JPH0215550B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 3-(1-piperidinylalkyl)-4H-pyrido[1,2-α]pyrimidine-4
-one derivatives, and their use as medicines. In JP-A-5-146497 and Ann.Rep.SankyoRes.Lab. 29 , 75-98
(1977), the amino group is morpholino-,
A number of 4H-pyrido[1,2-α]pyrimidin-4-one derivatives have been described bearing an aminoalkyl substituent in the 3-position which may be part of a piperidino- or piperazine residue. . Such compounds are useful as cardiovascular agents and are known to act on the central nervous system. The compounds of the present invention differ from conventional compounds in the presence of a special substituent on the piperidine ring and in their pharmacological activity. The present invention is based on the formula [wherein R ¹ and R ² are hydrogen, lower alkyl or halo; R ³ is hydrogen or lower alkyl; Alk is a lower alkylene group; R is hydrogen, lower alkyl, hydroxy or hydroxymethyl; ; X is C=O, CHOH,
[Formula] CH ₂ , [Formula] or C=NOH, and Ar is phenyl optionally substituted with one substituent selected from the group consisting of halo, lower alkyl and methoxy, or -X-Ar is the group as a whole Here, R ⁴ is hydrogen, lower alkyl, methoxy or hydroxy, or a pharmaceutically acceptable acid addition salt thereof. "Halo" as used in the above definitions generally refers to fluoro, chloro, bromo, and iodo; "lower alkyl" refers to straight and branched chain saturated hydrocarbon radicals having 1 to 6 carbon atoms; Examples include methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl, etc.; and "lower alkylene" as used in the definition of Alk refers to linear and Contains branched saturated alkylene. Preferred compounds within formula () are those in which R is hydrogen. Particularly preferred compounds are those in which R is hydrogen, X is C=O and Alk is a 1,2-ethanediyl group. Compound 3-[2
-[4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2
-α]pyrimidin-4-one is most preferred. The compounds of formula () are basic and therefore suitable acids such as inorganic acids such as hydrohalic acids such as hydrochloric acid, hydrobromic acid etc., and sulfuric acid, nitric acid,
or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, propanedioic acid, etc.
Butanedioic acid, (Z)-2-butenedioic acid,
(E)-2-Butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propanoic acid , alpha-hydroxymethylbenzenesulfonic acid, cyclohexane sulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc. can be converted into Conversely, the salt form can be converted to the free base form by treatment with alkali. Compounds of formula () can generally be prepared by reacting a suitable reactive ester of formula () with a suitably substituted piperidine of formula (). In the reactive ester (), R ¹ , R ² ,
R ³ and Alk are as defined above and W represents a reactive ester group such as halo, especially chloro, bromo or iodo, or a sulfonyloxy group such as methylsulfonyloxy, 4-methylphenylsulfonyloxy. In piperidine (),
R, X and Ar are as described above. The above reaction can be carried out according to standard N-alkylation methods. The reaction is preferably carried out using suitable reaction-inert organic solvents, such as lower alkanols such as methanol, ethanol, propanol, butanol, etc.; aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene, etc.; ethers such as 1,4-dioxane. ,1,
1′-oxybispropane etc.; ketones e.g. 4-
It is carried out in the presence of methyl-2-pentanone; N,N-dimethylformamide; nitrobenzene, etc. To scavenge the acid liberated during the reaction, suitable bases such as alkali or alkaline earth metal carbonates or bicarbonates can be used. Small amounts of suitable metal iodides, such as sodium or potassium iodide, can be added as reaction promoters. Some increase in temperature is appropriate to increase the rate of reaction, preferably the reaction is carried out at the reflux temperature of the reaction mixture. The compound of formula () is, for example, the Sankyo Research Institute Annual Report.
4H− as described in 29, 75–98 (1977).
It can also be produced according to a known cyclization method for producing pyrido[1,2-α]pyrimidin-4-one. For example, a compound of formula () may be used, for example, in J.
16 , 137-144 (1979), an appropriately substituted 2-aminopyridine () Expression ()
It can be produced by cyclization with a suitable cyclizing agent. R ¹ , R ² in reagents () and (),
R ³ , Alk, X, R and Ar are as described above,
and L is a suitable liberating group such as lower alkyloxy, hydroxy, halo, amino, mono- and di-
(lower alkyl)amino, etc. The cyclization reaction is optionally carried out in the presence of a suitable reaction-inert solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene; pyridine; N,N-dimethylformamide, etc. This can be done by stirring the reactants together. Elevating the temperature is appropriate to increase the reaction rate. Sometimes it is suitable to carry out the reaction at the reflux temperature of the reaction mixture. Compounds of formula () may also be derived from compounds of formula () in which P represents a precursor group of the desired Ar-X group, which is converted to the desired Ar-X group by known methods. For example, a compound of formula () in which Ar-X- is a suitably substituted 2-aminobenzoyl group, specifically a compound represented by formula (-a), is a compound of formula (-a) in which Ar-X- is an appropriately substituted 2-aminobenzoyl group. It can be produced by oxidative cleavage and subsequent hydrolysis of the formamide () formed. The oxidative cleavage may be carried out, for example, by reacting () with a suitable oxidizing agent such as sodium periodate in the presence of a catalytic amount of osmium tetroxide in a suitable solvent such as 1,4-dioxane. Can be done.
