DE1468758B1 - 3-Amino-tricyclo [4,3,1,1?] - undekane derivatives and process for their preparation - Google Patents

Description

As part of the development of more effective agents for treating viral infections, a new class of 3-amino- and substituted 3-aminotricyclo [4,3, l, l ³⁸ ] -undecans has been found that have excellent ability to treat infections with the to inhibit or prevent various 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

R.

; ³ -n

(D

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 the undecane component is substituted with dialkyl, the compounds of formula (I) are preferred because of their unique combination of unusual properties.

The hydrochlorides of the compounds mentioned are particularly preferred.

The compounds described above can be prepared by various methods known per se. 3-Amino-tricyclo [4,3, l, l ^3-8] -undekan can be readily prepared from the known compound 3-Carboxytricyclo [4,3, l, l ^3-8] To -undekan by conversion of the acid with thionyl chloride in 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 ³ⁱ⁸ ] -undecane, which under basic conditions gives the desired 3-aminotricyclo [4,3, l, l ^{3> 8} ] -undecane is hydrolyzed.

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. These two methods of making 3-aminotricyclo [4,3, l, l ^{3> 8} ] -undecane are illustrated by Examples 1 and 2.

One or both hydrogen atoms of the 3-amino nitrogen of 3-Amino-tricyclo [4,3, l, 3 ^38] can be replaced by methyl or ethyl -undekan. The easiest way to do this is by acylation, e.g. B. with an acyl halide, whereby a 3-acylaminotricyclo [4,3, l, l ³⁸ ] -undecane is formed, which then leads to the 3-N-methyl- or ethylaminotricyclo [4,3, l, l ³⁸ ] -undecane is reduced. 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 S-HN-dialkylaminotricyclo [4,3, l, l ³⁸ ] -undecane by renewed acylation and reduction will.

-Undekan-3-methylurethane% to - Although the formylation of the amino compound followed by reduction is a viable method for the preparation of N-methyl amino compound, but it may optionally also by reduction of tricyclo ^[8 4,3, l, l ^3] the manner described in Example 3 can be obtained. The N-methylamino compound is likewise obtained by reducing the 3-ethyl urethane.

In some cases, 3-N-alkylamino and dialkylaminotricyclo [4,3, l, l ³ⁱ⁸ ] undecanes can be easily prepared by alkylation with the corresponding alkyl halides without the aid of the acylation and reduction technique. 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-Amino-tricyclo [4,3, l, l ³ · ^8] -undekan with a molar amount of methyl iodide is the major product 3-N-Methylaminotricyclo- [4,3,1, l ^3-8] -undekan. 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 proposed i more advantageous because it involves fewer steps.

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

example 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. being obtained in a yield of 90%. 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. Then another 15 minutes at 0 ^c C, 15 minutes at 55 ° C and finally 30 minutes, stirred at the boiling point. The methanol is distilled off and the residue is recrystallized from dilute acetone. As product, 10 parts (yield 97%) of 3-Carbomethoxyaminotricyclo [4,3, l, l ^3-8] obtained -undekan as a white crystalline solid. This solid is hydrolyzed by refluxing it with excess powdered sodium hydroxide in diethylene glycol for 16 hours. After addition of a large excess of water, the 3-Amino-tricyclo [4,3, l, l ^3-8] -undekan extracted with chloroform from the reaction mixture. This solvent

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, the reaction mixture is heated under the reflux condenser for 1 hour, the ether is distilled off, the residue is made strongly alkaline with sodium hydroxide and the product is isolated by steam distillation. The steam distillate is extracted with ether, the extract dried with solid KOH, filtered and dry HCl into the

is removed and replaced by cyclohexane, whereupon i ₅ solution passed. The amine hydrochloride that forms, dry hydrogen chloride, is introduced into the solution, precipitates out of the ethereal solution and is filtered off. After recrystallization from ethyl acetate, the precipitated amine hydrochloride is filtered, dissolved in water and the free amine is regenerated, melting point 225 to 226 ° C. The yield is reduced by making the solution strongly alkaline. 6.8 g (34% of theory) 3-N-methylaminotricyclo-The free amine is taken up in chloroform, 20 [4.3, l, l ³⁸ ] -undecane hydrochloride. the solvent is removed and the free amine is added
0.2 mm Hg sublimed. The sublimate consists of
pure 3 -Aminotric \, elor4.3.Il ³ · * "] - undekan vom
Melting point 205 to 206.5C (closed capillary). 25th

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;

Analysis for C ₁₂ H ₂₂ NC ₁

Found N 6.52, Cl 16.45; N 6.41, Cl 15.98.

found .... 176.

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

Example 2

40

30 g (0.1545 mole) of 3-Carboxytricyclo [4,3, l, l ^3-8] are -undekan 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 mixed with water, 1% Na-

Example 4

A sample of 10.35 g (0.05 mol) of 3-acetylated tricyclo [4,3, l, l ^3-8] -undekan, prepared by acetalization of the corresponding amine with acetic anhydride containing one drop of sulfuric acid, in 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. As product 5.6 g of 3-N-Äthylaminotricyclo be [, l, 4.3 l ^3-8] obtained -undekanhydrochlorid. Fp .: 345 to 350 ⁰ C.

