NO820865L - PROCEDURE FOR THE PREPARATION OF TIADIAZOLD DERIVATIVES - Google Patents
PROCEDURE FOR THE PREPARATION OF TIADIAZOLD DERIVATIVESInfo
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- NO820865L NO820865L NO820865A NO820865A NO820865L NO 820865 L NO820865 L NO 820865L NO 820865 A NO820865 A NO 820865A NO 820865 A NO820865 A NO 820865A NO 820865 L NO820865 L NO 820865L
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- 238000000034 method Methods 0.000 title description 9
- 238000002360 preparation method Methods 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims description 46
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 7
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 210000002845 virion Anatomy 0.000 description 5
- 239000013543 active substance Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 230000009385 viral infection Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- PTVZQOAHCSKAAS-UHFFFAOYSA-N 4-methyl-3-thiosemicarbazide Chemical compound CNC(=S)NN PTVZQOAHCSKAAS-UHFFFAOYSA-N 0.000 description 2
- -1 5-substituted 2-amino-1,3,4-thiadiazole radical Chemical class 0.000 description 2
- 208000007514 Herpes zoster Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- MURGITYSBWUQTI-UHFFFAOYSA-N fluorescin Chemical compound OC(=O)C1=CC=CC=C1C1C2=CC=C(O)C=C2OC2=CC(O)=CC=C21 MURGITYSBWUQTI-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- DDIIAJRLFATEEE-UHFFFAOYSA-N 2-methyl-1,1-dioxo-1,2-benzothiazol-3-one Chemical compound C1=CC=C2S(=O)(=O)N(C)C(=O)C2=C1 DDIIAJRLFATEEE-UHFFFAOYSA-N 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010011026 Corneal lesion Diseases 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 241001352366 Leucoma Species 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000036796 hyperbilirubinemia Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical group [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 229940069265 ophthalmic ointment Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 231100000456 subacute toxicity Toxicity 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 150000003583 thiosemicarbazides Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av tiadiazolderivater med den generelle formel The present invention relates to a method for the production of thiadiazole derivatives with the general formula
hvori R er hydrogen, metyl, , etyl, isopropyl, n-butyl eller allyl og er hydrogen, metyl eller etyl, og det særegne ved fremgangmåten i henhold til oppfinnelsen er at in which R is hydrogen, methyl, , ethyl, isopropyl, n-butyl or allyl and is hydrogen, methyl or ethyl, and the distinctive feature of the method according to the invention is that
a) en forbindelse med formela) a compound with formula
hvori har den ovennevnte betydning, reageres med fosforpentasulfid i nærvær av pyridin eller en analog organisk vannfri umettet base ved en temperatur tilstrekkelig til å danne et salt av pyridin eller den nevnte analoge base av en forbindelse med formel b) det nevnte salt reageres med substituert tio-semikarba-zid med formel wherein it has the above meaning, is reacted with phosphorus pentasulfide in the presence of pyridine or an analogous organic anhydrous unsaturated base at a temperature sufficient to form a salt of pyridine or said analogous base of a compound of formula b) said salt is reacted with substituted thio -semicarbazide of formula
hvori R har den ovennevnte betydning, i nærvær av butanol eller et analogt organisk polart løsningsmiddel ved en temperatur tilstrekkelig til å danne den tilsvarende forbindelse med(formel (I) , og wherein R has the above meaning, in the presence of butanol or an analogous organic polar solvent at a temperature sufficient to form the corresponding compound with (formula (I) , and
c) forbindelsen isoleres fra blandingen.c) the compound is isolated from the mixture.
Disse trekk ved oppfinnelsen fremgår' av patentkravet.These features of the invention appear from the patent claim.
De fremstilte forbindelser har farmasøytisk virkning og kan på spesifikk og selektiv måte motvirke virusinfeksjonene i celler av høyere dyreorganismer, f.eks. varmblodige vertebrater, inklusive mennesker. The manufactured compounds have a pharmaceutical effect and can specifically and selectively counteract the virus infections in cells of higher animal organisms, e.g. warm-blooded vertebrates, including humans.
