DK161331B - Analogifremgangsmaade til fremstilling af 7beta-substitueret malonamido-1-oxadethia-7alfa-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-cephalosporiner - Google Patents
Analogifremgangsmaade til fremstilling af 7beta-substitueret malonamido-1-oxadethia-7alfa-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-cephalosporiner Download PDFInfo
- Publication number
- DK161331B DK161331B DK131277A DK131277A DK161331B DK 161331 B DK161331 B DK 161331B DK 131277 A DK131277 A DK 131277A DK 131277 A DK131277 A DK 131277A DK 161331 B DK161331 B DK 161331B
- Authority
- DK
- Denmark
- Prior art keywords
- acid
- methoxy
- oxadethia
- methyltetrazol
- thiomethyl
- Prior art date
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- -1 1-METHYLTETRAZOL-5-YL Chemical class 0.000 title claims description 72
- 238000000034 method Methods 0.000 title description 7
- 238000002360 preparation method Methods 0.000 title description 4
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- CJVFIJXEPCVCTK-LWMBYGOMSA-N (2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)C(C)C CJVFIJXEPCVCTK-LWMBYGOMSA-N 0.000 claims description 4
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- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000013081 microcrystal Substances 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 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
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium 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
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- 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
-
- 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
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; 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)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
i DK 1613b1 δ
Den foreliggende opfindelse angår en anal ogi fremgangsmåde til fremstilling af hidtil ukendte 7β-substitueret malonamido-l-oxadethia-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-cephalosporiner, som har følgende formel 5
OCH3 N-N
ToB2 CH3 1 7 hvori COB og COB hver for sig er carboxy eller carboxy beskyttet som 15 estere eller farmaceutisk acceptable salte, hvilken fremgangsmåde er ejendommelig ved det i kravets kendetegnende del angivne.
Cephalosporinanal oger, som indeholder oxygen i stedet for svovl i kernen, er beskrevet i Journal of Heterocyclic Chemistry, Vol. 5, p. 779 (1968) af J.C. Sheehan og M. Dadic, beskrivelsen til tysk patentansøg-20 ning nr. 2.219.601 (1972), Canadian Journal of Chemistry, Vol. 52, p.
3996 (1974) af Saul Wolfe et al., og Journal of American Chemical Society, Vol. 96, p. 7582 (1974) af B.G. Christensen et al.
Opfinderne af den foreliggende opfindelse har nu fremstillet forskellige 1-oxadethiacephalosporiner, som er nært beslægtede med kendte 25 1-thiacephalosporiner. I modsætning til hvad der anføres af B.G.
Christensen et al, nemlig at deres racemiske 1-oxacephalosporiner udviste omkring halvdelen af 1-thiacephalosporins styrke, var de øvrige af ovennævnte opfindere fremstillede optisk aktive produkter omkring 4-8 gange så aktive som de tilsvarende 1-thiacephalosporiner med hensyn til 30 deres antibakterielle egenskab. Imidlertid var disse 1-oxadethiacephalo-sporiners jS-lactamring mindre stabil ved anvendelse som kliniske medikamenter end 1-thiacephalosporinernes.
De her omhandlede forbindelser (I), som er udvalgt fra de optisk aktive forbindelser, løser denne mangelfuldhed ved 1-oxadethiacephalo-35 sporiner.
Yderligere udviste forbindelser (I) ved sammenligning med andre 1-oxadethiacephalosporiner de følgende kendetegn:
DK 161331B
2 1) stærkere antibakteriel aktivitet mod Gram-negative bakterier, 2) højere stabilitet af /3-1 actamringen, 3) snævrere minimal i nhi berende koncentration mellem /J-lactamase-producerende og -ikke-producerende bakterier, 5 4) mindre afhængighed af inoculumsstørrelse, 5) højere effektivitet mod bakterier, som er resistente mod visse andre cephalosporiner (f.eks. Enterobacteria, Serratia, indol-positiv Proteus), 6) højere bidrag med hensyn til baktericid karakter, og 10 7) højere bl od-koncentration.
Tillige har forbindelser (I) følgende fortrin: a) bredere antibakterielle spektre (f.eks. 3,6 7/ml eller mere mod Pseudomonas sp., anaerobiske bakterier (Bacteroid fragi li s), b) højere styrke mod /Mactamase-producerende bakterier, 15 c) højere stabilitet i blod, og d) lavere binding med serum-proteiner.
1 2
Grupperne COB og COB kan være carboxy eller carboxy beskyttet som estere eller farmaceutisk acceptable salte, som er sædvanlige i penicilliners og cephalosporiners kemi, og som sædvanligvis indeholder 20 op til 15 carbonatomer. De beskyttende grupper kan være ens eller forskellige for hver carboxy i molekylet. Sædvanligvis fjernes de beskyttende forestrende grupper til dannelse af fri carboxy eller salte ved et hvilket som helst ønsket trin af syntesen til fremstilling af forbindelserne (I). Derfor kan disse carboxybeskyttende gruppers 25 struktur være vidt forskellige uden at ændre opfindelsens hovedpunkt.
