DE2334984A1 - 2-CYCLOHEXYLMETHYLTETRAHYDRODICYCLOALK SQUARE BRACKET ON E.G SQUARE BRACKET TO ISOINDOLINE - Google Patents

Description

DR.-ING. BY KREISLER DR.-ING. SCHDNWALD DR.-ING. TH. MEYER DR. FUES DIPL-CHEM. ALEK FROM KRE IS LE R DIPL-CHEM. CAROLA KELLER DR.-ING. KLDPSCH DIPL.-ING. SELTING

COLOGNE 1, DEICHMANNHAUS

Cologne, July 5, 1973 AvK ^ Ax / IM

EGG. Du Pont de Nemours and Company, Wilmington, Del./USA

2-Cyclohexylmethyltetrahydrodicycloalk ^ e.a7isoindoline

To be considered a commercial candidate for the prophylaxis or therapy of mild upper respiratory tract disorders, those caused by rhinovirus or coronavirus infections must be taken into account meet a number of requirements. It must have adequate antiviral activity. She must be low Exhibit toxicity and be free from serious adverse side effects. For example, it may only be a small one or have no effect on the central nervous system and blood pressure. When administered orally or parenterally is to be, it must have antiviral concentrations reach in the tissues of the respiratory tract. If it is to be administered intranasally, it must not be excessive Can cause irritation to eyes or nasal tissues.

Belgian patent specification 773 174 (granted January 15, 1971) describes several 2-substituted tetrahydrodicycloalk- ^ e.g7isoindolines and their use as antiviral agents. A number of such compounds have been tested, but no commercial candidate has been found among them. Every these compounds did not meet one or more of the aforementioned requirements. For example reached 2 - benzyl-3A, 3B, 13A, 1 SB-tetrahydrodicyclohept- ^ e.g / isoindoline (the most active compound) is insufficient

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Concentrations in lung tissue, and 2-cyclopropylmethyl-3A, 3B, 13A, 13B-tetrahydrodicyclohept ^ e.27ieoindoline (the • compound that corresponds to the compounds according to the invention in most similar in structure) had an unacceptable effect on the central nervous system.

The invention relates to a class of antiviral compounds who meet the above requirements. These compounds are 2-Cyclohexylmethyltetrahydrodicycloalk ^ e.gyisoindoline, which by the formula

= ^ / ■ (CH ₀ )

2'm

in which m stands for 0, · 1, 2 or 3 can and their pharmaceutically acceptable acid addition salts.

The invention also includes pharmaceutical preparations which are used for the prophylaxis, control or healing of rhinovirus or coronavirus infections cause diseases of the upper respiratory tract in warm-blooded animals and essentially serve from a compound of the formula (I) or a pharmaceutically acceptable salt of this compound and a pharmaceutically acceptable carriers exist.

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The synthesis of the compounds according to the. Invention is possible by several methods.

Procedure I.

Compounds according to the invention can be prepared by reducing a lactam or imide of the formula

IT.

in which X is -CH2- or -C- and m is 0, 1, 2 or 3. The reduction can be carried out in an inert solvent using a suitable mixed metal hydride as the reducing agent, for example sodium bis (2-methoxyethoxy) aluminum hydride or lithium aluminum hydride.

Suitable solvents are, for example, aliphatic and aromatic hydrocarbons, halogenated hydrocarbons, linear and cyclic ethers, e.g. diethyl ether, dibutyl ether, dioxane and tetrahydrofuran, and certain highly polar solvents, e.g. dimethylformamide, dimethylacetamide and dimethyl sulfoxide.

The catalytic reduction with copper chromite according to that of

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-A-

Wolcik and Adkins, J. Am. Chem. Soc. 56, 2419 (1934) general method or electrolytic reduction can also be applied to a compound of formula (II) to convert into a compound of formula (I). The electrolytic reduction of lactams and imides is well known. Reference is made, for example, to the work of F.D. Popp and H.P. Schultz, Chem. Review 62, 19 (1962) and the work of T. Yamazaki and M. Nagata, Yakugaku Zasshi, 7jj_, 1222-4 (1959). The latter work will be briefly in CA. 54, 4596 (196o).