Similarly, the oxidation reaction can also be carried out by bubbling ozonated oxygen into the acetic acid solution of (), followed by decomposition of the intermediately formed ozonide with water. The (formylamino)phenylcarbonyl intermediate () thus prepared is then converted to (-a) by hydrolysis in an acidic medium. In the following reaction formula, R ¹ , R ² , R ³ , Alk and R are as described above, and R ⁴ and R ⁵ are each independently hydrogen, halo, lower alkyl, lower alkyloxy, trifluoromethyl, nitro, selected from the group consisting of amino and hydroxy. However, in the above formulas (), () and (-a),
The group R is present in the 4-position of the piperidinyl group. The same applies to all formulas below. The compounds of formula () and their pharmaceutically acceptable acid addition salts constitute a further feature of the invention as useful intermediates and as potent serotonin antagonists. The compound of formula () in which X is a CHOH group (-b) is generally a corresponding aroyl compound (-
It can be produced by reducing the carbonyl group in c) with a suitable reducing agent such as sodium borohydride or sodium cyanoborohydride. For example, when sodium borohydride is used as reducing agent, the reaction is carried out in an alkaline aqueous medium, optionally in a water-miscible organic solvent, such as an alicyclic ether such as tetrahydrofuran, 1,
It is advantageously carried out in a mixture with 4-dioxane or the like; or a lower alkanol such as methanol or propanol. Compounds ( ^-d ) of formula () in which X represents the group CH-O-C(O)-CH3 can be obtained by acylating the corresponding alcohol (-b) with a suitable acylating agent according to known methods. It can be induced by Suitable acylating agents that can be used for this purpose include lower alkanoic acids and acyl halides and anhydrides derived therefrom. Compounds of formula () in which X is a methylene group can be prepared by removing the carbonyl group of the corresponding carbonyl derivative by Clemenzene reduction using zinc amalgam and hydrochloric acid or by reducing the carbonyl group with a high-boiling polar solvent such as 1,2-
It can be prepared by ring reduction to a methylene group by reduction of the Wolff xyonar using hydrazine and an alkali in ethanediol. Compounds in which X is [Formula] can be produced by subjecting the corresponding carbonyl compound to a ketalization reaction by a generally known method. For example, the compounds described in Synthesis, 1974 , (1) 23-26 Compounds of formula () in which X represents a group of formula >C=NOH can be prepared by converting the corresponding carbonyl compound into hydroxylamino hydrochloride according to known methods for preparing oximes. A compound of formula (), in which R represents a hydroxymethyl group at the 4-position of the piperidine ring, (-f) can be easily produced by reacting with a salt.
is a compound (-g) of formula () in which R is hydrogen
It can be produced by reacting formaldehyde or its polymer, paraformaldehyde. The hydroxymethylation reaction is preferably carried out by stirring the starting compound (-g) in a suitable polar solvent such as pyridine, methanol, etc. and optionally heating. Suitable bases are, for example, methanaminium hydroxide, such as N,N,N-trimethylbenzene methanaminium hydroxide. Some of the intermediates and starting materials used in the above production methods are known compounds, others can be produced according to known methods for producing similar compounds, and some of them are new compounds. It is.
Its manufacturing method will therefore be described below. Intermediates of formula () can be prepared by reacting the corresponding alcohol () with thionyl chloride, sulfuryl chloride, phosphorus pentabromide, phosphoryl chloride, methanesulfonyl chloride, 4-methylbenzenesulfonyl chloride, etc. to form the hydroxyl functional group of the alcohol (). can be prepared by converting the compound into a reactive free group. The alcohol used here as a starting material is a suitably substituted 2-aminopyridine ()
the expression Cyclization with a reagent in which R ³ , Alk and L are as described above, and R ⁶ is hydrogen, or R ⁶ and L together form a direct bond. It can be manufactured by. This cyclization reaction is
It can be made according to the same method as described above for making () and () from (). A compound (intermediate) of formula () can be produced by removing the protecting group Z from a compound (intermediate) of formula (XI) by a known method depending on Z.
For example, if Z is a phenylmethyl group, the removal can be carried out by a catalytic hydrogenolysis reaction in the presence of a suitable catalyst such as palladium-activated carbon, or if Z is a lower alkyloxycarbonyl group,
Removal can be carried out by hydrolysis in acidic media. When Z represents phenylmethyl, it is advantageous to first convert the phenylmethyl group into a lower alkyloxycarbonyl group in a known manner and then remove the lower alkyloxycarbonyl group as described above. The piperidine (XI) used here as a starting material can be prepared by known methods depending on the nature of X. For example, intermediates of formula (XI) where X is CO may be prepared starting from a suitably substituted 4-piperidinone (XII) and a suitable arylacetonitrile, as shown in the following reaction scheme. The reaction of (XII) with () can be carried out by stirring the reactants together and optionally heating in the presence of a suitable base such as sodium methanolate in a suitable reaction-inert solvent. can be done. Formula () giving nitrile ()
The catalytic hydrogenation of may be carried out in a suitable reaction-inert solvent, such as methanol, in the presence of a suitable catalyst, such as palladium on activated carbon, and optionally in the presence of a catalyst poison, such as thiophene. ()
The oxidation is carried out by known methods, such as those described in J.Org.Chem. 40 , 267 (1975). R is other than hydroxy, and the intermediate of the formula (XI-a, (XI-a-1) represented by R' is an appropriately substituted 4
-It can also be produced by reacting piperidinylmagnesium halide () with a suitable nitrile (). Intermediates of formula () where X is other than CO (-b)
can be derived from the corresponding arylcarbonylpiperidine (-a) following the same method as described above for preparing (-b), (-d) and (-e) from (-c). . Intermediate (-d) of formula () in which R represents a hydroxymethyl group at the 4-position of the piperidine ring
can be derived from the corresponding piperidine (-c) where R is hydrogen following the same method described above for preparing (-f) from (-g). Intermediates of formula () can be prepared by converting a suitable keto-ester or keto-amide () into a suitably substituted piperidine () according to generally known alkylation methods.