Med andre ord har deres strukturer ingen særlig anden betydning end at skulle tjene til beskyttelse, afbeskyttelse og eventuel saltdannelse.
Eksempler på specifikke beskyttende grupper er estere (omfattende eventuelle substituerede al kyl estere,f.eks. t-butyl-, mono-hydroxy-t-30 butyl-, 2,2,2-trichlorethyl- og acyloxymethyl-estere, aral kyl estere, f.eks. benzyl-, p-tolylmethyl-, p-nitrobenzyl-, p-methoxybenzyl-, phthalidyl-, di phenylmethyl-, trityl- og phenacyl-estere, metal estere, f.eks. trimethylsilyl-, dimethylmethoxysilyl- og trimethylstannylestere, og andre let fjernelige alifatiske estere, samt aromatiske 35 estere, f.eks. phenyl-, tolyl-, 3,4-dimethyl phenyl- og 5-indanylestere) og farmaceutisk acceptable salte (omfattende alkalimetalsalte, f.eks. natrium- og kalium-salte, jordal kalimetal sal te, f.eks. magnesium-, calcium- og acyloxycalcium-salte, og salte med organiske baser, f.eks. pro-
DK 161331B
3 cain, tri ethylarnin og dicyclohexylamin). Hver carboxy i molekylet kan være fri eller beskyttet med ens eller forskellige grupper.
i p
Fortrinsvis kan COB og COB være fri carboxy eller farmaceutisk acceptable salte deraf. Andre foretrukne COB*-grupper er 5-indanyloxy-5 carbonyl, phenoxycarbonyl eller dimethylphenoxycarbonyl.
Sædvanligvis leveres forbindelser (I) som salte til administrering til mennesker eller veterinære individer. Mest foretrukne salte er natrium- eller kalium-salte eller salte med visse organiske baser. De udvælges under hensyn til sikkerhed, opløselighed, stabilitet, etc.
10 Forbindelser (I) er stærke antibakterielle medikamenter mod Gram negative bakterier og udviser samtidig mindre aktivitetstab ved højere inoculumsstørrelse og viser stærkere antiinfektionsvirkning in vivo end forventet ud fra in vi tro-data på grund af deres evne til opnåelse af en højere blodkoncentration.
15 Forbindelser (I), som har p-hydroxyphenylmalonamido i 7-stillingen, er stærke antibakterielle midler, som deaktiveres mindre i levende dyr på grund af deres lavere protein-binding og på grund af deres højere blodkoncentration end de tilsvarende usubstituerede arylmalonamido-for-bindelser. De udviser også stærkt intensiveret aktivitet mod Pseudomo-20 nas-stammer, omfattende de, som er resistente mod carbenicillin.
Forbindelserne (I) er hidtil ukendte forbindelser, som udviser stærk antibakteriel aktivitet mod Gram-positive og Gram-negative bakterier og er nyttige mediciner og veterinære medikamenter. F.eks. indgives de sædvanligvis oralt eller parenteralt til mennesker eller dyr 25 ved en daglig dosis på f.eks. 0,05 til 50 mg/kg legemsvægt til behandling eller hindring af bakteriel infektion.
Forbindelserne (I) leveres sædvanligvis i små glas, som indeholder steriliserede mikrokrystaller eller steriliseret lyofi1 isat, og gives som opløsninger, der fremstilles før brug. Endvidere kan en effektiv 30 mængde af forbindelserne sædvanligvis administreres oralt eller parenteral t med farmaceutisk acceptable bærestoffer, fortyndere eller stabilisatorer i form af præparater, som f.eks. små glas, injektioner, salver, opløsninger, tabletter, pulvere og kapsler. De kan være i enhedsdoseringsform. Saltene, omfattende alkalimetalsalte, anvendes hovedsageligt 35 til parenteral administrering. Acyloxymethyl-, indanyl- phenyl-, phtha-1idylestrene, samt lignende estere, er også velegnede til oral applikation.
Forbindelserne (I) kan f.eks. fremstilles ved en fremgangsmåde, som
DK 161331 B
4 er karakteriseret ved, at man omsætter en amin, som har formel (II) °CH3 . “2Nj=0i η 0^^Η β (II) C0B CH3 10 2 hvori COB har den tidligere anførte betydning, med en p-hydroxyphenyl-substitueret malonsyre, som har formel (III)
H0 \ VHC00H
15 I (III) COB1 hvori COB1 har den tidligere anførte betydning, eller reaktive derivater deraf.
20 Aminogruppen i 7-stillingen i aminen (II) kan være aktiveret ved hjælp af en silyl- eller stannyl-gruppe eller være beskyttet eller aktiveret ved hjælp af 1-halogenal kyl iden, 1-alkoxyalkyliden, alkylen, carbonyl, let fraspaltelig acyl eller lignende grupper til acyleringen.
