KR910000165B1 - Process for preparing 1.2-benzisoxaxol-3-y1 and 1.2-bengisothiazole-3yl derivatives - Google Patents

Abstract

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Description

Method for preparing 1,2-benzisoxazol-3-yl and 1,2-benzisothiazol-3-yl derivatives

The present invention relates to a method for preparing 1,2-benzisoxazol-3-yl and 1,2-benzisothiazol-3-yl derivatives.

The present invention is particularly useful for treating various diseases that have antipsychotic properties and serotonin release is very important. 3-piperidinyl-1,2-benziso-thiazole and 3-pyridinyl-1,2-benzisoxazole And it relates to a method for producing a pharmaceutically acceptable acid addition salt thereof.

U.S. Patent Nos. 4,352,811 and 4,458,076 describe 3-piperidinyl-1,2-benzisoxazole and 3-piperidinyl-1,2-benzisothiazole having antipsychotic and analgesic properties. It is. However, compounds of the present invention are compounds in which the substituent at the 1-position of the piperidine residue is different from these preceding compounds.

The present invention relates to 1,2-benzazole having the following general formula (I) and pharmaceutically acceptable acid addition salts thereof.

Wherein R is hydrogen or C _1-6 alkyl; R ¹ and R ² are each independently selected from the group consisting of hydrogen, halo, hydroxy, C _1-6 alkyloxy and C _1-6 alkyl; X is O or S; Alk is C _1-4 alkanediyl; Or Q is in general formula (a)

Or in formula (b)

의 기로서;

As a group of;

Wherein Y ¹ and Y ² are each independently O or S; R ³ is hydrogen, C _1-6 alkyl, C _1-6 alkyloxy, trifluoromethyl, nitro, cyano, hydroxy, (C _1-10 alkylcarbonyl) oxy, amino, mono-and-di ( Calculated from the group consisting of C _1-6 alkyl) amino, (C _1-10 alkylcarbonyl) amino, phenylmethoxy and azido; R ⁴ is hydrogen or halo; R ⁵ is hydrogen or C _1-6 alkyl; Z is -S-, -CH ₂ -or -CR ⁶ = CR ⁷ -so that R ⁶ and R ⁷ are each independently hydrogen or C _1-6 alkyl; And A is -CH ₂ -CH _2- , -CH ₂ -CH ₂ -CH ₂ -or -CR ₈ = CR ₉ -and R ⁸ and R ⁹ are each independently hydrogen, halo, amino or C _{1 -6} alkyl.

In the foregoing definitions, the term "halo" means fluoro, chloro, bromo and iodo; "C _1-6 alkyl" is a straight and branched chain saturated hydrocarbon having 1 to 6 carbon atoms such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like A group; "C _1-4 alkanediyl" means a divalent straight or branched alkanediyl group having 1 to 4 carbon atoms, such as methylene, ethylene, propylene, butylene and the like; Further, "C _1-10 alkyl" means a C _1-6 alkyl group defined earlier and heptyl, nonyl and 7 to 10 carbon atoms having their advanced analogs such analogs.

Preferred compounds in the present invention are those wherein Q is R ³ is hydrogen, halo, C _1-6 alkyl, C _1-6 alkyloxy, trifluoromethyl, hydroxy, amino or polydodo, and R ⁴ is hydrogen the compound attributable to (a); Or Q is R ⁵ is C _1-6 alkyl, or A is -CH ₂ -CH _2- , -CH ₂ -CH ₂ -CH ₂ -or -CR ⁸ = CR ^{9-, wherein} R ⁸ and R Are each independently a group of the formula (b) wherein hydrogen or C _1-6 alkyl. Particularly preferred compounds are those wherein R is hydrogen, R ¹ is hydrogen or halo, and R ² is hydrogen, halo, hydroxy or C _1-6 alkyloxy.

More particularly preferred compounds include compounds of formula (a) wherein Q is R ³ is hydrogen, halo or methyl and Y ¹ is 0 among the particularly preferred compounds described above; Or Q is -ZA- is -S-CH ₂ -CH ₂ , -S- (CH ₂ ) _3- , -S-CH ⁸ = CH ^9- , CH = CH-CR ⁸ -CR ⁹ -or -CH ₂ -CH ₂ -CH ₂ -CH _2- , wherein R ⁸ and R ⁹ are each independently a group of the formula (b) wherein hydrogen or methyl. Particularly preferred compounds are those in which R ¹ is hydrogen and R ² is hydrogen, halo, hydroxy or methoxy of the more particularly preferred compounds described above.

