DK168422B1 - Use of a 3-aryloxyazetidine carboxamide or carbothioamide or a pharmaceutically acceptable acid addition salt thereof for the preparation of a pharmaceutical composition for the treatment of anxiety states - Google Patents

Description

in DK 168422 B1

The present invention relates to the use of certain 3-aryloxyazetidine carboxamides or carbothioamides or pharmaceutically acceptable acid addition salts thereof for the preparation of pharmaceutical compositions for the treatment or prophylaxis of anxiety in humans and animals.

Some of the 3-aryloxyazetidine carboxamides used in the invention are described in U.S. Patent No. 4,226,861 as agents of anticonvulsant activity used to treat epilepsy. These compounds have the formula 15 wherein R is lower alkyl and R 1 is hydrogen, aminocarbonyl or trifluoromethyl.

Other 3-aryloxyazetidine carboxamides used according to the invention have the formula O Λ i-V (R '> n 20 HHt O- (Qr where R1 is H, F, lower alkyl, lower alkoxy, trifluoromethyl, acetyl or aminocarbonyl).

The latter compounds are known from EP 102 194 A1, which states that the compounds of US Patent No. 4,226,861 mentioned above have muscle relaxant properties and that the N-unsubstituted azetidine carboxamides do not have muscle relaxant effect in an effective anticonvulsant 30 swab dose. However, this information is based on a less sensitive test (loss of torsional reflex).

EP 102 740 A1 discloses N-formyl and N-hydroxymethyl-3-phenoxy-1-azetidine carboxamides having anticonvulsant activity.

The 3-aryloxyazetidine carboxamides carbothioamides used in the invention for the preparation of a pharmaceutical composition for the treatment of anxiety disorders have the formula

\ j__c— "°" Ar J

5 ** b wherein Ar is pyridyl (at any position), halogen-substituted pyridyl, phenyl or phenyl substituted with 1 or 10 substituents selected from chloro, bromo, iodo, fluoro, C (1-8) alkyl, C (1 -8) -alkoxy, nitro, aminocarbonyl and trifluoromethyl, Z is oxygen or sulfur, R 1 and R 2 are each hydrogen, C (1-8) -alkyl, aryl, allyl, C (1-8) -alkyl-substituted allyl, propargyl, cycloalkyl, C (1-8) -alkyl-cycloalkyl, cycloalkyl-C (1-8) -alkyl, aryl-C (1-8) -alkyl and di-c (1-8) -alkylamino-C (1-8) -alkyl, or R1 and R2 together with the neighboring nitrogen atom means imidazolyl and R3 is hydrogen, C (1-8) -alkyl or aryl, where aryl means phenyl or phenyl substituted with halogen, C (1-8) alkyl, C (1-8) alkoxy, nitro, cyano, trifluoromethyl, carbomethoxy or carboethoxy, and aryl-C (1-8) alkyl means an aryl group as defined above bonded over a straight or branched C (1-8) alkyl group to the amide nitrogen atom, or a pharmaceutically acceptable acid addition salt thereof, when R 1 and / el clay R2 has a salt-forming basic amino component or when Ar is pyridyl. Formula I comprises the geometric isomers including cis, trans, (E) and (Z) isomers thereof.

The compounds of formula I are novel except for the cases where Ar is phenyl or phenyl substituted with trifluoromethyl or aminocarbonyl while Z is oxygen, R 3 is hydrogen, and R 1 and R 2 are a combination of hydrogen and C (1- 8) -alkyl, and wherein Ar is phenyl or phenyl substituted by fluoro, C1-C8 alkyl, C1-C8 alkoxy, trifluoromethyl, acetyl or aminocarbonyl while Z is oxygen, and R 1, R 2 and R 3 are hydrogen.

The term "C (1-8) alkyl" encompasses straight-chain and branched groups of up to eight carbon atoms and is e.g. such groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, isoamyl, hexyl, heptyl and octyl. The term, 1C (1-8) -alkoxy, has the formula -0-0 (1-8) -alkyl.

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

As defined above under formula I, pharmaceutically acceptable salts are also included when R 1 and / or R 2 have a salt-forming amino component or when Ar is pyridyl. Salt-forming amino components occur, for example, when R 1 and / or R 2 are di-c (1-8) -alkylamino-C (1-8) -alkyl, or when they together form piperazinyl or imidazolyl groups.

Pharmaceutically acceptable acid addition salts are such salts that can be physiologically tolerated by humans and warm blooded animals. The acid addition salts can be formed by either strong or weak acids. Examples of strong acids are hydrochloric, hydrobromic, sulfuric and phosphoric. Examples of useful weak acids are fumaric acid, maleic acid, succinic acid, oxalic acid, citric acid, tartaric acid, hexamic acid and the like.

As stated above, the pharmaceutical compositions containing the 3-aryloxyazetidine carboxamides of formula I or pharmaceutically acceptable acid addition salts thereof are used to relieve anxiety in humans and animals. For the detection of an anti-anxiety response, the so-called "Vogel-Conflikt-Test", which is based on inhibited drinking behavior induced by shock, is used. This test is described in detail below.

The methods used to prepare the compounds of formula I can be divided into process types A, B and C.

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Process type A From phenoxyazetidine 5 HN 2 O - ^ + X) r "n = c = z -, R 3 Rs b) / \" 9 O / V Λ = Λίχ) η 10 Η '^ γ / "" O + r1r2k -C-C1 - »R1RsN-C- / y- ° - <Qr R3 -R3 H_lY ^ ° ~ 0 ^ + Η2Η-Ϊ-ΝΗΝ02 -> H2N-C - / ^ ° H ^ 'R3 R3 a) H / Yo_ <nfx) ”N / V» Λ-οJréx) *

20 Λ / c = 2 N, / 0

R3 ^ -1¾ C'2 R3 R3 35

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DK 168422 B1 5

Method type B

Via aryloxy-1-chlorocarbonylazetidine (Ar = phenyl, substituted phenyl, pyridyl) a) 3. Z λ, cl_C_jj \ -0-Ar + R®NHg -> I ^ HN-C-N \ ^ 0-Ar R3 R3 10 d) Z λ. / V

Cl-C-N \ -0-Ar + HN — n / j-N — C — N \ -0-Ar x O — Ό · x

15 R

Method type C

Via methane (or phenyl) sulphonylazetidine Z yv

H-N / \ - OSOsW Ra -N = C = 2 ^ RsNH-C-n \ -0S02-W

R3 w = CH3, phenyl,,

ii-CHg-phenyl Na% MF

25 7

X

R 2 NH-C -N 2> - 0

30 rS

35 DK 168422 B1 6

The Type A reactions comprise a process for preparing phenoxy compounds of formula I, wherein a compound of formula s. , -00 n R3 is reacted with one of the following types of compounds: a) R2N = C = Z, b) R1R2N-C-C1 /

II

0 15 0

II

c) h2n-c-nhno2, d) -C = Z, or e) the product of formula -C = Z 25 and R2NH2

The type B reactions comprise a process for the preparation of certain aryloxy compounds of formula If in which a compound of formula 30 Z / v ci - / V ° -Rr B3 is reacted with one of the following types of compounds: a) R 2 NH 2 or b) imidazole.

The Type C reactions include a process for preparing m-fluorophenoxy compounds of formula I

DK 168422 B1 7 by reacting a compound of the formula

Η — N 'S — OSO2 W

in

5 K

wherein W is CH3, σ6 / Η5 or 4-CH3-C5H5, with an isocyanate of the formula

R2-N = C = Z

10 <

to give a compound of the formula Rs NH-C-ί ^^ - DSO2 W

15 and then reacting with sodium hydride and a metafluoro-phenol of the formula to give a compound of the formula R £Nh-c - / -> - o - (Q

Rs F

Methods for preparing the starting phenoxyazidines used in process type A are outlined in Scheme I. Methods for preparing the starting aryloxy-1-carbonyllazetidines used in process type B are outlined in Scheme II.

The 1- (diphenylmethyl) -3-hydroxyazetidines used as starting materials of process type C (see Scheme III) can be prepared as stated by Anderson 35 & Lok. in J.Org.Chem. 73, 3953 (1972) from benzhydrylamine and a suitable epihalohydrin. The cis and trans isomers of the 1- (diphenylmethyl) -3-hydroxyazetidines may, when they occur, be separated by chromatography. The starting α-methylbenzyl-3-azetidinol is prepared as described by Tetsuya Okutani et al., Method Chem. Pharm. Bull. Vol. 22, 1490 (1974). Preparations 1-6 illustrate the methods.

Scheme I

Preparation of 1-unsubstituted substituted phenoxazazididines 10 R41 2 3/2 CH-N y-OH (see Preparation 2 & 5) C 2 H 2 X 1) CH 3 SO 2 Cl / th 3 R 2) NaOH, with or without + λ. phase catalyst (r-WX) "V H ° Ax" n1'1 '-' (see preparation \ cf. US Patent Specification

NaH 2 & 6) \ DMF 3} 1 379 151

20 V-V "°" 0 ^ 1> -P-a / g -> H ^ S-O-Q

cii Ύ, el:% + Pd (OH) 2 / C Y yy (see Preparation 4) R3 χ4 R4 = CH3, phenyl or subst. phenyl. ~ 2 X is limited to substituents which are electron-removing, e.g. fluorine, chlorine, bromine, iodine or CF3.

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

4 X cannot be chlorine, bromine or iodine in the product as hydrogenolysis removes these groups.

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Scheme II

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

5 'VCH-N // \ - 0H

c £ hs Y

r3 (see Preparation 1, when \ R3 = CH3) \ \ halogen 10 \ error \ halogen

\ NaH \ DMF

"i- ^ r / R3

(see Preparation in] f Z

Reaction Scheme 1) C-Clg Z (Z = 0 or S)

Cl-C-N> ~ 0Ar

X

25

Scheme III

Preparation of starting methane (or phenyl) sulfonylazetidine

R4-CH-l / A_0H wSOeCl R4-CH-l / \ - 0S0aW

30 ceBs HEt * C „Hj T,

toluene · R

R4 = CH3, CeHs- W = CH3, CeHg 1¾, -CeH4-4cH3 Pd / c 35 J, H-N Y-0S02W R3 DK 168422 B1 10 o

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

A mixture of 126.4 g (0.72 mole) of diphenylmethylamine and 100 g (0.66 mole) of 3-bromo-1,2-epoxybutane in 300 ml of methanol is stirred while protected from light for 96 hours , is then heated at reflux for 30 hours as the color changes from pale yellow to deep amber. A sample is analyzed by 1 H NMR to show 3 methyl duplicates. A fine beige colored precipitate is removed by filtration (diphenyl-10-methylamine hydrobromide) and the filtrate is evaporated on a rotary evaporator to give 174.6 g of crude oil. A sample of .1.5 g is neutralized and placed on a 4 mm thick

R

plate in a "Chromatotron" and eluted with 10% ethyl acetate / toluene. A total of 16 fractions are collected, comprising 15 of 6 clear spots by TLC. The largest component separated is 700 mg and appears to be the trans isomer. This sample is converted to the oxalate salt. The main concentrate is converted to the free base with ammonium hydroxide and excl. is extracted into toluene which is dried over magnesium sulfate 20 and evaporated. The reaction residue is dissolved in methanol and treated with 58 g of oxalic acid, heated to give a homogeneous solution and allowed to cool after inoculation with a sample of the trans-oxalate salt. Filtration gives 62 g of white granulate, mp 147-148.5 ° C. Still, an exchange of 25 g is obtained. The 1 H-NMR spectrum shows only a single CH 2 doublet with j (CH-j H) of 6.1 Hz, which corresponds to the trans compound [Robert H. Higgins and Norman H. Cromwell, J. Hetero. Chem. 8 (6), 1059-62 (1971)]. Total yield of the title compound is 30 88 g (38.8%).

