CN85106970A

CN85106970A - Be used as the preparation method of the aminoalkoxy benzopyrone of major tranquilizer and tranquillizer

Info

Publication number: CN85106970A
Application number: CN85106970.3A
Authority: CN
Inventors: 霍勒斯·A·杜尤德; 劳伦斯·D·怀斯; 托马斯·G·赫夫纳
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 1985-06-18
Filing date: 1985-09-17
Publication date: 1987-04-01
Also published as: CN1007351B; CA1248101A

Abstract

Herein disclosed is molecular formula as shown in the formula aminoalkoxy benzopyrone (I), (R in the formula ₁Be as above group) or and manufacture method, treatment anxiety disorder and psychosis are as schizoid medical components and methods of treatment.

Description

Process for the preparation of aminoalkoxybenzopyrones useful as antipsychotics and tranquilizers

Various aminoalkoxybenzopyranones have been reported in the literature. The molecular formula is:

Compounds in which R ₂ is lower alkyl are also described in U.S. patent No.3,810,898, which possess anti-edema activity, as well as the ability to reduce extended capillary permeability.

It has been found that existing benzopyranones have potent nerve (neuroleptic) relaxing properties and are therefore useful as antipsychotics and tranquilizers.

Accordingly, the present invention relates to a compound of the formula

Wherein n is an integer from 2 to 5, R is hydrogen, lower alkyl, trifluoromethyl, or lower alkoxy, R ₁ is a group of the formula:

Wherein the method comprises the steps of

Ar represents a single bond or a double bond, ar is phenyl or phenyl substituted by lower alkyl, lower thioalkoxy, halogen or trifluoromethyl, het is 2-,3-, or 4-pyridyl or 2-,3-, or 4-pyridyl 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-, furyl, 2-, or 5-thiazolyl or 2-, or 5-thiazolyl substituted by lower alkyl or halogen, or a pharmaceutically acceptable acidic addition salt thereof, which excludes the following compounds: n is 3, R is methyl, R ₁ is of the formula:

Wherein Ar is phenyl.

The invention also relates to a medicinal component which is formed by pharmaceutically acceptable acid addition salts of the compound of the formula I (antipsychotic effective amount or tranquilization effective amount) and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating a person suffering from a psychotic disorder, such as schizophrenia, or anxiety, by administering to the person an effective amount of a compound of formula I, wherein nIs an integer of 2 to 5, R is hydrogen, lower alkyl, lower alkoxy, or trifluoromethyl, and R ₁ is a group of the formula:

Wherein the method comprises the steps of

Ar represents a single bond or a double bond, ar is phenyl or phenyl substituted by lower alkyl, lower alkoxy, lower thioalkoxy, halogen or trifluoromethyl, het is 2-,3-, or 4-pyridyl or 2-,3-, or 4-pyridyl 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 3-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-furyl or 2-, or 5-thiazolyl substituted by lower alkyl or halogen, or a pharmaceutically acceptable acidic addition salt of a compound of formula I in unit dosage form.

The term "lower alkyl" in the compounds of formula I is meant to include straight or branched chain alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

Halogen is in particular fluorine, chlorine or bromine.

Lower alkoxy and lower thioalkoxy are as defined for "lower alkyl" for O-alkyl or S-alkyl having 1 to 6 carbon atoms.

One preferred embodiment of the invention is a compound of formula II:

Wherein n, R and R ₁ are as defined above, or a pharmaceutically acceptable acidic addition salt of the compound.

Another preferred embodiment of the invention are compounds of formula II, wherein n is an integer from 2 to 5, R is hydrogen, R ₁ is as previously defined, or a pharmaceutically acceptable acid addition salt of the compound.

Another preferred embodiment of the invention are compounds of formula II, wherein 2-5, R is hydrogen and R ₁ is a group of the formula:

Wherein the method comprises the steps of

Represents a single bond or a double bond, ar is a radical or a phenyl radical substituted by methyl, methoxy, thiomethoxy or chlorine, het is 2-,3-, or 4-pyridinyl, 2-,4-, or 5-pyrimidinyl, 2-pyrazinyl or 2-thiazolyl.

