GB2285977A - Antipsychotic and antidyskinetic azetidines - Google Patents

Abstract

Novel azetidines of the formula: <IMAGE> wherein R<1> and R<2> are H, F, Cl, Br, alkyl, alkoxy or cyano; R<3> is cycloalkylalkyl or substituted arylalkyl, optionally substituted with H, Cl, F, Br, alkyl or alkoxy; n=0-2; m=0-2; and X is CO or CH(OH), and salts thereof are useful as antipsychotic and antidyskinetic agents.

Description

TITLE NOVEL AZETIDINE ANTIPSYCHOTIC DRUGS FIELD OF THE INVENTION The present invention relates to novel azetidine compounds, pharmaceutical compositions thereof, and methods of using same in the treatment of physiological or drug-induced psychosis and as antidyskinetic agents.

BACKGROUND OF THE INVENTION In U.S. Patent No. 5,077,288, Lavielle et al.

disclose 4-fluorobenzoic compounds of Formula (A) as serotonin 5HT1, 5HT2 and a 1-adrenergic antagonists, useful for the treatment of hypertension and anxiety.

Moreover, these compounds are disclosed to have antihistaminic and anti-allergic properties.

In U.S. Patent No. 5,130,309, Shanklin et al.

disclose methods of using compounds of the formula

which were useful for treating cardiac arrythmias and convulsions in warm-blooded animals.

The compounds of the present invent Ion have the advantage over compounds of the prior art in that they have selectivity for the sigma receptor.

Traditionally, antipsychotic agents have been potent dopamine receptor antagonists. For example, phenothiazines such as chlorpromazine and most butyrophenones such as haloperidol are potent dopamine receptor antagonists. These dopamine receptor antagonists are associated with a high incidence of side effects, particularly Parkinson-like motor effects or extra-pyramidal side-effects (EPS), and dyskinesias including tardive dyskinesias at high doses. Many of these side effects are not reversible even after the dopamine receptor antagonist agent is discontinued.

Sigma receptors have been implicated in the etiology of central nervous system (CNS) diseases such as schizophrenia, dyskinesia, anxiety, depression and drug addiction (S.W. Tam, P.J. Gilligan, Current Opinions on Investlaational Drugs, 2, 295-303 (1993)).

Some benzomorphans (e.g. N-allylnormetazocine (SKF 10047) and pentazocine) were reported to induce psychotic effects in man. Studies in monkeys showed (+)-isomers to be more potent than their (-)counterparts in inducing psychotomimetic-like effects.

The (+)-benzomorphans bind with high affinity to a non-opioid, non-dopaminergic site, designated the sigma receptor. This sigma receptor has also been distinguished from the phencyclidine receptor.

Electrophysiology experiments support a role for sigma receptors in modulating dopamine neuronal activities.

Some sigma receptor ligands have been reported to active in animal models for detecting potential antipsychotic drugs (P.J. Gilligan et al., J. Med.

Chem., 35, 4344-4361 (1992); G.A. Cain et al., UzS.

Patent No. 5,109,002 (issued April 28, 1992)). The very low potential for sigma ligands to cause extrapyramidal side effects is suggested by the relative low density of sigma receptors in human striatum than in the cortex and nucleus accumbens.

Sigma receptor ligands have been reported to inhibit the catalepsy induced in the rat by the neuroleptic, haloperidol. Finally, a weak but selective sigma ligand, rimcazole, caused a partial reduction in schizophrenic symptomatology in a limited open-label clinical trial. Sigma receptor ligands have also been reported to block cocaine and D-amphetamine-induced locomotor activity in animals.

Therefore, potent sigma ligands may be antipsychotic drugs, which will not induce the extrapyramidal symptoms caused by current antipsychotic agents. They may also be useful for the treatment of dyskinesia or drug addiction. The compounds of the present invention are sigma receptor ligands, which may be useful for the treatment of physiological or drug-induced psychosis, dyskinesia or drug addiction.

SUMMARY OF THE INVENTION The present invention provides novel azetidine compounds useful for the treatment of physiological or drug-induced psychosis, dyskinesia or drug addiction, which have Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R1, R2 independently are hydrogen, F, C1, Br, lower alkyl, lower alkoxy, cyano; R3 is cycloalkylalkyl or substituted arylalkyl, optionally substituted with one of the following: hydrogen, C1, F, Br, alkyl of 1 to 2 carbons, or alkoxy of 1 to 2 carbons; n = 1-2; m = 0-2; X = C(=O), CH(OH); wherein cycloalkylalkyl consists of 4 to 6 carbons; and aryl may be a phenyl or naphthyl ring.

