BE829075A - 9,10-DIHYDROANTHRACEN-9,10-IMINES SUBSTITUTES AND THEIR HETEROCYCLIC ANALOGUES (AZA) - Google Patents

Description

       

   <EMI ID = 1.1>

  
substituted and their heterocyclic analogues

(AZA).

  
 <EMI ID = 2.1>

  
The present invention relates to certain substituted 9,10-dihydro-anthracen-9,10-imines and their heterocyclic analogs (aza) as well as their pharmaceutically acceptable salts, esters and amides derivatives which are useful as minor tranquilizers, anticonvulsants, blood release agents. muscles and in the treatment of extrapyramidal disorders such as Parkinson's disease. For reasons of convenience, the compounds according to the invention will be called hereinafter "anthracén- <EMI ID = 3.1>

  
The present invention also relates to methods for the preparation of these anthracenimines, to pharmaceutical compositions comprising such compounds and to methods of treatment comprising the administration of these compounds and compositions.

  
The compounds according to the invention can be represented generically by the following structural formula:

  

 <EMI ID = 4.1>


  
in which

  
 <EMI ID = 5.1>

  
alkoxycarbonyl, aralkyl, alkenyl, dialkyllaminoalkyl, hydroxyalkyl, alkynyl, trialkylsilyl, alkylcycloalkyl or cycloalkyl;

  
 <EMI ID = 6.1>

  
and the alkyl, haloalkyl, aralkyl, aryl, alk-

  
 <EMI ID = 7.1>

  
X and Y are independently selected from halogens such as chlorine, fluorine, bromine and iodine and groups

  
 <EMI ID = 8.1> alkylthio-, allyl, aralkyl, cycloalkyl, aroyl, aralkoxy, alkanoyl, aryl, substituted aryl, alcoylthio, alcoylsulfonyle,

  
 <EMI ID = 9.1>

  
carbamoyl, nitro and dialkylsulfamoyl;

  
n is an integer selected from 0 (X or Y is hydrogen, respectively), 1, 2, 3 or 3;

  

 <EMI ID = 10.1>


  
represents a heterocyclic or hetero-

  
unsaturated polycyclic in which the heteroatom (s),

  
 <EMI ID = 11.1>

  
where the symbol represents the benzo portion.

  
 <EMI ID = 12.1>

  
above), the preferred embodiments are those in which:

  
R1 and R2 are independently selected from hydrogen and lower alkyl groups having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms and dialkoylaminoalkyl having 3 to 15 carbon atoms;

  
R is hydrogen or a lower alkyl group having 1 to 6 carbon atoms, a lower hydroxy alkyl group having 1 to 6 carbon atoms, alkenyl having

  
2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkylcycloalkyl having 4 to 10 carbon atoms, benzyl (and benzyl substituted at the ring by X and R), lower alkoxy carbonyl having 2 to 7 atoms carbon or dialkylaminoalkyl having 3 to 15 carbon atoms;

  
Y and X are independently selected from lower alkyl groups having from 1 to 6 carbon atoms, halogens (fluorine, chlorine, bromine, iodine), lower alkoxy groups having from 1 to 6 carbon atoms, halo-alkoxy groups

  
 <EMI ID = 13.1>

  
lower having from 1 to 6 carbon, cyano, carboxy, haloalkylthio, alkylthio, haloalkylsulfonyl and carboxamido atoms;

  
n is an integer selected from 0 (X or Y is hydrogen, respectively), 1 or 2;

  

 <EMI ID = 14.1>


  
Particularly preferred embodiments of the present invention are those in which:

  

 <EMI ID = 15.1>


  
 <EMI ID = 16.1>

  
lower alkenyl such as vinyl, etc., lower alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, etc., trifluoromethyl, di-lower alkyl-amino, lower alkyl, such as dimethylaminopropyl, etc;

  
R is hydrogen, benzyl or substituted benzyl, lower alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, etc., cyclopropyl, cyclobutyl

  
 <EMI ID = 17.1>

  
aminopropyl, etc; <EMI ID = 18.1>

  
X and Y are chlorine, bromine, iodine, lower alkoxy group having 1 to 6 carbon atoms, lower alkyl having 1 to 6 carbon atoms, cyano, carboxy, carboxamido, trifluoromethoxy, trifluoromethyl, trifluoromethylsulfonyl , lower alkyl-thio such as methylthio, etc., and trifluoromethylthio;

  
n is an integer selected from 0 (X or Y is hydrogen, respectively), 1 or 2.

  
In general, the anthracenimines of the present invention are prepared by reacting an appropriately substituted hetaryne ("benzyne" in the case of the benzo substituent) with an appropriately substituted isoindole, Ia, according to the following reaction:

  

 <EMI ID = 19.1>


  
where all of the substituents are as defined above.

  
In practice, the hetaryne or benzyne reactant (hereinafter collectively referred to as "benzyne" for convenience) is produced in situ under conditions compatible with the final Diels-Alder condensation with isoindole. The preparation of these reactants and the operating conditions for the final preparation of the anthracenimines of the present invention are described below.

  
Preparation of isoindoles

  
Many of the isoindoles useful in the preparation of the anthracenimines of the present invention are known and readily available. Alternatively, such isoindoles can be readily prepared by reacting an ortho-disubstituted benzene with a halogenating agent, such as N-bromo-succinimide (BNS), followed by reaction of the product a, a'- dihalogen re-

  
 <EMI ID = 20.1>

  
the product with a base, we obtain the desired isoindole (Ia):

  

 <EMI ID = 21.1>


  
where all of the substituents are as defined above.

  
Typically, the halogenation step in the preparation of isoindole is carried out in the presence of an initiator such as benzoyl peroxide, etc., under ultraviolet irradiation. There is no critical requirement as to reaction temperature, solvent system or base used in the final step. Solvents which can be used for the reaction are, for example, hydrocarbons such as hexane, benzene, etc., and halohydrocarbons such as carbon tetrachloride, chlorobenzene, etc. Typically, the reaction temperature is between about 25 [deg.] C and the reflux temperature; the non-critical base can be chosen from sodium hydroxide, potassium hydroxide, potassium carbonate, etc.