Another preferred embodiment of the invention are compounds of formula II wherein n is 2 to 5, but preferably 3 to 4;R are hydrogen and R ₁ is a group of the formula:

wherein Het is 2-,3-, or 4-pyridyl, 2-,4-, or 5-pyrimidinyl, 2-pyrazinyl or 2-thiazolyl.

The best scheme of the invention is 7- [ 3- (4-phenyl-1-piperazinyl) propoxy ] -2H-1-benzopyran-2-one, 7- [ 3- (1, 2,3, 6-tetrahydro-4-phenyl-1-pyridinyl) propoxy ] -2H-1-benzopyran-2-one, 7- [ 3- [ 4- (2-pyrimidinyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one, and 7- [ 4-phenyl-1-piperazinyl ] butoxy ] -2H-1-benzopyran-2-one, or pharmaceutically acceptable acidic addition salts of the compounds.

In addition to the preferred compounds described above, the preferred method of the invention for treating psychosis is by administering to the patient an effective amount of 7- [3- [4 phenyl-1-piperazinyl ] -propoxy ] -4-methyl-2H-1-benzopyran-2-one in unit dosage form.

The compounds of the present invention react with organic or inorganic acids to form pharmaceutically acceptable acidic addition salts. Suitable acids for salt formation are, for example, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, pimelic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid, and the like. The salts are prepared by conventional methods by contacting the free base with a sufficient amount of the desired acid. The free base may be regenerated by treating the salt with a base (e.g., with a diluted aqueous base). Suitable bases for this purpose are, for example, dilute sodium hydroxide, potassium carbonate, ammonia, aqueous sodium hydrogencarbonate. The free bases and their respective salts being of a physical nature (e.g. solubility in polar solvents)Somewhat different. But the salts or their corresponding free bases are equally useful for the invention.

The compounds of the present invention may exist in an undissolved state, including a hydrated state. In general, the utility of the invention is the same for dissolved (with pharmaceutically acceptable solvents such as water, alcohol, etc.) and undissolved.

The compounds of the present invention and compounds of formula I may be prepared as follows. In the first step, the molecular formula is as follows

Wherein R is hydroxy-2H-1-benzopyran-2-one as defined above and of formula

Wherein n is an integer from 2 to 5, X and Y may be different and are a leaving group (e.g. halogen) or a sulfonyloxy group, e.g. methylsulfonyloxy or tosyloxy, and a second step of reacting the resulting compound of formula IV

With an amine of the formula,

Wherein Ar and Het are as defined above, and, if necessary, converting the free base formed into an acidic addition salt for pharmaceutical use, in a known manner.

The reaction of the benzopyran-2-one of formula III with the compound of formula IIIa is carried out in an inert solvent, preferably in a polar solvent such as ketone (e.g. acetone or methyl isobutyl ketone), in the presence of an acidic scavenger such as anhydrous sodium carbonate or preferably anhydrous potassium carbonate, at the reflux temperature of the solvent.

The intermediate of formula IV is then reacted with an appropriate amine in a polar aprotic solvent such as dimethylformamide in the presence of a neutralizing agent such as sodium bicarbonate. The reaction is carried out at elevated temperatures, such as about 50-150 ℃.

Another method for preparing the compounds of formula I is by the first step, according to Ind. The preparation of the compounds of formula (I) is described in J.chem.435 (1982)

Wherein X and R ₁ are as previously defined. In a second step, the compound of formula V is reacted directly with benzopyran-2-one of formula III. The reaction is preferably also carried out at elevated temperature, e.g. 50-150 ℃, in a solvent, e.g. dimethylformamide, in the presence of an acidic neutralizing agent, e.g. sodium bicarbonate.

Suitable hydroxy-coumarin derivatives, compounds of formula III, amine derivatives are usefulCommercially available or prepared by known methods. For example, 4-substituted-7-hydroxy-coumarin can be prepared by slightly modifying the process for preparing 4-methyl-7-hydroxy-coumarin by "organic synthesis" of Coll Vol3, P282.

The compound of the present invention is a novel chemical substance which is useful as a medicament for the treatment of psychosis such as schizophrenia. The antipsychotic activity of a typical compound of the invention can be determined by the following "Mouse activity and screen assay" (MAST) (Mouse ACTIVITY AND SCREEN TEST Procedure):

Animals 9 animals weighing 20-30g of non-fasted Suiss-Webster male mice (Buckberg Labs) were evenly divided into three groups corresponding to each agent tested. That is, data for each dose level was measured from three separate groups of three mice each.

