IL36644A - Bis-basic ketones of dibenzothiophene - Google Patents

Description

BIS-BASIC KETONES OP DIBENZOIH IOPHSHE iawim.ia» *m O»»O»P-1-T¾ taking The novel bis-baslo ketones of dlbenzothlophene of the present invention have antiviral activity when administered orally and parent-orally* These compounds are represented by the following general formula wherein each A is a straight or branched alkelene chain having from 1 to about 6 carbon atomst and each Y is (A) the group wherein and are individually hydrogen* lower alk l having from 1 to 6 carbfcn atomst or (B) the group wherein B is a whole integer of from ft to 6 and ft is hydrogen, lower alkyl of from 1 to about ft carbon atoms, and can be linked to any one of the carbon atoms of the heterocyclic group| or (c)the group or a pharmaceutically acceptable acid addition salt of said base.

These new compounds can bs prepared byfeeveral different methods which are desoribed* 36644/2 This invention relates to novel bis-basic ketones of dibenzothiophene, their method of preparation and use as antiviral agents. The compounds of this invention include both the base form and pharmaceutically acceptable acid addition salts of the base wherein the base form is represented by the general formula Formula I wherein each A is a straight or branched alkylene chain having from 1 to about 6 carbon atoms; and each Y is R1 (A) the group -N wherein R1 and R2 are individually hydrogen, lower alkyl having from 1 to 6 carbon atoms. 0 The basic ketone groups, that is, -C-A-Y of Formula I can be linked to the tricyclic ring system of dibenzothiophene by replacement of any of the four hydrogens of the benzenoid ring to which such group is attached. Thus, one of the groups can be in any of the positions of 1 through k of the tricyclic ring system, and the other can be in any of the positions 6 through . Preferably, one of the basic ketone groups is in the 2tposition and the other in either the 6- or 8-position of the tricyclic ring system.

It is apparent from the above Formula I and its description that 36644/2 N ,(CH2Jn as more fully shown by the following general Formula III, or wherein Y is the' group' -N 0. as more fully shown by the following general Formula IV, Formula II Formula III In the general Formulas II, III, and IV - the various symbols, that is, A, R1, R2, R3, n, ρ-, tf- and -r- have the meanings given hereinbefore.

. Each of the symbols A in the compounds of the above Formulas II, III, IV, ^and .VI is an alkylene group having from 1 to about 6 carbon atoms s is a whole integer o rom to )t or a ranc e c a n. e .alkylene groups as represented by A can be. the same or different. Preferably these groups are the same. Illustrative of alkylene groups as represented by A there can be mentioned for example: methylene, 1, 2-ethylene, 1,3-propylene, l, -butylene, 1, 5-pentylene, 1,6-hexylene, 2~me hyl-l,½- butylene, 2-ethyl-l, l+-butylene, 3-methyl-l, 5-pentylene and the like.

Each amino group of the compounds of Formula II, that is, can be a primary, a secondary or a tertiary amino group. Each R and R2 is individually hydrogen, lower alkyl having from 1 to about 6 carbon atoms,, Preferably each of the amino groups as represent- ed by -N is a tertiary amino group.

^R2 The term lower alkyl as used in reference to the compounds of Formula II relates to straight or branched alkyl chains having from 1 to 6 carbon atoms. Illustrative of lower alkyls as can be represented by each R1 or R2 in the compounds of Formula II there can be mentioned for example: methyl, ethyl, rt-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, n-amyl, isoamyl, n-hexyl and the like. ach heterocyclic group of Formula III, that is -N (C s)n can be a monocyclic heterocyclic group such as those generally equivalent to di (lower)alkylamino groups in the pharmaceutical arts or substituted monocyclic heterocyclic groups. The heterocyclic groups in the compounds of Formula III can be 5-, 6- or 7-membered rings, that is, n is from k to 6. The R3 group can be hydrogen, a straight or branched lower alkyl chain of from 1 to about k carbon atoms, phenyl, or benzyl and can be attached to any one of the heterocyclic carbon atoms. Illustrative of heterocyclic groups as represented by each there can be mentioned for ex ample: piperidino, pyrrolidino, -methylpiperidino, 3~methy lpiperidino, i+-tert-butylpiperidino, and the like-, -, As example , of f Illustrative of base compounds as represented by Formula I there can be mentioned for example: 2,8-bls (^diethylaminobutyryl)dibenzothiophene, 2, 8-bis (5-diethylaminovaleryl )dibenzothiophene, 2,8-bis (^-aminobutyryl )di- benzothiophene, 2, 8-bis (diethylaminoacetyl)dibenzothiophene, 2, 8-bis (k- ethylaminobutyryl )dibenzothiophene, 3, T"bis ( -diethylarainobutyryl )dibenzo- thiophene, . i. -, 2, 8rbis (3-piperi- dinopropionyl)dibenzothiophene, 2, 6-bis (if-piperidinobutyryl )dibenzothio- phene, 2, 8-bis (5-piperidino-if-methylvaleryl )dibenzothiophene, 2, 8-bis ( -mor- pholinobutyryl)dibenzotMophene, 2,8-bis[ - (U-methylpiperidino)butyryl]di- benzothiophene, 2,8-bis[5- (l,2,3,6-tetrahydropyridino)valeryl]dibenzothio- phene, and the like.

