JPH0699306B2 - 3-Allyloxyazetidinecarboxamides as anticonvulsant and antiepileptic agents - Google Patents

Description

TECHNICAL FIELD The present invention relates to novel 3-aryloxyazetidinecarboxamides, anticonvulsant effects thereof and a therapeutic method for epilepsy, and a pharmaceutical composition thereof.

(Prior Art) It has an anticonvulsant effect and is useful for treating epilepsy. (In the formula, R is a lower alkyl group, and R ¹ is hydrogen, an aminocarbonyl group, or a trifluoromethyl group.)
Mono-N-substituted azetidine carboxamides of the formula: are disclosed in U.S. Pat. No. 4,226,861.

formula (Wherein R ¹ is hydrogen, fluorine, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, an acetyl group or an aminocarbonyl group), and the azetidinecarboxamides in which N is not substituted are anticonvulsant. It has an action and is useful for treating epilepsy.
No. 4,571,393 (U.S. Patent Application No. 664,036, filed on 22nd August 1984). This application forms the basis of already published European patent application No. 102-194-A.
This is a continuation application of US Patent Application No. 409,476 filed on August 19, 1982.

The Japanese patent application filed by the applicant on the same day as the present application discloses a method for treating muscle tension, convulsions, and anxiety due to all the above-mentioned conventional compounds and the compounds disclosed in the present application.

DETAILED DESCRIPTION OF THE INVENTION 3-Aryloxyazetidinecarboxamides useful in the methods of the present invention have the formula (In the formula, Ar is a pyridyl group containing a pyridyl group substituted by halogen (including substitution at any position thereof), a phenyl group or a halogen (chlorine, bromine, iodine, fluorine), a lower alkyl group, a lower alkoxy group, Nitro group,
A phenyl group substituted with one or two groups selected from an aminocarbonyl group or a trifluoromethyl group, Z is oxygen or sulfur, R ¹ and R ² are hydrogen, an allyl group (2-propynyl) Group), a propargyl group (2-propynyl group) and a cyclopropyl group, and R ³ is hydrogen, a lower alkyl group, an aryl group or an aryl lower alkyl group), its cis, trans, Geometric isomers, including (E) and (Z) isomers, pharmaceutically acceptable salts thereof when Ar is a pyridyl group, provided that R ³ is hydrogen, Z is oxygen and Ar Is a phenyl group, or a phenyl group substituted with a trifluoromethyl group or an aminocarbonyl group, the condition that R ¹ and R ² cannot be hydrogen And further, R ³ is hydrogen, Z is oxygen, Ar is phenyl or fluorine, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, an acetyl group,
Alternatively, in the case of a phenyl group substituted with an aminocarbonyl group, both R ¹ and R ² must not be hydrogen.

For more detailed definitions of symbols, in the formulas herein and elsewhere in the specification and in the claims, the terms have the following meanings.

Unless otherwise specified, the term lower alkyl group as used herein includes straight chain and branched carbon chain groups having up to 8 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec- Butyl group, tert-butyl group,
Examples include groups such as amyl group, isoamyl group, hexyl group, heptyl group and octyl group. The term lower alkyl group is represented by the formula -O-lower alkyl.

The term cycloalkyl group as used herein includes cyclic alkyl groups mainly consisting of 3 to 9 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like. Including a group.

The term lower alkylcycloalkyl group means a cycloalkyl group substituted with an alkyl group of 1 to 8 carbons.

The term cycloalkyl lower alkyl group means a cycloalkyl group linked to the amide nitrogen by an alkyl chain of 1 to 8 carbons which may be a branched carbon chain.

The term substituted allyl group means an allyl group substituted with an alkyl group at any one of its three positions.

The term aryl group in the definitions of R ¹ .R ² and R ³ is phenyl group or halogen, lower alkyl group, lower alkoxy group, nitro group, cyano group, trifluoromethyl group, carbetoxy group, carbomethoxy group, carboethoxy group. It means a phenyl group substituted by a non-interfering group such as.

The term aryl lower alkyl group in the definition of R ¹ .R ² and R ³ refers to an aryl group as defined above linked to the amide nitrogen by an alkyl chain of 1 to 8 carbons which may be a branched carbon chain. Means

The term 4-substituted piperazinyl group in the definition of R ¹ and R ² means a piperazine group substituted by a conventional group including an aryl group as defined above and a lower alkyl group as defined above.

Pharmaceutically acceptable salts are included when R ¹ or R ² has a salt-forming amino moiety, or when Ar is a pyridyl group, as defined in Formula I. For example, a salt-forming amino component is present when R ¹ or R ^{2 is a} di-lower alkylaquinoalkyl group or when they form a piperazinyl group or an imidazolyl group. Pharmaceutically acceptable acid addition salts are physiologically compatible salts for mixed-race animals. The acid addition salts can be made from either strong or weak acids. Examples of useful strong acids include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Examples of useful weak acids include fumaric acid, maleic acid, succinic acid, acid, citric acid, tartaric acid, hexamic acid and the like.

The compounds of formula I exhibit pharmacological effects on the central nervous system and are therefore useful in the methods of the invention.

The method for testing the anticonvulsant effects of these compounds is EA.
Swinyard Epilesia 10: 107-19 (1969) and J.Pharmc.Exptl.Therap. 106: 319-30 (1952).
Year)) etc. based on the test method (details will be described later). It is understood that compounds that exhibit prophylactic activity against seizures both by metrazole and electrical stimulation are generally useful in the treatment of both small and large seizures.

DETAILED DESCRIPTION OF THE INVENTION The methods used in the synthesis of compounds of formula I are described in Method A.
It is classified as follows according to the reaction formula under BC.

Method A Application from phenoxyazetidine Method B Via aryloxy-1-chlorocarbonylazetidine (Ar = phenyl group, substituted phenyl group, pyridyl group) Method C Via methane (or phenyl) sulfonyl azetidine The reaction of Method A is the formula And a phenoxy compound of formula I by reacting a compound of formula (a) with any of the compounds of classes a) -f) below.

The reaction of Method B is The method for preparing certain aryloxy compounds of formula I by reacting a compound of formula I with either of the following compounds of class a) or b).

a) R ² NH ₂ b) Heterocyclic amino compound.

The reaction of Method C has the formula A compound of formula R ² —N═C═Z is reacted with an isocyanate of formula To prepare a compound of By reacting with metafluorophenol represented by And preparing m-fluorophenoxy compounds of formula I by obtaining a compound of formula I.

The method of synthesis of the starting phenoxyazetidines used in Method A is outlined by Chart I. The synthetic method for the starting aryloxy-1-carbonylazetidines used in Method B is outlined by the formula in Chart II.

The starting material 1- (diphenylmethyl) -3-hydroxyazetidines used in the route of Method C (see Chart III) is prepared from Anderson and Lok [J. Org. Chem., 37, benzhydrylamine and the appropriate epihalohydrin. Page 3953 (1972)]. If cis and trans isomers are present, they are separated by chromatography. The starting material α-methylbenzyl-3-azetidinol was prepared by Tetsuya Okutani et al. [Che
m.Pharm.Bull., Vol. 22, p. 1490 (1974)]. Synthesis 1-6 illustrates this method.

Chart I Raw material 1-Synthesis of unsubstituted phenoxyazetidines ^*R^Four= Methyl group, phenyl group, or substituted phenyl
Basis.^** X is, for example, fluorine, chlorine, bromine, iodine,
Or electron-withdrawing substituents such as trifluoromethyl
Limited.^*** X = 4-Cl.4-Br.4-I.4-F. Or 4-CF₃Ah
Yield is very low.^**** Hydrogenolysis removes chlorine, bromine and iodine
So in the product X cannot be these groups
Iatate II raw material 1-carbonyl-3-aryloxyazetidines
Synthesis ofChart III Raw material Methane- (or phenyl) -sulfonyl azeti
Gin synthesisSynthesis 1 trans-1- (diphenylmethyl) -2-methyl-3
-Azetidinol acid salt [1: 1] diphenylmethylamine 126.4 g (0.72 mol), 3-bromo
-1,2-epoxybutane 100g (0.66mol), methanol 3
Stir 00 ml of the mixture in the dark for 96 hours, then add 30 hours.
Heated to reflux. At this time, the color changed from pale yellow to dark brown.
Some samples¹H-NMR analysis revealed 3 methyl groups.
A double line was observed. Fine beige precipitate (Ziff
(Enylmethylamine hydrobromide) by filtration
The filtrate was concentrated with a rotary evaporator to give an oily crude product.
174.6 g of the product was obtained. Chromatotron neutralizes 1.5 g sample
Place it on a 4 mm thick plate of 10% ethyl acetate
Eluted with ruene. TLC clearly contains 6 spots
We collected a total of 16 fractions. Lord thus separated
Ingredient is 700 mg, which is a trans isomer
it was thought. This sample was converted to the acid salt. Main thick ahead
The crude product was converted to the free base with ammonium hydroxide and
It was extracted with ruene, dried over magnesium sulfate and concentrated.
Dissolve this reaction residue in methanol and add 58 g of acid to homogenize
Seed crystals of trans-acid salt by heating until a different solution is obtained.
And then cooled. White granular product due to filtration 62
got g. Melting point 147-148.5 ° C. 26g more as second crystal
Was given. this¹The H-NMR spectrum is J (CH₃-H) is 6.1H
z only one CH₃A double line is shown, which is the trans compound
[Robert H. Higgins and Norman H. Cromwell. J. Heter
Chem. 8 (6), 1059-62 (1971)].
It The total yield was 88 g (38.8%).

