AU599585B2 - 3-Aryloxyazetidine carboxamides as anticonvulsants and antiepileptics - Google Patents

Description

Coin Z so of tents TH UR S E CO.

;ATEN MARK ATTORNEYS

SYDNEY

(ZS G. SIELY F.I.P.A.A.

A.S.C. COCQMOMWEAITH OF AUST 2 PATENTS ACT,, 1952 1312) COM1PLETE SPEC IFI CATION.

(ORIGINAL.)

FOR OFFICE USE Short Title,.

Int. Cl S cc'tj2,n 2 CtsaedS T11 ctf~, )n 9g"Land Application NunL'er Lodged: e b -6~ Complete Specification-Lodg.ed Accepted.

Lapsed; Published.

Priority: Related Art; 4 4 TO BE COMPLETED BY APPLIC;IITT I (Name of Applicant; S 4 A.H. ROBINS COMPANY, INCORPORATED Address of Applicantj Richmond, Virginia, U.S.A.

Actual Inventor: Chandler Roy TAYLOR, Jr, Albert Duncan CALE, Jr and Harold Visher STAUFFER, Jr ARTHUR S. CAVP la! CO., Patent. and, Trade Marl- Attorneys, 1 A lfred Street, Sydney, New South Wales, Australia, 2000.

for Service, Complete Specification for the invention entitled: ~q:ccpomA~. o9S.% sc The following statement is a full description cf this invention, including the best method of performing it knowin to mei- -1- ASC-A49 ARTHUR S. CAVE CO.

PATENT AND TRADE MARK ATTORNEYS

SYDNEY

Signature of Declarant John Chalmers Gordon Assistant Secretary t la BACKGROUND OF THE INVENTION 1. Field of Invention.

This invention relates to certain novel 3-aryloxyazetidinecarboxamides, methods of treatment for anticonvulsant effect and epilepsy therewith and pharmaceutical compositions thereof.

2. Description of the prior art.

Certain mono-N-substituted azetidinecarboxamides are disclosed in U. S. Patent 4 22 6,8 6 1 as having anticonvulsant activity and useful in treating epilepsy having 10 the formula: 4 44 4d t 44 4 4( 44r f 4 4 4* 4 446 4 o *o o 0 0 R-NHC-N wherein R is loweralkyl and R 1 is hydrogen, aminocarbonyl or trifluoromethyl.

N-Unsubstituted-azetidinecarboxamides are disclosed and claimed in U. S. application Serial No. 664,036 filed on October 22, 1984, as having anticonvulsant activity and use in treating epilepsy having the formula: I I(R')

NH

2

-C-N

0H -C wherein R 1 H, F, loweralkyl, loweralkoxy, trifluoromethyl, F 2 acetyl or aminocarbonyl. That application is a continuationin-part application of U. S. application Serial No. 409,476 filed on August 19, 1982, which was the basis for European patent application Serial No. 102-194-A which has since been p u b l i s edC d Sggg.

-F S i p l i c t s i- N u i -l u u oan data harei-th., discloses a method of treating muscle tension and spasticity and anxiety with all of the prior art compounds mentioned above and the compounds disclosed in the present application.

SUMMARY OF THE INVENTION The 3-aryloxyazetidinecarboxamides useful in the method of this invention have the formula: R z N- -N O-Ar

R

2 2 R R 3 Formula I wherein Ar is selected from pyridyl in any of its positions, including pyridyl substituted by halo, from phenyl or phenyl substituted by 1 or 2 radicals selected from chloro, bromo, iodo, fluoro, loweralkyl, loweralkoxy, nitro, aminocarbonyl, trifluoromethyl; or acetyl; Z is oxygen or sulfur; 25 R 1 and R 2 are selected from hydrogen, loweralkyl, aryl, o0, 0 allyl, substituted allyl, propargyl, cycloalkyl, loweralkylcycloalkyl, cycloalkylloweralkyl, arylloweralkyl, and dialkylaminoalkyl, and R 1 and R 2 when taken together with the adjacent nitrogen atom may form a S, 0 heterocyclic amine radical including azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, imidazolyl, piperazinyl, 4-substituted piperazinyl and morpholinyl;

R

s is selected from hydrogen, loweralkyl, aryl or arylloweralkyl; the geometrical isomers including cis, trans, and isomers thereof, and the pharmaceutically acceptable acid addition salts thereof when R 1 and/or R 2 have a salt-forming basic amino component or when Ar is

Y

a I -3pyridyl, with the proviso that when R 3 is hydrogen, Z is oxygen, Ar is phenyl or phenyl substituted by trifluoromethyl or aminocarbonyl, then R 1 and R 2 cannot be a combination of hydrogen and loweralkyl, and the further proviso that when

R

3 is hydrogen, Z is oxygen, Ar is phenyl or phenyl substituted by fluoro, loweralkyl, loweralkoxy, trifluoromethyl, acetyl, or aminocarbonyl, then R I and R 2 cannot both be hydrogen.

In the further definition of symbols and in the formulas hereof and where they appear elsewhere throughout this specification and in the claims, the terms have the following significance.

The term "loweralkyl" as used herein, unless otherwise specified, includes straight and branched chain radicals of up to eight carbons inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, isoamyl, hexyl, hepty2, and octyl radicals and the like. The term "loweralkoxy" has the formula -0-loweralkyl.

The term "cycloalkyl" as used herein includes primarily cyclic alkyl radicals containing 3-9 carbon atoms inclusive and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "loweralkylcycloalkyl" refers to cycloalkyl S 25 substituted by alkyl radicals of 1-8 carbon length.

The term "cycloalkylloweralkyl" refers to a cycloalkyl radical linked via 1-8 carbon alkyl chains, including branched chains, to the amide nitrogen.

The term "substituted allyl" means allyl substituted by alkyl radicals in any one of its 3 positions.

o The term "aryl" under the definition of R 1

R

2 and R 3 refers to phenyl or phenyl substituted by non-interfering radicals nah- Paha1l, loweralkyl, loweralkoxy, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carboethoxy, and the like.

The term "arylloweralkyl" under the definition of R 1

R

2 and R 3 refers to an aryl group as defined above linked 44 via 1-8 carbon alkyl chains, including branched chains, to the amide nitrogen.

The term "4-substituted-piperazinyl" under the definition of R 1 and R 2 refers to a pi erazine radical (e'u!Me I Seecp- o q'Tt' substituted by usual radicals, i aryl as defined above and loweralkyl as defined above.

As defined above under Formula I, pharmaceutically acceptable salts are included when R 1 or R 2 have a saltforming amino component or when Ar is pyridyl. -Salt-forming amino components are present, for example, when either R 1 or R 2 are diloweralkylaminoloweralkyl or when they form piperazinyl or imidazolyl radicals. Pharmaceutically acceptable acid addition salts are those salts which are physiologically compatible in warm-blooded animals. The i. 15 acid addition-salts may be formed either by strong or weak acids. Representative of useful strong acids are hydrochloric, hydrobromic, sulfuric and phosphoric acids.

Representative of useful weak acids are fumaric, maleic, succinic, oxalic, citric, tartaric, hexamic, and the like.

S 20 The compounds of Formula I are useful in the method of this invention because of their pharmacological action on the central nervous system.

*t The procedure for testing the compounds for their 'anticonvulsant activity is based on evaluation techniques published by Swinyard, E. in EPILEPSIA 10: 107-19 (1969) and in J. PHARMAC. EXPTL. THERAP. 106: 319-30 (1952), and others as explained in greater detail below. The compounds demonstrate protective activity against seizures in both metrazole and electrical challenge and, consequently, are 30 projected to generally have utility in treating both petit and grand mal epilepsy.

DETAILED DESCRIPTION OF THE INVENTION The method used to prepare the compounds of Formula I are classified as follows by equation under method classes A, B, and C.

7 Method Class A From Phenoxyazetidine a) (X )n z 0- R =C=ZR 2

-NHC-N

b) x)n ()n

R'

2 N-1 -11R 0-- N--NR N-C-N 203 R 3 N x)n C)Z 0

R

3

R

2

-C

n e)(C 2 RF

(CH+

2 C)Z HC-N Li/v) k 2 f

C

1,* -6 Method Class B Via Aryloxy-l-chlorocarbonylazetidine (Ar=Phenyl, Substituted-phenyl, Pyridyl) z b) Z Cil--N -Ar z

R

2

NH

2 le RHN- C-N -0-Ar iN Z H H *(CH nN-C-N 0-Ar C) z 11 Cl-C-N 0--Ar HNDJR8

R

3 at a' a. j-t f I.

T t a t~ a It a *9 a a at, a d) Z 11 Cl-C-N Ar N C- N 0-Ar Method Class C Via Methane (or Phenyl) sulfony. azetidine a *0* a.

a I H-N 0Os0gw R 2

-N=C=Z

z

R

2 NH-CN 01 S0 2 aa a a a *1 a, a a.

a.

W CH3, C 8 1{ 5 ~4-CH 3 -CSH4 x NaH

DMF

z

RNH-C.

7 Method Class A reactions comprise a process for preparing phenoxy compounds of Formula I by reacting a compound of the formula: 0- ()n

R

s with one of the following classes of compounds: a) RN C Z b) R'R N-C-Cl

II

9O c) d) (C acN or, e) and f) the product of -C=Z Sand R 2 NHa or (CH)n N-(CHa )x-NH 0-8 SMethod Class B reactions comprise a process for preparing certain aryloxy compounds of Formula I by reacting a compound of the formula: Cl-C- 0-Ar R3 with one of the following classes of compounds: 30 R 2 NHa S'or, b) a heterocyclic amino compound.

Method Class C reactions comprise a process for preparing m-fluorophenoxy compounds of Formula I by reacting a compound of the formula: H- OS0 2

W

R

3 W=CHs, CeH, 4-CHs-CeHs

IMENERN.

I I -8with an isocyanate of the formula

R

2

-N=C=Z

to give a compound of the formula z

R

2 NH-C- -SO4W and thereafter reacting with sodium hydride and a metafluorophenol of the formula x to give a compound of the formula R2NH-C-N 0 a F1 20 R s Methods of preparing the starting phenoxyazetidinei used in Method Class A are outlined by ecuation in Chart I.