De fremstilte kjemiske forbindelser er derivater av et 5-substituert 2-amino-l,3,4-thiadiazol-radikal. The chemical compounds produced are derivatives of a 5-substituted 2-amino-1,3,4-thiadiazole radical.
I forbindelsene kan det foreligge tautomerisk resonans mellom nitrogenatomet i -NH-R gruppen og det nærliggende nitrogenatom, i 3-stillingen av thiadiazol-radikalet, med en skifting av hydrogenatomet og av dobbeltbindingen. In the compounds, there can be tautomeric resonance between the nitrogen atom in the -NH-R group and the neighboring nitrogen atom, in the 3-position of the thiadiazole radical, with a shift of the hydrogen atom and of the double bond.
Forbindelsene fremstilles fra det velkjente o-sulfobenzoimid (forbindelse III) med et ønsket substituent i R2, The compounds are prepared from the well-known o-sulfobenzoimide (compound III) with a desired substituent in R2,
idet denne forbindelse reageres med fosforpentasulfid i nærvær av pyridin eller en annen umettet organisk base av den samme type. this compound being reacted with phosphorus pentasulphide in the presence of pyridine or another unsaturated organic base of the same type.
Det oppnådde thioderivat (forbindelse II) reageres med et passende thiosemikarbazid som i sin tur har den ønskede substituent R, idet den etterfølgende reaksjon bringes til å foregå i nærvær av n-butanol eller et annet organisk polart løsningsmiddel av en lignende type, slik at forbindelsen I oppnås. The obtained thioderivative (compound II) is reacted with a suitable thiosemicarbazide which in turn has the desired substituent R, the subsequent reaction being brought about in the presence of n-butanol or another organic polar solvent of a similar type, so that the compound In is achieved.
Rent skjematisk illustreres reaksjonen ved hjelp av følgende reaksjonsskjema The reaction is schematically illustrated using the following reaction scheme
Oppfinnelsen skal illustreres ved hjelp av de etterfølgende eksempler på fortrukne utførelsesformer. The invention shall be illustrated by means of the following examples of preferred embodiments.
EKSEMPEL 1EXAMPLE 1
Fremstilling av forbindelsen II ( R^ =H)Preparation of the compound II ( R^ =H)
0,01 mol o-sulfobenzoimid (rent sakkarin) oppløses i 30 ml vannfritt pyridin og oppløsningen reageres med 0,012 mol ^ 2S^' i^et reaksjonsblandingen kokes under tilbakeløp i 3 timer. Løsningsmidlet avdestilleres og den tørre rest ekstraheres med kloroform. Kloroformekstraktene samles og tørkes over MgSO^og deretter avdestilleres kloroform og det oppnås på nytt en tørr rest. Denne krystalliseres fra etanol og gir forbindelsen II i form av dens pyridinsalt. 0.01 mol o-sulfobenzoimide (pure saccharin) is dissolved in 30 ml of anhydrous pyridine and the solution is reacted with 0.012 mol ^ 2S^' in which the reaction mixture is boiled under reflux for 3 hours. The solvent is distilled off and the dry residue is extracted with chloroform. The chloroform extracts are collected and dried over MgSO^ and then chloroform is distilled off and a dry residue is again obtained. This is crystallized from ethanol and gives the compound II in the form of its pyridine salt.
