NO159529B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 3-SUBSTITUTED TETRAHYDRO-1,2,4, TRIAZINES. - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 3-SUBSTITUTED TETRAHYDRO-1,2,4, TRIAZINES. Download PDFInfo
- Publication number
- NO159529B NO159529B NO78780201A NO780201A NO159529B NO 159529 B NO159529 B NO 159529B NO 78780201 A NO78780201 A NO 78780201A NO 780201 A NO780201 A NO 780201A NO 159529 B NO159529 B NO 159529B
- Authority
- NO
- Norway
- Prior art keywords
- compound
- formula
- methyl
- hydrogen
- tetrahydro
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000003918 triazines Chemical class 0.000 title 1
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- -1 3-substituted tetrahydro-1,2,4-triazines Chemical class 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 8
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- 239000000935 antidepressant agent Substances 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 5
- 229910052723 transition metal Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
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- 239000002249 anxiolytic agent Substances 0.000 claims description 4
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- 150000002367 halogens Chemical class 0.000 claims description 3
- 230000011987 methylation Effects 0.000 claims description 3
- 238000007069 methylation reaction Methods 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 230000010933 acylation Effects 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
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- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
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- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
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- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical class C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
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- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
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- RFKMCNOHBTXSMU-UHFFFAOYSA-N methoxyflurane Chemical compound COC(F)(F)C(Cl)Cl RFKMCNOHBTXSMU-UHFFFAOYSA-N 0.000 description 1
- 229960002455 methoxyflurane Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Description
Foreliggende oppfinnelse angår fremstilling av nye 3-substituerte tetrahydro-1,2,4-triaziner med angst-og depresjonsmotvirkende aktivitet og med formelen: The present invention relates to the production of new 3-substituted tetrahydro-1,2,4-triazines with anti-anxiety and anti-depression activity and with the formula:
hvor R er hydrogen, metyl eller acetyl, F^ er hydrogen eller metyl, og A og B uavhengig av hverandre er naftyl, where R is hydrogen, methyl or acetyl, F^ is hydrogen or methyl, and A and B independently of each other are naphthyl,
1,3-benzodioksol-5-yl, fenyl eller fenyl som kan være substituert med en eller to av gruppene C-^-C^ alkyl, 1,3-benzodioxol-5-yl, phenyl or phenyl which may be substituted by one or two of the groups C-^-C^ alkyl,
<"1~C3 a-Lkoksy, halogen og naftyl, under den forutsetning at A ikke kan være fenyl når B er fenyl eller naftyl, samt farmasøytisk akseptable salter derav. <"1~C3 α-Loxy, halogen and naphthyl, under the condition that A cannot be phenyl when B is phenyl or naphthyl, as well as pharmaceutically acceptable salts thereof.
Disse nye forbindelsene har vist.seg å ha både angst- These new compounds have been shown to have both anxiety-
og depresjonsmotvirkende aktivitet når de tilføres internt til pattedyr.. Slik betegnelsen "psykoaktivt middel" er and anti-depressant activity when administered internally to mammals.. As the term "psychoactive agent" is
benyttet i foreliggende sammenheng, forstås en forbindelse med egenskaper som motvirker både angst- og depresjoner. used in the present context, means a compound with properties that counteract both anxiety and depression.
Oppfinnelsen innbefatter også fremstilling av farmasøytisk akseptable salter av de nye 3-(1,2-diaryletyl)-1,4,5,6-tetrahydro-1,2,4-triaziner, og betegnelsen "farmasøytisk akseptable salter" refererer til ikke-toksiske syre-addisjonssalter av forbindelsene, og hvor anionene er relativt ufarlige for pattedyr i de doser som brukes når man oppnår god psykoaktiv virkning, slik at den fordel-aktige effekt av de frie baser ikke skades av bivirkninger som skyldes anionene. Farmasøytisk akseptable salter innbefatter dem som er fremstilt fra mineralsyrer som saltsyre og svovelsyre, og fra organiske syrer som melke-syre, maleinsyre, ravsyre, fumarsyre, glutarsyre, sitron-syre, eplesyre, p-toluensulfonsyre, metansulfonsyre og The invention also includes the preparation of pharmaceutically acceptable salts of the new 3-(1,2-diarylethyl)-1,4,5,6-tetrahydro-1,2,4-triazines, and the term "pharmaceutically acceptable salts" refers to non- toxic acid addition salts of the compounds, and where the anions are relatively harmless to mammals in the doses used when a good psychoactive effect is achieved, so that the beneficial effect of the free bases is not damaged by side effects caused by the anions. Pharmaceutically acceptable salts include those prepared from mineral acids such as hydrochloric acid and sulfuric acid, and from organic acids such as lactic acid, maleic acid, succinic acid, fumaric acid, glutaric acid, citric acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid and
vinsyre, o.l. tartaric acid, etc.
