 150 0c durchgeführt. Als Lösungs- oder Suspensionsmittel kommen vorzugsweise polare Lösungsmittel wie Wasser, Alkohole, Dioxan, Dimethylformamid, Dimethylsulfoxid sowie Gemische dieser Lösungsmittel in Betracht.The reaction is preferably carried out in a solvent or suspending medium carried out at temperatures between 0 ° and 150 ° C. As a solvent or suspending agent preferably polar solvents such as water, alcohols, dioxane, dimethylformamide, Dimethyl sulfoxide and mixtures of these solvents are suitable.
Es ist für die Durchführung der Reaktion vortei:;latt, wenn der Aldehyd der allgemeinen Formel III in situ aus geeigneten Vorstufen freigesetzt wird. Als solche Vorstufen kommen insbesondere Acetale der allgemeinen Formel IV in Frage, in der R die obengenannten Bedeutungen besitzt und R5 und R6, die gleich oder voneinander verschieden sein können, Alkylgruppen bedeuten, wobei R5 und R6 auch zusammen mit dem dazwischenliegenden Rest einen 5- bis 7-gliedrigen Ring bilden können, Zur Freisetzung der Aldehyde der allgemeinen Formel III aus Acew talen der allgemeinen Formel IV sind Säuren, insbesondere saure Ionenaustauscher, besonders geeignet.It is advantageous for carrying out the reaction if the aldehyde of the general formula III is released in situ from suitable precursors. Particularly suitable precursors are acetals of the general formula IV, in which R has the meanings given above and R5 and R6, which can be the same or different from one another, denote alkyl groups, where R5 and R6 also together with the radical in between can form a 5- to 7-membered ring. For releasing the aldehydes of the general formula III from acetals of the general formula IV, acids, in particular acidic ion exchangers, are particularly suitable.
Die Verbindungen der allgemeinen Formeln Is Ia bzw. Ib lassen sich gewünschtenfalls in ihre physiologisch verträglichen Säureadditionssalze mit anorganischen oder organischen Säuren überfUhren.The compounds of the general formulas Is Ia and Ib can be if desired into their physiologically compatible acid addition salts with inorganic ones or transfer organic acids.
Als Säuren kommen beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Essigsäure, Zitronensäure, Laurylschwefelsure, Stearinsäure, Heptagluconsäure, Lactobionsäure in Frage, Die Zuordnung der so hergestellten Verbindungen zu den allgemeinen Formeln I, Ia oder Ib war nicht möglich.Examples of acids are hydrochloric acid, hydrobromic acid, Sulfuric acid, acetic acid, citric acid, lauryl sulfuric acid, stearic acid, heptagluconic acid, Lactobionic acid in question, The assignment of the compounds so prepared to the general formulas I, Ia or Ib was not possible.
Die Ausgangsverbindung Erythromycylamin der Formel II ist literaturbekannt. Ihre Herstellung ist beispielsweise in J. med. Chem.The starting compound erythromycylamine of the formula II is known from the literature. Their production is for example in J. med. Chem.
17, 105 - 107 (1974) beschrieben.17, 105-107 (1974).
Aldehyde und Acetale der allgemeinen Formeln III und IV sind ebenfalls literaturbekannt oder lassen sich in Anlehnung an literaturbekannte Methoden herstellen.Aldehydes and acetals of the general formulas III and IV are also available known from the literature or can be produced on the basis of methods known from the literature.
Die Erythromycinderivate der allgemeinen Formeln I, Ia und Ib und ihre Salze besitzen wertvolle pharmakologische Eigenschaften; sie sind insbesondere wirksam gegen gram-positive und gram-negative Bakterien.The erythromycin derivatives of the general formulas I, Ia and Ib and their salts have valuable pharmacological properties; they are particular effective against gram-positive and gram-negative bacteria.
Die Untersuchungen auf die antibakterielle Wirksamkeit wurden nach dem Agar-Diffusionstest und nach dem Reihenverdünnungstest in Anlehnung an die von P. Klein in "Bakteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlagt 1957, Seiten 53 bis 76 und 87 bis 109, beschriebene Methodik durchgeführt.The studies on the antibacterial effectiveness were carried out after the agar diffusion test and after the serial dilution test based on that of P. Klein in "Bacteriological Basics of Chemotherapeutic Laboratory Practice, Springer-Verlag 1957, pages 53 to 76 and 87 to 109, carried out the method described.
