KR820001561B1 - Process for preparation of novel propanone derivatives - Google Patents

Abstract

Title compds. (I; A = OH, lower alkoxy, halo-substituted aryl or benzophenyl; R1 = H, lower alkyl, aryl; B = di-lower alkylamino, lower alkyl, aralkyl-substituted heterocyclic group with N) having anti-allergic activity, were prepd. Thus, mixt. of 125 ml nitromethane, 35 ml toluene, 20 ml ethanole, 1 ml conc. HCl was reacted with 18.6 g 4'-methyl propiophenone, 27.0 g N-isobutylpiperidine2hydrochloride salt and 8.5 g trioxane for 4 hr to give 2,4'-dimethyl-3-(4-iso butyl piperidino)-propiophenone -2 hydrochloride salt.

Description

Manufacturing method of new "propanone" derivative

1 and 2 are plots showing the relationship between the concentration of the compounds of the present invention and histamine free inhibition.

The present invention relates to a process for preparing novel propane derivatives and pharmaceutically acceptable salts thereof.

It is known that the in vivo chemical substances such as histamine, serotonin, bradykinin, acetylconin, and SRS-A, which are called chemical mediators, play an important role in the appearance of various allergic symptoms in the human body. Therefore, many compounds up to now have been synthesized for the purpose and are used in the clinic since their antagonists and / or drugs which inhibit their release are useful as therapeutic agents for allergic diseases.

The present inventors have found that any of the propanone derivatives have remarkable anti-SRS-A action and / or histamine free inhibitory action, experimental atobic asthma inhibitory action, and homo PCA reaction inhibitory action, and completed the present invention.

It is an object of the present invention to provide a novel propanone derivative useful as a therapeutic agent for allergic diseases, and another object is to provide a method for preparing a compound of the present invention, and another object of the present invention is to provide at least one active compound. The present invention provides a pharmaceutical composition comprising the same and a method of using the same.

The compound of the present invention is represented by the general formula (I)

(Wherein A represents an aryl group substituted by an unsubstituted or hydroxy group, a lower alkoxy group or a halogen or a benzo (b) phenyl group substituted by an unsubstituted or hydroxy group, a lower alkyl group, a lower alkoxy group, an aryl group or a halogen) B represents a heterocyclic group which contains a di-lower alkylamino group or at least one nitrogen atom and may be substituted by a lower alkyl group or an aralkyl group. However, when A is a paramethylphenyl group, B represents a group other than piperidino. , R ¹ represents hydrogen, a lower alkyl group or an aryl group), and a pharmaceutically acceptable salt thereof.

The compound of the present invention has remarkable anti-SRS-A action and / or histamine free inhibition, experimental atherosclerosis action, and homo PCA reaction suppression, as is apparent from the results of later pharmacological studies. It is useful as a therapeutic agent and as a therapeutic agent for bronchial asthma, allergic rhinitis and allergic dermatitis.

Among the compounds of the present invention, the compounds suitable for pharmacological action are represented by the above general formula (I), in which group A is one or more preferably substituted or unsubstituted phenyl group or one or two or more groups. Any of a naphthyl group, a detrahydronaphthyl group, an indanyl group, a benzo (b) chenyl group substituted or unsubstituted by two groups, and the aforementioned substituents are lower alkyl group, lower alkoxy group, aryl group, hydroxy group and Selected from halogen, and group B represents an unsubstituted pyridinino group, a pyridinino group, a piperazino group, or a molarino group substituted with a lower alkylamino or lower alkyl group or an aralkyl group, and R ¹ The compound which shows this hydrogen, methyl, aryl, or a phenyl group, and its pharmacologically acceptable salt are mentioned.