Elemental analysis: Calculated value C ₁₇ H ₁₉ NO ・ C ₂ H ₂ O ₄ As: C66.46, H6.16 N4.08 Analytical value C ₁₇ H ₁₉ NO ・ C ₂ H ₂ O ₄ As: C66.38, H6 .16 N4.07 Synthesis 2 1- (diphenylmethyl) 3-azetidinol methanesulfonate (ester) hydrochloride [1: 1] 1-diphenylmethyl-3-azetidinol hydrochloride 60.0
A mixture of 2 g (0.22 mol), triethylamine 48.94 g (0.484 mol) and toluene 800 ml was stirred for 24 hours and then cooled to 5 ° C. in an ice bath. To this was added 27.7 g (0.24 mol) of methanesulfonyl chloride at a rate such that the temperature did not exceed 15 ° C. The reaction mixture was stirred for 3 hours and filtered to remove triethylamine hydrochloride. 4-in this liquid
40 g (0.242 mol) of trifluoromethylphenol, followed by 19.35 g (0.484 mol) of sodium oxide dissolved in 60 ml of water and 1.6 g of tetrabutylammonium bromide.
(0.005 mol) was added. The reaction mixture was vigorously stirred under reflux for 18 hours, then left stirring for 72 hours, cooling to room temperature. Transfer the reaction mixture to a separatory funnel and add water.
Wash 4 times with 200 ml (resulting in emulsion). The toluene layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 82 g of an oily substance. This residue is added to isopropyl alcohol 200
20 ml of concentrated hydrochloric acid was added. The solid separated after cooling was removed by filtration (5.1 g). Isopropyl ether was added to this filtrate to make it an oil, which was treated later. The above solid was found by spectral analysis to be the methyl sulfonate of the starting azetidinol. Recrystallization from isopropyl alcohol gave 3.3 g of a fine white crystalline substance. Melting point 172-173 ° C (reduced at 167 ° C).

Elemental analysis: Calculated value As C ₁₇ H ₁₉ NO ₃ S ・ HCl: C57.70, H5.70 N3.96 Measured value As C ₁₇ H ₁₉ NO ₃ S ・ HCl: C57.80, H5.86 N3.92 Synthesis 3 trans-1- (diphenylmethyl) -2-methyl-3
-[3- (Trifluoromethyl) phenoxy] azetizate [1: 1] 1.2 g (0.03 mol) of sodium hydride (60% dispersed in mineral oil) suspended in 50 ml of dry dimethylformamide and stirred And then add trans-1-diphenylmethyl-2-methylazetidin-3-olate 3.45 g (0.0
1 mol) was added in small portions. When the addition was complete and the evolution of hydrogen ceased, it was heated at 80 ° C. for 2 hours and then 1.64 g (0.01 mol) of 3-fluoro-trifluoromethylbenzene was added dropwise. The reaction mixture was stirred at 80 ° C. for a further 18 hours. The reaction mixture was diluted with ice water and triturated with 25 ml toluene.
Extracted twice. The extracts were combined, dried over magnesium sulfate, filtered, and 1 g of acid was added to the filtrate. The produced solid was collected by filtration. Recrystallization from acetone-isopropyl ether gave 2.2 g (4.5%) of fine white crystals. Melting point 146-14
Proton NMR at 7 ° C. showed this to be the trans compound.

Elemental analysis: Calculated _{C 24 H 22 F 3 NO.C 2} H 2 O 4: C64.06, H4.96, as N2.87 measure _{C 24 H 22 F 3 NO.C 2} H 2 O 4: C64.26, H4.99, N2.89 Synthesis 4 trans-2-methyl-3- [3- (trifluoromethyl) phenoxy] azetidinate [1: 1] trans-1-diphenylmethyl-2-methyl-3 −
Ammonium hydroxide was added to a solution of 33 g (0.068 mol) of [3- (trifluoromethyl) phenoxy] azetidinate dissolved in methanol-warm water until it became alkaline, and then extracted with 150 ml of methylene chloride four times. Combine the methylene chloride extracts, wash with water, dry over magnesium sulfate, and concentrate under reduced pressure. A pale yellow oil was obtained. This oil was added to 190 ml of ethanol containing 5 ml of triethylamine.
After dissolving in 0 ml, 3.3 g of 5% palladium-carbon catalyst was added using a Parr apparatus, and hydrogenated at 70 ° C. for 12 hours under a hydrogen atmosphere of 40 psi. After absorbing the calculated amount of hydrogen, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 26.73 g of a crude product. Of this, 8 g was converted to an acid salt in isopropyl alcohol to obtain 6.1 g of a fine white powder. Melting point 155-156 [deg.] C.
The total yield calculated by converting a part of this into the acid salt was 84% of the theoretical yield.

Elemental analysis: Calculated value C ₁₁ H ₁₂ F ₃ NO ・ C ₂ H ₂ O ₄ As: C 48.61, H4.39, N4.36 Measured value C ₁₁ H ₁₂ F ₃ NO ・ C ₂ H ₂ O ₄ As: C48.67, H4.38, N4.34 Synthesis 5 trans-1- (diphenylmethyl) -2-methyl-3
-Azetidinol methanesulfonate (ester) hydrochloride [1: 1] trans-1-diphenylmethyl-2-methylazetidin-3-ol (the hydrochloride is distributed between an organic solvent and an alkaline aqueous solution, the organic layer is separated and concentrated Obtained) 6g (0.02
10 ml of triethylamine is added to a solution prepared by dissolving 5 mol) in 40 ml of dry benzene and cooled to 5 ° C. While stirring
3.54 g (0.03 mol) of methanesulfonyl chloride was added at such a rate that the temperature could be controlled below 10 ° C. After stirring for 3 hours, TLC (20% ethyl acetate on silica gel / methylene chloride) showed the reaction was not complete.
Further, 1.14 g (0.01 mol) of methanesulfonyl chloride was added and stirring was continued for 1 hour. The reaction mixture was diluted with 100 ml of water, the benzene layer was separated, washed with 300 ml of water, dried over magnesium sulfate and concentrated to give an oil. This oily substance was dissolved in isopropyl ether, and a hydrochloric acid ether solution was added. The solid salt formed was collected and recrystallized from 190 ethanol to obtain 3.4 g (37%) of fluffy white crystals. Melting point 152-153 [deg.] C.

Elemental analysis: Calculated value C ₁₈ H ₂₁ NO ₃ S ・ HCl: C58.77, H6.03, N3.81 Measured value C ₁₈ H ₂₁ NO ₃ S ・ HCl: C58.68, H6.08, N3.80 Synthesis 6 1- (Diphenylmethyl) -3- [3- (trifluoromethyl) phenoxy] azetidine N-diphenylmethyl-3-hydroxyazetidine hydrochloride (I) was derived from benzhydrylamine and epichlorohydrin from Anderson and Lok [J.Org. Chem., 37, 3953 (1972)]. 41.33 g (0.15 mol) of compound I and triethylamine 4 in 250 ml of toluene
2 ml (0.30 mol) was left stirring, and 12 ml (0.15 mol) of methanesulfonyl chloride was added dropwise thereto over 10 minutes while maintaining the temperature at 4 ° to 12 ° C. TLC (silica gel,
It was found that all the raw materials had reacted after 1 hour with 10% ethyl acetate in methyl chloride). The mixture was filtered to remove triethylamine hydrochloride and the salt washed twice with toluene. The above filtrate and washing solution were combined to give a solution of about 450 ml. To this solution, 27.5 g (0.17 mol) of m-trifluoromethylphenol, 2.4 g of tetrabutylammonium bromide, 24 g (0.3 mol) of 50% sodium hydroxide and 24 ml of water were added, and the mixture was vigorously stirred under a nitrogen stream of 2.5. Heated to reflux for hours. The toluene layer of this mixture was separated, washed once with water, dried over sodium sulfate and concentrated to give an oil. Crystal seeds were added to this oily substance, and the pressure was reduced overnight in an oil pump. 49.7 g of a solid mass was obtained. A portion of this solid was briefly warmed and dissolved in isopropanol. Water was then added until slightly cloudy. Crystal seeds were added to this to cool and promote crystallization. The resulting white solid was collected by filtration, washed with 50% aqueous isopropanol and dried under reduced pressure overnight. Proton NMR
It was found that the silicone oil was slightly mixed. Melting point 82.5-84 [deg.] C.

Elemental analysis: Calculated value As C ₂₃ H ₂₀ F ₃ NO: C72.05, H5.26, N3.65 Measured value As C ₂₃ H ₂₀ F ₃ NO: C71.62, H5.29, N3.61 Perform the following The examples show how to make compounds of formula I useful in the compositions of this invention. However, the scope of the invention is not limited by these examples.