  
Another method for preparing suitably substituted isoindoles is shown in the following scheme:

  

 <EMI ID = 22.1>


  
 <EMI ID = 23.1>

  
any lower alkyl portion such as methyl, ethyl, propyl, etc. According to the above process, o-acylbenzoic acid is first hydrogenated to reduce the carbonyl group by conventional procedures such as by hydrogenation over Pd / C in aqueous sodium hydroxide solution; then, the free carboxy group is esterified by treatment with diazomethane, sulfuric acid in methanol or HCl in ethanol or by other normal techniques. Halogenation of the resulting substituted benzoic acid ester affords the α-halogenated intermediate product illustrated above. The halogenation can be carried out, for example, by

  
 <EMI ID = 24.1>

  
ment of the α-halogenated intermediate product with the primary amine,

  
 <EMI ID = 25.1>

  
ether, THF or another polar organic solvent gives the

  
 <EMI ID = 26.1>

  
in ether, benzene, THF or another non-participating organic solvent heated to reflux or with a Grignard reagent,

  
 <EMI ID = 27.1> iodine) in anisol, THF, glyme or butyl oxide heated to reflux gives the desired isoindole (Ia). As regards the process which has just been illustrated, the esterification step can be eliminated according to the following scheme:

  

 <EMI ID = 28.1>


  
where the phthalimidine intermediate is obtained directly. by treating ortho-acylbenzoic acid with the primary amine,

  
 <EMI ID = 29.1>

  
uses polar aprotic solvents like acetonitrile,

  
 <EMI ID = 30.1>

  
there are no strict requirements as to reaction temperature, reaction time and the ratio of reactants; however, the following conditions are typically used when using the aprotic system:
the primary amine, in the form of an equimolar mixture of the free base and its acid addition salt, is present in

  
 <EMI ID = 31.1>

  
Another method of preparing Ia involves the treatment

  
 <EMI ID = 32.1>

  
 <EMI ID = 33.1>

  
according to the following reaction scheme (all symbols are as defined previously):

  

 <EMI ID = 34.1>


  
 <EMI ID = 35.1>

  
of hydrogen involves the treatment of phthalic anhydride

  
 <EMI ID = 36.1>

  
diary phthalimide which, on reduction with, for example, zinc powder in glacial acetic acid, gives phthalimidine which, upon treatment with a lithium-alkyl suitable

  
 <EMI ID = 37.1>

  
desired according to the following diagram:

  

 <EMI ID = 38.1>


  
Yet another process for preparing Ia, especially

  
 <EMI ID = 39.1>

  
of isoindole carries a substituent releasing electrons <EMI ID = 40.1>

  
pos of X and Y above), such as an alkyl group, halogen, etc., involves the Friedel-Crafts alkylation of a ben-

  
 <EMI ID = 41.1>

  
process:

  

 <EMI ID = 42.1>


  
The immediate Friedel-Crafts product spontaneously cyclizes to form the intermediate product phthalimidine which may be. N-alkylated by treatment with RI in the presence of a reducing agent

  
 <EMI ID = 43.1>

  
 <EMI ID = 44.1>

  
zene. The resulting N-substituted phthalimidine by treatment with an appropriate lithium alkyl (LiR) or a reagent

  
 <EMI ID = 45.1>

  
 <EMI ID = 46.1>

  
position X:

  

 <EMI ID = 47.1>


  
Friedel-Crafts reagents which can be used for the reaction

  
 <EMI ID = 48.1>

  
Preferred Friedel-Crafts is concentrated H2S04. Typically, the reaction is carried out without a solvent or in solvents such as H2SO4 and the like at a temperature of

  
 <EMI ID = 49.1>

  
It will be obvious to those skilled in the art that the methods described above can be used individually or that they can be combined in the most convenient manner for the synthesis of the isoindoles necessary = for the preparation of the anthracenimines herein. invention.

  
Preparation of "benzynes"

  
The benzyne intermediate reactant (defined herein to include both carbon-ringed and heterocyclic compounds) can be prepared by a variety of means including flash photolysis of a ring-substituted aromatic cyclic compound such as benzene or pyridine or by treatment of an ortho-dihalogenated or mono-halogenated aromatic cyclic compound with a strong base:

  

 <EMI ID = 50.1>


  
For the purposes of the present invention, it is preferred that the benzyne illustrated above be produced in situ for immediate Diels-Alder condensation with isoindole, Ia. The following equation representatively illustrates this reaction for the preferred benzo embodiments:

  

 <EMI ID = 51.1>
 

  
Suitable bases for the above reaction can be selected from alkali and alkaline earth metals and their oxides, hydrated oxides, alcoholates, alkali metal amides, metal alkyls derived from alkali metals, etc. Particularly preferred bases are metallic magnesium and metal alkyls such as methyllithium,

  
butyllithium, phenyllithium, potassium tert-butoxide and alkali metal amides such as lithium, diisopropylamide, lithium-2,2,6,6-tetramethylpiperidine, sodium amide, etc. There is no strict requirement as to the identity of the reaction solvent and suitable solvents can be selected from hydrocarbons, such as benzene, hexane, cyclohexane, etc., oxygenated solvents such as ether, dioxane, tetrahydrofuran, anisol, etc. Typically, the reaction is carried out between about -70 [deg.] C. and reflux temperature.

  
A second process for the preparation of the anthracenimines of the present invention involves the Diels-Alder condensation of a substituted 1,5-butadiene and a naphthalenimine followed by aromatization of the newly formed hexagonal ring.

  
 <EMI ID = 52.1>

  
intermediate product brominated with a base such as triethylamine:

  

 <EMI ID = 53.1>
 

  
where all of the substituents are as defined above.

  
 <EMI ID = 54.1>

  
substituted) are described in U.S. Patent Application No. [deg.] 498,485 filed August 19, 1974 which is incorporated herein by reference. Typically no solvent is needed for the Diels-Alder reaction of the first step, but solvents usable for this step include THF, p-dichlorobenzene, toluene, etc., at a reaction temperature of 25 [deg.] C approximately and the reflux temperature or at a higher temperature when the reaction is carried out under pressure. The bromine addition reaction can be carried out in sol-

  
 <EMI ID = 55.1>

  
zene, etc. The final elimination reaction is typically carried out in solvents such as benzene or THF in the presence

  
 <EMI ID = 56.1>

  
Finally, the anthracenimines of the present invention can be prepared by derivatization operations on the anthracenimine base nucleus to obtain certain embodiments of the present invention. The following reaction illustrates this process; the benzo embodiment is shown; however, the following procedures apply to all embodiments of the present invention:

  

 <EMI ID = 57.1>


  
or for purposes of illustration the benzoid rings are shown to be substituted only by the group leaving L; however, it is not essential or even preferred that L be the sole substituent on the benzoic ring for this aspect of the invention. L can be any chemically modifiable group such as amino, hydroxy, bromo, iodo, chloro, etc., which can be transferred to the X function by known techniques. X is as defined above and, especially for this aspect of the invention, embraces radicals such as cyano, trifluoromethylthio, methylthio, etc. Solvents useful for this process aspect of the invention include dimethylformamide, hexamethyl-

  
 <EMI ID = 58.1>

  
The reaction is carried out between about 25 [deg.] C and the reflux temperature.

