JPS5914467B2 - 3,3-diaryl-tetrahydro-2-furylidene ammonium salts - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is in the field of raw materials for 2,2-diaryl-4-piperisiptylamides useful as gastric content propulsion inhibitors and analgesic agents.

The prior art already describes some 2,2-diaryl-4-(4/-phenylpiperidino)butyronitriles (U.S. Pat. Nos. 2,898,340 and 3,
No. 539,579).

Among these is the well-known commercial product 2,2-diphenyl-4-[(4-carboethoxy-4-phenyno(ha)piperidino)butyronitrile, commonly known as DlphenOxylate. Other prior art compounds include various 2,2
1-diphenyl-4-piperidinobutyramides, but those substituted with hydroxy and aryl functional groups at the 4-position of the piperidine ring are not known.

The object of the present invention is to provide a new class of 2,2-diaryl-
The present invention provides a method for producing raw materials for 4-piperidinobutyramides.

The butyramides can be used alone or in combination with other therapeutically active agents as antidiarrheal agents and analgesics. The chemical structure of the butyramides is represented by the following formula. [In the formula, R is one member selected from the group consisting of hydrogen and methyl, and Arl and Ar2 are one member selected from the group consisting of phenyl and halophenyl.

In addition, -N=Z is a member selected from the group consisting of 1N(CH2CH=CH2)2, in which R1 and R2 are lower alkyl, and R3 is selected from the group consisting of lower alkyl and benzyl. and R4 is lower alkyl.

Further, Ar3 is a member selected from the group consisting of phenyl and substituted phenyl. ] The terms '5 lower alkyl '1 and '1 lower alkoxy 7 used in the present invention may be linear or branched. For example, methyl
ethyl, propyl, isopropyl, butyl, pentyl,
1 to 1 carbon atom, such as hexyl and similar alkyls
6 and the corresponding alkoxys as shown as methoxy, ethoxy, isopropoxy, etc., respectively. The term 7halo I (or 7halogen I) also relates to halogens having an atomic weight of 127 or less, namely fluoro, iodo, bromo and chloro.

Furthermore, the term 7-substituted phenyl 7 refers to substituents such as lower alkyl, lower alkoxy, halo and trifluoromethyl.
It means a phenyl group having one or more. When one or more substituents are present, they may be the same or different.

Typically said substituted phenyls include mono-, di- and trihalophenyl, trifluoromethylphenyl, halotrifluoromethylphenyl, mono-, di- and tri-lower alkyl phenyl and mono-, di- and trihalophenyl. Includes mono- and tri-lower alkoxyphenyl. Particularly preferred compounds are when Arl and Ar2 are the same, especially when they are phenyl, R is hydrogen, and -N-Z
and Ar3 are compounds as previously described.

Furthermore, when Arl or Ar2 is halophenyl, fluorophenyl is preferred, especially p-fluorophenyl.
The compounds of formula (1) in which R represents a methyl group may obviously have a stereochemical configuration in which the methyl group is in the cis or trans position with respect to the 4-hydroxy group.

The nomenclature of these compounds has been simplified in this application by, by convention, designating the isomer that first separates from the reaction mixture as the α-monoform, whereas the other isomers are designated the β-monoform. The organic base of formula (1) may be a suitable inorganic acid such as, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid and similar acids, or acetic acid, propionic acid, glycolic acid, lactic acid, etc. Yulic acid, malonic acid, tartaric acid,
They can be converted to the corresponding pharmaceutically acceptable acid addition salts by reaction with suitable organic acids such as citric acid, sulfamic acid, ascorbic acid and similar acids.

On the other hand, the salts of the above formula () can be converted into the corresponding bases by treatment with a suitable alkali in a conventional manner.

As shown in the chemical reaction formula above, the compound of formula (1) has the formula (
), for example, a 3,3-diaryl-tetrahydro-2-furylidene ammonium salt, preferably a bromide salt, and an appropriate 4-allyl-4-piperidinol of formula (11) to be produced by condensation reaction. I can do it.

The condensation reaction can be carried out in organic solvents such as aromatic hydrocarbons such as benzene, toluene, xylene and the like, lower alkanols and alkanones, preferably 4-methyl-2-pentanone. It is desirable to use an appropriate amount of a base, such as an alkali metal carbonate, during the condensation reaction. Also desirable is the presence of a catalytic amount of potassium iodide. This reaction can be illustrated by the following reaction formula.