Besonders gut antibakteriell noch in Konzentrationen von 0,3 bis 5 Sg/ml gegen Staphylococcus aureus SG 511 und von 10 bis 40 Fg/ml gegen Escherichia coli wirken folgende Substanzen: Kondensationsprodukt aus Erythromycylamin und Methylthioacetaldehyd, Kondensationsprodukt aus Erythromycylainin und Isopropylthioacetaldehyd, Kondensationsprodukt aus Erythromycylamin und Cyclohexylthioacetaldehyd, Kondensationsprodukt aus Erythromycylamin und Benzylthioacetaldehyd, Kondensationsprodukt aus Erythromycylamin und p-Methylphenylthioacetaldehyd, Kondensationsprodukt aus Erythromycylamin und Butyrylglykolaldehyd, Kondensationsprodukt aus Erythromycylamin und Dimethylcarboxamidomethoxyacetaldehyd, Kondensationsprodukt aus Erythromycylamin i.ld Diäthylphosphonoacetaldehyd.Particularly good antibacterial even in concentrations of 0.3 to 5 Μg / ml against Staphylococcus aureus SG 511 and from 10 to 40 μg / ml against Escherichia coli have the following substances: Condensation product of erythromycylamine and methylthioacetaldehyde, Condensation product of erythromycylainin and isopropylthioacetaldehyde, condensation product from erythromycylamine and cyclohexylthioacetaldehyde, condensation product from erythromycylamine and benzylthioacetaldehyde, condensation product of erythromycylamine and p-methylphenylthioacetaldehyde, Condensation product of erythromycylamine and butyryl glycol aldehyde, condensation product from erythromycylamine and dimethylcarboxamidomethoxyacetaldehyde, condensation product from erythromycylamine i.ld diethylphosphonoacetaldehyde.
Beispiele zur Herstellung der Endprodukte Beispiel 1 Methylthioacetaldehyd-Erythromycylamin-Kondensationsprodukt 1,3 g (0,008 Mol) Methylthioacetaldehyd-diäthylacetal werden in einem Gemisch von 20 ml Dioxan und 4 ml Wasser mit 4,0 g Amberlite IR-120 (H-Form) 15 Minuten bei Raumt<£ mperatur gerührt. Anschließend gibt man eine Lösung von 3,0 g (0,004 Mol) Erythromycylamin in 10 ml Dioxan zu und rührt das Reaktionsgemisch weitere 4 Stunden bei derselben Temperatur.Examples of the preparation of the end products Example 1 Methylthioacetaldehyde-erythromycylamine condensation product 1.3 g (0.008 mol) of methylthioacetaldehyde diethylacetal are in a mixture of 20 ml of dioxane and 4 ml of water with 4.0 g of Amberlite IR-120 (H-form) for 15 minutes Room temperature stirred. A solution of 3.0 g (0.004 Mol) erythromycylamine in 10 ml of dioxane and the reaction mixture is stirred further 4 hours at the same temperature.
Der Ionenaustauscher wird abfiltriert und mit Dioxan gewaschen, Das Filtrat wird eingedampft, der ölige Rückstand in Ather auf genommen, die Lösung filtriert und mit Petroläther bis zur beginnenden Kristallisation versetzt.The ion exchanger is filtered off and washed with dioxane, Das The filtrate is evaporated, the oily residue is taken up in ether, the solution filtered and petroleum ether was added until crystallization began.
Das weiße, feinkristalline Produkt wird abgesaugt, mit einem Äther/Petroläther-Gemisch gewaschen und getrocknet.The white, finely crystalline product is filtered off with an ether / petroleum ether mixture washed and dried.
Ausbeute: 2,5 g (80 % der Theorie) Schmelzpunkt: 100 - 105°C (Zers.).Yield: 2.5 g (80% of theory). Melting point: 100-105 ° C. (decomp.).
C40H74N2°12S (807,11) Ber.: C 59,52 H 9,24 N 3,47. S 3,96 Gef.: 59,18 9,46 3,20 4,18 Beispiel 2 Carbäthoxymethylthioacetaldehyd-Ery thromycylamin-Kondensationsprodukt Eine Emulsion von 13 g (0,055 Mol) Carbäthoxymethylthioacetaldehyd-diäthylacetal in 130 ml Wasser wird mit 55 g Amberlite IR 120 (H-Form) versetzt und 4 Stunden bei Raumtemperatur kräftig gerührt.C40H74N2 ° 12S (807.11) Calcd .: C 59.52 H 9.24 N 3.47. S 3.96 Found: 59.18 9.46 3.20 4.18 Example 2 Carbethoxymethylthioacetaldehyde-Ery thromycylamine condensation product An emulsion of 13 g (0.055 moles) of carbethoxymethylthioacetaldehyde diethyl acetal 55 g of Amberlite IR 120 (H-form) are added in 130 ml of water and the mixture is carried out for 4 hours stirred vigorously at room temperature.