The imides of the formula II can be prepared by reacting a 3,4,5,6-dicycloalkano-1,2, Sie-tetrahydro-phthalic acid anihydride -with cyclohexylinethylamine in tetrahydrofuran, which contains 1o% water, at a temperature of 18o to 2oo ° C under the intrinsic pressure for a time of 5 to 20 hours. The imide can also be formed without the use of pressure equipment, simply by pressing the Reactants brought together in the presence or absence of an inert solvent and the resulting mixture heated under an inert atmosphere to 19o to 22o ° C.

The lactams of the formula II can be prepared from imides of the formula II by the electrolytic process, which is described by Tafel and Stern in Chemical Reports, Volume 33, pp. 22-24 (1900).

Procedure II

Compounds according to the invention can also be prepared are made by reducing amides of the formula

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III

The above description of the reduction of lactams
and imides of the formula II also applies to the reduction of amides of the formula III.

The amides of the formula III can by reacting the appropriate unsubstituted tetrahydrodicycloalk ^ e.g / isoindoline with cyclohexylformyl chloride in the presence of a Acid acceptor produced - are.

Procedure IH X

The compounds according to the invention can also be prepared by alkylating compounds of the formula

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in which m is 0, 1 ·, 2 or 3 using Cyclohexyl methanesulfonate or a cyclohexylmethyl halide, e.g., cyclohexylinethyl chloride, as an alkylating agent. The reaction is carried out in a solvent at a temperature of about 3o to 100 ° C (preferably 45 to 55 ° C) carried out for about 1 to 2 hours in the presence of a stoichiometric amount of an acid acceptor. Preferred stoichiometric amounts of the reactants, but an excess of the tetrahydrodicycloalk ^ e.g / i'soindoline (Compound of Formula IV) can be used. Suitable solvents for the reaction for example N, N-dimethy1formamide, Ν, Ν-dimethylacetamide and dimethyl sulfoxide. Suitable acid acceptors are, for example, alkali metal carbonates and bicarbonates.

Procedure IV

The compounds of the formula I can also be prepared by reducing alkylation of corresponding compounds of the formula IV with cyclohexylformaldehyde in the presence of a catalyst, for example PtO ₂ or Raney nickel. The reaction can be carried out under the usual reducing alkylation conditions, as described, for example, in Organic Reactions, Vol. IV, pp. 174-255 and Vol. Ν, pp. 301-330.

Method V ■

This procedure, which is very similar to Procedure IV, consists of the reduction of an enamine of the formula

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with formic acid (Bull. Soc. Chim., France, 1761 (1963)) with diborane (Tetrahedron Letters, 2849 (197o)) or by catalytic hydrogenation in the presence of

Pharmaceutically acceptable salts of the compounds of the formula I can be obtained by neutralizing solutions of the free Bases with acids such as hydrochloric acid, hydrobromic acid, hydrogen iodide acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, citric acid, propionic acid, benzoic acid, Oleic acid and succinic acid can be produced. The salt is removed by filtration or by evaporation of the Solvent isolated.

example 1

2.3 g of cyclohexylmethylamine become a solution of 5.8 g of 3,4,5,6-dicycloheptane-i, 2,3,6-tetrahydrophthalic anhydride given in methylene chloride. The solvent is distilled off and the residue is under nitrogen at 190 ° C. for 1 hour held. The reaction product can be crystallized from ethanol, 4.5 g of N-cyclohexylmethyl-3,4,5,6-di-

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cycloheptane-1,2,3,6-tetrahydrophthalimide can be obtained. The imide is dissolved in 5o ml of tetrahydrofuran and a Mixture of 4 g of lithium aluminum hydride in 100 ml of tetrahydrofuran -given. The mixture is refluxed for 16 hours. The excess hydrides are saturated with decomposed with aqueous sodium sulfate solution. The solid is filtered off and the filtrate is concentrated. The residue is taken up in ether and dried over potassium carbonate. The desiccant is separated, wrauf Hydrogen chloride gas is passed into the solution until complete precipitation. The solid is isolated, dried and recrystallized from isopropanol, yielding 2.6 g of 2-cyclohexylmethyl-3A, 3B, 13A, UB-tetrahydrodicycJLohept ^ e.g / isoindoline hydrochloride from 'melting point 3o8.5' to 3o9 ° C.

