NO131836B - - Google Patents

Description

The present invention relates to an analogous process for the production of new bis-basic ketones from dibenzothiophene. The compounds prepared according to this invention include both the basic form and pharmaceutically acceptable acid addition salts of the base, which are represented by the following general formula

where each A is branched or unbranched alkylene of 1-6 carbon atoms, and each Y is (A) the group 1 2 where R and R are each hydrogen, or branched or unbranched alkyl of 1-h carbon atoms^ or (B) the group where n is an integer from k- to 6 and R-^ is hydrogen, branched or unbranched alkyl of 1 - h carbon atoms, or (C) the group

The basic ketone groups, i.e.

in formula I can be attached to the tricyclic ring system of dibenzothiophene by replacement of any of the four hydrogen atoms in the benzene ring to which such a group is attached. Thus, one of the groups can be in any of the positions 1-h in the tricyclic system, and the other can be in any of the positions 6-9. Preferably, one of the basic ketone groups is attached to the 2-position and the other is attached to the 6- or 8-position of the tricyclic ring system. It is apparent from the formula I shown above, and its description, that the compounds may have structures in which Y is the group as shown in the general formula II, or where Y is the group

as shown in the general formula III,

or where Y is the group

formula IV.

, as shown in the following general

In the general formulas II, III and IV, they have for-12 ^

different symbols, i.e. A, R , R and RJ the previously stated meanings.

The two alkylene groups represented by A may be the same or different. Preferably, these groups are similar. For example, the alkylene groups, which are represented by A, can be: methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 2-methyl-1,< 1>+-butylene, 2-ethyl-1,^-butylene, 3-methyl-1,5-pentylene.

Each amino group in the compounds of formula II, i.e.

can be a primary, secondary or a tertiary amino group, where R 1 and R 2 have the previously stated meanings. Preferably, each of the amino groups, represented by , is a tertiary amino group. Heterocyclic groups, which are represented by each

, for example piperidino, pyrrolidino,

^-methylpiperidino, 3-methylpiperidino, ^-tert-butylpiperidino.

As basic compounds, which are represented by formula I, can be mentioned, for example: piperi-dinobutyryl)-dibenzothiophene, 2,8-bis-(^-morpholinobutyryl)-dibenzothiophene, 2,8-bis(1—C+-methylpiperidino)^utyryl}dibenzothiophene.

From the U.S. patent 3,083,201, glyoxal derivatives of dibenzofuran and dibenzothiophene are known. The compounds according to this publication are stated to exhibit antiviral activity.

However, it has been found that a representative compound according to this patent does not exhibit any activity against encephalomyocarditis (EMC) virus.

Representative compounds prepared according to fore-er

lying method/investigated with regard to the antiviral activity against encephalomyocarditis (EMC) virus compared to a representative compound according to the U.S. 3,083,201, namely 1,1'-2,8-dibenzothiophendi-yl -bis-(2,2-dihydroxyethanone)

The survey was carried out in the following way:

Two groups of mice were inoculated with a lethal dose of EMC virus. Each mouse weighed approx. 20 gr and each of the two groups of mice consisted of from 10 to 30 animals. The mice in one of the groups were treated both prophylactically and therapeutically by subcutaneous injections of test compounds. The injections were given 28, 22 and 2 hours before inoculation with virus and 2 hours after inoculation. The volume of each injection of the test compounds was 0.25 ml and contained the test compound at a dosage level of 50 mg/kg dissolved in sterile water which also contained 1.05% hydroxy-cellulose. Control animals received an equal dose of the same volume of the vehicle without the test compound. Observation over a 10-day period provided the basis for determining STR, (survival time ratio).

qm-p _ average day of death for treated animals

blK ~ -"- -"- control animal

STR = 0.9-1.09 not active

STR = 1.10 - 1.19 weak activity

STR = 1.20 - 1.29 medium activity

STR = 1.30 and greater high activity.

The results of the survey were as follows

As can be seen from the tables, the compounds produced according to the method exhibit a strong antiviral activity against EMC virus. The known connection was inactive.

Particularly preferred compounds are 2,8-bis-(dimethylaminoacetyl)-dibenzothiophene and 2,8-bis-(diethylaminoacetyl)-dibenzothiophene because these exhibit a particularly strong activity when administered orally.