Such suitable compounds are more specifically, for example

2-methyl-3-dimethylamino-1-trilpropanone,

2-methyl-3-dimethylamino-1-trilpropanone,

2-methyl-3-dipropylamino-1-trilpropanone,

2-methyl-3-dimethylamino-1-kisyrylpropanone,

2-methyl-3-pyrrolidino-1-trilpropanone,

2-methyl-3- (methylsubstituted piperidino) -1-trilpropanone,

2-methyl-3-piperidino-1-kisylpropaneone,

2-methyl-3- (methylsubstituted piperidino) -1-kisylpropaneone,

2-methyl-3- (4-methylpiperadino) -1-trilpropanone,

2-methyl-3- (4-methylpiperadino) -1-kisylpropaneone,

2-methyl-3- (4-ethylpiperadino) -1-trilpropanone,

2-methyl-3- (4-isopropylpiperadino) -1-trilpropanone,

2-methyl-3- (4-isobutylpiperadino) -1-trilpropaneone,

2-methyl-3- (4-bendylpiperadino) -1-trilpropanone,

2-methyl-3- (4-ethylpiperadino) -1- (eryryl substituted phenyl) propanone,

2-methyl-3- (4-ethylpiperadino) -1- (ethylmethylphenyl) propanone,

2-methyl-3-molhorino-1-trilpropanone,

2-methyl-3-piperidino-1- (butylphenyl) propanone,

2-methyl-3-piperidino-1- (nuxylphenyl) propanone,

2-methyl-3-piperidino-1- (hydroxyphenyl) propanone,

2-methyl-3-piperidino-1- (methoxyphenyl) propanone,

2-methyl-3-piperidino-1- (dimethoxyphenyl) propanone,

2-methyl-3-piperidino-1- (ethoxyphenyl) propanone,

2-methyl-3-piperidino-1- (propoxyphenyl) propanone,

2-methyl-3-piperidino-1- (hydroxy-methoxyphenyl) propanone,

2-methyl-3-piperidino-1-biphenylpropanone,

2-phenyl-3-piperidino-1- (methoxyphenyl) propanone,

2-methyl-3-dimethylamino-propionaftone,

2-methyl-3-diethylamino-propionaftone,

2-methyl-3-diethylamino-1- (methylsubstitutednaphthyl) propanone,

2-methyl-3- (4-methyllidino) -propionaftone,

2-methyl-3- (4-methylpiperidino) -propionaftone,

2-methyl-3-piperidino-propionaftone,

2-methyl-3- (methylsubstituted piperidino) -propionaftone,

2-methyl-3-piperidino-1- (methylsubstituted naphthyl) propanone,

2-methyl-3-piperidino-1- (hydroxy substituted naphthyl) propanone,

2-methyl-3-piperidino-1- (methoxy substituted naphthyl) propanone,

2-methyl-3-piperidino-1- (ethyl-methoxy substituted naphthyl) propanone,

2-methyl-3-piperidino-1- (ethoxy substituted naphthyl) propanone,

2-methyl-3-molhorino-propionaftone,

2-methyl-3-piperidino-1- (ethylsubstituted naphthyl) propanone,

2-methyl-3-piperidino-1- (chlorosubstituted naphthyl) propanone,

2-methyl-3-piperidino-1- (chloro-methylsubstituted naphthyl) propanone,

2-methyl-3-piperidino-1- (promosubstituted naphthyl) propanone,

3-piperidino propionaftone,

2-methyl-3-piperidino-1- (5,6,7,8, -tetrahydronaphthyl) propanone,

2-methyl-3- (methylsubstitutedpiperidino) -1- (5,6,7,8, -tetra hydronaphthyl) propanone,

2-methyl-3-piperidino-1- (methylsubstituted-5,6,7,8, -tetra hydronaphthyl) propanone,

2-methyl-3-piperidino-1- (dimethylsubstituted-5,6,7,8, -tetra hydronaphthyl) propanone,

2-methyl-3-piperidino-1-benzo (b) cenyl propanone,

2-methyl-3- (methylsubstituted piperidino) -1-benzo (b) cenyl propanone,

2-methyl-3-piperidino-1- (methylsubstituted-benzo (b) chenyl propanone,

3-piperidino-1- (dimethyl substituted phenyl) propanone,

2-methyl-3-piperidino-1- (diethyl substituted phenyl) propanone,

2-methyl-3-piperidino-1- (propylsubstitutedphenyl) propanone,

2-methyl-3-piperidino-1- (trimethylsubstitutedphenyl) propanone,

2-methyl-3-piperidino-1- (pentamethylsubstitutedphenyl) propanone,

2-methyl-3-piperidino propiophenone,

2-methyl-3- (bendylsubstituted piperidino) propionapton,

2-methyl-3-piperidino propionapton and 2-methyl-3-piperidino-1-indanylpropaneone,

And other pharmaceutically acceptable salts thereof.