Example 1 26.0 g (0.078 mol) of N-methyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine-carbothioamide 1-benzhydryl-3- [3- (trifluoromethyl) phenoxy] azetidine Crude 3- [3- (trifluoromethyl) phenoxy] azetidine obtained by catalytic debenzylation was treated with 100 m of methylene chloride.
It was dissolved in 1 and treated dropwise with a solution of 5.0 g (0.0678 mol) of methyl isothiocyanate in 15 ml of methylene chloride under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours and left over the weekend. This solution was passed through a Celite pad to remove fine crystalline precipitate,
The liquid was evaporated under reduced pressure. The residual oil was crystallized from isopropyl ether to give 12.6 g of product, mp 79-86 ° C. A 5.0 g sample was recrystallized from isopropyl ether (activated carbon) to give 3.2 g of product, mp 89-93 ° C., which was found by TLC on silica gel (10% methanol-toluene) to be mixed with lower Rf material. did. The liquid was evaporated under reduced pressure, combined with 3.2 g of solid and dissolved in 100 ml of methylene chloride. This solution was stirred with 25 g of silica gel for 0.5 hours,
I passed through a glass filter. The silica gel was washed with a little methylene chloride and the liquid was evaporated under reduced pressure. Recrystallization of the residual solid from isopropyl ether, mp 96-98
1.3 g of pure product in ° C were obtained.

Calcd _{(C 12 H 13 F 3 N} 2 OS): C, 49.65; H, 4.51; N, 9.65 Found _{(C 12 H 13 F 3 N} 2 OS): C, 49.58; H, 4.48; N, 9.58 Example 2 N- (2,6-Dimethylphenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarbothioamide 1-benzhydryl-3- [3- (trifluoromethyl) ) Phenyloxy] azetidine 30.0 g (0.078 mol) was catalytically debenzylated to give crude 3- [3- (trifluoromethyl) phenoxy] azetidine in 100 m of methylene chloride.
It was dissolved in 1 and treated dropwise with a solution of 12.7 g (0.078 mol) of 2.6-dimethylphenyl isothiocyanate in 25 ml of methylene chloride under a nitrogen atmosphere. The product began to precipitate during the addition, so an additional 50 ml of methylene chloride was added to facilitate stirring. After stirring overnight at room temperature, the product was collected by filtration (13.5 g, mp 196-199 ° C). A 6.0 g sample was recrystallized from isopropanol to give 5.3 g of product, mp 197-199 ° C.
Got

Elemental analysis: Calculated value (C ₁₉ H ₁₉ F ₃ N ₂ OS): C, 59.99; H, 5.03; N, 7.36 Measured value (C ₁₉ H ₁₉ F ₃ N ₂ OS): C, 60.04; H, 5.04; N, 7.35 Example 3 N- (phenylmethyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 0.04 mol of 3- [3- (trifluoromethyl) phenoxy] azetidine was added to 100 ml of methylene chloride. It melt | dissolved, 6.12 g (0.046 mol) of benzyl isocyanate was dripped, stirring this solution by cooling (10-20 degreeC). The reaction mixture was stirred at room temperature for 2 hours and passed. The cake was washed with 2 x 50 ml petroleum ether, 2 x 50 ml dilute aqueous sodium hydrogen carbonate, and 2 x 50 ml water to give 12 g (86%) of product. Recrystallization twice from ethyl acetate gave 9.0 g of pure white flakes, mp 173.5-175 ° C.

Calcd _{(C 18 H 17 F 3 N} 2 O 2): C, 61.71; H, 4.89; N, 8.00 Found _{(C 18 H 17 F 3 N} 2 O 2): C, 61.57; H, 4.87; N, 7.99 Example 4 N- (2,6-dichlorophenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarbothioamide 3- [3- (trifluoro) in 100 ml absolute ethanol. A solution of 0.04 mol of methyl) phenoxy] azetidine was stirred in a water bath while 8.16 g (0.04 mol) of 2,6-dichlorophenyl isothiocyanate was added all at once. The reaction is slightly exothermic and isothiocyanic acid 2,6-
As the dichlorophenyl started to dissolve, the product started to precipitate. After stirring for 45 minutes, all isothiocyanic acid 2,
The reaction mixture was heated on a steam bath in order to dissolve the 6-dichlorophenyl. Then, the mixture was cooled and filtered to obtain 15.2 g of a white crystalline product. 7.9g part of this product
Was recrystallized from absolute ethanol to give 4.3 g of pure crystalline powder, mp 196-197 ° C.

Elemental analysis: Calculated value (C ₁₇ H ₁₃ F ₃ Cl ₂ N ₂ OS): C, 48.47; H, 3.11; N, 6.65 Actual value (C ₁₇ H ₁₃ F ₃ Cl ₂ N ₂ OS): C, 48.40; H, 3.07; N, 6.54 Example 5 N- [3- (diethylamino) propyl] -3- [3-
A solution of (trifluoromethyl) phenoxy] -1-azetidinecarbothioamide, acid salt [1: 1] 3- [3- (trifluoromethyl) phenoxy] azetidine 0.0584 mol was stirred at 10 ° C., during which isothiocyanic acid was added. 3- (diethylamino) propyl 10.66 g (0.
0584 mol) was added all at once. After stirring overnight at room temperature, the reaction mixture was concentrated using a rotary evaporator at 50 ° C. to give a viscous syrupy residue. The residue was dissolved in isopropanol, treated with 5.3 g of acid and warmed on a steam bath to dissolve the acid. Upon cooling, solid salt precipitated. An equal amount of isopropyl ether was added for complete precipitation. By filtration, 26 g of a crude product was obtained. 13 g of a part of the product was added to isopropanol / methanol / isopropyl ether (1000
/ 50/50) and recrystallized (cooled in a refrigerator) to give 7.5 g of a white product having a melting point of 155-157 ° C. Proton NMR confirmed that this was the desired product.

Calcd _{(C 18 H 26 F 3 N} 3 O · C 2 H 2 O 4): C, 50.10; H, 5.89; N,
8.76 Found (C ₁₈ H ₂₆ F ₃ N ₃ O ・ C ₂ H ₂ O ₄ ): C, 50.02; H, 5.97; N,
8.89 Example 6 N- [3- (dimethylamino) propyl] -3- [3-
(Trifluoromethyl) phenoxy] -1-azetidinecarbothioamide 3- [3- (trifluoromethyl) phenoxy] azetidine 0.0584 mol of a stirred solution at 10 ° C. with isothiocyanic acid 3
8.42 g (0.0584 mol) of-(dimethylamino) propyl was added all at once and stirred overnight at room temperature. The reaction mixture was treated with 5.3 g (0.0584 mol) of acid and diluted with 200 ml of isopropyl ether to give only 3.8 g of product. The volume was reduced to 100 ml at 50 ° C. in vacuum and diluted with 500 ml of isopropyl ether to give an additional 15.3 g of product. The combined solid product was dissolved in isopropyl alcohol, cooled and the fine precipitate (N, N-dimethyl-1,3-propanediamine acid salt) was removed by filtration. The product failed to crystallize and the addition of isopropyl ether only gave an amorphous gel. After 3 weeks of trying to obtain a more satisfactory product, the reaction product was converted to the free base and dissolved in isopropyl ether. The ether solution was stirred overnight with 300 ml of water to remove the diamine. The product crystallized from the homogeneous mixture as the free base form, yielding 11.3 g of fine tan crystals. Retreatment of the liquor gave an additional 2.3 g of product. A portion of the product, 8 g, was recrystallized from benzene / ligroin to give 5.8 g of very fine tan crystals (dried in vacuo at 82 ° C), mp 107-108 ° C.

Elemental analysis: Calculated value (C ₁₆ H ₂₂ F ₃ N ₃ OS): C, 53.17; H, 6.14; N, 11.63 Measured value (C ₁₆ H ₂₂ F ₃ N ₃ OS): C, 53.29; H, 6.15; N, 11.60 Example 7 N- (2-Propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide Crude 3- [3- dissolved in 100 ml of isopropyl ether.
While stirring a solution of (trifluoromethyl) phenoxy] azetidine (containing an equimolar amount of diphenylmethane) (18.9 g, 0.05 mol) under nitrogen, 4.16 g (0.05 mol) of 2-propenyl isocyanate was added with gentle stirring. The slightly cloudy reaction mixture became clear and after 1 hour fine crystalline precipitates began to form. After stirring for 18 hours, the product was separated by filtration, washed with fresh isopropyl ether and air dried to give 9.5 g of white crystals with a melting point of 75-76 ° C.

Elemental analysis: Calculated value (C ₁₄ H ₁₅ F ₃ N ₂ O ₂ ): C, 56.00; H, 5.04; N, 9.33 Actual value (C ₁₄ H ₁₅ F ₃ N ₂ O ₂ ): C, 55.98; H, 5.05; N, 9.31 Example 8 N-Cyclopropyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 1.9 g cyclopropylamine in 60 ml tetrahydrofuran.
(0.033 mol) and 1,1'-carbonyldiimidazole
4.9 g of the mixture was stirred at room temperature for 1 hour. The resulting clear solution was treated with a solution of 0.03 mol 3- [3- (trifluoromethyl) phenoxy] azetidine in 20 ml tetrahydrofuran. After stirring overnight, the solid precipitate was collected to obtain 4.4 g of an off-white powder. CI mass spectrum showed p + 1 to be 381 m / e, which was consistent with the desired product. Recrystallization from benzene / ligroin gave 23 g of a pale gray powder, mp 152-153 ° C.

