DK143849B - METHOD OF ANALOGUE FOR PREPARATION OF 5 (6) -SUBSTITUTED 1-THIAZOLINYL-2-AMINOBENZIMIDAZOLE COMPOUNDS - Google Patents
METHOD OF ANALOGUE FOR PREPARATION OF 5 (6) -SUBSTITUTED 1-THIAZOLINYL-2-AMINOBENZIMIDAZOLE COMPOUNDS Download PDFInfo
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(19) DANMARK (^)(19) DENMARK (^)
il (12) FREMLÆGGELSESSKRIFT od 143849 Bil (12) PUBLICATION OF 143849 B
DIREKTORATET FOB PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE FOB PATENT AND TRADEMARKET SYSTEM
(21) Ansøgning nr. 734/77 (51) IntCI.3 C 07 0 417/OA(21) Application No. 734/77 (51) IntCI.3 C 07 0 417 / OA
(22) Indleveringsdag 18. féb. 1977 (24) Løbedag 18. feb. 1977 (41) Aim. tilgængelig 19. aug. 1978 (44) Fremlagt 1 9 · okt · 1 981 (86) International ansøgning nr. -(86) International indleveringsdag -(85) Videreførelsesdag -(62) Stamansøgning nr. -(30) Prioritet - (71) Ansøger ELI LILLY AND COMPANY, Indianapolis, US.(22) Filing Day 18th Feb. 1977 (24) Running day Feb 18 1977 (41) Aim. available Aug. 19 1978 (44) Submitted 1 9 · Oct · 1 981 (86) International filing date - (86) International filing day - (85) Continuation day - (62) Master filing number - (30) Priority - (71) Applicant ELI LILLY AND COMPANY, Indianapolis, US.
(72) Opfinder Charles Johnson Paget, US: James Wesley Chamberlin, US: James Howard wikel, US.(72) Inventor Charles Johnson Paget, US: James Wesley Chamberlin, US: James Howard Wikel, US.
(74) Fuldmægtig Ingeniørfirmaet Hofman-Bang & Boutard.(74) Associate Engineer Hofman-Bang & Boutard.
(54) Analogifremgangsmåde til fremstil® ling af 5(6)-substituerede 1-thia= zoliny1-2-aminobenzimidazolforbin= delser.(54) Analogous procedure for the preparation of 5 (6) -substituted 1-thia = zoliny1-2-aminobenzimidazole compounds.
Forekomsten af virale sygdomstilfælde i den øvre del af luftvejs-systemet er enorm. Man har beregnet, at der findes henved 1.000.000.000 tilfælde om året i USA alene. Undersøgelser udført i England [Tyreli and Bynoe, Lancet 1» 76 (1966)3 har vist, at 74 % af personer med forkølelser var inficeret med rhinovira. Da der indtil nu er identificeret mere end 80 stammer af rhinovira, er det ikke muligt at ® udvikle en praktisk rhinovirusvaccine. Her har kemoterapien vist 5 sig at være mere velegnet.The incidence of viral disease in the upper part of the respiratory tract is enormous. It has been estimated that there are approximately 1,000,000,000 cases per year in the United States alone. Studies conducted in England [Tyreli and Bynoe, Lancet 1 »76 (1966) 3 have shown that 74% of people with a cold were infected with rhinoviruses. Since more than 80 strains of rhinoviruses have been identified so far, it is not possible to develop a practical rhinovirus vaccine. Here, chemotherapy has proved to be more suitable.
00 00 j- En kemisk forbindelses evne til at undertrykke vira in vitro vises let ved at anvende et virusplethæmningsforsøg analogt med det, der *00 00 j- The ability of a chemical compound to suppress viruses in vitro is readily demonstrated by using a virus stain inhibition assay analogous to that *
OISLAND
2 U3869 er beskrevet af Siminoff, Applied Microbiology, 9(1), 66 (1961).2 U3869 is described by Siminoff, Applied Microbiology, 9 (1), 66 (1961).
