AU679187B2 - Cyclic benzylamino, benzylamido and benzylimido derivatives as antipsychotic agents - Google Patents

Description

OPI DATE 12/04/94 APPLN. ID 48562/93 11111I 1111IIlIII11111I AOJP DATE 07/07/94 PCT NUMBER PCT/US93/08545 111111111111111 II III1 11111111I1 mi111miii..1 AU9348562 (51) International Patent Classification 5 1)ItrainlPbicto ubr O9/66 C07D 207/40, 209/48(209/54 (A )Itrainllulcto ube:XO9/66 C07D 211/76, 211/88, 295/12 A 43)1International Publication Date: 31 March 1994 (31.01.94) A61 K31/50, 31/445 (21) International Application Number: PCT/US93/08545 (74)Agerts: CIAMPORCERO, Audley, Jr. et al.; Johnson and Johnson, One Johnson and Johnson Plaza, New (22) International Filing Date: 10 September 1993 (10.09.93) Brunswick, NJ 08933-7003 (US).

Priority data: (81) Designated States: AT, AU, BB, BG, BR, BY, CA, ClH, 07/943,846 11 September 1992 (I I.09 92) US CZ, DE, DK, ES, Fl, GB, HU, JP, KP, KR, KZ, LK, 10 cpk~be' m 0Iq~qS) IS LU, MG, MN, MW, NL, NO, NZ, PL, PT, RO, RU, Ot/1-005 t seicinc~olqq 0 D, SE, SK, UA, VN, European patent (AT, BE, CH, (71)Applicant: MCNEILAB, INC. [US/US]; Welsh and DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, McKean Roads, Spring House, PA 19477-0776 SE), QAPI patent (BF, BJ, CF, CG, Ci, CM, GA, GN, M L, M R, N E, S N, TD, TG).

(72) Inventors: MARYANOFF, Cynthia, A. ,3204 Aquetong Road. New Hope, PA 18938 REITZ, Allen, B.; 109 Greenbriar Road, Lansdale, PA 19446 Published SCOTT, Malcolm, K. -,1036 Barley Way, Lansdale, PA Wlith: international search report.

19446 VILLANI,Frank Jr. 2 Pinewood Lane, Perkosie, PA 18944 (US).

679187104 (54)Title: CYCLIC BENZYLAMINO,

AGENTS

Ar- BENZYLAMIDO AND BENZYLIMIDO DERIVATIVES AS ANTIPSYCHOTIC (57) Abstract Compounds of general formula are disclosed as novel antipsychotic agents. Pharmaceutical compositions and methods of treating convulsions employing such compounds of formula are also disclosed.

L--~Clb 1 CYCLIC BENZYLAMINO, BENZYLAMIDO AND BENZYLIMIDO DERIVATIVES AS ANTIPSYCHOTIC

AGENTS

BACKGROUND OF THE INVENTION Antipsychotic drugs are known to alleviate the symptoms of mental 5 illnesses such as schizophrenia. Examples of such drugs include phenothiazine derivatives such as promazine, chlorpromazine, fluphenazine, thioridazine and promethazine, thioxanthenes such as chlorprothixene, butyrophenones such as haloperidol and clozapine. While these agents may be effective in treating schizophrenia, virtually all except clozapine produce 10 extrapyramidal side effects, such as facial tics or tardive dyskinesia. Since antipsychotics may be administered for years or decades to a patient, such pronounced side effects may complicate recovery and further isolate the individual from society.

The present invention describes novel compounds that combine S 15 antipsychotic effects with minimal or reduced side effects such as extrapyramidal symptomology relative to some of the compounds known in the art.

SUMMARY OF THE INVENTION Compounds of the general formula I: CH---Hz- Ar- A N- CH 2 wherein Ar, A and Z are as defined hereinafter, are potent antipsychotic agents useful in the treatment of psychotic conditions such as schizophrenia in mammals including humans. The compounds of the present invention may 4 also be useful in the treatment of other disorders of the central nervous system WO 94/06768 PC/US93/08545 2 such as anxiety and aggression. The present invention is also directed to pharmaceutical compositions containing the compounds of formula I and methods of treating psychotic conditions employing such compounds.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds of the general formula I: C. I Ar-_A N- CH-

J

wherein A is N or CH, but preferably N.

Ar is aryl or substituted aryl. The aryl group may be independently substituted with one or more of C1-C8 alkyl, C3-C10 cycloalkyl, C1-C8 hydroxyalkyi, C1-Cs alkoxy, aryloxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, C1-C8 alkylthio, halogen, nitro, C1-C8 haloalkyl, amino or C1-C8 monoor dialkylamino. More preferably, Ar is substituted phenyl. The more preferred substituents are selected from any of C1-C8 alkoxy. Most preferably, the substituent is isopropoxy. The preferred site of substitution is the 2-position on the phenyl ring.

Z is a 5- or 6- membered saturated, substituted or unsubstituted ring containing 1 ring nitrogen atom with the remaining ring atoms being carbon.

The ring nitrogen is the point of attachment of the 5 -or 6 -membered ring to the remainder of the molecule. The 5 or 6 membered ring contains 0, 1 or 2 carbonyls adjacent the ring N. Optionally, the 5- or 6- membered ring may be attached to a four membered carbon moiety to form a 6- membered fused aromatic ring or may be attached to a four membered carbon moiety to form a spirocycle. The substituents on the 5- or 6- membered ring are selected from any of C1-C4 alkyl.

