AP88A

AP88A - Arylpiperazinyl-ethyl (orbutyl) - phenyl-heterocyclic compounds.

Info

Publication number: AP88A
Application number: APAP/P/1988/000082A
Authority: AP
Inventors: Iii John Adams Lowe
Original assignee: Pfizer
Priority date: 1987-02-17
Filing date: 1988-02-16
Publication date: 1990-06-06
Also published as: CA1312080C; IE61258B1; NO880667L; IL85368A0; DE3884007T2; KR900004126B1; MA21183A1; AU583761B2; MX174210B; IN171858B; YU30388A; EP0279598A3; EP0279598A2; PL270653A1; HUT50334A; AP8800082A0; PL157118B1; YU46624B; DK78888D0; DE3884007D1

Abstract

Arylpiperazinyl-alkylenephenyl-p-heterocyclic compounds, and the pharmaceutically acceptable acid addition salts thereof are neuroleptic agents. They are useful in the treatment of psychotic disorders.

Description

ARYLPIPEPAZINYL-ALKYLENEPHENYL-HETEROCYCLIC COMPOUNDS

The invention relates to arylpiperazinyl-alkylenephenyl-p-heterocyclic compounds and the pharmaceu⁵ tically acceptable acid addition salts thereof, pharmaceutical compositions containing these compounds and a method of using them.

AryIpiperazinyl-ethylpheny1 compounds and their use in the treatment of psychiatric disorders are disclosed in U.S. Patent Nos. 2,927,924 and 3,170,926. These prior art compounds may be substituted in the phenyl but heterocyclic substitution is not disclosed.

The compounds of the invention are arylpiperazinyl-alkylenephenyl-p-heterocyclic compounds of the formula

AP000088 or a pharmaceutically acceptable acid addition salt thereof, wherein Ar is phenyl or 3-trifluoromethylphenyl; 3-cyanopyridy1; naphthyl, or a five or six membered aromatic heterocyclic ring said ring having one nitrogen, oxygen or sulfur, or two nitrogens one cf which may be replaced by oxygen or sulfur, or said heterocyclic ring is condensed with benzo; each of said groups optionally substituted by one fluoro, chloro or

bad ORIGINAL

C- (C₁-C₃) alk;

R is ?.’/

cr nitrogen, w

'.;’nen Z-Y is nitrogen, then X is net oxycen..

Specific compounds of the invention are those wherein n is 3 and Ar is benzisothiazole.

Preferred compounds of the invention are those wherein n is 2 and R is hydrogen, and those wherein n is 2 or 4, and Ar is naphthyl, a 5- or 6-membered aromatic heterocyclic ring condensed with benzo such as benzoisothiazolvl, or a 5- or 6-memhered aromatic heterocyclic ring condensed with benzo·, wherein said benzo is substituted by one of fluoro, chloro or trifluoromethyl.

Other preferred compounds are those wherein X is . sulfur, and Y is amino.

Specific preferred compounds are

4-(4-(2-(4-(1-naphthyl)piperaziny1)ethyl)phenyl)2-aminothiazole

4-(4-(2-(4-(3-trifluoromethylphenyl)piperazinyl)ethyl)phenyl)-2-aminothiazoie

4-(4-(2-(4-(1-naphthyl)piperazinyl)ethyl)phenyl)2-amino-5-methy1thiazole

4-(4-(2-(4-(3-trifluoromethylphenyl)piperazinyl) ethyl) phenyl)-2-amino-5-methylthiazole

4-(4-(2-(4-(1-naphthyl)piperazinyl) ethyl) phenyl) th i a z o 1 - 2 -o ne

4-(4-(2-(4-(3-trifluoromethylphenyl)piperazinyl) ethyl)phenyl)thiazol-2-one

BAD ORIGINAL ft

4-(4-(4-(4-(3-benzisothiazolyl)piperazinyl)butyl) phony 1) -2-amino th i a z ο1e

4-(4-(2-(4-(3-benzisothiazolyl)piperazinyl)ethyl)p h e n y 1) - 2 - m e t h y 11 h i a z ο 1 e

4- (4-(4-(4- (3-benzisothiazolyl)piperazinyl)butyl)phenyl)-2-methylthiazole

4-(4-(4-(4-(3-benzisothiazolyl)piperazinyl)butyl)phenyl)-thiazol-2-one

4-(4-(2-(3-(4-benzisothiazolyl)piperazinyl)ethyl)phenyl)-thiadiazole

4-(4-(4-(4-(3-benz i sothia zolyl)piperazinyl) butyl) phenyl)-thiadiazole .

The present invention also relates to pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier or diluent. Preferred compositions are those wherein the compound of formula I is a preferred compound or a specific preferred compound as described above.

This invention further comprises a method of treating a psychotic disorder by administering to a subject in need of treatment an effective amount of a compound of formula I. Preferred methods of treatment are those administering a preferred compound of formula I or a specific preferred compound as described above.

The term (C^-C.}) alky 1 wherever used in the definition of R or Y denotes methyl, ethyl, propyl or isopropyl.

The five or six membered aromatic heterocyclic ring having one nitrogen, oxygen or sulfur, or two nitrogens one of which may be replaced by oxygen or sulfur includes furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl·, pyridyl and pyrimidyl. The substituent in the heterocyclic ring may be at any position, e.g. at the 5-position in 5-fluoropyrimidyl.

AP000088

BAD ORIGINAL 4)* ca 15 'Τ>

Λ £>

The heterocyclic ring may be condensed with benzo at two neighborin'.: carbon atoms in the heterocyclic rinc. Examples oi such benzoheterccyc1ic groups ere quinolyl, quinazoiinyl, benroxazolyl, benzimidazolyl, benzothiazolyl, and benzisothiazolyl.

The substitution by one fluoro, chloro or trifluoromethyl in naphthyl or benzoheterocyclyl is in the ring not attached to the piperazinyl group. An example of such substituted group is 6-fluoronaphthyl. The benzoheterocyclic group may be attached to the piperazinyl through the heterocyclic or through the benzo ring, for instance, the piperazinyl may be substituted by 8-quinolyl.

When Z-Y is not nitrogen, the heterocyclic group of the formula

in formula 1 is imidazolyl when X is nitrogen, thiazolyl when X is sulfur, and oxazolyl when X is oxygen. When Z-Y is nitrogen and X is sulfur, the above heterocyclic group is thiadiazolyl; when Z-Y is nitrogen and X is nitrogen, then the above heterocyclic group is triazolyl.

The compounds of formula I are prepared by reacting piperazines of formula II with compounds of formula III as follows:

BAD ORIGINAL ft

wherein Hal is fluoro, chloro, bromo or iodo, and Ar,

R, X and Z-Y are as defined above with reference to formula I. This coupling reaction is generally conducted in a polar solvent such as a lower alcohol, for instance ethanol·, dimethyl formamide or methylisobutylketone, and in the presence of a weak base such as a tertiary amine base, for instance triethylamine or diisopropylethylaraine. Preferably, the reaction is in the further presence of a catalytic amount of sodium iodide, and a neutralizing agent for hydrochloride such as sodium carbonate or bicarbonate. The reaction is conducted at the reflux temperature of the solvent used. The piperazine derivatives of formula II may be prepared by methods known in the art. The compounds of formula III, wherein Z-Y and X are not both nitrogen, are prepared by reacting a compound of the formula

(CH_) Cl 2 n . IV

ΔΡ η η ο o 8 β wherein n is 2, 3 or 4 , with an acylchloride of the formula 0

Cl - C - CH₂R wherein R is hydrogen or (C.-C,) alky1, to form a

X J compound of the formula

BAD ORIGINAL &

.VII

Cl (CH.J

o

If

CH.,R

Dronunatmq to a comoouna of the fo:

Cl (CHJ 2 n

- C - CI-IBr

II t

R ··>

..3>

- w .·>

and reacting with (1) thiourea, urea or guanidine to form compounds (III) wherein X is sulfur, oxygen or nitrogen, respectively, and Z-Y is C-NH^, (2) formamide or acetamide to form compounds (III) wherein X is nitrogen, and Z-Y is C-H or C-CH^, respectively , (3) thioformamide or thioacetamide to form compounds (III) wherein X is sulfur, and Z-Y is C-H or C-CH₃, respectively, (4) thiocyanate or cyanate and hydrolyzing to form compounds (III) wherein X is sulfur or oxygen,

£		respectively,	and Z-Y	i s	C-OK
P*	15	(5) thi	ocyanate	or	cyan.
		with hydrogen	sulfide	to	form

hvdrosulfu:

is sulfur or oxygen, respectively, and Z-Y is C-SH (6) N-(C₁-C₃)alkyl thiourea or N-(C^-C^) alkylurea to form compounds (III) wherein X is sulfur or oxygen, respectively, and Z-Y is C-(C^-C^)aikylamino, or (7) ammonium formate or ammonium acetate to form compounds (III) wherein X is oxygen, and Z-Y is C-H or C-CH^, respectively.

The compounds (III) wherein X is nitrogen, and Z-Y is C-(C^-C-j) aikylamino may be formed by alkylating the corresponding compound wherein Z-Y is C-NH_?. Conventional alkylation methods may be used such as reaction with a (C^-C^)alkyliodiae in the presence of potassium carbonate and a solvent such as acetone.

BAD ORIGINAL ft

The compounds of formula III wherein S-Y is nitrogen, X is sulfur, and R is hydrogen, or (C^-C_o) alkyl, may be prepared by reacting tosyl hydrazide with a compound of formula VI, followed by ring closure with thionyl chloride.

The above reaction to form compounds of formula VI is a Friedel-Crafts reaction which is generally conducted in the presence of a halohydrocarbon solvent such as ethylene dichloride, and a Lewis acid such as aluminum chloride, zinc chloride or tin chloride.

The above alpha-bromination to form compounds of the formula VII may be conducted w’ith any brominating agent, such as bromine in acetic acid. The formed bromide (VII) is usually further reacted without isolation to form compounds (II) by cyclization. The above cyclization reactions (1) to (6) generally are conducted in a polar solvent such as ethanol or acetone under heating at reflux temperatures. The above cyclization reaction (7) is advantageously conducted with an excess of ammonium formate or acetate in formic acid or acetic acid, respectively, and heating to the boiling point of the mixture.

The compounds of formula III wherein X is nitrogen and Z-Y is C-GH or C-SH are prepared as follows. A compound of formula VII is reacted with hexamethylenetetramine in an organic solvent such as a chlorohydrocarbon, preferably chloroform, at about room temperature and the formed salt is hydrolyzed by conventional methods such as reaction with an acid,

e.g. hydrochloric acid, in an alcohol to form a compound of the formula

ΔΡ Π n 0 0 8 8

BAD ORIGINAL &

a

CH

in its acid addition salt form. The compound of formula VIII is reacted with chlorosulfonylisocyanate in an organic solvent such as a hydrocarbon solvent, e.g. toluene, in the presence of a trialkylamine such as triethylamine at about room temperature for about 1 to 5 hours, and then heated in a polar solvent such as aqueous dioxane with an acid such as acetic acid or hydrochloric acicl or a mixture thereof for about 1 to 5 hours to form a compound (III) wherein X is nitrogen and Z-Y is C-OH.

The compound (III) wherein X is nitrogen and Z-Y is C-SH is formed by reacting a compound (VIII) with potassium thioisocyanate in water at reflux for about minutes.

The compounds of formula III wherein Z-Y and X are both nitrogen and Hal is iodo may be prepared from the corresponding hydroxyl compound (IX) by stirring with tosyl chloride in pyridine at about 0°C, and then stirring at reflux with sodium iodide in acetone.

The hydroxyl compounds (IX) are formed from compounds of the formula X as follows:

BAD ORIGINAL ft

-9The compounds (X), wherein n is 2, 2 or 4, are first protected with a protecting group Pr, such as by reaction with dihydropyran with an acid such as p-toluenesulfonic acid in a solvent, e.g. benzene, and then reacted with morpholine and p-toluene sulfonic acid in a solvent such as benzene with removal of water to form compounds (XI). The compound of formula XI is refluxed with 2,4-dinitrophenylazide in chloroform for about three hours, the chloroform is removed and the reaction mixture taken up in hot aqueous acetic acid (1:1) to form compounds (XII). On reflux of compounds (XII) in an alcohol solvent in the presence of a base such as sodium hydroxide for more than 24 hours, compounds IX are formed.

The pharmaceutically acceptable acid addition salts of the compounds of formula I are prepared in a conventional manner by treating a solution or suspension of the free base (I) with about one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are employed in isolating the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic such as methanesulfonic, benzenesulfonic, and related acids.

The neuroleptic activity of the present compounds may be demonstrated by methods based on standard procedures. In one method, adult male Sprague-Dawley rats are pretreated with appropriate doses of the test compound by subcutaneous injection. One half hour later, all rats are injected intraperitoneally with 1 mg/kg apomorphine hydrochloride dissolved in an 0.1% ascorbate solution. The rats are rated behaviorallv according to the following scale at 5, 15, 25, 35 and

AP 0 0 0 0 8 8

BAD ORIGINAL $

-1010 ?n

Γό i HU t iter the apomorphin injection: 0 = alert but not moving, 1 c< r scon t inuos;

riovimi about the oenavio;

= coat miffing with discontinuous oral movemen a nu 4 = continuous licking and chewing movements.

The neuroleptic activity of the compounds of this invention makes them useful for treating psychotic disorders in human subjects. For example, these compounds are useful for treating psychotic disorders of the schizophrenic types, and in particular t’ne compounds are useful for removing or ameliorating such symptons as anxiety, agitation, excessive agression, tension, and social or emotional withdrawal in psychotic patients.

A neuroleptic compound of formula I, or a pharmaceutically-acceptable salt thereof, can be administered to a human subject either alone, or, preferably, in combination with pharmaceuticallyacceptable carriers or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. A compound can be administered orally or parenteraily. Parenteral administration includes especially intravenous and intramuscular administration. Additionally, in a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically-acceptable salt thereof, the weight ratio of active ingredient to carrier will normally be in the range from 1:6 to 2:1, and preferably 1:4 to 1:1. However, in any given case, the ratio chosen will depend on such factors as the solubility of the active component, the dosage contemplated and the precise route of administration.

For oral use of a neuroleptic agent of this invention, the compound can be administered, for example, in the form of tablets or capsules, or as an

BAD ORIGINAL

-1110 aqueous solution or suspension. In the case of tablets for oral use, carriers which can be used include lactose and corn starch, and lubricating agents, such as magnesium stearate, can be added. For oral administration in capsule form, useful diluents are lactose and dried corn starch. When aqueous’ suspensions are required for oral use, the active ingredient can be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added. For intramuscular and intravenous use, sterile solutions of the active ingredient can be prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparaton isotonic.

When a neuroleptic agent of this invention is to be used in a human subject to treat a psychotic disorder, the daily dosage will normally be determined by the prescribing physician. Moreover, the dosage will vary according to the age, weight and response of the individual patient as well as the severity of the patient's symptoms. However, in most instances, an effective amount for treating a psychotic disorder will be a daily dosage in the range from 5 to 500 mg, and preferably 50 to 100 mg, in single or divided doses, orally or parenterally. In some instances it may be necessary to use dosages outside these limits.