Visse thiazolinylbenzimidazol—forbindelser er beskrevet i følgende patentskrifter: I USA patentskrift nr. 3 749 717 er beskrevet l-thiazolinyl-2-(he-terocyclisk)-benzimidazoler, der er nyttige som ormemidler og anti-inflammatoriske midler.Certain thiazolinylbenzimidazole compounds are described in the following patents: US Patent No. 3,749,717 discloses 1-thiazolinyl-2- (heterocyclic) benzimidazoles useful as worms and anti-inflammatory agents.
I USA patentskrift nr. 3 825 537 er beskrevet l-thiazolinyl-2-amino-benzimidazoler, der er nyttige som ormemidler og antiinflammatoriske midler.U.S. Patent No. 3,825,537 discloses 1-thiazolinyl-2-amino-benzimidazoles useful as worms and anti-inflammatory agents.
I USA patentskrift nr. 3 833 574 er beskrevet en fremgangsmåde til fremstilling af l-thiazolinylbenzimidazolin-2-oner, der er nyttige som antiinflammatoriske midler.U.S. Patent No. 3,833,574 discloses a process for preparing 1-thiazolinylbenzimidazolin-2-ones useful as anti-inflammatory agents.
Det er et formål med opfindelsen at tilvejebringe hidtil ukendte benzimidazolforbindelser til anvendelse i farmakologiske midler til at undertrykke væksten af vira, især rhinovirus, poliovirus, Coxsackievirus, echovirus, Mengovirus og influenza.It is an object of the invention to provide novel benzimidazole compounds for use in pharmacological agents to suppress the growth of viruses, in particular rhinovirus, poliovirus, Coxsackie virus, echovirus, Mengovirus and influenza.
Opfindelsen angår således en analogifremgangsmåde til fremstilling af hidtil ukendte farmakologisk nyttige 5(6)-substituerede 1-thia-zolinyl-2-aminobenzimidazolforbindelser med den i kravets indledning anførte almene formel I, og fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del anførte .The invention thus relates to an analogous process for the preparation of novel pharmacologically useful 5 (6) -substituted 1-thiazolyl-2-aminobenzimidazole compounds of the general formula I set forth in the preamble of the invention and the process according to the invention is characterized by the characterizing part of the claim. .
Betegnelsen "tautomer benzimidazol" refererer til en 2-iminoben-zimidazol, der på begge ringnitrogenatomer indeholder et hydrogenatom. Benzimidazolreaktanten, der er usubstitueret på det ene ring-nitrogenatom, og som indeholder en substituentgruppe i 5-stillingen i benzendelen, har en tilsvarende tautomer form, der er i ligevægt hermed, hvori substituenten alternativt sidder i 6-stillingen. Den isomere blanding kan indiceres ved at nummerere de alternative positioner som 5(6).The term "tautomer benzimidazole" refers to a 2-iminobenzimidazole which contains on both ring nitrogen atoms a hydrogen atom. The benzimidazole reactant, which is unsubstituted on one ring nitrogen atom and which contains a substituent group at the 5-position of the benzene moiety, has a corresponding tautomeric equilibrium with the substituent alternatively sitting at the 6-position. The isomeric mixture can be indicated by numbering the alternative positions as 5 (6).
Betegnelsen alkyl med 1-7 carbonatomer refererer til ligekædede el- 143849 3 ler forgrenede alifatiske alkylgrupper med 1-7 carbonatomer omfattende methyl, ethyl, propyl, isopropyl, hutyl, isobutyl, sec.-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, 2,4-dimethyl- 3-pentyl, tert.-butyl, og neopentyl.The term alkyl of 1-7 carbon atoms refers to straight chain or branched chain aliphatic alkyl groups of 1-7 carbon atoms comprising methyl, ethyl, propyl, isopropyl, hutyl, isobutyl, sec.-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl , isoheptyl, 2,4-dimethyl-3-pentyl, tert-butyl, and neopentyl.
