JPS5857427B2 - 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-piperisiptylamides 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, R1 is lower alkyl, 1R2 is lower alkyl,
R1 and R2 may be the same or different):
Ar is phenyl or phenyl substituted with one or more halo or trifluoromethyl.

] Also included within the scope of the invention is the preparation of therapeutically active, non-toxic acid addition salts of the above compounds CI).

As used herein, lower alkyl contains 1 to about 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and similar alkyls.
own.

It may have a straight chain or a branched chain.

The term "halo" refers to halogens of atomic weight up to 127, namely fluoro, iodo, bromo and chloro.

The term "substituted phenyl" refers to 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-, di-, and trino-phenyl, trifluoromethylphenyl, and halotrifluoromethylphenyl.

Compounds of formula (I,) in which R is a methyl group obviously have
The methyl group may be in a stereochemical configuration in cis or trans relative to the 4-hydroxy group.

The nomenclature for these compounds is used throughout this specification to refer to the isomer that is conventionally first separated from the reaction mixture.
- 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 a method for preparing a compound of formula (V).
- reacting phenylbenzeneacetamide with an alkali metal donor, preferably sodium amide, and then converting the product into a suitable 1-(2-haloethyl) of formula (Vl)
-4-aryl-4-piperiditul, preferably at a reducing temperature.

The above reaction may be carried out in organic solvents such as aromatic hydrocarbons such as benzene, toluene, xylene, etc., lower alkanols, lower alkanones.

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

The reaction formula can be shown as follows.

In the following reaction equations, all have the same meaning as -N=Z defined in or have the same meaning as -Ar defined above.

Compounds of formula (I) in their reactive base or salt forms are highly active inhibitors of gastrointestinal propulsive force and defecation and are therefore useful in the treatment of diarrhea.

The anti-diarrheal activity of the antidiarrheal compound was observed in experimental animals such as rats according to the following test method.

Young female Wistar rats (body weight 230-250?) 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 dosed orally with 1/711 castor oil.

Each rat is placed in a cage one by one, and the presence or absence of diarrhea is observed at various time intervals (1, 2, 3, 4, 6, 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 (al l-or-nonec
riterium), if after castor oil treatment, 1
The test compound is considered to have a significant positive effect if severe diarrhea is not observed within hours.

The ED5o value, ie, the dose level at which such an effect is observed in 50% of the animals, is within the range of about 0.01 to about 10 In9/kg for the subject compounds.

■ Use a minimum of 5 doses per compound and test 10 times on different days with 10 rats for each dose.

Also, many of the compounds of the present subject matter have anti-diarrheal activity of 770
Eh, Arznei Mitstelf Orschung (Arznei Mitstelf Orschung)
m 1ttel-Forschung), 13
．． 502 (1963).
) has analgesic activity.

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 = E D5o antidiarrheal value Cm97 to 9 oral);
B = Oral ED5o value (η/yu) in the Krat tail withdrawal test; C = B/A ratio - relative constipation characteristic (relative co
5 specificity)
In view of their useful antidiarrheal 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.

All pharmacologically active side effects are encompassed 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.

Example 1 85.5 parts of a 50% xylene solution of sodium amide was suspended in 450 parts of toluene, and while this was being stirred, 59.5 parts of N-N-dimethyl was added in 90 parts of toluene. - Add a solution of α-phenylbenzene acetamide.

The mixture is stirred at reflux temperature for 3 hours.

After cooling to room temperature, a solution of 68.5 parts of 1-(2-chloroethyl)-4-(4-10 lophenyl)-4-piperiditul in 360 parts of toluene is added.

The whole is stirred at reflux temperature for 18-24 hours and after cooling to room temperature the reaction mixture is poured into ice water.

The organic phase is separated off, dried, filtered and evaporated. The residue was converted to the hydrochloride salt in 2-propanone and 2-propanol to give 4-(p-chlorophenyl)-4, mp 222-223°C.
55 parts of -hydroxy-N·N-dimethyl-α·α-diphenylpiperidine-1-butyramide hydrochloride were obtained.

In the above method, the following compound was obtained by appropriately replacing the starting materials.

4-(p-bromophenyl)-4- with a melting point of 123.7°C
Hydroxy-N-N-dimethyl-α.α-diphenylpiperidine-1-butylamide hydrate.

1-(4-(4-hydroxy-4-
7enylpiperidino)-2,2-diphenylbutyrylcopiperidine hydrochloride.

4-(p-chlorophenylcou N-) with a melting point of 215.8°C
Ethyl-4-hydroxy-N-methyl-α·α-diphenylpiperidine-1-butyramide hydrochloride.

Starting diphenylacetamides are known in the art.

Intermediate 4-aryl-1-(2-chloroethyl)-4
- Piperiditools are U.S. Patent No. 297 to Mr. Jansen.
No. 3363.

Additional Related Compounds of the Present Application, Formula CI) in which Ar is phenyl or norogen or trifluoromethyl-substituted phenyl.

) of 2,2-diaryl-4-(4-aryl-4'-
Hydroxypiperidino)butyramide is the object compound of the original application, having the formula Phenyl, Alk is a compound included in 2,2-diaryl-4-piperidinobutyramide, which is an alkylene having 2 or 3 carbon atoms, and the present invention has the same purpose and effects as the original application. The main part of the invention is the matter essential to the configuration between nuclear power plants.

Therefore, since the present invention relates to an improved method of inventing the compound of formula (1) above and can be patented independently, the present application falls under the provisions of Article 31, Paragraph 1 of the Patent Law. , and has an additional relationship with the original application and Patent No. 1-160032 (Japanese Patent Publication No. 57-54508).

Claims (1)

[Claims] 1 Formula (I) [In the above formula (I), R is hydrogen or methyl, and R1
is lower alkyl, R2 is lower alkyl,
R1 and R2 may be the same or different. ) Ar is phenyl or phenyl substituted with one or more halo or trifluoromethyl. A method as described above, characterized in that the compound of formula V is reacted with a compound of formula CVI, optionally converting the product into a therapeutically active acid addition salt.