DK169267B1 - 3-Aryloxyazetidine carboxamides, pharmaceutical compositions containing these compounds, method of preparation of the compounds, and their use in the preparation of a pharmaceutical composition for the treatment of epilepsy and / or convulsions - Google Patents
3-Aryloxyazetidine carboxamides, pharmaceutical compositions containing these compounds, method of preparation of the compounds, and their use in the preparation of a pharmaceutical composition for the treatment of epilepsy and / or convulsions Download PDFInfo
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DK 169267 B1 iDK 169267 B1 i
Den foreliggende opfindelse angår hidtil ukendte 3--aryloxyazetidincarboxamider, farmaceutiske præparater indeholdende disse forbindelser, en fremgangsmåde til deres fremstilling samt anvendelsen af forbindelserne til fremstil-5 ling af et farmaceutisk præparat til behandling af epilepsi og/eller konvulsioner.The present invention relates to novel 3-aryloxyazetidine carboxamides, pharmaceutical compositions containing these compounds, a process for their preparation, and the use of the compounds for the preparation of a pharmaceutical composition for the treatment of epilepsy and / or convulsions.
Fra US-patentskrift nr. 4.226.861 kendes visse mono--N-substituerede 3-aryloxyazetidincarboxamider, som angiveligt har virkning på centralnervesystemet, specielt antikon-10 vulsivisk aktivitet og derfor er anvendelige til behandling af epilepsi. Forbindelserne har formlen R-NHC- hvor R er lavere alkyl, og R1 er hydrogen, aminocarbonyl eller trifluormethyl.U.S. Patent No. 4,226,861 discloses certain mono-N-substituted 3-aryloxyazetidine carboxamides which are reported to have effects on the central nervous system, especially anticonvulsant activity, and are therefore useful in the treatment of epilepsy. The compounds have the formula R-NHC- wherein R is lower alkyl and R 1 is hydrogen, aminocarbonyl or trifluoromethyl.
N-Usubstituerede 3-aryloxyazetidincarboxamider kendes 20 fra beskrivelsen til EP-patentansøgning nr. 102.194, hvori det anføres, at de har antikonvulsivisk aktivitet og kan anvendes til behandling af epilepsi. Disse forbindelser har formlen f’' hvor R1 er H, F, lavere alkyl, lavere alkoxy, trifluormethyl, acetyl eller aminocarbonyl.N-Unsubstituted 3-aryloxyazetidine carboxamides are known from the disclosure of European Patent Application No. 102,194, which states that they have anticonvulsant activity and can be used to treat epilepsy. These compounds have the formula f '' wherein R 1 is H, F, lower alkyl, lower alkoxy, trifluoromethyl, acetyl or aminocarbonyl.
30 Fra EP-offentliggørelsesskrift nr. 102.740 kendes N-formyl- og N-hydroxymethyl-3-phenoxy-l-azetidincarboxamider med antikonvulsiv virkning og anvendelige til behandling af epilepsi.30 EP-A-102,740 discloses N-formyl and N-hydroxymethyl-3-phenoxy-1-azetidine carboxamides having anticonvulsant effects and useful in the treatment of epilepsy.
De hidtil ukendte 3-aryloxyazetidincarboxamider ifølge 35 opfindelsen er ejendommelige ved, at de har den almene formel DK 169267 B1 2The novel 3-aryloxyazetidine carboxamides of the invention are characterized in that they have the general formula DK 169267 B1 2
Ri-NH-C—°”Ar χ 5 Rs hvor Ar er phenyl eller phenyl substitueret med chlor, brom, iod, fluor, C(1-8)-alkyl, C(l-8)-alkoxy, nitro, aminocarbonyl 10 eller trifluormethyl, R-*- er C(3-9) -cycloalkyl, allyl, 2- methyl-2-propenyl, propargyl, 2-butenyl, 3-methyl-2-butenyl, phenyl eller phenyl substitueret med fluor, chlor, brom, iod, C(1-8)-alkyl, C(1-8)-alkoxy, nitro, cyano eller CF3, og R3 er hydrogen eller C(1-8)-alkyl.R 1 -NH-C— ° Ar χ 5 R 5 where Ar is phenyl or phenyl substituted with chlorine, bromine, iodine, fluorine, C (1-8) alkyl, C (1-8) alkoxy, nitro, aminocarbonyl or trifluoromethyl, R - * - is C (3-9) -cycloalkyl, allyl, 2-methyl-2-propenyl, propargyl, 2-butenyl, 3-methyl-2-butenyl, phenyl or phenyl substituted with fluoro, chloro, bromine, iodine, C (1-8) alkyl, C (1-8) alkoxy, nitro, cyano or CF3, and R3 is hydrogen or C (1-8) alkyl.
15 Formlen I omfatter de geometriske isomere, herunder cis-, trans-, (E)- og (Z)-isomere deraf.Formula I comprises the geometric isomers including cis, trans, (E) and (Z) isomers thereof.
Udtrykket "C(1-8)-alkyl" omfatter ligekædede og forgrenede grupper på op til otte carbonatomer og er f.eks. sådanne grupper som methyl, ethyl, propyl, isopropyl, butyl, 20 sek.butyl, tert.butyl, amyl, isoamyl, hexyl, heptyl og octyl.The term "C (1-8) alkyl" encompasses straight and branched groups of up to eight carbon atoms and is e.g. such groups as methyl, ethyl, propyl, isopropyl, butyl, 20 sec.butyl, tert.butyl, amyl, isoamyl, hexyl, heptyl and octyl.
I udtrykket "C(1-8)-alkoxy" har C(1-8)-alkyl samme betydning.In the term "C (1-8) -alkoxy", C (1-8) -alkyl has the same meaning.
Udtrykket "C(3-9)-alkyl" omfatter sådanne grupper som cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl og cycloheptyl.The term "C (3-9) alkyl" includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
25 3-Aryloxyazetidincarboxamiderne ifølge opfindelsen med formlen I adskiller sig væsentligt fra de kemisk nærmest liggende 3-aryloxyazetidin-l-carboxamider, som er kendt fra US-patentskrift nr. 4.226.861 og EP 102.194 Al, og som er substitueret på amidnitrogenatomet med lavalkyl og på pheno-30 xygruppen med aminocarbonyl, lavalkyl, lavalkoxy, trifluormethyl eller acetyl. I modsætning dertil er amidnitrogenatomet i forbindelserne ifølge opfindelsen substitueret med cycloalkyl, umættede carbonhydridgrupper, eller eventuelt substitueret phenyl. Da det eksempelvis er kendt, at man 35 ved at ombytte methyl i morphin med allyl får nalorphin, som ikke er et narkotisk analgetikum, men tværtimod en nar- 3 DK 169267 B1 kotisk antagonist, kan der ikke drages konklusioner med hensyn til den farmakologiske virkning af forbindelserne ifølge opfindelsen på baggrund af ovennævnte kendte forbindelsers virkning, 5 Forbindelserne med formlen I er anvendelige som far maceutiske midler på grund af deres overraskende virkning på centralnervesystemet.The 3-aryloxyazetidine carboxamides of the invention of formula I differ substantially from the chemically closest 3-aryloxyazetidine-1-carboxamides known from U.S. Patent No. 4,226,861 and EP 102,194 A1 and which are substituted on the lower alkyl amide nitrogen atom. and on the phenoxy group with aminocarbonyl, lower alkyl, lower alkoxy, trifluoromethyl or acetyl. In contrast, the amide nitrogen atom of the compounds of the invention is substituted by cycloalkyl, unsaturated hydrocarbon groups, or optionally substituted phenyl. For example, since it is known that by substituting methyl for morphine with allyl one obtains nalorphine, which is not a narcotic analgesic but, on the contrary, a narcotic antagonist, no conclusions can be drawn as to the pharmacological effect. of the compounds of the invention in view of the effect of the above-mentioned known compounds. The compounds of formula I are useful as pharmaceutical agents because of their surprising effect on the central nervous system.
Afprøvning af forbindelserne for antikonvulsivisk aktivitet er baseret på bedømmelsesmetoder offentliggjort 10 af E.A. Swinyard i Epilepsia 10, 107-119 (1969) og i J.Testing of the compounds for anticonvulsant activity is based on assessment methods published 10 by E.A. Swinyard in Epilepsy 10, 107-119 (1969) and in J.
Pharmac. Exptl. Therap. 106, 319-330 (1952) samt andre, der vil blive forklaret mere detaljeret nedenfor. Forbindelserne udviser beskyttende aktivitet mod anfald fremkaldt både med metrazol og ved elektrisk påvirkning, og de anses derfor 15 generelt for at kunne anvendes til behandling af begge former for epilepsi, dvs. petit og grand mal former.Pharmac. Exp. Therap. 106, 319-330 (1952) as well as others which will be explained in more detail below. The compounds exhibit protective activity against seizures induced both by metrazole and by electrical influence, and are therefore generally considered to be useful in the treatment of both forms of epilepsy, viz. petite and grand mal forms.
De farmaceutiske præparater ifølge opfindelsen er ejendommelige ved, at de indeholder en forbindelse med formlen I og et farmaceutisk acceptabelt bærestof.The pharmaceutical compositions of the invention are characterized in that they contain a compound of formula I and a pharmaceutically acceptable carrier.