Die klare Lösung wird vom Ionenaustauscher abfiltriert, mit Kochsalz gesättigt und 4 mal mit je 100 ml Äther extrahiert. Nach Trocknen über Natriumsulfat wird das Lösungsmittel abdestilliert, Der verbleibende Aldehyd ist chromatographisch rein und wird roh weiterumgesetzt.The clear solution is filtered off from the ion exchanger with common salt saturated and extracted 4 times with 100 ml of ether each time. After drying over sodium sulfate the solvent is distilled off, the remaining aldehyde is chromatographic pure and is further implemented raw.
Ausbeute: 7,6 g (85 g der Theorie) 5,5 g (0,0075 Mol) Erythromycylamin und 7,5 g (!),045 Mol) Carbäthoxymethylthioacetaldehyd werden in 50 ml Methanol p.a, gelöst und 24 Stunden bei Raumtemperatur gerührt. Nach Abdestillieren des Lösungsmittels im Vakuum verbleibt ein dunkelbraunes bl, aus dem durch Behandeln mit einem Chloroform/Äther-Gemisch dunkelgefärbte Nebenprodukte abgetrennt werden. Die Lösung wird eingedampft der hellbraune flüssige Rückstand in Chloroform aufgenommen, mit Aktivkohle entfärbt und filtriert. Das Filtrat versetzt man bis zur beginnenden Kristallisation mit Äther.Yield: 7.6 g (85 g of theory) 5.5 g (0.0075 mol) of erythromycylamine and 7.5 g (!), 045 mol) of carbethoxymethylthioacetaldehyde are dissolved in 50 ml of methanol p.a, dissolved and stirred for 24 hours at room temperature. After distilling off the solvent in the vacuum, a dark brown blue remains, from which treatment with a chloroform / ether mixture dark-colored by-products are separated. The solution is evaporated to the light brown liquid residue taken up in chloroform, decolorized with activated charcoal and filtered. The filtrate is mixed with until crystallization begins Ether.
Die ausgefallene, kristalline Substanz wird abgenutscht, mit Äther gewaschen und getrocknet.The precipitated, crystalline substance is suction filtered with ether washed and dried.
Ausbeute: 6,2 g (64 a der Theorie), Schmelzpunkt: 150 - 15500 (Zers.) C43H78N2014S (879,14) Ber.: C 58,75 H 8,94 N 3,19 s 3,65 Gef.: 59,ob 9,o6 3,11 3,54 Die folgenden Verbindungen lassen sich sowohl analog Beispiel 1 als auch Beispiel 2 erhalten: a) Thioglycolaldehyd-Erythroinycylamin-Kondensationsprodukt F.: 120 - 12500 (Zers.) b) Phenylthioacetaldehyd-ErytIiromycylamin-Kondensationsprodu1t F.: 117-120°C (Zers.).Yield: 6.2 g (64 a of theory), melting point: 150-15500 (decomp.) C43H78N2014S (879.14) Calc .: C 58.75 H 8.94 N 3.19 s 3.65 Found: 59, ob 9, o6 3.11 3.54 The following compounds can be used both analogously to Example 1 and Example 2 obtained: a) Thioglycolaldehyde-erythroinycylamine condensation product F .: 120 - 12500 (dec.) B) Phenylthioacetaldehyde-erytiromycylamine condensation product F .: 117-120 ° C (dec.).
c) p-Methylphenylthioacetaldehyd-Erythromycylamin-Kondensationsprodukt F.: 110 - 11200 (Zers.) d) o-Methoxyphenylthioacetaldehyd-Erythromycylamin-Kondensationsprodukt F.: 107 - 110°C (Zers.) e) Benzylthioacetaldehyd-Erythromycylamin-Kondensationsprodukt F.: 100 - 1050C (Zers.) f) (3-Phenyl)propylthioacetaldehyd-Erythromycylamin-Kondensationsprodukt F.: 99 - 1030C (Zers.) g) Isopropylthioacetaldehyd-Erythroxycylamin-Kondensationsprodukt F.: 100-115°C (Zers.) h) n-Pentylthioacetaldehyd-Erythromycylamin-Kondensationsprodukt F.: 107 - 1120C (Zers.c) p-methylphenylthioacetaldehyde-erythromycylamine condensation product F .: 110-11200 (decomp.) D) o-Methoxyphenylthioacetaldehyde-erythromycylamine condensation product F .: 107-110 ° C (dec.) E) Benzylthioacetaldehyde-erythromycylamine condensation product F .: 100-1050C (dec.) F) (3-Phenyl) propylthioacetaldehyde-erythromycylamine condensation product Q .: 99-1030C (dec.) G) isopropylthioacetaldehyde-erythroxycylamine condensation product F .: 100-115 ° C (dec.) H) n-Pentylthioacetaldehyde-erythromycylamine condensation product F .: 107 - 1120C (dec.