As used herein, unless otherwise noted alkyl and alkoxy whether used alone or as part of a substituent group, include straight and branched chains.

For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, is I WO 94/06768 PCr/US93/0854.0, 3 isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups.

Of course, if the alkyl or alkoxy substituent is branched there must be at least 3 carbon atoms.

The term "aryl" as used herein alone or in combination with other terms indicates aromatic hydrocarbon groups such as phenyl or naphthyl. With reference to substituents, the term independently means that when more than 1 0 one of such substituent is possible such substituents may be the same or different from each other.

There is a or 1,4-relationship of the CH 2 Z and 0H 2 -Piperidine or 0H 2 -piperazine substituents on the appropriate aromatic ring.

Examples of particularly preferred compounds include: 1 -[2-Cl -Methylethoxy)phenyl]-4-piperazinyl]methyl] p he nyl] met hyl]-pi peridi n-2-on e; 1 -1 2 -Methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl] methyl]-piperidin-2-one; 1 Methylethoxy)phenyl]-4-pipe razi nyl] methyl] phe nyl] me~'nyl]pipe ridi n-2-one; 1 -Methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methylpipe rid! ne-2,6-dione; Methylethoxy)ph enyl]-4-pipe razi nyl m ethyl] phe nyl] methyl]- 1 H-isoindole-1 ,3 (2H)-dione; 1 Methylethoxy)ph enyl]-4-pipe razi nyl m ethyl]ph e nyflm ethyl] -Methyl ethoxy)ph enyl]-4-pipe razi nyl m ethyl] phe nyl m ethyl] 8-azaspiro[4.5]decane-7,9-dione; WO 94/06768 PCr/US93/08545 4 1 -Methyl-i -f2-(1 -methylethoxy)phenyl]-4-piperazi nyl]methyl] phenyl]methyl]-piperidine-2,6-dione; and 1 -Met hylethoxy)ph enyl]- 1 -pipe razinyl) methyl]p henyl] methyl]pyrrolidine.

1 -Methylethoxy)phenyl]-4-piperidinyl] methyl] phenyl] methyl]-piperidin-2-one 1 0 Within the scope of the invention are compounds of the invention in the form of hydrates and other solvate forms.

Representative salts of the compounds of formula I which may be used include those made with acids such as hydrochloric, hydrobromic, hydrolodic, 1 5 perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, Q-toluenesulfonic, cyclohexanesulfamic, salicyclic, Q-ami nosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic or a salt made with saccharin. Such salts can be made by reacting the free base of formula I with the acid and recovering the salt.

The compounds of formula I may be prepared according to the following reaction schemes.

REACTION SCHEME 1 Ar-A NH 1 KIC03 BrCH 2 'CN CC Ar-kCN-CH 2 JU~cN 2 N CH A-A 2

NH

2 ArA''N-CH2

-I

2

CH

2

Z

M

WO 94/06768 PCr/US93/08545 In Reaction Scheme 1, the aryl piperazine or piperidines of formula I are reacted with 3-cyanobenzyl bromide in the presence of a base such as K 2

CO

3 and a suitable solvent such as CH 3 CN to produce compound 2. Compound 2 is then reduced in the presence of a suitable reducing agent such as LiAIH 4 in a suitable solvent such as ether or THF to produce amine 3.

Compounds of formula I are prepared by treating compounds of formula 3 with the appropriate cyclic anhydride in toluene to give imides, or with thionyl chloride in THF to afford sulfonamides, or in the presence of acetic anhydride or an acyl choride in THF, methylene chloride, or chloroform to provide amides.

The aryl piperazines and piperidines 1) are commercially available from Aldrich Chemical Co. or may be prepared by standard methods known in the art (for example, see G. E. Martin etal., J. Med. Chem. ,1989, 32, 1051).

The cyanobenzyl bromide is also commercially available from Aldrich Chemical Co.

REACTION SCHEME 2 CIcH 2 Ar-A NH 1

CH

2

CH

2

Z

CICH

2 Ar-A N -c H 2

Z

CH

2 In Reaction Scheme 2, compounds of formula I are prepared by treating a compound of formula 4 with a metal salt of a suitable lactam, or cyclic imide in DMF or THF, the metal being chosen from sodium, lithium, or potassium and the like or (ii) a suitable cyclic amine. This route utilizing compound 4 is useful in making compounds wherein there is a 1,3- or 1,4- substitution on the phenyl ring. Alternatively, compounds of formula I may be obtained by the reaction of

I-

WO 94/06768 PCr/US9308545 6 compounds of formula 5 with compounds of formula 1 in a suitable solvent such as DMF in the presence of a base such as triethylamine. Compounds of formula 4 are obtained by the reaction of suitable a,a'-di(chloromethyl)benzenes with compounds of formula 1 in a suitable solvent such as DMF or THF in the presence of bases such as diisopropylethyl amine. Compounds of formula 5 are prepared by treating a suitable a,a'-di(chloromethyl)benzene with a metal salt of a suitable lactam or cyclic imide in a suitable solvent such as THF, the metal being chosen from sodium, lithium, or potassium and the like. This route going through compound 5 is useful in making compounds wherein there is 1,3- or 1,4- substitution on the phenyl ring. The lactams, imides, cyclic imides, and cyclic amines are commercially available.