Når arylmalonsyren (III) anvendes som fri syre, udføres acyleringen 25 i et opløsningsmiddel (især nitril, ether, amid eller halogencarbonhy-drid eller blandinger deraf som opløsningsmiddel) i nærværelse af en kondenserende reagens [f.eks. Ν,Ν'-dialkylcarbodiimid (f.eks. Ν,Ν'-di-cyclohexylcarbodiimid); carbonyl forbindel se (f.eks. carbonyl di imidazol); acylamin (f.eks. 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinolin); isoxa- 30 zoliniumsalt (f.eks. N-ethyl-5-phenylisoxazolinium-3sulfonat, N-t-butyl- 5-methylisoxazoliumperchlorat) eller andet kondenserende reagens] ved ca. -10° til ca. 70°.
Når arylmalonsyren (III) anvendes i form af et reaktivt derivat til acyleringen, kan dette være et anhydrid [f.eks. blandet anhydrid med 35 alkylcarbonsyre, aral kyl carbonsyre, hydrogenhal ogenidsyre (surt halogenid), hydrogenazid (surt azid), phosphorsyre, phorphorsyrling, svovlsyre, svovlsyrling, hydrogencyanid (surt cyanid), symmetrisk interim)! ekylært anhydrid, blandet anhydrid med al i fati sk eller aromatisk 5 DK 16 13b 1 t$ sulfon- eller carboxylsyre, speciel intramolekylært anhydrid, som keten, isocyanat eller lignende reaktivt anhydrid], en reaktiv ester [f.eks. en enolester, arylester (f.eks. pentachlorphenyl-, p-nitrophenyl, 2,4-dini-trophenyl-, benzotriazol-ester)], en diacyliminoester, et reaktivt amid 5 [f.eks. amid med imidazol eller triazol, reaktivt amid, f.eks. 2-ethoxy-1,2-dihydroquinolin-l-amid] eller et formiminoderi vat (f.eks. N,N-di al -kyliminomethylester, N,N-diacylanilin).
Om nødvendigt kan disse acylerende reagenser anvendes i nærværelse af en syrereceptor [f.eks. uorganisk base (f.eks. hydroxid, carbonat el-10 ler hydrogencarbonat af al kalimetaller eller jordal kalimetaller), organisk base (f.eks. tertiær amin, aromatisk base), alkylenoxid (f.eks. ethylenoxid, propylenoxid), amid (f.eks. Ν,Ν-dimethylformamid, hexame-thylphosphortriamid), eller anden syrereceptor] eller en molekyl arsigte, fortrinsvis i et opløsningsmiddel (især keton-, ester-, ether-, nitril-, 15 amid- eller halogencarbonhydrid-opløsningsmiddel eller blanding deraf).
De fremstillede forbindelser kan først beskyttes ved hydroxy-grup-pen med en let fraspaltelig, beskyttende gruppe og bagefter afbeskyttes til dannelse af de ønskede p-hydroxyphenyl-forbinde!ser. Repræsentative, beskyttende grupper kan være sådanne, som danner ester [omfattende Cj_g 20 α-halogenalkanoyl (f.eks. tri fluoracetyl, trichloracetyl), Cj g alkanoyl (f.eks. acetyl, formyl), C^g /J-ketocarboxylacyl (f.eks. acetoacyl), C2 12 alkoxycarbonyl (f.eks. tbutoxycarbonyl, cyclopropylmethoxycarbonyl, norbornyloxycarbonyl, 2,2,2-trichlorethoxycarbonyl), Cg j5 aralkoxycar-bonyl (f.eks. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitro-25 eller p-methylbenzyloxycarbonyl, diphenylmethoxycarbonyl) og lignende acyler] og ethere [omfattende Cjg alkyl (f.eks. methyl, t-butyl, cyclo-propylmethyl, isobornyl, tetrahydropyranyl, methoxymethyl), C^jg aralkyl (benzyl, p-methoxy-, p-methyl- eller p-nitro-benzyl, diphenylmethyl, trityl) og lignende grupper]. Den beskyttende gruppe kan fortrinsvis 30 indføres på trinet for arylmalonsyren (III) eller reaktive derivater deraf. Afbeskytte!sen udføres ved f.eks. 1) spaltning af acylater eller ethere med en syre (f.eks. mineralsyre, Lewis-syre, stærk carboxylsyre, sulfonsyre), eller base (natrium- eller kalium-carbonat, -hydroxid, organisk base) ved stuetemperatur eller forhøjet temperatur, om nødvendigt 35 i nærværelse af kationfjerner, eller 2) hydrogenering af p-nitrobenzyl-oxycarbonyl eller benzyloxycarbonyl med hydrogen og platin eller palladium på konventionel måde.