Most preferred compounds are 3- [2- [4- (6-fluoro-1,2-benzisooxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one; And 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2- a] pyrimidin-4-one; And their pharmaceutically acceptable acid addition salts.

Compounds of general formula (I) can generally be prepared by reacting a suitable reactive ester of the general formula (II) with a suitably substituted piperidine of the general formula (III).

W in the reactive ester (II) is, for example, chloro, bromo or iodo and halo; Or a reactive ester residue such as a sulfonyloxy group such as methylsulfonyloxy, (4-methylphenyl) sulfonyloxy and the like.

Reaction of compound (II) and (III) is aromatic hydrocarbons, such as benzene, methylbenzene, dimethylbenzene, and the like, for example; Lower alkanols such as methanol, ethanol, 1-butanol and the like; Ketones such as 2-propanone, 4-methyl-2-pentanone and the like; Ethers such as 1,4-dioxane, 1,1-oxybisethane, tetrahydrofuran and the like; N, N-dimethylformamide (DMF), N, N-dimethyl acetamide (DMA), nitrobenzene; It can conveniently proceed in an inert organic solvent such as 1-methyl-2-pyrrolidinone and the like.

For example, alkali or alkaline earth metal carbonates, bicarbonates, hydroxides, alkoxides or hydrides such as sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydride and the like, or for example N, N- Tertiary amines, such as diethylethanamine, N- (1-methylethyl) -2-propanamine, 4-ethyl morpholine and the like, and suitable bases, such as organic bases, are added to remove acids released during the reaction. It can also be used to In certain cases the addition of iodine salts, preferably alkali metal iodine, is required. The reaction rate can be accelerated by increasing the temperature somewhat.

Compounds of general formula (I) may also be prepared according to known methods for preparing compounds containing groups of general formula Q in their structural formulas. For example, the compound of general formula (I) and the bamboo compound (Ib) which Q is a group of general formula (b) react with the amine of the following general formula (VI), and the cyclizing agent of the following general formula (VII), for example. Or a known cyclization method for producing pyrimidin-4-one, such as cyclizing a reagent of the following general formula and an amine of the following general formula.

The preceding cyclization reactions are generally, if necessary, for example aliphatic, cycloaliphatic or aromatic hydrocarbons such as hexane, cyclohexane, benzene and the like; Pyridine; The reaction can proceed by stirring the reactants together in a suitable reaction inert solvent such as N, N-dimethylformamide and the like amides thereof. It may be desirable to accelerate the reaction rate.

In the above schemes L and L 'are each independently suitable such as (C _1-6 alkyl) oxy, hydroxy, halo, amino, mono- and di- (C _1-6 alkyl) amino and analogs thereof. Leaving group.

According to the same cyclization method, the compound of formula (I-b) can also be prepared by cyclizing the intermediate of formula (VII) with the reagent of formula (VII).

Compounds of general formula (Ib) in which Z is S, ie compound (Ib-1), can also be prepared by cyclizing a 2-mercaptopyrimidinone of the following general formula (XI) with a reagent of the following general formula (XII): Can be.

W 'in the general formula (XII) has the same meaning as the definition described in the foregoing W.

인 일반식(I-b-1)의 화합물, 즉, 화합물(I-b-1-a)은 또한 일반식(XI)의 2-메르캅토피리미디논과 다음 일반식(XI)의 시약을 고리화 반응시켜 제조할 수 있다.A

The compound of phosphorus general formula (Ib-1), ie compound (Ib-1-a), is also prepared by cyclizing 2-mercaptopyrimidinone of general formula (XI) with a reagent of the following general formula (XI) can do.

Cyclization reactions to prepare compounds of formulas (Ib-1) and (Ib-1-a) are generally required, for example, aliphatic, cycloaliphatic or aromatic, such as hexane, cyclohexane, benzene and the like hydrocarbon; Pyridine; It can proceed by stirring the reactants together in a suitable reaction inert solvent such as N, N-dimethylformamide and the like amides thereof. The reaction temperature may be raised to accelerate the reaction rate. In certain cases it may be desirable to proceed with the reaction at the reflux temperature of the reaction mixture.

Compounds of formula (I) can also be converted to one another according to known functional group conversion methods.

For example, a compound of formula (la) in which R ³ is amino can be derived from the corresponding nitro substituted quinazoline according to known nitro-amine reduction methods. An example of a suitable nitro-amine reduction method may be a catalytic hydrogenation reaction carried out in a relatively polar solvent such as alcohol (eg methanol or ethanol) in the presence of a suitable catalyst such as charcoal attached platinum. In certain cases it may be useful to add a suitable catalyst poison, such as thiophene.

