News diaryl-l, L oxadiazole-L alkylamines and their method of preparation.

The present invention relates to novel compounds having

the general formula:

wherein "alk-" denotes a straight or branched chain alkylene in c2~c ^, wherein R denotes a hydrogen atom or an alkyl radical-Cj, X represents a hydrogen atom, a halogen atom, or a C alkyl radical - ^ the Cj, ARs denotes phenyl, pyridyl or phenyl mono-substituted, wherein the substituent is selected from halogen atoms and alkyl radicals in c ^ ^ - C.,^and ^^years the L^has< 9.ï^uEsH^I THE R '^and The R " together form, with

the nitrogen atom, in a azabicycloalkaneC,-C._Q , containing at least 5 atoms

O-O

in each cycle of the structure azabicycloalkane.

Examples of alkylene radicals designated by alk are ethylene, propylene, and trimethylene. The expression "alkyl radical" denotes for example methyl, ethyl, propyl or butyl. Examples of halogen are fluorine, chlorine, bromine and iodine. The R ' and R "together form with the nitrogen atom a azabicycloalkane, e.g. aza 2 bicycloZJ. 2. 27octyle, aza 6/3.2. bicydo Ooctyle" bicyclo-aza 3/3.2. 27nonyle and aza-7 bicydo £. 2. YF heptyl. Preferred 'aza 1 and 2/bicydo 2.2. 27octyle.

Organic bases according to the invention form acid addition salts with various non-toxic organic and inorganic acids. Lengths of such salts with acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic and the like.

The compounds of the invention can be suitably prepared by reacting a tetrazole of the general formula:

(iD.

wherein Aik, ARs, the X, the R ' and R " are as defined above, on a

acylating agent of the general formula:

0

(THE R '" CONCURRENT)₂ the O or R '" the c-LC

wherein R "¹ c alkyl radical represents a ^ - ^ c-or easily removed, leaving hydrogen, carbethoxy as, in a suitable solvent such as pyridine " or any inert solvent such as toluene, benzene, methylene chloride or hexane in the presence of an acid acceptor such as triethylamine, piperidine, or potassium carbonate, resulting in the oxadiazole of formula I.

The starting material of formula II can be prepared by reacting a compound of the general formula:

(III)

wherein Aik, ARs, the X, the R ' and R " are as defined above, on an ion tertiary by methods similar to those described by G. Moersch and

D Morow, J... The MED, Mal., 10, 149 (-1967).

Another method for the preparation of the compounds according to the invention comprises reacting a halogénoalkane of formula:

5 (XV FRAMES)

wherein AR, ALK3, R and X are as defined above, and wherein Z represents a chlorine atom or bromine atom, an amino of formula MST 'the R "' R-NR" is such defined above, in a suitable inert solvent such as toluene, benzene, methylene chloride, methyl-pentanone refrigerant-to-2, or cyclohexane, in the presence of an acid acceptor such as triethylamine, piperidine or potassium carbonate, resulting in the oxadiazole of formula I. to complete the reaction, it is necessary to heat the mixture. Preferably, the mixture is heated during several hours at the reflux temperature of the solvent, although it is possible to vary the temperature and duration of the treatment.

In another method for preparing compounds according to the invention, which comprises reacting a hydrazide of the formula:

wherein AR, ALK3, R., R.¹ , The R " and X are as defined above, on a dehydrating agent such as thionyl chloride or phosphoryl chloride, in a suitable solvent such as toluene inert, benzene, methylene chloride or cyclohexane, resulting in the oxadiazole

of formula I.

The compounds of the invention have pharma.-to-niogic interesting. They are potent agents for control enure diarrhea. These compounds also exhibit a very low degree year. lgesic. Antidiarrheal properties and the analgesic activity comoosés are particularly illustrated by the activity of the representative compound/diphenyl-,l 1 (aza 2/bicydo 2.2.27octyl and 2) -3 propyl7-to-5 methyl 2 oxa 1 diaza 3 ,a goose, during subsequent runs.

The antidiarrheal activity of the compounds according to the invention is demonstrated by their ability to inhibit gastrointestinal mobility, - which exits the following tests:

The method used in the following test is a variant techniques than described (gesund and Maasai elders-to-kid, 1931 and Janssen and Jageneau, 19571. Pretreated mice stem male-Charles riveting ' 20 - 25 gm, n=6), having previously fasted during 24 hours, using test compounds orally administered as a solution in water, or suspended in 0.5% methyl cellulose to. Used a constant volume of 10 ml/kg at 30 minutes after administration of test compounds, animals are given a single oral dose of activated carbon (0.2 ml per mouse of a coal suspension to 10% in methyl cellulose 1.0%). 3 hours 30 min after administration of coal, sacrificing the animals and the examined ceacum to rate the absence or presence of coal, all or nothing.

Determining the effective dose at 50% (of ^ -) for each compound, using the procedure of logistics (1953) Berkson cases.

Adult male rats of strain-Charles riveting fast in cages common during 24 hours, before testing, with free access to water. The compound is administered by intragastric (suspended in 0.5% methyl cellulose to) one hour before the administration of castor oil at the rate of 1.0 ml/rat by intragastric route. Then presented the release or absence of diarrhea in rats at intervals of 1 hour, up to 8 hours after administration of castor oil. ^ Of the calculated at the time of each observation, the observations being separated by one hour, for each compound, using method (1953) Berkson cases.

The determination of the analgesic effect of the compounds according to the invention is carried out in the mouse by the hot-plate test, and the test of toe-tail.

Placing a mouse (adult male, weighing 18 to 25 grams), held therein is a cylindrical cage, on a hot plate whose temperature is set to 55 + 0.3 °c. Measuring the reaction time of the mouse (for lifting a tab or skip), 60, 40 and 20 minutes before, and 30, 60, 90 and 120 minutes after administration of the test compound. The reaction time is determined "regular" as being the average of three reaction time preceding the treatment. A positive response is defined as corresponding to a response time greater than two times the normal time, at any test following treatment. A dose (50 mg/kg body weight, administered intraperitoneally) of the test compound is considered active when at least 50% of the animals exhibit a positive response.

It provides a special clamp based on the tail of the mouse (adult male, weighing 18 to 25 grams) and by determining the time it takes for the animal to rolling over to the bite. The sensitivity of each mouse is determined 1/2 hour before administration of the drug. Only the mouse trying to bite the clamp are part of the test. Then administered the test compound intraperitoneally, and measuring the response at pinch 30, 60, 90 and 120 minutes after the treatment. A response is considered as positive biting the clamp after a time equal to more than twice the time corresponding measured before drug treatment, at any observations. A test compound is considered active when at least 50% of the animals exhibit a positive response.

The following examples illustrate the invention without however limiting its scope year. In these examples, the temperatures are expressed in degrees centigrade and the parts are by weight, unless otherwise indicated.

Example 1

A mixture of 26.3 parts of diphenyl-2.2 (aza 2 bicyclo-octyl 2 of £2.2.27) butyronitrile to -4, 9.0 parts of sodium azide, 7.4 parts of ammonium chloride and 0.12 part of lithium chloride, in 60 parts by volume of dimethylformamide, is maintained at reflux during 12 hours. There is a solid product, is separated off by filtration, this leading to the GBP diphenyl-l, L-(aza 2/bicydo 2.2.27octyl and 2) -3 propylJ-to-5 lH tetrazole. 11.2 parts of the tetrazole and 13.04 parts of acetic anhydride are dissolved in

50 parts by volume of pyridine, and carrying out said reflux 2 hours, the solution is cooled and filtered to remove the solids. "

The filtrate is evaporated. dry. The resulting residue

/is. >moved in. suspension in the aqueous potassium carbonate, extracted this slurry. aqueous methylene chloride. The extracts at he and chloride méthylèfi ' *; have washed water W>ûehls, the concentration extracts duct has a solid product that is taken up in ether. At rest, the solution in ether produces a product which is the crystalline/diphenyl-,l 1 (aza 2 bicyclo£2..27octyl 2 and 2) propy -3The O-H bonds methyl 2 oxa 1 diaza 3.4 goose. F 100 - 102⁶ C..

Replacing acetic anhydride used above by 16.3 parts of acetyl chloride and implementation of substantially the mode ' - operative above, lead to the same product, the /] diphenyl-l, L-(bicyclo-aza 2 THE Q..2.2? octyl 2) -3 propyl7-to-5 methyl 2 oxa 1 diaza 3.4 goose.

Example 2

11.2 parts/diphenyl-,l 1 (aza 2/bicydo 2.2.27octyi and 2) -3 propyl7-to-5 IH tetrazole react on 13.5 parts of propionic anhydride.

by the procedure described in the example 1, which results in obtaining/diphenyl-,l 1 (aza 2 bicydo/2.2.2/octyl 2) -3 propyL7-to-5 ethyl 2 oxa 1 diaza 3.4 goose. F.; 96 AND 9S, 5 °C. By dissolving 0.9 level compound in 0.25 part phosphoric acid 85% and 30 parts by volume of acetone, and removing the solvent by evaporation under reduced pressure, obtaining a suspension, which, by recrystallization in methanol, duct phosphate/diphény 1 - 1, 1 (aza 2/bicydo 2.2.27octyl and 2) propy -3" Q.-5 ethyl-2 oxa 1 diaza 3.4 goose.

F 175 - 178^C C..

Example 3

Added 36 parts of diphenyl-2.2 (aza 3 bicyclo-nonyl 3/3.2.27) butyronitrile to -4, 9.8 parts of sodium azide, 8.06 parts of ammonium chloride and 0.15 part of lithium chloride, to 50 volume parts of dimethylformamide, and the mixture is heated to 125 °c during 12 hours. The solution is cooled and removed a white solid by filtration.

The solid material is washed by dimethylformamide and water and is then dried. This procedure provides the Zdiphényl and 1.1 (bicyclo-aza 3/3.2.

nonyl 3) -3-propyl/IH tetrazole - 5. F 284 AND 286°.

10.0 parts of this IH tetrazole and 20.5 parts of acetic anhydride are maintained at reflux during 1 hour in 100 parts by volume of pyridine, the solution is cooled and removed the pyridine by evaporation under reduced pressure. The residue is taken up in ether and the solution to ether is then washed with dilute sodium bicarbonate.

The ether is then removed by evaporation under reduced pressure and the residual solid product is recrystallized in a mixture of ether and n-pentane, before being iéché vacuum, obtained the Æiiphény 1 - 1, 1 (aza 3 bicycloqloq.l.lj nonyl 3) -3 propy£7-to-5 methyl 2 oxa-L diazâ-to-3.4 goose. F 137 - 140 * 0.

Example 4

When resumes mode of operation example 3 using equivalent quantities of suitable reagents to transform the corresponding nitrile is tetrazole, then within oxadiazola, obtained the following compounds:

The £pbényl L (pyridyl 2) - L-(aza 3 bicycloz3bicycloz3.£.2i7nonyl and 3) - 3propy of £7" 5 methyl 2 oxa L-diaza 3.4 goose, F., about 117.5 - 120 * 0.

Zphényl L (pyridyl 2) - L-(aza 3 bicycloz3bicycloz3.2.£7nonyl and 3) -4 butyl7 " 5 oéthyl-to-2 oxa L-diaza 3.4 goose.

Æîiphényl L, L-(aza 8 bicyçloZ£.,êi7nonyl 3 and 8) -3 propyl7-to-5 mëtbyl-to-2 oxa L-diaza 3.4 goose.

Example 5

15 parts of diphenyl-2.2 bromo 4 butyronltrile are condensed with 12.9 parts of aza-to-7 the bicyclo 2.2 00, 00 eptane 7:00, by refluxing in 100 parts by volume of ethylene glycol monomethyl ether. The reaction mixture. is cooled and extracted by dilute hydrochloric acid. The extract to aqueous hydrochloric acid is rendered basic by sodium hydroxide solution

and is extracted with ether. The ether are dried on sulfate

O,

anhydrous sodium, ' a filtering and removing ether by evaporation

under reduced pressure lead to the diphenyl-2.2 (aza 7 bicycloz5bicycloz5.2, l7heptyl above 7) -4 butyropitrile. 79 - 81 * C f, 4.9 parts of this butyronltrile, 1.5 part of sodium azide, 1.2 part 0,023 part ammonium chloride and lithium chloride are added to 50 parts by volume of diffléthylformamide, the mixture is heated to 125 * c during 12 hours. The mixture is cooled and the solid product is filtered with dimethylformamide. The solid material is washed by dimethylformamide and water. The solid product is dried/fdiphény1 and 1.1 (aza 7 bicyc 1ojj.. 2.i7hepty1 above 7) -3 lH tétrazôiepropyl7 and 5. F 284 - 286 * 0.

2.15 parts of the tetrazole above and 4.9 parts of acetic anhydride are maintained at reflux in 20 parts. volume of pyridine, 1 during time. The reaction mixture is cooled. The pyridine is removed by evaporation under reduced pressure, leaving a residue is taken up in ether. The ether is washed with a solution of sodium bicarbonate. The ether is then removed, and the crude product is obtained which, after recrystallization ODBC pentane, duct at the £aiphényl L, L-(aza 7 bicycloz2bicycloz2.2.jjheptyl above 7) -3 propyl7 " 5 methyl 2 oxa L-diaza 3.4 goose, which melts at 130 - 132 * c. •*, Example 6

2.0 parts/phény1-a 1 (pyridy1 and 3) -1 (aza 2 bicyclo-octyi-to-2/2, 2, 27) -3 propyi7-to-5 IH tetrazole react on 4.0 parts of acetic anhydride by the method described in the example 1, and obtained the/phenyl 1 - (pyridyl 3) L-(aza 2 bicydo /' 2.2 ,27octyl and 2) -3 propyl7-to-5 methyl 2 oxa 1 diaza 3.4 goose,

0.54 part oxadiazole above are associated with oxalic acida 0,215 portion in 6.0 parts methanol, thereby forming a solution. This solution is diluted by 6.0 ' phenol ether, resulting in a white precipitate is filtered from the liquors. This precipitate is washed by methanol-ether and with ether, then dried in vacuo and is, leading to 1' oxalate/phenyl-L(pyridyl 3) - L-(aza 2 bicyclo-octyl 2/2, 2, 27) -3 propyl7-to-5 methyl 2 oxa 1 diaza 3.4 goose. F 171 AND 172 DEGREES CELSIUS.

Example 7

1.6 parts by volume of ethyl chlotoglyoxylate is added to a stirred suspension of diphenyl-,l 1/(aza 2/bicydo 2.2.27octyl and 2) -3 propyl7-to-5 LP-tetrazole in pyridine. After stirring of the reaction mixture during 15 minutes to -6 °c, this mixture is heated with stirring at 60 °c, and maintained at this temperature for about 2 hours. The reaction mixture is subsequently cooled, and distilled, thereby obtaining a residue that is dissolved in water. Treatment of the solution with excess potassium carbonate in water gives a solid product.

This solid material is dissolved in ether. The solution to ether is washed with the each SAU, dried on sodium sulfate, treated with activated charcoal and filtered. The filtrates are distilled under vacuum, resulting in a brown gummy product. The gummy product is dissolved in the étkanol, and is treated with hydrogen chloride in excess. The precipitate which forms is removed by filtration, lâvé by a mixture of ethanol and ether -, and air-dried.

This procedure duct hydrochloride./ diphenyl-,l 1 (bicyclo-aza 2β. Ζ, 11 octyl Z-) -3 propylJ-to-5 oxa 1 diaza 3.4 goose ethyl carboxylate 2. 198.0 - 200 F^I C..

A suspension of 8.0 parts of the oxadiazole El-to-desaus in 200 parts by volume of sodium hydroxide to 5%. Said suspension is heated to reflux during 5 min. Cooling the solution to room temperature, a gummy precipitate.

This gum is dissolved in water. Is extracted from the resulting solution by I ' ether. Adjusting the pH of the aqueous phase to 6, thereby obtaining a gummy product, this gum is extracted several times with methylene chloride, a TES extracted equivalents are then collected and distilled souajvide, thereby obtaining a solid product. The solid product is taken up in methylene chloride, . The resulting solution is filtered, the filtrates are concentrated to low volume. A diluting these filtrates by methanol causes the formation of a solid product, the solid material is removed by filtration, washed with a mixture of methanol/ether, and dried, thereby obtaining the £acid hydrate 3iphényl L, L-(aza 2 bicyclo-octyl 2 of £l2.27) propy -3|7 - 5 oxa 1 diaza 3.4 goose-carboxylic 2. F about 128 - 129^I C..

3.1 Is heated portions of the oxadiazole above in an oil bath, during 15 min, oxadiazole being during this time melted and vaporized. The glassy product obtained by this operation is extracted with ether. The extracts are then vacuum distilled. The gum that results from these operations is treated with excess hydrogen chloride * d-n-propanol and 2, and is cooled to Q^I C. the precipitate which forms is removed by filtration, washed with acetone and dried under vacuum, and the obtained hydrochloride/diphenyl-,l 1 (aza 2 bicycloZ?. 2 .£7oetyl and 2)/5 - propylbiphenyl -3 oxa 1 diaza 3.4 goose.

F 233 - 234, 5 * 0.

Example 8

A mixture of $, 69 parts of phenyl-2 (pyridyl 2) -2 (aza 2 of £bicydo 5,2 .2i7octyl-to-2Mbutyronitrile, 1.67 part of sodium azide, 1.38 portion 0,025 part ammonium chloride and lithium chloride in 30 parts by volume is stirred during 12 hours diméthylforrnamide under nitrogen atmosphere, to 120 °c. After completion of the reaction, the product is cooled down and carrying out said filtering. The precipitate obtained is washed by the diméthylforrnamide and water. The precipitate is then dissolved in 100 parts by volume of NaOH 0, 2n. The resulting solution is filtered, filtrates are neutralized with dilute hydrochloric acid. The product which is separated is recrystallized in ethanol. This procedure leads to/phenyl-L(pyridyl 2) - L-(aza 2 bicycloz2bicycloz2.2, 27oçtyl and 2) -3 propyl7 " 5 lH tetrazole, 253 and 254 °g about f.

4.62 parts of the tetrazole-deasus, 40 parts by volume of pyridine, and 14 parts by volume of acetic anhydride are maintained at reflux during 2 hr 30 min. The solution is cooled and is decomposed by the addition of water. The solvent is removed by distillation, and the resulting residue is taken up in a saturated aqueous solution of sodium bicarbonate, and 1' étheréther.après separation, the aqueous layer is extracted several liver with ether. The ether are washed to neutrality with water, promulgated dried on sodium sulfate. The extracts are then filtered and the filtrate is evaporated. The residue is taken up in ether and is filtered.

An addition of an excess of hydrogen chloride in 1' isopropanol at this solution causes the formation of a precipitate, the precipitate is recovered,

it is dissolved in water, and washed with ether, the aqueous solution is then made alkaline, the product is then extracted by the Ither, ' the ether are washed to neutrality, dried on sodium sulfate, filtered and evaporated. Evaporation of the solvent produces a product ' crystalline: the GBP phenyl-L(pyridyl 2) - L-(aza 2 bicycloz2bicycloz2.2.27octyl and 2) -3 propylJ-to-5 methyl 2 oxa 1 diaza 3.4 goose. F l09>ll0^I C..

Example 9

4.08 portions (chloro 4 phenyl) phenyl-2 -2 (aza 2 bicyclo-octyl 2/2.2.27) -4 butyronltrile, 50 parts by volume of dimethylformamide, 1.09 part of sodium azide, 0.90 part 0,030 part ammonium chloride and lithium chloride are heated ' under stirring at 110 °c, during 13 hours.

The polymeric product is isolated as in example 8 is the/Jchloro-to-4 phenyl) -! phenyl-1 (aza 2 bicyelo of £2.2.: 2f7oçtÿl and 2) -3 propy£7-to-5 lH tetrazole. F., about.

277 AND 278 DEGREES CELSIUS. The tetrazole resulting from the above step, 25 parts by volume of pyridine, and 5.0 parts by volume of acetic anhydride are held. at reflux, assembly, during 2 hours 30 mins. After completion of the reaction time, the solution is cooled and the mixture is hydrolyzed by addition of water. The solvent is removed from the reaction mixture by distillation, and the resulting residue is taken up in a saturated aqueous solution of sodium bicarbonate and ether. The ether layer is separated and the solvent is evaporated, leaving a residue which crystallized in le/1 chloro 4 phenyl) - L-phenyl-1 (aza 2 bicycloiS..27octyl 2 and 2) -3 propylJ-to-5 methyl 2 oxa 1 diaza 3.4 goose.

97 - 102 F^I C..

Example 10

7.32 parts of bis - (chlorophenyl 4 phenyl) -2.2 (aza 2 bicycloZ ^. 2.27 octyl 2) -4 butyronltrile, 1.77 part of sodium azide, 1.45 portion of ammonium chloride, 0,020 part of lithium chloride and 60 parts by volume of dimethylformamide are mixed and stirred under a nitrogen atmosphere, 100 to^I C., overnight. The cooling of the reaction mixture leads to a solid product which is recovered by filtration. The solid material is washed with water and dried, and obtained the Tjbis - (chlorophenyl 4 phenyl) - L-, R. (aza 2/bicydo 2.2.27octyl and 2) -3 propylJ-to-5 tetrazole. F 263 AND 264 DEGREES CELSIUS.

5S₄ 4 parts of the tetrazole above, 50 parts by volume of pyridine, and 10 parts by volume of acetic anhydride are mixed. and maintained at reflux during 2 hours 30 mins. The reaction mixture is decomposed by water and the solvent is evaporated. The restorative|residues is mixed with

a saturated aqueous solution of sodium bicarbonate, and ether. The solvent (ether) is evaporated, and the residue is redissolved in ether before being treated with an excess of hydrogen chloride in isopropanol and 2.

The solid product formed is separated, and the obtained hydrochloride hemihydrate £of bis - (chlorophenyl 4 phenyl) - L-, L. (aza 2 bicycloz2bicycloz2.2.27octyl and 2) -3 propyî7-to-5 methyl 2 oxa 1 diaza 3.4 goose. F. for about 165 and 175 degrees Celsius.

E11 xemple

Using equivalent amounts, and following the procedure of the example 1, one transforms the phenyl-L(tolyl 3) - L-(aza 2 bicydo/2.2.2/octyl 2) -4 butyronitrile in the GBP phenyl-L(tolyl 3) - L-(bicyclo-aza 2 /?2■%.] octyl 2) -3 propylJ-to-5 IH tetrazole, and the converting the tetrazole in the/phenyl-L(tolyl 3) - L-(aza 2 bicydo ^ 2.2.2? octyl 2) -3 propy27-to-5 methyl 2 oxa 1 diaza 3.4 goose.

Example 12

By following the procedures of the example 1, reacted 27.3 parts (pyridyl 2) -2 (tolyl 3) -2 (aza 2 bicyclo-octyl 2/2, 2, 27) butyronitrile and -4 7.95 parts of ammonium chloride, sodium azide 9.75 portions, and 0.15 part of lithium chloride in 75 parts by volume of dimethylformamide, to obtain the Z (pyridyl 2) - L-(tolyl 3) - L-(aza 2/bicydo 2.2.27octyl and 2) -3 propylJ-to-5 lH tetrazole. Also by following the procedures in example 1, 1.1 is reacted portion of the tetrazole above and 1.15 portion acêtyle chloride in 10 parts by volume of pyridine, to obtain the/Jpyridyl and 2) the L - (tolyl 3) - L-(aza 2 bicyclo-octyl 2/2.2.27) -3 propyl7-to-5 methyl 2 oxa 1 diaza 3.4 goose.

Example 13

1.90 portion of diphenyl-2.2 (aza 2 bicydo/2.2 ,27octyl and 2) -4 valeronitrile, 1.13 part of sodium azide, 0.93 portion of ammonium chloride, 0.17 part of lithium chloride and 20 parts by volume of dimethylformamide are mixed. The reflux of the mixture is carried out during

12 hours. At reflux, a solid product separates out. This solid material is the diphenyl-,l 1/(aza 2/bicydo 2.2.27octyl and 2) -3 butylJ-to-5 lH tetrazole. Is dissolved 0,800 level tetrazole intermediate and 1.6 part of acetic anhydride in pyridine 8.0 parts by volume, after which the reflux 2 hours.

The solvent is removed by distillation, and the residue is extracted with ether. The ether are washed with water, dried on sodium sulfate. A concentration of the extracts results in a solid product is recrystallized in a mixture of n-pentane/ether. This procedure leads to the diphenyl-,l 1 ^ (aza 2/bicydo 2.2.27octyl and 2) -3 butyl7-to-5 methyl 2 oxa 1 diaza 3.4 goose. F 128 AND 133 DEGREES CELSIUS.

Replacement of the diphenyl-2.2 (aza 2 bicÿclo£2..27octyl 2 and 2) valeronitrile -4 used above with an equivalent amount of diphenyl-2.2 (aza 2 bicycloz2bicycloz2.2, 27octyl and 2) -4 methyl 3 butyronitrile to, and substantially the above procedure lead to/diphenyl-,l 1 (aza 2 bicyclo-octyl 2/2.2.27) methyl 2 -3 propylJ-to-5 methyl 2 oxa 1 diaza 3.4 goose.

Example 14

Is reacted 2.6 parts/cliphényl L, L-(aza 6 bicyclo-octyl 6/j. 2 .17) -3 propyl7-to-5 lH tetrazole with 10 parts of acetic anhydride, by the method described in the example 1, to obtain the/jdiphényl and 1, L-(aza 6 bicycloz3bicycloz3.2.l7octyl and 6) -3 propylJ-to-5 methyl 2 oxa 1 diaza ,' 3 4 goose. F 98 AND 101 DEGREES CELSIUS..

Example 15

A mixture of 1.07 portion (diphény1-to-1.1 bromo 3-propyl) methyl 2 -5 oxa 1 diaza 3.4 goose, 0.49 part isoquinuclidine hydrochloride, 0.46 part of potassium carbonate, 0.17 part of potassium iodide, 1 part water and 3.2 parts of methyl-4 pentanone refrigerant-to-2 is maintained at reflux during 2 hours. The solvent is evaporated, and the residue is partitioned between methylene chloride-and water. The organic layer is separated, washed by water and sodium chloride in a saturated aqueous solution, before drying over sodium sulfate. Evaporation of the solvent leaves a semisolid residue which is transformed into a suspension in ether, prior to filtering to remove ' solid products. The solvent is evaporated from the filtrate, leaving an oily residue that is taken up in 1' refluxing hexane. The solution in hexane is then decanted and cooled, and the solid product (oily) which forms is collected by filtration. Evaporation of the solvent of the filtrate leaves an oily residue, the biphenyl-1.1/(aza 2 bicydo/2.2 ,27octyl and 2) -3 propyl7-to-5 methyl 2 oxa 1 diaza 3.4 goose.

Of course, various modifications may be made by those skilled in the art to the devices and methods just described solely by way of non-limiting examples without departing from the scope of the iroentLon.

As will be understood the invention concerns the compounds described as new industrial products, as well as the manufacturing process of these products, but that the latter, as pharmaceutical compounds or remedies, are not part of the invention.