The following examples are provided solely for the purpose of further illustration.

Example 1

AP 0 0 0 0 8 8

A. 4-(2-Chloroethyl)-acetophenone

A solution was prepared by adding 7.11 ml (50 mmol) of acetyl chloride to a suspension of 7.34 g (55 mmol) of aluminum chloride in 35 ml of ethylene dichloride. This solution was added at room bad ORIGINAL Q co to

Ο

XI > ²⁰

S3 temperature to a solution of 6.58 ml (ICO mmol) of phenethyl chloride in 10 mi of ethylene dichloride.

T he solut i ο η ο* e g a n to c a r k e n a no g j_ v*; c ; f h yc roc n _ e r i < and was stirred at room temperature for 25 minutes, then poured into ice and water. The layers were separated and the organic layer washed with IN hydrochloride, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated to an oil, which was used directly in the following reaction. NMR (CDCl^): 2.16 (s, 3H), 2.68 , 6.85 (d, 2H) , 7.45 (d, 2H) . II (m, 2H), 3.30 (m, 2H) (cm 1, neat): 1680 (C=O).

B. 4-(4-(2-Chloroethyl) phenyl)-2-aminothiazole hydrobromide

To a 50 ml round-bottomed flask equipped with nitrogen inlet were added 0.91 g (5 mmol) of

4-(2-chloroethyl)-acetophenone and 5 ml acetic acid.

To the stirring solution was added 0.26 ml (5 mmol) of bromine dropwise over 2 minutes. The solution was stirred at room temperature for 1 hour, taken up in ethyl acetate, and washed with water, saturated aqueou sodium bicarbonate solution, and brine, dried, and evaporated to an oil. The oil was taken up in 25 mi acetone and treated with 0.38 g (5 mmol) of thiourea, and the reaction heated at reflux for 3 hours. The reaction was cooled to room temperature and allowed tc stand for 2.5 hours, then the precipitate was collected, washed with a little acetone, and dried to give 0.31 g (51;) of a white solid, m.p. 193-195^CC.

C. 4-(4-(2-(4-(1-Naphthyl)piperas iny1)ethyl) phenyl·) -2aminothiasole

To a 35 ml round-bottomed flask equipped with condenser and N^ inlet were added 3.19 g (10 mmol) of

BAD ORIGINAL ft

-134-(-1-( 2-chloroe Li <) pheny 1) - 2 -ami no thiazole hydrobromide, 2.12 g (10 nmol) of N-(1-naphthyl)piperazine,

2.79 ml (20 mmol) of triethylamine, 1.06 g (10 mmol·) cf sodium carbonate, 2 mg of sodium iodide, and 25 ml of ethanol. The reaction was heated at reflux for 5 days, cooled, and the precipitate filtered, and washed with ethanol and water. The orange solid was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent to give a white solid. The solid was taken up in ethyl acetate/methanol, ether saturated with HC1 added, the precipitate filtered, washed with ether, and dried to give a white solid, 1.61 g (311), m.p. 274-277°C.

Example 2

4-(4-(2-(4-(3-Tri fluoromethylphenyl)piperazinvl)ethyl) phenyl)-2-aminothiazole

To a 35 ml round-bottomed flask equipped with condenser and N₂ inlet were added 0.81 g (2.55 mmol) of 4-(4-(2-chloroethyl)phenyl)-2-aminothiazole hydrobro20 nice, 0.68 g (2.55 mmol) of N-(3-trifluoromethyIphenyl)piperazine hydrochloride, 1.06 ml (7.64 mmol) of triethylamine, 0.27 g (2.55 mmol) of sodium carbonate, mg of sodium iodide, and 10 ml of ethanol. The reaction was heated at reflux for 8 days, cooled, and the precipitate filtered, and the reaction mixture taken up in ethyl acetate/water. The layers were separated, the ethyl acetate washed with brine, dried, and evaporated to give a white solid, which was triturated with ethyl acetate. The solid was taken up in ethyl acetate/methanol, ether saturated with HC1 added, the precipitate filtered, washed with ether, and dried to give a white solid, 0.255 g (18%), m.p. 274-277°C.

Example 3

A. 4-(2-Chloroethyl)-propiophenone

A solution was prepared by adding 8.69 ml (50

AP 0 0 0 0 8 8

BAD OR*G^,nal gp mmol) of propionyl chloride tu a suspension of 7.34 y (55 mmol·) of a 1 amir.u:a chloride in 35 mi of ethylene dichloride. This solution was added at room temperature to a solution of 6.58 mi (100 mmol) of phenethyl chloride in 10 ml of ethylene dichloride. The solution began to darken and give off hydrochloride and was stirred at room temperature for 25 minutes, then poured into ice/water. The layers were separated and the organic layer washed with IN hydrochloride, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated to an oil, which was used directly in the following reaction. NXR (CDC1.

1.16

3H), 2.6-3.1

7.2 (d, 2H), 7.9 (d, 2H)

IR (cm m, 4 H -1 ), 3.68 (m, 2H), neat): 1690 ·“>

(C=O).

B. 4-(4-(2-Chloroethyl)phenyl)-2-amino-5-methy1thiazole hydrobromide

To a 50 ml round-bottomed flask equipped with N_ inlet were added 0.98 g (5 mmol) of 4-(2-chloroethyl)propiophenone and 5 ml acetic acid. To the stirring solution was added 0.26 ml (5 mmol) of bromine dropwise over 2 minutes. The solution was stirred at room temperature for 1 hour, taken up in ethyl acetate, and washed with water, saturated aqueous sodium bicarbonate solution, and brine, dried, and evaporated to an oil.

The oil was taken up in 25 ml acetone and treated with.

0.38 g (5 mmol·) of thiourea, and the reaction heated er reflux for 3 hours. The reaction was cooled to room temperature and allowed to stand for 2.5 hours, then the precipitate was collected, washed with a little acetone, and dried to give 0.75 g (52%) of a white solid, m.p. 209-211°C.

BAD ORIGINAL &

!- (4- (2- (·’ - (’ nvL) ethvl) ob.envl) -2To a 35 ml round-bottomed flask equipped with condenser and NR inlet were added 0.81 g (2.80 mmol) of 4 — f 4 — (2-chloroethyl)phenyl)-2-amino-5-methylthiazole hydrobromide, 0.59 g (2.80 mmol) of N-(1-naphthyl)piperazine, 0.78 ml (5.60 mmol) of triethylamine, 0.30 g (2.80 mmol) of sodium carbonate, 2 mg of sodium iodide, and 10 ml of ethanol. The reaction was heated at reflux for 5 days, cooled, and the reaction taken up in ethyl acetate, washed with water and brine, over sodium sulfate, and evaporated to an oil.

was chromatographed on silica gel using ethyl acetate/ methylene chloride as eluent to give a white solid.

The solid was taken up in ethyl acetate/methanol, ether saturated with HC1 added, the precipitate filtered, washed with ether, and dried to give a white solid, 160-165°C.

Examole 5 dried The oi

0.82 g (54o), m.p.