Analysis: Calculated for C 17 H 19 NO-C 2 H 2 4: C 66.46, H 6.16, N 4.08 Found: C 66.38, H 6.16, N 4.07.

35 11 DK 168422 B1 o

Preparation 2 1- (Diphenylmethyl) -3-azetidinol methanesulfonate (ester) hydrochloricl [1; 1]

A mixture of 60fo2 g (0.22 mol) of 1-diphenyl-s-methyl-3-azetidinol hydrochloride and 48.94 g (0.484 mol) of triethylamine in 800 ml of toluene is stirred for 24 hours, then cooled to 5 ° C in an ice bath. and treated with 27.7 g (0.24 mol) of methanesulfonyl chloride which is added at a rate to keep the temperature below 15 ° C. The reaction mixture is stirred for 3 hours and filtered to remove the triethylamine hydrochloride. The filtrate is treated with 40 g (0.242 mole) of 4-trifluoromethylphenol followed by 19.35 g (0.484 mole) of sodium hydroxide and 1.6 g (0.005 mole) of tert-butylammonium bromide in 60 ml of water. Reaction mixture 15 is rapidly stirred at reflux for 18 hours and then stirred for 72 hours while cooled to ambient temperature. The reaction mixture is transferred to a separatory funnel and washed with 4 x 200 ml water (emulsion). The toluene phase is dried over magnesium sulfate and evaporated in vacuo to 82 g of oil. This residue is dissolved in 200 ml of isopropyl alcohol and treated with 20 ml of concentrated hydrochloric acid. After cooling, a solid is removed which is removed by filtration (5.1 g). The filtrate is treated with isopropyl ether to give an oil which is subsequently worked up. The solid is identified by spectral analysis as the methyl sulfonate of the starting azetidinol. Recrystallization from isopropyl alcohol gives 3.3 g of fine white crystalline material, mp 172-173 ° C (contraction at 167 ° C).

Analysis: Calculated for C 17 H 18 NO 3 S.HCl: C 57.70, H 5.70, N 3.96 Found: C 57.80, H 5.86, N 3.92.

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Preparation 3 trans-1- (Diphenylmethyl) -2-methyl-3-13- (trifluoromethyl) phenoxy] azetidine oxalate [1; 1]

A stirred slurry of 1.2 g (0.03 mole) of sodium hydride (60% dispersion in mineral oil) in 50 ml of dry DMF is treated with 3.45 g (0.001 mole of trans-1-diphenylmethyl-2-methyllazetidine). 3-ol oxalate added in small portions.

When the addition is complete and hydrogen evolution has ceased, the reaction mixture is heated to 80 ° C for 2 hours, then dropping 1.64 g (0.01 mole) of 3-fluoro-trifluoro-methylbenzene. The reaction mixture is stirred at 80 ° C for another 18 hours. The reaction mixture is diluted with ice water and extracted with 3 x 25 ml of toluene. The extracts are combined, dried over magnesium sulfate, filtered, and the filtrate is treated with 1 g of oxalic acid. The solid obtained is collected by filtration. Recrystallization from acetone / isopropyl ether gives 2.2 g (4.5%) of fine white crystals, mp 146-147 ° C. Proton NMR shows that it is the trans compound.

Analysis: Calculated for C24H22F3NO * C2H2 ° 4: C 64.06, H 4.96, N 2.87 Found: C 64.26, H 4.99, N 2.89.

Preparation 4 trans-2-Methyl-3- [3- (trifluoromethyl) phenoxy] azetidine oxide [1: 1]

A methanol / hot water solution of 33 g (0.068 mol) of trans-1-diphenylmethyl-2-methyl-3- [3- (trifluoromethyl) phenoxy] azetidine oxalate is treated with ammonium hydroxide,

30 to basic, and then extracted with 4 x 150 ml of methylene chloride. The combined methylene chloride extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo to a pale yellow oil. This oil is dissolved in 200 ml of 190 ethanol plus 5 ml of triethylamine and hydrogenated on a Parr apparatus with 3.3 g of 5% palladium-on-charcoal catalyst at a hydrogen pressure of 2.8 kg / cin atm . at 70 ° C

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13 DK 168422 B1 for 12 hours. After the calculated amount of hydrogen has been absorbed, the catalyst is removed by filtration and the filtrate is evaporated in vacuo to give 26.73 g of crude product. A portion of 8 g is converted to the oxalate salt 5 in isopropyl alcohol to give 6.1 g of fine white powder, mp 155-156 ° C. Total yield extrapolated from the aliguous amount converted to the oxalate salt is 84% of theory.

Analysis: Calculated for cnHx2F3NO * C2H2 ^ 4: 10 C 48.61, H 4.39, N 4.36.

found; C, 48.67; H, 4.38; N, 4.34.

Preparation 5 trans-1- (Diphenylmethyl) -2-methyl-3-azetidinol-methanesulfonate (ester) hydrochloride [1: 1]

A solution of 6 g (0.025 mol) of trans-1-diphenylmethyl-2-methyllazetidin-3-ol (obtained from the hydrochloride salt by partitioning in organic solvent and aqueous base, separating and evaporating the organic phase ) in 40 ml of dry benzene is treated with 10 ml of triethylamine and cooled to 5 ° C. With stirring, the reaction mixture is treated with 3.54 g (0.03 mole) of methanesulfonyl chloride at a rate to keep the temperature below 10 ° C. After stirring for 3 hours, TLC (2Q,% ethyl acetate / methylene chloride on silica gel) shows that the reaction is incomplete. An additional 1.14 g (0.01 mole) of methanesulfonyl chloride is added and stirring is continued for one hour. The reaction mixture is diluted with 100 ml of water and the benzene layer is separated, washed with 300 ml of water, dried over magnesium sulfate and evaporated to an oil. The oil is dissolved in isopropyl ether and treated with ethereal hydrogen chloride. The solid salt is removed and recrystallized from 190 ethanol to give 3.4 g (37%) of fluffy white crystals, mp 152-153 ° C.

Analysis: Calculated for C-Lgl 2 -NO 3 SHCl: C 58.77, H 6.03, N 3.81.

Found: C, 58.68; H, 6.08; N, 3.80.

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Preparation 6 1- (Diphenylmethyl) -3- [3- (trifluoromethyl) phenoxy] azetidine N-Diphenylmethyl-3-hydroxyazetidine hydrochloride (I) is prepared from benzhydrylamine and epichlorohydrin 5 according to Anderson and Lok, J. Org. Chem. 37, 3953 (1972).

41.33 g (0.15 mole) of I and 42 ml (0.30 mole) of triethylamine are stirred in 250 ml of toluene, dropping 12 ml (0.15 mole) of methanesulfonyl chloride over 10 minutes with stirring, and the temperature is kept between 4 and 12 ° C. TLC (silica gel, 10 1% ethyl acetate in methylene chloride) after 1 hour shows that all starting materials are reacted. The mixture is filtered to remove the triethylamine hydrochloride, which is rinsed twice with toluene. The filtrate and washings are combined to approx. 450 ml of solution. To this solution is added 27.5 g (0.17 mol) of m-trifluoromethylphenol, 2.4 g of tetrabutylammonium bromide, 24 g (0.3 mol) of 50% sodium hydroxide and 24 ml of water, and the mixture is stirred vigorously and heated under reflux and under nitrogen for 2.5 hours. The toluene layer in the mixture is separated and washed once with water, dried over sodium sulfate and evaporated to an oil. This oil is seeded and pumped on an oil pump overnight. A solid cake weighing 49.7 g is obtained. Some of this solid is dissolved in isopropanol under short heating. Water is then added so that a slight haze appears. The mixture is seeded and cooled to induce crystallization. The white solid is collected by filtration, washed with 50% aqueous isopropanol and dried under vacuum overnight. Proton NMR shows slight contamination with silicone oil, mp 82.5-84 ° C.

Analysis: Calculated for C 23 H 20 F 3 NO 1 C 72.05, H 5.26, N 3.65.

Found: C 71.62, H 5.29, N 3.61.

35 15 DK 168422 B1

The following examples illustrate the preparation of 3 - aryloxyazetidine carboxamides or carbothioamides of formula I.

Example 1 N-Methyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carbothioamide Crude 3- [3- (trifluoromethyl) phenoxy] azetidine from catalytic debenzylation of 26.0 g (0.078 mol) 1 -benzhy-10-dry-3- [3- (trifluoromethyl) phenoxy] azetidine is dissolved in 100 ml of methylene chloride and a solution of 5.0 g (0.0678 mol) of methyl isothiocyanate in 15 ml of methylene chloride is added dropwise. The reaction mixture is stirred for 16 hours at ambient temperature and left for 15 a weekend. The solution is filtered through a Ce-lite filter pad to remove a fine crystalline precipitate and the filtrate is evaporated under reduced pressure. The residual oil is crystallized from isopropyl ether to give 12.6 g of product, mp 79-86 ° C. -20 ve of 5.0 g is recrystallized from isopropyl ether (charcoal) to give 3.2 g, mp 89-93 ° C which, by TLC on silica gel (10% methanol / toluene), is found to be contaminated by a material with Lower the Rf. The filtrate is evaporated under reduced pressure, combined with the -3.2 g of solid and dissolved in 100 ml of methylene chloride. The solution is stirred with 25 g of silica gel for 0.5 hour and filtered through a sintered glass filter. The residual solid is recrystallized from isopropyl ether to give 1.3 g of pure product, mp 96-98 ° C.

Analysis: Calculated for C 49.65, H 4.51, N 9.65 Found: C 49.58, H 4.48, N 9.58

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Example 2 N- (2,6-Dimethylphenyl) -3- [3- (trifluoromethyl) phenoxy] -1 - azetidinecarbothioamide Crude 3- [3- (trifluoromethyl) phenoxy] azetidine from catalytic debenzylation of 30.0 g (0.078 mol) of 1-benzhydryl-3- [3- (trifluoromethyl) phenoxy] azetidine is dissolved in 100 ml of methylene chloride and a solution of 12.7 g (0.078 mol) of 2,6-dimethylphenyl isothiocyanate is added dropwise. in 25 ml of methylene chloride. The product begins to precipitate during the addition, and an additional 50 ml of methylene chloride is added to agitate the stirring. After stirring overnight at ambient temperature, the product is collected by filtration (13.5 g, mp 196-199 °). A sample of 6.0 g was recrystallized from isopropanol to give 5.3 g of product, mp 197-199 ° C.

