CA1294274C - Method of treating muscle tension, muscle spasticity and anxiety with 3-aryloxy-azetidinecarboxamides - Google Patents

Abstract

METHOD OF TREATING MUSCLE TENSION, OXYAZETIDINECARBOXAMIDES

ABSTRACT OF THE DISCLOSURE

A method of treating animals to obtain muscle relaxation and/or to relieve anxiety is disclosed utilizing novel and known 3-aryloxyazetidinecarboxamides having the formula:

Description

~2~'~274 66l97-l77 MEI'HOD OF TREATING MUSCLE TENSION
MUSCLE SPASTICITY AND ANXIETY WITH
3-ARYL-OXYAZETIDINECARBOXAMIDES _ BACKGROUND OF THE INVENTION
1. Field of the Invention.
This invention rela-tes to a method of treating muscle tension, muscle spasticity and anxiety in living animals, including humans, with 3-aryloxyazetidinecarboxamides, certain of which are novel.

2. Information Disclosure Statement Certain o the compounds useful in the method of the present invention are disclosed in U.S. Patent No. 4,226,861 as having anticonvulsant activity and use in treating epilepsy having the formula: O ~ R
R-NHC-N ~ O - ~ ?

wherein R is loweralkyl and Rl is hydrogen, aminocarbonyl or trifluoromethyl.
Certain other of the compounds useful in the p.resent invention are dlsclosed European Patent Application ~o.~102,194 A
publlshed March 7, 1984, as having anti-convulsant activity and having the formula: 1 (R )n 2-C-~ 3 - ~

.

:'s'~
, ..

7~

wherein Rl = H, F, loweralkyl, loweralkoxy, trifluoromethyl, acetyl, or aminocarbonyl.
In European patent publication, it is stated that the compounds of U.S. Patent 4,226,861, mentioned above, have muscle relaxant property and based on another less reliable test states that the compounds in the European patent publication do not have muscle relaxant activity at an effective anticonvulsant dosage.
SUMMARY OF THE INVENTIO~
The 3-aryloxyazetidinecarboxamides useful in the method of treating muscle tension, muscle spasticity and/or anxiety in animals of this invention have the formula:
R z N- C ~ Ar 2/ Y Formula I

wherein Ar is selected from pyridyl in any of its positions including pyridyl or halo substituted pyridyl, from phenyl or phenyl substituted by 1 or 2 radicals selected from chloro, bromo, iodo, fluoro, loweralkyl, loweralkoxy, nitro, aminocarbonyl,or trifluoromethyl;
Z is oxygen or sulfur;
Rl and R2 are selected from hydrogen, loweralkyl, aryl, allyl, substituted allyl, propargyl, cycloalkyl, loweralkylcycloalkyl, cycloalkylloweralkyl, arylloweralkyl and diloweralkylaminoloweralkyl, and Rl and R2 when taken together with the adjacent nitrogen atom may form a heterocyclic amine radical including azetidinyl, pyrrolidinyl~ piperidinyl, .~.,~.

:~2~ 7~

homc~piperi~linyl; imidazolyl, piperazinyl, 4-substituted pip~razinyl and mc>rpholir~yl;
R9 i~ ~elect~d from hydrogen, loweralkyl, aryl or zlrylloweralkyl:
the geometrical i~omers including ci~, trans, (E) ~nd (Z) i~omer~ thereof, and the pharmaceutically acceptable ~alts thereof when Rl and/or R~ ~ave a ~alt-~orming basic amino componen~ or when P~r is pyridyl.
The compounds of Formula I are novel except wherein Ar is phenyl or phenyl ~ubsti'cut~d by trifluorome~hyl or aminoc3rb~nyl ~t ~he ~;ame time Z i~ oxygen, R~ is hydrogen, and Rl ænd R2 are a c:oTr~tination of hydrogen ~nd loweralkyl and wher~in Ar is phenyl or phenyl sub~tituted by i~luoro, loweralkyl, lowerallcoxy, tri~luoromethyl, acetyl or amino-c~rbollyl ~t the same time 2 i5 oxygen ~nd Rl, R2 and R3 are hydrogen.
In the ~urther de~Einition of 8ynlbO18 ~n~ in the ~ormulas hereo~ and wher2 they appear elsewhere throughout thi~ sp~ciication and in the claims, the terms havo the follow~ng ~ignificance.
~h~ term "low~rallcyl" as u~ed herein, unla~s otherwise sp~ci~i~d, includes straighlt and branched chain radicals o~ up to eight carbons inclu6ive and i8 e~emplified by such - grOUp8 rl8 me~thyl, ethyl, propyl, i~opropyl, butyl, ~ec-butyl, 25 t~rt-butyl, amyl, i~o~myl, hexyl, heptyl, and ~ctyl r~dis:al~
~nd ~ lik~. ThE term "loweralkoxy" has the ~ormula -O-lower~lkyl .
The term "cycloalkyl" el~ u~d herein includes pri2narily ~:y~lic alkyl radical~ c~n~aining 3-9 car~on atoms inclu~ive 30 and ~ncludes ~uch group~ ac c:yclopropyl, cyclobu tyl, cyclo-pentyl, cyclo~exyl, ~yclohep~yl ana th~ 1 ilce .
The term "loweralkylcycloalkyl" re~r~ to cyc:lc~alkyl ~ub~titute~d by alkyl ra~icals o~ 8 c:arbon length.
The tenn " cyclo~lkylloweralkyl" ref~rs tD il~ cyl::loalkyl 35 ra~ al lir~ced Vi21 1-8 caEbon ~lkyl ~h~ins, inc~luding branl:he~ chains, ~o the ~mide ni~rogen.
~ he term "substituted ~llyl" mean~ 211yl ~u~itut~d by ~lkyl radi~ in ~ny onle of it~ 3 po~i~ion~.

~ Z 9 ~

The term "aryl" under the definition o~ Rl, R2 and R3 re~rs ~o phenyl or phenyl ~ub~tituted by non-interferiny r~dical~ such a~ halo, loweralkyl, loweralkoxy, nitroj cyano, tri~luorome~hyl, carbomethoxy, carbo~thoxy, an~ the like.
The term l'arylloweralkyl" undex the d~inition ~f Rl, R2 and R9 refers to ~n aryl group as defined ~bsve linked via 1-8 carbon alkyl ~hainY, including brAnched ~hains, to the amide nitrogen.
Th~ term '14-~ub titu~d-pipera~inyl" under the de~inition o~ Rl and R2 refers t~ a piperazine radi~l ~ub~ituted by usual radical~ common in the art, including aryl as de$ine~ above and loweralkyl as defin~d above.
As de~ined ~b~ve under Formula I, pharmaceu~ically acceptable salt~q are included when Rl an~/or R2 have a salt-15 $orming ~mino ~omponent or when Ar ~8 pyridyl. Salt~formingamino componQnt~ ~re prese~t, for axample, when Rl and/or R2 are diloweralkylaminoloweralkyl, or when togather they form piperazinyl or imidazololyl radicals. Pharmaceutically accoptable aci~ addition ~alts are those salts which are 20 phy~iologically compatible in warm-bloode~l animal~. The acid addition 9alt8 may be formed by either ~trong or weak acid~. Repre~entative of ~trong acid~ are hydrochloric, hydrobromic, ~uliEuric, and pho~phoric acid~. Repre~entativa o:E U8efUl we~k acid~ nre ~umaric, mal~ic, succinic, oxalic, 25 citricl tartaric, h~xamic and the like.
A~ stat~d ~bove, the metho~ of ~his inv~n~ion employs the Gompound~ of Foranula I to rel i~ve muscle tenq ion and ~pas~icity (i.e." to relax ~mscle~) ~nd/or ~nxi~ty in an~mals, including human~ The ~roce~ure for tQ~ting ~0 compound~ for mu3~1e relaxant activity is ~he ~orphin~-Indu~ed ~tr~ub-Tail-In-Mic~ ~st an~ the procedure for indi~ating antianxiety re3pons~ i~ th~ Voyel Conflic~ T~t ba~ed on ~hock ~uppr~2d ~rinking ~havi~r. ~th t~t~
~r~ giv~n in detail h~reinbelow und~r ~I~.h~rmacologic~

3~ ~&t Pr~c~dur~s."
~ he m~tho~ utilizing ~n~ or m~re o~ th~ ~mpoun~s o~
Formul~ I i8 a~apt~bl~ ~or tr~t~ng t~-ed ~nd ~pastàc ~2~4~7~

muscles and ~or treating anxiety in the same individual or ~r treating tensed and spa~tic muscles when anxiety i8 not present or for treating anxiety when there are no muscle pro~lems. Examples o~ effective muscle treatment would be for muscular conditions arising from tetanus, whiplash, stroXe, multiple schlerosis, cerebral palsy and the like.
Compounds of Formula I wherein Rl and R2 h~ve an allyl, substi~uted allyl, propargyl or cycloalkyl value are pre~erred ~or their potency as muscle r~laxants.
DETAILED DESCRIPTIO~ OF THE INVENTION
The methods used to prepare the muscle relaxant~ and antianxiety agents of Fonmula I which are used in khe method ~ this inv~ntion are cla~si~ied as ~ollows by equation under Method Classes A, B, and C.

Method Class A
Frt~m Phenoxyaze t id ine El-N~ 0~ R2N=C=Z - R2 -NHC-N~ ~X) n ~~~~ + R P~ ~-C-Cl ~RlR2~-r-~ ~X)n H-N~O~+ H2N-c-NHNo2 --> H2N C ~ (X)n ~ -C=Z

e~ ReNH2 ~ (~)-C=Z ~ H-N~O~ Xlr ( ~n 9 ~-NHC-~0~

CH~N-(CH3) -~H3 + (~)-C~Z + H~ /7 x = o-8 : R3 ~3 ~ ~ (CE~-(cH23-NH

:: :

:

:

~Z~ 7 Method Class B
Via Aryloxy-l-ehlorocarbonylazetidine (Ar=Phenyl, Substituted-phenyl, Pyridyl) c~ N~O-Ar + R2NH2 ~ > R2HN-C-N~>_O-Ar ~9 ~ R9~

Cl-C-N ~ r + HN ~ CH2)n >(~ C-N ~ O-Ar R~ R3_ Cl-C-N ~ O-~r ~ EN ~ R~ RB-~ N-C-~ ~ O-Ar Cl_c_K?_O~r + a~ C--K?~O~r 20 Method Clas~ C
Via Methane (or Phenyl) suli~onyl azetidine H-N~OSoæw R2-N=C=Z ~ R2NH-C-N~OSOz-W

W = CH3, phenyl, X

4-CH9-phen~ F Na~

: ~ X
~ z ~_ - : RS

: 35 : ~ :

: ~ , ~52 Method Class A reactions comprise a process for preparing phenoxy compounds of Formula I by reacting a compound of the formula:

~-N ~ ~ ~X)n with one of the following cl~sses of compou~ds:
a) R2N = C = Z
b) RlR2N_C_cl c) H2N-C-NHN02 ( ~ ~)2 N
or, e) and f) the product of ( ~ ~ -C=Z
and R2NH2 or (CH4 ~ N-(CH2)X-NH2 ~ x 8 0 8 Method Class B reactions comprise a process for preparing certain aryloxy compounds of Formula I by reacting a compound of the formula:

Cl-C-~ ~ O-Ar \~
: R3 with one of the ~ollowing classes o~ compoundso a) R2NH2 : or3 b) a heterocyclic amino compound.

Method Class C reactions comprise a process ~or preparing m-fluorophen~xy ~omp~unds of Formula I by reacting a compound of the formula:
~5 , ~
H-~ ~ 0502W

~9 W=C~, C~H5, 4-CH3-C~H~

~ILZ9~Z~

g with an isocyanate of the formula R2 -~=C=Z
to give a compound of the formula Z ~
R2NH-C_N ~ SO2W

and thereafter reacting with s~dium hydride and a meta-fluoroph~ol of the f~rmula X

oE~J~ F
to give a compound of the formula R2NH-C-N ~ O

Methods of preparing the starting phenoxyazetidines used in Method class A are outlined by eauation in Chart I.
Methods of preparing the starting aryloxy-l-carbonylazetidines used in Method Class B are outlined by equation in Chart II.
The ~tarting l-(diphenylmethyl)~3-hydroxyazetidines used in Method class C route (See Chart III3 may be prepared by the method of Anderson & Lok., J. ORG. CHEM.
~1972) ~7: 3953 from benzhydrylamine and an appropriate epihaloh:ydrin. Cis and trans:isomers of the l-(diphenyl-methyl~)-3-hydroxyazetidines when they exist may be separated by chromatography. Starting ~-methylbenzyl-3-~zetidinol i~ prepared by the method o~ Tetsuya Okutani, et al., CHEM.
PH~RM. BULL., Vol 22 (1974) p. 1490. Preparations 1-6 : ~5 illustrata the methods.
, 7 ~

Chart I
Preparation of Starting l~Un3ub~tituted ph noxvaze~i~Lne~

R4* ~
~CH-N ~ OH (See Preparation~ 2 and 5) CBH5 ~R3 l) CH3SO2Cl~Et3 \ 2) ~aOH, with or without (X)n ~ X)n ¦DMF ati~n8 3 and 6)~ 4ee also U,S. Paten~
R~j ~ ~ X)n C~H5 . 9 or H~ ~ Pa(0~)2/C ~ ~
(See Preparation 4) R3 ~****

*R4 = CH3: phenyl or subst. phenyl.
**X is restricted to substituents that are electron withdrawings e.g.~ fluoro, chloro, bromo, iodo or CF~.
~**When X = 4-cl, 4-Br, 4-I, 4-~ or 4-CF~, yields are very low.
***~Exc~pt X cannot be chloro, bromo, or io~o in.the produ~t a~ hydrogenolysis removes these radicals.