I Methods of preparing the starting aryloxy-l-carbonylazetidines 25 used in Method Class B are outlined by equation in Chart II.

*0 The starting 1-(diphenylmethyl)-3-hydroxyazetidines p.halohydrin. Cis and trans isomers are separated by chromatography when they exist. Starting a-methylbenzyl- 3-azetidinol is prepared by the method of Tetsuya Okutani, Set al, CHEM. PHARM. BULL. Vol 22 (1974) p. 1490.

Preparations 1-6 illustrate the methods.

Chart I Preparation of Starting 1-Unsubstituted phenoxyazetidiles R4* C 8

H

5 X) (see Preparations 2 and 1) CHsSO2ClANEt3 2) NaGH, with-or without 3)phase catalyst Se also U.S. Patent (see Preparations 3 and 6~ or H2 Pd/c Pd (OH) 2

/C

H0%0-9 (see Preparation 4) 4.) 4) 4 .44 1 $1 4 ii 4@ 4 .4 -R4 CH 3 phenyl or subst. phenyl.

is restricted to substituents that are electron withdrawing; fluoro, chloro, bromo, iodo or CF 3 ***Wqhen X 4-cl, 4-Br, 4-1, 4-F or 4-CE' 3 yields are very low.

""*Except X cannot be chloro, bromo, or iodo in the product as hydrogenolysis removes these radicals.

.4 14 '44.4, 4 .4 4 4 4* -4 44 Chart 11 Preparation of Starting 1-Carbonyl-3--aryloxy azetidines CH-N,

OH

CeHs halo 'Nha lo NaH

DMF

R halo

CH

5

C

8

H

W

(see Preparation in Chart i) C- C 2 Z 0 o cl-CN OAr UI Chart III Preparation of Starting Methane-(Or phenyl)- sulfonylazetidine R 4-CH-N OH CeH 5 WS0 2 C1I NE t toluene W CH 3

CSH

5 4 eCs4

R

4 -CH-N -OSO 2

W

(H

2 H-N S0 2

W

I0 0 V I I I I

I

9 II @4 II o 4 4 I o 44 44 I 444 4 o 4* 4 4 4 44 p4 0 4 44 4. 4 4 4.

4 4.

p 0144444 .4 4 44 4 I 44 4 *4 I .454 12

I,

I t I It S*

I

i t a

I

i ii i 0 6 9« t S*4 44 i I-1 C S I Preparation 1 trans-l-(Diphenylmethyl).-2-methyl-3-azetidinol oxalate A mixture of 126.4 g (0.72 mole) of diphenylmethylamine and 100 g (0.66 mole) of 3-bromo-l,2-epoxybutane in 300 ml of methanol was stirred while being protected from light for 96 hr, then heated at reflux for 30 hr as the color changed from pale yellow to deep amber. A sample was assayed by 1 H-nmr and showed 3 methyl doublets. A fine beige precipitate was removed by filtration (diphenylmethylamine hydrobromide) and the filtrate concentrated on a rotary evaporator to yield 174.6 g of crude oil. A .1.5 sample was neutralized and placed on a 4 mm thick plate of a Chromatotron® and eluted with 10% ethyl acetate-toluene.

A total of sixteen fractions were collected which consisted of 6 distinct spots by TLC. The major component separated was 700 mg and appeared to be the trans isomer. This sample was converted to the oxalate salt. The main concentrate was converted to the free base with ammonium hydroxide and extracted into toluene which was dried over magnesium sulfate and concentrated. The reaction residue was dissolved in methanol and treated with 58 g of oxalic acid, heated to give a homogenous solution and allowed to cool after seeding with a sample of the trans oxalate salt. Filtration yielded 62 g of white granular product, m.p. 147-148.5°C. A second crop of 26 g was also obtained.

The 'H-nmr spectrum showed only a single CHs doublet with j (CHs-H) of 6.1 Hz which is consistent with the trans compound.* Total yield of title compound was 88 g *Robert H. Higgins and Norman H. Cromwell, J. Hetero. Chem., 8 1059-62 (1971).

Analysis: Calculated for C1 7 HisNO.C 2 HaO 2 4 c,66.46; H.6.16; N,4.08 Found c,66.38; H,6.16; N,4.07 7 r 4 54 13 Preparation 2 1-(Diphenylmethyl)-3-azetidinol methanesulfonate (ester) hydrochloride [1:11.

A mixture of 60.02 g (0.22 mole) of 1-diphenylmethyl- 3-azetidinol hydrochloride and 48.94 g (0.484 mole) of triethylamine in 800 ml of toluene was stirred for 24 hr, then cooled to 5°c. in an ice bath and treated with 27.7 g (0.24 mole) of methanesulfonyl chloride added at a rate which maintained the temperature below 150C. The reaction mixture was stirred for 3 hr and filtered to remove the triethylamine hydrochloride. The filtrate was treated with g (0.242 mole) of 4-trifluoromethylphenol followed by 19.35 g (0.

4 8 4 mole) of sodium hydroxide and 1.6 g (0.005 mole) of tetrabutylammonium bromide in 60 ml of water.

The reaction mixture was stirred rapidly at reflux for 18 hrs, then stirred for 72 hr while it cooled to ambient temperature.

The reaction mixture was transferred to a separatory funnel and washed with 4 x 200 ml of water (emulsion). The toluene phase was dried over magnesium sulfate and concentrated in vacuo to 82 g of oil. This residue was dissolved in 200 ml of isopropyl alcohol and treated with 20 ml of concentrated hydrochloric acid. Upon cooling, a solid t' separated and was removed by filtration (5.1 The filtrate was treated with isopropyl ether to give an oil which was worked up later. The solid was identified by i' 25 spectral analysis as the methylsulfonate of the starting azetidinol. Recrystallization from isopropyl alcohol gave 3.3 g of fine white crystalline material, m.p. 172-173 0

C.,

(shrinks 167 0 Analysis: Calculated for C 17

H

1 eNOsS.HC1: C,57.70; H,5.70; N,3.96 Found C,57.80; H,5.

8 6 N,3.92 14 Preparation 3 trans-l-(Diphenylmethyl) -2-methyl-3- 3-(trifluoromethyl) phenoxylazetidine oxalate [1:11.

A stirred slurry of 1.2 g (0.03 mole) of sodium hydride dispersion in mineral oil) in 50 ml of dry DMF was treated with 3.45 g (0.01 mole) of trans-l-diphenylmethyl-2methylazetidin-3-ol oxalate added in small portions. When the addition was complete and the evolution of hydrogen ceased, the reaction was heated to 80°C. for 2 hr then 1.64 g (0.01 mole) of 3-fluoro-trifluoromethylbenzene was added dropwise. The reaction mixture was stirred at 80 0 C. for an additional 18 hr. The reaction mixture was diluted with ice water and extracted with 3 x 25 ml of toluene. The extracts were combined, dried over magnesium sulfate, filtered, and the filtrate treated with 1 g of oxalic acid. The resulting solid was collected by filtration. Recrystallization from acetone-isopropyl ether yielded 2.2 g of fine white crystals, m.p. 146-147 0 C. Proton NMR shows it to be the trans compound.

Analysis: Calculated for C 2 4Ha 2 FsNO-C 2 HaO 4 C,64.06; H,4.96; N,2.87 Found c,64.26; H,4.99; N,2.89 Preparation 4 trans-2-Methyl-3-13-(trifluoromethyl)phenoxy]azetidine oxalate .l:l.

A methanol-warm water solution of 33 g (0.068 mole) of trans-l-diphenylmethyl-2-methyl-3-[3-(trifluoromethyl) phenoxy]azetidine oxalate was treated with ammonium hydroxide o ountil basic, then extracted with 4 x 150 ml of methylene chloride. The combined methylene chloride extracts were washed with water, dried over magnesium sulfate, and concentrated in vacuo to a pale yellow oil. This oil was dissolved in 200 ml of 190 ethanol plus 5 ml of triethylamine and hydrogenated on a Parr apparatus with 3.3 g of palladium-on-charcoal catalyst with a 40 psi atmosphere of hydrogen at 70°C. for 12 hr. After the calculated amount of hydrogen had been absorbed, the catalyst was removed by

_I_

-454 15 filtration and the filtrate concentrated in vacuo to yield 26.75 g of crude product. An 8 g portion was converted to the oxalate salt in isopropyl alcohol yielding 6.1 g of fine white powder; m.p. 155-156 0 C. Total yield extrapolated from the aliquot converted to the oxalate salt was 84% of theory.

Analysis: Calculated for CiH 1 a 2

F

3

NO-C

2

H

2 0 4 C,48.61; H,4.39; N,4.36 Found C,48.67; H,4.38; N,4.34 Preparation trans-l-(Diphenylmethyl)-2-methyl-3-azetidinol methanesulfonate (ester) hydrochloride r1:11.

A solution of 6 g (0.025 mole) of trans-l-diphenylmethyl-2-methylazetidin-3-ol (obtained from the hydrochloride salt by partitioning in organic solvent and aqueous base, separating and evaporating the organic phase) in 40 ml of dry benzene was treated with 10 ml of triethylamine and cooled to 5°C. While stirring, the reaction mixture was treated with 3.

5 4 g (0.03 mole) of methanesulfonyl chloride at a rate to control the temperature below 10°C. After stirring for 3 hr, TLC (20% ethyl acetate/methylene chloride on silica gel) showed the reaction to be incomplete. An S' additional 1.14 g (0.01 mole) of methanesulfonyl chloride was added and stirring continued for 1 hr. The reaction mixture was diluted with 100 ml of water and the benzene layer separated, washed with 300 ml of water, dried over magnesium sulfate and concentrated to an oil. The oil was dissolved in isopropyl ether and treated with ethereal hydrogen chloride. The solid salt was'removed and recrystallized from 190 ethanol to give 3.4 g of fluffy white crystals, m.p. 152-153 0

C.