20 Fremgangsmåden ifølge opfindelsen til fremstilling af forbindelser med formlen I eller farmaceutisk acceptable syreadditionssalte deraf er ejendommelig ved, at man (A) omsætter en forbindelse med den almene formel 25 E-NyV-°-Ar (II) med ^ 30 a) 1¾½ = C = 0 eller w "‘Τ'1· 0 35 i hvilke formler R1, R3 og Ar har de ovenfor i forbindelse med formlen I angivne betydninger, eller (B) omsætter en forbindelse med den almene formel DK 169267 B1 4 O ^ C1-C-n")-O-Ar 5 r3 med R1NH2 i hvilke formler R1, R3 og Ar har de ovenfor i forbindelse med den almene formel I anførte betydninger, eller 10 (C) til fremstilling af m-fluorphenoxyforbindelser med den almene formel I, omsætter en forbindelse med den almene formel 15 /vThe process of the invention for the preparation of compounds of formula I or pharmaceutically acceptable acid addition salts thereof is characterized by reacting (A) a compound of general formula 25 E-NyV-°-Ar (II) with ^ 30 a) 1¾½ = C = 0 or w '' 0'1 · 0 35 in which formulas R1, R3 and Ar have the meanings given above in connection with formula I, or (B) translates a compound of general formula DK 169267 B1 4 O ^ C1 -Cn ") - O-Ar 5 R 3 with R 1 NH 2 in which formulas R 1, R 3 and Ar have the meanings set forth above for the general formula I, or 10 (C) for the preparation of m-fluorophenoxy compounds of the general formula I, translates a compound of the general formula 15 / v
Η—«Ν V-0S02WΗ— «Ν V-0S02W
J (IV) R3 20 hvori R3 har den ovenfor i forbindelse med den almene formel I anførte betydning, og W betyder methyl, phenyl eller 4--methylphenyl, med et isocyanat med formlen R1-N=C=0 25 til dannelse af en forbindelse med formlen 0J (IV) R 3 wherein R 3 is as defined above for general formula I and W is methyl, phenyl or 4-methylphenyl, with an isocyanate of formula R1-N = C = 0 compound of formula 0
R1 NH-C-N^^-0S02WR1 NH-C-N ^^ - OSO2W
30 r3 som man derpå omsætter med natriumhydrid og m-fluorphenol med formlen 35 5 DK 169267 B130 r3 which is then reacted with sodium hydride and m-fluorophenol of formula 35 DK 169267 B1
AA
OH FOH F
5 til dannelse af en forbindelse med formlen 10 ri„k-K^o-C^ i hvilke formler R1 og R3 har de ovenfor i forbindelse med den almene formel I anførte betydninger.5 to form a compound of formula 10, wherein R 1 and K 3 o C in which formulas R 1 and R 3 have the meanings set forth above in connection with general formula I.
15 Fremgangsmåden ifølge opfindelsen illustreres i ne denstående reaktionsskema: 6The process of the invention is illustrated in the following reaction scheme: 6
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DK 169267 B1DK 169267 B1
Fremgangsmådetype A Ud fra phenoxyazetidin a) 5 H-N^)v-0-Ar + R1N=C=0 -* R^NHC-nX- O-ArProcess Type A From phenoxyazetidine a) 5 H-N 2) v-O-Ar + R1N = C = O - * R 1 NHC-nX-O-Ar
R3 VR3 V
10 H-^>-0-Ar + RlHN-i!-cl_^ R^XXV0"^ R3 R3H - ^> - O-Ar + RlHN-i! -Cl_ ^ R ^ XXV0 "^ R3 R3
15 Fremgangsmådetype BMethod Type B
Via aryloxy-1-chlorcarbonylazetidin (Ar = phenyl, substitueret phenyl) ° n y\Via aryloxy-1-chlorocarbonylazetidine (Ar = phenyl, substituted phenyl) ° n y
Cl-C-/Vo-Ar + R1NHa -> R1HN-C-N \-0-Ar R3 R3Cl-C- / Vo-Ar + R1NHa -> R1HN-C-N \ -0-Ar R3 R3
Fremgangsmådetype CMethod type C
Via methan-(eller phenyl-)-sulfonylazetidinVia methane (or phenyl) sulphonylazetidine
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H-N^N—0S02W R1 -N=C=Q RLNH-C-N \-OSO£-WH-N ^ N -SO2W R1 -N = C = Q RLNH-C-N \ -OSO £ -W
R3 R3 30 W = CH3, phenyl,R 3 R 3 W = CH 3, phenyl,
J)-CH3-phenyl jO-FJ) -CH 3 -phenyl jO-F
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35 R%-C-N^)-0-^ R3 7 DK 169267 B135 R% -C-N2) - 0- ^ R3 7 DK 169267 B1
Fremgangsmåder til fremstilling af udgangsphenoxy-azetidinerne, der anvendes ved fremgangsmådetype A, er skitseret i nedenstående reaktionsskema I. Fremgangsmåder til fremstilling af udgangsaryloxy-l-carbonylazetidinerne, der 5 anvendes i fremgangsmådetype B, er skitseret i nedenstående reaktionsskema II.Methods for preparing the starting phenoxy-azetidines used in process type A are outlined in Scheme I below. Methods for preparing the starting aryloxy-1-carbonyllazetidines used in process type B are outlined in Scheme II below.
De 1-(diphenylmethyl)-3-hydroxyazetidiner, der anvendes som udgangsmaterialer ved fremgangsmådetype C (jfr. reaktionsskema III), kan fremstilles som anført af Anderson lo & Lok. i J.Org.Chem. 73, 3953 (1972) ud fra benzhydrylamin og en passende epihalogenhydrin. Cis- og trans-isomere adskilles ved hjælp af chromatografi, når de forekommer. Ud-gangs-a-methylbenzyl-3-azetidinol fremstilles ved hjælp af Tetsuya Okutani m.fl.'s metode, Chem. Pharm. Bull. bd. 22, 15 1490 (1974). Fremstillingerne 1-3 belyser fremgangsmåderne.The 1- (diphenylmethyl) -3-hydroxyazetidines used as starting materials of process type C (cf. Scheme III) can be prepared as stated by Anderson lO & Lok. in J.Org.Chem. 73, 3953 (1972) from benzhydrylamine and a suitable epihalohydrin. Cis and trans isomers are separated by chromatography as they occur. Starting α-methylbenzyl-3-azetidinol is prepared by Tetsuya Okutani et al's method, Chem. Pharm. Bull. Vol. 22, 1490 (1974). Preparations 1-3 illustrate the methods.
Reaktionsskema IScheme I
Fremstilling af 1-usubstituerede udaanqsphenoxvazetidiner R4* a.Preparation of 1-unsubstituted unsubstituted phenoxazazididines R 4 * a.
20 '"'CH-N y—1OH {se fremstilling 1) C^Hs ^ --^ CH3s°2cl^Et3 R 2) Na OH, med eller uden + ## fasekatalysator \>H°A< *** W|HaH (se fremstilling2λ jfr. også US pat.skrift 25 DMF 1 079 15120 "" CH-N y-1OH {see Preparation 1) C ^ Hs ^ - ^ CH3s ° 2cl ^ Et3 R 2) Na OH, with or without + ## phase catalyst \> H ° A <*** W | HaH (see Preparation 2λ, cf. also U.S. Patent No. 25 DMF 1,079,151
4* * X4 * * X
N-O'0-©' _. b-»/V°-0 ci% Y, el. H, + Pi(OH)e/C γ ψ (se fremstilling 3) R3 X**** 30 * R4 = CH3, phenyl eller subst. phenyl.N-O'0- © '_. b - »/ V ° -0 ci% Y, el. H, + Pi (OH) e / C γ ψ (see Preparation 3) R3 X **** 30 * R4 = CH3, phenyl or subst. phenyl.
** X er begrænset til substituenter, der er elektron fjernende, f.eks. fluor, chlor, brom, iod eller CF3.** X is limited to substituents which are electron removing, e.g. fluorine, chlorine, bromine, iodine or CF3.
*** Når X = 4-C1, 4-Br, 4-1, 4-F eller 4-CF3, er udbytterne meget lave.*** When X = 4-C1, 4-Br, 4-1, 4-F or 4-CF3, the yields are very low.
35 **** x ]ζ3η ikke være chlor, brom eller iod i produktet, da hydrogenolyse fjerner disse grupper.35 **** x] ζ3η not be chlorine, bromine or iodine in the product as hydrogenolysis removes these groups.
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8 DK 169267 B18 DK 169267 B1
Reaktionsskema IIScheme II
Fremstilling af udgangs-l-carbonyl-3-aryloxy-azetidiner R4Preparation of starting 1-carbonyl-3-aryloxy-azetidines R4
5 ^CH-N^N-OH5 ^ CH-N ^ N-OH
ce4 Xce4 X
\ + \ halogen 10 \tei \ halogen\ + \ halogen 10 \ tei \ halogen
\ NaH \ DMF\ NaH \ DMF
15 /\ yr=rv «4 Λ haloqen R X / r3 (se fremstilling i η f 0 20 reaktionsskema' I) C-Cl2 Θ15 / \ yr = rv «4 Λ halogen R X / r3 (see Preparation in η f 0 20 Reaction Scheme 'I) C-Cl2 Θ
Cl-C-N/—0Ar ίΓ 25Cl-C-N / —0Ar Γ 25
Reaktionsskema IIIScheme III
Fremstilling af udgangs-methan-(el. phenyl)-sulfonylazetidinPreparation of starting methane (or phenyl) sulfonylazetidine
*T<>“ WSOaCl R«-CH-N^N-0S02W* T <> “WSOaCl R« -CH-N ^ N-0S02W
30 ceHs NEt, * CeHs T, toluen Λ W = CH3, CqHs H2 , 4 Me-CcII.- Pd/c 6 430 ceHs NEt, * CeHs T, toluene Λ W = CH3, CqHs H2, 4 Me-CcII.- Pd / c 6 4
H-N \_0S02WH-N \ _0S02W
yy
35 I35 I
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9 DK 169267 B19 DK 169267 B1
Fremstilling 1 trans-1-(Diphenylmethyl)-2-methyl-3-azetidinol-oxalat [1 ti] En blanding af 126,4 g (0,72 mol) diphenylme-thylamin og 100 g (0,66 mol) 3-brom-l,2-epoxybutan i 300 5 ml methanol omrøres, medens det beskyttes mod lys, i 96 timer, opvarmes derpå ved tilbagesvaling i 30 timer, da farven skifter fra bleggul til dyb ravfarvet. En prøve analyseres ved ^H-NMR og viser 3 methyl-dubletter. Et fint beigefarvet bundfald fjernes ved filtrering (diphen-10 ylmethylamin-hydrobromid), og filtratet inddampes på roterende fordamper, hvilket giver 174,6 g rå olie. En prøve på 1,5 g neutraliseres og anbringes på en 4 mm tyk plade i en "Chromatotron1® og elueres med 10% ethylace-tat/toluen. Der opsamles i alt 16 fraktioner, som består 15 af 6 klare pletter ved TLC. Den største komponent, der fraskilles, er på 700 mg og synes at være trans-isomeren. Denne prøve omdannes til oxalatsaltet. Hovedkoncentratet omdannes til den frie base med ammoniumhydroxid og eks-traheres over i toluen, som tørres over magnesiumsulfat 20 og inddampes. Reaktionsremanensen opløses i methanol og behandles med 58 g oxalsyre, opvarmes, så at der fås en homogen opløsning, og får lov at køle af efter podning med en prøve af trans-oxalatsaltet. Filtrering giver 62 g hvidt granulat, smeltepunkt 147-148,5°C. Endnu et ud-25 bytte fås på 26 g. ^H-NMR-Spektrummet viser kun en enkelt CH^-dublet med j (CHg-H) på 6,1 Hz, hvilket svarer til trans-forbindelsen [Robert H. Higgins og Norman H. Cromwell, J. Hetero. Chem. 8 (6), 1059-62 (1971)]. Samlet udbytte af den i overskriften nævnte forbindelse er 30 8 8 g (38,8%) .Preparation 1 trans-1- (Diphenylmethyl) -2-methyl-3-azetidinol oxalate [1 t] A mixture of 126.4 g (0.72 mole) of diphenylmethylamine and 100 g (0.66 mole) of 3- bromo-1,2-epoxybutane in 300 ml of methanol is stirred while protected from light for 96 hours, then refluxed for 30 hours as the color changes from pale yellow to deep amber. A sample is analyzed by 1 H NMR and shows 3 methyl duplicates. A fine beige colored precipitate is removed by filtration (diphenyl-10-methylamine hydrobromide) and the filtrate is evaporated on a rotary evaporator to give 174.6 g of crude oil. A sample of 1.5 g is neutralized and placed on a 4 mm thick plate in a "Chromatotron1® and eluted with 10% ethyl acetate / toluene. A total of 16 fractions are collected, consisting of 15 clear spots by TLC. the largest component that separates is 700 mg and appears to be the trans isomer This sample is converted to the oxalate salt The main concentrate is converted to the free base with ammonium hydroxide and extracted into toluene which is dried over magnesium sulfate 20 and evaporated. in methanol and treated with 58 g of oxalic acid, heated to give a homogeneous solution and allowed to cool after inoculation with a sample of the trans-oxalate salt Filtration gives 62 g of white granulate, mp 147-148.5 ° C A further yield of 26 g is obtained. The 1 H-NMR spectrum shows only a single CH 2 doubled with j (CH 3 -H) of 6.1 Hz, which corresponds to the trans compound [Robert H. Higgins and Norman H. Cromwell, J. Hetero. Chem. 8 (6), 1059-62 (1971)]. the title compound is 30 8 8 g (38.8%).