) is produced by reacting with Piperidine () can be prepared by N-alkylating a suitably substituted piperidine () with a suitable reagent (XI). Here, W′ is W
It has the same meaning as W insofar as it has a better release ability than W. Intermediates of formula () can be prepared by reacting a suitable reactive ester () with a suitably substituted piperidine () following the same method described above for preparing () from () and (). It can be manufactured by Intermediates of formula () may be prepared by N-alkylating piperidine () with a suitable reactive ester of formula () according to standard N-alkylation methods. The piperidine () used here as a starting material is described in Belgian patent no.
condensation with 1H-indole (), followed by reduction of the resulting dihydropyridine (), e.g. by hydrogenation in the presence of a suitable catalyst such as palladium on activated carbon, and the benzoyl derivative () in an alkaline medium. It can be produced by hydrolysis in a medium. Compounds of formula (), intermediates of formula () and pharmaceutically acceptable acid addition salts thereof have useful pharmacological activity. They are very potent serotonin antagonists and can be used as such in the treatment of various diseases in which the release of serotonin is of great importance. The ability of the present compounds as serotonin antagonists is evidenced by the results obtained in the following tests examining the antagonistic activity of compounds () and intermediates () on the effects of serotonin. Test 1: Antagonistic activity of serotonin on the rat tail artery The test involved fasted male rats (210-235
The tail artery from g) was used. Two spiral strips 5-6 cm long and 2 mm wide were obtained from each artery and mounted vertically in a 100 ml organ bath containing oxygenated Krebs-Henseleit solution. . Submaximal contraction of the arterial strip was created by adding a single dose (40 ng/ml) of serotonin to the organ bath for 2 minutes at 10 minute intervals each time. The differential contraction was measured before and 5 minutes after drug addition.
After washing out, the suppressant was added back three times to see if the yield recovered and normalized. Column 1 of Tables 1 and 2 shows that for many compounds of formula () and intermediates () in the above tests,
_ED50 values are given in ng/ml. In this context, the _ED50 value measures the range of contractions by 50% of their normal value.
% of the relevant drug. Test 2: Effect in the test of gastric lesions a Lesions induced by compound 48/80 Compound 48/80 (a mixture of oligomers obtained by condensation of 4-methoxy-N-methylbenzenethanamine and formaldehyde) , is a potent liberator of vasoactive amines such as histamine and serotonin from in vivo storage sites. Rats injected with compound 48/80 showed consistent changes in blood flow in different vascular beds; cyanosis of the ears and limbs became evident within 5 minutes of compound injection;
Rat died in the shot within 30 minutes. This shock and subsequent death could be avoided in rats pretreated with classical H1 antagonists. However, the stimulatory effect on gastric secretion is not suppressed, as rats treated with compound 48/80 and protected from shot with H1 antagonists show all signs of strong gastric gland activity: gross necropsy. showed a distended stomach with abnormal contents and coarse bright red spots over all mucosa corresponding to areas of decayed glands.
Many known serotonin antagonists, such as methycelguide, cyproheptadine, cinanserin, mianserin, vipamperone, spiperone, pizotifen and metergoline, completely prevented cyanosis of the ears and limbs as well as lesions in the glandular area of the stomach and abnormal gastric distension. b Method: Male Wistar rats weighing 220-250 g were fasted overnight. However, water was available ad libitum.
Test compounds were administered orally as solutions in aqueous media or as suspensions. Control rats and "blank" rats were administered test compounds. One hour later, among the histamine and serotonin released by administration of compound 48/80, 5-[4
-(diphenylmethyl)-1-piperazinyl-methyl]-1-methyl-1H-benzimidazole-2
- Methanol was administered subcutaneously to all rats in an amount of 2.5 mg/Kg. 2 from oral administration of test compound
After hours, all rats except the "blank" rat were injected intravenously with compound 48/80 (freshly dissolved in water at a concentration of 0.25 mg/ml). Compound 48/80
Four hours after intravenous injection, rats were decapitated and
The stomach was removed. The stomach is then distended and its contents (blood,
Observe for gastric juices, food) and wash thoroughly.
Lesions by visual inspection were expressed on a scale from 0 to +++. 0 corresponded to the complete absence of macroscopic lesions, and the best display corresponded to coarse reddish spots covering more than half of the glandular area. Column 2 of Tables 1 and 2 shows, for many of the compounds of formula () and intermediates (), the dosages at which gastric distension and lesions in the glandular area of the stomach are completely absent in 50% of the tested rats. (mg/kg body weight) (ED ₅₀
value). The compounds shown in Tables 1 and 2 are not shown for the purpose of limiting the present invention, but include all compounds falling within the scope of formula () and useful pharmacological properties of all intermediates falling within the scope of formula (). Activities are merely illustrative. [Table] [Table] [Table] [Table] Compounds of formula () and intermediates of formula () completely prevent lesions caused by excessive serotonin release, and are effective against bronchial tissues, blood vessels, arteries and Blocks serotonin-induced contractions in veins,
The compounds of the invention can therefore be used in the treatment of diseases caused by hyperemia, such as gastrointestinal ulcers, bronchial asthma, hemorrhoids, varises, etc. Due to its useful anticongestive properties, the present compounds can be formulated into a variety of pharmaceutical forms to suit the purpose of administration. To prepare the pharmaceutical compositions of the present invention, an anticongestively effective amount of the present compound, in base form or acid addition salt form, is combined as the active ingredient with a pharmaceutically acceptable carrier and mixed thoroughly. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in unit dosage forms suitable for administration by oral, rectal or parenteral injection. For example, when preparing a composition in oral dosage form, common pharmaceutical vehicles such as water, glycols, oils,
Oral liquid preparations such as suspensions, alcohol, etc.
Alternatively, solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc. can be used in the case of powders, pills, capsules and tablets. Tablets and capsules represent the most advantageous oral dosage unit form because of their ease of administration. In this case, a solid pharmaceutical carrier is obviously used; the carrier for parenteral compositions usually comprises sterile water, at least in large part, but may also include other ingredients, e.g., to aid solubility. can be done. Injectable solutions may be prepared, for example, in which the carrier comprises a saline solution, a glucose solution, or a mixture of saline and glucose solutions. Injectable suspensions are prepared using suitable liquid carriers, suspending agents, and the like.