EKSEMPEL 2 EXAMPLE 2
Fremstilling av forbindelsen II ( R^ = - CH^)Preparation of the compound II ( R^ = - CH^)
0,01 mol N-metylsakkarin oppløses i 3 ml vannfritt pyridin og oppløsningen reageres med 0, 012 mol P2^5 ^ e^- reaksjonsblandingen kokes under tilbakeløp i 3 timer. Løsningsmidlet avdestilleres og den tørre rest ekstraheres med kloroform. Kloroformekstraktene samles og tørkes over MgSO^og deretter avdestilleres kloroform til på nytt å gi en tørr rest. 0.01 mol of N-methylsaccharin is dissolved in 3 ml of anhydrous pyridine and the solution is reacted with 0.012 mol of P2^5^e^- the reaction mixture is boiled under reflux for 3 hours. The solvent is distilled off and the dry residue is extracted with chloroform. The chloroform extracts are collected and dried over MgSO4 and then the chloroform is distilled off to again give a dry residue.
Denne krytalliseres fra etanol:This is crystallized from ethanol:
EKSEMPEL 3 EXAMPLE 3
Fremstilling av forbindelsen I ( R = = H)Preparation of the compound I ( R = = H)
0,0035 mol av forbindelsen II, tidligere oppnådd som pyridinsalt, oppløses i 50 ml n-butano og oppløsningen reageres med 0,0076 mol thiosemikarbazid, idet reaksjonsblandingen kokes under tilbakeløp i 3 timer under nitrogenstrøm og omrøring. Løsningsmidlet avdestilleres og resten opptas i destillert vann. Det filtreres og krystalliseres fra etanol: 0.0035 mol of the compound II, previously obtained as a pyridine salt, is dissolved in 50 ml of n-butane and the solution is reacted with 0.0076 mol of thiosemicarbazide, the reaction mixture being refluxed for 3 hours under nitrogen flow and stirring. The solvent is distilled off and the residue is taken up in distilled water. It is filtered and crystallized from ethanol:
Smeltepunkt: 228°C på Kofler-benk.Melting point: 228°C on Kofler bench.
EKSEMPEL 4 EXAMPLE 4
Fremstilling av forbindelsen I ( R = - CH^; R^ =H)Preparation of the compound I (R = - CH^; R^ =H)
0,0035 mol av forbindelsen II, tidligere oppnådd som pyridinsalt, oppløses i 50 ml n-butanol.og oppløsningen reageres med 0,0076 mol N-metylthiosemikarbazid, idet reaksjonsblandingen 0.0035 mol of the compound II, previously obtained as a pyridine salt, is dissolved in 50 ml of n-butanol, and the solution is reacted with 0.0076 mol of N-methylthiosemicarbazide, the reaction mixture
kokes under tilbakeløp i 3 timer under nitrogenstrøm og om-røring. Løsningsmidlet avdestilleres og resten opptas i refluxed for 3 hours under nitrogen flow and stirring. The solvent is distilled off and the residue absorbed
destillert vann. Det filtreres og krystalliseres fra etanol: distilled water. It is filtered and crystallized from ethanol:
EKSEMPEL 5 EXAMPLE 5
Fremstiling av forbindelsen I ( R = H; R^ = - CHj)Preparation of the compound I (R = H; R^ = - CHj)
0,035 mol av forbindelsen II (R^= -CH3) oppløses i 50 ml n-butanol og oppløsningen^reageres med 0,076 mol thiosemikarbazid idet reaksjonsblandingen kokes under tilbakeløp i 3 timer under nitrogenstrøm og omrøring. Løsningsmidlet avdestilleres og resten opptas i destillert vann. Det. filt-i 0.035 mol of the compound II (R^ = -CH 3 ) is dissolved in 50 ml of n-butanol and the solution is reacted with 0.076 mol of thiosemicarbazide while the reaction mixture is boiled under reflux for 3 hours under a stream of nitrogen and stirring. The solvent is distilled off and the residue is taken up in distilled water. The. felt-in
reres og resten opptas i destillert vann. Det filtreres og krystalliseres fra etanol: is stirred and the remainder taken up in distilled water. It is filtered and crystallized from ethanol:
EKSEMPEL 6 EXAMPLE 6
Ved å følge samme fremgangsmåter som beskrevet i de foregående eksempler ble de resterende nye forbindelser fremstilt i samsvar med oppfinnelsen ved å erstatte thiosemikarbazid. og N-metylthiosemikarbazid i de forskjellige reaks-joner med den homologe reaksjonskomponent tilsvarende det ønskede produkt. By following the same procedures as described in the preceding examples, the remaining new compounds were prepared in accordance with the invention by replacing thiosemicarbazide. and N-methylthiosemicarbazide in the various reactions with the homologous reaction component corresponding to the desired product.