En foretrukken gruppe nye forbindelser med formel (I) omfatter de hvor R og R-^ er hydrogen, og hvor et av sym-bolene A og B representerer substituert fenyl mens den andre representerer fenyl eller substituert fenyl hvor substituentene er valgt fra C^ C-^ alkoksy og halogen, A preferred group of new compounds of formula (I) comprises those where R and R-^ are hydrogen, and where one of the symbols A and B represents substituted phenyl while the other represents phenyl or substituted phenyl where the substituents are selected from C^C -^ alkoxy and halogen,
samt farmasøytisk akseptable salter derav. as well as pharmaceutically acceptable salts thereof.
Det er beskrevet forskjellige substituerte 1,4,5,6-tetrahydro-1,2,4-triaziner med antidepressive egenskaper i US patent nr. 3.471.486. v Various substituted 1,4,5,6-tetrahydro-1,2,4-triazines with antidepressant properties are described in US patent no. 3,471,486. v
Forbindelsen 3-(1,2-difenyletyl)-1,4,5,6-tetrahydro-1,2,4-triazin er beskrevet i litteraturen som et anti-depressivt middel, i Journal of Medical Chemistry, 12, 257, (1969). Denne forbindelse er blitt prøvet for aktivitet mot nervøsitet, og er i alt vesentlig funnet å være inaktiv. De forbindelser som er beskrevet ovenfor, er blitt fremstilt ved å reagere et imino ester-hydrohalogenid oppløst i iseddik, metanol eller etanol med et 2-aminoalkyl-hydrazin. Denne fremgangsmåte er arbeids-krevende og gir dårlig utbytte og er således uøkonomisk for kommersiell anvendelse. The compound 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine is described in the literature as an anti-depressant, in Journal of Medical Chemistry, 12, 257, ( 1969). This compound has been tested for anti-nervous activity and has been found to be essentially inactive. The compounds described above have been prepared by reacting an imino ester hydrohalide dissolved in glacial acetic acid, methanol or ethanol with a 2-aminoalkyl hydrazine. This method is labor-intensive and gives a poor yield and is thus uneconomical for commercial use.
I litteraturen er det beskrevet hvorledes syntetiserte 2-imidazoliner kan fremstilles ved en ringslutning av et diamin med et nitril i nærvær av elementært svovel. Nippon Kagaku Zasshi 1968, 89 (8), 780 (Chem. Abs. 70:19983q). In the literature, it is described how synthesized 2-imidazolines can be prepared by a ring closure of a diamine with a nitrile in the presence of elemental sulphur. Nippon Kagaku Zasshi 1968, 89 (8), 780 (Chem. Abs. 70:19983q).
Ifølge foreliggende oppfinnelse fremstilles forbindelsene med formel (I) ved at man omsetter en 2-aminoetylhydrazinforbindelse med formelen: og en nitrilforbindelse med formelen: According to the present invention, the compounds of formula (I) are prepared by reacting a 2-aminoethylhydrazine compound with the formula: and a nitrile compound with the formula:
hvor R og R1 er hydrogen eller metyl, og A og B har den ovenfor angitte betydning, i nærvær av en katalytisk mengde av et overgangsmetallsalt eller elementært svovel og, i det tilfellet det oppnås en forbindelse med formel (I) hvor R og/eller B.^ er hydrogen, så kan nevnte forbindelse omdannes til den tilsvarende forbindelse med formel (I) wherein R and R 1 are hydrogen or methyl, and A and B have the above meaning, in the presence of a catalytic amount of a transition metal salt or elemental sulfur and, in which case a compound of formula (I) is obtained wherein R and/or B.^ is hydrogen, then said compound can be converted into the corresponding compound with formula (I)
hvor R er métyl eller acetyl, og R^ er metyl, ved vanlige metylerings- eller acetyleringsmetoder, og, om ønsket, omdannelse av en således oppnådd forbindelse til et farma-søytisk akseptabelt salt derav. where R is methyl or acetyl, and R 1 is methyl, by usual methylation or acetylation methods, and, if desired, conversion of a compound thus obtained into a pharmaceutically acceptable salt thereof.