Pharmaceutically acceptable acid addition~saIts oF he base compounds of this invention are those of any suitable inorganic or organic acids. Suitable inorganic acids are for example, hydrochloric, hydrobromic, sulfuric or phosphoric acids and the like. Suitable organic acids are, for example carboxylic acids such as, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic and the like, or sulfonic acids such as^eth ine sulfonic, 2-hydroxyethane sulfonic acid and the like. Mono- or di-acid salts may be formed, and the salts can be hydrated or substantially anhydrous.

A The compounds of the present invention can be administered to animals such as warm-blooded animals and particularly mammals to prevent or inhibit infections of: picornaviruses, for example, encephalomyocarditis; myxo-viruses, for example, Influenza ΑΞ (jap/305 ) ; arboviruses, for example, Semliki Forest; herpesvirus group, for example, herpes simplex; and poxviruses, for example, Vaccinia IHD. When administered prior to infection, that is, prophylactically, it is preferred that the administration be within 0 to 6 hours prior to infection of the animal with pathogenic virus. When administered therapeutically to inhibit an infection, it is preferred that the administration be within a day or two after infection with pathogenic virus.

The dosage administered will be dependent upon the virus for which treatment or prophylaxis is desired, the type of animal involved, its age, health, weight, extent of infection, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. Illustratively, dosage levels of the administered active ingredients can be: intravenous, 0. 1 to about 10 mg/kg; intraperitoneal, 0. 1 to about 50 mg/kg; subcutaneous, 0. 1 to about 250 mg/kg; oral, 0. 1 to about 500 mg/kg and preferably about 1 to 250 mg/kg; intranasal instillation, 0. 1 to about 10 mg/kg; and aerosol, 0. 1 to about 10 mg/kg of animal body weight.

The compounds may be administered, dissolved or suspended, in any conventional- non- toxic pharmaceutical carrier of the type that may be taken orally, applied topically, buccally, internasally or parenterally.

One of the methods used to prepare the compounds of this invention is illustrated by the following reaction: Formula I In this reaction A and Y have the meaning defined hereinbefore, and each Hal is either chlorine, bromine or iodine.

The bis- (tu-haloalkanoyl )dibenzothiophene derivative, 1, in which the position of substitution is 2,6- or 2,8- can be prepared by a Freidel-Crafts acylation of dibenzothiophene. Of suitable acylating agents which may be used there can be mentioned for example: chloroacetyl chloride, bromoacetyl bromide, 3"chloropropionyl chloride, ^-chlorobutyryl chloride, 5-chlorovaleryl chloride, 5-chloro-¾--methylvaleryl chloride, 5~chloro-3~ methylvaleryl chloride and the like.

It is obvious to those skilled in the art that the acylation reaction may be carried out in a variety of solvents and under catalysis of a variety of Lewis acids. The temperature and duration of the reaction may be varied to allow for optimum reaction conditions. A preferred procedure is to combine one equivalent of dibenzothiophene with 2.5 equivalents of an acylating agent in methylene chloride followed by portionwise addition of aluminum chloride. The temperature of the reaction is maintained below zero ( degrees with continuous stirring. After the additions are complete the temperature may be elevated to 25° ~k0° C for 12 to 36 hours. The reaction mixture is worked up in the usual manner by decomposing the complex with ice water/HCl. The product obtained is recrysta¾lized from methylene chloride, chloroform, or the like. The procedure may be varied such that there is a reverse addition of acylating agent and Lewis acid, or a reverse addition of aromatic hydrocarbon and Lewis acid. The more reactive halogen derivative that is, the bis- ((u-iodoalkanoyl)dibenzothiophene^ may be prepared from the corresponding bis-chloro derivative using a halogen exchange reaction under the conditions generally employed in the Conant-Finkelstein reaction.