Compounds of formula (Ia) in which R ³ is phenylmethoxy can be converted to compounds of formula (Ia) in which R ³ is hydroxy according to known catalytic hydrogenolysis reactions; Compounds of formula (Ia) wherein R ³ is amino or hydroxy are reacted with a suitable acylating agent such as acyl halide or acid anhydride such that R ³ is (C _1-10 alkylcarbonyl) amino or (C _1-10 Can be converted to a compound of formula (la) which is alkylcarbonyl) oxy; Compounds of general formula (Ia) in which R ³ is an amino group convert this amino group to a diazonium group using nitrous acid or a suitable alkali metal or earth metal salt thereof, followed by sodium azide or other suitable alkali metal or alkaline earth metal By converting into an azide group as a zide, R <^3> can be converted into the general formula (Ia) compound whose azido group.

Compounds of general formula (I) have basic properties and therefore these compounds can be converted to nontoxic acid addition salt forms having therapeutic activity by treatment with a suitable acid. Examples of suitable acids include halogen acids such as hydrochloric acid, bromic acid and the like and inorganic acids such as sulfuric acid, nitric acid, phosphoric acid and the like; Or acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z) -2-butenedioic acid, (E) -2 -Butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, And organic acids such as 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and organic acids thereof. Conversely, these salt form compounds can be converted to the free base form by treatment with alkali.

Many of the intermediates and starting materials in the above-mentioned preparations are known compounds which can be prepared according to known methods for preparing the compounds mentioned or similar compounds. For example, intermediates of Formula (II) and their preparation are described in US Pat. Nos. 4,35,127; 4,342,870; 4,342,870; 4,443,451 and 4,485,107. Other intermediates may be prepared according to known methods for preparing analogous compounds and some of these intermediates are described below.

The intermediate of general formula (III) is generally obtained by reacting benzoylpiperidine of general formula (XIV) with hydroxylamine, which is then halo is preferably fluoro, and then the oxime of general formula (XV) Benzoylpiperi of the following general formula (XIV) according to a known method such as cyclization reaction according to a known method, and thus obtaining an intermediate of the following general formula (III) in which X is O, that is, compound (III-a) It can be prepared from Dean.

Intermediates of general formula (III), wherein X is S, the following compound (III-b), can be prepared according to methods analogous to those described in US Pat. No. 4,458,076.

Compounds of formula (I) and their pharmaceutically acceptable acid addition salts act as potent antagonists of a series of neurotransmitters, and as a result these compounds have useful pharmacological properties. For example, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts have potent antipsychotic and haserotonin activity.

Due to the pharmacological activity of these compounds, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used for the treatment of mental disorders, for example, bronchial tissues, serotonin in blood vessels, veins, arteries, It can be used in the treatment of various diseases in which serotonin release is the main cause, such as blocking contraction. The compounds of the present invention also have useful properties as sedatives, anxiolytics, anti-asthmatics, antipsychotics, muscle and cardiovascular agents, and as a result these compounds are for example in stress situations such as during transportation and similar situations. Can be used to protect warm-blooded animals under The title compound may be useful as a protective agent for endotoxin shock and as a antidiarrheal agent.

Given the useful pharmacological properties of these compounds, the title compounds can be formulated in a variety of pharmaceutical forms for administration purposes. To prepare a pharmaceutical composition of the present invention, an effective amount of a base compound or an acid addition salt form of a specific compound as an active ingredient is mixed with a pharmaceutically acceptable carrier, and these carriers may be used in various forms depending on the type of preparation required for administration. There is a number. These agent compositions are preferably in unit dosage forms suitable for rectal, transdermal or parenteral injection. For example, any of the pharmaceutical carriers useful in the preparation of the composition in oral dosage form may be used, e.g. water, glycols, oils, alcohols in the case of oral solutions such as suspensions, syrups, elixirs and solutions. And analogues thereof, and solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrating agents may be used in the case of powders, agents, capsules and tablets. Because of the ease of administration, tablet o capsules are the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are used, of course. In parenteral compositions, the carrier may contain other ingredients, for example, to increase solubility, but usually the majority consists of sterile water. In injection solutions, for example, the carrier consists of a saline solution, a glucose solution or a mixture of these saline and glucose solutions. Injectable suspensions or suitable liquid carriers, suspensions light analogs thereof and the like can be prepared. In a composition suitable for transdermal administration, the carrier optionally consists of a permeation accelerator and / or a suitable wetting agent in combination with small amounts of certain additives that do not cause significant harm to the skin. These additives may facilitate the administration to the skin and / or may facilitate the preparation of the required composition. These compositions can be administered by various methods such as transdermal adhesives, sprays, ointments, and the like. Of course, the acid addition salt of compound (I) is more suitable for preparing an aqueous solution composition because of increased water solubility compared to the corresponding base form.

