DE1468758C - - Google Patents

Description

As part of the development of more effective agents for the treatment of viral infections, a new class of 3-amino and substituted 3-aminotricycIo [4,3, 1, l ³ ' ⁸ ] -undecanes has been found which have an excellent ability to To inhibit or prevent infections with a wide variety of harmful viruses and the growth of these viruses. The compounds prepared according to the invention have a unique combination of properties, as has been shown in conventional experiments with tissue culture and in animal experiments. The compounds according to the invention were found to be effective against influenza A (strains WSN and swine influenza), influenza A-2 (strains Michigan A / AA and JPC) and pseudorabies.

The compounds according to the invention have the formula

20th

(I)

wherein R ₁ and R _{2 are} hydrogen, methyl or ethyl.

The pharmaceutically acceptable addition salts of these also fall within the scope of the invention Links. Examples of such salts are the hydrochloride, hydrobromide, sulfate, phosphate, acetate, succinate, Adipate, propionate, tartrate, citrate and bicarbonate. Of these, the hydrochloride is preferred and the acetate. The above salts add to the value of the relatively insoluble ones Amines in pharmaceutical applications.

In cases where the amine of Undecankomponente is substituted with dialkyl, which are Ver · ¹ compounds of the formula (I) because of their unique combination of unusual properties preferred.

The hydrochlorides of the compounds mentioned are particularly preferred.

The compounds described above can be prepared by various methods known per se. 3-aminotricyclo [4,3, l, l ³ - ⁸ ] -undecane can easily be obtained from the known compound 3-carboxytricyclo [4,3, l, l ^{3 <8} ] -undecane by converting the acid with thionyl chloride into the acid chloride and subsequent amidation to produce the corresponding amide. The amide, in turn, is reacted with metallic sodium and bromine to give 3-carbomethoxyaminotricyclo (4,3, l, l ^3l8 ] -undecane, which is hydrolyzed under basic conditions to give the desired 3-aminotricyclo [4,3, l, l, ³¹⁸ ] -undecane .

This basically corresponds to Hofmann's method for converting carboxylic acids into the corresponding amines.

The acid can be reacted with methyl chlorocarbonate and sodium azide and the acyl acide obtained can be decomposed by heating to form the isocyanate, which can be reacted with methanol to form the methyl urethane. The latter is hydrolyzed to the amine with alkali. This is an adaptation of Curtius' degradation. Examples 1 and 2 illustrate these two methods of making 3-aminotricyclo [4,3, l,! - ^{18] -undecane.}

One or both hydrogen atoms of the 3rAminostickstoffs of 3-Amino-tricyclo [4,3, l, 3 ^38] can -undekan be replaced by methyl or ethyl. The easiest way to do this is by acylation, e.g. B. with an acyl halide, where. a 3-acylaminor tricyclo [4,3, l, l ³ⁱ⁸ ] -undecane is formed, which is then reduced to 3-N-methyl- or ethylaminotricyclo [4,3, l, l ³ · ⁸ ] -undecane. An excellent reducing agent for this purpose is lithium aluminum hydride, but the reduction can also be carried out by catalytic hydrogenation or in any other manner.

3-N-methyl- or ethylaminotricyclo [4,3, l, l ³ · ⁸ ] -undecane can be converted into corresponding SN.N-dialkylaminotricyclo [4,3,1, l ³⁸ ] -undecanes by renewed acylation and reduction will.

Although the formylation of the amino compound with subsequent reduction is a viable method for the preparation of the N-methylamino compound, this can, if necessary, also be achieved by reducing tricyclo [4,3, l, l ^3l8 ] -undecane-3-methyl urethane (to the method described in Example 3 The N-methylamino compound is likewise obtained by reducing the 3-ethyl urethane.

In some cases, 3-N-alkylamino and Dialkylaminotricyclo blank [4,3, l, l ^3-8] -undekane easily by alkylation with the appropriate alkyl halides without the use of the process of acylation and reduction produced. When the reagents are used in molar amounts, the monoalkylamino compound is generally formed as the main product, while the dialkylamino compound is obtained when larger amounts of the reagents are used. When using 3-aminotricyclo [4,3, l, l ³ · ⁸ ] -undecane with a molar amount of methyl iodide, the main product is 3-N-methylaminotricycIo- [4,3,1,1 ^3s ] -undecane. When using two molar amounts of methyl iodide, the main product is 3 - N, N - dimethylaminotricyclo [4,3, l, l ³ · ⁸ ] - undecane. This method is not as elegant as the acylation and reduction method, so it is less preferred. In some cases, however, it is more advantageous because it has fewer steps.

In the following examples, the quantities given are based on weight, unless otherwise specified.