The acid addition salts of () and () are clearly more suitable for the preparation of aqueous compositions because they are more water soluble than the corresponding base forms. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein and in the claims, refers to physically discrete units suitable as dosage units, each unit carrying the necessary pharmaceutical carrier to provide the desired therapeutic effect. containing a predetermined amount of active ingredient calculated in relation to Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder colors, wafers, injectable solutions or suspensions, and combinations thereof. etc. The amount of active ingredient administered can vary over a fairly wide range depending on the particular circumstances, e.g. the nature and stage of the disease, but when administered once or repeatedly it may range from about 0.005 to about 1 mg of active ingredient per dose. Weight Kg,
In particular, dosages of about 0.01 to about 0.5 mg/Kg body weight are generally satisfactory. All of the compounds listed in Tables 1 and 2 above did not cause mouse death even when administered to mice at a dose of 40 mg/Kg. That is,
It can be inferred that the LD ₅₀ value is much larger than 40 mg/Kg. The following formulations are representative of pharmaceutical compositions of anticonvulsants in dosage unit form suitable for systemic administration to animals and humans in accordance with the present invention. These examples are illustrative of the scope of the invention and are not intended to limit it. Oral Drops The following formulation contains 3-
[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one at 10 mg/ml
An oral infusion containing 50mg was given. AI 500g 2-hydroxypropanoic acid 0.5 Saccharin sodium 1750g Cocoa flavor 2.5 Purified water 2.5 Polyethylene glycol AI was dissolved in 2-hydroxypropanoic acid and polyethylene glycol 1.5 at 60-80°C until the total amount was 50. 30
After cooling to ~40℃, polyethylene glycol
35 was added and the mixture was stirred well. A solution of saccharin sodium in 2.5 liters of purified water was then added, and with stirring the cocoa flavor and polyethylene glycol were added to the desired amount. The resulting solution was placed in a suitable container. Oral Solution The following formulation contains 3- as the active ingredient (AI).
Contains 20mg/teaspoon (5ml) of [2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one An oral solution of 20% was given. AI 20g 2,3-dihydroxybutanedioic acid 10g Satucharin sodium 40g 1,2,3-propanetriol 12 Sorbitol 70% solution 3 Methyl 4-hydroxybenzoate 9g Propyl 4-hydroxybenzoate 1g Strawberry essence 2ml Gooseberry Essence 2 ml Purified water Methyl and propyl 4-hydroxybenzoate were dissolved in boiling purified water 4 until the total volume became 20. In this solution 3, first 2,3-dihydroxybutanedioic acid and then AI were dissolved. This latter solution was combined with the remainder of the former solution and to this was added the 1,2,3-propanetriol and sorbitol solution.
Sodium saccharin was dissolved in 0.5 of water and extracts of raspberry and gooseberry were added.
The latter solution was combined with the former, water was added to the specified amount, and the resulting solution was placed in a suitable container. Capsules: The following formulations each contain 3-[2-[4-(4-fluorobenzoyl)-1 as the active ingredient (AI)]
-piperidinyl]ethyl]-2,4-methyl-4H
-pyrido[1,2-a]pyrimidin-4-one 20
1000 capsules containing mg. AI 20g Sodium lauryl sulfate 6g Starch 56g Lactose 56g Colloidal silicon dioxide 0.8g Magnesium stearate 1.2g The composition was prepared by vigorously stirring the ingredients together. The resulting mixture was placed into suitable hard gelatin capsules. Film-coated tablets: From the following formulations, each containing 3-[2-[4-(4-
10,000 compression molded tablets were prepared containing 10 mg of fluorobenzoyl)-1-piperidinyl]ethyl-2-methyl-4H-pyrido[1,2-d]pyrimidin-4-one as the active ingredient. Core of tablets: AI 100g lactose 570g podium 200g polyvinyl pyloridon (KOLLIDONK90) 10g Crystal cellulose (AVICEL) 100g dodecyl sodium sodium hydrogenic vegetable oil (STEROTEX) 15g Covering: Methylcell 6 0HG) 10g ethylcellulose (Ethocel22CPS) 5g 1, 2,3-propanetriol 2.5 ml Polyethylene glycol 6000 10 g Concentrated dye suspension (Opaspray K-1-2109) 30 ml Polyvinylpyrrolidone (Povidone) 5 g Magnesium octadecanoate 2.5 g Tablet core preparation: Mixture of AI, lactose and starch were mixed well and then moistened with a solution of sodium dodecyl sulfate and polyvinylpyrrolidone in about 200 ml of water. The wet mixture was sieved, dried and sieved again. Microcrystalline cellulose and hydrogenated vegetable oil were then added. The whole was mixed well and compressed into tablets. Coating: To a solution of methylcellulose in 75ml of denatured ethanol was added a solution of ethylcellulose in 150ml of dichloromethane. Then 75 ml of dichloromethane and 1,2,3-propanetriol were added. Melt polyethylene glycol and dichloromethane
Dissolved in 75ml. This latter solution was added to the former, followed by the magnesium ocdecanoate, polyvinylpyrrolidone and concentrated dye suspension, and the whole was made homogeneous. The mixture thus produced was coated on the core of a tablet using a coating device. Injectable solution: The following formulation contains 3-[2-[4] as the active ingredient.
-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2
-d] Parenteral solution 1 containing 4 ml/ml of pyrimidin-4-one is provided. AI 4g Lactic acid 4g Propylene glycol 0.05g Methyl 4-hydroxybenzoate 1.8g Propyl 4-hydroxybenzoate 0.2g Total amount of purified water up to 1 Methyl and propyl 4-hydroxybenzoate were dissolved in approximately 0.5 g of boiling water for injection. . After cooling to about 50℃, lactic acid, propylene glycol and
AI was added with stirring. The solution was cooled to room temperature and refilled with water for injection to the specified volume.
The solution was sterilized by filtration (USPXp811) and placed in a sterile container. Suppositories: From the following formulations, each containing 3-[2-[4-(4-
100 suppositories containing 20 mg of fluorobenzoyl)-1-piperidinyl]ethyl-2-methyl-4H-pyrido[1,2-d]pyrimidin-4-one as active ingredient were prepared: AI 3g 2,3 -Dihydroxybutanedioic acid 3g Polyethylene glycol 400 25ml Surfactant (Span) 12mg Triglyceride (Witepsol 555) Total amount up to 300g AI in polyethylene glycol 400 2,3-
Dissolved in a solution of dihydroxybutanedioic acid.
The surfactant and triglyceride were melted together. The latter mixture was mixed well with the former solution.