  
Other derivative-forming reactions which do not have critical reaction parameters and which are representatively illustrated by the following examples include: N-alkylation; N-acylation and reduction; . N-alkylation by reduction; and electrophilic substitution on benzoid rings.

  
Also included within the general scope of this

  
 <EMI ID = 59.1>

  
salts, esters and amides of I. Acid addition salts are preferred. Such acid addition salts of anthracenimines are formed by mixing a solution of anthracenimines with

  
 <EMI ID = 60.1>

  
such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid and acids of the same kind.

  
In the method of treatment aspect of the present invention, the present anthracenimines used as minor tranquilizers are able to provide relief from anxiety without causing excessive sedation or sleep at unit dosage levels between 0.1 and 500. mg approximately

  
per kg of body weight or in daily doses of between approximately 0.4 and 2,000 mg per kg of body weight. Additionally, the anthracenimines of the present invention are useful as muscle relaxers, anti-convulsants, and in the treatment of extra-pyramidal disorders when indicated at comparable dosage levels. Obviously, it will be understood that the exact level of treatment will depend on the case history of the animal or human individual being treated and ultimately ana- <EMI ID = 61.1>

  
lines given above, is left to the discretion of the attending physician.

  
Also included within the general scope of the present invention are pharmaceutical compositions comprising these anthracenimines. Preferably, these compositions are in unit dosage forms such as tablets, pills, parenteral solutions, etc. For the preparation of solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, i.e. conventional tablet forming ingredients such as corn starch, lactose, sucrose, sugar. sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other pharmaceutical diluents, for example water, to form a solid composition

  
 <EMI ID = 62.1>

  
imine of the present invention, or a non-toxic, pharmaceutically acceptable derivative of the salt, ester or amide type. This solid preformulation composition is then subdivided to give unit dosage forms of the type described above containing from about 0.1 to 500 mg of the active ingredient of the present invention. Tablets or pills of the new composition can be coated or otherwise mixed so as to obtain a dosage form having the advantage of prolonged action of the present anthracenimines.

  
Liquid forms into which the novel composition of the present invention can be incorporated for oral administration or by injection include aqueous solutions, conveniently flavored syrups, aqueous or oily suspensions.

  
The anthracenimine-based pharmaceutical compositions according to the invention can be administered orally, parenterally or rectally. Orally, they can be administered in the form of tablets, capsules, suspensions or syrups, the preferred dosage form being a tablet containing from about 0.1 to 500 mg of the active ingredient. The optimal dosage obviously depends on the dosage form used. In any particular case, as mentioned previously, the doses <EMI ID = 63.1>

  
 <EMI ID = 64.1>

  
longed for.

  
The following non-limiting examples illustrate product aspects, processes, treatment methods or compositions of the present invention.

Example 1a

  
2,3-dimethylphthalimidine

  
 <EMI ID = 65.1>

  
benzoic acid in 25 cm <3> dp absolute methanol is treated with pre-

  
 <EMI ID = 66.1>

  
at reflux. After 1: - hours, the mixture is poured onto ice and the hay product is extracted into ether. Evaporating the washed extract (water, 5% aqueous solution of sodium bicarbonate and water) and dried under reduced pressure leaves methyl 2-ethylbenzoate as residual colorless oil.

  
 <EMI ID = 67.1>

  
A mixture of 10.7 g (0.065 mole) of methyl 2-ethylbenzoate, 12.5 g (0.07 mole) of N-bromosuccinimide,

  
 <EMI ID = 68.1>

  
of carbon is stirred at reflux until the reaction is complete within 2 hours. The precipitated succinimide is filtered off from the cooled mixture and the filtrate is evaporated to dryness under reduced pressure, leaving methyl 2- (1-bromoethyl) benzoate as a residual yellow oil in quantitative yield.

  
A solution of 0.156 mole of methyl 2- (1-bromomethyl) -benzoate and 24.0 g (0.312 mole) of aqueous methylamine in

  
 <EMI ID = 69.1>

  
room temperature for 20 hours. The solvent is evaporated off under reduced pressure and the residue is partitioned between chloroform and water. Evaporation under reduced pressure of the washed (water, 2N hydrochloric acid and water) and dried chloroform extract leaves the crude product as residual oil. By distillation, 2,3-dimethylphthalimidine is obtained in the form of a colorless fluid oil.

  
 <EMI ID = 70.1>

  
According to the procedure described in Example 1a, methyl 2- (1-bromoethyl) benzoate is reacted with the appropriate primary amine to obtain the following 2-alkyl-3-methylphthalimidines:

  
 <EMI ID = 71.1>

  
0.1 mm Hg.

  
2) 2-ethyl-3-methylphthalimidine, boiling point 97-105 [deg.] C /

  
0.1 mm Hg.

  
3) 2-cyclopropyl-3-methylphthalimidine, boiling point 120 [deg.] C /

  
0.2 mm Hg.

  
4) 2- (3-hydroxypropyl) -3-methylphthalimidine, boiling point

  
 <EMI ID = 72.1>

  
5) 2-propyl-3-methylphthalimidine, boiling point 98-104 [deg.] C /

  
0.1 mm Hg.

  
6) 2-butyl-3-methylphthalimidine, boiling point 109-114 [deg.] C /

  
0.1 mm Hg.

  
7) 2-allyl-3-methylphthalimidine, boiling point 102-104 [deg.] C /

  
0.15 mm Hg.

  
8) 2-cyclopropylmethyl-3-methylphthalimidine, boiling point

  
 <EMI ID = 73.1>

  
In a dry apparatus maintained in an atmosphere of

  
 <EMI ID = 74.1>

  
in ether to a stirred solution of 6.4 g (0.04 mol) of 2,3-dimethylphthalimidine in 100 cm of absolute ether. After

  
 <EMI ID = 75.1>

  
The cooled mixture is hydrolyzed by the dropwise addition of 40 cc of water. The ethereal layer is separated, washed several times with water and dried over anhydrous magnesium sulfate while stirred under nitrogen and cooled in an ice bath. The filtered solution is evaporated under reduced pressure and the dark yellow residual solid is dried under

  
0.5 mm to give 5.7 g (90%) of 1,2,3-trimethylisoindole.

