DE1468498C - Mono and dialkyled 1 Aminoadaman tanes and process for their preparation - Google Patents

Description

The invention relates to mono- and dialkylicrtes 1-Aminoadamantanes of the general formula

C-N

H ₇ C

and their physiologically acceptable salts, in which Ri _{denotes hydrogen and R 2} denotes an alkyl radical having 1 to 4 carbon atoms and R ₁ can also denote CH ₃ or C ₂ H ₅ if R ₂ also denotes CHj or C ₂ H ₅ , and those below cited process for their production.

Adamantanes can also be referred to as tricyclo (3,3, l, I ^V7 ) decanes. Their production has been described, for example, by Ludwig in US Pat. No. 2,937,121.

The special 1-amino-adamantanes, their production The subject of the invention are extremely effective active pharmaceutical ingredients that are of particular efficacy in the treatment of viral infections and similar diseases.

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 are also included under the invention, irrespective of whether they arise as such during synthesis or after production specially prepared.

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 I-aminoadamantane is dissolved in water or in another suitable solvent that has one or more equivalents contains 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! - (MethylaminoHidamanlanacctiit 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:

I-dimelhylaminoadamaiitaiihydiodilorid,

I-methylaminoadamantane succifiate,

I diet hylainino adamantane cilrate.

The salts listed above are also suitable as modifying agents for galvanic 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.

ίο The compounds according to the invention differentiate differs from 1-aminoadamantane in that it has lower volatility and lower melting points so that they are 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.

Compared to 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:

I-methylaminoadamantane,
I-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 Carbonsäurcamid and the obtained Amide hydrolyzed to an amine or

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

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

d) I-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 I-aminoadamantane reduced

and optionally the resulting alkylated I-aminoadamanlan compound converted into a physiologically compatible salt.

Compounds of formula (I) can be prepared by reacting equimolar amounts of 1-amino or a corresponding I-Alkylaminoadamantaiie and a corresponding ( "> speaking alkyl halide in a suitable solvent such as xylene, heated, and then the formed Halogeiiidsalz of the mono- or Dialkylaminoadamantane neutralized.

According to a different and preferred filling - (> <> form are the cHiiuluiigsgeinälkn I-N-Alkylaniinoadaniaiitanc manufactured according to a / wcistiilcnveifahivn, in your first stage I-N-Alkylacelamidoadiimantan from I-Hiomadamanlan or I-dialkyl-

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

Level I:

2AdBr + 2R'CONHR, + Ag ₂ SO ₄

•: ■ ·. ■■■ < . ■ /.

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

2AdN - C - R '+ 2AgBr + H ₂ SO ₄

Level 2:

AdN

R '+ NaOH ^ AdNHR ₁ + NaOOCR'

In the other two-stage reactions mentioned above becomes a l-dialkylaminoadamantane oxide trihydrate reacted with acetic anhydride to form the corresponding I-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:

LiAIH ₄

R.

AdN- CO - R "-

-> AdN- CH ₇ R "

35

The reaction takes place in a solvent, e.g. B. Diethylene glycol dimethyl ether, with increased Tcmpe- · ratures instead.

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

In addition to the processes described above, tertiary amines according to the invention can be prepared by adding the unsubstituted 1-aminoadamantane converted into a quaternary ammonium salt and this for example with aminoethanol converts to tertiary I-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. be done subcutaneously, intramuscularly, or intraperitoneally. As an alternative or at the same time the compounds are in the case of oral treatment effective. Since they are particularly effective against Infck ^ respiratory tract infections, e.g. against viral influenza and viral pneumonic, treatment can help be done with fumes or sprays through the mouth or nasal passages.

The found connections are valuable Agents for virus prophylaxis and therapy.

The dosage depends on what you are fighting Virus, 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. This 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

I-aminoadamantane and methyl iodide are used in equivalent amounts in about 1 liter of xylene for about 12 hours heated under the reflux condenser. After the reaction time, the reaction mixture is cooled and filtered. The solid product is then stirred with 5 (K) cm 'of water containing an equivalent amount of sodium hydroxide contains. The desired product is separated off by filtration.

In the manner described above, using the below-mentioned reaction components further compounds according to the invention are produced * where the likewise mentioned products are obtained. Also here are the I-aminoadamantane and the above Reaction constituents in equimolar "quantities" set.

ι ACCOUNTING COMPONENTS • product example Ethyl iodide
n-butyl bromide
Isopropyl bromide l-ethylaminoada-
mantan
l- (n-butylamino) -
adamantan
l-isopropylamino-
adamantan . 2
3
4 ·

B c i s ρ i c 1 5

Into a flask equipped with drying tube and Paddclrührer 500-cm ³ flask 102 g (1,40MoI) N-methylacetamide, 86 g (0.386 mol) of _{1-Bromadaman-! 5} tan and 121 g (0.0388 mol) of silver sulphate added. The yields are improved when the reaction mass is free from water and acetic acid. The reaction mixture is kept in an oil bath at 100 ^° C. for 1 hour. 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 IN-methylacetamidoadamantane, 12.0 g (0.30 mol) of sodium hydroxide and 120 cm ^{3 of diethylene glycol are placed in a 25 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 in the the table below, using the reaction components also mentioned produce. In Examples 6 to 9, the same amounts and conditions were used as in Example 5 applied.