Et alkylmagnesiumhalogenid med 1-7 carbonatomer er et egnet Grig-nard-reagens. Alkyllithium med 1-7 carbonatomer fører også til et produkt, der minder om et Grignard-reagens. Foretrukne opløsningsmidler til brug i alkyleringsprocessen er inerte organiske opløsningsmidler såsom tetrahydrofuran, aromatiske opløsningsmidler såsom benzen eller toluen, og ethere såsom diethylether. Der anvendes normalt temperaturer på fra ca. 25° C til kogepunktet for opløsningsmidlet .An alkyl magnesium halide having 1-7 carbon atoms is a suitable Grigard reagent. Alkyllithium with 1-7 carbon atoms also leads to a product similar to a Grignard reagent. Preferred solvents for use in the alkylation process are inert organic solvents such as tetrahydrofuran, aromatic solvents such as benzene or toluene, and ethers such as diethyl ether. Temperatures of approx. 25 ° C to the boiling point of the solvent.
Udgangsmaterialerne med formel II fremstilles som beskrevet i dansk patentansøgning nr. 3861/76.The starting materials of formula II are prepared as described in Danish Patent Application No. 3861/76.
Thiazolinylbenzimidazolforbindelseme isoleres ved kendte metoder, såsom filtrering og koncentrering af filtratet til frembringelse af krystallisation. Alternativt kan reaktionsblandingen inddampes til tørhed og remanensen behandles med et egnet opløsningsmiddel, såsom acetone eller methanol, til fraseparering og fjernelse af uopløselige stoffer. Opløsningen indeholdende produktet koncentreres til krystallisation af produktet eller inddampes til opnåelse af en anden remanens, der omkrystalliseres fra f.eks. methanol. Benzimidazol-forbindelsen udvindes ved filtrering efter centrifugering.The thiazolinylbenzimidazole compounds are isolated by known methods such as filtration and concentration of the filtrate to produce crystallization. Alternatively, the reaction mixture can be evaporated to dryness and the residue treated with a suitable solvent, such as acetone or methanol, to separate and remove insoluble matter. The solution containing the product is concentrated to crystallize the product or evaporated to obtain another residue which is recrystallized from e.g. methanol. The benzimidazole compound is recovered by filtration after centrifugation.
5(6)-isomerene kan separeres ved fraktioneret krystallisation eller ved kolonnechromatografi. Sædvanligvis krystalliserer 6-isomeren først fra en opløsning af blandingen.The 5 (6) isomers can be separated by fractional crystallization or by column chromatography. Usually the 6 isomer crystallizes first from a solution of the mixture.
Følgende eksempler illustrerer nærmere fremstillingen af de omhandlede forbindelser med formel I. Betegnelsen m/e, der anvendes ved karakterisering af forbindelserne, referer til forholdet mellem masse og ladning af de ioner, der findes i massespektret for forbindelsen. Generelt svarer værdien til molekylvægten af hovedfraktionerne.The following examples further illustrate the preparation of the subject compounds of formula I. The term m / e used in characterizing the compounds refers to the ratio of mass to charge of the ions present in the mass spectrum of the compound. In general, the value corresponds to the molecular weight of the main fractions.
143849 4 EKSEMPEL 1 4 g (12,4 mmol) l-(thiazolin-2-yl)-2-amino-6-benzoylbenzimidazol sattes til 1000 ml tetrahydrofuran under nitrogen ved en temperatur på -10° C. Til opløsningen sattes dråbevis under nitrogen 50 ml (l,6M) n-butyllithium i hexan. Temperaturen steg til -5° C. Temperaturen af opløsningen blev holdt på -5 til 10° C i 1 time. Opløsningen opvarmedes til 25° C og holdtes ved denne temperatur i 3 timer. Opløsningen udhældtes i 1 liter vand, inddampedes, vaskedes med tetrahydrofuran og filtreredes til opnåelse af 4,56 g 1-(thiazolin-2-yl)-2-amino-6-(a-hydroxy-a-n-butylbenzyl)benzimida-zol som et hvidt stof, Imip. 206-209° C.EXAMPLE 1 4 g (12.4 mmol) of 1- (thiazolin-2-yl) -2-amino-6-benzoylbenzimidazole was added to 1000 ml of tetrahydrofuran under nitrogen at a temperature of -10 ° C. To the solution was added dropwise under nitrogen 50 ml (1.6M) of n-butyllithium in hexane. The temperature rose to -5 ° C. The temperature of the solution was kept at -5 to 10 ° C for 1 hour. The solution was heated to 25 ° C and kept at this temperature for 3 hours. The solution was poured into 1 liter of water, evaporated, washed with tetrahydrofuran and filtered to give 4.56 g of 1- (thiazolin-2-yl) -2-amino-6- (α-hydroxy-an-butylbenzyl) benzimidazole as a white substance, Imip. 206-209 ° C.