: : ~

4~7~

Chart II
Pxeparation of Starting l-carbonyl-3-~rvlox~ azetidines CH-N ~ OH
C /Hs ~3 (See Preparation 1 for R3 = CH~) halo \~halo \ NaH
~DMF

C~s ~ ~( ) / ~-1;~

(See Preparation ~ ~
in Chart 1) . I c-c12 Z ~ ~ (Z=O or S) Cl-C-N ~ OAr \( : R3 :

:

:

Chart I II
Preparat ion of Start ing Methane~ ~or phenyl)- ~;ul:EonYlazetidine R4-CH_N~oH WS02Cl ~ R~-CH-N~OSO2W
C~Hs - NEt3 Ce~Hs 3 toluene R~ = CH~, Cs~s~ W = CH3, C~3Hs P~ .
-C3H4 -4CH3 Pd/~
~ , H-N/~_OS02 W

_ :

:

:

~ ~ ~ 4 2 7 ~ 452 Preparation 1 trans-1-(Diphenylmethyl~-2-m~thyl-3-azetidinol oxalate r 1 11.
~ ~ .
A mixture of 126.4 g (0.72 mole) of diphenylmethylamin~
and 100 g (o.66 mole) of 3-bromo-1,2-ep~xybutane in 300 ml o~ methanol was stirred while being protected from light for 96 hr, then heated at reflux for ~0 hr as the color changed from pale yellow to deep amber. A sample was assayed by lH-nmr and showed 3 methyl doublets. A fine beige precipitate was removed by filtration (diphenylmethylamine hydrobromide) and the filtrate concentrated on a rotary evap~rator to yield 174.6 g of crude oil. A 1.5 sample was neutralized and placed on a 4 mm ~hick plate of a Chromatotron~ and ~luted with 10~ ethyl acetate-toluene.
A total of sixteen fractions were collected which consisted f 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 concen-trate was converted to the free ba~e with ammonium hydroxide and extracted into toluene which was dried over magnesium ~ulfate a~d concentrated. The reaction residue was dissolved in methanol and treated with 58 g o~ oxalic acid, heated to give a homogenous solution and allowed to cool after seeding with a sample of the ~rans oxalate salt. Filtration yielded 62 g of white granular product, m.p. 147-148.5C. A second ~rop of 26 g was also obtained.
The lH-nmr ~pectrum showed only a ~ingle CH9 doublet with j (CH3-H) o~ 6.1 Hz which is consistent with the trans compound.* Total yield o~ title compound was 88 g (38.80 .
*Robert H. Higgins and Norman H. Cromwell, J. Hetero. Chem.
8 ( 6 ) ~ 1059-62 ( 1971 ) .
Analysis: Calculated for Cl7Hl~NO-C2~204: C,66.46: H,6.16;
~,4 .o8 Found : C,66.38: HJ6~16;
NJ 4.07 .

1 2 ~

Preparation 2 l-(DiphenylmethYl)-~-azetidinol methanesulfonate (ester) hYdrochloride Cl:l~
A mixture of 60.02 g (0.22 mole) of l-diphenylmethyl-3-a~etidinol hydrochloride and 48.94 g (o.484 mole) of triethylamine in 800 ml o~ toluene was stirred for 24 hr, then cooled to 5C. 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 15C. The reaction mixture was stirred for 3 hr and filtered to remove the triethylamine hydro~hloride. The filtrate was treated with 40 g (0~242 mole) of 4-trifluoromethylphenol followed by 19.35 g (o.484 mole) of sodium hydroxide and 1.6 g (0.005 mole) o~ tetrabutylammonium bromide in 60 ml of water. .
The reac'ion mixture was stirred rapidly at reflux for 18 hrs, then atirred for 72 hr while it cooled to an~bient temperature.
Th~ reaction mixture was transferred to a separatory ~unnel and washed with 4 x 200 ml of water (emulsion). The toluene phase was dried over magnesium sulfate and concen-trated 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 ~eparated and was removed by filtration (5.1 g). The $iltrate wa~ treated with isopropyl ether to give an oil which W2S worked up later. The solid was identified by spectral ~nalysis a~ the methylsul~onate of the starting azetidinol. Recrystallization from isopropyl alc~hol gave 3.3 g o~ fine white crystalline material, m.p. 172-173C., (s~rinks 167C. 3 .
Analysis: Calculated for Cl~Hl~N03S~HCl: c,s7ro; H,5.70;
~,3-96 Found : C,57.80; ~,5.86:
N,3.92 "5~;
3~Z~ 4 Pre,pa ra t lon 3 ]azetidine oxa~ate rl 11 A ~tirred 6}urry of :L.2 g (0.03 mol2) of sodium hydride (60% dispersion in mineral oil) in 50 ml of dry DMF WZ18 treated with 3.45 g (0.01 mole) of trans-1-dip~enylmethyl-2-m~thylazetidin-3-ol oxalate added in ~mall portion~. When the a~dition was ~omplete and th~ ev~lution of hydrogen c~as~d, the reaction wa~ heated to 80C. ~or 2 hr then 1.~4 g (0.01 mole) of 3-fluoro-tri~luorornethylbenzene was added 13 dropwise. The reaction mixture w~ sti~red at Boc. for an ~dditional 18 hr. The reaction mixture was diluted with ice water and extract~d with 3 x 25 ml of ~oluene. The extra~t~
were combined, dried o~rer magnesium aulfate, ~iltered, and the filtrate treated with 1 g of oxalic acid~ . The resulting 15 ~olid wa~ collected by ~iltration. R~crystallization ~rom acetone-isopropyl ether yielded 2.2 g (4~5O Of fine white crystal~, m.p. 146-147C. Proton NMR ~hows it to be the trans compound.
Analysis: Calculat~d ~or C2~H~2F9NO~C2H404: c,64.o6; H,4.96:
N,2.87 ao Found : C,64.26: H,4.~9:
Nl2.~9 Preparation 4 trans-2-Methyl-~-r3~(txil~1uoromethvl)phenox~ a.zetidine oxalate ~
A methanol-warm water ~olution o 33 g (o.o68 mole) of trans-l~diph~nylmethyl-2-methyl~ -(trifluor~methyl) ph~noxy3azetidine oxalate was treated with amm~nium hy~roxide unt~l ba~ic, then extracted with 4 x 150 ml of methylen~
chloride. The ~ombined m~thylene chl~ride extracts were ~0 waRh~ with wat~r, dri~d over m~gn~sium ~ul~ate, and con~entrat~d i~ acuo to a pale yellow oil. ~his oil was dissolved in 200 ml of 190 ~hanol plus 5 ml of ~ri~hyl-amin~ ænd hy~rogenated on a Parr ~pparatus with 3.3 g of 5% pall~dium-on-cha~coal cataly~t with a 40 p8i atmosphere o f hydrog~n at 70QC. ~or 12 hr. Ater the e~l~ulat~d ~moun~c of hydrogen had b~en ~hsorb~d, ~he cat~ly t wa~ rem~ved by ~ 74 _ 16 -~iltration and the ~iltrate concentrated in vacuo to yield 26.73 g o~ crude product. An 8 g portion was converted to the oxalate ~;alt in isopropyl alcohGl yielding 6 . 1 g o~ fine white powder; m.p. 155-156C. Total yield extrapolated from the aliquot converted to the oxalate salt was 84% of theory.
Analysis: Calculated for C~ 2F3NO CzH204: C,48.61; H,4.39;
N,4.36 Found : CJ48.67; H,4.38;
- N,4.34 Preparation ~
trans-l-(DiPhenylmethyl)-2-methyl-~-azetidinol methane-Eulfonate (ester) hydrochloride ~
A ~olution of 6 g (0.025 mole) of trans-l-diphenyl-methyl-2-methylazetidin-3-ol tobtained from the hydrochloride salt by partitioning in organic solvent and aqueous base, separating and avaporati.ng the organic phase) in 40 ml of dry benzene was treated with 10 ml of triethylamine and cooled to 5C. While stirring, the reaction mixture was treated with 3.54 g (0.0~ mole) of methanesulfonyl chloride at a rate to control the temperature below 10C. After stirriny for 3 hx, TLC (20~ ethyl acetate/methylene chloride on silica gel) showed the reaction to ~e incomplete. An additional 1.14 g (0.01 mole) of methanesulfonyl chloride was added and stirring continued for 1 hr. The reaction 25 mixture was dilute~ 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 di~solved in isopropyl ether and treated with ethereal hydrogen chloride. The solid ~alt was- removed and recrystal-lized from 190 ethanol to give 3.4 g (37%) of fluffy white crystals, m.p. 152-153C~
Analysis: Caleulated for Cl~H21N03S HCl: C~58.77; H,6.o3;
~.81 Fou~d : C,58.68; ~,6.o8, ~,3.80 lZ94Z~ ~52 PreParation 6 l-(Diphenvlmeth,yl)-7-r3-(trifluoromethyl~phen azetidine.
~-Diphenylmethy~ hydroxyazetidine hydrochloride (I) was prepared from benzhydrylamine and epichlorohydrin according to Anders~n and Lok, J. O~g. Chem., ~7:3953 (1972).
I ~41.~3 g, 0.15 mole) and triethylamine (42 ml, 0.30 mole) were ~tirred in toluene (250 ml) while methane sulfonyl-chlori~e (12 ml, 0.15 m) was ad~ed dropwise over 10 minute3 with stirrin~ and the temperature was maintained between 4 and 12C. TLC (silica gel, 10~ ethyl acetate in methylene chloride)at one hour ~howed all ~tartin~ materials had r~ac~ed. The mixture wa~ filtered to remove the ~riethyl-amine hydxo~hloride which was rinsed ~wice with toluene.
~he ~iltrate and washings ~ombined to about 450 ml of solution. To this ~olution wa~ added m-tri~luoromethyl-phenol (27.5 g, 0.17 mole),tetrabutyl ~mmonium bromide (2.4 g), 50% 30dium 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 mixtu~e wa~ s~parated and wa3h~d pnce with wat~r, dried over sodium sulate ~nd evaporated to an oil. This oil wa~ seeded and pumped on an oil pump overnight. A
solid caXe weighing 49.7 was obtained. Some of this solid w~s dissolved in isopropanol with brief heating. Water wa~ then added to cau~e ~light cloudines~. Th~ ~ixture was ~eeded ~nd c0012d to cause ~rystallization. ~he white soli~ wæ~
~ollected by filtration, wa~hed with 50% a~uous iæopropanol, : and dried under va~uum overnight. Proton ~M~ ~howed slight : cQntamination by sili~one oil, m.p. 82.5~C.
30 An~lysi~: Calculated for C29~4~F3No:C,72.05; ~,5.26; ~,3.65 Found :C,71.62; ~,5.29; N,3.61 3L294;27~ 45 The following examples illustrate preparation of compounds encompassed by Formuila 1 and useful in the method o~ treatment of the invention. The scope of the invention i8 not limited by the exampl~s, howe~er.
Example 1 carbothioamide.
Crude 3-t3-(tri~luoromethyl)p~enoxy~azetidine from catalytic debenzylation of 26.0 g (0.078 mole) ~ l-benzhydryl-3_E3-(tri~luoromethyl)phen~xy~azetidine was dissolved in 100 ml of methyl~ne chloride and treated dropwise under a ni~ro~en ~tmospher~ with a solu~ion o~ 5.0 g (o.o678 mole) of methylisothiocyana~e in 15 ml o~ methylene chloride. The reaction mixture was stirred for 16 hr at ambient temperature and let stand over th~ weekend. The solution was filtered ~ ~ . through a celitq~filter pad to remove a fine crystalline precipitate and the filtrate w~s evaporated under xeduced pressurQ. The xesidual oil was cryst~lliæed rom isopropyl ~ther to give 12.6 g of product, m.p. 79-86C. A 5.0 g ~ample was recrystallized ~rom i80propyl ether (charco~13 to give 3.2 g, m.p. 8~-93C., which was shown by TLC on ~ilica gel (10~76 methanol-toluene) to be contaminated by a lower Rf material. -The ~iltrate was ~vaporated under reduced pre~sure,combined with ~he 3.2 g of solid snd diss~lved in 100 ml of methylene chloride. The solution was ~tirr~d with 25 g o~ silica gel for 0.5 hr and ~iltered through a sintered glass filter. The ~ilica gel wa~ wa~hed with a small volume ~f methylene chloride and the iltrate evaporat~d under reduced pres~ure. The reYidual ~olid w~s recry~tallized ~rom isopropyl ether to give 1.3 9 o~ pure product, m.p. 96-98C.
An~lysis: Calculated ~or Cl2Hl9~N20S: C,49.65; H,4.51:
Found : C,49.58. ~,4 4~;
~,9-58 QC~e1nd~1~

lZ~27~ 452 Example 2 -(2,6-Dimethylphenyl)-3{ ~(triflu~romethyl)p~enoxy azetidinecarbothioamide.
Crude 3-~3-(trifluoromethyl)phenoxy~azetidine from catalytic debenzylation of 30.0 g (0.078 mole) of 1-benzhydryl-3-r3-(tri~luoromethyl)phenoxy~azetidine was dissolved in 100 ml of methylene chloride and treated drop-wise under a ni~rogen atmocphere with a solution of 12.7 g ~0.078 mole) of 2,6-dimethylphenylisothiocyanate in 25 ml of methylene chloride. The pxoduct began to precipitate during the addition and an additional 50 ml of methylene chloride was added to faeilitate stirring. After stirring overnight at ambient temperature, the product was collected by filtration (13.5 g, m.p. 196-199C). A 6.o g sample was recrystallized from isopropanol to give 5.~ g of 15product, m.p. 197-199C.
Analysis: Calculated for Cl~Hl~F3~20S: C,59.99; H,5.03;
N,7.~6 Found : C,60.01l; H,5.o4;
~,7-35 Example 20N-(Phenylmethyl~trifluoromethyl~hen azetidinecarboxamide.
To a stirred and chilled (10-20C.) solution of 0.04 m4le of 3-t3-(trifluoromethyl)phenoxy3azetidine in 100 ml of methylene chloride was added dropwise 6.12 g (o.o46 mole) of benzyl isocyanate. The reaction mixture was stirxed at room temperature for 2 hr and was filter~d. The filter cake was washed with petroleum ether (2 x 50 ml), dilute a~ueous so~ium bicarbonate (2 x 50 ml), and water (2 x 50 ml)~
yielding 12 g (86%)o Recrystallization twice from ethyl acetate gave 9.0 g of clear white flakes~ m.p. 173.5-175C.
Analysis: calculated for CleHl7F9N202: C,61.71; H,4.89;
~, ~ .00 Found : C,61.57; H,4.87:
~,7-99 lZ94~7~ 452 ExamPl~ 4 -~? .6~DichlorophenYl)-3-r3-(trifluoromethyl)phen l-azetidinecarbothioamide.
A solution of 0.04 mole of ~-~3-(trifluoromethyl) ph~noxy~azetidine in 100 ml of absolute ethanol was stirred in a tap water bath while 8.16 g (0.04 mole) of 2,6-di~hloro-phenyl i~3othiocyanate was added all ~t on~:e. T~e reaction was ~;lightly ext~th~nic and as the isothiocyanate began to ~i~solve, product began to precipitate. After ~tirring ~or 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 ~rystallin~
product. A portion of this material (7.9 g) was r~crystal-lized fxom absolute ethanol to give 4.3 g of p~re cry~talline powder, m.p. 195-197C.
Analysis: calculated or Cl7Hl9F9Cl2N20S: C,48.47; H,3 11:
Found : C,48,40: ~,3.07:
N,6.~4 Example ~
-L~-(Diethylamino)prop~l~ 3-(trifluorometh~l) phenoxy~-l-azet inecarbothioamide oxal~t~L~Ll.
A solution of (0.0584 mole) of 3-~(trifluoromethyl) p~enoxy~azetidine was stirred at 10C. while 10.66 g (0.0584 mole) of 3-(diethylamino)propyl iqothio~yanate was added all at on~e. A~ter ~tirxing overnight a~ ambient temperature~
25 the reaction mixture was concentr~t~d at 50C. on a rotary evaporator to a thicX ~yrup xesidue. The reRidue was dissolved in i~opropanol and treated with 5.3 g of oxalic ~id, warmed or~ a steam bath ~o di~olve ths acid, and upon cooling, a ~oli~ ~alt precipitated. An ~ual volume of isopropyl eth~r was added to en~ure complete : pre~ipitation. ~iltration gave 26 g of crude product.
~:portion (13 g) was recrystalliz~d from isoprop~nol/
methanol/i~opropyl e~her (100/50/50) (cooled in ~ r~rig-2rator) to yield upon ~iltration 7.5 g of whit~ p~oduc~, m.p. 155-157C~ Proton NMR con~irmed that thi~ wa3 the ~xpected product.