The major product in the Friedel-Crafts acylation reaction is 2,8-bis- ((£-haloalkanoyl)dibenzothiophene. However, the course of the reaction is such that the major isomer is generally accompanied by significant quantities of other isomeric forms of bis- (tu-haloalkanoyl)dibenzothiophene. By the proper choice of crystallizing solvents these isomers can be separated.

Of amines, 2, useful in the above reaction there can be mentioned for example: ammonia, or a compound which is a potential source of ammonia such as, for example, hexamethylenetetramine and the like; primary amines such as ethylamine, propylamine and the like; and secondary amines such as diethylamine, dibutylamine, piperidine, i)--methylpiperidine, morpholine, 1, 2, 3 > 6~tetra- hydropyridine and the like.

The amination of bis- (u)-haloalkanoyl)dibenzothiophene may be carried out under a variety of conditions. For example, compound 1 may be heated together with a large excess of the amine, 2, the excess amine serving as the reaction medium and the hydrohalide acceptor. This method is particularly suitable for readily available amines, the excess of which can be easily removed from the reaction mixture by, for example, distillation at reduced pressure or by washing the product with water. Or, one equivalent of compound 1 and four equivalents of the amine, 2, may be heated together 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-di-methylacetamide, dimethyl sulfoxide and the like; or mixtures of these solvents with water. The reaction between compound 1 wherein the halogen is CI and the amine, 2, is frequently promoted by the addition of either sodium or potassium iodide, the iodide being used in either catalytic or stoichiometric amounts. In some cases, it may be advantageous to use only two equivalents of the amine, 2, for each equivalent of the bis- (cu-haloalkanoyl)-dibenzothiophene, 1, an excess of an inorganic base such as powdered sodium or potassium carbonate being used as the hydrohalide acceptor. The reaction will proceed normally in 12 to 72 hours at temperatures of 20° to 150°C. As volatile amines are employed, the reaction is best carried out under pressure in a suitable pressure reactor or autoclave.

Alternately, the amination reaction may be carried out on a derivative of compound 1 such as, the bis-ketal dibenzothiophene derivative that may be prepared by allowing bis (uj-haloalkanoyl)dibenzothiophene and an excess of ethyl orthoformate to react in the presence of an acid catalyst such as hydrochloric acid for several days in a polar solvent such as ethanol, tetrahydrofuran and the like.

The compounds of Formula I wherein A is an alkylene chain of 3 to 6 carbon atoms may also be prepared by the reaction of a Grignard reagent with a dinitrile of dibenzothiophene as represented by the following reaction: r In the above reaction X is bromine or chlorine, z is 3 to 6 and Y may be any of the groups defined hereinbefore except those which contain a hydrogen attached to the nitrogen atom.

The reaction will proceed in from 1 to 2h hours at a temperature ranging from room temperature to about 80°C. The Grignard reagent, h, may be prepared by reacting magnesium and an aminoalkyl halide of the formula X(CH2)2Y wherein X, z, and Y have the meaning defined hereinabove. A preferred solvent for this reaction is tetrahydrofuran.

The dicyanodibenzothipphene derivative, , may be prepared from known diamines by a Sandmeyer reaction on the tetrazonium salts or from known dibenzothiophene dicarboxylic acids by dehydration of the corresponding amides by standard procedures.

The compounds of Formula I wherein A is -CH2CH2- and each Y is any secondary amine defined hereinbefore may also be prepared by the Mannich reaction represented by the following reaction: 8 By combining one equivalent of compound 6 and two or more equivalents of compound 2 with three or more equivalents of formaldehyde, 7> the reaction will proceed in from 1 to 2k hours in solvents such as water, acetic acid, ethanol, butanol, dioxane, tetrahydrofuran and the like and at temperatures equivalent to the reflux temperature of the solvent. In this reaction two sources of formaldehyde may be employed. When formalin is used the reaction may be conducted with a suspension of compound 6 or a co-solvent such as methanol may 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 those mentioned above. it is sometimes desirable to add a slight excess of hydrochloric acid to promote depolymerization of paraformaldehyde either during the reaction or at the end of the reaction.

