DK155005B - ANALOGY PROCEDURE FOR PREPARING 2-CARBAL COOXYAMINOBENZIMIDAZOLD DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR PREPARING 2-CARBAL COOXYAMINOBENZIMIDAZOLD DERIVATIVES Download PDFInfo
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- DK155005B DK155005B DK351774AA DK351774A DK155005B DK 155005 B DK155005 B DK 155005B DK 351774A A DK351774A A DK 351774AA DK 351774 A DK351774 A DK 351774A DK 155005 B DK155005 B DK 155005B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
- C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
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Description
iin
DK 155005 BDK 155005 B
Patent nr. 137.329 angår en analogif remgangsmåde til fremstilling af 2-karbalkoxyaminobenzimidazolderivater med den almene formel IPatent No. 137,329 relates to an analogous process for the preparation of 2-carbalkoxyaminobenzimidazole derivatives of the general formula I
5 R1--T 2 C-N-COOR (I) i6 10 hvor R er en alkylgruppe med 1-4 carbonatomer, Ri er -S0R2, 15 -SO2R2, -SCN, -SR5, -OR5 eller M'(CH2)nMR7, hvor M og M' uaf hængigt af hinanden er 0, S, SO eller SO2, R? er alkyl med 1-4 carbonatomer eller fenyl, der eventuelt er substitueret med halogen, methyl eller smethoxy, og n er 1-4, R2 er alkyl med 1-6 carbonatomer, der eventuelt er substitueret med halogen 20 eller cyano, cykloalkyl med 3-7 carbonatomer, alkenyl med 3-6 carbonatomer eller alkynyl med 3-6 carbonatomer eller benzyl, naftyl eller fenyl, der eventuelt er substitueret med Ci«4~alkyl, Cj_4 alkoxy eller halogen, og R5 er alkenyl med 3-6 carbonatomer, der eventuelt er substitueret med halogen, 25 eller alkynyl med 3-6 carbonatomer eller benzyl el ler fen ætyl', der begge eventuelt er substitueret med halogen, 0^-4 alkyl eller Cj_4 alkoxy, og R6 er H eller N-Ci_4-alkylcarbamoyl, og R1 substitutionen er i 5(6)-sti 11 i ngen, eller ugiftige salte deraf, hvilken fremgangsmåde er ejendommelig ved, at en 3 0 1,2-diaminobenzen med formlen R1-- (II) 35 r hvor Ri og R5 har den ovennævnte betydning, og R5 fortrinsvis er H, omsættes med et l,3-bis(alkoxycarbonyl)-S-alkylisotio- 2R 1 - T 2 CN-COOR (I) 16 wherein R is an alkyl group of 1-4 carbon atoms, R 1 is -SOR 2, -SO 2 R 2, -SCN, -SR 5, -OR 5 or M '(CH 2) nMR 7, where M and M 'are independently 0, S, SO or SO2, R? is alkyl of 1-4 carbon atoms or phenyl optionally substituted with halogen, methyl or smethoxy, and n is 1-4, R2 is alkyl of 1-6 carbon atoms optionally substituted with halogen or cyano, cycloalkyl of 3 -7 carbon atoms, alkenyl of 3-6 carbon atoms or alkynyl of 3-6 carbon atoms or benzyl, naphthyl or phenyl optionally substituted with C 1-4 alkyl, C 1-4 alkoxy or halogen, and R 5 is alkenyl of 3-6 carbon atoms, optionally substituted with halogen, or alkynyl with 3-6 carbon atoms or benzyl or phenethyl, both optionally substituted with halogen, O4 -4 alkyl or C1-4 alkoxy, and R6 is H or N-C1-4 alkylcarbamoyl and the R 1 substitution is in 5 (6) -type 11 at a time, or non-toxic salts thereof, characterized in that a 30 1,2-diaminobenzene of formula R 1 - (II) 35 r wherein R 1 and R 5 has the aforementioned meaning, and R 5 is preferably H, reacted with a 1,3-bis (alkoxycarbonyl) -S-alkylisothio-2