The antipsychotic activity of the compounds of the invention may be determined by the Block of Conditioned Avoidance Responding (Rat) test (CAR), references being Cook, L. and E. Weidley in Ann. N.Y. Acad. Sci., 1957, 6, 740-752, and Davidson, A.B. and E. Weidley in Life Sci., 1976, 18, 1279-1284. This test was performed for compounds disclosed in this invention, and the data are listed in Table 1.

Block of Conditioned Avoidance Resoonding (Rat) Apparatus: Rat operant chambers, housed within sound attenuated booths, both from Capden Instruments Ltd., were used in this test. The test chamber H x 90-3/8" W x 9" D) is constructed of aluminum and plexiglass with floor grid bars of stainless-steel spaced 9/16" apart. A stainless-steel operation level 1-1/2" wide projects 3/4" into the chamber and is positioned 2-2/8" above the grid floor. The shock stimulus is delivered via the grid floor by a Coulbourn Instruments solid state module. The parameters of the test and the collection of data are controlled automatically.

Training: Male, Fischer 344 rats obtained from Charles River (Kingston, NY) weighing more than 200 g, are individually housed with chow and water provided ad libitum. The rats are trained for two weeks to approach criterion levels in the avoidance test (90% avoidance rate). One-hour training sessions are run at about the same time each day for four or five days a week. The training session consists of 120 trials, with the conditioned stimuli presented every 30 sec. A trial begins with presentation of the conditioned stimuli (a light and a tone). If the rat responds by depressing the operant lever during the second presentation of the conditioned stimuli, the trial is terminated and the ~L I M I _R I WO 94/06768 PCUS93/08545 7 animal is credited with a CAR. Failure to respond during the conditioned stimuli causes the presentation of the unconditioned stimulus (UCS), a 0.7 mA shock which is accompanied by a light and tone for five seconds. If the rat depressed the lever within the ten-second period, the shock and trial are terminated and an escape response recorded. If the rat fails to depress the lever during the UCS (shock), the trial is terminated after ten seconds of shock and the absence of a response is scored as a failure to escape. Intertrial level presses have no effect. If a rat performs at the 90% CAR level for two weeks, it is then run twice a week on the test schedule (see below) until baseline performance stabilized. Before any drug is administered, two weeks of CAR at a rate of 90% or better is required.

Determination of ED Values Trained rats are run in a one-hour session on two consecutive days at the same time and in the same test chamber each day. The sessions consist of trials, one every minute. The conditioned stimuli are presented for 15 sec (maximum) and the unconditioned stimuli five sec (maximum). On Day 1, a vehicle solution is administered to the rats at a time preceding the trial run corresponding to the pretreatment time for the test compound. The route of administration and the volume of vehicle are also matched to that of the test compound. Only animals that exhibited greater than 90% CAR on Day 1 are given the test compound on Day 2.

Statistical Computations: EDs50 values (that dose required to reduce the mean number of CARS to 50% of the control mean) are determined in the following manner. The percent change in CAR on the drug treatment day compared to vehicle pretreatment day is the key measure. The percent change change) in CAR is determined using the following formula: change CAR ((Day 2 CAR/Day 1 CAR) x 100)-1 00 A negative number indicates a blockade of CAR, whereas a positive number would indicate increased CAR. The test results are reported as the mean change for the group of rats. A reading of -20% is generally taken to represent a minimum value for a compound to be designated as active at a given dose in the CAR test. Failure to escape was calculated for each animal as follows: I i-- WO 94/06768 PCrUS93/08545 8 Failures of Failures to Escape/# of trials The failures, viz., loss of escape, is also reported as a group mean.

Failures to escape are monitored closely and a session is terminated if ten failures occurred. ED50 values and 95% confidence limits are calculated using linear regression analysis. The results of the CAR tests are shown in Table 1.

Receptor Binding Assay The dopamine D 2 binding activity of compounds was determined using a P 2 fraction (synaptosomal membranes) prepared from male, Wistar rats. The

D

2 assay employed a P 2 fraction from the striatum, the ligand 3 H-spiperone at a concentration of 0.05 nM, and 1 mM haloperidol as a blank determinant.

Incubation was in 3 mM potassium phosphate buffer for 45 min at 370C. Under these conditions, specific binding constituted 75% of total binding, and the K: values for some known drugs were: 0.37 nM for haloperidol and 82 nM for clozapine The data from this assay were analyzed by calculating the percent inhibition of the binding of the tritiated ligands by given concentrations of the test compound. KI values, where given, were obtained from the logit analysis of concentration-inhibition curves. A value of 1000 or less is generally taken to represent the value for a compound to be designated as active in this screen.

If a compound is active in this screen, but not in the CAR screen, it is still considered an active antipsychotic agent because the CAR screen negative result may be due to site delivery problems which may be solved by a suitable delivery mechanism. The D 2 binding results are shown in Table 1. The compound numbers used in Table 1 refer to specific compounds described in the Examples.

TABLE 1 Receptor Binding inhibition Kn M) CP# CAR. 5mok. o escape loss D2 1 -89 117 I- lr d--r WO 94/06768 PCrT/US93/08545 9 iAULE_!_!Cont'd.) Receptor Binding Kin M) nq inhibition mk. cpA Acte-nnP I n M., 2 3 4 -29 -16 5.6 25.4 To prepare the pharmaceutical compositions of this invention, one or more compounds or salts thereof of the invention, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by ~s ii II I.a WO 94/06768 PC/US93/08545 standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will preferably contain per dosage unit, tablet, capsule, powder, injection, teaspoonful and the like, from about 50 to about 100 mg of the active ingredient, although other unit dosages may be employed.