Pharmaceutically acceptable acid addition salts of the basic compounds, according to the present invention, are those of any inorganic or organic acid. Suitable inorganic acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acids and the like. Suitable organic acids are, for example, carboxylic acids such as acetic acid, propionic acid, glyeolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, ascorbic acid, malic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2- phenoxybenzoic acid and the like, or sulphonic acids such as methanesulphonic acid, 2-hydroxyethanesulphonic acid and the like. Mono- or di-acid salts can be formed and the salts can be hydrated or essentially anhydrous.

The compounds according to the present invention can be administered to animals, such as warm-blooded animals, and especially mammals, to prevent or inhibit infections by: picornavirus, e.g. encephalomyocarditis, myxoviruses, e.g. Influenza A2 (Jap/305), arbovirus, e.g. Semliki Forest, herpes virus group, e.g. herpes simplex and poxviruses, e.g. Vaccinia IHD. When the compounds are administered for infection, i.e. prophylactically, it is preferred that the administration takes place within 0-96 hours before the animal is infected with a pathogenic virus. In the case of therapeutic administration to inhibit an infection, it is preferred that the administration takes place within 1 to 2 days after infection by a pathogenic virus.

The administered dose will depend on the type of virus for which treatment is given or prophylaxis is desired, the species of animal being treated, its age, health, weight, degree of infection, the nature of any other treatment, the frequency of the treatment and the intended effect. For example, dose levels for the administered active ingredients can be: intravenously, 0.1 - 10 mg/kg, intraperitoneally,

0.1 - 50 mg/kg, subcutaneous, 0.1 - 2^0 mg/kg, oral, 0.1 - 500 mg/kg

and preferably approx. 1 - 250 mg/kg, intranasal drip 0.1 - 10

mg/kg, or as an aerosol 0.1 - 10 mg/kg of the animal's body weight.

The compounds may be administered dissolved or suspended in any conventional non-toxic pharmaceutical carrier of such type as may be taken orally, topically, buccally, intranasally or parenterally.

The analogous method for preparing the compounds of formula I is characterized in that

(I) a compound formula

is reacted with an amine of the formula Y-H, where A and Y have the previously given meanings, and Hal is chlorine, bromine or iodine, or (II) to produce a compound of the formula: where z is 3 - 6 and Y can be any of the previously indicated groups with the exception of those having hydrogen attached to the nitrogen atom, a dinitrile of dibenzothiophene of the formula is reacted with a Grignard reagent of the formula where X is bromine or chlorine, or (III) for the preparation of a compound of the formula: where Y is a secondary amine as previously indicated, a compound of the formula: is reacted with formaldehyde and a compound of the formula Y-H.

In this reaction, A and Y have the previously given meanings, and each Hal is either chlorine, bromine or iodine.

The bis-(w-haloalkanoyl)-dibenzothiophene derivative 1, in which the substitution position is 2,6- or 2,8-, can be prepared by a Friedel-Craft acylation of dibenzothiophene. Of suitable acylating agents that can be used, the following can be mentioned, for example: chloroacetyl chloride, bromoacetyl bromide, 3-chloropropionyl chloride, 4-chlorobutyryl chloride, 5-chlorovaleryl chloride, 5-chloro-1!-methylvaleryl chloride, 5-chloro-3-methylvaleryl chloride.

It will be obvious to one skilled in the art that the acylation reaction can be carried out in a number of solvents catalyzed by a number of

Lewis acids. The temperature and reaction time can be varied to allow optimal reaction conditions. A preferred method is to react one equivalent of dibenzothiophene with 2.5 equivalents of the acylating agent in methylene chloride, followed by a portionwise addition of aluminum chloride. The reaction temperature is kept below 0°C, with continuous stirring. After the addition is finished, the temperature can be raised to 25 - Lt-0°C for 12 - 36 hours. The reaction mixture is worked up in the usual way by cleavage of the formed complex with ice water/HCl. The product obtained is recrystallized from methylene chloride, chloroform or the like. The procedure can be varied so that the addition of the acylating agent and the Lewis acid takes place in reverse order, or the addition of the aromatic hydrocarbon and the Lewis acid is carried out in reverse order. The more reactive halogen derivative, i.e. bis-(«-iodoalkanoyl)-dibenzothiophene, can be prepared from the corresponding bis-chloro derivative using a halogen exchange reaction, under the conditions usually used in the Conant-Finkelstein reaction.

The main product of the Friedel-Craft acylation reaction is 2,8-bis-(u>-haloalkanoyl)-dibenzothiophene. However, the course of the reaction is such that the major isomer is formed along with significant amounts of the second isomeric form of bis-(u)-haloalkanoyl)-dibenzothiophene. With the correct choice of solvents for recrystallization, these isomers can be separated.