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urinstof med formlen IIIurea of formula III
5 ROOCN = (j^- NH - COOR (III)ROOCN = (j 2 - NH - COOR (III)
hvor R er Cx_4-alkyl, ved forhøjet temperatur i nærværelse af 10 et opløsningsmiddel, og om ønsket en forbindelse med formlen IVwherein R is Cx_4 alkyl, at elevated temperature in the presence of a solvent and, if desired, a compound of formula IV
16 r1+—C00R (IV) i hvor R har den ovennævnte betydning, og Rl+ er -SR2 eller 20 M'(CH2)nMRf hvor M og M1 har den ovennævnte betydning, men mindst et af symbolerne betyder -S- eller -SO-, og R2, R7 og n har den ovennævnte betydning, oxyderes til den tilsvarende sulfinyl- eller sulfonylforbindelse med formlen I, hvor Ri er -SOR2, -SO2R2 eller -M*(CH2)nMR7f og mindst et af symbolerne M 25 og M' er -SO- eller SO2, og R, R2 og R7 og n har den ovennævnte betydning, R*> er hydrogen, og/eller Nl-hydrogenet i et 2-carbalkoxyaminobenzimidazolderivat med formlen Ib E1-^p-NH COOR (Ib)16 r1 + -C00R (IV) in which R has the above meaning and R1 + is -SR2 or 20 M '(CH2) nMRf where M and M1 have the above meaning, but at least one of the symbols means -S- or -SO- and R 2, R 7 and n have the above meaning, oxidized to the corresponding sulfinyl or sulfonyl compound of formula I wherein R 1 is -SOR 2, -SO 2 R 2 or -M * (CH 2) n M R 7 f and at least one of the symbols M 25 and M ' is -SO- or SO2, and R, R2 and R7 and n are as defined above, R *> is hydrogen, and / or the N1 hydrogen of a 2-carbalkoxyaminobenzimidazole derivative of the formula Ib E1- ^ p-NH COOR (Ib)
HH
35 hvor R og Ri har den ovennævnte betydning, på i og for sig kendt måde ombyttes med N-Ci_4-alkylcarbamoyl, og der eventuelt fremstilles et salt af en forbindelse med formlen I.Wherein R and R 1 have the above meaning, are exchanged in known manner with N-C 1-4 alkylcarbamoyl and optionally a salt of a compound of formula I. is prepared.
33
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Nærværende opfindelse angår en videreudvikling af opfindelsen ifølge nævnte patent og består i en analogifremgangsmåde til fremstilling af 2-carbalkoxyaminobenzimidazolderivater af den i patent nr. 137.329 omhandlede art og med formlen 5 jS N. jg r1-(-Q I --NCOdCHg (I) 1° „The present invention relates to a further development of the invention according to said patent and consists in an analogous process for the preparation of 2-carbalkoxyaminobenzimidazole derivatives of the kind referred to in Patent No. 137,329 and of the formula 5 µS N. µg r1 - (- QI - NCOdCH ° "
C-NHRC-NHR
hvor R1 er -S0R2, hvor. R2 er phenyl eller metho-.where R1 is -SOR2, where. R 2 is phenyl or metho-.
^5 xymethyl, og R® er phenyl, alkyl med 1-4 carbonatomer eller lavere alkyl substitueret med en -COOR-gruppe, hvor R er alkyl med 1-4 carbonatomer, idet Rl-substitutionen er i 5(6)-stTiling, eller et farmaceutisk anvendeligt salt deraf.5 is xymethyl, and R® is phenyl, alkyl of 1-4 carbon atoms or lower alkyl substituted by a -COOR group, where R is alkyl of 1-4 carbon atoms, the R1 substitution being in 5 (6) -stiling, or a pharmaceutically useful salt thereof.
