DE1793612C - - Google Patents

Description

(H)

The present invention relates to new basic derivatives of the ethanoanthracene series of the general Formula I (numbering of the Chemical Abstracts),

(D

in which X is hydrogen and chlorine and Z is hydrogen or the methyl group, A is a straight or branched alkylene group with 1 to 3 carbon atoms, R ₁ and R _{2 are} hydrogen or a lower alkyl group with 1 to 4 carbon atoms or R ₁ and R ₂ together with the Nitrogen atom denotes a piperidine radical or a piperazine radical which is optionally substituted by a 1-methyl,! - (// - acetoxyethyl) or l - (/ i-hydroxyethyl) group and where R, and R ₂ cannot both be hydrogen, when X, Y and Z denote hydrogen and A denotes the methylene group, as well as their salts with inorganic odci »... panic acids.

As has now been found, such compounds and their pharmaceutically acceptable salts have with inorganic and organic acids valuable

35 in which X and Z have the meaning given under formula 1 and A ', R ₁ ' and R _{2 have} that of A, R ₁ and R ₂ , but in at least one of these groups A ', R ₁ ' and R _{2 is} a nitrogen-bonded methylene group is replaced by a carbonyl group, or R, "is a lower alkoxycarbonyl group and A 'and R _{2 have} the meanings of A and R ₂ , or by means of a complex metal hydride, in particular lithium aluminum hy-

drid, in an organic solvent, e.g. B. an ethereal liquid such as diethyl ether, dibutyl ether, Tetrahydrofuran or dioxane, which reduces the carbonyl to the methylene group. The reduction of the Compounds of general formula II can be used in

Room temperature to boiling point of the solvent used. Compounds of Formula I. with a hydroxyethylimino group can, if desired, be acetylated in a manner known per se will.

The starting materials, which are summarized in general formula II, form three groups of compounds which contain a carbonyl group in A ', those in R' and those which each have a carbonyl group _{in A 'and in R 1'.}

The first group, carboxamides which can be used in accordance with the invention and which come under the general formula mel Il fall, you get z. B. from the known 9.10-dihydro-9,10-ethano-anthracene-11 -carbon acids, e.g. B. from the desired if «-alkylated

6s 9,10-üihydro-9, IO-ethano-anthracun-11 -acetic acid or 9,10-dihydro-9.10-ethano-anthracene-l 1-propionic acids by using these carboxylic acids: Thionyl chloride into the carboxylic acid chlorides and diesi

with amines of the general formula III

H - N

(III)

in which R ₁ and R _{2 have} the meaning given under formula I, converted into the corresponding amides. Examples are methylamide, 4- (2'-hydroxyethyl) piperazide of 9,10-dihydro-9,10-ethano-anthracene-11-carboxylic acid, further examples of methylamide, diethylamide, piperidide of 9.10 -Dihydro-9,10-ethano-anthracene-11-acetic acid and the α-methyl and α-ethyl derivatives of this acid, finally the methyl amide, diethyl amide, propyl amide and isopropyl amide, 4'-methyl piperazide der ^ lO-Dihydro- ^ lO -ethano-anthracene-ll-propionic acid. The second group of starting materials of the general formula II which can be used _{according to the invention, in which R 1} 'contains a caibonyl group or is an alkoxycarbonyl group, A' corresponds to A and Ri is hydrogen, is obtained. by 1 l-aminomethyl-9,10-dihydro-9,10-ethano-anthracene or amines of the general formula IV

(IV)

ON

Solvent, such as benzene, condensed to the carboxamides, which z. B. with lithium aluminum hydride reduce to the primary amines in an organic solvent such as tetrahydrofuran leave.

Examples in which R ₁ 'is a carbonyl group or is an alkoxycarbonyl group include the ll- (r-propionylamino-ethyl) -, the ll- (2'-formylamino-ethyl) -9, lO-dihydro-9, 10-ethano-anthracene and the (9, lO-dihydro-9,10-ethano-anthracene-11 -ylmethyl) carbamic acid ethyl ester. Analogous processes can also be used to prepare compounds which are substituted in the 9,10-dihydro-9,10-ethano-anthracen-ll-yl radical, of which 11-formylaminomethyl -1-chloro-9,10-dihydro-9, 10 - ethanoanthracene should be mentioned.

The third group of starting materials of the general formula) II which can be used _{according to the invention, in which A 'and R 1} ' each have a carbonyl group, are obtained by z. B. 9,10-dihydro-9,10-ethano-anthracene-11-carbonyl chloride, 9,10-dihydro-9,10-ethano-anthracene-1 l-acet \ lchloride, its α-alkylated derivatives and the 9,10-dihydro-9,10-ethano-anthracene-11-propionyl chloride condensed with alkali metal compounds of lower N-alkyl carboxamides. An example is N-acetyl ^ 10-dihydro ^ 10-gthano-anthracene-11-carboxylic acid methylamide. Compounds which are substituted in the 9,10-dihydro-9,10-ethano-anthracen-ll-yl radical, such as N-acetyl-1-chloro-9,10-dihydro-9,10- älhanoanthracen-11-acetic acid methylamide.

