CA1257839A - Aminoalkoxybenzopyranones as antipsychotic agents - Google Patents

Abstract

ABSTRACT

A pharmaceutical composition, comprising: an antipsychotic effective amount of a compound of general formula:

Description

Thi!q i a divisional application of copending application 490,241, filed September 9, 1985.

BACKGROUND OF THE INVENTION
Various aminoalkoxybenzopyranones have been described in the literature. Compounds of the formula:

O ~o ~ (C~2)nN 3 R3 wherein R2 is lower alkyl have been described in US Patent 3,~10,898 as having antioedematous activity and the ability to reduce increased capillary permeability.
The pres-nt benzopyranones have been found to have valuable neuroleptic properties and as such are useful as antipsychotic agents.

SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a compound of the formula:

0 ~ ~ -O~CH~)n Rl wherein n is an integer from 2-5; R is hydrogen, lower alkyl, trifluoromethyl, or lower alkoxy; Rl is a radical of the formulae:

- ~ N-Ar , -N N -Het , or -N 3 Ar , ~ -2- ~2S7~39 in which --- represents a single or double bond, Ar is phenyl or phenyl substituted by lower alkyl, lower alkoxy, lower thioalkoxy, halogen, or trifluoromethyl, and Het is 2-, 3- or 4-pyridinyl or 2-, 3- or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen; 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or - 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, or halogen; 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, or halogen; 2- or 3-thienyl or 2- or 3-thienyl substituted by lower alkyl or halogen; 2- or 3-furanyl or 2- or 3-furanyl substituted by lower alkyl or halogen, or 2- or 5-thiazolyl or 2- or 5-thiazolyl substituted by lower alkyl or halogen, or a pharmaceutically acceptable acid addition salt thereof, with the exclusion of the compound wherein n is 3, R is methyl, and Rl is a radical of the formula -N ~ N-Ar in which Ar is phenyl.
The present invention also relates to a pharmaceu-tical composition comprising an antipsychotic effective amount of a compound of formula I as a pharmaceutically acc~ptable acid addition salt thereof with a pharmaceutically acceptable carrier.
The present invention further relates to a method of treating psychoses, e.g., schizophrenia, in a subject suffering therefrom comprising administering to said subject an effective amount of a compound of the formula I, wherein n is an integer from 2-5; R is hydrogen, lower alkyl, lower al~oxy, or trifluoromethyl;
~1 is a radical of the formulae -N N-Ar , -N ~ N-~et , or -~Ar v l u -3- ~.257~339 in which = represents a single or double bond, Ar is phenyl or phenyl substituted by lower alkyl, lower alkoxy, lower thioalkoxy, halogen, or trifl~oromethyl, and Het is 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl, or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, or halogen; 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, or halogen; 2- or 3-thienyl, lû or 2- or 3- thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substituted by lower alkyl or halogen, or 2- or 5-thiazolyl or 2- or 5-thiazolyl substituted by lower alkyl or halogen, or a pharmaceutically acceptable acid addition salt thereof in unit dosage form.

DETAIL~:D DESCRIPTION
In the compounds of the formula I, the term "lower alkyl" is meant to include a straight or branched alkyl group having from one to six carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, amyl, isoamyl, neopentyl, hexyl, and the like.
Halogen includes particularly fluorine, chlorine, or bromine.
Lower alkoxy and thioalkoxy are 0-alkyl or S-alkyl of from one to six carbon atoms as defined above for n lower alkyl. n A preferred embodiment of the present invention is a compound of the formula II

0 ~ 0 ~ 0(CL2)n 1 L~ l U ~
~4- 1257~339 wherein n, R, and Rl are as defined above, or a pharmaceutically acceptable acid addition salt thereof.
Another preferred embodiment of the present invention is a compound of the formula II, wherein n is an integer of 2-5; R is hydrogen, and Rl is as defined previously, or a pharmaceutically acceptable acid addition salt thereof.
Another preferred embodiment is a compound of the formula II, wherein n is 2-5; R is hydrogen, and Rl is a radical of the formulae -N ~ -Ar , - ~ -Het or -N 3 Ar in which --- is a single or double bond; Ar is phenyl or phenyl substituted by methyl, methoxy, thiomethoxy, or chloro, and Het is 2-, 3-, or 4-pyridinyl; 2-, 3-, or 4-pyridinyl substituted by methyl, chloro, or bromo;