Analyse: Beregnet for ^17^9^.02^0^: C 66,46, H 6,16, N 4,08 Fundet: C 66,38, H 6,16, N 4,07.Analysis: Calculated for C 17 17 9 O 2 O 2: C 66.46, H 6.16, N 4.08 Found: C 66.38, H 6.16, N 4.07.
35 o 10 DK 169267 B135 o 10 DK 169267 B1
Fremstilling 2 trans-1-(Diphenylmethyl)-2-methyl-3-[3-(trifluorme thyl)--phenoxyjazetidin-oxalat [1:1]Preparation 2 trans-1- (Diphenylmethyl) -2-methyl-3- [3- (trifluoromethyl) phenoxyjazetidine oxalate [1: 1]
En omrørt opslæmning af 1,2 g (0,03 mol) natri-5 umhydrid (60% dispersion i mineralolie) i 50 ml tør DMF behandles med 3,45 g (0,001 mol trans-l-diphenylmethyl--2-methylazetidin-3-ol-oxalat tilsat i små portioner.A stirred slurry of 1.2 g (0.03 mole) of sodium hydride (60% dispersion in mineral oil) in 50 ml of dry DMF is treated with 3.45 g (0.001 mole of trans-1-diphenylmethyl-2-methyllazetidine). 3-ol oxalate added in small portions.
Når tilsætningen er afsluttet, og hydrogenudviklingen er ophørt, opvarmes reaktionsblandingen til 80°C i 2 timer, 10 hvorpå der tildryppes 1,64 g (0,01 mol) 3-fluor-trifluor-methylbenzen. Reaktionsblandingen omrøres ved 80°C i y-derligere 18 timer. Reaktionsblandingen fortyndes med isvand og ekstraheres med 3 x 25 ml toluen. Ekstrakterne kombineres, tørres over magnesiumsulfat, filtreres, 15 og filtratet behandles med 1 g oxalsyre. Det opnåede faststof opsamles ved filtrering. Omkrystallisation ud fra acetone/isopropylether giver 2,2 g (4,5%) fine hvide krystaller, smeltepunkt 146-147°C. Proton-NMR viser, at det er trans-forbindelsen.When the addition is complete and hydrogen evolution has ceased, the reaction mixture is heated to 80 ° C for 2 hours, then dropping 1.64 g (0.01 mole) of 3-fluoro-trifluoro-methylbenzene. The reaction mixture is stirred at 80 ° C for another 18 hours. The reaction mixture is diluted with ice water and extracted with 3 x 25 ml of toluene. The extracts are combined, dried over magnesium sulfate, filtered, and the filtrate is treated with 1 g of oxalic acid. The solid obtained is collected by filtration. Recrystallization from acetone / isopropyl ether gives 2.2 g (4.5%) of fine white crystals, mp 146-147 ° C. Proton NMR shows that it is the trans compound.
20 Analyse: Beregnet for C24H22F3NO*C2H2°4s C 64,06, H 4,96, N 2,87 Fundet: C 64,26, H 4,99, N 2,89.Analysis: Calculated for C24H22F3NO * C2H2 ° Cs C 64.06, H 4.96, N 2.87 Found: C 64.26, H 4.99, N 2.89.
Fremstilling 3 25 trans-2-Methyl-3-[3-(trifluormethyl)phenoxy]azetidin-oxa lat [1:1]Preparation 3 trans-2-Methyl-3- [3- (trifluoromethyl) phenoxy] azetidine oxide [1: 1]
En methanol/varmt vand-opløsning af 33 g (0,068 mol) trans-l-diphenylmethyl-2-methyl-3- [ 3- (trifluormethyl) - phenoxy]azetidin-oxalat behandles med ammoniumhydroxid, 30 indtil den er basisk, og ekstraheres så med 4 x 150 ml me- thylenchlorid. De kombinerede methylenchloridekstrakter vaskes med vand, tørres over magnesiumsulfat og inddampes i vakuum til en bleggul olie. Denne olie opløses i 200 ml 190 ethanol plus 5 ml triethylamin og hydrogeneres på 35 et Parr-apparat med 3,3 g 5%:s palladium-på-trækul-kata- 2 oA methanol / hot aqueous solution of 33 g (0.068 mol) of trans-1-diphenylmethyl-2-methyl-3- [3- (trifluoromethyl) phenoxy] azetidine oxalate is treated with ammonium hydroxide until basic and extracted. then with 4 x 150 ml of methylene chloride. The combined methylene chloride extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo to a pale yellow oil. This oil is dissolved in 200 ml of 190 ethanol plus 5 ml of triethylamine and hydrogenated on a Parr apparatus with 3.3 g of 5% palladium-on-charcoal catalyst.
lysator ved et hydrogentryk på 2,8 kg/cnr atm. ved 70°Clysator at a hydrogen pressure of 2.8 kg / cm @ atm. at 70 ° C
o 11 DK 169267 B1 i 12 timer. Efter at den beregnede hydrogenmængde er blevet absorberet, fjernes katalysatoren ved filtrering, og filtratet inddampes i vakuum, hvilket giver 26,73 g råprodukt. En portion på 8 g omdannes til oxalatsaltet 5 i isopropylalkohol, hvilket giver 6,1 g fint hvidt pulver, smeltepunkt 155-156°C. Samlet udbytte ekstrapoleret ud fra den aliquote mængde omdannet til oxalatsaltet er 84% af det teoretiske.o 11 DK 169267 B1 for 12 hours. After the calculated amount of hydrogen has been absorbed, the catalyst is removed by filtration and the filtrate is evaporated in vacuo to give 26.73 g of crude product. A portion of 8 g is converted to the oxalate salt 5 in isopropyl alcohol to give 6.1 g of fine white powder, mp 155-156 ° C. Total yield extrapolated from the aliquot amount converted to the oxalate salt is 84% of theory.
Analyse: Beregnet for 02^0^: 10 - C 48,61, H 4,39, N 4,36.Analysis: Calculated for O₂O ^: 10 - C 48.61, H 4.39, N 4.36.
Fundet: C 48,67, H 4,38, N 4,34.Found: C, 48.67; H, 4.38; N, 4.34.
Opfindelsen belyses nærmere ved hjælp af nedenstående 15 eksempler.The invention is further illustrated by the following 15 examples.
Eksempel 1 N-(2-Propenyl)-3-[3-(trifluormethyl)phenoxy]-l-azetidin-20 carboxamidExample 1 N- (2-Propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine-carboxamide
En opløsning af 18,9 g (0,05 mol) rå 3-[3-(tri-fluormethyl)phenoxy]azetidin (indeholder en lige så stor molær mængde diphenylmethan) i 100 ml isopropylether omrøres under nitrogen, meden der langsomt tilsættes 4,16 25 g (0,05 mol) 2-propenylisocyanat. Reaktionsblandingen, der er noget uklar, klares, og efter en times forløb begynder der at dannes et fint krystallinsk bundfald. Efter omrøring i 18 timer fjernes produktet ved filtrering, vaskes med frisk isopropylether og lufttørres, hvilket 30 giver 9,5 g hvide krystaller, smeltepunkt 75-76°C.A solution of 18.9 g (0.05 mole) of crude 3- [3- (trifluoromethyl) phenoxy] azetidine (contains an equal molar amount of diphenylmethane) in 100 ml of isopropyl ether is stirred under nitrogen while slowly adding 4 , 16 g (0.05 mole) of 2-propenyl isocyanate. The reaction mixture, which is somewhat cloudy, is clarified, and after an hour a fine crystalline precipitate begins to form. After stirring for 18 hours, the product is removed by filtration, washed with fresh isopropyl ether and air dried to give 9.5 g of white crystals, mp 75-76 ° C.
Analyse: Beregnet for ci4Hi5F3N2°2: C 56,00, H 5,04, N 9,33.Analysis: Calculated for C 14 H 15 F 3 N 2 O 2: C 56.00, H 5.04, N 9.33.
Fundet: C 55,98, H 5,05, N 9,31.Found: C, 55.98; H, 5.05; N, 9.31.
35 .1235 .12
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DK 169267 B1DK 169267 B1
Eksempel 2 N-Cyclopropyl-3-[3-(trifluormethyl)phenoxy]-1-azetidin-carboxamidExample 2 N-Cyclopropyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En blanding af 1,9 g (0,033 mol) cyclopropyl-5 amin og 4,9 g 1,1'-carbonyldiimidazol i 60 ml tetrahy-drofuran omrøres ved omgivelsernes temperatur i en time.A mixture of 1.9 g (0.033 mol) of cyclopropyl-5amine and 4.9 g of 1,1'-carbonyldiimidazole in 60 ml of tetrahydrofuran is stirred at ambient temperature for one hour.