It is particularly advantageous to prepare the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to a physically divided unit suitable in a single dose, each containing a certain amount of the active ingredient calculated to achieve the required therapeutic effect with the required pharmaceutical carrier . Examples of such dosage unit forms include tablets (including narcotics or dragees), capsules, pills, powder pockets, wafers, injection solutions or suspensions, teaspoon doses, tablespoon doses, and the like, as well as many divided forms thereof.

In view of the usefulness of the title mixture in the treatment of mental disorders, it is obvious that the present invention provides a treatment method for a warm-blooded animal suffering from mental disorders, and the treatment method is a compound of formula (I) in an effective amount of a pharmaceutical amount. Or systemic administration of a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutical carrier. Those skilled in treating on-time disease will be able to easily calculate the effective amount from the experimental results presented herein. In general, the effective amount is estimated to be from 0.01 mg / kg body weight to 4 mg / kg body weight, more preferably from 0.04 mg / kg body weight to 2 mg / kg body weight.

The following examples are provided to illustrate the present invention, but the scope of the present invention is not limited thereto. Unless otherwise noted, all parts are parts by weight and all temperatures are in degrees Celsius.

Example 1

While cooling a solution of 95 parts of 1-acetyl-4-piperidine carbonyl chloride in 65 parts of dichloromethane in a stirred mixture of 65 parts of 1,3-difluorobenzene, 130 parts of aluminum chloride, and 195 parts of dichloromethane, Added dropwise. After the dropwise addition, stirring was continued for 3 hours at room temperature. The reaction mixture was poured into a mixture of crushed ice and hydrochloric acid and the product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated to yield 48 parts (36%) of 1-acetyl-4- (2,4-difluorobenzoyl) piperidine as a residue (Intermediate 1).

A mixture of 48 parts 1-acetyl-4- (2,4-difuorobenzoyl) piperidine and 180 parts 6N hydrochloric acid solution was stirred and heated to reflux for 5 hours. The reaction mixture was evaporated and the residue was stirred in 2-panol. The product was filtered off and dried to afford 39 parts (83%) of (2,4-difluorophenyl) (4-piperi-mono) methanone hydrochloride (Intermediate 2).

A mixture of 12 parts of (2,4-difluorophenyl (4-piperidinyl) methanone hydrochloride, 12 parts of hydroxylamine hydrochloride and 12 parts of ethanol was stirred at room temperature and further 10.5 parts of N, N-dimethylethane The amine was added and the whole solution was stirred and heated to reflux for 3 h After cooling, the precipitated product was filtered off and dried to give 11 parts (100%) of (2,4-difluorophenyl) (4 -Piperidinyl) methanone, oxime (D intermediate 3).

A mixture of 11 parts (2,4-difluorophenyl (4-piperidinyl) methanone, oxime, 25 parts potassium hydroxide and 25 parts water was stirred and heated at reflux for 2 hours. The extract was dried, filtered and evaporated, and the residue was crystallized in petroleum ether to give 6.8 parts of 6-fluoro-3- (4-piperidinyl) 1,2-benz-isooxa. A sol was obtained (intermediate 4).

Example 2

Stir a mixture of 50 parts 2-thiazolamine, 76 parts 3-acetyl-4,5-dihydro-2- (3H) -furanone, 1.2 parts concentrated hydrochloric acid and 270 parts methylbenzene and using a water-separator Heated to reflux for 2 hours. The reaction mixture was cooled and 340 parts phosphoryl chloride was added at 20-30 ° C. The entire solution was slowly heated to 100-110 ° C. and stirring continued at this temperature for 2 hours. The reaction mixture was evaporated and the residue was poured into a mixture of crushed ice and ammonium hydroxide. The product was extracted with trichloromethane. This extract was dried, filtered and evaporated. This residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (95: 5 volume ratio) as eluent. Pure fractions were collected and the eluent was evaporated. The residue was crystallized in a mixture of 2-propanol and 1,1-oxybisethane to give 36 parts of 6- (2-chloroethyl) -7-methyl-5H-thiazolo- [3,2-a] pyrimidine-5- One was obtained (intermediate 5).