EKSEMPEL 2EXAMPLE 2
Fremgangsmåden i eksempel 1 blev gentaget, idet der anvendtes 5 g (15,5 mmol) l-(thiazolin-2-yl)-2-amino-6-benzoylbenzimidazol, 500 ml tetrahydrofuran og 50 ml (2,1M i diethylether) isopropylmagne-siumbromid, hvorved der opnåedes 1,24 g l-(thiazolin-2-yl)-2-amino- 6-(a-hydroxy-a-isopropylbenzyl)benzimidazol, smp. 212-215° C.The procedure of Example 1 was repeated using 5 g (15.5 mmol) of 1- (thiazolin-2-yl) -2-amino-6-benzoylbenzimidazole, 500 ml of tetrahydrofuran and 50 ml (2.1M in diethyl ether) isopropylmagnet -sium bromide to give 1.24 g of 1- (thiazolin-2-yl) -2-amino-6- (α-hydroxy-α-isopropylbenzyl) benzimidazole, m.p. 212-215 ° C.
EKSEMPEL 5EXAMPLE 5
Fremgangsmåden i eksempel 1 blev gentaget, idet der anvendtes'2,0 g (6,22 mmol) l-(thiazolin-2-yl)-2-amino-6-benzoyl-benzimidazol, 23 ml (1,25 M i benzen) ethyllithium og 500 ml tetrahydrofuran, hvorved der opnåedes 2,5 g l-(thiazolin-2-yl)-2-amino-6-(a-hydroxy-a-ethylbenzyl)benzimidazol, smp. 206-208° C. m/e 352.The procedure of Example 1 was repeated using 2.0 g (6.22 mmol) of 1- (thiazolin-2-yl) -2-amino-6-benzoyl-benzimidazole, 23 ml (1.25 M in benzene). ) ethyl lithium and 500 ml of tetrahydrofuran to give 2.5 g of 1- (thiazolin-2-yl) -2-amino-6- (α-hydroxy-α-ethylbenzyl) benzimidazole, m.p. 206-208 ° C m / e 352.
Afprøvningsmetodertesting Methods
Celler fra nyren af afrikanske aber (BSC-1) eller Hela-celler (5-3) dyrkedes i 25 ml Falcon-kolber ved 37° C i medium 199 med 5 % in-aktiveret oksefosterserum (FBS), penicillin (150 enheder, 1 ml) og streptomycin (150yug/ml). Når sammenflydende monolag blev dannet, fjernedes det ovenfor værende vækstmedium, og 0,3 ml af en passende fortynding af virus (echo, Mengo, Coxsackie, polio, eller rhino-virus) sattes til hver kolbe. Efter absorption i 1 time ved stue- 5 U3849 temperatur blev det med virus inficerede cellelag overhældt med et medium indeholdende én del 1 % ionagar nr. 2 og én del dobbelt-styrkemedium 199 med FBS, penicillin og streptomycin, der indeholdt den aktive forbindelse i koncentrationer på 100, 50, 25, 12, 6, 3, 1,5 og 0,75/ug pr. milliliter. Kolben, der ikke indeholdt aktiv forbindelse, tjente som kontrol ved forsøget. Stamopløsninger af thiazolinylbenzimidazol-forbindelser med formel I blev fremstillet i dimethyl sul f oxid ved en koncentration på lO^ug/ml. Kolberne inkuberedes i 72 timer ved 37° C, når det drejede sig om polio, Coxsackie, echo og Mengovirus, og 120 timer ved 32° C for rhino-virus. Influenzavira af typen Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a og Taylor C (typerne A,B) inkuberedes i 72 timer ved 37° C, idet der anvendtes MDCK celler (Madin-Darby kanin-nyreceller). Pletter kunne observeres i områder, hvor virus inficerede og blev reproduceret i cellerne. En opløsning af 10 formaldehyd og 2 % natriumacetat sattes til hver kolbe for at inaktivere virus og fiksere cellelaget til overfladen af kolben. Viruspletter blev, uanset størrelse, talt efter farvning af de omgivende celleområder med krystalviolet. Pletantallet sammenlignedes med kontrolantallet for hver koncentration af aktiv forbindelse. Aktiviteten af den omhandlede forbindelse blev udtrykt som den procentvise reduktion i pletantal eller procent inhibering. Alternativt kan koncentrationen af aktiv forbindelse angives ved symbolet I^q, hvilket angiver den koncentration, der hæmmer dannelsen af pletterne med 50 %.Cells from