Elemental analysis: Calculated value (C ₁₄ H ₁₅ F ₃ N ₂ O): C, 56.00; H, 5.04; N, 9.33 Found value (C ₁₄ H ₁₅ F ₃ N ₂ O): C, 55.97; H, 5.07; N, 9.28 Example 9 N- [3- (diethylamino) propyl] 3- [3-
(Trifluoromethyl) phenoxy] -1-azetidinecarboxamide [2: 3] 4.3 g (0.033 mol) of 3-diethylaminopropylamine and 4.9 g (0.033 mol) of 1,1′-carbonyldiimidazole in 60 ml of methylene chloride. ) Was stirred at room temperature for 1 hour. The resulting solution is treated with 3- [3-
Treated with (trifluoromethyl) phenoxy] azetidine (obtained from 9.21 g (0.03 mol) acid salt). 1
After stirring for 8 hours, transfer the reaction mixture to a separatory funnel and water 3 x 20 m.
Wash with l, dry over magnesium sulfate, and concentrate in vacuo to give a black oil. 8 g of this residue was added to a neutral alumina column 15
Chromatograph at 0 g, eluting with chloroform. The initial fractions were concentrated to give the product as an amber oil,
This was dissolved in methyl isobutyl ketone and treated with 2 g of acid. Dilution with isopropyl ether gave an oil which solidified and was recrystallized from acetone / isopropyl ether to give 6.25 g (41%) of tan crystals, mp 91-93 ° C.

Elemental _{analysis: (C 18 H 26 F 3} N 3 O 2 · 1.5C 2 H 2 O 4) Calcd C, 49.61; H, 5.75; N, 8.26 Found C, 49.56; H, 5.75; N, 8.24 carried Example 10 N- (2-propenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 8.7 g of crude 3- [4- (trifluoromethyl) phenoxy] azetidine in 75 ml of isopropyl ether ( 0.04 mol)
4.2 g (0.05 mol) of 2-propenyl isocyanate was added dropwise to the above solution under stirring under a nitrogen atmosphere. After stirring for 3 days, no crystalline product precipitated. The reaction mixture was concentrated to give a dark red oil. TLC (silica gel, 20% ethyl acetate / methylene chloride) showed at least 6 spots well separated. The residue was dissolved in chloroform, chromatographed on a 350 g silica gel column and eluted with chloroform until the reddish initial runoff was removed. The column was then eluted with an ethyl acetate / chloroform gradient to 4% ethyl acetate. All fractions were combined and concentrated to give 4.8 g of an orange oil which was left to crystallize. Recrystallization from acetone / cyclohexane gave 3.3 g (27.5%) of tan crystals, mp 91-92.5 ° C.

Elemental analysis: Calculated value (C ₁₄ H ₁₅ F ₃ N ₂ O ₂ ): C, 56.00; H, 5.04; N, 9.33 Actual value (C ₁₄ H ₁₅ F ₃ N ₂ O ₂ ): C, 55.98; H, 5.17; N, 9.36 Example 11 N- (Cyclopropylmethyl) -3- (3- (trifluoromethyl) phenoxy] -1-acetidinecarboxamide 2.6 g (0.024) of (aminomethyl) cyclopropane hydrochloride in 50 ml of pyridine. 1.9 g (0.024 mol) of 1,1'-carbonyldiimidazole was added while stirring the solution of (1 mol) under a nitrogen atmosphere.After stirring for 45 minutes, TLC (silica gel, 5% methanol / methylene chloride) showed no reaction. Not even shown.
Therefore, 2 ml of triethylamine was added. After 10 minutes the reaction mixture was cloudy and TLC showed new product. This reaction is 3- [3- (trifluoromethyl) phenoxy]
Treated with 6.2 g (0.02 mol) of the azetizate. After stirring for 1 hour, a sample was collected and diluted with water to precipitate a solid. CI mass spectrum showed it to be the product. After 2 days, the reaction mixture was diluted with 5 volumes of water and the resulting precipitate was collected by filtration to give 6.5 g of a pale yellow crystalline product. Recrystallization from ethanol / water gave white tabular crystals. This was dried in a drying pistol in vacuum at 82 ° C for 3 hours. The product weighed 5.8 g (92%) and had a melting point of 13
The temperature was 2 to 133 ° C.

Calcd _{(C 15 H 17 F 3 N} 2 O 2): C, 57.32; H, 5.45; N, 8.91 Found _{(C 15 H 17 F 3 N} 2 O 2): C, 57.22; H, 5.44; N, 8.86 Example 12 N, N-diethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 3- [3- (trifluoromethyl) phenoxy] azetidic acid in 50 ml of tetrahydrofuran. A stirred slurry of 5 g (0.0163 mol) salt was treated with 5 ml triethylamine,
After 1 hour 2.5 g (0.018 mol) of diethylcarbamoyl chloride
Was added. After stirring for an additional 15 hours, the reaction mixture was washed with water (10 mL).
Treated with ml to saturate calcium chloride. Tetrahydrofuran was decanted from the solid residue and concentrated in vacuo to give an oil. The crude oil was washed with Waters Prepoo LC (Wa
ter's Prep-LC) and eluted with 50% ethyl acetate / toluene. The main fraction was concentrated to give 3.1 g (60.1%) of a pale yellow oil.

Calcd _{(C 15 H 19 F 3 N} 2 O 2): C, 56.96; H, 6.05; N, 8.86 Found _{(C 15 H 19 F 3 N} 2 O 2): C, 56.69; H, 6.01; N, 8.77 Example 13 N, N-Dimethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 3- [3- (Trifluoromethyl) phenoxy] azetidic acid in 50 ml of tetrahydrofuran. A stirred slurry of 5 g (0.0163 mol) salt was treated with 5 ml triethylamine,
After 1 hour 1.95 g (0.018 mol) of dimethylcarbamoyl chloride
Was added. After stirring for a further 15 hours the reaction mixture was treated with 20 ml of water and 10 g of calcium chloride. The tetrahydrofuran layer was decanted, the residue was triturated with 20 ml of ethyl acetate and then decanted. The combined tetrahydrofuran / ethyl acetate solution was concentrated in vacuo and the crude residue obtained was chromatographed on a Waters Prep-LC.
Elute with 50% ethyl acetate / toluene. The main fraction was concentrated to give 3.6 g (76.6%) of a pale yellow oil.

Elemental analysis: Calculated value (C ₁₃ H ₁₅ F ₃ N ₂ O ₂ ): C, 54.17; H, 5.25; N, 9.72 Measured value (C ₁₃ H ₁₅ F ₃ N ₂ O ₂ ): C, 53.73; H, 5.20; N, 9.60 Example 14 N- (2-propynyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 3.9 g (0.024) of 1,1'-carbonyldiimidazole in 50 ml of tetrahydrofuran. Mol) and 1.32 g (0.024 mol) of 2-propynylamine are stirred at room temperature for 1 hour,
Then it was treated with 6.2 g of 3- [3- (trifluoromethyl) phenoxy] azetidine. The reaction mixture was treated with 3 ml triethylamine and stirred for 18 hours. It was then diluted with an equal volume of water to give 8 g of the moist product. Recrystallize from isopropyl ether to give a gray solid product and starting 2
3.8 g of a mixture of propynylamine with symmetrical urea was obtained.
A second recrystallization from ethanol / water gave 2.6 g (43.6%) of pure product, mp 105-106 ° C.

Elemental analysis: Calculated value (C ₁₄ H ₁₃ F ₃ N ₂ O ₂ ): C, 56.38; H, 4.39; N, 9.39 Found value (C ₁₄ H ₁₃ F ₃ N ₂ O ₂ ): C, 56.32; H, 4.34; N, 9.44 Example 15 N-cyclohexyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 5 g of 3- [3- (trifluoromethyl) phenoxy] azetidinate in 50 ml of tetrahydrofuran. A stirred mixture of (0.0163 mol) and cyclohexyl isocyanate 2.04 g (0.018 mol) was treated with 2 ml of triethylamine and then stirred for 18 hours. The reaction mixture was diluted with water and the solid precipitate was collected by filtration to give 12 g of crude product. Recrystallization from acetone / water gave 5 g of fine white crystals, mp 148-150 ° C. TLC (silica gel, ethyl acetate) showed the presence of traces of symmetrical cyclohexylurea and product.
White powder upon second recrystallization from isopropanol
1.65 g (29.6%) was obtained, which was dried under 0.5 mm Hg vacuum. Its melting point was 153-154 ° C.