2-, 4- or 5-pyrimidinyl; 2-pyrazinyl, or 2-thiazolyl.
Still another preferred embodiment is a compound of the formula II, wherein n is 2-5, but more preferably 3 or 4; R is hydrogen, and Rl is a radical of the formulae -N ~ ~ , -N ~ N-Het or -N ~
.

in which Het is 2-, 3-, or 4-pyridinyl; 2-, 4-, or 5-pyrimidinyl; 2-pyrazinyl or 2-thiazolyl.

.

-- ~2 S~3~
Particularly preferred embodiments of the present invention are; 7-[3-(4-phenyl-l-piperazinyl)propoxy]-2H-l-benzopyran-2-one, 7-[3-(l,2,3,6-tetrahydro-4-phenyl-l-pyridinyl)propoxy]-2H -l-benzopyran-2-one, 7-13-~4-(~-pyrimidinyl)-l-piperazinyl~propoxy]-2~-l-benzopyran- , -2-one, and 7-~4-phenyl-l-piperazinyl)butoxy]-2H-l-benzopyran-2-one, or a pharmaceutically acceptable acid addition salt thereof.
In addition to the previous preferred compounds, a particular preferred embodiment of the method for treating psychoses aspec~ o~ the invention comprises treating a host with an effective amount of 7-13-(4-phenyl-l~piperazinyl)-propoxy~-4-methyl-2H-l-benzopyran-2-one in unit dosage form.

The compounds of the invention form pharmaceu-tically acceptable acid addition salts with organic and inorganic acids. Examples of suitable acids for salt formulation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and the li~e. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid in the conventional manner. The free base forms may be regenerated by treating the salt form with a base. For example, dilute aqueous base solutions may be utilized. Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
The compounds of the invention can exist in unsol-vated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceu-tically acceptable solvents such as water, ethanol, and IJlU--I
-6 -~.257839 the like are equivalent to the unsolvated forms for purposes of the-invention.
The compounds of the present invention and of the formula I may be prepared by first reacting a hydroxy-2H-l~benzopyran-2-one of the formula:

0~\0~

III
wherein R is as defined previously, with a compound of the formula:

X-(cH2)n~Y
IIIa wherein n is an integer of 2-5; X and Y are the same or different and are a leaving group such as halogen or a sulfonyloxy group, for example, methanesulfonyloxy or p-toluenesulfonyloxy; and secondly, reacting the resulting product of the formula IY

~O(CH2)n-X(Y) IV

DIU-7. . -~7~ 1257~39 with an amine selected from the formulae ~ r~ r~ .
H~ - Ar , HN ~- Het or H~Ar wherein Ar and Het are as defined previously, and, if desired, converting the resulting free base by known met~Jods to a pharmaceutically acceptable acid addition salt.
The reaction of the benzopyran-2-one of formula III
with a compound of formula IIIa is carried out in an inert solvent, preferably a polar solvent such as a ketone, for example, acetone or methyl isobutyl ketone, in the presence of an acid scavenger, such as, for example, sodium or preferably, potassium carbonate in anhydrous form, at the reflux temperature of the solvent.
The intermediate product of formula IV is then reacted with the appropriate amine in a polar aprotic solvent such as, for example, dimethylformamide and in the- presence of a neutralizing agent such as, for example, sodium bicarbonate. The reaction is carried out at elevated temperatures, e.g., from about 50 to 150C.
An alternate method for the preparation of a compound of formula I is to first prepare a compound of the formula:

X(C~2)nRl V

- z -- 1257~339 wherein Rl and X are as defined above, according to a method described in Ind. J. Chem. 435 (1982), and react said compound of formula V directly with a benzopyran-2-one of formula III. This reaction is also best carried out at elevated temperatures, e.g., 50-150C, in a solvent such as dimethylformamide and in the presence of an acid neutralizing agent such as sodium bicarbonate.
The appropriate hydroxy-coumarin derivatives, compounds of formula III, and amine derivatives are available commercially or may be prepared by well-known methods. For example, 4-substituted-7-~ydroxy-coumarins are prepared by slight variations on the method described in Organic Synthesis, Coll Vol 3, p 282, for preparing 4-methyl-7-hydroxy-coumarin.
The compounds of the present invention are new chemical substances which are useful as pharmaceutical agents for the treatment of psychoses such as, for example, schizophrenia. The antipsychotic activity of representative compounds of the invention was estab-lished b~ the Mouse Activity and Screen Test Procedure (MAST) described below:
A~IMALS: Nine unfasted Swiss-Webster male mice (Buckberg Labs) weighing 20-30 g are equally divided into three groups for each drug dose to be tested. m at is, data for each dose level was generated by three separate groups of three mice each.
DRUGS: A minimum of three dose levels (10, 30, and 100 mg/kg) are tested or each drug. Treatments are administered intraperitoneally one hour prior to testing. All dosages are calculated as parent compound and given in volumes of 10 mg/kg. Compounds are dissolved or suspended in 0.2% Methocel. Control animals are injected with Methocel.

-9- ~LZ57839 TESTING: A two-part testing procedure is started one hour postinjection. ~irst, the screen test is per-formed ~see Pharmac Biochem Behav 6, 351-353, 1977).
Briefly, this test consists of placing mice on indivi-dual wire screens which are then rotated 180 degrees at the start of a 60-second observation period. m e number of mice falling off the inverted screen is recorded.
Immediately following the screen test, the final phase of testing is initiated by placing each group of three mice in one actophotometer (Life Sciences, 22, 1067-1076, 1978). T&e actophotometer consists o~ a cylindrical chamber whose center is occupied by another cylinder which contains the illumination for six photo-cells located on the perimeter of the chamber. Six light-beam interruptions equal one count Locomotor activity is recorded by computer at ten-minute intervals for 60 minutes.
DATA: The data obtained from the screen test are expressed as percent of mice falling off the screen.
Data derived from locomotor ac~ivity of drug-treated mice are compared to the activity of vehicle-treated animals and are expressed as percent inhibition of spontaneous locomotion. All percentages reported for inhibition of locomotion are based upon data accumulated for one hour. Both phases of testing are graded:
A = 60-100%; C = 31-59%; and N = 0-30%. An overall dose rating is obtained by the following criteria.

Inhibition of Screen Test Dose Locomotion rating with Failure Rating = Rating A - N or C = A
A - A = C
C - N or C = C
All other combinations = N

- -1 - 1257~33~3 Compo~nds which exhibit an overall dose rating of A
at a dose of 100 milligrams/kilogram or less are con-sidered active. Utilizing this procedure, an overall dose rating of A was obtained for the noted compounds at the indicated dose as reported in Table 1.