Analysis: Calculated for CisH 2 1 NOsS'HC1: C,58.77; H,6.03; N,3.81 Found C,58.68; H,6.08; N,3.80 454 16 Preparation 6 1-(Diphenylmethvl)-3-r3-(trifluoromethyl)phenoxyl azetidine.

N-Diphenylmethyl-3-hydroxyazetidine hydrochloride (I) was prepared from benzhydrylamine and epichlorohydrin according to Anderson and Lok, J. Org. Chem., 2:3953 (1972).

I (41.33 g, 0.15 mole) and triethylamine (42 ml, 0.30 mole) were stirred in toluene (250 ml) while methane sulfonylchloride (12 ml, 0.15 m) was added dropwise over 10 minutes with stirring and the temperature was maintained between 40 and 120C. TLC (silica gel, 10% ethyl acetate in methylene chloride) at one hour showed all starting materials had reacted. The mixture was filtered to remove the triethylamine hydrochloride which was rinsed twice with toluene.

The filtrate and washings combined to about 450 ml of solution. To this solution was added m-trifluoromethylphenol (27.5 g, 0.17 mole), tetrabutyl ammonium bromide (2.4 50% sodium hydroxide (24 g, 0.3 mole) and water (24 ml) and the mixture was stirred vigorously and heated to reflux under nitrogen for 2.5 hr. The toluene layer of the mixture was separated and washed once with water, dried over sodium sulfate and evaporated to an oil. This oil was seeded and pumped on an oil pump overnight. A solid cake weighing 49.7 was obtained. Some of this solid was dissolved in isopropanol with brief heating. Water 25 was then added to cause slight cloudiness. The mixture was seeded and cooled to cause crystallization. The white solid was collected by filtration, washed with 50% aquous isopropanol, and dried under vacuum overnight. Proton NMR showed slight I contamination by silicone oil, m.p. 82.5-84°C.

Analysis: Calculated for CsH 2 oFsNO:C,72.05; H,5.26; N,3.65 Found :C,71.62; H,5.29; N,3.61 S 454 17 The following examples illustrate preparation of compounds encompassed by Formula I and useful in the method of treatment of the invention. The scope of the invention is not limited by the examples, however.

Example 1 N-Methyl-3-[4-(trifluoromethyl)phenoxy] -l-azetidinecarbothioamide.

Crude 3-[3-(trifluoromethyl)phenoxy]azetidine from catalytic debenzylation of 26.0 g (0.078 mole) of l-benzhydryl- 3-[3-(trifluoromethyl)phenoxy]azetidine was dissolved in 100 ml of methylene chloride and treated dropwise under a nitrogen atmosphere with a solution of 5.0 g (0.0678 mole) of methylisothiocyanate in 15 ml of methylene chloride. The reaction mixture was stirred for 16 hr at ambient temperature and let stand over the weekend. The solution was filtered through a celite filter pad to remove a fine crystalline precipitate and the filtrate was evaporated under reduced pressure. The residual oil was crystallized from isopropyl ether to give 12.6 g of product, m.p. 79-86 0 c. A 5.0 g 20 sample was recrystallized from isopropyl ether (charcoal) to give 3.2 g, m.p. 89-93 0 which was shown by TLC on silica gel (10% methanol-toluene) to be contaminated by a lower Rf material. The filtrate was evaporated under reduced pressure,combined with the 3.2 g of solid and dissolved in I 25 100 ml of methylene chloride. The solution was stirred 4 with 25 g of silica gel for 0.5 hr and filtered through a sintered glass filter. The silica gel was washed with a small volume of methylene chloride and the filtrate r evaporated under reduced pressure. The residual solid was recrystallized from isopropyl ether to give 1.3 g of pure product, m.p. 96-98 0

C.

Analysis: Calculated for C12HisFsN 2 OS: C,49.65; H,4.51; N,9.65 Found C,49.58; H,4.48; N,9.58 454 18 Example 2 N-(2,6-Dimethylphenyl) -3{3(trifluoromethyl)phenoxyhlazetidinecarbothioamide.

Crude 3-t3-(trifluoromethyl)phenoxy]azetidine from catalytic debenzylation of ,30.0 g (0.078 mole) of 1benzhydryl-3-[3-(trifluoromethyl)phenoxy~azetidine was dissolved in 100 ml of methylene chloride and treated dropwise under a nitrogen atmosphere with a solution of 12.7 g (0.078 mole) of 2,6-dimethylphenylisothiocyanate in 25 ml of methylene chloride. The product began to precipitate during the addition and an additional 50 ml of methylene chloride was added to facilitate stirring. After stirring overnight at ambient temperature, the product was collected by filtration (13.5 g, m.p. 196-199 0 A 6.0 g sample was recrystallized from isopropanol to give 5.3 g of product, m.p. 197-199 0

C.

Analysis: Calculated for CeHie 9

F

3

N

2 0S: C,59.997 H,5.03; N,7.36 Found C,60.04; H, 5 .o4 N,7.35 Example 20 N-(Phenylmethyl)-3-r3-(trifluoromethyl)phenoxyl-1- .azetidinecarboxamide.

*4 (To a stipred and chilled (10-20 0 solution of 0.04 mole of 3-[3-(trifluoromethyl)phenoxy]azetidine in 100 ml of methylene chloride was added dropwise 6.12 g (0.046 mole) of benzyl isocyanate. The reaction mixture was stirred at room 4 temperature for 2 hr and was filtered. The filter cake was washed with petroleum ether (2 x 50 ml), dilute aqueous it sodium bicarbonate (2 x 50 mi), and water (2 x 50 ml), yielding 12 g Recrystallization twice from ethyl acetate gave 9.0 g of clear white flakes, m.p. 173.5-175 C.

Analysis: Calculated for CIaH1 7 FsNa 2 C,61.71; H,4.89; N,8.00 an Found C,61.57; H,487; N,7.99 19 Example 4 N-(2,6-Dichlorophenyl)-3-[3-(trifluoromethyl)phenoxy 1-azetidinecarbothioamide.

A solution of 0.04 mole of 3-[3-(trifluoromethyl) phenoxy]azetidine in 100 ml of absolute ethanol was stirred in a tap water bath while 8.16 g (0.04 mole) of 2,6--dichlorophenyl isothiocyanate was added all at once. The reaction was slightly exothermic and as the isothiocyanate began to dissolve, product began to precipitate. After stirring for 45 minutes the reaction mixture was heated on a steam bath to assure that all the isothiocyanate dissolved, and upon cooling, filtration yielded 15.2 g of white crystalline product. A portion of this material (7.9 g) was recrystallized from absolute ethanol to give 4.3 g of pure crystalline powder, m.p. 196-197 0

C.

Analysis: Calculated for C 1 7 yHsFC1 2

N

2 0OS: C,48.47; H,3.11; N,6.65 Found C,48.40; H,3.07; N,6.54 Example N-r3-(Diethylamino)propyll-3-[3-(trifluoromethyl) phenoxyl-l-azetidinecarbothioamide, oxalate 1:11].

A solution of (0.0584 mole) of 3- [-(trifluoromethyl) phenoxy]azetidine was stirred at 10 0 C. while 10.66 g (0.0584 mole) of 3-(diethylamino)propyl isothiocyanate was added all at once. After stirring overnight at ambient temperature, the reaction mixture was concentrated at 50°C. on a rotary evaporator to a thick syrup residue. The residue was dissolved in isopropanol and treated with 5.3 g of oxalic acid, warmed on a steam bath to dissolve the acid, and upon cooling, a solid salt precipitated. An equal volume of isopropyl ether was added to ensure complete precipitation. Filtration gave 26 g of crude product.

A portion (13 g) was recrystallized from isopropanol/ methanol/isopropyl ether (100/50/50) (cooled in a refrigerator) to yield upon filtration 7.5 g of white product, m.p. 155-157°C. Proton NMR confirmed that this was the expected product.

454 20 Analysis: Calculated for C 8

H

28

F

3 Ns 3 OCa 2 Ha0 4 C,50.10; H,5.89 N,8.76 Found C,50.02; H,5.97; N,8.89 Example 6 N-r3-(Dimethylamino)propyll-3-r3-(trifluoromethyl)phenoxy -l-azetidinecarbothioamide.

A stirred solution of 0.0584 mole of 3-[3-(trifluoromethyl)phenoxy]azetidine at 10 0 C. was treated with 8.

4 2 g (0.0584 mole) of 3-(dimethylamino)propyl isothiocyanate all at once and allowed to stir at ambient temperature overnight. The reaction mixture was treated with 5.3 g (0.0584 mole) of oxalic acid and diluted with 200 ml of isopropyl ether which yielded only 3.8 g of product. The volume was reduced to 100 ml at 50 0 C. in vacuo and diluted with 500 ml of isopropyl ether to yield an additional 15.3 g of product. The combined solid material was dissolved in isopropyl alcohol and upon cooling, a fine precipitate formed (N,N-dimethyl-l,3-propanediamine oxalate) which was removed by filtration. The product failed to crystallize; addition of isopropyl ether gave only an amorphous gel.

After trying to obtain a more satisfactory product for 3 weeks, the reaction material was converted to the free base and taken up in isopropyl ether. The ether solution was stirred with 300 ml of water overnight to remove the diamine. The product crystallized as the free base from the heterogenous mixture and was filtered to give 11.3 g of fine beige crystals. Rework of the filtrate gave an additional 2.3 g of product. A portion (8 g) was recrystallized from benzene/ligroin to yield 5.8 g of very fine beige crystals which were dried at 82 0 C. under vacuum, m.p. 107-108 0

C.

Analysis: Calculated for CleHa 2 FsNsOS: C,53.17; H,6.14; N,11.63 35 Found C,53.29; H,6.15; N,11.60 e 0 *O 44 4r 04

I

E Lf 5lFow 4" Example 7 1N-(2-.Propenyl)-3-[3-(trifluoroniethyl)phenoxy]-lazetidinecarboxamide.