In therapeutic use as an antipsychotic agent, the compounds of this invention may be administered in an amount of from about 0.5 to 5 mg/kg per day, and more preferably 1-3 mg/kg per day. The dosages, however may be varied dp ending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of optimum dosages for a particular situation is within the skill of the art.

The following examples describe the invention in greater detail and are intended to illustrate the invention, but not to limit it. In the Examples, the CP refers to the CP in Table 1 and not to the numbers employed in the Reaction Scheme. In the Examples, the terms 1 H NMR, mass spectral analysis FAB-MS and IR indicate that the compounds produced were analyzed using such analyses and the results confirmed the structure.

EXAMEPLEJ.

-Methylethoxy)phenvl]-4-piperazinyl]methvl]phenvylmethvl]piperidin-2-one Hydrochloride (3:2A (CP #1) A solution of N-[2-(1-methylethoxy)phenyl]piperazine (11.95 C, 54.3 mmol, prepared as described by Martin and Scott, et. al. J. Med. Chem., 1989, 32, 1052-1056), in THF (250 mL) was treated with a,ac'-dichloro-m-xylene (23.7 mL, 0.163 mol) and refluxed. After 4 h, diisopropylethylamine (10.4 mL, mmol) was added and the solution was refluxed an additional 1.5 h.

Treatment with 1N HCI (120 mL), water (50 mL), and ether (200 mL) caused a white solid to form which was collected by filtration. This material (7.40 g, 18.73 mmol) was partitioned into saturated aqueous NaHCO 3 to give 6.0 g of an oil. A solution of this material in THF (10 mL) was added to a solution of gamma-valerolactam (1.74 g, 17.5 mmol) in THF (80 mL) which had been treated at 0°C with 2.5 M n-BuLi/hexane (7.0 mL. 1 mol-eqiv). The resulting solution was heated at reflux for 1.5 h, treated with a suspension of gamma- 1 r WO 94/06768 P(7r/US93/08545 11 valerolactam (500 mg, 5.05 mmol) and 2.5 M n-BuLi/hexane (2.0 mL) in THF mL) and refluxed an additional hour. The solution was cooled and partitioned between water and ether. The ether layer was separated, dried, filtered, and concentrated to give a yellow oil. This material was purified on two Waters Prep-500 silica gel columns (EtOAc/hexane; affording -methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]-methyl-piperidin-2one as an oil, 4.80 g. A solution of this oil in i-PrOH (30 mL) was treated with conc HCI (1.15 mL) followed by ether (ca. 500 mL). A white solid was collected by filtration and recrystallized from i-PrOH/ether affording methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidin-2-ono hydrochloride as a white crystalline solid (3.74 g, m. p. 206-2080C.

Both 1 H-NMR and FAB-MS supported the assigned structure.

Elemental Analysis: Calculated for C 26

H

35

N

3 0 2 -1.5 HCI: C, 65.57; H, 7.72; N, 8.82; Cl, 11.17. Found: C, 65.29; H, 7.78; N, 8.68; CI, 10.95.

EXAMPLE 2 1 -Methvlethoxvchenvl]-4-piperazinyl methyll h e n methvyl- Diperidin-2-one Hydrochloride (5:1) (CP #2) Prepared as in Example 1, using a,a'-dichloro-p-xylene in place of a,a'-dichloro-m-xylene, was -methylethoxy)phenyl]-4piperazinyl]methyl]phenyl]methyl]-piperidin-2-one hydrochloride 2.45 g, m. p. 196-2060C.

Elemental Analysis: Calculated for C 26

H

35

N

3 0 2 -0.2 HCI: C, 63.15; H, 7.54; N, 8.49. Found: C, 63.60; H, 7.44; N, 8.51 EXAMPLE 3 -Methylethoxvy)henvyl-4-piperazinvllmethvl]phenyllmethvllpiperidin-2-one Hydrochloride (3:2) (CP #3) A solution of y-valerolactam (7 g, 70.5 mmol) in THF (150 mL) and DMSO (20 mL) was treated with NaH (2.83 g of a 60% oil dispersion) at 0°C under nitrogen atmosphere. After a total of 15 min, a,a'-dichloro-o-xylene g, 140 mmol) was added and the solution was allowed to warm and stir at room temperature. After 4 h, 100 mL of ether and 100 mL of 0.2 N HCI were added. The water was withdrawn, and the organic layer was washed 2X more i I WO 94/06768 PCUS93/08545 12 with water, dried (MgSO4), filtered and concentrated. This material was purified on ca. 400 g of silica gel (flash chromatogra! EtOAc/hexane 7:3) to yield N-[2-(chloromethyl)benzyl]-y-valerolactam (6.6 g, 1 H NMR and mass spectral analysis supported the assigned structure. A solution of this lactam (5.0 g, 21.09 mmol), 2-(isopropoxy)phenylpiperazine fumarate (6.38 g, 18.99 mmol), and triethylamine (8.82 mL, 62.37 mmol) in DMF (75 mL) was heated for 3 h at 50-600C. After 3 h, the solution was added to a 3:1 solution of ether/ethyl acetate (ca. 100 mL) and extracted 3X with water, dried (MgSO 4 filtered and concentrated. The residual oil was purified on ca. 400 g of silica gel (flash chromatography, EtOAc/hexane, 6:4) to give 5.41 g of white semisolid, pure by thin layer chromatography. It was then dissolved in iPrOH, filtered through a Millipore filter, treated with 2.44 mL of conc. aqueous HCI (ca.