Analysis: Calculated for C ^ gH ^F₂N₂OS: C 59.99, N 5.03, N 7.36.

Found: C, 60.04; H, 5.04; N, 7.35.

20

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

To a stirred and cooled (10-20 ° C) solution of 0.04 mole of 3- [3- (trifluoromethyl) phenoxy] azetidine in 100 ml of methylene chloride is added dropwise 6.12 g (0.046 mole) of benzyl isocyanate. The reaction mixture is stirred at room temperature for 2 hours and filtered. The filter cake is washed with 2 x 50 ml petroleum ether, 2 x 50 ml dilute aqueous sodium bicarbonate and 2 x 50 ml water to give 12 g (86%). Recrystallization twice. from ethyl acetate gives 9.0 g clear white flakes, mp 173.5-175 ° C

Analysis: Calculated for C18H17F3N2 ° 2: C 61.71, H 4.89, N 8.00 Found: C 61.57, H 4.87, N 7.99.

DK 168422 B1 17 O -

Example 4 N- (2,6-Dichlorophenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarbothioamide

A solution of 0.04 mole of 3 · 1- [3- (trifluoromethyl) -5 phenoxy] azetidine in 100 ml of absolute ethanol is stirred in a bath of tap water, while adding at once 8.16 g (0.04 mol 2,6-dichlorophenyl isothiocyanate. The reaction is slightly exothermic and as the isothiocyanate begins to dissolve, product precipitation begins.

After stirring for 45 minutes, the reaction mixture is heated on a steam bath to ensure that all the isothiocyanate is dissolved and after cooling, filtration gives 15.2 g of white crystalline product. A portion (7.9 g) of this material is recrystallized from absolute ethanol to give 4.3 g of pure crystalline powder, mp 196-197 ° C.

Analysis: Calculated for C ^H ^FgCl₂ OS: C, 48.47; H, 3.11; N, 6.65.

Found: C, 48.40; H, 3.07; N, 6.54.

Example 5 N- [3- (Diethylamino (propyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carbothioamide oxalate [1: 1]

A 0.0548 molar solution of 3- [3- (trifluoromethyl) phenoxy] azetidine is stirred at 10 ° C, while 10.66 g (0.0584 mol) of 3- (diethylamino) propyl isothio is added. -cyanate all at once. After stirring overnight at ambient temperature, the reaction mixture is evaporated at 50 ° C on a rotary evaporator to a thick syrupy residue. The residue is dissolved in isopropanol and treated with 5.3 g of oxalic acid, heated on a steam bath to dissolve the acid, and upon cooling a solid salt precipitates. An equal volume of isopropyl ether is added to ensure complete precipitation. Filtration gives 26 g of crude product. A portion (13 g) is recrystallized from isopropanol / methanol / isopropyl ether = 100: 50: 50 (cooled in a refrigerator) to give 7.5 g of white propylene after filtration.

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18 DK 168422 B1 cloth, mp 155-157 ° C. Proton NMR confirms that this is the expected product.

Analysis: Calculated for C 18 H 26 F 3 N 3 • 2H 2 ° C 45.10, H 5.89, N 8.76.

Found: C, 50.02; H, 5.97; N, 8.89.

Example 6 N- [3- (Dimethylamino) propyl] -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarbothioamide A stirred solution of 0.0584 mol of 3- [3-C'-trifluoromethyl ) phenoxy Jazetidine at 10 ° C is treated with 8.42 g (0.0584 mole) of 3- (dimethylamino) propyl isothiocyanate at one time and stirred at ambient temperature overnight. The reaction mixture is treated with 5.3 g (0.0584 mole) of oxalic acid and diluted with 200 ml of isopropyl ether to give only 3.8 g of product. The volume is reduced to 100 ml at 50 ° C in vacuo and diluted with 500 ml of isopropyl ether to give an additional 15.3 g of product. The combined solid is dissolved in isopropyl alcohol and after cooling, a fine precipitate (N, N-dimethyl-1,3-propane diamine oxalate) is formed which is removed by filtration. The product does not crystallize; addition of isopropyl ether gives only an amorphous gel. After trying for 3 weeks to obtain a more satisfactory product, the reaction material is converted to the free base and taken up in isopropyl ether. The ether solution is stirred with 300 ml of water overnight to remove the diamine. The product crystallizes as the free base from the heterogeneous mixture and filtered to give 11.3 g of fine beige crystals. Reconstitution of the filtrate gives an additional 2.3 g of product.

A portion of 8 g is recrystallized from benzene / ligroin to give 5.8 g of very fine beige crystals which are dried at 82 ° C under vacuum, mp 107-108 ° C.

Analysis: Calculated for C 16 H 22 F 3 N 3 OS: 35 C 53.17, H 6.14, N 11.63.

Found: C, 53.29; H, 6.15; N, 11.60.

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

A solution of 18.9 g (0.05 mole) of crude 3- [3- (trifluoromethyl) phenoxy] azetidine (containing an equal molar amount of diphenylmethane) in 100 ml of isopropyl ether is stirred under nitrogen while slowly adding 4.16 g (0.05 mole) of 2-propenyl isocyanate. The reaction mixture, which is somewhat cloudy, is clarified, and after an hour, a fine crystalline precipitate begins to form. After stirring for 18 hours, the product is removed by filtration, washed with fresh isopropyl ether and air dried to give 9.5 g of white crystals, mp 75-76 ° C.

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

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

Example 8 N-Cyclopropyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine-carboxamide

A mixture of 1.9 g (0.033 mol) of cyclopropylamine and 4.9 g of 1,1'-carbonyldiimidazole in 60 ml of tetrahydrofuran is stirred at ambient temperature for one hour.

The clear solution formed is treated with a solution of (0.03 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine in 20 ml of tetrahydrofuran. After stirring overnight, the solid precipitate is removed by filtration to give 4.4 g of greyish white powder. The CI mass spectrum shows a p + 1 at 381 m / e, which corresponds to the expected product. Recrystallization from benzene / ligroin gives 2.3 g of light gray powder, mp 152-153 ° C.

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

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

35 DK 168422 B1 20 o

Example 9 N- [3- (Diethylamino) propyl] -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide oxalate [2: 3]

A mixture of 4.3 g (0.033 mol) of 3-diethylamino-S nopropylamine and 4.9 g (0.033 mol) of 1,1'-carbonyldiimidazole in 60 ml of methylene chloride is stirred at ambient temperature for one hour. The obtained solution is treated with 3- [3- (trifluoromethyl) phenoxy] azetidine (obtained from 9.21 g (0.03 mol) of the oxalate salt) in 30 ml of methylene chloride.

After stirring for 18 hours, transfer the reaction mixture to a separatory funnel and wash with 3 x 20 ml of water, dry over magnesium sulfate and evaporate in vacuo to a dark oil. The residue (8 g) is chromatographed on a 150 g neutral alumina column eluting with chloroform.

Concentration of the starting fraction gives the product as an amber oil which is dissolved in methyl isobutyl ketone and treated with 2 g of oxalic acid. Dilution with isopropyl ether gives an oil which solidifies and recrystallizes from acetone / isopropyl ether to give 6.25 g (41%) of 20 beige crystals, mp 91-93 ° C.

Analysis: Calculated for C ^ gH ^F ^NgC ^.1 / S

C 49.61, H 5.75, N 8.26.

Found: C 49.56, H 5.73, N 8.24.

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

A solution of 8.7 g (0.04 mol) of crude 3- [4- (trifluoromethyl) phenoxy] azetidine in 75 ml of isopropyl ether is stirred under a nitrogen blanket while dropping 4.2 g (0.05 mole) 2-propenyl isocyanate. After stirring for 3 days, no crystalline product precipitates. The reaction mixture is evaporated to a dark red oil. TLC (20% ethyl acetate / methylene chloride on silica gel) shows at least 35 6 spots, all well separated. The residue is dissolved in chloroform, chromatographed on a 350 g silica gel column and

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B1 is eluted with chloroform until the reddish course is removed. The column is then eluted with an ethyl acetate / chloroform gradient to 4% ethyl acetate. All the fractions are combined and evaporated to give 4.8 g of orange-colored oil which crystallizes on standing. Recrystallization from acetone / cyclohexane gives 3.3 g (27.5%) of beige crystals, mp 91-92.5 ° C.

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

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

Example 11 N- (Cyclopropylmethyl) -3- [3- (trifluoromethyl) phenoxy] -1-: -acetidine carboxamide A solution of 2.6 g (0.024 mol) (aminomethyl) cyclpropane hydrochloride in 50 ml of pyridine is stirred under nitrogen blanket , while adding 3.9 g (0.024 mol) of 1,1'-carbonyl diimidazole. After stirring for 45 minutes, TLC (5% methanol / methylene chloride on silica gel) shows in-reaction; therefore, 2 ml of triethylamine is added. The reaction mixture becomes cloudy after 10 minutes and TLC shows a new product. The reaction is treated with 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate. After stirring for one hour, a sample is taken and 25, after dilution with water, a solid precipitates. The CI-Mas spectrum shows that it was the product. After 2 days, the reaction is diluted with 5 parts by volume of water and the precipitate obtained is collected by filtration to give 6.5 g of pale yellow crystalline product. Recrystallization from ethanol / water gives white plate-like crystals which are dried at 82 ° C for 3 hours in a drying gun under vacuum; the product weight is 5.8 g (92%), mp 132-133 ° C.

Analysis: Calculated for C 15 H 17 F 3 N 2 2: 35 C 57.32, H 5.45, N 8.91.

Found: C 57.22, H 5.44, N 8.86.

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22 DK 168422 B1

Example 12 N, N-Diethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine - carboxamide

A stirred slurry of 5 g (0.0163 mol) of 3- [3-5 - (trifluoromethyl) phenoxyazetidine oxalate in 50 ml of tetrahydrofuran is treated with 5 ml of triethylamine and after one hour 2.5 g (0.018 mol) of diethylcarbamo is added. -ylchlorid. After stirring for an additional 15 hours, the reaction is treated with 10 ml of water and saturated with calcium chloride. The tetrahydrofuran is decanted from the solid residue and evaporated in vacuo to an oil. The crude oil is chromatographed on "Water's Prep-LC" using 50% ethyl acetate / toluene as the eluent. After evaporation of the main fractions, 3.1 g (60.1%) of pale yellow oil is obtained.

Analysis: Calculated for C 15 H 19 F 3 N 2 O 2: C 56.96, H 6.05, N 8.86.