Elemental analysis: Calculated value (C ₁₇ H ₂₁ F ₃ N ₂ O ₂ ): C, 59.64; H, 6.18; N, 8.18 Measured value (C ₁₇ H ₂₁ F ₃ N ₂ O ₂ ): C, 59.52; H, 6.20; N, 8.17 Example 16 N-Cyclopropyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 1,1′-carbonyldiimidazole 4.4 g (0.027 mol) in 50 ml methylene chloride. Was stirred under nitrogen with 1.54 g (0.027 mol) of cyclopropylamine. After a short induction period (2 minutes), the clear solution suddenly exothermed to a gentle reflux. After 1 hour, the reaction mixture was cooled to room temperature,
Purity 56.66% (containing diphenylmethane) 3- [4-
(Trifluoromethyl) phenoxy] azetidine 9.6g
(0.025 mol) were added all at once and stirred for 18 hours. The reaction mixture was concentrated on a rotary evaporator to give a partially crystalline residue. Partition the residue into 30/60 petroleum ether / water,
The resulting waxy solid was collected. Recrystallized from isopropyl ether to give 5.7g (7g
5.9%). After drying at 80 ℃ under 0.5 mmHg vacuum, its weight did not decrease, but the melting point reached 152-153 ℃.

Elemental analysis: Calculated value (C ₁₄ H ₁₅ F ₃ N ₂ O ₂ ): C, 56.00; H, 5.04; N, 9.33 Measured value (C ₁₄ H ₁₅ F ₃ N ₂ O ₂ ): C, 55.77; H, 4.98; N, 9.44 Example 17 N- (Cyclopropylmethyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 4.4 g 1,1'-carbonyldiimidazole in 50 ml methylene chloride ( To a stirred mixture of 0.027 mol) and (aminomethyl) cyclopropane hydrochloride 2.9 g (0.027 mol) was added triethylamine 2.73 g (0.027 mol) dropwise. The reaction was exothermic. The mixture was cooled with stirring for 1 hour, then 9.6 g (0.025 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine with a purity of 56.66% (containing diphenylmethane) was added all at once and stirred for 18 hours. The reaction mixture was concentrated on a rotary evaporator to give an amber residue. This residue is mixed with 30/60 petroleum ether 2 × 2
Trituration with 0 ml gave only an insoluble oil. The residue was treated with water to give a white solid which was recrystallized from isopropyl ether to give 4.8 g (61.8 g) of white tabular crystals.
%) Was obtained. The melting point after drying at 80 ° C under vacuum of 0.5 mmHg is 132
It was at ~ 133 ° C.

Elemental analysis: Calculated value (C ₁₅ H ₁₇ F ₃ N ₂ O ₂ ): C, 57.32; H, 5.45; N, 8.91 Actual value (C ₁₅ H ₁₇ F ₃ N ₂ O ₂ ): C, 57.26; H, 5.46; N, 8.93 Example 18 N- [3- (diethylamino) propyl] -3- [4-
(Trifluoromethyl) phenoxy] -1-azetidinecarbothioamide A stirred solution of 1.92 g (0.005 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine having a purity of 56.66% (containing diphenylmethane) in 20 ml of isopropyl ether was added. , 3- (diethylamino) propyl isothiocyanate
Treated with 0.88 g (0.005 mol) and stirred for 3.5 hours. The reaction mixture was treated with 0.5 g of acid dissolved in 2 ml of methanol. After stirring for 18 hours, the solid was collected by filtration, melting point 147-1.
1.9 g of fine yellow-brown powder at 50 ° C. was obtained. This solid was dissolved in water and treated with dilute sodium hydroxide solution. The oil that separated solidified and was collected by filtration. Recrystallized from cyclohexane, 1.1 g of fine tan crystals with a melting point of 109-110 ℃.
(56.5%) was obtained.

Calcd _{(C 18 H 26 F 3 N} 3 OS): C, 55.51; H, 6.73; N, 10.79 Found _{(C 18 H 26 F 3 N} 3 OS): C, 55.68; H, 6.67; N, 10.73 Example 19 N- [3- (diethylamino) propyl] -3- [4-
(Trifluoromethyl) phenoxy] -1-azetidinecarboxamidate [1: 2] 3- (diethylamino) under nitrogen to a stirred mixture of 4.4 g (0.027 mol) of 1,1′-carbonyldiimidazole in 50 ml of methylene chloride. 3.52 g (0.027 mol) of propylamine was added dropwise. Cooling the slightly exothermic reaction mixture to room temperature 1
After stirring for an hour, 9.6 g (0.025 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine (purity 56.66%, containing diphenylmethane) were added all at once. After stirring for 18 hours, the reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in toluene. The toluene solution was washed with 3 × 20 ml of water and then treated with 2.5 g of acid in 10 ml of isopropanol. The resulting solid was collected by filtration and triturated with boiling acetone. After passing, unidentified fine white precipitate
1.8 g was formed, which was separated by filtration. The acetone solution was concentrated to give a solid which was recrystallized from isopropyl alcohol / isopropyl ether to give 9.2 g of crude product (4 spots on TLC; silica gel, 10% methanol / methylene chloride). Recrystallization from methyl ethyl ketone gave 6.8 g (49.1%) of a fine white powder, mp 129-130 ° C.

Elemental _{analysis: (C 18 H 26 F 3} N 3 O 2 · 2C 2 H 2 O 4): Calculated C, 47.74; H, 5.46; N, 7.59 Found C, 47.82; H, 5.68; N, 7.76 carried Example 20 N- (2-propynyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide A solution of 4.4 g (0.027 mol) of 1,1'-carbonyldiimidazole in 50 ml of tetrahydrofuran is charged with nitrogen. 1.49 g (0.027 mol) of 2-propynylamine with stirring underneath
Was added by a needle through a septum placed on one neck of the reaction flask. After stirring for 2 hours, 3- [4- (trifluoromethyl) phenoxy] azetidine (purity 56.66
%, Containing diphenylmethane) (9.6 g, 0.025 mol) was added all at once and the mixture was stirred for another 18 hours. The reaction mixture was diluted with ice water and extracted with 30/60 petroleum ether to remove diphenylmethane. Oily aqueous portion of methylene chloride 4 x 50 ml
It was extracted with. These extracts were combined, dried over sodium sulfate and concentrated on a rotary evaporator to give an amber oil. This oil is a small amount of isopropyl ether (50 ml)
It solidified when finely ground with. By filtration, 6.1 g of a light red solid product was obtained. TLC (silica gel, 10% methanol / methylene chloride) showed a mixture of three products and some starting material. Recrystallization from ethanol / water gave the product in several small fractions. These fractions were combined and recrystallized from isopropyl ether to obtain 4.1 g of a pale tan powder having a melting point of 135 to 137 ° C. TLC still showed the presence of some symmetrical 2-propynyl urea. The solid is recrystallized from ethanol / water and has a melting point of 140-1.
3.5 g (46.9%) of a pale yellow crystalline product at 41 ° C was obtained.

Elemental analysis: Calculated value (C ₁₄ H ₁₃ F ₃ N ₂ O ₂ ): C, 56.38; H, 4.39; N, 9.39 Found value (C ₁₄ H ₁₃ F ₃ N ₂ O ₂ ): C, 56.34; H, 4.36; N, 9.32 Example 21 N- (2-methyl-2-propenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 1,1'-carbonyldi in 75 ml methylene chloride. While stirring a solution of 3.6 g (0.022 mol) of imidazole under nitrogen,
Then, through a septum installed in one neck of the reaction flask, 1.6 g of 2-methyl-2-properamine was injected with an injection needle.
(0.022 mol) was added. After stirring for 1 hour, 3- [4-
(Trifluoromethyl) phenoxy] azetidate
6.2 g (0.02 mol) was added all at once, and after 30 minutes, 5 ml of triethylamine was added and the mixture was stirred for 3 hours. The reaction mixture was washed with 2 × 25 ml water, dried over magnesium sulfate and concentrated in vacuo. The oily residue is left to solidify and is recrystallized from isopropyl ether to give a melting point of 101-102.
3.7 g (58.9%) of fine white crystals at ℃ were obtained.

Elemental analysis: Calculated value (C ₁₅ H ₁₇ F ₃ N ₂ O ₂ ): C, 57.32; H, 5.45; N, 8.91 Actual value (C ₁₅ H ₁₇ F ₃ N ₂ O ₂ ): C, 57.45; H, 5.51; N, 9.23 Example 22 N- (2-Methyl-2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 1,1'-carbonyldi in 75 ml methylene chloride. While stirring a solution of 3.6 g (0.022 mol) of imidazole under nitrogen,
To this, 1.6 g (0.022 mol) of methallylamine was added by a needle through a septum placed in one neck of the reaction flask. The reaction was slightly exothermic. 1 reaction mixture
After stirring for an hour, the mixture was treated with 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidinate, and 0.5 hour later, 5 ml of triethylamine was added and the mixture was stirred for 16 hours. The reaction mixture is washed with 2 × 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator to give an oily residue 6.
7 g was obtained and solidified. This solid was recrystallized from isopropyl ether to give fine white crystals (melting point 90-91 ° C).
5.4 g (85.9%) was obtained.