O ~ O(CH7)nRl I I Dose R I n I Rl ¦ mg/kg H ¦ 3 ¦ - ~ N ~ ¦ 3.0 CH3 ¦ 3 ¦ ~ ~ ¦ 1.0 H 3 ~ ~ N ~ 3.0 H 3 -N/ ~ . ¦ 1.0 Thioridazine ¦ ~ ¦ 10.0 2 S~9~9 The antipsychotic activity of representative com-po~nds of the invention was also established by the ~3H] haloperidol binding assay method (HRBA) which is described in Mol. Pharmacol. 1~, 800 (1976) and reports excellent correlation between the amount of binding and clinical potency.
[3H] Haloperidol Binding Assay. The relative affinities of compounds for dopamine receptors were evaluated on the basis of their ability to displace [3H] haloperidol from striatal membranes prepared from Long-Evans hooded rats. Rats were decapitated; the - brains were removed, and the corpus striata were dissected. The corpus striata were homogenized in 40 volumes of 50 nM Tris buffer (p~ 7.6) and centri-fuged. Pellets were rehomogenized in 50 volumes of the same buffer and used for the binding assay. Incubations were carried out in 10 ml of 50 nM Tris-HCl buffer (pH 7.6) containing 2 mg/ml of original wet tissue weight of homogenate, 100 ~1 o test agent or solvent, and 0.6 nM of [3H] haloperidol. Nonspecific binding was determined in the presence of 0.1 ~M (+)-butaclamol.
Szmples were incubated in reciprocating water bath at 25C for 40 minutes. Incubation was terminated by rapid filtration under reduced pressure through glass fiber filters (Whatman~GF/B). The filters were rinsed three times with 10 ml of Tris-HCl buffer. The filters were placed in 10 ml of scintillation coctail (Bechman Ready-Solv HP) and shaken for one hour. Radioactivity retained on the filter was determined by liquid scintillation spectrophotometry. Compounds were initially evaluated at 10 nM. ICsos when determined wére calculated from a nonlinear computer curve, fit on the data from four or more concentrations, each done in triplicate.
ICsos for representative compounds of the present invention are reported in Ta~le 2.

-1 2- ~L2~7839 - HRBA Assay R

~ (CH2) nRl .
R¦ n I Rl IIC50 H1 3 1 3 ~ ,1 5 x 10--8 CH3¦ 3 --N N~> ~ 5. x 10--8 H 3 ~ 93 x 10--8 H 3 ~ 1. 6 x 10--8 Thioridazine ¦ I 1. 9 x 10-9 I

. .

-13- ~2S~93~9 The compounds o~ the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of formula I, a corresponding pharmaceutically acceptable salt of a compound of formula I, or a mixture of such compounds and/or salts.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceu-tically acceptable carriers can be either solid or liquid. Solid form preparations incluae powders, tablets, dispersable granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. m e powders and tablets preferably contain from 5 or 10 to about 70 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium sterate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxy-methyl cellulose, a low-melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsu-lating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, ~IU-7 -~257~39 cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid form preparations include solutions, suspen-sions, and emulsions. As an e~ample may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared ~ by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions suitable for oral use can be maae by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. Ihe unit dosage form can be a packaged preparation, the package con-taining discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these packaged forms The quantity of active compound in a unit dose af preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient.
In therapeutic use as antipsychotic agents, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.1 mg to about 100 mg per kilogram daily. A

-l5- ~257839 daily dose range of about l.0 mg to about 50 mg per kilogram is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the opti~um dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The following nonlimiting examples illustrate the inventor's preferred methods for preparing the compounds of the invention.

7-[3-(4-Phenyl-l-piperazinyl)propoxy]-2H-l-benzopyran-2-one.
7-(3-halopropyloxy~-2~ benzopyran-2-one.
A mixture of 32 g (0.3 mol) of 7-hydroxy-2H-l-benzopyran-2-one, 43 g (0.3 mol) anhydrous potassium carbonate, and 48 g (0.3 mol) of l-bromo-3-chloropropane in 350 ml of acetone is stirred under reflux for 18 hours.
The mixture is filtered, and the filtrate is evaporated in vacuo. The residue is dissolved in dichloromethane and washed with water. The organic phase is dried over anhydrous magnesium sulfate and evaporated in vacuo.
The remaining crude product is recrystallized from ethyl acetate - petroleum ether. m ere is obtained 32 g (68%1 of solid, mp. 92-98C, which is a mixture of 7-(3-chloropropoxy)- and 7-l3-bromopropoxy)-2H-l-benzopyran-2-one.

L~l U--I
-16- 3L2~i7~

- - 7-l3-(4-phenyl-l-piperazinyl) propoxY~ -2H-l-benzopyran-2-one.
A mixture of 6.3 g (0.025 mol) of 7-(3-halopropoxy)-2H-l-benzopyran-2-one, 10 g (0.12 mol) sodium bicarbo-nate, and 4.1 g (0.025 mol) of l-phenylpiperazine in 100 ml of dimethylformamide is stirred and heated at 80C for 16 hours. I~ne mixture is filtered, and the filtrate is evaporated in vacuo. The residue is dissolved in dichloromethane and extracted with water.
The organic phase is dried over anhydrous magnesium sulfate and evaporated in vacuo. Il~e residue is crystallized from ethyl acetate to give 5.9 g (61%) of title compound, mp. 117-118C.