20 Forbindelserne fremstillet ifølge opfindelsen og de ugiftige salte deraf dannet med farmaceutisk anvendelige, uorganiske eller organiske syrer har en bredspektret virkning over for parasitter hos pattedyr, herunder både fuldt udvoksne og umodne parasitiske former, repræsenteret f.eks. ved slægterne Trichostronglylus, Haemonchus, Ostertagia, 25 Cooneria, Nematodirus og Stronglyoides og især f.eks. over forThe compounds of the invention and the non-toxic salts thereof formed with pharmaceutically useful, inorganic or organic acids have a broad spectrum effect on mammalian parasites, including both fully grown and immature parasitic forms, represented e.g. in the genera Trichostronglylus, Haemonchus, Ostertagia, Cooneria, Nematodirus and Stronglyoides and in particular e.g. transfer
Nematosoiroides dubius. Hymenolepls hana, Syphacia obvelata og/eller Asniculuris tetraptera. Specielt har disse forbindelser vist sig at udvise høj virkning over for forskellige helmintiske infektioner af fordøjelseskanalen hos økonomisk betydningsfulde dyr og i forbindelse dermed en lav systemisk toxicitet for værtdyret.Nematosoiroides dubius. Hymenolepls hana, Syphacia obvelata and / or Asniculuris tetraptera. In particular, these compounds have been shown to exhibit high efficacy against various helminthic gastrointestinal infections in economically significant animals and, consequently, a low systemic toxicity to the host animal.
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Forbindelserne er kraftigere virkende end det kendte, beslægtede anthelmintiske stof 5(6)-n-butyl-2-carbomethoxyaminobenz-imidazol.The compounds are more potent than the known related anthelmintic substance 5 (6) -n-butyl-2-carbomethoxyaminobenzimidazole.
35 Hvor forbindelsen har en basisk molekyldel, refererer udtrykket "ugiftige salte" til de farmaceutisk anvendelige salte af forbindelserne, som ikke skadeligt påvirker de anthelmintiske 4Where the compound has a basic molecular moiety, the term "non-toxic salts" refers to the pharmaceutically acceptable salts of the compounds which do not adversely affect the anthelmintic 4
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egenskaber af den grundlæggende forbindelse, såsom de salte, der anvendes almindeligvis inden for dette tekniske område. Disse ugiftige salte indbefatter f.eks. salte af uorganiske syrer, såsom f.eks. svovlsyre, sulfonsyre, sulfaminsyre, salpetersyre, phosphorsyre, saltsyre 5 og lignende, og salte af organiske syrer, som f.eks. eddikesyre, citronsyre, mælkesyre, palmitinsyre, vinsyre, ravsyre, maleinsyre, benzoesyre og lignende. Hvor forbindelsen har en sur molekyldel, indbefatter de ugiftige salte cationsalte, som f.eks. saltene af natrium, kalium, ammonium og lignende.properties of the basic compound, such as the salts commonly used in this art. These non-toxic salts include e.g. salts of inorganic acids, such as e.g. sulfuric acid, sulfonic acid, sulfamic acid, nitric acid, phosphoric acid, hydrochloric acid and the like, and salts of organic acids, such as e.g. acetic acid, citric acid, lactic acid, palmitic acid, tartaric acid, succinic acid, maleic acid, benzoic acid and the like. Where the compound has an acidic moiety, the non-toxic salts include cation salts, such as e.g. the salts of sodium, potassium, ammonium and the like.