Agent for each agent, the minimum of three dose levels (10, 30,100 mg/kg) were tested. 1 hour prior to testing, intraperitoneal administration treatment was performed. All doses were calculated for the starting compound and were dosed at 10 mg/kg. The compound was dissolved or suspended in 0.2% methylcellulose. Control animals were injected with methylcellulose.

Test 1 hour after injection, a two-step test method was started. In the first step, the screen test was completed (see Pharmac Biochem Behav.6, 351-353.1977). Briefly, this test involves placing mice on a separate wire screen, then rotating the screen 180 ° while starting a 60 second observation period, and recording the number of mice falling from the inverted screen.

Following the screen test, the second step of the overall analysis was performed. Each of the three groups of mice was placed in a motion camera (actphotometer) (the "life sciences") 22,1067-1076,1978 having a cylindrical chamber centered on another cylinder with 6 photocells mounted on its perimeter for illumination. The 6 beam interventions formed a single spike, and the activity of the movable mice was recorded by the computer every 10 minutes for 60 minutes.

Data the data obtained from the screen test are expressed as a percentage of mice falling from the screen. The ratio of the obtained activity data of mice after taking the drug to that of mice after taking the shape agent represents the percentage of inhibition of spontaneous locomotion. The total percentage of motion inhibition was based on data accumulated over 1 hour. Both phases of analysis were divided into a=60-100%, c=31-59%, n=0-30%, the full dose level being obtained from the following rules:

Dose rating for moving screen analysis

Equal failure level for the suppression isocline

A-N or c=a

A - A = C

C-N or c=c

All other combinations = N

Compounds that are inhibited to full dose level a with a dose of 100mg/kg or less are considered active compounds. In this way, table 1 (listed are compounds that reached full dose class a at the indicated dose) was obtained:

TABLE 1

Dose of RnR ₁

mg/kg

H 3

3.0

CH₃3

1.0

H 3

3.0

H 3

1.0

Thioridazine ^＊ 10.0.0

(Thiorida-

zine)

^＊ Injection of antipsychotic

The antipsychotic activity of typical compounds of the invention may also be measured using the [ ³ H ] haloperidol binding assay (HRBA). The method is extremely different from Mol. Pharmacol.12,800,1976) and reports excellent compliance between the combined amounts and the clinically effective amounts.

[ ³ H ] Haloperidol binding assay the relative affinity of a compound for a dopamine receptor can be determined based on the ability of the compound to replace [ ³ H ] Haloperidol in a striped septum (Rtriatal membranes) obtained from rats of different Long-Evans head-body colors. Mice were sacrificed by cervical scission and brains were removed and the mice were dissected for body lines (corpus Dtriata). The rat body line was homogenized in 40 parts (volume) of 50nm Tris buffer (ph=7.6) and compressed by centrifugation. The patch was stirred in 50 parts of the same buffer again and used for binding assay. 10ml of 50nM Tris-HCl buffer (pH=7.6) containing 2mg/ml initial tissue homogenate, 100. Mu.l of assay reagent or solvent, and 0.6nM [ ³ H ] haloperidol was incubated. Nonspecific binding was determined in the presence of 0.1. Mu.M (+) -butaclamol (buckminsterform, an antipsychotic). The samples were incubated in a reciprocating water bath at 25℃for 40 minutes. And (3) rapidly filtering through a glass fiber filter screen (WHAT MAN GF/B) under reduced pressure, and stopping heat preservation. The filter material was rinsed three times with 10ml Tris-HCl buffer. Filter examples in 10ml luminescence Coctail (Beckman Ready-Solu HP) shake for 1 hour. Radioactivity present on the filter material was measured with a liquid blaze spectrophotometer. The compound was initially estimated at 10nM. In determining IC5os, the data should be collected 4 or more times, three times per point, calculated from the non-linear computer curve.

The IC50s of typical compounds of the invention are shown in Table 2.

