NO751545L - - Google Patents

Description

Process for the preparation of substituted 9,10-dihydroanthracene-9, 10-imines and their heterocyclic (aza) analogues

The present invention relates to a process for the preparation of certain substituted 9,10-dihydroanthracene-9,10-imines and their heterocyclic (aza) analogues and their pharmaceutically acceptable salts, esters and amide derivatives which are useful as psychosedatives, anticonvulsants, muscle relaxants agents, and in the treatment of extrapyramidal disorders such as Parkinson's disease. For convenience, the process compounds will hereinafter be referred to as "anthracenimines".

The process compounds have the following structural formula:

where

R is hydrogen, acyl, alkyl, aryl, alkoxycarbonyl, aralkyl, alkenyl, dialkylaminoalkyl, hydroxyalkyl, alkynyl, trialkylsilyl, alkylcycloalkyl or cycloalkyl;

R 1 and R 2 , which are the same or different, are hydrogen, alkyl, haloalkyl, aralkyl, aryl, alkenyl or dialkylaminoalkyl;

X and Y, which are the same or different, are halogen such as chlorine, fluorine, bromine or iodine, alkoxy, dialkoxymethyl, alkyl, cyano, dialkylaminoalkyl, carboxy, carboxamido, halogen substituted alkoxy, haloalkyl, haloalkylthio, allyl, aralkyl, cycloalkyl, aroyl, armethoxy, alkanoyl, aryl, substituted aryl, alkylthio, alkylsulfonyl, haloalkylsulfonyl, alkylsulfinyl, haloalkylsulfinyl, arylthio, haloalkyloxy, amino, alkylamino, dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, nitro or dialkylsulfamoyl;

n is 0 (X, Y, respectively, is hydrogen), 1, 2, 3 or 4;

is an unsaturated heterocyclic or heteropolycyclic group where the heteroatom or atoms, A, is N or NR where R is as indicated above, or the symbol denotes a benzo group.

With respect to the anthracenimines (formula I), the preferred compounds are those where: R 1 and R 2 , which are the same or different, are hydrogen, lower alkyl, alkenyl of 2-6 carbon atoms or dialkylaminoalkyl of 3-15 carbon atoms; R is hydrogen, lower alkyl, hydroxy-lower alkyl, alkenyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, alkylcycloalkyl of 4-10 carbon atoms, benzyl (and X- and R-ring-substituted benzyl), lower alkoxy- carbonyl of 2-7 carbon atoms or dialkylaminoalkyl of 3-15 carbon atoms; X and Y, which are the same or different, are lower alkyl, halogen (fluoro, chloro, bromo, iodo), lower alkoxy, halogen-substituted-lower alkoxy, halogen-lower alkyl, cyano, carboxy, haloalkylthio, alkylthio, haloalkyl- sulfonyl or carboxamido; n is 0 (X or Y, respectively, is hydrogen), 1 or 2;

The most preferred method compounds are those wherein: is the benzo group,

R 1 and R 2 are hydrogen, lower alkenyl such as vinyl, lower alkyl such as methyl, ethnyl or propyl, trifluoromethyl, di-lower alkylamino-lower alkyl such as dimethylaminopropyl;

R is hydrogen, benzyl or substituted benzyl, lower alkyl such as methyl, ethyl or propyl, cyclopropyl, cyclobutyl or di-lower-alkylamino-lower alkyl such as dimethylaminopropyl;

X and Y are chlorine, bromine, iodine, lower alkoxy, lower alkyl, cyano, carboxy, carboxamido, trifluoromethoxy, trifluoromethyl, trifluoromethylsulfonyl, lower alkylthio such as methylthio, or trifluoromethyl thio;

n is 0 (X, respectively Y, is hydrogen), 1 or 2.

In general, the present anthracenimines are prepared

by reacting an appropriately substituted hetaryne ("benzyne" in the case of the benzo substituent) with an appropriately substituted iso-

indole, Ia, by the following reaction:

where the substituents are as indicated above.

For practical reasons, the hetaryne or benzene reactant (hereafter collectively referred to as "benzene" for convenience) is formed in situ under conditions compatible with the final Diels-Alder condensation with the isoindole. Preparation of such reactants and process conditions for the final preparation of the anthracenimines are described below.

Isoindole production

Many of the isoindoles useful in manufacture

of the present anthracenimines 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-bromosuccinimide (NBS), followed by reacting the resulting α,α'-dihalogenated product with an N-substituted hydrazine (RNHNH2); and treatment of the formed compound with base gives the desired isoindole:

where the substituent is as indicated above.

Typically, the halogenation step is carried out in the preparation of the isoindole in the presence of an initiator such as benzoyl peroxide or the like, under ultraviolet irradiation. There is nothing critical about the reaction temperature, the solvent system or the base used in the final step. Suitable solvents for the reaction include hydrocarbons such as hexane and benzene, and halogenated hydrocarbons such as carbon tetrachloride and chlorobenzene. Typically, the reaction temperature is from approx. 25° C to the return temperature. The non-critical base can be sodium hydroxide, potassium hydroxide, potassium carbonate and the like.

Another procedure for the preparation of suitably substituted isoindoles appears from the following scheme:

where the symbols are as previously indicated, and R° is any lower alkyl group such as methyl, ethyl, propyl or the like. According to the above procedure, o-acylbenzoic acid is first hydrogenated to reduce the carbonyl group by conventional methods such as 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 hydrogen chloride in ethanol or other standard methods . Halogenation of the substituted benzoic acid ester formed gives the α-halogen intermediate illustrated above. Halogenation can be carried out, e.g. by treating the ester with NBS in carbon tetrachloride under reflux. The treatment of the α-halogen intermediate with the primary amine, RNH2/in methanol, ethanol,

acrylonitrile, ether, THF or another polar organic solvent gives the phthalimidine shown above which, when treated with R 2Li in ether, benzene, THF or another inert organic solvent under reflux, or with a Grignard reagent, R 2MgX1 (X' is halogen such as chlorine, bromine or iodine) in anisole, THF, glyme or dibutyl ether under reflux gives the desired isoindole (Ia). In connection with the process illustrated just above, the esterification step can be skipped according to the following method:

where the phthalimidine intermediate is obtained directly by treating the ortho-acylbenzoic acid with the primary amine, RNH2/i. in the presence of NaCHBH3n^r protic solvents such as methanol or ethanol, are used or in the presence of NaBH^, MgSO4 and the hydrochloride of the primary amine when polar aprotic solvents such as acetonitrile, DMF, 'or HMPA are used. In both solvent systems, it is not particularly critical with regard to reaction temperature, time and ratio between reactants, but the following conditions are typically used when the aprotic system is used: the primary amine, as an equimolar mixture of the free base and its acid addition salt, are present in excess relative to the acylbenzoic acid, and the sodium borohydride is added portionwise over several hours to the solution of the amine and the acylbenzoic acid-MgSO 4 slurry. Another method for the preparation of the compound Ia involves treatment of an o-diacylbenzene with a primary amine, RNH2/ in the presence of a reducing agent such as NaBH^ or the like, in a protic solvent at a reaction temperature of 20 - 35° C according to the following reaction core where all symbols are as previously indicated:

Another method for preparing the compound of formula Ia where either R 1 or R 2 is hydrogen involves treating the phthalic anhydride with the primary amine, RNH 2 / to obtain a phthalimide intermediate as reduction with e.g. zinc dust in glacial acetic acid gives the phthalimidine which, on treatment with a suitable lithium alkyl, LiR 2 , or Grignard reagent, R 2MgX', gives the desired isoindole according to the following scheme: Another method for the preparation of the compound 12 o of formula Ia, especially when either R or R is hydrogen and when the benzoidation of the isoindole has an electron-releasing substituent (herein denoted by X' selected from the group set forth under X and Y as set forth above), such as alkyl, halogen, or the like, the Friedel-Crafts alkylation of a meta-X<1->substituted benzoic acid. The following equation shows this method:

The Friedel-Crafts product formed spontaneously cyclizes to form the phthalimidine intermediate which can be N-alkylated by treatment with RI in the presence of a reducing agent such as sodium hydride in a solvent system such as dimethylformamide or a 1:1 mixture of DMF and benzene. The formed N-substituted phthalimidine gives, on treatment with a suitable lithium alkyl (LiR^) or Grignard reagent (R^MgX) as previously stated, the desired R 1 - or R 2 -substituted isoindole which has X' substituted in the 5-position :

Suitable Friedel-Crafts reagents for the above reaction may be N-hydroxymethylchloroacetamide or N-hydroxymethylphthalimide. The preferred Friedel-Crafts catalyst is concentrated sulfuric acid. Typically, the reaction is carried out without a solvent, or in solvents such as sulfuric acid and the like, at a temperature from approx. 0° C to approx. 30°C.

The above-mentioned methods can be used individually or can be modified according to the most convenient way in the preparation of the isoindoles required for the preparation of the present anthracenimines.

"Gasoline" production

The unstable benzene reactant (used herein to include both carbocyclic and heterocyclic compounds) can be prepared by a variety of methods including flash photolysis of a core-substituted cyclic aromatic compound such as benzene or pyridine, or by treatment with an ortho-dihalogen or a monohalogen -substituted cyclic aromatic compound with a strong base:

For the purposes of the present invention, it is preferred that the benzene illustrated above is formed in situ for instantaneous Diels-Alder condensation with the isoindole Ia. The following equation representatively illustrates this reaction for the preferred benzoic embodiments:

Suitable bases for the above reaction can be selected from among the alkali and alkaline earth metals and their corresponding oxides, hydroxides, alkoxides, alkali metal amides, alkali metal alkyls and the like. The most preferred bases are magnesium metal, and alkali metal alkyls such as methyllithium, butyllithium, phenyllithium, potassium t-butoxide, and alkali metal amides such as lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidide and sodium amide. It is not particularly critical with regard to the identity of the reaction solvent, and suitable solvents can be selected from hydrocarbons such as benzene, hexane and cyclohexane, oxygenated solvents such as ether, dioxane, tetrahydrofuran and anisole. Typically, the reaction is carried out at from approx. -70° C to the return temperature.

Another method of preparing the present anthracenimines involves the Diels-Alder condensation of a substituted 1,3-butadiene and a naphthalene imine followed by aromatization of the newly formed 6-membered ring by addition of bromine and elimination of hydrogen bromide by treatment of the brominated intermediate with a base such as triethylamine:

where all substituents are as previously indicated.jj

Such naphthaleneimines, Ib, (substituted 1,4-dihydro-naphthalene-1,4-imines) are described in US Patent Application No. 498,485 filed August 19, 1974, which application is incorporated herein by reference. Typically, no solvent is required for the first step Diels-Alder reaction, but suitable solvents for this step include THF, p-dichlorobenzene and toluene, at a reaction temperature of from ca. 25° C to 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 solvents such as acetic acid, carbon tetrachloride, chloroform, THF or benzene. The final elimination reaction is typically carried out in solvents such as benzene or THF in the presence of a base such as triethylamine, sodium hydroxide or dibenzoe-cyclononane (DBN).

Finally, the present anthracenimines can be prepared by derivatization operations on the anthracenimine ring itself to provide certain embodiments of the invention. The foal-. The following reaction illustrates such a case, the benzo embodiment being shown, but the following methods apply to all embodiments of the present invention:

where for illustration the benzoide rings are shown to be substituted only with the leaving group L, but it is not critical and even preferred that L is the only benzoide substituent in this embodiment of the invention. L can be any chemically modifiable group such as amino, hydroxy, bromine, iodine, chlorine and the like which can be transferred to the function X by known methods. X is as previously indicated, and particularly in this aspect of the invention, it includes groups such as cyano, trifluoromethylthio, methylthio and the like. Suitable solvents for this process feature according to the invention include dimethylformamide, hexamethylphosphoramide (HMPA), THF, quinoxaline and the like. Typically, the reaction is carried out at from approx. 25° C to the return temperature.

Other derivation reactions which do not include critical reaction parameters and which are representatively illustrated by the examples which follow9 include: N-alkylation, N-acylation and reduction, reductive N-alkylation, and electrophilic substitution on the benzoide rings.

Reductive alkylation

The imine nitrogen in the present anthracenimines can be alkylated, e.g. by the Borch method, according to the following:

where- all symbols are as above, and R defined by R, is equal to or different from R. The reaction is carried out in a polar organic solvent such as methanol, in the presence of a reducing agent such as NaCNBH3 at a temperature from approx. 20° C to the supply return temperature. Preferably, R is alkyl, alkylcycloalkyl, aryl, aralkyl such as benzyl, or hydrogen.

N-alkylation

As above, the NH-imine (Ic) can be N-alkylated by treatment with RX where X is halogen, such as iodine or bromine, or an ester group such as tosyl, e.g. in the presence of a base such as sodium bicarbonate, sodium methoxide or the like, in a polar organic solvent such as methanol, HMPA, DMF or DMSO, at a temperature from approx. 20° C to the return temperature. In this reaction, R is preferably alkyl, alkenyl, alkylcyclbalkyl or aralkyl such as benzene.

Acylation/reduction

.As above, the NH-imine (Ic) can be N-acylated by treatment with an acyl halide such as RCOC1 or N-carboalkoxylated by treatment with RCC^Cl as C2H5C02C1. Both methods are carried out in the presence of a non-critical base such as triethylamine in an organic solvent such as benzene or chloroform at from approx. 20° C to the return temperature. By reduction with reducing agents such as lithium aluminum hydride, in solvents such as ether, THF or benzene or the like, respectively:

and such N-acylated and N-carboalkoxylated (carbamate) compounds are also useful in serving to protect the imine nitrogen during other derivatization methods below.

1) Nitriding

With regard to the preferred embodiments of the present invention, e.g. The 2-nitro derivatives according to the following equation:

where the conditions are not critical and nitrating agents such as nitronium tetrafluoroborate, in solvents such as tetramethylene sulfone, are suitable.

2) Amination

From the above-mentioned nitro compounds, e.g. The 2-amino compound by mild reduction, as by hydrogenation over palladium-on-carbon.

3) Diazotization

The corresponding diazonium salt is prepared by treating the 2-amino compound with sodium nitrite in an aqueous acid such as hydrochloric or sulfuric acid. Such diazonium intermediates are useful in the preparation of other ring-substituted compounds listed below.

4) Carbinol formation

Hydrolysis of diazonium salts such as the above in aqueous acid yields ring-substituted hydroxyl compounds, such as the above-described 2-hydroxy compounds.

5) Esterification

Ring-substituted alkoxy compounds are prepared from the carbinol described above, e.g. the 3-alkyl compounds are readily prepared by forming the 2-carbinol with dialkyl sulfate in the presence of a base such as sodium hydroxide in a suitable solvent.

6) Further diazotizations

Based on the above preferred embodiments (II), halogen- and cyano-ring-substituted compounds are prepared from the corresponding diazonium salt by treating the latter with an acidic solution of an alkali metal halide or cuprocyanide. Thus, e.g. The 2-iodo, 2-bromo and 2-chloro compounds of formula II by treating the 2-diazonium chloride of the compound of formula II with potassium iodide, potassium bromide or potassium chloride in acid.

7) Removal of ring substituents

Ring substituents, X and Y, in formula I and especially formula II can replace hydrogen according to the following equations:

where e.g. X is chlorine or amino (reaction 1), or X is amino (reaction 2).

8) Direct replacement of halogen

The ring substituents Z or Y in formula I or II which are halogen, especially iodine, can be replaced by alkyl according to known methods. Thus gives e.g. treatment of the 2-iodo compound of formula I with a mercury dialkyl, Hg(SCF2)2', e.g. in a solvent such as HMPA or a cupric dialkyl (e.g. Cu(CH 3 ) 2 in benzene or the like) the corresponding 2-alkyl compound of formula II, e.g. The 2-SCF3 compound of formula II and the 2-CH3 compound of formula II.

9. Halogenation

Halogenation (especially chlorination and bromination) by known methods, e.g. in the presence of an iron catalyst, easily gives halogen ring-substituted compounds of formula I. 2-halogen compounds of formula II are easily obtained in this way.

10) Carbination of Grignard compound

To illustrate, the 2-COOH compound of formula II is readily prepared from the 2-iodo compound of formula II or the 2-bromo compound of formula II by reacting the latter with Mg metal in a solvent such as THF to form the Grignard reagent The 2-MgI or 2-MgBr compound of formula II which is then treated with carbon dioxide and then water to form the 2-COOH compounds.

11) Electrolytic oxidation

The preferred compounds of formula II can be prepared according to the generally known method (Chem. Comm.,

870 (1974)):

• The invention also encompasses the preparation of non-toxic, pharmaceutically acceptable salts, esters and amide derivatives of compounds of formula I. Acid addition salts are preferred. Such acid addition salts of the anthracenimine compounds are prepared by mixing a solution of the anthracenimine compounds with a solution of a pharmaceutically acceptable, non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid and the like.

The method compounds which are psychosedatives (minor tranquilizers) are capable of producing anxiety relief without causing excessive sedative effect or sleep at a unit dose level of from approx. 0.1 to approx. 500 mg per kg body weight, or a daily dose level of from approx. 0.4 to approx. 2000 mg per kg body weight. In addition, the anthracenimines produced according to the invention are useful as muscle relaxants, anticonvulsants and in the treatment of extrapyramidal disorders in the above dose levels. Of course, the exact level used will depend on the disease history of the animal or human being treated, and ultimately the exact treatment level that falls within the above stated limits will be left to

doctor's discretion.

The process compounds can be used in pharmaceutical preparations and preferably in unit dose forms such as tablets, pills, parenteral solutions or the like. In the manufacture of solid preparations such as tablets, the active ingredient is mixed with a pharmaceutical carrier, i.e. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other pharmaceutical diluents, e.g. water, to form a solid for preparation containing a homogeneous mixture of one of the present anthracenimines, or a non-toxic, pharmaceutically acceptable salt, ester or amide derivative thereof.

Such a pre-preparation is then divided into unit dose forms of the type described above containing from 0.1 to approx. 500 mg of the active ingredient produced according to the invention. The tablets or pills with the new compounds can be coated or otherwise worked up into a dosage form which gives the advantageous prolonged action of the present anthracenimines.

The liquid forms in which the process compounds can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions.

The pharmaceutical anthracenimine preparations can be administered orally, parenterally or rectally. Orally, they can be administered in tablets, capsules, suspensions or syrups, the preferred dosage form being a pressed tablet containing from 0.1 to approx. 500 mg active ingredient.

The following examples further illustrate the invention.

Example la

2, 3-dimethylphthalimidine

A solution of 11.8 g (0.076 mol) of 2-ethylbenzoic acid

in 25 ml of absolute mgethanol is carefully treated with 2.5 ml of concentrated sulfuric acid and heated at reflux. After 4 hours, the mixture is poured onto ice and the oily product is extracted into ether. Evaporation of the washed (water; 5% aqueous sodium bicarbonate

nat and water) and dried extract under reduced pressure gives methyl-2-ethylenezoate as the remaining colorless oil in a yield of 86%.

A mixture of 10.7 g (0.065 mol) methyl-2-ethylbenzoate, 12.5 g (0.07 mol) N-bromosuccinimide, 50 mg benzoyl peroxide and 125 ml carbon tetrachloride is stirred under 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 giving methyl 2-(1-bromomethyl)benzoate as the remaining yellow oil in quantitative yield.

A solution of 0.156 mol of methyl-2-(1-bromomethyl)-benzoate and 24.0 g (0.312 mol.) of 40% aqueous methylamine in 230 ml of absolute methanol is kept at room temperature for 20 hours. The solvent is evaporated under reduced pressure and the residue is distributed between chloroform and water. Evaporation of the washed (water, 2N hydrochloric acid and water) and dried chloroform extract under reduced pressure gives the crude product as the residual oil. Distillation gives pure 2,3-dimethylphthalimidine as a liquid, colorless oil.

2- alkyl- 3- methylphthalimidines

Following the procedure in Example 1a, methyl-2-(1-bromomethyl)benzoate is reacted with the appropriate primary amine to give the following 2-alkyl-3-methylphthalimidines:

1) 2-benzyl~3-methylphthalimidine,

k.p. 158 - 162° C/0.1 mm Hg

2) 2-ethyl-3-methylphthalimidine,

k.p. 97 - 105° C/o.l mm Hg

3) 2-cyclopropyl-3-methylphthalimidine,

k.p. 120° C/0.2 mm Hg

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

k.p. 172 - 175° C/0.2 mm Hg

5) 2-propyl-3-methylphthalimidine,

k.p. 98 - 104°C/0.1 mm Hg

6) 2-butyl-3-methylphthalimidine,

k.p. 109 -. 114° C/0.1 mm Hg

7) 2-allyl-3-methylphthalimidine,

k.p. 102 - 104° C/0.15 mm Hg

8) 2-cyclopropylmethyl-3-methylphthalimidine,

. k.p. 131 - 133° C/0.1 mm Hg

Example lb

1, 2, 3-trimethylisoindole

In a dry apparatus kept in a nitrogen atmosphere, 25 ml of 1.9 M methyllithium in ether is added dropwise to a stirred solution of 6.4 g (0.04 mol) of 2,3-dimethylphthalimidine in 100 ml of absolute ether. After stirring overnight at room temperature, the cooled mixture is hydrolysed by the dropwise addition of 40 ml of water. The ether layer is separated, washed repeatedly with water and dried over anhydrous magnesium sulfate while stirring under nitrogen and cooling in an ice bath. The filtered solution is evaporated under reduced pressure and the remaining dark brown solid is dried at 0.5 mm, whereby 5.7 g (90%) of 1,2,3-trimethylisoindole is obtained.

2-substituted-1,3-dimethylisoinddler

Following the procedure described in Example 1b, the appropriate 2-substituted-3-methylphthalimidine is treated with methyllithium to obtain the following 2-alkyl-1,3-dimethylisoindoles:

1) 2-benzyl-1,3-dimethylisoindole

2) 2-ethyl-1,3-dimethylisoindole

3) 2-cyclopropyl-1,3-dimethylisoindole

4) 2-propyl-1,3-dimethylisodinol

5) 2-butyl-1,3-dimethylisoindole

6) 2-allyl-1,3-dimethylisoindole

7) 2-(3-(tetrahydropyranyl-2-oxy}-propyl-1,3-dimethylisoindole).

8) 2-cyclopropylmethyl-1,3-dimethylisoindole

9) 5-chloro-, 5-iodo- and 5-bromo-2-cyclopropyl-1,3-dimethylisoindole 10) 5-chloro-, 5-iodo- and 5-bromo-2-(3-(tetrahydropyranyl)- 2-oxy)-propyl-1,3-dimethylisoindole 11) 5-chloro-, 5-iodo- and 5-bromo-2-propyl-1,3-dimethylisoindole 12) l-butyl-2,3-dimethylisoindole from n -butyllithium and 2,3-dimethylphthalimidine 13) l-ethyl-2,3-dimethylisoindole, from ethyllithium and 2,3-dimethylphthalimidine 14) l-vinyl-2,3-dimethylisoindole from vinyllithium and 2,3-dimethylphthalimidine

Example lc

2- f 3-( tetrahydropyrariyl- 2- oxy)- propyl)- 3- methylphthalimidine

A mixture of 7.35 g (0.036 mol) 2-(3-hydroxypropyl)-3-methylphthalimidine, 3.3 g (0.039 mol) dihydropyran, 80 mg p-toluenesulfonic acid monohydrate and 75 ml absolute ether is stirred at room temperature for 24 hours. The 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 the residue at 0.5 mm Hg gives 2-(3-tetrahydro-pyranyl-2-oxy)-propyl}-3-methylphthalimidine as a viscous yellow oil in quantitative yield.

Example ld

11-(3-dimethylaminopropyl)-9,10-dimethyl-9,10-dihydroanthracene-9, 10- imine

To a stirred solution of 1.45 g (0.0052 mol) 11-(3-hydroxypropyl)-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 1/4 g (0.00525 mol ) triphenylphosphine and 17 ml of dry benzene at room temperature and under nitrogen, 0.95 g (0.00535 mol) N-bromosuccinimide is added in portions. 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 under reduced pressure and the residue is triturated with absolute ether. The precipitate of succinimide is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue is triturated with hot hexane and this mixture is cooled. After filtering off the precipitated triphenylphosphine oxide, the hexane filtrate is evaporated to dryness under reduced pressure, which gives the product as a residual oil. Short path distillation at 95 - 105° C and 0.2 mm Hg gives 0.9 g (56%) of viscous yellow oil.

The base is transferred to the hydrochloride salt by treatment with an ethanolic solution of one equivalent of hydrogen chloride in ethanol. Dilution with absolute ether precipitates the salt, which is recrystallized from cold absolute ethanol-ether, whereby 11-(3-dimethylaminopropyl)-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine hydrochloride is obtained as white crystals.

By following the procedure described in example ld except that the 11-(3-hydroxypropyl)-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine from example ld is replaced by an equivalent amount of 2-chloro-, 2- iodo- and 2-bromo-11-(3-hydroxypropyl)-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 2-chloro-, 2-iodo- and 2-bromo-11 are obtained respectively -(3-dimethylaminopropyl)-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine.

Example

9, 10, ll- trimethyl- 9, lO- dihydroanthracene- 9, 10- imine Step A: 1, 2, 3- trimethylisoindole

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

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

The remaining a,a<1->dibromo-o-diethylbenzene is dissolved in 800 ml of absolute ether. A solution of 40 g (0.87 mol) methylhydrazine in 50 ml of absolute ether is added dropwise to the stirred solution under nitrogen. A gummy precipitate separates. After 3 hours of stirring and standing overnight, the ether is decanted. The residue is dissolved in 625 ml of water and treated with 375 ml of 40% d.g sodium hydroxide solution and the mixture is stirred under reflux for 1.5 hours. After cooling, the precipitated crude product is collected, washed with water and dissolved in 600 ml of ether. The ether solution is washed repeatedly with water and dried over aqueous magnesium sulfate while stirring and cooling in an ice bath. The filtered solution is evaporated under reduced pressure and the remaining dark yellow solid is triturated with petroleum ether, filtered and dried in vacuum, whereby 15.56 g of 1,2,3-trimethylisoindole is obtained.

Step B: 9,10,ll-trimethylanthracene-9,10-dihydro-9,10-imine

In a dry apparatus kept under a nitrogen atmosphere, 1.7 g (0.07 mol) of magnesium shavings are suspended in 10 ml of dry tetrahydrofuran and the mixture is heated under reflux. The reaction is initiated by adding a few drops of 2-fluorobromobenzene and a mixture of 9.65 g (0.06 mol) of 1,2,3-trimethylisoindole and 12.3 g.

(0.07 mol) of 2-fluorobromobenzene in 70 ml of dry tetrahydrofuran is added dropwise over the course of 1 hour. Stirring under reflux is continued for 2 hours. The cooled mixture is hydrolyzed by the dropwise addition of 25 ml of water and the organic layer is decanted. The solvent is evaporated under reduced pressure and the remaining dark oil is dissolved in benzene. The solution is filtered through diatomaceous earth, diluted with ether and washed with water. The dried extract is evaporated to dryness under reduced pressure giving 15.6 g of crude 9,10,11-trimethylanthracene-9,10-dihydro-9,10-imine as a residual dark red oil which is transferred to the fumaric acid salt by dissolution in 30 ml of ethyl acetate and addition to a solution of 10.4 g (0.09 mol) of fumaric acid in 100 ml of absolute methanol. Dilution with 320 ml of ethyl acetate and inoculation precipitates 10.05 g of the crude salt as a purple solid. Two recrystallizations from methanol:ethyl acetate (1:1), using decolorizing charcoal, give 4.38 g of the fumarate salt of 9,10,11-trimethylanthracene-9,10-dihydro-9,10-imine as white crystals, C -^^H^yN • 1, 5C^H^O .

By following the procedure in Example 1, step A, except that the o-diethylbenzene in Example 1 is replaced by an equivalent amount of: o-ethyltoluene, o-dipropylbenzene, 2-propyl-ethylbenzene, o-bis-(B,B,B -trifluoroethyl)-benzene, o-dibutylbenzene and 2-butyl-propylbenzene are obtained respectively. 1,2-dimethylisoindole, 1,3-diethyl-2-methylisoindole, 1,2-dimethyl-3-ethylisoindole, 1,3-bis-(trifluoromethyl)-2-methylisoindole, 1,3-dipropyl-2-methylisoindole and 1-ethyl-2-methyl-3-propylisoindole.

When the above-mentioned isoindoles individually replace the 1,2,3-trimethylisoindole in example 1, step B, the following are obtained respectively: 9,11-dimethyl-9,10-dihydroanthracene-9,10-imine, 9,10-diethyl -11-methyl-9,10-dihydroanthracene-9,10-imine, 9,11-dimethyl-10-ethyl-9,10-dihydroanthracene-9,10-imine, 9,10-trifluoromethyl-11-methyl-9 ,10-dihydroanthracene-9,10-imine, 11-methyl-9,10-dipropyl-9,10-dihydroanthracene-9,10 and 11-methyl-9-ethyl-10-propyl-9,10-dihydroanthracene-9 ,10-imine.

Following the procedure in Example 1, Step A, except that the o-diethylbenzene in Example 1 is replaced by an equivalent amount of 4-chloro-, 4-iodo-, and 4-bromo-1,2-diethylbenzene,

and the methylhydrazine is replaced by an equivalent amount of pro-

pylhydrazine, cyclopropylhydrazine and yTHP-oxy-propylhydrazine, 5-chloro-, 5-iodo- and 5-bromo-2-propyl-1,3-dimethylisoindole are obtained respectively, 5-chloro-, 5-iodo- and 5-bromo- 2-cyclopropyl-1,3-dimethylisoindole and 5-chloro-, 5-iodo- and 5-bromo-2-(γ-THP-oxy-propyl)-1,3-dimethylisoindole, where THP denotes tetrahydropyranyloxy.

When the above-mentioned isoindoles are individually replaced by 1,2,3-trimethylisondole from example 1, step B, 2-chloro-, 2-iodo- and 2-bromo-11-propyl-9,10-dimethyl-9 ,10-dihydroanthracene-9,11-imine, 2-chloro-, 2-iodo- and 2-bromo-11-cyclopropyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine and 2-chloro -, 2-iodo and 2-bromo-11-(γ-THP-oxy-propyl)-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, and mild acid hydrolysis of the latter compounds gives 2- chloro-, 2-iodo—-and 2-bromo-11-hydroxypropyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine.

Example 2 (a).

11th yl-1,4,9,10-tetramethyl-9,10-dihydroanthracene-9,10-imine

A solution of 1.0 g (0.004 mol). 1,4,9,10-tetra-methyl-9,10-dihydroanthracene-9,10-imine and 1.8 g (0.04 mol) of acetaldehyde in 20 ml of acetonitrile are stirred and treated with 0.75 g (0.012 mol ) sodium cyanoborohydride. 0.5 ml of glacial acetic acid is added in portions over the course of 10 minutes and the mixture is stirred at room temperature for 2 hours. After the addition of a further 0.5 ml of glacial acetic acid, stirring is continued overnight. The bulk of the solvent is evaporated under reduced pressure and the residue distributed between 5% aqueous sodium hydroxide and ether.The washed and dried ether extract is evaporated under reduced pressure to give 0.£5 g (58%) of the product as a residual oily solid.

The base is transferred to the hydrogen oxalate salt by dissolving it in absolute ethanol saturated with oxalic acid. The salt is separated and recrystallized twice from absolute ethanol, whereby 11-ethyl-1,4,9,10-tetramethyl-9,10-dihydroanthracene-9,10-imine hydrogen oxalate is obtained as white crystals.

Example 3 (a)

9, 10- dimethyl- 9, lO- dihydroanthracene- 9, 10- imine

A solution of 2.3 g (0.0074 mol) of 11-benzyl-9,10-methyl-9,10-dihydroanthracene-9,10-imine in 25 ml of glacial acetic acid is stirred with 200 mg of 5% palladium/carbon under hydrogen at atmospheric pressure until the absorption of hydrogen is complete. The catalyst is removed by filtration and evaporation of the filtrate under reduced pressure gives the crude product as the remaining oily solid. A solution of the residue in benzene ether (1:1) is extracted with 0.5 M citric acid. The aqueous acidic extract is cooled and made strongly basic with 40% aqueous sodium hydroxide. The oily base is extracted in benzene-ether (1:1). Evaporation of the washed and dried organic extract under reduced pressure gives the product as oily white crystals. Sublimation at 70° C. and 0/05 mm Hg gives 0.35 g (21%) of white crystals.

Example 4 (a),

H- carboethoxy- 9 710- dimethyl- 9, lO- dihydroanthraceri- 9, 10- imine

22/1 g of 9,10-dimethyl-9,10-dihydroanthracene-9,10-imine in 150 ml of chloroform and 10.1 g of triethylamine are reacted at 0° C with stirring, 12.7 g of ethyl chloroformate in 25 ml of chloroform are added while stirring is continued for 2 hours at 25° C. The mixture is poured into 300 ml of ice water. The organic phase is separated and washed with ice water, 5% hydrochloric acid, 5% aqueous sodium bicarbonate and then with water, and dried.

Example 5a i

11-carboethoxy-2-nitro-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine

14.6 g of the product from example 4a in 25 ml of tetramethylene sulfone is added dropwise to a stirred suspension of 7.3 g of nitronium tetrafluoroborate in 50 ml of tetramethylene sulfone at 15° C. The reaction mixture is poured after 2 hours at 30° C into 300 g of ice water and the product is collected by filtration .

The 2-nitro-9,10-trimethyl product is obtained when the product

from example 4a is replaced with the product from example 1 in example 5a.

Example 6a

11-carboethoxy-2-amino-9,10-dimethyl-9,10-dihydroanthracene-9, 10- imine

16.9 g of the product from example 5a in 100 ml of ethanol is hydrogenated over 1.0 g of 5% Pd/C at 25° C and atmospheric pressure for 2 hours, and the product is collected by filtration and evaporation.

Example 7a

11-carboethoxy-2-hydroxy-9,10-dimethyl-9,10-dihydroanthracene-9, 10-imine

9.9 g of the product from example 6a in 150 ml of ice water and 6.4 ml of concentrated sulfuric acid are treated dropwise with 2.34 g of sodium nitrite in 20 ml of water at 0° C. The resulting solution (diazonium salt) is added to 6.4 g of concentrated sulfuric acid in 200 ml of water at 80° C. The reaction mixture is cooled to 0° C after 20 minutes, and the product is collected by filtration..

Example 8a

11-carboethoxy-2-methoxy-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine

4.9 g of the product from example 7a in 100 ml of methanol and 5.0 g of diazomethane in ether are left overnight at 25° C. Evaporation of the solvent gives the product.

Example 9a

9, 10, 11- trimethyl- 2- methoxy- 9, 10- dihydroanthracene- 9, 10- imine

2.5 g of the product from example 8a in 50 ml of ether is added dropwise to a suspension of 2.0 g of lithium aluminum hydride in 100 ml of ether. Heating under reflux is continued for 8 hours. Water is added carefully and the inorganic material is separated by filtration. Evaporation of the filtrate gives the product.

Example 10a

2- bromo- 9, 10- ll- trimethyl- 9, lO- dihydroanthracene- 9, 10- imine

2.35 g of the product from example 1 and 0.03 mol of thallium (III) acetate in 100 ml of carbon tetrachloride are added dropwise while the mixture is refluxed for 30 minutes. The mixture is filtered, washed with aqueous sodium metabisulfite, aqueous sodium bicarbonate and water. The solvent is evaporated and the residue taken up in chloroform and filtered through a short column of aluminum oxide to obtain the product.

Example lia

2- amino- 9, 10- 11- trimethyl- 9, 10- dihydroanthracene- 9, 10- imine

7.2 g of the 2-iodo product from example 34a and bis-trimethylsilylamidocopper, prepared in situ from hexamethyldi-silazane, n-butyllithium and copper (I)-iodide in 100 ml of dry pyridine are heated under reflux for 20 hours. The solvent is evaporated and 100 ml of methanol is added. The methanol suspension is stirred at 35° C. for 2 hours and then the solvent is evaporated. The reactive ion mixture is extracted with dilute aqueous fumaric acid. The acid extract is made alkaline with aqueous ammonia and then extracted with ether. The ether extract is dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated to obtain the product.

Example 12a

9, 10-dimethyl-II-ethyl-9, 10-dihydroanthracene-9, 10-imine

2.21 g of the product from example 3a and 1.56 g of ethyl iodide in 100 ml of acetonitrile are suspended with 2.0 g of sodium bicarbonate at 45° C. for 6 hours, the solvent is evaporated, and the residue is distributed between 5% aqueous ammonia and ether. The ether solution is separated, dried over sodium sulfate, filtered and evaporated to obtain the product.

Example 13a

9, 10- dimethyl- 11- propyl- 9, 10- dihydroanthracene- 9, 10- imine

2.21 g of the product from example 3a and 1.06 g of propanal in 45 ml of acetonitrile are added to 2.5 g of sodium cyanoborohydride. The pH is adjusted to 7.0 with aqueous acetic acid, and the mixture is stirred overnight. After removal of the solvent, aqueous potassium hydroxide is added and the mixture is extracted with ether. The extract is dried, filtered and evaporated to obtain the product.

Example 14a

11-carboethoxy-2-acetyl-9,10-dimethyl-9,10-dihydroanthracen-9, 10-imine

14.6 g of the product from example 4a is added to a solution of 13.9 g of methyl-oxocarbonium-hexa'-fluoroantimonate in 50 ml of nitromethane. The reaction mixture is poured into water after 3 hours at 45° C, extracted with ether and the extract is washed with water and dried over sodium sulphate, filtered and the filtrate is evaporated to obtain the product.

Example 15a

3, 9, ll- trimethyl- 9, lO- dihydroanthracene- 9, 10- imine Step A: 2, 5- dimethylphthalimidine (A)

48.63 g of 4-methylphthalic anhydride, 40.5 g of methylamine hydrochloride, 49.23 g of sodium methylcarbonate and 1000 ml of acetic acid as a mixture are heated under reflux for 2 hours. The mixture is filtered and cooled to 75° C, 95 g of zinc dust is quickly added and the mixture is refluxed for 4 hours, then filtered and the solvent is evaporated to a small volume.

600 ml of saturated aqueous sodium bicarbonate are added and the solution is extracted with 4 x 200 ml of chloroform. The extracts are washed with 100 ml sodium bicarbonate solution, 100 ml water, 250 ml saturated sodium chloride solution and dried over magnesium sulphate. Removal of the solvent gives 25.1 g of product A as a waxy solid.

Step B: 1, 2, 5- trimethylisoindole ( B)

55 ml (1.8 M) of methyllithium in ether is added dropwise to a solution of 11.9 g of compound A in 200 ml of ether under nitrogen, the mixture is stirred for 5 hours, and 100 ml of water is added dropwise. The ether layer is washed with saturated sodium chloride solution and dried over potassium carbonate. Removal of the solvent gives the product B.

Step C:

A portion of a solution of 12.25 g of 2-bromofluorobenzene in 50 ml of THF is added to a mixture of 1.68 g of magnesium, 9.2 g of 1,2,5-trimethylisoindole and 50 ml of THF under nitrogen. The Grignard reaction is initiated and the remainder of the bromofluorobenzene solution is added dropwise. The mixture is heated under reflux for 3 hours and the solvent is removed. The residue in 250 ml of benzene is washed with 2 x 100 ml of saturated ammonium chloride, 3 x 100

ml of water, 150 ml of saturated sodium chloride and dried over sodium sulphate, the solvent is removed and the residue is extracted with hexane. The oil obtained by evaporation of the hexane extracts is purified by chromatography over silica gel by elution with chloroform. The pure base from the chromatography (1.1 g) is dissolved in 15 ml of ethyl acetate and added to 15 ml of a warm, saturated solution of furaic acid in 2-propanol. The solid that forms is collected (1.1 g) and recrystallized from ethyl acetate to give 3,9,11-trimethyl-9,10-dihydroanthracene-9,10-imine-sesqui-hydrogen fumarate.

Example 16a

2, 9, ll- trimethyl- 9, 10- dihydroanrhtacene- 9, 10- imine

Step A: 6-methylphthalimidine (A)

A mixture of 27.2 g of m-toluenecarboxylic acid, 35.44 g of N-hydroxyphthalimide and 200 ml of concentrated sulfuric acid is heated

at 100° C for 24 hours. The cooled solution is poured onto crushed.

ice and the solid is collected, washed with benzene, followed by 5% sodium hydroxide solution and dried, thereby obtaining 12.85 g of compound A after recrystallization from benzene.

Step B: 2, 6-dimethylphthalimidine (B)

5.0 g of a 57% oil dispersion of sodium hydride is added to a stirred solution of 14.5 g of compound A and 40 g of methyl iodide in 400 ml of DMF under nitrogen. The mixture is kept at 25° C. for 24 hours, the solvent is removed and the residue is dissolved in 400 ml of water. The aqueous solution is extracted with chloroform and the chloroform is evaporated. The remaining oil is dissolved in ether, dried over magnesium sulphate and the ether is evaporated. The residue is dissolved in ethyl acetate (50 ml) and gradually diluted with 200 ml of hexane, the solid is collected and dried, thereby obtaining 6.3 g of compound B.

Step C: 1, 2, 6-trimethylisoindole (C)

By applying the method in step B of example 15a, product C is obtained as a yellow-orange powder.

Step D: 2,9,11-trimethyl-9,10-dihydroanthracene-9,10-imine (D)

By applying the procedure in step C of example 15a with 1,2,6-trimethylisoindole, compound D and its sesqui-hydrogen fumarate salt are obtained.

Example 17a

9,11-dimethyl-9,10-dihydroanthracene-9,10-imine.

Step A: 1, 2-dimethylisoindole (A)

53 ml of a 1.9 M methyllithium ether solution is added dropwise to a suspension of 14.1 g of N-methyl-phthalimidine in 200 ml of ether and nitrogen, the mixture is stirred for 4 hours followed by the dropwise addition of 150 ml of water. The layers are separated and the water phase is extracted with 100 ml of ether. The organic extracts are washed with saturated sodium chloride and dried over potassium carbonate, the solvent is removed and the residue is dried, whereby compound A is obtained as a yellow-orange oil.

Step B: 9, 11- dimethyl- 9, 10- dihydroanthracene- 9, 10- imine (B)

Applying the procedure in step C of Example 15a with 1,2-dimethylisoindole gives compound B and (using oxalic acid instead of fumaric acid) its hydrogen oxalate salt.

Example 18a

2- chloro- 9, 11- dimethyl- 9, 10- dihydroanthracene- 9, 10- imine Step A: , 6- chlorophthalimidine ( A)

8.86 g of N-hydroxymethylphthalimide is added to a solution of 7.83 g of m-chlorobenzoic acid in 250 ml of concentrated sulfuric acid, the solution is kept at 100° C. for 18 hours, cooled, and poured over 1500 g of ice. The solid that separates is collected, washed with water and dried, whereby 8.0 g of product is obtained. Recrystallization from 2-propanol gives compound A.

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

To a mixture of 4.3 g (0.1 mol) of sodium hydride as a 57% oil dispersion, and 100 ml of benzene is added a suspension of 16.75 g of compound A in 250 ml of dimethylformamide. When the evolution of gas subsides, the mixture is heated on a steam bath for 2 hours and cooled, 21.3 g of methyl iodide in 100 ml of benzene are added dropwise, after 18 hours the mixture is filtered and the filtrate is evaporated. The residue is mixed with water, filtered and dried, whereby 10.52 g of compound B are obtained after recrystallization from carbon tetrachloride-hexane.

Step C: 6-chloro-1,2-diethylisoindole (C)

By following the procedure in step B of example 15a, compound C is obtained when B in example 18a is used instead of compound A in example 15a.

Step D: 2-chloro-9,11-dimethyl-9,10-dihydro-

anthracene-9,10-imine (D)

By following the procedure in step C of example 15a, compound D (and its hydrogen fumarate salt) is obtained when compound B from example 15a is replaced by compound C from example 18a.

Example 19a

9- ethyl- 11- methyl- 9, 10- dihydroanthracene- 9, 10- imine Step A: 1- ethyl- 2- methylisoindole ( A)

A solution of 110 ml (0.95 M) ethyllithium. in

benzene is added to a suspension of 14.7 g of N methylphthaiimide in 200 ml of ether under nitrogen, stirred for 24 hours, 100 ml of water is added dropwise and the layers are separated. The ether layer is washed with 100 ml of saturated sodium chloride and dried over potassium carbonate. Evaporation of the solvent gives 15.05 g of compound A.

Step B: 9-ethyl-11-methyl-9,10-dihydroanthracene-9,10-imine (B)

By following the procedure in step C of example 15a, compound B (and its sesqui-hydrogen fumarate salt) is obtained when compound A from example 19a is used instead of compound B 1 example 15a.

Example 20a

11- henzyl- 9- methyl- 9, 10- dihydroanthracene- 9, 10- imine Step A: 2- benzyl- 1- methylisoindole ( A)

A solution of 50 ml (1.8 M) methyllithium in ether is added dropwise to a stirred solution of 13.1 g of N-benzyl-phthalimidine in 400 ml of ether under nitrogen and after 6 hours, 100 ml of water is added dropwise and the layers are separated. The aqueous layer is extracted with 100 ml of ether and the combined ether solutions are washed with 400 ml of saturated sodium chloride and dried over potassium carbonate. The solvent is removed, whereby 12.8 g of compound A is obtained.

Step B: 11-benzyl-9-methyl-9,10-dihydroanthracene-9,10-imine (B)

By following the procedure in step C of example 15a, compound B (and its sesqui-hydrogen fumarate salt) is obtained when compound A from example 20a is used instead of compound B in example 15a.

Example 21a

ll- ethyl- 9- methyl- 9, T0- dihydroarithracén- 9, 10- imine Step A: 2- ethyl- l- méthyTisoindole ( A)

60 ml of a 1.8 M solution of methyllithium in ether is added dropwise to a stirred solution of 16.1 g of 2-ethyl-phthalimidine in 300 ml of ether under nitrogen, the mixture is stirred for 18 hours, 200 ml of water is added dropwise and the layers are separated . The ether layer is washed with saturated sodium chloride and dried over potassium carbonate. The solvent is removed to obtain 15.1

g of compound A.

Step B: 11-ethyl-9-methyl-9,10-dihydroanthracene-9,10-imine (B)

By following the procedure in step C of example 15a, compound B (and its hydrogen fumarate salt) is obtained when compound A in example 21a is used instead of compound B in example 15a.

Example 22a

l- aza- 5, 10- dihydro- ll- methylanthracene- 5, 10- imine

30 ml of ethyl ether and 12 ml of 1.9 molar butyllithium in hexane are added to a dry flask under nitrogen and cooled to -70° C. in a dry ice/acetone bath. To this is added dropwise while stirring a solution of 4.0 g of 3-bromo-2-chloropyridine in 20 ml of ether, followed by 80 ml of a solution of 4.0 g of N-methylisoindole in ether, and the mixture is stirred at -70° C for 5 minutes. The reaction mixture is then heated rapidly to 20° C. and left with stirring overnight at 25° C. The reaction mixture is poured into water and extracted with 3 x 100 ml chloroform. The united

chloroform extracts are dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel eluting with 2% methyl alcohol/chloroform. The crude product obtained from the eluate is treated with fumaric acid in isopropanol to obtain the fumaric acid salt, after recrystallization from isopropanol-ethyl acetate (1:1).

By following the procedure in example 22a, 2-aza-5,10-dihydro-11-methylanthracene-5,10-imine is obtained when 3-bromo-2-chloropyridine from example 22a is replaced by, 4-bromo-3- chloropyridine; 2-aza-5,10-dihydro-5,10,11-trimethylanthracene-5,10-imine is obtained when N-methylisoindole and 3-bromo-2-chloropyridine from example 22a are replaced by 1,2,3-trimethylisoindole and 4 -bromo-3-chloropyridine; and 1-aza-5,10-dihydro-5,10,11-trimethylanthracene-5,10-imine is obtained when N-methylisoindole from example 22a is replaced by 1,2,3-trimethylisoindole.

Example 2 3a

1/ 3- diaza- 5, 10- dihydro- 11- methylanthracene- 5, 10- imine

In a dry apparatus kept in a nitrogen atmosphere, 11.7 ml of 1.8 molar methyllithium in ether is added dropwise to a stirred solution of 2.82 g (0.02 mol) 2,2,6,6-tetramethylpiperidine in 15 ml dry tetrahydrofuran. The solution obtained is added dropwise to a stirred solution of 2.62 g (0.02 mol) of N-methyl-isoindole and 2.05 g (0.02 mol) of 5-chloropyrimidine in 20 ml of dry tetrahydrofuran. After boiling overnight under reflux, the mixture is poured into a saturated ammonium chloride solution containing 3% concentrated ammonium hydroxide. The tetrahydrofuran layer is separated and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluted with 5% methanol/chloroform, to obtain the purified product as a residue by evaporation of the eluate.

When the N-methylisoindole from example 23a is replaced with one equivalent amount of 1,2,3-trimethylisoindole or 5-bromo-1,2,3-trimethylisoindole and 5-iodo-1,2,3-trimethylisoindole are obtained respectively. 1,3-diaza-5,10-dihydro-5,10,11-trimethyl-anthracene-5,10-imine, (6- and 7-)bromo and -iodo-1,3-diaza-5,10- dihydro-5,10,11-trimethyl-anthracene-5,10-imine. Similarly, when the 5-chloropyrimidine from example 23a is replaced by an equivalent amount of 5-chloro-1,2-diazine, 1,2-diaza-1-methyl-5,10-dihydroanthracene-5,10-imine is obtained.

Example 24a

1, lO-dimeth. yl- 4, 9- dihydro- 1H- naphth-(2, 3- d)- imidaz6T- 4, 9- imine

By following the procedure in Example 23a, 1,10-dimethyl-4,9-dihydro-1H-naphth-(2,3-d)-imidazol-4,9-imine is obtained from N-methylisoindole and the hetaryne formed in situ from 5-chloro-1-methyl-imidazole.

When the N-methylisoindole in example 24a is replaced with an equivalent amount of 1,2,3-trimethylisoindole, 2-cyclopropyl-1,3-dimethylisoindole or 2-(3-hydroxypropyl)-1,3-dimethylisondole, obtained respectively 1,4,9,10-tetramethyl-4,9-dihydro-1H-naphth-(2,3-d)-imidazole-4,9-imine, 1,4,9-trimethyl-10-cyclopropyl-4, 9-dihydro-1H-naphtho-(2,3-d)-imidazol-4,9-imine and 1,4,9-trimethyl-10-(3-hydroxypropyl)-4,9-dihydro-1H-naphtho- (2,3-d)-imidazole-4,9-imine.

Example 25a

6, 11, 13- trimethyl- 6, ll- dihydro- 4- azanaphthacene- 6, 11- imine

By following the procedure described in example 22a, 6,11,13-trimethyl-6,11-dihydro-5-azanaphthacen-6,11-imine is obtained from 1,2,3-trimethylisoindole and the hetaryne formed in situ from 3-bromo- 2-chloroquinoline.

Example 26a

7, 12, 13-trimethyl-7, 12-dihydrobeirzo-(j)-phenarithridin-7, 12-imine

By the method in example 22a, 7,12,13-trimethyl-7,12-dihydrobenzo-(j)-phenanthridin-7,12-imine is obtained from 1,2,3-trimethylisoihdol and the hetaryne formed in situ from 3-bromo-4 -chloro-quinoline.

Example 27a

13- methyl- 7, 12- dihydrobenzo-(b)- phenanthridine- 7, 12- imine

By the method in example 23a, 13-methyl-7,12-dihydrobenzo-(b)-phenanthridin-7,12-imine is obtained from N-methylisoindole and the hetaryne is formed in situ from 4-bromoisoquinoline.

Example 28a

13- methyl- 5, 12- dihydroriaphtho-( 3, 2-c)-( 1, 5)- naphthyridine- 5, 12- imine

By the procedure in example 23a, 13-methyl-5,12-dihydronaphtho-(3,2-c)-naphthyridine-5,12-imine is obtained from N-methylisoindole and the hetarynet formed in situ from 4-bromo-1,5-naphthyridine .

Claims (3)

1. Procedure for the preparation of a compound with the formula: where: R is hydrogen, acyl, alkyl, aryl, alkoxycarbonyl, aral alkyl, alkenyl, dialkylaminoalkyl, hydroxyalkyl, alkynyl, trialkylsilyl, alkylcycloalkyl or cycloalkyl; R 1 and R 2 , which are the same or different, are hydrogen, alkyl, haloalkyl, aralkyl, aryl, alkenyl or dialkylaminoalkyl; X and Y, which are the same or different, are halogen such as chlorine, fluorine, bromine, iodine; alkoxy, dialkoxymethyl, alkyl, cyano, dialkylaminoalkyl, carboxy, carboxamido, halogen substituted alkoxy, haloalkyl, haloalkylthio, allyl, aralkyl, cycloalkyl, aroyl, aralkyl, alkanoyl, aryl, substituted aryl, alkylthio, alkylsulfonyl, haloalkylsulfonyl, alkylsulfinyl, haloalkylsulfinyl, arylthio, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, nitro or dialkylsulfamoyl; n is 0 (X and/or Y is hydrogen), 1, 2, 3 or 4; is an unsaturated heterocyclic or heteropolycyclic group where the heteroatom or atoms A is N or NR where R is as indicated above; or the symbol represents the carbocyclic group benzo; with the caveat (when is benzo) that when X, Y, 1 2 R and R are hydrogen, R cannot be phenyl, methyl or hydrogen; and that when R 1 and R 2 are phenyl, (X)n is 1,4-dimethyl and Y is hydrogen, R cannot be methyl, benzyl or phenyl; and that when R 1 and R 2 are methyl, (X)n is 1,4-dimethyl and Y is hydrogen, R cannot be benzyl; and that when R<1> and R 2 are hydrogen, (X)n is 1,2,3,4-tetrafluoro and Y is hydrogen, R cannot be methyl; and that when R 1 and R 2 are phenyl, and X and Y are hydrogen, R cannot be hydrogen, carboxyethyl or methyl; and the non-toxic, pharmaceutically acceptable acid addition salts thereof, characterized in that an isoindole of the formula: is reacted with a hetaryne or benzyne with the formula: or, the imine nitrogen a compound of the formula: is subjected to reductive alkylation with a compound of the formula RCHO or RR'CO7 in. a polar organic solvent in the presence of a reducing agent, where R' is as defined under R and is equal to or different from R, and where R is preferably alkyl, alkylcycloalkyl, aryl, aralkyl or hydrogen; or by N-alkylation of the imine nitrogen in a compound of formula III with a compound of the formula RX <1> , where X' is halogen such as iodine or bromine, or an ester group such as tosyl; and wherein the reaction is carried out in a polar organic solvent in the presence of a base; and where R is preferably alkyl, alkenyl, alkylcycloalkyl or aralkyl; or a compound of formula III is subjected to acylation with a compound of the formula RCOX <1> , or carboalkylation with a compound of the formula ROOCX', where X <1> is halogen, in an organic solvent in the presence of a base, or N-protecting groups are reduced according to the following equations: or a compound with the formula: is nitrated to a compound with the formula: by treatment with a nitrating agent known per se, or by subjecting a compound of the formula V to reduction of the nitro group, or formation of derivatives of a diazonium intermediate as follows: in a manner known in and of itself, or esterification of a compound of formula VII in a manner known per se; or a ring substituent, X', which is chlorine or amino, is removed from a compound of the formula: by hydrogenation, or when X' is amino, by treatment with nitric acid in phosphoric acid, or by other known methods, or X <1> which is halogen in formula X is replaced by R with a compound of formula MR, where M is a metal and R is an organic group, by known methods, or a compound of formula I is subjected to halogenation with a compound of formula X, where X <1> is halogen, by known methods, or a Grignard compound carbinates according to the equation: where X' is halogen, by known methods, or a compound with the formula: is subjected to electrolytic oxidation with a compound of the formula RNH2 by methods known per se. 2. Method according to claim 1, characterized in that compounds are used where R 1 and R 2, which are the same or different, are hydrogen, lower alkyl, alkenyl of 2-6 carbon atoms or dialkylaminoalkyl of 3-15 carbon atoms, R is hydrogen, lower alkyl, hydroxy-lower alkyl, alkenyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, alkylcycloalkyl of 4-10 carbon atoms, benzyl (and X- and R-ring-substituted benzyl), lower alkoxycarbonyl of 2-7 carbon atoms or dialkylaminoalkyl with 3-15 carbon atoms, Y and X , which are the same or different, are lower alkyl, fluoro, chloro, bromo. iodo, lower alkoxy, halogen-substituted lower alkoxy, halogen-lower alkyl, cyano, carboxy or carboxamido, n is 0 (X, respectively Y is hydrogen), 1 or 2, is selected from the group consisting of benzo 3. Process according to claim 1, characterized in that R 1 and R 2 are hydrogen, lower alkenyl. such as vinyl, lower alkyl such as methyl, ethyl, or propyl, trifluoromethyl, di-lower alkylamino-lower alkyl such as dimethylaminopropyl, R is hydrogen, benzyl or substituted benzyl, lower alkyl such as methyl, ethyl or propyl, cyclopropyl, cyclobutyl or di-lower alkylamino-lower alkyl such as dimethylaminopropyl, X and Y are chloro, bromo, iodo, lower alkoxy, lower alkyl, cyano, carboxy, carboxamido, trifluoromethoxy, trifluoromethyl, trifluoromethylsulfonyl, lower alkylthio such as methylthio, and trifluoromethyl thio, n is 0 (X, respectively Y is hydrogen), 1 or 2, and