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

Description

DK 169267 B1 i

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.

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-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 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.

The novel 3-aryloxyazetidine carboxamides of the invention are characterized in that they have the general formula DK 169267 B1 2

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.

Formula I comprises the geometric isomers including cis, trans, (E) and (Z) isomers thereof.

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.

In the term "C (1-8) -alkoxy", C (1-8) -alkyl has the same meaning.

The term "C (3-9) alkyl" includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

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.

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. 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.

The pharmaceutical compositions of the invention are characterized in that they contain a compound of formula I and a pharmaceutically acceptable carrier.

The 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-0S02W

J (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 ^^ - OSO2W

30 r3 which is then reacted with sodium hydride and m-fluorophenol of formula 35 DK 169267 B1

A

OH F

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.

The process of the invention is illustrated in the following reaction scheme: 6

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DK 169267 B1

Process Type A From phenoxyazetidine a) 5 H-N 2) v-O-Ar + R1N = C = O - * R 1 NHC-nX-O-Ar

R3 V

H - ^> - O-Ar + RlHN-i! -Cl_ ^ R ^ XXV0 "^ R3 R3

Method Type B

Via aryloxy-1-chlorocarbonylazetidine (Ar = phenyl, substituted phenyl) ° n y

Cl-C- / Vo-Ar + R1NHa -> R1HN-C-N \ -0-Ar R3 R3

Method type C

Via methane (or phenyl) sulphonylazetidine

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H-N ^ N -SO2W R1 -N = C = Q RLNH-C-N \ -OSO £ -W

R 3 R 3 W = CH 3, phenyl,

J) -CH 3 -phenyl jO-F

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35 R% -C-N2) - 0- ^ R3 7 DK 169267 B1

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.

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.

Scheme I

Preparation of 1-unsubstituted unsubstituted phenoxazazididines R 4 * a.

20 "" 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 * * X

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 is limited to substituents which are electron removing, e.g. fluorine, chlorine, bromine, iodine or CF3.

*** When X = 4-C1, 4-Br, 4-1, 4-F or 4-CF3, the yields are very low.

35 **** x] ζ3η not be chlorine, bromine or iodine in the product as hydrogenolysis removes these groups.

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8 DK 169267 B1

Scheme II

Preparation of starting 1-carbonyl-3-aryloxy-azetidines R4

5 ^ CH-N ^ N-OH

ce4 X

\ + \ halogen 10 \ tei \ halogen

\ NaH \ DMF

15 / \ 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 Γ 25

Scheme III

Preparation of starting methane (or phenyl) sulfonylazetidine

* T <> “WSOaCl R« -CH-N ^ N-0S02W

30 ceHs NEt, * CeHs T, toluene Λ W = CH3, CqHs H2, 4 Me-CcII.- Pd / c 6 4

H-N \ _0S02W

y

35 I

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9 DK 169267 B1

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%).

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 B1

Preparation 2 trans-1- (Diphenylmethyl) -2-methyl-3- [3- (trifluoromethyl) phenoxyjazetidine oxalate [1: 1]

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.

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.

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.

Preparation 3 trans-2-Methyl-3- [3- (trifluoromethyl) phenoxy] azetidine oxide [1: 1]

A 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 at a hydrogen pressure of 2.8 kg / cm @ atm. at 70 ° C

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.

Analysis: Calculated for O₂O ^: 10 - C 48.61, H 4.39, N 4.36.

Found: C, 48.67; H, 4.38; N, 4.34.

The invention is further illustrated by the following 15 examples.

Example 1 N- (2-Propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine-carboxamide

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.

Analysis: Calculated for C 14 H 15 F 3 N 2 O 2: C 56.00, H 5.04, N 9.33.

Found: C, 55.98; H, 5.05; N, 9.31.

35 .12

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DK 169267 B1

Example 2 N-Cyclopropyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

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.

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.

15

Analysis: Calculated for C 14 H 15 F 3 N 2 O: C 56.00, H 5.04, N 9.33.