lZ~4~7 Analysis: Calculated for Cl8H~F3N30-CzH204: C,50.10; ~,~.89 N, .76 Found : C,50.02; H,5.97;
N,8.89 5Example 6 3-(Dimethylamino)propyl~-3-r~-(trifluoromethvl) ~henoxyl-l-azetidinecarbothioamide.
A stirred solution of o.o584 mole of 3-[3-(trifluor methyl)phenoxy~azetidine at 10C. was treated with 8.42 g lt) (0.0584 mole) of 3-~dimethylamino)propyl isothiocyana'ce all at once and allowed to ~tir at an~ient temperature overnight. The reaction mixture was tr~ated 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 15~ume was reduced to 100 ml at 50C. ln vacuo and diluted wi~h 500 ml of isopropyl ether to yield an additional 15.~ g of product. ~h~ combined solid m~terial Wa3 di~solved in i~opropyl alcohol and upon cooling, a ~in~ precipitate formed (~ dimethyl-1,3-propanediamine oxalate) which was removed by ~iltration. The product fail~d to ~rystallize:
addition o~ isopropyl ether gave only an ~morphous gel.
After trying to obtain a more satis~actory product ~or 3 weeks, the reaction material was conver~d to the free ~ase and taXen up in isopropyl eth~r. ~he ether ~olution was stirred with 300 ml of water overni~ht to remove the diamine. The product crystallized ~s~the free base ~rom the hetexogenous mixture and was ~iltered to give 11.~ g of fine beige crystal~. Xework of the filtrate gave an additional 2.3 g of product. A portion (8 g) was re~ry~tal- -30 ~ lized from benzene/ligroin to yi~ld 5.~ g of very :Eineb~ige cry~tals which were dried at 82C. und~r vacuum, m.p. 107-108C~ ~
Analysi : cal~ulated for C-~Hæ2F3~30S: CsS3.17 ~ J, 6.14;
~,11.63 ~5Found : C,53.2~; X~6.15;
N,11.60 7 ~ 4~2 ~xample 7 -(2-Propenyl~ 3-(trifluoromethyl~phenoxyl-1 azetidinecarboxamide.
A ~olution of 18.9 g (0.05 mole) of crude 3-~3-(tri~luoromethyl)phenoxy~azetidine (contain~ an equhl ~olar amount of diphenylmethane) in 100 ml of i30propyl ether was stirred under nitrogen while 4.16 q ~0.05 mole) o~ 2-propenyl is~cyanate was slowly added. The reaction mixture which was somewhat turbid, ~leared and ~fter 1 hr a fine crystalline precipitate began to form. After stirrin~ for 18 hrs, the product was removed by filtxation, washed with fresh isopropyl ether and air dried to yield 9.5 g of white crystals, m.p. 75-76C.
Analysis: Calculated for Cl4HlsF3~202: C,56.00; ~,5.04;
~ 3 Found : C,55.98; H,5.05:
~,9-31 ~æm~
N-Cycloprop~1~ 3-~trifluoromethyl)Phenoxy~
azetidinecarboxamide.
A mixture o~ 1.9 ~ (0.0~3 mole) of cyclopr~pylamine and 4.9 g of l~1'-carbonyldiimidazole in 60 ml of tetra-hydrofuran wa3 stirred at ambient temperature or 1 hr.
The clear solution which fonmed wa~ tre~ted with a solution of (0.03 mole) o 3-C3-(trifluoromethyl)phenoxy~zetidi~e in 20 ml of tetrahydrofuran. After ~tirring overnight, the 501id precipitate was removed by filtration to give 4.4 g o~ gray-white powder. The CI mass spectrum showed a p~l at 381 m/e which wa~ consist~nt with the expected product.
Recrystallization from benzene/ligroin gave 2.~ g of a light gray powder, m.p. 152-15~C.
Analysis: Calculated ~or Cl~HlsFgN20: C,56.00 ~,5.04;
N99-3~
Found : C,55-97; ~.5~7;
N,9.28 .

~2 Exampl~_~
N-~3-~ViethYlaminc~?propvl~-3-t3-çtrifluorometh ph no~ zetidinecarboxamide_oxalate (.2:3).
A mixture of 4.~ g (0.03~ mole) of 3-diethylamino-propylamine and 4.9 g (0.0~ mol~) of l,l'-carbonyldiimidazole in 60 ml ~ methylene ehlQride was ~tirred at ambient tèmperature ~or 1 hr. The resulting ~olution wa~ treated with ~-t~-(trifluoromethyl)ph~noxy~azetidine (~btained from 9.21 g (0.0~ mole) of the oxalate salt) in 30 ml of methylene chloride. After stirring ~or 18 hr, the r~action mixture was transferred to a ~eparatory ~unnel and washed with 3 x 20 ml of water, dried over magnesium sulfate and concen-trated in vacuo to a dark oil. The.resi~ue (8 g) was chromatosarphed on a 150 ~ neutral alumina column by eluting with chloroform. Concentration of the initial fra~tion gave 15 the product as an amber oil which was dissolved in methyl-isobutyl ketone and treated with 2 g of oxalic acid.
Dilution w$th isopropyl ether gave an oil which solidified and was recrystallized ~rom ~cetone/isopropyl ~ther to give 6.25 g (410 of beige crystals, m.p. 91-~3C.
Analysis: Calculated ~or Cl0H2~F3N302-1.5 C2H4O4 C,49.61: H,5.75, M,8.26 ~ound C,49.56, H,5.73; N,8.24 Example 10 N 2 ( ~ luoromethYl)Phenoxy~
azetidinecarboxamide.
A solution of 8.7 g (0.04 mole~ of crude 3-~4-(tri-fluoromethyl)phenoxy]az~tidine in 75 ml of i50pr~pyl ether was stirred under ~ blanket o~ nitrogen while 4.2 g (0.05 mole) of 2-propenyl i~ocyanate wa~ added dropwi3e. After tirring for 3 day~, no ~rystalline pr~duct precipitated.
T~e reaction mixture wa~ con~entr~t~ to ~ d~rX rs~ddi3h oil. TLC (20% ethyl a~etate/me~hylene chloride on ~ilica gel) showed at lea~t 6 ~p~tG, all well ~eparate~. The residu~ was di~solved in chloro~orm, chromatograp~d on 8 350 g ~ilica gel column and eluted with ~hloro~orm until the reddi~h forerun wa~ remo~ed. Th~ ~olumn was then ~luted ~2~94 with an ethyl acetate/chloroform gradient to 4% ethyl ~cetate. All the fractions were combined and concentrated to give 4.8 of orange oil, which crystallized on standing.
Recrystallization from acetone/cyclohexane gave 3.~ g (27.5%~ of beige crystals, m.p. 91-92.5~C.
AnalyQis: calculated ~or C14Hls~3N2o2: C,56 00 R,5.04:
~,g.33 Found : C,55.98: ~,5.17;
~.9.36 Exa~le 11 N-(Cyclc)propylmethyl? -;~-r3 (trifluoromethyl ~phenox~-l-azetidinecarboxamide.
A solution of 2.6 g (0.024 mole~ o~ (aminomethyl) cyclopropane hydrochloride in 50 ml of pyridine was stirred under a blanket o~ nitrogen while 3.9 g (0.024 mole) of l,l'-carbonyldiimidazol~ was added. A~ter stirring for 45 minutes, the TLC (5% methanol/methylene chloride on ~ilica gel) showed no reaction; therefore, 2 ml o~ tri-ethylamine was added. The reaction mixture after 10 ~inutes became cloudy and the TLC showed a new product.
~he reaction was treated with 6.2 g (0.02 mole) of 3-(~-~trifluoromethyl)phenoxy~azetidine oxalate. After stirring ~or 1 hr, a sample was removed, and upon dilution with waterJ a ~olid precipitated. The CI mas~ spectrum indicated it was product. After 2 daysl the reaction w~s diluted wi~h 5 volumes of water and the resulting precipitate ~ollected by filtra~ion to yield 6.5 g of pale yellow cry~talline product. Recrystallization from ethanol/water produced white plate-lik~ crystal~ which were dried at ~C. for 3 hr in a drying pistol under vacuum; weight of the product was 5.8 g (92%), m.p. 1~2-1~3C.
Analysis: Calculated for l5Hl7F3N20z: C,57-32; H,~-45;
N,~.91 Found : C,57.22; H,5.44;
~,8.86 ~ Z ~ 7 ~ 452 Example 12 !N-Diethyl-3-~3-(trifluoromethYl)phenoxy~ azetidine-carboxamide.
~ . _ A stirred slurry of 5 g (0.0163 mole) of 3-~3-(trifluoro-methyl~phen~xy azetidine oxalate in 50 ml of tetrahydrofuran was treated with 5 ml of triethylamine and after 1 hr, 2.5 g (0.018 mole) of die~hylcarbamoyl chloride wa~ added. Aft~r stirring an additional 15 hr, the reaction wa treated with 10 ml of water and saturated with calcium chloride. The tetrahydrofuran was decanted from the solid residue and concentrated ln vacuo to an oil. The crude oil was chroma-tographed on a Water's Prep-LC using 50% ethyl acetate/
toluene as the eluent. After concentration of the main fractions 3.1 g (60.1%) of pale yellow oil was obtained.
Analysis: C~lculated for Cl5Hl9F3N202: C,56.96; H,6.o5;
~8.86 Found : C,56.69: H,6.01;
N,8.77 ExamPle l;~
N,N-DimethYl-3-~trifluoromethyl~n azetidinecarboxamide.
A ~tirred slurry of 5 g (0.016~ mole) Of ~-~3-(trifluoro-methyl)phenoxy]azetidine oxalate in 50 ml oP tetrahydrofuran was treated with 5 ml of triethylamine and after 1 hr, 1.95 g (0.018 mole) of dimethylcarbamoyl chloride was added. After stirring an additional 15 hrJ the reaction mixture was treated with 20 ml of w~ter and 10 g of calcium chloride.
The tetrahydrofuran layer was decanted and the residue triturated with 20 ml of ~thyl acetate,then decanted. The combined tetrahydrofuran and ethyl acetate ~olution was concentrated in vacuo. The crude residue was chro~atographed 0 on a Waters Prep ~ sing 50% ethyl acetate/toluene as the eluent. After concentration of the main fractions, 3.6 g (76.6%) of pale yellow oil was obtained.
Analysis: Calculated for Cl9Hl5F3N202: C,54.17; ~,5.25, ~,~.72 Found : C,53.73; ~,5.20;
N,9.60 ~ nqr k l~52 xample 14 -(2-Propynyl)-3-~3-(trifluoromethyl ph noxy~
azetidinecarboxamide.
A mixture of ~.9 g (0.02~ mole) o~ l,l'-carbonyl-diimidazole and 1.32 g (0.024 mole) of 2-propynylamine in 50 ml of tetrahydrofuran was 6tirred at ambient temperature for 1 hr, then treated with 6.2 g of ~-t~-(trifluorom2thyl3 phenoxy]azetidine. The reaction mixture was ~reated with 3 ml of triethylamine and stirred ~or 18 hr. ~he reaction mixture was diluted with an equal volume of water and ~iltered to yield 8 g of wet product. ~ecrystallization $rom isopropyl ether gave 3.8 g o~ gray solid, a ~xture ~f product and the ~ymmetrical urea o~ starting 2-propynylamine.
A second recrystallization ~rom ethanol water yielded 2.6 g (43.6%) of pur~ product, m.p. 105-106C.
Analy8is: Calculated for Cl~Hl3F~02: C,56.38: H,4.39:
.9-39 ~ound : C, 56 . 32; H,4.34;.
N, 9 . 44 ExamPle 15 N-Cyclohex~1-3-~3-(trifluoromethyl)phenoxy~
azetidinecarboxamide.
- --A stirred mixture of 5 g (0.016~ mole) of 3-~-(tri-fluoromethyl)ph~noxyJazetidine oxalate an~ 2.04 g (0.018 mol~) o~ cycloh~xyl isscyanate in 50 ml of tatrahydrofuran was treated with 2 ml uf triethylamine then stirre~ for 25 18 hr~ Dilution of the mixture with w~ter gave a solid precipitate which w~s collected by filtration to yield 12 9 of crude produot. Recrystallization from ace~one/water - gave 5 g ~f ~ine white ~rys~als, m.p. 148 150C. TLC (ethyl aceta~e on 5il ica gel) ~howed a ~race of symmetrical cyclo-~0 hexyl urea ~s well ~s` the produ~t. A s~cond re~ry~al-lization fr4m isopropanol yielded 1.65 9 ~29.6%) o~ white powdex; dri~d under 0.5 ~n/Hg vacuum" m.p. 153-154Q~.
Analysis: Calculated ~or Cl7H2aF~202: C~59.64: ~,6.18:
: ~,8.18 Found : C,59.52; ~,6-20;
~,~.17 :