the kidney of African monkeys (BSC-1) or Hela cells (5-3) were cultured in 25 ml Falcon flasks at 37 ° C in medium 199 with 5% inactivated bovine serum (FBS), penicillin (150 units, 1 ml) and streptomycin (150 µg / ml). When confluent monolayers were formed, the growth medium above was removed and 0.3 ml of a suitable dilution of virus (echo, Mengo, Coxsackie, polio, or rhino virus) was added to each flask. After absorption for 1 hour at room temperature, the virus-infected cell layers were poured with a medium containing one part 1% ionagar # 2 and one part double strength medium 199 with FBS, penicillin and streptomycin containing the active compound in concentrations of 100, 50, 25, 12, 6, 3, 1.5 and 0.75 / µg per day. milliliter. The flask, which did not contain active compound, served as a control in the experiment. Stock solutions of thiazolinylbenzimidazole compounds of formula I were prepared in dimethyl sulphoxide at a concentration of 10 µg / ml. The flasks were incubated for 72 hours at 37 ° C for polio, Coxsackie, echo and Mengovirus, and 120 hours at 32 ° C for rhino virus. Influenza viruses of type Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a, and Taylor C (types A, B) were incubated for 72 hours at 37 ° C using MDCK cells (Madin-Darby rabbit kidney cells) . Stains could be observed in areas where viruses were infected and reproduced in the cells. A solution of 10 formaldehyde and 2% sodium acetate was added to each flask to inactivate the virus and fix the cell layer to the flask surface. Virus stains, regardless of size, were counted after staining the surrounding cell areas with crystal violet. The spot number was compared to the control number for each active compound concentration. The activity of the subject compound was expressed as the percentage reduction in stain number or percent inhibition. Alternatively, the concentration of active compound may be indicated by the symbol I q, which indicates the concentration which inhibits the formation of the spots by 50%.
Forsøgsresultaterne er udtrykt i form af poliovirus type I inhibering, da dette virus er let at dyrke og giver ensartede forsøgsresultater. Imidlertid er virkningen af de omhandlede forbindelser med formel I bekræftet over for andre viruskulturer, såsom Coxsackie (A9, A21, B5), echo virus (stammer 1-4), Mengo rhinovirus (25 stammer), Polio (type I, II, III), og influenza-vira, såsom Ann Arbor, Maryland B, Massachusetts B, Hong Kong A; Pr-8Å og Taylor C (typerne A,B). Forsøgsresultater for de ifølge eksemplerne 1-3 fremstillede forbindelser er anført i tabel I nedenfor og sammenlignet med forbindelsen A (l-(thiazolin-2-yl)-2-amino-5-ethoxy-carbonylbenzimidazol), som er kendt fra USA patentskrift nr.The test results are expressed in the form of poliovirus type I inhibition, as this virus is easy to grow and gives consistent test results. However, the effect of the present compounds of formula I is confirmed against other viral cultures such as Coxsackie (A9, A21, B5), echo virus (strains 1-4), Mengo rhinovirus (25 strains), Polio (type I, II, III ), and influenza viruses such as Ann Arbor, Maryland B, Massachusetts B, Hong Kong A; Pr-8Å and Taylor C (types A, B). Test results for the compounds of Examples 1-3 are set forth in Table I below and compared to Compound A (1- (thiazolin-2-yl) -2-amino-5-ethoxy-carbonylbenzimidazole), which is known from U.S. Pat. .