Example 3

A mixture of 30 parts 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 25 parts potassium carbonate, 270 parts N, N-dimethylacetamide and 75 parts water was stirred at room temperature, followed by 36 parts 1 , 3-dibromopropane was added all at once; (Temperature rises to 50 ° C). The whole solution was stirred overnight at room temperature. The reaction mixture was evaporated and water was added to the residue. The solid product was washed with water and dried under vacuum at 100 ° C. to give 21 parts (58%) of 3,4-dihydro-7- (2-hydroxyethyl) -8-methyl-2H, 6H-pyrimido [ 2,1-b] [1,3] thiazin-6-one was obtained. Melting point 155 ° C. (intermediate 6).

The following compounds were also prepared following the same method and using the same equivalents of suitable starting material: 2,3-dihydro-6- (2-hydroxyethyl) -7-methyl-5H-thiazolo [3,2 -a] pyrimidin-5-one; Melting point 148.7 ° C. (intermediate 7).

Example 4

20 parts 3,4-dihydro-7- (2-hydroxyethyl-8-methyl-2H, 6H-pyrimido [2,1-b] [1,3] thiazin-6-one, 50 parts acetic acid The mixture of 180 parts of 67% bromic acid-acetic acid solution was stirred and heated to reflux, stirring was continued at this reflux temperature overnight The reaction mixture was evaporated and the solid residue was triturated in 2-propanol. And dried to 24 parts (100%) of 7- (2-bromoethyl) -3,4-dihydro-8-methyl-2H, 6H-pyrimido- [2,1-b] [1,3 ] Thiazine-6-one, monohydrobromide was obtained; melting point 215 ° C. (intermediate 8).

The following compounds were prepared using the same equivalents of suitable starting material according to the same method; 6- (2-bromoethyl) -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one, monohydrocollide; Melting point 237.2 ° C. (Intermediate 9).

B. Preparation of Final Compound

Example 5

5.3 parts 3- (2-chloroethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride, 4.4 parts Stir the mixture of 6-fluoro-3- (4-piperidinyl) 1,2-benzisoxazole, 8 parts sodium carbonate, 0.1 parts potassium iodide and 90 parts N, N-dimethylformamide at 85-90 ° C. overnight It was. After cooling, the reaction mixture is poured into water. The product is filtered off and crystallized in a mixture of N, N-dimethylformamide and 2-propanol. The product was filtered off and dried to obtain 3.8 parts (46%) of 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl ] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one; Melting point 170.0 ° C. (Compound 1).

The following compounds were also prepared following the same method and using the same equivalents of a suitable starting material. 6- [2- [4- (6-fluoro-1,2-benzisooxazol-3-yl) -1-piperidinyl] ethyl] -7-methyl-5H-thiazolo [3,2-a ] Pyrimidin-5-one was obtained; Melting point 165.1 ° C. (Compound 2); 3- [2- [4- (6-fluoro-1,2-benzisooxazol-3-yl) -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a ] Pyrimidin-4-one; Melting point 177.9 ° C. (Compound 3). 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,7-dimethyl-4H-pyrido [1,2 -a] pyrimidin-4-one; Melting point 186.9 ° C. (Compound 4); 3- [2- [4- (1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one; Melting point 183.1 ° C. (Compound 5); 3- [2- [4- (1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,4 (1H, 3H) -quinazolindione monohydrochlorolide; Melting point> 300 ° C. (decomposition) (compound 6); 3- [2- [4- (1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one; Melting point 145.7 ° C. (Compound 7); 3- [2- [4- (6-hydroxy-1,2-benzisooxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl -4H-pyrido [1,2-a] pyrimidin-4-one; Melting point 213.1 ° C. (Compound 8).

In a similar manner, the following compounds were prepared: 3- [2- [4- (5-methoxy-1,2-benzisooxazol-3-yl) -1-piperidinyl] ethyl] -2-methyl-4H -Pyrido [1,2-a] pyrimidin-4-one; (Compound 9); 3- [2- [4- (6-fluoro-1,2-benzisooxazol-3-yl) -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a ] Pyrimidin-4-one; (Compound 10).