Example 2

When using 3,4,5,6-dicyclooctane-i, 2,3,6-tetrahydrophthalic anhydride instead of 3,4,5,6-dicycloheptane-1,2,3,6-tetrahydrophthalic anhydride in the experiment described in Example 1 2-Cyclohexylmethyl-3A, 3B, 15A, 1SB-tetrahydrodicyclooct ^ eg _i 7isoindoline hydrochloride with a melting point of 344 to 346 ° C. is obtained after recrystallization from butanol.

Example 3

A mixture of 3.4 g of cyclohexanemethylamine, 7 g of 3,4,5,6-dicyclopentane-1,2,3,6-tetrahydrophthalic anhydride, 5o ml of tetrahydrofuran and 5 ml of water is 18 hours in one closed reaction vessel. held at 190 ° C. The reaction mixture is evaporated and the residue is taken up in ether and the ether solution dried over anhydrous magnesium sulfate. The ether is under reduced pressure removed. The imide obtained as an intermediate is taken up in 5o ml of tetrahydrofuran and added to a mixture of Added 5 g of lithium aluminum hydride in -1oo ml of tetrahydrofuran. The mixture is refluxed for 16 hours.

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heats. The excess hydride is saturated with sodium sulfate solution decomposed. The solid is filtered off and the filtrate is concentrated. The residue is taken up in ether and dried over anhydrous potassium hydroxide granules. The ether solution is decanted and free of water Hydrogen chloride passed into the ether until it was completely precipitated. The solid is isolated and dried and then recrystallized from nitromethane, leaving 3 g of 2-cyclohexylmethyl-3A, 3B, 9A, 9B-tetrahydrodicyclopent / e.27-isoindoline hydrochloride with a melting point of 254.5 to 255.5 ° C. ·

Example 4 . .

:. When using 3 ^- , 4,5, e-dicyclohexane-L, 2, 3, 6r-tetrahydrq- :. phthalic anhydride (mixture of equal parts of 2 possible Diels-Alder isomers) instead of 3,4,5,6-bicyclopentane-1,2,3,6-tetrahydrophthalic anhydride in the experiment described in Example 3, 2-cyclohexylmethyl-3A, 3B, HAjHB-tetrahydrodicyclohex ^ eg / isoindoline hydrochloride from melting point 2o9 to 211oc obtained after recrystallization from tetrahydrofuran

Example 5

A mixture of 2-cyclohexylmethyl-3A, 3B, 13A, 13B-tetrahydrodicyclohept / e.gjisoindoline hydrochloride, Ether and 10% sodium hydroxide solution are shaken until no more solid can be detected. The water is separated off and the solution dried over potassium hydroxide. The ether is distilled off after the drying agent has been separated off. 2-Cyclohexylmethyl-3A, 3B, 13A, 13B-tetrahydrodicyclohept / e.gyisoindoline remains as a residue from a melting point of 101 to 1o3 ° C after recrystallization from ethanol.

Example 6

A repetition of the experiment described in Example 5 with 2-cyclohexylmethyl-3A, 3B, 15A, ISB-tetrahydrodicyclooct- ^ e.g / isoindoline hydrochloride instead of 2-cyclohexylmethyl-

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3A, 3B, 13A, 1SB-tetrahydrodicyclohept / e.g / isoindoline hydrochloride gives 2-cyclohexylmethyl-3A, 3B, 15Λ, 15B-tetrahydrodicyclooct ^ e.g / isoindoline from melting point 1o6 to 1o7 ° C.

