JPS5936973B2 - Bicycloalkyl derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to useful new drugs having activity on the central nervous system.

These drugs have a core of 2-phenylubicyclo[2,27,
2] It is characterized by having an octane nucleus. The present invention provides a method for producing the above novel drug as well as a pharmaceutical composition containing the above drug. The novel 2-phenylbicyclooctane compound of the present invention has the general formula: R-(CH2)n-
NPIR2I [where n is an integer of 1 to 3, R1 is C, -4 alkyl, P2 is hydrogen or C1-4 alkyl, and R is a formula (however, R4 and R5 are hydrogen, halogen, nitro, amino 8C2-5 acylamino, mono- or di-C1-alkynogemi 8C1-4 alkyl or C1-4
trans-2-phenylubicyclo[2,2,2] representing the same or different substituents selected from alkoxy
oct-3-yl group], and the present invention includes acid addition salts of the compound.

Preferred compounds of formula 1 have one or more of the following properties: (a) n is 1 to 2; (b) R5 is hydrogen and R4 is halogen, nitro, amino, methyl-amino or ethyl-amino, dimethyl-amino or diethyl-amino,
acetyl-amino or propionyl-amino, methyl, ethyl, methoxy or ethoxy: (c) R
4 and R5 are both hydrogen; (d) R4 and R5 are both halogen in their 3.4 position; (e) R1 is a C1-4 alkyl group and R2 is hydrogen, methyl or ethyl; be.

Most advantageously, the compound of general formula 1 has the above-mentioned properties (a)
, (b) and (e), (a), (c) and (e), or (a), (d) and (e).
For the avoidance of doubt, the terms "C1-4" used herein are
Alkyl (expressly absolute, as in the term "C2~, acylamino") includes any straight-chain or branched alkyl group having from 1 to 4 carbon atoms.

Therefore, R1 and/or R2 are methyl, ethyl, n
-propyl, itupropyl, n-butyl, isobutyl,
It may be a s-butyl or t-butyl group. -General formula 1
The compounds of (wherein R is as previously defined and m is 1, 2 or 3) are prepared according to the invention by reacting the compounds of (R is as previously defined and m is 1, 2 or 3) with formaldehyde, acetone, an alkyl aldehyde or an alkyl chloroformate and a reducing agent. It is produced based on a method of alkylation.

Alkylation is carried out in conventional manner, e.g. by reductive alkylation, reaction with an alkyl chloroformate, and the urethane formed may then be reduced, and when methylation is carried out, by reaction with formic acid or formaldehyde. is desirable. The compound of formula 1 produced by the above method can be isolated as such or in the form of an acid addition salt.

Acid-adding acids are inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, or organic acids such as organic carboxylic acids such as glycolic acid, maleic acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid, salicylic acid, o −
Acetoxybenzoic acid, nicotinic acid or isonicotinic acid; or organic sulfonic acids such as methanesulfonic acid,
Ethanesulfonic acid, 2-hydroxyethanesulfonic acid,
Desirably, it is a pharmaceutically acceptable non-toxic addition salt with a suitable acid such as toluene-p-sulfonic acid or naphthalene-2-sulfonic acid.

Other salts other than pharmaceutically acceptable acid addition salts are also encompassed within the scope of acid addition salts. For example, the product acid addition salts with picric acid or oxalic acid.
They serve as intermediates for the purification of the compound or for the preparation of other compounds such as pharmaceutically acceptable acid addition salts, or are useful in the identification, characterization or purification of its bases. The acid addition salts produced can be converted to the free compounds by well known methods. For example, by treating it with a base such as a metal hydroxide or metal alkoxide, such as an alkali metal hydroxide, or an alkaline earth metal hydroxide, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; an alkali metal or an alkaline earth metal bicarbonate or an alkaline earth metal bicarbonate by treatment with a base such as sodium carbonate, potassium carbonate or calcium carbonate or sodium bicarbonate, potassium bicarbonate or calcium bicarbonate, or with ammonia. The free compound may be converted to the free compound by treatment with chlorine, such as with chlorine, or with a hydroxy ion exchange product, or with any other suitable reagent. The resulting acid addition salts can also be converted to other acid addition salts by well known methods.

For example, salts with inorganic acids may be treated with metal salts, such as the sodium, barium or silver salts of the acid in a suitable diluent. However, the resulting salts with inorganic acids are insoluble and can be removed from the reaction medium. Acid addition salts can also be converted to other acid addition salts by treatment of anion exchange products. The starting material compound necessary for the above method of the present invention of the formula is trans-6-phenylpicyclo[2,2,2]
Octo-2-ene-5-carboxaldehyde (Dels-A
from the next reaction step (where R, Rl, R2R4, R, are as defined above, and R6 and R7 are each independently hydrogen or C1-4
alkyl and R8 is C1-4 alkyl).

Step A in the above reaction is carried out by reducing a compound of formula with hydrogen in the presence of a suitable catalyst such as palladium on charcoal to produce an aldehyde of formula where m is O.

Step B is carried out by oxidation methods well known to those skilled in the art,
The resulting carboxylic acid is converted in step D to the substituted acetic acid in a conventional manner, for example with thionyl chloride, and then the latter is converted to the substituted acetic acid by the Arndt-Elstert synthesis method (step F), and in steps D and F. It can be repeatedly converted to its corresponding substituted propionic acids and substituted butyric acids. The substituted propionic acids mentioned above can also be prepared from aldehydes (R-CHO) by steps 1 and j, in which step 1 produces the well-known nobenacrylic acid. Step j makes it possible, for example, to prepare the desired substituted propionic acid by reduction of acrylic acid with hydrogen over a palladium catalyst. By step C the carboxylic acid, substituted acetic acid or substituted propionic acid described above is converted to the corresponding nitrile of the formula where m is 011 or 2.

Step C is carried out by treating the acid with ammonia in the presence of alumina at elevated temperatures. Nitriles of the formula where m is O can be prepared directly by the following reaction steps.

In this case, step A is as described above, and the compound of formula v is obtained by a Diers-Alder reaction of the appropriate trans-β-cyanostyrene and 1,3-cyclohexadiene.

The acid chloride prepared by Step D above is readily converted to the desired amide of formula HNR6R7 by reaction with the appropriate amine of formula HNR6R7 according to Step E.

The desired aldehyde is obtained by the above step G. The well known ROsenmund reaction provides one means of accomplishing this reduction reaction. The substituted acetic acids, propionic acids and butyric acids mentioned above are also converted by step H to the desired isocyanates. This conversion reaction is performed by treating the corresponding acid chloride with sodium azide or by forming the corresponding acid hydrazide and treating the latter with nitrous acid to produce the acid azide, which is then dissolved in benzene or chloroform. This can be achieved by heating in a. Step K is a conventional esterification step of the corresponding acid, for example by reaction with alcohol R, -0H.

The ester can also be produced by the following reaction steps:
However, Step A is as described above, and the compound of the formula is obtained by a Diers-Alda reaction between an appropriate trans-cinnamate alkyl ester and 1,3-cyclohexadiene.

When the resulting ester is processed and hydrolyzed, its corresponding acid is obtained. As mentioned above, step A is reduction, for example by the method of catalytic hydrogenation.

Thus, it will be appreciated by those skilled in the art that if R4 or R, is a nitro group, the latter can be partially or completely reduced to give the corresponding amino-substituted product. Thus, if a nitro-substituted end product is desired, the appropriate compound is preferably obtained by nitration after the reaction of Step A has taken place. Conversion of the nitrated compound to the desired compound of formula 1 is carried out under conditions that do not reduce the nitro substituent. For example, reductive amination of a nitrated aldehyde of the formula is carried out with sodium borohydride, followed by conversion of the resulting alcohol to an alkyl or aryl sulfonate derivative, the latter of the formula 1-FS! React with amine of R6R7. Compounds of the type exemplified above are converted by reduction to compounds of formula. In the case of nitriles and amides, the reduction is carried out using complex hydride reducing agents such as lithium aluminum hydride or sodium borohydride, while in the case of isocyanates the reduction is carried out as desired by treatment with concentrated mineral acids such as hydrochloric acid. A transformation takes place. Aldehydes and esters may be reductively aminated to compounds of the desired formula, for example by reducing the alcohol to the corresponding alkyl sulfonate or aryl sulfonate using a complex hydride reducing agent. (by reaction using an alkylsulfonyl chloride such as methylsulfonyl chloride or an arylsulfonyl chloride such as p-toluenesulfonyl chloride). Reaction of the sulfonate type with ammonia aldehyde can also be accomplished by catalytic hydrogenation in the presence of ammonia. It will also be appreciated by those skilled in the art that the product compound of Formula 1, where R4 or R5 is an amino group, can be converted to other compounds of Formula 1 by conventional methods.

that is, the amino-substituted compound is acylated to produce the desired product of formula 1, where R4 or R5 is a C,~5 acylamino group, or the amino-substituted compound is mono- or diacylated to produce the desired product, where R4 or R5 is a C,~5 acylamino group. or R5 is a mono- or di-C1-4 alkylamino group). Additionally, the amino-substituted product can be diazotized and the resulting diazonium salt converted to various other products. For example, the corresponding C1-4 alkoxy-substituted compounds can be obtained by decomposition in alcohol, or the corresponding halogous-substituted compounds of formula 1 can be obtained by reaction with halogenated Daiichi Steel. The compounds of the present invention have antihyperactive, antipsychotic and antitremor paralytic activity.

It is therefore also useful for treating various debilitating conditions in mammals as well as relieving tremor paralysis symptoms. The usefulness of compounds of formula 1 is demonstrated in the treatment of reserpine hypothermia in rats and reserpine catalepsy in rats.
pinecatalepsy) has been demonstrated by well-known test methods. Certain compounds of Formula 1 also have AnOrectic and/or analgesic activity. As noted above, the compounds of the invention form acid addition salts.

Where the salts are pharmaceutically acceptable, they are equally effective for the aforementioned treatments. The compounds of this invention, as well as their pharmaceutically acceptable acid addition salts, are effective over a wide range of dosages. The actual dose administered will depend on factors such as the particular compound employed, the conditions being treated, and the type and size of the mammal being treated. However, the required dosage will normally be in the range of 0.1-100 η/Kg per day. For example, 0.5-15W1f/Kg for treatment of adult diseases.
A dose of 5 to 75 η/Kg is used to treat disease in test animals such as rats and mice. The compounds and salts of the invention are commonly administered orally or by injection.

For this purpose, the above-mentioned compounds and salts are usually utilized in the form of pharmaceutical compositions. Such compositions are prepared by methods well known in the pharmaceutical arts and usually contain at least one active compound or salt according to the invention in combination with a pharmaceutically acceptable carrier. In preparing the compositions according to the invention, the active ingredient is usually mixed with, diluted with, or contained within a carrier. i.e. packaged in capsules, sachets, paper bags or other containers. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material, which serves as a vehicle, excipient or vehicle for the active ingredient. Examples of some suitable carriers are lactose, textulose, sucrose, solpitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gum tragacanth, gelatin, syrup, methylcellulose, methyl and propyl oxybenzoate,
Such as talc, magnesium stearate or mineral oil. The compositions of the present invention are formulated so that their active ingredients provide rapid relief and long-lasting relief after administration to a patient, as is well known to those skilled in the art. Depending on the mode of administration, the aforementioned compositions are formed into oral tablets, capsules, or suspensions and injection solutions.

Desirably, the composition is formed into dosage unit form, with each dose containing from 1 to 500 η, more usually from 5 to 250 η, of the active ingredient of the composition. The following examples illustrate the preparation of new compounds of the above formula.

Example 1 (Reference example) Trans-6-phenylbicyclo[2,2,2]oct-2-ene-5-carboxaldehyde (70.79)
Take 5% palladium on carbon at 29 in 250 ml of ethyl acetate and take 4.21<f! /Cd (60 psi) for 1 hour at room temperature.

When the catalyst was removed and the product was separated by distillation, trans-2-phenylubicyclo[2,2,2]octane-3-carboxaldehyde (639) was obtained. Boiling point: 112-114 C/0.2110 The following aldehydes were prepared in the same manner: trans-2-p-chlorophenylbicyclo[2,2,2]octane-3-carboxyaltehyde, melting point: 70-71 ℃.

Example 2 (Reference example) (a) 2-phenylaldehyde obtained in Example 1 (5.7
59) was dissolved in 15 ml of pyridine and 300 η of piperidine and 9.01 ml of malonic acid was added.

The mixture was gradually heated on a steam bath for 1.25 hours, then when the CO2 evolution time had slowed down completely, the solution was heated to reflux for 1 hour, and then an excess of
The mixture was extracted three times into cyclomethane. The extracts were dried over MgSO4, evaporated, and the resulting crystals were reconstituted from ethanol using 3-(trans-2
-Phenylubicyclo[2,2,2]oct-3-yl)acrylic acid (6.09) was obtained. Melting point 138~1
39℃. (b) 14.69 obtained in step (a) above
of acrylic acid was dissolved in 200111 ethanol and 4.2 kg/C7l on 5% palladium on carbon (19).
(60 psi) for 1.5 hours at room temperature.

A white solid is obtained when the solution is evaporated and reconsolidated from dichloromethane and petroleum ether.
(trans-2-phenylbicyclo[2,2,2]oct-3-yl)propionic acid (13.19) was obtained. Melting point 112-114°C. (c) The acid 20.649 obtained in step (b) above was dissolved in 100 ml of acetone and the solution was cooled to 0°C.

Add 10.19 of triethylamine, then 9.5
A white precipitate was obtained when adding ethyl chloroformate in Step 9.

The suspension was stirred at 0° C. for 45 minutes, then 9.0 fl of ammonia (specific gravity 0.88) was added and the solution was allowed to warm to room temperature with stirring overnight. The resulting solution was heated on a steam bath and water was added until crystallization began. When reconstituted from ethanol and water, 3-(trans-2-phenylbicyclo[2,2,2]oct-3-yl)propionic acid amide was obtained. Melting point 122-123℃o example
3 (Reference example) Dissolve 3-(trans-2-phenylpinglo[2,2,2]oct-3-yl)propionic acid with a weight of 25.89 in 500 ml of acetone and add 12.19 of triethylamine. did.

100ml of water was added and the solution was cooled to 0°C.

11.939 of ethyl chloroformate was added dropwise to the cooled solution and stirring continued for 30 minutes at 0°C.

When a solution of 9.79 parts of sodium azide in 50 ml of water was added, sodium chloride precipitated immediately.

The solution was allowed to reach room temperature and after 1 hour most of the acetone was removed under reduced pressure. Approximately 500 ml of water was added and the solution was extracted three times with methylene chloride. The extracts were combined, dried over magnesium sulfate, and upon evaporation an oil was obtained. The water remaining in the oily substance in toluene was removed by vacuum distillation. The infrared absorption spectrum of the oily substance is 2140cm-? The azide band was shown. The yield of azide was 28.39. The latter was dissolved in dry benzene and the temperature was raised to the boiling point of the mixture.
Nitrogen was continuously generated for about 10 minutes. Heating was then continued for an additional 15 minutes, at which point the infrared absorption spectrum demonstrated that no azide remained. When evaporating a benzene solution, 2-(trans-2-phenylbicyclo[
2,2,2]oct-3-yl)ethyl isocyanate was obtained as an oil. Example 4 (Reference example) trans-2-phenylbicyclo[2,2,2]octane 3-carboxaldehyde (109)
The corresponding 3-carboxylic acid was prepared by oxidation using a chromium trioxide and sulfuric acid reagent (Chromium trioxide and sulfuric acid).

When carrying out the treatment described in Example 2(c), trans-2-phenylbicyclo[2,2,2]octane-3-carboxamide was obtained. When reconstituted twice from ethanol and water, the melting point was 121-122°C. Similarly,
Example 2(c) using dimethylamine instead of ammonia
When performing the above operation, N,N-dimethyltrans-2-phenylbicyclo[2,2,2]octane-3-carboxamide was obtained.

Example 5 (reference example) When trans-2-phenylbicyclo[2,2,2]octane-3-carboxaldehyde (0.1 mol) is oxidized as described in Example 4, the corresponding 3 A carboxylic acid was obtained.

That is, the acid was converted to the acid chloride by treatment with thionyl chloride. When the acid chloride was reacted with 0.2 mole of diazomethane, then water was added and heated in the presence of silver oxide, the expected 2-(trans-2-phenylbicyclo[2,2,2]oct-3- Yyl acetic acid was produced.
The latter can be converted into the corresponding amide by the procedure of Example 2(c) and into the corresponding isocyanate by the method of Example 3 with C1-4
The corresponding ester is formed by reaction with alcohol, the corresponding trans-2-phenylbicyclo[2,2,2]oct-3-ylacetonitrile by heating with ammonia in the presence of alumina, or the corresponding acetyl chloride. By subjecting the latter to the Rosenmund reduction method, it was possible to convert it to the corresponding trans-2-phenylbicyclo[2,2,2]oct-3-ylacetaldehyde. A 2-monosubstituted phenyl compound of the formula was prepared in a similar manner. Example 6 (Reference example) Trans-p
- Ethyl cinnamate (49), 10ml to cyclo? Diene and 5 ml of benzene at 155°C
Heated.

Next, when distilling the mixture, it is 6-p-methylphenylbicyclo[2, deaf, 2] oct-2-? Ethyl carboxylate was obtained. Boiling point 15'C/0.1
7nm0 which is reduced as described in Example 1 to give trans-2-p-methylphenylbicyclo[2,2,2]
Ethyl octane-3-carboxylate was obtained as an oil. Similarly, the corresponding 2-p-methoxyphenylbicyclo[2,2,2]oct-2-ene-5-carboxylic acid ester, boiling point 1700C/10.17! L''
was manufactured. Example 7 (Reference Example) Trans-3,4-dichlorocinnamonitrile (209) and cyxadiene 169 were heated at 150°C for 3 weeks.

When the solution is evaporated and the resulting oil is purified by column chromatography and crystallized from methanol, 5-
Crystals of cyano-6(3!,4'-dichlorophenyl)pinglo[2,2,2]oct-2-ene were obtained.
When the latter compound of 149 is hydrogenated as described in Example 1, trans-3-cyano-2-(3t4'-
Dichlorophenyl)bicyclo[2,2,2]octane was obtained as white crystals (04 g) with a melting point of 94.5-95.5°C.

The following compounds were produced in the same manner. Trans-3-cyano-2-m-chlorophenylbicyclo[2,2,2]octane, melting point 112-113°C.

trans-3-cyano-2-0-chlorophenylbicyclo[2,2,2]-octane, melting point 105-107°C
0 trans-3-cyano-2-0-promphhenylbicyclo[2,2,2]octane, melting point 72-75 C0 Example 8 (Reference example) Orthophosphoric acid (407 ffj) was dissolved in 21. 49 trans-2-phenylbicitaro [2
,2,2]octane-3-carboxaldehyde at 0°C.

After 1 hour, 9 ml of nitric acid (specific gravity 1.42) was added dropwise at 0°C, and the temperature was raised to 20°C and left overnight.

The mixture was then stirred for 3 hours in 400 ml of water and 20 ml of concentrated hydrochloric acid and then extracted with dichloromethane.
After washing with saturated sodium carbonate solution, drying over magnesium sulfate and evaporation of the dichloromethane extract an oil was obtained. The latter was mixed with 120ml of ethanol, 8
．． 2 in a solution containing 0 ml of concentrated sulfuric acid and 80 ml of water.
Heated at reflux for - hours. A large excess of water 2.
...0 was added, followed by extraction with dichloromethane.

The extract was shaken with saturated sodium carbonate solution, dried and evaporated to give an oil. Add it to petroleum ether (
When crystallizing from a boiling point of 60 to 8 ``C'', trans-2-
p-Nitrophenyl-bicyclo[2,2,2]octane-3-carboxaldehyde was obtained. Melting point 92-9
3℃. The following examples illustrate the preparation of compounds of formula 1 above.

Example 9 2-(trans-2-phenylbicyclo[
2,2,2]oct-3-yl)ethyl isocyanate was suspended in 200 ml of concentrated hydrochloric acid and heated under reflux for 16 hours until the evolution of carbon dioxide had ceased.

The acid solution was removed by evaporation under reduced pressure, the resulting hydrochloride was dissolved in chloroform, the solution was filtered, and petroleum ether was added until crystallization began. is 2-(trans-2-phenylbicyclo[2,2,2]octo-3-
yl)ethylamine hydrochloride was obtained. Melting point 209~2
11aC0 Also, the reduction method described in item 1 of Example 10 was applied to trans-2-phenylbicyclo[2,2,2]oct-3
The same compound was prepared by application to -yruacetamide or acetonitrile.

weight 16.31 of 2-(trans-2-phenylbicyclo[2,2,2]oct-3-yl)ethylamine hydrochloride, 4.25 ml of formaldehyde (37% W/V solution), 5.49 of formic acid and A solution of 1.619 sodium formate was heated to mild reflux overnight. 4 to this
．． 25,111 parts of formaldehyde and 5.49 parts of formic acid were added and heating continued for an additional 12 hours. 2 of the generated solution
It was dissolved in N-hydrochloric acid and washed with methylene chloride. After basification with 2N sodium monohydroxide, the solution was extracted three times with methylene chloride, the combined extracts were dried over magnesium sulfate, and upon evaporation the free amine was obtained as an oil.

N,N- by treatment with an ethereal solution of hydrogen chloride
Dimethyl 2-(trans-2-phenylbicyclo[2,
2,2]oct-3yl)ethylamine hydrochloride was obtained. Melting point 221-223 ChiC0 Example 10 3-(trans-2-phenylpinglo[2,2,2]oct-13-yl)propionamide weighing 6.4259 was dissolved in 100 ml of tetrahydrofuran, and the solution was dissolved in 50 ml of tetrahydrofuran. of lithium aluminum hydride (29) dissolved in tetrahydrofuran.

The suspension was stirred at room temperature for 24 hours and worked up with careful addition of water. The solution was dried over magnesium formate, filtered and evaporated to give 3-(trans-2-phenylpinglo[2,2,2]oct-3-yl)-propylamine as an oil. . When the latter compound is alkylated by the method described in Example 9 or Example 11, N,
N-dimethyl-3-(trans-2-phenylpinglo[2,2,2]oct-3-yl)-propylamine hydrochloride (melting point 192-194°C) and N-methyl-3
-(trans-2-phenylbicyclo[2,2,2]oct-3-yl)propyl-amine hydrochloride (melting point 164
~165°C) were obtained, respectively.

Example 11 2-(trans-2-phenylpinglo[2,2,2]oct-3-yl)ethylamine weighing 5.319 was dissolved in 25 ml of ethanol and 5.19 of triethylamine was added to the solution at 0°C. Added with.

When adding 2.389 g of ethyl chloroformate, a precipitate was immediately obtained.

The solution was stirred for 30 minutes while warming to room temperature. Water was added and the solution was acidified with hydrochloric acid and extracted three times with methylene chloride. The extracts were collected, dried and evaporated to give an oil. It was identified as urethane by nuclear magnetic resonance and infrared absorption spectroscopy. The latter compound was dissolved in 50 ml of dry ether and 1.2
9 of lithium aluminum hydride was added. The suspension was stirred at room temperature overnight and then worked up by carefully adding water and magnesium sulfate. When the solution is filtered and evaporated, N-methyl-2-(trans-2-phenylbicyclo[2,2,2]-oct-13-yl)ethylamine is obtained as an oily substance, from which hydrochloride is prepared. did. Melting point: 211-212°C. Example 12 N-methyltrans-2-phenylbicyclo[2,2,
2] Reductive alkylation of oct-3-yl-methylamine with acetone, propionaldehyde and butyraldehyde to produce N-methyl-N-isopropyltrans-2-phenylbicyclo[2,2,2
] Oct-3-ylmethylamine hydrochloride (melting point 164~
165°C), N-methyl-N-n-propyl-trans-2-phenylbicyclo[2,2,2]oct-3-ylmethylamine hydrochloride (melting point 151°C) and N-methyl-Nn-butyl trans-2-phenylbicyclo [
2,2,2]oct-3-ylmethylamine (melting point 13
0-132°C) was obtained.

Example 13 (Reference Example) When using the method of Example 9 and using trans-2-p-N-acetylaminophenylbicyclo[2,2,2]oct-3-ylmethylisocyanate as the starting compound, N, N-methyl-trans-2-p-N-acetylaminophenyl-bicyclo[2,2,2]oct-3-ylmethylamine hydrochloride was obtained.

Melting point 230-235°C. The latter compound was also obtained by acylation of the acyl compound of the corresponding 2-p-aminophenyl compound. 39 N dissolved in dichloromethane (50d) and 57n1, triethylamine
, N-dimethyl-trans-2-p-aminophenylbicyclo[2,2,2]oct-3-ylmethylamine, 3 ml of acetic anhydride was added.

After stirring overnight 10 ml of dilute hydrochloric acid were added and the mixture was extracted with ether. When made basic and re-extracted with ether, an oil was obtained upon drying and evaporation. When it was treated with a hydrochloric acid solution in ethanol, the desired hydrochloride salt was obtained. Melting point 232-235 is C0 Example 14 trans-3-cyano-2-(3',41-dichlorophenyl)bicyclo[2,2,2]octane (4.19)
0.559 dissolved in 55ml of tetrahydrofuran
of lithium aluminum hydride.

After 3 hours, water was added and the mixture was extracted with ether.

When evaporating the ether extract, 2-(3',4'-dichloropheno(ha)bicyclo[2,2,2]octo-3
-ylmethylamine was obtained as an oil of 49.
The latter compound, 25W11 ether, 7ml acetic acid, 10% palladium on carbon (0.59) and 3.7
A mixture of ml formaldehyde (40% solution) was hydrogenated at normal pressure for 24 hours. The catalyst was removed and dilute hydrochloric acid was added. After extraction with ether, the aqueous layer was made basic and extracted again with ether. An oil was obtained when the ether extracts were collected and evaporated. When it is treated with a hydrochloric acid ethanol solution, N,N-dimethyl-trans-2-(3!
,4'-dichlorophenyl)bicyclo[2,2,2]oct-3-yl-methylamine hydrochloride was obtained. This compound gave satisfactory elemental analysis values for C, H, N and Cl. Similarly, N,N-dimethyl-trans-2
-p-chlorophenylbicyclo[2,2,2]oct-3-ylmethylamine hydrochloride (melting point 244-245°C)
and N-methyl-N-ethyl-trans-2-p-chlorophenylbicyclo[2,2,2]oct-3-ylmethylamine hydrochloride (melting point 187-189°C) were also prepared.

Example 15 (Reference Example) The following compounds were also produced by the methods described in Examples 9-14.

Melting points refer to those compounds isolated as hydrochloride salts. N,N-dimethyl-trans-2-phenylbicyclo[2,2,2]oct-3-ylmethylamine, melting point 231-232°C.

N-ethyl-trans-2-phenylbicyclo[2,2
,2] oct-3-ylmethylamine, melting point 214-2
16-C (decomposition) N,N-diethyl-trans-2-phenylbicyclo[2,2,2]oct-3-ylmethylamine, melting point 164-165CN-methyl-N-ethyl-trans-2-phenylbicyclo [2,2,2]oct-3-ylmethylamine, melting point 178-180C
Example 16 (a) Production of trans m-chlorcinnamitrile:
m-chlorobenzaldehyde (210.759; 1.
5m), cyanacetic acid (127.59; 1.5m) and pyridine (150m0) were heated under reflux for 2 days.

Evaporation of this solution yielded an oil which, when distilled, contained a mixture of isomers (72(f) trans/23% cis;
5 (F6 aldehyde) was given. Yield 1299 (53%
), boiling point 70-85°C/0.8ml10 This product was dissolved in isopropanol and fractionally crystallized at 0°C. The solid matter was filtered out and freeze-dried. Pure trans isomer yield is 159
(6.1%). Boiling point 104-106℃/1 time;
Melting point 26-28°C. (b) Production of trans-6-(m-chlorophenyl)bicyclo[2,2,2]-oct-2-ene-5-carbonitrile: Trans-m-chlorocinnamtrile ( 9.29;0.
056m) and 1,3-cyclohexadiene (8.0
3m1; 0.084m) of the hydroquinone and 1
, 150-1 sealed in a tube with 2-dichlorobenzene
It was heated to 60°C for 2 weeks.

When this solution was evaporated, a golden oil (129) was obtained. This was washed several times with cold (40-60°C) petroleum and then repeatedly with hot (60-80°C) petroleum. When the latter washing liquid is collected and reduced, a viscous oily substance (10.29;
75%) was obtained.

(c) Production of trans-2-(m-chlorophenyl)bicyclo[2,2,2]-octane-3-carbonitrile: trans-6-(m-chlorophenyl)bicyclo[2,2] obtained by the above operation. ,2]-oct-2-ene-5-carbonitrile (9.49; 0.038 m) was hydrogenated in ethanol under pressure in the presence of 5% palladium on carbonite (1.09).

When the catalyst was removed from the furnace after the theoretical amount of hydrogen had been absorbed, an oily substance (9.19; 97%) was obtained as a reduced solution.

This was dissolved in ethanol and crystallized. Melting point 112
~113℃. Analysis value: Calculated value: C73.32; H6.5
6; N5.7; Cll4.43 experimental value: C73.43;
H6.4l; N5.82; Cll4.38(d) trans-2-(m-chlorophenyl)bicyclo[
2,2,2] Production of oct-3-ylmethylamine hydrochloride: Trans-2-(m-chlorophenyl)bicyclo[2,2,2]octane-3-carbonitrine (8. 0f1; 0.032 m) dissolved in dry tetrahydrofuran (20 ml) was added dropwise to a cooled stirred solution of lithium aluminum hydride (1.619; 0.042 m) in dry tetrahydrofuran (20 ml).

After the addition was complete, the solution was allowed to warm up to room temperature and was stirred overnight. In contrast, 5N sodium hydroxide (
When adding 1.6 ml) and then carefully adding more water (7 ml), a fine white precipitate formed which was filtered.
The filtrate was dried over magnesium sulphate, evaporated and filtered to give an oil. When dissolving hydrochloric acid in an ethanol solution and gradually adding ether, use hydrochloric acid (6.8I; 74C
$) was obtained. Melting point: 220-222°C. (e) N,
N-dimethyl-trans-2-(m-chlorophenyl)
Production of synchro[2,2,2]oct-3-ylmethylamine hydrochloride: Trans-2 obtained by the above operation
-(m-chlorophenyl)bicyclo[2,2,2]oct-3-ylmethylamine hydrochloride (3.09; 0.0
11m) to sodium hydrogen carbonate (0.929; 0.
011m) and methylformamide (30ml) were added.

The flask was cooled to 0.degree. C. and 90% formic acid (2.29 g;0.
A mixture of 0.055 m) and 37-40Cf6 formaldehyde (3.78 ml; 0.055 m) was slowly added. After the addition, the solution was slowly heated to reflux.
After 5 hours the solution was cooled, added to water (80ml) and made alkaline (PH) using solid potassium hydroxide.
= 8) and extracted with ethyl acetate (3x30ml). The combined organic layer was washed with water (2 x 30ml), dried over magnesium sulphate, filtered and the solvent was removed under vacuum to give an oil (2.109; 61%). The hydrochloride salt was prepared using a solution of hydrochloric acid in ethanol and the title compound was reconsolidated from ethanolic ether (2.19). Melting point 217
~219℃. Analytical value: Calculated value: C64.96; H8. O
l;4.45;Cl22.56 Experimental value: C64.67;H7.82;N4.44:Cl
22.64

Claims (1)

[Claims] 1 General formula R-(CH_2)_n-NP_1R_2 I [However, n
is an integer from 1 to 3, R_1 is C_1_ to_4 alkyl, R_2 is hydrogen or C_1_ to_4 alkyl, and R is a formula: ▲A mathematical formula, a chemical formula, a table, etc.▼ (However, R_4 and R_5 are trans 2- of (representing the same or different substituents selected from hydrogen, halogen, nitro, amino, C_2_-_5 acylamino, mono- or di-C_1_-_4 alkylamino, C_1_-_4 alkyl or C_1_-_4 alkoxy) phenylbicyclo[2,2,2]oct-3-yl group]
and its acid addition salts, a compound of the formula R-(CH_2)_m-NH_2III (wherein R is as defined above and m is 1, 2 or 3) is treated with formaldehyde, acetone, alkyl Alkylated by reaction with an aldehyde or alkyl chloroformate and a reducing agent to form the formula
A process characterized by obtaining the desired compound of I and optionally reacting the compound obtained with an acid to obtain an acid addition salt.