HRBA determination

TABLE 2

R n R₁IC₅₀

H 3

1.5×10.8

CH₃3 5.0×10^-8

H 3

93×10^-8

H 3

1.5×10^-8

Thioridazine 1.9X10 ^-9

The compounds of the invention are novel chemicals which are also useful as agents for the treatment of anxiety disorders, i.e. as tranquilizers (anxiolytic agents). The anxiolytic activity of a typical compound of the invention, i.e. of a compound of formula I of the invention, can be measured in an anxiety animal model by the Geller-Seifter conflict test described in Psychopharmacologihl:482 (1960). It should be noted that the method begins with a rapid response, followed by a trial conflict, and the animal is tested after it has been trained to a more stable performance. Each animal served as its own control and the test method was described as follows;

The subjects had a body weight of 300-350g and matured male mice with different head and body colors (Long-Evans line).

The device comprises a laboratory structure, an inner test compartment with a lever on one side wall, a grid bottom plate, an automatic feeding device and a loudspeaker. The laboratory is enclosed by a sound-proof chamber. The shock is issued by a LVE type 1531 stationary flow electric shock, the white noise is generated by a LVE type 1524 noise generator, and the tone (tone) is generated by a LVE 1664.5 KC tone generator. All events and recordings are automated, and the program is controlled by appropriate electrical timers and relays.

The steps were shifting interval (VI) =2 minutes, test period=4, shock=0.6-0.8 ma, food reward=borden's sweetened condensed milk (diluted with 2 parts of water per milk), cancelling 70% of the animal's free feed to starve for 23 hours, test time=12 minutes.

The conflict is created by having the hungry mice forced to habituate to pull the lever down to obtain a food reward. With the lever pulled down, there was an unexpected compensation, repeated at 2 minute intervals-VI 2 minutes on average every 2 minutes. (see Ferster; C.B; and Qkinner B.F.; procedure for compensation "Appleton-centre-Crofts, new York, 1957).

4 Cycles of 3 minutes were performed at intervals during the test. During these test periods of time,A single tone indicates that there is one food Compensation (CRF) per lever pull down, while there is also one painful on-foot shock as a penalty.

In other words, the mice that were on diet were trained to pull the lever down to get the food (sweetened condensed milk). Typically, the mice accomplish this at planned change intervals (VI), i.e., once every two minutes on average, with the lever pulled down, and the food is delivered to, and the time interval of the two successive food-available cycles is continuously adjustable, based on the animal's response to the occasional low but steady rate of food.

After 12 minutes of animal action following this procedure, the laboratory lights were turned off and only two small lights were turned on to indicate the food available each time the lever was pulled down during a 3 minute test period. In the test, each lever pull down, a slight shock (0.8 am,0.25 seconds) was generated through the grid floor (punishment). This creates a proximity-evasion conflict, accompanied by anxiety, that food is readily available for each response, but that each response is penalized (see Miller, N, e., "conflict morphology and some near-term for drugs", american pharmacist, 16: 12,1961). In this test procedure we used four consecutive tests, 12 minutes each for a period during which food compensation VI was effective.

In the non-dosing test period, mice generally have a steady response rate in the VI units, but have little response during the punished test period.

Administration of 7- [3- [ 4- (2-pyrimidinyl) -1-piperazinyl ] propoxy ] -2H-benzopyran-2-one at a dose of 55 and 80mg/kg PO, rather than 27.5mg/kg PO, to mice increases their response during the test period. This effect is not achieved on the condition that the number of responses in the VI cell is reduced. In other words, there is no significant overall sedative effect. Three of the four mice tested had increased response times with penalties at a dose of 55mg/kg, and four of the four mice tested had increased response times with penalties at a dose of 80 mg/kg. The following is the total number of punishment responses in the pre-test and test period for the indicated compounds for four mice tested:

Compound dose (mg/kgPO) with penalty test for total response number in pre-test

7-〔3-〔4- 27.5 39 44

(2-Pyrimidinyl) radicals

1-Piperazinyl) propan 55 78 147

Oxy ] -2H-benzene

Benzopyran-2-one 80 23 77

The pre-test response number is the number of responses accumulated during the test period within 3 minutes of the start of non-dosing.