Den klare opløsning, der dannes, behandles med en opløsning af (0,03 mol) 3-[3-(trifluormethyl)phenoxy]azetidin i 20 ml tetrahydrofuran. Efter omrøring natten over fjernes det faste bundfald ved filtrering, hvilket giver 4,4 g gråhvidt pulver. CI-Massespektret viser en p+1 ved 381 m/e, hvilket svarer til det forventede produkt. Omkrystallisation fra benzen/ligroin giver 2,3 g lysegråt pulver, smeltepunkt 152-153°C.The clear solution formed is treated with a solution of (0.03 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine in 20 ml of tetrahydrofuran. After stirring overnight, the solid precipitate is removed by filtration to give 4.4 g of greyish white powder. The CI mass spectrum shows a p + 1 at 381 m / e, which corresponds to the expected product. Recrystallization from benzene / ligroin gives 2.3 g of light gray powder, mp 152-153 ° C.
1515
Analyse: Beregnet for ci4Hi5F3N20: C 56,00, H 5,04, N 9,33.Analysis: Calculated for C 14 H 15 F 3 N 2 O: C 56.00, H 5.04, N 9.33.
Fundet: C 55,97, H 5,07, N 9,28.Found: C, 55.97; H, 5.07; N, 9.28.
20 Eksempel 3-: N-(2-Propenyl)-3-[4-(trifluormethyl)phenoxy]-1-azetidin-carboxamidExample 3-: N- (2-Propenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En opløsning af 8,7 g (0,04 mol) rå 3-[4-(tri-fluormethyl)phenoxy]azetidin i 75 ml isopropylether om-25 røres under et nitrogentæppe, medens der tildryppes 4,2 g (0,05 mol) 2-propenylisocyanat. Efter omrøring i 3 dage udfældes der intet krystallinsk produkt. Reaktionsblandingen inddampes til en mørkerødlig olie. TLC (20% ethylacetat/methylenchlorid på silicagel) viser mindst 30 6 pletter, alle godt adskilt. Remanensen opløses i chlo roform, chromatograferes på en 350 g silicagelkolonne og elueres med chloroform, indtil den rødlige forløb er fjernet. Kolonnen elueres derpå med en ethylacetat/chlo-roform-gradient til 4% ethylacetat. Alle fraktionerne 35 kombineres og inddampes, hvilket giver 4,8 g orangefarvet olie, der krystalliserer ved henstand. Omkrystal- o 13 DK 169267 B1 lisation fra acetone/cyclohexan giver 3,3 g (27,5%) beigefarvede krystaller, smeltepunkt 91-92,5°C.A solution of 8.7 g (0.04 mole) of crude 3- [4- (trifluoromethyl) phenoxy] azetidine in 75 ml of isopropyl ether is stirred under a nitrogen blanket while dropping 4.2 g (0.05 mole) 2-propenyl isocyanate. After stirring for 3 days, no crystalline product precipitates. The reaction mixture is evaporated to a dark red oil. TLC (20% ethyl acetate / methylene chloride on silica gel) shows at least 30 6 spots, all well separated. The residue is dissolved in chloroform, chromatographed on a 350 g silica gel column and eluted with chloroform until the reddish process is removed. The column is then eluted with an ethyl acetate / chloroform gradient to 4% ethyl acetate. All the fractions 35 are combined and evaporated to give 4.8 g of orange oil which crystallizes on standing. Recrystallization from acetone / cyclohexane gives 3.3 g (27.5%) of beige crystals, mp 91-92.5 ° C.
Analyse: Beregnet for ci4Hi5F3N2°2: C 56,00, H 5,04, N 9,33.Analysis: Calculated for C 14 H 15 F 3 N 2 O 2: C 56.00, H 5.04, N 9.33.
5 Fundet: C 55,98, H 5,17, N 9,36.Found: C, 55.98; H, 5.17; N, 9.36.
Eksempel 4 N-(2-Propynyl)-3-[3-(trifluormethyl)phenoxy]-1-azetidin-carboxamid 10 En blanding af 3,9 g (0,024 mol) l,l'-carbonyl- diimidazol og 1,32 g (0,024 mol) 2-propynylamin i 50 ml tetrahydrofuran omrøres ved omgivelsernes temperatur i en time og behandles derpå med 6,2 g 3-[3-(trifluormethyl)-phenoxy]azetidin. Reaktionsblandingen behandles med 3 15 ml triethylamin og omrøres i 18 timer. Reaktionsblandingen fortyndes med et lige så stort volumen vand og filtreres, hvilket giver 8 g vådt produkt. Omkrystallisation ud fra isopropylether giver 3,8 g gråt faststof, en blanding af produkt og det symmetriske urinstof af ud-20 gangs-2-propynylaminen. Endnu en omkrystallisation fra ethanol/vand giver 2,6 g (43,6%) råprodukt, smeltepunkt 105-106°C.Example 4 N- (2-Propynyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide A mixture of 3.9 g (0.024 mol) of 1,1'-carbonyl diimidazole and 1.32 g (0.024 mol) of 2-propynylamine in 50 ml of tetrahydrofuran is stirred at ambient temperature for one hour and then treated with 6.2 g of 3- [3- (trifluoromethyl) phenoxy] azetidine. The reaction mixture is treated with 3 mL of triethylamine and stirred for 18 hours. The reaction mixture is diluted with an equal volume of water and filtered to give 8 g of wet product. Recrystallization from isopropyl ether gives 3.8 g of gray solid, a mixture of product and the symmetrical urea of the starting 2-propynylamine. Another recrystallization from ethanol / water gives 2.6 g (43.6%) of crude product, mp 105-106 ° C.
Analyse: Beregnet for : C 56,38, H 4,39, N 9,39.Analysis: Calculated for: C 56.38, H 4.39, N 9.39.
25 Fundet: C 56,32, H 4,34, N 9,44.Found: C 56.32, H 4.34, N 9.44.
Eksempel 5 N-Cyclohexyl-3-[3-(trifluormethyl)phenoxy]-1-azetidin-carboxamid 30 En omrørt blanding af 5 g (0,0163 mol) 3-[3- -(trifluormethyl)phenoxy]azetidin-oxalat og 2,04 g (0,018 mol) cyclohexylisocyanat i 50 ml tetrahydrofuran behandles med 2 ml triethylamin og omrøres derpå i 18 timer. Fortynding af blandingen med vand giver et fast 35 bundfald, som opsamles ved filtrering, hvilket giver 12 g råprodukt. Omkrystallisation fra acetone/vand giver 5 g fine hvide krystaller, smeltepunkt 148-150°C.Example 5 N-Cyclohexyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide A stirred mixture of 5 g (0.0163 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate and 2.04 g (0.018 mol) of cyclohexylisocyanate in 50 ml of tetrahydrofuran are treated with 2 ml of triethylamine and then stirred for 18 hours. Dilution of the mixture with water gives a solid 35 which is collected by filtration to give 12 g of crude product. Recrystallization from acetone / water gives 5 g of fine white crystals, mp 148-150 ° C.
1414
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DK 169267 B1 TLC (ethylacetat på silicagel) viser spor af symmetrisk cyclohexylurinstof samt produktet. Endnu en omkrystallisation fra isopropanol giver 1,65 g (29,6%) hvidt pulver, der tørres under 0,5 mm Hg—vakuum, smeltepunkt 5 153-154°C.DK 169267 B1 TLC (ethyl acetate on silica gel) shows traces of symmetrical cyclohexylurea as well as the product. Another recrystallization from isopropanol gives 1.65 g (29.6%) of white powder which is dried under 0.5 mm Hg vacuum, mp 5 153-154 ° C.
Analyse: Beregnet for ^7^21^3^2^2! C 59,64, H 6,18, N 8,18.Analysis: Calculated for ^ 7 ^ 21 ^ 3 ^ 2 ^ 2! C 59.64, H 6.18, N 8.18.
Fundet: C 59,52, H 6,20, N 8,17.Found: C 59.52, H 6.20, N 8.17.
1010
Eksempel 6 N-Cyclopropyl-3-[4-(trifluormethyl)phenoxy]-1-azetidin-carboxamidExample 6 N-Cyclopropyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En omrørt opslæmning af 4,4 g (0,027 mol) 1,1’-15 -carbonyldiimidazol i 50 ml methylenchlorid under nitro gen behandles med 1,54 g (0,027 mol) cyclopropylamin.A stirred slurry of 4.4 g (0.027 mol) of 1,1'-15-carbonyldiimidazole in 50 ml of methylene chloride under nitrogen is treated with 1.54 g (0.027 mol) of cyclopropylamine.
Efter en kort (2 min.) induktionsperiode bliver den klare opløsning pludselig eksotermisk, idet reaktionen bringes til mild tilbagesvaling. Efter 1 time, når reak-20 tionsblandingen er afkølet til omgivelsernes temperatur, tilsættes på én gang 9,6 g (0,025 mol) 3-[4-(trifluormethyl )phenoxy]azetidin, 56,66% renhed (indeholder diphe-nylmethan), og omrøringen fortsættes i 18 timer. Reaktionsblandingen inddampes på en roterende fordamper, hvil-25 ket giver en delvis krystallinsk remanens. Remanensen deles mellem 30/60 pertoleumether og vand, og det opnåede voksagtige faststof fjernes ved filtrering. Omkrystallisation ud fra isopropylether giver 5,7 g (75,9%) pladelignende sølvagtige krystaller, smeltepunkt 145-147°C.After a short (2 min) induction period, the clear solution suddenly becomes exothermic, bringing the reaction to gentle reflux. After 1 hour, when the reaction mixture has cooled to ambient temperature, at the same time 9.6 g (0.025 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine, 56.66% purity (containing diphenylmethane) is added and stirring is continued for 18 hours. The reaction mixture is evaporated on a rotary evaporator, which gives a partially crystalline residue. The residue is partitioned between 30/60 pertoleum ether and water and the obtained waxy solid is removed by filtration. Recrystallization from isopropyl ether gives 5.7 g (75.9%) of plate-like silvery crystals, mp 145-147 ° C.
30 Efter tørring ved 80°C under 0,5 mm Hg-vakuum formindskes vægten ikke, smeltepunkt 152-153°C.After drying at 80 ° C under 0.5 mm Hg vacuum, the weight does not decrease, mp 152-153 ° C.
Analyse: Beregnet for cx4Hi5F3N2°2: C 56,00, H 5,04, N 9,33.Analysis: Calculated for cx4H15F3N2 ° 2: C 56.00, H 5.04, N 9.33.
Fundet: C 55,77, H 4,98, N 9,44.Found: C, 55.77; H, 4.98; N, 9.44.