The mixture thus obtained was poured into a mold at a temperature of 37-38°C to form suppositories. Regarding the anticongestive activity of the present compounds, the present invention provides an effective anticongestant amount of a compound of formula () or an intermediate of formula () or a pharmaceutically acceptable acid addition salt thereof in a pharmaceutical carrier. A method of treating hyperemic diseases in warm-blooded animals by systemically administering the mixture is provided. The following examples are illustrative and do not limit the scope of the invention. Unless otherwise noted, all parts are by weight and all temperatures are by Mr. Setsu. A Production example of intermediate 80 parts of sodium methoxide and 160 parts of methanol
50 parts of 2-thiopheneacetonitrile and then 1-(phenylmethyl)-4-
66 parts of piperidinone were added dropwise and continuously. Upon completion, the whole was heated to reflux and stirring at reflux temperature was continued for 1 hour. The reaction mixture was cooled and evaporated. Distill the residue using a molecular distillation device,
About 70 parts of α-[1-(phenylmethyl)-4-piperidinylidene]-2-thiopheneacetonitrile was obtained as a residue. In a similar manner, 4-methyl-α-[1-(phenylmethyl)-4-piperidinylidene]benzeneacetonitrile, melting point 193.4°C, was obtained. Example α-[1-(phenylmethyl) in 800 parts of methanol
A mixture of 70 parts of -4-piperidinylidene]-2-thiopheneacetonitrile was hydrogenated at normal pressure and temperature using 10 parts of a 10% palladium-activated carbon catalyst. After the calculated amount of hydrogen has been captured, the catalyst is separated, the liquid is evaporated, and 1-(phenylmethyl)-α-(2-
70 parts of (thienyl)-4-piperidineacetonitrile were obtained as a residue. In a similar manner, dl-α-(4-methylphenyl)
-4-piperidineacetonitrile was obtained as a residue. Example dl-α- in 1840 parts of 4-methyl-2-pentanone
To a mixture of 74 parts of (4-methylphenyl)-4-piperidine acetonitrile, 95.4 parts of sodium carbonate, and several crystals of potassium iodide, 39.21 parts of (chloromethyl)benzene was added in portions. After the addition was complete, the whole was stirred and refluxed for 24 hours. The reaction mixture was cooled and 400 parts of water were added. The organic layer was separated, dried over potassium carbonate, filtered and evaporated. The oily residue was dissolved in 1,1'-oxybisethane and gaseous hydrogen chloride was introduced into the solution. Separate and dry the precipitated hydrochloride, with a melting point of 212-213℃.
68 parts of dl-α-(4-methylphenyl)-1-(phenylmethyl)-4-piperidine acetonitrile monohydrochloride were obtained. EXAMPLE To a stirred mixture of 29.6 parts of 1-(phenylmethyl)-α-(2-thienyl)-4-piperidineacetonitrile in 100 parts of dimethyl sulfoxide, 4 parts of a 60% sodium hydride dispersion were added in portions. Upon completion, stirring was continued overnight. The reaction mixture was poured onto water. The precipitated product was separated and extracted with trichloromethane. The extract was dried, filtered and evaporated. This residue was crystallized from 2,2'-oxybispropane to give [1-(phenylmethyl)-4-piperidinyl](2-thienyl) with a melting point of 100.5°C.
- 10 parts (35%) of methanone were obtained. In a similar manner, (4-methylphenyl)[1-phenylmethyl)-4-piperidinyl]methanone with a melting point of 83.9°C was also prepared. Example 5 parts of magnesium, 1,2-dibromoethane
The reaction was started by adding 218 parts and a small amount of iodine. Then, while heating the mixture to 70 DEG C., a solution of 28 parts of 4-chloro-1-methylpiperidine in 180 parts of tetrahydrofuran was added dropwise. After cooling,
A solution of 14 parts of 3-methylbenzonitrile in 90 parts of tetrahydrofuran was added dropwise. Upon completion, stirring was continued for 1 hour at reflux temperature. The mixture was cooled and poured onto an aqueous solution of ammonium chloride. The product was extracted with 2,2'-oxybispropane. The extract was washed with water, dried, filtered and evaporated (3
35 parts of -methylphenyl)(1-methyl-4-piperidinyl)methanone were obtained as an oily residue. EXAMPLE A solution of 50 parts of 1-bromo-2-methylbenzene in 140 parts of 1,1'-oxybisethane was added dropwise to 7 parts of magnesium while the mixture was refluxing. The whole was stirred under reflux for 15 minutes. The Grignard complex was cooled to 10 DEG C. and a solution of 30 parts of 1-(phenylmethyl)-4-piperidinecarbonitrile in 70 parts of 1-1'-oxybisethane was added dropwise. Upon completion, stirring was continued for 4 hours at room temperature. The reaction mixture was decomposed with a solution of 40 parts of ammonium chloride in 400 parts of water. Separate the organic phase, dry and filter.
By evaporation, (2-methylphenyl)
31 parts of [1-(phenylmethyl)-4-piperidinyl]methanone were obtained as an oily residue. In a similar manner (4-fluorophenyl)
[4-Methyl-1-(phenylmethyl)-4-piperidinyl]methanone was obtained as an oily residue. Example: To a Grignard complex prepared beforehand from 13.5 parts of 4-chloro-1-methylpiperidine and 2.4 parts of magnesium in 68 parts of tetrahydrofuran, under stirring and cooling (10-15°C), 4-chloro-1-methylpiperidine in 22 parts of tetrahydrofuran was added.
A solution of 10 parts of bromobenzonitrile was added dropwise. Upon completion, stirring was continued for 1 hour at reflux temperature.