4-(4-(2-(4-(3-Trifluoromethylphenyl)piperaz invl)ethy1)phenyl)-2-amino-5-methylthiazole

To a 35 mi round-bottomed flask equipped with condenser and ly inlet were added 0.75 g (2.59 mmol) of 4-(4-(2-chloroethyl) phenyl)-2-aminothiazoie hydrobromide , 0.69 g (2.59 mmol) of b-(3-trifluoromethylphenyl) piperazine hydrochloride, 1.08 ml (7.78 mmol) of triethvlamine, 0.27 g (2.59 mmol) of sodium carbonate, 5 me of sodium iodide, and 9.5 ml of ethanol. The reaction was heated at reflux, cooled, and taken up in ethyl acetate/water. The layers were separated, the ethyl acetate washed with brine, dried, and evaporated to give an oil. The oil was chromatographed on silica gel using ethyl acetate as eluent to give an oil. The oil was taken up in ethyl acetate/methanol, ether saturated

ΔΡ (1 0 0 0 8 8 bad original β

HCi iCtu stiiC'r, ciiaa uL'icu io give a (501), m.p. ii0-115°C.

T.xample 6

A. 4-(4-( 2-Chloroethy1) phenyl·) -thiazol-2-one

To a 125 ml roumnd-bottomed flask equipped with inlet were added 9.1 g (50 mmol) of 4-(2-chloroethyl) acetophenone and 25 ml acetic acid. To the stirred solution was added 2.58 ml (50 mmol) of bromine dropwise over 2 minutes. The reaction was stirred at room temperature for 30 minutes, taken up in ethyl acetate, washed with water, saturated aqueous sodium .:.3

Λ bicarbonate solution, and brine, dried over sodium sulfate, and evaporated to an oil. The oil was taken up in 250 ml of acetone, treated with 4.9 g (50 mmol) of potassium thiocyanate, and stirred at room temperature for 3 hours. The precipitate was filtered and the filtrate evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to a solid. The solid was taken up in ICO mi of boiling ethanol and treated slowly with S3 ml of IN KCi, then refluxed for 14 hours. The reaction was cooled and the precipitate filtered, washed with water, and dried to give S.2 g (68¾) of a white solid, m.p. 226-229°C.

4-(4-(2-(4-(3-Trifluoromethy ipheny1) piperaz1ny11 ethyl) phenyl) tf. iazol-2-cne

To a 35 mi round-bottomed flask equipped with condenser and inlet were added 1.89 g (7.89 mmol) of 4-(4-(2-chloroethyl)phenyl)thiazcl-2-one, 2.10 g (7.89 mmol) of N-(3-trifluoromethylphenyl)piperazine hydrochloride, 2.20 ml (15.8 mmol) of triethvlamine, 0.84 g (7.89 mmol) of sodium carbonate, 2 mg of sodium iodide, and 20 ml of methylisobutylketone. The reaction was heated at reflux for 6 days, cooled, and

BAD ORIGINAL evaporated. The residue was taker, up in ethyl acetate/water, the layers separated, and the ethyl acetate layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromato5 graphed on silica gel using ethyl acetate/methylene chloride as eluent. The product fractions were evaporated, and the residue triturated with ether, taken up in hot ethyl acetate, treated with ethyl acetate saturated with hydrochloride, precipitated with ether, filtered, washed with ether, and dried to give 0.787 g (20%) of a white solid, m.p. 285-287°C.

Example 7

4-(4-(2-(4-(1-Naphthyl)piperazinyl)ethyl) phenyl)thiazol-2-one

To a 35 ml round-bottomed flask equipped with condenser and inlet were added 1.40 g (5.84 mmol) of

4-(4-(2-chloroethyl)phenyl)thiazol-2-one, 1.24 g (5.84 mmol) of N-(1-naphthyl)piperazine, 0.81 ml (5.84 mmol) of triethylamine, 0.62 g (5.84 mmol) of sodium carbonate, 2 mg of sodium iodide, and 12 mi of methylisobutylketone. The reaction was heated at reflux for 5 days, cooled, and evaporated. The residue was taken up in ethyl acetate/water, the layers separated, and the ethyl acetate layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent. The product fractions were evaporated, and the residue taken up in hot methylene chloride/methanol, treated with ethyl acetate saturated with hydrochloride, precipitated with ether, filtered, washed with ether, and dried to give 0.523 g (18%) of a white solid, m.p. 307-309°C.

AP 0 0 0 0 8 8

BAD ORIGINAL Q

1ΰ (-(4-(2-(4-(3-2

JO

Example 8

*.·n·.·. j. so th ia ly 1) pipe ra?. Iny l·) ? t h y ’ ) p h n y 1) - 2 - a π i η o 2 3 i a z o 1 e

To a 50 ml round-bottomed flask equipped with condenser and inlet were added 2.4 g (7.53 mmol) of 4-(4-(2-chloroethyl)phenyl)-2-aminothiazole hydrobromide, 1.65 g (7.53 mmol) of N-(3-benzisothiazolyl) piperazine (prepared according to the method of US Patent 4,411,901), 1.3 ml (7.53 mmol) of diisopropylethylamine, 1.6 g (15.1 mmol) of sodium carbonate, 2 mg of sodium iodide, and 25 ml of methylisobutylketone.

The reaction was heated at reflux for 5 days, cooled, evaporated, and taken up in ethyl acetate/water. The ethyl acetate layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate as eluent to give a solid. The solid was taken up in hot ethyl acetate, precipitated by addition of hydrochloride gas, the precipitate filtered, washed with ether, and dried to give a beige solid, 1.536 g (38%), m.p.^> 300°C (dec.). NMR (DMSO-d6): 3.2-3.8 (m, 10H) , 4.1 (ni, 2H) , 7.25 (s, 1H) , 7.4-3.2 (m, 8H) ,

11.5 (bs, 2H).

Example 9

4-(4-(2-(4-(3-Quinolyl)piperazinyl)ethyl)pheny1) 2-aminothiazole

To a 35 ml round-bottomed flask equipped with condenser and N,, inlet were added 0.746 g (2.34 mmol) of 4-(4-(2-chloroethyl)pheny1-2-aminothiazole hydrobromide, 0.50 g (2.34 mmol) of N-( 8-quinolyl)piperazine (prepared from 8-aminoquinoline by reaction with diethanolamine in hydrobromide at 200°C), 0.621 g (5.S6 mmol) of sodium carbonate, 50 mg of sodium iodide, and 10 ml of ethanol. The reaction was heated at reflux for 25 hours, cooled, and the reaction mixture taken up

BAD ORIGINAL ft

-19in ethyl ace La Le .'va tar. The layers were separated, tha ethyl acetate layer dried and evaporated. The residue was chromatographed on silica gel using' chloroform./ methanol as eluent and the produc dried tactions combined in methanol and precipitated with a solution of hydrochloride in ether. The precipitate was stirred with ether/methanol to afford a crystalline solid, m.p.^> 225°C, 277 mg (27%). NMR (free base in CDC1₃): 2.8 (m, 8H), 3.5 (m, 4H), 7.0-8.2 (m, 11H).

Example 10

A. 4 - (4 - (2-Chlorcethy1)phenyl)-2-methy1aminothiazolehydrobromide

To a 500 ml round-bottomed flask equipped with X inlet and condenser were added 32.7 g (.125 mol) of bromomethyl(p-chloroethyl)phenyl ketone, 11.3 g (0.125 mol, N-methylthiourea, 250 ml acetone and 5 ml methanol. The reaction was refluxed for 14 hours, cooled, and evaporated to a gum. The gum was extracted with boiling acetone, and the extracts cooled to give a solid, which was filtered. Thue filtrate was evaporated and cooled further to give a white solid, m.p. 103-107°C, 6.6 g (16¾). NMR (DMSO-d6): 3.10 (t, 2H), 3.10 (s, 3H), 3.93 (t, 2H), 7.20 (s, 1H), 7.3-7.8 (m,

4H) .