Example 7

1 mole of hydrobromic acid becomes 1 mole of 2-cyclohexylinethyl-3A, 3B, 13A, 13B-tetrahydrodicyclohept ^ e.g7isoindoline given in ether. The solid is isolated and dried. Recrystallization from ethanol gives 2-cyclohexylmethyl-3A, 3B, 13A, 13B-tetrahydrodicyclohept ^ e.g7isoindoline hydrobromide obtained from melting point 266 to 268 ° C.

Example 8

When using hydriodic acid instead of hydrobromic acid in the experiment described in Example 7 becomes 2-cyclohexylmethyl-3A, 3B, 13A, 13B-tetrahydrodicyclohept ^ e.g / isoindoline hydroiodide obtained from melting point 232 to 233 ° C. after recrystallization from ethanol.

Example 9

When using sulfuric acid instead of hydrobromic acid in the experiment described in Example 7 becomes 2-cyclohexylmethyl-3A> 3B, 13A, 1SB-tetrahydrodicyclohept ^ e.g7isoindoline sulfate obtained from! melting point 245 to 249 ° C after recrystallization from ethanol.

Example Io

By adding acetic acid to an ether solution of 2-cyclohexylmethyl-3A, 3B, 13A, 1SB-tetrahydrodicyclohept- ^ e.g / isoindoline is the acetate from melting point 116 to 117.5 ° C precipitated.

Example 11

1 mole of citric acid is put into the thimble of a Soxhlet extraction apparatus given. 2 moles of 2-cyclohexylmethyl-3A, 3B, 13A, 13B-

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tetrahydrodicyclohept ^ e.g / isoindoline given in an ethereal solution. The ether is heated on the reflux condenser, and. during the extraction of citric acid separate Crystals of 2-cyclohexylniethyl-3A, 3B, 1 3Λ, 13B-tetrahydrodicyclohe.pt/e. gyisoindoline citrate. The crystals are isolated and have after recrystallization from ethanol a melting point of 166 to 168 ° C (dec.).

Example 12

6 g of 2-cyclohexylmethyl-3A, 3B, 13A, ISB-tetrahydrodicyclohept- / 6 ^ / isoindoline in 40 ml of ethane, 85% phosphoric acid is added dropwise until a strongly acidic reaction observed on indicator paper. A phosphate salt is deposited and filtered off; by recrystallization Ethanol, the pure phosphate is obtained, which is a consisting of 1 molecule of base and 2 molecules of phosphoric acid Salt is. The salt decomposes at 140 ° C.

Example 13

The experiment described in Example 12 is carried out with 2-cyclohexylmethyl-3A, 3B, 15A, 1SB-tetrahydrodicyclooct ^ e.g / isoindoline repeated using tetrahydrofuran instead of ethanol to obtain the corresponding phosphate which decomposes at 154 ° C.

Example 14

A solution of 2-cyclohexylmethyl-3A, 3B, 15A, 15B-tetrahydrodicyclooct ^ e.g / isoindoline in ether is acidified by adding methanesulfonic acid drop by drop. The one here The solid formed is isolated and dried. Uracrystallization from water produces pure 2-cyclohexylmethyl-3A, 3B, 15A, ISB-tetrahydrodicyclooct / e.g / isoindoline methanesulfonate obtained from melting point 2o3 to 2o5 ° C.

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Belspiel 15

By repeating the experiment described in Example 14 with 2-cyclohexylmethyl-3A, 3B, 13A _/ 13B-tetrahydodicyclohept / e.gyisoindoline, the corresponding methanesulfonate with a melting point of 216.5 to 217.5oc is obtained.

Similarly, salts of other acids can be prepared. In addition to the acid mentioned above, the the following acids are used: benzoic acid, nitric acid, maleic acid, mandelic acid, tartaric acid, 4,4'-methylenebis (3-hydroxy-2-naphthoic acid), ethanedisulfonic acid, succinic acid and gluconic acid.