As a more suitable compound

2,4'-dimethyl-3-dimethylamino propiophenone, 2,4'-dimethyl-3-diethylamino propiophenone,

2,4'-dimethyl-3-molhorino propiophenone, 2,4'-dimethyl-3-piperidino propiophenone,

2,4'-dimethyl-3- (4-methylpiperidino) propiophenone,

2,4'-dimethyl-3- (4-ethylpiperadino) propiophenone,

2,4'-dimethyl-3- (4-isophthylpiperadino) propiophenone,

4'-methoxy-2-methyl-3-piperidino propiophenone,

4'-ethoxy-2-methyl-3-piperidino propiophenone,

2-methyl-3-piperidino-β-propionapton, 2-methyl-3-dimethylamino-β-propionapton,

2-methyl-3-molhorino-β-propionapton, 2-methyl-3-piperidino-β-propionapton,

2,3 ', 4'-trimethyl-3-piperidinopropiophenone,

3 ', 4'-dimethoxy-2-methyl-3-piperidino propiophenone,

2 ', 4'-dimethyl-3- (4bendylpiperadi) noproriophenone,

4'-methoxy-2-phenyl-3-piperidinopropiophenone,

4'-hydroxy-2-methyl-3-piperidinopropiophenone,

4'-hydroxy-3'-methoxy-2-methyl-3-piperidino propofenone,

2-methyl-3-piperidino-α-propionaftone, 2-methyl-3-piperidino-4'-phenylpropiophenone,

2-methyl-3-piperidino-1- (benzo (b) geophen-3'-yl) -propanone-1,

4'-nuxyl-2-methyl-3-piperidino propiophenone,

2-methyl-3-piperidino-5'6'7'8'-tetrahydro-2'-propionaftone,

2-methyl-3- (3'-methylpiperidino) -β-propionaftone,

2-methyl-3- (4'-methylpiperidino) -β-propionaftone,

2-methyl-3- (2-methylpiperidino) -β-propionaftone,

2-methyl-3- (4-bendylpiperidino) -β-propionaftone,

3'4'-dimethyl-3-piperidino propiophenone, 3-piperidino-β-propionaftone,

2-ethyl-3-piperidino-β-propionaftone,

1- (5-indanyl) -2-methyl-3-piperidino propane,

3'4'-diethyl-2-methyl-3-piperidino propiophenone, 2-methyl-3-piperidino propiophenone,

4'-n-propyl-2-methyl-3-piperidino propiophenone,

2,2'4'6'-tetramethyl-3-piperidino propiophenone,

2,2'3'4'5'6'-hexamethyl-3-piperidino propiophenone,

And pharmaceutically acceptable salts thereof.

The compound of the present invention is represented by general formula (II)

(Wherein A and R ¹ represent the significance mentioned above)

Formaldehydes and compounds represented by

General formula (Ⅲ)

(Where B denotes the meaning mentioned above)

It is obtained by making a compound or its salts represented by it react. In carrying out the above reaction, it is preferable to use azeotropic solvent system, and especially to use a solvent system such as separation from water when azeotropically condensing with water.

Examples of such a solvent system include ethanol, benzene, toluene, nitroalkanes and lower esters of lower fatty acids. These are used alone or in combination, and by appropriately combining them, the reaction temperature can be controlled to a suitable range.

Formaldehydes used in the aforementioned reaction include formaldehyde and linear or cyclic polymers thereof.

The compound of the present invention is obtained in the form of a free base or a salt thereof. This salt can be converted to the free base by methods known to those skilled in the art. On the other hand, this free base can be made into a pharmaceutically acceptable salt by contacting with an inorganic acid or an organic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acid, lactic acid, tartaric acid, citric acid and the like.

The manufacturing method of the compound of this invention is demonstrated in detail according to the following Example.