B e i s ρ i e 1 1

3-Carboxytricyclo [4,3, l, l ³ ' ⁸ ] -undecane is prepared from 1-hydroxymethyladamantane by the method of Stetter, Schwarz and Hirschhorn, Chemischeberichte, Vol. 92 (1959), p. 1634. The acid is converted into the acid chloride by refluxing with excess thionyl chloride. The excess reagent is removed under reduced pressure and the crude acid chloride is slowly added dropwise to concentrated ammonia at 0 to 5 "C. The amide obtained is recrystallized from an acetone-water mixture, a white crystalline solid with a melting point of 180 to 181" C. in a yield of 90% is obtained. 8 parts of the amide are added to a solution of 2.1 parts of metallic sodium in 175 parts of methanol. After cooling the solution to 0 ° C., 8 parts of liquid bromine are used

added dropwise to the solution with thorough stirring. The mixture is then ^{stirred for a further 15 minutes at 0} ° C., 15 minutes at 55 ° C. and finally 30 minutes at the boiling point. The methanol is distilled off and the residue is recrystallized from dilute acetone. The product obtained is 10 parts (yield 97%) of 3-carbomethoxyaminotricyclo [4,3, l, l ³ ' ⁸ ] -undecane as a white, crystalline solid. This solid is hydrolyzed by refluxing it with excess powdered sodium hydroxide in diethylene glycol for 16 hours. After adding a large excess of water, the 3-aminotricyclo [4,3, l, l, ³ⁱ⁸ ] -undecane is extracted from the reaction mixture with chloroform. This solvent is removed and replaced with cyclohexane, whereupon dry hydrogen chloride is bubbled into the solution. The precipitated amine hydrochloride is filtered off, dissolved in water and the free amine regenerated by making the solution strongly alkaline. The free amine is taken up in chloroform, the solvent removed and the free amine sublimed at 0.2 mm Hg. The sublimate consists of pure 3-Amino-tricyclo [4,3, l, l ^3-8] -undekan a melting point of 205 to 206.5 ⁰ C (sealed capillary).

Analysis for C ₁₁ H ₁₉ N:

Calculated ... C 79.94, H 11.59, N 8.48;
found .... C 81.68, H 11.72, N 8.59.

Neutralization equivalent:
Calculated ... 165.27;
found .... 176.

The infrared spectrum and the nuclear magnetic resonance spectrum agree with those for this connection expected values.

Example 2

30 g (0.1545 mol) of 3-carboxytricyclo [4.3, l, l, ³ⁱⁱ ] -undecane are dissolved in 200 cm ^{3 of} acetone. A solution of 12.7 g (0.16 mol) of pyridine in 25 cm ^{3 of} acetone is slowly added to the solution. The reaction mixture is cooled to 3 ° C and a solution of 16 g (0.17 mol) of methyl chlorocarbonate in 25 cm ^{3 is} slowly added while the temperature is kept below 5 ° C. The mixture is stirred for 1 hour and a solution of 11.8 g (0.18 mol) of sodium azide in 30 cm ^{3 of} water is slowly added. After the addition, the reaction mixture is stirred for 16 hours at room temperature, diluted with four times the volume of water and extracted with toluene. The toluene extract is washed with water, l% strength sodium hydroxide, 1 ° / _o hydrochloric acid and then with water. The toluene solution is then dried with calcium chloride and heated to 100 ° C. until no more nitrogen is evolved from the acyl azide. The toluene is removed under reduced pressure and the residue is refluxed with methanol for 16 hours. After removal of the methanol, a solid residue remains, consisting of 26.16 g (76% conversion) of tricyclo [4,3, l, l ³⁸ ] -undecane-3-methyl urethane. After recrystallization from an acetone-water mixture, this compound melts at 104 to 106 "C. Alkaline hydrolysis-Amino-3 is [4,3, U ^3-8] obtained -undekan.

Example 3 ^:

A solution of 20.5 g (0.092 mol) of 2 prepared in accordance with Example tricyclo [4,3, l, l ^3-8] -undekan-3-methyl-urethane in 100 cm ³ of dry diethyl ether is slowly added to a suspension of 5 , 65 g of lithium aluminum hydride in 100 cm ^{3 of} dry ether. After the addition has taken place, the reaction mixture is heated under the reflux condenser for 1 hour

ίο ether distilled off, the residue made strongly alkaline with sodium hydroxide and the product isolated by steam distillation. The steam distillate is extracted with ether, the extract is dried with solid KOH, filtered and dry HCl is passed into the solution. The amine hydrochloride which forms precipitates out of the ethereal solution and is filtered off. After recrystallization from ethyl acetate, the melting point is 225 to 226 ° C.: The yield is 6.8 g (34% of theory) of 3-N-methylaminotricyclo [ ^4,3,1,1,318 ] -undecane hydrochloride.