Når carboxy-gruppen i 4-stillingen eller i sidekæden ved 7-stil-
DK 161331 B
6 lingen beskyttes, kan den beskyttende gruppe fjernes til dannelse af de frie syreforbindelser (I) på konventionel måde til fjernelse af de beskyttende grupper» F.eks. 1) hydrolyseres stærkt reaktive estere let med en syre eller 5 base, 2) spaltes 2-halogenethyl-, benzyl-, methyl benzyl -, nitrobenzyl-og di arylmethyl-estere ved mild reduktion (f.eks. med tin, zink eller divalente chromsalte i nærværelse af syrer, med natriumdithionit, ved katalytisk hydrogenering med hydrogen over katalysator, f.eks. platin, palladium, nikkel), 3) spaltes benzyl-, methoxybenzyl-, methyl benzyl -, 10 dimethoxybenzyl-, t-alkyl-, tri tyl-, diarylmethyl- og cyclopropylmethyl-estere ved indvirkning af syrer eller ved solvolyse (f.eks. med mineralsyrer, såsom saltsyre, Lewis-syrer, f.eks. aluminiumchlorid, sul fonsyrer, f.eks. toluen-p-sulfonsyre, stærkt sure carboxylsyrer, f.eks. tri fluoreddikesyre, myresyre, om nødvendigt i nærværelse af en 15 kationacceptor, f.eks. anisol), 4) spaltes phenacyl-, ethynyl-, p-hydroxy-3,5-di-t-butylbenzyl-estere ved indvirkning af base (f.eks. al kalimetalthiophenoxider, uorganisk base, basiske salte) eller ved lignende metoder.
Forbindelserne (I) med en eller to frie carboxygrupper kan omdannes 20 til salte ved indvirkning af al kalimetal hydroxider, -carbonater eller alkanoat-salte eller ved indvirkning af organiske baser, ionbytterharpikser.
De følgende eksempler skal detaljeret belyse den foreliggende opfindelse. Produkternes grundstofanalyser og fysiske konstanter er i 25 hvert eksempel konsistent med de givne strukturer. I de følgende eksempler indeholder produkterne sædvanligvis en omtrent lige stor mængde af de med hensyn til α-asymmetrisk carbon i amidsidekæden isomere forbindelser. Fremstillingen af begge de isomere er omfattet af opfindelsen og adskilles om nødvendigt ved kromatografisk teknik eller andre konventio-30 nelle metoder. Nomenklaturen er i overensstemmelse med det i japansk fremlæggelsesskrift nr. 49-133594 anførte.
Det følgende eksempel belyser fremstilling af 7j3-amino-forbin-delser.
Eksempel 1 (1) Til en opløsning af diphenylmethyl-7)3-phenylacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylat (955 35
DK 161331 B
7 mg) i methylenchlorid (24 ml) sættes phosphorpentachlorid (666 mg) og pyridin (0,258 ml) i nitrogengas ved -20°. Efter omrøring ved -20° i 30 minutter og ved stuetemperatur i 30 minutter blandes blandingen med methanol (12 ml) ved -20° og omrøres ved stuetemperatur i 30 minutter.
5 Reaktionsblandingen fortyndes med vand (6 ml), omrøres i 30 minutter og koncentreres under formindsket tryk. Remanensen opløses i 5% vandig natriumhydrogencarbonat-opløsning under isafkøling og ekstraheres med ethyl acetat. Ekstrakten udvaskes med vand, tørres over natriumsulfat og koncentreres under formindsket tryk. De udskilte krystaller opsamles ved 10 filtrering og udvaskes med ether til opnåelse af diphenylmethyl-7/?-ami-no-3-(1-methyltetrazol-5-yl)thi omethyl-1-oxadethi a-3-cephem-4-carboxylat (661 mg). Smeltepunkt 151 - 156°. Udbytte: 86,5%.
IR: 7CJnax3 3420> 3345> 1790> 1718’ 1630 cm l 15 NMR: $CDC13 1,75,bred s,2H, 3,81,s,3H, 4,28,bred s,2H, 4,50,d, (4Hz)lH, 4,64 bred s,2H, 4,98,s,(4Hz)lH, 6,90,s,IH, 7,20 -7,70,m,10H.
20 UV: ^CHj]£S0 286 nm (e = 8695).
[or] 2p’5-232,8 ± 7,6° (c=0,360, (CH3)2SO).
Det følgende eksempel belyser indføring af 7or-methoxy.