LOLO
Den mængde af forbindelsen, som skal administreres, afhænger af den faktisk anvendte forbindelse og af vægten af det behandlede dyr. I almindelighed vil det daglige doseringsniveau dog være mellem ca.The amount of compound to be administered depends on the compound actually used and the weight of the animal being treated. However, in general, the daily dosage level will be between about
5 mg/kg og 100 mg/kg legemsvægt af det behandlede dyr. Den aktive L5 bestanddel er egnet til at administreres til dyret ved blanding af den med dyrets kost, såsom med en foderblanding, eller ved at sammensætte den med en ugiftig bærer til dannelse af anthelmintiske midler.5 mg / kg and 100 mg / kg body weight of the treated animal. The active L5 component is suitable for administration to the animal by mixing it with the animal's diet, such as with a feed mixture, or by combining it with a non-toxic carrier to form anthelmintic agents.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at en forbindelse af formlen 20 (I11The process of the invention is characterized in that a compound of formula 20 (I11
NN
>5> 5
AA
hvor ' r·1 har den ovenfor anførte .heiiydning,, bringes, til at reagere med et substitueret isocyanat af formlen OCNR8, hvor R8 har den ovenfor anførte betydning, og det fremkomne produkt om ønsket overføres til et farmaceutisk anvendeligt salt deraf. Reaktionen kan ud-l0 føres i et indifferent organisk opløsningsmiddel, f.eks. tetrahydro= furan, ved ca. 0-40°C, i almindelighed ca. stuetemperatur, i ca. 1/2 time til ca. 96 timer, i almindelighed ca. 20-48 timer. Derefter fraskilles produktet og renses på enhver egnet måde. Typiske adskillelsesmetoder indbefatter f.eks. filtrering, ekstraktion, inddampning, j5 og typiske rensningsmetoder indbefatter krystallisation og både tyndt-wherein R 1 is of the above elevation is reacted with a substituted isocyanate of the formula OCNR 8, wherein R 8 has the meaning given above and the resulting product is, if desired, transferred to a pharmaceutically useful salt thereof. The reaction may be carried out in an inert organic solvent, e.g. tetrahydro = furan, at ca. 0-40 ° C, generally approx. room temperature, for approx. 1/2 hour to approx. 96 hours, generally approx. 20-48 hours. The product is then separated and purified in any suitable manner. Typical separation methods include e.g. filtration, extraction, evaporation, J5, and typical purification methods include crystallization and both
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5 lagskromatografi og søjlekromatografi. Optimal adskillelse og isolering kan fås for ethvert givet trin ved rutineforsøg, som er indlysende for fagfolk. Det fremkomne produkt er en blanding af 1,5-dlsubsti- tuerede og 1,6-disubstituerede forbindelser, hvori substituenterne R, 1 8 5 R og R er de samme med hensyn til hver forbindelse.5 layer chromatography and column chromatography. Optimal separation and isolation can be obtained for any given step by routine experiments which are obvious to those skilled in the art. The resulting product is a mixture of 1,5-dsubstituted and 1,6-disubstituted compounds, wherein the substituents R, 1.8 and R are the same with respect to each compound.
Forbindelserne af formel II og fremgangsmåder til fremstilling deraf er beskrevet i patent nr. 137.329.The compounds of Formula II and processes for their preparation are described in Patent No. 137,329.
*-0 Af forbindelser f remst i llet ifølge opfindelsen foretrækkes 1 -n-butylcarbamoylforbindelser, herunder 1-n-butylcarbamoyl-5(6)-phenylsulfinyl-2-carbomethoxyaminobenzimidazol og 1-n-buty1 carbamoyl-5(6)-methoxymethy1su1fi ny1-2-carbomethoxyamino-benzimidazol, fordi de har vist væsentlig aktivitet over for 15 visse af de ovenfor specielt nævnte helminter.Of compounds of the invention according to the invention, 1-n-butylcarbamoyl compounds, including 1-n-butylcarbamoyl-5 (6) -phenylsulfinyl-2-carbomethoxyaminobenzimidazole and 1-n-butylcarbamoyl-5 (6) -methoxymethyl -2-carbomethoxyamino-benzimidazole because they have shown significant activity against some of the helmets mentioned above.