Example 6

3.3 parts 3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, 3.3 parts 6-fluoro-3- (4-piperidinyl)- A mixture of 1,2-benzisoxazole, 8 parts sodium carbonate, 1 part potassium iodide and 120 parts 4-methyl-2-pentanone was stirred and heated to reflux for 3 hours. The reaction mixture was cooled, and water was added to separate the layers. The organic phase was dried filtered and evaporated. The residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (95: 5 volume ratio) as eluent. Pure fractions were collected and the eluent was evaporated. The residue was crystallized in 4-methyl-2-pentanone to yield 1.2 parts (19%) of 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-pi. Ferridinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one was obtained; Melting point 170.4 ° C. (Compound 11).

Example 7

6.75 parts 3- (2-chloroethyl) 2,4- (1H, 3H) -quinazolindione, 6.61 parts 6- pullouro-3- (4-piperidinyl) 1,2-benzoisoxazole, 10 A mixture of parts sodium bicarbonate, 0.1 parts potassium iodide and 90 parts N, N-dimethylformamide was stirred and heated at 100-110 ° C. overnight. After cooling, the reaction mixture was poured into water, stirred and the product was filtered off and crystallized in N, N-dimethylformamide to crystallize in 4.8 parts (39%) of 3- [2- [4- (6-fluoro). -1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,4- (1H, 3H) -quinazolindione was obtained; Melting point 253.4 ° C. (Compound 12).

Example 8

7.4 parts 6- (2-bromethyl) -3,7-dimethyl-5H-thiazolo [3,2-a] pyrimidin-5-one monohydrobromide, 4.4 parts 6-fluoro-3- (4- Piperidinyl) -1,2-benzisoxazole, a mixture of 10 parts sodium carbonate and 90 parts N, N-dimethylformamide was stirred overnight at 80-85 ° C. After cooling, the reaction mixture was poured into water. The product was filtered off and purified by silica gel column chromatography using a mixture of trichloromethane and methanol (95: 5 volume ratio) as eluent. Pure fractions were collected and the eluent was evaporated. 2-propanol was added to the residue and the product was filtered off and dried to give 5.3 parts (62%) of 6- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl). -1-piperidinyl] ethyl] -3,7-dimethyl-5H-thiazolo [3,2-a] pyrimidin-5-one was obtained; Melting point 231.0 ° C. (Compound 13).

In a similar manner the following compounds were also prepared; 6- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thia Zolo [3,2-a] pyrimidin-5-one; Melting point 135.0 ° C. (Compound 14); 7- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -3,4-dihydro-8-methyl-2H, 6H -Pyrimido [2,1-b] [1,3] thiazin-6-one; Melting point 169.3 ° C. (Compound 15); 6- [2- [4- (1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2 -a] pyrimidin-5-one; Melting point 154.5 ° C. (Compound 16); 3- [2- [4- (6-fluoro-1,2-benzisooxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl -4H-pyrido [1,2-a] pyrimidin-4-one; (Compound 17); 3- [2- [4- (6-fluoro-1,2-benzisooxazol-3-yl) -1-piperidinyl] ethyl] -2,3-dihydro-2-thioxo-4 ( 1H) -quinazolinone; (Compound 18).

C. Pharmacological Experiment

The activity of the title compound as an antipsychotic agent was tested in two different test methods: apomorphine (C ₁₇ H ₇ NO ₂ ) in mice, tryptamin and norepinephrine (C ₈ HuNO ₃ ), and apomorphine testing in dogs. It was validated with experimental data obtained in more than two tests. These tests were conducted according to the method described below, and the experimental data are summarized in Table 1 below.

Example 9

Apomorphine (APO), Trytamine (TRY) and Norepinephrine (NOR) in Rats

In the present invention, a competent male wistar rat (body weight 240 ± 10 g) was used. After fasting overnight, these test mice were injected subcutaneously with an aqueous solution of the compound to be tested (1ml / 100g; time = 0) and transferred to an isolated observation cage. After 30 minutes (time = 30 minutes) 1.25 mg / kg of apomorphine hydrochloride (APO) was injected intravenously and observed for 1 hour for the presence of the following apomorphine-induced symptoms in these mice. Was done; Induced during frenzy and chewing homology.

After 1 hour (time = 90 minutes), 40 mg / kg of trytamine (TRY) was injected intravenously into the same experimental rats, and a strong seizure of typical left and right trytamine induced was observed. Two hours after pretreatment (time = 120 minutes), the same experimental rats were finally injected intravenously with 1.25 mg / kg of norepinephrine (NOR) and the possible mortality was investigated up to 60 minutes later.

The ED ₅₀ values of the compounds tested were listed in Table 1. The ED ₅₀ value referred to herein means a dose that can protect 50% of the life and death of experimental animals from apomorphine-, tryptamine- or norepinephrine-induced phenomena.