An increase in the number of responses (decrease in conflict) during the test period of (a) indicates less calm activity. This can be represented by an increase in the test/pre-test ratio. The overall response rate is a measure of debilitating side effects. A decrease in the total response number indicates a side effect.

The compounds of the present invention may be prepared and administered in a variety of oral or parenteral dosage forms. Pharmaceutical forms, either as compounds of formula I or as pharmaceutically acceptable salts of the corresponding compounds of formula I, or as mixtures of these compounds and/or salts, as active ingredients, will be apparent to the person skilled in the art.

The inert pharmaceutically acceptable carrier used to prepare the pharmaceutical compositions from the compounds described herein may be either solid or liquid. Solid state patent medicine includes powder, tablet, dispersed granule, capsule, cachet and suppository. The solid carrier can be one or more substances, can also be used as a diluent, a flavoring agent, a solubilizer, a lubricant, a suspending agent, an adhesive or a tablet dispersing agent, and can also be a sealing material. In the case of powders, the carrier is a finely divided solid which is admixed with the finely divided active compound, and in the case of tablets, the active compound is admixed with a proportion of the carrier having the desired binding properties to form the desired shape and size. Powders and tablets preferably contain 5 or 10 to about 70% of the active ingredient. Suitable solid carriers are, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparing" refers to the process of preparing by mixing the active compound with a sealing material as a carrier to form a capsule in which the active ingredient (with or without other carriers) is surrounded by a carrier. Similarly, cachets were also prepared. The tablet, powder, cachets and sachets can be used in solid dosage forms and are suitable for co-administration.

Liquid formulations include solutions, suspensions and emulsions. For example, water or a water-propylene glycol solution, can be used for parenteral injection. Liquid formulations may also be produced in aqueous polyethylene glycol solutions. Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water, and then adding suitable colorants, flavoring agents, stabilizers or thickening agents, as desired, and suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water containing viscous materials.Such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents.

Preferably, the medicine is in unit dosage form. In this way, the patent is once again divided into unit doses containing the active component. The unit dosage form may be a packaged product, each containing a quantity of a pharmaceutical, such as a packaged tablet, sachet and vial or ampoule powder. The unit dosage form may also be a sachet, cachet or tablet itself or an appropriate number of these packaged forms.

In unit dose formulations, the amount of active compound may vary or be adjusted between 1mg and 100mg depending upon the particular application and the potency of the active ingredient.

For use as an antipsychotic therapy, the compounds used in the methods of treatment of the present invention are initially administered at a dosage of about 0.1mg to about 10mg per kilogram per day, with a daily dosage of about 1.0mg to about 10mg per kilogram being more effective.

The compounds used in the methods of treatment of the present invention, when used as tranquilizer treatments, are initially administered at a dosage of about 0.1mg/kg to about 20mg/kg per day, with about 1mg/kg to about 3mg/kg being more effective.

However, the dosage may vary depending on the needs of the patient, the severity of the condition, and the compound being used. Determining the appropriate dosage for a particular situation is within the skill of the artisan. Generally, at the time of treatment, a smaller dose is started, which is smaller than the optimum dose of the compound. The dosage is then stepped up with smaller increments until the optimum effect under the particular condition is reached. For convenience, the total daily dose is subdivided into several portions and, if desired, taken in proportion throughout the day.

The following non-limiting examples illustrate preferred methods by which the inventors prepare the compounds of the present invention.

Example 1

7- [3- (4-Phenyl-1-piperazinyl) propoxy ] -2H-1-benzopyran-2-one 7- (3-halopropoxy) -2H-1-benzopyran-2-one

A mixture of 32g (0.3 mol) of 7-hydroxy-2H-1-benzopyran-2-one, 43g (0.3 mol) of anhydrous potassium carbonate and 48g (0.3 mol) of 1-bromo-3-chloropropane is stirred in 350ml of acetone under reflux for 18 hours. The mixture was filtered and the filtrate evaporated under vacuum. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated under vacuum. The remaining crude product was recrystallized from ethyl acetate-petroleum ether. Thus, 32g (68%) of a solid was obtained, i.e. a mixture containing 7- (3-chloropropoxy) -and 7- (3-bromopropoxy) -2H-1-benzopyran-2-one having a melting point of 92-98 ℃.