Analysis for C ₁₂ H ₂₂ NC ₁ :

Calculated ... N 6.52, Cl 16.45;
found ..... N 6.41, Cl 15.98.

Example 4

A sample of 10.35 g (0.05 mol) of 3-acetylated tricyclo [4.3, l, l, ^3-8 ] -undecane, prepared by acetalizing the corresponding amine with acetic anhydride containing a drop of sulfuric acid, is poured into 200 cm ^{3 of} dry tetrahydrofuran dissolved and added to a suspension of 3.0 g of lithium aluminum hydride in 350 cm ^{3 of} dry ether. After the addition has taken place, the mixture is heated under the reflux condenser for 1 hour and the solvent is distilled off from the reaction vessel. Steam is then passed in until a clear distillate is obtained. The distillate is then extracted with ether and the extract is dried with solid sodium hydroxide. Then dry hydrogen chloride is passed into the filtered solution and the precipitated amine hydrochloride is removed by filtration and recrystallized from ethyl acetate-methanol. The product obtained is 5.6 g of 3-N-ethylaminotricyclo [4.3, l, l ³ ' ⁸ ] -undecane hydrochloride. Fp .: 345 to 350 ⁰ C.

Analysis for C ₁₃ H ₂₄ NCl:

Calculated ... N 6.09, Cl 15.4;
found .... N 6.66, Cl 15.57.

Example 5

The 3-N-methylaminotricyclo [4,3, l, l ³⁸ ] -undecane prepared in the manner described in Example 3 is converted into the acetyl derivative by gently warming the compound with a slight excess of acetic anhydride containing a drop of sulfuric acid . The resulting solution is poured onto ice and extracted with chloroform. Removal of the chloroform gives 3-N-methylacetaminotricyclo [4,3, l, l ³⁸ ] -undecane, which is purified by distillation. A solution of the amide in tetrahydrofuran is slowly added to a suspension of one molar equivalent of lithium aluminum hydride in diethyl ether. After the addition, the reaction mixture is heated for 4 hours on the reflux condenser, the solvent is removed and the amine is isolated by distillation with steam. The distillate is extra-

hiert and the extract dried with solid sodium hydroxide. The dry ethereal solution is saturated with hydrogen chloride. After removing the ether, the hydrochloride of 3- (N-methyl-N-ethylamino) -tricyclo [4,3, l, l ³ⁱ⁸ ] -undecane is obtained. Mp .: 245 to 249 ° C.

Example 6

A mixture of 0.10 mol of 3-aminotricyclo [4.3, l, l ³⁸ ] -undecane and 9.87 g (0.10 mol) of 38% strength hydrochloric acid in 100 cm ^{3 of} water is under reduced pressure at 60.degree constricted. The salt obtained, 3 - aminotricyclo [4.3, l, l ³ · ⁸ ] undecane hydrochloride, is dried in vacuo at 60 ° C. M.p .: 205 ° C.

The experiment described above is repeated, but using the reaction components mentioned below and the following products will be obtained:

Product of
example

(0.10 mole)

(Free
Amine)
(0.10 mole)

(Free
Amine)
(0.10 mole)

(Free
Amine)
(0.10 mole)

(Free
Amine)
(0.10 mole)

2
(0.10MoI)

(0.10MoI)

acid

48% hydrogen hydrogen
acid
(0.10 mole)

85% phosphoric acid
(0.33 moles)

Tartaric acid
(0.10 mole)

Tartaric acid
(0.050 moles)

Maleic acid
(0.050 moles)

Mandelic acid
(0.10MoI)

Lactic acid
(0.10MoI)

product

3-Aminotricyclo- [4,3,1, l ^38] -undekan, hydrobromide

3-N-Methylaminotricyclo [4,3, l, l ^3-8] -undekan, phosphate

3- (N-methyl-N-ethyl) aminotricyclo [4,3, l, l ³⁸ ] -undecane, bitartrate

3-N-Äthylaminotricyclo [4,3, l, l ^3-8] -undekan, tartrate

3-N-MethyIaminotricyclo [4,3, l, l ^3-8] -undekan, maleate

3-Aminotricyclo- [4,3,1, l ^38] -undekan, mandelate

3-Aminotricyclo- [4,3,1, l ^38] -undekan, lactate

finds. Is obtained -undekan - the precipitation of the bicarbonate of 3-Amino-tricyclo ^[8 4,3, l, l ^3] is filtered off and dried under reduced pressure. In the preceding examples, equivalent amounts of other suitable starting materials can be used to prepare other compounds within the scope of the invention, including those listed above.

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 and after the start of the infection. For example, can treatment parenterally, d. H. subcutaneously, intravenously, intramuscularly, or intraperitoneally. As 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 pneumonia, treatment can be with vapors or spray by mouth or the Nasal passages.