26 mmol), and then triturated out of solution by the addition of ether. The resultant white solid was recrystallized in MeOH/ether to give methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidin-2-one hydrochloride as a white powder (5.50 g, m.p. 249.5-252.5°C. 1

H

NMR and mass spectral analysis supported the assigned structure.

Elemental Analysis Calculated for C 26

H

35 N302-1.5HCI-0.3H 2 0: C, 64.83; H, 7.76; N, 8.72; Cl, 11.04; H 2 0, 1.12. Found: C, 64.90; H, 7.69; N, 8.70; Cl, 13.40; H 2 0, 0.96.

EXAMPLE 4 -Methvlethoxy)phenvll-4-piperazinvl]methvllDhenvllmethyl1piperidine-2.6-dione (Z)-2-Butenedioate (1:1) (CP #4) A mixture of NaH (0.224g, 7.48 mmol) and DMF (10 mL) was treated slowly with 2,6-piperidinedfone (0.846 g, 7.48 mmol) at room temperature.

After the addition was complete, the mixture was cooled to 0°C and a solution of -methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl chloride (2.46 g, 7.12 mmol) and DMF (10 mL) was added dropwise. The cooling bath was removed and the reaction was stirred at room temperature overnight. A small portion of water was added and the reaction was concentrated under vacuum. The residue was partitioned between CH2C1 2 /water and the organic layer was separated, dried, and evaporated to give methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidine-2,6-dione as an oil, 3.25 g. This material was dissolved in i-PrOH (13 mL) and treated

M

WO 94/06768 PMUS93/08545 13 with maleic acid (0.83 g, 7.15 mmol). Trituration with ether, filtration, and drying afforded 1 -methylethoxy)phenyl]-4-piperazinyl] methyl] phenyl]methyl]-piperidine-2,6-dione (Z)-2-butenedioate as a white solid (2.73 g, m. p. 103-1 0500. I NMR and mass spectral analysis supported the assigned structure.

Elemental Analysis Calculated for 0 26

H

33

N

3 0 2

*C

4

H

4 0 4 C, 65,32; H, 6.76; N, 7.62. Found: C, 65.32; H, 6.94; N, 7.62.

EXAMPLE 24(r34[1[2-(1 -Methvlethoxy)phenyll-4-oiperazinyl]methyllphenyllmethv-hJ]isoindole-1 .3 (2H)-dione (Z-2-Butenedioate(1) (CP 1 5 Prepared as described in Example 4 using phthalimide in place of 2,6piperidinedione, was -methylethoxy)phenyl]-4piperazinyljmethyljphenyl]methyl]-1 H-isoindole-1 ,3 (2H)-dione butenedioate 3.89 g, m. p. 143-1450C. 'H NMR and mass spectral analysis supported the assigned structure.

Elemental Analysis Calculated for C 29

H

3 1 N 3

O

3

'C

4

H

4 0 4 C, 67.68; H, 6.02; N, 7.17. Found: C, 67.71; H, 5.93; N, 7.16.

EXAMPLE 6 1 -1[31[1 -Methylethgxy)phenyll-4- (Z)-2-Butenedioate (OP #6) Prepared as described in Example 4, using succinimide in place of 2 6piperidinedione, was -methylethoxy)phenyl]-4- (Z)-2-butenedioate 3.54 g, m. p. 105-1080C. 1H NMR and mass sperftral analysis supported the assigned structure.

Elemental Analysis Calculated for C 25

H

3 lN 3

O

3

'C

4

H

4

O

4 C, 64.79; H, 6.56; N, 7.82. Found: C, 64.57; H, 6.48;, N, 7.82.

WO 94/06768 PCrUS93/08545 14 EXAMPLE 7 8-[[3-f[1-[2-(1-Methylethoxy)Dhenyvl-4-pie razinyl]methyll]henylm ethvl]-8azaspirof4.5}decane-7.9-dione Dihydrochloride (CP #7) A solution of 3-cyanobenzyl bromide (10.0 g, 0.051 mol), commercially available from Aldrich Chemical, and acetonitrile (250 mL) was added to a mixture of N-[2-(methylethoxy)phenyl]piperazine hydrochloride (13.10 g, 0.051 mol, prepared according to Martin, G. et al, J. Med. Chem., 1989, 32, 1052), K2CO3 (21.15 g, 0.153 mol) and acetonitrile (250 mL) and the resulting mixture was stirred at reflux under nitrogen for 6.75 hours. The reaction was cooled, concentrated to dryness, and the residue partitioned between CH2CI2 and aqueous NaHCO3. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated to give a gummy residue. This material was chromatographed on silica gel (CH30H:CH2CI2/2:98 eluant) to produce 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzonitrile as a yellow gum, 10.86 g. A solution of this material (10.36 g, 0.031 mol) and anhydrous ether (500 mL) was added dropwise to a slurry of LiAIH4 (1.17 g, 0.031 mol) in anhydrous ether (500 mL) under N2 at room temperature. The reaction was stirred at reflux for 5.5 hours at which point additional LiAIH4 (1.17 g, 0.031 mol) was added. After stirring at reflux for 12 hours, the reaction was cooled in an ice bath and treated slowly with H20 (100 mL), 20% aqueous NaOH (100 mL), and H20 (100 mL) in that order, followed by extraction with diethyl ether.

