JPS5857425B2 - 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, R is hydrogen or methyl; (here, R1 is lower alkyl, R2 is lower alkyl, and R1 and R2 may be the same or different); Ar is phenyl or one or more 710 above or phenyl substituted with trifluoromethyl.

The preparation of therapeutically active, non-toxic acid addition salts of compound I) above is also encompassed within the scope of the 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" refers to halogens of atomic weight up to 127, namely fluoro, iodo, bromo and chloro.

The term "substituted phenyl" means a phenyl group having one or more substituents on the phenyl group, such as 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 trihalophenyl, trifluoromethylphenyl, and halotrifluoromethylphenyl.

Obviously, compounds of (1) in which R is a methyl group may have a stereochemical configuration in which the methyl group is in cis or trans position 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.

The organic base of formula (1) can 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, oxalic acid, malonic acid. It 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 ff1) can be converted into the corresponding base form by conventional treatment with a suitable alkali.

The compound of formula (1) is a suitable 4-oxo-α・α of RM>
-diphenyl-1-piperidinebutyramide with a corresponding amount of 1-bromobenzene under Grignard conditions.

Good reaction conditions consist of reaction with magnesium in tetrahydrofuran under reflux.

If desired, the products may be converted to acid addition salts.

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

In the following reaction formulas, all have the same meaning as -N=Z as defined above, and have the same meaning as -Ar as defined above.

Compounds of formula (1) in their base or salt forms are highly active inhibitors of gastrointestinal propulsion and defecation and are therefore useful in the treatment of diarrhea.

The antidiarrheal 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 230-25 Or) 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 orally administered with ITLl 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 (all -or -nonec)
The test compound is considered to have a significant positive effect if no severe diarrhea is observed within 1 hour after castor oil treatment.

The ED5o value, ie, the dose level at which such an effect is observed in 50% of the animals, is generally within the r range of about 0.01 to about 107 Q/kg for the subject compounds.

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

Many of the compounds of the present invention also have antidiarrheal activity,
Arzneimi
ttel-Forsehung), 13,502
(1963) in the rat tail withdrawal test (
It has analgesic activity as shown in the tail withdrawal test.

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

However, it is understood that the compounds listed in this table are not intended to limit the invention thereto, but rather to demonstrate the useful performance of all compounds within the scope of formula (1). It will be.

A-ED5o anti-diarrheal value (drops/kg oral); B-oral ED5o value in rat tail withdrawal test (In9/kg oral);
kg); C=B/A ratio-relative constipation characteristic (relative co
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 various pharmaceutical forms for administration purposes according to conventional pharmaceutical technology, 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.

The pharmacologically active side effects of the present invention are encompassed within the scope of the present invention.

The following examples serve 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 1 28.6 parts of 1,4-dioxa-8-azaspiro [4.
5] A mixture of decane, 64 parts of sodium carbonate, 1 part of potassium iodide and 480 parts of 4-methyl-2-pentanone is stirred and heated under reflux for 30 minutes with a water separator.

The mixture is cooled and 76.2 parts of dimethyl (tetrahydro-3,3-diphenyl-2-furiritin 9 ammonium bromide) are added.

The whole is stirred and heated under reflux for 10 hours and then left at room temperature.

Water is added and the organic phase is separated off, dried and evaporated.

The oily residue solidified when triturated in diisopropyl ether (activated carbon) and 63.8 parts of N-N-dimethyl-α
-α-diphenyl-1,4-dioxa-8-azaspiro[4,5]decane-8-butylamide is produced.

The melting point of this product is 126.6°C. Note: The raw material compound dimethyl (tetrahydro-3,3-diphenyl-
2-7 Liritene) ammonium bromide is described in Japanese Patent No. 1160032 (Japanese Patent Publication No. 57-54508).

Reference example 2 50 parts of N-N-dimethyl-α・α-diphenyl-1・
4-dioxa-8-azaspiro[4.5]decane-8-
A mixture of butyramide and 500 parts of 2N hydrochloric acid solution is stirred and heated under reflux for 15 hours.

The reaction mixture is cooled, made alkaline with caustic soda solution and the product is extracted with toluene.

The latter is dried and evaporated.

Stir the solid residue in diisopropyl ether.

The product was filtered off, dried and
-N-dimethyl-4-oxo-α・α-diphenyl-1
-37 parts of piperidine butyramide were obtained.

Example 1 To a stirred Grignard complex prepared starting from 48 parts of 1-bromo-4-chlorobenzene and 6 parts of magnesium in 80 parts of tetrahydrofuran and heated to reflux, 73 parts of N- A solution of N-dimethyl-4-oxo-α·α-diphenyl-1-piperidinebutyramide in 45 parts of tetrahydrofuran is added dropwise.

Once the dropwise addition is complete, stirring under reflux is continued for 1 hour.

The reaction mixture is decomposed by pouring it into a mixture of glacial acetic acid and crushed ice.

The product is extracted with chloroform and the extract is dried, filtered and evaporated.

The residue was converted to the hydrochloride salt in 2-propanone and 2-propanol to give 4-(p-chlorophenyl)-4-hydroxy-N-N-dimethyl-α·α with a melting point of 222-223°C.
-diphenylpiperidine-1-butyramide hydrochloride 52
I got the department.

By replacing the starting materials with appropriate ones in the above method, the following compounds can be obtained.

4-(4-chloro-α・α・α-trifluoro-m-tolyl)-4-hydroxy-N-N- with a melting point of 215.3°C
Dimethyl-α・α-diphenylpiperidine-1-butyramide hydrochloride.

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

α-Izan-4-hydroxy-N・N・ with a melting point of 218.8°C
3-trimefruα-α-diphenyl-4-(α・α・
α-Trifluoro-m-MJl)piperidine-1-butyramide hydrochloride.

1 with a melting point of 240.3°C. -(4-(4-hydroxy-4
-phenylpiperidino)-2,2-diphenylbutyryl]piperidine hydrochloride.

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

Additional Related Compounds of Interest of the Application, QI) (wherein Ar is phenyl or halogen or trifluoromethyl-substituted phenyl).

) of 2,2-diaryl-4-(4'-aryl-4'
-Hydroxypiperidino)butyramide is the object compound of the original application, with the formula (wherein Ar ] and Ar2 are each phenyl or substituted phenyl, and Ar3 is phenyl or alkyl, alkoxy, halogen or trifluoromethyl. Substituted phenyl 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.
They have the same effect, and the essential parts of the invention are those that are essential to the structure of the original invention.

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

Claims (1)

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