(In the formula, Arl, Ar2, Ar3, -N=Z and R are the same as defined above.) In the present invention, the immonium ether of the formula () is an appropriate acyl halide of the formula,
Preferably the chloride has the formula H-N=Z, in which A
rl, Ar2 and -N2Z are the same as defined above).

The condensation reaction can be carried out in organic bath media such as aromatic hydrocarbons, chloroform and the like. Water or a suitable amount of a suitable base, such as an alkali metal carbonate, may also be added to the solvent to bind the released acid. The thus obtained 3,3-diaryl-tetrahydro-2-furylidene-ammonium quaternary salt of formula () is novel, and in view of its usefulness as a precursor for the synthesis of compounds of formula (), such The compounds, of course, constitute a feature of the invention.

In the foregoing, many 4-aryl-4-hydroxypiperidines of formula (NI) have been described in the literature (see, eg, US Pat. No. 3,438,991).

In general they are prepared by combining a suitable 1-(lower alkoxy)carbonyl-3-R-4-piperidone (IV) in which the lower alkoxy functionality allows methoxy or ethoxy with a suitable phenyl-magnesium halide (under the conditions of the Grignard reaction). Then, the thus obtained 1-
(lower alkoxy)carbonyl-3-R-4-Ar3-
The protecting group at position 11 of 4-hydroxypiperidine (V1) is removed by heating compound (V1) with a suitable alkali, such as potassium hydroxide, to give the desired starting material (). The above condensation reaction is exemplified by the following reaction formula. Compounds of formula (1) in base or salt form are highly active gastrointestinal tract propulsion and defecation inhibitors and are therefore useful in the treatment of diarrhea.

The antidiarrheal effect of such compounds is observed in experimental animals such as rats by the following test method. Young female Wista rats (weight 230-2509 kg) are fasted overnight and the next morning each animal is orally administered the respective dose of the compound to be tested.

One hour later the animals are given 1 ml of castor oil orally.

Each rat is placed in a cage one by one, and the presence or absence of diarrhea is observed at different time intervals (1, 2, 3, 4, 6, and 8 hours) after castor oil administration. 95 of 500 control test animals
%, severe diarrhea was observed 1 hour after castor oil treatment.

This all or zero evaluation (All-0r-ZerOeri
A significant inhibitory effect of the test compound is determined if no diarrhea is observed 1 hour after castor oil treatment. ED5O value, i.e. the animal's 50
%, the dose at which the above-mentioned effects are observed for the subject compounds is from about 0.01 to about 1 K'/K' of body weight.
It is within the range of 0m7/Kf. A minimum of 5 doses per compound are used, 10 rats are used for each dose, and the rats are administered the same dose on different days over a period of 10 days.

In addition to their antidiarrheal activity, many of the subject compounds also have antidiarrheal properties.
teI-FOrschung), 13,502 [196
Rat tail avoidance test described in 3). TailWl
It has an analgesic effect as shown in the thdrawal test). The following table contains data regarding the antidiarrheal and antiphlegm effects of several compounds (1).

A = ED5O diarrhea prevention value (119/K2, oral) B = Oral ED5O value in rat tail avoidance test (1 nV/K
2) Ratio of C=B/A=relative constipation property The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention.

All parts are by weight unless otherwise noted. Reference Example 1 23.6 parts of 2-oxo-3,3-diphenyl-tetrahydrofuran are melted at 100° C. in an oil bath and gaseous hydrogen bromide gas is introduced for 3 hours.

The reaction mixture is cooled and triturated in benzene. The product was collected, washed with petroleum ether, dried in a desiccator,
-Bromo-2,2-diphenylbutyric acid was obtained. Melting point 127
．． 16 parts of thionyl chloride was added dropwise to a stirred suspension of 16 parts of 4-bromo-2,2-diphenylbutyric acid and 150 parts of chloroform at 5°C, and the whole was stirred and refluxed for 2 hours.

Evaporation of the reaction mixture leaves 4-bromo-2,
2-diphenylbutyryl chloride is obtained. Reference example 2 A. 2-(p-fluorophenyl)acetonitrile 70
83 parts of bromine are added to the mixture and stirring is continued for 30 minutes.