Exam~le 16 ~-Cyclopropyl-3-~4-(trifluoromethyl)phenc)xy azetidinecarboxamide.
A stirred slurry of 4.4 g (0.027 mole) of l,1'-carbonyl-diimidazole in 50 ml of methylene chloride under nitrogen was treated with 1.54 g (0.027 mole) of cyclopropylamine.
After a sh~rt (2 min) induction period, the lear ~olution became suddenly exothermic, bringing ~he reaction to a gentle r~flux. 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) wa~ a~ded all at ~nce and stirring continued ~or 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 (75.9~) of silver plate-like crystals, m.p. 145-147C.
After drying at 80C. under 0.5 mm/Hg vacuumJ the weight was not diminished, m.p. 152-153C.
Analysis: Calculated for C~ 5F3N202: C,56.00, HJ5.04;
N~9.33 Found : CJ55.77; HJ4~98 NJ9.44 ~xample 17 ~-(CyclopropvlmethYl)~ 4-(trifluoromethyl)phenox~l-l-azet idinecarboxamide .... .. ... ........... ... ..
A stirred mixture of 4.4 q (0.027 mole) of 1J1~-carbonyldiimidazole and ~.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) of triethylamine. The reaction was exothermic. The mixture was cooled while ~tirring ~or 1 hrJ then 9.6 g (0.025 mole) of 3-~4-(trifluoromethyl)phenoxy]azetidine 56.66% (contains diphenylmethane) was added all at once and stirri~g continued for 18 hr. The reaction mixture was co~centr~ted ~n a rotary evap~rator to give an amber residue. Trituration of this xe~idue with ~o/60 petroleum ~ther gave only an ~ 28 --insoluble oil. The trituration step was repeated with 2 x 20 ml of 30/60 petroleum ether and the residue treated with water to yield a white solid. The solid was recrystal-lized from isopropyl ether to yield 4.8 g (61.B%) of white platelike crystals, after during at 80C. under 0.5 mm ~g vacuum, m.p. 132-1~3C.
Analysis: Calculated for Cl5H117F3N202: C,57.~2; H,5.45;
N,~.91 Found : C,57.26; H,5.46;
N,8-93 Ex~m~ 18 -~3-(Dlethylamino~pro~yl~ S-L4-~tri:1uoromethYl) phenoxy~ azetldinecarbothioamide.
A stirred solution of 1~92 g (0.005 mole) of 3-[4-(tri~louromethyl)phenoxy]azetidineJ 56.66% (contains diph~nylmethane) in 20 ml of isopropyl ether was treated with o.88 g (0.005 mole) o~ 3-(diethylamino)propyl isothiocyanate and ~tirred for ~.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.
147-150C. The solid was di~solved in water and treated with dilute sodium hydroxide. An oil separated which solidified and was collected by filtration. Recrystal-lization from cyclohexane yielded 1.1 g (56.5%) of ~ine 25 tan crystals, m.p. 109-110C.
Analysis: Calculated for Cl8H26F3N30S: C,55.51; H,6.73;
~,10.79 Found C,55.68; H,6.67 N,10.73 - ~xample l9 N-c3-(Diethylamino)propyll-3-C4- ~ rifluoromethyl) phenoxy~ azetidinecarboxamide oxalate ~1-21.
A ~tirred solution of 4.4 g (0.027 mole) of 1,1'-carbonyldiimidazole in 50 ml of methylene chloride under nitrogen was treated with the dropwise addition of ~52 g ~5 (0.027 mole) of 3-(diethylamino)propylamine. The reaction mixture was stirred for 1 hr as the ~omewhat ~xothermic reaction ~ooled to ambient temperature then tr~ated with 7~ 452 9.6 g (0.025 mole) of ~-t4-(trifluoromethyl)phenoxy~azetidine, 56.66% (contains diphenylmethane) all ~t once. A~ter stirring for 18 hr, the reaction mLx~ure was concentrated on a xotary evaporator and the residue dissolved in toluene.
The toluene solution was washed with ~ x 20 ml of water, then treated with 2.5 g of oxalic acid in 10 ml o~ i~opropanol 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 ~eparated by filtration. The acetone solution was concen-trated to a solid which was recrystallized from isopropyl al~ohol/isopropyl ether to yield 9.2 g of crude product t4 spots on TLC; 10~ methanol/methylene chloride on silica gel). Recrystallization from methyl ethyl ketone yielded 6.8 g (49.1%) of fine white powder, m.p. 129-1~0C.
Analysis: Calculated for Cl~H~F3N30~-2C2H404:
C,47.74; H,5.46: N,7.59 Found C,47.82: H,5.68; N,7.76 ExamPle 2Q
N-(2-prop~ynyl L-~
~zetidinecarboxamide.
. ~
A solution of 4.4 g (0.027 mole) l,l'-carbonyl-diimidazole in 50 ml of tetrahydrofuran was stirred under nitrogen while 1.49 g (0.027 mole) of 2-propynylamine was add~d with a syringe and needle through a ~eptum installed in one neck o~ the reaction ~lask. After stirring for 2 hr, 9.6 g (0.025 mole) of 3-~4-(trifluoromethyl)ph~noxy~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 witb 30/60 petroleum ether to rem~ve the diphenylmethane.
The oily a~ueous portion was extracted with 4 x 50 ml o$
methylene chloride. These extracts were combinedJ dried over sodium 6ulfate and concentrated to an amber oil on a rotary evaporator. The oil solidified when triturat~d with a small amsunt of i~opropyl ether (50 ml). Filtration yielded 6.1 g o~ rose-tinted ~olid product. TLC (10~
methanol/methylene chloride on silica gel) showed a mixture of 3 products and ~ome starting material. Recrystallization iFrom ethanol/water gave the product in several small fxactions. These were combined and recrystallized ~rom isopr~pyl ether to yield 4.1 g of pale beige p~wder, m.p.
135-137C. TLC ~till ~howed 60me symmetrical 2-propynyl urea. The solid was recrystallized again ~rom ethanol/
water to yield 3.5 g (46.9%) of pale yellow crystalline product, m.p. 140-141C.
Analysis: Calculated for Cl4Hl3F3N202: C,56.38; H,4.39;
~,9-39 Found : C,56.34; H~4.36;
~,9.32 ~xample 21 N-(?-Methyl-2-propenyl)-~-r4-(txifluoromethyl)phenoxy~-l-azetidinecarboxamide.
A stirred solution of 3.6 g (0.022 mole) o~ 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 ~eptum placed in one neck of the reaction flask). After stirxing for 1 hrJ 6.2 g (0.02 mole) of 3-~4-(trifluoro-methyl)phenoxy~azetidine oxalate was added all at once followed in 30 min with 5 ml of triethylamine and stirring was continued for 3 hr. The reaction mixture was washed with water (2 x 25 ml), dried over magnesium sulfate and concentrated in vacuo. The oily residue solidified on tanding and was recrystallized from isopropyl ether to yield 3.7 g (58.9%) of fine white crystals, m.p. 101-102C.
Analysis: Calculated for C15Hl7F3~202: C,57-32 ; H,5-45;
N,8.91 Found : C,57.45; H,5.51:
N,9.23 2~ ~ ~ 7~ 452 Example 22 N-(?-Methyl-2-}~openyl)~ (trifluoxomethyl)phenoxv l-azetidinecarboxamide.
A solution of 3.6 g (0.022 mole) of l,l'-carbonyl-diimidazole in 75 ml of methylene chloride was stirred under nitrogen while 1.6 g (0.022 mole) of methallylamine w~s added with a syringe and needle through a ~eptum 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-(tri-fluoromethyl)phenoxy~azetidine oxalatP followed in 0.5 hr with 5 ml of triethylamine and stirring continued for 16 hr.
The reaction mixture was washed with 2 x ~0 ml of water, dried over magnesium sulfate, and ~oncentrated on a rotary evaporatvr to yield 6.7 g of oily residue which solidified.
1$ The residue was recrystallized fxom isopropyl ether to yield 5.4 g (85.90 of fine white crystals, m.p. 90-91C.
Analysis: calculated for C15Hl7F3N202: C,57-~2; H,8-45:
N, .91 Found : C,57.20; H,5.50;
N,~-95 Example 2~
N-(3-MethYl-2-butenYl)-3-C4-(trifluoromethyl ~henoxy]-l-azetidinecarboxamide.
A solution of ~.6 g. (0.022 mole) of l,l'-carbonyl-diimidazole in 100 ml of methylene chloride was cooled in a tap water bath and while 3tirring under nitrogen, 1.87 g (0.022 mole) of 3-methyl-2-butenylamine was added dropwise.
After stirring for 1 hrJ 6.2 g (0.02 mole) of ~-~4-(tri-fluoxomethy})phenoxy~azetidine oxalate was added all at once followed in 0.5 hr with 5 ml o triethylamine and ~tirring continued for an additionaI 16 hr. The xeaction mixtur~ was washed with 7 x:50 ml o~ water, dried over magnesium sulfate and concentrated on a rotary svaporator to yield a semi--~olid~residue. Trituration with isopropyl ether and filtration yielded 7 g of crude produ~t whi~h was recrystallized from ethanol-water to give 5.5 g ~87.8%) of white ~rystals 9 m.p. 156.5-158 C.

~ ~ 4 ~ 452 Analysis: calculated for CloHleF3~202: C,58.53; B,~-8~;
Fou~d : C,58.81; ~ 5 ~9:
~,~.58 Example 24 -(3-Methyl-2-butenyl)-~-~3-(trifluoromethyl)phenoxy A solution of 3.6 g (0.022 mole) of l,l'-carbonyl~
diimidazole in 100 ml of tetrahydrofuran was csolea with a tap water bath and stirred under nitrogen while 1.6 g (0.022 mol~) 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-~tri~luoro-methyl)phenoxy~azetidine oxalate followed in 0.5 hr with 5 ml of triethylamine and stirring continued for 72 hr.
The reaction mixture was diluted with 500 ml of ice water and extxacted with 6 x 50 ml o~ methylene chloride. The combined extracts were washed with water, dried over magnesium ~ulfate and concentrated to a solid residue on a rotary evaporator. Recrystallization ~rom ethanol-water yielded 6 g of white crystals, m.p. 143-144C.
Analysis: Calculated for Cl~Hl~F9N202: C,58.53; H,5.83;
N,8-5~
Found : C,58.46: H,5.86:
~,8.69 (E)-N-(2-~utenyl)-3-L4-(trifluoromethyl)phenoxy~
azetidinecarboxamide.
A mixture of 3.6 g (0.022 mole) of l,l'-carbonyl-dii~idazole and 1.6 g (0.022 mole~ of trans-crotylamine was stirred for 1 hr, then treated with 6.2 g ~0.02 mole) ~0 of 3-~4-(trifluorom~thyl)phenoxy]azetidine oxal~te and followed in 0.5 ~ with 5 ml o~ triethylamine with stirring continued for 16 hr. The partially crystalline mixture was washed with 2 x 50 ml o~ wat~r, dried over magnesiu~
~ulfate and ~oncentrat~d on a rotary ~vaporator to a solid 35 residue, 14.2 g. Recrystallization fxom methanol-water yielded 5.35 g (85.1%) of ~ine white crystals, m.p.
157 158C.
.

~ 4 452 Analysis: Calculated for C15Hl7F3N202: C,57-32; H~-45;
N, .91 Found: C,57.47, H,5.~9:
N,9.00 Example 26 (E)-azetidinecarboxamide.
A ~olution of 3.6 g (0.022 mole) of l,l'-c~rbonyl-diimidazole in 60 ml of methylen~ chlori~e was ~ooled in an ice ba~h while ~tirring under nitrcg~n while 1.6 g (0.022 mole) of tran~-crotylamine wa~ add~d dropwi~e.
After warming t~ ambient temperature, 602 g (0.02 mol~) o~
3-~3-(tri~luoromethyl)phenoxy~azetidine oxalate was added all at once followed in 0.25 hr by 5 ml of triethyla~ine with stixring continued for 72 hr. The reaction solution 15 was wa~hed with 2 x 50 ml of water, dried over magnesium sulfate and concentrated on a rotary evaporator to a soli~ residue, 7 g. Recrystallization from methanol-wa~er ~ave 5.5 g o~ ~lightly yellow product. A second .
recrystallization with charcoal treatment from i~opropyl ethar yielded 3.75 g (59.7%) of fine white cry~tals, m .p . 12 7-12 8C .
Analysis: Calculated for Cl5Hl7F3N202: C,57.32; H,~.45;
~, .91 Found : C,57.35, H,5.47:
N,8.94 Example A..?~
N-Phenyl-3-~3-( ~r~ azet~dino-carboxamide.
, A stirred ~1urry o~6.2 g (0.02 ~ole) Of 3~r3-(tri-fluorom~thyl)phenoxy~az~tidine oxalate in 60 ml of tetra-hydrofuran wa~ treat~d with 5 ml of triethylamine followed :by :2.62 g (0.022 mole) of phenyl i ocyanate and ~tirring con~inued ~or 16 hr. ~he reaction mixture was diluted with w~ter until an oil ~eparat~d which quickly ~olidified.
The aqueous tetrahydro~uran was:dec~nted and the ~olid r~idue recrystalliYed from ~hanol-water to yield 5.3 g (80.1f) o~ whit~ cry~t~l~, ~.p. 137-138c.

4 ~7 ~ 452 Analysis: calculated ~or Cl7Hl5F3N202: C,60.71; H,4.50 N, 8.33 Found : C,~io.Bl; H,4.47, ~,8-35 carb~xamide .
A tirred slurry of 6.2 g (0.02 mole) of 3-~4-(tri-fluoromethyl)phenoxy~azetidine oxalate and 2.62 ~ (0.022 mole) of pher~yl isc>cyanate in 60 ml of tetrahydrofuran was treated wi~h 5 ml of ~riethylamine and tirring continued ~or 16 hr. The reaction mixture was diluted with water until an oil 3epar~ted. The tetrahydrofuran-water portion was decanted ~nd the residue solidified on standing.
Recrystallization from ethanol-water yielded 3.5 g t~3.4 o~ fine white crystal~J m.p. 174.5-176C.
Analysis: calculated for Cl7HlS~3~202:C,60.71: H,4.50;
N,8.33 Found :C,60.91; H,4.53;
~,8.35 Exam~le 2~
trans-~,2-Dimet~Yl~ -(tri~luoromethyl)~henoxy~-l-azetidinecarboxamide.
A stirred solution of 6 g (0.015 mole) o~ crude trans-2-methyl-3-~3-(tri~luoromethyl)phenoxy]azetidine in 50 ml of tetrahydrofuran was treated with 0.94 g (0.0165 mole) of methyl isocyanate ~dded dropwlse and ~tir~d for 16 hr under a blanXet o~ nitrogen. Dilution of the reaction _ mixture with water produced~an oil whi~h solidified. After decanting the a~ueous tetr~hydrofuran pha3e, the solid residue was recrys~allized from:ethanol-water to yield ~.95 g : (91.4%) of:fine white cry~tals, m.p. 104.5-106C.
~Analysis: Calculate~ ~or Cl3Rl5F3N202: C,54.17: H,5.25;
~,g.72 Found : C,54.50: ~,5.29;