3535
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15 DK 169267 B115 DK 169267 B1
Eksempel 7 N-(2-Propynyl)-3-[4-(trifluormethyl)phenoxy]-1-azetidin-carboxamidExample 7 N- (2-Propynyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En opløsning af 4,4 g (0,027 mol) 1,11-carbon-5 yldiimidazol i 50 ml tetrahydrofuran omrøres under nitrogen, medens der tilsættes 1,49 g (0,027 mol) 2-propynyl-amin med en sprøjte og nål gennem en væg monteret i den ene hals på reaktionskolben. Efter omrøring i 2 timer tilsættes på én gang 9,6 g (0,025 mol) 3-[4-(trifluorme-10 thyl)phenoxy]azetidin (56,66% renhed, indeholder diphenyl-methan), og omrøringen fortsættes i yderligere 18 timer. Reaktionsblandingen fortyndes med isvand og ekstraheres med 30/60 petroleumether for at fjerne diphenylmethanen.A solution of 4.4 g (0.027 mol) of 1,11-carbon-5-yldiimidazole in 50 ml of tetrahydrofuran is stirred under nitrogen while adding 1.49 g (0.027 mol) of 2-propynylamine with a syringe and needle through a syringe. wall mounted in one neck of the reaction flask. After stirring for 2 hours, 9.6 g (0.025 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine (56.66% purity, containing diphenylmethane) are added at once, and stirring is continued for an additional 18 hours. hours. The reaction mixture is diluted with ice water and extracted with 30/60 petroleum ether to remove the diphenylmethane.
Den olieagtige vandige del ekstraheres med 4 x 50 ml me-15 thylenchlorid. Disse ekstrakter kombineres, tørres over natriumsulfat og inddampes til en ravfarvet olie på en roterende fordamper. Olien størkner, når den udrives med en lille mængde (50 ml) isopropylether. Filtrering giver 6,1 g rosafarvet fast produkt. TLC (10% methanol/methyl-20 enchlorid på silicagel) viser en blanding af 3 produkter og noget udgangsmateriale. Omkrystallisation fra e- j thanol/vand giver produktet i flere små fraktioner. Disse kombineres og omkrystalliseres fra isopropylether, hvilket giver 4,1 g blegt beigefarvet pulver, smeltepunkt 25 135-137°C. TLC viser stadig noget symmetrisk 2-propynyl- urinstof. Faststoffet omkrystalliseres igen fra ethan-ol/vand, hvilket giver 3,5 g (46,9%) bleggult krystallinsk produkt, smeltepunkt 140-141°C.The oily aqueous portion is extracted with 4 x 50 ml of methylene chloride. These extracts are combined, dried over sodium sulfate and evaporated to an amber oil on a rotary evaporator. The oil solidifies when applied with a small amount (50 ml) of isopropyl ether. Filtration gives 6.1 g of rose-colored solid product. TLC (10% methanol / methyl-20 enchloride on silica gel) shows a mixture of 3 products and some starting material. Recrystallization from e thanol / water gives the product in several small fractions. These are combined and recrystallized from isopropyl ether to give 4.1 g of pale beige powder, mp 135-137 ° C. TLC still shows some symmetrical 2-propynyl urea. The solid is recrystallized from ethanol / water to give 3.5 g (46.9%) of pale yellow crystalline product, mp 140-141 ° C.
Analyse: Beregnet for ci4Hi5F3N2^2: 30 C 56,38, H 4,39, N 9,39.Analysis: Calculated for C 14 H 15 F 3 N 2 2: 30 C 56.38, H 4.39, N 9.39.
Fundet; C 56,34, H 4,36, N 9,32.found; C 56.34, H 4.36, N 9.32.
3535
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16 DK 169267 B116 DK 169267 B1
Eksempel 8 N-(2-Methyl-2-propenyl)-3-[4-(trifluormethy1)phenoxy]-1--azetidincarboxamidExample 8 N- (2-Methyl-2-propenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide
En omrørt opløsning af 3,6 g (0,022 mol) 1,1'-5 -carbonyldiimidazol i 75 ml methylenchlorid under nitrogen behandles med 1,6 g (0,022 mol) 2-methyl-2-propenyl-amin (tilsættes via sprøjte og nål gennem en væg anbragt i reaktionskolbens ene hals) . Efter omrøring i en time tilsættes på én gang 6,2 g (0,02 mol) 3-[4-(trifluormeth-10 yl)phenoxy]azetidin-oxalat efterfulgt i løbet af 30 mi nutter af 5 ml triethylamin, og omrøringen fortsættes i 3 timer. Reaktionsblandingen vaskes med 2 x 25 ml vand, tørres over magnesiumsulfat og inddampes i vakuum. Den olieagtige remanens størkner ved henstand og omkrystalli-15 seres fra isopropylether, hvilket giver 3,7 g (58,9%) fine hvide krystaller, smeltepunkt 101-102°C.A stirred solution of 3.6 g (0.022 mol) of 1,1'-5-carbonyldiimidazole in 75 ml of methylene chloride under nitrogen is treated with 1.6 g (0.022 mol) of 2-methyl-2-propenylamine (syringe added). needle through a wall disposed in one neck of the reaction flask). After stirring for one hour, 6.2 g (0.02 mol) of 3- [4- (trifluoromethyl-10-yl) phenoxy] azetidine oxalate are added at once, over 30 ml of 5 ml of triethylamine, and stirring is continued. in 3 hours. The reaction mixture is washed with 2 x 25 ml of water, dried over magnesium sulfate and evaporated in vacuo. The oily residue solidifies upon standing and recrystallized from isopropyl ether to give 3.7 g (58.9%) of fine white crystals, mp 101-102 ° C.
Analyse; Beregnet for ci5Hi7F3N2°2: C 57,32, H 5,45, N 8,91.Analysis; Calcd. For c15 H17 F3 N2 ° 2: C 57.32, H 5.45, N 8.91.
Fundet; C 57,45, H 5,51, N 9,23.found; C 57.45, H 5.51, N 9.23.
2020
Eksempel 9 N- (2-Methyl-2-propenyl)-3-[3-(trifluormethyl)phenoxy]-1--azetidincarboxamid 25 En opløsning af 3,6 g (0,022 mol) 1,11-carbonyl diimidazol i 75 ml methylenchlorid omrøres under nitrogen, medens 1,6 g (0,022 mol methallylamin tilsættes med sprøjte og nål gennem en væg monteret i reaktionskolbens ene hals. Reaktionen er let eksotermisk. Reaktionsblandin-30 gen omrøres i én time, behandles så med 6,2 g (0,02 mol) 3-[3-(trifluormethyl)phenoxy]azetidin-oxalat efterfulgt 1 løbet af 0,5 time af 5 ml triethylamin, og omrøringen fortsættes i 16 timer. Reaktionsblandingen vaskes med 2 x 30 ml vand, tørres over magnesiumsulfat og inddampes 35 17Example 9 N- (2-Methyl-2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide A solution of 3.6 g (0.022 mol) of 1,11-carbonyl diimidazole in 75 ml methylene chloride is stirred under nitrogen while 1.6 g (0.022 mol of methallylamine is added with syringe and needle through a wall mounted in one neck of the reaction flask. The reaction is slightly exothermic. The reaction mixture is stirred for one hour, then treated with 6.2 g ( 0.02 moles of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate followed by 0.5 hours of 5 ml of triethylamine and stirring is continued for 16 hours. The reaction mixture is washed with 2 x 30 ml of water, dried over magnesium sulfate. and evaporated 17
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DK 169267 B1 på en roterende fordamper, hvilket giver 6,7 g olieagtig remanens, som størkner. Remanensen omkrystalliseres ΰ fra isopropylether, hvilket giver 5,4 g (85,9%) fine hvide krystaller, smeltepunkt 90-91°C.DK 169267 B1 on a rotary evaporator, giving 6.7 g of oily residue which solidifies. The residue is recrystallized ΰ from isopropyl ether to give 5.4 g (85.9%) of fine white crystals, mp 90-91 ° C.
5 Analyse: Beregnet for ci5Hi7F3N2°2: C 57,32, H 5,45, N 8,91.Analysis: Calculated for c15 H17 F3 N2 ° 2: C 57.32, H 5.45, N 8.91.
Fundet: C 57,20, H 5,50, N 8,95.Found: C 57.20, H 5.50, N 8.95.
Eksempel 10 10 N-(3-Methyl-2-butenyl)-3-[4-(trifluormethyl)phenoxy]-1- -azetidincarboxamidExample 10 N- (3-Methyl-2-butenyl) -3- [4- (trifluoromethyl) phenoxy] -1- -azetidine carboxamide
En opløsning af 3,6 g (0,022 mol) 1,1'-carbonyl-diimidazol i 100 ml methylenchlorid afkøles i ledningsvandbad, og under omrøring under nitrogen tildryppes 1,87 15 g (0,022 mol) 3-methyl-2-butenylamin. Efter omrøring i en time tilsættes på én gang 6,2 g (0,02 mol) 3-[4-(tri-fluormethyl)phenoxy]azetidin-oxalat efterfulgt i løbet af 0,5 time af 5 ml triethylamin, og omrøringen forsættes i yderligere 16 timer. Reaktionsblandingen vaskes med 20 2 x 50 ml vand, tørres over magnesiumsulfat og inddampes på en roterende fordamper, hvilket giver en halvfast remanens. Udrivning med isopropylether og filtrering giver 7 g råprodukt, som omkrystalliseres fra ethanol/ vand, hvilket giver 5,5 g (83,8%) hvide krystaller, smel-25 tepunkt 156,5-158°C.A solution of 3.6 g (0.022 mol) of 1,1'-carbonyl-diimidazole in 100 ml of methylene chloride is cooled in tap water bath and, while stirring under nitrogen, 1.87 15 g (0.022 mol) of 3-methyl-2-butenylamine are added dropwise. After stirring for one hour, 6.2 g (0.02 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate are added at once, followed by 0.5 hour of 5 ml of triethylamine, and stirring is continued. for another 16 hours. The reaction mixture is washed with 20 x 50 ml water, dried over magnesium sulfate and evaporated on a rotary evaporator to give a semi-solid residue. Purification with isopropyl ether and filtration yields 7 g of crude product which is recrystallized from ethanol / water to give 5.5 g (83.8%) of white crystals, mp 156.5-158 ° C.
Analyse: Beregnet for cxgHl9F3N202: C 58,53, H 5,83, N 8,53.Analysis: Calculated for C c cHl9F3N₂O₂: C 58.53, H 5.83, N 8.53.
