JPS5936991B2 - 3,3-diphenyl-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-diphenyl-4-piberidinobutyramides useful as gastrointestinal tract propulsion inhibitors and analgesics.

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

Among these is the well-known commercial product 2,2-diphenyl-4-[(4-carboethoxy-4-phenyl)piperidino]butyronitrile, commonly known as DipheIxylate.
Other prior art compounds are known that include various 2,2-diphenyl-4-piperidinobutyramides or substituted with hydroxy and ali monofunctional groups at the 4-position of the piperidino ring, among others. do not have. An object of the present invention is to provide a method for producing a new class of raw materials for 2,2-diphenyl-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 shown by the following formula. ~ [wherein R is 1 selected from the group consisting of hydrogen and methyl]
and A'k is -CH2CH2- and -CH(C
H3) A member selected from the group consisting of CH2-.

Furthermore, Ar3 is a member selected from the group consisting of phenyl and substituted phenyl. The term "lower alkyl" as used in the present invention includes, for example, methyl, ethyl, propyl and similar alkyls.

The term "substituted phenyl" refers to a phenyl group having one or more substituents such as lower alkyl, lower alkoxy, halo and trifluoromethyl. 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. In the present invention, the term I butyramide does not relate to a specific compound in the Examples and Claims described below, but in a broad sense to butyramides (i.e., when the alkylene group between the α-carbon and the piperidine nitrogen is -CH2CH2
-) and valeramides (i.e., when the alkylene group is -CH(CH3)CH2-). The compound of the above formula (1) in which R represents a methyl group clearly has a methyl group of 4
-It may have a stereochemical configuration in cis or trans position relative to the hydroxy group.

The nomenclature of these compounds has been simplified in this application by customarily 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, for example, acetic acid, propionic acid, glycolic acid, lactic acid, sulfuric acid, etc. The corresponding pharmaceutically acceptable acid addition salts can be converted into the corresponding pharmaceutically acceptable acid addition salts by reaction with suitable organic acids such as acid, malonic acid, tartaric acid, citric acid, sulfamic acid, ascorbic acid and similar acids.

On the other hand, the salts of formula (1) can be converted into the corresponding bases by treating with a suitable alkali in a conventional manner.

(In the formula (y), Ph means a phenyl group.

Hereinafter, the phenyl group will be abbreviated as Ph. ) As shown in the above chemical reaction formula, a compound in which Alk is -CH2CH2- in formula (1) (Iy is a compound of formula can be produced by subjecting a bromide salt to a condensation reaction with a suitable 4-aryl-4-piperidinol of formula ().

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 advisable to use an appropriate amount of a suitable base, such as an alkali metal carbonate, during the condensation reaction. Also desirable is the presence of a catalytic amount of potassium iodide. As shown in the chemical reaction formula above, in formula (1),
Compounds in which Alk is one CH(CH3)CH2- can be obtained by combining a suitable 3,3-diphenyl-4-methyl-tetrahydro-2olylidene ammonium salt, preferably an iodo salt, of formula (Y) with a piperidinol of formula (1). It can be produced by condensing in the same manner as above.

The present invention relates to a method for producing a novel intermediate useful in the production of 2,2-diphenyl-4-piperidinobutyramides.

That is, the present invention is based on (1) the general formula (wherein R5 is a member selected from the group consisting of a hydrogen atom and a methyl group);

) is treated with a lower alkyl halide. 2
-Production method of frilidene ammonium salts and (2)
General formula (wherein R5 is one member selected from the group consisting of a hydrogen atom and a methyl group).

) is treated with an alkali metal amide, the obtained alkali metal salt is treated with a lower alkyl halide to obtain a compound of the general formula, which is then treated with a lower alkyl halide.
1-Z.

(wherein, -N=Z2 represents -N(lower alkyl)2), 3,3-diphenyl-tetrahydro-2-
This invention relates to a method for producing frilidene ammonium salts.

(a) Formation of alkali metal salt in the above reaction, (b)
N-alkylation with a lower alkyl halide and (iii) formation of a quaternary salt are carried out according to conventional methods.

For example, the formation of the alkali metal salt in (a) can be achieved by heating the raw material compound with the alkali metal amide in an aprotic inert medium, stirring and inactivating the alkali metal amide. (b) N-Alkylation with a lower alkyl halide can be carried out by treating the alkali metal salt obtained as described above with a lower alkyl halide in an aprotic inert medium under heating and stirring.

The quaternary salt formation using a lower alkyl halide (c) can be carried out by heating the alkylated compound with the lower alkyl halide in an aprotic inert medium and stirring to inactivate the compound.

The above alkylation with the lower alkyl halide and quaternary salt formation may be carried out at once using an excess of the lower alkyl halide. The compound of formula 9, which is one of the starting materials of the present invention, is prepared as follows.