i) Cyclohexylthioacetaldehyd-Erythromycylamin-KondensationsDrodukt F.: 100-105°C (Zers.) j) (2-Hydroxy ) äthy lthioacetaldehyd-Erythromycylamin-Kondensationsprodukt F.: 114 - 1170 (Zers.) k) (2-Diäthylamino ) äthylthioacetaldehyd-Erythromycylamin-Kondensationsprodukt F.: 103 - 1080C (Zers.) 1) (2-Carbmethoxy)äthylthioacetaldehyd-Erythromycylamin-Kondensationsprodukt F.: 118 - 12100 (Zers.) m) Cyanomethylthioacetaldehyd-Erythromycylamin-Kondensationsprodukt F.: 120 - 12500 (Zers.).i) Cyclohexylthioacetaldehyde-erythromycylamine condensation product F .: 100-105 ° C (dec.) J) (2-Hydroxy) ethioacetaldehyde-erythromycylamine condensation product F .: 114 - 1170 (decomp.) K) (2-diethylamino) ethylthioacetaldehyde-erythromycylamine condensation product Q .: 103-1080C (decomp.) 1) (2-Carbmethoxy) ethylthioacetaldehyde-erythromycylamine condensation product F .: 118 - 12100 (decomp.) m) cyanomethylthioacetaldehyde-erythromycylamine condensation product F .: 120-12500 (dec.).
Beispiel 3 Acetylglykolaldehyd-Erythromycylamin-Kondensationsprodukt 2,3 g (0,003 Mol) Erythromycylamin und 1,1 g (0,006 Mol) Acetylglykolaldehyd-diäthylacetal werden in 20 ml Dioxan und 2 ml Wasser mit 12 g Dowex 50 W bei Raumtemperatur gerührt. Nach 6 Stunden wird der Ionenaustauscher abfiltriert und mit Dioxan gewaschen.Example 3 Acetyl glycol aldehyde-erythromycylamine condensation product 2.3 grams (0.003 moles) of erythromycylamine and 1.1 grams (0.006 moles) of acetyl glycol aldehyde diethyl acetal are stirred in 20 ml of dioxane and 2 ml of water with 12 g of Dowex 50 W at room temperature. After 6 hours, the ion exchanger is filtered off and washed with dioxane.
Das Filtrat wird eingedampft und der Rückstand säulenchromatographisch gereinigt (Aluminiumoxid basisch, Aktivitätsstufe 3, Chloroform/Methanol = 4:1). Die Fraktion mit Rf : 0,6 wird eingedampft und durch Behandeln mit Chloroform/Ather zur Kristallisation gebracht. Man erhält 2,4 g farblose Kristalle vom Schmelzpunkt 105-110°C.The filtrate is evaporated and the residue is column chromatographed purified (aluminum oxide basic, activity level 3, chloroform / methanol = 4: 1). The fraction with Rf: 0.6 is evaporated and treated with chloroform / ether brought to crystallization. 2.4 g of colorless crystals with a melting point are obtained 105-110 ° C.
C42H76N2°14 (833» 4) Ber.: C 60,55 H 9,20 N 3,36 Gef.: 60,83 9,05 3,12 Beispiel 4 Benzoylglykolaldehyd-Erythroxycylamin-Kondensationsprodukt 2,3 g (0,003 Mol) Erythromycylamin und 1,0 g (0,006 Mol) Benzoylglykolaldehyd werden in 60 ml absolutem Dioxan 24 Stunden bei Raumtemperatur gerührt. Nach Verdampfen des Dioxans wird der Rückstand in Chloroform aufgenommen und mit Äther versetzt. Es scheiden sich 0,8 g farblose Kristalle ab, die bei 200C im Vakuum getrocknet werden.C42H76N2 ° 14 (833 »4) Calc .: C 60.55 H 9.20 N 3.36 Found: 60.83 9.05 3.12 Example 4 Benzoyl glycol aldehyde-erythroxycylamine condensation product 2.3 g (0.003 mol) erythromycylamine and 1.0 g (0.006 mol) benzoyl glycol aldehyde are in 60 ml of absolute dioxane were stirred at room temperature for 24 hours. After evaporation of the Dioxane, the residue is taken up in chloroform and ether is added. It 0.8 g of colorless crystals separate and are dried at 200 ° C. in vacuo.