Fundet: C 58,81, H 5,89, N 8,58.Found: C, 58.81; H, 5.89; N, 8.58.
30 Eksempel 11 N-(3-Methyl-2-butenyl)-3-[3-(trifluormethyl)phenoxy]-1--azetidincarboxamidExample 11 N- (3-Methyl-2-butenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide
En opløsning af 3,6 g (0,022 mol) 1,11-carbonyl--diimidazol i 100 ml tetrahydrofuran afkøles med led-35 ningsvandbad og omrøres under nitrogen, medens 1,6 g (0,022 mol) 3-methyl-2-butenylamin tilsættes med sprøj- o 18 DK 169267 B1 te og nål. Reaktionsblandingen omrøres i en time og behandles derpå med 6,2 g (0,02 mol) 3-[3-(trifluormethyl)-phenoxy]azetidin-oxalat efterfulgt i løbet af 0,5 time af 5 ml triethylamin, hvorefter omrøringen fortsættes i 5 72 timer. Reaktionsblandingen fortyndes med 500 ml is vand og ekstraheres med 6 x 50 ml methylenchlorid. De kombinerede ekstrakter vaskes med vand, tørres over magnesiumsulfat og inddampes til en fast remanens på en roterende fordamper. Omkrystallisation fra ethanol/ 10 vand giver 6 g hvide krystaller, smeltepunkt 143-144°C. Analyse: Beregnet for C^gH-^F^NjOj! C 58,53, H 5,83, N 8,53.A solution of 3.6 g (0.022 mol) of 1,11-carbonyl-diimidazole in 100 ml of tetrahydrofuran is cooled with tap water bath and stirred under nitrogen while 1.6 g (0.022 mol) of 3-methyl-2-butenylamine be added with spray 18 and 169267 B1 tea and needle. The reaction mixture is stirred for one hour and then treated with 6.2 g (0.02 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate followed by 0.5 hour of 5 ml of triethylamine, then stirring is continued. 5 72 hours. The reaction mixture is diluted with 500 ml of ice water and extracted with 6 x 50 ml of methylene chloride. The combined extracts are washed with water, dried over magnesium sulfate and evaporated to a solid residue on a rotary evaporator. Recrystallization from ethanol / 10 water gives 6 g of white crystals, mp 143-144 ° C. Analysis: Calculated for C ^ gH- ^F ^N₂O₂! C, 58.53; H, 5.83; N, 8.53.
Fundet: C 58,46, H 5,86, N 8,69.Found: C 58.46, H 5.86, N 8.69.
1515
Eksempel 12 (E)-N-(2-Butenyl)-3-[4-(trifluormethyl)phenoxy]-1-azeti-dincarboxamidExample 12 (E) -N- (2-Butenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En blanding af 3,6 g (0,022 mol) 1,1'-carbonyl--diimidazol og 1,6 g (0,022 mol) trans-crotylamin omrø- 20 res i en time, behandles derpå med 6,2 g (0,02 mol) 3—[4— -(trifluormethyl)phenoxy]azetidin-oxalat efterfulgt i løbet af 0,5 time af 5 ml triethylamin, idet omrøringen fortsættes i 16 timer. Den delvis krystallinske blanding vaskes med 2 x 50 ml vand, tørres over magnesiumsulfat og 25 inddampes pa en roterende fordamper til en fast remanens på 14,2 g. Omkrystallisation fra methanol/vand giver 5,35 g (85,1%) fine hvide krystaller, smeltepunkt 157-158°C.A mixture of 3.6 g (0.022 mol) of 1,1'-carbonyl-diimidazole and 1.6 g (0.022 mol) of trans-crotylamine is stirred for one hour, then treated with 6.2 g ( 2 mol) 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate followed by 0.5 hours of 5 ml of triethylamine, stirring being continued for 16 hours. The partially crystalline mixture is washed with 2 x 50 ml of water, dried over magnesium sulfate and evaporated on a rotary evaporator to give a solid residue of 14.2 g. Recrystallization from methanol / water gives 5.35 g (85.1%) of fine white crystals, mp 157-158 ° C.
Analyse: Beregnet for : 30 C 57,32, H 5,45, N 8,91.Analysis: Calculated for: C 57.32, H 5.45, N 8.91.
Fundet: C 57,47, H 5,49, N 9,00.Found: C 57.47, H 5.49, N 9.00.
35 19 DK 169267 B1 o35 19 DK 169267 B1 o
Eksempel 13 (E)-N-(2-Butenyl)-3-[3-(trifluormethyl)phenoxy]-1-azeti-dincarboxamidExample 13 (E) -N- (2-Butenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En opløsning af 3,6 g (0,022 mol) l,l'-carbon-5 yldiimidazol i 60 ml methylenchlorid afkøles i isbad under omrøring under nitrogen, medens der tildryppes 1,6 g (0,022 mol) trans-crotylamin. Efter opvarmning til omgivelsernes temperatur tilsættes på én gang 6,2 g (0,02 mol) 3-[3-(trifluormethyl)phenoxy]azetidin-oxalat efterfulgt 10 i løbet af 0,25 time af 5 ml triethylamin, idet omrøringen forsættes i 72 timer. Reaktionsopløsningen vaskes med 2 x 50 ml vand, tørres over magnesiumsulfat og inddampes på en roterende fordamper til en fast remanens på 7 g. Omkrystallisation fra methanol/vand giver 5,5 g 15 let gult pulver. Endnu en omkrystallisation med trækulbehandling fra isopropylether giver 3,75 g (59,7%) fine hvide krystaller, smeltepunkt 127-128°C.A solution of 3.6 g (0.022 mol) of 1,1'-carbon-5-yl diimidazole in 60 ml of methylene chloride is cooled in an ice bath while stirring under nitrogen, while dropping 1.6 g (0.022 mol) of trans-crotylamine. After heating to ambient temperature, 6.2 g (0.02 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate is added at once, followed by 0.25 hours of 5 ml of triethylamine, stirring is continued. 72 hours. The reaction solution is washed with 2 x 50 ml of water, dried over magnesium sulfate and evaporated on a rotary evaporator to give a solid residue of 7 g. Recrystallization from methanol / water gives 5.5 g of slightly yellow powder. Another recrystallization with charcoal treatment from isopropyl ether gives 3.75 g (59.7%) of fine white crystals, mp 127-128 ° C.
Analyse: Beregnet for C15H17F3N2°2i C 57,32, H 5,45, N 8,91.Analysis: Calculated for C 15 H 17 F 3 N 2 O 2 C 57.32, H 5.45, N 8.91.
^ Fundet: C 57,35, H 5,47, N 8,94.Found: C 57.35, H 5.47, N 8.94.
Eksempel 14 N-Phenyl-3-[3-(trifluormethyl)phenoxy]-1-azetidin-carbox-25 amidExample 14 N-Phenyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En omrørt opslæmning af 6,2 g (0,02 mol) 3— [3— -(trifluormethyl)phenoxy]azetidin-oxalat i 60 ml tetra-hydrofuran behandles med 5 ml triethylamin efterfulgt af 2,62 g (0,022 mol) phenylisocyanat, og omrøringen fort-30 sættes i 16 timer. Reaktionsblandingen fortyndes med vand, indtil en olie udskilles, som hurtigt størkner.A stirred slurry of 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate in 60 ml of tetrahydrofuran is treated with 5 ml of triethylamine followed by 2.62 g (0.022 mol) of phenyl isocyanate and stirring is continued for 16 hours. Dilute the reaction mixture with water until an oil is separated, which solidifies rapidly.
Det vandige tetrahydrofuran dekanteres, og den faste remanens omkrystalliseres ud fra ethanol/vand, hvilket giver 5,3 g (80,1%) hvide krystaller, smeltepunkt 137-138°C.The aqueous tetrahydrofuran is decanted and the solid residue is recrystallized from ethanol / water to give 5.3 g (80.1%) of white crystals, mp 137-138 ° C.
35 Analyse: Beregnet for ; C 60,71, H 4,50, N 8,33.Analysis: Calculated for; C, 60.71; H, 4.50; N, 8.33.
Fundet: C 60,81, H 4,47, N 8,35.Found: C, 60.81; H, 4.47; N, 8.35.
DK 169267 B1 20 oDK 169267 B1 20 o
Eksempel 15 N-Phenyl-3-[4-(trifluormethyl)phenoxy]-1-azetidin-carb-oxamldExample 15 N-Phenyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En omrørt opslæmning af 6,2 g (0,02 mol) 3— 14— 5 -(trifluormethyl)phenoxy]azetidin-oxalat og 2,62 g (0,022 mol) phenylisocyanat i 60 ml tetrahydrofuran behandles med 5 ml triethylamin, og omrøringen fortsættes i 16 timer. Reaktionsblandingen fortyndes med vand, indtil en olie udskilles. Tetrahydrofuran/vand-delen dekanteres, 10 og remanensen størkner ved henstand. Omkrystallisation fra ethanol/vand giver 3,5 g (53,4%) fine hvide krystaller, smeltepunkt 174,5-176°C.A stirred slurry of 6.2 g (0.02 mol) of 3- 14-5 - (trifluoromethyl) phenoxy] azetidine oxalate and 2.62 g (0.022 mol) of phenyl isocyanate in 60 ml of tetrahydrofuran is treated with 5 ml of triethylamine and the stirring continued for 16 hours. Dilute the reaction mixture with water until an oil is separated. The tetrahydrofuran / water portion is decanted, and the residue solidifies upon standing. Recrystallization from ethanol / water gives 3.5 g (53.4%) of fine white crystals, mp 174.5-176 ° C.
Analyse: Beregnet for ci7Hi5F3N2°2: C 60,71, H 4,50, N 8,33.Analysis: Calculated for C 17 H 15 F 3 N 2 O 2: C 60.71, H 4.50, N 8.33.
15 Fundet: C 60,91, H 4,53, N 8,35.Found: C, 60.91; H, 4.53; N, 8.35.
Eksempel 16 trans-2-Methyl-N-(2-propenyl)-3-[3-(trifluormethyl)phen-20 oxy]-1-azetidincarboxamidExample 16 trans-2-Methyl-N- (2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide
En opløsning af 6 g (0,015 mol) rå trans-2-me-thyl-3-[3-(trifluormethyl)phenoxy]azetidin (56,6%) i 50 ml tetrahydrofuran behandles med 1,54 g (0,0165 mol) 2--propenylisocyanat på én gang og omrøres under nitrogen-25 tæppe i 16 timer. Reaktionsblandingen fortyndes med vand, indtil en olie udskilles. Olien krystalliserer ikke, og efter 7 uger udrives den med 3 x 25 ml isopropylether.A solution of 6 g (0.015 mole) of crude trans-2-methyl-3- [3- (trifluoromethyl) phenoxy] azetidine (56.6%) in 50 ml of tetrahydrofuran is treated with 1.54 g (0.0165 mole) 2 - Propenyl isocyanate at once and stirred under nitrogen blanket for 16 hours. Dilute the reaction mixture with water until an oil is separated. The oil does not crystallize and after 7 weeks it is rubbed off with 3 x 25 ml of isopropyl ether.
