KR790001840B1 - Process for pruducing 1,1-diaryl-1-oxadiazol-alkylamines - Google Patents

Abstract

Title compds. (I; Alk = C2-4 straight side chain alkylene ; R = H, C1-7 alkyl ; X = H, halogen, C1-7 alkyl ; Ar = Ph, phridyl, mono substituted phenyl by halogen or C1-7 alkyl; R1, R" =(C5 azabicycloalkane), useful as antidiarrhea agent and analgesis, were prepd. by reaction of II with R"' (C = O) C1. Thus, 2,2-diphenyl 4-[2- azabicyclo (2,2,2) Oct-2-y1 butyronitrile was treated with sodium azid, NH4C1, LiC1 followed by refluxing with Ac2O in pyridine 2hr gave 5-[1,1-diphen-y1-3-(2-azabicyclo [2,2,2 oct-2-y1) propyl -2- methyl-1,3,4-oxadiazole.

Description

Method for preparing 1, 1-diaryl-1-oxadiazole alkylamine

The present invention relates to a method for producing a compound represented by the following general formula (I).

In the above formula

Alk is a straight or branched alkene containing 2-4 carbon atoms:

R is hydrogen or an alkyl group containing from 1 to 7 carbon atoms, X is hydrogen, halogen or an alkyl group containing from 1 to 7 carbon atoms, and Ar is a single compound in which phenyl, pyridyl or substituent is halogen or an alkyl group containing from 1 to 7 carbon atoms Substituted phenyl and R ¹ and R ″ together with N are azabicycloalkane structures containing 6-8 carbon atoms and at least 5 carbon atoms in each ring of the azabicyclo alkane structure.

Examples of alkylene groups represented by Alk include ethylene, propylene or trimethylene, and examples of alkyl groups include methyl, ethyl, propyl and butyl, and halogens are, for example, pullouro, chloro, bromo or iodo and N Together with R ′ and R ″ are 2-azabicyclo (2, 2, 2) octyl, 6-azabicyclo (3, 2, 1) octyl, 3-azabicyclo (3, 2, 2) nonyl and 2-azabicyclo (2, 2, 2) octyl is more suitable for forming alkanes such as 7-azabiscro (2, 2, 1) heptyl to form alkanes. Together with non-toxic acid-addition salts such as sulfuric acid, phosphoric acid, hydrochloric acid, bromic acid, iodic acid, sulfamic acid, citric acid, lactic acid, maleic acid, malic acid, malic acid, tartaric acid, cinnamic acid, acetic acid, benzoic acid, It is formed from acids such as gluconic acid, ascorbic acid, etc. Compounds of the present invention include acids such as triethylamine, piperidine or potassium carbonate. In the presence of a scavenger, tetrazole of formula (II) is reacted with an acylating agent of formula (IIa) in a suitable solvent such as pyridine or an inert solvent such as toluene, benzene, methylene chloride or cyclohexane The oxadiazole of (I) can be obtained, and it can manufacture conveniently.

In the above formula

Alk, Ar, X, R 'and R "are as described above and R"' is a group that can be easily removed by liberating hydrogen, such as an alkyl group of 1-7 carbon atoms or carbuethoxy.

Starting materials of formula (II) were prepared by J. Med. Compounds of the following general formula (III) can be prepared by reacting azide ions by methods analogous to those described in Chem, 10, 149 (1967).

In the above formula

Alk, Ar, X R 'and R "are the same as described above.

Other methods for the preparation of the compounds of the present invention are suitable in the presence of acid scavengers such as triethylamine, piperidine or potassium carbonate, such as toluene, benzene, methylene chloride, 4-methyl-2-pentanol or cyclohexane. The haloalkyl compound of the following general formula (IV) is reacted with an amine of the general formula HNR′R ″ in an inert solvent to give the oxadiazole of general formula (I).

In the food

Ar, Alk, R and X are the same as described above and Z is chlorine or bromine.

The mixture needs to be heated to complete the reaction, although it is possible to change the time and temperature, but it is better to heat for several hours at the reflux temperature of the solvent.