A solution of 18.9 g (0.05 mole) of crude 3-[3- (trifluoromethyl)phenoxy~azetidine (contains an equpal molar amount of diphenylmethane) in 100 ml of isopro~pyl ether was stirred under nitrogen while 4.16 g (0.05 mole) of 2-propenyl isocyanate was slowly added. The reaction mixture which was somewhat turbid, cleared and after 1 hr a fine crystalline precipitate began to form. After stirring for 18 hrs, the product was removed by filtration, washed with fresh isopropyl ether and air dried to yield g of white crystals, M.P. 75-76 0 c.

Analysis: Calculated for C 14

H

15

F

3

N

2 0 2 C,56.00; H,5.04, N,9.33 Found :C,55.98; H,5.05; N,9.31 Example 8 N-Cvclopropyl-3-r3-(trifluoromethvl)phenoxy]-lazetidinecarboxamide.

andA mixture of 1.9 g (0.033 mole) of cyclopropylamine Thean 4.9 g of l,l'-carbonyldiimidazole in 60 ml of tetrahydrofuran was stirred at ambient temperature for 1 hr.

*The clear solution which formed was 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 was removed by filtration to give 4.I4 g of gray-white powder. The CI.mass spectrum showed a p+l at 381 m/e which was consistent with the expected product.

Recrystallization from benzene/ligroin gave 2.3 g of a light gray powder, m-p. 152-153 0

C.

a. 4 Analysis: Calculated for C1 4

HISF

3 N20: C,56.oo H,5.0o4; N,9.33 Found .C,55-97; H,5.07; N,9.28 1 454 22 Example 9 -(Diethylamino)propyll-3-r[-(.trifluoromethyl) phenoxyl-l-azetidinecarboxamide bxalate A mixture of 4.3 g (0.033 mole) of 3-diethylaminopropylamine and 4.9 g (0.033 mole) of 1,l'-carbonyldiimidazole in 60 ml of methylene chloride was stirred at ambient temperature for 1 hr. The resulting solution was treated with 3-[3-(trifluoromethyl)phenoxy]azetidine (obtained from 9.21 g (0.03 mole) of the oxalate salt) in 30 ml. of methylene chloride. After stirring for 18 hr, the reaction mixture was transferred to a separatory funnel and washed with 3 x 20 ml of water, dried over magnesium sulfate and concentrated in vacuo to a dark oil. The residue (8 g) was chromatogarphed on a '150 g neutral alumina column by eluting with chloroform. Concentration of the initial fraction gave the product as an amber oil which was dissolved in methylisobutyl ketone and treated with 2 g of oxalic acid.

Dilution with isopropyl ether gave an oil which solidified and was recrystallized from acetone/isopropyl ether to give 6.25 g of beige crystals, m.p. 91-930C.

Analysis: Calculated for C1sH2eFsN 3 0-.l.5 C 2 H20 4 C,49.61; H,5.75; N,8.26 t t Found C,49.56; H,5.73; N,8.24 Example N-2-(Propenyl) -3-r4-(trifluoromethyl)phenoxy -1azetidinecarboxamide.

S« A solution of 8.7 g (0.04 mole) of crude 3-[4-(trifluoromethyl)phenoxy]azetidine in 75 ml of isopropyl ether was stirred under a blanket of nitrogen while 4.2 g (0.05 mole) of 2-propenyl isocyanate was added dropwise. After stirring for 3 days, no crystalline product precipitated.

The reaction mixture was concentrated to a dark reddish ,a oil. TLC (20% ethyl acetate/methylene chloride on ailica gel) showed at least 6 spots, all well separated. The residue was dissolved in chloroform, chromatographed on a 350 g silica gel column and eluted with chloroform.until the reddish forerun was removed. The column was then eluted 23 with an ethyl acetate/chloroform gradient to 4% ethyl acetate. All the fractions were combined and concentrated to give 4.8 of orange oil, which crystallized on standing.

Recrystallization from acetone/cyclohexane gave 3.3 g of beige crystals, m.p. 91-92.5 0

C.

Analysis: Calculated for C1 4

H

1 sFsN 2 0 2 C,5 6 .00 H,5.0 4 N,9.33 Found C,55.98; H,5.17; N,9.36 Example 11 N- (Cyclopropylmethyl)-3- 3-(trifluoromethyl)phenoxy 1-azetidinecarboxamide.

A solution of 2.6 g (0.024 mole) of (aminomethyl) cyclopropane hydrcchloride in 50 ml of pyridine was stirred under a blanket of nitrogen while 3.9 g (0.024 mole) of 1,l'-carbonyldiimidazole was added. After stirring for minutes, the TLC methanol/methylene chloride on silica gel) showed no reaction; therefore, 2 ml of triethylamine was added. The reaction mixture after minutes became cloudy and the TLC showed a new product.

The reaction was treated with 6.2 g (0.02 mole) of 3-(3- (trifluoromethyl)phenoxy]azetidine oxalate. After stirring for 1 hr, a sample was removed, and upon dilution with water, a solid precipitated. The C" mass spectrum indicated it was product. After 2 days, the reaction was diluted with 5 volumes of water and the resulting precipitate collected by filtration to yield 6.5 g of pale yellow crystalline product. Recrystallization from ethanol/water produced white plate-like crystals which were dried at 82°C. for 3 hr in a drying pistol under vacuum; weight of the product was 5.8 g m.p. 132-1330C.

Analysis: Calculated for CisHTFs 3

N

2 0 2 C,57.32; H,5.4 5 N,8.91 Found C,57.22; H,5.44; N,8.86 -24 Example 1.2 NN-Diethyl-3-[3-(trifluoromethl)phenoxy-.-azetidinecarboxamide.

A stirred slurry of 5 g (0.0163 mole) of 3-[3-(trifluoromethyl )phenoxy azetidine oxalate in 50 ml of tetrahydrofuran was treatcd with 5 ml of triethylamine and after 1 hr, 2.5 g (0.018 mole) of diethylcarbamoyl chloride was added. After stirring an additional 15 hr, the reaction was treated with ml of water and saturated with calcium chloride. The tetrahydrofuran was decanted from the solid residue and concentrated in vacuo to an oil. The crude oil was chromatographed on a Water's Prep-Lc using 50% ethyl acetate/ toluene as the eluent. After co~ncentration of the main fractions 3.1 g of pale yellow oil was obtained.

Analysis: Calculated for C1 5 HlSF 3

N

2 0 2 C,56.96; H 6.05; :C,56.69; N,68.86 V7, 8.77 Example 13 N,N-Dimethyl-3-r3-( trifluoromethyl)phenoxy1-lazetidinecarboxamide.

A stirred slurry of 5 g (0.0163 mole) of 3-[3-(trifluoromethyl)phenoxy~azetidine oxalate in 50 ml of tetrahydrofuran was treated with 5 ml of triethylamine and after 1 hr, 1.95 g .4 (0.018 mole) 6f dimethylcarbamoyl chloride was added. After 441 stirring an additional 15 hr, the reaction mixture was treated with 20 ml of water and 10 g of calcium chloride.

The tetrahydrofuran layer was decanted and the residue triturated with 20 ml of ethyl acetate~ then decanted. The combined tetrahydrofuran and ethyl acetate solution was concentrated in vracuo. The crude residue was chromatographed on a Waters Prep-LC using 50% ethyl acetate/toluene as the eluent. After concentration of the w~ain fractions, 3.6 g of pale yellow oil was obtained.

Analysis: Calculated for C 13

H

25

FSN

2 0 2 C,541.17; H,5-25; t1 N,9-72 Found :c,53.73; H,5.20; ZN,9.6o 454 25 Example 14 N-(2-Propynyl)-3-[3-(trifluoromethyl)phenoxy]-lazetidinecarboxamide.

A mixture of 3.9 g (0.024 mole) of 1,1'-carbonyldiimidazole and 1.32 g (0.024 mole) of '"propynylamine in 50 ml of tetrahydrufuran was stirred at -bient temperature for 1 hr, then treated with 6.2 g of 3- :-(trifluoromethyl) phenoxy]azetidine. The reaction mixti was treated with 3 ml of triethylamine and stirred for 18 hr. The reaction mixture was diluted with an equal volume of water and filtered to yield 8 g of wet product. Recrystallization from isopropyl ether gave 3.8 g of gray solid, a mixture of product and the symmetrical urea of starting 2-propynylamine.

A second recrystallization from ethanol-water yielded 2.6 g of pure product, m.p. 105-106 0

C.

Analysis: Calculated for C 14 Hs 1

F

3

N

2 0 2 C,56.38; H,4.39; N,9.39 Found C,56.32; H,4.34; N,9.44 4. Example N-Cyclohexyl-3-r3-(trifluoromethyl)phenoxy -1- S .o 20 A stirred mixture of 5 g (0.0163 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate and 2.04 g (0.018 0 0* mole) of cyclohexyl isocyanate in 50 ml of tetrahydrofuran was treated with 2 ml of triethylamine then stirred for 18 hr. Dilution of the mixture with water gave a solid precipitate which was collected by filtration to yield 12 g of crude product. Recrystallization from acetone/water gave 5 g of fine white crystals, m.p. 148-1500C. TLC (ethyl o 4 'acetate on silica gel) showed a trace of symmetrical cyclohexyl urea as well as the product. A second recrystallization from isopropanol yielded 1.65 g of white powder; dried under 0.5 mm/Hg vacuum, m.p. 153-154 0

C.

Analysis: Calculated for CT 7 HaiFsN 2 0 2 C,59.64; H,6.18; N,8.18 Found C,59.52; H,6.20; N,8.17 454 26 Example 16 N-Cyclopropyl-3- 4-(trifluoromethyl)phenoxy] -lazetidinecarboxamide.

A stirred slurry of 4.4 g (0.027 mole) of 1,1'-carbonyldiimidazole in 50 ml of methylene chloride under nitrogen was treated with 1.54 g (0.027 mole) of cyclopropylamine.