Elemental analysis: Calculated value (C ₁₅ H ₁₇ F ₃ N ₂ O ₂ ): C, 57.32; H, 5.45; N, 8.91 Actual value (C ₁₅ H ₁₇ F ₃ N ₂ O ₂ ): C, 57.20; H, 5.50; N, 8.95 Example 23 N- (3-Methyl-2-butenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 1,1'-carbonyldi in 100 ml of methylene chloride. A solution of imidazole 3.6g (0.022mol) is cooled with tap water and stirred under nitrogen with stirring 3-methyl-2-butenylamine 1.87g.
(0.022 mol) was added dropwise. After stirring for 1 hour, 3- [4-
(Trifluoromethyl) phenoxy] azetidate
6.2 g (0.02 mol) were added all at once, then 0.5 ml later, 5 ml of triethylamine was added, and the mixture was stirred for another 16 hr. The reaction mixture was washed with 2 × 50 ml of water, dried over magnesium sulfate and concentrated on a rotary evaporator to give a semi-solid residue. Triturated with isopropyl ether to give 7 g of crude product, recrystallized from ethanol / water, mp 156.5-1
5.5 g (83.8%) of white crystals at 58 ° C were obtained.

Elemental analysis: Calculated value (C ₁₆ H ₁₉ F ₃ N ₂ O ₂ ): C, 58.53; H, 5.83; N, 8.53 Actual value (C ₁₆ H ₁₉ F ₃ N ₂ O ₂ ): C, 58.81; H, 5.89; N, 8.58 Example 24 N- (3-Methyl-2-butenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 1,1'-carbonyldiimidazole in 100 ml of tetrahydrofuran. 3.6 g (0.022 mol) of the solution was cooled in a tap water bath and 1.6 g (0.022 mol) of 3-methyl-2-butenylamine was added by syringe under nitrogen with stirring. After stirring this reaction mixture for 1 hour, 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidinate
With 0.5 ml, followed by 5 ml of triethylamine after 0.5 h and stirred for 72 h. 500 ml of ice water in the reaction mixture
It was diluted with and extracted with 6 × 50 ml of methylene chloride. The combined extracts were washed with water, dried over magnesium sulfate and concentrated on a rotary evaporator to give a solid residue. Recrystallization from ethanol / water gave 6 g of white crystals with a melting point of 143-144 ° C.

Elemental analysis: Calculated value (C ₁₆ H ₁₉ F ₃ N ₂ O ₂ ): C, 58.53; H, 5.83; N, 8.53 Actual value (C ₁₆ H ₁₉ F ₃ N ₂ O ₂ ): C, 58.46; H, 5.86; N, 8.69 Example 25 (E) -N- (2-butenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 1,1'-carbonyldiimidazole 3.6 g (0.022) Mol) and 1.6 g (0.022 mol) of trans-crotylamine were stirred for 1 hour and treated with 6.2 g (0.02 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidinate, after 30 minutes 5 ml of triethylamine. Was added and stirred for 16 hours. The partially crystalline mixture was washed with 2 × 50 ml of water, washed with magnesium sulfate and concentrated on a rotary evaporator to give a solid residue, 14.2 g. Recrystallized from methanol / water, melting point 157
Obtained 5.35 g (85.1%) of fine white crystals at ˜158 ° C.

Calcd _{(C 15 H 17 F 3 N} 2 O 2): C, 57.32; H, 5.45; N, 8.91 Found _{(C 15 H 17 F 3 N} 2 O 2): C, 57.47; H, 5.49; N, 9.00 Example 26 (E) -N- (2-butenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 1,1'-carbonyldi in 60 ml of methylene chloride. A solution of 3.6 g (0.022 mol) of imidazole was cooled in an ice bath and trans-crotylamine 1.6 g (0.022 mol) with stirring under nitrogen.
Mol) was added dropwise. After warming to room temperature, 6.2 g of 3- [3- (trifluoromethyl) phenoxy] azetidinate (0.
(02 mol) was added all at once, and after 0.25 hours, 5 ml of triethylamine was added and stirred for 72 hours. 2 x 50 ml of reaction solution in water
Washed with, dried over magnesium sulfate, and concentrated on a rotary evaporator to give a solid residue, 7 g. Recrystallization from methanol / water yielded 5.5 g of slightly yellow product. Recrystallized from isopropyl ether using activated carbon and melting point 127-128 ° C.
To obtain 3.75 g (59.7%) of fine white crystals.

Elemental analysis: Calculated value (C ₁₅ H ₁₇ F ₃ N ₂ O ₂ ): C, 57.32; H, 5.45; N, 8.91 Actual value (C ₁₅ H ₁₇ F ₃ N ₂ O ₂ ): C, 57.35; H, 5.47; N, 8.94 Example 27 N-phenyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 6.2 g 3- [3- (trifluoromethyl) phenoxy] azetidine in 60 ml of tetrahydrofuran. A stirred slurry of 0.02 mol) was treated with 5 ml of triethylamine, followed by 2.62 g (0.022 mol) of phenyl isocyanate and stirred for 16 hours. The reaction mixture was diluted with water until an oil separated. The oil solidified quickly. Decant the aqueous tetrahydrofuran and remove the residue with ethanol /
Recrystallized from water, white crystals 5.3 g (80.1
%) Was obtained.

Elemental analysis: Calculated value (C ₁₇ H ₁₅ F ₃ N ₂ O ₂ ): C, 60.71; H, 4.50; N, 8.33 Measured value (C ₁₇ H ₁₅ F ₃ N ₂ O ₂ ): C, 60.81; H, 4.47; N, 8.35 Example 28 N-phenyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide 3- [4- (trifluoromethyl) phenoxy] azetidinate 6.2 in 60 ml of tetrahydrofuran 6.2. A stirred slurry of g (0.02 mol) and phenyl isocyanate (2.62 g, 0.022 mol) was treated with 5 ml triethylamine and stirred for 16 hours. The reaction mixture was diluted with water until an oil separated. The tetrahydrofuran / water portion was decanted and the residue was left to solidify. Recrystallized from ethanol / water to give 3.5g (5g) of fine white crystals with melting point 174.5-176 ℃.
3.4%).

Elemental analysis: Calculated value (C ₁₇ H ₁₅ F ₃ N ₂ O ₂ ): C, 60.71; H, 4.50; N, 8.33 Actual value (C ₁₇ H ₁₅ F ₃ N ₂ O ₂ ): C, 60.91; H, 4.53; N, 8.35 Example 29 trans-N, 2-Dimethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide Crude trans-2-methyl- in 50 ml tetrahydrofuran.
To a stirred solution of 3- [3- (trifluoromethyl) phenoxy] azetidine 6 g (0.015 mol) was added methyl isocyanate.
0.94 g (0.0165 mol) was added dropwise, and the mixture was stirred under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water to give an oil,
Solidified. After decanting the aqueous tetrahydrofuran phase, the solid residue was recrystallized from ethanol / water to give a melting point of 10
There were obtained 3.95 g (91.4%) of fine white crystals at 4.5-106 ° C.

Elemental analysis: Calculated value (C ₁₃ H ₁₅ F ₃ N ₂ O ₂ ): C, 54.17; H, 5.25; N, 9.72 Calculated value (C ₁₃ H ₁₅ F ₃ N ₂ O ₂ ): C, 54.50; H, 5.29; N, 9.71 Example 30 trans-2-Methyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide Crude trans-2-methyl-3- [3-] in 40 ml acetone.
(Trifluoromethyl) phenoxy] azetidine (purity
A mixture of 6 g (0.015 mol) of 56.6%, containing diphenylmethane) and 2.4 g (0.0225 mol) of nitrourea was treated with 4 ml of water and then heated until a clear homogeneous solution was obtained.
The reaction mixture was stirred overnight with cooling to room temperature and diluted with water until an oil separated. The oily substance was solidified and recrystallized from ethanol / water to obtain 4.3 g of a white tabular crystal having a melting point of 117 to 118 ° C. The product was recrystallized from benzene to give 3.35 g (96.8%) of crystals, mp 118-119 ° C.

Calcd _{(C 12 H 13 F 3 N} 2 O 2): C, 52.56; H, 4.78; N, 10.22 Found _{(C 12 H 13 F 3 N} 2 O 2): C, 52.54; H, 4.74; N, 10.17 Example 31 trans-2-methyl-N- (2-propenyl) -3-
[3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide crude trans-2-methyl- in 50 ml of tetrahydrofuran.
To a solution of 3- [3- (trifluoromethyl) phenoxy] azetidine (purity 56.6%) 6 g (0.015 mol) was added 2-propenyl isocyanate 1.54 g (0.0165 mol) all at once and stirred under nitrogen for 16 hours. . The reaction mixture was diluted with water until an oil separated. The oil did not crystallize and after 7 weeks was triturated with 3 x 25 ml isopropyl ether. These were combined to obtain 400 mg (8.5%) of white granular crystals having a melting point of 55 to 57 ° C.

Elemental analysis: Calculated value (C ₁₅ H ₁₇ F ₃ N ₂ O ₂ ): C, 57.32; H, 5.45; N, 8.91 Actual value (C ₁₅ H ₁₇ F ₃ N ₂ O ₂ ): C, 57.36; H, 5.50; N, 8.97 Example 32 3- (3-Chlorophenoxy) -N-methyl-1-azetidinecarboxamide 1-chlorocarbonyl-3 in 20 ml of tetrahydrofuran.
-(3-Chlorophenoxy) azetidine To a solution of 0.01275 mol of 4% 40% aqueous methylamine solution (0.05 mol) was added and stirred for 16 hours. The reaction mixture was diluted with water until an oil started to separate, then extracted with 3 x 50 ml benzene. The combined extracts were dried over magnesium sulphate, concentrated and the residual solid recrystallized from benzene / ligroin to give 1.2 g (40.0%) of fine white crystals, mp 140-141 ° C.