This reaction mixture was mixed with 50 parts of ammonium chloride in 250 parts of water.
of the mixture. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated. This residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as the eluent. The pure fractions were collected, the developing agent was evaporated, and the (4-bromphenyl)
-(1-methyl-4-piperidinyl)methanone 10
% was obtained as a residue. Example 12 parts of ethyl carbonochloridate, 31 parts of (2-methylphenyl)[1-(phenylmethyl)-4-piperidinyl]methanone and dimethylbenzene
270 parts of the mixture was stirred and refluxed for 4 hours. The reaction mixture was evaporated and the residue was dissolved in trichloromethane. This solution was washed with dilute hydrochloric acid solution. The organic phase was separated, dried, filtered and evaporated to give 20 parts of ethyl 4-(2-methylbenzoyl)-1-piperidinecarboxylate as an oily residue. EXAMPLE By following the method of the example and using equivalent amounts of the appropriate starting materials, ethyl 4-(2-thienylcarbonyl)-1-piperidinecarboxylate was obtained as a residue; 4-(4-methylbenzoyl)-1-piperidine ethyl carboxylate as a residue; and 4
-(4-fluorobenzoyl)-4-methyl-1-
It was produced using ethyl piperidine carboxylate as a residue. Example 22 parts of ethyl carbonochloridate were added dropwise at 20°C to a stirred mixture of 35 parts of (3-methylphenyl)(1-methyl-4-piperidinyl)methanone, 1 part of sodium carbonate and 225 parts of dimethylbenzene. . Upon completion, stirring was continued for 6 hours at reflux temperature. The reaction mixture was evaporated and 4-(3-
12 parts of ethyl (methylbenzoyl)-1-piperidinecarboxylate were obtained as an oily residue. In a similar manner, ethyl 4-(4-brombenzoyl)-1-piperidinecarboxylate was prepared as a residue. Example XI A mixture of 103 parts of ethyl 4-(4-methylbenzoyl)-1-piperidinecarboxylate and 900 parts of 48% hydrobromic acid in water was stirred and refluxed for 3 hours. The reaction mixture was stirred and cooled in an ice bath. The precipitated product was separated, washed with water and stirred in 2-propanone to give (4-methylphenyl) (4-methylphenyl), melting point 300°C.
piperidinyl) methanone hydrobromide 91 parts (86
%) was obtained. Example XII Following the same hydrolysis method as Example XI (3-methylphenyl)(4-piperidinyl)
Methanone hydrobromide; (4-bromphenyl)(4-piperidinyl)
Methanone hydrobromide; (2-methylphenyl)(4-piperidinyl)
Methanone hydrobromide; (4-piperidinyl)(2-thienyl)methanone hydrobromide; and (4-fluorophenyl)(4-methyl-4-
piperidinyl) methanone hydrobromide, was prepared. Example 3-(2-chloroethyl)-2,8-dimethyl-
3.8 parts of 4H-pyrido[1,2-d]pyrimidin-4-one, 3 parts of 3-(4-piperidinyl)-1H-indole, 10 parts of sodium carbonate, potassium iodide
A mixture of 0.1 part and 240 parts of 4-methyl-2-pentanone was stirred and refluxed for 20 hours. The reaction mixture was heated through Hyflo and the liquid was evaporated. This residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as the eluent. Pure fractions were collected and the developer was evaporated. The residue was crystallized from a mixture of 2-propanol, 2,2'-oxybispropane and 4-methyl-2-pentanone to give 3-[2-
4.7 parts of [4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2,8-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one were obtained. EXAMPLES By following the method of the examples and using equivalent amounts of the appropriate starting materials, 3-[2-[4-(1H-indol-3-yl)-
1-piperidinyl]ethyl]-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-
on, melting point 203.7℃; 7-chloro-3-[2-[4-(1H-indole-
3-yl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidine-
4-one, melting point 240.9°C; 3-[2-[4-(1H-indol-3-yl)-
1-piperidinyl]ethyl]-2,6,8-trimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, melting point 223.4°C; and 7-bromo-3-[2-[4-(1H -Indre-
3-yl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidine-
4-one, melting point 224.8°C, was produced. Example 3-(2-chloroethyl)-2,6-dimethyl-
Stir a mixture of 4.8 parts of 4H-pyrido[1,2-a]pyrimidin-4-one, 4 parts of 3-(4-piperidinyl)-1H-indole, 8.5 parts of sodium carbonate, and 120 parts of 4-methyl-2-pentanone. The mixture was stirred overnight using a water separator. The reaction mixture was cooled, water was added and the precipitated product was separated. This was dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The solution was passed through silica gel and the liquid was evaporated. The residue was crystallized from 2-propanol,
3-[2-[4-(1H-indole-) with melting point 224.9℃
3-yl)-1-piperidinyl]ethyl]-2,6
2.5 parts of -dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one were obtained. EXAMPLES By following the method of the examples and using equivalent amounts of the appropriate starting materials, 3-[2-[4-(1H-indole-3-yl)-
1-piperidinyl]ethyl]-2-methyl-4H-
Pyrido[1,2-a]pyrimidin-4-one, melting point 209.2°C. was manufactured. Example 155 parts of 1-fluoro-3-methoxybenzene,
A mixture of 75 parts of aluminum chloride and 650 parts of 1,2-dichloroethane was stirred and 113 parts of 1-acetyl-4-piperidinecarbonyl chloride were added dropwise. Upon completion, stirring was continued for 1 hour at 40-50°C. The reaction mixture was poured onto a mixture of crushed ice and hydrochloric acid. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated. This residue was purified by high performance liquid chromatography on silica gel using trichloromethane, hexane and methanol (47.5:47.5:5 volume ratio) as the eluent. The first fraction (A-isomer) was collected and the developer was evaporated to yield 1-acetyl-4-(2-fluoro-4-methoxybenzoyl)-piperidine. The second fraction (B-isomer) was collected, the developer was evaporated and 1-acetyl-4-(4-fluoro-
2-hydroxybenzoyl)piperidine 40 parts (25
%) was obtained. A mixture of 40 parts of 1-acetyl-4-(4-fluoro-2-hydroxybenzoyl)piperidine and 150 parts of 6N hydrochloric acid solution was stirred and refluxed for 3 hours.