Apomorphine test in dogs

Arzneim. Frosch. (Drug Res.), 9, pp. 765-767 (1959). Janssen and C.J.E. The method described by Niemefeers was used. The compounds listed in Table 1 were injected subcutaneously at different doses and were subcutaneously administered apomorphine at a standard dose of 0.31 mg / kg after 1 hour.

The ED ₅₀ values of the compounds tested were listed in Table 1. An ED ₅₀ value referred to herein means a dose at which 50% of the experimental animals do not cause vomiting.

The compounds listed in Table 1 are not presented to limit the scope of the invention to these compounds, but merely to illustrate the useful pharmacological activity of all compounds within the scope of formula (I).

TABLE 1

D. Formulation Composition

The following formulations illustrate typical pharmaceutical compositions in dosage unit form suitable for systemic administration to animals and humans in accordance with the present invention.

The active ingredient (A.I.) used in these examples is a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

Example 10

[Oral Drops]

500 g of active ingredient (A.I.) was dissolved in 0.5 L of 2-hydroxy propanoic acid and 1.5 L of polyethylene glycol at 60-80 ° C. After cooling to 30 to 40 ° C., 35 L of polyethylene glycol was added and the mixture was well stirred. Then, a solution of 1750 g of sodium saccharin dissolved in 2.5 liters of purified water was added thereto, followed by stirring. Then, 2.5 liters of cocoa flavor and an appropriate amount of polyethylene glycol were added to make a volume of 50 liters. Was prepared. This obtained solution was filled into a suitable container.

Example 11

[Oral solution]

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxy benzoate were dissolved in 4 L boiling purified water. In 3 liters of this solution, 10 g of 2,3-dihydrocybutanedioic acid was first dissolved, followed by 20 mg of the active ingredient. The latter solution was mixed with the former residual solution and to this was added 12 L of 70% sorbitol solution. 40 g sodium saccharin was dissolved in 0.5 L water and 2 ml raspberry and 2 ml gooseberry stock solution were added. The latter solution was mixed with the former solution and an appropriate amount was added so that the total volume was 20 l to obtain an oral solution containing 20 mg of active ingredient per teaspoon (5 ml). The resulting solution was filled into a suitable container.

Example 12

[Product made in capsule]

20 g of the active ingredient (A.I.) 6 g sodium lauryl sulfate, 56 g lactose, 0.8 g clad phase silicon dioxide and 1.2 g magnesium stearate were vigorously stirred together. The resulting mixture was then filled into 1000 suitable hard gelatin capsules to give a capsule containing 20 mg of each active ingredient.

Example 13

[Film coating]

[Preparation of Tablet Co-A]

)을 용해한 용액으로 습윤시켰다. 이 습윤분말 혼합물을 사별 건조하고 또 재차 사별하였다. 이어 여기에 100g 미세 결정 셀루로즈(Avicel

)와 15g 경화식물유(Sterotex

)를 첨가하였다. 전체 용액을 잘 혼합하고 또 압착시켜서 정체 10,000개를 수득하였으며 이때 각 개 정체는 10mg의 활성 성분을 함유하였다.After a well-mixed mixture of 100 g active ingredient, 570 lactose and 200 g starch, it is mixed in about 20 mg water with 5 g sodium dodecyl sulfate and 10 g polyvinyl pyrrolidone (Kollidon-k90).

) Was wetted with a dissolved solution. This wet powder mixture was quenched and dried again. This is followed by 100 g microcrystalline cellulose.

) And 15g hardened vegetable oil (Sterotex)

) Was added. The whole solution was mixed well and pressed to yield 10,000 tablets, each containing 10 mg of active ingredient.

[covering]

)를 용해시킨 용액에 150ml 디클로로메탄중에 5g의 에틸셀루로즈(Ethocel 22cps

)를 용해시킨 용액을 첨가하였다. 이어 여기에 75ml의 디클로로 메탄과 2.5ml의 1,2,3-프로판트리올을 첨가하였다. 10g의 폴리에틸렌 글리콜을 응용시키고 또 75ml의 디클로로메탄에 용해하였다. 후자 용액을 전자 용액에 첨가하고 또 이어 2.5g의 마그네슘 옥타데칸오에이트, 5g의 폴리비닐피롤리돈과 30ml의 농축 색소현탁액(Opaspray K-1-2109

)을 첨가하고 또 전체 용액을 균질화시켰다. 이같이 수득된 혼합물을 사용해서 피복장치로서 정제 코-아를 피복하였다.10 g of methyl cellulose (Methocel 60 HG) in 75 ml modified ethanol

5 g of ethylcellulose (Ethocel 22cps) in 150 ml dichloromethane

) Was added to the solution. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were added thereto. 10 g of polyethylene glycol was applied and dissolved in 75 ml of dichloromethane. The latter solution was added to the former solution followed by 2.5 g magnesium octadecane oate, 5 g polyvinylpyrrolidone and 30 ml concentrated pigment suspension (Opaspray K-1-2109).