25
Eksempel 2 (1) En opløsning af diphenylmethyl-7/?-amino-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylat (600 mg) og 3,5-di-t-bu-tyl-4-hydroxybenzaldehyd (353 mg) i en blanding af benzen (15 ml) og 30 methylenchlorid (5 ml) opvarmes under tilbagesvaling i 1 time under fjernelse af vand ved hjælp af molekyl arsigte i en Dean Stark vand-udskiller. Den resulterende opløsning af diphenylmethyl-7>3-(3,5-di-t-butyl-4-hydroxybenzal)amino-3-(l-methyltetrazol-5-yl)thio-methyl-1-oxadethi a-3-cephem-4-carboxylat afkøles ved -10 til -15°, blandes med vand-35 fri magnesiumsulfat (1 g) og derpå med nikkelperoxid (0,69 g) under omrøring, og omrøres ved -10 til -15° i 30 minutter og ved stuetemperatur i 15 minutter. Reaktionsblandingen filtreres, og faststoffet vaskes med benzen. Til den resulterende opløsning af diphenylmethyl-7-(3,5-di-t-bu-
8 DK 161331B
tyl-4-oxo-2,5-cyclohexadienylidenmethyl)imino-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylat sættes methanol (10 ml), og opløsningen henstilles ved stuetemperatur i 1 time og koncentreres til tørhed under formindsket tryk. Remanensen kromatograferes på silica-5 gel (30 g) indeholdende 10% vand og elueres med en blanding af benzen og ethyl acetat (4:1) til dannelse af diphenylmethyl-7/l-(3,5-di-t-butyl-4-hydroxybenzal)amino-7a-methoxy-3-carboxylat (906 mg) som praktisk taget rent gult skum. Udbytte: 99,7%.
(2) Til en opløsning af ovennævnte produkt i en blanding af metha-10 nol (10 ml) og tetrahydrofuran (5 ml) sættes Girard T reagens (315 mg), og blandingen omrøres i 1 time ved stuetemperatur, fortyndes med vand og ekstraheres med methylenchlorid. Ekstrakten udvaskes med vand, tørres over natriumsulfat og inddampes til tørhed under formindsket tryk. Remanensen renses ved kromatografi på silicagel (30 g) indeholdende 10% vand 15 og elueres med en blanding af ethylacetat: benzen:methylenchlorid (1:1:1) til dannelse af diphenylmethyl-7/J-amino-7a-methoxy-3-(l-methyl-tetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylat (469 mg). Totaludbytte for dette eksempel: 73,6%, smeltepunkt 160 - 162° (dekompo-nering).
20 IR: ^inax3 3425, 3350’ 1792’ 1724 cm NMR: 5CDC13 2,00,bred s,2H, 3,38,s,3H, 3,87,s,3H, 4,32,s,2H, 4,73,s,2H, 4,92,s,IH, 7,00,s,IH.
25
Som det fremgår af ovenstående eksempel har nikkel peroxid vist sig at være et af de bedste oxidationsreagenser for det phenoliske mellemprodukt til indføring af en methoxygruppe i 7a-stillingen i 1-oxa- og også 1-thia-cephemringe.
30
Eksempel 3
Til en opløsning af α-diphenylmethoxycarbonyl-a-p-hydroxyphenyl-eddikesyre (254 mg) i methylenchlorid (3 ml) sættes triethylamin (0,083 ml) og oxalylchlorid (0,051 ml) ved 0°. Efter omrøring i 15 minutter 35 sættes blandingen til en opløsning af di phenyl methyl-7/J-amino-7a-meth-oxy-3-(l-methyltetrazol-5-yl)-thiomethyl-l-oxadethia3-cephem-4-carboxy-lat (101,7 mg) og pyridin (0,048 ml) i methylenchlorid (4 ml) ved O0.
Efter omrøring i 30 minutter ved 0° fortyndes blandingen med ethylace-
DK 161331B
9 tat, udvaskes med vandig natriumhydrogencarbonat, vand, saltsyre og vand, tørres over natriumsulfat og inddampes under formindsket tryk. Den opnåede remanens kromatograferes på silicagel (20 g) indeholdende 10% vand og elueres med en blanding af benzen og ethyl acetat (2:1) til dan-5 nel se af diphenylmethyl-7j8-(a-diphenylmethoxycarbonyl-a-p-hydroxyphenyl-acetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-4-carboxylat (86,4 mg) som farveløst skum, udbytte: 49,6%.
IR: ymx3 3585> 3315, 179°’ 1722> 1700>skulder cm'1.