2-Bromo-2-(''-fluorophenyl)acetonitrile in the resulting reaction mixture was treated with 85% aluminum chloride.
and 200 parts of fluorobenzene (at room temperature) (exothermic reaction: temperature rises to 50 °C)
After stirring for 30 minutes at 50° C., the reaction mixture is poured onto a mixture of crushed ice and 75 parts of hydrochloric acid solution. Extract the product with toluene. Dry the extract and evaporate. The residue is recrystallized twice from 2-propanol to obtain 2,2-bis(p-fluorophenyl)acetonitrile, melting point 63.5°C. To a stirred mixture of 50 parts of 2,2-bis(p-fluorophenyl)acetonitrile, 66 parts of 1,2-dibromoethane, and 4 parts of benzyltrimethylammonium chloride, 50% Add 100 parts of sodium hydroxide solution.

After completion, stirring is continued initially at 50° C. for 2 hours and then at room temperature overnight. Extract the product with toluene. The extract is washed with water, dried and evaporated. Crystallization of the solid residue from 2-propanol provides 4bromo-2,2-bis(p-fluorophenyl)butyronitrile. Continuously add 50.5 parts of triethylamine (dropwise) to 33 parts of glacial acetic acid at a melting point of 125.5°C.
and 110 parts of 4-bromo-2,2-bis(p-fluorophenyl)butyronitrile. The mixture is heated to reflux and stirred for 1 hour at reflux temperature. After cooling to about 90° C., 225 parts of hydrochloric acid are carefully added and the whole is stirred and refluxed for a further 12 hours. The reaction mixture is cooled and extracted with chloroform. The organic layer is dried, filtered and evaporated. Pour the residue onto diisopropyl ether. A large amount of the crystalline product is collected and dried to obtain 2,2-bis(p-fluorophenyl)-4-hydroxybutyric acid and γ-lactone. Melting point: 82.3-91.9°C. A mixture of 2,2-bis(p-fluorophenyl)-4-hydroxybutyric acid, 67 parts of γ-lactone, and 260 parts of a 48% solution of hydrobromic acid/glacial acetic acid is stirred at room temperature for 48 hours.

Add water and collect the precipitate that forms. Dissolve it in diisopropyl ether and separate the water. The organic layer is dried, filtered and evaporated. Triturate the residue with petroleum ether,
It is filtered and dried again to obtain 4-bromo-2,2-bis(p-fluorophenyl)butyric acid. Melting point 131.9-136
．． 53.5 parts of 4diC04-bromo-2,2-bis(p-fluorophenyl)monobutyric acid and 36 parts of thionyl chloride,
and 225 parts of chloroform and stirred for 4 hours.
Reflux.

Evaporate the reaction mixture. 4-bromo-2,2-bis(p
- Obtain fluorophenino(ha)butyryl chloride as a residue.

This is used in the next example without further purification. Example 1 4-bromo-2,2-diphenylbutyl chloride 15
1 part is dissolved in 40 parts of benzene.

This solution is added dropwise with cooling (room temperature) to a suspension of 7.1 parts of pyrrolidine in 40 parts of benzene. After completion, stirring is continued for 2 hours. The reaction mixture is evaporated, the residue is taken up in water and the product is extracted with chloroform. Dry the extract and evaporate. The residue is recrystallized from 4-methyl-2-pentanone to obtain 1-(tetrahydro-3,3-diphenyl-2-furylidene)pyrrolidinium bromide. Melting point 185.4 DEG-188.8 DEG C. The procedure of Example 1 was repeated replacing the pyrrolidine with an equivalent amount of the appropriate -N::Z amine.

1-(Tetrahydro-3,3-diphenyl-2-furylidene)piperidinium bromide; melting point) 118.2~
121.2℃0 4-(tetrahydro-3,3-diphenyl-2-furylidene) morpholinium bromide; melting point 175.7-1
78.9℃.

Dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide; melting point 169-17
1.5℃.

Diethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide; melting point 171.8~
177.8℃.

Dipropyl (tetrahydro-3,3-diphenyl-2-
Frilidene) ammonium bromide: melting point 165.5
~167.6°C.

Dibutyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide; oily residue.

Benzylmethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide; melting point 111
．． 8-113.6 diC0 diallyl (tetrahydro 3,
3-Diphenyl-2-furylidene) ammonium bromide; melting point 97.5-100.1°C.

Example 2. 4-bromo-2,2-diphenylbutyryl chloride 5
0.6 parts and 1 part of triethylamine in 320 parts of toluene
17.3 parts of 2,6-dimethylmorpholine are added dropwise to the stirred mixture with 7.5 parts of 2,6-dimethylmorpholine.