4 008 243. I tabellen angiver kolonne 1 en henvisning til de be- 6 143849 skrevne eksempler, i kolonne 2 er anført isomere i 5(6)-stilling, og kolonnerne 3-10 angiver reduktionen af pletter ved forskellige fortyndinger af den aktive forbindelse, nærmere bestemt fra 0,75-lOOyug pr. milliliter.In the table, column 1 gives a reference to the examples described in column 2, isomer is listed in 5 (6) position, and columns 3-10 indicate the reduction of stains at various dilutions of the active compound. , more specifically, from 0.75 to 100 µg per day. milliliter.
Tabel I Polio-I pletreduktion med 5(6)-substituerede l-thiazolin-2-yl-2-aminobenzimidazolforbin-delser.Table I Polio-I stain reduction with 5 (6) -substituted 1-thiazolin-2-yl-2-aminobenzimidazole compounds.
_Koncentration ^ug/ml)S_Concentration (µg / ml) S_
For- Isomer h bin- ¥.T 100 50 25 12 6 3 1,5 0,75 ® delse Λ * 4 ---- --——. φ eks. 3 6 toxisk toxisk lidt 86 43 19 0 0 c ______toxisk______g; eks. 1 6 toxisk toxisk toxisk to- 74 26 7 0 o __ ____xisk________ ,3 eks. 2 6 toxisk toxisk mod. 87 0 0 0 0 ______toxisk_______ A 5 100 97 74 44 0 0 0 0 5 Koncentration af aktiv forbindelse i ug pr. ml M Tallene 5 eller 6 angiver den respektive isomerPre- Isomer h bin .T 100 50 25 12 6 3 1.5 0.75 ® Distribution 4 * 4 ---- --——. φ ex 3 6 toxic toxic slightly 86 43 19 0 0 c ______toxic______g; Ex. 1 6 Toxic Toxic Toxic To- 74 26 7 0 o __ ____xic________, 3 Ex. 2 6 Toxic Toxic To. 87 0 0 0 0 ______ toxic_______ A 5 100 97 74 44 0 0 0 0 5 Concentration of active compound in µg per ml. ml M The numbers 5 or 6 indicate the respective isomer
De omhandlede 1-thiazolinylbenzimidazol-forbindelser afprøvedes både som rene forbindelser og som isomere blandinger. Begge isomere hæmmer virusvæksten, idet dog 6-isomeren generelt er mere aktiv end 5-isomeren.The present 1-thiazolinylbenzimidazole compounds were tested both as pure compounds and as isomeric mixtures. Both isomers inhibit viral growth, although the 6-isomer is generally more active than the 5-isomer.
De omhandlede forbindelser kan indgives oralt til varmblodede pattedyr og mennesker i doser på 1 til 300 mg/kg legemsvægt. Indgivelsen kan om nødvendigt gentages. Ifølge generel praksis kan den antivirale forbindelse indgives hver fjerde til sjette time.The present compounds may be administered orally to warm-blooded mammals and humans at doses of 1 to 300 mg / kg body weight. The administration may be repeated if necessary. According to general practice, the antiviral compound can be administered every four to six hours.
iin
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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DK73477A DK143849C (en) | 1977-02-18 | 1977-02-18 | METHOD OF ANALOGUE FOR PREPARATION OF 5 (6) -SUBSTITUTED 1-THIAZOLINYL-2-AMINOBENZIMIDAZOLE COMPOUNDS |
DK342979A DK148021B (en) | 1977-02-18 | 1979-08-16 | ANALOGY PROCEDURE FOR THE PREPARATION OF 5 (6) -SUBAN ANALOGY PROCEDURE FOR PREPARATION OF 5 (6) -SUBTITUATED 1-THIAZOLINYL-2-AMINOBENZIMIDAZOLFIN-SUBLINED-1-THIAZOLINED |
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DK73477A DK143849C (en) | 1977-02-18 | 1977-02-18 | METHOD OF ANALOGUE FOR PREPARATION OF 5 (6) -SUBSTITUTED 1-THIAZOLINYL-2-AMINOBENZIMIDAZOLE COMPOUNDS |
DK73477 | 1977-02-18 |
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DK73477A DK73477A (en) | 1978-08-19 |
DK143849B true DK143849B (en) | 1981-10-19 |
DK143849C DK143849C (en) | 1982-04-05 |
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