  
 <EMI ID = 76.1>

  
According to the procedure described in Example 1b, the appropriate 2-substituted-3-methyl-phthalimidine is treated with <EMI ID = 77.1>

  
9) 5-chloro; 5-iodo-; and 5-bromo-2-cyclopropyl-1,3-dimethyl-

  
isoindole,

  
10) 5-chloro-; 5-iodo-; and 5-bromo-2- [3- (tetrahydropyranyl) -2-

  
 <EMI ID = 78.1>

  
isoindole,

  
12) 1-butyl-2,3-dimethylisoindole from n-butyllithium

  
and 2,3-dimethyl-phthalimidine,

  
13) 1-ethyl-2,3-dimethylisoindole; from ethyllithium and

  
2,3-dimethylphthalimidine,

  
14) 1-vinyl-2,3-dimethylisoindole; from vinyllithium

  
and 2,3-dimethylphthalimidine.

Example 1c

  
 <EMI ID = 79.1>

  
A mixture of 7.35 g (0.036 mole) of 2- (3-hydroxypropyl) -

  
 <EMI ID = 80.1>

  
 <EMI ID = 81.1>

  
absolute ether is stirred at room temperature for

  
24 hours. Stirring is continued for several hours after the addition of 1.0 g of anhydrous potassium carbonate and the mixture is filtered. Evaporation of the filtrate under reduced pressure and drying of the residue under 0.5 mm Hg leave.

  
 <EMI ID = 82.1>

  
the form of a viscous yellow oil with quantitative yield.

  
 <EMI ID = 83.1>

  
9,10-imine

  
Has a stirred mixture of 1.45 g (0.0052 mole) of 11- (3-

  
 <EMI ID = 84.1>

  
1.4 g (0.00525 mole) of triphenylphosphine and 17 cm <3> of anhydrous benzene at room temperature and under nitrogen, 0.95 g (0.00535 mole) of N- are added in portions. bromo-succinimide. Stirring is continued for 6 hours while a fine white precipitate slowly separates. After cooling in an ice bath, the mixture is saturated with gaseous dimethylamine and stirring is continued overnight at room temperature. The solvent is evaporated off under reduced pressure and

  
the residue is triturated with absolute ether. The succinimide precipitate is separated by filtration and the filtrate is evaporated.

  
dry under reduced pressure. The residue is triturated with hot hexane and this mixture is cooled. After filtering off the precipitate of triphenylphosphine oxide, the hexane filtrate is evaporated to dryness under reduced pressure, leaving the product as

  
 <EMI ID = 85.1>

  
under 0.2 mm Hg, 0.9 g (56%) of viscous yellow oil is obtained.

  
The base is converted to the hydrochloride salt by treating the ethanolic solution with one equivalent of hydrochloric acid in ethanol. -Dilution with absolute ether precipitates the salt which is recrystallized from a cold absolute ethanol-ether mixture to give 11- (3-dimethyl- hydrochloride).

  
 <EMI ID = 86.1>

  
the shape of white crystals.

  
According to the procedure described in Example 1d, except that 11- (3-hydroxypropyl) -9,10-dimethyl-9,10-dihydro-

  
 <EMI ID = 87.1>

  
 <EMI ID = 88.1>

  
imine, respectively.

  
 <EMI ID = 89.1>

  
Step A: 1,2,3-trimethylisoindole

  
A mixture of 50 g (0.374 mol) of o-diethyl-benzene,

  
146 g (0.822 mol) of IT-bromosuccinimide, 0.1 g of benzoyl peroxide and 800 cc of carbon tetrachloride is heated to reflux, with stirring and ultraviolet irradiation, until the reaction is complete. The precipitated succinimide is separated by filtration, washed with carbon tetrachloride and the filtrate is evaporated to dryness under reduced pressure.

  
 <EMI ID = 90.1>

  
800 cc of absolute ether. A solution of 40 g (0.87 mol) of methyl hydrazine in 50 cm of absolute ether is added dropwise to the solution stirred under nitrogen. A gummy precipitate separates. After 3 hours of stirring and leaving it overnight, the ether is decanted. The residue dissolved in 625 cm <3>

  
 <EMI ID = 91.1>

  
sodium and the mixture is stirred at reflux for 1.5 hours.

  
After cooling, the precipitate of the crude product is collected, washed with water and dissolved in 600 cc of ether. The ethereal solution is washed several times with water and dried over anhydrous magnesium sulfate, with stirring and cooling in a

  
ice bath. The filtered solution is evaporated under reduced pressure and the residual dark yellow solid is triturated with petroleum ether, separated by filtration and dried in vacuo to give 15.56 g of 1,2,3-trimethyl-isoindole.

  
 <EMI ID = 92.1>

  
In a dry apparatus maintained in a nitrogen atmosphere,

  
 <EMI ID = 93.1>

  
 <EMI ID = 94.1>

  
fairy ebb. The reaction is initiated by adding a few drops of 2-fluorobromobenzene and a mixture of 9.65 g (0.06 mole) of 1,2,3-trimethylisoindole and 12.3 g (0.07 mole) of

  
 <EMI ID = 95.1>

  
is added dropwise over 1 hour. Stirring is continued with heating under reflux for 2 hours. The cooled mixture

  
 <EMI ID = 96.1>

  
and the organic layer is decanted. The solvent is evaporated off under <EMI ID = 97.1>

  
reduced pressure and the residual dark oil is dissolved in benzene. The solution is filtered through diatomaceous earth, diluted with ether and washed with water. The dried extract

  
 <EMI ID = 98.1> of a dark red residual oil which is converted into a fumaric acid salt by dissolving in 30 cm <3> ethyl acetate and adding to a solution of 10.4 g (0.09 mole) of fuma-

  
 <EMI ID = 99.1>

  
 <EMI ID = 100.1>

  
 <EMI ID = 101.1>

  
Sations from methanol-ethyl acetate (1: 1), using bleaching charcoal, give 4.38 g of the 9,10,11-trimethyl-anthracen-9,10-dihydro fumarate salt. -9,10-imine in the form

  
 <EMI ID = 102.1>

  
According to the procedure of Example 1, Step A, except that the o-diethylbenzene of Example 1 is replaced by an equivalent amount of o-ethyltoluene, o-dipropylbenzene, 2-

  
 <EMI ID = 103.1>

  
o-dibutylbenzene and 2-butyl-propylbenzene, respectively, the following compounds are obtained: 1,2-dimethylisoindole; 1,3-diethyl-2-methylisoindole; 1,2-dimethyl-3-ethylisoindole; 1,3-bis-
(trifluoromethyl) -2-methylisoindole; 1,3-dipropyl-2-methyliso-

  
 <EMI ID = 104.1>

  
When the isoindoles indicated above individually replace the 1,2,3-trimethylisoindole of Example 1, Step B, the following compounds are obtained: 9,11-dimethyl-9,10-dihydro-

  
 <EMI ID = 105.1>

  
dihydroanthracen-9,10-imine, respectively.