Example 1

125 ml of nitromethane, 35 ml of toluene, 20 ml of ethanol, 1 ml of concentrated hydrochloric acid, 18.6 g of 4'-methylpropiophenone, 27.0 g of N-isobutyl piperidine dihydrochloride and 8.5 g of trioxane were added to the resulting solution. The mixture is stirred under heating and reflux for 4 hours while being distilled off.

After cooling, ether was added to precipitate the precipitate, which was dissolved in water to prepare pH 5 as 5N sodium hydroxide, washed with ether, and then 5N sodium hydroxide was added thereto to extract pH from the solution prepared at pH 7, and the extract was dried. Then, white crystals precipitated through dry hydrogen chloride are filtered and dried.

This is recrystallized with ethanol and acetone mixed solvent, and 2,4'- dimethyl- 3- (4-isobutyl piperadino)-propiophenone and a dihydrochloric acid are obtained. (Yield 46.5%) m. p. 215-220 ℃

Elemental Analysis (C ₁₉ H ₃₀ N ₂ O. 2HCl)

C% H% N% Cl%

Theoretic Value: 60.79 8.59 7.46 18.89

Measured value: 60.54 8.65 7.60 18.80

Example 2

283 ml of an azeotrope solvent (200 ml of nitromethane, 28 ml of ethanol, 55 ml of toluene) were added, 36.8 g of β-propionaphtone, 36.5 g of piperidine hydrochloride, 13.5 g of paraformaldehyde and 1 ml of concentrated hydrochloric acid were added, and the mixture was heated and refluxed for 2 hours. The resulting water is distilled off, cooled by adding nitromethane, and the precipitated precipitate is filtered off and dried.

Methanol: Acetone (1: 3) was then recrystallized from ethanol to obtain 33 g of a crystal powder of 2-methyl-3-piperidino-β-propionapton hydrochloride. (Yield 52.0%) m. p 196-197 ℃

Elemental Analysis (C ₁₉ H ₂₃ NO.HCl)

C% H% N%

Theoretic Value: 71.80 7.61 4.41

Measured value: 71.66 7.74 4.49

Example 3

Water produced by the reaction was added to 200 ml of azeotropic solvent (140 ml of nitromethane, 21 ml of ethanol, and 39 ml of toluene) by adding 2 ml of concentrated hydrochloric acid to 36.0 g of β-propionate, 24.5 g of dimethylamine hydrochloride, and 13.5 g of paraformaldehyde. Heat to reflux for 1.5 hours while distilling off. After cooling, the solvent is distilled off by concentration under reduced pressure, and the residue is dissolved by adding water.

This is washed with ether, which is made alkaline with 5N sodium hydroxide, extracted with ether, washed with water and dried. Subsequently, 24.0 g of white crystals of 2-methyl-3-dimethylamino-β-propionaphtone hydrochloride were obtained by filtering crystals formed through dry hydrogen chloride and recrystallization from ethanol and acetone.

(Yield 43.2%) m. p. 160-161 ℃

Elemental Analysis (C ₁₆ H ₁₇ NO.HCl)

C% H% N% Cl%

Theoretic Value: 69.18 7.26 5.04 12.76

Measured value: 69.07 7.19 5.08 12.65

Example 4

40 g of β-propionatone, 12.5 g of paraformaldehyde and 37 g of molhorin hydrochloride were dissolved in 300 ml of an azeotrope solvent (210 ml of nitromethane, 30 ml of ethanol, 60 ml of benzene), and 1 ml of concentrated hydrochloric acid was added to the reaction. The mixture was stirred under reflux for 2 hours while distilling off the moisture produced.

The reaction solution was concentrated under reduced pressure, and the precipitated crystals were washed with ether, which was suspended in ethanol, heated to reflux, and filtered to cool to obtain a crude product.