Eksempel IExample I
En suspension af 1,1+1 g 5(6)-methoxymethylsulfinyl-2-carbomethoxy= 2 0 aminobenzimidazol i 1*+0 ml tetrahydrofuran behandles med 2,1+ g n-butylisocyanat ved stuetemperatur (20-25°C). Efter 2k timer tilsættes 1^-0 ml methylenchlorid, og opløsningen koncentreres under vakuum ved 20-30°C. Det fremkomne bundfald frafiltreres, vaskes med tetrahydrofuran og tørres og giver l-n-butylcarbamoyl-5(6)-meth= 2 5 oxymethylsulfinyl-2-carbomethoxyaminobenzimidazol, smp. 190° under dekomponering.A suspension of 1.1 + 1 g of 5 (6) -methoxymethylsulfinyl-2-carbomethoxy = 20 aminobenzimidazole in 1 * + 0 ml of tetrahydrofuran is treated with 2.1+ g of n-butyl isocyanate at room temperature (20-25 ° C). After 2h hours, 1 ml of methylene chloride is added and the solution is concentrated in vacuo at 20-30 ° C. The resulting precipitate is filtered off, washed with tetrahydrofuran and dried to give 1-n-butylcarbamoyl-5 (6) -meth = oxymethylsulfinyl-2-carbomethoxyaminobenzimidazole, m.p. 190 ° during decomposition.
Eksempel IIExample II
En suspension af 0,63 g 5(6)-phenylsulfinyl-2-carbomethoxyamino= *3 Λ benzimidazol i 50 ml tetrahydrofuran behandles ved 20-25°C med 0,5 g phenylisocyanat. Efter 20 timer koncentreres opløsningen under vakuum ved 20-30°C, og remanensen tritureres med acetone og frafiltreres og giver l-phenylcarbamoyl-5(6)-phenylsulfinyl-2-car= bomethoxyaminobenzimidazol., smp. 220°C under dekomponer ing.A suspension of 0.63 g of 5 (6) -phenylsulfinyl-2-carbomethoxyamino = * 3 Λ benzimidazole in 50 ml of tetrahydrofuran is treated at 20-25 ° C with 0.5 g of phenylisocyanate. After 20 hours, the solution is concentrated in vacuo at 20-30 ° C and the residue is triturated with acetone and filtered off to give 1-phenylcarbamoyl-5 (6) -phenylsulfinyl-2-carbomethoxyaminobenzimidazole. 220 ° C under decomposition ing.
3535
6 DK 155005 B6 DK 155005 B
Eksempel IIIExample III
En suspension af 0,95 g 5(6)-phenylsulfinyl-2-carbomethoxyamino= benzimidazol i 50 ml tetrahydrofuran behandles ved 20-25°C med 0,7 g 5 n-butylisocyanat. Efter 24 timer koncentreres opløsningen under vakuum ved 20-30°C. Remanensen tritureres med methanol, filtreres og vaskes med methanol til dannelse af l-n-butylearbamoyl-5(6)-phenyl= sulfinyl-2-carbomethoxyaminobenzimidazol, smp. 130°C under dekomponer ing.A suspension of 0.95 g of 5 (6) -phenylsulfinyl-2-carbomethoxyamino = benzimidazole in 50 ml of tetrahydrofuran is treated at 20-25 ° C with 0.7 g of 5 n-butyl isocyanate. After 24 hours, the solution is concentrated in vacuo at 20-30 ° C. The residue is triturated with methanol, filtered and washed with methanol to give 1-n-butylearbamoyl-5 (6) -phenyl = sulfinyl-2-carbomethoxyaminobenzimidazole, m.p. 130 ° C under decomposition ing.