After a short (2 min) induction period, the clear solution became suddenly exothermic, bringing the reaction to a gentle reflux. After 1 hr when the reaction mixture had cooled to ambient temperature, 9.6 g (0.025 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine, 56.66% purity (contains diphenylmethane) was added all at once and stirring continued for 18 hr. The reaction mixture was concentrated on a rotary evaporator to give a partially crystalline residue. The residue was partitioned between 30/60 petroleum ether and water and the resulting waxy solid removed by filtration. Recrystallization from isopropyl ether yielded 5.7 g of silver plate-like crystals, m.p. 145-147 0

C.

After drying at 80°C. under 0.5 mm/Hg vacuum, the weight was not diminished, m.p. 152-153 C.

Analysis: Calculated for C 4

H

15 FsN 2 0 2 C,56.00; H,5.04; N,9.33 Found C,'55.77; H,4.98 -N,9.44 a Example 17 a: N-(Cyclopropylmethyl)-3-r4-(trifluoromethvl)phenoxy 1-azetidinecarboxamide.

A stirred mixture of 4.4 g (0.027 mole) of 1,1'carbonyldiimidazole and 2.9 g (0.027 mole) of (aminoethyl) cyclopropane hydrochloride in 50 ml of methylene chloride was treated with the dropwise addition of 2.73 g (0.027 mole) 3' 0 of triethylamine. The reaction was exothermic. The mixture was cooled while stirring for 1 hr, then 9.6 g (0.025 mole) o 3-[4-(trifluoromethyl)phenoxy]azetidine 56.66% (contains .diphenylmethane) was added all at once and stirring continued for 18 hr. The reaction mixture was concentrated on a rotary evaporator to give an amber residue. Trituration of this residue with 30/60 petroleum ether gave only an -27insoluble oil. The trituration step was iepeated with 2 x 20 ml of 30/60 petroleum ether and the residue treated with water to yield a white solid. Tbe solid was recrystallized from isopropyl ether to yield 4.8 g of white platelik~e czrystals; after during at 80 0 C. under 0.5 um Hg vacuum, m-p. 132-133 0

C.

Analysis: Calculated for C 15

H

17

F

3

N

2 0 2 C,57.32; H,5.45; Found .C,57.26; H,8.9l; -N8.93 Example 18 N- r3-(Diethylamino )propyli-3-r 4 trifluoromethyl) phenoxyl-l-azetidinecarbothioamide., A stirred colution of 1.92 g (0.005 mole) of -4 (triflouromethyl)phenoxyiazetidine, 56.66% (contains diphenylmethane) in 20 ml of isopropyl ether was treated with 0.88 g (0.005 mole) of 3-(diethylamino)propyl isothiocyanate and stirred for 3.5 hr. The reaction mixture was treated with 0-5 g of oxalic acid dissolved in 2 ml of methanol. After stirring for 18 hr, the solid was collected by filtration, yielding 1.9 g of fine tan powder, m.p.

147-1 5 00C. The solid was dissolved in water and treated with dilute sodium hydroxide. An oil separated which .~.'.solidified and was collected by filtration. Recrystallization from cyclohexane yielded 1.1 g of fine 4 0 4S4 25 tan crystals, m.p. 109-110 C.

Analysis: Calculated for C 18

H

26 8F 3

N

3 0S: C,55-51; H,6-73; N1,10 .79 Found C,55.68; H,6.67 4.01-0N,10.73 'lit4 Example 19 N-r3-(Diethyla ino)propyll-3-r4-(trifluoromethyl) ph-enoxy1-l-azetidinecarboxamide oxalate r l:21.

A stirred solution of 4. g (0.027 mole) of 1,1'carbonyldiimidazole in 50 ml of methylene chloride under nitrogen was treated with the dropwise addition of 3.52 g (0.027 mole) of 3-(diethylamino)propylamine. The reaction mixture was stirred for 1 hr as the somewhat exothermic reaction cooled to ambient temperature then treated with t 454 5 28 9.6 g (0.025 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine, 56.66% (contains diphenylmethane) all at once. After stirring for 18 hr, the reaction mixture was concentrated on a rotary evaporator and the residue dissolved in toluene.

The toluene solution was washed with 3 x 20 ml of water, then treated with 2.5 g of oxalic acid in 10 ml of isopropanol The resulting solid was collected by filtration and triturated with boiling acetone. After filtration, 1.8 g of unidentified fine white precipitate formed which was separated by filtration. The acetone solution was concentrated to a solid which was recrystallized from isopropyl alcohol/isopropyl ether to yield 9.2 g of crude product (4 spots on TLC; 10% methanol/methylene chloride on silica gel). Recrystallization from methyl ethyl ketone yielded 6.8 g of fine white powder, m.p. 129-130 0

C.

Analysis: Calculated for C 1 sH 2 6 FsN 3 0 2 *2Ca 2 H0 4 c,47.74; H,5.46; N,7.59 Found C,47.82; H,5.68; N,7.76 Example 20 N-(2-Propynyl)-3-r4-(trifluoromethyl)phenoxyl-1azetidinecarboxamide.

I A solution of 4.4 g (0.027 mole) 1,l'-carbonyl- °o diimidazole in 50 ml of tetrahydrofuran was stirred under S' nitrogen while 1.49 g (0.027 mole) of 2-propynylamine was 25 added with a syringe and needle through a septum installed in one neck of the reaction flask. After stirring for 2 hr, ,9.6 g (0.025 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine (56.66% purity; contains diphenylmethane) was added all at once and stirring continued for an additional 18 hr. The 30 reaction mixture was diluted with ice-water and extracted with 30/60 petroleum ether to remove the diphenylmethane.

The oily aqueous portion was extracted with 4 x 50 ml of methylene chloride. These extracts were combined, dried over sodium sulfate and concentrated to an amber oil on a 35 rotary evaporator. The oil solidified when triturated with a small amount of isopropyl ether (50 ml). Filtration 4 5 1-"q9 29 yielded 6.1 g of rose-tinted solid product. TLC methanol/methylene chloride on silica gel) showed a mixture of 3 products and some starting material. Recrystallization from ethanol/water gave the product in several small fractions. These were combined and recrystallized from isopropyl ether to yield 4.1 g of pale beige powder, m.p.

135-137 0 C. TLC still showed some symmetrical 2-propynyl urea. The solid was recrystallized again from ethanol/ water to yield 3.5 g of pale yellow crystalline product, m.p. 140-141 0

C.

Analysis: Calculated for C 14

H

1 sFNa 2 0 2 C,56.38; H,4-39; N,9.39 Found ,56.34; H,4.36; N, 9.32 Example 21 N-(2-Methyl-2-propenyl)-3-r4-(trifluoromethyl)phenoxyl- 1-azetidinecarboxamide.

A stirred solution of 3.6 g (0.022 mole) of 1,1'carbonyldiimidazole in 75 ml of methylene chloride under nitrogen was treated with 1.6 g (0.022 mole) of 2-methyl- 2-propenylamine (added via a syringe and needle through a j septum placed in one neck of the reaction flask). After stirring for 1 hr, 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once I followed in 30 min with 5 ml of triethylamine and stirring was continued for 3 hr. The reaction mixture was washed l with water (2 x 25 ml), dried over magnesium sulfate and concentrated in vacuo. The oily residue solidified on Sstanding and was recrystallized from isopropyl ether to yield 3.7 g of fine white crystals, m.p. 101-102 C.

Analysis: Calculated for Cg 1

H

17

F

3

N

2 0 2 C,57.32 H,5.45; N,8.91 Found C,57.45; H,5.51; N,9.23 I 30 Example 22 N-(2-Methyl-2-propenyl)-3-r3-(trifluoromethyl)phenoxyl- 1-azetidinecarboxamide.

A solution of 3.6 g (0.022 mole) of l,l'-carbonyldiimidazole in 75 ml of methylene chloride was stirred under nitrogen while 1.6 g (0.022 mole) of methallylamine was added with a syringe and needle through a septum installed in one neck of the reaction flask. The reaction was slightly exothermic. The reaction mixture was stirred for 1 hr, then treated with 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate followed in 0.5 hr with 5 ml of triethylamine and stirring continued for 16 hr.

The reaction mixture was washed with 2 x 30 ml of water, dried over magnesium sulfate, and concentrated on a rotary evaporator to yield 6.7 g of oily residue which solidified.

The residue was recrystallized from isopropyl ether to yield 5.4 g of fine white crystals, m.p. 90-91 0

C.

Analysis: Calculated for CisH17FsNOa 3 C,57.32; H,5.

1 N,8.91 t Found C,57.20; H,5.50, S*N,8.95 20 Example 23 t N-(3-Methyl-2-butenyl)-3-[r-(trifluoromethyl)phenoxyl- 1-azetidinecarboxamide.

A solution of 3.6 g. (0.022 mole) of 1,1'-carbonyldiimidazole in 100 ml of methylene chloride was cooled in a tap water bath and while stirring under nitrogen, 1.87 g 't O (0.022 mole) of 3-methyl-2-butenylamine was added dropwise.

.After stirring for 1 hr, 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once followed in 0.5 hr with 5 ml of triethylamine and stirring continued for an additional 16 hr. The reaction mixture was washed with 2 x 50 ml of water, dried over I'S' magnesium sulfate and concentrated on a rotary evaporator to yield a semi-solid residue. Trituration with isopropyl ether and filtration yielded 7 g of crude product which was recrystallized from ethanol-water to give 5.5 g (83.8%) of white crystals, m.p. 156.5-158 0

C.

31 Analysis: Calculated for CleH 8 FaNe 2 0 2 C,58.53; H,5.83; N,8.53 Found C,58.81; H,5.89; N,8.58 Example 24 N-(3-Methyl-2-butenyl)-3-r3-(trifluoromethyl)phenoxyl- 1-azetidinecarboxamide.

A solution of 3.6 g (0.022 mole) of l,1'-carbonyldiimidazole in 100 ml of tetrahydrofuran was cooled with a tap water bath and stirred under nitrogen while 1.6 g (0.022 mole) of 3-methyl-2-butenylamine was added with a syringe and needle. The reaction mixture was stirred for 1 hr, then treated with 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate followed in 0.5 hr with ml of triethylamine and stirring continued for 72 hr.