10 NMR: 6CDC13 (3,45,s + 3,48,s)3H, (3,72,s + 3,75,s)3H, 4,18,s,2H, 4,45,s,2H, (4,67,s + 4,70,s)lH, 5,02,s,IH.
Eksempel 4 15 Til en opslæmning af a-(5-indanyl)oxycarbonyl-a-p-hydroxyphenyl-eddikesyre (370 mg) i methylenchlorid (4 ml) sættes tri ethylamin (139 /zl. og oxalylchlorid (85/μ1) ved 0° i nitrogen til dannelse af en klar opløsning. Efter omrøring i 20 minutter ved 0° sættes blandingen til en opløsning af diphenylmethyl-7/1-amino-7a-methoxy-3-(1-methyltetrazol-5-20 yl)-thiomethyl-l-oxadethia-3-cephem-4-carboxylat (203 mg) i methylen-chlorid (5 ml) og pyridin (80 μΐ), og blandingen omrøres 10 minutter. Reaktionsblandingen fortyndes med ethylacetat, udvaskes med 2N saltsyre, vand, 5% vandig natriumhydrogencarbonatopløsning og vand, tørres over natriumsulfat og koncentreres under formindsket tryk til dannelse af 25 bleggult skum, som kromatograferes på silicagel (50 g) indeholdende 10% vand og elueres med en blanding af benzen og eddikesyre (1:1) til dannelse af diphenylmethyl-7j8-[>-p-hydroxyphenyl-a-(5-indanyl)-oxycarbonyl-acetamido]-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethi a-3-cephem-4-carboxylat som krystallinsk remanens (230 mg, udbytte: 71,6%), 30 som omkrystalliseres fra en blanding af chloroform og ether til dannelse af rene krystaller, som smelter ved 114-116°.
UV; Ύ°ίη1χΗ 272 = 9500)’ 284 = 9260) nm* 35 NMR: 6CD3C0CD3 2,l,m,2H, 2,87,t,(7Hz)4H, 3,43,s,3H, 3,91,s,3H,
4,31,s,2H, 4,65,s,2H, 5,07,s,IH, 5,13,s,IH, 6,92,bred s3H
IR: /¾ 3590, 3335, 1789, 1736, 1722, 1700, 1601 cm"1.
ΠΙοΧ
DK 161331B
10
Eksempel 5
Til en opløsning af diphenylmethyl-7/i-[at-(p-benzyloxyphenyl)-α-benzyloxycarbonylacetamido]-7a-methoxy-3-(l-methyltetrazol-5-yl)thio-methyl-l-oxadethia-3-cephem-4-carboxylat (100 mg) i methylenchlorid (2 5 ml) sættes anisol (0,2 ml) og en opløsning af aluminiumchlorid (250 mg) i nitromethan (1,2 ml) under isafkøling. Efter omrøring i 2 timer under isafkøling og i 1 time ved stuetemperatur hældes blandingen i en blanding af ethylacetat og methanol (5:1), udvaskes med 2N saltsyre og mættet saltvandsopløsning, tørres over natriumsulfat og koncentreres.
10 Remanensen udvaskes med ether til dannelse af 7/J-(a-p-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)thi omethyl-1-oxa-dethia-3-cephem-4-carboxylsyre (35 mg).
IR·’ Æ 1780’ 1719> 1632 cm-1.
'max 15 Eksempel 6
Til en opløsning af diphenylmethyl-7j3-[a-p-(p-methoxybenzyl)oxyphe-nyl-2-di phenylmethoxycarbonylacetami do]-7a-methoxy-3-(1-methyltetrazol- 5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylat (170 mg) i methylen-chlorid (3,5 ml) sættes anisol (0,35 ml) og trifluoreddikesyre (0,35 ml) 20 ved 0°, og blandingen omrøres i 45 minutter ved 0°. Efter afdampning af opløsningsmidlet tritureres produktet til dannelse af 7/}-(a-p-hydroxy-phenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl -l-oxadethia-3-cephem-4-carboxylsyre (91 mg) som farveløst pulver, udbytte: omtrent kvantitativt, smeltepunkt 125 - 132° (dekomponering).
25
Eksempel 7
Ved en fremgangsmåde i lighed med den i eksempel 6 beskrevne behandl es diphenylmethy1-7β-[α-ρ-(p-methoxybenzyl)oxyphenyl-a-pmethoxy-benzyloxycarbonylacetamido]-7a-methoxy-3-(l-methyltetrazol-5-yl)-thio-30 methyl-l-oxadethia-3-cephem-4-carboxylat (1,45 g) med anisol (4 ml) og trifluoreddikesyre (4 ml) i methylenchlorid (8 ml) ved 0° i 40 minutter til dannelse af 7/S-(a-p-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)-thiomethyl-l-oxadethia-3-cephem-4-carboxylsyre, smeltepunkt 125 - 132° (dekomponer!ng), udbytte: kvantitativt.
Eksempel 8 1) Til en opløsning af diphenylmethyl-7j8-[Q!-p-(p-methoxybenzyl)oxy-phenyl-a-p-methoxybenzyloxycarbonyl-acetamido]-7a-methoxy-3-(l-methyl te- 35 11
DK 161331 B
trazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylat (1,20 g) i methylenchlorid (24 ml) sættes anisol (2,4 ml) og en opløsning af alumi-niumehlorid (2,58 g) i nitromethan (12 ml) ved 0° under nitrogen. Efter omrøring i 15 minutter ved 0° hældes blandingen i kold 5% vandig natri -5 umhydrogencarbonatopløsning (100 ml) og filtreres til fjernelse af det dannede bundfald. Filtratet udvaskes to gange med methylenchlorid (2 x 100 ml), gøres sur med 2N saltsyre til pH-værdi 2,60 og hældes i en søjle af stærk porøs polymer HP-20 (60 ml), som sælges af Mitsubishi Chemical Industries, Ltd. Søjlen udvaskes med vand (300 ml) og elueres 10 med methanol. Eluatet koncentreres under formindsket tryk ved stuetemperatur. Remanensen opløses i methanol, behandles med aktivt carbon og koncentreres under formindsket tryk til dannelse af 7β-{α-ρ-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyl-tetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylsyre som pulver (595 mg), 15 der dekomponerer ved 125 - 132°, udbytte: 88,5%.