This was recrystallized from methanol, and 55.3 g of milky white crystalline powder of 2-methyl-3-molhorino- (beta)-propionaphtone hydrochloride was obtained. (Yield 79.6%) m. p. 182.5-182.8 ℃

Elemental Analysis (C ₁₈ H ₂₁ NO _21.HCl )

C% H% N% Cl%

Theoretic Value: 67.60 6.93 4.38 11.08

Measured value: 67.55 6.88 4.36 10.94

Example 5

72.0 g of 3'4'-dimethylpropiophenone, 59.4 g of piperidine hydrochloride, and 20.0 g of paraformaldehyde were stirred together with 300 ml of ethyl acetate and 1 ml of concentrated hydrochloric acid under heating and refluxed under heating and reflux for 2.5 hours. .

After cooling, the precipitated crystals were filtered off, recrystallized from alcohol-acetone to obtain the desired white crystals.

The combined filtrates are concentrated under reduced pressure, dried, dried in water, washed with ether, and then basicized with 5N sodium hydroxide. The extract is washed with ether, concentrated hydrochloric acid is added, the ether is distilled off, and the residue is recrystallized from alcohol acetone. White crystals of 2,3 ', 4'-trimethyl-3-piperidinopropiophenone hydrochloride were obtained.

(All yield 61.3%) m. p. 184-185 ℃

Elemental Analysis (C ₁₇ H ₂₅ NO.HCl)

C% H% N% Cl%

Theoretic Value: 69.02 8.86 4.73 11.98

Measured value: 68.81 8.60 4.88 11.90

Example 6

36.8 g of β-propionaphtone, 13.5 g of paraformaldehyde and 21.5 g of pyridine were dissolved in 285 ml of an azeotrope solvent (200 ml of nitromethane, 301 ml of ethanol, 55 ml of toluene), and 30 ml of concentrated hydrochloric acid were added to the reaction. The mixture is heated to reflux for 2 hours while distilling raw water.

The reaction solution is concentrated under reduced pressure, and the precipitated crystals are washed with acetone and filtered. This is dissolved in water, washed with ether, and alkaline with 5N sodium hydroxide, followed by extraction with ether.

This was washed with water, dried over anhydrous sodium sulfate, and the crystals formed through dry hydrogen chloride were filtered out.

Recrystallization was carried out in alcohol acetone and water to obtain 10.5 g of a crystalline powder of 2-methyl-3-pyrrolidino-β-propionaphtone hydrochloride. (Yield 17.3%) m. p. 189-190 ℃

Elemental Analysis (C ₁₈ H ₂₁ NO.HCl)

C% H% N% Cl%

Theoretic Value: 71.16 7.30 4.61 11.67

Measured value: 71.05 7.34 4.61 11.58

Example 7

To a mixture of 210 ml of nitromethane, 32 ml of ethanol, and 58 ml of toluene, 38.8 g of 3 ', 4'-dimethoxy propiophenone, 64.8 g of hydrochloric acid hydrochloride, and 9.0 g of paraformaldehyde were added to the mixed solution. The mixture is heated to reflux for 1.5 hours while distilling off the moisture. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were washed by filtration as acetone, and recrystallized from alcohol and acetone to obtain white crystalline powder as a target product.

The recrystallized mother liquor was concentrated under reduced pressure, dissolved in water, washed with ether, alkaline with 5N sodium hydroxide, extracted with ether, washed with water and dried with anhydrous sodium sulfate.

Crystals formed through dry hydrogen chloride were filtered off and recrystallized in ethanol-acetone to obtain white crystalline powder of 3 ', 4'-dimethoxy-2-methyl-3-piperidino propiophenone hydrochloride.

(All yield 32.0%) m. p. 171-172 ℃

Elemental Analysis (C ₁₇ H ₂₅ NO ₃ .HCl)

C% H% N% Cl%

Theoretic Value: 62.28 7.99 4.27 10.81

Measured value: 62.40 7.97 4.19 10.78

Example 8

22.6 g of P-methoxyphenyl benzyl ketone, 18.2 g of piperidine hydrochloride and 6.9 g of paraformaldehyde were added to a mixed solution of 125 ml of nitromethane, 20 ml of ethanol, and 35 ml of toluene, and distilled off the water produced by the reaction. Heat to reflux for 1.5 hours.

After cooling, the solvent was distilled off by concentration under reduced pressure, and the residue was dissolved in water. After ether extraction, benzene is precipitated and dried over anhydrous sodium sulfate. After solvent distillation, recrystallization was carried out in acetone and methanol-acetone to obtain 14.5 g of white crystals of 4'-methoxy-2-phenyl-3-piperidino-propiophenone hydrochloride.