7-~3-[4-(2,3-Dimethylphenyl~-l-piperazinyl] propoxy]-2H-l-benzopyran-2-one.
By the same procedure as in Example 1 but using 4.8 9 (0.025 mol) of 1-(2,3-dimethylphenyl)piperazine in place of l-phenylpiperazine, there is obtained 3.7 g (37%) o title compound, mp. 89C, from ethyl acetate.
The corresponding hydrochloride salt was obtained by dissolving the free base in 1096 isopropanolic hydrogen chloride and dilution with ethyl acetate, mp. 247-250C.

In an analagous manner as in Example 1, the following compounds were prepared:
7-13-(4-phenyl-1-piperazinyl)-propoxy]-4-methyl-2H-l-benzopyran-2-one, m.p. 127-130C, its hydrochloride, m.p. 253C;
7-[3-14-~2,3-dimethylphenyl)-1-piperazinyl]propoxy]-4-methyl-2H-l-benzopyran-2-one hydrochloride, m.p. 253-255C;
7-[3-[4-~2-methylphenyl~-1-piperazinyl] propoxy]-2H-benzopyran-2-one, m.p. 123-125C;

-17~

7-[4-(4-phenyl-1-piperazinyl)butoxy~-2H-l-benzopyran-2-one, m.p. 145-147C;
7-[3 (4-phenyl-1-piperazinyl)propoxy]-4-trifluoromethyl-2H-l-benzopyran-2-one, dihydrochloride, m.p. 190C;
7-[3-[4-(3-methylphenyl-1-piperazinyl]propoxy~-2H-l-benzopyran-2-one hydrochloride, m.p. 217-220C;
7-[3-[4-(4-methylphenyll-1-piperazinyl]propoxy]-2H-l-benzopyran-2-one, m.p. 140-142C;
7-[3-[4-(3-chlorophenyl)-1-piperazinyl~propoxy]-2H-l-benzopyran-2-one hydrochloride, m.p. 228C;
7-13-[4-(4-chlorophenyl)-1-piperazinyl]propoxy~-2H-l-benzopyran-2-one, m.p. 129-131C;
7-[3-[4-(2,3-dichlorophenyl)-1-piperazinyl]-proxy]-2H-l-benzopyran-2-one hydrochloride, m.p. 215C.
7-~3-14-(3,4-dimethylphenyl)-1-piperazinyl]propoxy]-2H-l-~enzopyran-2-one, m.p. 132C, its hydrochloride, m.p.
220C;
7-[3-[4-t3,4-dichlorophenyl)-1-piperazinyl]propoxy]-2H-1-benzopyran-2-one, m.p. 135-136C;
8-[3-(4-phenyl-1-piperazinyl)propoxy]-2H-l-benzopyran-2-cne, m.p. 95-97C;
7-¦3-[4-(2-pyrimidinyl)-1-piperazinyl]propoxy]-2H-l-benzopyran-2-one, m.p. 135-137C;
7-[3-[4-(3-chloro-2-pyridinyl)-1-piperazinyl~propoxy]-2H-l-benzopyran-2-one hydrochloride, m.p. 235-238C;
7-l3-[4-(3-pyridinyl)-1-piperazinyl]propoxy]-2H-l-benzopyran-2-one, m.p. 122-12SC;
7-13-[4-(6-fluoro-2-pyridinyl)-1-piperazinyl]propoxy]-2H-l-benzopyran-2-one hydrochloride, m.p. 241-243C;
7-13-[4-(6-bromo-2-pyridinyl1-1-piperazinyl]propoxy -2H-l-benzopyran-2-one, m.p. 95-97C;
7-13-[4-(5-methyl-2-pyridinyl)-1-piperazinyl]propoxy]-2H-lbenzopyran-2-one, m.p. 120-122C;
7-[3-~4-(3-methyl-2-pyridinyl1-1-piperazinyl]propoxy]-2H-l-benzopyran-2-one hydrochloride, m.p. 210-215C;

