JPS5857428B2 - 2,2-Diaryl-4- (4'-aryl-4'-hydroxypiperidino) Butylamidoino Seizouhouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel method for producing 2,2-diphenyl-4-piperidinobutyramides having both hydroxy and aryl substituents at the 4-position of the piperidine ring. The purpose is to

The above-mentioned butyramides may be used alone or in combination with other therapeutically active agents as diarrhea treatments and analgesics.

2,2-diphenyl-4 produced by the method of the present invention
The chemical structure of -(4'-aryl-4'-hydroxypiperidino)butyramide can be represented by the following formula.

In the above formula, R is hydrogen or methyl: (here, R8 is lower alkyl, R2 is lower alkyl, and R1 and R2 may be the same or different): Ar is phenyl or one or more It is phenyl substituted with the above halo or trifluoromethyl.

The preparation of therapeutically active, non-toxic acid addition salts of Compound (I) above is also encompassed within the scope of this invention.

As used herein, lower alkyl contains 1 to about 6 carbon atoms, such as methyl, ethyl, propyl, inglovil, butyl, pentyl, hexyl and similar alkyls.
It may have a straight chain or a branched chain.

"The term halo 1 refers to halogens having an atomic weight of 127 or less, namely fluoro, iodo, bromo and chloro.

"Substituted phenyl-1 means a phenyl group having one or more substituents such as di, halo or trifluoromethyl.

When more than one substituent is present, the substituents may be the same or different.

Representative substituted phenyls include mono-, cy-, and trihalophenyl, trifluoromethylphenyl, and halotrifluoromethylphenyl.

Obviously, compounds of formula (I) in which R is a methyl group may have a stereochemical configuration in which the methyl group is in cis or trans position with respect to the 4-hydroxy group.

Throughout this specification, the nomenclature for these compounds is, by convention, initially relative to the reaction mixture or isomers to be separated.
- form, while the other isomer is simplified by designating the β- form.

Organic bases of formula (I) are suitable inorganic acids 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, oxalic acid, malonic acid. 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 tartaric acid, citric acid, sulfamino acid, ascorbic acid and similar acids.

On the other hand, the salts of formula (I) can be converted into the corresponding basic form by conventional treatment with a suitable alkali.

A method for producing a compound of formula (I) is to prepare a suitable compound of formula (■).
-Aryl-4-hydroxy-1-[4-N=Z)-4
-Oxo-3,3-diphenylbutyl (benzyl or methyl)piperidinium halide is dequaternized (deq.
uaternizing).

The product may be converted into an acid addition salt if desired.

The reaction formula, including the production of intermediates, can be shown as follows.

(In the above formula, R3 is methyl or benzyl, and HAn is acid.

) Compounds of formula (I) in base or salt form are highly active inhibitors of gastrointestinal propulsion and defecation and are therefore useful in the treatment of diarrhea.

The antidiarrheal activity of such compounds was observed in experimental animals such as rats according to the following test method.

Young female Wistar rats (body weight 230-251') 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 and observed for the presence of diarrhea at various time intervals (1, 2, 3, 46, and 8 hours) after castor oil administration.

More than 95% of the 500 control test animals had severe diarrhea in the mouth for 1 hour after castor oil treatment.

This all-or-none evaluation (all -or -none)
The test compound is considered to have a significant positive effect if no severe diarrhea is observed 1 hour after castor oil treatment using the following criteria:

The ED5o value, ie, the dose level at which such effects are achieved in 50% of the animals, generally ranges from about 0.01 to about 10 kg/kg for the subject compounds.

A minimum of 5 doses per compound are used, and each dose is subjected to 10 N1 experiments with 10 rats on different days.

In addition to anti-diarrheal activity, many of the compounds of the present subject matter also have
Arzneim
Ittei-Forschung), 13.50
2 (1963).
It has analgesic activity as shown in .

In the following table, data regarding the antidiarrheal and analgesic activity of some compounds are presented.

It is understood, however, that the compounds listed in this table are not mentioned for the purpose of limiting the invention thereto, but rather to demonstrate the useful performance of all compounds within the scope of formula (I). right.

A = ED5o anti-diarrheal value (my/kg oral): B- Oral ED5o value in rat tail withdrawal test (m
9/kg): C=B/A ratio-relative constipation characteristics (relative
constipating 5 specificity
): In view of their useful anti-diarrheal and analgesic activities, the present compounds and their therapeutically useful acid addition salts can be prepared in accordance with conventional pharmaceutical technology in various pharmaceutical forms for administration purposes, such as solutions, powders, It can be formulated into injections, tablets, capsules, etc.

Based on the asymmetric carbon atoms present in the compounds, it is clear that they can exist in the form of stereochemical isomers (enantiomorphs).

If desired, partitioning and isolation or production of specific forms can be accomplished by applying general principles and techniques known in the art.

Such pharmacologically active laterality is included within the scope of the present invention.

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 indicated.

Reference Example 67 parts of 1-methyl-4-(p-chlorophenyl)-4
- A mixture of piperiditur, 8 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of acetonitrile is azeotropically distilled.