Formulation and application '■ ■ ■' · - '- ■ ■ · - ■ · ■ · The compounds of the formula I and their pharmaceutically acceptable salts are valuable for the prophylaxis, control and / or cure of infections of the above caused by rhinoviruses or coronaviruses Airways in warm-blooded animals. They can be administered parenterally, orally or intranasally or in preparations which are customary for these application forms. In general, these pharmaceutical preparations contain about 0.1 to 75% by weight of active ingredient (compound of the formula I or its salt) and a pharmaceutically acceptable carrier. Various types of preparations suitable for oral administration are mentioned below. 1. Hard gelatin capsules

A. General formulation

Active ingredients o, 1 - 75%

Lubricant, lubricant O - 15% filler as required

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B. Specific examples

Amount per capsule

(1) Active Ingredient 50 mg Magnesium Stearate 8 mg Talc 4o mg anhydrous lactose 3o2 mg

The materials are sieved to 0.3 mm and mixed well Ensuring evenness and fills with usual Capsule filling machines in size 1 capsules.

Amount per capsule l

(2) Active Ingredient 50 mg Magnesium Stearate 3.5 mg '. . '

''"Lactose"'■'''12'1; S cowardly " ^: " -

The materials are sieved to 0.3 mm, mixed well to ensure uniformity and filled with the usual Capsule filling machines on size 3 capsules.

2. Soft gelatin capsules

A. General formulation

Active ingredients - 0.1 - 5o%

Oil base 'as required

B. Specific Example Amount Per Capsule Active Ingredient 50 mg Soybean Oil 125 mg Wax Mix 12 mg Soy Lecithin 4 mg

The wax mixture consists of
1 part hydrogenated soybean oil
1 part yellow beeswax

4 parts partially hydrogenated mixed vegetable oils (Primex B

and C)

Add the melted wax mixture to the soybean oil and mixes well. Add the soy lecithin and stir until the mixture is uniform. The active ingre-

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Add diens and stir until the mixture is even. Man grinds the mixture and mixes well before filling on capsules. The mixture is injected to form soft gelatin capsules into the gelatin contained in molds.

3. tablets

A. General composition

Active ingredients 0.1 - 75% Lubricants and lubricants 1 - 7%

Disintegrant 5 - 15%

Binder O - 5% '

Filler as needed

B. Specific examples Amount per tablet

(1) Active ingredient 25 mg anhydrous lactose 16o mg microcrystalline cellulose 2o mg Magnesium stearate 4 mg fumed silica 0.2 mg

The active ingredient, magnesium stearate and pyrogenic silica are sieved to 0.3 mm. You mix all the ingredients together until a uniform mixture is formed and pressed into tablets.

Amount per tablet

(2) Active ingredient 50 mg

Lactose 150 mg

Corn starch 25 mg

Magnesium stearate 5 mg

Fumed silica 0.2 mg

Gelatin 12 mg

The active ingredient, the lactose, half of the corn starch and the fumed silica are sieved to 0.3 mm. Mix well and granulate with an aqueous gelatin solution. You sieve, dry and sieve today. You give them Add remaining corn starch and magnesium stearate, mix well and compress into tablets.

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OBiGiNAL INSPECTED

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4. Syrups

A. General Composition Active Ingredient Flavor Coloring

Preservatives sweeteners

sweetened diluent water

o, 1 - 25% as required as required as required - 2%
- 95% as required

B. Specific Example Active Ingredient 1N HCl
Methyl paraben propyl paraben flavoring dye
glycerin
Sorbitol solution sucrose
purified water 25 mg

upon need

4 mg ■ "- ·" - ■

ο, 4 mg as required as required ο, 2 5 mg 1 , 5 mg 5 oo mg 5 ml

Sufficient 1N HCl is added to the active ingredient to dissolve the material. One gives the paraben compounds, Add the flavor, color, glycerin, sucrose and some of the water and mix well. After adding the Sorbitol solution is diluted to the desired volume with water.