7- [3- (4-Phenyl-1-piperazinyl) propoxy ] -2H-1-benzopyran-2-one

A mixture consisting of 6.3g (0.025 mol) of 7- (3-halopropoxy) -2H-1-benzopyran-2-one, 10g (0.12 mol) of sodium bicarbonate and 4.1g (0.025 mol) of 1-phenylpiperazine was stirred in 100ml of dimethylformamide and heated at 80℃for 16 hours. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in dichloromethane and extracted with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated under vacuum. The residue was crystallized from ethyl acetate to give 5.9g (61%) of the title compound having a melting point of 117-118 ℃.

Example 2

7- [3- [4- (2, 3-Xylyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one

By the same method as in example, but replacing 1-phenylpiperazine with 4.8g (0.025 mol) of 1- (2, 3-xylyl) piperazine, 3.7g (37%) of the title compound was obtained from ethyl acetate and had a melting point of 89 ℃. The corresponding hydrochlorides can be obtained by dissolving the free base in hydrochloric acid containing 10% isopropanol and diluting with ethyl acetate, the melting point of which is 247-250 ℃.

Example 3

In a similar manner to example 1, the following compounds were prepared:

7- [ 3- (4-phenyl-1-piperazinyl) -propoxy ] -4-methyl-2H-1-benzopyran-2-one having a melting point of 127-130 ℃, hydrochloride thereof having a melting point of 253 ℃;

7- [3- [4- (2, 3-xylyl) -1-piperazinyl ] propoxy ] -4-methyl-2H-1-benzopyran-2-one hydrochloride having a melting point of 253-255 ℃;

7- [3- [4- (2-tolyl) 1-1 piperazinyl ] propoxy ] -2H-benzopyran-2-one with a melting point of 123-125 ℃;

7- [4- (4-phenyl-1-piperazinyl) -butoxy) -2H-1-benzopyran-2-one having a melting point of 145-147 ℃;

7- [3- (4-phenyl-1-piperazinyl) propoxy ] -4-trifluoromethyl-2H-1-benzopyran-2-one, dihydrochloride, melting point 190 ℃;

7- [ 3- (4- (3-tolyl-1-piperazinyl) propoxy ] -2H -1-Benzopyran-2-one hydrochloride having a melting point of 217-220 ℃;

7- [3- [4- (4-tolyl) -1-piperazinyl) propoxy ] -2H-1-benzopyran-2-one with a melting point of 140-142 ℃;

7- [ 3- [4- (3-chlorophenyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one hydrochloride having a melting point of 228 ℃;

7- [3- [4- (4-chlorophenyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one having a melting point of 129-131 ℃;

a hydrochlorid compound of 7- [3- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one, with a melting point of 215 ℃;

7- [3- [4- (3, 4-xylyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one having a melting point of 132 ℃ and a hydrochloride having a melting point of 220 ℃;

7- [3- [ 4- (3, 4-dichlorophenyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one with a melting point of 135-136 ℃;

8- [3- [ 4-phenyl-1-piperazinyl) propoxy ] -2H-1-benzopyran-2-one having a melting point of 95-97 ℃;

7- [3- [4- (2-pyrimidinyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one with a melting point of 135-137 ℃;

7- [3- [ 4- (3-chloro-2-pyridinyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one hydrochloride having a melting point of 235-238 ℃;

7- [3- [4- (3-pyridyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran having a melting point of 122-125 ℃;

7- [3- [ 4- (6-fluoro-2-pyridinyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one hydrochloride having a melting point of 241-243 ℃;

7- [ 3- [4- (6-bromo-2-pyridinyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one, melting point 95-97 ℃;

7- [3- [4- (5-methyl-2-pyridinyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one, melting point 120-122 ℃;

7- [3- [4- (3-methyl-2-pyridinyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one hydrochloride having a melting point of 210-215 ℃;

7- [3- [4- (4-methyl-2-pyridinyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one, melting point 113-115 ℃;

7- [3- [4- (6-methyl-2-pyridinyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one, melting point 105-107 ℃;

7- [3- [1,2, 3, 6-tetrahydro-4-phenyl-1-pyridinyl) propoxy ] -2H-1-pyran-2-one, melting point 127 ℃;

