DE1468498B1 - Mono- and dialkylated 1-aminoadamantanes and processes for their preparation - Google Patents

Description

The invention relates to mono- and dialkylated 1-aminoadamantanes of the general formula

CH ₂ -C-CH ₂
H ₂ C _V I ^ CH ₂

CH ₂

and their physiologically acceptable salts, in which R _{1 is} hydrogen and R _{2 is} an alkyl radical having 1 to 4 carbon atoms and R _{1 can} also be CH ₃ or C ₂ H ₅ when R _{2 is} also CH ₃ or C ₂ H ₅ , and the below mentioned process for their production.

Adamantanes can also be referred to as tricyclo (3,3, l, l ³ " ⁷ ) decanes. Their preparation has been described, for example, by Ludwig in US Pat. No. 2,937,121.

The particular 1-amino-adamantanes, the production of which is the subject of the invention, are extraordinary effective active pharmaceutical ingredients that are of particular effectiveness in the treatment of Viral infections and similar diseases are.

Since the compounds of formula (I) contain a basic amino group, they form non-toxic ones with Acids salts which are also encompassed by the invention. These salts expand the pharmaceutical Possible uses of the connections. Representative of these salts are the hydrochloride, Hydrobromide, sulfate, phosphate, acetate, lactate, succinate, propionate, tartrate, citrate and bicarbonate. Of these, the hydrochloride and acetate are preferred.

Of course, mixtures of these compounds also fall under the invention, regardless of whether they are as those accrue during the synthesis or are specially prepared after production.

The compounds according to the invention can be prepared by various methods.

The salts of mono ^: and dialkylated 1-aminoadamantanes can be prepared as follows: A mono- or dialkylated 1-aminoadamantane is dissolved in water or in another suitable solvent which contains one or more equivalents of an acid.

It is also possible to use the aforementioned salts from solutions in the organic solvent to manufacture. For example, one dissolves l- (methylamino) -adamantane in ethyl alcohol and gives an alcoholic Solution of one molar equivalent of acetic acid to it. The obtained l- (methylamino) adamantane acetate can be isolated by concentrating the solution in vacuo at moderate temperatures.

As specific examples of various salts obtained using the appropriate acid to the above can be produced in the manner described:

1-dimethylaminoadamantane hydrochloride,
1 -methylaminoadamantane succinate,
1-Diethylaminoadamantane citrate.

The salts listed above are also suitable as modifying agents for electroplating baths. The compounds according to the invention show favorable toxicity properties, especially when relatively high dosages. The absorption speeds, the ease of use, the stability and compatibility with pharmaceutical excipients are noted for many of these compounds also improved.

The compounds according to the invention differ from 1-aminoadamantane in that they Have lower volatility and lower melting points, making them particularly suitable for purposes where these properties are desired.

For example, because of their favorable vapor pressure, the compounds are significantly better for Uses such as nasal treatments including spray and steam treatment. They can also be used as antioxidants.

Of the compounds of the formula (I), the dialkylamino compounds are particularly advantageous Because of their activity and the notable lack of undesirable side effects, as evidenced by the has shown tests carried out so far. The monoethylamino and higher monoalkylamino compounds also have great advantages in this regard.

Particularly preferred due to their excellent combination of properties are the salts, especially the hydrochloride and acetate, of the following compounds:

1 -methylaminoadamantane,
1 -ethylaminoadamantane,
1-dimethylaminoadamantane.

The processes for the preparation of compounds according to the invention are characterized in that one in a known manner

a) Reacts 1-bromoadamantane with a corresponding carboxamide and the obtained Amide hydrolyzed to an amine or

b) 1-aminoadamantane is alkylated with an appropriate alkylating agent or

c) a corresponding acylated 1-aminoadamantane to the corresponding alkylated 1-aminoadamantane reduced or

d) 1-aminoadamantane is reacted with a corresponding carbonyl compound and the resulting

Schiff's base with a suitable reducing agent to give a corresponding alkylated one 1-aminoadamantane reduced

and optionally the obtained alkylated 1-aminoadamantane compound converted into a physiologically compatible salt.