F.: 110-115°C (Zers.) C46H76N2014 (881,08) Ber.: C 62,70 H 8,69 N 3,18 Gef.: 62,95 8,42 3,35 Die folgenden Verbindungen lassen sich sowohl analog Beispiel 3 als auch Beispiel 4 erhalten: a) Butyrylglykolaldehyd-Erythromycylamin-Kondensationsprodukt F.: 6500.M.p .: 110-115 ° C (dec.) C46H76N2014 (881.08) Calc .: C 62.70 H 8.69 N 3.18 Found: 62.95 8.42 3.35 The following compounds can be both analogously Example 3 and Example 4 obtained: a) Butyrylglycolaldehyde-erythromycylamine condensation product F .: 6500.
b) Phenylacetylglykolaldehyd-Erythromycylamin-Kondensationsprodukt F.: 70-7EO c) N-Phenylcarbamoylacetaldehyd-Erythromy .ylamin-Kondensationsprodukt F.: 90950C.b) Phenylacetylglycolaldehyde-erythromycylamine condensation product Q .: 70-7EO c) N-phenylcarbamoylacetaldehyde erythromyylamine condensation product Q .: 90950C.
d) Dimethylcarboxamidomethoxyacetaldehyd-Erythromycylamin-Kond sationsprodukt F.: 1601650C.d) Dimethylcarboxamidomethoxyacetaldehyde-erythromycylamine condensation product Q .: 1601650C.
Beispiel 5 Diäthylphosphonoacetaidehyd-Erythroinycylamin-Kondensationsprodukt 2,3 g (0,003 Mol) Erythromycylamin und 1,4 g (0,006 Mol) DiSthylphosphonoacetaldehyd-dimethylacetal werden in 20 ml Dioxan und 2 ml Wasser mit 12 g Dowex 50 W bei Raumtemperatur gerührt. Nach 6 Stunden wird der Ionenaustauscher abfiltriert und mit Dioxan gewaschen. Das Filtrat wird mit Wasser bis zur beginnenden Kristallisation versetzt. Das weiße Produkt wird abgesaugt, mit wäßrigem Dioxan gewaschen und getrocknet.Example 5 Diethylphosphonoacetaldehyde-Erythroinycylamine Condensation Product 2.3 grams (0.003 moles) of erythromycylamine and 1.4 grams (0.006 moles) of diSthylphosphonoacetaldehyde dimethyl acetal are stirred in 20 ml of dioxane and 2 ml of water with 12 g of Dowex 50 W at room temperature. After 6 hours, the ion exchanger is filtered off and washed with dioxane. That Water is added to the filtrate until crystallization begins. The White Product is filtered off with suction, washed with aqueous dioxane and dried.
Ausbeute: 1,4 g (52 % der Theorie) Schmelzpunkt: 110-113°C (Zers.) C43H81N2°15P (897,11) Ber.: C 57,50 H 9,10 N 3,12 Gef.: 57,21 9,19 3,08 Beispiel 6 Diäthylphosphonoacetaldehyd-Erythromycylamin-Kondensationsprodukt 23 g (0,03 Mol) Erythromycylamin und 10 g (0,055 Mol) Diäthylphosphonoacetaldehyd werden in 300 ml absolutem Dioxan 24 Stunden bei Raumtemperatur gerührt. Nach Verdampfen des Lösungsmittels wird der Rückstand in 150 ml heißem Acetonitril aufgenommen und die Lösung mit 750 ml Wasser versetzt. Beim Erkalten scheiden sich 13 g (43 % der Theorie) farblose Kristalle ab, die bei 800C im Vakuum getrocknet werden.Yield: 1.4 g (52% of theory) Melting point: 110-113 ° C (decomp.) C43H81N2 ° 15P (897.11) Calc .: C 57.50 H 9.10 N 3.12 Found: 57.21 9.19 3.08 Example 6 Diethylphosphonoacetaldehyde-erythromycylamine condensation product 23 g (0.03 mole) erythromycylamine and 10 g (0.055 mole) diethylphosphonoacetaldehyde are stirred in 300 ml of absolute dioxane for 24 hours at room temperature. After evaporation of the solvent, the residue is taken up in 150 ml of hot acetonitrile and 750 ml of water are added to the solution. When cooling down, 13 g (43% of the Theory) from colorless crystals, which are dried at 800C in a vacuum.
F.: 110-113°C (Zers,), Die Verbindungen der allgemeinen Formel I lassen sich in an sich bekannter Weise in die üblichen pharmazeutischen Zubereitungsformen, zum Beispiel in Lösungen, Suppositorien, Tabletten, einarbeiten. Die Einzeldosis beträgt für Erwachsene bei peroraler Applikation 50 bis 500 mg, die bevorzugte Einzeldosis 100 bis 250 mg, die Tagesdosis 0,5 g bis 4 g, die bevorzugte Tagesdosia 1 bis 2 g.F .: 110-113 ° C (dec,), The connections of the general Formula I can be converted into the customary pharmaceutical in a manner known per se Incorporate preparation forms, for example into solutions, suppositories, tablets. The single dose for adults is 50 to 500 mg for oral administration, the preferred single dose 100 to 250 mg, the daily dose 0.5 g to 4 g, the preferred Daily dose 1 to 2 g.