Of amines 2, which are useful in the reaction shown above, the following examples can be mentioned: - ammonia or a compound which is a potential source of ammonia, for example hexamethylenetetramine and the like, primary amines such as ethylamine, propylamine and the like, secondary amines such as diethylamine, dibutylamine, piperidine, β-methylpiperidine, morpholine.

Amination of bis-(1H-haloalkanoyl)-dibenzothiophene can be carried out under various conditions. For example, the compound 1 can be heated with a large excess of the amine 2, whereby the excess of amine serves as a reaction medium <p>g as a hydrogen halide acceptor. This method is particularly suitable for readily available amines, excess amines can be easily removed from the reaction mixture, for example by distillation under reduced pressure or by washing the product with water. Or, an equivalent of compound 1

and h equivalents of the amine 2, can be heated together in one of a number of different solvents, for example in aromatic solvents

solvents such as "benzene, toluene, xylene and the like or others such as tetrahydrofuran, dioxane and the like, or ketones such as acetone, butanone and the like, or aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and the like, or mixtures of these solvents with water.The reaction between compound 1, where the halogen is Cl,

and the amine 2, can often be promoted by the addition of sodium or potassium iodide, where the iodide is used either in catalytic or stoichiometric amounts. In certain cases it may be advantageous to use only two equivalents of the amine 2, for each equivalent of bis-(w-haloalkanoyl)-dibenzothiophene 1, using an excess of an inorganic base, such as powdered sodium or potassium carbonate , as a hydrogen halide acceptor. The reaction will normally proceed for 12 - 72 hours at temperatures in the range 20 - 150°C When volatile amines are used, the reaction is best carried out under pressure in suitable pressure reactors or autoclaves.

(II) Compounds of formula I, where A is an alkylene chain of 3-6 carbon atoms, can also be prepared by reacting a Grignard reagent with a dinitrile of dibenzothiophene, as shown by the following reaction:

In the reaction shown above, X is bromine or chlorine, z is from 3 to 6 and Y can be any of the previously defined groups

except those containing a hydrogen directly attached to the nitrogen atom.

The reaction will proceed for 1 - 2 hours at a temperature in the range from room temperature to approx. 80°C. The Grignard reagent h can be prepared by reacting magnesium with an aminoalkyl halide of the formula

where X, z and Y have the previously stated meanings. A preferred solvent for this reaction is tetrahydrofuran.

The dicyandibenzothiophene derivative 3 can be prepared from known diamines by Sandmeyer reaction on the tetrazonium salts or from known dibenzothiophenedicarboxylic acids by dehydration of the corresponding amides, by standard methods.

(III) The compounds' of formula I, where A is -CH^CR^- and each Y is any secondary amine, as previously defined, can also be prepared by means of a Mannich reaction, as shown in the following reaction:

By reacting one equivalent of compound 6 with two or more equivalents of compound 2 with three or more equivalents of formaldehyde 7, the reaction will proceed for 1 - 2 hours in solvents such as water, acetic acid, ethanol, butanol, dioxane, tetrahydrofuran and the like, at temperatures corresponding to the reflux temperature for the solvent used. In this reaction, two sources of formaldehyde can be used. When formalin is used, the reaction is carried out with a suspension of compound 6 or an additional solvent such as methanol can be added to allow the reaction to proceed in a homogeneous medium. When the source of formaldehyde is paraformaldehyde, the reaction is carried out in an organic solvent, such as mentioned above. In some cases, it is desirable to add a small excess of hydrochloric acid to promote the depolymerization of formaldehyde, either during the reaction or at the end of the reaction.

The secondary amine, compound 2, which is used in this reaction, can be added to the reaction medium either as a salt or as the base, with subsequent in situ formation of the salt by addition of acid. Preferred acids are inorganic acids, for example hydrochloric acid. Examples of typical secondary amines that can be used in the reaction shown above include: dimethylamine, dibutylamine, piperidine, h-methylpiperidine, morpholine.

The diacetyldibenzothiophene compound 6 can be prepared by a Friedel-Craft acylation reaction on dibenzothiophene, or by a Grignard reaction between dicyandibenzothiophene 3 and methylmagnesium halide. The dicyandibenzothiophene compound can be obtained by the previously described methods.

In the following, the preparation of starting materials and the preparation of compounds according to formula I are illustrated.