Found: C 65.69, H 6.01, N 8.77.

Example 13 N, N-Dimethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

A stirred slurry of 5 g (0.0163 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate in 50 ml of tetrahydrofuran is treated with 5 ml of triethylamine and after 25 hours, 1.95 g is added. (0.018 µl) dimethylcarbamoyl chloride. After stirring for an additional 15 hours, the reaction mixture is treated with 20 ml of water and 10 g of calcium chloride. The tetrahydrofuran layer is decanted and the residue is triturated with 20 ml of ethyl acetate and then decanted.

The combined tetrahydrofuran and ethyl acetate solution is evaporated in vacuo. The crude residue is chromatographed on "Water's Prep-LC" using 50% ethyl acetate / toluene as the eluent. After evaporation of the main fractions 3.6 g (76.6%) of pale yellow oil is obtained.

Analysis: Calculated for C- gHH ^-Fg ^ And: C 54.17, H 5.25, N 9.72.

Found: C, 53.73; H, 5.20; N, 9.60.

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23 DK 168422 B1

Example 14 N- (2-Propynyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

A mixture of 3.9 g (0.024 mol) of 1,1'-carbonyl-5-diimidazole and 1.32 g (0.024 mol) of 2-propynylamine in 50 ml of tetrahydrofuran is stirred at ambient temperature for one hour and then treated with 6.2 g 3- [3- (trifluoromethyl) phenoxy] azetidine. The reaction mixture is treated with 3 ml of triethylamine and stirred for 18 hours. The reaction mixture is diluted with an equal volume of water and filtered to give 8 g of wet product. Recrystallization from isopropyl ether gives 3.8 g of gray solid, a mixture of product and the symmetrical urea of the starting 2-propynylamine. Another recrystallization from ethanol / water gives 2.6 g (43.6%) of crude product, mp 105-106 ° C.

Analysis: Calculated for C ,HH, ~F ~N₂O: C 56.38, H 4.39, N 9.39.

Found: C 56.32, H 4.34, N 9.44.

20

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

A stirred mixture of 5 g (0.0163 mole) of 3- [3-25 - (trifluoromethyl) phenoxy] azetidine oxalate and 2.04 g (0.018 mole) of cyclohexyl isocyanate in 50 ml of tetrahydrofuran is treated with 2 ml of triethylamine and then stirred. for 18 hours. Dilution of the mixture with water gives a solid precipitate which is collected by filtration to give 12 30 g of crude product. Recrystallization from acetone / water gives 5 g of fine white crystals, mp 148-150 ° C.

TLC (ethyl acetate on silica gel) shows traces of symmetrical cyclohexylurea as well as the product. Another recrystallization from isopropanol gives 1.65 g (29.6%) of white powder, dried under 0.5 mm Hg vacuum, mp 153-154 ° C.

24 DK 168422 B1

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Analysis: Calculated for C 17 H 21 F 3 N 2 2: C 59.64, H 6.18, N 8.18.

Found: C 59.52, H 6.20, N 8.17.

Example 16 N-Cyclopropyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

A stirred slurry of 4.4 g (0.027 mol) of 1,1 '- carbonyl diimidazole in 50 ml of methylene chloride under nitrogen is treated with 1.54 g (0.027 mol) of cyclopropylamine.

After a short (2 min) induction period, the clear solution suddenly becomes exothermic, bringing the reaction to gentle reflux. After 1 hour, when the reaction mixture is cooled to ambient temperature, 9.6 g (0.025 mol) of 3- [4- (trifluoromethyl) phenoxy] Jazetidine, 56.66% purity (containing diphenylmethane), is added at once. continued for 18 hours. The reaction mixture is evaporated on a rotary evaporator to give a partially crystalline residue. The residue 20 is partitioned between 30/60 pertoleum ether and water and the obtained waxy solid is removed by filtration. Recrystallization from isopropyl ether gives 5.7 g (75.9%) of plate-like silvery crystals, mp 145-147 ° C.

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

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

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

Example 17 N- (Cyclopropylmethyl) -3- [4- (trifluoromethyl) phenoxy] -1 - azetidinecarboxamide

To a stirred mixture of 4.4 g (0.027 mol) of 1,1 '- carbonyl diimidazole and 2.9 g (0.027 mol) of (aminoethyl) cyclopropane hydrochloride in 50 ml of methylene chloride is added dropwise 2.73 g ( 0.027 mol) of triethylamine. The reaction is exo-

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25 DK 168422 B1 thermal. The mixture is cooled with stirring for one hour then 9.6 g (0.025 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine is added at 56.66% (containing diphenylmethane) and stirring is continued for 18 minutes. hours. The reaction mixture is evaporated on a rotary evaporator to give an amber residue. Extraction of this residue with 30/60 petroleum ether gives only an insoluble oil. The rubbing step is repeated with 2 x 20 ml of 30/60 petroleum ether and the residue is treated with water to give a white solid. The solid is recrystallized from isopropyl ether to give 4.8 g (61.8%) of the plate-like crystals; after drying at 80 ° C under 0.5 mm Hg vacuum, mp 132-133 ° C.

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

. Found: C 57.26, H 5.46, N 8.93.

Example 18 N- [3- (Diethylamino) propyl] -3- [4- (trifluoromethyl) phenoxy] -20 -1-azetidinecarbothioamide

A stirred solution of 1.92 g (0.005 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine, 56.66% (containing diphenyl kethane) in 20 ml of isopropyl ether is treated with 0.88 g (0.005 mole) of 3 - (diethylamino) propyl isothiocyanate and stirred for 3.5 hours. The reaction mixture is treated with 0.5 g of oxalic acid dissolved in 2 ml of methanol. After stirring for 18 hours, the solid is collected by filtration to give 1.9 g of fine golden brown powder, mp 147-150 ° C. The solid is dissolved in water and treated with dilute sodium hydroxide. An oil is separated which solidifies and is collected by filtration. Recrystallization from cyclohexane gives 1.1 g (56.5%) of fine golden-brown crystals, mp 109-110 ° C.

Analysis: Calculated for C ^ g ^FFN NO: 35 c 55.51, H 6.73, N 10.79.

Found: C 55.68, H 6.67, N 10.73.

26 DK 168422 B1

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Example 19 N- [3- (Diethylamino) propyl] -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide oxalate [1: 2]

To a stirred solution of 4.4 g (0.027 mol) of 1,1'-5-carbonyldiimidazole in 50 ml of methylene chloride under nitrogen is added 3.52 g (0.027 mol) of 3- (diethylamino) propylamine. The reaction mixture is stirred for one hour, after which the somewhat exothermic reaction is cooled to ambient temperature and then treated at one time with 9.6 g (0.025 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine, 56.66% (contains diphenylmethane ). After stirring for 18 hours, the reaction mixture is evaporated on a rotary evaporator and the residue is dissolved in toluene. The toluene solution is washed with 3 x 20 ml of water, then treated with 2.5 g of oxalic acid in 10 ml of isopropanol. The solid obtained is collected by filtration and triturated with boiling acetone. After filtration, 1.8 g of unidentified fine white precipitate is formed, which is separated by filtration. The acetone solution is evaporated to a solid which is recrystallized from isopropyl alcohol / isopropyl ether to give 9.2 g of crude product (4 spots on TLC, 10% methanol / methylene chloride on silica gel). Recrystallization from methyl ethyl ketone gives 6.8 g (49.1%) of white powder, mp 129-130 ° C.

Analysis; Calcd for cigH26F3N3 ° 2.202 ° C: 25 C 47.74, H 5.46, N 7.59.

found; C 47.82, H 5.68, N 7.76.

Example 20 N- (2-Propynyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

A solution of 4.4 g (0.027 mol) of 1,1'-carbonyl diimidazole in 50 ml of tetrahydrofuran is stirred under nitrogen while adding 1.49 g (0.027 mol) of 2-propynylamine with a syringe and needle mounted through a wall. in the one neck of the reaction flask. After stirring for 2 hours, 9.6 g (0.025 mol) of 3- [4- (trifluoromethyl)

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B (thyl) phenoxy] azetidine (56.66% purity, containing diphenylmethane) and stirring is continued for an additional 18 hours. The reaction mixture is diluted with ice water and extracted with 30/60 petroleum ether to remove the diphenylmethane.

The oily aqueous portion is extracted with 4 x 50 ml of methylene chloride. These extracts are combined, dried over sodium sulfate and evaporated to an amber oil on a rotary evaporator. The oil solidifies when applied with a small amount (50 ml) of isopropyl ether. Filtration gives 10 6.1 g of rose-colored solid product. TLC (10% methanol / methylene chloride on silica gel) shows a mixture of 3 products and some starting material. Recrystallization from e-4 thanol / water gives the product in several small fractions. These are combined and recrystallized from isopropyl ether to give 4.1 g of pale beige powder, mp 135-137 ° C. TLC still shows some symmetrical 2-propynyl urea. The solid is recrystallized from ethanol / water to give 3.5 g (46.9%) of pale yellow crystalline product, mp 140-141 ° C.

Calcd. For C 14 H 15 F 3 N 2 O 2: C 56.38, H 4.39, N 9.39.

Found: C 56.34, H 4.36, N 9.32.

Example 21 N- (2-Methyl-2-propenyl) -3- [4- (trifluoromethyl) phenoxy] -1- -azetidine carboxamide

A stirred solution of 3.6 g (0.022 mol) of 1,1 '- carbonyl diimidazole in 75 ml of methylene chloride under nitrogen is treated with 1.6 g (0.022 mol) of 2-methyl-2-propenyl-amine (added via syringe and needle through a wall disposed in one neck of the reaction flask). After stirring for one hour, 6.2 g (0.02 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate is added at once, followed by 30 minutes of 5 ml of triethylamine and stirring is continued for 3 hours. . The reaction mixture is washed with 2 x 25 ml of water, dried over magnesium sulfate and evaporated in vacuo. DK 168422 Bl

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28 oily residue solidifies on standing and recrystallizes from isopropyl ether to give 3.7 g (58.9%) of fine white crystals, mp 101 ~ 102 ° C.

Analysis: Calculated for c15 H17 F3 N2 ° 2: 5 C 57.32, H 5.45, N 8.91.

Found: C 57.45, H 5.51, N 9.23.

Example 22 N- (2-Methyl-2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-10 -acetidine carboxamide

A solution of 3.6 g (0.022 mol) of 1.13 carbonyl-diimidazole in 75 ml of methylene chloride is stirred under nitrogen, while 1.6 g (0.022 mol of methallylamine is added with syringe and needle through a wall mounted in one neck of the reaction flask The reaction is slightly exothermic The reaction mixture is stirred for one hour, then treated with 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate followed by 0.5 hour of 5 ml of triethylamine. The reaction mixture is washed with 20 x 30 ml of water, dried over magnesium sulfate and evaporated on a rotary evaporator to give 6.7 g of oily residue which solidifies. The residue is recrystallized from isopropyl ether to give 5 4 g (85.9%) of fine white crystals, mp 90-91 ° C.