The reaction mixture was diluted with 500 ml of ice water and extracted with 6 x 50 ml of methylene chloride. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a solid residue on a rotary evaporator. Recrystallization from ethanol-water 20 yielded 6 g of white crystals, m.p. 143-144 0 c.

,o Analysis: Calculated for ClsHlsF s Na0 2 C,58.53; H,5.83; N,8.53 Found C,58.46; H,5.86; S" N,8.69 a 9 Example 2 25 (E)-N-(2-Butenyl)-3-r4-(trifluoromethyl)phenoxy]-lazetidinecarboxamide.

SO*o A mixture of 3.6 g (0.022 mole) of l,1'-carbonyldiimidazole and 1.6 g (0.022 mole) of trans-crotylamine o was stirred for 1 hr, then treated with 6.2 g (0.02 mole) 'a.o 30 of 5-[4-(trifluoromethyl)phenoxy]azetidine oxalate and followed in 0.5 r with 5 ml of triethylamine with stirring continued for 16 hr. The partially crystalline mixture was washed with 2 x 50 ml of water, dried over magnesium t, sulfate and concentrated on a rotary evaporator to a solid residue, 14.2 g. Recrystallization from methanol-water yielded 5.35 g of fine white crystals, m.p'.

157-158 0

C.

-r 32 Analysis: Calculated for C 1 sH 7

F

3

N

2 0 2 C,57.32; H,5.

4 N,8.91 Found c,57.47; H,5.49; N,9.00 Example 26 (E)-N-(2-Butenyl)-3-[r-(trifluoromethyl)phenoxy]-1azetidinecarboxamide.

A solution of 3.6 g (0.022 mole) of l,l'-carbonyldiimidazole in 60 ml of methylene chloride was cooled in an ice bath while stirring under nitrogen while_J.6 g (0.022 mole) of trans-crotylamine was added dropwise.

After warming to ambient temperature, 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once followed in 0.25 hr by 5 ml of triethylamine with stirring continued for 72 hr. The reaction solution was washed with 2 x 50 ml of water, dried over magnesium sulfate and concentrated on a rotary evaporator to a solid residue, 7 g. Recrystallization from methanolwater gave 5.5 g of slightly yellow product. A second recrystallization with charcoal treatment from isopropyl ether yielded 3.75 g of fine white crystals, m.p. 127-128 0

C.

Analysis: Calculated for C 1 5

H

1 7

F

3

N

2 0 2 C,57.32; H,5.45; SN,8.91 Found C,57.35 H,5.47; N,8.94

I

*o Il 4I

I

ec Example 27 N-Phenyl-3-[3-(trifluoromethyl)phenoxy -l-azetidinecarboxamide.

A stirred slurry of 6.2 g (0.02 mole) of 3-[3-(trio fluoromethyl)phenoxy']azetidine oxalate in 60 ml of tetrahydrofuran was treated with 5 ml of triethylamine followed by 2.62 g (0.022 mole) of phenyl isocyanate and stirring continued for 16 hr. The reaction mixture was diluted with water until an oil separated which quickly solidified.

S

The aqueous tetrahydrofuran was decanted and the solid S" residue recrystallized from ethanol-water to yield 5.3 g of white crystals, p. '137-138 0

C.

-33- Analysis: Calculated for C 1 jrHj 5

F

3

N

2 0 2 c0.71; H N, 8.33 Found :C'60.81; H, 1 4.

1 47; N, 8.-35 Example 28 N-Phenyl-3-r4I-( trifluoromethyl)phenoxy]-1-azetidine-, carboxamide.

A stirred slurry of 6.2 g (0.02 mole) of 3-E 1 4-(trifluoromethyl)phenoxyjazetidine oxalate and 2 .62_g (0.022 mole) of .phenyl isocyanate in 60 ml of tetrahydrofuran was treated with 5 ml of triethylamine and stirring continued for 16 hr. The reaction mixture was diluted with water until an oil separated. The tetrahydrofuran-water portion was decanted and the residue solidified on standing.

Recrystallization from ethanol-water yielded 3.5 g (53.4L) of fine white crystali, m.p. l14.5-l76 0 c.

Analysis: Calculated for Cj 7

H

15

FSN

2 0 2 :C,60.71; H,4.50 N, 8.33 Found :C,60.91; H,'4.53; N,8.35 Example 29 0 04 trans-N,2-Dimethvl-3- 3-(trifluoromethvl )DhenoxyJ.-lazetidinecarboxamide.

A stirred solution of 6 g (0.015 mole) of crude trans- 2-methyl-3-[3-(trifluoromethyl)phenoxy~azetidine in 50 ml of tetrahydrofuran was treated with o-94 g (0.0165 mole) of methyl isocyanate added dropwise and stirred for 16 hr under a blanket of nitrogen. Dilution of the reaction mixture with water produced an oil which solidified. After decanting the aqueous tetrahydrofuran phase, the solid residue was recrystallized from ethanol-water to yield 3.95 g 4( 9 1.J 4 of fine whit6 crystals, m.p. 104-5-106'c.

Analysis: Calculated for C 13

H

15

F

3

N

2 0 2 C,5 1 4.17; H,5.25; N, 9.72 Found .C,54.50; H,5.29; N,9-71 4514 -314 Example trn--ehl3r-tilooehlpe--~ 11aeiie carboxamide.

A mixture of 6 g (o.o:15 mole) of crude trans-2-methyl- 3-[3-(trifluoromethyl)phenoxy~azetidine (Purity 56.6% contains diphenylmethane) and 2.14 g (0.0225 mole) of nitrourea in 40 ml of acetone was treated with 14 ml of water, then heated until a clear homogenous solution was obtained. The reaction mixture was stirred overnight as it cooled to ambient temperiture and diluted with water until an oil separated. The oil solidified and was recrystallized from ethanol/water, yielding 4.3 g of white d plate-like crystals; m.p. 117-1180C. The product was recrystallized from benzene, yielding 3.35 g of crystals, m.p. 118-119 0

C.

Analysis: Calculated for C 12

H

13

F

3

N

2 0 2 C,52.56; H,14.78; N,10.22 Found :C,52.54; 1H,4.74; N,10.17 Example 31 trans-2-Methyl-N-(2-propenyl) ,3-r3-(trifluoromethyl) phenoxyl -1-azetidinecarboxamide.

A solution of 6 g (0.015 mole) of crude trans-2-methyl- .43-[3-(trifluoromethyl)phenoxy~azetidine in 50 ml of tetrahydrofuran was treated with 1.54 g (0.0165 mole) of 2 -propenyl isocyanate all at once and stirred under a blanket of nitrogen for 16 hr. The reaction mixture was diluted with water until an oil separated. The oil failed to crystallize and after 7 weeks it was triturated with isopropyl ether (3 x 25 ml). The combined triturates gave 400 mg of white granular crystals m-p. 55-570C.

Analysis: Calculated for C 15

H

17

F

3

N

2 0 2 C,57-32; H,5.

1 N,8.91 Found :C,57.36; H,5.50; N, 8.97 Example 32 3-(3-Chlorophenoxy)-N-rnethyl-l-azetidinecarboxamide.

A solution of 1-chlorocarbonyl-3-(3-chlorophenoxy) azetidine (0.01275 mole) in 20 ml of tetrahydrofuran was treated with 4i ml (0.05 mole) of 40% aqueous methylamine and stirred for 16 hr. The reaction mixture was diluted with water until an oil began to separate, then extracted with 3 x 50 ml of benzene. The combined extracts were dried over magnesium sulfate and concentrated to a solid which was recrystallized from benzene/ligoin to yield 1.2 g of fine white crystals, m.p. l40ol4lc.

Analysis: Calculated for CjjHj 3

CIN

2 0:C,5 1 4.89, H,5.44;- N,11.64 Found :c,55.05; H,5.58; N, 11 .52 Example 33 2L"hoohnx)N(-propenyl)-l-azetidinecarboxamide.

A solution of 5.4 g (0.017 mole) of l-chlorocarbonyl- 3-(3-chlorophenoxy)azetidine in 20 ml of tetrahydrofuran was treated with 2.3 g (0.04 mole) of 2-propenylamine and stirred for 2 hr. The reaction solution was concentrated in vacuo to a rose beige solid. Trituration of the solid 9, .9 with water gave, after filtering, 4.4 g of crude product.

9 After drying, the solid was recrystallized with charcoal treatment from 2% acetone/isopropyl ether to yield 1.7 g *l 125 of pale beige crystals, m.p. 87-89 0

C.

Analysis: Calculated for C1 3 H1 5 ClN 2 0 2 C,58-54; Hi,5.67; *94% N,10-50 6#6Found :C,58.48, H,5-72; N,l0.

1 49 S tt _r 454 36 Example 34 N-Methyl-3-(2-pyridinyloxy)-l-azetidinecarboxamide.

A 2M benzene solution of phosgene (40 ml, 0.08 mole) was added to a suspension of 10 g of finely ground potassium carbonate in 40 ml of methylene chloride. The mixture was stirred for 15 min. at room temperature and 10 g (0.056 mole of l-(l-phenylethyl)-3-(2-pyridyloxy)azetidine in 50 ml of methylene chloride was added with mild cooling. The mixture was stirred at room temperature for 1 hr and concentrated on a rotary evaporator (25 0 c./30 min). The residue was treated with 100 ml of tetrahydrofuran and cooled with an j ice bath. To the cooled, stirred mixture was added 20 ml of 40% aqueous methylamine. The mixture was stirred for min and partitioned between methylene chloride and water. The methylene chloride was dried over sodium sulfate and concentrated. The residue was crystallized from benzene-ethanol and recrystallized from ethyl acetateisopropyl alcohol. Yield of title compound was 2.3 g m.p. 165-168 0 c.

Analysis: Calculated for CO 1

H

1 lN 3 0 2 C,57.96; H,6.32; ;N,20.28 Found c,57.93; H,6.3 4 I' N,20.12 S" Example N-(2-Propenyl)-3.-(2-pyridinyloxy)-l-azetidinecarboxamide.

To a stirred suspension of 10 g (0.072 mole) of finely ground potassium carbonate in 90 ml of methylene chloride was added 32 ml (0.062 mole' of 2M phosgene in benzene.