DETAILED DESCRIPTION OF THE INVENTION Compounds of Formula (I), where n = 1 or 2, may be prepared according to the procedures outlined in Scheme 1. A compound of Formula (II) is treated with a sulfonylating agent (preferably methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoro methanesulfonic anhydride) in the presence of a base, such as a trialkylamine (preferably triethylamine), an alkali metal hydride (preferably sodium hydride), an aromatic amine (preferably pyridine), or an alkali metal carbonate or alkoxide. Such a sulfonylation is performed in an inert solvent such as a halocarbon of 1 to 6 carbons (preferably dichloromethane), ethereal solvents (such as diethylether or tetrahydrofuran), aromatic or non-aromatic hydrocarbons of 6 to 10 carbons, or lower alkanenitriles (preferably acetonitrile). Compounds of Formula (II) are synthesized by literature procedures (N.H. Cromwell, B. Phillips, Chem. Rev., 1979, 79, 337-346; R.H.

Higgins, Q.L. Eaton, L. Worth, M.V. Peterson, J.

Heterocyclic Chem. 1987, 24, 255-259; R.H. Higgins, M.R. Watson, W.J. Faircloth, Q.L. Eaton, H. Jenkins, J. Heterocvclic Chem. 1988, 25, 383-387; A.G.

Anderson, R. Lok, J Ora. Chem., 1972, 37, 3953-3955) A compound of Formula (III) (preferably where R4 is O2SCH3, O2SC6H4-CH3-p or O2SCF3) is reacted with a malonate ester (where R5 is preferably CH3 or C2Hs) and a base in an inert solvent to afford a compound of Formula (IV). Such bases include a trialkylamine, an alkali metal hydride (preferably sodium hydride), an aromatic amine (preferably pyridine), or an alkali metal carbonate or alkoxide. The choice of inert solvent must be compatible with the choice of base (see J. March, Advanced Organic Chemistry (New York:J.

Wiley and Sons, 1985) pp. 323-325, 412; H.O. House, Modern Synthetic Reactions (New York: W.A. Benjamin Inc., 1972, pp. 510-536)). Solvents include lower alkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons (preferably tetrahydrofuran or dioxane), dialkylformamides (preferably N,N-dimethylformamide), dialkylacetamides, (preferably N,N-dimethylacetamide), cyclic amides, (preferably N-methylpyrrolidinone), hydrocarbons of 5 to 10 carbons (preferably dimethyl sulfoxide) or aromatic hydrocarbons to 6 to 10 carbons. A diester of Formula (IV) is converted to a monoester of Formula (V) by treatment with an alkali metal hydroxide (preferably potassium hydroxide), or an alkaline earth metal hydroxide, in an inert solvent, followed by reaction with an inorganic acid, (preferably hydrochloric acid), or an organic acid in an inert solvent. Alternatively, compounds of Formula (V) may be treated with an alkali metal halide or cyanide (preferably sodium cyanide), in an inert solvent. Inert solvents include water, lower alkyl alcohols, lower alkanenitriles, etheral solvents, such as diethyl ether and tetrahydrofuran, lower dialkyl alkaneamides (preferably N,N-dimethylformamide), a dialkylsulfoxide (preferably dimethylsulfoxide) or any combination of these. Esters (V) may be converted to amides (VI) by treatment with a amine, HNR6R7, with or without a trialkylaluminum compound (such as trimethylaluminum), in an inert solvent, as taught by the literature (S. Nahm, S.M. Weinreb, Tetrahedron Lett., 22, 3815-6 (1981) or T. Imamoto et al., J.

Amer. Chem. Soc., 111, 4392-98 (1989)). R6 and R7 may independently be lower alkyl groups (preferably CH3) or lower alkoxy groups (preferably OCH3) or together may form with the nitrogen a heterocyclic ring such as pyrrolidine, piperidine or morpholine. An amide of Formula (VI) is reacted with an organometallic reagent of Formula (VII), sometimes in the presence of an inorganic salt as taught by the above Imamoto reference, in an inert solvent to generate a compound of Formula (I), where X = C(=O). Such organometallic reagents (VII) are defined such that M may be alkali metals (preferably lithium), or alkaline earth halides (preferably MgBr). Inorganic salts include transition metal halides, preferably CeCl3.