B. 4-(4-(2-(4-(1-Naphthyl)piperazinyl)ethyl)phenyl) 2-methyl amine-thiazole

To a 125 ml round-bottomed flask equipped with condenser and N_n inlet were added 2.50 g (7.5 mmol) cf 4-(4-(2-chloroethyl)phenyl)-2-methylaminothiazole hydrobromide, 1.59 g (7.5 mmol) of N-(1-naphthyl) piperazine, 1.31 ml (7.5 mmol) of diisopropylethylamine, 1.59 g (15 mmol) of sodium carbonate, 5 mg of sodium iodide, and 50 ml of methylisobutvlketone. The reaction was heated at reflux for 4 days, cooled, and the precipitate filtered, and the filtrate evaporated.

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The residue was taken up in methylene chloride and chromatographed on silica gel using methylene chloride/ethy1 acetate as eluent to give an oil.

oil was taken up in methylene chloride, precipitated by addition of methylene chloride saturated with hydrochloride, and the precipitate filtered, washed with ether, and dried to give a white solid, m.p. 272-273°C., 2.37 g (63%).

Example 11

4-(4-(2-(4-(3-Tri fluorenethy1phenyl)piperaziny1) ethyl) phenyl)-?-methylaminothiazole

To a 125 ml round-bottomed flask equipped with condenser and inlet were added 2.50 g (7.5 mmol) of 4-(4-(2-chloroethyl)phenyl)-2-methy1aminothiazole hydrobromide, 2.0 g (7.5 mmol) of N- (3-trifluoromethylphenyl)piperazine hydrochloride, 2.62 ml (15.0 mmol) of diisopropylethylamine, 1.59 g (15.0 mmol) of sodium carbonate, 5 mg of sodium iodide, and 50 ml of methylisobutylketone. The reaction was heated at reflux for 3.5 days, cooled, and the precipitate filtered, and the filtrate evaporated. The residue was chromatographed on silica gel using methylene chloride ' ethyl acetate and ethyl acetate as eluents. The product fractious were concentrated, taken up in methylene chloride/methanol, precipitated by addition of ethyl acetate saturated with hydrochloride, and the precipitate filtered, washed with ace tone/ether, and dried to give a white solid, m.p. 190-195°C. Further material from the precipitate formed in the reaction gave a total yield of 1.16 g (305).

Example 12

A. 4 - (4-(2-Chloroethyl)phenyl)-2-methy1thiazole hydrobromide

To a 500 ml round-bottomed flask equipped with inlet and condenser were added 32.7 g (0.125 mol) of

BAD ORIGINAL ft bromomethyl(p-chlorcethvl)phenyl ketone, 9.39 g (0.125 mol) thioacctamide, and 250 ml acetone. The reaction was refluxed for 16 hours, cooled, and the precipitate which formed on cooling filtered, washed with acetone and ether, and dried to afford a white solid, m.p. 85-89°C, 13.25 g (33%).

B. 4-(4-(2-(4-(1-Naphthyl)piperazinyl)ethyl)phenyl)-2methy1thiazole

To a 125 ml round-bottomed flask equipped with condenser and N₂ inlet were added 2.39 g (7.5 mmol) of 4-(4-(2-chlcroethyl)phenyl)-2-methylthiazole hydrobromide , 1.59 g (7.5 mmol) of N-(1-naphthyl)piperazine ,

l. 31 ml (7.5 mmol) of diisopropylethylamine, 1.59 g (15 mmol) of sodium carbonate, 5 mg of sodium iodide, and 50 ml of methylisobutylketone. The reaction was heated at reflux for 5 days, cooled, and the precipitate filtered. The solid was taken up in methylene chloride, washed with sodium bicarbonate, dried over sodium sulfate, treated with methylene chloride saturated with hydrochloride, evaporated, and the residue triturated with ether to afford a white solid,

m. p. 305-307°C, 1.76 g (48%).

Examole 13

AP000088

4-(4-(2-(4-(3-Trifluoromethylphenyl)piperazinyl)ethyl)25 phenyl)-2-methylthiazole

To a 125 ml round-bottomed flask equipped with condenser and N_n inlet were added 2.39 g (7.5 mmol) of

4.

4-(4-(2-chloroethyl)phenyl)-2-methylthiazole hydrobromide, 2.0 g (7.5 mmol) of N-(3-trifluoromethylphenyl)piperazine hydrochloride, 2.62 ml (15.0 mmol) of diisopropylethylamine, 1.59 g (15.0 mmol) of sodium

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CO carbonate, 5 mg of sodium iodide, and 50 ml of methyiisobutylketone. The reaction was heated at reflux for

4.5 days, filtered hot tc remove inorganic material, cooled, and the precipitate filtered and washed with ether and ethyl acetate. The solid was taken up in methylene chloride, hydrochloride gas bubbled through to precipitate the salt, and the resulting solid filtered, washed with methylene chloride, and dried to give a solid, m.p. 170-175°C, 1.93 g (51%).

Example 14

A. 4-(4-(4-Chlorobntyl)phenyl)-2-amincthiazole hydrobromide

To a 500 ml round-bottomed flask equipped with hw inlet and condenser were added 25 g (86 mmol) of bromomethyl(p-chlorobutyi)phenyl ketone, 6.55 g (86 mol) thiourea, and 200 ml acetone. The reaction was refluxed for 1 hour 15 minutes, cooled, and the precipitate filtered, washed with acetone, and dried tc a white solid, m.p. 208-211°C, 23.77 g (80%).

B. 4-(4-(4-(4-(3-TriflucrcmethyIpheny1)piperazinyl) butyl)-phenyl)-2-aminothiazole

To a 125 ml round-bottomed flask equipped with condenser and N₂ inlet were added 2.61 g (7.5 mmol) of 4-(4-(4-chlorobutyl)phenyl)-2-aminothiazole hydrobromide, 2.0 g (7.5 mmol) of N-(3-trifluoromethylphenyl)piperazine hydrochloride, 2.62 ml (15.0 mmol) of diisopropylethylamine, 1.59 g (15.0 mmol) of sodium carbonate, 5 mg of sodium iodide, and 50 mi of methyiisobutylketone. The reaction was heated at reflux for

3.5 days, cooled,.and the precipitate filtered, and the filtrate evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate

BAD ORIGINAL ft and ethyl acetate as eluents. The product fractions were concentrated, taken up in methylene chloride/ methanol, precipitated by addition of ethyl acetate saturated with hydrochloride, evaporated, and the residue triturated with ether/ethyl acetate to afford a white solid, m.p. 174-179°C, 0.87 g (23%) .

Example 15

4-(4-(4-(4-(1-Naphthyl)piperazinyl)butyl)phenyl)-2aminothiazole

To a 125 ml round-bottomed flask equipped with condenser and inlet were added 2.61 g (7.5 nmol) of 4-(4-(4-chlorobutyl)phenyl)-2-methy1aminothiazole hydrobromide, 1.59 g (7.5 mmol) of N-(1-naphthy1) piperazine, 1.31 ml (7.5 mmol) of diisoprcpylethyl15 amine, 1.59 g (15 mmol) of sodium carbonate, 5 mg of sodium iodide, and 50 ml of methylisobutyIketone. The reaction was heated at reflux for 4.5 days, cooled, and the precipitate filtered, and the filtrate evaporated. The residue was taken up in methylene chloride and chromatographed on silica gel using methylene chloride/ ethyl acetate as eluent to give an oil. The oil was taken up in ethyl acetate, precpitated by addition of ethyl acetate saturated with hydrochloride, and the precipitate filtered, washed with ethyl acetate, and dried to give a white solid, m.p. 242-245°C., 1.67 g (43%) .