Die nachfolgenden Beispiele sollen die Herstcllung einiger pharmazeutischer Zubereitungen verdeutlichen: Beispiel I Tabletten mit 100 mg Kondensationsprodukt aus Erythromycylamin und Butyrylglykolaldehyd Zusammensetzung: 1 Tablette enthält: Wirkstoff 100,0 mg Milchzucker 63,0 mg Kartoffelstärke 50,0 mg Polyvinylpyrrolidon 5,0 mg Magnesiumstearat 2,0 mg 220,0 mg Herstellungsverfahren: Die Mischung der Wirksubstanz mit Milchzucker und Kartoffelstärke wird mit einer 10 %igen wässrigen Lösung des Polyvinylpyrrolidons befeuchtet, durch ein Sieb der Maschenweite 1,) mm granuliert, bei 450C getrocknet und nochmals durch obiges Sieb gerieben. Das so erhaltene Granulat wird mit Magnesiumstearat gemischt und zu Tabletten verpreßt.The following examples are intended to illustrate the manufacture of some pharmaceutical products Preparations clarify: Example I Tablets with 100 mg condensation product from erythromycylamine and butyrylglycolaldehyde Composition: 1 tablet contains: Active ingredient 100.0 mg lactose 63.0 mg potato starch 50.0 mg polyvinylpyrrolidone 5.0 mg Magnesium stearate 2.0 mg 220.0 mg Manufacturing process: The mixture of Active ingredient with milk sugar and potato starch is made with a 10% aqueous Solution of the polyvinylpyrrolidone moistened, through a sieve of mesh size 1,) mm granulated, dried at 450C and rubbed through the above sieve again. That Granules obtained in this way are mixed with magnesium stearate and compressed into tablets.
Tablettengewicht: 220 mg Stempel: 9 mm flach, mit Teilkerbe Beispiel II Dragees mit 100 mg Kondensationsprodukt aus Erythromycylamin und Methy lthioacet aldehyd Zusammensetzung: 1 Dragéekern enthält: Wirkstoff 100,0 mg Milch zucker 30,0 mg Maisstärke 30,0 mg Gelatine 3,0 mg Cellulose, mikrokristallin 6,0 mg Magnesiumstearat 1,O mg 170,0 mg Herstellungsverfahren: Die Mischung der Wirksubstanz mit Milch zucker und Maisstärke wird mit einer 12%igen wässrigen Lösung der Gelatine befeuchtet, durch ein Sieb der Maschenweite 1,5 mm granuliert, bei 4500 getrocknet und nochmals durch ein Sieb der Maschenweite 1,0 mm gerieben. Das so erhaltene Granulat wird mit Cellulose und Magnesiumstearat gemischt und zu Dragéekernen verpreßt. Tablet weight: 220 mg Punch: 9 mm flat, with dividing notch example II coated tablets with 100 mg condensation product of erythromycylamine and methyl lthioacet aldehyde Composition: 1 tablet core contains: Active ingredient 100.0 mg milk sugar 30.0 mg corn starch 30.0 mg gelatine 3.0 mg cellulose, microcrystalline 6.0 mg magnesium stearate 1.0 mg 170.0 mg Manufacturing process: Mixing the active ingredient with milk sugar and corn starch is moistened with a 12% aqueous solution of gelatin, Granulated through a sieve with a mesh size of 1.5 mm, dried at 4500 and again rubbed through a sieve with a mesh size of 1.0 mm. The granulate thus obtained is mixed with cellulose and magnesium stearate and pressed into tablet cores.
Kerngewicht: 170 mg Stempel: 7 mma gewölbt. Core weight: 170 mg Stamp: 7 mma convex.
Die so erhaltenen Dragéekerne werden nach bekanntem Verfahren mit einer Hülle überzogen, die im wesentlichen aus Zucker und Talkum besteht. Die fertigen Dragees werden mit Hilfe von Bienenwachs poliert.The tablet cores obtained in this way are with a known method coated in a shell consisting essentially of sugar and talc. The finished Dragees are polished with the help of beeswax.
Dragéegewlcht: 210 mg. Dragee weight: 210 mg.