  
 <EMI ID = 106.1>

  
According to the procedure of Example 1, Step A, to

  
an equivalent amount of: 4-chloro-, 4-iodo- and 4-bromo-1,2-diethylbenzene and that the methylhydrazine is replaced by an equivalent amount of propyl hydrazine, cyclopropylhydrazine <EMI ID = 107.1>

  
te 4604 00 and gamma-THP-oxy-propyl hydrazine, respectively, the 5-chloro-; 5-iodo-; and 5-bromo-2-propyl-1,3-dimethylisoindole;

  
5-chloro-; 5-iodo-; and 5-bromo-2-cyclopropyl-1,3-dimethyliso-.

  
 <EMI ID = 108.1> hydropyranyloxy.

  
when the isoindoles indicated above replace indi-

  
 <EMI ID = 109.1>

  
the following compounds are obtained: 2-chloro-; 2-iodo-; and 2bromo-11-propyl-9,10-dimethyl-9,10-dihydroanthracen-9,11-imine;

  
2-chloro-; 2-iodo-; and 2-bromo-11-cyclopropyl-9,10-dimethyl9,10-dihydroanthracen-9,10-imine; and 2-chloro-; 2-iodo-; and

  
 <EMI ID = 110.1>

  
anthracen-9,10-imine, respectively; mild acid hydrolysis of the last three compounds mentioned gives 2-chloro-, 2-iodo- and 2-bromo-11-hydroxypropyl-9,10-dimethyl-9,10-dihydroanthracen-9,10-imine.

  
According to the procedure of Example 1, the following anthracenimines of the present invention are obtained:

  

 <EMI ID = 111.1>


  

 <EMI ID = 112.1>
 

  

 <EMI ID = 113.1>


  

 <EMI ID = 114.1>
 

  

 <EMI ID = 115.1>


  

 <EMI ID = 116.1>
 

  

 <EMI ID = 117.1>


  

 <EMI ID = 118.1>
 

  

 <EMI ID = 119.1>


  

 <EMI ID = 120.1>
 

  

 <EMI ID = 121.1>


  

 <EMI ID = 122.1>
 

  

 <EMI ID = 123.1>


  

 <EMI ID = 124.1>
 

  
 <EMI ID = 125.1>

  
of acetaldehyde in this acetonitrile is stirred and treated with 0.75 g (0.012 mole) of sodium cyanoborohydride. We add

  
 <EMI ID = 126.1>

  
and the mixture is stirred at room temperature for 2 hours. After the addition of a further 0.5 cc of glacial acetic acid, stirring is continued overnight. Most of the solvent is evaporated off under reduced pressure and the residue is partitioned between a 5% aqueous solution of sodium hydroxide and ether. The washed and dried ether extract is evaporated under reduced pressure, leaving 0.65 g (58%) of the product as a residual oily solid.

  
The base is converted to its acid oxalate salt by dissolving it in absolute ethanol saturated with oxalic acid. The salt precipitates and is recrystallized twice from absolute ethanol to give 11-ethyl-1,4,9,10tetramethyl-9,10-dihydroanthracen-9,10-imine acid oxalate in the form of crystals. white.

Example 3 (a)

  
 <EMI ID = 127.1>

  
Glacial acetic is stirred with 200 mg of 5% palladium / carbon under hydrogen at atmospheric pressure until absorption of hydrogen is complete. The catalyst is removed

  
 <EMI ID = 128.1>

  
The pickle leaves the crude product as a residual oily solid. A solution of the residue in a benzene: ether mixture
(1: 1) is extracted with 0.5 M citric acid. The aqueous acid extract is cooled and made strongly basic

  
 <EMI ID = 129.1>

  
is extracted into a benzene-ether mixture (1: 1). Evaporation under reduced pressure of the washed and dried organic extract leaves the product in the form of oily white crystals. Sublimation at 7C [deg.] C and under 0.05 mm Hg gives 0.35 g (21%) of white crystals.

  
 <EMI ID = 130.1>

  
 <EMI ID = 131.1>

  
 <EMI ID = 132.1>

  
 <EMI ID = 133.1>

  
The organic phase is separated and washed with ice-cold water,

  
 <EMI ID = 134.1>

  
dried.

  
Example_ 5 a

  
 <EMI ID = 135.1>

  
imine

  
 <EMI ID = 136.1>

  
methylenesulfone is added dropwise to a stirred slurry of nitronium tetrafluoroborate in 50 cm of tetramethylene-

  
 <EMI ID = 137.1>

  
poured into 300 grams of ice water and the product is collected by filtration.

  
The product 2-nitro-9,10,11-trimethyl is obtained when the product of Example 1 replaces the product of Example 4a in Example 5a.

Example 6a

  
 <EMI ID = 138.1>

  
imine

  
 <EMI ID = 139.1>

  
nol is hydrogenated over 5% Pd / C (1.0 g) at 25 [deg.] C under atmospheric pressure for 2 hours; the product is collected by filtration and evaporation.

Example 7a

  
 <EMI ID = 140.1>

  
9,10-imine

  
The product of Example 6a (9.9 g) in 150 cm <3> of water

  
 <EMI ID = 141.1>

  
 <EMI ID = 142.1>

  
 <EMI ID = 143.1>

  
at 0 [deg.] C after 20 minutes and the product is collected by filtration.

  
 <EMI ID = 144.1>

  
9 &#65533; 10-imine

  
The product of Example? A (4.9 g) in 100 cc? of CH30H and 5.0 g of diazomethane in ether are left

  
 <EMI ID = 145.1>

  
the product.