;27~ 2 Example 30 txans-? -Methyl-3-r3-( trifluoromethyl)P}ienoxv~ -l-azetidine-_arboxamide .
A mixture of 6 ~ (0.015 mole3 of crude trans-2-methyl-~-~3-(trifluoromethyl)phenoxy]azetidine (purity 56.6%
contains diphenylmethane~and 2.4 g (0.0225 mole) ~f nitrourea in 40 ml of acetone was treated with 4 ml of water, then heated until a clear homogenous solution was obtained. The reaction mixture was ctirred ov~rnight as it cooled to ambient temperature and diluted with water until an oil separated. The oil solidified and was xecrystallized from ethanol/water, yielding 4.3 g of white plate-like crystals: m.p. 117-118C. The product was recrystallized from benzene, yielding 3.35 g (96.8%) of crystals, m.p. 118-119C.
Analysis: Calculated for Cl2Hl3F3N202: C,52.56; H,4.78;
~,10.22 Found : C,52.54; H,4.74;
N,10.17 Example 31 trans-2 Methyl-N-(2-propenYl)-3-r~-ttrifluoromethyl) phenoxY~ azetidinecarboxamide.
A solution o~ 6 g (0.015 mole) of crude trans-2-methyl-~-~3-(trifluoromethyl)phenoxy~azetidine t~6.6%) 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 nitr~gen ~or 16 hr. The rea~tion mixtur~ was diluted with water until an oil separa~ed. The oil failed _ to crystallize and after 7 weeks it was triturated with i~opropyl ether (3 x 25 ml). The combin~d triturates g~ve 400 mg of white gr~nular ~ryst~ls (8.5 0 , m.p. 55-57 C.
~ Analysis: Calculated ~or Cl5Hl7F9N202 C,57 32; H,5.45;
~,8.gl Found : C,57.~6; H,5.50;
N,8.97 27~ 452 Example ~2 3-(3-Chloro~henoxY)-N-methyl-l-azetidinecarboxamids.
A solution of l-chlor4carbonyl-3-(~-chlorophenoxy) azetidine (0.01275 mole) in 20 ml of tetrahydrofuran was treated with 4 ml (0.05 mole) of 40% a~u~ous methylamine and fitirred for 16 hr. The reaction mixture was diluted with water until asl 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 ~olid which was recrystalliz~d from benzene/liyoin to-yield 1.2 g (40.0%) of fine white crystals, m.p. 140 141C.
Analysis: Calculated for CllHl3ClN202:C,54.89; H,5.44;
~ ,11.64 Found :CJ55OO5; H,5.58;
N,11.52 E amRle 33 ~ 3-Chlorophenox~ ~N-~2-propenyl)-1-azetidine-carboxamide._ ~ solution of 5.4 g (0.017 mole) of l-chlorocarbonyl-3-(3-chlorophenoxy)azetidine in 20 ml of tetrahydro~uran was treated with 2.3 g (0.04 mole) oP 2-propenylamine and ~tirred for 2 hr. The reaction solution was concentrated ln vacuo to a rose beige solid. Trituration of the solid with water gave, a~ter filtering, 4.4 g o~ crude product.
A~ter drying, the ~olid was recrystallized with charcoal treatment ~rom 2% acetone/isopropyl ether to yield 1.7 g 25 (37 5%) of paIe beige crystal~, m.p~ 87-89C.
Analysis: Calculated for Cl3Hl5Cl~202: C,58.54; H,5.67;
N,10.50 Found : C,58.4~: H,5.72;
~ ~ N,10.49 ~2~ ~ ~ 7 Exam~le 34 N-Methyl-3- L2 -pyridinylox ~ -l-azetidinscarboxamide.
A 2M benzene &olution of p~o~gene (40 ml, o.o8 mole) was added to a ~u~pension of 10 g of finely ground potassium ~arbonate in 40 ml of methylene chloride. The mixture was ~tirred for 15 min. at room temperature and 10 g (0.056 mole o~ l-(l-phenylethyl)-3-(2-pyridyloxy)azetidine in 50 ml of methylene chloride was added with mild coolin~. Ihe mixture was stirred at room ~emperature for 1 hr ~nd concentrated on a rotary evaporator (25~C./30 min). Th~ residue was treated with 100 ml of tetrahydrofuran and cooled with an ice bath. To the cooled, stirr~d mixture was added 20 ml of 40~ aqueous methylamine. ~he mixtur~ was ~tirred for 20 min and partitioned between methylene chloride and water. Th~ methylene chloride was dried over sodium sulfate and concentrated. The residue was crystallized from benzene-ethanol and recrystallized from ~thyl acetate-i~opropyl alcohol. ~ield o~ title compound was 2.3 g ( 14 %), m .p . 165-168C.
Analysis: Calculat~d for CloHl3N~02: C,57.96; H,6.32:
M,20.28 Found : C,57.93: H,6.34:
N,20.12 Examlple ~5 N- ~ Propenyl)-3-(2-pvridinYloxv ~ l-azetidinecarboxamide.
To a stirred suspension of 10 g (0.072 mole) of finely ground pota~sium carbonate in 90 ml of methylene ~hloride was added 32 ml (0.062 mole) o~ 2M phosgene in ben~ene.
The mixture was fitirred $or 15 min and 8 g (0.031 mole) of l-(l-phenylethyl)-3-(2-pyridyloxy)azetidine in 50 ml o~
methylene chloride was 2dded. The mixture was stirred at ~0 25C. for 2 hr and eoncentrated on a rot~ry evap3ra~0r at 25C. ~0 min and the residue wa~ ~reated with 100 ml of tetrahydro~uran. The ~irred mixture was cooled with an ice bath and ~reated dropwi~e with 4 g (0.07 mole) of allyl amine. After ~tirring ~0 min at 2~C., the ma~eriæl wa~
partitione~ b~ween w~ter ~nd methylene ~hloride. The : methylen~ ehloride was dried ~nd coneentrated. Th~ r~sidue 1~4~74 4 - ~8 -was chromatographed on a Waters@ PREP-500 HPLC using a silica column and eluting with 50% ethylacetate-hexane. The produ~t was crystallized twice rom isopropyl ether. Yield of title compound was 1.5 g (21%), m.p. 72-76 C.
Analysis: calculat~d for Cl2Hls~302: C,61.79; ~,6.48; N,18.01 Found : C,61.5~; HJ 6.50; ~,17.96 ExamPle 36 A 2M ~enzene solution of phosgene (~2 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 ~ phenylethyl)-3-(2-pyridyloxy)azetidine in 50 ml of methylene chloride added. The mixture was stirred for 35 min and concentrated on a rotary evaporator (25C./30 min).
The residue was treated with 100 ml of tetrahydrofuran, cooled with an ice bath and 20 ml of concentrated ammonium hydroxid~ added slowly while stirring vigorously. The mixture was stirred 1 hr at room temperature and partitioned between m~thylene chloride and water. The water layer was extracted 2 times with methylene chloride and the combined organic layers were concentrated. The residue was crystallized from benzene and recrystallized ~rom isopropyl ether. Yield of title compound was 1.4 g, m.p. 133-137C.
Analysis: Calculated for C~HllN902: C,55.95, H,5.74; N,21.75 ~ound : CJ55.73: HJ5~71; N,21.10 Example ~7 2-r ~ PhenYlethvl~ azetidinyloxy~pyridine.
The maleate salt of l-(l-phenylethyl)-3-azetidinol (65 g,.2~ mole) was partitioned be~ween toluene and dilute sodium hydroxide and was extracted once with toluene. The organi~ layer was dried (~odium sul~ate) and co~centrated.
The residue was dissolved in 125 ml o~ dlmethylformamid~ and ~dded dropwi e ~ ~ stirred suspension o~ 9.~ g (.24 mole) of sodium hydride (washed three times with isooctane) in 400 ml of dimethylformamide It 25-35C. ~he ~olution was .

~ 4~2 heated to 65C. and 35 g (.22 mole) of 2-br~mopyridine was added dropwise while heating to 75C. The solution was stirred and heated at goc. for 1 hr followed by heating at 120C. for 2.75 hr. The mixture was stirred at room temperature overnight and concentrated. The residue was partitioned between water and isopropyl ether. The organi layer was washed twice with water9 dried (sodium sulfate), filtered and concentrated. Crude yield was 30 g. The residue was distilled to give 8 g, bp 128-134 C./.01 ~ of product.
Analysis: calculated for Cl~Hl8N20: C,75.57; H,7.13; N,ll.01 Found : C,75.20; H,7.18; ~,10.90 Example 38 1-~3-~4-(Trifluoromethyl)phenoxy ~l-azetidinylcar lH-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 :
extracted with 3 x 50 ml o~ methylene chloride. The extracts upon concentrating ln vacuo gave an ambex residue which was dissolved in 20 ml of benzene and washed with dilute hydro-chloric acid, then washed with waker. 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 (41.8O of fine gray crystals, m.p. 139-140C.
Analysis: calculated for Cl~H12F3N902: C,54.02; H,~.89;
N,13.50 Found : C,54.33; H,3.96;
N,1~.89 ~
~
The ~ompound was prepared from the methane sulfonate of 3-phenoxyazetidine and methylisocyanate as described in Example 1 of U. S. Patent 4,226,851, m.p. 139-141C.

Exam~le 40 N-Methyl~ rifluoromethyl)phenoxyl-l- zetidine-carboxamide.
The compound was prepared from 3-~4-(trifluoromethyl-phenoxy~azetidine and methylisocyanate as described in Example 3 of U. S. Patent 4,226,861, m.p. 154-157 C.
Example 41 N-MethYl-~-~( trifluoromethYl)phenoxvl ~
~arboxamide.
The compound was prepared from 3-~3~irifluoromethyl~-phenoxy)azetidine and methylisoeyanate as described inExample ~ of U. S. Patent 4,226,861, m.p. 145-147C.
Example 42 N-Methyl-3-~ trifluoromethyl)phenox~-l-azetidine-carboxamide.
The compound was prepared from 3-~2-(tri~luoromethyl)-phenoxy)azetidine and methylisocyanate as des~ribed in Example 5 of U. S. Patent 4~226,851, m.p. 134-1~6C.
Example 43 N-Meth~1-3-t2 ~mlnocarbonyl)phenoxY~-l-azetidine-carboxamide.
The compound was prepared from 2-(3-azetidinyloxy) benzamide and-methylisocyanate as described in Example 2 of U. S. Patent 4,226,861, m.p. 236-240C.
Example 44 -MethYl-7-C3-(aminocarbonvl~phenoxy~ azetidine=
carboxamide.
The compound was prepared from 3-(3-azetidinyloxy) benzamide and methylisocyanate as described in Example 6 of U. S. Patent 4,226,861, m.p. 238 240C.
3 Example 4 N-Methyl-3-t4-(aminocarbonyl)phenoxy~ azetiaine carbox~mide.
The compound was prepared from 4-(3-azetidinyloxy) benzamide and methylisocyanate as described in Example 7 o~ U. S. Patent 4,226,861, mOp. 208-210C.

~ 2 ~4 Example 46 fTrifluorometh 1~ henox l-l-azetidinPcarboxamide.
~ ` Y ~ P _ X.~ _ .
A mixture o~ 30.6 9 (0.141 mole) of ~ (trifluoro-methyl)phenoxy]aze~idine and 42 g (0.321 mole) of nitrourea (800 in 500 ml of acetone was ~tirred for 5 days (5 days not requir~d, but convenient~ at room temperature. The mixture was iltered an~ the filtrate concentrated in vacuo.
The residue was partitioned between 150 ml of water and 100 ml of ethyl ~cetate and the layers ~eparated. ~he a~ueous layer was washed with 100 ml of ethyl acetate. The ethyl acetate layers were washed with 75 ml of 5~ aqueous sodium hydroxide solution followed by 75 ml of water9 dried over sodium ~ulfate and concentrated in vacuo. The residual oil was crystallized from ethyl alcohol-ethyl acetate to give 22 g (60%) substantially the title compound.
15 Recrystallization twice from ethyl alcohol gave 9.9 g of white crystalline solid, m.p. 151-152.5C.
Analysis: Calculated for CllHllF3N20z: C,50.77; H,4.26;
N,10 .76 ~ound : CJ50~90; El,4.29;
NJ 10 .71 ExamE~e 47 N-EthYl-3-t3--(trifluoromethyl)ehenoxy~-l-azetidine carboxamide.
To a stirred and c~illed (15-20C.~ solution of 00024 mole of ~-t3-(trifluoromethyl)phenoxy]azetidine in 50 ml o dry benzene was added dropwise 1.99 g (0.028 mole) of ethyl i~ocyanate. The reaction mixture was ~tirred at room temperature overnight and was diluted with 50 ml of methylene chloride. The solution was washed with 5% sodium hydroxide ~2 x 50 ml), water (50 ml), aturated sodium chloride (25 ml), dried over ~odium hydroxide, and concen-trated in acuo. The sesidue (9.6 g) was twice recrystal-lized from ethyl acetate-isopropyl ether t~ give 5.4 9 o~
a white ~olidJ m.p. 125-126C.
Analysis: Cal~ulated for C~Hl5F3N202: C,54.16: H,5.24:
~,9.72 ~5 Found : C,54.247 H,~.23, N,9.74 ~ Z~ ~ 2 7 - ~2 -Example 48 N~ MethylethYl)-3-r~-(trifluoromethyl)~henoxY~
azetidinecarboxamide.
To a stirred and chilled (10-20C.~ solution of 9.0 g (0.042 mole) of 3-C3-(trifluoromethyl)phenoxy]azetidine in 100 ml of dry methylene chloride was added dropwise 4.1 g (o.o48 mole) of isopropyl isocyanate. The reaction mixture was stirred at room temperature for 2 hr and was diluted with 100 ml of methylene chloride. The solution was washed with 5% sodium hydroxide t2 x 40 ml), water (50 ml), saturated sodium chloride (50 ml), dried(sodium sulfate) and concentrated in vacuo. The residue was crystallized from ethyl acetate, affording 7.6 g (60.6%). Recrystal-lization from ethyl acetate gave 5.0 g of clear white needles, m.p. 150-151.5C. 5 Analysis: calculated ~or Cl4Hl7F9N202: C,55.62; H,5.68;
~,9.27 Fou~d : CJ55.77~ H,5.68;
N,9.22 Example 49 -Propyl-3-~3 (trifluoromethyl)phenoxy~ azetidine- 0 carboxamide.
.
To a stirred and chilled (10-15C.) solution of 0.027 mole of 3-~3-(trifluoromethyl)phenoxy~azetidine in 100 ml ~ of dry b~nzene was added dropwise 4.0 g (0.047 mole~ of n-propyl isocyanate. The reaction mixture was stirred at 25 room temperature for 30 minutes. ~he benzene was washed with dilute sodium bicarbonate (50 ml), water (25 ml), saturated sodium chloride (25 ml), and dried(sodium sulfate). The solution volume was reduced to 50 ml, and 30 ml of petroleum ether was add~d, yielding 6-5 g (81O
of product. Recrystallization from isopropyl ether--isopropyl alcohol gave 6.o g of small white needles, m.p.
115-117~.
Analysis: Calculated for C14Hl7F3N202: C~55-63; H~5-67;
~,9.27 Found : C,55.65; H,5.68;
N,9-25 Exam~le ~0 N-Butyl-3-~3-(trifluoromethyl)phenoxyl-1-azetidine-carboxamide.
.
A solution of 18.9 to.o5 mole) of crude 3-t3-(tri-fluoromethyl)-phenoxy~azetidi'nc (contains an ~ual molar amount o diphenylmethane) in 100 ml of isopropyl ether was stirred under nitrogen while 4.96 g (0.05 mole) of N-butyl isocyanate was slowly added. The clear reaction solution became warm to the touch, and after 20 minutes a white crystalline solid began to precipitateO After stirring for 16 hr, the solid was removed by filtration, washed with fresh isopropyl ether and air dried to yield 8 g of pale beige crystals, m.p. 108-109C.
Analysis: Calculated for Cl5Hl~F3N202: C,56.96; H,6.o5;
N,8.86 Found : C 9 56.78; H,6.o5;
N,8.83 _ample ~
N-Ethyl-3-C4-(trifluoromethyl)phenoxy~ azetldine-carboxamide.
_ A solution of 6.5 g (0.03 mole) of crude ~-[4-ttri-~luoromethyl)phenoxy]azetidine in 50 ml of isopropyl ether was stirred under a blanket of nitrogen while 2.85 g (0.04 mole) of ethyl isocyanate was added dropwise. After stirring for 2 hr at amhient temperature, a solid began to precipitate, and after 4 hr, the solid was collected by filtration to yield 3.7 g of beige product, m.p. 94-95C.
Rework of the filtrate gave only a trace of additional ~ product. The product was recrystallized from isopropyl ether/hexane (treated with charcoal) to yield 2.61 9 (30%) of product, m.p. 109-110C.
Analysis: Calculated for Cl3HlsF~N2O2: C,54.17; H,5.25;
3 N,9.72 Found : C,54.40; H,5.33;
N,9.89 ~4 ' 452 - 44 _ Example 52 -Butyl-3-L4-(trifluoromethyl)phenoxy-1-azetidine-carboxamide.
A solution of 6.5 g (0.03 mole) of crude 3-~4-(tri-~luoromethyl)phenoxy~azetidine in 50 ml of isopropyl ether 5 was tirred under a blanket of nitrogen while 4 9 (0.04 mole) of n-butyl isocyanate was added dropwise. The reaction was slightly.-exothermic and after 30 min, a solid ~eparated. The ~olid wa~; collected by filtration after 3 hr to give ~.85 g of crystalline product, m.p. 135-136C.
After 24 hr, a second batch of crystals was obtained;
1.5 g; m.p. 132-134C. The two fractions were combined and recrystallized from cyclohexane to yield 3.6 g of product (38%), m.p. 136-137C.
Analysis: Calculated for Cl5Hl3F3N202: C,56.96; H,6.o5;
. ~,8.86 Found : C,57.12; H,6.1~;
~,8.93 Example 5~
M-Propyl-3-C, ~ trifluoromethyl)phenoxyl-l-azetidine-carboxamide.
A solution of 8.7 g (0.0~ mole) of crude ~-~4-(tri-~luoromethyl)phenoxy~azetidine in 75 ml of isopropyl ether was ~tirred under a blanket of nitrogen while 4.3 g (0.05 mole) of n-propyl isocyanate was adde~ dropwise. After ~tirring for 2 hr, only a trace of crystalline precipitate formed in the reaction mixture, a~d after stirring for 18 hr, filtration yielded only 1.1 g of product, m.p.
_ 112-I14C. The filtrate was concentrated in vacuo to give : a dark amber residue. After 3 days, only 1.3 g of additional crude product could be obtained from isopropyl ether ~ exane. All of the reaction products were dissolved in chloroform and chromatographed on a 200 g silica gel column. Elution wi h chloroform gave a reddi~h forerun, which wa~ discarded. The elution was changed to 2% ~thyl acetate/chloroform, then to 4% ethyl acetate, and ~inally to 2% methanol/chloroform. All the fractions wer~ combined 7~ 452 ~ 45 ~