Beispiel III Schüttelmixtur mit 1 % Kondensationsprodukt aus Erythromycylamin mit Butyrylglyk-laldehyd Zusammensetzung: Wirkstoff 1,0 g Sorbitanmonopalmitat (Span 40) 1,0 g Cremophor 0 (Pa. BASF) 2,0 g Cetylstearylalkohol (Lanette 0) 2,0 g Walrat 1,0 g Ölsäuredecylester 5,0 g Paraffinöl 1,0 g Dest. Wasser 87 je g 100,0 g Herstellungsverfahren: Die Substanzen der dispersen Phase werden zusammengeschmolzena auf 700C gebracht und anschließend in Wasser der gleichen Temperatur einemulgiert. Man kühlt auf 400C ab und suspendiert mit Hilfe eines Eintauchhomogenisators die feingemahlene Wirksubstanz. Anschließend wird auf Raumtemperatur abgekühlt.Example III Shaking mixture with 1% condensation product from erythromycylamine with butyrylglyc-laldehyde Composition: Active ingredient 1.0 g sorbitan monopalmitate (Span 40) 1.0 g Cremophor 0 (Pa. BASF) 2.0 g cetostearyl alcohol (Lanette 0) 2.0 g Walrat 1.0 g oleic acid decyl ester 5.0 g paraffin oil 1.0 g distilled water 87 per g 100.0 g Manufacturing process: The substances of the disperse phase are melted together and brought to 700C and then emulsified in water at the same temperature. It is cooled to 400C and suspends the finely ground active substance with the aid of an immersion homogenizer. It is then cooled to room temperature.
Beispiel IV Dragées mit 50 mg Kondensationsprodukt aus Erythromycylamin mit Diäthylphosphonoacetaldehyd Zusammensetzung: 1 Dragéekern enthält: Wirkstoff 50,0 mg Papaverin 25,0 mg Maisstärke 32,0 mg Gelatine 3,0 mg Cellulose, mikrokristallin Magnesiumstearat 9,0 mg 1,0 mg 120,0 mg Herstellungsverfahren: Die Mischung der Wirksubstanzen mit Maisstärke wird mit einer 12%igen wässrigen Lösung der Gelatine befeuchtet, durch ein Sieb der Maschenweite 1a5 mm granuliert, bei 450C getrocknet und nochmals durch ein Sieb der Maschenweite 1,0 mm gerieben. Das so erhaltene Granulat wird mit Cellulose und Magnesiumstearat gemischt und zu DragZekernen verpreßt.Example IV Dragées with 50 mg of condensation product from erythromycylamine with diethylphosphonoacetaldehyde Composition: 1 tablet core contains: active ingredient 50.0 mg papaverine 25.0 mg corn starch 32.0 mg gelatin 3.0 mg Cellulose, microcrystalline magnesium stearate 9.0 mg 1.0 mg 120.0 mg Manufacturing process: The Mixing the active ingredients with corn starch is made with a 12% aqueous solution the gelatine is moistened and granulated through a sieve with a mesh size of 1a5 mm 450C and rubbed again through a sieve with a mesh size of 1.0 mm. That The granulate obtained in this way is mixed with cellulose and magnesium stearate and made into dragons pressed.
Kerngewicht: 120 mg Stempel: 7 mm gewölbt. Core weight: 120 mg Stamp: 7 mm convex.
Die so erhaltenen Dragéekerne werden nach bekanntem Verfahren mit einer Hülle überzogen, die im wesentlichen aus Zucker und Talkum besteht. Die fertigen Dragees werden mit Hilfe von Bienenwachs poliert.The tablet cores obtained in this way are with a known method coated in a shell consisting essentially of sugar and talc. The finished Dragees are polished with the help of beeswax.
Drageegewicht: 160 mg.Dragee weight: 160 mg.
Claims (13)
Priority Applications (34)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19762606030 DE2606030A1 (en) | 1976-02-14 | 1976-02-14 | Condensn products of erythromycyl-amine with aldehydes - antibiotic erythromycin derivs active against gram negative and gram positive bacteria |
AT149976A AT342770B (en) | 1975-04-07 | 1976-03-01 | PROCESS FOR PRODUCING NEW ERYTHROMYCINE DERIVATIVES |
GR50399A GR60374B (en) | 1975-04-07 | 1976-03-26 | New erythromycin derivatives and process for the preparation thereof |
US05/671,421 US4048306A (en) | 1975-04-07 | 1976-03-29 | Aldehyde-erythromycylamine condensation products |
BG7632727A BG27380A3 (en) | 1975-04-07 | 1976-03-29 | Method of obtaining of erythromycilamine derivaties |
DK145276A DK138656C (en) | 1975-04-07 | 1976-03-30 | ANALOGICAL PROCEDURE FOR THE PREPARATION OF ERYTHROMYCIN DERIVATIVES OR ACID ADDITIONAL SALTS THEREOF |
FI760845A FI63244C (en) | 1975-04-07 | 1976-03-30 | FOERFARANDE FOER FRAMSTAELLNING AV ANTIBAKTERISKA ERYTROMYSINDERIVATER |