1010
Eksempel IVExample IV
En opslemning af 0,31 g 5(6)-phenylsulfinyl-2-carbomethoxyamino= benzimidazol i 18 ml tetrahydrofuran behandles med 0,26 g ethoxy= carbonylmethylisocyanat ved 20-25°C i 2b timer. Koncentration af L5 opløsningsmidlet under vakuum og filtrering giver l-ethoxycarbonyl= methylcarbamoyl-5(6)-phenylsulfinyl-2-carbomethoxyaminobenzimidazol, smp. 170°C pinder dekomponer ing.A slurry of 0.31 g of 5 (6) -phenylsulfinyl-2-carbomethoxyamino = benzimidazole in 18 ml of tetrahydrofuran is treated with 0.26 g of ethoxy = carbonylmethyl isocyanate at 20-25 ° C for 2b hours. Concentration of the L5 solvent in vacuo and filtration yields 1-ethoxycarbonyl = methylcarbamoyl-5 (6) -phenylsulfinyl-2-carbomethoxyaminobenzimidazole, m.p. 170 ° C sticks decompos ing.
Eksempel VExample V
20 En suspension af 0,95 g 5(6)-phenylsulfinyl-2-carbomethoxyamino= benzimidazol i 35 ml tetrahydrofuran behandles med O,1! g methyl= isocyanat ved 20-25°C. Efter **8 timer frafiltreres produktet og tørres under vakuum og giver l-methylcarbamoyl-5(6)-phenylsulfi= nyl-2-carbomethoxyaminobenzimidazol, smp. 140°C under dekomponering.A suspension of 0.95 g of 5 (6) -phenylsulfinyl-2-carbomethoxyamino = benzimidazole in 35 ml of tetrahydrofuran is treated with 0.1 ml. g of methyl = isocyanate at 20-25 ° C. After ** 8 hours, the product is filtered off and dried under vacuum to give 1-methylcarbamoyl-5 (6) -phenylsulfinyl-2-carbomethoxyaminobenzimidazole, m.p. 140 ° C during decomposition.
!5 Eksempel VI.Example VI.
Fire unge svejtsiske Webster hanmus (16-20 g) inficeres kunstigt med 200 larver af arterne Nematospiroides dubius (rundorm) og Hyme= nolepis nana (bændelorm) og injiceres naturligt med 15-40 larver af Syphacia obvelata og Aspiculuris tetraptera (børneorm). Lægemidlet >0 administreres i et industrielt rotte/muse-foder i de anførte doser fra dag 1 til dag 18 (infektionen blev givet dag O). Dyrene dræbes den 18. dag, og parasitterne, der er tilbage i hele tyndtarmen, coecum og tyktarm tælles og adskilles. Gennemsnitsantallet af hver parasit, der er tilbage i hver behandlet gruppe, sammenlignes medFour young Swiss Webster male mice (16-20 g) are artificially infected with 200 larvae of the species Nematospiroides dubius (roundworm) and Hyme = nolepis nana (tapeworm) and naturally injected with 15-40 larvae of Syphacia obvelata and Aspiculuris tetraptera (baby worm). The drug> 0 is administered in an industrial rat / mouse feed at the indicated doses from day 1 to day 18 (the infection was given day 0). The animals are killed on the 18th day and the parasites left throughout the small intestine, coecum and colon are counted and separated. The average number of each parasite remaining in each treated group is compared
7 DK 155005 B7 DK 155005 B
gennemsnitsantallet, der er tiltage i kontrollen. Denne sammenligning udtrykkes som % reduktion af parasitterne i kontrolgruppen. Data for nogle forbindelser fremstillet ifølge opfindelsen er vist i nedenstående tabel.average number of increases in control. This comparison is expressed as% reduction of the parasites in the control group. Data for some compounds of the invention are shown in the table below.
