JPS5857426B2 - 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
-(4,'-ary-4'-hydroxypiperidino)
Butyramide can be represented by the following chemical structure.

[In the above formula, 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 phenyl substituted with more halo or trifluoromethyl.

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

It may have a straight chain or a branched chain.

The term "halo" refers to halogens with an atomic weight up to 127, including 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 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.

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 preparing a compound of formula (I) is to prepare a suitable 4-ary-root 2,3,6-titrahydro α,α- of formula (IV).
It consists of reacting diphenyl-1-pyridine butanamide with hydrogen halide and then alkalizing the product.

If desired, the product may be converted into an acid addition salt.

The hydrogen halide used in the above reaction is preferably gaseous hydrogen bromide, and the compound (IV) above is dissolved in a suitable solvent, preferably chloroform.

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

In the following reaction equation, all has the same meaning as 1N=Z defined above has is defined above as -Ar and have the same meaning.

reaction formula (In the formula, HAn is an 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 Kamata's compound was observed in experimental animals such as rats according to the following test method.

Young female Wistar rat (weight 2
30-25C1) 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 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
ri terium), and if after castor oil treatment,
The test compound is considered to have a significant positive effect if no severe diarrhea is observed within 1 hour.

E.D. Values, ie, dosage levels at which such effects are observed in 50% of the animals, generally range 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 tested 10 times on different days with 10 rats.

Many of the compounds of the subject matter of the present invention can also be processed to have anti-diarrheal activity.
Arzneimi
ttel-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 (~/ky oral): B-Oral ED5o value in rat tail withdrawal test (~/ky)
ky); 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, separation 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.

Reference Example 5.8 parts of 4-(4-chlorophenyl)-1, 2, 3,
A mixture of 6-titrahydropyridine, 8 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred azeotropically and heated to reflux for 1 hour.

After cooling to 75-80°C, 12.12 parts of dimethyl (
tetrahydro-3,3-diphenyl-2-furylidene)
Add ammonium bromide in portions.

Once the addition is complete, stirring is continued under reflux for 3 hours.

The reaction mixture is cooled to room temperature, water is added and the layers are separated.

The organic phase was dried, filtered and evaporated to give -4.58 parts of 4-(
4-chlorophenyl)-1,2,3,6-tetrahydro-N-N-dimethyl-α,α-diphenyl-1-pyridinebutanamide was obtained.

Example 4.58 parts of 4-(4-chlorophenyl)-1.2.3
・A solution of 6-tetrahydro-N-N-dimethyl-α・α-diphenyl-1-pyridinebutanamide dissolved in 750 parts of chloroform is stirred, and gaseous hydrogen bromide is poured into the solution for 60 minutes. .

The solvent is removed under vacuum and the residue is stirred with warm water (50° C.).

The whole is alkalized with a dilute 5% solution of caustic soda and the product is extracted with 4-methyl-2-pentanone.

The extract is dried, filtered off and evaporated under vacuum.

The residue was converted to the hydrochloride salt in 2-propanol, mp 22
2.8 parts of 4-(p-chlorophenyl)-4-hydroxy-N·N-dimethyl-α·α-diphenylpiperidine-1-butylamide hydrochloride at 2.1°C was obtained.

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

4-(p-bromophenyl)-4-hydroxy-NN-dimethyl-α·α-diphenylpiperidine-1-butylamide hydrate having a melting point of 1235°C.

1-(4-(4-hydroxy-4-
phenylpiperidino)-2,2-diphenylbutyryl]
Piperidine hydrochloride.

Melting point 215°C (04-(p-chlorophenyl)-N-ethyl-4-hydroxy-N-methyl-α·α-diphenylpiperidine-1-butyramide hydrochloride.

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'-aryl-4'
-Hydroxypiperidino)butyramide is the object compound of the original application, having the formula 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.
The effects are the same, and the essential parts of the invention are essential for the configuration between nuclear power plants.

Therefore, since the present invention relates to an improved method of inventing the compound of formula (I) 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 (Patent No. 1160032 (Japanese Patent Publication No. 57-54, No. 508) 1).

Claims (1)

[Claims] 1 Formula (I) [In the above formula (I), (where 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. ] In the method for producing 2,2-diphenyl-4-piperidinobutyramide or a therapeutically active acid addition salt thereof,
A process as described above, characterized in that the compound of formula (IV) is reacted with hydrogen halide, after which the product is alkalized and optionally converted into a therapeutically active acid addition salt.