De kombinerede triturater giver 400 mg hvide granulære krystaller (8,5%), smeltepunkt 55-57°C.The combined triturates give 400 mg of white granular crystals (8.5%), mp 55-57 ° C.
30 Analyse: Beregnet for : C 57,32, H 5,45, N 8,91.Analysis: Calculated for: C 57.32, H 5.45, N 8.91.
Fundet: C 57,36, H 5,50, N 8,97.Found: C 57.36, H 5.50, N 8.97.
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21 DK 169267 B121 DK 169267 B1
Eksempel 17.Example 17
3-(3-Chlorphenoxy)-N-(2-propenyl)-1-azetidincarboxamid En opløsning af 5,4 g (0,017 mol) 1-chlorcar-bonyl-3-(3-chlorphenoxy)azetidin i 20 ml tetrahydrofuran 5 behandles med 2,3 g (0,04 mol) 2-propenylamin og omrøres i 2 timer. Reaktionsopløsningen inddampes i vakuum til et rosa-beigefarvet faststof. Udrivning af faststoffet med vand giver efter filtrering 4,4 g råprodukt. Efter tørring omkrystalliseres faststoffet med trækulbehand-10 ling fra 2% acetone/isopropylether, hvilket giver 1,7 g (37,5%) blegt beigefarvede krystaller, smeltepunkt 87-89°C.3- (3-Chlorophenoxy) -N- (2-propenyl) -1-azetidinecarboxamide A solution of 5.4 g (0.017 mol) of 1-chlorocarbonyl-3- (3-chlorophenoxy) azetidine in 20 ml of tetrahydrofuran is treated with 2.3 g (0.04 mole) of 2-propenylamine and stirring for 2 hours. The reaction solution is evaporated in vacuo to a pink-beige solid. Purification of the solid with water gives, after filtration, 4.4 g of crude product. After drying, the solid is recrystallized from charcoal treatment from 2% acetone / isopropyl ether to give 1.7 g (37.5%) of pale beige crystals, mp 87-89 ° C.
Analyse: Beregnet for C.0H,_ClN_0o: ±J Ib Δ Δ C 58,54, H 5,67, N 10,50.Analysis: Calculated for C, H, ClCl 2 O: ± J Ib Δ Δ C 58.54, H 5.67, N 10.50.
15 Fundet: C 58,48, H 5,72, N 10,49.Found: C, 58.48; H, 5.72; N, 10.49.
Pharmakologipharmacology
Den antikonvulsiviske aktivitet bestemmes for 20 forbindelserne med formlen I ved hjælp af kemisk eller elektrisk eksposition på følgende måde:The anticonvulsant activity is determined for the compounds of formula I by chemical or electrical exposure as follows:
Kemisk "Metrazol'^rekspositicn (Swinyardmetoden)Chemical Metrazole Series Positic (Swinyard Method)
Grupper på 8 voksne hunmus anbringes vilkår-25 ligt i doseringsgrupper ifølge den af R.G.D. Steel og J.H. Torrie beskrevne metode i "Principles and Procedures of Statistics", McGraw-Hill Book Company, Inc., side 99-100 og 428-431. Hver mus identificeres med en farvekode på halen. Prøveforbindelserne indgives som 30 opløsninger eller suspensioner i 10 ml/kg musekropsvægt af 0,5% vandig methylcellulose inden for 15 minutter, efter at suspensionen er fremstillet. Der fremstilles "Metrazol" (pentylentetrazol) som en opløsning i fysiologisk saltvandsopløsning. Musene faster ikke før prø-35 ven. Der behandles 8 mus for hvert doseringsniveau.Groups of 8 adult female mice are randomly placed in dosing groups according to that of R.G.D. Steel and J.H. Torrie described methodology in "Principles and Procedures of Statistics", McGraw-Hill Book Company, Inc., pages 99-100 and 428-431. Each mouse is identified by a color code on its tail. The test compounds are administered as 30 solutions or suspensions in 10 ml / kg mouse body weight of 0.5% aqueous methyl cellulose within 15 minutes of preparation of the suspension. "Metrazole" (pentylenetetrazole) is prepared as a solution in physiological saline solution. The mice do not fast until the test friend. 8 mice are treated for each dosing level.
22 DK 169267 B1 o22 DK 169267 B1 o
Hver mus får én dosis af prøvepræparatet (i reglen 100 mg/kg til screening) i 0,5% vandig methylcel-lulose eller i kontrolproduktet (0,5% vandig methylcel-lulose alene) intraperitonealt. Der gives derpå 80 mg/ 5 kg "Metrazol"® subcutant i en løs hudfold på halsens rygside, dvs. en halv time, efter at prøveforbindelsen eller kontrolproduktet er indgivet. Injektionerne gives med en 1 ml glastuberkulinsprøjte med en passende størrelse hypodermisk kanyle (nr. 7 til opløsninger, nr.Each mouse is given one dose of the test preparation (usually 100 mg / kg for screening) in 0.5% aqueous methylcellulose or in the control product (0.5% aqueous methylcellulose alone) intraperitoneally. Subsequently, 80 mg / 5 kg "Metrazol" ® is administered subcutaneously in a loose skin fold on the back of the neck, ie. half an hour after the test compound or control product is administered. The injections are given with a 1 ml glass tuberculin syringe of appropriate size hypodermic cannula (# 7 for solutions, no.
10 23 til suspensioner). Alle injektionerne gives i et volumen på 10 ml/kg musekropsvægt. Hver mus observeres i 30 minutter efter " Me trazol®-injektion. Hvis dyrene ikke udviser et tærskelanfald (en enkelt episode med kloniske spasmer af mindst 5 sekunders varighed), 15 defineres dette som beskyttelse. Antikonvulsiviske data opstilles som % beskyttelse, dvs.10 23 for suspensions). All injections are given in a volume of 10 ml / kg mouse body weight. Each mouse is observed for 30 minutes after "Me trazol® injection. If the animals do not exhibit a threshold attack (a single episode with clonic spasms of at least 5 seconds duration), this is defined as protection. Anti-convulsive data is set as% protection, ie.
antal beskyttede mus χ antal afprøvede mus 20 ^50' ®^% ^onfidensgrænse og styrkeforhold kan udregnes ved hjælp af probitetsanalyse på computerbasis som beskrevet af D.J. Finney, Statistical Method in Biological Assay, 2. udg., New York, (1964), Hefner Publishing Co.number of protected mice χ number of tested mice 20 ^ 50 '® ^% ^ confidence limit and strength ratio can be calculated by computer-based probability analysis as described by D.J. Finney, Statistical Method in Biological Assay, 2nd ed., New York, (1964), Hefner Publishing Co.
25 Elektrisk eksposition25 Electrical Exposure
Voksne hunmus i grupper på 8 indgives prøvepræparatet intraperitonealt (i reglen 100 mg/kg indledningsvis til screening) i flydende bærer, i reglen fysiologisk saltvandsopløsning eller vand. Dyrene ekspone-30 res elektrisk, ved at der anbringes messingelektroder på hornhinden og påføres en elektrisk stimulus (60 Hz, 5 m sek. pulsbredde, 34 m ampere styrke) i 0,2 sekund ved hjælp af en "Grass Stimulator"® og konstant strømenhed og en "Hunter Timer'®. Manglen på toniske anfald ved ophør 35 af stimuli noteres som beskyttelse hos det pågældende dyr. Det antal dyr, der beskyttes mod toniske anfaldAdult female mice in groups of 8 are administered the sample preparation intraperitoneally (usually 100 mg / kg initially for screening) in liquid vehicle, usually physiological saline or water. The animals are electrically exposed by applying brass electrodes to the cornea and applying an electrical stimulus (60 Hz, 5 m sec pulse width, 34 m amperes strength) for 0.2 sec using a "Grass Stimulator" ® and constant power unit and a "Hunter Timer'®. The lack of tonic seizures at discontinuation 35 of stimuli is noted as protection in that animal. The number of animals protected from tonic seizures
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23 DK 169267 B1 ved en bestemt dosis prøvepræparat/ bestemmes. ED,--.23 DK 169267 B1 at a specific dose of sample preparation / determined. OATH,--.
50 konfidensgrænser og styrkeforhold kan beregnes ved hjælp af J.T. Litchfield og F. Wilcoxon's metode, J. Pharmacol. Exp. Ther. 96, 99-113 (1949).50 confidence limits and strength ratios can be calculated using J.T. Litchfield and F. Wilcoxon's method, J. Pharmacol. Exp. Ther. 96, 99-113 (1949).
5 Nogle af de mere aktive forbindelser som i eksemplerne 5, 6, .7, 11, 13 og 17 udviser EDr„-værdi- Æ) 50 er ved "Me trazol "^prøven på 5-30 mg/kg og ED^værdier ved den elektriske ekspositionsprøve på ca. 10-30 mg/kg.5 Some of the more active compounds, as in Examples 5, 6, .7, 11, 13 and 17, exhibit the EDr "value" - 50 are in the "Me trazole" test of 5-30 mg / kg and ED by the electrical exposure test of approx. 10-30 mg / kg.
1010
Tilberedning og indgiftPreparation and administration
De pharmakologisk aktive 3-phenoxy-l-azetidin-carboxamider ifølge opfindelsen er effektive til behandling af såvel petit-mal-epilepsi som grand-mal-epilepsi.The pharmacologically active 3-phenoxy-1-azetidine carboxamides of the invention are effective in treating both petit-mal epilepsy and grand-mal epilepsy.
15 Effektive mængder af disse forbindelser kan indgives til dyr oralt i form af kapsler, tabletter eller eliksirer. Det er blot nødvendigt, at den aktive bestanddel udgør en effektiv mængde, dvs. så at der opnås en passende effektiv dosering i overensstemmelse med den 20 anvendte doseringsform. Den nøjagtige individuelle dosering samt daglige doseringer vil naturligvis blive bestemt i overensstemmelse med medicinske standardprincipper under ledelse af en læge eller dyrlæge.Effective amounts of these compounds may be administered to animals orally in the form of capsules, tablets or elixirs. It is only necessary that the active ingredient constitute an effective amount, ie. so that a suitable effective dosage is obtained in accordance with the dosage form used. The exact individual dosage as well as daily dosages will, of course, be determined in accordance with standard medical principles under the guidance of a physician or veterinarian.