Scheme 1

OH OR4 sulfonylating J ) base, n1 base, ivent R3N fri (lI) (111) I CH2(Co2R5)29 1 ba&num;,soivent C02R5 CH 2(CO 2R5h k( ester cleavage R3N ester cleavage R3 (V) R3 (IV) HNR HNR6R7, (+1- trialkylalumlnum), solvent D1 CONR6R7 R1 RImM R1 R3Nfl (vll 3\$flXlRI%/ia salt1 solvent R2 (I) where X = C(=O) -luclng agent, icing agent, solvent R SX)ft R3 R2 (I) where X = CHOH Inert solvents include ethereal solvents (such as diethyl ether and tetrahydrofuran), or aromatic or non-aromatic hydrocarbons of 6 to 10 carbon atoms.

Compounds of Formula (I), where X = C(=O), may be reduced to compounds of Formula (I), where X = CH(OH), by treatment with a reducing agent in an inert solvent. Such reducing agents include but are not limited to, alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal borohydrides (preferably lithium borohydride), alkali metal trialkoxyaluminum hydrides (such as lithium tri-tbutoxyaluminum hydride), dialkylaluminum hydrides (such as di-isobutylaluminum hydride), borane, dialkylboranes (such as di-isoamyl borane), alkali metal trialkylboron hydrides (such as lithium triethylboron hydride). Inert solvents include lower alkyl alcohols of 1 to 6 carbons, ethereal solvents (such as diethyl ether or tetrahydrofuran), aromatic or non-aromatic hydrocarbons of 6 to 10 carbons.

Reaction temperatures for the reduction range from about -780 to 2000C, preferably about 250 to 1200C.

The choice of reducing agent and solvent is known to those skilled in the art as taught in the above cited March reference (pp. 1093-1110).

Compounds of Formula (I), where n = 0, may be prepared from compounds (V), where n = 0, according to the procedures outlines above. Intermediates (V), where n = 0, are prepared as described in the literature (J.Shanklin, M.R. Hellberg, U.S. Patent No. 5,130,309, 1992; Higgins, 1988; and Andersen, 1972; all cited above).

Compounds of Formula (I) may also be prepared according the processes outlined in Scheme 2.

Intermediates of Formula (VIII) (where Z = -OCH2CH2O-, (OR8)2, where R8 is lower alkyl) are treated with compounds of the Formula R3L in the presence of a base in an inert solvent. L is bromine, chlorine, iodine, O2SCH3, 02SC6H4-CH3-p or O2SCF3. Such bases include a tertiary amine (preferably triethylamine, 1,4 diazabicyclo[2.2.2]-octane, 1,8-diazabicyclo[5.4.0]- undec-7-ene), an alkali metal hydride (preferably sodium hydride), an aromatic amine (preferably pyridine), or an alkali metal carbonate or alkoxide.

Scheme 2

R1 t) R34 Z rl 1, 2) br, R1 2) c fvmt IIJx (VIII) (I) where X = C(=O) Solvents include lower alkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons, cyclic ethers of 4 to 10 carbons (preferably tetrahydrofuran or dioxane), dialkylformamides (preferably N,Ndimethylformamide), dialkylacetamides, (preferably N,N-dimethylacetamide), cyclic amides, (preferably Nmethylpyrrolidinone), hydrocarbons of 5 to 10 carbons or aromatic hydrocarbons to 6 to 10 carbons. The choice of base and solvent is known to those skilled in the art as taught in the above cited March reference (pp. 298-322, 364-380). Reaction temperatures range from about -78 to 2000C, preferably about 200 to 1200C. Deprotection by treatment with aqueous acid (preferably hydrochloric or sulfuric acids) provides compounds of Formula (I), where X = C(=O). Intermediates of Formula (VIII) may be prepared by those skilled in the art, using a combination of literature procedures (Lavielle et al., U.S. Patent No. 5,077,288 (1991); P.A.J. Janssen, et al., J. Med. Pharm. Chem., 1, 281-297 (1959); W.D.

Langley, Org. Syn. Coll. Vol. 1, 127 (1944); and the above cited House reference, pp. 510-536).

Compounds of Formula (I) may also be prepared according to the methods outlined in Scheme 3. A compound of Formula (IX),wherein Z is halogen, (preferably fluorine) [Formula (I), wherein R1 is 4-Z R2 is H, m = 0, X = C(=O)] is reacted with a compound MY [M is an alkali metal (preferably Na) and Y is a nucleophile selected from the group: alkoxide of 1 to 6 carbon atoms or cyanide] in an inert solvent at a reaction temperature of about 25-200 and preferably 100-1500C, to yield a compound of Formula (X) [Formula (I) wherein m = o, R1 = 4-Y, R2 = H and X = C(=O)].

The inert solvent may be the same as those defined in the second step of Scheme 1. Compounds of formula MY may be generated in situ from a compound of formula HY and a base chosen from the bases defined for the second step of Scheme 1.