Compounds of the formula (I) can be prepared by adding equimolar amounts of 1-amino or equivalent 1-alkylaminoadamantanes and a corresponding alkyl halide in a suitable solvent, such as xylene, heated and then the halide salt formed of mono- or dialkylaminoadamantane neutralized.

According to another and preferred embodiment, the 1 -N-alkylaminoadamantanes according to the invention produced by a two-stage process, in which 1-N-alkylacetamidoadamantane in the first stage from 1-bromoadamantane or 1-dialkyl

aminoadamantanoxydtrihydrat produced and in the second stage the 1-N-Alkylacetamidoadamantan with Sodium hydroxide converted into the desired 1-N-alkylaminoadamantane at elevated temperature

Step 1:

will. This process based on 1-bromoadamantane is illustrated by the following equations, where the adamantane component for the sake of simplicity is represented by "Ad":

2AdBr + 2R ^ ONHR ₁ + Ag ₂ SO ₄ - * 2AdN - C - R '+ 2AgBr + H ₂ SO ₄

Level 2:

AdN-CR '+ NaOH - AdNHR ₁ + NaOOCR'

In the other two-step reactions mentioned above, a 1-dialkylaminoadamantane oxide trihydrate is used reacted with acetic anhydride to form the corresponding 1-N-alkylaminoadamantane.

According to a further advantageous method for the preparation of the compounds according to the invention, 1-N-alkylacetamidoadamantanes, which were expediently prepared in the manner described above, are _{reduced with LiAlH 4} according to the following equation: ™

LiAIR

Ri

AdN - CO - R "-

- + AdN-CH ₂ R "

35

The reaction takes place in a solvent, e.g. B. diethylene glycol dimethyl ether, at elevated temperatures instead of.

Of course, further compounds according to the invention can be prepared _{from the aforementioned Schiff bases by reduction with LiAlH 4.}

In addition to the processes described above, tertiary amines according to the invention can be prepared by converting the unsubstituted 1-aminoadamantane into a quaternary ammonium salt and this reacts, for example, with aminoethanol to form the tertiary 1-aminoadamantane.

Additional methods of making other compounds of the invention are as follows Examples described.

The compounds of formula (I) 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. This of course includes the areas before the start of the infection and afterwards. For example, the Administration parenterally, d. H. subcutaneously, intramuscularly or intraperitoneally. As an alternative or at the same time, the compounds are effective when administered orally. Because they are particularly effective against infections of the respiratory tract, e.g. B. against viral influenza and viral pneumonia, the treatment can be done with fumes or sprays through the mouth or nasal passages.

The compounds according to the invention are valuable agents for virus prophylaxis and for therapy.

The dosage depends on the virus to be controlled, age, health and weight of the patient, the extent of the infection, the nature of any concurrent treatment, the Frequency of treatment and the desired effect. In general, the daily dose is applied Active ingredient between about 1 and 200 mg / kg body weight, but lower amounts can also be used z. B. 0.5 mg, or higher. Quantities are applied. Usually 1 to 50, preferably 1 to 20 mg / kg / day, all at once or spread over the day are given to obtain the desired results.

The active ingredient of the formula (I) can be used in drugs such as tablets, capsules, powders or liquid solutions, Suspensions or elixirs, for oral administration or in liquid solutions for parenteral use Use and in certain cases in suspensions for parenteral use (except intravenous).

In addition to the active ingredient of the formula (I), the antiviral agent contains a solid or liquid, non-toxic pharmaceutical carrier or excipient for the active ingredient.