SThe mixture was stirred for 15 min and 8 g (0.031 mole) of ,1 l-(l-phenylethyl)-3-(2-pyridyloxy)azetidine in 50 ml of methylene chloride was added. The mixture was stirred at '30 25 C. for 2 hr and concentrated on a rotary evaporator at 0 C./30 min and the residue was treated with 100 ml of tetrahydrofuran. The stirred mixture was cooled with an ice bath and treated dropwise with 4 g (0.07 mole) of allyl i. amine. After stirring 30 min at 25 0 the material was partitioned between water and methylene chloride. The methylene chloride was dried and concentrated. The residue

-I

454 37 was chromatographed on a Waters® PREP-500 HPLC using a silica column and eluting with 50% ethylacetate-hexane. The product was crystallized twice from isopropyl ether. Yield of title compound was 1.5 g m.p. 72-76°C.

Analysis: Calculated for C 12 HIsN 3 0 2 C,61.79; H,6.48; N,18.01 Found C,61.53; H,6.50; N,17.96 Example 36 3-(2-Pyridinyloxy)-l-azetidinecarboxamide.

A 2M benzene solution of phosgene (32 ml, 0.062 mole) was added to a stirred suspension of 10 g of finely ground potassium carbonate in 80 ml of methylene chloride. The mixture was stirred for 15 min and 8 g (0.031 mole) of l-(l-phenylethyl)-3-(2-pyridyloxy)azetidine in 50 ml of methylene chloride added. The mixture was stirred for min and concentrated on a rotary evaporator (25 0 C./30 min).

The residue was treated with 100 ml of tetrahydrofuran, cooled with an ice bath and 20 ml of concentrated ammonium hydroxide added slowly while stirring vigorously. The mixture was stirred 1 hr at room temperature and partitioned between methylene chloride and water. The water layer was o"o extracted 2 times with methylene chloride and the combined organic layers were concentrated. The residue was crystallized from benzene and recrystallized from isopropyl ether. Yield of title compound was 1.4 g, m.p. 133-137 0

C.

25 Analysis: Calculated for Ce 9 i2Ns 3 0 2 C,55.95; H,5.74; N,21.75 Found C,55.73; H,5.71; N,21.10 Example 7 2-rl-(l-Phenvlethyl)-3-azetidinyloxylpyridine.

The maleate salt of l-(l-phenylethyl)-3-azei nol.

g,.22 mole) was partitioned between to ne and dilute sodium hydroxide and was extracted e with toluene. The organic layer was dried (so u sulfate) and concentrated.

The residue was diss led in 125 ml of dimethylformamide and added dropwis o a stirred suspension of 9.6 g (.24 mole) of so hydride (washed three times with isooctane) in J ml nf Timint-hylfornnmi At P-35Or. ThP SMlt nn W -38added dropwise while heating to 75 OC. The solution stirred and heated at 900C. for 1 hr followed eating at 120 C. for 2.75 hr. The mixture was sti at room temperature overnight and concentr d.The residue was partitioned between water an sopropyl ether. The organic layer was washed twice th water, dried (sodium sulfate), filtered and con trated. Crude yield was 30 g. The residue was distil to give 8 g, bp 128-l3I4 0 c./.0l m of product.

Anal s: Calculated for C1 8

H

18

N

2 O: C,75.57; H,7-13; N,11.01 Example 38 1-[3-rl4-(Trifluoromethyl)phenoxy]'i-.azetidinylcarbonyl..

1H-imidazole.

A mixture of 1.7 g (0.01 mole) l,l'-carbonyldiimidazole in 50 ml of tetrahydrofuran and 3 g (0.015 mole) of 3-[4-(trifluoromethyl)phenoxy~azetidine was stirred for 6 hr. The reaction mixture was diluted with water and *xtracted with 3 x 50 ml of methylene chloride. The extracts upon concentrating in vacuo gave an amber residue which was dis solved in 20 ml of benzene and washed with dilute hydrochloric acid, then washed with water. The benzene portion was concentrated to give a semi-solid residue which when triturated with isopropyl ether gave 1.4 g of gray material.

Recrystallization from acetonitrile gave 1.3 g (41l.8%) of fine gray crystals, m.p. 139-140 0

C.

Analysis: Calculated for C1 4 H1 2

F

3

N

3 0 2 Co5 1 4.02; H,3-89; Found C 96;5

C,

5 4.33; HO396 N,li.89 1I 14514 -39 Exa~mple 39 1:-(3-Chlorophenoxy) -1-azetidinecarboxamide.

A solution of 5.14 g (0.017 mole) of 1-chiorocarbonyl- 3-(3-chlorophenoxy)azetidine in 20 ml of tetrahydrofuran was treated with 3 ml of ammonium hydroxide and stirred for 1 hr. The reaction mixture was concentrated in vacuo to a wet solid, 14 g, which was recrystallized after drying, from benzene to yield 1.5 g of white crystalline powder, m-p. 163-1614.5 0 c. Yield calculated from the 1-{2-phenylethyl)azetidine c6mpound was 38.9%.

Analysis: calculated for CjOH 12 .C1N 2 0 2 C,52.99; H,14.89; N, 12 .36 Found :C,52.99; H, 1 4.91 N, 12.32 Example 140 3-(3-Fluorophenoxy)-N-methyl-l-azetidinecarboxamide.

A stirred mixture of 5.14 g (0.02 mole) of 3-(3-fluorophenoxy)-azetidine oxalate and 1.7 g (0.022 mole) of methyl isocyanate in 20 ml of tetrahydrofuran was treated with ml of triethylamine then stirring was continued for 3 hr.

The reaction was diluted with water and the fine crystalline precipitate obtained was collected by filtration and dried at 6o C. under vacuum to yield 3 g of product, m-P. 155-156 0 c. Yield: 66.9%.

Analysis: Calculated for CIIH13FN 2 0 2 C,58.92; H,5.84; N, 12-.49 Found .c,58.93; H,5.91; K 25 N,l2 .26 454 40 Pharmacology Anticonvulsant activity was determined for compounds of Formula I as evidenced by using chemical or electrical challenge as follows, Metrazole Chemical Challenge (Swinyard Method) Groups of 8 adult female mice were randomly assigned to dosage groups according to the method of Steel, R.G.D., and Torrie,J.H. (1960) in "Principles and Procedures of Statistics", McGraw-Hill Book Company, Inc., pp 99-100, pp 428-31. Each mouse was identified with a color code on its tail. The test compounds were administered as solutions or suspensions in 10 ml/kg mouse body weight of aqueous methyl cellulose within 15 minutes of preparation of the suspension. Metrazole®(pentylenetetrazol) was prepared as a solution in physiological saline. The mice were not fasted prior to the test. Eight mice were tested at each dosage level.

Each mouse received one dose of the test drug (usually 100 mg/g for screening) in the 0.5% aqueous methylcellulose S 20 or the control article aqueous methylcellulose alone) 4. ,intraperitoneally. Metrazole (80 ng/kg was then given in a loose fold of skin on the back of the neck; i.e., i 1/ hr after the test compound or control article was given.

Injections were given with a 1 ml glass tuberculin syringe with appropriate size hypodermic needle (27 gauge for solutions; 23 gauge for suspensions). All injections were Si- given in a volume of 10 ml/kg mouse body weight. Each mouse was observed for 30 minutes following Metrazol I A injection. Failure of the animals to exhibit a threshold 3 0 seizure (a single episode of clonic spasms at least 5 seconds in duration) was defined as protection. Anticonvulsant data were tabulated as the percent protection, i.e, No. Mice Protected x 100.

No. Mice Tested The ED 5 o, 95% confidence limits and potency ratio may be ascertained by the computer-based probit analysis ascribed to Finney, D. J. (1964) Statistical Method in Biological 4 454 41 Assay, 2nd Ed., New York. Hefner Publishing Co.

Electrical Challenge Adult female mice in groups of eight were administered the test drug intraperitoneally (usually 100 mg/kg initially for screening) in liquid carrier, usually physiological saline or water. Animals were challenged electrically by placing brass electrodes on the corneas and applying an electrical stimulus (60 Hz, 5 m sec. pulse width, 34 m A intensity) for 0.2 seconds by way of a Grass Stimulator® and constant current unit and a Hunter Timer®. The absence of tonic seizures upon cessation of the stimuli was scored as protection in that animal. The number of animals protected from tonic seizures at a given dose of test drug was determined. The EDso, 95% confidence limits and potency ratio may be ascertained by the method of J. T.

Litchfield and F. Wilcoxon (1949) J. PHARMACOL. EXP. THER.

96, 99-113.

Some of the more active compounds such as in Examples 7, 8, 10, 14, 16 and 20 exhibit EDso's in the metrazole test of 5 to 30 mg/kg and EDso's in the electrical challenge test of about 10 to 30 mg/kg.

454 42 Formulation and Administration The pharmacologically active 3-phenoxy- 1-azetidinecarboxamides of this invention are effective in the treatment of both petit mal epilepsy and grand mal epilepsy. Effective quantities of these compounds may be administered to a living animal body orally as in capsules, tablets or elixirs. It is only necessary that the active ingredient constitute an effective amount, such that a suitable effective dosage will be obtained consistent with the dosage form employed. The exact individual dosage as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian.

Based upon a comparison with known anticonvulsant compounds, daily dosages appear to preferably range from about 0.5 to 1.5 milligrams per kilogram of body weight in the treatment of petit mal epilepsy and about 25 to milligrams per kilogram of body weight in the treatment of grand mal epilepsy. Very small quantities of the active materials of the present invention, even as low as 0.1 milligram, are effective when minor therapy is involved.

Unit dosages are usually 5 milligrams or above and preferably 25, 50 or 100 milligrams per unit dose. The active ingredients of the invention may be combined with other pharmacologically active agents as previously indicated, or with buffers, antacids or the like, for administration and the proportion of the active agent in the composition may ibe varied widely.

a I I 6. 454 09-II 43 Capsules Capsules of 5 mg., 25 mg., and 50 mg. of active ingredient per capsule are prepared; with higher amounts of ingredient reduction may be made in the amount of lactose.