Scheme 3

Z)Gk?t)onNR3 MY, soIv-iI Y > < NR3 (lx) (x) All above mentioned references are hereby incorporated by reference.

Experimental Section Analytical data were recorded for the compounds described below using the following general procedures. Infrared spectra were recorded on a Perkin-Elmer Model 1600 FT-IR spectrometer; absorbances are recorded in cm'l and intensities are denoted s (strong), m (moderate) and w (weak). Proton NMR spectra were recorded on a IBM-Bruker FT-NMR spectrometer (300 MHz); chemical shifts were recorded in ppm (s) from an internal tetramethylsilane standard in deuterochloroform or deuterodimethylsulfoxide and coupling constants (J) are reported in Hz. Chemiionization mass spectra (CI-MS) or high resolution mass spectra (CI-HRMS) were recorded on Finnegan MAT 8230 spectrometer or Hewlett Packard 5988A model spectrometer. Melting points (mp) were recorded on a Buchi Model 510 melting point apparatus and are uncorrected. Boiling points (bp) are uncorrected.

Reagents were purchased from commercial sources and, where necessary, purified prior to use according to the general procedures outlined by D. D. Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals, 3rd ed., (New York:Pergamon Press, 1988).

Chromatography was performed on silica gel using the solvent systems indicated below. For mixed solvent systems, the volume ratios are given. Parts and percentages are by weight unless otherwise specified.

Common abbreviations include DMSO (dimethylsulfoxide), mL (milliliter), THF (tetrahydrofuran), MeOH (methanol), MgSOq (magnesium sulfate), HCl (hydrochloric acid), CH2C12 (dichloromethane), and NaHCO3 (sodium bicarbonate).

Intermediate 1 Dimethyl 2- (1-benzyl-3-azetidinyl) -propane-1, 3-dioate Dimethyl malonate (14.0 mL, 122 mmol) was added to a magnetically stirred suspension of sodium hydride (60% dispersion in mineral oil, 5.33 g, 111 mmol, washed with hexanes) in anhydrous THF (200 mL) under a nitrogen atmosphere. After 15 min, 1-benzyl-3-methanesulfonyloxy azetidine (13.4 g, 55 mmol) was added in anhydrous THF (100 mL). The clear solution was then refluxed for 18 h. After being cooled to room temperature, it was poured into water (500 mL) and extracted three times with CHCl3. The combined extracts were filtered, dried over MgSO4, and evaporated under vacuum to give a light yellow oil. The oil was purified by column chromatography with 3% MeOH in CHCl3 (Rf 0.31) to give a pale yellow oil (12.3 g, 80% yield). 1H NMR (CDCl3) 6 2.95 (m, 2H), 3.05 (m, 1H), 3.45 (t, 2H, J=5 Hz), 3.6 (s, 2H), 3.7 (m, 1H), 3.75 (s, 6H), 7.25 (m,5H); CI-MS (NH3): 278 (M+H); CI-HRMS (NH3): Calcd for C15H19NO4: 278.1392 (M+H); Found: 278.1381.

Intermedlate 2 Methyl 2- (1-benzyl-3-azetidinyl) acetate A solution of dimethyl 2-(1-benzyl-3-azetidinyl) propane-1,3-dioate (8.58 g, 30.9 mmol), sodium cyanide (4.90 g, 100 mmol), and water (1.17 mL, 65 mmol) in DMSO (500 mL) was heated at 1100C for 6 h. After being cooled to room temperature, it was poured into a mixture of water (2 L) and a saturated NaHCO3 solution (50 mL) and extracted three times with CHCl3. The combined extracts were washed once with water, dried over MgSOq, filtered, and evaporated under vacuum to give a pale yellow oil (3.33 g, 49% yield). 1H NMR (CDC13) 6 2.6 (d, 2H, J=7 Hz), 2.8 (m, 1H), 2.9 (m, 2H), 3.45 (t, 2H, J=7 Hz), 3.6 (s, 2H), 3.65 (s, 3H), 7.2-7.4 (m, 5H); CI MS (NH3): 220 (M+H).

Intermediate 3 Dimethyl 2- (1-benzyl-3-azetidinyl) acetamide Dimethylamine (7.2 mL, 108 mmol) was added dropwise under a nitrogen atmosphere via a cooled (-78 C) addition funnel to cooled (-lO0C) solution of trimethylaluminum (2 M in toluene, 54 mL, 108 mmol) and anhydrous CH2Cl2 (150 mL) with mechanical stirring.