The compounds of the invention are particularly effective against swine influenza. These Infection can be combated by adding an active ingredient to the feed of the infected animals. For the For most purposes, the active ingredient will be in an amount of about 0.001 to 0.1 percent by weight, preferably from 0.001 to 0.02 percent by weight, based on the total weight of the ingested feed, is used.

example 1

1-Aminoadamantane and methyl iodide are heated in equivalent amounts in about 11 xylene for about 12 hours under the reflux condenser. After the reaction time, the reaction mixture is cooled and filtered. The solid product is then ^{stirred with 500 cm 3 of} water which contains an equivalent amount of sodium hydroxide. The desired product is separated off by filtration.

In the manner described above, using the reaction components mentioned below further compounds according to the invention are prepared, the likewise mentioned products are obtained. Here too, 1-aminoadamantane and the above are used Reaction component used in equimolar amounts.

example Reaction component product 2
3
4th Ethyl iodide
n-butyl bromide
Isopropyl bromide 1 -ethylaminoada-
mantan
l- (n-butylamino) -
adamantan
1 -I sopropylamino-
adamantan

Example 5

102 g (1.40 mol) of N-methylacetamide, 86 g (0.386 mol) of 1-bromoadamantane and 121 g (0.0388 mol) of silver sulfate are placed in a ^{500 cm 3} flask equipped with a paddle stirrer and drying tube. The yields are improved when the reaction mass is free of water and acetic acid. The reaction mixture is kept in an oil bath for 1 hour at 100 ⁰ C. The product is ^{poured into 100 cm 3 of} cold water. The mixture is extracted with ether, which is dried with magnesium sulfate and evaporated. The residue is crystallized from hexane, 34.2 g (43%) of 1-N-methylacetamidoadamantane having a melting point of 122 to 123 ° C. being obtained.

15.5 g (0.06 mol) of 1-N-methylacetamidoadamantane, 12.0 g (0.30 mol) of sodium hydroxide and 120 cm ^{3 of diethylene glycol are placed in a 250 cm 3} flask equipped with a magnetic stirrer and reflux condenser. This mixture is refluxed for 5 hours. The cooled product is ^{poured into 900 cm 3 of} water. After extraction with ether, drying with anhydrous potassium carbonate and evaporation of the ether, 13.0 g of crude 1-N-methylaminoadamantane are obtained. The infrared spectrum of this product shows no amide band.

In the manner described above, further compounds according to the invention, which are mentioned in the table below, can be prepared using the reaction components also mentioned. In Examples 6 to 9, the same amounts and conditions as in Example 5 were used in each case. t

example N-substituted acetamide End product 6th N-propylacetamide 1-propylamino
adamantan 7th N-ethylacetamide 1 -ethylamino-
adamantan 8th N-butylacetamide 1 -Butylamino-
adamantan 9 NI sopropy lacet-
amide 1 -isopropylamino-
adamantan

In these cases, good results are also obtained if instead of the N-substituted acetamide the corresponding N-substituted propionamide and butyramide is used.

The alkylaminoadamantanes according to the invention can easily be converted into their salts in a known manner convert as follows:

Example 10

Anhydrous HCl is passed into an ethereal solution of 1-N-methylaminoadamantane prepared according to Example 5. The hydrochloride obtained is dissolved in hot acetonitrile with the aid of a small amount of methanol. The hydrochloride precipitates in the form of gray crystals with a melting point of 226 ° C. (temperature gradient block) in an amount of 11.1 g (79%). For analysis, a portion is recrystallized once from ethanol and once from acetonitrile-methanol, and then 24 hours at 100 ⁰ C on an oil pump dried. Melting point 250 to 251 ° C.

Analysis for C ₁₁ H ₂₀ NCl:

Calculated ... C 65.48, H 9.99, N 6.94;

found .... C 65.74, H 10.36, N 6.73;

C 65.57, H 9.98, N 7.11.