Reaksjonen mellom nitrilet og 2-aminoetylhydrazinforbindel-sen kan utføres i et egnet oppløsningsmiddelsystem, vanligvis en høytkokende alkohol, men reaksjonen kan også utføres i fravær av et oppløsningsmiddel ved kun å blande reaktantene og en katalytisk mengde av et overgangsmetallsalt eller elementær svovel. Reaksjonen skjer vanligvis raskere i fravær av oppløsningsmiddel, men når produktet fremstilles i store porsjoner, er det også ofte ønskelig å bruke noe oppløsningsmiddel for å senke viskositeten på reaktantene slik at man letter blandingen. Slik det brukes her, betegner begrepet "katalytisk mengde" en mengde av et overgangsmetallsalt eller elementært svovel som er til-strekkelig til å omdanne ekvimolare mengder av hydrazinet og nitrilet til det ønskede 1,2,4-triazinprodukt. Overgangs-metallsalter som jernklorid og sinkacetat gir tilfreds-stillende resultater. Elementært svovel er spesielt foretrukket fordi det er lett tilgjengelig og unnviker fra reaksjonsmassen slik at man i sluttproduktet bare finner spormengder av svovel. Svovel er således den foretrukne katalysator i foreliggende oppfinnelse. Reaksjonen utføres ved temperaturer fra 70 til 100°C, foretrukket ved 85-95°C. Man kan anvende lavere temperaturer, men da er reaksjonen langsommere. Temperaturer over 120°C gjør at hydrazin/- svovelkomplekset fordamper fra reaksjonsblandingen og fører til nedsatt utbytte og dannelse av store mengder urenheter. The reaction between the nitrile and the 2-aminoethylhydrazine compound can be carried out in a suitable solvent system, usually a high-boiling alcohol, but the reaction can also be carried out in the absence of a solvent by mixing only the reactants and a catalytic amount of a transition metal salt or elemental sulphur. The reaction usually occurs faster in the absence of solvent, but when the product is prepared in large portions, it is also often desirable to use some solvent to lower the viscosity of the reactants so that mixing is facilitated. As used herein, the term "catalytic amount" denotes an amount of a transition metal salt or elemental sulfur sufficient to convert equimolar amounts of the hydrazine and nitrile to the desired 1,2,4-triazine product. Transition metal salts such as ferric chloride and zinc acetate give satisfactory results. Elemental sulfur is particularly preferred because it is readily available and escapes from the reaction mass so that only trace amounts of sulfur are found in the final product. Sulfur is thus the preferred catalyst in the present invention. The reaction is carried out at temperatures from 70 to 100°C, preferably at 85-95°C. Lower temperatures can be used, but then the reaction is slower. Temperatures above 120°C cause the hydrazine/sulphur complex to evaporate from the reaction mixture and lead to a reduced yield and the formation of large amounts of impurities.
De forskjellige nitrilmellomprodukter kan fremstilles ved kjente fremgangsmåter, slik disse er beskrevet i litteraturen. Se f.eks. Synthesis 441-456, August 1973; J. Org. Chem. 36, 2948 (1971), og Tetrahedron Letters No. 14, sidene 1509-1511 (1966). Også 2-aminohydraziner kan fremstilles ved hjelp av kjente fremgangsmåter. De fremstilte tetra-hydrotriazinproduktene kan lett omdannes til hydrohalogenid-salter hvis dette er ønskelig, ved en surgjøring av et forvalgt hydrohalogenid. The various nitrile intermediates can be prepared by known methods, as described in the literature. See e.g. Synthesis 441-456, August 1973; J. Org. Chem. 36, 2948 (1971), and Tetrahedron Letters No. 14, pages 1509-1511 (1966). 2-aminohydrazines can also be prepared using known methods. The produced tetrahydrotriazine products can easily be converted into hydrohalide salts if this is desired, by acidifying a preselected hydrohalide.
Forbindelser med formel (I) hvor er metyl, og R er hydrogen, metyl eller acetyl, kan lett fremstilles fra de tilsvarende N-substituerte forbindelsene ved vanlig metyle-ring eller acetylering. Fremstillingen av 3-(1,2-difenyl-etyl) -1 , 4 , 5 , 6-tetrahydro-l , 2 , 4-triazin ble gjennomført både med eksperimentelle studier i laboratoriet og i en større produksjonsserie med store porsjoner. Compounds of formula (I) where is methyl, and R is hydrogen, methyl or acetyl, can be easily prepared from the corresponding N-substituted compounds by ordinary methylation or acetylation. The production of 3-(1,2-diphenyl-ethyl)-1,4,5,6-tetrahydro-1,2,4-triazine was carried out both with experimental studies in the laboratory and in a larger production series with large portions.