In another process for the preparation of the compounds of the present invention, the hydrazide of formula (V) is dehydrated, such as thionyl fluoride or phosphoryl fluoride, in a suitable inert organic solvent such as toluene, benzene, methylene fluoride, or cyclohexane React with to obtain oxadiazole of general formula (I).

In the above formula

Ar, Alk, R, R 'R "and X are as described above.

The compounds of the present invention have valuable pharmaceutical properties, which are particularly potent antidiarrheal agents or have very low analgesic action.

The antidiabetic and analgesic action of the present invention is represented by the following test method as 5-1, 1-diphenyl-3- (2-azabicyclo [2, 2, 2] oct-2-yl) propyl-2-methyl- It demonstrates by the action of 1, 3, 4-oxadiazole.

The use of the compounds as antidiabetic agents was confirmed by the ability of the compounds to inhibit gastrointestinal motility as described in the next test.

[Carbon powder test]

The method used in this test is by application of the method described in Macht and Barba-Gose 1931 and Jassen and Jageneau 1957.

10 cc / kg oral of a test compound in which Charles River male rats (20 g-25 g) are suspended in an aqueous solution or 0.5 methylcellulose.

30 minutes after administration of the test compound, one oral dose of carbon powder (0.2 cc of 10% carbon powder suspension in 1.0% methylcellulose) is orally administered.

Determines whether or not bullet powder is present.

Berkson's algebraic method (1953) is used to calculate the 50% effective dose (ED 50) of each compound.

Diarrhea in Rats Caused by Castor Oil

Mature charles river male rats are fasted 24 hours before being used for testing. In the meantime, water is supplied freely.

The compound is suspended in 0.5% methylcellulose and administered in the stomach, and after 1 hour, 10cc / castor oil is administered.

Diarrhea is observed every 1 hour until 8 hours after castor oil administration, and the Berkson (1953) method calculates the effective average dose every hour.

The analgesic effect of the compound of the present invention is evaluated by a rat-heating plate test and a tail cutting test.

[Rat-Heating Plate Test]

The reaction time of rats (18-25 g of mature male) placed on a cylindrically sealed hotplate adjusted to 55-0.3 ° C. and weak to lick their feet was 60, 40 and 20 minutes before the test compound and 30 days after the feeding. Measure at 60, 90 and 120 minutes.

The reaction time before the three treatments is averaged to be the "normal" reaction time. Positive reactions occur when the "normal" reaction time is two or more times after treatment. Doses of the test compound (orally administered 50 mg / kg) are considered active when at least 50% of the animals used are positive.

[Tail Cutting Test]

Make a special cut at the base of the tail of a rat (18-25 grams of mature male) and measure the number of times the rat turns to bite the cut. The sensitivity of each rat is determined for an hour and a half before feeding. Rats are tested for attempts to bite the cuts and then the test compound is fed by intramuscular injection and the response to the cuts is measured at 30, 60, 90 and 120 minutes after treatment. The response is considered positive if the animal has more than two attempts to bite the cut at any time interval. If at least 50% of the animals used show a positive response, the test compound is considered to be active.

The following examples are set forth to illustrate the compounds of the present invention in detail. In the examples to be described below, the temperature is in degrees Celsius and the state amount of material by wealth is by weight.

Example 1

26.3 parts 2, 2-diphenyl-4- (2-mazabicyclo [2,2,2] oct-2-yl) butyronitrile, 9.0 parts sodium azide dissolved in 60 parts dimethylformamide at a capacity A mixture of 7, 4 parts ammonium chloride and 0.12 parts of lithium chloride was refluxed for 12 hours and then the resulting solid was separated by filtration to give 5- [1, 1-diphenyl-3- (2-mazabiscro [2 , 2, 2] oct-2-yl) propyl] -1 tetrazole. 11.2 parts of this tetrazole and 13.04 parts of vinegar anhydride are dissolved in 50 parts of pyridine in a volume and refluxed for 2 hours. The solution is cooled and filtered to remove excess solids. The filtrate is evaporated to dryness and the remaining residue is suspended in an aqueous potassium carbonate solution and extracted with merylene chromide. The merylene chromide extract is washed with water, dried and concentrated to ether.