L~ ~ u~
-18- 12~7~39 7-~3-~4-(4-methyl-2-pyridinyl)-1-piperazinyl]propoxy~-2H-l-benzopyran-2-one, m.p. 113-115C;
7-~3-~4-(6-methyl-2-pyridinyl)-1-piperazinyl]propoxy]-2H-l-benzopyran-2-one, m.p. 105-107C;
7-~3-(1,2,3,6-tetrahydro-4-phenyl-1-pyridinyl)propoxy]
-2H-l-benzopyran-2-one, m.p. 127C;
7-12-(1.2,3,6-tetrahydro-4-phenyl-1-pyridinyl)ethoxy]-2H-l-benzopyran-2-one, m.p. 120-125C;
7-[4-(1,2,3,6-tetrahydro-4-phenyl-1-pyridinyl)butoxy]-2H-l-benzopyran-2-one hydrochloride, m.p. 195C; and _ 7-[3-(1,2,3,6-tetrahydro-4-phenyl-1-pyridinyl)propoxy~-4-methyl-2H-l-benzopyran-2-one hydrochloride, m.p. 215-221C;
7-~3-[4-(2-methylthiophenyl)-1-piperazinyl]propoxy~-2H-benzopyran-2-one hydrochloride, m.p. 228-232C;
7-L3-[4-(2-methoxyphenyl)-1-piperazinyl]propoxy]-2H-benzopyran-2-one hydrochloride, m.p. 228-231C;
7-[3-(1,2,3,4,5,6-hexahydro-~-phenyl-1-pyridinyl]propoxy]
-2H-l-benzopyran-2-one hydrochloride, m.p. 218-221C;
7-[3-[4-(2-pyrazinyl)-1-piperazinyl]propoxy~-2H-l-benzopyran-2-one, m.p. 176-179C; and 7-[3-14-(2-thiazolyl)-1-piperazinyl]propoxy]-2H-l-benzopyran-2-one hydrochloride, m.p. 167-170C.

7-[3-(4-Phenyl-l-piperazinyl)propoxy]-4-propyl-2H-l-benzopyran-2-one.
Nl-(3-chloropropoxy)N4-phenylpiperazine was prepared as described in Ind. J. Chem. 435 (1982) by adding dropwise 87 g (0.55 mole) of 1-bromo-3-chloro-propane to a stirred solution of 81 g (0.5 mole) of N-phenylpiperazine in 100 ml acetone and 75 ml of 25 aqueous sodium hydroxide. The organic layer was separated, concentrated, slurried with ethyl acetate, washed, dried over magnesium sulfate, and concentrated . .

DIU-?
19- ~2S7~3~9 to an oil weighing 85 g and analyzed by thin layer chromatography and mass spectrometry to be the title compound.

The above compound as an oil, 4.6 g (0.02 mole~, was reacted with 4.4 g (0.02 mole) of 7-hydroxy-4-propyl coumarin in 100 ml of dimethylformamide and 4 g of anhydrous potassium carbonate. m e reaction mixture was stirred at 85-95C for 16 hours. The mixture was filtered, concentrated, and the oil taken up in methylene chloride which solution was washed with sodium bicarbo-nate, dried over anhydrous magnesium sulfate, and concentrated. The oil solidified on standing and was recrystallized from ethyl acetate to afford 5 g o~
7-[3-~4-phenyl-1-piperazinyl~propoxy]-4-propyl-2H-l-benzopyran-2-one, m.p. 114-116C.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition, comprising: an anti-psychotic effective amount of a compound of general formula:

wherein:
n is 2 or 3, and R2 represents a group selected from phenyl and phenyl substituted by a group selected from F, Cl, Br, C1-6alkyl and C1-6alkoxy, and a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.