As shown in the chemical reaction formula above, a suitable 4-bromo-2,2
- can be obtained by reacting diphenylbutyryl chloride (Xl) with aqueous ammonia and then neutralizing the thus obtained hydrobromide salt of formula (-a) to give the free base () .

Incidentally, the butyryl chloride (Xl) can be obtained by converting the corresponding 4-bromo-2,2-diphenylbutyric acid (XIV) into the acid chloride form by treating it with thionyl chloride, oxalyl chloride, and similar compounds in a conventional manner. You can easily go and get it. The compound of formula (X), which is another raw material of the present invention, can be prepared by the following reaction sequence.

As shown in the above reaction formula, 3-cyano-3,3-diphenylisobutyric acid (X) is first converted to its corresponding alcohol form (
XVI). Such reduction uses standard acid to acid chloride techniques, e.g. with thionyl chloride or oxalyl chloride, to convert the acid (X) into its corresponding acid chloride form (X
-a) and then treating the acid chloride thus obtained with a suitable reducing agent, such as sodium borohydride. Closure of alcohol (XVI) to furanimine (X) is then accomplished by treatment with gaseous HCI in a suitable organic solvent, preferably under cooling. 3,3-diphenyl-tetrahydro-2 of formula () of the present invention
-furylidene-ammonium salts are new and have the formula [1
] In view of their usefulness as precursors of 4 for the synthesis of compounds, the quaternary salts constitute a feature of the present invention.

In the above, the formula ([
Many of the 4-aryl-4-hydroxypiperidines are
as described in the literature (e.g., U.S. Pat. No. 3,438
(See No. 991).

In general, they involve the Grignard reaction of a suitable 1-(lower alkoxy)carbonyl-3-R-4-piperidone (5) allowing a lower alkoxy function or methoxy or ethoxy with a suitable phenyl-magnesium halide (V). It can be formed by condensation under certain conditions.

Next, 1 of the thus obtained 1-(lower alkoxy)carbonyl-3-R-4-Ar3-4-hydroxypiperidine
The protecting group in the 1-position is removed by heating the compound (2) with a suitable alkali, such as potassium hydroxide, to give the desired starting material (1). The condensation reaction is exemplified by the following reaction formula. Separately, 1-benzyl-3-R-4-piperidone was condensed with formula (V) and then the 1-benzyl-3-R-4-Ar3-4-
The desired starting compound (
Get [.

Compounds of formula (1) in base or salt form are highly active gastrointestinal tract propellant 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 (body weight 230-2509) are incubated 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 within 1 hour after castor oil treatment. ED5O value, i.e. the animal's 50
For the subject compound, the dosage at which the above-mentioned effects are observed in % is about 0.01 to about 1% per kg of body weight.
It is within the range of 0r19/Kg. Minimum 5 per compound
Different doses are used, 10 rats are used for each dose, and the same doses are administered to the rats on different days within 10 days.

In addition to their antidiarrheal properties, many of the subject compounds also have antidiarrheal properties.
el-FOrschung), 13502 (1963)
The rat tail avoidance test (TaHWithd) described in
It has an analgesic effect as shown in the rawal test). The following table contains data regarding the antidiarrheal and analgesic effects of several compounds [1].

A = ED5O diarrhea prevention value (W9/Kg, oral) B Oral ED5O value in the tail avoidance test of Niratu (~/1<g)
C=Ratio of B/A=Relative Constipation Special 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 stated. Reference Example 1 23.6 parts of 2-oxo-3,3-diphenyl-tetrahydrofuran are melted in an oil bath at 100" CIIC. Gaseous hydrogen bromide gas is introduced for 3 hours.

The reaction mixture is cooled and triturated in benzene. Collect a lot of the product, wash with petroleum ether, dry 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,
Synthesis of 2-diphenylbutyrylchlora: 3-cyano-3
, 3-diphenylisobutyric acid (C.A.55,2565
(1961)), 48 parts of thionyl chloride, and 300 parts of chloroform were stirred for 2 hours.
Reflux.

The mixture is evaporated and the residue (acid chloride derivative) is dissolved in 40 parts of dimethylformamide. 20 liters of the latter solution
7.5 parts of sodium borohydride in 160 parts of dimethylformamide at a temperature of 5° C. are added dropwise. After completion, the whole is stirred overnight at room temperature and further stirred at 75° C. for 1 hour. The reaction mixture is cooled and 15 parts of glacial acetic acid are added dropwise. The whole is poured onto a mixture of crushed ice and water and the product is extracted with diisopropyl ether. Dry the extract and evaporate. The residue is dissolved in 200 parts of diisopropyl ether and the solution is saturated with gaseous hydrogen chloride while cooling. The solution is left at O 0 C overnight. Decant the ether and leave a semi-solid residue with 4-
Boil in methyl-2-pentanone. After cooling, the product is collected and dried to give tetrahydro-4-methyl-3
, 3-diphenyl-2-furanimine hydrochloride is obtained. Synthesis with melting point 185.2-193.6°C: 5.7 ml of tetrahydro-4-methyl-3,3-diphenyl-2-furanimine hydrochloride in 45 parts of tetrahydrofuran
0.92 part of lithium amide is added dropwise to 5 parts of the stirred suspension and the whole is stirred for a further 2 hours at reflux temperature.