Oral suspension

A. General Composition Active Ingredient Wetting Agent

Preservatives Sweets

Suspending agent water

309885/1412 ORIGINAL INSPECTED o, 1 - 25% 0 - 1%

as required 0 - 5%

o, 1 - 5% as required

ο ο 4 α 3

B. Special example

Active ingredient 50 mg

surfactant

"Tween 8o" 5 mg

Methyl paraben 4 mg

Propyl baraben 0.4 mg

Sorbitol 10 mg

Methyl cellulose, 100 cP 10 mg

Water ad 5 ml

The paraben compounds "Tween 80", sorbitol and methyl cellulose are dissolved in part of the water. You give that active ingredients and grinds until an even suspension is formed. One dilutes to volume and grinds again. "Tween 8o" is a polyoxyethylene sorbitan monooleate.

Preparations to be administered intranasally should be used as aqueous solutions, be isotonic, buffered between pH 5.5 and 6.5, and contain an antimicrobial agent. Small amounts of surface-active compounds, for example ^rt polysorbate 80 ", or other solvents, for example propylene glycol, can be used to prepare a solution.

Specific example - intranasal preparation

Active ingredient 0.25 g

Propylene glycol 5, oo ml

NaH ₂ PO ₄ . H ₂ O o, 65 g

NaIIPO ₄ . 7H ₉ O o, 54 g

NaCl 0.45 g

Benzalkonium chloride o, o1 - o, 1%

distilled water ad loo ml

Suspensions for parenteral administration-can can also be produced in the usual way.

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ORIGINAL INSPECTED

Specific example - parenteral preparation

Active ingredient, microfine Io mg

Polysorbate 80 4 mg

Sodium carboxymethyl cellulose 5 mg

Sodium chloride 9 mg

Benzyl alcohol x 9 mg

Water for injection ad 1 ml

The dose administered depends on many factors including the age, state of health and weight of the recipient, the severity of the infection, type of simultaneous Treatment and frequency of treatment. In general, the daily dose of the active ingre should be diens for oral or parenteral administration between about 1 and 20 mg / kg of body weight and all at once or given in divided doses. Intranasal is the active ingredient as a drop or spray in a preparation administered the 0.1 to 10% of the active ingredient contains.

Biological experiments

To determine whether a compound meets the above criteria for commercial candidates, it is subjected to a series of tests. The experiments are carried out gradually in the manner described below Way done. If the connection fails any of these tests, subsequent tests will be run in the generally no longer carried out.

A. Primary tests

1. Determination of the antiviral effect after the liquid overlay test

A monomolecular layer of human cells becomes infected with a strain of virus that, in the absence of one Antiviral plaques (grows on the monomolecular cell layer and destroys sections of the same) after incubation caused for 2-5 days. About the monomolecular

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An agar culture medium is placed on the 2nd layer. When this hardens, becomes a layer of liquid that contains the test compound contains, placed over the agar surface. The connection then diffuses into the cell layer. After sufficient incubation, the monomolecular layer will open Checked for the presence or absence of plaques caused by the virus. For a given test compound this test is done with four rhinovirus strains (1A, 2, 39 and 51) and coronavirus strain 229E. The compound is tested at three concentrations of 50, 10 and 2 µg / ml on each strain. To pass this test, the compound must inhibit at least three of the four rhinovirus strains at 10 µg / ml or less.

2. CNS selection test

Mice are given the test compound orally in graduated doses and are then observed for mortality and a number of effects on the central nervous system. Around To pass this test, a compound must not produce any stronger effects at 100 mg / kg or below. Preferably, the compound should not show greater effects at 200 mg / kg or below.

B. Secondary Tests
1. Gradient plate test

Monomolecular layers of human cells become infected as in the liquid overlay test. One The first agar layer is applied, the plates being tilted so that a wedge of agar extends over it the surface forms. The plates are then laid flat, on top of which is a second layer of agar, which is now the test compound contains, is poured over the wedge. This results in a gradient in the concentration of the compound across the plate. For example, if the compound is contained in the upper layer at a concentration of 5 µg / ml is, the effective dose is at one edge of the

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233A98A

Plate 5 µg / ml, at the other end essentially O and in the middle 2.5 µg / ml. After incubation, plaques appear in the areas of the cell layer where there is an inhibitory effect Concentration of the compound has not been established. The dividing line between the area in which plaques are present and the area that is free of plaques indicates the minimum inhibitory concentration.