(Yield 40.3%) m. p. 148-149 ℃

Elemental Analysis (C ₂₁ H ₂₅ NO ₂ .HCl)

C% H% N% Cl%

Theoretic Value: 70.08 7.28 3.89 9.85

Measured value: 69.83 7.44 3.87 9.71

Example 9

A mixed solution of 140 ml of nitromethane, 40 ml of toluene, 20 ml of ethanol, and 2 ml of concentrated hydrochloric acid, 37.7 g of 6-propionyltetrarin, 26.8 g of piperidine hydrochloride, and 40% polmarin (9.0 g of paraformaldehyde) were added thereto, followed by reaction. It heats under reflux for 1 hour, distilling water produced | generated by

After cooling, the precipitated crystals were filtered off and recrystallized from alcohol-acetone to obtain the target product of white crystalline powder.

The recrystallized filtrate was concentrated under reduced pressure to dryness, dissolved in water, washed with ether, and alkaline washed with 1N sodium hydroxide to perform ether extraction.

The extract is washed with water, dried over anhydrous sodium sulfate, and filtered through dry hydrogen chloride.

This crystal was recrystallized from alcohol-acetone to obtain a white crystalline powder of 2-methyl-3-piperidino-5 ', 6', 7 ', 8'-tetrahydro-2'-propionafph hydrochloride. . (Yield 54.1%) m. p. 175.5-176.5 ℃

Elemental Analysis (C ₁₉ H ₂₇ NO.HCl)

C% H% N% Cl%

Theoretic Value: 70.90 8.77 4.35 11.01

Measured value: 70.74 8.92 4.39 10.95

Example 10

A mixture of 18.4 g of β-propionaphtone, 14.9 g of 3-methylpiperidine hydrochloride, 4.5 g of paraformaldehyde, 1 ml of hydrochloric acid, and 250 ml of ethyl acetate was heated to reflux for 2.5 hours while distilling off the water produced by the reaction.

After cooling, the precipitated crystals were filtered off, recrystallized from alcohol-acetone, and purified to obtain 15.2 g of white crystalline powder of 2-methyl-3- (3'-methyl-piperidino) -β-propionapton hydrochloride. (Yield 45.8%) m. p. 175.5-177 ° C.

Elemental Analysis (C ₂₀ H ₂₅ NO.HCl)

C% H% N% Cl%

Theoretic Value: 72.38 7.90 4.22 10.68

Measured value: 71.80 7.92 4.10 10.66

[Examples 11 to 38]

Subsequently, the products of the second table were obtained from the starting materials of the first table, following the method of Example 1-10.

TABLE 1

TABLE 2

* MEK: Methylethylgetone, MtoH: Methanol, EtoH: Ethanol

** Upper part: theoretical value Lower part: measured value

The results of the toxicity and pharmacological tests indicated below indicate the activity of the compounds of the invention, in particular the fragrance allergic activity.

Acute Toxicity

Examine the acute toxicity of the method using a first group (群) ICR-based Hung (雄) sex mice 10 animals (average weight 20g) for the invention compound upon administration and oral administration, the abdominal cavity, and each of the LD ₅₀ Ridge Obtained by the Field-Wilcoxon method.

As a result, the compound of the present invention such as 2-methyl-3-piperidino-β-propionapton, hydrochloride is 120 mg / kg as intraperitoneal administration, 370 mg / kg as oral administration,

2-methyl-3-molhorino-β-propionaftone, hydrochloride was 190 mg / kg as intraperitoneal administration, 540 mg / kg as oral administration,

2 ', 3', 4'-trimethyl-3-piperidinopropiophenone hydrochloride denotes LD ₅₀ of 117 mg / kg as intraperitoneal administration and 325 mg / kg as oral administration, and about other compounds of the present invention. LD ₅₀ of the same degree was obtained.

Pharmacological examination

(1) anti-SRS-A action

The anti-SRS-A action of the compound of the present invention was measured by the Magnus method using a morphmot venue.