2) Det samme produkt kan fremstilles ved en fremgangsmåde i lighed med den under 1) ovenfor beskrevne, hvori a) p-methoxy-benzylether erstattes med benzyl ether, b) p-methoxybenzyloxycarbonylgruppe erstattes med benzyloxy-carbo- 20 ny1 gruppe, og/eller c) di phenylmethyl ester erstattes med benzyl ester.
Eksempel 9
Til en opløsning af 7j8-(a-p-hydroxyphenyl-a-carboxyacetamido)-7a-25 methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4~car-boxylsyre (359 mg) i methanol (7 ml) sættes en opløsning af natrium-2-ethylhexanoat i methanol (2 mol/liter; 1,73 ml) ved stuetemperatur.
Efter omrøring i 10 minutter fortyndes reaktionsblandingen med ethyl acetat, omrøres i 5 minutter og filtreres til opsamling af udskilt fast-30 stof, som udvaskes med ethyl acetat og tørres til dannelse af dinatriumsalt af 7/S-(o!-p-hydroxyphenyl-Qr-carboxyacetamido)-7a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-l-oxadethia-3-cephem-4-carboxylsyre (342 mg), udbytte: 88,8%, farveløst pulver, smeltepunkt dekomponering fra 170°.
IR: γΝυίη°χ1768’ 1675’ 1608 cm ]-UV: fiCHSiax max 273 nm = 1110°)· 35
Claims (1)
- 5 OCH3 N-N “^-ογΗ-λ 1J toB cMXh/Y (i) i0B2 CH3 1 2 10 hvori COB og COB hver for sig er carboxy eller carboxy beskyttet som estere eller farmaceutisk acceptable salte, k e n d e t e g n e t ved, at man a) omsætter en amin med formel och3 15 "^S-VS ini 0J3yLc„2SJI ] on COb2 éH3 2 hvori COB har den ovenfor anførte betydning, med en p-hydroxyphenyl-20 substitueret malonsyreforbindelse med formel H0~“ ~CHC00H I (ΠΙ) COB1 hvori COB1 har den ovenfor anførte betydning, eller et reaktivt derivat 25 deraf, eller b) fjerner den beskyttende gruppe på Ar' med syre, base eller ved hydrogenering i en forbindelse med formel pCH3 Ar' CHCONIL i | » J33L/V ™ COB2 CH3 1 2 hvori Ar' er p-beskyttet hydroxyphenyl, og COB og COB har den ovenfor anførte betydninger. 35
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3340176 | 1976-03-25 | ||
| JP3340176A JPS52122386A (en) | 1976-03-25 | 1976-03-25 | Cephalosporin analogous compounds as antibacterials |
| JP5029576 | 1976-04-30 | ||
| JP5029576A JPS52133997A (en) | 1976-04-30 | 1976-04-30 | Cephalosporin antibiotics |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK131277A DK131277A (da) | 1977-09-26 |
| DK161331B true DK161331B (da) | 1991-06-24 |
| DK161331C DK161331C (da) | 1991-12-09 |
Family
ID=26372085
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK131277A DK161331C (da) | 1976-03-25 | 1977-03-24 | Analogifremgangsmaade til fremstilling af 7beta-substitueret malonamido-1-oxadethia-7alfa-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-cephalosporiner |
Country Status (19)
| Country | Link |
|---|---|
| AR (1) | AR224606A1 (da) |
| BG (1) | BG31074A3 (da) |
| CY (1) | CY1158A (da) |
| DD (1) | DD129792A5 (da) |
| DE (1) | DE2713370C2 (da) |
| DK (1) | DK161331C (da) |
| ES (5) | ES457174A1 (da) |
| GR (1) | GR61146B (da) |
| HK (1) | HK46882A (da) |
| HU (1) | HU172720B (da) |
| IE (1) | IE44794B1 (da) |
| IL (1) | IL51743A (da) |
| MX (1) | MX4348E (da) |
| NO (2) | NO158505C (da) |
| NZ (1) | NZ183687A (da) |
| PT (1) | PT66346B (da) |
| RO (2) | RO71742A (da) |
| SE (1) | SE443143B (da) |
| YU (2) | YU44038B (da) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1557552A (en) * | 1977-02-15 | 1979-12-12 | Shionogi & Co | 1 oxadethiacepham compounds |
| US4252953A (en) * | 1979-05-01 | 1981-02-24 | Eli Lilly And Company | Antibiotic crystalline epimer |