Example 9a

  
 <EMI ID = 146.1>

  
 <EMI ID = 147.1>

  
is added dropwise. to a slurry of 2.0 g of hydride

  
of lithium and aluminum in 100 cm <3> of ether. Heating under reflux is continued for 8 hours. Water is carefully added and the inorganic material is filtered off.

  
Evaporation of the filtrate gives the product.

Example 10a

  
 <EMI ID = 148.1>

  
To the product of Example 1 (2.35 g) is added dropwise 0.03 mol of thallium (III) acetate in 100 cm of

  
 <EMI ID = 149.1>

  
filter the mixture and wash it with an aqueous solution of

  
 <EMI ID = 150.1>

  
is evaporated and the residue is taken up in chloroform and filtered through a short column of alumina to give the product.

Example 11a

  
 <EMI ID = 151.1>

  
 <EMI ID = 152.1>

  
of anhydrous pyridine is. heated at reflux for 20 hours. The

  
 <EMI ID = 153.1>

  
The methanolic acid is stirred at 35 [deg.] C for 2 hours and then the solvent is evaporated off. The reaction mixture is worked up by extraction with dilute aqueous fumaric acid. The acid extract is made basic with aqueous ammonia solution and then treated by extraction with ether. The ethereal extract is dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated to give the product.

  
 <EMI ID = 154.1>

  
 <EMI ID = 155.1>

  
 <EMI ID = 156.1>

  
 <EMI ID = 157.1>

  
and ether. The ethereal solution is separated, dried over sodium sulfate, filtered and evaporated to give the product.

Example 13a

  
 <EMI ID = 158.1>

  
To the product of Example 3a (2.21 g) and 1.06 g of

  
 <EMI ID = 159.1>

  
 <EMI ID = 160.1>

  
is stirred overnight. After removing the solvent, an aqueous solution of KOH is added and the mixture is worked up by extraction with ether. The extract is dried, filtered and evaporated to give the product.

Example 14a

  
 <EMI ID = 161.1>

  
9 &#65533; 10-imine

  
To a solution of methyl oxocarbonium hexafluoroantimonate (13.9 g) in 50 cm 3 of nitromethane is added 14.6 g of the product of Example 4a. The reaction mixture is poured into water after 3 hours at 45 [deg.] C, treated by extraction with ether and the ether extract is washed with water and dried over sodium sulfate, filtered and the filtrate is evaporated to give the product.

Example 15a

  
 <EMI ID = 162.1>

  
A mixture is heated under reflux for two hours.

  
 <EMI ID = 163.1>

  
 <EMI ID = 164.1>

  
filtered and cooled to 75 [deg.] C; Zn powder (95 g) is quickly added and heated under reflux for 4 hours; then the mixture is filtered and the solvent evaporated to a small volume.

  
 <EMI ID = 165.1>

  
 <EMI ID = 166.1>

  
 <EMI ID = 167.1>

  
 <EMI ID = 168.1>

  
As a waxy solid, 25.1 g. Step B: 1,2,5-trimethylisoindole (B)

  
 <EMI ID = 169.1>

  
 <EMI ID = 170.1>

  
ether under nitrogen; the mixture is stirred for 5 hours, 100 cm 3 of water are added dropwise. The ethereal layer is washed with saturated NaCl solution and dried (K2CO3). Removal of the solvent gives product B.

  
Step C

  
A portion of a 2-bromofluorobenzene solution

  
 <EMI ID = 171.1>

  
 <EMI ID = 172.1>

  
under nitrogen. The Grignard reaction is initiated and the remainder of the bromo-fluorobenzene solution is added dropwise. The mixture is heated at reflux for 3 hours and the mixture is driven off.

  
 <EMI ID = 173.1>

  
 <EMI ID = 174.1>

  
with saturated NaCl solution (150 cc) and dried (Na2SO4); the solvent is removed and the residue is extracted with hexane. The oil which is obtained by evaporation of the extracts with hexane is purified by chromatography on silica gel,

  
 <EMI ID = 175.1>

  
(1.1 g) is dissolved in ethyl acetate (15 cm <3>) and added to a hot saturated solution of fumaric acid in

  
 <EMI ID = 176.1>

  
lie (1.1 g) and recrystallized from ethyl acetate to

  
 <EMI ID = 177.1>

  
anthracen-9,10-imine.

Example 16a

  
 <EMI ID = 178.1>

  
 <EMI ID = 179.1>

  
on crushed ice and the solid is collected, washed <EMI ID = 180.1> <EMI ID = 181.1>

  
from benzene.

  
Step B: 2,6-dimethylphthalimidine (B)

  
 <EMI ID = 182.1>

  
 <EMI ID = 183.1>

  
 <EMI ID = 184.1>

  
for 24 hours; the solvent is removed and the residue is dissolved in water (400 cc). The aqueous solution is treated by extraction with chloroform and the chloroform is evaporated off.

  
 <EMI ID = 185.1>

  
and the ether is evaporated off. The residue is dissolved in acetate

  
 <EMI ID = 186.1>

  
 <EMI ID = 187.1>

  
chée, 6.3 g, B.

  
 <EMI ID = 188.1>

  
Using the procedure from Step B, Example
15a, product C is obtained in the form of a yellow-orange powder.

  
Step D: 2,9, <1> 1-trimethyl-9,10-dihydroanthracen-9,10-imine (D)

  
Using the procedure from Step C, Example
15a, with 1,2,6-trimethylisoindole, we obtain D and its acid sesqui-fumarate salt.

Example 17a

  
 <EMI ID = 189.1>

  
A solution of CH3Li in ether (53 cm <3>, 1.9 M) is added dropwise to a suspension of N-methyl-

  
 <EMI ID = 190.1>

  
stir the mixture for 4 hours, after which water is added

  
 <EMI ID = 191.1>

  
 <EMI ID = 192.1>

  
organic extracts are washed with a saturated solution of

  
 <EMI ID = 193.1>

  
dried to give A as a yellow-orange oil.

  
 <EMI ID = 194.1> <EMI ID = 195.1>

  
acid oxalate.

Example 18a

  
 <EMI ID = 196.1>

  
 <EMI ID = 197.1>

  
H2S04 concentrated; the solution is maintained at 100 [deg.] C for
6 p.m., chill it and pour it over ice
(1500 g). The solid which separates is collected, washed with water and dried, 8.0 g. Recrystallization from 2-propanol gives A.

  
Step B: 6-chloro-2-methylphthalimidine (B)

  
 <EMI ID = 198.1>

  
oil, 0.1 mole) and benzene (100 cm &#65533;), a

  
 <EMI ID = 199.1>

  
of gas decreases, the mixture is heated in a boiling water bath.