Forbindelsen 3-(1,2-difenyletyl)-1,4,5,6-tetrahydro-l,2,4-triazin kan hensiktsmessig fremstilles ved først å tilveie-bringe mellomproduktet 2,3-difenylpropionitril ved en såkalt faseovergangskatalysereaksjon som innbefatter benzylcyanid og benzylklorid i nærvær av vandig natriumhydroksyd. Reaksjoner av denne, type er vel beskrevet i litteraturen. Deretter blir nevnte 2,3-difenylpropionitril og 2-aminoetyl-etylhydrazin ringsluttet i nærvær av svovel, hvorved man får 3- (1, 2-dif enyletyl). -1,4,5, 6-tetrahydro-l, 2, 4-triazin. Triazinet kan lett omdannes til hydrohalogenidsaltet hvis dette er ønskelig ved surgjøring med et på forhånd valgt hydrohalogenid. Som nevnt ovenfor kan de nye substituerte 3-diaryletyl-tetrahydro-l,2,4-triazin-forbindelser lett fremstilles ved samme type fremgangsmåte. De nervøsitets-motvirkende og antidepressive egenskaper for de nye substituerte 3-diaryletyl-tetrahydro-l,2,4-triaziner ifølge foreliggende oppfinnelse ble bevist ved hjelp av farmako-logiske eksperimenter. The compound 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine can conveniently be prepared by first providing the intermediate product 2,3-diphenylpropionitrile by a so-called phase transition catalysis reaction involving benzyl cyanide and benzyl chloride in the presence of aqueous sodium hydroxide. Reactions of this type are well described in the literature. Next, said 2,3-diphenylpropionitrile and 2-aminoethylethylhydrazine are ring-closed in the presence of sulphur, whereby 3-(1,2-diphenylethyl) is obtained. -1,4,5,6-tetrahydro-1,2,4-triazine. The triazine can easily be converted to the hydrohalide salt if this is desired by acidification with a preselected hydrohalide. As mentioned above, the new substituted 3-diarylethyl-tetrahydro-1,2,4-triazine compounds can be easily prepared by the same type of process. The anti-anxiety and antidepressant properties of the new substituted 3-diarylethyl-tetrahydro-1,2,4-triazines according to the present invention were proven by means of pharmacological experiments.
Forbindelser som har egenskaper som motvirker nervøsitet, Compounds that have anti-anxiety properties,
vil blokkere en stressindusert hevning av serum corticosteroid-nivået, kfr. British Medical Journal, 1971 (2), sidene 310-313. Corticosteroid-nivået i stressede hann-rotter som var forbehandlet med 20 mg/kg av den aktive forbindelse gitt ved intraperitoneal injeksjon, ble sammenlignet med corticosteroid-nivåene i stressede hann-rotter som var forbehandlet med en saltoppløsning. 3 ml blod ble oppsamlet ved hjelp av en metoksyfluranbedøvelse. Etter koagulering ble blodet sentrifugert for å utskille will block a stress-induced elevation of the serum corticosteroid level, cf. British Medical Journal, 1971 (2), pages 310-313. Corticosteroid levels in stressed male rats pretreated with 20 mg/kg of the active compound given by intraperitoneal injection were compared with corticosteroid levels in stressed male rats pretreated with saline. 3 ml of blood was collected using a methoxyflurane anaesthetic. After coagulation, the blood was centrifuged to separate
det serum som ble brukt ved analyse for corticosteroider. Analysen ble utført ved å tilsette 5 ml metylenklorid til 300m ^ul av serumprøven og røre den i 15-20 sekunder. the serum used in the analysis for corticosteroids. The assay was performed by adding 5 ml of methylene chloride to 300 µl of the serum sample and stirring it for 15-20 seconds.