5 1- (R%HC- )-5(6) -R^-2-carbomethoxyaminobenzimidazol v 0 o Dosisx Art (% reduktion) R R° Eks. -—j- 1Q P'P*m* Nd Hn So At1- (R% HC-) -5 (6) -R 2 -2-carbomethoxyaminobenzimidazole v Dosex Art (% reduction) R R ° Ex. -—J- 1Q P'P * m * Nd Hn So At
Methoxymethyl= n-butyl I 62(2) 100 0 83 97,5 sulfinyl 31(2) 87,5 0 82 79 phenylsulfinyl phenyl II 62 100 0 100 100 31 73 0 53 100 15 phenylsulfinyl n-butyl III 125 100 72 100 100 62 100 0 100 100 31(2) 98 0 98 100 16 0 0 0 100 8 0 O 0 32 phenylsulfinyl ethoxycar= IV 62 100 0 100 100 bonylmethyl 31 84 0 40 100 phenylsulfinyl methyl V 62 100 0 100 100 31 93 0 . 66 98 n-butyl - * 125 59 0 100 100 ____ 62,5 0 1 0 1 100 0 1 25 Nd = Nematospiroides dubiusMethoxymethyl = n-butyl I 62 (2) 100 0 83 97.5 sulfinyl 31 (2) 87.5 0 82 79 phenylsulfinyl phenyl II 62 100 0 100 100 31 73 0 53 100 15 phenylsulfinyl n-butyl III 125 100 72 100 100 62 100 0 100 100 31 (2) 98 0 98 100 16 0 0 0 100 8 0 O 0 32 phenylsulfinyl ethoxycar = IV 62 100 0 100 100 bonylmethyl 31 84 0 40 100 phenylsulfinyl methyl V 62 100 0 100 100 31 93 0 . 66 98 n-Butyl - * 125 59 0 100 100 ____ 62.5 0 1 0 1 100 0 1 25 Nd = Nematospiroides dubius
Hn = Hymenolepis nanaHn = Hymenolepis nana
So = Syphacia obvelataSo = Syphacia obvelata
At = Aspiculuris tetraptera * Sammenligningsstoffet Parbendazol 30 x Tallet i parentes angiver det antal forsøg, hvoraf den procentiske reduktion blev beregnet og gennemsnittet taget for at få de data, der er anført for den pågældende dosis.At = Aspiculuris tetraptera * Comparative substance Parbendazole 30 x The number in parentheses indicates the number of trials by which the percent reduction was calculated and the average taken to obtain the data indicated for that dose.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47386574 | 1974-05-28 | ||
| US473865A US3929822A (en) | 1972-12-29 | 1974-05-28 | 1,5(6)-Disubstituted benzizimidazole-2-carbamate derivatives having anthelmintic activity |
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| Publication Number | Publication Date |
|---|---|
| DK351774A DK351774A (en) | 1975-11-29 |
| DK155005B true DK155005B (en) | 1989-01-23 |
| DK155005C DK155005C (en) | 1989-06-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK351774A DK155005C (en) | 1974-05-28 | 1974-06-28 | ANALOGY PROCEDURE FOR PREPARING 2-CARBAL COOXYAMINOBENZIMIDAZOLD DERIVATIVES |
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|---|---|
| JP (1) | JPS50155612A (en) |
| AR (1) | AR221575A1 (en) |
| AT (1) | AT337714B (en) |
| BE (1) | BE817164Q (en) |
| BR (1) | BR7406197A (en) |
| CH (1) | CH614943A5 (en) |
| CS (1) | CS222211B2 (en) |
| DD (1) | DD115494A6 (en) |
| DE (1) | DE2431093C2 (en) |
| DK (1) | DK155005C (en) |
| ES (1) | ES430794A1 (en) |
| GB (1) | GB1480722A (en) |
| HU (1) | HU169779B (en) |
| IE (1) | IE41199B1 (en) |
| IT (1) | IT1046279B (en) |
| PL (1) | PL100057B1 (en) |
| RO (1) | RO64921A (en) |
| SE (1) | SE414174B (en) |
| SU (1) | SU644385A3 (en) |
| YU (1) | YU37331B (en) |