A. Preparation of starting materials

1) 2,8-bisC+-chlorobutyryl)-dibenzothiophene

To a solution of 200 g (1.09 mol) dibenzothiophene and 380 g (2.7 mol) Lf-chlorobutyryl chloride in 2 liters of methylene chloride, which had previously been cooled to 0°C, 360 g (2.7 mol) were added in portions aluminum chloride while stirring. The reaction mixture was stirred at room temperature for 2 hours, after which the reaction mixture was split with a mixture of ice water and hydrochloric acid. Methylene chloride was removed and the crude product recrystallized from a mixture of chloroform and acetone to give the desired compound.

Sm.p. 131 133 °C,^^ks3 263' E?cm<1>7°°-

2) 2,6-bi s (>+-chlorobutyryl)-dibenzothiophene

By applying the method according to 1), but using chloroform in the recrystallization of the impure product,

the desired connection was obtained. Sm.p. 1^7 - 1^8.5°C,

71 CH1C13 256, 1190.

maxJ y ' limb y

3)

By applying the method according to 1), but replacing β-chlorobutyryl chloride with chloroacetyl chloride, a mixture of 2,6- and 2,8-bis(chloroacetyl)-dibenzothiophene is obtained, which is recrystallized from a mixture of dimethylformamide and methanol.

Sm.p. 210 - 212 °C.

V) 2,8-bis-(bromoacetyl)-dibenzothiophene

To a solution of 5.0 g (0.019 mol) of 2,8-diacetyldibenzothiophene in 200 ml of chloroform was added dropwise, with stirring and gentle reflux, 6.1 g (0.038 mol) of bromine in 25 ml of chloroform. After refluxing for a further 1 hour, the reaction mixture was cooled and the desired product filtered off and recrystallized from acetic acid. Sm.p. 187 - 189°C (decomposition).

B. Preparation of compounds of formula I

Example 1

2,6-bi s-(h-piperidinobutyryl)-dibenzothiophene

A mixture of 1^.0 g (0.036 mol) 2,6-bis-(^-chloro-butyryl)-dibenzothiophene(2)), 2<1>+.7 g (0.29 mol) piperidine and 12, 0 g (0.072 mol) of potassium iodide in 300 ml of butanone was refluxed for 3 days after which the reaction mixture was cooled and diluted with 1000 ml of water. The precipitated solid was filtered off, washed with water and recrystallized from a mixture of chloroform and acetone to give the desired compound, m.p. 106 - 108°C,

*£a£s3 256, E^m 9^7.

Example 2

2,8-bi s-(!+-mor f olinobutyryl)-dibenzothiophene-dihydro chlor id

A mixture of 20 g (0.05 mol) 2,8-bis-(1-chlorobutyl)-dibenzothiophene (l)), 32 g (0.32 mol) morpholine and 2.0 g potassium iodide in 500 ml p- dioxane was refluxed for 72 hours, after which the reaction mixture was cooled and filtered. The filtrate was concentrated to half the original volume and diluted with 700 ml of water, whereby a semi-solid precipitate was obtained which was washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over magnesium sulfate and treated with an ethereal solution of HCl, whereby the desired compound was obtained which was recrystallized from a mixture of methanol and ethyl acetate, m.p.

2hl - 2^2°C, /?E\°H 2h0, E^ 968.

' "max ' limb '

Example 3

2,8-bi s-(h-piperidinobutyryl)-dibenzothiophene

A mixture of 28.0 g (0.072 mol) 2,8-bis-(If-chlorobutyryl)-dibenzothiophene (l)), >+9.4- g (0.58 mol) piperidine and 2.0 g potassium iodide in 200 ml of tetrahydrofuran was heated at 125°C with stirring for 2 hours in a Paar bomb. The reaction mixture was cooled, filtered and the filtrate evaporated in vacuo to give a residue which was washed with water and recrystallized twice from acetone to give the desired compound, m.p. 93 - 95 o C, /\ Etk OH 260,

-in df mon. b

<E>h/0<1>350.

limb Jy

Example k-

2,8-bi s-(■+-(!+-methylpiperidino)-butyryl)-dibenzothiophene

By using the method according to Example 3 but replacing piperidine with 57.2 g (0.58 mol) of n-methylpiperidine and recrystallizing from a mixture of chloroform and acetone, the desired compound is obtained. Sm.p. 136 - 137.5°C /l^aks260' Elcm 128°-

Example 5

2,8-bis(h-(dimethylamino)butyryl)dibenzothiophene dihydrochloride

By using the method according to example 3, but replacing piperidine with 200 ml of a 25 µg aqueous solution of dimethylamine, 2,8-bis(1+-(dimethylamino)butyryl)dibenzothiophene is obtained, which is dissolved in ether and treated with an ethereal solution of HC1 and recrystallized from a mixture of methanol and acetone, whereby the dichloride salt is obtained, m.p. 276 - 277.5°C,

^H2,° 261, E^ 12h0.