Prøvene ble så sentrifugert ved 41 xg i 5 minutter. Lipidlager ble fjernet ved oppsuging, og 3 ml av metylen-kloridfraksjonen ble overført til et rent rør. Denne prøve ble så tilsatt 3 ml fluoressensreagens (25% etanol og 75% konsentrert svovelsyre) og omrørt i 5 sekunder. Fluoressensutviklingen var fullstendig i løpet av 20 minutter og ble avlest i en Perkin-Elmer (<R>) fluorometer modell 204 204 ved en eksiteringsbølgelengde på 470 mu og en analyseringsbølgelengde på 53 0 mu. Denne prøve måler fri kortisol og corticosteron. Corticosteroidverdien ble beregnet på følgende måte: The samples were then centrifuged at 41 xg for 5 minutes. Lipid stock was removed by aspiration, and 3 ml of the methylene chloride fraction was transferred to a clean tube. This sample was then added to 3 ml of fluorescence reagent (25% ethanol and 75% concentrated sulfuric acid) and stirred for 5 seconds. Fluorescence development was complete within 20 minutes and was read in a Perkin-Elmer (<R>) fluorometer model 204 204 at an excitation wavelength of 470 mu and an analysis wavelength of 530 mu. This test measures free cortisol and corticosterone. The corticosteroid value was calculated as follows:
Ved å bruke denne fremgangsmåte viste det seg at forbindelser fremstilt ifølge foreliggende oppfinnelse hadde aktivitet som motvirket nervøsitet. Resultatene er vist i tabell II nedenfor. Verdier under 100% indikerer aktivitet. Den antidepressive effekt ble vist ved hjelp av Reserpin ptosis prøve. Grupper på fire mus ble tilført By using this method, it was found that compounds produced according to the present invention had activity that counteracted nervousness. The results are shown in Table II below. Values below 100% indicate activity. The antidepressant effect was shown using the Reserpin ptosis test. Groups of four mice were added
30 mg/kg kroppsvekt av 3-(1,2-diaryletyl)-1,4,5,6-tetrahydro-1,2,4-triazin-forbindelsene ved intraperitoneal injeksjon via en vandig væske. En lignende gruppe mus var kontrollgruppe og ble bare injisert den vandige væske. Etter 30 minutter ble begge gruppene injisert subkutant med 2,5 mg/kg resperin. Tilførselen av resperin til kontrollgruppen resulterte i en klassisk utvikling av symptomer som begynte med at øyelokkene (ptosis) begynte å falle igjen og kulminerte senere i en generell depresjon med nedsatt spontan motorisk aktivitet og nedsatt respons både overfor lyd og befølingsstimuli. Dyr injisert med triazin-forbindelsen ble etter 45 minutter gradert på følgende basis: ingen ptosis = 0, delvis ptosis = 1, fullstendig ptosis = 2. Fullstendig beskyttelse mot reserpin-indusert ptosis gir en verdi på null eller 100%. Prosentbeskyttelse for hver av forbindelsene er gitt i tabell 1. 30 mg/kg body weight of the 3-(1,2-diarylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine compounds by intraperitoneal injection via an aqueous liquid. A similar group of mice was the control group and was only injected with the aqueous liquid. After 30 minutes, both groups were injected subcutaneously with 2.5 mg/kg resperine. The administration of resperine to the control group resulted in a classic development of symptoms that began with the eyelids (ptosis) beginning to droop and later culminated in a general depression with decreased spontaneous motor activity and decreased response to both sound and sensory stimuli. Animals injected with the triazine compound were graded after 45 minutes on the following basis: no ptosis = 0, partial ptosis = 1, complete ptosis = 2. Complete protection against reserpine-induced ptosis gives a value of zero or 100%. Percent protection for each of the compounds is given in Table 1.
Det fremgår fra tabell 1 at forbindelsene fra eksemplene It appears from table 1 that the compounds from the examples
4, 5, 12, 13 og 17 er spesielt aktive som midler mot nervøsitet. De andre forbindelser i tabellen er noe mindre aktive enn de nevnte forbindelser, men viser betydelig aktivitet som midler mot nervøsitet. I tillegg til denne egenskap ble de følgende forbindelser også funnet å være meget aktive som antidepressive midler, og er som sådan spesielt foretrukket som psykoaktive midler, dv-s. 4, 5, 12, 13 and 17 are particularly active as remedies for nervousness. The other compounds in the table are somewhat less active than the compounds mentioned, but show significant activity as anti-nervous agents. In addition to this property, the following compounds were also found to be very active as antidepressants, and as such are particularly preferred as psychoactive agents, i.e.
som midler med både egenskaper mot nervøsitet og depresjoner: 3- (2- (4-klorfenyl)-1-fenyletyl)-1,4,5,6-tetrahydro-l,2 , 4-triazinmonohydroklorid (eksempel 5) ; as agents with both properties against nervousness and depression: 3-(2-(4-chlorophenyl)-1-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride (Example 5);
3-(1-(4-metylfenyl)-2-fenyletyl)-1,4,5,6-tetrahydro-l,2,4-triazinmonohydroklorid (eksempel 7); 3-(1-(4-methylphenyl)-2-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride (Example 7);
3-(2-(2,6-diklorfenyl)-1-fenyletyl)-1,4,5,6-tetrahydro-1,2,4-triazinmonohydroklorid (eksempel 14). 3-(2-(2,6-Dichlorophenyl)-1-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride (Example 14).
Ved behandling av angst hos pattedyr foretas administrasjon av en effektiv mengde av en forbindelse med formel (I) som motvirker angst. Med en effektiv mengde som motvirker angst, forstås en mengde av en eller flere forbindelser som vil motvirke angst i sentralnervesystemet. In the treatment of anxiety in mammals, an effective amount of a compound of formula (I) which counteracts anxiety is administered. An effective amount that counteracts anxiety is understood to mean an amount of one or more compounds that will counteract anxiety in the central nervous system.