In other words, the extraction site of the molmot was suspended in a Magnus bath preserved at 31 ± 1 ° C and pretreated as mepyramine to remove the effect of histamine, and then 10 ^-8 -10 ^-4 g / ml of the compound under test. After 1 minute, 1 ml of ethanol solution was applied to 80% of SRS-A (150 mg / kg), and the shrinkage inhibition rate (%) of the ileum was measured. The results are shown in Table 3 for a representative example.

TABLE 3

(2) histamine free inhibitory action

The histamine free inhibition of the compound of the present invention was examined by the following method.

Peritoneal cells obtained from 6-8-week-old Wistar male rats at 37 ° C. for 2 hours, rats, anti-warming albamine serum (Goose et al. J. Goose, Immuno Logy 16, 749, 1969], incubated and sensitized to prepare a cell suspension as phosphate buffer (containing 0.1% gelatin), and 0.5 ml of each was collected in a tube made of polyethylene. 1 ml of a solution of the test compound of various concentrations was added, followed by 0.5 ml of a 200 µg / ml egg white albine solution, followed by incubation at 37 ° C. for 20 minutes, and the release ratio of histamine was measured. It was.

Histamine levels were measured by fluorescence as a variant of Shore. 2,4'-dimethyl-3-piperidino propiophenone and disodium chromogritate (DSCG) were used as controls.

The results of the representative example are shown in Tables 4, 5, 1, and 2.

TABLE 4

Test compound concentration is 0.02mM

** Free ratio is the ratio of histamine release from the sensitized peritoneal cells not by antigen-antibody reaction.

TABLE 5

* Average value of 3-4 measurements ± S.E.

As evident from the above pharmacological test results, the compound of the present invention has significant anti-SRS-A action and histamine free inhibitory action, and its action also indicates dose-dependent dependence.

(3) experimental atopic asthma

4 strains, 1 male, 250-300 g male Hartley system, 7 days obtained by the method of Levin, etc. (Levine, BB, etal: J. Immunol., 106, 29 (1971)) in the heart of morphot. Passive sensitization was performed by injecting 0.25 ml / molmot of anti-bendyl penicillyl bovine gamma Grobrin serum (anti- (BPO) ₆₃ -BGG serum) showing a titer of homologose PCA 2048 times. , 48 hours later, under the Uratan anesthesia, the famine is cut and connected to Transjusser (manufactured by Japan Photoelectric Industry Co., Ltd., MFP-IT and MP-24T type) and versatile monitoring recorder (manufactured by Japan Photoelectric Industry Co., Ltd.) -150 type) to record the respiratory flow rate and respiratory flow rate simultaneously.

At respiratory flow rate, the ratio of exhalation time to exhalation time and inspiration time (exhalation / inspiration) was measured.

Cause antigen (惹起杭原) is a method such as Levin (Levin etal J. clin. Invest. , 47, 556 (1968)) bendil penny Shiro Sun Wu (牛) of serum al beumin ((BPO) obtained as the same manner as ₂₃ -BSA) 200ug / kg was injected into the jugular vein via cannuure to induce a response.

The compound of the present invention and 2,4'-dimethyl-3-piperidinopropiophenone were orally administered 1 hour prior to the reaction at a dose of 50 mg / kg. The results are shown in Table 6.

In this experiment, the control group displays the same pattern of aerobic respiratory distress as seen in a person's asthma attack, and the transient increase in respiratory rate and respiratory flow immediately after the onset of reaction, and subsequent continual decrease. And an increase in the expiration / intake ratio from 3 minutes after the reaction was induced.

On the other hand, the compound of the present invention strongly inhibited the fluctuation from the normal value seen in the control group, and the 2,4'-dimethyl-3-piperidino propiophenone-administered group showed a weaker inhibitory effect than the compound of the present invention. It was.

In addition, the compound of Example 5 was orally administered to rats, and the inhibition rate of the homo PCA response was investigated. As a result, the drug was inhibited by about 70% by the administration of 200 mg / kg (control compound 2,4'-dimethyl-3-piperidinopropiope). The case of discussion indicates a suppression of about 40%)

The action also indicated dose dependence.