The secondary amine, compound 2, employed in this reaction may be added to the reaction medium as a salt or as the base form with subsequent in situ formation of the salt by the addition of acid. Preferred acids are inorganic acids such as hydrochloric. Of typical secondary amines which may be utilized in the above reaction there can be mentioned for example: dimethyl-amine, dibutylamine, piperidine, -methylpiperidine, morpholine. M othyt i ara Tina ¾ τ-hi u c lo , i .1,] or? tano and the lil¾0i The diacetyldibenzothiophene compound, 6, may be prepared by a i Friedel-Crafts acylation reaction on dibenzothiophene, or by a Grignard reaction of dicyanodibenzothiophene, 3, with methylmagnesium halide. The di- cyanodibenzothiophene compound may be obtained by the methods described here inbefore.

Representative compounds of the present invention and several of the methods of preparing them, mentioned above, are illustrated in the following specific examples.

EXAMPLE 1 2,8-BIS( -CHL0R0BUTYRYL)DIBENZ0THI0PHENE To a solution of 200 g (1.09 moles) of dibenzothiophene and 38Ο g (2.7 moles) of 4-chlorobutyryl chloride in 2 1 of methylene chloride previously cooled to 0° C, was added portionwise 36Ο g (2.7 moles) of aluminum chloride with stirring. Stirring was continued at room temperature for 2k hours after which the reaction mixture was decomposed with ice water and hydrochloric acid. The methylene chloride was removed and the crude pro duct was recrystallized from chloroform-acetone to give the desired product. M.p. I3 ^l-l33°c,' xmCHaxCl3 263^, E1cm 1700.

EXAMPLE 2 2.6-BIS ( -CHLOROBUTYRYL)DIBENZOTHIOPHENE Following the procedure of Example 1 only recrystallizing the crude product from chloroform gave the desired product. M. P. 1 T-1U8.5°C, XCHC13 6 ∑l n max 1cm EXAMPLE Following the procedure of Example 1, only substituting for -chlorobutyryl chloride, chloroacetyl chloride, yields a mixture of 2,6-and 2,8-bis (chloroacetyl)dibenzothiophene which was recrystallized from dimethylformamide-methanol. M.P. 210-212° C.

EXAMPLE k 3. -DICYANODIBENZOTHIOPHENE etf al. J. Am. Che . Soc. dissolved Jn dilu - hy . ·· acid and cooled to & C waa added 2.2 equivalents of .sodium nitr'ie, the mixture was cautiously neutralized wi h sodium carbonate. .-The was added portionwise to a cold solution of . 5 equivalents of cuprou cyanide with' stirring to give the desired product which was purifi recrystallization from a dimothylformamide-water combination.

EXAMPLE 5 2, 8-DICYANODIBENZOTHIOPHENE To a mixture of one equivalent of 2, 8-dibenzothi ophenedi ylic acid, prepared by a Friedel-Grafts reaction between dibenzc thi.-and oxalyl chloride, and 2. 2 equivalents of £-toluenesulfonamide was if.5 equivalents of phosphorous pentachloride. After the initial r ac'. had subsided the reaction mixture was heated to 200 ° C to remove ti e. tile secondary products. The solid residue remaining was cooled anci .. with pyridine and water. The suspension was filtered, washed with >.·.■<;· suspended in a dilute sodium hydroxide solution followed by filtratm. washing with water to give 2, 8-dicyanodibenzothiophene which can be rt tallized from a dime thyIformamide-wa er combination. In like manne." . cyanodibenzothiophene can be prepared.

EXAMPLE 6 2, 8-BIS (S- ffl.OROVALERYrODIBEHZOTHIOPHENE A mixture of 26. 1 g (θ.1^ mole) of dibenzothiophe.ne ana (0.35*4- mole) of |5-chlorovaleryl chloride in 1500 ml of methylene C' was chilled to -20° C, and 29.8 g (0.2 8 mole) of aluminum chloride ;.. added with rapid stirring. Stirring was continued for Ik hours at TOO temperature, then the reaction mixture was, poured onto a mixture of a.; HCl, and the organic layer which separated was washed with a satura. J bicarbonate solution, dried over magnesium sulfate and filtered. The: trate. was evaporated to dryness leaving a residue which was rccn's L c, 1 from ethyl acetate to yield th desired product.