7- [2- [1,2, 3, 6-tetrahydro-4-phenyl-1-pyridinyl) ethoxy ] -2H-1-benzopyran-2-one, melting point 120-125 ℃;

7- [ 4- [1, 2,3, 6-tetrahydro-4-phenyl-1-pyridinyl) propoxy ] -2H-1-benzopyran-2-one hydrochloride having a melting point of 195 ℃, and

7- [ 3- [1,2, 3, 6-Tetrahydro-4-phenyl-1-pyridinyl) propoxy ] -4-methyl-2H-1-benzopyran-2-one hydrochloride having a melting point of 219-221 ℃;

7- [ 3- [4- (2-methylthiophen) -1-piperazinyl ] -2H-benzopyran-2-one hydrochloride having a melting point of 228-232 ℃;

7- [3- [4- (2-methoxyphenyl) -1-piperazinyl ] propoxy ] -2H-benzopyran-2-one hydrochloride having a melting point of 228-231 ℃;

7- [3- [1,2, 3,4,5, 6-hexahydro-4-phenyl-1-pyran-2-one hydrochloride having a melting point of 218-221 ℃;

7- [ 3- [4- (2-pyrazinyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one having a melting point of 176-179 ℃, and

7- [3- [4- (2-Thiazolyl) -1-piperazinyl ] propoxy ] -2H-1-benzopyran-2-one hydrochloride having a melting point of 167-170 ℃.

Example 4

7- [3- (4-Phenyl-1-piperazinyl) propoxy ] -4-propyl-2H-1-benzopyran-2-one

N- (3-chloropropoxy) N ⁴ -phenylpiperazine was prepared as described in journal Ind.J.chem.435 (1982). That is, 87g (0.55 mole) of 1-bromo-3-chloropropane was added dropwise to a stirred solution of 81g (0.5 mole) of N-phenylpiperazine, 100ml of acetone and 75ml of 25% aqueous sodium hydroxide. The organic layer was separated, concentrated, slurried with ethyl acetate, then washed, dried over magnesium sulfate, and finally concentrated to an oil weighing 85g, which was confirmed by thin layer chromatography and mass spectrometry as the title compound.

4.6G (0.02 mole) of the above oily compound was reacted with 4.4g (0.02 mole) of 7-hydroxy-4-propylcoumarin and 4g of anhydrous potassium carbonate in 100ml of dimethylformamide. The reaction mixture was stirred at 85-95 ℃ for 16 hours, and the mixture was filtered, concentrated, and the methylene chloride solution was washed with sodium bicarbonate to extract an oil, which was then dried over magnesium sulfate and concentrated. The oil was left to solidify and recrystallised from ethyl acetate to give 5g of 7- [ 3- (4-phenyl-1-piperazinyl) propoxy ] -4-propyl-2H-1-benzopyran-2-one having a melting point of 114-116 ℃.

Example 5

7- [3, 6-Dihydro-4- (2-thienyl) -1 (2H) -pyridinyl ] -propoxy-2H-1-benzopyran-2-one, 4- (2-thienyl) tetrahydropyridine

A nitrogen-deficient solution of 1.3g (0.01 mole) AlCl ₃ and 40ml diethyl ether was added at 15℃to a stirred suspension of 1.2g (0.03 mole) LAN, 100ml diethyl ether and 75ml tetrahydrofuran, and then stirred for a further 15 minutes. To the stirred suspension was slowly added a solution of 3g (0.018 mole) 4- (2-thienyl) -pyridine and 30ml tetrahydrofuran. The mixture was stirred at room temperature for 5 hours, and then dissociated by careful addition of 2ml of H ₂ O, 3ml of 40% NaOH and 2ml of H ₂ O. The mixture was filtered and evaporated under vacuum. The residue was dispersed in 1N HCl-diethyl ether. The aqueous fraction was mixed with dichloromethane and basified with concentrated NaOH, the dichloromethane layer was dried (MgSO ₄) and evaporated in vacuo to give 2g of 4- (2-thienyl) -tetrahydropyridine.