Følgende eksempler illustrerer forbindelsen. The following examples illustrate the connection.
Eksempel 1 Example 1
Fremstilling av 3-(1,2-difenyletyl)-1,4,5,6-tetrahydro-1, 2, 4- triazlnmonohydroklorid Preparation of 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1, 2, 4-triazln monohydrochloride
Trinn 1: Et reaksjonskar bestående av en 2-liters rundkolbe utstyrt med mekanisk rører, termometer, nitrogen-tilførselsrør og tilbakeløpskjøler ble tilsatt 585 g (574 ml; 5,0 mol) benzylcyanid, 250 ml 50% natriumhydroksyd og 12,5 g Step 1: A reaction vessel consisting of a 2-liter round-bottomed flask equipped with a mechanical stirrer, thermometer, nitrogen supply tube, and reflux condenser was charged with 585 g (574 mL; 5.0 mol) of benzyl cyanide, 250 mL of 50% sodium hydroxide, and 12.5 g
(0,055 mol; 4,4 mol-%) benzyltrietylammoniumklorid. Mens temperaturen ble holdt på ca. 50°C, tilsatte man 224,4 g (1,77 mol) benzylklorid dråpevis i løpet av 1 time. Reaksjonsmassen ble omrørt i ytterligere 1 time, hvoretter man tilsatte 400 ml deionisert vann for å oppløse natrium-kloridet og få en adskillelse av de vandige og organiske lag. Hvis det på dette trinn dannet seg en emulsjon, tilsatte man etylenklorid. Det organiske lag ble destil-lert for å skille 2,3-difenylpropionitril fra de andre reaktantene og urenhetene. Identiteten av forbindelsen ble bekreftet ved elementæranalyse, NMR, IR og masse-spektrofotometri-data. (0.055 mol; 4.4 mol%) benzyltriethylammonium chloride. While the temperature was kept at approx. 50°C, 224.4 g (1.77 mol) of benzyl chloride were added dropwise over the course of 1 hour. The reaction mass was stirred for a further 1 hour, after which 400 ml of deionized water was added to dissolve the sodium chloride and obtain a separation of the aqueous and organic layers. If an emulsion formed at this stage, ethylene chloride was added. The organic layer was distilled to separate 2,3-diphenylpropionitrile from the other reactants and impurities. The identity of the compound was confirmed by elemental analysis, NMR, IR and mass spectrophotometry data.
Trinn 2: Nitrilmellomproduktet fremstilt i trinn 1 (35,0 g: 0,169 mol) ble oppvarmet under nitrogen med 0,379 g (0,012 gramatom, 7 mol-%) svovel fra ca. 70°C i en 100 ml rundkolbe inntil svovelet var oppløst, noe som tok ca. 2 timer. Reaksjonskaret ble så tilsatt 25,4 g (0, 338 mol; 2 ekv.) av 2-aminoetylhydrazin. Temperaturen ble hevet til ca. 100°C og holdt her i ca. 5 timer. Step 2: The nitrile intermediate prepared in Step 1 (35.0 g: 0.169 mol) was heated under nitrogen with 0.379 g (0.012 gram atom, 7 mol %) of sulfur from ca. 70°C in a 100 ml round bottom flask until the sulfur was dissolved, which took approx. 2 hours. To the reaction vessel was then added 25.4 g (0.338 mol; 2 equiv.) of 2-aminoethylhydrazine. The temperature was raised to approx. 100°C and held here for approx. 5 hours.
Reaksjonsmassen ble avkjølt til ca. 50°C, hvoretter man tilsatte 75 ml toluen og ekstraherte det hele med 75 ml vann. 35 ml absolutt alkohol ble tilsatt, og blandingen kokt under tilbakeløp samtidig som hydrogenklorid ble boblet igjennom massen. The reaction mass was cooled to approx. 50°C, after which 75 ml of toluene was added and the whole was extracted with 75 ml of water. 35 ml of absolute alcohol was added, and the mixture boiled under reflux while hydrogen chloride was bubbled through the mass.
Det fremstilte 3-(1,2-difenyletyl)-1,4,5,6-tetrahydro-1,2,4-triazin monohydroklorid ble utskrystallisert og fra-filtrert og så vasket med en 90/100 toluen/etanol-blanding. Produktet ble så tørket i vakuum. Elementæranalyse, røntgenkrystallografi, NMR og masse-spektrofotometri ble brukt for å bekrefte strukturen. The 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride produced was crystallized and filtered off and then washed with a 90/100 toluene/ethanol mixture. The product was then dried in vacuum. Elemental analysis, X-ray crystallography, NMR and mass spectrophotometry were used to confirm the structure.