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

Found: C 57.20, H 5.50, N 8.95.

Example 23 N- (3-Methyl-2-butenyl) -3- [4- (trifluoromethyl) phenoxy] -1- -azetidine carboxamide

A solution of 3.6 g (0.022 mol) of 1,1'-carbonyl-diimidazole in 100 ml of methylene chloride is cooled in tap water bath and, while stirring under nitrogen, 1.87 35 g (0.022 mol) of 3-methyl-2-butenylamine are added dropwise. After stirring for one hour, 6.2 g (0.02 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate are added at one time followed by

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Of 0.5 hour of 5 ml of triethylamine and stirring is continued for an additional 16 hours. The reaction mixture is washed with. 2 x 50 ml of water, dried over magnesium sulfate and evaporated on a rotary evaporator to give a semi-solid residue. Purification with isopropyl ether and filtration yields 7 g of crude product which is recrystallized from ethanol / water to give 5.5 g (83.8%) of white crystals, mp 156.5-158 ° C.

Analysis: Calculated for C 18 H 19 F 3 N 2 2: 10 C 58.53, H 5.83, N 8.53.

Found: C, 58.81; H, 5.89; N, 8.58. _1

Example 24 N- (3-Methyl-2-butenyl) -3- [3- (trifluoromethyl) phenoxy] -1-15-azetidine carboxamide

A solution of 3.6 g (0.022 mol) of 1,1'-carbonyl-diimidazole in 100 ml of tetrahydrofuran is cooled with tap water bath and stirred under nitrogen while 1.6 g (0.022 mol) of 3-methyl-2-butenylamine is added with syringe and needle. The reaction mixture is stirred for one hour and then treated with 6.2 g (0.02 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate followed by 0.5 hour of 5 ml of triethylamine, then stirring is continued. 72 hours. The reaction mixture is diluted with 500 ml of ice-25 water and extracted with 6 x 50 ml of methylene chloride. The combined extracts are washed with water, dried over magnesium sulfate and evaporated to a solid residue on a rotary evaporator. Recrystallization from ethanol / water gives 6 g of white crystals, mp 143-144 ° C.

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

Found: C 58.46, H 5.86, N 8.69.

35 30

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DK 168422 Bl

Example 25 (E) -N- (2-Butenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

A mixture of 3.6 g (0.022 mol) of 1,1'-carbonyl-5-diimidazole and 1.6 g (0.022 mol) of trans-crotylamine is stirred for one hour, then treated with 6.2 g (0.02 mol) 3 - [4- (trifluoromethyl) phenoxy] azetidine oxalate followed by 0.5 hour of 5 ml of triethylamine, stirring being continued for 16 hours. The partially crystalline mixture 10 is washed with 2 x 50 ml of water, dried over magnesium sulfate and evaporated on a rotary evaporator to give a solid residue of 14.2 g. Recrystallization from methanol / water gives 5.35 g (85.1%) of fine white crystals, mp 157-158 ° C.

Analysis: Calculated for [15H] -7F3N2 ° 2: C 57.32, H 5.45, N 8.91.

Found: C 57.47, H 5.49, N 9.00.

Example 26 (E) -N- (2-Butenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

A solution of 3.6 g (0.022 mol) of 1,1'-carbon-yldiimidazole in 60 ml of methylene chloride is cooled in an ice bath while stirring under nitrogen while 1.6 g (0.022 mol) of trans-crotylamine is added dropwise. After heating to ambient temperature, 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate is added at once, followed by 0.25 hours of 5 ml of triethylamine, stirring is continued. 72 hours. The reaction solution is washed with 2 x 50 ml of water, dried over magnesium sulfate and evaporated on a rotary evaporator to give a solid residue of 7 g. Recrystallization from methanol / water gives 5.5 g of slightly yellow powder. Another recrystallization with charcoal treatment from isopropyl ether gives 3.75 g (59.7%) of 35 fine white crystals, mp 127-128 ° C.

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31 DK 168422 B1

Analysis: Calculated for c15 H17 F3 N2 ° 2: C 57/32, H 5.45, N 8.91.

Pound: C 57.35, H 5.47, N 8.94.

Example 27 N-Phenyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

A stirred slurry of 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate in 60 ml of tetrahydrofuran is treated with 5 ml of triethylamine followed by 2.62 g (0.022 mol) phenyl isocyanate, and stirring is continued for 16 hours. Dilute the reaction mixture with water until an oil is separated, which solidifies rapidly.

The aqueous tetrahydrofuran is decanted and the solid residue is recrystallized from ethanol / water to give 5.3 g (80.1%) of white crystals, mp 137-138 ° C. Analysis: Calculated for: C, 60.71; H, 4.50; N, 8.33.

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

20

Example 28 N-Phenyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

A stirred slurry of 6.2 g (0.02 mol) of 3- [4-25 - (trifluoromethyl) phenoxy] azetidine oxalate and 2.62 g (0.022 mol) of phenyl isocyanate in 60 ml of tetrahydrofuran is treated with 5 ml of triethylamine, and stirring is continued for 16 hours. Dilute the reaction mixture with water until an oil is separated. The tetrahydrofuran / water portion is decanted, and the residue solidifies upon standing. Recrystallization from ethanol / water gives 3.5 g (53.4%) of fine white crystals, mp 174.5-176 ° C.

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

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

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32 DK 168422 B1

Example 29 trans-N, 2-Dimethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinylcarboxamide

To a stirred solution of 6 g (0.015 mole) of crude trans-5 -2-methyl-3- [3- (trifluoromethyl) phenoxy] azetidine in 50 ml of tetrahydrofuran is added 0.94 g (0.3165 mole) of methyl isocyanate, and stirring for 16 hours under nitrogen blanket. Dilution of the reaction mixture with water gives an oil which solidifies. After decanting the aqueous tetrahydrofurfuran phase, the solid residue is recrystallized from ethanol / water to give 3.95 g (91.4%) of fine white crystals, mp 104.5-106 ° C.

Analysis: Calculated for ci3Hi5F3N2 ° 2! C 54.17, H 5.25, N 9.72.

Found: C 54.50, H 5.29, N 9.71.

Example 30 trans-2-Methyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide A mixture of 6 g (0.015 mole) of crude trans-2-methyl-2- [3- (trifluoromethyl) phenoxy] azetidine (purity 56.6%, contains diphenylmethane) and 2.4 g (0.0225 mole) of nitro urea in 40 ml of acetone are treated with 4 ml of water "and then heated until a clear homogeneous resolution.

The reaction mixture is stirred overnight, where it is cooled to ambient temperature and diluted with water until an oil is separated. The oil solidifies and recrystallizes from ethanol / water to give 4.3 g of white plate-like crystals, mp 117-118 ° C. The product is recrystallized from benzene to give 3.35 g (96.8%) of crystals, mp 118-119 ° C.

Analysis: Calculated for ΐ2Η13 Η 3Ν2 2 2: C 52.56, H 4.78, N 10.22.

Found: C, 52.54; H, 4.74; N, 10.17.

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33 DK 168422 B1

Example 31 trans-2-Methyl-N- (2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide

A solution of 6 g (0.015 mole) of crude trans-2-methyl-3- [3- (trifluoromethyl) phenoxy] azetidine (56.6%) in 50 ml of tetrahydrofuran is treated with 1.54 g (0.0165 mole) 2 - propenyl isocyanate at once and stirred under nitrogen blanket for 16 hours. Dilute the reaction mixture with water until an oil is separated. The oil does not crystallize and, after 7 weeks, it is rubbed off with 3 x 25 ml isopropyl ether.

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

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

Found: C 57.36, H 5.50, N 8.97.

Example 32 3- (3-Chlorophenoxy) -N * -methyl-1-azetidinecarboxamide

A solution of 0.01275 mol of 1-chlorocarbonyl-3-20 - (3-chlorophenoxy) azetidine in 20 ml of tetrahydrofuran is treated with 4 ml (0.05 mol) of 40% aqueous methylamine and stirred for 16 hours. The reaction mixture is diluted with water until an oil begins to separate and then extracted with 3 x 50 ml of benzene. The combined extracts are dried over magnesium sulfate and evaporated to a solid which is recrystallized from benzene / ligroin to give 1.2 g (40.0%) of fine white crystals, mp 140-141 ° C. Analysis: Calculated for cuHl3 ClN2 ° 2: C 54.89, H 5.44, N 11.64 Found: C 55.05, H 5.58, N 11.52.

Example 33 3- (3-Chlorophenoxy) -N- (2-propenyl) -1-azetidinecarboxamide A solution of 5.4 g (0.017 mole) of 1-chlorocarbonyl-3- (3-chlorophenoxy) azetidine in 20 ml tetrahydrofuran is treated with 2.3 g (0.04 mole) of 2-propenylamine and stirred

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34 DK 168422 B1 for 2 hours. The reaction solution is evaporated in vacuo to a pink-beige solid. The filtration of the solid with water gives 4.4 g of crude product after filtration. After drying, the solid is recrystallized from charcoal treatment from 2% acetone / isopropyl ether to give 1.7 g (37.5%) of pale beige crystals, mp 87-89 ° C.

Analysis: Calculated for C- HH ^ j-Cl ^C ^: C 58.54, H 5.67, N 10.50.

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

Example 34 N-Methyl-3- (2-pyridinyloxy) -1-azetidine carboxamide

A 2 molar benzene solution of 40 ml (0.08 mol) of phosgene is added to a suspension of 10 g of finely ground potassium carbonate in 40 ml of methylene chloride. The mixture is stirred for 15 minutes at room temperature and 10 g (0.056 mol) of 1- (1-phenylethyl) -3- (2-pyridyloxy) azidine is added in 50 ml of methylene chloride under gentle cooling. The mixture is stirred at room temperature for one hour and evaporated on a rotary evaporator at 25 ° C for 30 minutes. The residue is treated with 100 ml of tetrahydrofuran and cooled in an ice bath. To the cooled stirred mixture is added 20 ml of 40% aqueous methylamine. The mixture is stirred for 20 minutes and partitioned between methylene chloride and water. The methylene chloride is dried over sodium sulfate and evaporated. The residue is crystallized from benzene / ethanol and recrystallized from ethyl acetate / isopropyl alcohol. The yield of the title compound is 2.3 g (14%), mp 165-168 ° C.

Analysis: Calculated for C ;qH33NNO₂: C 57.96, H 6.32, N 20.28.

Found: C 57.93, H 6.34, N 20.12.