| JPS60123490A (ja) * | 1983-12-07 | 1985-07-02 | Shionogi & Co Ltd | マロニルオキサセフェムカルボン酸誘導体 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL178005C (nl) * | 1972-11-06 | 1986-01-02 | Merck & Co Inc | Werkwijze voor het bereiden van een farmaceutisch preparaat met antibacteriele werking, alsmede werkwijze ter bereiding van een cefalosporine-antibioticum. |
| US3962232A (en) * | 1973-11-05 | 1976-06-08 | Eli Lilly And Company | 7-methoxycephalosporins |
| GB1449420A (en) * | 1973-11-26 | 1976-09-15 | Sankyo Co | 7alpha-methoxycephalosporing derivatives |
-
1977
- 1977-03-23 SE SE7703325A patent/SE443143B/xx not_active IP Right Cessation
- 1977-03-23 GR GR53086A patent/GR61146B/el unknown
- 1977-03-23 CY CY1158A patent/CY1158A/xx unknown
- 1977-03-23 NO NO771023A patent/NO158505C/no unknown
- 1977-03-24 IE IE622/77A patent/IE44794B1/en not_active IP Right Cessation
- 1977-03-24 NZ NZ183687A patent/NZ183687A/xx unknown
- 1977-03-24 DK DK131277A patent/DK161331C/da not_active IP Right Cessation
- 1977-03-24 HU HU77SI00001565A patent/HU172720B/hu not_active IP Right Cessation
- 1977-03-24 RO RO7789781A patent/RO71742A/ro unknown
- 1977-03-24 RO RO7799076A patent/RO78228A/ro unknown
- 1977-03-24 DD DD7700198053A patent/DD129792A5/xx unknown
- 1977-03-24 PT PT66346A patent/PT66346B/pt unknown
- 1977-03-24 BG BG035796A patent/BG31074A3/xx unknown
- 1977-03-24 ES ES457174A patent/ES457174A1/es not_active Expired
- 1977-03-25 AR AR266992A patent/AR224606A1/es active
- 1977-03-25 DE DE2713370A patent/DE2713370C2/de not_active Expired - Lifetime
- 1977-03-25 MX MX775582U patent/MX4348E/es unknown
- 1977-03-25 IL IL51743A patent/IL51743A/xx unknown
-
1978
- 1978-04-28 ES ES469287A patent/ES469287A1/es not_active Expired
- 1978-04-28 ES ES469284A patent/ES469284A1/es not_active Expired
- 1978-04-28 ES ES469285A patent/ES469285A1/es not_active Expired
- 1978-04-28 ES ES469286A patent/ES469286A1/es not_active Expired
-
1982
- 1982-11-11 HK HK468/82A patent/HK46882A/xx unknown
-
1983
- 1983-08-23 YU YU1737/83A patent/YU44038B/xx unknown
- 1983-08-23 YU YU1738/83A patent/YU44039B/xx unknown
-
1986
- 1986-05-28 NO NO862107A patent/NO862107L/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE44794L (en) | 1977-09-25 |
| ES457174A1 (es) | 1978-08-16 |
| IL51743A (en) | 1980-10-26 |
| DK161331C (da) | 1991-12-09 |
| ES469285A1 (es) | 1979-09-16 |
| BG31074A3 (en) | 1981-10-15 |
| SE7703325L (sv) | 1977-09-26 |
| CY1158A (en) | 1983-01-28 |
| NZ183687A (en) | 1979-01-11 |
| PT66346A (en) | 1977-04-01 |
| IE44794B1 (en) | 1982-04-07 |
| ES469286A1 (es) | 1979-09-16 |
| YU173783A (en) | 1983-12-31 |
| NO862107L (no) | 1977-09-27 |
| MX4348E (es) | 1982-04-05 |
| NO158505B (no) | 1988-06-13 |
| RO71742A (ro) | 1982-02-26 |
| ES469284A1 (es) | 1978-11-16 |
| GR61146B (en) | 1978-09-27 |
| NO158505C (no) | 1988-09-21 |
| DE2713370C2 (de) | 1994-04-21 |
| NO771023L (no) | 1977-09-27 |
| YU44039B (en) | 1990-02-28 |
| RO78228A (ro) | 1982-02-01 |
| YU44038B (en) | 1990-02-28 |
| HU172720B (hu) | 1978-11-28 |
| DD129792A5 (de) | 1978-02-08 |
| AR224606A1 (es) | 1981-12-30 |
| ES469287A1 (es) | 1979-09-16 |
| SE443143B (sv) | 1986-02-17 |
| DE2713370A1 (de) | 1977-09-29 |
| YU173883A (en) | 1983-12-31 |
| PT66346B (en) | 1978-08-16 |
| HK46882A (en) | 1982-11-19 |
| DK131277A (da) | 1977-09-26 |
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