Eksempel 2 og 3 Examples 2 and 3
Ved å bruke samme fremgangsmåte som angitt ovenfor ble følgende eksempler fremstilt, hvilke har den generelle struktur: Using the same method as stated above, the following examples were produced, which have the general structure:
hvor k er 1 eller 2. Disse forbindelser er vist tabell where k is 1 or 2. These compounds are shown in the table
II. II.
Eksempel 4 Example 4
Fremstilling av 3-(2-(4-fluorfenyl)-1-fenyletyl)-1,4,5,6-tetrahydro- 1, 2, 4- triazinmonohydroklorid Preparation of 3-(2-(4-fluorophenyl)-1-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride
En blanding inneholdende 5,0 g 1-fenyl-2-p-fluormetyl-propionitril og 0,5 g elementær svovel ble plassert i en 50 ml rundkolbe utstyrt med en kjøler, magnetisk rører og holdt under en nitrogenatmosfære. En minimal mengde på 5 ml 2-metoksyetanol ble tilsatt, og blandingen holdt på 90°C i 2 timer for å oppløse svovelet. En oppvarmet opp-løsning ble langsomt injisert med 3,3 g 2-aminoetylhydrazin, og den resulterende blågrønne reaksjonsmassen ble holdt på 90°C i 18 timer. Massen ble så avkjølt ved å tilsette 30 ml toluen, overført til en skylletrakt, hvoretter man tilsatte ytterligere 70 ml toluen. A mixture containing 5.0 g of 1-phenyl-2-p-fluoromethyl-propionitrile and 0.5 g of elemental sulfur was placed in a 50 ml round bottom flask equipped with a condenser, magnetic stirrer and maintained under a nitrogen atmosphere. A minimal amount of 5 ml of 2-methoxyethanol was added and the mixture held at 90°C for 2 hours to dissolve the sulphur. A heated solution was slowly injected with 3.3 g of 2-aminoethylhydrazine, and the resulting blue-green reaction mass was held at 90°C for 18 hours. The mass was then cooled by adding 30 ml of toluene, transferred to a rinsing funnel, after which a further 70 ml of toluene was added.
Toluen ble vasket med vann og en mettet natriumklorid-oppløsning. Det organiske lag ble utskilt, tørket med natriumsulfat og filtrert. Tørr hydrogenkloridgass ble boblet inn i toluenoppløsningen, og man fikk 3-(2-(4-fluorfenyl)-1-fenyletyl)-1,4,5,6-tetrahydro-l,2,4-triazinmonohydroklorid. Dette råproduktet ble tørket under vakuum og omkrystallisert fra.isopropanol. Saltet hadde et smeltepunkt på 220-222°C. The toluene was washed with water and a saturated sodium chloride solution. The organic layer was separated, dried with sodium sulfate and filtered. Dry hydrogen chloride gas was bubbled into the toluene solution, and 3-(2-(4-fluorophenyl)-1-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride was obtained. This crude product was dried under vacuum and recrystallized from isopropanol. The salt had a melting point of 220-222°C.
Elementæranalyse viste karbon 63,95%, hydrogen 6,0 2% og nitrogen 13,09%, sammenlignet med de teoretiske verdier på 63,84%, hydrogen 5,79% og nitrogen 13,14%. Elemental analysis showed carbon 63.95%, hydrogen 6.0 2% and nitrogen 13.09%, compared to the theoretical values of 63.84%, hydrogen 5.79% and nitrogen 13.14%.
- E ksempel 5- 18 - Example 5-18
Ved å bruke samme fremgangsmåte som angitt i eksempel 4 fremstilte man en rekke andre 3-(1,2-diaryletyl)-1,4,5,6-tetrahydro-1, 2, 4-triazi'ner med følgende generelle formel: By using the same procedure as stated in example 4, a number of other 3-(1,2-diarylethyl)-1,4,5,6-tetrahydro-1,2,4-triazines with the following general formula were prepared:
Disse forbindelser angitt i tabell III. These compounds are listed in Table III.
I tillegg ti de forbindelser som er vist i tabell III,ble det også fremstilt to forbindelser med substitusjoner på triazinringen. Disse forbindelser var følgende: Eksempel 19 In addition to the compounds shown in Table III, two compounds with substitutions on the triazine ring were also prepared. These compounds were the following: Example 19
3- (2-(4-klorfenyl)-1-fenyletyl)-1,4,5,6-tetrahydro-l-metyl-1,2,4-triazinmonohydroklorid, smp. 212-213°C. 3-(2-(4-chlorophenyl)-1-phenylethyl)-1,4,5,6-tetrahydro-1-methyl-1,2,4-triazine monohydrochloride, m.p. 212-213°C.