Found: C, 55.97; H, 5.07; N, 9.28.

Example 3-: N- (2-Propenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

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.

Analysis: Calculated for C 14 H 15 F 3 N 2 O 2: C 56.00, H 5.04, N 9.33.

Found: C, 55.98; H, 5.17; N, 9.36.

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.

Analysis: Calculated for: C 56.38, H 4.39, N 9.39.

Found: C 56.32, H 4.34, N 9.44.

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.

14

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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.

Analysis: Calculated for ^ 7 ^ 21 ^ 3 ^ 2 ^ 2! C 59.64, H 6.18, N 8.18.

Found: C 59.52, H 6.20, N 8.17.

10

Example 6 N-Cyclopropyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

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.

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.

After drying at 80 ° C under 0.5 mm Hg vacuum, the weight does not decrease, mp 152-153 ° C.

Analysis: Calculated for cx4H15F3N2 ° 2: C 56.00, H 5.04, N 9.33.

Found: C, 55.77; H, 4.98; N, 9.44.

35

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Example 7 N- (2-Propynyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

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.

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.

Analysis: Calculated for C 14 H 15 F 3 N 2 2: 30 C 56.38, H 4.39, N 9.39.

found; C 56.34, H 4.36, N 9.32.

35

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Example 8 N- (2-Methyl-2-propenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide

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.

Analysis; Calcd. For c15 H17 F3 N2 ° 2: C 57.32, H 5.45, N 8.91.

found; C 57.45, H 5.51, N 9.23.

20

Example 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 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.

Analysis: Calculated for c15 H17 F3 N2 ° 2: C 57.32, H 5.45, N 8.91.

Found: C 57.20, H 5.50, N 8.95.

Example 10 N- (3-Methyl-2-butenyl) -3- [4- (trifluoromethyl) phenoxy] -1- -azetidine carboxamide

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.

Analysis: Calculated for C c cHl9F3N₂O₂: C 58.53, H 5.83, N 8.53.

Found: C, 58.81; H, 5.89; N, 8.58.

Example 11 N- (3-Methyl-2-butenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide

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.

Found: C 58.46, H 5.86, N 8.69.

15

Example 12 (E) -N- (2-Butenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

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.

Analysis: Calculated for: C 57.32, H 5.45, N 8.91.

Found: C 57.47, H 5.49, N 9.00.

35 19 DK 169267 B1 o

Example 13 (E) -N- (2-Butenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

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.

Analysis: Calculated for C 15 H 17 F 3 N 2 O 2 C 57.32, H 5.45, N 8.91.

Found: C 57.35, H 5.47, N 8.94.

Example 14 N-Phenyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

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.

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.

Analysis: Calculated for; C, 60.71; H, 4.50; N, 8.33.

Found: C, 60.81; H, 4.47; N, 8.35.

DK 169267 B1 20 o

Example 15 N-Phenyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

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.

Analysis: Calculated for C 17 H 15 F 3 N 2 O 2: C 60.71, H 4.50, N 8.33.

Found: C, 60.91; H, 4.53; N, 8.35.

Example 16 trans-2-Methyl-N- (2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide

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.

The combined triturates give 400 mg of white granular crystals (8.5%), mp 55-57 ° C.

Analysis: Calculated for: C 57.32, H 5.45, N 8.91.

Found: C 57.36, H 5.50, N 8.97.

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21 DK 169267 B1

Example 17

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.

Analysis: Calculated for C, H, ClCl 2 O: ± J Ib Δ Δ C 58.54, H 5.67, N 10.50.

Found: C, 58.48; H, 5.72; N, 10.49.

pharmacology

The anticonvulsant activity is determined for the compounds of formula I by chemical or electrical exposure as follows:

Chemical Metrazole Series Positic (Swinyard Method)

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 o

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 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.

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 Electrical Exposure

Adult 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 at a specific dose of sample preparation / determined. OATH,--.