Typical blend for encapsulation Active ingredient Lactose Starch Magnesium stearate Per Capsule, mg.

296.7 129.0 4.3 1435.0 mg.

Total Uniformly blend the selected active ingredient with lactose, starch and magnesium stearate and encapsulate the blend.

Additional capsule formulations preferably contain a higher dose of active ingredient and are as follows: 100 mg. per 250 mg.per 500 mg. per Ingredients Capsule Capsule Capsule Active ingredient Lactose Starch Magnesium stearate 100.0 231.5 99.2 4.3 250.0 126.5 54.2 4.3 500.0 31.1 13.4 Total, mg. 435.0 435.0 550.0 Tablets A typical formulation for a tablet containing 5'.0 mg.

of active ingredient per tablet follows. The formulation may be used for other strengths of active ingredient by adjustment of weight of dicalcium phosphate.

Ingredients 1 Active ingredient 2Corn Starch SCorn Starch (paste) SLactose Dicalcium phosphate 6Calcium Stearate Total Per Tablet, mg.

13.6 3.4 79.2 68.0 0.9 170.1 ag.

1454 44 Uniformly blend 1, 2, 4 and 5. Prepare 3 as a percent paste in water. Granulate the blend with the starch paste and pass the wet mass through a number eight mesh screen. The wet granulation is dried and passed through a number twelve mesh screen. The dried granules are blended with calcium stearate and compressed.

Additional tablet formulations preferably contain a higher dosage of the active ingredient and are as follows.

mg. Tablet Ingredients Per Tablet, mg.

Active ingredient 50.0 Lactose .90.0 Corn starch 58.0 Calcium stearate Total 200.0 Uniformly blend the active ingredient, lactose, and corn starch. The blend is granulated, using water as a granulating medium. The wet granules are passed through an eight mesh screen and dried at 140 to 160 degrees Fahrenheit overnight. The dried granules are passed 20 through a number ten mesh screen and blended with the proper amount of calcium stearate and this blend is then converted 0 t into tablets on a suitable tablet press.

0 06 0 t 0 0 0 00 00 0

Claims (4)

1. A method of treatment for anticonvulsant effect which comprises administering to a living animal an effective amount of a 3-aryloxyazetidinecarboxamide compound selected from the group having the formula: R Z N-C-N 0-Ar wherein; R 3 Ar is selected from pyridyl in any of its positions, including pyridyl substituted by halo, from phenyl or phenyl substituted by 1 or 2 radicals selected from chloro, bromo, iodo, fluoro, loweralkyl, loweralkoxy, nitro, aminocarbonyl, trifluoromethyl, or acetyl; Z is oxygen or sulfur, R 1 and R 2 are selected from hydrogen, loweralkyl, aryl, allyl, substituted allyl, propargyl, cycloalkyl, loweralkylcycloalkyl, cycloalkylloweralkyl, arylloweralkyl, cycloalkylamino, loweralkyl, and diloweralkylaminoloweralkyl, 1 2 and R and R when taken together with the adjacent nitrogen atom may form a heterocyclic amine radical selected from azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, imidazolyl, piperazinyl, 4-substituted piperazinyl and morpholinyl, R 3 is selected from hydrogen, loweralkyl, aryl or arylloweralkyl; the geometrical isomers including cis, trans, and isomers thereof, and the pharmaceutically acceptable acid addition salts thereof when R and/or R2 have a salt-forming basic amino component or when Ar is pyridyl, with the proviso that when R 3 is hydrogen, Z is oxygen and Ar is phenyl or phenyl substituted by trifluoror- methyl, aminocarbonyl, then R 1 and R 2 cannot be a combination of hydrogen and loweralkyl, and the further proviso than when R is hydrogen, Z is oxygen and Ar is phenyl or phenyl substituted by fluoro, loweralkyl, loweralkoxy, trifluoromethyl, acetyl or aminocarbonyl, R 1 and R 2 cannot both be hydrogen. 4 4~

2. The method of claim 1 wherein the compound is N.-methyl-3-3-(trifluoromethyl)phenoxyJ.-l-azetidifle- carbothioamide or N-(2,6--dimethylphenyl)-3-[3-(trifluoromfethyl)pheloxy]-1- azetidinecarbothioanide; or N-(phenylmethyl)-3-E3-(trifluoromethyl)phenoxy]-l- azetidinecarboxamide; or N-(2 ,6-dichlorophenyl)-3-[3-(trifluoromethyl)phenoxy-1- azetidinecarbothioamide; or N-[3-(diethylamino)pr'pylJ-3-[ 3.-Ctrifluoromethyl)phenoxy- -azetidinecarbothioamide or a pharmaceutically acceptable acid addition salt thereof; or N-3-(dimethylamino)propyl)-3-[3-(trifluoromethyl)phenoxy>- 1-azetidinecarbothioamide or a pharmaceutically acceptable acid addition salt thereof; or N-(2-propenyl)-3-[3-(trifluoromethyl)pheloxyJ-l- azetidinecarboxamide; or 25N-cyclopropyl-3-[3-( trifl'uoromethyl)phenoxy3-l-azetidine- carboxamide; or N-[3-(diethylamino)propyl-3-[3-(trifluorornethyl)phenoxy)- 1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof; or N-2-(propenyl)-3-[14-(trifluoromethyl)phenoxy3-1-azetidine- carboxamide; or 477 N-(cyclopropylmethyl)-3-[3-(trifluoromethyl)phenoxy]-l- azetidinecarboxamide; or N,N-diethyl-3-r3-(trifluoromethyl)phenoxyl-1-azetidine- carboxamide; or N,N-dimethyl-3-[3-( trifluoromethyl )phenoxy]-l-azetidine- carboxamide; or N-(2-propynyl)-3-[3-(trifluoromethyl)phenoxy]-l-azetidiie- carboxarnide or N-cyclohexyl-3-[3-(trifluoroxnethyl)phenoxyJ-l-azetidine- carboxamide or N-cyclopropyl-3-[JI-(trifluoromethyl)phenoxyj-l-azetidine- ,carboxamide or 0 0 00o 00020 N-(cyclopropylniethyl)-3-[4-(trifluoromethyl)phenoxy]-l- CI -0 azetidinecarboxamide or 0 N-[3-(diethylarnino)propyl3-3-[l4-(trifluoromethyl)phenoxyJ- 1-azetidinecarbothioamide or a pharmaceutically acceptable N-[3-(diethylamino)propyl--3-EJI-(trifluoromethyl)phenoxyj- 1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof; or N-(2-propynyl)-3-[4--(trifluororethyl)phenoxy]-1-azetidine- carboxarnide; or N-(2-methyl-2-propeny1)-3-[i4-(trifluoromethyl)phenoxyJ-1- azetidinecarboxamide or N-(2-methyl-2-propenyl) -3-[3-(trifluorornethyl)phenoxy-l- azetidinecarboxamide; or N-3mty--uey)3[-(rfurmty~hnx31 azetidinecarboxamide ;or N-(3-methyl-2-butenyl)-3-[3-(trifluoronethyl)phenoxy]-l- azetidinecarboxamide; or (E)-N-(2-butenyl)-3-CJ.-(trifluoromethy)phenoxy>1l-azetidine- carboxamide; or (E)-N-(2-butenyl)-3-[3-(trifluorometi-iyl)phenoxyJ-l-azetidine- carboxarnide; or 20 N-phenyl-3-[3-(trifluoromethy1)phenoxyl-1-azetidine- carboxamide; or carboxamide; or trans-N,2-dimethYl-3-[3-(trifluoronethyl)phenoxyl- azetidinecarboxamide; or trans-2 -me thyl-3-[3-( trifluioromethyl)phenoxy)-1-azetidine- carboxamide; or trans-2-rethy1-N-(2-propeny)-3-[3-(trifluoromethyl)phenoxym- 1-azetidinecarboxamide; or 454 -48- N-(2-methyl-2-propeny)-3-[4-(trifluoromrethyl)phenoxyJ-l- azetidinecarboxamide; or N-(2-nmethy1-2-propenyl)-3-[3-(trifluoromethyl)phenoxy-l- azetidinecarboxamide; or N-(3-rnethyl-2-buteny1)-3-[4-(trifluoromethyl)phenoxyj-1- azetidinecarboxamide or N-(3-methyl-2-butenyl)-3-C3-(trifluoromethyl)phenoxy]-l- azetidinecarboxamide; or (E--2btnl--4(rfurmty~hnx]laeiie carboxamide; or (E)-N-(2-buteny1)-3-[3-(trifuoromethy)phenoxy--azetidine- carboxamide; or 1 4 p ~*20 N-phenyl-3-E3-(trifluorornethyl)phenoxyl-1-azetidine- carboxamnide; or *4 4 44 N-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidine- carboxaniide; or trans-N,2-dimetbYl-3-[ trif luoromnethyl )phienoxyl- azetidinecarboxamide; or trans-2-nmethyl-3-[3-( trifluoronmethyl)phenoxy)-1-azetidine- carboxamide; or 1-azetidinecarboxamide; or 49 49

3-(3-chlorophenoxy)-N-methyl-l-azetidinecarboxamide; or 3-(3-chlorophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide; or N-methyl-3-(2-pyridinyloxy)-1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof; or N-(2-propenyl-3-(2-pyridinyloxy)-1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof; or 3-(2-pyridinyloxy)-1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof; or 0g, 2-(1-(l.-phenylethyl)-3-azetidinyloxy] pyridine or a pharmaceutically acceptable acid addition salt thereof; or 4 4p 1-[3-[4-(trifluoromethyl)phenoxy]-l-azetidinylcarbonyl]- S 1H-imidazole or a pharmaceutically acceptable acid addition salt thereof. 3. A method of treatment for anticonvulsant effect substantially as herein described with reference to any one of 4,444 the Examples.

4 DATED this 3rd day of May, 1990. U A.H. ROBINS COMPANY, INC. By Its Patent Attorneys ARTHUR S. CAVE CO.