After 20 min, the cooling bath was removed and stirring was continued for 1 h. A solution of methyl 2-(1benzyl-3-azetidinyl)acetate (11.8 g, 54 mmol) in anhydrous CH2Cl2 (25 mL) was slowly added via syringe.

The reaction was then heated to reflux for 18 h. After being cooled to room temperature, it was cautiously quenched with an aqueous solution of HCl (0.67 N, 25 mL). After being stirred for 30 min, the aqueous mix was made basic with a saturated NaHCO3 solution and extracted three times with CH2Cl2. The combined extracts were washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to afford a tan oil (11.27 g, 89% yield). 1H NMR (CDC13) 6 2.65 (d, 2H, J=7 Hz), 2.85 (m, 3H), 2.9 (s, 3H), 3.0 (s, 3H), 3.5 (t, 2H, J=7 Hz), 3.6 (s, 2H), 7.2-7.3 (m, 5H); CI-MS (NH3): 233 (M+H); CI-HRMS (NH3): Calcd for C14H20N20: 233.1654 (M+H); Found: 233.1653.

Example 1 1- (4-Fluorophenyl) -2- ((1- (phenylmethyl) -3- azetidinyl))ethanone, hydrochloride salt Cerium trichloride heptahydrate (4.77 g, 19.4 mmol) was heated to 1400C at 0.3 torr for 2 h. A nitrogen atmosphere was introduced into the flask, and it was cooled in an ice bath. Anhydrous THF (75 mL) was added, the cooling bath was removed, and the suspension stirred for 20 h at room temperature. Dimethyl 2-(1-benzyl-3azetidinyl) acetamide (3.0 g, 12.9 mmol) was added in annydrous THF (15 mL) via syringe, and the reaction was magnetically stirred for 1 h. It was then cooled in an ice bath, and a solution of p-fluorophenyl magnesium bromide in diethyl ether (2 M, 9.7 mL, 19.4 mmol) was slowly added via syringe. After 75 min, the reaction was quenched with a 10% acetic acid solution (120 mL).

It was then made basic with a saturated NaHCO3 solution and extracted three times with CH2C12. The combined extracts were dried over MgSO4, filtered, and evaporated under vacuum to give a brown oil. The oil was purified by column chromatography (95/5/0.5 CH2Cl2/MeOH/NH4OH; Rf =0.4) to give a pale yellow oil (1.17 g, 32% yield).

1H NMR (CDC13) 6 2.9-3.0 (m, 3H), 3.3 (d, 2H, J=7 Hz), 3.55 (m, 2H), 3.6 (s, 2H), 7.1 (t, 2H, J=7 Hz), 7.2-7.35 (m, 5H), 7. 95 (m, 2H) The oil was dissolved in ethanol (15 mL) and a solution of HCl in ether (1 N, 6 mL) was added with mixing. The solvent was evaporated under vacuum yielding a tan solid which was recrystallized from isopropanol to give white plates (0.80 g, 60% yield).

mp 137-1380C; Anal. Calcd for C18H19ClFNO: C, 67.60; H, 5.99; Cl, 11.09; F, 5.94; N, 4.38. Found: C, 67.49; H, 5.93; Cl, 11.21; F, 5.92; N, 4.35.

Example 2 1- (4-Fluorophenyl) -2- (1- (4-fluorobenzyl) -3- azetidinyl) ethanone, hydrochloride salt Part A: A mixture of 1-fluorophenyl-2-(3- azetidinyl)ethanone, ethylene glycol hetal (0.5 g, 2.1 mmol), 4-fluorobenzyl chloride (0.25 mL, 2.1 mmol) and sodium carbonate (0.56 g, 5.3 mmol) in toluene (10 mL) was stirred at reflux temperature under a nitrogen atmosphere for 18 h. After being cooled to room temperature, the reaction mixture was poured onto water and extracted three times with chloroform. The combined organic layers were dried over MgSO4 and filtered.

Solvent was removed in vacuo to give an oil. Column chromatography (95/5/0.5: CH2Cl2/MeOH/NH4OH) afforded the ethylene glycol ketal of the free base of the title compound as an oil (236 mg, 32% yield): 1H NMR (CDC13) 6 7.45-7.35 (m, 2H),7.25-7.25 (m, 2H), 6.9-7.1 (m, 4H), 3.9-4.0 (m, 4H), 3.75-3.65 (m, 2H), 3.5 (s, 2H), 3.453.35 (m, 2H), 2.7-2.6 (m, 2H), 2.1 (d, 2H, J=7 Hz).