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 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.

10

Preparation and administration

The pharmacologically active 3-phenoxy-1-azetidine carboxamides of the invention are effective in treating both petit-mal epilepsy and grand-mal epilepsy.

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.

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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B1 spheres, antacids or the like for administration, and the proportion of active substance in the composition can be greatly varied.

capsules

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.

Typical blend for enclosure Pr. capsule, mg Active ingredient 5.0 10 Lactose 296.7

Starch 129.0

Magnesium stearate 4.3

Total 435.0 15 The selected active substance is homogeneously mixed with lactose, starch and magnesium stearate and the mixture is encapsulated.

Other capsule preparations preferably contain a larger dose of active substance and are as follows: 20 100 mg / 250 mg / 500 mg /

Ingredients_capsule capsule capsule

Active substance 100.0 250.0 500.0

Lactose 231.5 126.5 31.1

Starch 99.2 54.2 13.4 Magnesium stearate _4.3_4.3_5.5

Total mg 435.0 435.0 550.0

tablets

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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DK 169267 B1

Ingredients 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

A total of 170.1 10 Ingredients 1, 2, 4 and 5 are mixed homogeneously.

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.

Further tablet preparations preferably contain a higher dose of the active substance and have the following composition.

20 mg tablet

Bestanddel_Pr. tablet, mg

Active substance 50.0

Lactose 90.0 25 Corn starch 58.0

Calcium stearate 2.0

Total 200.0

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)

26 DK 169267 B1 PATENT REQUIREMENT. 1. 3-Aryloxyazetidine carboxamides, characterized in that they have the general formula R 1 -NH-C-O-Ar 1 wherein Ar is phenyl or phenyl substituted with chlorine, bromine, 10 iodo, fluoro, C (1-8) - alkyl, C (1-8) alkoxy, nitro, aminocarbonyl or trifluoromethyl, R 1 is C (3-9) -cycloalkyl, allyl, 2-methyl-2-propenyl, propargyl, 2-butenyl, 3-methyl-2- butenyl, phenyl or phenyl substituted with fluoro, chloro, bromo, iodo, C (1-8) alkyl, C (1-8) alkoxy, nitro, cyano or CF3, and R3 is hydrogen or C (1-8) ) alkyl. A compound according to claim 1, characterized in that Ar is trifluoromethyl-substituted phenyl. A compound according to any one of claims 1-2, characterized in that R 1 is allyl, propargyl or C (3-9) -20-cycloalkyl. Pharmaceutical composition, characterized in that it contains a compound according to any one of claims 1-3 as well as a pharmaceutically acceptable carrier. A compound according to any one of claims 1-3 for use in human or veterinary medicine. Use of a compound according to any one of claims 1-3 for the preparation of a pharmaceutical composition for the treatment or prophylaxis of epilepsy and / or convulsions. Process for the preparation of a compound 30 according to one of claims 1-3, characterized in that one (A) is reacted with a compound of the general formula H-O-Ar (II) R3 27 a 169 R7N with a) R3N = C = O or b) R1HN-C-C1, II O in which formulas rI, R3 and Ar have the meanings given above in connection with formula I, or (B) translates into a compound of general formula 10 C1-CN O-Ar (ni) R3 with R1NH2 in which formulas R1 , R 3 and Ar have the meanings set forth above for the general formula I, or 20 (C) for the preparation of m-fluorophenoxy compounds of the general formula I, react with a compound of the general formula H-1N OSO2W Y (IV) R3 wherein R3 is as defined above in the general formula 30I and W is methyl, phenyl or 4-methylphenyl, with an isocyanate of formula r1-n = c = o 35 to form a compound of formula DK 169267 B1 28 O R1 MH-CN R 3 which is then reacted with sodium hydride and m-fluorophenol of formula OH F to give a compound of formula R 1 RH-CN γ-O) / R 3 20. which Formulas R 1 and R 3 have the above compounds of general formula I meanings stated.