I den etterfølgende tabell er sméltepunktene på Kofler-benk referert for forbindelsen I med substituenter R og/eller R^oppnådd ved å anvende tilsvarende N-alkylthiosemikarbazid. In the following table, the melting points on the Kofler bench are referenced for the compound I with substituents R and/or R^ obtained by using the corresponding N-alkylthiosemicarbazide.
I alle tilfeller ble de således oppnådde forbindelser ana-lysert og hadde elementæranalyseresultater tilsvarende de teoretiske verdier og deres IR-spektrum bekreftet den respektive struktur. In all cases, the compounds thus obtained were analyzed and had elemental analysis results corresponding to the theoretical values and their IR spectrum confirmed the respective structure.
Farmakologisk antiviralaktivitetPharmacological antiviral activity
Forbindelsene er nyttige og effektive antivirale midler i varmblodige vertebrater og i mennesker. The compounds are useful and effective antiviral agents in warm-blooded vertebrates and in humans.
Tester for antiviralaktivitet ble gjennomført ved å anvende forskjellige aktive forbindelser mot forskjellige virusstammer. Tests for antiviral activity were carried out using different active compounds against different virus strains.
I det følgende beskrives tester hvori forbindelsen G-413The following describes tests in which the compound G-413
(R = R1= H) ble anvendt.(R = R1 = H) was used.
Det ble fastslått at forbindelsen var absolutt ikke-giftig overfor celler anvendt i testene under ellers like andre be-tingelser. It was determined that the compound was absolutely non-toxic to cells used in the tests under otherwise identical conditions.
Testene ble gjennomført ved inokkulering av virus av forskjellige typer på levende celler fra forskjellige kilder som dannet de respektive kulturer i vevdyrkingskolber i henhold til metoden vel kjent for den fagkyndige. The tests were carried out by inoculating viruses of different types onto living cells from different sources which formed the respective cultures in tissue culture flasks according to the method well known to the person skilled in the art.
Viruset danner et flertall voksesteder på bunnen av vevs-dyrkingskolbene, avhengig av viruskonsentrasjonen og test-betingelsene, idet punktene lett kan sees med det blotte øye. På denne måte er det mulig å etablere kontroller. Samtidig ble det i vevs-dyrkingskolbene hvori forbindelsen ble innført, ved forskjellige konsentrasjoner, iaktatt en inhibering, som vist ved et antall voksesteder lavere enn for kontrollene. Denne inhibering ble beregnet i prosent som referert i de etterfølgende tabeller. The virus forms a plurality of growth sites on the bottom of the tissue culture flasks, depending on the virus concentration and the test conditions, the points being easily seen with the naked eye. In this way, it is possible to establish controls. At the same time, in the tissue culture flasks into which the compound was introduced, at different concentrations, an inhibition was observed, as shown by a lower number of growth sites than for the controls. This inhibition was calculated in percentage as referred to in the following tables.
Tester på antiviral aktivitet " in vitro" Tests for antiviral activity "in vitro"
Tester ble gjennomført under anvendelse av virus Herpes simplex, type 2 (HSV2) og virus Coxackie B, type 4 (C0XB4). Tests were conducted using Herpes simplex virus type 2 (HSV2) and Coxackie B virus type 4 (C0XB4).
Resultatene er gjengitt i de etterfølgende tabeller A og B. The results are reproduced in the subsequent tables A and B.
Alle kontroller i de tre tester vist seg optimale i forhold til standard-krav. All controls in the three tests proved optimal in relation to standard requirements.