45

example N-substituted acetamide End product 6th N-propylacetamide 1-propylamino
adamantan 7th N-ethylacetamide 1-ethylamino
adamantan 8th N-butyl octamide 1-butylamino
adamantan 9 N-isopropyl acetate
■ ■■ amide 1-isopropylamino
adamantan

55

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:

ν - - Example 10

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

Analysis for C ₁₁ H ₂₀ NCI:

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 results in a standard tissue culture Efficacy against Influenza A (WSN, Pig) and Influenza A-2 (Jap 305, JPC, Michigan A / AA) and excellent activity in mice against InfluenzeA (pig) and InfluenzaA-2 (JPC, Michigan A / AA).

The hydrochlorides of the compounds mentioned in Examples 3, 4, 6, 8 and 9 can also be used in a similar manner getting produced. The 1-propylaminoadamantane hydrochloride melts at 342 ° C. (decomposition). The 1-isopropyladamantane hydrochloride melts at 289 "C. The 1-butylaminoadamantane% hydrochloride melts at 293.7 to 295.1 "C. The 1-ethylaminoadamantane hydrochloride melts at 312 up to 316 "C (decomposition).

Example 11

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 uhd in an oil bath for 8 hours at 6O ⁰ C finally 2 hours at 120 "C. After cooling, the reaction mixture is treated with water to decompose excess LiAlH ₄ The insoluble aluminum compounds are formed by addition of a 20% solution of. 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} 1N hydrochloric acid, whereupon 10 cm ^{3 of} 70% perchloroacetic acid are added The product is cooled in the refrigerator, the crystals formed are filtered off and dried, giving 19.7 g (70%) of perchlorate of 1-N-ethylaminoadamantane with a melting point of 285 to 290 ° C. (with decomposition).

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

Analysis for C ^ Hii ^ N; '· ■' ■■ '■'. '■'' ^{: ii} ' ■ ■ ■ '· ■ ^f v' ^: ' ^: ■ ·

Calculated ... C 80.38, .H 1I ₇ HlV ^! "'C ^;

found ...'.'C80Ü9; H lllfi ?. ; "^{; i:} -; ■ · ■"'■

The connection according to this example rack is remarkable for its good effectiveness

the treatment of mice against influenza D (Sendai strain) as well as against influenza A (swine) and influenza A-2 (Michigan A / AA), both therapeutic as well as prophylactic. Of course, others can follow the procedure in this example N-alkylaminoadamantanes according to the invention are prepared, 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 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 QH- or NH ₂ -bands, a sign that the oil free from ■ "■ - is minoäthanol Weak bands at 3.75 and 9.08 microns are characteristic of the adamantane The free base.. is converted into the perchlofate 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 are obtained from the cooled mixture receive ° C. for analysis, the perchlorate is recrystallized from water 3 times and dried at 100 ⁰ C using 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 prepared according to this example shows excellent activity against Jap 305, Michigan A / AA and Vaccina in tissue cultures and against swine and J PC influenza in mice. The free base of this example is effective against swine and Michigan A / AA influenza in both tissue cultures and 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 is prepared. .-. ■■. ■■ "■ :: ■■■ '

For the compounds given in the summary below, the antiviral dose was definitely. The antiviral dose is the dose of the compound in milligrams per kilogram of body weight, which is an obvious 3.2-fold reduction in the infectivity of a standard test dose of the vaccine virus (Influ-.

enzavirus A, strain S-15), which is 20 times the LD ₅₀ , the LD ₅₀ dose being the dose that 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:

20th 1.5.10 35 connection .Antivirals Examples dose 2S ² ' ⁷ ' ⁿ 1 -Methylaminoadamantane (mg / kg) 3.8 hydrochloride 17th 1-ethylaminoadamantane 4.9 1 -n-butylaminoadamantane 3.7 hydrochloride 16 3 ° 6 1-isopropylaminoadamantane hydrochloride 6.1 12th 1 -propylaminoadamantane hydrochloride 35 1 -Ν, Ν-dimethylaminoada- mantane hydrochloride 4.8 1-Ν, Ν-diethylaminoada- mantane hydrochloride 2.9

Patent claims:

1. Mono- and dialkylated 1-aminoadamantanes of the general formula

HC C-N

H / ^N

CH ₂ -C-CH ₂

H ₂ C ^ 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 if R _{2 is} also CH ₃ or C ₂ H ₅ .

2. 1-methylaminoadamantane.

3. 1 -Methylaminoa: amantane hydrochloride.

4. 1-dimethylaminoadamantane.

5. l-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

109620/334

a) 1-bromoadamantane with a corresponding one Carboxamide converts and the amide obtained hydrolyzed to an amine or

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

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

d) Reacting 1-aminoadamantane with a corresponding carbonyl compound and the resulting Schiff's base with a suitable reducing agent to a corresponding one alkylated 1-aminoadamantane reduced

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