  
 <EMI ID = 200.1>

  
 <EMI ID = 201.1>

  
18 hours, the mixture is filtered and the filtrate is evaporated. The residue is mixed with water, filtered and dried to give

  
 <EMI ID = 202.1>

  
According to the procedure of Step B, Example 15a, C is obtained when B of Example 18a replaces A of Example 15a.

  
 <EMI ID = 203.1>

  
imine

  
According to the procedure of Step C, Example 15a, D (and its acidic fumarate salt) is obtained when B of Example 15a is replaced by C of Example 18a.

Example 19a

  
 <EMI ID = 204.1>

  
 <EMI ID = 205.1>

  
layers. The ethereal layer is washed with a saturated solution <EMI ID = 206.1>

  
According to the procedure of Step C, Example 15a, B (and its sesqui-fumarate acid salt) is obtained when A of

  
 <EMI ID = 207.1>

  
A solution of methyllithium in ether (50 cm <3>, 1.8 M) is added dropwise to a stirred solution of

  
 <EMI ID = 208.1>

  
 <EMI ID = 209.1>

  
and we separate the layers. The aqueous layer is treated eg

  
 <EMI ID = 210.1>

  
 <EMI ID = 211.1>

  
 <EMI ID = 212.1>

  
 <EMI ID = 213.1>

  
According to the procedure of Step C, Example 15a, B (and its sesqui-fumarate acid salt) is obtained when A of Example 20a replaces B of Example 15a.

  
 <EMI ID = 214.1>

  
 <EMI ID = 215.1>

  
 <EMI ID = 216.1>

  
1.8 is added dropwise. dropwise to a stirred solution of 2-ethyl-phthalimidine (16.1 g) in 300 cm 3 of ether under nitrogen; the mixture is stirred for 18 hours, water is added

  
 <EMI ID = 217.1>

  
 <EMI ID = 218.1>

  
 <EMI ID = 219.1>

  
According to the procedure of Step C, Example 15a, B (and its acid fumarate salt) is obtained when A of Example 21a

  
 <EMI ID = 220.1>

  
 <EMI ID = 221.1>

  
 <EMI ID = 222.1>

  
 <EMI ID = 223.1> <EMI ID = 224.1>

  
 <EMI ID = 225.1>

  
 <EMI ID = 226.1>

  
 <EMI ID = 227.1>

  
isoindole in ether (80 cc) and the mixture is stirred at
-70 [deg.] C for 5 minutes. Then the reaction mixture is heated rapidly to 20 [deg.] C and stirred overnight at 25 [deg.] C. Pour the reaction mixture into water and <EMI ID = 228.1>

  
 <EMI ID = 229.1>

  
under reduced pressure. The residue is chromatographed on gel.

  
 <EMI ID = 230.1>

  
in chloroform. The crude product obtained from the eluent is treated with fumaric acid in isopropanol to give the fumaric acid salt, after recrystallization from isopropanol-ethyl acetate (1: 1).

  
According to the procedure of Example 22a, one obtains

  
 <EMI ID = 231.1>

  
trimethylanthracen-5,10-imine is obtained when IT-methylisoindole and 3-bromo-2-chloropyridine from Example 22a are

  
 <EMI ID = 232.1>

  
Example 22a is replaced by 1,2,3-trimethylisoindole.

Example 23a

  
 <EMI ID = 233.1>

  

 <EMI ID = 234.1>


  
In a dry apparatus maintained in an atmosphere of

  
 <EMI ID = 235.1>

  
added dropwise to a stirred solution of 2.82 g (0.02 <EMI ID = 236.1>

  
anhydrous hydrofuran. The resulting solution is added dropwise to a stirred solution of 2.62 g (0.02 mole) of N-methylisoindole and 2.05 g (0.02 mole) of 5-chloro-pyrimidine in
20cm &#65533; of anhydrous tetrahydrofuran. After a period of overnight heating at reflux, the mixture is poured into a saturated solution of ammonium chloride containing 3% concentrated ammonium hydroxide. The tetrahydrofuran layer is separated and concentrated under reduced pressure. The residue is chromatographed on silica gel, the elution being carried out.

  
with 5% methanol in chloroform, to give the purified product as a residue from the evaporation of the eluent.

  
When the N-methylisoindole of Example 23a is replaced by an equivalent amount of 1,2,3-trimethylisoindole, 5-bromo-1,2,3-trimethylisoindole and 5-iodo-1,2,3-trimethylisoindole , respectively, we obtain 1,3-diaza-5,10-dihydro-

  
 <EMI ID = 237.1>

  
inines, respectively. Similarly, when the 5chloropyrimidine of Example 23a is replaced by an equivalent amount of 5-chloro-1,2-diazine, 1,2-diaza-
11-methyl-5,10-dihydroanthracen-5,10-imine.

Example 24a

  
&#65533; &#65533; * &#65533; &#65533; &#65533; '-

  
 <EMI ID = 238.1>

  

 <EMI ID = 239.1>


  
According to the procedure described in Example 23a, one

  
 <EMI ID = 240.1> <EMI ID = 241.1> imine, respectively.

  
 <EMI ID = 242.1>

  
 <EMI ID = 243.1>

  

 <EMI ID = 244.1>


  
According to the procedure described in Example 22a, it is

  
 <EMI ID = 245.1>

  
ryne produced in situ from 3-bromo-2-chloro-quinoline.

Example 26a

  
 <EMI ID = 246.1>

  

 <EMI ID = 247.1>


  
According to the procedure described in Example 22a,

  
 <EMI ID = 248.1> <EMI ID = 249.1>

  

 <EMI ID = 250.1>


  
According to the procedure described in Example 23a,

  
 <EMI ID = 251.1>

  
in situ from 4-bromoisoquinoline.

Example 28a

  
 <EMI ID = 252.1>

  

 <EMI ID = 253.1>


  
According to the procedure described in Example 23a,

  
 <EMI ID = 254.1>

  
produced in situ from 4-bromo-1,5-naphthyridine.

Example 29a

  
Preparation of intravenous solutions

  
 <EMI ID = 255.1>

  
is prepared as follows.