The compound prepared according to this example shows excellent activity in a standard tissue culture against influenza A (WSN, pig) and influenza A-2 (Jap 305, JPC, Michigan A / AA) and excellent activity in mice against influenza A (pig) and influenza A-2 (JPC, Michigan A / AA). The hydrochlorides of the compounds mentioned in Examples 3, 4, 6, 8 and 9 can also be prepared in a similar manner. The 1-propylaminoadamantane hydrochloride melts at 342 ^° C. (decomposition). The 1-Isopropyladamantanhydrochlorid melts at 289 ° C. The 1-Butylaminoadamantanhydrochlorid melts at 293.7 to 295.1 ⁰ C. The l-Äthylaminoadamantanhydrochlorid melts at 312-316 ° C (decomposition).

Example

19.3 g (0.10 mol) of 1-acetamidoadamantane, 100 cm ^{3 of} diethylene glycol dimethyl ether and 5.7 g (0.15 mol) of lithium aluminum hydride are placed in a 250 cm ^{3 flask equipped with a reflux condenser, drying tube and stirrer.} The mixture is maintained in an oil bath for 8 hours at 60 ° C and finally 2 hours at 12O ⁰ C. After cooling, the reaction mixture is treated with water in order to decompose _{excess LiAlH 4.} The insoluble aluminum compounds are dissolved by adding a 20% solution of sodium potassium tartrate. The organic base is extracted with ether. The ether solution is dried with anhydrous potassium carbonate, filtered and evaporated. The residue is dissolved in 120 cm ^{3 of} 1 η-hydrochloric acid, whereupon 10 cm ^{3 of} 70% strength perchloroacetic acid are added. The product is chilled in the refrigerator. The crystals formed are filtered off and dried. There are obtained 19.7 g (70%) of perchlorate of 1-N-Äthylaminoadamantan having a melting point 285-290 ⁰ C (with decomposition).

The free base is ^{regenerated with 60 cm 3 of} 10% sodium hydroxide. The base is extracted with ether and the ether is dried with anhydrous potassium carbonate, filtered and evaporated. Distillation of the oily residue gives 8.96 g (50%) of a colorless liquid which ^{boils at 101 to 102.5 o} / 7.0 mm and solidifies at room temperature to form a low-melting solid. The nuclear magnetic resonance spectrum shows the characteristics of the ethyl group and a single NH proton.

Analysis for C ₁₂ H ₂₁ N:
₆ , Calculated ... C 80.38, H 11.81;
found .... C 80.39, H 11.67.

The compound prepared according to this example is notable for its good effectiveness in

the treatment of mice against influenza D (Sendai strain) and against Influen2aA (pigs) and Influenza A-2 (Michigan A / AA), both therapeutically and prophylactically. Naturally Further N-alkylaminoadamantanes according to the invention can be prepared by the process of this example for example the propyl- and butyl-substituted aminoadamantanes.

Example 12

In a 250 cm ³ flask are 15.1 g (0.1 mol) of 1-aminoadamantane, 40 cm ³ (91 g, 0.64 mol) of methyl iodide, 25.2 g (0.3 mol) of sodium bicarbonate and 150 cm ^{3 of} methanol given. The mixture is stirred magnetically and refluxed overnight. The insoluble material is filtered off and the filtrate is evaporated to dryness. The residue is extracted repeatedly with hot chloroform, which is filtered off and evaporated to give 31.1 g (97%) of crude 1-adamantyltrimethylammonium iodide. For analysis, a portion is recrystallized twice from water and dried at 8O ⁰ C on an oil pump. Melting point 313 ° C (closed, evacuated capillary).

Analysis for C ₁₃ H ₂₄ NJ:

Calculated ... C 48.60, H 7.53; found .... C 49.15, H 8.14.

12.8 g (0.40 mol) of 1-adamantyldimethylammonium iodide and 25 g (0.40 mol) of 2-aminoethanol are placed in a 50 cm ^{3 flask equipped with a reflux condenser and magnetic stirrer.} The mixture is brought to reflux temperature and refluxed for 15 minutes. The cooled product is ^{poured into 100 cm 3 of} water. The mixture is extracted with ether, which is dried with anhydrous potassium carbonate and evaporated. The infrared spectrum of the oily residue shows no OH or NH ₂ bands, a sign that the oil is free from aminoethanol. Weak bands at 3.75 and 9.08 microns are characteristic of the adamantane framework. The free base is converted into the perchlorate by dissolving it in 1N HCl and adding perchloric acid. 8.2 g (73%) of white crystals of Ι-Ν, Ν-dimethylaminoadamantane perchlorate with a melting point of 180 to 184 ° C. are obtained from the cooled mixture. For analysis, the perchlorate is recrystallized 3 times from water and dried at 100 ° C. on an oil pump.

Analysis for C ₁₂ H ₂₂ ClNO ₄ :

Calculated ... C 51.51, H 7.93; found .... C 51.59, H 8.03.

The free base is changed to that described in Example 11 Way regenerated and recovered. The hydrochloride is made by adding HCl to the free base educated. It sublimes at 250 ° C (closed, evacuated capillary).

The perchlorate produced according to this example shows excellent activity against Jap305, Michigan A / AA and vaccina in tissue culture and against swine and J PC influenza in mice. the The free base of this example is effective against swine and Michigan A / AA influenza in both tissue cultures as well as in mice and is also effective for the therapy and prophylaxis of influenza B (Lee) and Influenza D (Sendai) in mice. Similarly, Ι-Ν, Ν-diethylaminoadamantane hydrochloride with a melting point of 248 ° C.

The antiviral dose was determined for the compounds listed in the summary below. The antiviral dose is the dose of the compound in milligrams per kilogram of body weight that causes an apparent 3.2-fold decrease in the infectivity of a standard test dose of the vaccine virus (influenza virus A, strain S-15), which is 20 times the LD ₅₀ , the LD ₅₀ dose is the dose which causes the death of 50% of the untreated test animals. The numbers in the first column of the abstract refer to the examples in which the compounds tested were originally disclosed:

link Antivirals Examples dose 1 -Methylaminoadamantane (mg / kg) 1.5.10 hydrochloride 17th 1-ethylaminoadamantane 2, 7, 11 1 -n-butylaminoadamantane 3.7 3.8 hydrochloride 16 1 -isopropylaminoadamantane 4.9 hydrochloride 6.1 1 -propylaminoadamantane 6th hydrochloride 35 \ -Ν, Ν-dimethylaminoada- 12th mantane hydrochloride 4.8 1 -Ν, Ν-diethylaminoada- mantane hydrochloride 2.9

Claims (8)

Patent claims: 1. Mono- and dialkylated 1-aminoadamantanes of the general formula C-N , R ₁ H ₂ C. and their physiologically acceptable salts, in which R _{1 is} hydrogen and R _{2 is} an alkyl radical having 1 to 4 carbon atoms and R _{1 can} also be CH ₃ or C ₂ H ₅ if R _{2 is} also CH ₃ or C ₂ H ₅ . 2. 1-methylaminoadamantane. 3. 1 -Methylaminoadamantane hydrochloride. 4. 1-dimethylaminoadamantane. 5. 1-Dimethylaminoadamantane hydrochloride. 6. 1-ethylaminoadamantane. 7. 1-Ethylaminoadamantane hydrochloride. 8. A method for the preparation of compounds according to claim 1, characterized in that one in a manner known per se 009 540/384 9 10 a) 1-bromoadamantane with a corresponding d) 1-aminoadamantane with a corresponding Carboxamide converts and the carbonyl compound obtained converts and the er amide hydrolyzed to an amine or hold Schiff's base with a suitable one b) 1-aminoadamantane is alkylated with a corresponding reducing agent to give a corresponding alkylating agent or ^5- alkylated 1-aminoadamantane is reduced c) a corresponding acylated 1-aminoada and optionally the resulting alkylated 1-amimantane to the corresponding alkylated noadamantane compound into a physiologically ver-1-aminoadamatane reduced or transferred to tolerable salt.