35

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Example 35 N- (2-Propenyl) -3- (2-pyridinyloxy) -1-azetidinecarboxamide To a stirred suspension of 10 g (0.072 mol) of finely ground potassium carbonate in 90 ml of methylene chloride, 32 ml (0.062 mol) of 2 molar are added. phosgene in benzene. The mixture is stirred for 15 minutes and 8 g (0.031 mol) of 1- (1-phenylethyl) -3- (2-pyridyloxy) azetidine in 50 ml of methylene chloride are added. The mixture is stirred at 25 ° C for 2 hours and evaporated on a rotary evaporator at 25 ° C for 30 minutes and the residue is treated with 100 ml of tetrahydrofuran. The stirred mixture is cooled in an ice bath and 4 g (0.07 mol) of allylamine is added dropwise. After stirring for 30 minutes at 25 ° C, the material is partitioned between water and methylene chloride. The methylene chloride is dried and evaporated.

(The residue is chromatographed on Waters, vv Prep-500 HPLC using a silica column and eluted with .50% ethyl acetate / hexane. The product is crystallized twice from isopropyl ether. The yield of the title compound is 1.5 g (21%), mp 72-76 ° C.

Calcd. For C 21 H 15 Y 3 ° 2: C 61.79, H 6.48, N 18, '01.

Found: C 61.53, H 6.50, N 17.96.

Example 36 3 (2-Pyridinyloxy) -1-azetidinecarboxamide

A 2 molar benzene solution of phosgene (32 ml, 0.062 mol) is added to a stirred suspension of 10 g of finely ground potassium carbonate in 80 ml of methylene chloride. The mixture is stirred for 15 minutes and 8 g of 30 (0.031 mol) of 1- (1-phenylethyl) -3- (2-pyridyloxy) azetidine is added in 50 ml of methylene chloride. The mixture is stirred for 35 minutes and evaporated on a rotary evaporator (25 ° C for 30 minutes). The residue is treated with 100 ml of tetrahydrofuran, cooled with an ice bath and slowly stirred under vigorous stirring 20 ml of concentrated ammonium hydroxide. The mixture is stirred for one hour at room temperature and

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36 DK 168422 B1 is split between methylene chloride and water. The water layer is extracted twice with methylene chloride and the combined organic layers are evaporated. The residue is crystallized from benzene and recrystallized from isopropylg ± here.

The yield of the title compound is 1.4 g, mp 133-137 ° C.

Analysis: Calculated for C c cNN30O₂: C 55.95, H 5.74, N 21.75.

Found: C, 55.73; H, 5.71; N, 21.10.

10

Example 37 1- [3- [4- (Trifluoromethyl) phenoxy] -1-azetidinylcarbonyl] -1H-imidazole A mixture of 1.7 g (0.01 mole) of 1,1'-carbonyl-diimidazole in 50 ml tetrahydrofuran and 3 g (0.015 mol) of 3- [4- (trifluoromethyl 1) phenoxy] azetidine are stirred for 6 hours. The reaction mixture is diluted with water and extracted with 3 x 50 ml of methylene chloride. After 20 evaporation in vacuo, the extracts give an amber residue which is dissolved in 20 ml of benzene and washed with dilute hydrochloric acid and then with water. The benzene portion is evaporated to give a semi-solid residue which, when triturated with isopropyl ether, gives 1.4 g of gray matter. Recrystallization from acetonitrile gives 1.3 g (41.8%) of fine gray crystals, mp 139-140 ° C.

Analysis: Calculated for C 14 H 12 F 3 N 3 O 2: C 54.02, H 3.89, N 13.50.

Found: C, 54.33; H, 3.96; N, 13.89.

30

Example 38 N-Methyl-3-phenoxy-1-azetidinecarboxamide

The compound is prepared from the methanesulfonate of 3-phenoxyacetidine and methyl isocyanate as described in Example 1 of U.S. Patent No. 4,226,861, m.p. 139-141 ° C.

DK 168422 B1 37 O.

Example 39 N-Methyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide

The compound is prepared from 3- [4- (trifluoromethylphenoxy) azetidine and methylioscyanate as described in Example 3 of U.S. Patent No. 4,226,861, m.p. 154-157 ° C.

Example 40 N-Methyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide

The compound is prepared from 3- [3- (trifluoromethyl) phenoxy] azetidine and methyl isocyanate as described in Example 4 of OSA Patent No. 4,266,861, m.p. 145-147 ° C.

Example 41 N-Methyl-3- [2- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide The compound is prepared from 3- [2- (trifluoromethyl) phenoxy] azetidine and methyl isocyanate as described in Example 5 of the United States Patent Application No. 4,226,861, m.p. 134-136 ° C.

Example 42 N-Methyl-3- [2- (aminocarbonyl) phenoxy] -1-azetidinecarboxamide The compound is prepared from 2- (3-azetidyloxy) benzamide and methyl isocyanate as described in Example 2 of U.S. Patent No. 4,226,861. , mp 236-240 ° C.

Example 43 N-Methyl-3- [3- (aminocarbonyl) phenoxy] -1-azetidinecarboxamide The compound is prepared from 3- (3-azetidinylxy) benzamide and methyl isocyanate as described in Example 6 of U.S. Patent No. 4,226,861. , mp 238-240 ° C.

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38 DK 168422 B1

Example 44 N-Methyl-3- [4- (aminocarbonyl) phenoxy] -1-azetidinecarboxamide The compound is prepared from 4- (3-azetidinyl-oxy) benzamide and methyl isocyanate as described in Example 57 in U.S. Patent No. 4,226,861. , mp 208-210 ° C.

Example 45 '3- [3- (Trifluoromethyl) phenoxy] -1-azetidinecarboxamide A mixture of 30.6 g (0.141 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine and 42 g ( 0.321 mol) of nitro-urea (80%) in 500 ml of acetone is stirred for 5 days (5 days is not necessary but advantageous) at room temperature. The mixture is filtered and the filtrate is evaporated in vacuo. The residue is partitioned between 150 ml of water and 100 ml of ethyl acetate and the layers are separated. The aqueous layer is washed with 100 ml of ethyl acetate. The ethyl acetate layers are washed with 75 ml of 5% aqueous sodium hydroxide solution followed by 75 ml of water, dried over sodium sulfate and evaporated in vacuo. The residual oil is crystallized from ethyl alcohol / ethyl acetate to give 22 g (60%) of mainly the title compound. Twice recrystallization from ethyl alcohol gives 9.9 g of white crystalline solid, mp 151-152.5 ° C.

Calcd. For C 18 H 18 F 3 N 2 ® 2: C 50.77, H 4.26, N 10.76.

Found: C, 50.90, 4 · 4.24, N, 10.71.

Example 46 N-Ethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide

To a stirred and cooled (15-20 °) solution of 0.024 mol of 3- [3- (trifluoromethyl) phenoxy] azetidine in 50 ml of dry benzene is added 1.99 g (0.028 mol) of ethyl isocyanate. The reaction mixture is stirred at room temperature overnight and diluted with 50 ml of methylene chloride. The solution is washed with 5% sodium hydroxide (2 x 50 ml), 50 ml water,

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25 ml of saturated sodium chloride, dried over sodium hydroxide and evaporated in vacuo. The residue of 9.6 g is twice recrystallized from ethyl acetate / isopropyl ether to give 5.4 g of white solid, mp 125-126 ° C.

Analysis: Calculated for C 13 H 5 F 3 N 2 ® 2: C 54.16, H 5.24, N 9.72.

Found: C, 54.24; H, 5.23; N, 9.74.

Example 47 N- (1-Methylethyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

To a stirred and cooled (10-20 ° C) solution of 9.0 g (0.042 mol) of 3- [3-trifluoromethyl) phenoxy] acetidine in 100 ml of dry methylene chloride is added 4.1 g (0.048 mol) of isopropyl isocyanate. . The reaction mixture is stirred at room temperature for 2 hours and diluted with 100 ml of methylene chloride. The solution is washed with 2 x 40 ml of 5% sodium hydroxide, 50 ml of water, 50 ml of saturated sodium chloride, dried (sodium sulfate) and evaporated in vacuo. The residue 20 is crystallized from ethyl acetate to give 7.6 g (60.6%). Recrystallization from ethyl acetate gives 5.0 g clear white needles, mp 150-151.5 ° C.

Analysis: Calculated for C 14 H 7 F 3 N 2 O 2: C 55.62, H 5.68, N 9.27.

Found: C, 55.77; H, 5.68; N, 9.22.

Example 48 N-Propyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide To a stirred and cooled (10-15 ° C) solution of 0.027 mol of 3- [3- (trifluoromethyl) phenoxy] azetidine 4.0 g (0.047 mol) of n-propyl isocyanate are dropped into 100 ml of dry benzene. The reaction mixture is stirred at room temperature for 30 minutes. The benzene is washed with 50 ml of dilute 35 sodium bicarbonate, 25 ml of water, 25 ml of saturated sodium chloride and dried (sodium sulfate). The volume of the solution

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B1 is induced to 50 ml and 30 ml of petroleum ether is added to give 6.5 g (81%) of product. Recrystallization from isopropyl ether / isopropyl alcohol gives 6.0 g of small white needles, mp 115-117 ° C.

Analysis: Calculated for C 14 H 17 F 3 N 2 O 2: C 55.63, H 5.67, N 9.27.

Found: C 55.65, H 5.68, N 9.25.

Example 49 N-Butyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide A solution of 18.9 g (0.05 mol) of crude 3- - [3- (trifluoromethyl) phenoxy] azetidine (contains a equimolar amount of diphenylmethane) in 100 ml of isopropyl ether is stirred under nitrogen while slowly adding 4.96 g (0.05 mole) of N-butyl isocyanate. The clear reaction solution becomes warm to the touch and after 20 minutes a white crystalline solid begins to precipitate. After stirring for 16 hours, the solid is removed by filtration, washed with fresh isopropyl ether and air dried to give 8 g of 20 pale beige crystals, mp 108-109 ° C.

Analysis: Calculated for C 15 H 19 F 3 N 2 O 2: C 56.95, H 6.05, N 8.86.

Found: C 56.78, H 6.06, N 8.83.

Example 50 N-Ethyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide A solution of 6.5 g (0.03 mol) of crude 3- [4- (trifluoromethyl) phenoxy] azetidine in 50 ml of isopropyl ether stirred under nitrogen blanket while dropping 2.85 g (0.04 mole) of ethyl isocyanate. After stirring for 2 hours at ambient temperature, a solid begins to precipitate and after 4 hours the solid is collected by filtration to give 3.7 g of beige colored product, mp 94-96 ° C. Reprocessing of the filtrate gives only traces of γ-35 additional product. The product is recrystallized from isopropyl ether / hexane (treated with charcoal) to give

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41 2. 16 g (30%) of product, mp 109-110 ° C.

Analysis: Calculated for C 13 H 15 F 3 N 2 O 2: C 54.17, H 5.25, H 9.72.

Found: C 54.40, H 5.33, H 9.89.

5

Example 51 N-Butyl-3- [4- (trifluoromethyl) phenoxy-1-azetidinecarboxamide A solution of 6.5 g (0.03 mol) of crude 3- [4- (trifluoromethylphenoxy] azetidine in 50 ml of isopropyl ether The reaction is lightly exothermic and after 30 minutes a solid is separated, the solid is collected by filtration after 3 hours to give 3.85 g. crystalline product, mp 135-136 ° C.