After completion (exothermic reaction; temperature rises to 50° C.), stirring is continued for 30 minutes at room temperature. The reaction mixture is filtered and the furnace liquor is washed successively with water, hydrochloric acid solution, and water. The toluene was distilled off, the resulting oily residue was dissolved in diisopropyl ether,
Stir overnight. Collect a lot of the precipitated product, dry it, and add 2,6
-dimethyl-4-(tetrahydro-3,3-diphenyl-2-furylidene) morpholinium bromide is obtained.
Melting point: 143.4-144.5°C. Example 3 11 parts of 4-methyl-piperidine and 10 parts of sodium carbonate
．． A solution of 33.8 parts of 4-bromo-2,2-diphenylbutyryl chloride in 100 parts of water is added dropwise to the stirred, cooled mixture of 6 parts of chloroform and 150 parts of chloroform at a temperature of 0°C to 5°C. .

After completion, stirring is continued for 1.5 hours. Separate the layers and extract the aqueous phase twice with chloroform. The combined organic layers were dried and evaporated. The residue is dissolved in hot 4-methyl-2-pentanone and cooled with stirring to crystallize the product. This is filtered and dried in vacuo to obtain 4-methyl-1-(tetrahydro-3,3-diphenyl-2-furylidene)piperidinium bromide. Melting point 192.7-19
The following imino-ethers are obtained by repeating the procedure of the example and replacing the 4-methylpiperidine with an equivalent amount of the appropriate -N=Z amine. Ethylmethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide melting point 172.1-173°C.
3-Methyl-1-(tetrahydro-3,3-diphenyl-2-furylidene)piperidinium bromide; melting point 1
97.8-199°C.

Methylpropyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide; melting point 170
．． 2-171.8°C o methylisopropyl(tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide; oily residue.

Example 4 Stirring of 20 parts of dimethylamine (40% in water), 150 parts of water, and 19 parts of sodium carbonate, cooled (
-5°C) 4-bromo-2 in 120 parts of toluene
, 56 parts of 2-bis(p-fluorophenyl)butyryl chloride are added dropwise.

After completion, stirring is continued for 2 hours. The whole is extracted with chloroform and the organic layer is separated, dried, filtered and evaporated. The residue was boiled in 4-methyl-2-pentanone, the product was collected hot and after drying in vacuo, [3,3-bis(p-fluorophenino(ha)tetrahydro-2-furylidene])
Dimethylammonium bromide was obtained. Melting point 194.
Reference Example 3 6.33 parts of 4-(p-chloropheno(c)-4-piperidinol), 8 parts of sodium carbonate, and 0.2 parts of potassium iodide
and 240 parts of 4-methyl-2-pentanone are azeotropically distilled.

Next, dimethyl (tetrahydro-3,3-diphenyl-2
12.12 parts of -furylidene) ammonium bromide are added and the whole is stirred and refluxed for about 15 hours. The reaction mixture is filtered while hot and the bottom liquid is evaporated. The oily residue is dissolved in 2-propanol and an excess of 2-propanol, previously saturated with gaseous hydrogen chloride, is added to this solution. The whole is evaporated and the oily residue is warmed in dilute hydrochloric acid solution. Addition of toluene will precipitate the salt. This was filtered, boiled in acetone, cooled, filtered again, and 4-(p-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,
α-diphenylpiperidine-1-butylamide hydrochloride is obtained. ; Melting point: 222.1°C. Repeat the method of Reference Example 3,
Dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide is replaced by an equivalent amount of a suitable imino-ether of formula () and a suitable 3-R of formula ()
If -4-Ar3-4-hydroxypiperidine is used, the compounds listed in the following table can be obtained.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc., characterized by causing a condensation reaction between a compound of general formula ▲ Numerical formula, chemical formula, table, etc. ▼ and a compound of general formula H-N=Z. There are tables, etc. ▼ [However, -N=Z ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼ and -N (CH_2CH=CH_2)_2. (In the above formula, R_1 and R_2 are lower alkyl, R_3 is a member selected from the group consisting of lower alkyl and benzyl, and R_4 is lower alkyl.
) Furthermore, Ar_1 and Ar_2 represent one member selected from the group consisting of phenyl and halophenyl. ] A method for producing 3,3-diaryl-tetrahydro-2-furylidene ammonium salts.