Examole 16 ----- —_*

A. 4-(2-chloroethyl)-acetophenone tosyIhydrazone

To a 500 ml round-bottomed flask equipped with condenser and inlet were added 32 g (176 mmol) of

4-(2-chloroethyl)acetophenone, 32.7 g (176 mmol) tosyl hydrazide, and 250 ml ethanol. The reaction was reflused for 3 hours, cooled, and evaporated. The product crystallized on standing in ether to give a solid, m.p. 122-125°C, 20.3 g (33%).

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Β . 4- ( 2-chloroethyl) -phenyl-1 , 2 , 3-thiadazole

To a 100 ml round-bottomed flask equipped with inlet were added 1.3 g (3.71 mmol) of the above tosyl hydrazone and 3.0 ml (41.1 mmol) thionyl chloride. The reaction gave a crystalline precipitate on standing at room temperature for 1 hour, which was collected with hexane to give a solid, m.p. 80-81°C, 0.33 g (39%).

The remainder of the reaction was chromatographed using methylene chloride to afford an additional 0.33 g of product.

C. 4-(4-(2-(4-(3-Eenzisothiazolyl)piperazinvl)ethyl)phenyl)-1,2,3-thiadiazole

To a 100 ml round-bottomed flask equipped with condenser and N₂ inlet were added 0.90 g (4 mmol)

4-(4-(2-chloroethyl)phenyl)-1,2,3-thiadiazole, 0.88 g (4 mmol) N-benzisothiazolylpiperazine, 0.84 g (8 mmol) sodium carbonate, 1.39 ml (8 mmol) diisopropylethyl amine, 2 mg sodium iodide, and 40 ml methylisobutyl ketone. The reaction was refluxed 2.5 days, cooled, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent to afford an oil, which was taken up in methylene chloride and precipitated by addition of ether saturated with HC1.

The solid was filtered, washed with ether, dried under nitrogen, washed with acetone, and dried to afford a white solid, m.p. 257-259°C, 1.02 g (57.4¾).

Example 17

A. 4-(4-(4-Chlorobutyl)phenyl)-1,2,3-thiadiazole

To a 125 ml round-bottomed flask equipped with condenser and inlet were added 6.25 g (29.65 mmol) p-(4-chlorobutyl)acetophenone , 5.57 g (29.65 mmol) tosylhydrazine, and 50 ml ethanol. The reaction was refluxed 3.5 hours, cooled, and evaporated. The residue was taken up in 23.4 ml (326 mmol) thionyl chloride and stirred at room temperature for 3 hours.

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The reaction m	x X t ’J. L'	e wa	s evaporated	and	the residue
caroma tog r aρ.a -		s i 1 i	c a gel u s i ng	hoxa	r. t ? / m o is h v l· c 11 c
chloride as cd		to a	fiord an oil,	(>. i	g ( S 1 . 5 7 ) .
NMR (CDCi₃) :	1 Π 4 i . O 4	(m,	4H), 2.73 (m,	2H)	, 3.53 (m, 2 I-I ) ,

7.3 and 7.95 (m, 4H), 8.59 (s, 1H) .

B. 4-(4-(4-(4-(3-Benzisothiazolyl)piperazinyl)butyl)phenyl)-1,2,3-thiadiazole

To a 65 ml round-bottom flask equipped with condenser and inlet were added 1.43 g (5.66 mmol)

4-(4-(4-chlorobutyl)phenyl)-1,2,3-thiadiazole, 0.90 g (4.11 mmol) N-benzisothiazolylpiperazine, 1.43 ml (3.22 mmol)diisopropylethyi amine, 0.S7 g (8.22 mmol) sodium carbonate, 2 mg sodium iodide, and 30 ml methylisobuty1 ketone. The reaction was refluxed for 24 hours, cooled, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent to give an oil, which was taken up in ethyl acetate and precipitated by addition of ethyl acetate saturated with HC1. The solid was filtered, washed with ethyl acetate, and dried to afford 1.70 g (87.6%), m.p. 246-247°C, white so 1 id .

Example 13

A. 6-Fluoro-l-naphthoic acid

To a 1 liter round-bottomed flask equipped with condenser and N? inlet were added 345 mi (3.68 mol) of fluorobenzene and 48 g (0.428 mol) of furore acid. To the stirring suspension was added in portions 120 g (0.899 mmol of aluminum chloride. The reaction mixture was stirred at 95°C for 16 hours and then quenched by addition to ice/water/lN HC1. After stirring 1 hour, the aqueous layer was decanted, and benzene and a saturated aqueous solution of sodium bicarbonate were added. After stirring 1 hour, the layers were separated, the aqueous layer washed with benzene, 'BAD ORIGINA

acidified, and extracted	into ethyl	acetate. The	e t h y 1
acetate layer was washed	with water	and brine, dr	ied
over sodium sulfate, and	evaporated	to a solid.	The
solid was triturated wit	h isopropyl	ether to give	5.0 g

{6.1%) of a white solid, NMR (DMSO-dg): 7.0-8.0 (m,

5H), 8.6 (m, 1H).

B. 6-Fluoro-1-amino-naphthalene

To a 125 ml round-bottomed flask equipped with condenser, addition funnel, and N₂ inlet were added

5.0 g (26.3 mmol) of 6-fluoro-l-naphthoic acid and 50 ml acetone. To the stirring suspension were added dropwise 6.25 ml (28.9 mmol) of diphenyl phosphoryl azide and 4 ml (28.9 mmol) of triethylamine. The reaction was refluxed 1 hour, poured into water/ethyl acetate, and filtered. The filtrate was washed with water and brine, dried over sodium sulfate, and evaporated. The residue was further treated with HCl to form the hydrochloride salt and then liberated with sodium hydroxide to afford the free base as an oil,

l.Og. (24%).

C . 1-Benzyl-4-(6-flucronaphthyl)-piperazine

To a 125 ml round-bottomed flask equipped with condenser and N_? inlet were added 1.0 g (6.21 mmol) of 6-fluoro-l-amino naphthalene, 1.8 g (7.76 mmol) of

N-benzyl bis (2-chloroethyl) amine , 3.3 ml (19.2 mmol) of diisopropylethylamine, and 50 ml isopropanol. The reaction was refluxed 24 hours, cooled, and evaporaated to an oil. The oil was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to an oil. The oil was chromatographed on silica gel using methylene chloride as eluent to afford 1.5 g (75.5%) of an oil.

D. N-(1-(6-fluoro)naphthyl) piperazine

To a 125 ml round-bottomed flask equipped with N₂ inlet were added 1.5 g (4.69 mmol) of l-benzyl-4-(6AP 0 0 0 0 8 8

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fluoronaphthyl)-ρLperazine, 1.2 ml (31.3 mmol) cf formic acid, 3.0 g 51 palladium on carbon, and 50 mi ethanol. The reaction was stirred at room temperature for 16 hours, the catalyst filtered under and the solvent evaporated. The oil (0.420 g, 39%) was used directly in the following step.

E. 4- (4-(2-(4-(6-Fluoronaphth-l-yl)piperazinyl)ethyl)phenyl)-2-aminothiazole

To a 100 ml round-bottomed flask equipped with condenser and inlet were added 500 mg (2.17 mmol) N(1-(6-fluoro)naphthyl)piperazine , 700 mg (2.17 mmol) 4-(4-(2-chloroethy1)phenvi)-2-aminothiazole hydrobromide, 460 mg (4.35 mmol) sodium carbonate,

0.37 ml (2.17 mmol) diisopropylethylamine, and 25 ml methylisobutylketone. The reaction was refluxed 24 hours, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethy1 acetate as eluent. The product fractions were combined, dissolved in methylene chloride/methanol, treated with ethyl acetate saturated with HC1, and the precipitate collected and dried to give a white solid, m.p. 220-225°C, 297 mg (25.35) .