Fra tabellene A og B bemerkes en meget høy prosentvis inhibering ved en dose på 10^ug G-413 for HSV2 og 5 yUg G-413 for COXB4. From Tables A and B, a very high percentage inhibition is noted at a dose of 10 µg G-413 for HSV2 and 5 µg G-413 for COXB4.
For å fastslå aktiviteten av forbindelsen G-413 "in vitro" ved en dose på 10^,ug på Herpes simplex virus type 2 for forskjellige tilførselstider ble det gjennomført en test ved innføring av forbindelsene i cellene etter virusinfeksjonen. In order to determine the activity of the compound G-413 "in vitro" at a dose of 10 µg on Herpes simplex virus type 2 for different administration times, a test was carried out by introducing the compounds into the cells after the virus infection.
Resultatene er referert i den etterfølgende tabell C.The results are referenced in the following table C.
Det sees at maksimal inhibering oppnås ved en tilførsel gjen-nomført omtrent 8 timer etter innføringen av virusinfeksjonen. It is seen that maximum inhibition is achieved by an application carried out approximately 8 hours after the introduction of the virus infection.
Test med inhibering av virion- dannelseTest with inhibition of virion formation
Aktiviteten av forbindelsen G-413 ble bedømt ved inhiberings testen for virion-produksjonen. The activity of compound G-413 was assessed by the virion production inhibition test.
En prøve inneholdende IO<6>celler ved 20°C i 1 time ble in-fisert ved et flertall infeksjoner tilsvarende 10 infiserende enheter pr. celle. Den infiserte prøve ble vasket 3 ganger i HBSS og inkubert ved 37°C. Den aktive forbindelse ble til-satt ved O.P.I. tidspunktet. Etter 24 timer ble hele kulturen frosset og tint fra -70 til +20°C 3 ganger og cellerestene ble fjernet ved sentrifugering ved 3000 omdreininger pr. minutt i 3 minutter. De virion-infiserende enheter ble bestemt ved frem-gangsmåten med titrering i plater i henhold til Dulbecco. A sample containing 10<6> cells at 20°C for 1 hour was infected by a majority of infections corresponding to 10 infecting units per cell. The infected sample was washed 3 times in HBSS and incubated at 37°C. The active compound was added at O.P.I. the time. After 24 hours, the entire culture was frozen and thawed from -70 to +20°C 3 times and the cell debris was removed by centrifugation at 3000 rpm. minute for 3 minutes. The virion-infecting units were determined by the plate titration method according to Dulbecco.
Testen ble gjennomført med forskjellige typer av virus påThe test was carried out with different types of virus on it
HEp-2 celler.HEp-2 cells.
Resultatene er referert i de følgende tabeller. The results are referenced in the following tables.
Aktivitetstester for forbindelsen G- 413 på nvre- primærceller av kaniner i forhold til HSV2 Activity tests for the compound G-413 on nvre primary cells of rabbits in relation to HSV2
Et slikt cellesystem ble selektert for gjennomføring av testene, for å differensiere aktiviteten av en konsentrasjon av forbindelsen G-413 i nærvær av forskjellige cellesystemer. Som metode ble fulgt som beskrevet i testen for inhibering av viriondannelsen illustrert i det foregående. Such a cell system was selected for carrying out the tests, in order to differentiate the activity of a concentration of the compound G-413 in the presence of different cell systems. The method was followed as described in the test for inhibition of virion formation illustrated above.
Resultatene er referert i den følgende tabell I.The results are referenced in the following Table I.
Samme test ble gjennomført med nyre-sekundære celler fra kanin YRK og resultatene er gjengitt i den etterfølgende tabell J. The same test was carried out with kidney secondary cells from rabbit YRK and the results are reproduced in the subsequent table J.