Elemental analysis: Calculated value (C ₁₁ H ₁₃ ClN ₂ O ₂ ): C, 54.89; H, 5.44; N, 11.64 Measured value (C ₁₁ H ₁₃ ClN ₂ O ₂ ): C, 55.05; H, 5.58; N, 11.52 Example 33 3- (3-Chlorophenoxy) -N- (2-propenyl) -1-azetidinecarboxamide 1-Chlorocarbonyl-3 in 20 ml of tetrahydrofuran.
2.3 g (0.04 mol) of 2-properamine was added to a solution of 5.4 g (0.017 mol) of-(3-chlorophenoxy) azetidine, and the mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo to give a reddish tan solid. The solid was finely ground with water to give 4.4 g of crude product. After drying, it was treated with activated carbon and recrystallized from 2% acetone / isopropyl ether to obtain 1.7 g (37.5%) of pale tan crystals with a melting point of 87 to 89 ° C.

Elemental analysis: Calculated value (C ₁₃ H ₁₅ ClN ₂ O ₂ ): C, 58.54; H, 5.67; N, 10.50 Actual value (C ₁₃ H ₁₅ ClN ₂ O ₂ ): C, 58.48; H, 5.72; N, 10.49 Example 34 N-Methyl-3- (2-pyridinyloxy) -1-azetidinecarboxamide 40 ml (0.08 mol) of a 2M solution of phosgene in benzene are added to a suspension of 10 g of fine potassium carbonate in 40 ml of methylene chloride.
The mixture is stirred at room temperature for 15 minutes and methylene chloride 50
10 g (0.056 mol) of 1- (1-phenylethyl) -3- (2-pyridyloxy) azetidine in ml were added with gentle cooling. The mixture was stirred at room temperature for 1 hour and concentrated on a rotary evaporator (25 ° C / 30 minutes). The residue was treated with 100 ml of tetrahydrofuran and cooled in an ice bath. To the cooled and stirred mixture was added 20 ml of 40% aqueous methylamine solution. The mixture was stirred for 20 minutes and partitioned between methylene chloride and water. The methylene chloride phase was dried over sodium sulfate and concentrated. The residue was crystallized from benzene / ethanol and recrystallized from ethyl acetate / isopropyl alcohol. The yield of the title compound was 2.3g (14%) and its melting point was 165-168 ° C.

Calcd _{(C 10 H 13 N 3 O} 2): C, 57.96; H, 6.32; N, 20.28 Found _{(C 10 H 13 N 3 O} 2): C, 57.93; H, 6.34; N, 20.12 Example 35 N-2-propenyl-3- (2-pyridinyloxy)-
1-azetidinecarboxamide 32 ml of a 2M benzene solution of phosgene in a stirred suspension of 10 g (0.072 mol) of fine potassium carbonate in 90 ml of methylene chloride.
062 mol) was added. The mixture is stirred for 15 minutes and 1- (1-phenylethyl) -3- (2
8 g (0.031 mol) of -pyridyloxy) azetidine were added. The mixture was stirred for 2 hours at 25 ° C and concentrated on a rotary evaporator at 325 ° C / 30 minutes and the residue was added to 100m of tetrahydrofuran.
treated with l. The stirred mixture was cooled in an ice bath and 4 g (0.07 mol) of allylamine was added dropwise. After stirring at 25 ° C for 30 minutes,
The mixture was partitioned between water and methylene chloride. The methylene chloride phase was dried and concentrated. The residue was chromatographed on a Waters Prepoo 500 HPLC on a silica gel column, eluting with 50% ethyl acetate / hexane. The product was crystallized twice from isopropyl ether. The yield of the title compound is 1.5 g (21%), its melting point is 72-76.
It was ℃.

Elemental analysis: Calculated value (C ₁₂ H ₁₅ N ₃ O ₂ ): C, 61.79; H, 6.48; N, 18.01 Actual value (C ₁₂ H ₁₅ N ₃ O ₂ ): C, 61.53; H, 6.50; N, 17.96 Example 36 3- (2-Pyridinyloxy) -1-azetidinecarboxamide To a stirred suspension of 10 g of fine potassium carbonate in 8 ml of methylene chloride was added 32 ml (0.062 mol) of a 2M benzene solution of phosgene. The mixture was stirred for 15 minutes and 8 g (0.031 mol) 1- (1-phenylethyl) -3- (2-pyridyloxy) azetidine in 50 ml methylene chloride was added. The mixture was stirred for 35 minutes and concentrated on a rotary evaporator (25 ° C / 30 minutes).
The residue is treated with 100 ml of tetrahydrofuran, cooled in a water bath and 20 ml of concentrated ammonium hydroxide with vigorous stirring.
Was gradually added. The mixture was stirred at room temperature for 1 hour and partitioned between methylene chloride and water. Aqueous phase 2 with methylene chloride
It was extracted twice and the combined organic phases were concentrated. The residue was crystallized from benzene and recrystallized from isopropyl ether. The yield of the title compound is 1.4 g, its melting point is 133-1
It was 37 ° C.

Elemental analysis: Calculated value (C ₉ H ₁₁ N ₃ O ₂ ): C, 55.95; H, 5.74; N, 21.75 Measured value (C ₉ H ₁₁ N ₃ O ₂ ): C, 55.73; H, 5.71; N, 21.10 Example 37 2- [1- (1-phenylethyl) -3-azetidinyloxy] pyridine 1- (1-phenylethyl) -3-azetidinol maleate 65 g (0.22 mol) of toluene and dilute sodium hydroxide. The mixture was partitioned into solutions and extracted once with toluene. The organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in 125 ml of dimethylformamide and added dropwise at 25-35 ° C. to a stirred suspension of 9.6 g (0.24 mol) of sodium hydride (3 washes with isooctane) in 40 ml of dimethylformamide. This solution is heated to 65 ° C., while heating at 75 ° C.
35 g (0.22 mol) of bromopyridine was added dropwise. The solution was heated and stirred at 90 ° C. for 1 hour, and then heated at 120 ° C. for 2.75 hours. The mixture was stirred at room temperature overnight and concentrated. The residue was partitioned between water and isopropyl ether, the organic phase was washed twice with water, dried over sodium sulfate and concentrated. The crude yield was 30 g. Distill the residue (boiling point 128 ~ 13
4 ° C./0.01 mmHg) to obtain 8 g of product.

Elemental analysis: Calculated value (C ₁₆ H ₁₈ N ₂ O): C, 75.57; H, 7.13; N, 11.01 Actual value (C ₁₆ H ₁₈ N ₂ O): C, 75.20; H, 7.18; N, 10.90 Performed Example 38 1- [3- [4- (trifluoromethyl) phenoxy]
-1-Azetidinylcarbonyl] -1H-imidazole 1,1'-carbonyldiimidazole 1.7 g (0.01 mol) and 3- [4- (trifluoromethyl) phenoxy] azetidine 3 g (0.015 mol) in 50 ml of tetrahydrofuran.
The mixture was stirred for 6 hours. The reaction mixture was diluted with water and extracted with 3 x 50 ml methylene chloride. The extract was concentrated in vacuo to give an amber residue, which was dissolved in 20 ml of benzene, washed with dilute hydrochloric acid and then with water. The benzene phase was concentrated to give a semi-solid residue, which was triturated with isopropyl ether to give 1.4 g of a gray substance. Recrystallized from acetonitrile, 1.3 g (4 g) of fine gray crystals with a melting point of 139-140 ° C.
1.8%).

Calcd _{(C 14 H 12 F 3 N} 3 O 2): C, 54.02; H, 3.89; N, 13.50 Found _{(C 14 H 12 F 3 N} 3 O 2): C, 54.33; H, 3.96; N, 13.89 Example 39 3- (3-Chlorophenoxy) -1-azetidinecarboxamide 1-chlorocarbonyl-3- (3-chlorophenoxy)
Tetrahydrofuran 20m with azetidine 5.4g (0.017mol)
3 ml of ammonium hydroxide was added to the solution dissolved in 1 and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give a wet solid, 4 g.
This was dried and recrystallized from benzene to obtain 1.5 g of white crystalline powder. Mp 163-14.5 ° C. The yield calculated from the 1- (2-phenylethyl) azetidine compound is 38.9%.
It was.

Calcd _{(C 10 H 11 ClN 2 O} 2): C, 52.99; H, 4.89; N, 12.36 measured values _{(C 10 H 11 ClN 2 O} 2): C, 52.99; H, 4.91; N, 12.32 Example 40 3- (3-Fluorophenoxy) -N-methyl-1-azetidinecarboxamide 5.4 g (0.02 mol) of 3- (3-fluorophenoxy) -azetidinate and ityl in 20 ml of tetrahydrofuran. 1.7g (0.022mol) of isocyanate was stirred,
To this, 5 ml of triethylamine was added and stirring was continued for another 3 hours. The reaction mixture was diluted with water and the resulting microcrystalline precipitate was collected by filtration and dried under vacuum at 60 ° C to give 3 g of product.
(66.9%) was obtained. Melting point 155-156 ° C.