The reaction mixture was cooled. The precipitated product was separated, washed with 2-propanone and dried, melting point
29 parts (4-fluoro-2-hydroxyphenyl)(4-piperidinyl)methane hydrochloride (87
%) was obtained. Example 12 parts of ethyl 3-oxobutanoate were added dropwise at room temperature to a stirred mixture of 4 parts of a 60% dispersion of sodium hydride in 180 parts of methylbenzene. Then N,
1 part of N,N-tridecylmethanammonium was added and the whole was warmed to 40°C. At this temperature, in 45 parts of methylbenzene, [1-(3-chloropropyl)-4-
A solution of 25 parts of piperidinyl](4-fluorophenyl)methanone was slowly added. The whole was heated to reflux temperature and stirring was continued at reflux temperature overnight.
The reaction mixture was cooled to room temperature and passed through Hyflo. Evaporate the liquid to obtain α-acetyl-4
24 parts of ethyl -(4-fluorobenzoyl)-1-piperidinepentanoate was obtained as a residue. B Preparation Example of Final Compound 3-(2-chloroethyl)-2-methyl)-2-
5 parts of methyl-4H-pyrido[1,2-a]pyrimidin-4-one, (4-fluorophenyl)(4-
4.9 parts of (piperidinyl) methanone hydrochloride, 5 parts of sodium carbonate, and 160 parts of 4-methyl-2-pentanone
The mixture was stirred and refluxed for 24 hours. The reaction mixture was cooled, washed with water, and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was dissolved in trichloromethane and methanol (92:8 volume ratio).
The mixture was purified by column chromatography on silica gel using as a developing agent. Pure fractions were collected and the developer was evaporated. This residue was crystallized from a mixture of ethanol and 1,1'-oxybisethane to give 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]- with a melting point of 139°C.
Three parts of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one were obtained. EXAMPLES The following were also prepared according to the methods of the examples and using equivalent amounts of the appropriate starting materials: [Table] Example 3-(2-chloroethyl)-2-methyl-4H-
Pyrido[1,2-a]pyrimidin-4-one 5.6
A mixture of 240 parts of 4-methyl-2-pentanone, 6 parts of phenyl(4-piperidinyl)methanone hydrobromide, 8 parts of sodium carbonate, 0.1 part of potassium iodide, and 240 parts of 4-methyl-2-pentanone was stirred using a water separator. Refluxed for an hour. The reaction mixture was heated through Hyflo and the liquid was evaporated. This residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as the eluent. Pure fractions were collected and the developer was evaporated. The residue was crystallized from a mixture of ethanol and 1,1'-oxybisethane to give 3-[2-(4-benzoyl-
1-piperidinyl)ethyl]-2-methyl-4H-
6 parts of pyrido[1,2-a]pyrimidin-4-one were obtained. EXAMPLES The following were prepared by following the methods of the examples and using equivalent amounts of the appropriate starting materials: The following compounds were obtained analogously to the above. (Z)-3-[2-[4-(4-fluorophenyl)(hydroxyimino)methyl]-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,
2-α]pyrimidin-4-one Melting point 225.0°C; 3-[2-[4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidinyl]ethyl]- 2-Methyl-4H-pyrido[1,2-α]pyrimidin-4-one Melting point 131.2
°C; 3-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-
2-Methyl-4H-pyrido[1,2-α]pyrimidin-4-one Melting point 136.0°C; 3-[2-[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-2 -Methyl-
4H-pyrido[1,2-α]pyrimidin-4-one Melting point: 106.3°C [Table] The following compounds were produced in the same manner as above. 3-[2-[4-(4-fluorobenzoyl)-1
-piperidinyl]ethyl]-4H-pyrido[1,2
-α]pyrimidin-4-one Melting point 160.7°C Example 3-[2-[4-(4-fluorobenzoyl)-1
-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 7.9 parts,
3 parts paraformaldehyde, 40% N,N,N-trimethylbenzenemethanaminium hydroxide
A mixture of 2 parts of methanol solution and 100 parts of pyridine was stirred at 60-70°C over the weekend. The reaction mixture was evaporated and the residue was stirred in water. This product was extracted with trichloromethane. The extract was dried, filtered and evaporated. This residue was mixed with trichloromethane and methanol (95:5 volume ratio).
was purified by column chromatography using a developing agent. Pure fractions were collected and the developer was evaporated. This residue was converted to the hydrochloride salt in 2-propanol. This salt was separated and crystallized from ethanol, 3-[2-[4-(4
-fluorobenzoyl)-4-(hydroxymethyl)-1-piperidinyl]ethyl]-2-methyl-
1.7 parts (16.5%) of 4H-pyrido[1,2-a]pyrimidin-4-one dihydrochloride monohydrate was obtained. Example 3-[2-[4-(4-
A solution of 2 parts of fluorobenzoyl)-1-piperidinyl]ethyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one was warmed and acidified with 2-bropanol saturated with hydrogen chloride. . The hydrochloride formed was crystallized. This was separated and dried to produce 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2- with a melting point of 300°C.
2 parts (85.5%) of methyl-4H-pyrido[1,2-a]pyrimidin-4-one dihydrochloride were obtained. In a similar method, 3-[2-[4-(4-fluorobenzoyl)-1
-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one sulfate (1:2), mp 254.7°C; Orbenzoyl)-1
-Piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one phosphate (1:2), melting point 243.8°C, was prepared. Example 3-[2-[4-(4-
To a stirred solution of fluorobenzoyl)-1-piperidinyl]ethyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one was added (Z)-2-butenedionic acid in 16 parts of 2-bropanol. 0.59 part of solution was added. This product was crystallized. This is separated, dried, and 3-[2-
[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,
2-a] 2.1 parts (82%) of pyrimidin-4-one (Z)-2-butanedioate (1:1) were obtained. In a similar method, (10)-3-[2-[4-(4-fluorobenzoyl)
-1-piperidinyl]ethyl]-2-methyl-4H
-Pyrido[1,2-a]pyrimidin-4-one[R-R ^* ,R ^* )]-2,3-dihydroxybutanedioate (1:1), melting point 155.3°C, was obtained. Example α-acetyl-4-(4-fluorobenzoyl)
A mixture of 24 parts of ethyl-1-piperidinepentanoate, 30 parts of 2-pyridineamine, and 6 parts of polyphosphoric acid was stirred and heated to 160°C. A violent reaction occurred (temperature rose to 210°C). The reaction mixture was left in 2N sodium hydroxide solution overnight.