The compounds are tested for activity against ten human rhinovirus strains (1A, 1B, 2, 3, 5, 14, 15, 39, 51, 1134) and a strain of horse rhinovirus tested, pm this test to exist, a compound must be effective against 8 of the 10 human tribes at a concentration of 5 μg / ml or less, preferably 1 µg / ml or less.

2. Animal toxicity tests

a) Antihypertensive selection test (rat)

The test compound is orally administered to rats at a certain dose (50 mg / kg). The effect on blood pressure is being measured. To pass this test, a compound must not significantly increase or decrease blood pressure cause.

b) Five-day test on rats to determine the tolerance Rats are given 2oo mg / kg of the test compound orally once daily for a period of 5 days. The effects on mortality and weight gain are assessed over time. To commit a compound must not cause mortality or substantial weight loss

c) Emesis test (dogs)

Dogs are given the test compound orally in several different Concentrations and be thin on any toxic phenomena including vomiting observed. In order to exist, a connection must not have a substantial emesis

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or cause symptoms at 25 mg / kg.

C. Concentrations in the lungs

Mice received the test compound orally at a dose of 10 mg / kg (10 ppm). The lungs are removed at various times up to 4 hours after administration. The amount of the compound in the lungs is determined in µg / g lung tissue (µg or ppm). To pass this test, the compound must reach a concentration such that the ratio A / B is at least 5, where A is the maximum concentration achieved in the lungs in µg / g and B is the mean minimum inhibitory concentration in µg / ml for the ten rhinovirus species r tested in the gradient plate rat tissue culture test. The ratio A / B is preferably at least 10.

In the tests described above, 2-cyclohexylmethyl-3A, 3B, 13A, 13B-tetrahydrodicyclohept / e.g / isoindoline hydrochloride get the following results:

Liquid Overlay Antiviral Test: Efficacy against all strains at 2 µg / ml or less

C NS selection test : No adverse effect at 200 mg / kg and below

Gradient plate test : efficacy against all strains in the range below 0.5 to 2 µg / ml

Average minimum inhibitory concentration about 1 µg / ml

Antihypertensive selection test : no influence on blood pressure at 50 mg / kg

Five-day test on rats to determine tolerability : no mortality and only slight effect on weight gain at 2oo mg / kg.

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—21- Emesis test on dogs;

25 mg / kg 50 mg / kg

0/2 dogs ** 0/2 dogs

+) A few ml immediately after treating a bitch, lung concentrations ;

Removal of the lungs after concentration, ug / g minutes '

15 4.6

3o 7.2

12o 7.2

24o 4.2

Ratio A / B = 7.3

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Claims (5)

233-984 Claims Compounds of the formula (CH ₉ ) (CH ₂ ), in which m stands for 0, 1, 2 or 3 and their pharmaceutical harmless acid addition salts. 2. 2-Cyclohexylmethyl-3A, 3B, 13A, 13B-tetrahydrodicyclohept [e .. 27isoindoline hydrochloride. 3. Pharmaceutical preparations for the prophylaxis, control or healing of rhinovirus or coronavirus infections caused minor diseases of the upper respiratory tract, consisting essentially of one A compound according to claims 1 and 2 and a pharmaceutically acceptable carrier. 4. A method for the preparation of compounds according to claim 1, characterized in that compounds of the formula 309885/1412 233Λ98Α or Il wherein X is -CH ₂ - or -C- and m is 0, 1, 2 or 3, reduced. 5. Process for the preparation of compounds according to claim 1, characterized in that one is a cyclohexylmethyl radical in the 2-position of compounds of the formula H H ^(CK 2> m in which m stands for 0, 1, 2 or 3, introduces, 7 ' 309885 / U12