The ether layer was separated, dried over anhydrous Na2SO4, filtered, and evaporated to give 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl amine as a pale yellow gum, 8.07 g.

A solution of 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]-benzyl amine (2.50 g, 7.37 mmol), prepared as described above, 3,3tetramethyleneglutaric anhydride (1.12 g, 6.66 mmol), and toluene (30 mL) was heated to reflux, cooled slightly, and treated with thionyl chloride (9.72 mL, 13.32 mmol). The resulting slurry was refluxed for 30 min, cooled and the solid collected by filtration. This material was partitioned between CH 2

C!

2 /3N NaOH and the organic layer was separated, dried, filtered and evaporated giving 8- -methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-8azaspiro[4.5]decane-7,9-dione as a crude oil. The oil was converted to the maleate salt in i-PrOH. The isolated residue was converted back to the free base which was obtained as an oil (2.10 Chromatography of this material on flash silica using EtOAc/hexane of varying proportions gave an oil which I i I was dissolved in ether-.and added to ethereal HCI causing. formatinnof -Ia soid Filtration afforded methyl eth oxy) ph enyl]-4-pi perazi nyl] methyl] phenyllmethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (0.94 g, m. p. 212-2160C (dec). 1 H NMR and mass spectral analysis supported the assigned structure.

Elemental Analysis Calculated for 0 30

H-

39

N

3 0 3 -2.0 HCI: C, 64.05; H, 7.35; N, 7.47; Cl, 12.60. Found: C, 63.90; H, 7.32; N, 7.40; Cl, 12.72.

4 -Methyl-i -Methylethoxy)Qhenyfl-4- Difer11fylmet hyflp h enfl m ethyll-D2ip~e rdi ne-2.6-dioPre Dihydrochloride to :o (OP #8'1 6*a 0:00 methylglutaric anhydride (0.88 g, 6.84 mmol), and THF (20 ml-) was stirred at 0000 room temperature for 3 h and then concentrated to an oily residue. This material was dissolved in acetic anhydride (25 mL), heated at 10000C for 4 h, cooled, and added slowly to saturated aqueous NaHCO3. Extraction with CH2CI2, separation of the organic layer, drying, filtration and evaporation 0 tooafforded an oil. This material was chromatographed on flash grade silica using 0e*@t e0g. 97:3/CH 2

CI

2 :MeOH to give 4-methyl-i -[[3-([l1-[2-(l1-methylethoxy)phenyl]-4- 0:89piperazinyl]methyl]phenyl]methyl]piperidine-2,6-dione as an oil. This was 000 0 25 dissolved in ether and added to ethereal HCI causing a solid to form. Filtration afforded 4-methyl-i -methylethoxy)phenyl]-4-piperazinyl]methyl] phenyl]methyl]piperidine-2,6-dione dihydrochloride (1.43 g, m. p. 196- 20000. H-i NMR and mass spectral analysis supported the assigned CC structure.

Elemental Analysis Calculated for C27H35N3Ox-2.0 HCl-0.25 H 2 0: C, 61.53; H, 7.17; 7.97; H 2 0, 0.90. Found: C, 61.57; H, 7.27; N, 7.89; H 2 0, 1.90.

WO 94/06768 PCT/US93/08545 16 -Methylethoxy)phe nyll-4pi~erazinyllmethylllphenyllmethyllpyrrolidine Dihydrochioride hydrate (4:3) (OP #9) A solution of c,c'-dichoro-p-xylene(30.40 g ,0.174 mol), methylethoxy)phenyl]piperazine (12.70 g, 0.058 mol), triethylamine (6.08 g, 0.06 mol) and THF (200 mL) was refluxed for 4 h. Ether (100mL) andl1N HOI (100 ml-) were added producing a white suspension which was filtered to 1 0 give (1 methyl et hoxy) ph enyl]-4-pipe razi nyl]m ethyl) be nzyl chloride hydrochloride.

A solution of -methyl ethoxy)phenyl]-4-piperazinyl]methyl]benzy chloride hydrochloride (5.0 g, 0.012 mol), pyrrolidlne (8.95 g, 0.126 mol), 1 5 excess triethylamine, and THF (5OmL-) was stirred at room temperature for 24h.

The reaction was then diluted with methylene chloride and washed with water.

The organic layer was separated, dried (Na2SO4), filtered, and evaporated to a yellow oil. The residue was chromatographed on silica gel using 95:4.5:0.5/CHCl3:MeOH:NH 4 OH as eluant to give 1-[[4-[[1-[2-(1-methylethoxy) phenyl]-4-piperazinyl]methyl]phenyl]methyl]pyrrolidine as an oil, 5.00 g This material (4.95 g, 0.013 mol) was dissolved in i-PrOH (lO0mL-) and acidified with concentrated HCl to pH 3. The resulting solid was collected by filtration to give 1 methyl et hoxy) phe nyl]-4-pipe razi nyl m ethyl] phenyl]methyl]pyrrolidine dihydrochloride hydrate as a white powder, 4.83 g m. p. 270-280 (browning) 280-3000C. I H NMVR and mass spectral analysis supported the assigned structure.