The reaction mixture was cooled to room temperature and 14.2 parts of methyl iodide was added dropwise. After stirring and refluxing overnight, the reaction mixture is evaporated.
The residue was stirred in water, which resulted in undissolved oily N-(
tetrahydro-3,3-diphenyl-2-furylidene)
Separate the methylamine. The aqueous phase is separated and the oil is dissolved in 80 parts of 4-methyl-2-pentanone. The solution is stirred and refluxed with 14.2 parts of methyl iodide overnight. After cooling, the product precipitates. A lot of this is collected and dried to obtain about 1.5 parts of the first fraction (tetrahydro-4-methyl-3,3-diphenyl-2-furylidene)dimethylammonium iodide. : Melting point 180.1°C. The aqueous phase (separated) is extracted with chloroform. The latter is dried and evaporated. The residue is boiled in 80 parts of 4-methyl-2-pentanone and, after cooling, the product is precipitated. Take a lot of this,
If dried, the second fraction (tetrahydro-4-methyl-3
, 3-diphenyl-2-furylidene) dimethylammonium iodide is obtained. Melting point 184.2-18
8.7iC Instead of methyl iodide, ethyl iodide and n iodide
- repeating Example 1-B using each equivalent of propyl;
The corresponding diethyl and dipropylammonium iodides, respectively, are obtained.

According to the method of Example 1-B, 2-imino-3,3-diphenyltetrahydrofuran (J.Chem.SOc.,
5lO (1949)) and methyl iodide as a raw material to obtain (tetrahydro-3,3-diphenyl-2-furylidene)dimethylammonium iodide.

Melting point 217-218C Reference Example 2 100 parts of aqueous methylamine (35%), 106 parts of sodium carbonate, 1000 parts of water, and 800 parts of toluene
Stir and cool the mixture with 2 parts of toluene for 30 minutes.
The mixture is added dropwise to a solution of 373 parts of 4-bromo-2,2-diphenylbutyryl chloride in 0.00 parts while maintaining the temperature at 00 to 5°C.

Once complete, remove the cooling bath and continue stirring for 2 hours. Collect the precipitated product and suspend it in water. The solids are again stripped off and dissolved in chloroform. The solution is washed with water and evaporated to dryness. The thick oily residue is poured onto hot 4-methyl-2-pentanone with stirring to crystallize the product. This is collected and dried to obtain N-(tetrahydro-3,3-diphenyl-2-furylidene)methylamine hydrobromide. Melting point 154. “C Example 2)
'12.6 parts of N-(tetrahydro-3,3-diphenyl-2-furylidene)methylamine hydrobromide obtained in Reference Example 2 and 14.2 parts of methyl iodide
1 part was dissolved in 4-methyl-2-pentanone and the solution was stirred and refluxed overnight.

Next, the solvent was distilled off under reduced pressure, and the residue was recrystallized from 4-methyl-2-pentanone to obtain 12.4 parts of (tetrahydro-3,3-diphenyl-2-furylidene)dimethylammonium iodide. Melting point 217-218℃ reference example
34-(p-chlorophenyl)-4-piperidinol 6
．． A mixture of 33 parts of sodium carbonate, 8 parts of sodium carbonate, 0.2 parts of potassium iodide, and 240 parts of 4-methyl-2-pentanone is 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 filtrate 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. A lot of this was collected, boiled in acetone, cooled, and then collected again. get it.
; Melting point: 222.1°C. The method of Reference Example 3 is repeated, dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) amonium bromide is replaced with an appropriate imino-ether of formula (y), and a suitable imino-ether of formula (1) is -R4
Using -Ar3-4-hydroxypiperidine, the compounds listed in the following table are obtained.

Reference example 4 4-(p-chlorophenyl)-4-piperidinol2.
1 part, 2.67 parts of sodium carbonate, and 80 parts of 4-methyl-2-pentanone are distilled azeotropically and dried using a water separator.

Claims (1)

[Claims] 1. A compound of the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_5 is a member selected from the group consisting of a hydrogen atom and a methyl group.) A lower alkyl halide 3,3-diphenyl-tetrahydro-2 having the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula, -N=Z_2 represents -N (lower alkyl)_2)
- A method for producing frilidene ammonium salts. 2. A compound with the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. A compound of the general formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ is obtained by treating an alkali metal salt with a lower alkyl halide, and then treating it with a lower alkyl halide. There are chemical formulas, tables, etc. ▼ (In the formula, -N=Z_2 represents -N (lower alkyl)_2), 3,3-diphenyl-tetrahydro-
Method for producing 2-furylidene ammonium salts.