Eksempel 20 Example 20
4- acetyl-3-(1,2-difenyletyl)-1,4,5,6-tetrahydro-l-metyl-1,2,4-triazinmonohydroklorid, olje. 4-Acetyl-3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1-methyl-1,2,4-triazine monohydrochloride, oil.
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/761,177 US4071684A (en) | 1977-01-21 | 1977-01-21 | Process for producing 3-substituted 1,2,4-triazines |
US05/803,927 US4263295A (en) | 1977-06-06 | 1977-06-06 | Psychoactive 3-(1-2-diarylethyl)-1,4,5,6-tetrahydro-1,2,4-triazines and their method of use |
Publications (3)
Publication Number | Publication Date |
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NO780201L NO780201L (en) | 1978-07-24 |
NO159529B true NO159529B (en) | 1988-10-03 |
NO159529C NO159529C (en) | 1989-01-11 |
Family
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Application Number | Title | Priority Date | Filing Date |
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NO78780201A NO159529C (en) | 1977-01-21 | 1978-01-19 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 3-SUBSTITUTED TETRAHYDRO-1,2,4, TRIAZINES. |
Country Status (13)
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JP (1) | JPS5395987A (en) |
AT (1) | AT360032B (en) |
CH (1) | CH639080A5 (en) |
DE (1) | DE2800385A1 (en) |
DK (1) | DK152755C (en) |
ES (1) | ES466205A1 (en) |
FR (1) | FR2378019A1 (en) |
GB (1) | GB1576579A (en) |
IE (1) | IE46246B1 (en) |
IT (1) | IT1111157B (en) |
NL (1) | NL7800535A (en) |
NO (1) | NO159529C (en) |
SE (1) | SE447380B (en) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US3497509A (en) * | 1966-12-05 | 1970-02-24 | Dow Chemical Co | Imino ester method for producing 1,4,5,6-tetrahydro-as-triazine |
US3428635A (en) * | 1966-12-05 | 1969-02-18 | Dow Chemical Co | Substituted 1,4,5,6 - tetrahydro - as - triazines and a method for their production |
US3471486A (en) * | 1967-10-23 | 1969-10-07 | Dow Chemical Co | 3-aralkyl-as-triazines |
-
1978
- 1978-01-05 DE DE19782800385 patent/DE2800385A1/en active Granted
- 1978-01-17 NL NL7800535A patent/NL7800535A/en not_active Application Discontinuation
- 1978-01-17 DK DK023078A patent/DK152755C/en not_active IP Right Cessation
- 1978-01-18 IE IE115/78A patent/IE46246B1/en not_active IP Right Cessation
- 1978-01-19 IT IT19422/78A patent/IT1111157B/en active
- 1978-01-19 NO NO78780201A patent/NO159529C/en unknown
- 1978-01-19 JP JP378478A patent/JPS5395987A/en active Granted
- 1978-01-20 SE SE7800737A patent/SE447380B/en not_active IP Right Cessation
- 1978-01-20 AT AT44378A patent/AT360032B/en not_active IP Right Cessation
- 1978-01-20 CH CH65378A patent/CH639080A5/en not_active IP Right Cessation
- 1978-01-20 FR FR7801672A patent/FR2378019A1/en active Granted
- 1978-01-20 ES ES466205A patent/ES466205A1/en not_active Expired
- 1978-01-20 GB GB2389/78A patent/GB1576579A/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB1576579A (en) | 1980-10-08 |
SE447380B (en) | 1986-11-10 |
NL7800535A (en) | 1978-07-25 |
AT360032B (en) | 1980-12-10 |
DK152755B (en) | 1988-05-09 |
CH639080A5 (en) | 1983-10-31 |
DK23078A (en) | 1978-07-22 |
NO159529C (en) | 1989-01-11 |
SE7800737L (en) | 1978-07-22 |
ES466205A1 (en) | 1979-06-01 |
IE780115L (en) | 1978-07-21 |
DK152755C (en) | 1988-10-03 |
IT7819422A0 (en) | 1978-01-19 |
NO780201L (en) | 1978-07-24 |
FR2378019A1 (en) | 1978-08-18 |
JPS6241227B2 (en) | 1987-09-02 |
FR2378019B1 (en) | 1980-08-22 |
DE2800385C2 (en) | 1989-01-26 |
IE46246B1 (en) | 1983-04-06 |
IT1111157B (en) | 1986-01-13 |
JPS5395987A (en) | 1978-08-22 |
DE2800385A1 (en) | 1978-07-27 |
ATA44378A (en) | 1980-05-15 |
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