Elemental Analysis Calculated for C 25

H

35

N

3 0-2 HCI-0.75 H 2 0: 0, 62.55; H, 7.87; N, 8.75; Cl, 14.77; H 2 0, 2.81. Found: 0, 62.47; H, 7.19; N, 8.75; Cl, 14.93; H 2 0, 1.21.

EXAMPLE 1 -f -Methvlethoxyuphenyll-4-piperidinyllmethyl] ph enlm eth yll-pi p eridi n-2-o ne A biphasic solution of ax-dichloro-m-xylene (2.40 g 0.01 37 mol), N-[2- (1 -methylethoxy)phenyllpiperidine (3.00 g, 0.0137 mol), sodium carbonate (2.19 g, 0.020 mol) ethyl acetate (20 mL), and H20 (20 mL) was refluxed for 3 WO 94/06768 PCT/US93/08545 17 h. The organic layer was separated, dried (MgSO 4 filtered, and evaporated to an oil. The residue was chromatographed on silica gel using chloroform as eluant to give 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperidinyl]methyl]benzyl chloride (1.25 g, A solution of 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperidinyl]methyl]benzyl chloride (5.25 g, 0.0147 mol) in THF (90 mL) was added dropwise to a solution of y-valerolactam (2.06 g, 0.02 mol) in THF (50 mL) which had been treated at 0°C with 1.6 M n-BuLi/hexane (12 mL, 1 mol equiv). The resulting solution was heated to reflux for 3 h, cooled, and quenched with MeOH (20 mL). The solution was evaporated to dryness to give a yellow oil. The residue was chromatographed on silica gel using 99:1/CHC1 3 :MeOH as eluant to give -methylethoxy)phenyl]-4-piperidinyl]methyl]phenyl]methyl]-piperidin-2one as a light yellow oil, 1.41 g MS (CI CH 4 m/e 421 1 H NMR

(CDCI

3 8 1.3 6H), 1.8 4H), 2.0 2H), 2.4 1 2.9 3H), 3.2 (m, 2H), 3.6 1H), 3.7 1H), 4.6 3H), 5.0 1H), 6.9 2H), 7.1 2H), 7.3-7.6 4H).

i

Claims (6)

18- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:- 1. A compound of the formula I: CH 2 -Z Ar-A N-CH 2 wherein 5 AisNorCH A is aryl or substituted aryl wherein the aryl substituents for the aryl group are selected from any of C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, Ci-Cs hydroxyalkyl, Ci-Cs alkoxy, aryloxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, CI-C 8 alkylthio, halogen, nitro, Ci-Cs haloalkyl, amino or C 1 -C 8 mono- or di- alkylamino; Z is a 5 or 6 membered saturated, substituted or unsubstituted ring containing 1 ring nitrogen atom, with the nitrogen being the point of ring attachment to the molecule, said ring containing 0, 1 or 2 carbonyls adjacent to the ring nitrogen atom, said ring optionally being attached to a four- membered moiety to form a 6 membered fused aromatic ring or said ring optionally being attached to a four membered moiety to form a 15 5 membered spirocycle; there is a or 1,4-relationship of the CH 2 Z and CH 2 -piperazine or CH 2 piperidine moieties on the appropriate aromatic ring. 2. The compound of Claim 1, wherein A is N. 3. The compound of Claim 1 or 2, wherein Ar is substituted phenyl. 4. The compound of Claim 3, wherein the substituent is C 1 -C 8 alkoxy. The compound of Claim 3, wherein the substituent is isopropoxy. i7882sP.Doc/RC c I pl-- 19 6. The compound of Claim 5, wherein the substituent is substituted in the 2 position on the phenyl ring. 7. The compound of any one of Claims I to 6, wherein the Z ring is independently substituted with any Of CI-C 4 alkyl. 8. The compound of Claim 7, wherein the substituent is a single methyl. 9. The compound of Claim 1, having the name 1-[[3-[[-[2-(1-methylethoxy)phenyl]- 4-piperazinyl]methyllphenyljmethiyl]-piperidin-2-one. *10. The compound of Claim 1, having the name 1-[[4-[[1-[2-(1-methylethoxy)phenyl]- S. 4-piperazinyllmethyl]phenyl]methyl]-piperidin-2- one. 11. The compound of Claim 1, having the name 1-[[2-[[1-[2-(1-methylethoxy)phenyl]- 4-piperazinyljmethyl]phenyljmethylj-pipei.din-2-one. 12. The compound of Claim 1 having the nanme 1-[[3-[[1-[2-(1-methylethoxy)phenyl]- 4-pipprazinyljmethyl~phenyl]methylj-piperidine-2, 6-dione. 13. The compound of Claim 1, having the name 2-[[3-[[1-[2-(1-methylethoxy)phenyl]- 4-piperazinyllmetliyl]phenyl]methyl]- 1H-isoindole- 1,3 (2m-dione. 14. The compound of Claim 1, having the name 1-[[3-[[1-[2-(1-methylethoxy)phenyl]- 4-piperazinyl]methyl]phenyl]methyl]-pyrrolidine-2, The compound of Claim 1, having the name 8-[[3-[[1-[2-(1-methylethoxy)phenyl]- 4-piperazinyl]methyl]phenyllmethyl]-8-azaspiro[4. 5]decane-7,9-dione. 16. The compound of Claim 1, having the name 4-methyl-1-[[3-[[1-[2-(1- methylethoxy)phenyl]-4-piperaziny1]methyl]phenyl~methyl]-piperidine-2,6-dione. 17. The compound of Claim 1, having the name 1-[[4-[[1-[2-(1-methylethoxy)phenyl]- 4-piperazinyljmethyl]phenyllmethyl]pyrrolidine. 1788spsmoc/RC M 18. The compound of Claim 1, having the name 1-[[3-[[1-[2-(1-me,hylethoxy)phenyl]- 4-piperidinyl]methyl]phenyl]methyl]piperidin-2-one.