Part B: A mixture of the free base from Part A, a 2N HCl soultion (5 mL) and THF (5 mL) were stirred at reflux temperature for 40 min. Solvent was removed in vacuo to give an oily solid. Recrystallization from 2propanol gave the title product (69 mg, 38% yield): mp 161-163 OC; 1H NMR (DMSO-d6) 6 8.1-7.9 (m, 2H), 7.7-7.5 (m, 2H), 7.4 (t, 2H, J=8 Hz), 7.2 (t, 2H, J=8 Hz), 4.44.3 (m, 1H), 4.3-4.1 (m, 1H), 4.1-4.0 (m, 1H), 3.95-3.85 (m, 1H), 3.8-3.7 (m, 1H), 3.65 (d, 1H, J=7 Hz), 3.5 (d, 1H, J=7 Hz), 3.35 (m, 1H), 3.15-3.05 (m, 1H); Anal.

Calcd for C18H17F2NO'HC1: C, 64.00, H, 5.37, N, 4.15, C1, 10.50, F, 11.25; C, 63.92, H, 5.41, N, 3.95, Cl, 10.67, F, 11.17.

Examples 3-6 Examples 3 through 6 were prepared according to the general procedure described for Example 2. Experimental data is reported in Table 1.

Table 1

Example B3 Salt mp( CL Analysis (Note) 3 CH2-c- -- oil (a) C3H5 4 CH2-2- HCl 158-161 C22H2OFNOHCl(b) napthyl 5 CH2C6H4- HCl 144-145 C19H21ClFNO2HCl (c) 4-OCH3 6 CH2-4- -- -- (d) CsH4N Notes: (a) CI-HRMS: Calcd: 248.1451 (M+H), found: 248.1452.

(b) Calcd: C, 71.44, H, 5.72, N, 3.74, C1, 9.59, F, 5.14; Found: C, 71.11, H, 5.76, N, 3.65, Cl, 9.53, F, 5.09.

(c) Calcd: C, 65.23, H, 6.05, N, 4.00, C1, 10.13, F, 5.43; Found: C, 65.20, H, 6.13, N, 3.94, C1, 10.31, F, 5.40.

(d) CI-HRMS: Calcd: 285.1403 (M+H); found: 285.1415.

Example 7 1-(4-Cyanophenyl)-2-((1-(phenylmethyl)-3- azetidinyl))ethanone, hydrochoride salt A mixture of the free base of Example 1 (92 mg, 1.74 mmol) and sodium cyanide (4.90 g, 100 mmol) in DMF (20 mL) was stirred at 120 C for 90 h under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was poured into 10% NaHCO3 solution and extracted three times with CHCl3. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated in vacuo to provide an oil.

The residue was dissolved in ether and treated with a 1 N HCl solution in ether. The solid was collected and recrystallized from ethanol. Drying in vacuo afforded the title product (37 mg): mp 166-168 oC; 1H NMR (DMSOd6) 6 8.1-8.0 (m, 4H), 7.6-7.4 (m, 2H), 7.5-7.4 (m, 3H), 4.45-4.35 (m, 1H), 4.3 (m, 1H), 4.25-4.15 (m, 1H), 4.154.05 (m, 1H), 3.95-3.85 (m, 1H), 3.85-3.75 (m, 1H), 3.7 (d, 1H, J=6 Hz), 3.6 (d, 1H, J=6 Hz), 3.1-3.0 (m, lH); Anal. Calcd for ClgHl8N2o-HCl: C, 69.83, H, 5.86, N, 8.57, Cl, 10.85; C, 69.03, H, 5.92, N, 8.35, Cl, 10.80.

UTILITY The compounds of this invention and their pharmaceutically acceptable salts possess psychotropic properties, particularly antipsychotic activity of good duration with selective sigma receptor antagonist activities while lacking the typical movement disorder side-effects of standard dopamine receptor antagonist antipsychotic agents. These compounds may also be useful as antidotes for certain psychotomimetic agents such as phencyclidine (PCP), and as antidyskinetic agents.

The compounds provided by this invention are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the sigma receptor. These would be provided in commercial kits comprising a compound provided by this invention.

In vitro Testing Sigma Receptor Bindind Assay Male Hartley guinea pigs (250-300 g, Charles River) were sacrificed by decapitation. Brain membranes were prepared by the method of Tam (Proc. Natl. Acad. Sci.

USA 80: 6703-6707, 1983). Whole brains were homogenized (20 seconds) in 10 vol (wt/vol) of ice-cold 0.34 M sucrose with a Brinkmann Polytron (setting 8). The homogenate was centrifuged at 920 x g for 10 minutes.