5- [1,1-diphenyl-3- (2-azabicyclo [2,2,2] oct-2-yl) propyl] -2-methyl-, which melts at 100-120 ° C. upon leaving the ether solution Crystalline material of 1, 3, 4-oxydiazole is obtained. Repeating the above procedure by replacing the vinegar anhydride used above with 16.3 parts of acetyl chromide, the same product, 5- [1, 1-diphenyl-3- (2-azabicyclo [2, 2, 2] oct-2 -Yl) propyl] -2-methyl-1, 3, 4-oxadiazole.

Example 2

11.2 parts of 5- [1,1-diphenyl-3- (2-azabicyclo [2,2,2 oct-2-yl) propyl] -1H-tetrazole by 13 as described in Example 1 , 5- [1,1-diphenyl-3- (2-azabicyclo [2,2,2] oct-2-yl), which melts at 96-98 at 5 ° C. when reacted with 5 parts pyrionic anhydride. Propyl] -2-ethyl-1, 3, 4-oxadiazole can be obtained. 0.9 parts of the obtained compound was dissolved in 30 parts of acetone in a capacity of 0.25 parts of 85% phosphoric acid, and the solvent was removed under reduced pressure, and the obtained slurry was recrystallized from methanol, which was melted at 175-178 ° C. 3- (2-azabicyclo [2,2,2] oct-2-yl) propyl] -2-ethyl 1,3,4-oxadiazole phosphate is obtained.

Example 3

36 parts 2, 2-diphenyl-4- (3-azabicyclo 3, 2, 2 non-3-yl) butyronitrile, 9.8 parts sodium azide 8.06 parts ammonium chloride and 0.15 parts lithium chloride 50 parts of dimethylformamide was added, heated at 125 ° C. for 12 hours, and the solution was cooled to filter the resulting white solid.

5- [1,1-diphenyl-3- (3-azabicyclo [3,2,2] non-3-yl), which is washed with dimethylformamide and water and then dried at 284-286 ° C. Propyl] -1H-tetrazole can be obtained.

프로필〕-2-메틸-1, 3, 4-옥사디아졸을 수득한다.Pyridine is removed by refluxing 10.0 parts of 1M-tetrazole and 20.5 parts of vinegar anhydride in a volume of 100 parts of pyridine for 1 hour, cooling and evaporating under reduced pressure. The residue was added to ether, the ether solution was washed with dilute sodium bicarbonate, the ether was removed by evaporation under reduced pressure, and the residue was recrystallized from a mixture of ether and n-pentane and dried under vacuum. [1, 1-diphenyl-3 (3-azabicyclo (3, 2, 2) non-3-yl)

Propyl] -2-methyl-1, 3, 4-oxadiazole.

Example 4

The process of Example 3 is repeated using an equivalent amount of a suitable reagent to convert the appropriate nitrile to tetrazole followed by oxydiazole to afford the following products.

5- [1-phenyl-1- (2-pyridyl) -3- (3-azabicyclo [3, 2, 2] non-3-yl) propyl] -2-methyl-1, 3, 4- Oxadiazole Melting Point 117.5-120 ℃

논-3-일) 부틸〕-2-메틸-1, 3, 4-옥사디아졸5- [1-phenyl-1- (2-pyridyl) -4- (3-azabicyclo [3, 2, 2]

Non-3-yl) butyl] -2-methyl-1, 3, 4-oxadiazole

프로필〕-2-메틸-1, 3, 4-옥사디아졸5- [1,1-diphenyl-3- (8-azabicyclo 4,3,0non-8-yl)

Propyl] -2-methyl-1, 3, 4-oxadiazole

Example 5

Condensation with [2, 2, 1] heptane into 12.9 parts of 7-azabicyclo by refluxing in 15 parts of 2, 2-diphenyl-4-bromo butyronitrile in 100 parts of ethylene glycol monoethyl ether. Let's do it. The reaction mixture is cooled, extracted with dilute hydrochloric acid, and the aqueous hydrochloric acid extract is made of a base using sodium hydroxide solution and extracted with ether.