NMR (DMSO-d,): 3.3-3.6 (m, 10H), 3.7-3.8 (m, 2K),

7.2-8.3 (m, UK) , 11.6 (bs, 2H) .

example 19

4- ( 4 - ( 2-(4-( G-Fluoronaphth-1-yl)piperazinyl)ethyl1 phenyl)-thiazol-2-one

To a 100 ml round-bottomed flask equipped with condenser and K inlet were added 750 mg (3.27 mmol)

N-(1-(6-fluoro)naphthyl)piperazine , 1.05 g (3.27 mmol) 4-(4-(2-chloroethyl)phenyl)-thiazol-2-one hydrobromide , 700 mg (6.52 mmol) sodium carbonate, 0.60 ml (3.27 mmol)

BAD ORIGINAL ft diisopropylethylamine, 2 mg sodium iodide, and 35 ml methyliscbutylketcre. The reaction mixture was refluxed 24 hours, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent. The product fractions were collected to give a solid,

281 mg (19%), m.p. 228-270°C. NMR (DMSO-d_g): 2.7-3.3 (m, 12H) , 6.30 (s, 1H) , 7.1-8.2 (10H) , 11.8 (bs, 1H) .

Example 20

4- (4-(2-(4-(6-Chloronaphth-l-yl)piperazinyl)ethyl·)phenyl) 2- aminothiazole

To a 100 ml round-bottomed flask equipped with condenser and inlet were added 440 mg (1.55 mmol)

N-(1-(6-chloro)naphthyl)piperazine (prepared in analogy to the fluoro compound in Example 19D), 500 mg (1.55 mmol) 4- (4-(2-chloroethyl)phenyl)-2-aminothiazole hydrobromide, 500 mg (4.66 mmol) sodium carbonate 2 mg sodium iodide, and 30 mi methylisobutylketone. The reaction was refluxed 24 hours, cooled, and evaporated.

The residue was taken up in ethyl aceate, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was taken up in ether''methylene chloride and precipitated by addition of HC1 gas.

The precipitate was filtered, washed with ether, and dried to give a solid, 425 mg (42.5 7), m.p. 210-215'C.

NMR (DMSO-dJ : 3.0-4.0 (m, 12K), 7.2-S.2 (m, 11H) ,

11.1 (bs, 2H).

Example 21

4-(4-(2-(4-(3-Benzisothiazolyl)piperazinyl)ethyl)thiazol-2-one

To a 100 ml round-bottomed flask equipped with condenser and N₂ inlet were added 1.0 g (4.57 mmol)

3- piperazinyl-benzisothiazole, 1.46 g (4.57 mmol)

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-29LO

X

4-(4-( 2-ohloroe th9 70 me; (9.13 mmol mmol) di ;o.

.) phenyl)th :o

-3-₍ nydrooromice, ,;m carbonate, 600 mg (4.57 roovleth •’lam:

mg ,'dium iooi.ee, and ml methylisobutyiketone. The reaction was refluxed 24 hours, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent. The product fractions were dissolved in methylene chloride/ethyl acetate and precipitated with HC1 gas. The precipitate was filtered to give a solid, m.p. 190°C, 455 mg (21.9%) .

Example 22

4-(4-(4-(4-(3-Benz isothiazoly1)piperazinyl)butyl)phenyl·)2-aminothiazole

To a 100 ml round-bottomed flask equipped with condenser and N_n inlet were added 1.22 g (3.52 mmol) (4-(4-(4-chlorobuty1) phenyl)-2-aminothiazole, 0.90 g (3.52 mmol) 3-piperazinyl-benzisothiazole, 1.84 ml (10.57 mmol) diisopropylethyiamine, 0.75 g (7.04 mmol) sodium carbonate, 2 mg sodium iodide, and 35 ml methyiisobutyIketone. The reaction mixture was refluxed 6 days, cooled, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent, and the product fractions dissolved in methylene chloride/methanoi and precipitated by addition of methylene chloride saturated with HC1. The precipitate was filtered and dried to give a solid, 242 mg (13%) , m.p. 258-261°C.

NMR (DMSO-dJ: 1.6-1.8 (m, 4H), 2.7 (t, 2H), 3.2-3.6 o

(m, 8H), 4.1 (m, 2H), 7.20 (s, 1H), 7.3-8.2 (m, 3H).

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Example 23

- n t? b ί: y 11 h i a s ο 1 e

To a 100 ml round-bottomed flask equipped with condenser and inlet were added 0.95 g (4.34 mmol)

3- piperazinyl-benzisothiazole, 1.3ff g (4.34 mmol)

4- (4-(2-chloroethyl)phenyl)-thiazol-2-one hydrobromide,

l. 51 ml (8.68 mmol) diisopropylethylamine, 0.92 g (8.68 mmol) sodium carbonate, 2 mg. sodium iodide, and 40 ml methylisobutylketone. The reaction was refluxed 6 days, cooled, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent and the product fractions taken up in ether/methylene chloride and precipitated by addition of ether saturated with HC1.

The precipitate was filtered and dried to give a solid,

m. p. 135-140°C, 1.09 g (51%). NMR (DMSO-άθ) : 2.74 (s, 3H), 3.1-3.7 (m, 10H), 4.1 (d, 2h), 7.3-8.2 (m, 9H).

Example 24

4-(4-(2-(4-(Naphth-1-yl)piperaz inyl) ethyl)phenyl) 1,2,3-thiadiazole

To a 100 ml round-bottomed flask equipped with condenser and N^ inlet were added 0.64 g (2.83 mmol) (4-(4-(2-chloroethyl)phenyl)-1,2,3-thiadiazole, 0.60 g (2.83 mmol) N-(1-naphthyl)piperazine , 0.49 ml (2.83 mmol) diisopropylethylamine, 0.60 g (5.66 mmol) sodium carbonate, 2 mg sodium iodide, and 20 ml· methylisobuty1ketone. The reaction was refluxed 4 days, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent and the product fractions dissolved in ethyl acetate and precipitated with ethyl acetate saturated with HC1. The precipitate was filtered and dried to

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3.0

Jigive a solid, 0.02 g (303) , m.p. 23C-233°C. d.'-'.R (DMSO-d, and TFA): 3.6 (m, 2H), 3.9 (m, 2H), 4.4-4.7 (m, SH), 7.5-8.2 (m, 11H), 9.42 (s, 1H).

Example 25

4-(4-(4-(4-(3-Cyanopyridin-2-y1)piperazinyl)butyl) phenyl)-2-amino-thiazole

To a 100 ml round-bottomed flask equipped with condenser and N₂ inlet were added 2.37 g (6.81 mmol)

4-(4-(4-chlorobutyl)phenyl)-2-aminothiazole hydrobromide,

I. 28 g (6.81 mmol) 3-cyano-2-piperazinylpyridine, 2.38 ml (13.6 mmol) diisopropylethylamine, 1.44 g (13.6 mmol) sodium carbonate, 2 mg sodium iodide, and 40 ml methylisobutylketone. The reaction was refluxed 4 days, cooled, and evaporated. The residue was triturated with ethyl acetate and the resulting solid chromatographed on silica gel with methylene chloride/ethyl acetate. The product fractions were dissolved in ethyl acetate, precipitated with ethyl acetate saturated with HC1, and the precipitate filtered and dried to give a solid, 1.34 g (55%) , m.p.