The compounds prepared according to the invention are valuable agents for prophylaxis and Therapy of viral infections.

The dosage depends on the virus to be combated, the age, and the state of health 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 50 mg / kg body weight, but lower amounts can also be used z. B. 0.5 mg, or higher amounts can be used. Usually amounts from 1 to 20 mg, preferably 1 to 10 mg / kg / day, given all at once or spread over the day, get the results you want.

The active ingredient of the formula (I) can be used together with a customary solid or liquid non-toxic pharmaceutical carrier or excipient for the active ingredient in drugs, such as tablets, capsules, Powders or liquid solutions, suspensions or elixirs for oral application or in liquid form Solutions for parenteral use and in certain cases in suspensions for parenteral use (except intravenously). These preparations contain the active ingredient usually in an amount of at least 0.5 and at most 90 percent by weight based on the total weight of the preparation.

Example 7

A solution of 0.20 mole of the hydrochloride of 3-Amino-tricyclo [4,3, l, l ^3-8] -undekan in 100 cm ³ of water is added to a solution of 0.1 moles of the disodium salt of 4,4'-methylene -bis- (3-hydroxy-2-naphthoic acid) in 500 cm ^{3 of} water. The precipitate obtained is filtered, washed well with water and dried under reduced pressure, whereby the embonate of 3-aminotricyclo [4,3, l, l, ³⁸ ] -undecane is obtained.

B e i s ρ i e 1 8

Carbon dioxide is introduced into a solution of 0.10 mole of 3-Amino-tricyclo [4,3, l, l ^3-8] -undekan in 100cm ³ of diethyl ether passed through until no more precipitation instead of test report

Comparative tests were carried out to demonstrate the pharmacological effect. The compound to be investigated was administered to white mice (Swiss-Webster strain) which had been infected intranasally with a strain of the test virus adapted to mice. The vaccine virus was carefully standardized to produce a standard infection. The test compound was administered intraperitoneally 30 minutes before infection. The standard dose of the vaccine virus is 20 times the LD ₅₀ , ie the dose which causes the death of 50% of the untreated test animals.

The mean survivor day (MSD) is calculated as follows:

MSD =

Σ Wd-I)]

Here / is the number of mice reported dead on day 1 and N is the number of mice in the test group. The amount of the compound is calculated from the MSD, which is necessary to the infection to be reduced to a "height a log reduction of ¹ J ₁ of the vaccine virus is equivalent to (AVI ^ _0). In other words, the AVI ₅₀ is the dose, expressed in milligrams of test compound per kilogram of body weight, that causes an apparent 3.2 fold decrease in the infectivity of the virus.

The compounds listed below have been tested for effectiveness against Influenza A / Pig / S 15 examined.

The following results were obtained:

Tested connection Melting point
° C AVI ₅₀ 3-aminotricyclo [4,3, l, l ³ · ⁸ ] -
undekane hydrochloride
3-N-methylaminotricyclo-
[4,3, l, l ³ - ⁸ ] -undekan-
hydrochloride 205
225 3.5
13.0

The following minimum doses were used for the compounds according to the invention listed below determined:

connection Melting point
"C Minimal
dose 3-N, N-dimethylaminotri- 276 25.0 cyclo [4,3, l, l ^Si8 ] -ündekan- hydrochloride S-iN-ethyl-N-methylamino) ^ 245 to 249 13.0 tricyclo [4,3, l, l ³ - ⁸ ] -und- kan hydrochloride 3-N-ethylaminotricyclo- 345 to 350 33.9 [4,3, l, l ³⁸ ] -undekan- hydrochloride

In contrast, the compounds showed p-fluorophenylalanine, 4 - (o - chlorobenzyl) - 5 - oxo - 4 - phenyl - hexanoic acid, isatin-zS-thiosemicarbazone of the state of Technology against the influenza virus A / pig / S 15 and the influenza virus A 2 / AA / 2/60 no effect.

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. For the most Purpose, the active ingredient in an amount of about 0.0001 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.

Claims (2)

Patent claims: 1. 3-amino - tricyclo [4,3, l, I ³⁸ ] - undecane - derivatives of the general formula wherein R ₁ and R _{2 are} hydrogen, methyl or ethyl, and their pharmaceutically acceptable acid addition salts. 2. Process for the preparation of compounds according to claim 1, characterized in that one in a manner known per se a) Corresponding derivatives of 3-carboxylic acids from Hoffmann, Curtius or Subjects Schmidtschenabbau or b) Compounds of general formula I in which the group —NH ₂ or —NHR ₁ is present, acylated and the acylamide reduced or c) compounds of the general _{formula in which the group —NH 2} or —NHR ₁ is present, with a methyl or ethyl halide.