  
 <EMI ID = 256.1> <EMI ID = 257.1>

  
n-propyl-p-hydroxy-benzoate (propyl paraben) with the other solids before adding water to dissolve the solids. The solution is prepared and stored in such a way that it is suitably protected against the harmful effects of the atmosphere. The resulting solution is sterilized by autoclaving. In a similar manner, injectable solutions comprising 0.1, 1.0, 100.0 mg, respectively, of A per cm of solution are prepared. Bulk injection solutions of convenient volume for subsequent delivery in unit dosage forms are readily prepared according to the above procedure.

  
According to the procedure of Example 29a, other injectable solutions representative of the present invention are prepared when A of Example 29a is replaced by an equivalent amount of 2-fluoro-9,10,11-trimethyl-9, 10-dihydroanthracen-9,10-imine or by an equivalent amount of any of the anthracenimines of the present invention illustrated in the Examples.

Example 30a

  
Preparation of tablets

  
Tablets containing 1.0, 2.0, 25.0, 26.0, 50.0 and

  
 <EMI ID = 258.1>

  
 <EMI ID = 259.1>

  
 <EMI ID = 260.1>

  

 <EMI ID = 261.1>
 

  
 <EMI ID = 262.1>

  

 <EMI ID = 263.1>


  
 <EMI ID = 264.1>

  
anthracen-9,10-imine, lactose and part of the corn starch are mixed and granulated so as to give a paste to
10% corn starch. The resulting granule is sieved, dried and mixed with the rest of the corn starch and the magnesium stearate. The resulting granule is pressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0 mg, 50.0 mg and 100.0 mg of 9,10,11-trimethyl-9, 10-dihydroanthracen-9,10-imine per tablet.

  
According to the procedure of Example 30a, tablets comprising 2-fluoro-9,10,11-trimethyl-9,10-dihydro- <EMI ID = 265.1> dihydroanthracen-9,10-imine. Further tablets are prepared using the same procedures and equivalent amounts of excipients together with equivalent amounts of the anthracenimines of the present invention prepared according to the invention.
-ment to the previous Examples.


    

Claims (1)

<EMI ID = 266.1> 1 - A compound having the formula: <EMI ID = 267.1> in which R is hydrogen, acyl, alkyl, aryl, alkoxycarbonyl, aralkyl, alkenyl, dialkylaminoalkyl, hydroxyalkyl, alkynyl, trialkylsilyl, alkylcycloalkyl or cycloalkyl; <EMI ID = 268.1> <EMI ID = 269.1> alkenyl and dialkylaminoalkyl; X and Y are independently selected from the group consisting of halogens such as chlorine, fluorine, bromine, <EMI ID = 270.1> dialkylaminoalkyl, carboxy, carboxamido, haloalkoxy, haloalkoxy, haloalkylthio, allyl, aralkyl, cycloalkyl, aroyl, aralkoxy, alkanoyl, aryl, substituted aryl, <EMI ID = 271.1> n is an integer selected from 0 (X or Y is hydrogen, respectively), 1, 2, 3 or 4; <EMI ID = 272.1> <EMI ID = 273.1> <EMI ID = 274.1> <EMI ID = 275.1> or the symbol represents the carboxyclic moiety, benzo; with the condition that when <EMI ID = 276.1> <EMI ID = 277.1> R and R <2> are hydrogen, R cannot be a phe- <EMI ID = 278.1> <EMI ID = 279.1> hydrogen, R cannot be methyl, benzyl or <EMI ID = 280.1> represents 1,4-dimethyl and Y is hydrogen, R cannot <EMI ID = 281.1> represents 1,2,3,4-tetrafluoro and Y is hydrogen, <EMI ID = 282.1> phenyl groups and X and Y are hydrogen, R cannot be hydrogen or a carboxyethyl or methyl group; and pharmaceutically acceptable non-toxic acid addition salts of such a compound. 2 - A compound according to claim 1, characterized in that <EMI ID = 283.1> lower alkyl groups having from 1 to 6 carbon atoms approximately, alkenyl having from 2 to 6 carbon atoms approximately or <EMI ID = 284.1> R is hydrogen or a lower alkyl group having from 1 to about 6 carbon atoms, lower hydroxyalkl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, cycloalkl having from 5 to 6 carbon atoms approximately, alkylcycloalkyl having from 4 to 10 carbon atoms approximately, benzyl (and benzyl substituted at the ring by X and by R), lower alkoxycarbonyl having from 2 to about 7 carbon atoms or dialkylaminoalkyl having from -3 to 15 atoms about carbon; Y and X are independently selected from lower alkyl groups having from 1 to 6 carbon atoms approximately, fluorine, chlorine, bromine, iodine, lower alkoxy groups <EMI ID = 285.1> laughing having from 1 to 6 carbon atoms approximately, halo-lower alkyl having from 1 to 6 carbon atoms approximately, cyano, carbon <EMI ID = 286.1> n is an integer selected from 0 (X or Y is hydrogen, respectively), 1 and 2; <EMI ID = 287.1> 3 - A compound according to claim 1, characterized in this aue: <EMI ID = 288.1> lower alkenyl such as vinyl, lower alkyl having from 1 to 6 carbon atoms approximately such as methyl, ethyl, propyl, trifluoronethyl, di-lower alkyl-amino-lower alkyl, <EMI ID = 289.1> R is hydrogen, benzyl or substituted benzyl, lower alkyl having from 1 to about 6 carbon atoms such as methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or di- <EMI ID = 290.1> propyl; X and Y are chlorine, bromine, iodine, a group <EMI ID = 291.1> <EMI ID = 292.1> and trifluoromethylthio; <EMI ID = 293.1> hydrogen, respectively), 1 and 2; and <EMI ID = 294.1> represents the benzo group <EMI ID = 295.1> 4 - A compound according to claim 1, characterized in that it is chosen from. following: <EMI ID = 296.1> <EMI ID = 297.1> imine; <EMI ID = 298.1> <EMI ID = 299.1> 5 - A process for preparing a compound according to claim 1, in which an isoindole having the structure is reacted: <EMI ID = 300.1> with a benzyne or hetaryne of the structure <EMI ID = 301.1> 6 - A process for preparing a compound according to claim 1, in which an isoindole having the structure is reacted: <EMI ID = 302.1> with a benzyne of the structure <EMI ID = 303.1> 7 - A pharmaceutical composition comprising, in unit dosage form, a therapeutically effective amount of a compound according to one of claims 1 to 4 or of a pharmaceutically acceptable salt of such a compound and an appropriate pharmaceutical vehicle. 8 - A method of treatment comprising the administration of a therapeutically effective amount of a compound according to one of claims 1 to 4 or of a pharmaceutically acceptable salt of such a compound.