Det etterfølgende er tester på antiviral aktivitet av forbindelsene med formel I fremstilt i samsvar med oppfinnelsen, hvori substituenten R er et metylradikal (forbindelsen G-444) henholdsvis et allylradikal (forbindelsen G-445). The following are tests on the antiviral activity of the compounds of formula I prepared in accordance with the invention, in which the substituent R is a methyl radical (compound G-444) or an allyl radical (compound G-445).
Testen med Polio 1 viriondannelse på HEp-2 i nærvær av G-44 og G-445 i henhold til metoden tidligere beskrevet i testen for viriondannelse, ga resultater som gjengitt i den etterfølgende tabell K. The test of Polio 1 virion formation on HEp-2 in the presence of G-44 and G-445 according to the method previously described in the test for virion formation gave results as reproduced in the following Table K.
Tester for antiviral aktivitet " in vivo" Tests for antiviral activity "in vivo"
Aktiviteten "in vivo" av forbindelsene fremstilt i samsvar med oppfinnelsen ble bedømt for HSV2 podet på en kanin-cornea og ved iaktagelse av utviklingen av corneale lesjoner. The "in vivo" activity of the compounds prepared in accordance with the invention was assessed for HSV2 inoculated on a rabbit cornea and by observing the development of corneal lesions.
Forbindelsene som ble testet ble påført to ganger daglig og etter 8 døgn ble en endelig undersøkelse foretatt. Denne undersøkelse vist at i det venstre øye (behandlet) ble det iaktatt en fullstendig remisjon av endringen, mens i det høyre øye (ikke behandlet) utviklet de initiale dendritiske dan-nelser seg til en ulcerasjon med overliggende leucoma. I dette trinn ble dyrene drept og øynene fjernet for homogeni-enr "i r^n r\ rr eonf ri Pnrtor-i nn \7i ra 1 i r»n"nrtl /^af Kl o o=s hoet- om+" fra The compounds tested were applied twice a day and after 8 days a final examination was carried out. This examination showed that in the left eye (treated) a complete remission of the change was observed, while in the right eye (not treated) the initial dendritic formations developed into an ulceration with overlying leucoma. In this step the animals were killed and the eyes removed for homogeni-enr "i r^n r\ rr eonf ri Pnrtor-i nn \7i ra 1 i r»n"nrtl /^af Kl o o=s hoet- om+" from
Resultatene kan oppsummeres på følgende måte:The results can be summarized as follows:
Kontrolløye: innhold HSV-2 = 4xl0<6>PFU/ml.Control eye: content HSV-2 = 4xl0<6>PFU/ml.
Behandlet øye: innhold HSV-2 = lxlO<1>PFU/mlTreated eye: content HSV-2 = lxlO<1>PFU/ml
Resultatene viser at behandlingen ved den oftalmiske salve,The results show that the treatment with the ophthalmic ointment,
i tillegg til å bevirke en avbrytelse av utviklingen av den keralytiske prosess (bedømt ved foregående farging ved fluor-escin) også bevirker en inhibering, in vivo, av virusformer-ingen, som bedømt ved det forhold at i det behandlede øye var viralinnholdet lavere enn 1x10 PFU/ml. in addition to causing an interruption of the development of the kerolytic process (judged by previous staining with fluorescin) also causes an inhibition, in vivo, of virus formation, as judged by the fact that in the treated eye the viral content was lower than 1x10 PFU/ml.