19. A composition for treating psychotic conditions in mammals comprising the compound of any one of claims 1 to 18 and a pharmaceutically acceptable carrier, said compound being present in a therapeutically effective amount for treating psychotic conditions in mammals.

20. A method for treating psychotic conditions in mammals comprising administering to a mammal in need of such treatment the compound of any one of claims 1 to 18 or a composition according to claim 19 in an amount sufficient to treat such conditions. 10 21. The method of claim 20, wherein the condition is schizophrenia.

22. The method of claim 20 or 21, wherein the effective amount is about 0.5 to per day.

23. A compound of formula I as claimed in claim 1, substantially as herein described with reference to any one of Examples. *•o DATED this 17th day of APRIL 1997 McNEILAB, INC. Attorney: RUTH M. CLARKSON Fellow Institute of Patent Attorneys of Australia of SHELSTON WATERS

17882-.l.DOC/IlItml L I INTERNATIONAL SEARCH REPORT I I N IntemnJ al Application No PCT/JS 93/08545 A. CLASSIFICATION OF SUBJECT MATTER IPC 5 C07D207/40 C070209/48 C07D209/54 C07D211/76 C07D211/88 C070295/12 A61K31/50 A61K31/445 According to International Patent Clasfication (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searchd (classification system followed by clasificaton symbols) IPC 5 C07D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electromc data base consulted durnng the international search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category" Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. P,A WO,A,93 04684 (MCNEILAB) 18 March 1993 1-20 see the whole document P,A WO,A,93 04682 (MCNEILAB) 18 March 1993 1-20 see the whole document A EP,A,0 312 345 (MCNEILAB) 19 April 1989 1-20 see the whole document A EP,A,O 241 053 (DUPHAR) 14 October 1987 1-20 see the whole document A EP,A,O 288 575 (YOSHITOMI) 2 November 1988 1-20 see the whole document A EP,A,O 185 429 (DUPHAR) 25 June 1986 1-20 see the whole document SFurther documents are listed in the continuation of box C. Patent family members are listed in annex. *Special categories of cited documents: 'T later document published after the international filing date or prionty date and not in conflict with the application but document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international 'X document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is ated to establish the publicaton date of another document of particular relevance; the claimed invention ctation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the pnority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 11, 22 November 1993 3 Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NI 2280 HV Rijswijk T I. (+31-70) 340-2040, Tx. 31 651 epo nl, KISSLER B ax: (+131-70) 340-3016 L Form PCT SA/21 (second Sheet) (July 1992) I IIIL L~ aternational application No, INTERNATIONAL SEARCH REPORT PCT/US 93/08545 Box I Observations where certain claims were found unsearchable (Continuation of item I of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. O Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: Although claims 21-23 are directed to a method of treatment of (diagnostic method practised on) the human/animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second ard third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. O As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. D As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. No required -dditional search fees were timely paid by the applicant. Consequently, this international search report is restricted to tne invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest D The additional search fees were accompanied by the applicant's protest. No protest accompanied the payment of additional search fees, Form PCT/ISA210 (continuation of first sheet (July 1992) ~I rli -pl-lqqSllsC- INTERNATIONAL SEARCH REPORT IneNWApiaono ,'ormatdon on patent family members PIUS3/85 patent document Publication Patent family Publecaion cited in search report daemember(s) -Tdate WO-A-9304684 18-03-93 AU-A- 1363392 05-04-93 AU-A- 2659992 05-04-93 CA-A- 2095826 12-03-93 CA-A- 2095847 12-03-93 EP-A- 0562049 29-09-93 EP-A- 0563345 06-10-93 WO-A- 9304682 18-03-93 WO-A-9304682 18-03-93 AU-A- 1363392 05-04-93 AU-A- 2659992 05-04-93 CA-A- 2095826 12-03-93 CA-A- 2095847 12-03-93 EP-A- 0562049 29-09-93 EP-A- 0563345 06-10-93 WO-A- 9304684 18-03-93 EP-A-0312345 19-04-89 AU-A- 2362288 20-04-89 JP-A- 1193264 03-08-89 US-A- 4992441 12-02-91 EP-A-0241053 14-10-87 AU-B- 58513-1 08-06-89 AU-A- 6924787 03-09-87 DE-A- 3782525 17-12-92 JP-A- 62205058 09-09-87 US-A- 4772604 20-09-88 US-A- 4874770 17-10-89 EP-A-0288575 02-11-88 WO-A- 8803136 05-05-88 JP-A- 63233971 29-09-88 US-A- 4931443 05-06-90 EP-A-0185429 25-06-86 AU-B- 589387 12-10-89 5139085 17-07-86 AU-A- 5139&25 26-06-86 EP-A,B 0190472 i3-08-86 JP-A- 61152662 11-07-86 JP-A- 61152666 11-07-86 US-A- 4782061 01-11-88 L. Form PCr/ISA/211 (patent family annex) (July 1992)