Elemental analysis: Calculated value (C ₁₁ H ₁₃ FN ₂ O ₂ ): C, 58.92; H, 5.84; N, 12.49 Measured value (C ₁₁ H ₁₃ FN ₂ O ₂ ): C, 58.93; H, 5.91; N, 12.26 Pharmacological activity Anticonvulsant activity was measured against compounds of formula I and was demonstrated by chemical or electrical stimulation as shown below.

Chemical stimulation with metrazole (Swinyard
yard method] A group of 8 adult female mice was treated with R.G.D. Steel (Steel).
And J.H. Torrie ["Principles and Procedu
res of Statistics "(Principles and methods of statistics), McGraw-
Hill Book Company, Inc., pages 99-100 and 42-31 (19
60 years)] and assigned to the administration groups. each
Mice were identified by a color code on their tail. Trial
Compound is a 0.5% aqueous methylcellulose solution or suspension
10 ml / kg of mouse body weight as
Was administered internally. Metrazole (Pentylene tetrazo
Was prepared as a solution of physiological saline. Mouse tested
I had never fasted before. 8 mice for each dose
Tested with uss.

Each mouse received a single intraperitoneal injection of test drug in 0.5% aqueous methylcellulose (100 mg / kg for normal screening) or control (0.5% aqueous methylcellulose only). Thirty minutes after administration of the test compound or control, metrazole (80 mg / kg S.C.) was administered to the slack part of the back of the neck. Injection was carried out using a 1 ml glass tuberculin syringe with an appropriately sized hypodermic needle (27 gauge for solution, 23 gauge for suspension). All injections were made in a volume of 10 ml / kg of mouse body weight. Each mouse was observed for 30 minutes after the injection of metrazol. Protection was defined as the animals showing no minimal seizures (one episode of clonic convulsions lasting at least 5 seconds or more). Data on anticonvulsiveness are% protection, ie As shown in the table.

ED ₅₀ value, 95% confidence limit, and efficacy ratio are DJ finy (F
inney) 〔Statistical Method in Biological Assay
(Statistical methods in biological tests), 2nd edition, New York, Hefner Publishing Co. (1964)].

Electrical Stimulation Adult female mice in groups of 8 were treated with the test drug (usually the initial strain).
For cleaning 100 mg / kg) liquid medium, usually
It was dissolved in physiological saline or water and administered by intraperitoneal injection.
Place the brass electrode on the cornea and place the glass stain
- ， Constant current unit and hunter timer To
Electrical stimulation for 0.2 seconds (60Hz, 5msec pulse width, 34mA
The animals were electrically stimulated by applying the intensity. So
In animals with stressful seizures when resting the above stimuli
The absence was recorded as a protective effect. Predetermined amount of test drug
Determines the number of animals protected from tension seizures on treatment
did. ED₅₀Value, 95% confidence limit, and efficacy ratio are J.T. Litch
field and F. Wilcoxon [J.Pharmacol.Exp.Ther., 96,
Page 99-113 (1949)].

Some of the more active compounds, as shown in Examples 7,8,10,14,16 and 20, have ED ₅₀ values of 5 in the metrazol test.
To 30 mg / kg, and about 10 to 3 in electrical stimulation tests
It showed 0 mg / kg.

The results of the above-mentioned pharmacological test for chemical and electrical stimulation with metrazole are shown in the table.

As is clear from the above table, the compounds of the present invention are
57-64665, JP 59-80657 and JP 60
-1161 compared to the similar compounds described in the publication,
Remarkably excellent anticonvulsant activity.

Formulation and Administration The pharmacologically active 3-phenoxy-1-azetidinecarboxamides of the present invention are effective in the treatment of both small and large seizures. Effective amounts of these compounds are capsules, tablets,
Alternatively, it can be administered orally as an elixir to a living animal body. The active ingredient need only be contained in an effective amount, ie, an appropriate effective administration will be achieved corresponding to the dosage form used. Of course, the daily dosage as well as the individual dosage can be determined according to standard drug principles under the guidance of a physician and veterinarian.

Based on comparison with known compounds having anticonvulsant activity, the daily dose is preferably about 0.5 to 1.5 mg / kg body weight in the treatment of small seizures and about 25 to 35 mg / kg body weight in the treatment of large seizures. Would be good Even a very small amount of the active substance of the present invention, for example 0.1 mg, is effective in the case of mild treatment. Unit dosage is usually 5 mg or more, preferably per unit dosage
25, 50 or 100 mg. The active ingredients of the present invention may be combined for administration with other pharmacologically active agents previously indicated, or with buffers, antacids and the like.

Capsules Capsules of 5 mg, 25 mg and 50 mg of active ingredient are prepared per capsule. It may be made by reducing the amount of lactose if it contains higher amounts of active ingredient. Typical encapsulation for encapsulation mg Active ingredient 5.0 Lactose 296.7 Starch 129.0 Magnesium stearate 4.3 Total 435.0 mg The active ingredients selected are mixed homogeneously with lactose, starch and magnesium stearate and the mixture is encapsulated.

In addition to the above, capsule formulations preferably contain higher dosages of the active ingredient, as indicated below.

Tablets A typical formulation for tablets containing 5.0 mg of active ingredient per tablet is as follows: This formulation can also be used for other strength active ingredients by adjusting the weight of dicalcium phosphate. Ingredients per tablet, mg (1) active ingredient 5.0 (2) corn starch 13.6 (3) Corn starch (paste) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate 0.9 Total 170.1Mg 1 Mix 2, 2, 4 and 5 evenly. Add 3 to water to make a 10% paste. The starch mixture is granulated with starch paste and the wet mass is passed through a number 8 mesh screen. The moist granules are dried and passed through a 12 mesh screen. The dried granules are mixed well with calcium stearate and compression molded.

The tablet formulation in addition to the above preferably contains higher doses of the active ingredient, as indicated below.

50mg tablets Ingredients per tablet, mg active ingredient 50.0 Lactose 90.0 Corn starch 58.0 Calcium 2.0 Total 200.0 The active ingredient stearic acid to uniformly mix the lactose and corn starch. The mixture is granulated with water as the granulating medium.
Pass the wet granules through an 8 mesh screen and
Dry overnight at ~ 160 ° F. Number this dried granules
Pass through a 10 mesh screen and mix with the appropriate amount of calcium stearate, which is then tabletted in a suitable tablet press.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Harold Fuchsia Stouffer Junier 23113, Virginia, United States, Mid-Russian, Old Footx Trail 4415 (56) Reference JP-A-57-64665 (JP, A) JP 59-80657 (JP, A) JP 60-1161 (JP, A)

Claims (9)

[Claims] 1. A formula [In the formula, Ar may be a pyridyl group substituted with halogen, 2-.3- or 4-pyridyl group, a phenyl group,
Alternatively, it is selected from a phenyl group substituted by 1 or 2 groups selected from halogen, a lower alkyl group, a lower alkoxy group, a nitro group, an aminocarbonyl group or a trifluoromethyl group, Z is oxygen or sulfur, and R is R. ¹ and R ² are selected from hydrogen, allyl group, propargyl group and cyclopropyl group, R ³ is selected from hydrogen, lower alkyl group, aryl group or aryl lower alkyl group, provided that R ³ is hydrogen, When Z is oxygen and Ar is a phenyl group or a phenyl group substituted with a trifluoromethyl group and an aminocarbonyl group, R ¹ and R ² cannot be a combination of hydrogen and a lower alkyl group, respectively. , still, R ³ is hydrogen, Z is oxygen, Ar is a phenyl group or a fluorine, a lower alkyl group, lower alkoxycarbonyl Shi group, a trifluoromethyl group, when a phenyl group substituted with an acetyl group or an amino carbonyl group, R ¹
And R ² cannot both be hydrogen. ] A 3-aryloxyazetidinecarboxamide compound selected from the group represented by
Geometric isomers, including (E) and (Z) isomers, and
An anticonvulsant for administering an pharmaceutically acceptable acid addition salt of Ar having a pyridyl group to an animal as an active ingredient. 2. The compound is N- (2-propenyl) -3.
The anticonvulsant according to claim 1, which is-[3-trifluoromethyl) phenoxy] -1-azetidinecarboxamide. 3. The above compound is N-cyclopropyl-3-
The anticonvulsant according to claim 1, which is [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide. 4. The compound is N- (2-propenyl) -3.
The anticonvulsant according to claim 1, which is-[4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide. 5. The above compound is N- (2-propynyl)-
The anticonvulsant according to claim 1, which is [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide. 6. The compound is N-cyclopropyl-3-
The anticonvulsant according to claim 1, which is [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide. 7. The compound is N- (2-propynyl) -3.
The anticonvulsant according to claim 1, which is-[4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide. 8. The compound is trans-2-methyl-N-
The anticonvulsant according to claim 1, which is (2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide. 9. The compound is N- (2-propenyl) -3.
The anticonvulsant according to claim 1, which is-(2-pyridinyloxy) -1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof.