DE2521519A1 - SUBSTITUTED 9,10-DIHYDROANTHRACEN-9,10-IMINE AND HETEROCYCLIC (AZA) ANALOGS THEREOF AND METHOD FOR PREPARING THESE COMPOUNDS - Google Patents

Description

Substituted 9 »10-dihydroanthracene-9,10-imines and heterocyclic ones (Aza) analogues thereof and methods of preparation

The present invention relates to certain substituted 9,10-dihydroanthracene-9 »10-imines, their heterocyclic (aza) Analogs and their pharmaceutically acceptable salt, ester and amide derivatives which are used as low-level tranquilizers, spasm agents (anticonvulsants), muscle relaxants and in the treatment of extrapyramidal disorders such as Parkinson’s vision Disease, are useful. For the sake of convenience, the compounds according to the invention are hereinafter referred to as "Anthracenimine" designated.

The present invention also relates to methods of making such anthracenimines and pharmaceutical agents which contain such compounds.

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

Herein mean:

E hydrogen, acyl, alkyl, aryl, alkoxycarbonyl,

Aralkyl, alkenyl, dialkylaminoalkyl, hydroxyalkyl, Alkynyl, trialkylsilyl, alkylcycloalkyl or

Cycloalkyl,

1 2

R and R independently of one another are hydrogen, alkyl, halogen

alkyl, aralkyl, aryl, alkenyl or dialkylaminoalkyl,

X and Y independently of one another halogen, such as chlorine, fluorine, bromine and iodine, alkoxy, dialkoxymethyl, alkyl, Cyano, dialkylaminoalkyl, carboxy, carboxamido, halogen-substituted alkoxy, haloalkyl, haloalkylthio, allyl, aralkyl, cycloalkyl, aroyl, Aralkoxy, alkanoyl, aryl, substituted aryl, alkylthio, alkylsulfonyl, haloalkylsulfonyl, Alkylsulfinyl, haloalkylsulfinyl, arylthio, Haloalkoxy, amino, alkylamino, dialkylamino, Hydroxy, carbamoyl, N-alkylcarbamoyl, ΪΤ, Ν-dialkylcarbamoyl, Nitro or dialkylsulfamoyl,

η is an integer, namely O (X or Y stand for Hydrogen), 1, 2, 3 or small unsaturated heterocyclic or heteropolycyclic Proportion in which the heteroatom or the heteroatoms A mean N or NR, where R has the meaning given above, or the benzo component.

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With reference to the anthracenimines of the structural formula above I the preferred embodiments are those in which:

1 2

R and R independently of one another are hydrogen, lower alkyl, with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms or dialkylaminoalkyl with 3 to 15 carbon atoms,

R ■ hydrogen or lower alkyl with 1 to 6 carbon atoms, Hydroxy-lower alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, Cycloalkyl with 3 to 6 carbon atoms, alkylcycloalkyl with 4 to 10 carbon atoms, benzyl (or benzyl substituted for the X or R ring), medrigalkoxycarbonyl with 2 to 7 carbon atoms or dialkylaminoalkyl with 3 to 15 carbon atoms,

Y and X independently of one another lower alkyl with 1 to 6 carbon atoms, halogen (fluorine, chlorine, bromine, Iodine), lower alkoxy with 1 to 6 carbon atoms, Halosubstituted lower alkoxy having 1 to 6 carbon atoms, halo lower alkyl having 1 to 6 carbon atoms, cyano, carboxy, haloalkylthio, alkylthio, haloalkylsulfonyl or carboxamido,

η is an integer, namely 0 (X or Y stand for hydrogen), 1 or 2,

- "\

Benzo

CM"

6 0 9 8 4 B / 1 U 0

610Y ^H

or

The most preferred embodiments of the present invention are those in which:

the benzo group

R and R hydrogen, lower alkenyl, such as vinyl and the like., Lower alkyl of 1 to 6 carbon atoms such as methyl, ethyl, propyl and the like, trifluoromethyl or di-lower alkylamino-lower alkyl, such as dimethylaminopropyl and the like,

R is hydrogen, benzyl or substituted benzyl, lower alkyl having 1 to 6 carbon atoms, such as Methyl, ethyl, propyl and the like, cyclopropyl, cyclobutyl or di-lower alkylamino-lower alkyl, such as dimethylaminopropyl and the like.,

X and Y chlorine, bromine, iodine, lower alkoxy with 1 to 6 carbon atoms, Lower alkyl with 1 to 6 carbon atoms, cyano, carboxy, carboxamido, trifluoromethoxy, Trifluoromethyl, trifluoromethylsulfonyl, lower alkylthio such as methylthio and the like., Or Trifluoromethylthio,

η is an integer, namely 0 (X or Y represent Hydrogen), 1 or 2.

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In general, the anthracenimines according to the invention by reacting a suitably substituted hetarin ("gasoline" in the case of the benzo substituent) with a appropriately substituted isoindole Ia according to the following reaction (all substituents have the above given meaning) produced:

(Y) _n | g 1 2 NO

Yes

In practice, the hetarine or gasoline reactant (hereinafter for the sake of convenience, referred to as the entirety "gasoline") in situ under conditions similar to those ultimately carried out Diels-Alder condensation compatible with the isoindole are generated. The preparation of such reactants and ■ process conditions for the final preparation of the anthracenimines according to the invention are described below.

Many of those used in the preparation of the anthracenimines according to the invention useful isoindoles are known and readily available. On the other hand, such isoindoles can also easily by reacting an o-disubstituted benzene with a halogenating agent such as N-bromosuccinimide (NBS), the following Reacting the α, α'-dihalogenated product obtained with an N-substituted hydrazine (RNHNHo) and treat the latter can be made with base. This results in the desired isoindole (Ia):

_ 5 _
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(X or I) _n -I- j! _R 2

NBS ..

(X or Y)

Br

(X or Y)

+) NC (X or Y) _n

NH.

Base,

Yes

(all substituents have the meanings given above)

Typically, the halogenation step is used in manufacture of the isoindole in the presence of an initiator such as benzoyl peroxide and the like., carried out under ultraviolet radiation. The reaction temperature, the solvent system or the base used in the final stage are not critical. To suitable Solvents for the reaction include hydrocarbons such as hexane, benzene and the like, and halogenated hydrocarbons, such as carbon tetrachloride, chlorobenzene and the like. Typically the reaction temperature is about 25 ° C up to reflux temperature; the non-critical base can be selected from the group consisting of sodium hydroxide, potassium hydroxide and potassium carbonate and the like. Be selected.

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

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COOH

1)

2) esterification

I if BS ^

^^^ COoR ⁰

Br

OC

₂ rows

ENH,

R ² Li ν Ia

Here all symbols have the meanings given above, and R ⁰ denotes any lower alkyl moiety, such as methyl, ethyl, propyl and the like. According to the process described above, the o-acylbenzoic acid is first prepared by conventional procedures, such as hydrogenation over Pd / C in aqueous sodium hydroxide solution , hydrogenated to reduce the carbonyl group, and then the free garboxy group is esterified by treatment with diazomethane, sulfuric acid in methanol or HCl in ethanol or other standard methods. Halogenation of the resulting substituted benzoic acid ester gives the cc-halogen intermediate illustrated above. The halogenation can be brought about, for example, by treating the ester with NBS in CCl ^ under reflux. By treating the a-halogen intermediate with the primary amine, RNHo, in methanol, ethanol, acetonitrile, ether, THF or another polar organic solvent, the phthalimidine illustrated above is obtained when treated with R Li in ether, benzene, THF or another organic solvent not participating in the reaction under reflux or with a Grignard reagent, R MgX ¹ (X ^f stands for halogen, such as chlorine, bromine or iodine) in anisole, THF, glyme or dibutyl ether under reflux the desired isoindole ( Ia) results. What the above illustrated

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driving is concerned, the esterification stage can be according to the following Way of working

be eliminated. The phthalimidine intermediate is obtained directly by treating the ortho-acylbenzoic acid with the primary amine, ENHp, in the presence of NaCHBH ,, if protic solvents such as methanol, ethanol and the like are used, or in the presence of NaBH ₂ ,, MgSO ₂ , and the primary amine hydrochloride when polar aprotic solvents such as acetonitrile, DMF, HMPA and the like are used. In either of the two solvent systems, the reaction temperature, the reaction time and the reactant ratio are not overly critical. However, the following conditions are typically used when working in the aprotic system: The primary amine is present as an equimolar mixture of the free base with its acid addition salt in excess with respect to the acylbenzoic acid, and the sodium borohydride is partly in the course of several hours of the solution of the amine and -NgSO ₂ , slurry added to the acylbenzoic acid.

Another method for preparing the compounds Ia comprises treating an o-diacylbenzene with a primary amine, RNHp, in the presence of a reducing agent such as NaBH ₂ , or

C.

Like., in a protic solvent at a reaction temperature of 20 to 35 ° C according to the following reaction scheme (all symbols have the meanings given above):

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Yes

Another method for preparing compounds Ia comprises, when either R or R is hydrogen, the treatment of phthalic anhydride with the primary amine RNHp to form a phthalimide intermediate product which, when reduced with, for example, zinc dust in glacial acetic acid, the phthalimidine provides that when treated with an appropriate lithium alkyl

2 2

LiR or Grignard reagent R MgX ¹ gives the desired isoindole according to the following scheme:

RNH,

or

LiR ²

R ² MgX ¹

Yet another way of making connections

1 2

Ia includes in particular when either R or R denotes hydrogen and when the benzoid nucleus of the isoindole bears an electron-releasing substituent (referred to here as X ¹ ; X 'denotes a radical from the group of radicals previously defined for X and 1) ), such as alkyl, halogen or the like, the Friedel-Crafts alkylation of a meta-X ¹ -substituted benzoic acid · The following equation summarizes this

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Method together:

Friedel-Crafts

COOH

CH ₂ IiHCOCH ₂ Cl OOH

The immediate Friedel-Crafts product cyclizes spontaneously to form the phthalimidine intermediate, which can be N-alkylated by treatment with EJ 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 can. The resulting N-substituted phthalimidine provides on treatment with an appropriate lithium alkyl

Ί Ί

(LiE) or Grignard reagent (E MgX), as previously defined,

1 2
the desired E- or E -substituted isoindole, which has the X'-substituent in the 5-position:

Suitable Friedel-Crafts reagents for the reaction indicated above are N-hydroxymethylchloracetamide and N-hydroxymethylphthalimide. The preferred Friedel-Crafts catalyst is concentrated H ₂ SO ^. Typically, the reaction is carried out in the absence of a solvent or in solvents such as ₂ and the like, at a temperature of from about 0 ° C to about 30 °.

The person skilled in the art is familiar with the fact that the processes described above can be used individually or in combination according to the most expedient route in the synthesis of the isoindoles which are required for the preparation of the anthracenimines according to the invention.

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The temporarily occurring "gasoline" reactant (here like this defines that 'both carbo compounds and heterocyclic compounds Compounds are included) can be carried out by a variety of methods including flash photolysis of a core-substituted, cyclic, aromatic compound such as benzene or pyridine, or treatment of an ortho-dihalogen or a Monohalo-substituted, cyclic aromatic compound with a strong base, can be prepared:

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

halogen

I — halogen

or (X)

alogen

Base ^

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Suitable bases for the reaction indicated above can be selected from the following group: alkali and alkaline earth metals and their corresponding oxides, hydrous oxides, alkoxides, alkali amides, alkali alkyls, and the like. The most preferred Bases are magnesium metal and alkali alkyls such as methyllithium, Butyllithium, phenyllithium, potassium tert-butoxide and alkali amides, such as lithium diisopropylamide, lithium-2,2,6,6-tetramethylpiperidide, Sodium amide and the like. The identity of the reaction solvent is not inappropriately critical; suitable Solvents can be selected from hydrocarbons such as benzene, hexane, cyclohexane and the like, oxygenated solvents, such as ether, dioxane, tetrahydrofuran, anisole and the like., can be selected. Typically the response will be around -70 C to the reflux temperature.

A second method for preparing the anthracenimines according to the invention includes the Diels-Alder condensation of a substituted Butadiene- (1,3) and a naphthalene imine and the subsequent aromatization of the newly formed 6-membered Ring by adding bromine and leaving HBr by treating the brominated intermediate with a base such as triethylamine:

(X or Y)

+ (X or Y)

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Here all substituents have the meanings given above. Such naphthalene imines Ib (substituted 1,4-dihydronaphthalene-1,4-imines) are described in US Pat. No. 498,485. Typically, no solvent is needed for the first stage Diels-Alder reaction; however, suitable solvents for this stage are, for example, THF, p-dichlorobenzene, toluene and the like. At a reaction temperature of about 25 ° C. to the reflux temperature or at a higher temperature if the reaction is carried out under pressure. The bromine addition reaction can be carried out in solvents such as acetic acid, CCl ^, chloroform, THF, benzene and the like. The elimination reaction carried out at the end is typically carried out in solvents such as benzene or THF, in the presence of a base such as (C ₂ Hc) ₅ N, NaOH or DBN (dibenzocyclononane).

Finally, the anthracenimines according to the invention can by derivative-forming operations performed on the anthracenimine core to achieve certain embodiments of the present Invention can be made. The following reaction is representative of this method. The benzo embodiment is illustrated; however, the following modes of operation are applicable to all embodiments of the present invention:

In these formulas, for the purpose of illustration, the benzoid rings are used only in relation to the occurring L group shown substituted; but it is not critical and not even preferred that L in this aspect of the invention is the is the only benzenoid substituent. L can be any chemical

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be a modifiable group, such as amino, hydroxy, bromine, iodine, chlorine and the like, which can be converted into the function X according to known procedures »X has the meanings given above and in particular includes radicals such as cyano for this purpose of the invention , Trifluoromethylthio, methylthio, and the like. Suitable solvents for this process aspect of the invention include dimethylformamide, hexamethylphosphoramide (HMPA), THF, quinoxaline, and the like. Typically, the reaction is carried out at about 25 ° C to reflux temperature.

Other reactions leading to derivatives which do not include critical reaction parameters and are represented by the following examples representatively illustrated include: N-alkylation, the N-acylation and reduction, the reductive IT-alkylation and electrophilic substitution on the benzoid nuclei.

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Also within the scope of the present invention are non-toxic, pharmaceutically acceptable salt, ester and amide derivatives of compound I. Acid addition salts are preferred. Such acid addition salts of the anthracenimine compounds are formed by mixing a solution of the anthracenimine compounds with a solution of a pharmaceutical acceptable, non-toxic acid, such as hydrochloric acid, Formic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid and the like

The inventive, acting as weak tranquilizers Anthracenimines can be used at unit dosage levels of about 0.1 to about 500 mg per kg of body weight or at one Daily dosage level from about 0.4 to about 2000 mg per kg Body weight to relieve anxiety without inducing excessive sedation or sleep. In addition, the inventive Anthracenimines as muscle relaxants, as anticonvulsants, and in the treatment of extrapyramidal disorders useful when indicated at comparable dosage levels. It goes without saying, of course, that the exact The level of treatment depends on the individual medical history of the animal or human being treated, and in the end, the exact treatment prescription remains, the falls under the guidelines above is at the discretion of the therapist.

The scope of the present invention also includes pharmaceuticals Agents containing such anthracenimines. Preferably these agents are in unit dosage forms, as in tablets, pills, parenteral solutions or the like., before .. For the production of solid agents, such as tablets, is the principal active ingredient with a pharmaceutical carrier, d. H. conventional tableting ingredients, such as corn starch, Lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and others pharmaceutical diluents, such as water, under

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Formation of a solid preform that is a homogeneous mixture an inventive anthracenimine or one non-toxic, pharmaceutically acceptable salt, ester or Containing amide derivatives thereof, mixed. This solid pre-formulation then becomes in unit dosage forms that described above Species containing 0.1 to about 500 mg of the active, contain inventive component, divided. The tablets or pills from the novel remedy can be coated or otherwise compounded to give a dosage form which has the benefit of an extended duration Effect of the anthracenimines according to the invention offers.

The liquid forms to which the novel Agents for administration by the oral route or by injection may be incorporated include aqueous solutions, conveniently tasty syrups, aqueous or oily suspensions.

The pharmaceutical anthracenimine formulations according to the invention can be administered orally, parenterally or rectally. They can be taken orally in tablets, capsules, suspensions, or syrups with the preferred dosage form being a compressed tablet containing 0.1 to about 500 mg on the active ingredient. The optimal dosage will of course depend on the dosage form in question. In each special ITaIl depends on the correctly selected dosage, as previously mentioned, continues to depend on factors in the patient which may affect the response to the remedy; such are, for example, the general state of health, age, weight and the desired effect.

Example 1a

2,3-diflethylphthalimidine

A solution of 11.8 g (0.076 mol) of 2-ethylbenzoic acid in 25 ml absolute methanol is carefully concentrated with 2.5 ml

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Treated sulfuric acid and heated to reflux temperature. After 4 hours the mixture is poured onto ice and the oily Product extracted with Xther. When evaporating the washed

(Water; 5% aqueous sodium bicarbonate and water) and the dried extract under reduced pressure, methyl 2-ethylbenzoate remains as a residual, colorless oil in a yield of 86 % .

A mixture of 10.7 g (0.065 mol) of methyl 2-ethyl benzoate, 12.5 g (0.07 mol) of N-bromosuccinimide, 50 mg of benzoyl peroxide and 125 ml of carbon tetrachloride is so at reflux temperature stirred for a long time until the reaction is complete in 2 hours. The precipitated succinic acid imide is of the The cooled mixture is filtered off and the filtrate is evaporated to dryness under reduced pressure. Methyl 2- (1-bromoethyl) benzoate remains as a yellow, oily residue in quantitative yield.

A solution of 0.156 moles of methyl 2- (i-bromomethyl) benzoate and 24.0 g (0.312 mol) of 40% aqueous methylamine in 230 ml absolute methanol is kept at room temperature for 20 hours. Solvent is evaporated under reduced pressure, and the residue is partitioned between chloroform and water. On evaporation of the washed (water; 2N hydrochloric acid; and water) and dried chloroform extract under reduced pressure, the crude product remains as remaining oil back. The distillation gives purified 2,3-dimethylphthalimidine as a flowable, colorless oil.

2-alkyl-3-methyl-phthalimidines

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

1.) 2-Benzyl-3-methylphthalimidine, Sp-.158 to 162 ° C / 0.1 mm Hg

2.) 2-ethyl-3-methylphthalimidine, Sp. 97 Ms 105 ° C / 0.1 mm Hg

3.) 2-CycloOropyl-3-methylphthalimidine _i Sp. 120 * 0 / 0.2 mm Hg

4.) 2- (3-hydroxypropyl) -3-methylphthalimidine, Sp. 172 to 175 ° C / O, 2 mm Hg

5.) 2-propyl-3-methylphthalimidine, Sp. 98 to 194 ° C / 0.1 mm Hg

6.) 2-Butyl-3-methylph.thalimidine ₁ . Sp. 109 to 114 ° C / 0.1 mm Hg

7.) 2-Allyl-3-methylphtlialimidiii, Sp. 102 to 104 ° C / 0.15 mm Hg

8.) 2-Cyclopropylmethyl-3-methylphthalimidine, Sp. 131 to 133 ° C / O, 1 mm Hg

Example 1b

1,2,3-trimethylisoindole

In a dry, kept in a nitrogen atmosphere 25 ml of 1.9m methyllithium in ether are added dropwise to the apparatus to a stirred solution of 6.4 g (0.04 mole) 2,3-dimethylphthalimidine given in 100 ml of absolute ether. After stirring overnight at room temperature, the cooled mixture becomes hydrolyzed by the dropwise addition of 40 ml of water. The ether layer is separated off and 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 dark yellow solid that remains is dried at 0.5 mm. 5.7 g (90%) of 1,2,3-trimethylisoindole are obtained.

2-substituted-1,3-dimethylisoindoles

According to the procedure described in Example 1b, the matching 2-substituted 3-methylphthalimidine with methyllithium to form the following 2-alkyl-1,3-dimethylisoindoles treated:

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1 . ) 2-Benzyl-1,3-dimethylisoindole 2.) 2-Ethyl-1,3-dimethylisoindole 3 «) '2-Cyclopropyl-1,3-c-limethylisoindole 4.) 2-propyl-1,3-dimethylisoindole

5.) 2-butyl-1,3-dimethylisoindole 6.) 2-Allyl-1,3-dimethylisoindole

7 ·) 2- / B- (tetrahydropyranyl> -2-ox27-propyl-1,3-dimethylisoindole

8.) 2-Cyclopropylmethyl-1,3-dimethylisoindole

9 ·) 5-chloro-, 1-iodo- and 5-bromo-2-cyclopropyl-1,3-dimethylisoindole

10.) 5-chloro-, 5-iodo- and 5-Bfom-2- / 3- (tetrahydropyranyl) -2-oxy / -propyl-1,3-dimethylisoindole

11.) 5 ~ chlorine, 5-iodine and 5-bromo-2-propyl-1,3-dimethylisoindole

12.) 1-Butyl-2,3-dimethylisoindole from n-butyllithium and
2,3-dimethylphthalimidine

13 ») 1-ethyl-2,3-dimethylisoindole from ethyl lithium and 2,3-dimethylphthalimidine

14.) 1-vinyl-2,3-dimethylisoindole from vinyllithium and 2,3-dimethylphthalimidine

Example 1c
2- / 3- (Tetrahydropyranyl-2-oxy) -propyl7-3-niethylphthalimidine

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 of 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. When evaporating the filtrate under reduced pressure and
Drying the residue at 0.5 mm Hg leaves 2- / 3- (tetrahydropyranyl-2-oxy) propyl7-3-methylphthalimidine as a viscous, yellow oil in quantitative yield.

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Example 1d

11 ~. (3-Dimethylaminopropyl) -9 »IO-dimethyl-9,10-dihydroanthracene-9> 10-imine

To a stirred mixture of 1.45 g (0.0052 mol) 11- (3-hydroxypropyl) -9, IO-dimethyl-9,10-dihydroanthracene-9,10-imine, 1.4 g (0.00525 mol) of triphenylphosphine and 17 ml of dry benzene are partially at room temperature and under nitrogen 0.95 g (0 * 00535 moles) of N-bromosuccinimide were added. The stirring continues for 6 hours; a fine, white precipitate slowly separates out. After cooling down In an ice bath, the mixture is saturated with gaseous dimethylamine and stirring is continued overnight at room temperature continued. The solvent is evaporated under reduced pressure and the residue is triturated with absolute ether. The succinic acid imide precipitate is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue is triturated with hot hexane and the mixture is quenched. After filtering off the triphenylphosphine oxide precipitate the hexane filtrate is evaporated to dryness under reduced pressure. The product remains as a oily residue back. Short path distillation at 95 to 105 ° C and 0.2 mm Hg gives 0.9 g (56%) of a viscous, yellow Oil.

The base is converted into the hydrochloride salt by treating an ethanol solution with one equivalent of hydrogen chloride in ethanol converted. When diluted with absolute ether, the salt precipitates. It is made from cold, absolute ethanol-ether recrystallized. 11- (3-Dimethylaminopropyl) -9,10-dimethyl-9,10-dihydroanthracene-9,10-iminehydric chloride is obtained as white crystals.

According to the procedure described in Example 1d, if the 11- (3-hydroxypropyl) -9,10-dimethyl-9,10-dihydroanthracene-9 »10-imine is obtained of Example 1d by equivalent amounts

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replaced by 2-chloro-, 2-iodo- or 2-bromo-11- (3-hydroxypropyl) -9,10-dimethyl-9 »10-dihydroanthracene-9 _l 10-imine, 2-chloro-, 2- Iodo- or 2-bromo-11- (3-dimethylaminopropyl) -9 »10-dimethyl-9, IO-dihydroanthracene-9,10-imine.

example 1

9,10,11-trimethyl-9,10-dihydroanthracene-9,10-imine Step A: 1,2,3-trimethylisoindole

A mixture of 50 g (0.374 x mole) o-diethylbenzene, 146 g (0.822 mol) of N-bromosuccinimide, 0.1 g of benzoyl peroxide and 800 ml of carbon tetrachloride is carried out with ultraviolet radiation heated to reflux until the reaction is complete. The precipitated succinic acid imide is filtered off, washed with carbon tetrachloride and the filtrate is evaporated to dryness under reduced pressure. The α, α'-dibromo-o-diethylbenzene residue is in 800 ml of absolute ether dissolved. The stirred solution is A solution of 40 g (0.87 mol) of methylhydrazine in 50 ml of absolute ether is added dropwise under nitrogen. A gummy precipitate separates. After stirring for 3 hours and the material left to stand overnight one decants the ether. The one dissolved in 625 ml of water The residue is treated with 375 ml of 40% sodium hydroxide solution, and the mixture is stirred at reflux for 1.5 hours. After cooling, the precipitate becomes the crude Product collected, washed with water and dissolved in 600 ml of ether. The ether solution is washed repeatedly with water and dried over anhydrous magnesium sulfate with stirring and cooling in an ice bath. The filtered solution is under evaporated under reduced pressure and the remaining dark yellow solid triturated with petroleum ether, filtered and im Vacuum dried. 15 »56 g of 1,2,3-trimethylisoindole are obtained.

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Step B: 9,10,11-trimethylanthracene-9,10-dihydro-9,10-imine

In a dry apparatus kept in a nitrogen atmosphere, 1.7 S (0 »0 mol) of magnesium turnings are suspended in 10 ml of dry tetrahydrofuran, and the mixture is heated to reflux temperature. The reaction is initiated by adding a few drops of 2-fluorobromobenzene and a mixture of 9.65 g (0.06 mol) 1,2,3-trimethylisoindole and 12.3 g (0.07 mol) 2-fluorobromobenzene in 70 ml dry tetrahydrofuran is added dropwise in the course of 1 hour. Stirring under reflux is continued for 2 hours. The cooled mixture is hydrolyzed by adding 25 ml of water dropwise and the organic layer is decanted. The solvent is evaporated under reduced pressure and the dark oil that remains 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. 15.6 g of crude 9,10,11-trimethylanthracene-9,10-dihydro-9,10-imine remain as a dark red oily residue. The residue is converted into fumaric acid by dissolving in 30 ml of ethyl acetate and adding a solution of 10.4 g (0.09 mol) of formic acid in 100 ml of absolute methanol. On dilution with 320 ml of ethyl acetate and inoculation, 10.05 g of the crude salt precipitate as a purple solid. Recrystallization twice from methanol / ethyl acetate (1: 1) using decolorizing charcoal gives 4.38 g of the fumarate salt of 9,10,11-trimethylanthracene-9,10-dihydro-9,10-imine as white crystals (C. ₁₇ H ₁₇ NI, 5 C ₄ H ₄ O).

Following the procedure of Example 1, stage A, one obtains if the o-diethylbenzene of Example 1 by an equivalent Amount of o-ethyltoluene, o-dipropylbenzene, 2-propylethylbenzene, o-bis- (ß, ß, ß-trifluoroethyl) benzene, o-dibutylbenzene or 2-butylpropylbenzene replaced, 1,2-dimethylisoindole, 1,3-diethyl-2-methylisoindole, 1,2-dimethyl-3-ethylisoindole,

- 22 609848/1. UO

1,3-bis (trifluoromethyl) -2-methylisoindole, 1,3-dipropyl-2-methylisoindole or i-ethyl ^ -methyl ^ -propylisoindole.

If the isoindoles listed above are used individually instead of the 1,2,3-trimethylisoindole of Example 1, stage B ₁ , the following is obtained: 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-9,1O-dipropyl-9,10-dihydroanthracene-9,10-imine and 11-methyl-9-ethyl-10-propyl-9.10, respectively -dihydro anthracene-9,10-imine.

Following the procedure of Example 1, stage A, if the o-diethylbenzene of Example 1 is replaced by an equivalent Amount of: 4-chloro-, 4-iodo- and 4-bromo-1,2-diethylbenzene and the methylhydrazine by an equivalent amount of propylhydrazine, cyclopropylhydrazine or γ-THP-oxypropylhydrazine replaced, 5-chloro-, 5-iodo- and 5-bromo-2-propyl-1,3-dimethylisoindo1, 5-chloro-, 5-iodo- and 5-bromo-2-cyclopropyl-1,3-dimethylisoindole and 5-chloro-, 5-iodo- and 5-bromo-2-Y-THP-oxypropyl7-1,3-dimethylisoindo1. THP means tetrahydropyranyloxy.

If the isoindoles listed above are used individually instead of the 1,2,3- ^ 3? Iniethylisoindo3s of Example 1, stage B, one obtains: 2-chloro-, 2-iodo- and 2-bromo-11-propyl-9,10-dimethyl-9,10-dihydroanthracene-9i10-imine, 2-chloro-, 2-iodo- and 2-bromo-11-cyclopropyl-9,10-dimethyl-9,10-dihydro anthracene-9,10-imine or 2-chloro-, 2-iodo- and 2-bromo-11- / y-THP-oxypropyl7-9 , IO-dimethyl-9,10-dihydro to thr ac en-9,10-imine. By mild acid hydrolysis of the last three compounds gives 2-chloro-, 2-iodo- and 2-bromo-11-hydroxypropyl-9, IO-dimethyl-9 , 10-dihydroanthracene-9,10-imine.

Following the operation of Example 1, the following are obtained Anthracenimines according to the invention:

- 23 -

B098A8 / 1 1

Tabel

example R. R ¹ R ^fc X Y 2a CH, H H 2-bromine n »o cn 2 CH ₃ H H 1-CH ₃ n «o ο
co 3 CH, H H 2-OCH ₃ n »o S
oo ro
^ _ Jr
1 I. 4th
5
6th / TTT
CH,
P.
/ tTT
V / Xl -.
3 H
H
CH, H
H
CH ₃ 1-Cl
2-CH ₃ n »o
n «o
n »o - » 7th CH ₃ CH ₃ 2-CI n = o O 8th CH, / ^ TT
v / Xl ^ CH ₃ 1-fluoro n = o 9 ^ ITT CH ₃ 2-OCH, n = o 10 / TfT
3 CH ₃ CH ₃ fluorine n »o 11 CH, CH ₃ CH ₃ 1-CH ₃ n »o 12th / TTT CH ₃ CH,
P. 2-CF,
P. n = o 13th CH ₃ CH, CH, 2-fluoro n = o 14th CH,
P. H H 1,3-di
fluorine n-o

General remarks; Conditions; Reactants (where appropriate)

Butyllithium replaces Mg; Solvent ether 1-bromo-2-fluorobenzene

2-CH ₃ isoindole

2-CH, -isoindole
ρ

5-bromo-2-CH ₃ -isoindole + 2-bromo-3-Cl-toluene + 2-iodo-4-0CH ₃ -1-bromobenzene

2-CH, -isoindole + 1-bromo-2,6-dichlorobenzene 2-CH, -isoindole

ts: κ ο a

1-bromo-2,6-difluorobenzene 1,2,3-tri-CH ₃ -isoindole + 3-Cl-4-Cl-toluene 1,2,3-tri-CH, -isoindole
1,2,3-tri-CH ₃ -isoindole
1,2,3-tri-CH, -isoindole

2,5-Di-Cl-1-bromobenzene

2,6-difluoro-1-bromobenzene

4-bromo-3-iodo-anisole

Butyllithium replaces Mg; Solvent hexane-1,2,3-tri-CH, -isoindole + 1-bromo-2,4,5-trifluorobenzene ^p

1,2,3-tri-CH, -isoindole + 2-bromo-3-Cl-toluene 1,2,3-tri-CH, -isoindole
benzene ^

2-bromo-4-CF, -1-Cl-

1,2,3-tri-CH, -isoindole + 2,4-difluoro-1-bromobenzene butyllithium replaces Mg in hexane. 2-CH, -isoindole + 1-bromo-2,4,6-trifluorobenzene ⁵

Table I (continued)

Example R

15th

16
17th

18th
19th

20th

21

22nd

CH,

CH-

CH,

CH _: CH-

CH,

CH

CH,

H H H

et

CH;

CH,

CH,

CH-

H 2,3-Di- n = o fluorine

H 2-fluoro 5-CH _:

H 2-fluoro 6-CF-

Benzyl CH, CH-

CH _x 2-bromine no

CH, 2-CN 3

CH, 2-C00H no

1,4-dimethyl general remarks; Conditions; Reactants (where appropriate)

According to Example 14. 2-CH, -isoindole + 1-bromo-2,4,5-trifluorobenzene °

5-fluoro-2-CH _x -isoindole (from 3,4-di-CH, -1-fluorobenzene) + 2-bromo-3-Cl-toluene ^

5-fluoro-2-CH, -isoindole + 2-Cl-5-CF, -1-bromobenzene; Isomers are made through fractional <crystallization

7-Ci ^ separated

According to Example 14. 5-Bromo-1,2,3-tri-CHv-isoindole (from 3 »4-diethyl-1-bromobenzene) + 2-bromofluorobenzene

Prepared from the product of Example 18 (1.95 g) and 4.25 g Hg (SCF,) _p , 2.8 g Cu powder, 9.8 ml quinoline in 8.4 ml pyrldine. Reaction overnight at 195 ° C. The product was isolated and washed with benzene

Prepared from the product of Example 18 (3.14 g) and 0.89 g of CuCN in 70 ml of DMF under reflux for 6 hours. Purified by column chromatography on silica gel.

The product of Example 18 (1.6 g) is in 5 ml Ether treated with 2.3 ml of 2.2m butyllithium in hexane. The obtained Grignard intermediate is treated with CO2 and the mixture then passed through hydrolyzed dropwise addition of water. By. Neutralizing the aqueous phase will result in the product of example 21 failed.

2-benzyl-1,3,4,7-tetramethylisoindole + 2-bromo-1-fluorobenzene

Example R

B <

Table I (continued) X ■ X

23

24
25th

CH

CH

CH;

CH-CH,

1,4-di- n = o methyl

CH, 1,4-dimethyl

CH, 2-SCH, n * = o 3 3

cn 26th Propyl CH ₃ 3 2-bromine n-o O 27 Propyl CH ₃ CH, 2-Cl n «o CO 28 Propyl CH ₃ CH, 2-iodine n = o OO I 29 - <! CH ^ CH ₃ 2-bromine n = o 30th - «el CEt; CH,
CH ₃ 2-Cl n = o _v · 31 -O CH ₃ CH, 2- iodine n = o 32 3-OH-propyl CH ₃ CH, 2-bromine n = o O 33 3-OH-propyl CH ₃ CH ₃ 2-Cl n = o 34 3-OH-propyl CH ₃ ' CH ₃ S 2-iodine n = o 34a CH ₃ CH ₃ CH ₃ 2-iodine n = o 35 CH, CH,
3 1-iso- n = o 3 propyl

General remarks; Conditions for reactants (where appropriate)

The product of Example 22 is made in ethanol with 10% Pd on carbon under Hp and under atmospheric pressure hydrogenated.

1,2,3i4,7-pentamethylisoindole + 2-bromofluorobenzene cr>

Lithium 2,2,6,6-tetramethylpiperidide (LiTMP)

(23 »4 ml of 1.8m methyllithium in ether slowly to 5-64 g of 2,2,6,6-tetramethylpiperidine given in 25 ml of THF). This solution will be slow added to 0.036 mol of 1,2,3-tri-CH, -isoindole and 0.04 mol (4-chlorophenyl) -methyl sulfide in 40 ml of THF. Boiling under reflux for 15 hours. The mixture is poured into 150 ml of saturated aqueous NH /, C1. The product is extracted with ether.

According to the operation of Example 25, jt is obtained the products of Examples 26 to 34a from the pas- € " send 1,4-dihalobenzene and the matching 1,3-dimethyl-2-substit.-isoindole. The products of Examples 32 to 34 are obtained according to Example 1, whereby the hydroxyl group is protected by the THP ether.

According to Example 25. 1,2,3-Tri-CH, -isoindole + 2-Cl-cumene ^p

'Example R

36 CH,
3 37 CH,
3 38 CH,
3 38a CH ₅ O
CD
OO
4>
O3 ΓΟ 39 CH,
3

40

41
42

43
44

45

Benzyl C ₂ H ₅

CH; CH; CH;

CH;

CH,

CH,

CH,

Table I (port setting) XY

CH, 2-1so- n »o ^ propyl

CH

- ⁵ cj

CH

CH,

CH;

CH ^

CH; CH;

CH ^

N (CH |) ₂

CH, 2-CH- n »o

* (OC ₂ H ₅ )

CH, 2-CHO n «o 3

CH ₃ 2-CN

n «o

n »o

n »o n »0 n »o n «o 2-Cl n = o 2-iodine n = o 2-bromine n »o

General remarks; Conditions, reactants (if appropriate)

According to Example 25. 1,2,3-Tri-CH ₉ -isoindole + 4-Cl-cumene *

According to Example 25. 1,2,3-Tri-CH, -Isoindole + 4-Cl-N, N-dimethylbenzenesulfonamide

According to example 25 (ie using LiTKP) the diethylacetal (example 38) is obtained from 1,2,3-TrI-CH, -isoindole + 4-C1-1-CH (0C ₂ Hc) -benzene. The aldehyde (Example 38a is prepared from it by hydrolysis.

The product of Example 38a (2.5 g) is treated as the hydrogen oxalate hydrate salt in 50 ml of 95% strength EtOH with 0.6 g of hydroxylamine · HCl in 10 ml of water and then with 12 ml of 1.7 M aqueous NaOH. The resulting 2-carboxaldehyde oxime precipitates when the above solution is poured into 300 ml of water (pH = 8; Q- ⁰ C). A solution (1.8 g) of the oxime in 7 ml of pyridine treated with 1.6 g of trifluoroacetic anhydride gives the product after standing overnight. It is purified from Ither.

2-benzyl-1,3-di-CH, -isoindole
benzene ^

2-fluoro-1-bromo

2-C ₂ H ₅ -I, 3-di-CH, -isoindole + 2-i ^l luor-1-bromobenzene 2-cyclopropyl-1,3-di-CH, 2- -isoindole + ¹ IuOr-I-bromobenzene ^p

The products of Examples 43 to 45 are according to Example 42 made using the appropriate 5-halo substituted isoindole

Table I (port setting)

Example R

CD
X>
CO

46 47

48 49 50 51

52 53 54 55 56

57 58

Benzyl

3-0H-propyl

3-0H-propyl

3-0H-propyl

3-0H-propyl

Propyl butyl

Allyl

CH _x

CH,

CH-

CH

CH

CH

CH

CH CH CH

CH,

CH

CH _x

CH;

CH *

CH, 2-CH 3

CH

n = o

3 CH _x
3 2-Cl 3 CH _x 2-bromine 3 CH _x
3 2-iodine 3 CH,
3 -ο KN KN t CH _x
3
CH, n »o
1-Cl
n »= o

CH

n-

n = o

n = o

Butyl -CpHq n = o -Vinyl n = <

General remarks; Conditions; Reactants (if appropriate)

2-benzyl-1,3-di-CH, -isoindole and 3-bromo-4-cltoluene

2- / 3- (0? HP-2-Oxy) -propyl7-1,3 -di-CH _x -isoindole + 2-fluoro-1-bromobenzene. The ether obtained is converted into the product of Example 47 by hydrolysis in 1.0m HCl at 25 ° C. The product is purified from the ether extract.

The products of Examples 48 to 50 are obtained as in Example 47 if the appropriate 5-halogen-substituted isoindole is used

2-propyl-1,3-di-CH, -isoindole + 2-fluorine-i-bromo- * benzene ^

2-butyl-1,3-di-CH, -isoindole + 2-fluorine-1-bromobenzene 1,2,3-tri-CH, -isoindole + 2,6-dichlorobromobenzene

2-allyl-1,3-di-CH, -isoindole + 2-fluorine-1-bromobenzene

2-Cyclopropylmethyl-i, 3-di-CH _x -isoindole! Fluorine-1-bromobenzene ^

1-butyl-2,3-di-CH _x -isoindole benzene ^

1-ethyl-2,3-di-CH, -isoindole + 2-fluoro-1-bromobenzene 1-vinyl-2,3-di-CH _x -isoindole + 2-fluoro-1-bromobenzene

2-

2-fluorine-1-bromine-

CTi ΓΌ

Example 2 (a)

11-ethyl-1,4,9, IO-tetramethyl-9, IO-dihydroanthracene-9,10-imine

A solution of 1.0 g (0.004 mol) 1,4,9,10-tetramethyl-9, IO-dihydroanthracene-9, 10-imine and 1.8 g (0.04 mol of acetaldehyde in 20 ml of acetonitrile, is stirred and with 0.75 g (0.012 mol) Treated sodium cyanoborohydride. 0.5 ml of glacial acetic acid are added in portions over the course of 10 minutes, and the mixture is stirred at room temperature for 2 hours. After adding another 0.5 ml of glacial acetic acid is stirred overnight. Most of the solvent is reduced under Pressure evaporated, and the residue is between 5%, aqueous sodium hydroxide and ether. The washed and dried ether extract is under reduced pressure evaporates. There remain 0.65 S (58%) of the product as oily, solid Backlog.

The base is converted to the hydrogen oxalate salt by dissolving in absolute ethanol saturated with oxalic acid. The salt precipitates and is recrystallized twice from absolute ethanol. 11-Ethyl-1,4,9,1O-tetramethyl-9,10-dihydroanthracene-9,10-imine hydrogenoxalate is obtained as white crystals.

Example 5 (a)

9,10-dimethyl-9 + IO-dihydroanthracene-9,10-imine

A solution of 2.3 g (0.0074 mol) of 11-benzyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine in 25 ml of glacial acetic acid, 200 mg of palladium (5%) / carbon is added under hydrogen at atmospheric pressure Stirred until hydrogen absorption is complete. The catalyst is removed by filtration, and when the filtrate is evaporated under reduced pressure, the crude product remains as an oily, solid residue return. A solution of the residue in benzene / ether (1: 1)

- 29 -

50984 8/1140

is extracted with 0.5m citric acid. The watery, acidic one The extract is cooled and made strongly basic with 40% aqueous sodium hydroxide. The oily base is mixed with benzene / Ether (1: 1) extracted. On evaporation of the washed and dried organic extract under reduced pressure the product remains as oily, white crystals. Sublimation at 70 ° C and 0.05 mm Hg gives 0.35 g (21%) white Crystals.

Example 4a H-carbethoxy-9,10-dimethyl-9, IO-dihydroanthracene-9,10-imine

22.1 g of 9,1O-dimethyl-9,10-dihydroanthracene-9,10-imine in 150 ml of HCCl ₅ and 10.1 g (C ₂ Hc) ₅ N are reacted at 0 ° C. with stirring. 12.7 g of ethyl chloroformate in 25 ml of HCCl 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 off and washed with ice water, 5% HCl, 5% aqueous UaHCO ₅ and then with water and dried.

Example 5a

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

The product of Example 4a (14.6 g) is dissolved in 25 ml of tetramethylene sulf on dropwise to a stirred slurry of 7 »3 g of nitronium tetrafluoroborate in 50 ml of tetramethylene sulf given on at 15 ° C. After 2 hours at 30 ° C., the reaction mixture is poured into 300 g of ice water, and the product is collected by filtration.

The 2-nitro-9 »10,11-trimethyl product is obtained if one the product of Example 1 is used instead of the product of Example 4a in the procedure according to Example 5a.

- 30 509848/114

Example 6a

ii-Carbethoxy ^ -amino ^ »IO-dimethyl-9,1O-dihydroanthracengi

The product of Example 5a (16.9 g) is dissolved in 100 ml of ethanol over Pd (5%) / C (1.0 g) at 25 ° C and atmospheric pressure for 2 hours long hydrated. The product is collected by filtration and evaporation.

Example Va il-Carbethoxy ^ -hydroxy-9 »IO-dimethyl-9,10-dihydroanthracene-9,10-imine

The product of Example 6a (9.9 g) is dissolved in 150 ml of ice water and 6.4 ml of concentrated H ^ SO ^ dropwise with 2.34 g

treated in 20 ml of water at 0 ° C. The solution obtained (Diazonium salt) becomes 6.4 g of concentrated HgSO ^ in 200 ml

Given HoO at 80 ° C. The reaction mixture is after 20 minutes ten cooled to 0 ° C and the product collected by filtration.

Example 8a

11-carbethoxy-2-methoxy-9, IO-dimethyl-9,10-dihydroanthracene-9,10-imine

The product of Example 7a (4.9 g) in 100 ml of CH ₅ OH and 5.0 g of diazomethane in ether is left to stand at 25 ° C. overnight. Evaporation of the solvent gives the product.

Example 9a

9,10,11-trimethyl-2-methoxy-9,10-dihydro anthracene-9 ”. 10-imin

The product of Example 8a (2.5 g) is added to 50 ml of ether

- 31 -

509848/1 1 40

dropwise to a slurry of 2.0 g lithium aluminum hydride in 100 ml of ether. Heating to reflux temperature continues for 8 hours. Water is carefully added and the inorganic material is separated off by filtration. Evaporation of the filtrate gives the product.

Example 10a

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

The product of Example 1 (2.35 g) and 0.03 mol of thallium (III) acetate in 100 ml of CCl ^ are added dropwise. The mixture is refluxed for 30 minutes. The mixture is filtered, with aqueous sodium metabisulphite, aqueous NaHCO, and water. The solvent is evaporated and the residue is taken up in chloroform and filtered down through a short column of alumina. The product is obtained.

Example 11a

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

The 2-iodine product of Example 34a (7.2 g) and bis-trimethylsilylamido copper _{prepared in situ from hexamethyldisilazane, n-butyllithium and copper (i) _j O} did in 100 ml of dry pyridine are used for 20 hours heated to reflux temperature. The solvent is evaporated and 100 ml of methanol are added. The methanolic slurry is stirred for 2 hours at 35 ° C and then the solvent is evaporated. The reaction mixture is extracted with dilute, aqueous fumaric acid. The acidic extract is made basic with aqueous ammonia and then extracted with ether. The ether extract is dried over anhydrous sodium sulfate and filtered, and the filtrate is evaporated. The product is obtained.

- 32 -

509848/1 HO

Example 12a

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

The product of Example 3a (2.21 g) and 1.56 g of C ₂ HcI are slurried in 100 ml of acetonitrile with 2.0 g of NaHCO 3 at 45 ° C. for 6 hours. The solvent is evaporated. The residue is partitioned between 5% strength aqueous NH and ether. The ether solution is separated off, dried over sodium sulfate, filtered and evaporated. The product is obtained.

Example 15a

9,10-dimethyl-H-propyl-9,10-dihydro anthracene-9,10-imine

2.5 S NaCNBH are added to the product of Example 3a (2.21 g) and 1.06 g of CH ₅ CH _{2 CHO in 45 ml of acetonitrile.} The pH is adjusted to 7.0 using aqueous CBuCOOH. The mixture is stirred overnight. After removing the solvent, aqueous KOH is added and the mixture is extracted with ether. The extract is dried, filtered and evaporated. The product is obtained.

example

11-carbethoxy-2-acetyl-9,10-dimethy1-9,10-dihydroanthracene-9,10-imine

To a solution of 13 * 9 g methyloxocarbonium hexafluoroantimonate in 50 ml of nitromethane, 14.6 g of the product des Example 4a given. The reaction mixture is after 3 hours Poured into water at 4-5 ° C and extracted with ether, and the extract is washed with water and over sodium sulfate dried and filtered and the filtrate is evaporated. Man receives the product.

- 33 509848/1 1 40

example

3 «9, H-trimethyl-9 * 10-dihydroanthracene-9, 10-imine Level A: 2,5-dimethylphthalimidine (A)

48.63 g of 4-methylphthalic _{anhydride, 40.5 S 52} 49.23 g of NaCH ₅ CO ₂ and 1000 ml of CH ₅ CO ₂ H as a mixture are heated to reflux temperature for 2 hours. The mixture is filtered and cooled to 75 ° C. 95 g of Zn dust are quickly added and the mixture is refluxed for 4 hours. It is then filtered and the solvent evaporated until a small volume remains. 600 ml of saturated, aqueous NaHCO _{5 are} added, and the solution is extracted with HCCl (4 × 200 ml). The extracts are washed with 100 ml of NaHCO ₅ solution, 100 ml of water and 250 ml of saturated NaGl solution and dried (MgSO ^). After the solvent has been removed, the product A remains as a waxy solid (25.1 g).

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

55 ifil (I18 21) methyl lithium are added dropwise in ether to a solution of 11.9 g of A in 200 ml of ether under N ₂ . The mixture is stirred for 5 hours. 100 ml of water are added dropwise. The ether layer is washed with saturated NaCl solution and dried (K ₂ CO ₅ ). The product B is obtained by removing the solvent.

Level 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 Mg, 9.2 g of 1,2,5-trimethylisoindole and 50 ml of THF under N ₂ . The Grignard reaction is started and the remainder of the bromofluorobenzene solution is added dropwise. The mixture is refluxed for 3 hours and solvent removed. The residue in benzene (250 ml) is

- 34 509848/1140

with saturated NH ^ Cl (2 χ 100 ml), water (3 x 100 ml) and saturated NaCl (150 ml) and dried (Na ^ SO ^). Solvent is removed and the residue is extracted with hexane. The oil that you get when evaporating the hexane extracts is purified by silica gel chromatography, eluting with HCCl. The obtained from the chromatography, pure base (1.1 g) is dissolved in 15 ml of ethyl acetate and a hot, saturated solution of fumaric acid in Added 2-propanol (15 ml). The solid formed will collected (1.1 g) and recrystallized from ethyl acetate. 3.9 ί 11-trimethyl-9,10-dihydroanthracene-9,10-iminsesqui-hydrogenf are obtained umarat.

Example 16a

2,9 »11-trimethyl-9,10-dihydroanthracene-9,10-iin in stage A: 6-methylphthalimidine (A )

A mixture of 27 »2 g of m-methylbenzoic acid, 35 ^ 44 g of N-hydroxyphthalimide and 200 ml of concentrated H ^ SO ^ is for 24 hours

heated to 100 ° C. The cooled solution is poured onto crushed ice and the solid is collected with benzene and subsequently washed with 5% sodium hydroxide solution and dried. 12.85 g of A are obtained after recrystallization from benzene.

Grade B: 2,6-dimethylphthalimidine (B)

5.0 g NaH (57% oil dispersion) become a stirred solution of 14-, 5 g of A and 40 g of CH, J in 400 ml of DMF under N ~. The mixture is held at 25 ° C for 24 hours; Solvent is removed and the residue is poured into 400 ml Dissolved in water. The aqueous solution is extracted with chloroform and the chloroform is evaporated. The oily residue is dissolved in ether and dried (MgSO ^), and the ether is evaporated. The residue is dissolved in 50 ml of ethyl acetate dissolved and gradually diluted with 200 ml of hexane. Of the

- 35 50 98 48/1140

Collect solid and dry (6.3 SB).

Stage C: 1,2,6-Trimethylisoindole (C) '

Following the procedure of stage B of Example 15a. receives the product C as an orange-yellow powder.

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

Following the procedure in Stage C of Example 15 & obtained with the 1,2,6-trimethylisoindole compound D and its sesqui hydrogen fumarate salt.

Example 17a

9,11-Whore thyl-9,10-dihydro anthracene-9,1 0-imine Level A: 1,2-Dimethylisoindole (A)

A solution of CH-, Li in ether (53 mlj 1.9 M) is added dropwise to a suspension of 14.7 g of N-methyiphthalimidine in Put 200 ml of ether under Np. The mixture will last for 4 hours stirred, and then 150 ml of water are added dropwise. The layers are separated and the aqueous phase is extracted with 100 ml of ether. The organic extracts will be washed with saturated NaCl and dried (KgCO ;,). That Solvent is removed and the residue is dried. A is obtained as an orange-yellow oil.

Level B: 9.11-dimethyl-9,10-dihydr oanthracene-9 _? 10-imin (B)

According to the procedure of Step C of Example 15a is obtained with the 1.2-Dimethylisoindol compound B and, if Qsalsäure instead of fumaric _s uses its hydrogen oxalate salt.

- 36 509848/1 140

Example 18a

2-chloro-9 -, 11-dimethyl-9 > 10-dihydro anthracene-9,10-imine Level A: 6-chlorophthalimidine (A)

8.86 g of N-Hydroxymethy! Phthalimid become a solution of 7 »83 g of m-chlorobenzoic acid in 250 ml of concentrated HpSO ^ given. The solution is kept at 100 ° C. for 18 hours, cooled and poured over 1500 g of ice. The separating Solid is collected, washed with water and dried (8.0 g). Recrystallization from 2-propanol gives A.

Level B: S-chloro ^ -methylphthalimidine (B)

A mixture of 4.3 g NaH (57% oil dispersion; 0.1 mol) and 100 ml of benzene is mixed with a slurry of 16.75 g -A-in 250 ml of DMF are added. When the gas evolution subsides, the mixture is heated on the water steam bath for 2 hours and cooled down. 21.3 g of CH, J in 100 ml of benzene are added dropwise. After mixing for 1 hour, filter and evaporate the filtrate. The residue is mixed with water, filtered and dried. 10.52 g of B are obtained after recrystallization from CCl ^ hexane.

Stage C: 6-chloro-i, 2-dimethylisoindole (C)

Following the procedure of stage B of Example 15a, one obtains C, if one uses connection B of example 18a instead of Compound A of Example 15a was used.

Stage D: 2-ChIOr ^, ii-dimethyl-gjiO-dihydroanthraeen ^, 10-imine (D) '.

Following the procedure of stage C of Example 15a, one obtains D (and its hydrogen fumarate salt) when using B of Example 15a replaced by C of Example 18a.

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509848/1 UO

Example 19a

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

A solution of 110 ml (0.95 M) C ₂ HcLi in benzene is added to a suspension of 14.7 S N-methylphthalimidine in 200 ml of ether under Ho. It is stirred for 24 hours, 100 ml of water are added dropwise and the layers are separated. The ether layer is washed with saturated NaGl (100 ml) and dried (KpCO,). Evaporation of the solvent gives A (i5iO5 g)

Level B: gy

imine (B)

Subject of the procedure of stage C of Example 15a is obtained

one B (and its sesquihydrogen fumarate salt) when one A

of Example 19a is used in place of B of Example 15a.

Example 20a

11-Benzyl-9-methyl-9,10-dihydroanthracene-9,10-imine Stage A: 2-Benzyl-1-methylisoindole (A)

A solution of methyl lithium in ether (50 ml; 1.8 M) is added dropwise to a stirred solution of 13.1 g of N-benzylphthalimidine in 400 ml of ether under II ₂ . After 6 hours, 100 ml of water are 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 saturated NaCl (400 ml) and dried (K ₂ CO ^). The solvent is removed and A (12.8 g) is obtained.

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509848/1140

15 610Y · 39 · 252Ί

Stage B: ii-Benzyl-g-methyl ^ iO-dihydroanthracene ^ iO-imine (B)

Following the procedure of stage C of Example 15a, one obtains B (and its sesquihydrogen fumarate salt) when using A of Example 20a in place of B of Example 15a.

Example 21a

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

A solution of methyl lithium in ether (60 ml; 1.8 M) is added dropwise to a stirred solution of 16.1 g of 2-ethylphthalimidine given in 300 ml of ether under ^. The mixture is stirred for 18 hours, 200 ml of water are added, and the layers are separated. The ether layer is washed with saturated NaGl and dried (KpCO,). The solvent is removed and we get A (15 ^ 1 δ)

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

Obtained after the procedure of Stage C of Example 15a one B (and its hydrogen fumarate salt) when using A of Example 21a instead of B of Example 15a.

Example 22a

1-Aza-5 ^ 10 ~ dihydro-11-methylanthracene-5 ^ 10-imiQ

30 ml of ethyl ether and 1.9 molar butyllithium in hexane (12 ml) are placed in a dry flask under N ^ and in a Dry ice / acetone bath cooled to -70 ° C. This is done under Stir a solution of 4.0 g of 3-bromo-2-chloropyridine in 20 ml of ether and then a solution of 4.0 g of N-methylisoindole added to 80 ml of ether, and the mixture is stirred at -70 ° G for 5 minutes.

- 39 -

50984 8 / 1UO

The reaction mixture is then warmed to 20 ° C. and over Stirred at 25 ° C. overnight. The reaction mixture is poured into water and extracted with chloroform (3 × 100 ml). The United Chloroform extracts are dried over NapSO ^ and filtered and concentrated under reduced pressure. The residue is chromatographed on silica gel, with 2% Methyl alcohol / chloroform is eluted. The crude product obtained from the eluent is treated with fumaric acid in isopropanol treated to the fumaric acid sal after recrystallization obtained from isopropanol-ithylacetat (1: 1).

Following the procedure of Example 22a, 2-aza-5,10-dihydro-11-methylanthracene-5,10-imine is obtained when the 3-bromo-2-chloropyridine of Example 22a is replaced by 4-bromo-3-chloropyridine ; 2-Aza-5,10-dihydro-5? 10,11-trimethylanthracene-5,10-imine is obtained when the N-methylisoindole and the 3-bromo-2-chloropyridine of Example 22a are replaced by 1,2,3 -Trimethylisoindole and 4- bromo-3-chloropyridine replaced; and 1-aza-5,10-dihydro-5 _> 10,11-trimethylanthracene-5,10-imine is obtained when the N-methylisoindole of Example 22a is replaced by 1,2,3-trimethylisoindole.

Example 23a

1,3-Diaza-5i10-dihydro-11-methylanthracene |?, 10-imine

In a dry, kept in a nitrogen atmosphere apparatus 1.8 molar methyl lithium in ether (11.7 ml) was added dropwise to a stirred solution of 2.82 g _(0? 02 mol) of _2? 2,6,6-tetramethylpiperidine was added to 15 ml of dry tetrahydrofuran. The resulting solution is added dropwise to a stirred solution of 2.62 g (0.02 mol) of N-methylisoindole and

-MO-

509848/1 Ί 40

Added 2.05 g (0.02 mol) of 5-chloropyrimidine in 20 ml of dry tetrahydrofuran. After refluxing the mixture overnight, it is poured into a saturated ammonium chloride solution containing 3% concentrated ammonium hydroxide. The tetrahydrofuran layer is separated and concentrated under reduced pressure. The residue is chromatographed on silica gel, eluting with 5% methanol / chloroform to obtain the purified product as a residue upon evaporation of the eluent.

If the N-methylisoindole of Example 23a by a equivalent amount of 1,2,3-trimethylisoindole ,. 5-bromo-1,2,3-trimethylisoindole or 5-iodine-i, 2,3-trimethylisoindole replaced, 1,3-diaza-5,10-dihydro-5,10,11-tΓimethylanthΓacen-5,10-imine is obtained, (6- and 7-) bromo- or iodine-1,3-diaza-5,10-dihydro-5,10,11-trimethylanthracene-5,10-imine. In a similar manner, if the 5-chloropyrimidine of Example 23a replaced by an equivalent amount of 5-chloro-1,2-diazine, 1 ^ -Diaza-ii-methyl ^ jiO-dihydroanthracene ^^ O-imine.

Example 24a

Λ , 10-dimethyl-4,9-dihydro-1H-naphth (2,3-d) imidazole-4,9 ~ imine

According to the procedure given in Example 23a, 1 _{i of} 10-dimethyl-4,9-dihydro-1H-naphth (2,3-d) imidazole-4-, 9-imine is obtained from N-methylisoindole and the in situ from 5- Chloro-1-methylimidazole formed hetarine.

If the N-methylisoindole of Example 24a by a equivalent amount of 1,2,3-triniethylisoindole, 2-cyelopropy1-

- 41 509848/1 UU

15 610Y

1,3-dimethylisoindole or 2- (3-hydroxypropyl) -1 _t 3-dimethylisoindole is replaced, 1,4,9 »10-tetramethyl-4,9-dihydro-1H-naphth / 2,3-d7imidazole- 4,9-imine, 1,4,9-trimethyl-IO-cyclopropyl - ^^ - dihydro-IH-naphth / SiJ-dZ-imidazol-4,9- imine or 1,4,9-trimethyl-10- (3-hydroxypropyl) -4,9-dihydro-1H-naphth / 2,3-.d7-imidazole-4,9-imine.

Example 25a

6,11,15 -trimethyl-e, 11-dihydro-5-azanaphthacene-6,11-imine

After the procedure described in Example 22a is obtained one 6,11,13-TI * imethyl-6,11-dihydro-5-azanaphthacen-6,11-imine from 1,2,3-irimethylisoindole and that in situ from 3-bromo-2-chloroquinoline educated hetarin.

Example 26a

7,12,13-ffrimethyl-7,12-dihydrobenzo (., J) phenanthridine-7,12-imine

The procedure described in Example 22a gives 7,12,13-trimethyl-7,12-dihydrobenzo (j) phenanthridine-7,12-

509848/1 UO

15 610Y

imine from 1,2,3-triniethylisoindole and that from 3-bromo-4-chloroquinoline hetarine formed in situ.

Example 27a

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

The procedure described in Example 23a gives 13-methyl-7,12-dihydrobenzo (b) phenanthridine-7 »12-imine from N-methylisoindole and that formed in situ from 4-bromoisoquinoline Hetarin.

Example 28a

13-methyl-5,12-dihydronaphtho (3,2-C) - (1,5) naphthyridin-5,12-imine

The procedure described in Example 23a is used to obtain 13-methyl-5,12-dihydronaphtho (3,2-C) -naphthyridine-5,12-imine from N-methylisoindole and that in situ from 4-bromo-1,5-naphthyridine educated hetarin.

- 43 5098 4 8/1140

Example 29a Preparation of intravenous solutions

A solution containing 10 mg of 9 _i 10,11-trimethyl-9 ₎ 10-dihydroanthracene-9i10-imine (A) per ml of the injectable solution is prepared in the following manner.

A mixture of 10 mg A and 9 mg UaCl is put in for injection dissolved in a sufficient amount of water, and 1 ml of solution is made up. The pH is adjusted using aqueous HCl or NaOH adjusted to about 7 * 0.

If it is desired to use the intravenous solution for multiple doses, add 1.0 mg of methyl p-hydroxybenzoate (Methyl paraben) and 0.10 mg n-propyl p-hydroxybenzoate (propyl paraben) mixed with the other solids before adding water to dissolve the solids. The solution will be manufactured and stored in such a way that they are suitably protected against the harmful effects of the atmosphere can be. The solution obtained is sterilized by treatment in the autoclave »Injectable solutions that 0.1, 1.0 or 100.0 mg A per ml of solution are used in made in a similar way. Following the procedure given above, easily injectable solutions can be produced in larger sizes Amount required for subsequent administration in unit dosage form Have appropriate volumes, produce.

the procedure of Example 29a can be prepared other representative, inj'izisrbare solutions © rfindungsgemässen Yerfoindungen when A of Example 29a through ne ® ± equivalent amount of 2-5 ^l luor-9,10 ₅ 11-t2? imethyl-9 _} 10-di- "hydroanthracene-9» 10-imi2i or by its equivalent amount of any of the anthracenimines illustrated in the examples according to the invention

509848 / 1UO

15 610Y

Example 30a

Tablet manufacturing

Tablets containing 1.0, 2.0, 25.0, 26.0, 50.0 or 100.0 mg of 9 _i 10,11-trimettiyl-9 _> 10-diliydroanthracen-9 _i 10-imine, are made as illustrated below.

Table of doses containing 1 to 25 mg of the anthracenimine compound

9,1O, 11-trimethyl-9,1O-dihydroanthracene-9,10-imine Microcrystalline cellulose Modified feed corn starch Magnesium stearate

Tabel

Amount, mg 25.0 1.0 2.0 37.25 49.25 48.75 37.25 49.25 43.75 0.50 0.50 0.50

Doses containing 26 to 100 mg of the anthracenimine compound

9,10,11-trimethyl-9,10-dihydroanthracene-9,10-imine Microcrystalline cellulose Modified feed corn starch Magnesium stearate

Amount, mg 100.0 26.0 50.0 200.0 52.0 100.0 8.5 2.21 4.25 1.5 0.39 0.75

All of the 9,10,11-trimethyl-9,10-dihydroanthracene-9,10-imine, Lactose and a portion of the corn starch are mixed and granulated to form a 10% corn starch paste. The granules obtained is sieved, dried and mixed with the corn starch and magnesium stearate. The granules obtained is then compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0 mg, 50.0 mg and 100.0 mg 9,10,11-trimethyl-9, IO-dihydroanthracene 9, 10-imine per tablet included.

509848/1 140

Following the procedure of Example 30a, tablets containing 2-fluoro-9-10,11-trimethyl-9 »IO-dihydroanthracene-9,10-imine can be prepared if the 9» 10,11-Q} rimethyl is used -9 ₇ IO-dihydroanthracene-9, 10-imine of Example 29a replaced by an equivalent amount of 2-fluoro-9,10, H-trimethyl-9, IO-dihydroanthracene-9, 10-imine. Other tablets can be produced by the same procedures using equivalent amounts of carriers together with equivalent amounts of the anthracenine compounds according to the invention, prepared according to the preceding examples.

- Jl6 -

5098Λ8 / 1 UO

Claims (1)

Claims _v Ii compounds of the formula in which: R ¹ and R ² X and X .A Hydrogen, acyl, alkyl, aryl, alkoxycarbonyl, aralkyl, alkenyl, dialkylaminoalkyl, hydroxyalkyl, Alkynyl, trialkylsilyl, alkylcycloalkyl or cycloalkyl, independently of one another hydrogen, alkyl, haloalkyl, aralkyl, aryl, alkenyl or dialkylaminoalkyl, independently of one another halogen, such as chlorine, fluorine, bromine, iodine and the like, alkoxy, dialkoxymethyl, Alkyl, cyano, dialkylaminoalkyl, carboxy, Carboxamido, halogen-substituted alkoxy, Haloalkyl, haloalkylthio, allyl, aralkyl, cycloalkyl, aroyl, aralkoxy, alkanoyl, aryl, substituted aryl, alkylthio, alkylsulfonyl, Haloalkylsulphonyl, alkylsulphinyl, haloalkyl sulfinyl, arylthio, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, carbamoyl, N-alkyl carbainoyl, N, N-dialkylcarbamoyl, nitro or dialkylsulfamoyl, an integer, namely 0 (X or Y means Hydrogen) 1, 2, 3 or small saturated heterocyclic or heteropolycyclic Proportion in which the heteroatom or the heteroatoms A mean N or NR, where R has the meaning given above, - 47 509848/1140 or the carbocyclic fraction benzo with the -rA
Condition (if J \ stands for Benzo), 1 2 that when X, Y, R and R are hydrogen, R does not mean phenyl, methyl or hydrogen 1 2 th, and that if R and R are phenyl, (X) _n 1,4-dimethyl and Y denote hydrogen, R cannot denote methyl, benzyl or phenyl, and that when R and R denote methyl, (X) _n 1,4-dimethyl and Y denote hydrogen, R cannot denote benzyl can mean, and that when R ¹ and R ^{2 are} hydrogen, (X) _n 1,2,3? ^ - Tetra- fluorine and Y are hydrogen, R is not 1 can mean methyl, and that if R and R Phenyl and Ί. and Y denote hydrogen, R cannot denote hydrogen, carboxyethyl or methyl, as well as the non-toxic, pharmaceutically acceptable acid addition salts of these compounds. 2c ¥ connections according to claim 1, characterized in that mean: 2
R and R independently of one another are hydrogen, low- alkyl having 1 to about 6 carbon atoms, Alkenyl of 2 to about 6 carbon atoms or dialkylaminoalkyl having 3 to about 15 carbon atoms, H is hydrogen or lower alkyl of about 1 to about 6 carbon atoms, hydroxy lower alkyl of 1 to about 6 carbon atoms, alkenyl with 2 to about 6 carbon atoms, cycloalkyl of 5 to about 6 carbon atoms, alkylcycloalkyl with 4 to about 10 carbon atoms, benzyl (or X- or R-ring-substituted benzyl), Lower alkoxycarbonyl of 2 to about 7 carbon atoms or dialkylaminoalkyl with 3 to about 15 carbon atoms, -Ü8- 509848/1 UO 15 610Y T and X independently of one another lower alkyl with 1 to about 6 carbon atoms, fluorine, chlorine, bromine, Iodine, lower alkoxy having 1 to about 6 carbon atoms, halogen-substituted lower alkoxy having 1 to about 6 carbon atoms, halo-lower alkyl having 1 to about 6 carbon atoms, Cyano, carboxy or carboxamido, an integer, namely 0 (X or Y stands for hydrogen), 1 or 2, Benzo or 3. Compounds according to claim 1, characterized in that that mean: E ¹ and Hydrogen, lower alkenyl such as vinyl and the like, lower alkyl having 1 to about 6 carbon atoms, such as methyl, ethyl, propyl and the like, trifluoromethyl, di-lower alkylamino-lower alkyl, such as dimethylaminopropyl and the like, hydrogen, benzyl or substituted benzyl, Lower alkyl having 1 to about 6 carbon atoms, such as methyl, ethyl, propyl and the like., Cyclopropyl, cyclobutyl or di-lower alkylamino-lower alkyl such as dimethylaminopropyl and the like, - 49 - 509848/1 UO X and T chlorine, bromine, iodine, medrigalkoxy with 1 to about 6 carbon atoms, lower alkyl having 1 to about 6 carbon atoms, cyano, carboxy, Carboxamido, trifluoromethoxy, trifluoromethyl, Trifluoromethylsulfonyl, lower alkylthio, like methylthio and the like, or trifluoromethylthio, η is an integer, namely 0 (X or Y stand for hydrogen), 1 or 2, and .— A the benzo group Compounds according to spoke 1 _s , namely 2-bromo-11-methyl-9 »10-dihydroanthracene-9,10-imine, 1,11-bimethyi-9, IO-dihydroanthracene-9,10-imine, 2-methoxy-11 -methyl-9,10-dihydroanthracene-9,10-imine _t 1-chloro-11-methyl-9,10-dihydroanthracene-9,10-imine, 1-fluoro-11-methyl-9,10-dihydronaphthalene-9 , 10-imine, 9.10-dihydro-9,10 ^ 11-trimethyl8nthracene-9,10-imine, 9j11-dimethyl-9, IO-dihydroanthracene-9,10-imine, 9 810-diethyl-i1-methyl-9 , 10-dihyäroanthracen-9,10-imine, 9 _s H-dimethyl-IG-äthyl-9 ₁ 10-dihydroanthracen-9,10-imine, 9,10-trifluoromethyl-1'i-methyl-9,10-dihydroanthracene-9,10-imine, 11-methyl-9,10-dipropyl-9, IO-dihydroanthracene-9,10-imine, 11-methyl-9-ethyl-10-propyl-9, IO-dihydroanthracene-9,10-imine, 2-chloro-11-propyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 2-iodo-11-propyl-9,10-dimethyl-9, IO-dihydroanthracene-9,10-imine, 2-bromo-11-propyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 2-chloro-11-cyelopropyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 2-iodine-11-cyclopropyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 2-bromo-11-cyclopropyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, "50-509848 / 1 UO 2-chloro-11- (3-hydroxypropyl) -9,10-dimethyl-9,10-dihydroanth.racen-9,10-imine, 2- iodine-11- (3-hydroxypropyl) -9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 2-bromo-11- (3-hydroxypropyl) -9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 9,10-dihydro-2,9,10,11-tetramethylanthracene-9,13-imine 2-chloro-9,10-dihydro-9,10, H-trimethylanthracene-9,10-imine, 9,10-dihydro-1-fluorine-1-fluorine-9 ϊ 10,11-trimethylanthracene-9 »10-imine, 9,10-dihydro-2-methoxy-9,10, H-trimethylanthracene-9,10-imine, 2,3-difluoro-9,10-dihydro-9,10,11-trimeth.ylanthracene-9,10- 9,10-dihydro-i, 9 ^ 0, H-tetramethylanthracene-9,10-imine, 9 i 10-Mhydro-2-trifluoromethyl-9,10,11-trimethylanthracene-9,10-imine, 9,10-dihydro-2-fluorine-9,10,11-trimethylanthracene-9,10-imine, 1,3-difluoro-9,10-dihydro-11-meth.ylantliracen-9,10-imine, 1-aza-5,10-dihydro-1 i-methylanthracene-5,10-imine, 2-aza-5,10-dihydro-11-methylanthracene-5,10-imine, 1-aza-5,10-dihydro-9,10, H-trimethylanthracene-5,10-imine, 1,3-diaza-5,10-dihydro-11-methylanthracene-5,10-imine, 2,3-difluoro-9,10-dih.ydro-11-methylanthracene-9,10-imine, 9,10-dihydro-5,11-dimetilyl-2-fluoroanthracene-9) 10-imine, 9,10-dihydro-8,11-dimethyl-2-fluoroanthracene-9,10-imine, 9,10-dihydro-2-fluorine-11-methyl-6-trifluoromethylanthracene 9,10-imine, 9,10-dihydro-2-fluorine-11-methyl-7-trifluoromethylanthracene-9,10-imine, ' "- 2-bromo-9,10-dihydro-9,10, H-trimethylanthracene-9,10-imine, 9,10-ditiydro-2-trifluoromethylthio-9,10,11-trimethylanthracene-9,10-imine, 2-cyano-9,10-dihydro-9,10,11-trimethylanthracene-9,10-imine, 2-carboxy-9,10-dihydro-9,10, ii-trimethylanthracene-9,10-imine, 11- / p-chlorobenzyl7-9,10-dihydro-9,10-dimethyl anthracene-9,10-imine, 9,10-dihydro-1,4,9, IO-tetramethylanthracene-9,10-imine, 9,10-dihydro-1,4,9,10,11-pentamethylanthracene-9,10-imine, 9,10-dihydro-9,10-dimethyl-H-cyclopropylanthracene ^, 10-imine, - 51 - 5 0 9 8 A 8/1 U 0 9,10-Mhydro-9, ii-dimethyl-IO-γ-dimethylaminopropylanthracene-9 , 10-imin, 2-methylthio-9,10, H-trimethyl-9,10-dihydroanthracene-9,10-imine, 1- isopropyl-9,10,11-trimethyl-9 »10-diliydroantiiracen-9,10-imine, 2-isopropyl-9,10,11-trimethyl-9, IO-dihydroanthracene-9,10-imine, 2- (N, N-dimethylsulfamoyl) -9,10,11-trimethyl-9,10-dihydroanthracene-9,10-imine, 2-diethoxymetllyl-9,10 _ί 11-tΓimethyl-9,10-dillydroanthracene-9,10-imine, 2-carboxaldehyde-9,10,11-trimethyl-9,10-dihydroanthracene-9,10-imine, 11-benzyl-9,1-dimethyl-9,10-dihydroanthracene-9,10-imine, 11-ethyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 11-benzyl-2,9? 10-trimethyl-9j10-dihydroanthracene-9,10-imine, 11- (3-hydroxypropyl) -9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 11-propyl-9,10-dimethyl-9, IO-dihydroanthracene-9,10-imine, 11-butyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 1-chloro-9,10,11-trimethyl-9,10-dihydroanthracene-9,10-imine, 11-allyl-9,1O-dimethyl-9, IO-dihydroanthracene-9,10-imine, 11-cyclopropylmethyl-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 11- (3-dimethylaminopropyl) -9,10-dimethyl-9,10-dihydroanthrac en-9,10-imine, 2-iodo-11- (3-dimethylaminopropyl) -9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 2-bromo-11- (3-dimethylaminopropyl) -9,10-dimethyl-9, IO-dihydroanthracene-9 , 10-imin, 11-ethyl-1,4,9,10-tetramethyl-9, IO-dihydroanthracene-9,10-imine, 2-chloro-11- (3-dimethylaminopropyl) -9,10-dimethyl-9, IO-dihydroanthracene-9 , 10-imin, 9, IO-dimethyl-9, IO-dihydroanthracene-9,10-imine, 10-butyl-9,11-dimethyl-9,10-dihydroanthracene-9,10-imine, 11-15> -methoxybenzyl7-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 10-vinyl-9,11-dimethyl-9,10-dihydroanthracene-9,10-imine, 9,10,11-triethyl-9,1O-dihydroanthracene-9,10-imine, 11-Garbäthoxy-9,10-dimethyl-9, IO-dihydroanthracen-9,10-imine, - 52 509848/1140 2-nitro-11-carbethoxy-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 2-Amino-11-carbethoxy-9, IO-dimethyl-9,10-dihydroanthracene-9,10-imine., 2-hydroxy-11-carbethoxy-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 2-methoxy-11-carbethoxy-9,10-dimethyl-9,10-dihydroanthracene-9,10-imine, 2-methoxy-9,10,11-trimethyl-9 * IO-dihydroanthracene-9110-imine, 2-chloro- and 2-iodo-9 "10,11-trimethyl-9 _i 10-dihydroanthracene-9,10-imine, 2-ITitro-9,10,11-trimethyl-9, IO-dihydroanthracene-9,10 -imine, 2-amino-9,10,11-trimethyl-9, IO-dihydroanthracene-9,10-imine, 9,10-butyl-11-ethyl-9, IO-dihydroanthracene-9,10-imine, 9,10-butyl-11-propyl-9, IO-dihydroanthracene-9,10-imine, 11-carbethoxy-2-acetyl-9,10-dimethyl-9,10-dihydro anthracene-9,10-imine, 3,9,11-trimethyl-9, IO-dihydroanthracene-9,10-imine, 2,9, H-trimethyl-9, IO-dihydroanthracene-9,10-imine, 9,11-dibutyl-9, IO-dihydroanthracene-9,10-imine, 2-chloro-9, H-dimethyl-9, IO-dihydroanthracene-9,10-imine, 9-ethyl-11-methyl-9,10-dihydro anthracene-9,10-imine, 11-benzyl-9-methyl-9,10-dihydroanthracene-9,10-imine, 11-ethyl-9-methyl-9, IO-dihydroanthracene-9,10-imine. 5. Method for producing connections according to claim 1, characterized in that one is an isoindole of the structural formula (X or with a "gasoline" or hetarin of the structural formula - 53 - 509848/1140 15 610Y (X or Y) implements. 6. · Method for establishing connections according to claim 3 » characterized in that one is an isoindole of the structural formula (X or Y) with a "gasoline" of the structural formula (X or Y) implements. 7 · Pharmaceutical agent contained in unit dosage form a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable one Salt thereof and a pharmaceutical suitable therefor Carrier. ■ / - 54 509848/1 UO