Analysis for C ₁₃ H ₂₄ NCl:

Calculated
found .

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

trium hydroxide, 1% hydrochloric acid and then washed with water. The toluene solution is then heated and dried at 100 ⁰ C with calcium chloride until no more nitrogen developed 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) tricyclo [4.3, l, l ³ - ⁸ ] -und-

Example 5

The manner described in Example 3 prepared 3-N-Methylaminotricyclo [4,3,1,1 ^3-8] is -undekan transformed into the acetyl derivative by treating the compound with a slight excess of acetic anhydride containing one drop of sulfuric acid, slightly is heated. The resulting solution is poured onto ice and extracted with chloroform. By removal of the chloroform is 3-N-Methylacetaminotricyclo [4,3, l, l ^3-8] -undekanerhalten 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. To

kan-3-methyl urethane obtained. After recrystallization from an acetone-water mixture melts 65 and the addition is carried out, the reaction mixture is heated for 4 hours at 104 to 106 ° C. By alkaline the reflux condenser, the solvent hydrolysis is 3-aminotricyclo [4,3, l, l ³⁸ ] -undecane removed and the amine obtained by distillation with water, isolated vapor. The distillate is extra-

hiert and the extract dried with solid sodium hydroxide. The dry ethereal solution is saturated with hydrogen chloride. After removal of the ether, the hydrochloride of 3- (N-methyl-N-ethylamino) -tricycIo is [4,3, l, l ^3-8] obtained -undekan. Fp .: 245 to 249 ^: C.

Example 6

A mixture of 0.10 mole of 3-AminotricycIo- -undekan [4.3.1.l ^38] and 9,87g (0,10MoI) 38% hydrochloric acid in 100 cm ³ of water is concentrated under reduced pressure at 60 ⁰ C. The obtained salt, 3 - Amino-tricyclo [4,3, l, l ³ * ^8] - undekanhydrochlorid, is dried in vacuo at 60 ⁰ C. Fp .: 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 moles)

(Free

(Free
Amine)
(0.10 mole)

(Free
Amine)
(0.10 mole)

(Free
Amine)
(0.10 moles)

(0.10 moles)

(0.10 moles)

acid

48% hydrogen bromide
acid
(0.10 moles)

85 ⁽ V ige 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
(0.10 mole)

product

3-aminotricyclo- [4.3,1.l ³⁸ ] -undecane, hydrobromide

3-N-Methylaminotrieyclo [4.3.U ^3-8] -undekan. phosphate

3- (N-methyl-N-ethyl) -aminotricyclo- [4,3,1, l ^3-8] -undekan, bitartrate

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

3-N-Methylaminotricyclo -undekan [4,3, l, l ^38], maleate

3-aminotricyclo-

[4,3, l, l ³⁸ ] -undekan,

Mandelate

3-Aminotricyclo- [4,3,1, l ^3-8] -undekan, lactate

40

45 finds. The precipitation whereby the bicarbonate of 3-Amino-tricyclo [4,3, l, l ^{3 '8]} is obtained -undekan is filtered and dried under reduced pressure.

In the above examples, equivalent amounts of other suitable starting materials can be used Preparation of further compounds falling under the invention, including those listed above be used.

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 with Steaming or spray can be done by mouth or 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 controlled, the age, the state of 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 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 intravenous). 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 mol of the hydrochloride of 3-aminotricyclo [4,3, I, l ³⁸ ] -undecane in 100 cm ^{3 of} water is converted into a solution of 0.1 mol of the disodium salt of 4,4'-methylene-bis- (3-hydroxy-2-naphthoic acid) in 500 cm ^{3 of} water. ^8] is obtained -undekans - the precipitation obtained with the embonate of 3-Amino-tricyclo [4,3.1,] ³ is filtered, washed well with water and dried under reduced pressure.

Example 8

Carbon dioxide is passed into a solution of 0.10 mol of 3-aminotricycIo [4,3, I, l ³ ' ⁸ ] -undecane in 100 cm ^{3 of} diethyl ether until no more precipitation takes place.

55 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.

MSD =

Σ If (d -I)]
N

Here / is the number of mice reported dead on day 1 and JV is the number of mice in the test group. The amount of compound necessary to reduce the infection to a level _{equivalent to a V 2} log reduction of the vaccine virus is _{calculated from the MSD (AVI 50} ). 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:

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

link

3-N, N-dimethylaminotri-

cyclo [4,3, l, l ^l8 ] -undekan-

hydrochloride
3- (N-ethyl-N-methylamino) -

tricyclo [4,3, l, l ³ - ⁸ ] -und-

kan hydrochloride
3-N-ethylaminotricyclo-

[4,3, l, l ^{3> 8} ] -undekan-

hydrochloride

Melting point

⁰ C

276

245 to 249
345 to 350

Minimum dose

25.0

13.0

33.9

In contrast, the compounds showed p-fluorophenylalanine, 4 - (o - chlorobenzyl) - 5 - oxo - 4 - phenyl - hexanoic acid, isatin-ß-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 [4,3,1,1 ³ · ⁸ ] - 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 Schmidtschen degradation or b) Compounds of the 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 I in which the group —NH ₂ or —NHR ₁ is present, with a methyl or ethyl halide. 009 522/244