EXAMPLE 7 · g,8-BIS(5-CH )RO-^-METttYI.VALERYl,)))inr: ZQTIlIOPIIE E By the method of Example 1, only substituting for Ί-chloro-butyryl chloride, the appropriate molar equivalent amount of 5"c 1oro-^-methylvaleryl chloride, which can be prepared by treating p-methyl-6-valero-lactone with thionyl chloride and anhydrous zinc chloride [0. Wheeler and E. de Rodriquez, J. Org. Chera. 29., 1227 (16 )] the desired product is obtained.

EXAMPLE 8 2,8-BIS (5-CHLORO- -METHYLVAI-ERYL)DIBEHZOTHIOPHENE BIS-DIETHYL KETAL ' A mixture, of k2.1 g (0/12 mole) of 2,8-bis(5-chloro-j5-methylval-eryl)dibenzothiophene, 95·0 g (0.6- mole) of ethyl ojrthofonnate and 10 ml of ethanolic HCl in 800 ml of tetrahydrofuran was stirred at room temperature, for 5 days. Following neutralization of the excess acid, the solution was poured into 2.0 1 of cold water, and washed with water, dried and the solvent evaporated to give the amber viscous oily product.

EXAMPLE 9 2,6-BIS( -PIPERIDINOBUTYRYT,)DIBE ZOTHIOPHENE A mixture of 1^.0 g (Ο.Ο36 mole) of 2,6-bis (If-chlorobutyryl )-dibenzothiophene, 2h.T g (0.29 mole) of piperidine and 12.0 g (0.072 mole) of potassium iodide in 3 0 ml of butanone was refluxed for three days cfter which the reaction mixture was cooled and diluted with 1000 ml of w The solid whijch precipitated was filtered, washed with water and recr s-tallized from chloroform-acetone to give the desired product. M.P. 10 -108°C, CHCI3 6 1* K max ^ ' 1cm EXAMPLE ' 10 2.8-BIS(4-M0RPHOLINOBUTYRYL) PIBENZ0TKI0PHEKE DIHYDROCHLORIDE A solution of 20 g (0.05 mole) of 2,8-bis(>+-chlorobutyryl )-dibenzothiophene, J2 g (0.J2 mole) of morpholinc and 2.0 g of poiasKiu., iodide in 500 ml of -dioxane v/as refluxed for 2 hours after which th<\ re semi-solid which was washed with water and di.KSol.vcd in methylene chloride^ The methylene chloride, solution was washed with water, dried over magnesium s A mixture of 28.0 g (0.0T2 mole) of 2,8-bis( -chlorobutyryl )-dibenzothiophene, k$. k g (Ο.58 mole) of piperidine and 2.0 g of potassium iodide in 200 ml of tetrahydrofuran was heated at 125° C with sitrring for 2k hours in a Paar general purpose'bomb. The reaction mixture was cooled, then filtered, and the filtrate was evaporated in vacuo leaving a residue which was washed with water and recrystallized twice from acetone to give the desired product. M.P. 3- 5° C.

EXAMPLE 12 . 2.8-BIS Ik" (^-HETHYLPIPE IDINO) BDTYRYL] DIBENZOTHIOPHENE Fojllowing the procedure of Example 11 , but substituting for piperidine, 5J.k2 g (Ο.58 mole) ^-methylpiperidine and rec.rystallizing from chloroform-acetone the desired product was obtained. M.P. I36- lj$7. 5° c» XEt0H 26Ο, E}* 1280. . max ' 1cm 1 EXAMPLE 1¾ 2,8-BIS [k- (DIHETHYLAMINO)BUTYRYL] DIBENZOTHIOPHENE PIHYDROCHLORIDE Following the procedure of Example 11 , only substituting for piperidine 200 ml of 25$ aqueous solution of dimethylamine, yields , 8-bis [k- (dimethylamino)butyryl]dibenzothiophene which was dissolved in oLher, treated witli ethereal- HCl and recrystallizcd from methanol-acetone to give the dihydrochloride salt. M.P. 276-277 - 5° C, EXAMPLE lk - A mixture of }k.O g (0. 0'n2 mole) of 2,6- and ;_*, 8-bj (chloro-acetyl )dibenzothiophene and 100 ml of die h lamine in ml o f iv. tr.'i hyd ro-furan was ref luxed for 2 hours then cooled to room temper.-iture nd £ J t._red. ! · '■ · : ' ' . » · in ether, treated with ethereal HCl · aud c ystal J ized from methanol -ethyl acetate to give a mixture', of 2, 6- and 8~bi.¾ (liothylamiuoacety 1 Jdibunzo- thiophene dihydrochloride dihydrate. M. P . 203-207° C, λ^°Π 257, EJJ ^2.