The supernatant was centrifuged at 47,000 x g for 20 minutes. The resulting membrane pellet was resuspended in 10 vol (original wt/vol) of 50 mM Tris HC1 (pH 7.4) and incubated at 370C for 45 minutes to degrade and dissociate bound endogenous ligands. The membranes were then centrifuged at 47,000 x g for 20 minutes and resuspended in 50 mM Tris HCl (50 mL per brain).

0.5 mL aliquots of the membrane preparation were incubated with unlabeled drugs, 1 nM (+)-[3H]SKF 10,047 in 50 mM Tris HCl, pH 7.4, in a final volume of 1 mL.

Nonspecific binding was measured in the presence of 10 RM (+)-SKF 10,047. The apparent dissociation constant (Kd) for (+)-[3H]SKF 10,047 is 50 nM. After 45 minutes of incubation at room temperature, samples were filtered rapidly through Whatman GF/C glass filters under negative pressure, and washed 3 times with ice- cold Tris buffer (5 mL).

IC50s were calculated from log-logit plots.

Apparent Kis were calculated from the equation, Ki = IC50/[1 + (L/Kd)] (4), where L is the concentration of radioligand and Kd is its dissociation constant. Data are shown in Table 2.

Dopamine Receptor Binding Membranes were prepared from guinea pig striatum by the method described for sigma receptor binding. The membranes were then resuspended in 50 mM Tris HCl (9 mL per brain).

0.5 mL aliquots of the membrane preparation were incubated with unlabeled drugs, and 0.15 nM [3H]spiperone in a final volume of 1 mL containing 50 mM Tris HCl, 120 mM NaCl and 1 mM MgC12 (pH 7.7).

Nonspecific binding was measured in the presence of 100 nM (+)-butaclamol. After 15 minutes of incubation at 370C, samples were filtered rapidly through Whatman GF/C glass filters under negative pressure, and washed three times with ice-cold binding buffer (5 mL).

ICsos were calculated from log-logit plots.

Apparent Kjs were calculated from the equation Ki=IC50[l+(L/Kd)) (4), where L is the concentration of radioligand and Kd is its dissociation constant.

Representaive compounds of the present invention were tested in this assay and the data shown in Table 2 fall into three discrete ranges: +++ = less than l0nM; ++ = 11-100 nM; + = 101-500 nM; - = greater than 501 nM.

The data in Table 2 indicates that haloperidol, a typical antipsychotic drug, has potent binding affinity for both the sigma and dopamine receptors. This binding profile of haloperidol reflects the therapeutic activity as well as the motor side effects caused by antagonism of the dopamine receptors. In contrast, the examples of this invention shown in Table 2 indicate potent and selective b 3 4 5 6 7 In Vivo Testing Mescaline-Induced Scratch Paroxvsms This is a modification of the procedure of Fellows and Cook (Pyschotropic Drugs, Garrattinni and Ghatti, eds, pp. 397-404 Elsevier:Amsterdam, 1959) and Deegan and Cook (J. Pharmacol. End. Ther. 122:17A (1958)).

Male CF1 mice (Charles River Breeding Laboratory) weighing 18-25 g were injected with mescaline HCl at 25 mg/kg p.o. and placed singly into square (13 cm) Lucite cages with wire mesh bottoms. The number of scratching paroxysms were counted for 5 min beginning 20 min after treatment. A scratching paroxysm is defined as a brief (1-2 sec) burst of scratching of the head or ear with the hind foot. The mean number of scratching paroxysms for all the animals in each treatment condition was the score. All compounds were administered 45 min prior to mescaline injection and antagonism of the effect relative to the control group were measured. Using this test, representative compounds of the invention, especially Example 1, were found to have potent activity in this assay. The results of this test are shown in Table 3.

Induction of Catalepsy This is a modification of the method of Costall and Naylor (Psychopharmacologia (beryl.), 43, 69-74, 1975).

Male CD rats (Charles River) weighing 250-300 g were treated with test drugs and standards by the oral route and tested for the presence of catalepsy 30 minute, 60 minute, and 90 minute after treatment. To test for catalepsy, each rat is placed with its front paws over a 10 cm high horizontal bar. The intensity of catalepsy is measured by the length of time it takes the animal to move both forelegs to the table. A time of 20 seconds is considered maximal catalepsy. Data is shown in Table 3.

In the catalepsy test (Table 3), which is a model for extrapyramidal symptoms, haloperidol is very potent in producing catalepsy and this agrees well with the side-effect profile of haloperidol in the clinic. In contrast, Example 1 does not produce catalepsy and suggests very low potential for extrapyramidal symptoms and tardive dyskinesia.