Then 1212 parts of dimethyl(tetrahydro-3.3-diphenyl-2-furiritin) ammonium bromide are added and the mixture thus obtained is stirred overnight and heated to reflux.

The reaction mixture is filtered hot and the filtrate is evaporated.

Dissolve the residual oil in 2-gropanol and add to this solution,
An excess of a saturated solution of gaseous hydrogen chloride in 2-gropanol is added.

The solvent is evaporated and the remaining oil is warmed in dilute aqueous hydrochloric acid.

Salt precipitates when toluene is added. This is filtered off, the residue is boiled in 2-propanol, cooled and filtered off again.

After drying, 4-(p-chlorophenyl) with a melting point of 2238°C
-4-hydroxy-1-(4-(dimethylamino)-4
-oxo-3,3-diphenylbutyl]methylbiperidinium bromide hemiisopropyl alcoholate is 19
I got 2 copies.

The above reference example is repeated, but the 1-methyl-4-(p-chlorophenyl)-4-pipejl cinol in that example is replaced with an equivalent amount of 1-benzyl-4-(p-chlorophenyl).
-4- Take the piperidi tool! Kikaete, 4- (
1;)-chlorophenyl)-4-hydroxy-1-(4
-(dimethylamino)-4-oxo-3,3-diphenylbutyl]benzylpiperidinium bromide was obtained.

Example 1 1.5 parts of 4-(p-chlorophenyl)-4-hydroxy-1-(C4-(dimethylamino)-4-oxo-) in 4 parts of hexamethylphosphoramide (distilled from CaH2) A solution of 3,3-diphenylbutyl]methylpiperidinium bromide hemiisopropyl alcoholate was cooled to 0-5°C, 0.16 parts of lithium hydride was added, followed by freshly distilled n-propyl mercaptan 0. .Add 63 parts.

The solution was stirred for 30 minutes at 0°C under a nitrogen atmosphere,
Then dilute with water and extract with cyclohexane.

The solvent is evaporated and the oily residue is warmed in dilute hydrochloric acid solution.

Salt precipitates when toluene is added.

This was filtered, heated to boiling in acetone, cooled, and filtered again to produce 4-(p-chlorophenyl) with a melting point of 222.1°C.
-4-Hydroxy-N-N-7-dimethyl-α.α-diphenylpiperidine-1-butyramide hydrochloride was obtained.

Example 2 7.8 parts of 4-(p-chlorophenyl)-4-hydroxy-1-(4-(dimethylamino)-4=oxo-3.
A mixture of 3-diphenylbutyl]benzylpiperidinium bromide, 19 parts of thiophenol, and 70 parts of a 5% aqueous solution of caustic soda was heated with stirring for 5 hours at a temperature of 40 to 50%.
Warm to ℃.

After cooling, the reaction mixture is mixed with diethyl ether and extracted with a 10% aqueous solution of hydrochloric acid.

The extract is neutralized with a concentrated solution of ammonium hydroxide,
The whole is extracted with chloroform, washed with water and dried over sodium sulfate.

Evaporate the chloroform and dissolve in ingropanol, previously saturated with gaseous hydrogen chloride.

Crystallization is carried out and the product is filtered, melting point 2221°C + 7).
4-(p-chlorophenyl)-4-hydroxy-N-N
-Dimethyl-α·α-diphenylpiperidine-1-butylamide hydrochloride was obtained.

Additional Related Compounds of the present invention are of the formula (I) in which Ar is phenyl or halogen or trifluoromethyl-substituted phenyl.

) of 2,2-diaryl-4- (4 is aryl-47-
Hydroxypiperidino)butyramide is the target compound of the original application, and has the formula (wherein Ar and Ar2 are each phenyl or substituted phenyl, and Ar3 is phenyl or alkyl, alkoxy,
Phenyl substituted with halogen or trifluoromethyl, Alk is alkylene having 2 or 3 carbon atoms.

) is a compound included in 2,2-diaryl-4-piperidinobutyramide, and the present invention is a compound contained in 2,2-diaryl-4-piperidinobutyramide.
The main part of the invention is the matter that has the same effect and is indispensable for the configuration between nuclear power plants.

Therefore, the present invention relates to a method for improving the compound of formula (I) above, and can be patented independently. Therefore, the present application is subject to the provisions of Article 31, Paragraph 1 of the Patent Law. , and has an additional relationship with the original application F Patent No. 1160032 (Japanese Patent Publication No. 57-54508)).

Claims (1)

[Scope of Claims] 1 Formula (I) [In the above formula (I), R is hydrogen or methyl (where R3 is lower alkyl, R2 is lower alkyl, and R1 and R2 are the same) ) Ar is phenyl or phenyl substituted with one or more halo or trifluoromethyl. In the method for producing an active acid addition salt, a compound of formula (■) (in the above formula, R3 is methyl or benzyl) is dequaternized using a mercaptan in the presence of an alkali metal donor, and when A process as described above, characterized in that the product is converted into a therapeutically active acid addition temperature by.