an~ ¢oncentrated to yield 4.1 g o~ white solid. Recrystal-lization ~rom cyclohexane yielded 2.86 (23.6%) of ~ine white crystalline pr~duct, m.p~ 119-120C.
Analy~is: calculat~d for C~H-7F3~z02: ~,55-63; ~,5.67;
~,9.27 Found : C,55.50; H,5.77;
~9-~9 ,~
3-r4-(Trifluoromethy~
A solution of 9.6 g (0.025 mole) o~ 4-(trifluoro-10 methyl)phenoxy~azet~dine 56.66% (contains ~iphenylm~thane~
in 50 ml of acetone was treated with 4~22 9 (0.045 mole) of ~itrourea and 5 ml o~ water. The mix~ure was h2ated on a ho~ plate until a clear ~olution wa~ obtained then alIowed to ~ool to ambient temperature ~uring the next 4 hr. The reaction mixture wa~ diluted with 200 ml o~ ice water ~nd an oil separat~d ~diphenylm~thane) which~wa~ dissolved in 30/60 petroleum et~r ~nd ~eparated. Upon ~t~nding, a fine white prscipitate formed in the aqueous 801ution. Filtratio~
yielded 3.6 g of fine white crystal~, m.p. 176-178C.
After drying und~r 0.5 mm Hg vacuum at 80C., tha product weight w~s reduced to 3.1 g (47.7%), m.p. 178-179C.
Analysi8s Calculated fox CllHl~F3N2~ ~,50.74; H,4.26, N,10.77 Fou~a ~l: J50 .72; HJ4 .24;
~,10.72 azetidine~arboxamide.
.
A stirred z~urry o~ 6.2 g (0.02 mol~) o~ 3-~4-(tri-~luoromethyl)phenoxy~a2etidine oxalate in 60 ml of ~e~ra-hydro~uran was tr~ated with 1.8 y (0.022 mol~) o l-methyl-~thyl i~o~yan~e ~nd a~r 0.5 hr, 5 ml o~ gri~hyl min~
was ~dded. A cl~ar yellow solution wa~ obtain~d ~nd WD8 ~tirr~ for 18 hrJ then tr~t~ with 10 ml of wat~r, y~olding 5.~ g t87070 o~ pal~ yellow ~ry~tals, ~.p.
151~15~
Analy~i30i c~lculat~a ~or C~4~l7F~N20~ :C,55.63; ~,5..67: ~,9.27 Fou~d sC,55.80; ~,5~71: ~,9.24 2~ 452 - 1~6 -Exam~le ~6 D imethylethvl ) -3- ~ 4 - ( t r i~luorome~rl ~ phen~xv ] -l~azetidinecarboxamide.
. .
A stirred slurry of 6.2 g (0.02 mole) ~f 3-~4-(tri-~luoromethyl)p~enoxy]azetidinej oxalate in 60 ml of tetra-hydrofuran was tr~ated with 2 g (0.022 mole) of 1,1-dimethylethyl isocyanate and after 0.5 hr 5 ml of tri2thyl-amine was added. The reacti~n slurry quickly turned to a pale yellow solution which was stirred for 18 hr, then treated with 10 ml of water. After 20 min~ th~ tetra-hydrofuran portion was separated, dxied over magnesium sulfate and concentrated on a rotary evaporator. ~he solid re~idue was recrystallized ~rom isopropyl ether to yield 5 g (79.0%) o~ fine white çrystal~, m.p. 145-146C.
Analysis: Calculated for ClsHl~3N20~: C,56.96J H,6.o5;
~,8.86 Found : C,56.97, H,6.15:
N,8.86 ~xample ~7 N-(2-Methy~propyl)-3 1 3- ~ rifluoromethyl)phenoxy azetidinecarboxamide.
_ _ . . . . .
A stirred solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 100 ml of methylene chloride under nitrogen wa~ treated with 1.6 g (0.022 mole) of 2-methyl-propylamine (added via a ~yringe and needle through a septum placed in one ne~k of the reaction flask). After stirring for 1 hr, 6,2 g (0.02 mole~of 3-~3-(txifluoromethyl)phenoxy~
azetidine oxalate was ~dded all at once f~llowed in 30 min with 5 ml of triethylamine and stirring continued for 18 hrO
The reaction mixture was washed with water (2 x 25 ml), dried over magnesium sulfate and coneentrated 1n vacuo, ~Q yielding 13 g of crude ~olid residue. Recrystallizati~n from ethanol/water yield~d 5.9 g of product having a pink ~as~. A ~econd recry~allization from cyclohexane yielded 4.8 g of fine white cry~tal~ m.p. 124-125C. Rewoxk of the ~iltrates yielded 1.2 g a~ditional beige ~rystal~.
~5 Total yield of product was 75~6% of theory.
Analysis: Cal~ulated ~or Cl5~ F~202: C,56.96: ~,6.05; N,8.86 Found : C~57.01; HJ6.1~: ~,8.88 ~4274 N-(l,l-Dimethyleth _ -3- ~-(trifluoromethyl)phenoxy~-l-azetidinecarboxamide.
A ~tirred slurry of 6.2 g (0.02 mole) of 3-t3-(tri-fluoromethyl)phenoxylazetidine oxalate in 60 ml of tetra-hydrofuran was treated with 2 g (0.02 mole) of 101-dimethyl-ethyl isocyanate followed in 30 min with 5 ml of triethyl-amine. The clear solu~ion which developed was stirred fsr 18 hr. The reaction mixture was treated with 10 ml of water and after 20 minJ the tetrahydrofuran porti~n was separa ted, dried over magnes ium ~ul~ate, and concentrated on a rotary evaporator. The solid residue was recrystal~
lized from ethanol/water, yielding 5.8 g (91-7 0 Of fine white cry~tals, m.p. 105-107~C.
Analysiæ: calculated ~or Cl5Hl3F3N202: C556-96; H,8 8~:
Found : C,56.95: H,6,14:
~,8.92 Example 59 ~-(2-Methylpropyl)-3- ~ tri~luoromethyl)Phen azetidinecarboxamide.
A ~tirred solution of 3.6 g (0~022 mole) of 1,1-carbonyldiimidazole in 100 ml of methylene chloride under nitrogen was treated with 1.6 g (0.022 mole) of 2-methyl-.
propylamine (added via a syxinge ~nd needle through a septum placed in one neck of the reaction flask). After stirring ~or 1 hr, 6.2 g (0.02 mole) of 3-~4 (trifluoro-methyl)phenoxy]azetidine oxalate was added all at once followed in 30 min with 5 ml of triethylamine and stirring was continued for 18 hr. The reaction mixture was washed with water (2 x 25 ml), dried over magnesium sulfate, and concentrated in vacuo. The solid resi~ue was r2crystalli~ed _ from ethanol/water, yielding 5.4 g (85.4%~ of pale yellow crystals.
~alysis: Calculated for Cl~Hl~F~202: C,56.g6; B,6.o5;
N,8.86 Found : C,57.02; H,6. o8 , 1~52 4t274 ~ 48 -ExamPl~ 60 ~- -~ r~henoxy~-l-azet idinecarboxamide .
A solution of 5.4 g (0.017 mole) of l-chlorocarbonyl-3-(3 chlorophenoxy)azetidine in 20 ml of tetrahydrofuran was treated with 3 ml of ammonium hydroxide and stirred for 1 hr. ~he reaction mixture was concentrated in vacuo to a wet ~olid, 4 g, which was recry tallized after drying, ~rom benzene to yield 1.5 g o~ white ~rystalline powder, m.p. 16~-164.5C. Yield calculated from the 1-(2-phenyl-ethyl)azetidine compound was ~8.9%.
10Analy~is: cal~ulated ifor Cl~HllClN202: C,52099; H,4.89, N,12.36 Found : C~52.99; H,4.91 ~,12.32 ~ FluorophenoxY)-N-methyl-l-azetidinecarboxamide.
15A stirred mixture of 5.4 g (0.02 mole) of 3-(~-fluoro-phenoxy)-azetidine oxalate and 1.7 g (0.022 mole) of m~thyl isocyanate in 20 ml o tetrahydrofuran was treated with 5 ml of triethylamine then ~tirring was continued for 3 hr.
~he reaction was diluted with water and the fine crystalline precipitate obtained was collected by filtration and dried at 60C. under vacuum to yield 3 g (66.9%) of product, m.p. 155-156C.
Analysis: calculated for CllHl3FN202: C,58.92; H,5.84;
~,12.49 - Found : CJ58.93; H,5.91:
25N,12.26 ExamPle ~6?
3-~ Fluorophenoxv)-N-methyl-l-azetidinecarboxamide.
A stirred slurry of o.38 g (0.02 mole~ o~ 60% sodium hydride as a mineral oil su~pension in 10 ml of dry 30 dimethylformamide was treated under nitrogen with the dropwise addition of 1.12 g (0.01 mole) of ~-fluorophenol in 20 ml of dimethylfonnamide. After 1 hr, the mixture was heated at 90C. fox 20 min then 2.1 g (0.01 mole) of ~-methyl-~-r(methanesulfonyljoxy~ a~etidinecar~oxamide ~5 wa added as a ~olid. The reaction mixture was then stirred at 90C. for 8 hr. The reaction mixture wa~
cooled by adding iFe water then further dilut~d ~o 200 ml --- 12~27~ 452 with water and extracted with 3 x 50 ml of methylen~
chloride. Less than 1 g of oil was obtained upon concen-trations of the extracts. ~xtraction with 4 x 50 ml sf benzene gave only a trace of product. The mass ~pectrum (CI) showed the expected p+l at 225 m/e. The produ~t ~olidified on standing and was recrystallized from methanol/
water to yield 650 mg (29.0%) of flake-like sil~er crystals3 m.p. 156-158~C.
~nalysis: Calculated for CllHl FN202: -C,5~.92; H,5.84; N,12.49 Found C,58.93; H,5.91; ~,12.42 Pha~TIacological Test Procedures Muscle Relaxant Test ~ rhe test prt~cedure relied on to indicate positivemuscle relaxant activity i5 the morphine-Induc~d Str~ub Tail in Mice Test de~cribed by G. D. ~ovak in DRUG DEVELOPMENT
RESEA~CH (19~2) 2: 383-~86, ~xcept 8 animals per group were used per te~t rather than 10. The test i~ $umm~rized as : ~ollow~: The test drug, ref rence drug, and control articles to be admi~istered are prepared in saline, 0.5%
aqueous methylcellulose suspe~sion or other, depending on solubility, in ~uch ~oncentration that the volum~ adminis-tered i~ 10 ml/~g. The initial screening dose of the test drug is u-~ually 100 mg~ky. Group~ of 8 mice are given an IP dose of a compound or vehicle prepared as de~cribed ~bove. Aftex 15 min, mice are admin i8 ter~d morphine ~ulfate, 60 mg/kg, subcutaneously. Fîfteen minutes after admini~tration of morphine ~i.e., 30 min after test compound administration), mice were scored for presence of Straub Tail defined as an elevation of the tail ~t least 90 degrees from the horizontal. An ED50 value may be determined from at least three logarithmically ~paced doses by the method o~ Litchfield and Wilcoxon (1949), J. PH~RM~COL. EXP. THER.
~ : 99-113. Compared to a reference compound, methocarbamol~
which exhibited ~n ED50 of 75-110 in the above S~raub Tail Test, the more active compounds of Formula I were 5-10 times more active.
~ 2~ A35~ 3~
~ The test screening procedure relied on to indicate : positive antianxiety resp~nse i8 a modification of the Vogel Conflict Test whiah i~ ba~ed on ~hock-~uppressed drinXing behavior in rat~ outlined by J. R. Vogel, et al in PSYCHOP~RMACOLOGY 21: 1-7 (1971~. T~e procedure u~ed i~
: as follow~: The t:est re~erence and control articles to be administered intraperitoneally in phy~iological salinQ, 0.5% aoueous methylcellu}ose or other ~epending on ~
solubility in such ~oncentration that the volume ~dminister~d 35 i~ 5 n~ sg. The initial ~creening dose of ~he t~st article lZ~ 74 is usually 100.0 mg/kg initially, and the reference drug (diazepam) is 5 mg/kg.
Prior to dosing, rats are housed 2 per cage and deprived of water for 48 hr and thereafter randomized into treatment groups of five. Feed is available ad libitum. Thirty minutes af~er dosing, each rat is placed individually in a plexiglass cage measuring 18 cm in width, 13 ~m in height and 29.5 cm in length and equipped with a stainl~ss steel grid floor. The cage is ~overed with a plastic lid containing holes to facilitate introduction of a water bottle t30 ml plastic ~entrifuge tube) with a rubber stopper and metal drinking tube. A Drinkometer circuit (Omniteck Electronics, IncO, 3000 Cortona Road, Columbus, Ohio 43204j is conn~cted between the drinking tube and the grid floor of the apparatus 80 that the rat ~ompletes the circuit whenever it licks the tube. The procedure is to allow the rat to ind the drinking tube and complete 20 licks (as displayed on the Drinkometer digital readout) prior to the start of the experimental ~ession. Rats not xeaching this criterion are discarded.
A three minute experimental session is initiated by a 0.25 mA shock at the 20th lick. Rats that continue drinking will experience a shock at each successive 20th lick. The total number of shocks during the experimental session are recorded as follows:
total licks + 1 = total shocks Stati~tical analysis i8 performed by the Dunn's Multiple Comparison Test described by O. J. Dunn (1964) TECH~OMETRICS
6(3):241-52. The mean number of sho~ks experienced by the control group is compared with those of each drug-treated group. Signi~icance is considered at pc 0.1. The higher ~he ~otal ~hocks compared to con~rol, the more active is the compound. Active compounds may th~n be similarly tested at reduced d~sage IllustrativelyJ one preferred compound, 35 the compound of Example 16J namely, ~-cyclopropyl-3-t4-(tri-81uoromethyl)phenoxy~ l-azetidinecarboxamide wa~ active at as low a dosage as 10 m~ per kg, where total number o~ shocks taken as calculated above over ~ont~ol was 14/4.6 (P=0.03) ~ompared to ~b~ut 12-15/4 for diazepam.