Table .3 In Vivo Testing Example Catalepsy Mescaline Scratch Haloperidol +++ 1 - +++ Dosage Forms Daily dosage ranges from 1 mg to 2000 mg. Dosage forms (compositions) suitable for administration ordinarily will contain 0.5-95% by weight of the active ingredient based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the 1-ke. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or entericcoated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.

Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.

Also used are citric acid and its salts and sodium EDTA.

In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

Claims (14)

WHAT IS CLAIMED IS:

1. A compound having the formula:

(I) or a pharmaceutically acceptable salt thereof, wherein: R1, R2 independently are hydrogen, F, Cl, Br, lower alkyl, lower alkoxy, cyano; R3 is cycloalkylalkyl or substituted arylalkyl, optionally substituted with one of the following: hydrogen, C1, F, Br, alkyl of 1 to 2 carbons, or alkoxy of 1 to 2 carbons; n = 0-2; m = 0-2; X = C(=O), CH(OH); wherein cycloalkylalkyl consists of 4 to 6 carbons; and aryl group may be phenyl or naphthyl ring.

2. The compound of Claim 1 which is 1-(4-fluorophenyl) 2- ((1- (phenylmethyl) -3-azetidinyl) ) ethanone.

3. The compound of Claim 1 which is 1-(4-fluorophenyl) 2-((1-(phenylmethyl)-3-azetidinyl))ethanonet hydrochloride salt.

4. The compound of Claim 1 which is 1-(4-fluorophenyl) 2-((1-(4-fluorophenyl)-3-azetidinyl))ethanone.

5. The compound of Claim 1 which is 1-(4-fluorophenyl) 2-((1-(cyclopropylmethyl)-3-azetidinyl))ethanone.

6. The compound of Claim 1 which is 1-(4-fluorophenyl) 2- ((2- (naphthalenyl) -3-azetidinyl) ) ethanone.

7. The compound of Claim 1 which is 1-(4-fluorophenyl) 2-((1-(4-methoxyphenyl)-3-azetidinyl))ethanone.

8. The compound of Claim 1 which is 1-(4-fluorophenyl) 2-((1-(4-pyridinylmethyl)-3-azetidinyl))ethanone.

9. The compound of Claim 1 which is 1-(4-cyanophenyl) 2- ((1- (phenylmethyl) -3-azetidinyl) ) ethanone.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antipsychotic effective amount of a compound of Claims 1-9.

11. A method of treating physiological or drug induced psychosis or dyskinesia in a mammal comprising administering to the mammal an antipsychotic or antidyskinetic effective amount of a compound of Claims 1-9.

Amendments to the claims have been filed as follows 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein: R1, R2 independently are hydrogen, F, Cl, Br, lower alkyl, lower alkoxy, cyano; R3 Is cycloalkylalkyl or substituted arylalkyl, optionally substituted with one of the following: hydrogen, Cl, F, Br, alkyl of 1 or 2 carbons, or alkoxy of 1 or 2 carbons; n = 0-2; m = 0-2; X = C(=O), CH(OH); wherein cycloalkylalkyl consists of 4 to 6 carbon; and aryl group may be phenyl or naphthyl ring.

2. The compound of claim 1 which is l-(4-fluorophenyl) -2- ((1- (phenylmethyl) -3-azetidinyl)) ethanone or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 which is 1-(4 fluorophenyl)-2-((1-phenylmethyl)-3- azetidinyl) ) ethanone, hydrochloride salt.

4. The compound of claim 1 which is 1-(4 fluorophenyl) -2- ((1- (4-fluorophenyl) -3- azetidinyl))ethanone; or a pharmaceutically acceptable salt thereof.

5. The compound of claim ; which is 1-(4 fluorophenyl) -2- ((1- (cyclopropylmethyl) -3- azetidinyl))ethanone; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 which is 1-(4fluorophenyl)-2-((2-(naphthalenyl)-3azetidinyl))ethanone; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 which is 1-(4 fluorophenyl) -2- ((1- (4-methoxyphenyl) -3-azetidinyl)) ethanone; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 is l-(4-fluorophenyl)-2- ((1- (4-pyridinylmethyl) -3-azetidinyl) ) ethanone; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 which is 1-(4-cyanophenyl)2-((1-(phenylmethyl)-3-azetidinyl))ethanone; or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antipsychotic effective amount of a compound of any one of claims 1-9.

11. Use of a compound of any one of claims 1 to 9 for preparing a composition for treating physiological or drug induced psychosis or dyskinesia in a mammal.

12. A compound of claim 1, substantially as described herein.

13. A compound of claim 1, substantially as described herein with reference to any one of the Examples.

14. The use as claimed in claim 11, substantially as described herein.