After 24 hours another portion of crystals of 1.5 g, m.p. 132-134 ° C is obtained. The two fractions are combined and recrystallized from cyclohexane to give 3.6 g of product (38%), mp 136-137 ° C.

Analysis: Calculated for c15 H19 F3 N2 ° 2: C 56.96, H 6.05, N 8.86.

Found: C 57.12, H 6.13, N 8.93.

Example 52 N-Propyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide

A solution of 8.7 g (0.04 mole) of crude 3- [4- (trifluoromethyl) phenoxy] azetidine in 75 ml of isopropyl ether is stirred under nitrogen blanket while 4.3 g (0.05 mole) of n- propylisocyanate. After stirring for 2 hours, only traces of crystalline precipitate form in the reaction mixture, and after stirring for 18 hours, filtration yields only 1.1 g of product, mp 112-114 ° C. The filtrate is evaporated in vacuo to give a dark amber residue. After 3 days, only 1.3 g of additional crude product from isopropyl ether / hexane can be obtained. All the reaction products are dissolved in chloroform and chromatographed

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on a silica gel column of 200 g. Chloroform elution gives a reddish fraction which is discarded. The elution is changed to 2% ethyl acetate / chloroform, then to 4% ethyl acetate and finally to 2% methanol / chloroform.

5 All the fractions are combined and evaporated to give 4.1 g of white solid. Recrystallization from cyclohexane gives 2.86 g (23.6%) of fine white crystalline product, mp 119-120 ° C.

Analysis: Calculated for C, H-F-N-O: C, 55.63; H, 5.67; N, 9.27.

Found: C, 55.50; H, 5.77; N, 9.19. -

Example 53 3 - [4 - (Trifluoromethyl) phenoxy] -1-azetidine carboxamide 15

A solution of 9.6 g (0.025 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine 56.66% (containing diphenylmethane) in 50 ml of acetone is treated with 4.22 g (0.045 mole) of nine nitrogen. and 5 ml of water. The mixture is heated on a hot plate until a clear solution is obtained, and then allowed to cool to ambient temperature over the next 4 hours. The reaction mixture is diluted with 200 ml of ice water and an oil is separated (diphenylmethane) which is dissolved in 30/60 petroleum ether and separated. Upon standing, a fine white precipitate is formed in the aqueous solution. Filtration gives 3.6 g of fine white crystals, mp 176-178 ° C. After drying under 0.5 mm Hg vacuum at 80 ° C, the weight of the product is reduced to 3.1 g (47.7%), mp 178-179 ° C.

Analysis: Calculated for: C, 50.74; H, 4.26; N, 10.77.

Found: C, 50.72; H, 4.24; N, 10.72.

35

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43 DK 168422 B1

Example 54 N- (1-Methylethyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

A stirred slurry of 6.2 g (0.02 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate in 60 ml of tetrahydrofuran is treated with 1.8 g (0.022 mol) of 1-methylethyl isocyanate , and after 0.5 hour, 5 ml of triethylamine is added.

A clear yellow solution is obtained, which is stirred for 18 hours and then treated with 10 ml of water to give 5.3 g (87.7%) of 10 pale yellow crystals, mp 151-152 ° C.

Analysis; Calcd for C 14 H 17 F 3 N 2 O 2: C 55.63, H 5.67, N 9.27.

found; C, 55.80; H, 5.71; N, 9.24.

Example 55 N- (1,1-Dimethylethyl) -3- [4- (trifluoromethyl) phenoxy] -1 - azetidinecarboxamide

A stirred slurry of 6.2 g (0.02 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate in 60 ml of tetrahydrofuran is treated with 2 g (0.022 mol) of 1,1-dimethylethyl isocyanate and after 0.5 hour 5 ml of triethylamine is added. The reaction quickly becomes a pale yellow solution, which is stirred for 18 hours and then treated with 10 ml of water. After 20 minutes, the tetrahydrofuran portion is separated, dried over magnesium sulfate and evaporated on a rotary evaporator. The solid residue is recrystallized from isopropyl ether to give 5 g (79.0%) of fine white crystals, mp 145-146 ° C.

Analysis; Calcd. For c15 HigF3 N2 ° 2: 30 C 56.96, H 6.05, N 8.86.

Found: C 56.97, H 6.15, N 8.86.

35 44 DK 168422 B1

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Example 56 N- (2-Methylpropyl) -3 "[3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide

A stirred solution of 3.6 g (0.022 mol) of 1,1'-5-carbonyldiimidazole in 100 ml of methylene chloride under nitrogen is treated with 1.6 g (0.022 mol) of 2-methylpropylamine (added via syringe and needle through a wall placed in one neck of the reaction flask). After stirring for one hour, 6.2 g (0.02 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate are added at one time followed by 5 minutes of 5 ml of triethylamine and stirring is continued for 18 hours. The reaction mixture is washed with 2 x 25 ml of water, dried over magnesium sulfate and evaporated in vacuo to give 13 g of crude solid residue. Recrystallization from ethanol / water gives 5.9 g of product with a pink tone. Another recrystallization from cyclohexane gives 4.8 g of fine white crystals, mp 124-125 ° C. Reprocessing of the filtrates gives 1.2 g of additional beige colored crystals. Overall product yield is 75.6% of the theoretical.

Analysis: Calculated for: C 56.96, H 6.05, N 8.86.

Found: C 57.01, H 6.11, N 8.88.

Example 57 N- (1,1r> Dimethylethyl) -3- [3- (trifluoromethyl) phenoxy] -1-a-zetidine carboxamide

A stirred slurry of 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate in 60 ml of tetrahydrofuran is treated with 2 g (0.02 mol) of 1,1-dimethylethyl -isocyanate followed over 30 minutes by 5 ml of triethylamine. The clear solution which is formed is stirred for 18 hours. The reaction mixture is treated with 10 ml of water and after 20 minutes the tetrahydrofuran portion is separated, dried over magnesium sulfate and evaporated on a rotary evaporator. The solid residue is recrystallized

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451 from ethanol / water to give 5f8 g (91.7%) of fine white crystals, mp 105-107 ° C.

Analysis: Calculated for c15 H19 F3 N2 ° 2: C 56.96, H 6.05, N 8.86.

Found: C, 56.95; H, 6.14; N, 8.92.

Example 58 N- (2-Methylpropyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide A stirred solution of 3.6 g (0.022 mol) of 1,1-carbonyldiimidazole in 100 ml of methylene chloride under nitrogen is treated with 1.6 g (0.022 mole) of 2-methylpropylamine (added via a syringe and cannula through a wall placed in one neck of the reaction flask). After stirring for one hour, 6.2 g (0.02 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate are added at one time followed by 5 minutes of 5 ml of triethylamine and stirring is continued for 1 hour. 18 hours. The reaction mixture is washed with 2 x 25 ml of water, dried over magnesium sulfate and evaporated in vacuo.

The solid residue is recrystallized from ethanol / water to give 5.4 g (85.4%) of pale yellow crystals.

Analysis: Calculated for C15 H18 F3 N2 O2: C 56.96, H 6.05, N 8.86.

Found: C 57.02, H 6.08, N 8.82.

25

Example 59 3- (3-Chlorophenoxy) -1-azetidinecarboxanide

A solution of 5.4 g (0.017 mol) of 1-chlorocarbonyl-3- (3-chlorophenoxy) azetidine in 20 ml of tetrahydrofuran is treated with 3 ml of ammonium hydroxide and stirred for one hour. The reaction mixture is evaporated in vacuo to 4 g of wet solid which is recrystallized after drying from benzene to give 1.5 g of white crystalline powder, mp 163-164.5 ° C. The yield calculated from the 1- (2-phenyl-35-ethyl) azetidine compound is 38.9%.

46 DK 168422 B1

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Analysis: Calculated for C 10 H 11 ClN 2 O 2 · C 52.991 H 4.89, N 12.36.

Found: C, 52.99; H, 4.91; N, 12.32.

Example 60 3- (3-Fluorophenoxy) -N-methyl-1-azetidine carboxamide

A stirred mixture of 5.4 g (0.02 mol) of 3- (3-fluorophenoxy) azetidine oxalate and 1.7 g (0.022 mol) of methyl isocyanate in 20 ml of tetrahydrofuran is treated with 5 ml of triethylamine, then the stirring continue for 3 hours.

The reaction is diluted with water and the obtained fine crystalline precipitate is collected by filtration and dried at 60 ° C under vacuum to give 3 g (66.9%) of product, mp 155-156 ° C.

Analysis: Calculated for C11 H13 FN2 O2: C, 58.92, H. 5.84, N, 12.49.

Found: C, 58.93; H, 5.91; N, 12.26.

Example 61 3- (3-Fluorophenoxy) -N-methyl-1-azetidine carboxamide

To a stirred slurry of 0.38 g (0.02 mol) of 60% sodium hydride. As a mineral oil suspension in 10 ml of dry dimethylformamide, 1.12 g (0.01 mole) of 3-fluorophenol in 20 ml of dimethylformamide is added dropwise. After one hour, the mixture is heated at 90 ° C for 20 minutes, then 2.1 g (0.01 mole) of N-methyl-3 - [- (methanesulfonyl) oxy] -1-azetidinecarboxamide is added as a solid. Then, the reaction mixture is stirred at 90 ° C for 8 hours. The reaction mixture is cooled by the addition of ice water and then further diluted to 200 ml with water and extracted with 3 x 50 ml of methylene chloride. Less than 1 g of oil is obtained after evaporation of the extracts. Extraction with 4 x 50 ml benzene gives only traces of product. Mass spectrum (CI) shows the expected p + 1 at 225 m / e. The product solidifies on standing and recrystallized from methanol / water, yielding 650 mg (29.0% flag-like silvery crystals, mp 165-158 ° C).

Analysis: Calculated for C11 H13 FN2 O2: C 58.92, H 5.84, N 12.49.

5 Pounds: C 58.93, H 5.91, N 12.42.

Anti-anxiety test. The sample screening method used to show positive anti-anxiety results is a modification of the Vogel Conflict Test, which is based on the shock-suppressed drinking behavior of rats, described by J.R. Vogel et al. in Psychopharmacology 21, __ l-7 (1971). The method used is as follows: Sample ference and control preparations are administered intraperitoneally in physiological saline solution, 0.5% aqueous methyl cellulose or otherwise depending on a solubility at such a concentration that the volume administered is 5 ml / kg. The initial screening dose of the sample is usually 100 mg / kg and the reference preparation ("Diazepam") is 5 mg / kg.

Prior to administration, rats are maintained at 2 pr. cages and evacuates water for 48 hours and is then randomly assigned to treatment groups of 5. Food is available ad libitum.