EXAMPLE I ¾.7-BIS( - PIPE IDINOBU rYRYL ) DIJ3EN?.OrHIOP'HEHR DIHYDROCHLORIDE ' 1 To a solution of 2. 5 equivalents of ^-piperidinopropylmagnesiutnl chloride, prepared from magnesium and 3"Piperidinrtpropyl chloride in tetra-hydrofuran, was added dropwise a solution of 1 equivalent of 3,7-dit ano-dibenzothiophene dissolved in tetrahydrofuran. After the addition was complete the reaction mixture was gently refluxed for 2 hours and stirred at room temperature for an additional hours. The Grignard complex was decomposed by treating the reaction mixture with saturated ammonium chloride until the precipitation of magnesium salt was complete. The mixture was filterjed and the filtrate concentrated in vacuo. The residue was dissolved in dilute hydrochloric acid with warming then filtered. The aqueous solution was made alkaline and extracted with several portions of ether. The ether layers were combined, dried oven; magnesium sulfate and treated with ethereal HCl to yield the desired product which was purified by recrystallization from methanol-ethyl acetate.

I .EXAMPLE 16 Following the procedure of Example I , only substituting for 3i7~dicyanodibenzothiophene the appropriate molar equivalent amounts of 2, 6-or 2, 8-dicyanodibcnzothiophene the following compounds are prepared: 2, -Bis ( -piperidinobutyryl)dibenzothiophene dihydrochloride 2, 8-Bis (k-piperidinobu yry 1 )dibenzothiophene dihydrochloride.

EXAMPLE 17 A mixture of lJ+.O g (0.0'i2 mole) of 2, 6- and 2, 8-bis (chloro-acetyl )diben othiophene and a large excess of liniethylamina in I O ;r,j of tetrahydrofuran was heated at 6 -75° C for 20 hours in a Paar reaction bomb then filtered. The filtrate 'was evaporated in vacuo leaving- a residue which Following the procedure of Example 17» only substituting for dimethylamine a large excess of piperidine a mixture of 2,6- and 2,8-bis- (piperidinoacetyl)dibenzothiophene dihydrochloride was obtained.

EXAMPLE 19 2.8-ΒΙ5( -ΡΙΒυΤΥΙ,ΑΜΙΝ0νΑίΕ ^)ΡΙΒΕΝΖ0ΤΗΙ0ΡΗΕ Ε A mixture of 31.1 g (0.0†^ mole) of 2,8-bis (5-chlorovaleryl )-dibenzothiophene, 150 ml. of dibutylamine, 2.0 g of potassium iodide; and 100 mj of tetrahydrofuran was heated in a Paar bomb at 120° C for 20 hours. The volume of the reaction mixture was concentrated to 100 ml, and 600 ml of water was added. The resulting precipitate was filtered to give the de , 1 sired product which was recrystallized from ether-acetone.

EXAMPLE 20 , ' 2.6-BIS( -PIPERIDINOBUTYRYL)DIBEN20miOPHE E BIS-DIHYDROGEN CITRATE i By the procedure of Example 9» 2,6-bis ( -piperidinobutyryl)-dibenzothlophene was prepared and treated with 2 equivalents of citric aci in hot butanone to give the desired product which -was recrystallized from methanol-butanone.

' EXAMPLE 1 Following the procedure of Example 11 only substituting for piperidine the appropriate molar equivalent amounts of 3~azabicyclof3.2.2] nonane, 1,2,3,6-tetrahydropyridine, Nr-methylpiperazino, l-phenylpiperidine N-methylcyclohexylamine or d allylamine, the following compounds are prepared : 2, 8-Bis [h- (j-azabicycLo'fj .2.2] nonan-J-yl )butyry1]dibenzothiophene 2,8-Bis [b- (1, , 3, 6 tetrahydro-1-pyridyl )butyryl]dibenzothiophene 2,8-Bis [h- (N-mebnylpiperazino)butyryl]dibenzothiophene 2, 8-Bis [h- (' phenylpiperidino)butyryl] dibGnzothiopliene 2,8-Bis [k {N-me hylcyclohexylami no)butyryI ]dibenzothiophene EXAMPLE ae 21 2, 8-BIS (5-AMINO-^-METHYLVALERYL)DIBENZOTHIOPHENE DIHYDROCHLORIDE An ethanolic solution of 1 equivalent of 2,8-bis (5~chloro-3-methylvaleryl)dibenzothiophene bis-diethyl ketal and 2.k equivalents of hex-amethylenetetramine were reacted at reflux for 8 hours. The reaction mixture was acidified with HCl, digested for several hours and the solvent removed under reduced pressure to give the desired product which was purified by recrystallization from methanol-eth l acetate.