CH417476A CH621800A5 (en) | 1975-04-07 | 1976-04-02 | |
LU88563C LU88563I2 (en) | 1975-04-07 | 1976-04-05 | Dirithromycin |
LU74702A LU74702A1 (en) | 1975-04-07 | 1976-04-05 | |
DD192208A DD125218A5 (en) | 1975-04-07 | 1976-04-05 | NEW ERYTHROMYCIN DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
PT64977A PT64977B (en) | 1975-04-07 | 1976-04-06 | NEW ERYTHROMYCIN DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
GB13942/76A GB1520963A (en) | 1975-04-07 | 1976-04-06 | Erythromycin derivatives |
IL49359A IL49359A (en) | 1975-04-07 | 1976-04-06 | Condensation products of erythromycylamines with aliphaticor araliphatic aldehydes their preparation and pharmaceutical compositions containing them |
JP51038681A JPS51128991A (en) | 1975-04-07 | 1976-04-06 | Production of nvel erythromycine derivatives |
MX000145U MX3277E (en) | 1975-04-07 | 1976-04-06 | PROCEDURE FOR THE PREPARATION OF ERYTHROMYCIN DERIVATIVES |
RO85433A RO68441B (en) | 1975-04-07 | 1976-04-06 | Process for preparing erythromycinamine derivatives |
PL1976188538A PL101880B1 (en) | 1975-04-07 | 1976-04-06 | A METHOD OF PRODUCING NEW DERIVATIVES OF ERYTROMYCIN |
HU76TO1026A HU175186B (en) | 1975-04-07 | 1976-04-06 | Process for producing new erythromycin derivatives |
AU12722/76A AU498418B2 (en) | 1975-04-07 | 1976-04-06 | Erythromycin derivatives and pharmaceuticals |
CS762265A CS196304B2 (en) | 1975-04-07 | 1976-04-06 | Process for preparing new derivatives of erythromycine |
NO761172A NO141411C (en) | 1975-04-07 | 1976-04-06 | ANALOGY PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE ERYTHROMYCIN DERIVATIVES |
ES446737A ES446737A1 (en) | 1975-04-07 | 1976-04-06 | Aldehyde-erythromycylamine condensation products |
NLAANVRAGE7603569,A NL180107C (en) | 1975-04-07 | 1976-04-06 | PROCESS FOR MANUFACTURING A PHARMACEUTICAL PREPARATION WITH ANTIBACTERIAL ACTION BASED ON A CONDENSATION PRODUCT OF ERYTHROMYCYLAMINE AND AN ALDEHYDE, AND A METHOD FOR PREPARING A CONDENSATION PRODUCT OF ETHYTHYDEYDEHYTHYLYTHYCHYCYLYTHYCYLYTHYCYCLYDEYTHYCYLYCYLYCYLENE |
SE7604052A SE425566B (en) | 1975-04-07 | 1976-04-06 | PROCEDURE FOR THE PREPARATION OF ERYTHROMYCIN DERIVATIVES AND ACID ADDITIONAL SALTS THEREOF |
SU762343016A SU682134A3 (en) | 1975-04-07 | 1976-04-06 | Method of preparation of erytromycin derivatives or salts thereof |
YU00876/76A YU87676A (en) | 1975-04-07 | 1976-04-06 | Process for preparing new erythromycin derivatives |
CA249,700A CA1060005A (en) | 1975-04-07 | 1976-04-06 | Erythromycine derivatives and processes for their preparation |
NZ180529A NZ180529A (en) | 1975-04-07 | 1976-04-06 | Erythromyc-9-yl-amine derivatives and pharmaceutical compositions |
IE732/76A IE43598B1 (en) | 1975-04-07 | 1976-04-07 | Erythromycin derivatives |
FR7610144A FR2306703A1 (en) | 1975-04-07 | 1976-04-07 | NEW ERYTHROMYCIN DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICINAL PRODUCTS CONTAINING THEM |
ES456567A ES456567A1 (en) | 1975-04-07 | 1977-03-05 | Aldehyde-erythromycylamine condensation products |
AT281677A AT343813B (en) | 1975-04-07 | 1977-04-22 | PROCESS FOR PRODUCING NEW ERYTHROMYCINE DERIVATIVES |
CH277580A CH624413A5 (en) | 1975-04-07 | 1980-04-10 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19762606030 DE2606030A1 (en) | 1976-02-14 | 1976-02-14 | Condensn products of erythromycyl-amine with aldehydes - antibiotic erythromycin derivs active against gram negative and gram positive bacteria |
Publications (1)
Publication Number | Publication Date |
---|---|
DE2606030A1 true DE2606030A1 (en) | 1977-08-25 |
Family
ID=5969952
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19762606030 Withdrawn DE2606030A1 (en) | 1975-04-07 | 1976-02-14 | Condensn products of erythromycyl-amine with aldehydes - antibiotic erythromycin derivs active against gram negative and gram positive bacteria |
Country Status (1)
Country | Link |
---|---|
DE (1) | DE2606030A1 (en) |
-
1976
- 1976-02-14 DE DE19762606030 patent/DE2606030A1/en not_active Withdrawn
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