Kliniske tester på antiviral aktivitetClinical tests on antiviral activity
Forutgående kliniske tester ble gjennomført med forbindelsene fremstilt i samsvar med oppfinnelsen for topisk og systemisk (oral) bruk på frivillige pasienter som led av: herpes zooster (topisk og systemisk bruk); Preliminary clinical tests were carried out with the compounds prepared in accordance with the invention for topical and systemic (oral) use on volunteer patients suffering from: herpes zoster (topical and systemic use);
viral hepatitis av type B (systemisk bruk); viral hepatitis of type B (systemic use);
onkologi (pasienter som har metastasert lunge CA og mamma CA),oncology (patients who have metastasized lung CA and mammary CA),
i en dose på 5 til 3000 mg/dag pr. os og 5 til 3000 mg/dag for topisk bruk. En terapeutisk aktivitet i sammenligning med ikke-behandlede individer ble gjennomført ved klinisk og kropps-væske-undersøkelser. For type B hepatitis ble faktisk behandlingen med de vanlige medisiner redusert med omtrent 10 døgn og samtidig returnerte standarder for SGPT og SGOT, y-globuliner, alkalisk pHA, bilirubinaemia og VES til normale verdier. in a dose of 5 to 3000 mg/day per os and 5 to 3000 mg/day for topical use. A therapeutic activity in comparison with non-treated subjects was carried out by clinical and body-fluid examinations. For type B hepatitis, treatment with the usual medications was actually reduced by approximately 10 days and at the same time standards for SGPT and SGOT, y-globulins, alkaline pHA, bilirubinaemia and VES returned to normal values.
Med hensyn til herpes zooster forsvinner vesikler<p>g smerte-symptomer i løpet av meget få dager i sammenligning med pasienter behandlet med de vanlige medisiner, som for oppnåelse av samme forsvinning av deh smertende og cutane symptomatologi, vanligvis krever omtrent 20 døgn. With regard to herpes zoster, the vesicles<p>g pain symptoms disappear within a very few days in comparison with patients treated with the usual medicines, which usually require approximately 20 days to achieve the same disappearance of deh painful and cutaneous symptomatology.
Undersøkelsen av kroppsvæskene viser ikke noe av interesse.The examination of the body fluids shows nothing of interest.
da utgangsverdiene falt til de normale. Det påpekes bare en ikke-betydningsfull økning av y-globulinene. when the output values fell to the normal ones. Only a non-significant increase in the y-globulins is noted.
I det onkologiske området viser pasienter behandlet med de farmasøytiske forbindelser fremstilt i samsvar med oppfinnelsen, ved den høyeste dosering, en høyere motstand mot overliggende bakterieinfeksjoner og følgelig bekreftes et bedre klinisk forløp ved en y-globulinøkning av T-lymfocyter og B-lymfocyter, som også indikerer en immunitetsstimulerende aktivitet av forbindelsene fremstilt i samsvar med oppfinnelsen . In the oncological area, patients treated with the pharmaceutical compounds prepared in accordance with the invention, at the highest dosage, show a higher resistance to overlying bacterial infections and consequently a better clinical course is confirmed by a γ-globulin increase of T-lymphocytes and B-lymphocytes, which also indicates an immunity-stimulating activity of the compounds produced in accordance with the invention.
Akutte qiftighetstesterAcute fertility tests
Akutt giftighet ble testet på hannmus og hunnmus av stammen Swiss, med en gjennomsnittsvekt på 20 i 2 g, på hannrotter og hunnrotter av stammen Wistar med en gjennomsnittsvekt på 150 - 10 g, og på hannhunder og hunnhunder av Beagle-rasen. Acute toxicity was tested on male and female mice of the Swiss strain, with an average weight of 20 in 2 g, on male and female rats of the Wistar strain with an average weight of 150 - 10 g, and on male and female dogs of the Beagle breed.
Forbindelsene som ble testet ble tilført oralt til grupper på 10 dyr i form av 0,0% suspensjon i "Twen 80". The compounds tested were administered orally to groups of 10 animals in the form of a 0.0% suspension in "Twen 80".
Dyrene ble holdt under observasjon i 7 døgn og bestemmelse av LDj-q ble gjennomført ved hjelp av en grafisk metode. Giftighetsveridene var høyere enn 1500 mg/kg i mus og høy-ere enn 3000 mg/kg i rotter og hunder. The animals were kept under observation for 7 days and determination of LDj-q was carried out using a graphical method. The toxicity values were higher than 1500 mg/kg in mice and higher than 3000 mg/kg in rats and dogs.