| ZA (2) | ZA746666B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK130293B (en) * | 1971-12-27 | 1975-02-03 | Hoechst Ag | Analogous process for the preparation of 2-carbalkoxy-amino-benzimidazole-5 (6) -phenyl ethers. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3578676A (en) * | 1968-06-21 | 1971-05-11 | Smith Kline French Lab | Benzimidazole-2-carbamates substituted on the benzene ring with an acyloxyalkyl group |
| US3722322A (en) * | 1971-05-05 | 1973-03-27 | E Coeppert | Speed control device |
-
1974
- 1974-05-28 RO RO74473865A patent/RO64921A/en unknown
- 1974-06-19 SE SE7408108A patent/SE414174B/en not_active IP Right Cessation
- 1974-06-26 JP JP49073160A patent/JPS50155612A/ja active Pending
- 1974-06-27 YU YU1813/74A patent/YU37331B/en unknown
- 1974-06-27 CS CS744553A patent/CS222211B2/en unknown
- 1974-06-28 DK DK351774A patent/DK155005C/en not_active IP Right Cessation
- 1974-06-28 DE DE2431093A patent/DE2431093C2/en not_active Expired
- 1974-07-02 BE BE146141A patent/BE817164Q/en not_active IP Right Cessation
- 1974-07-03 GB GB29574/74A patent/GB1480722A/en not_active Expired
- 1974-07-05 AT AT556274A patent/AT337714B/en not_active IP Right Cessation
- 1974-07-05 IE IE1434/74A patent/IE41199B1/en unknown
- 1974-07-09 DD DD179816A patent/DD115494A6/xx unknown
- 1974-07-12 CH CH967674A patent/CH614943A5/en not_active IP Right Cessation
- 1974-07-19 SU SU742047767A patent/SU644385A3/en active
- 1974-07-26 BR BR6197/74A patent/BR7406197A/en unknown
- 1974-08-09 HU HUSI1425A patent/HU169779B/hu unknown
- 1974-08-20 PL PL1974173572A patent/PL100057B1/en unknown
- 1974-10-08 ES ES430794A patent/ES430794A1/en not_active Expired
- 1974-10-21 ZA ZA00746666A patent/ZA746666B/en unknown
- 1974-10-21 ZA ZA00746665A patent/ZA746665B/en unknown
- 1974-10-25 IT IT70183/74A patent/IT1046279B/en active
-
1981
- 1981-07-18 AR AR254768A patent/AR221575A1/en active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK130293B (en) * | 1971-12-27 | 1975-02-03 | Hoechst Ag | Analogous process for the preparation of 2-carbalkoxy-amino-benzimidazole-5 (6) -phenyl ethers. |
Also Published As
| Publication number | Publication date |
|---|---|
| ES430794A1 (en) | 1977-08-01 |
| BR7406197A (en) | 1976-03-23 |
| SE7408108L (en) | 1975-12-01 |
| AT337714B (en) | 1977-07-11 |
| JPS50155612A (en) | 1975-12-16 |
| DE2431093C2 (en) | 1982-12-02 |
| BE817164Q (en) | 1975-01-02 |
| IE41199B1 (en) | 1979-11-07 |
| DK155005C (en) | 1989-06-05 |
| AR221575A1 (en) | 1981-02-27 |
| DK351774A (en) | 1975-11-29 |
| ZA746666B (en) | 1976-06-30 |
| YU181374A (en) | 1983-04-27 |
| SE414174B (en) | 1980-07-14 |
| PL100057B1 (en) | 1978-08-31 |
| HU169779B (en) | 1977-02-28 |
| ATA556274A (en) | 1976-11-15 |
| CH614943A5 (en) | 1979-12-28 |
| IT1046279B (en) | 1980-06-30 |
| RO64921A (en) | 1979-07-15 |
| ZA746665B (en) | 1976-05-26 |
| DD115494A6 (en) | 1975-10-05 |
| GB1480722A (en) | 1977-07-20 |
| IE41199L (en) | 1975-11-28 |
| CS222211B2 (en) | 1983-05-27 |
| SU644385A3 (en) | 1979-01-25 |
| YU37331B (en) | 1984-08-31 |
| DE2431093A1 (en) | 1975-12-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUP | Patent expired |