The compound of the present invention is useful as an antiallergic agent and is useful as a therapeutic agent for bronchial asthma, allergic rhinitis and allergic dermatitis, and can be administered alone or by suitable combination, and in suitable formulation forms such as tablets, capsules, powders, research, aerosols. It can be found in solid or liquid form, such as in solvents, suspensions or emulsions.

The compounds of the present invention are in the form of tablets, capsules, powders, oral preparations orally or subcutaneously, intravenously, intramuscularly, rectally, intranasally, or in the mucosa of the nose, throat and trachea. Microparticles | fine-particles of are spray | sprayed and administered parenterally as a dry powder form or a liquid aerosol, or a form of ointment.

As the unit dosage form of the above-mentioned solids, crystalline cellulose, cellulose derivatives, gum arabic, as well as conventional bases such as the compound of the present invention and a carrier such as lactose, mannite, corn starch, and maryeongseo starch Or tablets or ointments by combining a binder such as corn starch or gelatin, a corn starch, horseshoe starch, or a disintegrant such as carboxymethyl cellulose calcium and lubricants such as talc, stearic acid and magnesium It can be combined with the base to form an ointment.

The compounds of the invention may also be injectable solutions or suspensions with physiologically acceptable diluents, with or without surfactant and other pharmaceutically acceptable preparations.

Generally, distilled water for injection, saline solution, aqueous dextrose solution, vegetable oil for injection, glyco oil such as propylene glycol, polyethylene glycol and the like are suitable liquid carriers.

In use as an azole agent, the compound of the present invention is filled into an azole container, in the form of a liquid or micropowder, together with a gas or liquid spray and, optionally, a common aid such as a humectant or a dispersant.

The compound of the present invention may be administered in a non-pressure form such as that of a nebraser or an atomizer.

The desired dosage of the compound of the present invention depends on the condition of the patient and the method of administration. Generally speaking, in order to achieve the desired effect, the compound of the present invention is administered at a level of 0.1-100 mg per kg of body weight per day. It is preferred to administer orally, and in normal cases, 1-10 units per day of 5-500 mg of the compound of the present invention is administered.

For parenteral administration (eg injections), the daily dose is approximately three to one-tenth the dose level of the previous dose, with a generally equivalent effect being obtained and in unit dosage forms containing 0.5-170 mg of the compound of the invention. It is preferable to administer 1-10 units.

Next, some of the specific examples of the pharmaceutical composition containing the compound of the present invention are shown by the prescription example.

Prescription Example 1 (Tablet 500 mg Tablets)

2-methyl-3-piperidino-β-propionaftone

Prescription Example 2 (Capsule of 210g Filling Weight)

2,3 ', 4'trimethyl-3-piperidino propiophenone

Prescription Example 3 (1 ampoule, 1ml injectable ampoule)

1.0% (by weight) of 2-methyl-3-dimethylamino-β-propionaflon hydrochloride

Prescription Example 4 (whole 101g ointment)

1 g of 2-methyl-3-pyrrolidino-β-propionaflon hydrochloride

Prescription Example 5 (2 g suppository)

3'4'-dimethoxy-2-methyl-3-piperidino propionapron hydrochloride 10mg

Cacao fat 1990mg

Prescription Example 6 (Aerosol)

5.0% by weight of 2-methyl-3-molhorino-β-propionaflon hydrochloride

Claims (1)

Formaldehyde and the compound represented by general formula (III) or its salt are made to react with the compound represented by general formula (II), and the novel propanone derivative represented by general formula (I), and its pharmaceutically acceptable salt How to prepare.

Wherein A represents an unsubstituted or hydroxy group, lower alkoxy or aryl group substituted by halogen or an unsubstituted or hydroxy group, lower alkyl group, lower alkoxy group, aryl group or benzo [b] phenyl group substituted by halogen, R ¹ represents a hydrogen, a lower alkyl group or an aryl group, B represents a heterocyclic group containing a lower alkylamino group or at least one nitrogen atom and also substitutable by a lower alkyl group or an aralkyl group, Provided that when A is a paramethyl phenyl group, B represents a group of piperidinos.

Images