Mass spectrum is calculated to be 165.25

Theoretical value (Found) of 165

2.9G (0.012 mole) of the 7- (3-chloropropoxy) -2H-1-benzopyran-2-one sample prepared in example 1 above, 2g (0.012 mole) of 4- (2-thienyl) tetrahydropyridine and 5g of NaHCO ₃ were stirred in 80ml of DMF at 80-90℃for 7 hours, then at room temperature overnight, then filtered and evaporated in vacuo. The residue in dichloromethane was washed with NaHCO ₃, dried over MgSO ₄ and then in true senseEvaporating under air. Thus, 4.3g of 7- [3, 6-dihydro-4- (2-thienyl) 1- (2H) -pyridinyl ] propoxy ] -2H-1-benzopyran-2-one were obtained as a dark oil. The oil was dissolved in 20ml of 2-propanol and treated with 3ml (20% 2-propanol in hydrogen chloride solution) to give 2.4g of the individual hydrochlorides with a melting point of 235-7 ℃.

The following analysis and calculation: C ₂₁H₂₁NO₃S.HCl.0.5H₂ O

C,60.99;H,5.62;N,3.39

Theoretical value (Found) is C,61.06, H,5.60, N,3.27

Claims

1. A process for preparing a compound of the formula or an acid addition salt thereof,

Wherein n is an integer of 2 to 5, R is hydrogen, lower alkyl, trifluoromethyl, or lower alkoxy, R ₁ is a group represented by the following formula;

In the middle of

Ar is phenyl, or phenyl substituted by lower alkyl, lower alkoxy, lower thioalkoxy, halogen or trifluoromethyl, het is 2-,3-, or 4-pyridinyl or by lower alkyl, lower alkoxyOr halogen-substituted 2-, 3-, or 4-pyridinyl, 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-furyl, or 2-or 3-furyl substituted by lower alkyl or halogen, or 2-or 5-thiazolyl substituted by lower alkyl or halogen, except that the following compounds, i.e. n is 3, R is methyl and R ₁ is a group of the formula:

(wherein Ar is phenyl) except for the compounds represented by the formula,

Characterized in that the molecular formula is as follows

(Wherein X is a leaving group)

The compounds and the formula are as follows

Wherein Ar and Het are as defined above) in an inert solvent in the presence of a neutralizing agent at elevated temperature.

2. A process according to claim 1, characterized in that the compound produced has the following structure:

3. A process according to claim 2, characterized in that R is hydrogen.

4. A method according to claim 3, characterized in that R ₁ is one of the groups of the formula:

In the middle of

Ar is phenyl or phenyl substituted by methyl, methoxy, thiomethoxy or chlorine, het is 2-, 3-or 4-pyridinyl, 2-, 3-or 4-pyridinyl substituted by methyl, chlorine or bromine, 2-, 4-or 5-pyrimidinyl, 2-pyrazinyl or 2-or 5-thiazolyl.

5. A process according to claim 4, wherein R ₁ is one of the groups of the formula:

Wherein Het is 2-, 3-or 4-pyridinyl, 2-, 4-or 5-pyrimidinyl, 2-pyrazinyl, or 2-or 5-thiazolyl.

6. The method according to claim 5, wherein n is equal to 3 or 4.

7. A process according to claim 6, wherein the compound obtained is 7- [3- (4-phenyl-1-)

Oxazinyl) -propoxy ] -2H-1-benzopyran-2-one or a pharmaceutically acceptable acid addition salt of said compound.

8. A process according to claim 6, wherein the compound obtained is 7- [3- [4- (2-pyrimidinyl) -1-)Oxazinyl-propoxy) -2H-1-benzopyran-2-one or a pharmaceutically acceptable acid addition salt of said compound.

9. A process according to claim 6, wherein the compound obtained is 7- [ 3- (1, 2,3, 6-tetrahydro-4-phenyl-1-pyridinyl) -propoxy ] -2H-1-benzopyran-2-one or a pharmaceutically acceptable acid addition salt of the compound.

10. A process according to claim 6, wherein the compound obtained is 7- [ 4- (4-phenyl-1-)

Oxazinyl) butoxy ] -2H-1-benzopyran-2-one or a pharmaceutically acceptable acid addition salt of the compound.

11. A process according to claim 6, wherein the compound obtained is 7- [3, 6-dihydro-4- (2-thienyl) -1 (2H) -pyridinyl ] -propoxy ] -2H-1-benzopyran-2-one.