The ether extract was dried over anhydrous sodium sulfate, filtered and evaporated to remove the ether under reduced pressure. Then, 2, 2-diphenyl-4- (7-azabicyclo (2, 2, 1) hept was melted at 79-81 ° C. -7-yl) butyronitrile is obtained.

4.9 parts of the above butyronitrile, 1.5 parts of sodium azide, 1, 2 parts of ammonium chloride, and 0.023 parts of lithium chloride are placed in 50 parts of dimethylformamide in a capacity and heated at 125 ° C. for 12 hours, after which the reaction mixture is cooled and the solid is cooled. Filtered.

The filtered solid was washed with dimethylformamide and water, and the dried solid was washed with dimethylformamide and water, and the dried solid was melted at 284-286 ° C. in 5- [1,1-diphenyl-3- (7-azabisich). Low [2, 2, 1] hept-7-yl) propyl] -1 H-tetrazole.

2.15 parts of the above-mentioned tetrazole and 49 parts of vinegar anhydride were refluxed in 20 parts of pyridine in a capacity for 1 hour, then cooled and evaporated pyridyl by evaporation under reduced pressure, and the remaining residue was put in ether.

The ether solution was washed with sodium bicarbonate solution and then the ether was removed and the resulting impure product was recrystallized from pentane to 5- [1,1-diphenyl-3- (7-azabicyclo) which melted at 130-132 ° C. [2, 2, 1] hept-7-yl) propyl] -2-methyl-1, 3, 4-oxadiazole.

Example 6

2.0 parts of 5- [1-phenyl-1- (3-pyridyl) -3- (2-azabicyclo [2, 2, 2] oct-2-yl propyl] -1 H-tetrazole were prepared in Example 1 Reaction with 4.6 parts of vinegar anhydride by the described method to yield 5- [1-phenyl-1- (3-pyridyl-3 (2-azabicyclo [2, 2, 2] oct-2-yl (propyl)] 2-methyl-1, 3, 4-oxadiazole is obtained.

0.54 parts of the oxadiazole is combined with 0.215 parts of hydroxyl in 6.0 parts of methanol to make a solution, which is diluted with 6.0 parts of ether to give a white precipitate.

This precipitate was filtered off, washed with methanol and ether and then dried under vacuum to afford 5- [1-phenyl-1 (3-pyridyl) -3- (2-azabicyclo [2] which melted at 171-172 ° C. , 2, 2] oct-2-yl) propyl] -2-methyl-1, 3, 4-oxadiazole oxalate.

Example 7

-5 [1,1-diphenyl-3- (2-azabicyclo [2,2,2] oct-2-yl) propyl] -5, in which 1.6 parts of ethyl chromlogoxylate was suspended in pyridine at a capacity. Add to a stirred suspension of 1H-tetrazole.

The reaction mixture was stirred at -6 ° C for 15 minutes, then heated to 60 ° C with stirring to hold at this temperature for 2 hours, then cooled to remove solvent and the residue dissolved in water. Treatment of this solution with an excess of aqueous potassium potassium solution yields a solid which is dissolved in ether, the ether solution is washed with water, dried over sodium sulphate and filtered through charcoal.

The filtrate is removed under vacuum to give a brown gum.

The gum phase is dissolved in ethanol and treated with excess hydrogen chloride to precipitate the resulting precipitate, washed with a mixture of ethanol and ether and air-dried. Ethyl-5- [1,1-diphenyl-3- (2-azabicyclo [2,2,2] oct-2-ylpropyl] -1,3,4, melting at 198.0-200 ° C in this process Oxadiazole-2-carboxylate hydrochloride was prepared.

8.0 parts of the oxadiazole is suspended in 200 parts of 5% sodium hydroxide in a capacity, and the suspension is heated to reflux for 5 minutes, and then the solution is cooled to room temperature to precipitate a gum phase. This gum phase is dissolved in water, extracted with ether, and the aqueous phase is adjusted to pH 6 to form a gum phase. This gum phase is extracted several times with methylene fluoride, the extracts are combined and the solvent is removed in vacuo to give a solid.

This solid is placed in methylene fluoride, the resulting solution is filtered, the filtrate is concentrated and diluted with methanol to produce a solid. The solid material was filtered off, washed with an ether / methol mixture and dried, and then dissolved in 5- [1,1-diphenyl-3- (2-azabicyclo [2, 2, 2] oct- 2-yl) propyl-1, 3, 4-oxadiazole-2-carboxylic acid hydrate.

When 3.1 parts of the oxadiazole is heated in an oil bath for 15 minutes, the oxadiazole melts and the gas is discarded.

The heating from this process is extracted with ether and the extract is removed in vacuo and the gum phase obtained is treated with excess 2-propanol hydrogen chloride and cooled to 0 ° C.

The precipitate formed was filtered off, washed with acetone and dried in vacuo to give 233-234: 5- [1, 1-diphenyl-3- (2-azabicyclo [2, 2, 2] oct- 2-yl) propyl] -1, 3, 4-oxadiazole hydrochromide.

Example 8

5.69 parts 2-phenyl-2- (2-pyridyl) -4- (2-azabicyclo 2, 2, 2 oct-2-yl) butyronitrile, 1.67 parts dissolved in 30 parts dimethylformamide at a capacity A mixture of sodium azide, 1.38 parts ammonium chloride and 0.025 parts lithium chloride is stirred for 12 hours at 120 ° C. under a nitrogen atmosphere.

After completion of the reaction, the mixture was cooled and the precipitates collected after filtration were washed with dimethylformamide and water, and the precipitates were dissolved in 1.2 parts of 100 parts by volume.

The formed solution is filtered and the filtrate is neutralized with dilute hydrochloric acid to recrystallize the separated product from ethanol. This process is 5- [1-phenyl-1- (2-pyridyl) -3- (2-azabicyclo [2,2,2] oct-2-yl) propyl] melting at 253-254 ° C. Provide 1-tetrazole.

4.62 parts of the above tetrazole, pyridine in volume and 14 parts of vinegar anhydride in volume were refluxed for 2.5 hours and then cooled to decompose by addition of water.

The solvent is removed, the resulting residue is added to a saturated aqueous solution of sodium bicarbonate and ether, the aqueous solution is extracted several times with ether, and the ether extract is washed with water to be neutral and dried over sodium sulfate. The extract was filtered, the filtrate was evaporated, the residue was put in ether, and excess precipitated hydrogen chloride in isopropynol was added to the filtered solution. The precipitate is recovered, dissolved in water, washed with ether and the aqueous solution is alkaline. The product was extracted with ether, the ether extract was washed to neutrality, dried over sodium sulfate, filtered, and the solvent was evaporated to yield 5- [1-phenyl-1- (2-pyridyl) -3- (8), which was melted at 109-110 ° C. 2) Azabicyclo [2, 2, 2] oct-2-yl) propyl] -2-methyl-1, 3, 4-oxadiazole to obtain a crystal product.

Example 9

4.08 parts 2- (4-chlorophenyl) -2-phenyl-4- (2-azabicyclo [2,2,2] oct-2-yl) burionitrile, 50 parts by volume dimethylformamide, 1.09 Sodium azide, 0.90 part ammonium chloride and 0.030 part lithium chloride are heated at 110 ° C. for 13 hours with stirring.

The isolated product as in Example 8 was 5- [1- (4-chlorophenyl) -1-phenyl-3- (2-azabicyclo [2, 2, 2] oct, melting at 277-278 ° C. -2-yl) propyl] -1H-terazole. Tetrazole obtained from the above process, 25 parts of pyridine at a dose and 5.0 parts of anhydrous vinegar anhydride are refluxed together for 2.5 hours. After the reaction is completed, the solution is cooled and the mixture is hydrolyzed by the addition of water.

The solvent was removed from the obtained mixture, the residue was added to a saturated aqueous solution of sodium bicarbonate and ether, the ether layer was separated, and the solvent was evaporated. 5- [1- (4-chlorophenyl) -1- melted at 97 ° C-102 ° C. Phenyl-3- (2-azabicyclo [2, 2, 2] oct-2-yl) propyl] -2-methyl 1, 3, 4-oxadiazole is obtained.

Example 10

7.32 parts 2,2-bis- (4-chlorophenyl) -4- (2-azabicyclo [2,2,2] oct-2-yl) butyronitrile, 1.77 parts sodium azide, 1.45 parts chloride Ammonium, 0.020 parts of lithium chloride and 60 parts of dimethyl formamide are combined and stirred for 1 night at 100 ° C. under a nitrogen atmosphere.

After cooling the reaction mixture, the solid material was filtered, washed with water, and then dried, and then melted at 263-264 ° C., 5- [1,1-bis (4-chlorophenyl) -3- (2-azabicyclo [2]. , 2, 2] oct-2-yl (propyl) tetrazole remains.

The mixture was refluxed for 2.5 hours with 5.44 parts of the above tetrazole, 50 parts of pyridine in a volume and 10 parts of vinegar anhydride in a volume, and then the reaction mixture was decomposed with water and the solvent was evaporated.

The residue is mixed with saturated aqueous sodium bicarbonate solution and ether, the ether phase is separated and the ether solvent is evaporated, the residue is redissolved in ether and treated with excess 2-propanol hydrogen chloride. When the solid formed is separated, 5- [1, 1-bis- (4-chlorophenyl) -3- (2-azabicyclo [2, 2, 2,] oct-2-yl is melted at 165-175 ° C. ) Propyl] -2-methyl-1, 3, 4-oxadiazolehydro chromide hemihydrate.

Example 11

Use 1-phenyl-1 [3-tolyl) -4- (2-azabicyclo [2, 2, 2] -oct-2-yl) butyronitrile using the equivalent and following the procedure described in Example 1 -[1-phenyl-1- (3-tolyl) -3- (2-azabicyclo [2, 2, 2] oct-2-yl) propyl-1H-tetrazol and then convert this tetrazol to 5- [1-phenyl-1- (3-tolyl-3- (2-azabicyclo [2, 2, 2] oct-2-yl) propyl] propyl] -2-methyl-1, 3, 4-oxadiazole Let's do it.

Example 12

27.3 g of 2- (2-pyridyl) -2- (3-toryl) -4- (2-azabicyclo [2, 2, 2] oct-2-yl) buty according to the process described in Example 1 7.95 parts of ammonium chloride, 9.75 parts of sodium azide and 0.15 parts of lithium chloride dissolved in 75 parts of dimethyl formamide in a capacity of ronitrile to react with 5- [1- (2-pyridyl) -1- (3-toryl (-3- (2-azabicyclo [2,2,2] oct-2-yl) propyl] -1H-tetrazole was prepared. According to the process of Example 1, 1, 1 part of the tetrazole was prepared. By reacting with 1.15 parts of acetyl chloride dissolved in 10 parts of pyridine at a capacity of 5- [1- (2-pyridyl) -1- (3-toryl) -3- (2-azabicyclo [2, 2, 2] Oct-2-yl) propyl] -2-methyl-1,3,4-oxadiazole.

Example 13

1.90 parts 2.2-diphenyl-4- (2-azabicyclo [2,2,2] oct-2-yl] baretonitrile, 1,13 parts sodium azide, 0.93 parts ammonium chloride and 20 parts Dimethylformamide is mixed and refluxed for 12 hours.

Solids of 5- [1,1-diphenyl-3- (2-azabicyclo [2,2,2] oct-2-yl) butyl] -1H-tetrazole are separated at reflux. 0.800 parts of the tetrazole intermediate and 1.6 parts of vinegar anhydride are dissolved in 8.0 parts of pyridine in a volume and refluxed for 2 hours. The solvent is removed and the residue is extracted with ether, the ether extract is washed with water and dried over sodium sulfate. The solid obtained by concentrating the extract was recrystallized from an ether / n-pentane mixture, and 5- [1, 1-diphenyl-3- (2-azabicyclo [2, 2, 2] oct- was melted at 128-133 ° C. 2-yl) butyl] -2-methyl-1, 3, 4-oxadiazole.