EXAMPLE 22 2,8-BIS(5~ETHYLAMINO- 5~METHYLVALERYL)PIBENZOTHIOPHENE DIHYDROCHLORIDE Following the procedure of Example 22, only substituting for hexamethylenetetramine, a hundred fold excess of ethylamine, the desired product is qbtained.

EXAMPLE e*r 23 2,8-BIS (5-PIPERIDIN0PR0PI0NYL)DIBENZ0THI0PHENE DIHYDROCHLORIDE A solution of l^.k g (0.05 mole) of 2, 8-diacetyldibenzothiophene, .5 g (O. I5 mole) of paraformaldehyde and 12.2 g (O.l mole) of piperidine hydrochloride in 200 ml of butanol was refluxed for 5 hours. The crude product which crystallized on cooling was purified by recrystallization from methanol-ethyl acetate to give the desired product.

EXAMPLE g?2 2,8-BIS (BROMOACETYL)DIBENZQTHIOPHENE To a solution of 5. 0 g (0. 019 mole) of 2,8-diacetyldibenzothiophene in 200 ml of chloroform was added dropwise 6. 1 g (Ο.Ο38 mole) of bromine in 25 nil of chloroform with stirring under gentle reflux. After refluxing for an additional hour the reaction mixture was cooled and the desired product filtered and crystallized from acetic acid. M. P. I87~l8s C (dec).

EXAMPLE g& 25 2.6-BIS(BROMOACETYL)DIBENZOTHIOPHENE 2k Following the procedure of Ex mple^, only substituting for 2, 8-diacetyldibenzothiophene, 5 - 0 g (0.019 mole) of 2, 6-diacetyldibenzo-thiophene, the desired product was obtained.

EXAMPLE 8¾ 26 , 8-BIS (DIMETHYLAMINOACETYL)DIBENZOTHIOPHE E DIHYDROCHLORIDE A mixture of 18.4 g (0.05 mole) of 2, 8-bis (bromoacetyl)diben-zothiophene and 25 g (0.57 mole) of dimethylamine in 35Ο ml of tetrahydro-furan was heated at 60° C for 3 hours in a stainless steel reaction bomb.

The excess amine and solvent were then removed in vacuo, and the resulting residue was dissolved in ether and treated with ethereal HCl to give the desired product which was recrystallized from methanol-ether. M. P. >340°C, λΗ2° 261, E^ 1236. max 1cm EXAMPLE - 27 26 Following the procedure of Example only substituting for dimethylamine, a large excess of diethylamine or piperidine the following compounds were prepared: 2,8-Bis (2-diethylaminoacetyl)dibenzothiophene dihydrochloride 2, 8-Bis (2-piperidinoacetyl)dibenzothiophene dihydrochloride.

EXAMPLE age 28 2,6-BIS (DIMETHYLAMINOACETYL)DIBENZOTHIOPHE E DIHYDROCHLORIDE 26 Following the procedure of Example only substituting for 2, 8-bis(bromoacetyl)dibenzothiophene, 18 g (0.05 mole) of 2, 6-bis (bromo-acetyl)dibenzothiophene, the desired product is obtained.

EXAMPLE y¾ 9 26 Following the procedure of Example <£Jf, only substituting for 2, 8-bis (bromoacetyl)dibenzothiophene, 18.4 g (0.05 mole) of 2, 6-bis (bromo-acetyl)dibenzothiophene and substituting for dimethylamine 41.6 g (Ο.57 mole) of diethylamine or 48.4 g (Ο.57 mole) of piperidine, the following respective compounds were prepared.' ,6-Bis (diethylaminoacetyl )dibenzothiophene dihydrochloride , 6-Bis (piperidinoacetyl )dibenzothiophene dihydrochloride .