) Was added and the whole solution was homogenized. The mixture thus obtained was used to coat the purified co-a as a coating device.

Example 14

Injection solution

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl-4-hydroxy bezoate were dissolved in about 0.5 L of boiling water for injection. After cooling to about 50 ° C., 4 g of lactic acid, 0.05 g of propylene glycol and 4 g of active ingredient (A.I.) were added thereto while stirring. The solution was cooled to room temperature and supplemented with an appropriate amount of distilled water for injection to a volume of 1 l to give a solution having 4 mg of active ingredient per 7 ml. This solution was filtered sterilized (U.S.P. XⅦ p. 811) and filled into sterile containers.

Example 15

[Canceling]

)와 트리글리세리드(witepsol 555

) 혼합물 300g을 함께 용융시켰다. 이 후자 혼합물을 전자 용액과 잘 혼합하였다. 이같이해서 수득된 혼합물을 37 내지 38℃ 온도에서 모울드에 부어 넣어서 각각 30mg의 활성 성분을 함유하는 좌제 100개를 조제하였다.3 g of active ingredient was dissolved in a solution of 3 g of 2,3-dihydroxy butanedioic acid in 25 ml polyethylene glycol 400. 12g surfactant (SPAN

) And triglycerides (witepsol 555

) 300 g of the mixture were melted together. This latter mixture was mixed well with the former solution. The mixture thus obtained was poured into a mold at a temperature of 37 to 38 ° C. to prepare 100 suppositories each containing 30 mg of the active ingredient.

Claims (7)

A method for producing a compound of formula (I-b) or an acid addition salt thereof, wherein the compound of formula (II) is reacted with piperidine or acid addition salts of formula (III) in an inert solvent.

In the formula above, R ¹ is hydrogen, halo, hydroxy or C _1-4 alkyloxy, R ² is hydrogen or halo, X is O or S, Alk is C _1-4 alkanediyl, R ⁵ Is hydrogen or C _1-4 alkyl, Z is -S-, -CH ₂ -or -CR ⁶ = CR ^7- , R ⁶ and R ⁷ are each hydrogen or C _1-4 alkyl, and A is -CH ₂ -CH _2- , -CH ₂ -CH ₂ -CH ₂ -or -CR ₈ = CR ₉ -is a divalent group, R ⁸ and R ⁹ are each hydrogen, halo, amino or C _1-4 alkyl, W Is a reactive leaving group. The compound of claim 1, wherein 3- [2- [4- (6-fluoro-1,2-benziso-oxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one or 3- [2- [4- (6-fluoro-1,2-benzisoxazole-3 -Yl) -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, to prepare a compound of formula (Ib) or an acid addition salt thereof Way. The compound of claim 2, wherein 3- [2- [4- (6-fluoro-1,2-benzisooxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9- A method for producing a compound of the general formula (Ib) or an acid addition salt thereof, which is tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one. The compound according to claim 2, wherein 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2-methyl-4H-pyrido A process for producing a compound of the general formula (Ib) or an acid addition salt thereof that is [1,2-a] pyrimidin-4-one. The compound of claim 1, wherein R ⁵ is C _1-4 alkyl, A is a _{divalent group} of —CH ₂ —CH ₂ —, —CH ₂ —CH ₂ —CH ₂ —, or —CR ₈ = CR ₉ −, and R is ⁸ and R ⁹ are each hydrogen or C _1-4 alkyl, or a process for producing a compound of formula (Ib) or an acid addition salt thereof. The process for producing a compound of formula (Ib) or an acid addition salt thereof according to claim 5, wherein R ¹ is hydrogen or halo. The compound of claim 6, wherein ZA is -S-CH ₂ -CH _2- , -S- (CH ₂ ) _3- , -S-CR ⁸ = CR ^9- , wherein R ⁸ and R are each hydrogen or methyl, -CH = CH-CR ⁸ = CR ^9- , wherein R ⁸ and R ⁹ are each hydrogen or methyl, or -CH ₂ -CH ₂ -CH ₂ -CH _2- ; Method for producing the acid addition salt thereof.