155-162°C. NMR (DMSO-d,): 1.6-1.8 (m, 4H), 2.67 (t,

2H) , 3.1-4.4 (m, 10H) , 7.34 (s, IK) , 7.1-8.5 (m, ~K) ,

II. 3 (bs, 2H).

Example 26

A. 4-Chlorobutylacetophenone

To a 250 ml round-bottomed flask were added 5.0 g (29.65 mmol) 4-c’nloropheny Ibutane and 10 ml 1, 2-dichloroethane. To the stirred solution was added a solution of 4.35 g (32.62 mmol) aluminum chloride and 4.22 ml (59.31 mmol) acetyl chloride in 50 ml 1,2-dichloroethane. The solution evolved HC1 as it was stirred at room temperature for 1 hour. It was then poured into water, the layers were separated, and the organic layer was washed with IN KC1, aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated to

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-3210 an oil, 6., g (^ 10O'i) . NMR (CDC 1^): 1.76 (m , 4R) , 2 . a 4 ίπι, 3H) , 2.66 (m, 2H) , 3.50 (m, 2K) , 7.2 and 7.85 (m, 4H) . IR (cm. neat) : 167S (C=O) .

B. 4-(4-Chlorobutyl)phenyl-2-methyIthiazole hydrobromide

The above oil was added to a 100 ml round-bottomed flask equipped with N₂ inlet along with 15 ml acetic acid. Bromine (1.53 ml, 29.65 mmol) was added dropwise and the solution stirred at room temperature for 15 minutes (decolorizes in about 7 minutes,. The solution was carefully taken up in ethyl acetate, washed with water, aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated to an oil,

8.9 g (about 100 % yield).

The oil was dissolved in 70 ml acetone, treated with 2.23 g (29.65 mmol) thioacetamide and refluxed for 15 hours. The reaction was cooled, evaporated to 10 ml volume to afford a precipitate. After filtration, the precipitate was washed with 10 ml acetone, then thoroughly washed with ether, and dried to a white solid, m.p. 128-129°C, 6.8 g (66.2 5).

C. 4-(4-(4 - (4 - ( 3-Bens isoth iatolyl)piperaz invl) butyl) phenyl)-2-methylthiazole

To a 100 ml round-bottomed flask equipped with condenser and N₂ inlet were added 1.43 g (4.11 mmol)

4-(4-chlorobuty1) phenyl)-2-methylthiazole hydrobromide , 0.90 g. (4.11 mmol) K-benzisothiazolylpiperazine,

0.72 g (4.11 mmol) diisopropylethvl amine, 0.87 g (8.22 mmol) sodium carbonate, 2 mg sodium iodide, and 40 ml methylisobutyl ketone. The reaction was refluxed 31 hours, cooled, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent to afford an oil, which was taken up in methylene chloride and precipitated by addition of ether saturated with HC1.

ΔΡ000088 >·

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The solid was filtered, washed with ether, dried

briefly, then washed with a minimal amount of acetone and dried to afford a white solid, m.p. 207-212°C,

1.37 g (87.2%). NMR (DHSO-d-): 1.6-1.8 (m, 4K), 2.64 (t, 2H), 2.72 (s, 3H), 3.1-3.3 (m, 4H), 3.4-3.6 (m,

4H) , 4.0 (d, 2H) , 7.2-8.1 (m, 8H) , 7.85 (s, 1H) .

Example 27

A. 4-(4-(4-Chlorobutyl)phenyl)-thiazol-2-one

To a 500 ml round-bottomed flask equipped with N₂ inlet were added 18 g (60 mmol) bromomethyl-(p-chlorobutyDphenyl ketone, 5.76 g (60 mmol) potassium thiocyanate, and 150 ml acetone. The resulting reaction mixture rapidly deposited a white precipitate as it was stirred at room temperature for 3 hours. It was then filtered and the filtrate was evapoated to an oil. The oil was taken up in 100 ml boiling ethanol, and 50 ml IN HC1 was added very slowly so as to maintain a solution over 1.5 hours. Then 1 ml concentrated sulfuric acid was added and the reaction refluxed for 24 hours. The reaction mixture was cooled and dec o'* off a small aqueous mixture was s precipitate filtered, rred for 20 minutes, and the ashed with water and hexane, and 111-117°C, 11.59 g

2.64 (t,2H), 3.53 dried to a yellow solid, m.p (74.9%). NMR (CDCl-j) : 1.79 (m, 4H (t, 2H), 6.23 (d, 1H), 7.2-7.4 (m, 4H).

B. 4-(4-(4-(4-(3-benzisothlazolyl)plperaziny1)butyl) ohenvl)-thiazol-2-one

To a 125 ml round-bottomed flask equipped with condenser and N^inlet were added 1.10 g (4.11 mmol)

4-(4-(4-chlorobutyl)phenyl)-thiazol-2-one, 0.90 g (4.11 mmol) N-(3-benzoisothiazolyl)piperazine, 0.87 g (8.22 mmol) sodium carbonate, 2 mg sodium iodide, and 40 ml methylisobutylketone. The reaction mixture was heated at reflux for 44 hours, cooled, filtered, and the bad original

-34filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate as eluent, and the product fractions collected and evaporated.

The residue was taken up in methylene chloride/methanol, treated with ether saturated with HC1, and evaporated.

The resulting solid was triturated with acetone to afford 1.10 g (55%) of white solid, m.p. 140-145°C.

NMR (DMSO-dg) : 1.6-1.8 (m, 4H) , 2.62 (t, 2H) , 3.1-3.3 (m, 4H), 3.4-3.6 (m, 4H), 4.0-4.1 (m, 2H), 6.75 (d,

1H), 7.2-8.1 (m, 8H).

Claims

1. A compound of the formula

Ar - N

N-(CHJ_n/ 2 n or a pharmaceutically acceptable acid addition salt thereof, wherein

Ar is phenyl or 3-trifluoromethylphenyl; 3-cyanopyridyl; naphthyl, or a five or six membered aromatic heterocyclic ring said ring having one nitrogen, oxygen or sulfur, or two nitrogens one of which may be replaced by oxygen or sulfur, or said heterocyclic ring is condensed with benzo; each of said naphthyl, heterocyclic ring or benzoheterocyclic ring optionally substituted by one fluoro, chloro or trifluoromethyl, said substitution in the case of said naphthyl or benzoheterocyclic ring being in the ring not attached to the piperazinyl group;

nis2,3or4;

R is hydrogen or (C^-C^) alkyl;

X is nitrogen, oxygen or sulfur, and

Z-Y is C-H, C-OH, C-SH, C-NH₂, C-(C_L~C₃) alky1,

C— (C., —C^) alkylamino or N, with the proviso that when Z-Y is nitrogen then X is not oxygen.

BAD ORIGINAL &

2. A compound according to claim 1 characterized in that n is 2 and R is hydrogen.

3. Pi compound according to claim 1 or 2 characterized in that Ar is naphthyl or a five or six membered aromatic heterocyclic ring condensed with benzo.

4. A compound according to any one of claims 1 to 3 characterized in that X is sulfur, and Y is amino.

5. A pharmaceutical composition comprising a compound according to claim 1 in an amount effective in the treatment of a psychotic disorder and a pharmaceutically acceptable carrier or diluent.

6. A composition according to claim 5 characterized in that n is 2 and R is hydrogen.

7. A composition according to claim 5 or 6 characterized in that Ar is naphthyl or a five or six membered aromatic heterocyclic ring condensed with benzo.

8. A composition according to any one of claims 5 to 7 characterized in that X is sulfur, and Y is amino .

9. A compound according to claim 1 for the treatment of a psychotic disorder.