Claims (7)

VHAT IS CLAIMED IS:

1. Λ compound selected from a base of the formula wherein each A is a straight or branched alkylene chain having from 1 to about 6 carbon atoms; and each Y is a member selected from the group consisting of (A) the group wherein R1 and R- are individually hydrogen, lower alkyl having from 1 to h carbon atoms, (B) the group -N (CH2)n wherein n is a whole integer of from h to 6 and R3 is hydrogen, lower alkyl of from 1 to about k carbon atoms, and can be linked to my one of the carbon atoms of the heterocyclic group; or (C) the group -N υ , -.-.

2. A compound of claim 1 wherein one of said ~OA-Y groups 0 is in the 2-position of the dibenzothiophene ring and the remaining -C-A group is in either 6- or 8-position of the dibenaothiophene ring. ,RJ J.

3. A compound of claim 2 wherein each Y is the group -N ^R2 k.

4. A compound of claim 3 wherein A is a lowe alkylcne chain having from 1 to h carbon atoms, and each R¾ and Rs is lower alkyl.

5. · A compound of claim 2 wherein each Y is the group

6. A compound of claim 5 wherein each A is a lo er alkylene chain having from 1 to it- carbon atoms, and each n is the integer 5-

7. A compound of claim 2 wherein each Y is the group -N ° TO —ΤΓΰϋΠΐροΛΙΙΚΐ Of Claim Wherein ¥ is the group 8^¾ri. A compound of claim 1 which is 2,6-bis (dimethylaminoacetyl)- dibenzothioptiene or a pharmaceutically acceptable acid addition salt thereof. 9.t5". A compound of claim 1 which is 2, 8-bis (dimethylaminoace- tyl)dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof. 19· .4*3. A compound of claim 1 which is 2,6-bis (diethylaminoace- tyl)dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof. ^«-ΛΤ A compound of claim 1 which is 2, 8-bis (diethylaminoacetyl)- dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof. ^•15C A compound of claim 1 which is 2,6-bis (piperidinoacetyl)- dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof. "^·*6". A compound of claim 1 which is 2,8-bis(piperidinoacetyl)- dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof. Vf. A compound of claim 1 which is 2,8-bis (^-piperidinobutyryl)- dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof. *S8'. A compound of claim 1 which is 2,8-bis[k-(¾--methylpiperi- dino)butyryl] dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof. "^r^: A compound of claim 1 which is 2,8-bis ( -morpholinobutyryl)- dibenzothiophene or a pharmaceutically acceptable acid addition Salt thereof. A compound of claim 1 which is 2,8-bis (^-dimethylamino- butyryl)dibenzothiophene or a pharmaceutically acceptable acid addition salt thereof. 36644/2 RMI ia« A process for the preparation of a compound selected from a bar.e of the formula wherein each A is a straight or branched alkylene chain having from 1 to about 6 carbon atoms; and each Y is a member selected from the croup consisting of (A) the group wherein Rl and Ra are individually hydrogen, lower alkyl having from 1 to carbon atoms, (B) the group is a whole integer of from 4 to 6 and R is hydrogen, lower alkyl of from 1 to about 4 carbon atoms, and can be linked to any one of the carbon atoms of the heterocyclic group; (C) or a pharmaceutically acceptable acid addition salt of said base which comprises a process selected from RMI 623-M (I) reacting a compound of the formula with an amine, Y-H, wherein A and Y have the meaning defined hereinbefore, and Hal is selected from chlorine, bromine or iodine; (il) when A is an alkylene chain of 3 to 6 carbon atoms, reacting a dinitrile of dlbenzothlophene of the formula with a Grignard reagent of the formula XMg(CHa)zY to produce a compound of the formula wherein X is bromine or chlorine, z is 3 to 6 and Y may be as first defined except those groups which contain a hydrogen attached to the nitrogen atom; (ill) when A is -CHaCHa- and each Y is a secondary amine as first defined hereinbefore, reacting a compound of the formula with formaldehyde and a compound of the formula Y-H to produce a compound of the formula RMI 623-M wherein Y is a secondary amine as first defined hereinbefore; and (IV) whenever the pharmaceutically acceptable acid addition salt is desired, reacting the base compound of the formula with a pharmaceutically acceptable acid, wherein A and Y are as first defined hereinbefore. COHEN ZEDE & SPISBACH P.0. Box 33116 , Tel-Aviv Attorneys for Applicant - 27