En undersøkelse av dyrene og en anatomisk-patologisk observasjon av døde dyr viser følgende forhold: den toksiske symptomatologi var overveiende av den eksiter-ende type; An examination of the animals and an anatomical-pathological observation of dead animals shows the following: the toxic symptomatology was predominantly of the exciting type;
ingen merkbare endringer ble bemerket i fordøyelseskanalen til dyrene som døde i de første 24 timer; no noticeable changes were noted in the digestive tract of the animals that died in the first 24 hours;
forskjeller i reaksjon avhenger av kjønn var av liten betydning. ( differences in reaction depending on gender were of little importance. (
Subakutte qiftiqhetstesterSubacute qiftiqhet tests
Tester med subakutt giftighet gjennomført med noen av forbindelsene i rotter og hunder for 90 døgn, ved to tilførselsmåter, med tre doseringsnivåer (fra 50 til 800 mg/kg/døgn) har vid- Tests with subacute toxicity carried out with some of the compounds in rats and dogs for 90 days, by two routes of administration, with three dosage levels (from 50 to 800 mg/kg/day) have
ere vist en lav giftighet av de samme forbindelser etter en gjentatt behandling. have shown a low toxicity of the same compounds after a repeated treatment.
De i det foregående nevnte resultater, i kombinasjon av fra-vær av giftighet av forbindelsene fremstilt i samsvar med oppfinnelsen overfor levende celler, gjør forbindelsene nyt- The previously mentioned results, in combination with the absence of toxicity of the compounds produced in accordance with the invention towards living cells, make the compounds useful
tige for behandling av virale infeksjoner av forskjellig opphav. tige for the treatment of viral infections of various origins.
For dette formål kan forbindelsene fremstilt i samsvar med oppfinnelsen anvendes som aktive midler i farmasøytiske preparater, hvori de inneholdes, sammen med farmasøytisk tålbare hjelpestoffer. For this purpose, the compounds produced in accordance with the invention can be used as active agents in pharmaceutical preparations, in which they are contained, together with pharmaceutically acceptable excipients.
Preparatene kan ha form av enhetsdoser inneholdende 5 tilThe preparations can take the form of unit doses containing 5 to
500 mg av den aktive forbindelse, for tilførsel i en mengde på 5 til 3000 mg/dag..aktivt middel. 500 mg of the active compound, for administration in an amount of 5 to 3000 mg/day..active agent.
Preparatet kan tilføres oralt i en dose inneholdende 5 tilThe preparation can be administered orally in a dose containing 5 to
500 mg aktivt middel, i en takt på 25 til 3000 mg/dag.500 mg of active agent, at a rate of 25 to 3000 mg/day.
Preparatet kan tilføres parenteralt i en dose inneholdendeThe preparation can be administered parenterally in a dose containing
5 til 50 mg aktivt middel, i en takt på 5 til 200 mg/dag.5 to 50 mg of active agent, at a rate of 5 to 200 mg/day.
De farmasøytiske preparater kan fremstilles i form avThe pharmaceutical preparations can be produced in the form of
tabletter, overtrukne tabletter, emulsjoner, pulvere, kaps-tablets, coated tablets, emulsions, powders, capsules
ler, siruper, salver, injeksjonsoppløsninger eller stikkpil-clays, syrups, ointments, injection solutions or syringes
ler for oral, parenteral, rektal eller topisk tilførsel. ler for oral, parenteral, rectal or topical administration.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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IT4704781 | 1981-03-18 |
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Publication Number | Publication Date |
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NO820865L true NO820865L (en) | 1982-09-20 |
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ID=11260668
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Application Number | Title | Priority Date | Filing Date |
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NO820865A NO820865L (en) | 1981-03-18 | 1982-03-17 | PROCEDURE FOR THE PREPARATION OF TIADIAZOLD DERIVATIVES |
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Country | Link |
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NO (1) | NO820865L (en) |
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1982
- 1982-03-17 NO NO820865A patent/NO820865L/en unknown
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