The product was extracted with trichloromethane while stirring. The extracts were washed with water, dried, filtered and evaporated. The oily residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia as the eluent. Pure fractions were collected and the developer was evaporated. The residue was converted to the hydrochloride salt in 2-propanone and 2-propanol. Separate the salt and crystallize from acetonitrile, melting point
3-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2-methylpyrido[1,2-a]pyrimidine-4-(3H)- at 217.8°C
4.2 parts of ONE dihydrochloride monohydrate were obtained. Example 3-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-2
A mixture of 3.4 parts of -methyl-4H-pyrido[1,2-α]pyrimidin-4-one, 1.85 parts of N,N-dimethyl-4-pyridinamine and 26 parts of dichloromethane was stirred, and 1.25 parts of acetic anhydride was added thereto. The whole was stirred at room temperature overnight. Water was added and the solution was treated with ammonia. Separation of the layers was performed. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (volume ratio 97:3) as the eluent. Pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was separated, dried and -(4-fluorophenyl)-1-
[2-(2-methyl-4-oxo-4H-pyrido[1,2-α]pyrimidin-3-yl)ethyl]-
2.3 parts (61%) of 4-piperidine methanol acetate (ester) having a melting point of 141.0°C was obtained.

Claims (1)

[Claims] 1 formula [wherein R ¹ and R ² are hydrogen, lower alkyl or halo; R ³ is hydrogen or lower alkyl; Alk is a lower alkylene group; R is hydrogen, lower alkyl, hydroxy or hydroxymethyl; ; X is C=0, CHOH,
[Formula] CH ₂ , [Formula] or C=NOH, and Ar is phenyl optionally substituted with one substituent selected from the group consisting of halo, lower alkyl and methoxy, or -X-Ar is the group as a whole A compound or a pharmaceutically acceptable acid addition salt thereof, wherein R ⁴ is hydrogen, lower alkyl, methoxy, or hydroxy. 2. The compound according to claim 1, wherein R is hydrogen. 3. The compound according to claim 1, wherein R is hydrogen and X is C=O or [Formula]. 4 R is hydrogen and X is C=O, and
The compound according to claim 1, wherein Alk is a 1,2-ethanediyl group. 5 3-[2-[4-(4-fluorobenzoyl)-
1-piperidinyl]ethyl]-2-methyl-4H-
2. A compound according to claim 1 selected from the group consisting of pyrido[1,2-α]pyrimidin-4-one and pharmaceutically acceptable acid addition salts thereof. 6 formula [wherein R ¹ and R ² are hydrogen, lower alkyl or halo; R ³ is hydrogen or lower alkyl; Alk is a lower alkylene group; R is hydrogen, lower alkyl, hydroxy or hydroxymethyl; Yes; X is C=O, CHOH,
[Formula] CH ₂ , [Formula] or C=NOH, and Ar is phenyl optionally substituted with one substituent selected from the group consisting of halo, lower alkyl and methoxy, or -X-Ar is the group as a whole wherein R ⁴ is hydrogen, lower alkyl, methoxy or hydroxy, a method for producing a compound represented by the formula or a pharmaceutically acceptable acid addition salt thereof, the method comprising: Here, W represents a reactive ester group, R ¹ ,
The definitions of R ² , R ³ and Alk are the same as above, and a compound with the formula Here, the definitions of R, Here, the definitions of R ¹ , R ² , R ³ , Alk, R and Ar are the same as above, and by acetylating the compound of formula Here, the definitions of R ¹ , R ² , R ³ , Alk, R and Ar are the same as above; or (ii) the compound of formula Here, the definitions of R ¹ , R ² , R ³ , Alk, By heating the reaction the formula wherein the definitions of R ¹ , R ² .R ³ , Alk, X and Ar are the same as above, and optionally a pharmaceutically acceptable acid addition of the product of the above step. A method of producing salt. 7 formula [wherein R ¹ and R ² are hydrogen, lower alkyl or halo; R ₃ is hydrogen or lower alkyl; Alk is a lower alkylene group; R is hydrogen, lower alkyl, hydroxy or hydroxymethyl; Yes; X is C=O, CHOH,
[Formula] CH ₂ , [Formula] or C=NOH, and Ar is phenyl optionally substituted with one substituent selected from the group consisting of halo, lower alkyl and methoxy, or -X-Ar is the group as a whole wherein R ⁴ is hydrogen, lower alkyl, methoxy or hydroxy, a method for producing a compound represented by the formula or a pharmaceutically acceptable acid addition salt thereof, the method comprising: Here, the definitions of R ¹ and R ² are the same as above, and a compound of formula Here, the definitions of R ³ , Alk, X, R and Ar are the same as above, and L represents a suitable leaving group. Cyclization by stirring the reagents together; and optionally, (i) Here, the definitions of R ¹ , R ² , R ³ , Alk, R and Ar are the same as above, and by acetylating the compound of formula Here, the definitions of R ¹ , R ² , R ³ , Alk, R and Ar are the same as above; or (ii) the compound of formula Here, the definitions of R ¹ , R ² , R ³ , Alk, By heating the reaction the formula wherein the definitions of R ¹ , R ² , R ³ , Alk, X and Ar are the same as above, and optionally a pharmaceutically acceptable acid addition of the product of the above step. A method of producing salt. 8 formula [wherein R ¹ and R ² are hydrogen, lower alkyl or halo; R ³ is hydrogen or lower alkyl; Alk is a lower alkylene group; R is hydrogen, lower alkyl, hydroxy or hydroxymethyl; ; X is C=O, CHOH,
[Formula] CH ₂ , [Formula] or C=NOH, and Ar is phenyl optionally substituted with one substituent selected from the group consisting of halo, lower alkyl and methoxy, or -X-Ar is the group as a whole where R ⁴ is hydrogen, lower alkyl, methoxy or hydroxy, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier. agent.