'1 max ' limb

Example 6

A mixture of 1^.0 g (0.0^2 mol) of 2,6- and 2,8-bis-(chloroacetyl)-dibenzothiophene (3)) and 100 ml of diethylamine in 150 ml of tetrahydrofuran was refluxed in 2 hours, cooled to room temperature and filtered. The filtrate was evaporated in vacuo and the residue dissolved in ether, treated with the ethereal solution of HCl and recrystallized from a mixture of methanol and ethyl acetate to give a mixture of 2,6- and 2,8-bis-(diethylaminoacetyl)-dibenzothiophene- dihydrochloride dihydrate, m.p. 203 - 207°C, A max 257 > Elim 9h2'

Example 7

A mixture of l<>>+.0 g (0.0^-2 mol) of 2,6- and 2,8-bis-(chloroacetyl)-dibenzothiophene (3 j) and a large excess of dimethylamine in l^0 ml tetrahydrofuran was heated at 65~75Ci20 hours in a Paar reaction bomb, then filtered. The filtrate was evaporated

in vacuo and the residue dissolved in ether and treated with an ethereal solution of HCl, whereby a mixture of 2,6- and 2,8-bis-(dimethylaminoacetyl)-dibenzothiophene dihydrochloride dihydrate was obtained, which was recrystallized from a mixture of methanol and ethyl acetate, 217°C, A Six 2^, 4cm

Example 8

2,8-bis-(dimethylaminoacetyl)-dibenzothiophene dihydrochloride

A mixture of 18.1 g (0.05 mol) of 2,8-bis-(bromoacetyl)-dibenzothiophene (^j) and 25 g (0.57 mol) of dimethylamine in 350 ml of tetrahydrofuran was heated to 60°C for 3 hours. in a stainless steel reaction bomb. Excess amine and solvent were removed in vacuo and the resulting residue dissolved in ether and treated with an ethereal solution of HCl to give the desired compound which was recrystallized from a mixture of methanol and ether. Sm.p.^0°C, A JJ§£s 261, E^m 1236.

Example 9

By following the procedure according to example 8, but replacing dimethylamine with a large excess of diethylamine, 2,8-bis-(2-diethylaminoacetyl)-dibenzothiophene-dihydro-chloride is prepared.

Claims (3)

1. Analogous procedure for the preparation of a compound with an antiviral effect, with the general formula: where each A is branched or unbranched alkylene with 1-6 carbon atoms, and each Y is (A) the group 1 2 , where R and R are each hydrogen, or branched or unbranched alkyl with 1 - h carbon atoms, or (B) the group where n is an integer from ■+ to 6 and R is hydrogen, branched or unbranched alkyl with 1 - m carbon atoms, or (C) the group and acid addition salts thereof, characterized in that (I) a compound of the formula is reacted with an amine of the formula Y-H, where A and Y have the previously given meanings, and Hal is chlorine, bromine or iodine, or (II) to produce a compound of the formula: where z is 3 - 6 and Y can be any of the previously indicated groups with the exception of those having hydrogen attached to the nitrogen atom, a dinitrile of dibenzothiophene of the formula is reacted with a Grignard reagent of the formula where X is "bromine or chlorine, or (III) for the preparation of a compound of the formula: where Y is a secondary amine as previously indicated, a compound of the formula: is reacted with formaldehyde and a compound of the formula Y-H, and if desired, that a base obtained is reacted with a pharmaceutically acceptable acid to a pharmaceutically acceptable acid addition salt. 2. Method according to claim 1 for the production of 2,8-bis-(dimethylaminoacetyl)-dibenzothiophene, characterized in that 2,8-bis-(bromoacetyl)-dibenzothiophene is reacted with dimethylamine. 3. Process according to claim 1 for the production of 2,8-bis-(diethylaminoacetyl)-dibenzothiophene, characterized in that 2,8-bis-(bromoacetyl)-dibenzothiophene is reacted with diethylamine.