Ved hjælp af sammenligning med kendte antikon-25 vulsiviske forbindelser synes den daglige dosering fortrinsvis at ligge i intervallet fra ca. 0,5 til 1,5 mg pr. kg legemsvægt ved behandling af petit-mal-epilepsi og ca. 25-35 mg/kg legemsvægt ved behandling af grand--mal-epilepsi. Meget små mængder af de aktive stoffer, 30 endog så lidt som 0,1 mg, ifølge opfindelsen er effektive, når der kræves lettere behandling. Enhedsdoserne ligger i reglen på 5 mg eller derover og fortrinsvis på 25, 50 eller 100 mg pr. enhedsdosis. De aktive stoffer ifølge opfindelsen kan kombineres med andre pharmakolo-35 gisk aktive midler, som tidligere anført, eller med puf-By comparison with known anticonvulsant compounds, the daily dosage appears to be preferably in the range of about 5 to about 5%. 0.5 to 1.5 mg per kg body weight in the treatment of petite-mal epilepsy and approx. 25-35 mg / kg body weight in the treatment of grand mal epilepsy. Very small amounts of the active substances, even as little as 0.1 mg, according to the invention are effective when easier treatment is required. The unit doses are usually 5 mg or more and preferably 25, 50 or 100 mg per day. unit dose. The active substances according to the invention can be combined with other pharmacologically active agents, as previously stated, or with buffering agents.
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24 DK 169267 B1 fere, antacider eller lignende til indgift, og andelen af aktivt stof i sammensætningen kan varieres stærkt.B1 spheres, antacids or the like for administration, and the proportion of active substance in the composition can be greatly varied.
Kapslercapsules
Der fremstilles kapsler på 5 mg, 25 mg og 50 5 mg aktivt stof pr. kapsel; når mængden af aktivt stof er større, kan der foretages reduktion i lactosemængden.Capsules of 5 mg, 25 mg and 50 5 mg of active substance are prepared per day. capsule; when the amount of active substance is greater, the amount of lactose may be reduced.
Typisk blanding til indkapsling Pr. kapsel, mg Aktivt stof 5,0 10 Lactose 296,7Typical blend for enclosure Pr. capsule, mg Active ingredient 5.0 10 Lactose 296.7
Stivelse 129,0Starch 129.0
Magnesiumstearat 4,3Magnesium stearate 4.3
Ialt 435,0 15 Det valgte aktive stof blandes homogent med lactose, stivelse og magnesiumstearat, og blandingen indkapsles.Total 435.0 15 The selected active substance is homogeneously mixed with lactose, starch and magnesium stearate and the mixture is encapsulated.
Andre kapseltilberedninger indeholder fortrinsvis en større dosis aktivt stof og er som følger: 20 100 mg/ 250 mg/ 500 mg/Other capsule preparations preferably contain a larger dose of active substance and are as follows: 20 100 mg / 250 mg / 500 mg /
Bestanddele_kapsel kapsel kapselIngredients_capsule capsule capsule
Aktivt stof 100,0 250,0 500,0Active substance 100.0 250.0 500.0
Lactose 231,5 126,5 31,1Lactose 231.5 126.5 31.1
Stivelse 99,2 54,2 13,4 25 Magnesiumstearat _4,3_4,3_5,5Starch 99.2 54.2 13.4 Magnesium stearate _4.3_4.3_5.5
Ialt mg 435,0 435,0 550,0Total mg 435.0 435.0 550.0
Tablettertablets
En typisk tilberedning til en tablet indeholden-30 de 5,0 mg aktivt stof pr. tablet ses nedenfor. Tilberedningen kan anvendes til andre styrker af aktivt stof ved justering af vægten af dicalciumphosphat.A typical preparation for a tablet containing 5.0 mg of active substance per ml. tablet is shown below. The preparation can be used for other strengths of active substance by adjusting the weight of dicalcium phosphate.
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25 DK 169267 B1DK 169267 B1
Bestanddele pr. tablet, mg (1) Aktivt stof 5,0 (2) Majsstivelse 13,6 (3) Majsstivelse (pasta) 3,4 5 (4) Lactose 79,2 (5) Dicalciumphosphat 68,0 (6) Calciumstearat 0,9Ingredients per tablet, mg (1) Active ingredient 5.0 (2) Corn starch 13.6 (3) Corn starch (paste) 3.4 5 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate 0.9
Ialt 170,1 10 Ingredienserne 1, 2, 4 og 5 blandes homogent.A total of 170.1 10 Ingredients 1, 2, 4 and 5 are mixed homogeneously.
Bestanddel nr. 3 fremstilles som en 10%'s pasta i vand. Blandingen granuleres med stivelsespastaen, og den våde masse passeres gennem en sigte mesh 8. Det våde granulat tørres og passeres gennem en sigte mesh 12. Det 15 tørrede granulat blandes med calciumstearat og tabletteres .Ingredient # 3 is prepared as a 10% paste in water. The mixture is granulated with the starch paste and the wet mass is passed through a sieve mesh 8. The wet granulate is dried and passed through a sieve mesh 12. The dried granulate is mixed with calcium stearate and tabulated.
Yderligere tablettilberedninger indeholder fortrinsvis en højere dosis af det aktive stof og har følgende sammensætning.Further tablet preparations preferably contain a higher dose of the active substance and have the following composition.
20 50 mg tablet20 mg tablet
Bestanddel_Pr. tablet, mgBestanddel_Pr. tablet, mg
Aktivt stof 50,0Active substance 50.0
Lactose 90,0 25 Majsstivelse 58,0Lactose 90.0 25 Corn starch 58.0
Calciumstearat 2,0Calcium stearate 2.0
Ialt 200,0Total 200.0
Det aktive stof, lactose og majsstivelse blan-30 des homogent. Blandingen granuleres, idet der anvendes vand som granuleringsmiddel. Det våde granulat passeres gennem en 8 mesh sigte og tørres ved 60-70°C natten over. Det tørrede granulat passeres gennem en 10 mesh sigte og blandes med den rigtige mængde calciumstearat, 35 og denne blanding slås derefter til tabletter på en passende tablettéringsmaskine.The active substance, lactose and corn starch are homogeneously mixed. The mixture is granulated, using water as the granulating agent. The wet granules are passed through an 8 mesh screen and dried at 60-70 ° C overnight. The dried granules are passed through a 10 mesh sieve and mixed with the correct amount of calcium stearate, and this mixture is then turned into tablets on a suitable tableting machine.
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US70662185A | 1985-02-28 | 1985-02-28 | |
| US70662185 | 1985-02-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK90086D0 DK90086D0 (en) | 1986-02-27 |
| DK90086A DK90086A (en) | 1986-08-29 |
| DK169267B1 true DK169267B1 (en) | 1994-09-26 |
Family
ID=24838379
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK90086A DK169267B1 (en) | 1985-02-28 | 1986-02-27 | 3-Aryloxyazetidine carboxamides, pharmaceutical compositions containing these compounds, method of preparation of the compounds, and their use in the preparation of a pharmaceutical composition for the treatment of epilepsy and / or convulsions |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPH0699306B2 (en) |
| AU (1) | AU599585B2 (en) |
| DK (1) | DK169267B1 (en) |
| GR (1) | GR860549B (en) |
| NZ (1) | NZ215313A (en) |
| PH (1) | PH25455A (en) |
| PT (1) | PT82117B (en) |
| ZA (1) | ZA861210B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA861210B (en) * | 1985-02-28 | 1987-10-28 | Robins Co Inc A H | 3-aryloxyazetidinecarboxamides as anticonvulsants and antiepileptics |
| DE3641343A1 (en) * | 1986-12-03 | 1988-06-16 | Hoechst Ag | CARBAMOYLIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS FUNGICIDES |
| JP4507390B2 (en) * | 2000-11-13 | 2010-07-21 | 宇部興産株式会社 | 1-alkyl-1-substituted-3-organosulfonyloxyazetidinium salts and process for producing the same |
| US8691804B2 (en) | 2008-05-08 | 2014-04-08 | Evotec Ag | Azetidines and cyclobutanes as histamine H3 receptor antagonists |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4226861A (en) * | 1978-04-18 | 1980-10-07 | A. H. Robins Company, Inc. | N-Lower-alkyl 3-phenoxy-1-azetidinecarboxamides |
| IL68699A (en) * | 1982-08-19 | 1986-08-31 | Robins Co Inc A H | 3-phenoxy-1-azetidine-carboxamides,their preparation and pharmaceutical compositions containing them |
| US4505907A (en) * | 1982-09-02 | 1985-03-19 | A. H. Robins Company, Inc. | N-Formyl and N-hydroxymethyl-3-phenoxy-1-azetidinecarboxamides |
| US4594189A (en) * | 1983-07-06 | 1986-06-10 | A. H. Robins Company, Inc. | Process for preparing 3-phenoxy-1-azetidines and carboxamide derivatives |
| ZA861210B (en) * | 1985-02-28 | 1987-10-28 | Robins Co Inc A H | 3-aryloxyazetidinecarboxamides as anticonvulsants and antiepileptics |
-
1986
- 1986-02-18 ZA ZA861210A patent/ZA861210B/en unknown
- 1986-02-21 AU AU53887/86A patent/AU599585B2/en not_active Ceased
- 1986-02-26 PH PH33450A patent/PH25455A/en unknown
- 1986-02-26 GR GR860549A patent/GR860549B/en unknown
- 1986-02-27 NZ NZ21531386A patent/NZ215313A/en unknown
- 1986-02-27 DK DK90086A patent/DK169267B1/en not_active IP Right Cessation
- 1986-02-28 JP JP61043905A patent/JPH0699306B2/en not_active Expired - Lifetime
- 1986-02-28 PT PT8211786A patent/PT82117B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61210031A (en) | 1986-09-18 |
| NZ215313A (en) | 1990-02-26 |
| PT82117B (en) | 1988-07-01 |
| AU5388786A (en) | 1986-09-04 |
| AU599585B2 (en) | 1990-07-26 |
| DK90086A (en) | 1986-08-29 |
| PT82117A (en) | 1986-03-01 |
| DK90086D0 (en) | 1986-02-27 |
| ZA861210B (en) | 1987-10-28 |
| GR860549B (en) | 1986-06-24 |
| PH25455A (en) | 1991-07-01 |
| JPH0699306B2 (en) | 1994-12-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |