DE1468813C - Aminoalkyl derivatives of bicyclo square brackets to 2,2,2 square brackets to -octans, process for their preparation and pharmaceutical preparations containing them - Google Patents

Description

1 CH

H2C i CH2

, R

R_C - R

in which the radicals R, which can be identical or different, denote hydrogen or methyl, as well as their salts.

2. a, 4 - dimethylbicyclo [2.2.2] octane -1 - methylamine hydrochloride.

3. ", a ^ -trimethylbicyclops ^^ joktane-1-methylamine hydrochloride.

4. 4-Methylbicyclo [2.2.2] octane-1-methylamine hydrochloride.

5. Process for the preparation of compounds according to claim 1, characterized in that one in a manner known per se

a) a 4-methylbicyclo [2.2.2] octane-1-carboxylic acid into the corresponding 4-methylbicyclo- [2.2.2] ok tan -1-carboxamide and converts this to a 4-methylbicyclo [2.2.2] octane-1-methylamine reduced or

b) a bicyclo [2,2,2] octyl- (l) -methylketonoxime reduced or

c) an a, a-dimethylbicyclo [2.2.2] octane-1-methanol subject to the Ritter reaction with subsequent hydrolysis or

d) a bicyclo [2.2.2] octane-1-methylamine, 4-methylbicyclo [2.2.2] octane - 1 - methylamine, ■ a ^ -Dimethylbicycloss ^^ octane-l-methylamine or a, a, 4-trimethylbicyclo [2.2.2] octane-1-methylamine methylated and

e) optionally a compound obtained according to a) to d) with a corresponding acid converts to salt formation.

6. Pharmaceutical preparations consisting of compounds according to claim 1 to 4 as an active ingredient and usual carriers and auxiliaries.

35

40

45 H-C

CH,

CH,

CH2

60

As part of the development of more effective means of combating viral infections has been Found a new class of 1-aminobicyclooctanes and bicyclooctane-1-methylamines that are extremely effectively inhibit the growth of various harmful viruses and the attack · with these viruses impede.

C '

in which the radicals R, which can be identical or different, are each hydrogen or methyl, and their salts.

The compounds falling under the formula (1) which contain a basic amino group are easy to form Salts. These salts, which contain a non-toxic anion, also fall within the scope of the invention. Examples such salts are the hydrochlorides, hydrobromides, sulfates, phosphates, acetates, succinates, adipates, Propionates, tartrates, citrates, bicarbonates, pamoates, cyclohexylsulfamates and acetylsalicylates. Of these, the hydrochlorides, acetates and cyclohexylsulfamates are preferred. The ^ Gyclohexylsulfamate taste pleasant and are therefore particularly advantageous for the production of syrups for oral use Application. They are also suitable for the production of uncoated tablets that are not unpleasant have a bitter taste, for oral application. Other salts are those with caprochlorone and with penicillin in question.

The above salts increase the value of the relatively insoluble amines in pharmaceuticals Applications.

Particularly unique in terms of the combination of antiviral effectiveness and other properties are dimethylamine-substituted compounds.

N.NATrimethylbicycloP ^^ octane-l-methyl-

amine,

N, 4-Dimethylbicyclo [2.2.2] octane-l-methylamine,

N.N-DimethylbicycloP ^^ octane-l-methylamine,

4-methylbicyclo [2,2,2] octane-1-methylamine,

N-methylbicyclo [2,2,2] octane-1-methylamine,

Bicyclo [2,2,2] octane-l-methylamine,

«, 4- dimethylbicyclo [2,2,2] octane -1 - methylamine-

hydrochloric !, a particularly effective compound,

«, Oc ^ -trimethylbicyclo [2,2,2] ο ktan-1-methylamine hydrochloride.

The above-mentioned compounds can be prepared by various methods.

Production of bicyclooctane-l-methylamines

1-Aminobicyclo [2.2.2] octane and various derivatives of this compound can be easily sorted according to the Produce the method that is the subject of the earlier German patent application P 14 68 759.3-42.

4-Methylbicyclo [2.2.2] octane-1-carboxylic acids can be used to prepare the new aminomethyl-substituted bicyclooctanes into the corresponding 4-methylbicyclops ^^ octane-l-carboxamides being transformed. The latter can be mixed with lithium aluminum hydride to form 4-methylbicyclo [2.2.2] octane-1-methylamines be reduced.

α-Methylbicyclo [2,2,2] octane-1-methylamines can produced by the reduction of bicyclo [2,2,2] octyl- (l) methylketone oximes with lithium aluminum hydride will. The ketones from which these oximes are derived are conveniently obtained by reacting the Cadmium dimethyl with a bicyclo [2.2.2] octane-1-carboxylic acid chloride manufactured.

λ, κ - Dimethylbicyclo [2.2.2] octane - 1 - methylamines can be prepared by reacting acetonitrile and sulfuric acid (Ritter reaction) with the corresponding "," - dimethylbicyclo [2.2.2] octane-1-methanol the N-acetyl- «, a: -dimethylbicyclo {2,2,2] octane-1-methylamine is obtained. The amine is obtained by alkaline hydrolysis. The bicyclooctane methanol used as starting materials for this reaction are prepared by reacting the corresponding bicyclo [2.2.2] octane -1-carboxylic acid chlorides with methyl Grignard compounds.

Preparation of N-substituted bicyciooctane-1-methylamines

1-carboxamide from the bicyclo [2.2.2] octane-1-car ~ To produce bonsäurechlorid and accordingly substituted amine and it to the desired N-methy ^ lated or Ν, Ν-dimethylated compound to reduce. The implementation of, for example, bicyclo [2.2.2] octane-1-carboxylic acid chloride with methylamine gives N-methylbicyclo [2.2.2] octane-1-carboxamide. The reduction of this compound with lithium aluminum hydride leads to N-methylbicyclo [2,2,2] ok-

Ip tanmethylamine.

The formylation of the amino compound with subsequent reduction is a viable method for the production of N-methylamino compounds, but these can also be achieved by using N-methylacetamide in a modification of the Ritter reaction be prepared as described in the above-mentioned earlier patent application.

In addition, the same can be used for the preparation of methyl-substituted bicyclooctane-1-methylamines Methods are used as they are in the said earlier patent application for the 1-amino compounds are described.

The invention also relates to pharmaceutical preparations consisting of compounds according to Claims 1 to 4, as active ingredient and customary carriers and auxiliaries.

The compounds of formula (1) can be administered in any way in antiviral treatment in which the active ingredient is delivered to the area in the body affected by the virus infection. A detailed description can be found in the earlier patent application mentioned.

The compounds prepared according to the invention are particularly effective against swine influenza.

An important application of the compounds prepared according to the invention is therefore control this infection by adding an active ingredient to the feed of the infected animals. More details about this can be found in the earlier patent application mentioned.

example 1

45

One or both hydrogen atoms of the amino nitrogen of bicyclo [2.2.2] octane-l-methylamine, the 4-methyl-bicyclo [2.2.2] octane-l-methylamines, α-4-dimethylbicyclo [2.2, 2] octane -1 - methylamines or oc, oc, 4 - trimethylbicyclo [2.2.2] octane -1 - methylamines can be replaced by methyl. This is most conveniently done by formylation, e.g. B. with a formyl halide, whereby a formylamino compound is formed, which is then reduced to the N-methylamino compound. Lithium aluminum hydride is excellently suited for this purpose, but catalytic hydrogenation or any other type of reduction can also be carried out. The N-methylamino compounds can again be formylated and reduced, the Ι-Μ, Μ-dimethylannno compounds being obtained.

The N-methylated bicydo {2,2,2] o-oct-1-methylamines and 4-methylbicyclo [2,2,2] octane-1-methylamines can indeed be produced by formylation and reduction or by methylation with methyl balogenides but the best and easiest method is to find the appropriate bicyclo [2,2,2] o.k.tan-

A. A solution of 2.5 g (0.0149 mol) of 4-methylbicyclo [2.2.2] octane-1-carboxylic acid in 10 cm ³ (16.55 g, 0.139 mol) of thionyl chloride was refluxed for 2 hours and then cooled to room temperature. The excess thionyl chloride was removed under reduced pressure, leaving the acid chloride as a brown oil. Ammonia was passed into a cooled solution (-10 ° C.) of the acid chloride in 100 cm ^{3 of} dry chloroform for 10 minutes with stirring. The reaction mixture was then stirred overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in 100 cm ^{3 of} benzene. Insoluble ammonium chloride was filtered off and the filtrate was evaporated to dryness, giving 3.13 g (100%) of 4-methylbicyclo [2.2.2] octane-1-carboxamide with a melting point of 190 to 192.5 ° C.
Analysis for C ₁₀ H ₁₇ No:

Calculated ... C 71.8, H 10.2, N 8.38;
Found ... C 71.83, H 10.3.3, N 8.48.

The following table shows the results of tests in which other 4-methylbicyclops ^^ octane-l-carboxamides was produced ».

5 Amine 6th product Starting acid Methylamine
Dimethylamine N-methyl-4-methylbicyclo [2.2.2] octane
1-carboxamide
N ₅ N-dimethyl-4-methylbicyclo [2.2.2] octane
1-carboxamide 4-methylbicyclo [2.2.2] octane-1-carboxylic acid
4-methylbicyclo [2.2.2] octane-1-carboxylic acid

B. In a 200 cm ³ round bottom flask fitted with a Soxhlet extractor, 1.56 g of lithium aluminum hydride and 200 cm ^{3 of} diethyl ether were added. 2.7 g (0.0162 mol) of 4-methylbicyclo [2.2.2] octane-1-carboxamide were placed in the thimble of the extractor. The reaction was carried out overnight while the contents of the flask were stirred with a magnetic stirrer. The reaction mixture was cooled to room temperature and the excess lithium aluminum hydride destroyed by carefully adding 3.32 cm ³ (0.184 mol) of water with stirring. The mixture was then stirred for a further 1 hour. The mixture was then filtered and the solid washed well with ether. The filtrate and wash were combined, dried with solid potassium hydroxide and then with anhydrous magnesium sulfate. Dry hydrogen chloride gas was passed into the ethereal solution. When the precipitation had ended, the product was filtered off and dried. The yield of 4-methylbicyclo [2.2.2] octane-1-methylamine hydrochloride was 1.25 g (41%).
Analysis for C ₁₀ H ₂₀ NCl:

Calculated ... C 63.4, H 10.0, N 7.38;
Found ... C 63.08, H 10.34, N 7.35.

The following table contains the results obtained with those prepared in the manner described Carboxamides were obtained in this process.

Carboxamide used product Analysis values N-methyl-4-methylbicyclo [2.2.2] ok-
tan-1-carboxamide
N, N-dimethyl-4-methyl-
bicyclo [2.2.2] octane-l-carbon
acid amide N, 4-Dimethylbicyclo [2.2.2] octane
1-methylamine hydrochloride
N, N, 4-trimethylbicyclo [2.2.2] ok-
tan-1-methylamine hydrochloride for C ₁₁ H ₂₂ NCl: 6.88% N
found: 6.70% N
calculated found
for C ₁₂ H ₂₄ NCl
C 66.2 66.1
H 11.03 11.13
N 6.44 6.47

Example 2

A. A mixture of 3.6 g of magnesium turnings, a small crystal of Jcd, 11 cm ^{3 of} anhydrous benzene and 1 cm ^{3 of} absolute ethanol is heated until a reaction begins. The heating is then stopped and a mixture of 24.0 g of diethyl malonate, 7.0 g of absolute ethanol and 10 cm ^{3 of} benzene is added dropwise at a rate such that the reaction mixture is refluxed. When the addition is complete, the mixture is refluxed until the magnesium has dissolved. The excess ethanol is removed by azeotropic distillation with part of the benzene. A solution of 18.6 g of 4-methylbicyclo [2.2.2] octane-1-carboxylic acid chloride in 30 cm ^{3 of} anhydrous benzene is added dropwise over 50 minutes to the solution of ethoxymagnesium diethyl malonate obtained. The reaction mixture is refluxed for a further hour and then cooled in an ice bath. To the cold mixture are added 50 g of ice and then 10% strength sulfuric acid in such an amount that two clear layers are formed. The layers are separated. The aqueous layer is ^{extracted with two 25 cm 3} portions of benzene. The extracts are combined with the organic layer, ^{washed with 30 cm 3 of} water and dried with anhydrous sodium sulfate. The benzene is removed by concentration under reduced pressure at 40 ⁰ C. A solution of 64 cm ^{3 of} glacial acetic acid, 39 cm ^{3 of} water and 7 cm ^{3 of} concentrated sulfuric acid is added to the residue (weight of the residue 32 g). The mixture is heated in a reflux condenser for 7 hours. It is then cooled and ^{poured into 350 cm 3 of} water. The mixture is extracted twice with 50 cm ^{3 of ether each time.} The ether extracts are combined, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methylbicyclo [2.2.2] octyl (1) methyl ketone.

A mixture of 14 g of hydroxylamine hydrochloride, 65 cm ^{3 of} anhydrous pyridine and 65 cm ^{3 of} anhydrous ethanol is heated on the steam bath until a clear solution has formed. 12.5 g of 4-methylbicyclo [2.2.2] octyl (l) methyl ketone are added to this solution. The mixture is refluxed for 2 hours and then cooled. It is evaporated to dryness under reduced pressure at 70 ° C. The residue is ^{suspended in 150 cm 3 of} water and stirred well. The solids are filtered off and dried to give 4-methylbicyclo [2.2.2] octyl (1) methyl ketone oxime.

This compound is added in an amount of 7.8 g to a mixture of 3.3 g of lithium aluminum hydride in 150 cm ^{3 of} anhydrous tetrahydrofuran. The mixture is refluxed with stirring for 3 hours. It is chilled in an ice bath. The excess lithium aluminum hydride is destroyed with a water-tetrahydrofuran mixture. A few cm ^{3 of} 10% sodium hydroxide solution is added to accelerate the coagulation of the solids. the

Solids are filtered off, ^{washed with 50 cm 3 of} chloroform and discarded. The filtrate, consisting of the tetrahydrofuran solution and the chloroform solution is saturated with dry hydrogen chloride and then concentrated under reduced pressure at 5O ⁰ C to dryness. The residue is placed in a separatory funnel and washed with a mixture of 100 cm ³ 10 ° / ₀ sodium hydroxide and 300 cm ³ shaken ether. The aqueous layer is discarded and the ether solution is dried over granulated potassium hydroxide. Dry hydrogen chloride is passed into the ethereal solution until it is completely precipitated. The amine hydrochloride obtained is filtered off and dried. This crude salt is dissolved in water, treated with an excess of 50 ° / ₀ sodium hydroxide solution and extracting the free amine with ether. The ether extract is dried over potassium hydroxide granules and decanted. Hydrogen chloride is then passed in until it has precipitated completely. The precipitate is filtered off and dried, a, 4-dimethylbicyclo [2.2.2] octane-1-methylamine hydrochloride being obtained.

B. 4 - methylbicyclo [2.2.2] octane -1 - carboxylic acid (4.95 g, 0.0295 mol) was dissolved in 100 cm ^{3 of} dry tetrahydrofuran. With stirring, 31 cm ³ (0.062MoI) of 2n-methyllithium in ether were added under nitrogen over a period of 3 to 4 minutes. The mixture was refluxed overnight and cooled to room temperature. After adding 25 cm ^{3 of} water, the product was extracted with ether. After drying over magnesium sulfate, the ether was extracted, whereby 5.80 g (100 ° / ₀ ) of 4-methylbicyclo [2.2.2] octyl- (l) -methyl ketone were obtained as an oil in Α £ "'χ °' = 1700 cm- ¹ .

To a mixture of 5.80 g of ketone, 3.22 g (0.0463 mol) of hydroxylamine hydrochloride and 15 cm ^{3 of} ethanol, 3 cm ^{3 of} water and 5.9 g (0.147 mol) of powdered sodium hydroxide were added in portions with stirring. The reaction mixture was refluxed with stirring for 5 minutes and then poured into an ice-cold solution of 20 cm ³ (0.240 mol) of concentrated hydrochloric acid in 110 cm ^{3 of} water. The colorless solid was filtered off and washed with water. After drying over phosphorus pentoxide, 3.84 g (72%) of 4-methylbicyclo [2.2.2] octyl (l) methyl ketone oxime were obtained in A ^ _x ⁰ '= 3200 cm ^-1 .

A solution of 3.84 g of the oxime in 50 cm ^{3 of} tetrahydrofuran was added with stirring to a suspension of 2.93 g (0.077 mol) of lithium aluminum hydride in 75 cm ^{3 of} ether. The mixture was refluxed with stirring overnight. After cooling to room temperature, 7 cm ³ (7 g, 0.0389 mol) of water was added dropwise. The mixture was stirred at room temperature for 1 hour. The solid was filtered off and washed well with ether. The ether was dried with solid potassium hydroxide and then with magnesium sulfate. The product was precipitated with gaseous hydrogen chloride. The ammonium hydrochloride was filtered off and washed with ether, 1.7 g (39 ° / ₀ ) oc, 4-dimethylbicyclops ^^ octane-1-methylamine hydrochloride were obtained.
Analysis for C ₁₁ H ₂ N · HCl:

Calculated ... C 64.8, H 10.8, N 6.88, Cl 17.45; Found ... C 64.92, H 10.93, N 7.65, Cl 16.97.

Example 3

^{150 cm 3 of} technical 3 molar methyl magnesium bromide are added dropwise under nitrogen to a solution of 27.4 g of bicyclo [2.2.2] octane-1-carboxylic acid chloride in 500 cm ^{3 of} anhydrous ether at such a rate that gentle reflux is maintained. After the addition has taken place, the reaction mixture is heated for 1 hour and then cooled. The metal complex is ^{decomposed by adding 300 cm 3 of} saturated ammonium chloride. The ether layer is separated off and the aqueous layer is ^{extracted with 100 cm 3 of} chloroform. This extract

ίο is united with the ethereal layer. The mixture is dried with anhydrous magnesium sulfate and concentrated to dryness under reduced pressure at 35 ° C. The residue is distilled with steam until the distillate is no longer milky. About 31 distillates are collected. After cooling, the steam distillate is extracted ^{twice with 250 cm 3 of ether each time.} The ether extracts are combined, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, with «, oc-Di-

ao methyl-l-bicyclo [2.2.2] octane methanol is obtained. 35 cm ^{3 of} concentrated sulfuric acid are added dropwise to 160 cm ^{3 of} acetonitrile with cooling, which keeps the temperature below 10 ^{° C.} Then 18.2 ga, <x -dimethyl-1-bicyclo [2.2.2] octane methanol are added. The temperature is increased to 48 ^° C. and held at this value for 45 minutes. The reaction mixture is left to cool to room temperature and then slowly ^{poured into 1000 cm 3 of} ice water. The solids which separate out are filtered off and dried and then taken up in 500 cm ^{3 of} ether. Dry hydrogen chloride is passed into the ethereal solution until no further precipitation takes place. The solids are filtered off, dried and placed in a separatory funnel ^{containing 200 cm 3 of} water and 500 cm ^{3 of} ether. The mixture is shaken until the solids dissolve. The aqueous layer is separated and discarded. The ether solution is dried with anhydrous sodium sulfate and concentrated to dryness.

Here, N-acetyl-oc, «- dimethylbicyclo [2.2.2] octane-1-methylamine receive.

A mixture of 2.0 g of N-acetyl-aa-dimethylbicyclo [2.2.2] octane-1-methylamine, 10 g of potassium hydroxide and 40 cm ^{3 of} methanol is kept in a sealed tube at 225 ° C. for 18 hours and then cooled . The content of the pipe becomes 100 cm ^! Given water. The mixture is extracted twice with 50 cm ^{3 of ether each time.} The extracts are combined, dried with potassium hydroxide granules, whereupon dry hydrogen chloride is passed in until the precipitation is complete. The precipitate is filtered off and dried, a crude salt being obtained. This: ³ salt is dissolved in water 80 cm and treated in excess of 50 ° / ₀ aqueous sodium hydroxide and extracted twice dam with 50 cm ³ of ether. The ether extracts are combined and dried with potassium hydroxide granules. Then hydrogen chloride is passed in until the precipitation is complete. The hydrochloride is filtered off and dried, a, oc-Di methylbicyclo [2.2.2] octane-1-methylamine hydrochloride being obtained.

The compounds according to the invention were compared with the l-methylamino-adamantane hydrochloride known as antivirals from the documents published in Belgian patent 646 581 by determining the antiviral dose and the LD ₅₀ and d <quotient of both, as the table below shows.

209 536/5

9 Melting point 10 Antivirals
dose LD ₆₀ Antiviral dose connection ° q mg / kg mg / kg 300 to 312 4.1 171 LD ₅₀ Bicycloss ^^ Joktane-l-methylamine hydrochloride decomposition 42 241 2.1 171 4-methylbicyclo [2,2,2] octane-l-methylamine-hydro- 81 chloride 284 to 287 5.1 126 N ^ -DimethylbicycloP ^^ Joktane-l-methylamine- decomposition 25th hydrochloride 258 to 259 .8.4. . , 126. NjN ^ -Trimethylbicycloss. ^ Joktane-l-methylamine- 15th hydrochloride 280 to 300 3.0 108 a-MethylbicycloP ^^ Joktan-l-methylaminhydro- decomposition 36 chloride 322 to 324 0.5 147 a, 4-Dimethylbicyclo [2.2.2] octane-1-methylamine- decomposition 294 hydrochloride 340 to 350 2.2 79 «,« - DimethylbicycloP ^^ Joktan-l-methylamine- Sublimated 36 hydrochloride 290 to 308 1.3 147 «,« ^ - TrimethylbicycloP ^^ Joktane-l-methylamine- decomposition 113 hydrochloride 245 17th 60 to 100 1- (methylamino) adamantane hydrochloride 5

It can be seen from this that the compounds according to the application are used as antivirals compared to the comparison substance are superior in effectiveness.

Claims (1)

Patent claims: 1. Aminoalkyl derivatives
general formula R — C —R H ₂ C CH. The compounds of this class have been shown to have a remarkable breadth of activity in tissue culture and found in animal experiments. For example, the bicyclooctane was found in tissue cultures against influenza A (strains WSN and swine influenza), influenza A-2 (Michigan A / AA, JPC and Jap 305 strains), and influenza D (Sendai strain) were observed. When trying to live- -. the mice showed effectiveness against swine influenza viruses, Michigan A / AA, JPC and Sendai ίο as well as against the herpes virus and Semliki forest virus. The compounds prepared according to the invention were found to be prophylactically as well as therapeutically effective. The invention relates to aminoalkyl derivatives of bicyclooctane of the general formula CH ₂