Pharmaceutical comp~sitions The methods of treating anxiety, muscle tension, and spasticity in mammals is best carried out by administering as active ingredients in a pharmaceutical composition at least one of the comp~unds of Formula I in associ2tion with a p~armaceutical carrier or excipient. Ihe compounds are thu6 presented in a therapeutic composition ~uitable for oral, rectal, parenteral, subcutaneous, intramuscular, intraperitoneal, or intravenous admini~tration. Thus, for example, the composition for oral administration can take the form of elixirs, capsules, tablets, or coated tablets containing carriers conveniently used in the pharmaceutical axt. Suitable tableting excipients include lactose, potato, and maize starches, talc, gelatin, stearic and ~ilicic acids, magnesium stearate and polyvinyl pyrrolidone.
For parenteral administration, the carrier can be comprised o~ a sterile parenterally acceptable li~uid;
e.g., water or arachis oil contained in ampoules.
In compositions for rectal administration, the carrier can be comprised of a suppo~itory ba~e, e.g., cocoa butter or glyceride.
Advantageously, the compositions are formulated as dosage units, each unit being adapted to supply a fixed do~e of active ingredients. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage forms according to the invention. It is only necessary that the active ingredient constitute an effective amount; i.e., such that a suitable effective dosage will be consistent with the dosage form employed.
The exact individual dc~ages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian.
Testing ~uggests that rompound~ of Formula I will be efective in man or muscle relaxant effect~ ~t ~bout 4-40 mg~kg body weight per day. Illustratively, one compound, nam~ly, ~-methyl-3-~3-(trifluorome$hyl3phencxy~ azetidine carb3xamide ~Example 41), w~ found to be ~out 5 tïmes a~

3~Z~274 ~ 53 ~ 66197-177 p~ent a~ Methocarbamol as a muscle relaxant.
The suggested regimen, ~or example, for the compound of Example4l s a muscle relaxant appears to be about lO mg~kg/
day or for a 75 kg individual ~bout a unit do~age of 250 mg, t.i.d.
E~fective daily dosages of compounds of Formula I as antianxiety agents are projected to be about l-lO mg ~g/day body weight based on animal data.

The pharmaceutical compositions according to khe present invention in the ready-to-use dosage unit form, in practical use, may be put into containers which bear instructions that the composition should be used for treating muscle tension, muscle spasticity and anxiety of animals including humans.

Claims (105)

1. A 3-aryloxyazetidinecarboxamide of the formula:

(I) wherein;
Ar is pyridyl (which may be substituted by halo), or phenyl (which may be substituted by 1 or 2 radicals selected from the group consisting of chloro, bromo, iodo, fluoro, lower alkyl, lower alkoxy, nitro, aminocarbonyl and trifluoro-methyl), Z is oxygen or sulfur, R1 and R2 are the same or different and are taken alone hydrogen, C1-8-alkyl, phenyl (which may be substituted by halo, lower alkyl, lower alkoxy, nitro, cyano, trifluoro-methyl, carbomethoxy or carboethoxy), allyl (which may be substituted in any one of its three positions by lower alkyl), propargyl, C3-9-cycloalkyl, C1-8-alkyl-C3-9-cyclo-alkyl, C3-9-cycloalkyl-C1-8-alkyl, phenyl-C1-4-alkyl or di(C1-8-alkyl)amino-C1-8-alkyl, or R1 and R2 taken together with the adjacent nitrogen atom form a heterocyclic amino radical selected form the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, homo-piperidinyl, imidazolyl, piperazinyl, 4-phenylpiperazinyl, 4-[C1-4-alkyl]piperazinyl and morpholinyl, and R3 is hydrogen, C1-8-alkyl, phenyl(which may be substituted by halo, lower alkyl, lower alkoxy, nitro, cyano, trifluoromethyl, carbomethoxy or carboethoxy, or phenyl-C1-4-alkyl, with the proviso that R1 and R2 cannot be a combination of hydrogen and C1-8-alkyl when R3 is hydrogen, Z is oxygen and Ar is phenyl (which may be substituted by trifluoromethyl or aminocarbonyl) and further proviso that R1 and R2 can not both be hydrogen when, R3 is hydrogen, Z is oxygen and Ar is phenyl (which may be substituted by fluoro, lower alkyl, lower alkoxy, aminocarbonyl or trifluoromethyl) or a pharmaceutically acceptable acid addition salt thereof when R1 and R2 have a salt-forming basic amino component or Ar is pyridyl.

2. A process for producing a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises:
(A) reacting a 3-phenoxyazetidine of the formula:

(II) (wherein R3 is as defined in claim 1 and Ar is phenyl which may be substituted as defined in claim 1), with an isocyanate or isothio-cyanate of the formula:

R2-N=C=Z (III) (wherein R2 is as defined in claim 1 taken alone, except for hydrogen), to produce a compound of formula (I) wherein Ar is phenyl (which may be substituted) and R1 is hydrogen and R2 is as defined in claim 1 taken alone except for hydrogen, (B) reacting a 3-phenoxyazetidine of formula (II) defined above with an acid chloride of the formula:

R1R2N-CO-Cl (IV) (wherein R1 and R2 are as defined in claim 1, to produce a compound of formula (I) wherein Ar is phenyl (which may be substituted) and Z is oxygen, (C) reacting a 3-phenoxyazetidine of formula (II) defined above with nitrourea of the formula:

H2N-CO-NHNO2 (V) to produce a compound of formula (I) wherein Ar is phenyl (which may be substituted), Z is oxygen and R1 and R2 are each hydrogen, (D) reacting a 3-phenoxyazetidine of formula (II) defined above with 1,1'-(thio)carbonyldiimidazole of the formula:

(VI) (wherein Z is as defined above), to produce a compound of formula (I) wherein Ar is phenyl (which may be substituted) and R1 and R2 together with the adjacent nitrogen atom form 1-imidazolyl, (E) reacting a 3-phenoxyazetidine of formula (II) defined above with 1,1'-(thio)carbonyldiimidazole of formula (VI) defined above and a primary amine of the formula:

R2-NH2 (VII) (wherein R2 is as defined in claim 1 above taken alone), to produce a compound of formula (I) wherein Ar is phenyl (which may be substituted), R1 is hydrogen and R2 is as defined in claim 1 taken alone, (F) reacting a 3-arloxy-1-chlorocarbonylazetidine of the formula:

(VIII) (wherein Ar, R3 and Z are as defined in claim 1 with a primary amine of formula (VII) defined above, to produce a compound of formula (I) wherein R1 is hydrogen and R2 is as defined in claim 1, taken alone, (G) reacting a 3-arloxy-1-chlorocarbonylazetidine of formula (VIII) defined above with a secondary amine of the formula:

(IX) (wherein R1 and R2 taken together with the adjacent nitrogen atom form one of the heterocyclic amino radical defined in claim 1,) to produce a compound of formula (I) wherein R1 and R2 are as defined in (G), or (H) reacting a 4-sulfonyloxyazetidine of the formula:

(X) (wherein R3 and Z are as defined in claim 1, R2 is as defined in claim 1 taken alone, and W is methyl, phenyl or p-tolyl) with a

3- fluorophenol or its derivative of the formula:

(XI) (wherein X is hydrogen, fluoro, chloro, bromo, iodo, lower alkyl, lower alkoxy, nitro, aminocarbonyl or trifluoromethyl) in the presence of sodium hydride to produce a compound of formula (I) wherein R1 is hydrogen, R2 is as defined in claim 1 taken alone and Ar is phenyl corresponding to the fluorophenol of formula (XI), and if required, converting a thus-produced compound of formula (I) wherein R1 and R2 have a salt forming basic component or Ar is pyridyl into a pharmaceutically acceptable acid addition salt thereof.

3. A compound according to claim 1, wherein Ar is trifluoromethylphenyl, chlorophenyl, pyridinyl, phenyl, aminocarbonylphenyl, or fluorophenyl.

4. A compound according to claim 1, wherein R3 is hydrogen, Z is oxygen and Ar is phenyl, 3-trifluorophenyl, 4 trifluoro-phenyl, 2-aminocarbonylphenyl, 3-aminocarbonylphenyl or 4-amino-carbonylphenyl.

5. A compound according to claim 1, wherein R3 is methyl, Z is oxygen and Ar is phenyl, 3-trifluorophenyl, 4-trifluoro-phenyl, 2-aminocarbonylphenyl, 3-aminocarbonylphenyl or 4-amino-carbonylphenyl.

6. A compound according to claim 1, wherein R3 is hydrogen or methyl, Z is oxygen and Ar is chlorophenyl, or fluorophenyl.

7. A compound according to claim 4, wherein R1 is hydrogen and R2 is phenyl (which may be substituted by halo, lower alkyl, lower alkoxy, nitro, cyano, trifluoromethyl, carbomethoxy or carboethoxy), allyl (which may be substituted by lower alkyl), propargyl, C3-9-cycloalkyl, C1-8-allkyl-C3-9-cycloalkcyl, C3-9-cycloalkyl-C1-8-alkyl, phenyl-C1-4-alkyl or di(C1-8-alkyl)amino-C1-8-alkyl.

8. A compound according to claim 7, wherein R1 is hydrogen and R2 is 2,6-dimethylphenyl, phenylmethyl, 2,6-dichlorophenyl, 3-diethylaminopropyl, 3-dimethylaminopropyl, 2-propenyl, cyclopropyl, cyclopropylmethyl, 2-propynyl, cyclohexyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 2-butenyl or phenyl.

9. A compound according to claim 1, wherein R3 is hydrogen or methyl, Z is oxygen or sulfur, Ar is phenyl, 3- or 4-trifluoro-methylphenyl, 3-chlorophenyl, 3-fluorophenyl or 2-, 3- or 4-amino-carbonylphenyl and R2 is 2,6-dimethylphenyl, phenylmethyl, 2,6-di-chlorophenyl, 3-diethyl-aminopropyl, 3 dimethylaminopropyl, 2-propenyl, cyclopropyl, cyclopropylmethyl, 2-propynyl, cyclo-hexyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 2-butenyl or phenyl.

10. A compound according to claim 1, wherein R3 is hydrogen or methyl, Z is oxygen or sulfur, Ar is 3-chlorophenyl or 3-fluorophenyl and R2 is methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl, 1-methylpropyl, 2,6-dimethylphenyl, phenylmethyl, 2,6-dichlorophenyl, 3-diethyl-aminopropyl, 3-dimethylam1noPropyl, 2-propenyl, cyclopropyl, cyclopropylmethyl, 2-propynyl, cyclohexyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 2-butenyl or phenyl.

11. A compound according to claim 1, wherein R3 is hydrogen or methyl, R1 and R2 are each methyl or ethyl, and Ar is phenyl, 3- or 4-trifluoromethylphenyl, 3-chlorophenyl, 3-fluorophenyl, or 2-, 3- or 4-aminocarbonylphenyl.

12. A compound according to claim 1, wherein R3 is hydrogen or methyl and Ar is phenyl, 3- or 4-trifluoromethylphenyl, 3-chlorophenyl, 3-fluorophenyl, or 2-, 3- or 4-aminocarbonyl-phenyl.

13. A compound according to claim 1, wherein Z is oxygen or sulfur, R3 is hydrogen or methyl and Ar is phenyl, 3- or 4-trifluoromethylphenyl, 3-chlorophenyl, 3-fluorophenyl, or 2-, 3-or 4-aminocarbonylphenyl.

14. A compound according to claim 1, wherein R3 is hydrogen or methyl, Z is oxygen or sulfur, Ar is pyridyl or chlorophenyl and R2 is hydrogen.

15. A compound according to claim 1, wherein R3 is hydrogen or methyl, Z is oxygen or sulfur and R2 is methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl, 1-methylpropyl, 2,6-dimethylphenyl, phenylmethyl, 2,6-dichlorophenyl, 3-diethyl-aminopropyl, 3-dimethylaminopropyl, 2-propenyl, cyclopropyl, cyclopropylmethyl, 2-propynyl, cyclohexyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 2-butenyl or phenyl.

16. A process for producing N-(2,6-dimethylphenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbothioamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]- azetidine with 2,6-dimethylphenylisothiocyanate.