30 minutes after administration, each rat is placed individually in a plexiglass cage measuring 18 cm in width, 13 cm in height and 29.5 cm in length and provided with a stainless steel grating floor 25. The cage is covered with a plastic lid with holes to facilitate the insertion of a water bottle (30 ml plastic center in sealing glass) with rubber stopper and metal drinking pipe. A "Drinkometer" circuit (Omniteck Electronics, Inc., 3000 Cortona Road, Columbus, Ohio 43204) is connected to the beverage tube and the appliance's grille floor so that the rat closes a circuit every time it licks the tube. The method involves letting the rat find the drinking tube and licking 20 times (as shown on the "Drinkometer" digital reading) before starting the experiment. Rats that do not meet this criterion are discarded. A three-minute trial begins with a shock of 0.25 milliamps at the 20th.

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48 DK 168422 B1 candy. Rats that continue to drink are subjected to a shock for each subsequent 20th candy. The total number of shocks during the trial round is noted as follows: 5 total number of sweets. , _. . . ,, -2q- + 1 = total number of shocks

Statistical analysis is performed using Dunn's multiple comparison test described by O.J. Dunn, Technometrics 6 (3), 241-252 (1964). The average number of shocks experienced by the control group is compared to those experienced by each preparation group. Significance is set at P <0.1. The higher the total number of shocks compared to the control group, the more active the connection. Active compounds can then be tested similarly at reduced doses. For example, a preferred compound is the compound of Example 16, i. N-cyclopropyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, active at a dose as low as 10 mg / kg, with the total number of shocks obtained calculated in comparison with the control group being 14 / 4.6 (P = 0.03) compared with ca. 12-15/4 for "Diazepam". The test results obtained are shown in the table below.

25 30 35 DK 168422 B1 49

Table

Dose IP Treated / Control

Ex. No. mg / kg Shock 5 - 7 50 (PO) 2.3 / 2.0 8 100 (PO) 7.8 / 1.0 56.2 (PO) 3.2 / 1.0 10 9 100 (PO) 1/6 / 1.8 10 56.2 (PO) 8.4 / 1.1 * 31.6 (PO) 6.0 / 1.2 15 11 200 (PO) 1.75 / 1.25 12 56.2 10.2 / 2.6 31.5 6.8 / 5.4 20 13 56.2 10.2 / 2.6 31.6 18.8 / 2.2 14 31.6 18.0 / 4.8 25 17.8 14.6 / 4.8 15 16 17.8 13.0 / 3.8 30 10.0 14.2 / 4.6 17 18 56.2 10.5 / 2.4 35 31.6 15 , 0 / 2.4 17.8 4.6 / 2.4 20 10.0 6.6 / 2.4 40 22 31 56.2 12.4 / 4.2 37 100 (PO) 2.2 / 1 , 2 45 38 39 50 40 45 56.2 (PO) 3.2 / 1.2 31.6 (PO) 2.0 / 1.2 55 * Average of two or more values 50 DK 168422 B1

Pharmaceuticals for the treatment of anxiety disorders.

The active compounds for the treatment of anxiety in humans and mammals are administered in the form of a pharmaceutical composition containing at least one of the compounds of Formula 5 in combination with a pharmaceutical carrier or excipient. Thus, the compounds are present in a therapeutic composition suitable for oral, rectal, parenteral, subcutaneous, intramuscular, intraperitoneal or intravenous administration. Thus, e.g. the oral preparations are in the form of elixirs, capsules, tablets or coated tablets containing carriers commonly used in the field of pharmacology. Suitable tablet excipients include lactose, potato and corn starch, talc, gelatin, stearic and silicic acid, magnesium stearate and polyvinylpyrrolidone.

For parenteral administration, carriers may comprise a sterile, parenterally acceptable fluid, e.g. water or arachis oil contained in ampoules.

In rectal administration preparations, the carrier may comprise a suppository base, e.g. cocoa butter or glyceride.

The compositions can advantageously be prepared as dosage units, each unit being adapted to provide a fixed dose of active substances. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage forms. It is only necessary that the active ingredient constitute an effective amount, i.e., that a suitably effective dose will be in accordance with the dosage form used. The exact individual dosages as well as the daily dosage are, of course, determined in accordance with standard medical principles under the supervision of a physician or veterinarian.

An effective daily dosage of compounds of formula I as anti-anxiety agents is estimated to be approx. 1-10 mg / kg / day body weight based on data obtained from animal studies.

35

Claims (8)

Use of a 3-aryloxyazetidine carboxamide or carbothioamide of the formula Rv 25 - C-N 2 - ° Ar Ar R8 ^ R3 wherein Ar is pyridyl (at any position), halogen-substituted pyridyl, phenyl or phenyl substituted with 1 or 2 substituents selected from chloro, bromo, iodo, fluoro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, nitro, aminocarbonyl and trifluoromethyl, Z is oxygen or sulfur, R 1 and R 2 each is hydrogen, C (1-8) -alkyl, aryl, allyl, C (1-8) -alkyl-substituted allyl, propargyl, cycloalkyl, C (1-8) -alkyl-cycloalkyl, cycloalkyl -C (1-8) -alkyl, aryl-C (1-8) -alkyl and di-C (1-8) -alkylamino-C (1-8) -alkyl, or R 1 and R 2 together with the neighboring nitrogen atom means imidazolyl and R 3 is hydrogen, C 1 -C 8 alkyl or aryl, where aryl means phenyl or phenyl substituted with halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, nitro, cyano , trifluoromethyl, carbomethoxy or carboethoxy, and aryl-C (1-8) alkyl means an aryl group as defined above bonded over a straight or branched chain C (1-8) alkyl group for the amide nitrogen atom, or a pharmaceutically acceptable acid addition salt thereof when R 1 and / or R 2 have a salt-forming basic amino component, or when Ar is pyridyl, to prepare a pharmaceutical composition for the treatment of anxiety states. Use according to claim 1 of a compound of formula I, wherein Ar is trifluoromethyl-substituted phenyl, 2-pyridinyl or aminocarbonyl-substituted phenyl. Use according to claim 1 or 2 of a compound of formula I, wherein R 3 is hydrogen or C 1-8 alkyl. Use according to claim 1, 2 or 3 of a compound of formula I, wherein at least one of the substituents R 2 and R 2 is hydrogen. DK 168422 B1 52 Use according to claim 1 of a compound which is N-methyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarbothioamide, N- (2,6-dimethylphenyl) -3- [3- (trifluoromethyl) ) phenoxy] -1-azetidine carbothioamide, N- (phenylmethyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, N- (2,6-dichlorophenyl) -3- [3- ( trifluoromethyl) phenoxy] -1-azeti-dincarbothioamid, N- [3- (diethylamino) propyl] -3- [3- (trifluoromethyl) phenoxy] -1- -azetidine carbothioamide or a pharmaceutically acceptable acid addition salt thereof, N- [3- (dimethylamino) propyl] -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarbothioamide or a pharmaceutically acceptable acid addition salt thereof, N- (2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, N-cyclopropyl-3- [ 3-trifluoromethyl) phenoxy] -1-azetidincarbox-amide, N- [3- (diethylamino) propyl] -3- [3- (trifluoromethyl) phenoxy] -1- -azetidine carboxamide or a pharmaceutically acceptable acid addition salt thereof, N-2- (propenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine-carboxamide, N- (cyclopropylmethyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, N, N-diethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N, N -dimethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N- (2-propynyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, N- -cyclohexyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidincarbox-amide, N-cyclopropyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, DK 168422 B1 53 N- (cyclopropylmethyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N - [3- (diethylamino) propyl] -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carbothioamide or a pharmaceutically acceptable acid addition salt thereof, N- [3- (diethylamino) propyl] -3- [4- ( trifluoromethyl) phenoxy] -1 - azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof, N- (2-propynyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine-carboxamide, N- (2-methyl -2-propenyl) -3- [4- (trifluoromethyl) phenyl] -1-azetidinecarboxamide, N- (2-methyl-2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide . N- (3-methyl-2-butenyl) -3- (4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N- (3-methyl-2-butenyl) -3- [3- (trifluoromethyl) phenoxy ] -1 - azetidinecarboxamide, (E) -N- (2-butenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, (E) -N- (2-butenyl) - 3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, N-phenyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N-phenyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, trans-N, 2-dimethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, trans-2-methyl-3- [3- (trifluoromethyl) phenoxy ] -1-azetidinecarboxamide, trans-2-methyl-N- (2-propenyl) -3- [3- (trifluoromethyl) phenoxy-30-azetidinecarboxamide, 3- (3-chlorophenoxy) -N-methyl-1- azetidinecarboxamide, 3- (3-chlorophenoxy) -N- (2-propenyl) -1-azetidinecarboxamide, N-methyl-3- (2-pyridinyloxy) -1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof, N- (2-propenyl) -3- (2-pyridinyloxy) -1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof, DK-168422 B1 54 3- (2-pyridinyloxy) -1-azetidinecarboxamide or a pharmaceutically acceptable acid addition salt thereof, - [3- [4- (trifluoromethyl) phenoxy] -1-azetidinylcarbonyl] -1H-imidazole or a pharmaceutically acceptable acid addition salt thereof, N-methyl-3-phenoxy-1-azetidinecarboxamide, N-methyl-3- [4 - (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N-methyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N-methyl-3 - [2- (trifluoromethyl) phenoxy] -1 -azetidincarboxamid, N-methyl-3- [2- (aminocarbonyl) phenoxy] -1-azetidinecarboxamide, N-methyl-3- [3- (aminocarbonyl) phenoxy] -1-azetidinecarboxamide, N-methyl-3 - [4- (aminocarbonyl) ) phenoxy] -1-azetidinecarboxamide, 3- [3- (trifluoromethyl) phenoxy) -1-azetidinecarboxamide, N-ethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N- (1-methylethyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, N-propyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N-butyl-3 - [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N-ethyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N-butyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N-propyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, N- (1-methylethyl 1) - 3- [4- (Trifluoromethyl) phenoxy] -1-azetidine carboxamide, N- (1,1-dimethylethyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, N- ( 2-Methylpropyl 1) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, N- (1,1-dimethylethyl) -3- [3- (trifluoromethyl) phenoxy-1-azetidine carboxamide . N- (2-methylpropyl 1) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide, 3- (3-chlorophenoxy) -1-azetidinecarboxamide or 3- (3-fluorophenoxy) N-methyl-l-azetidinecarboxamide. DK 168422 B1 55 Use of a compound of formula I according to claim 1 for the preparation of a pharmaceutical composition for the treatment of muscle tension and / or muscle plasticity. Use of a compound of formula I according to claim 1, wherein R 1 and / or R 2 are allyl, C 1 -C 8 -alkyl substituted allyl, propargyl or cycloalkyl, for the preparation of a pharmaceutical composition for treating muscle tension and / or muscle spasticity. Use of a compound of formula I according to claim 1 for the preparation of a pharmaceutical composition for the treatment of anxiety.