Equivalent amount of 2-2-diphenyl-4- (2 instead of 2, 2-diphenyl-4- (2-azabicyclo [2, 2, 2] oct-2-yl) varerinolitryl used above -Azabicicyclo [2,2,2] oct-2-yl) -3-methylbutyronitrile and repeat the above procedure to repeat 5- [1,1-diphenyl-3- (2-azabicyclo [2, 2, 2] oct-2-yl) -2-methyl propyl] 2-methyl-1, 3, 4-oxadiazole is obtained.

Example 14

2.6 parts of 5- [1,1-diphenyl-3- (6-azabicyclo [3,2,1] oct-6-yl) propyl] -1H-tetrazole were prepared by the method described in Example 1. 5- [1,1-diphenyl-3- (6-azabicyclo [3,2,1] oct-6-yl) propyl] whose melting point is 98-101 ° C. by reaction with 10 parts of vinegar anhydride. Prepare -methyl-1, 3, 4-oxadiazole.

Example 15

1.07 parts 5- (1,1-diphenyl-3-bromopropyl) -2-methyl-1,3,4-oxadiazole 0.4.9 parts isoquinucridin hydrochloride, 0.46 parts potassium carbonate, 0.17 The mixture of parts potassium iodide, 1 part water and 3.2 parts 4-methyl-2-pentanone is refluxed for 2 hours, after which the solvent is evaporated and the residue is decomposed into water of methylene chromide. The organic phase is separated, washed with water and with saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent is evaporated and the remaining semisolid residue is slurried in ether to remove solids by filtration. Evaporation of the solvent from the filtrate yields an oily residue which is placed in reflux hexane, decanted and cooled to remove the oily solid produced by filtration. Removal of the solvent from the filtrate gave 5- [1,1-diphenyl-3- (2-azabicyclo [2,2,2] oct-2-yl) propyl] -2-methyl-1 as an oily residue. , 3, 4-oxadiazole remains.

Example 16

Pharmaceutical forms are prepared by the following methods in amounts that indicate a relative amount per tablet.

2.5 parts of 5- [1,1-diphenyl-3- (2-azabicyclo [2,2,2] oct-2-yl) propyl] -2-methyl-1,3,4-oxadiazole Mix sufficiently with 41.0 parts of previnylpyriolidone and sift.

The mixture is granulated with isopropyl alcohol and dried on a tray for 16 hours at 50 °.

The dried granules are sieved again and the granules are thoroughly mixed with 1.0 part of magnesium stearate and compressed into tablets.

Tablets are 90.0 mg in weight and contain 2.5 mg of active ingredient per tablet.

Various preparations may be used in the preparation of tablets from the compounds of the invention, for example sugars such as lactose, sucrose or mannitol: starches such as soybean starch, papioca starch or potato starch: ethyl cellulose, methyl cellulose or agent. Cellulose derivatives, such as Latin cellulose: Acetate phthalate: Calcium phosphate, such as dicalcium phosphate or tricalcium phosphate, sodium sulfate, medium grass, calcium sulfate, polyvinyl acetate phthalate, alkaline earth metal stearates such as steargan, magnesium, stearate: peanut oil Vegetable oils, such as cottonseed oil, sesame oil, olive oil, soybean oil, etc .: Surfactants (nonionic, cationic, anionic): Ethylene glygolic polymers: β-cyclodextrins, aliphatic alcohols, as well as other non-toxic substances normally used in pharmaceutical forms. Filler binders, disintegrants and lubricants are used.

Claims (1)

A method for preparing 1, 1-diaryl-1-oxadiazole alkylamine derivative of general formula (I) characterized by reacting a compound of general formula (II) with a compound represented by general formula (IIa)

In the above formula Alk is a straight or branched chain alkene containing 2-4 carbon atoms R is hydrogen or an alkyl group having 1-7 carbon atoms, Ar is mono-substituted phenyl where phenyl, pyridyl or substituent is a halogen or alkyl group having 1-7 carbon atoms and R 'and R "are 6- with N An azabicyclo alkane structure containing eight carbon atoms and containing at least five carbon atoms in each ring of the azabicyclo alkane structure, X is an alkyl group of address, halogen or 1-7 carbon atoms R ″ 'is an alkyl group of 1-7 carbon atoms or a group that is easily removed to liberate hydrogen.