17. The compound N-(2,6-dimethylphenyl)-3-[3-(trifluoro-methyl)phenoxy]-1-azetidinecarbothioamide.

18. A process for producing N-(phenylmethyl)-3-[3-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]azetidine with benzyl isocyanate.

19. The compound N-(phenylmethyl)-3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

20. A process for producing N-(2,6-dichlorophenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbothioamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]azetidine with 2,6-dichlorophenyl isothiocyanate.

21. The compound N-.(2,6-dichlorophenyl)-3-[3-(trifluoro-methyl)phenoxy]-1-azetidinecarbothioamide.

22. A process for producing N-[3-(diethylamino)propyl]-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbothioamide or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]
azetidine with 3-(diethylamino)propyl isothiocyanate, and where required, converting the reaction product into a pharmaceu-tically acceptable acid addition salt thereof.

23. The compound N-[3-(diethylamino)propyl]-3-[3-(tri-fluoromethyl)phenoxy]-1-azetidinecarbothioamide or a pharma-ceutically acceptable acid addition salt thereof.

24. A process for producing N-[3-(dimethylamino)propyl]-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbothioamide or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]
azetidine with 3-(dimethylamino)propyl isothiocyanate, and where required, converting the reaction product into a pharma-ceutically acceptable acid addition salt thereof.

25. The compound N-[3-(dimethylamino)propyl]-3-[3-(tri-fluoromethyl)phenoxy]-1-azetidinecarbothioamide or a pharma-ceutically acceptable acid addition salt thereof.

26. A process for producing N-(2-propenyl)-3-[3-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]azetidine with 2-propenyl isocyanate.

27. The compound N-(2-propenyl)-3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

28. A process for producing N-cyclopropyl-3-[3-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reac-ting 3-[3-(trifluoromethyl)phenoxy]azetidine with cyclopropylamine and 1,1'-carbonyldiimidazole.

29. The compound N-cyclopropyl-3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

30. A process for producing N-[3-(diethylamino)propyl]-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide or a phar-maceutically acceptable acid addition salt thereof, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy] azetidine with 3-diethylaminopropylamine and 1,1'-carbonyldiimidazole, and where required, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

31. The compound N-[3-(diethylamino)propyl]-3-[3-(tri-fluoromethyl)phenoxy¦-1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof.

32. A process for producing N-2-(propenyl)-3-[4-(tri-fluoromethyl)phenoxy]-1-azetidinccarboxamide, which process comprises reacting 3-[4-(trifluoromethyl)phenoxy]azetidine with 2-propenyl isocyanate.

33. The compound N-2-(propenyl)-3-[4-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

34. A process for producing N-(cyclopropylmethyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy] azetidine with (aminomethyl)cyclopropane and 1,1'-carbonyldiimidazole.

35. The compound N-(cyclopropylmethyl)-3-[3-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide.

36. A process for producing N,N-diethyl-3-[3-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]azetidine with diethyl-carbamoyl chloride.

37. The compound N,N-diethyl-3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

38. A process for producing N,N-dimethyl-3 [3-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]azetidine with dimethyl-carbamoyl chloride.

39. The compound N,N-dimethyl-3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

40. A process for producing N-(2-propynyl)-3-[3-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]azetidine with 2-propynylamine and 1-1'-carbonyldiimidazole.

41. The compound N-(2-propynyl)-3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

42. A process for producing N-cyclohexyl-3-[3-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]azetidine with cyclohexyl isocyanate.

43. The compound N-cyclohexyl-3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

44. A process for producing N-cyclopropyl-3-[4-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[4-(trifluoromethyl)phenoxy]azetidine with cyclopropylamine and 1,1'-carbonyldiimidazole.

45. The compound N-cyclopropyl-3-[4-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

46. A process for producing N-(cyclopropylmethyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[4-(trifluoromethyl)phenoxy]azetidine with (aminoethyl)cyclopropane and 1,1'-carbonyldiimidazole.

47. The compound N-(cyclopropylmethyl)-3-[4-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide.

48. A process for producing N-[3-(diethylamino)propyl]-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarbothioamide or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 3-c4-(trifluoromethyl)phenoxy]
azetidine with 3-(diethylamino)propyl isothiocyanate, and where required, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

49. The compound N-[3-(diethylamino)propyl]-3-[4-(tri-fluoromethyl)phenoxy]-1-azetidinecarbothioamide or a pharmaceu-tically acceptable acid addition salt thereof.

50. A process for producing N-(3-diethylamino)propyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide or a phar-maceutically acceptable acid addition salt thereof, which process comprises reacting 3-[4-(trifluoromethyl)phenoxyl azetidine with 3-diethylaminopropylamine and 1,1'-carbonyldiimidazole, and where required, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

51. The compound N-(3-diethylamino)propyl-3-[4-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide or a pharmaceu-tically acceptable acid addition salt thereof.

52. A process for producing N-(2-propynyl)-3-[4-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[4-(trifluoromethyl)phenoxy]azetidine with 2-propynylamine and 1,1'-carbonyldiimidazole.

53. The compound N-(2-propynyl)-3-[4-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

54. A process for producing N-(2-methyl-2-propenyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[4-(-trifluoromethyl)phenoxy]azetidine with 2-methyl-2-propenylamine and 1,1'-carbonyldiimidazole.

55. The compound N-(2-methyl-2-propenyl)-3-[4-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide.

56. A process for producing N-(2-methyl-2-propenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]azetidine with 2-propynylamine and 1,1'-carbonyldiimidazole.

57. The compound N-(2-methyl-2-propenyl)-3-[3-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide.

58. A process for producing N-(3-methyl-2-butenyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[4-(trifluoromethyl)phenoxylazetidine with 3-methyl-2-butenylamine and 1,1'-carbonyldiimidazole.

59. The compound N-(3-methyl-2-butenyl)-3-[4-(trifluoro-methyl)phonoxy]-1-azetidinecarboxamide.

60. A process for producing N-(3-methyl-2-butenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[3-(triflouoromethyl)phenoxy]azetidine with 3-methyl-2-butenylamine and 1,1'-carbonyldiimidazole.

61. The compound N-(3-methyl-2-butenyl)-3-[3-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide.

62. A process for producing (E)-N-(2-butenyl)-3-[4-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[4-(trifluoromethyl)phenoxy]azetidine with trans-crotylamine and 1,1'-carbonyldiimidazole.

63. The compound (E)-N-(2-butenyl)-3-[4-(trifluoro-methyl)phenoxy-1-azetidinecarboxamide.

64. A process for producing (E)-N-(2-butenyl)-3-[3-(tri-fluoromethyl)phenoxy]-1-azetidincarboxamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy azetidine with trans-crotylamine and 1,1'-carbonyldiimidazole.

65. The compound (E)-N-(2-butenyl)-3-[3-(trifluoro-methyl)phenoxy]-1-azetidincarboxamide.

66. A process for producing N-phenyl-3-[3-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[3-(trifluoromethyl)phenoxy]azetidine with phenyl isocyanate.

67. The compound N-phenyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide.

68. A process for producing N-phenyl-3-[4-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting 3-[4-(trifluoromethyl)phenoxy]azetidine with phenyl isocyanate.

69. The compound N-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide.

70. A process for producing trans-N,2-dimethyl-3-[3-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting trans-2-methyl-3-[3-(trifluoromethyl) phenoxy]azetidine with methyl isocyanate.

71. The compound trans-N,2-dimethyl-3-[3-(trifluoro-methyl)phenoxy]-1-azetidinecarboxamide.

72. A process for producing trans-2-methyl-3-[3-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting trans-2-methyl-3-[3-(trifluoromethyl) phenoxy]azetidine with nitrourea.

73. The compound trans-2-methyl-3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

74. A process for producing trans-2-methyl-N-(2-pro-penyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide, which process comprises reacting trans-2-methyl-3-[3-(tri-fluoromethyl)phenoxy]azetidine with 2-propenyl isocyanate.

75. The compound trans-2-methyl-N-(2-propenyl)-3-[3-(tri-fluoromethyl)phenoxy]-1-azetidinecarboxamide.

76. A process for producing 3-(3-chlorophenoxy)-N-methyl-1-azetidinecarboxamide, which process comprises reacting 1-chlorocarbonyl-3-(3-chlorophenoxy)azetidine with methylamine.

77. The compound 3-(3-chlorophenoxy)-N-methyl-1-azetidinecarboxamide.

78. A process for producing 3-(3-chlorophenoxy)-N-(2-pro-penyl)-1-azetidinecarboxamide, which process comprises reacting 1-chlorocarbonyl-3-(3-chlorophenoxy)azetidine with 2-propenyl-amine.

79. The compound 3-(3-chlorophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide.

80. A process for producing N-methyl-3-(2-pyridinyloxy)-1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
reacting 1-(1-phenylethyl)-3-(2-pyridyloxy)azetidine with phosgene to give 1-chlorocarbonyl-3-(2-pyridyloxy)azetidine, reacting the resulting 1-chlorocarbonyl compound with methylamine, and where required, converting the thus-produced desired compound into a pharmaceutically acceptable acid addition salt thereof.

81. The compound N-methyl-3-(2-pyridinyloxy)-1-azetidine-carboxamide or a pharmaceutically acceptable acid addition salt thereof.

82. A process for producing N-(2-propenyl)-3-(2-pyridinyloxy)-1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof, whlch process comprises:
reacting 1-(1-phenylethyl)-3-(2-pyridyloxy)azetidine with phosgene to give 1-chlorocarbonyl-3-(2-pyridyloxy)azetidine, reacting the resulting 1-chlorocarbonyl compound with allylamine, and where required, converting the thus-produced desired com-pound into a pharmaceutically acceptable acid addition salt thereof.

83. The compound N-(2-propenyl)-3-(2-pyridinyloxy)-1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof.

84. A process for producing 3-(2-pyridinyloxy)-1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
reacting 1-(1-phenylethyl)-3-(2-pyridyloxy)azetidine with phosgene to give 1-chlorocarbonyl-3-(2-pyridyloxy)azetidine, reacting the resulting 1-chlorocarbonyl compound with ammonia, and where required, converting the thus-produced desired com-pound into a pharmaceutically acceptable acid addition salt thereof.

85. The compound 3-(2-pyridinyloxy)-1-azetidinecarbox-amide or a pharmaceutically acceptable acid addition salt thereof.

86. A process for producing 1-[3-[4-(trifluoromethyl) phenoxy]-1-azetidinylcarbonyl]-1H-imidazole or a pharmaceu-tically acceptable acid addition salt thereof, reacting 3-[4-(trifluoromethyl)phenoxyazetidine with 1,1'-carbonyldiimidazole, and where required, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

87. The compound 1-[3-[4-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]-1H-imidazole or a pharmaceutically accept-able acid addition salt thereof.

88. A process for producing 3-(3-fluorophenoxy)-N-methyl-1-azetidinecarboxamide, which process comprises:
(a) reacting 3-(3-fluorophenoxy)azetidine with methyl isocyanate, or (b) reacting N-methyl-3-[(methanesulfonyl)oxy]-1-azetidinecarboxamide with 3-fluorophenol in the presence of sodium hydride.

89. The compound 3-(3-fluorophenoxy)-N-methyl-1-azetidinecarboxamide.

90. A process for producing 3-(3-chlorophenoxy)-1-azetidinecarboxamide which process comprises reacting 1-chlorocarbonyl-3-(3-chlorophenoxy)azetidine with ammonia.

91. The compound 3-(3-chlorophenoxy)-1-azetidinecarbox-amide.

92. A pharmaceutical composition comprising a 3-aryloxyazetidinecarboxamide of formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof in an amount effective in treating muscle tension, muscle spasticity or anxiety in animals, together with a pharmaceutical carrier or excipient.

93. A pharmaceutical composition comprising a 3-aryloxyazetidinecarboxamide of formula (I) as defined in any one of claims 3 to 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89 and 91 or a pharmaceutically acceptable acid addition salt thereof in an amount effective in treating muscle tension, muscle spasticity or anxiety in animals, together with a pharmaceutical carrier or excipient.

94. The composition according to claim 92, which contains the compound of the formula (I) in an amount of 4-40 mg/kg body weight per day.

95. The composition according to claim 92, which contains the compound of the formula (I) in an amount of about 10 mg/kg body weight per day.

96. The composition according to claim 93, which contains the compound in an amount of 4-40 mg/kg body weight per day.

97. The composition according to claim 93, which contains the compound in an amount of about 10 mg/kg body weight per day.

98. The composition according to claim 92, which contains the compound of the formula (I) in an amount of 1-10 mg/kg body weight per day.

99. A use for treating muscle tension, muscle spasticity and anxiety in animals, including humans, of a compound selected from the group having the 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, amino-carbonyl or trifluoromethyl;
Z is oxygen or sulfur;
R1 and R2 are selected from hydrogen, loweralkyl, aryl, allyl, substituted allyl, propargyl, cycloalkyl, loweralkylcycloalkyl, cycloalkylloweralkyl, arylloweralkyl, and diloweralkylaminoloweralkyl, and R1 and R2 when taken together with the adjacent nitrogen atom may form a heterocyclic amine radical including azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, imidazolyl, piperazinyl, 4-substituted piperazinyl and morpholinyl;
R3 is selected from hydrogen, loweralkyl, aryl, or arylloweralkyl; geometrical isomers including cis, trans, (E) and (Z) isomers thereof, and the pharmaceutically acceptable acid addition salts thereof when R1 and/or R2 have a salt-forming basic amino component or Ar is pyridyl.

100. The use of claim 99, wherein the compound used is N-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidine-carbothioamide.

101. The use of claim 99, wherein the compound used is N-(2,6-dimethylphenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinacarbothioamide.

102. A pharmaceutical composition for treating muscle tension, muscle spasticity and anxiety in animals, including humans, said composition comprising an effective amount of a compound of formula (I') as defined in claim 99 in admixture with a pharmaceutically acceptable carrier or diluent, wherein in formula (I') (A) R1 is hydrogen, R2 is lower alkyl, Z is oxygen, R3 is hydrogen and Ar is phenyl (which may be sub-stituted by aminocarbonyl or trifluoromethyl) or (B) R1 and R2 are both hydrogen, Z is oxygen, R3 is hydrogen and Ar is phenyl (which may be substituted by fluoro, lower alkyl, lower alkoxy, trifluoromethyl or aminocarbonyl).

103. A composition according to claim 102, which is in the ready-to-use dosage unit form and is in a container which bears instructions that said composition should be used for treating muscle tension, muscle spasticity and anxiety in animals, including humans.

104. A composition according to claim 103, wherein the compound of formula (I') is N-methyl-3-[3-(trifluoromethyl) phenoxy]-1-azetidinecarboxamide.

105 A process for producing a pharmaceutical composition in the ready-to-use dosage unit form as defined in claim 103, which process comprises, admixing said compound of formula (I') with the carrier or diluent, forming the admixture into the ready-to-use dosage unit form and packaging the units into the container.