According to a second process, compounds of the general formula I are obtained by Compounds of the general formula V

in which X and Z the in form! I have given meaning and A "an unbranched or branched alkylene or alkylidene radical of 1 to 3 carbon atoms means, starting out, these amines with reactive functional derivatives of lower alkanoic acids such as esters, halides or Anhydrides, to alkanoylaminoalkyl-9,10-dihydro-9,10-ethano-anthracene derivatives condensed or with lower alkyl haloformates, such as Chlorocarbonic acid methyl ester, or lower dialkyl carbonates, such as diethyl carbonate, to (9.10-dihydro-9,10-ethano-anthracene-1 l-yl-alkyl) -carbamic acid alkyl esters.

Primary amines of the general formula IV are z. B. obtained by a-alkylicrte 9,10-dihydro - 9,10 - ethano - anthracene - 11 - acetonitrile with lithium aluminum hydride in an organic solvent. WIo ether, tetrahydrofuran or N-methyl-morpholine, or catalytically by means of hydrogen, e.g. B. in the presence of RanevNickcl or of Palladium on charcoal in an organic solvent such as methanol or ethanol, if necessary I-alkylated 1 l- (2'-amino-ethyl) -9.10-dihydro-9,10-ethano-anthracene derivatives reduced. To produce the homologous 1 l - (. V-amino-propyl) -9.10 - dihydro - 9.10 - ethuno - anthracene compounds one goes z. B. of the above-described 9.10-dihydro-9,10-ethano-anthracene-11-propionyl chlorides out. These carboxylic acid chlorides are, for example, with aqueous ammonia in an organic

(V)

Z A —N

in which X, Z, A and R _{2 have} the meaning given under formula I, are reacted with a saturated aliphatic oxo compound of 1 to 5 carbon atoms and the reaction product is then reduced or in the same operation. The reduction of the intermediates, e.g. B. that of mines, for example by means of sodium hydride. Lithium aluminum hydride, formic acid or by catalytic methods by hydrogenation. Aliphalic oxo compounds are formaldehyde, acetaldehyde, propionaldehyde and butyraldehyde. Isobutyraldchyd. Acetone. Butanone. Called isopropyl methyl ketone.

The secondary amines used as starting materials and already falling under the general formula I can be prepared 7 .. B. by the first process, the primary by methods that were subsequently described for the first process. Compounds of the general formula I are obtained by a three-step process by

Compounds of Formula VI

VV \

(VI)

Z Z

in which X and Z have the meaning given above and Z 'is branched or unbranched Cyanoalkyl-. or hydroxyiminoalkyl radical each with a maximum of 3 carbon atoms or, if at least one of the symbols X and Z is different from hydrogen. the cyano group means up to conversion the cyano group into the aminomethyl group. or Hydroxyimino- reduced to the amino group, or hydrogenated.

The reduction of the connection of the allgcmcir.cn Formula VI is made using a complex metal hydride. especially lithium aluminum hydride in an organic solvent, e.g. B. an ethereal liquid such as diethyl ether. Dibutyl ether. Tetrahydrofuran or dioxane. or with metallic sodium in an organic solvent such as Butanol. Starting materials of the general formula VI. in which Z 'denotes the cyano group, one obtains. by adding substituted anthracemic bonds of the general formula VH in the rings A ** and C **

B ** lc ** j-X

J ι

(VIII

V V \ /

in which X has the meaning given above. with acrylonitrile or methacrylonitrile.

Examples of starting materials are the 1 l-cyano-9.H) -dihydro-9.10-ethunoanthracenes substituted in the benzene rings named: 1-chloro-11-cyano-9.10-dihydro-9.10-ethanoanthracene. 4-Chlor-9.HWIihydro-9.10-athanoanthrac.cn.

Starting materials of the general formula VI. in which Z 'is a branched or unbranched Cyanoalkyl radicals with a maximum of 3 carbon atoms are produced by reacting to reactive Esters, especially the p-toluenesulfonic acid esters of 9,10-dihydro-9,10-ethano-anthracene-11-alkanols in an inert organic solvent such as dimethyl sulfoxide sodium cyanide can act. 9,10-dihydro-9, IO-alhano-anthraeen-11-acetonitrile can in this way from the p-toluenesulfonic acid - (9,10 - dihydro - 9,10 - ethanoanlhraccn-

I l-yl) methyl ester can be obtained. Other raw materials of the general formula Vl. in which Z is a hydroxyiminoalkyl radical of at most 3 carbon atoms means one receives. by adding substituted or unsubstituted 9.10-Dihydm-9.10 - ethano - anthracene - 11 - carboxaldehyde or

I1 -oxoalky 1-9,10-dihydro-9,10-ethano-anthracene refluxed with hydroxylamino hydrochloride in the presence of pyridine.

According to a fourth process for the preparation of compounds of the general formula I cleaves one compounds of the general formula VIII

(VIII)

in which X, Z, R ₁ and A have the meaning given under formula I, R _{4 is} a carboxylic acid residue. or the remainder of a monofunctional derivative of carbonic acid, or a mononuclear sulfonic acid residue, or R ₁ and R ₄ together with the anlic-

2c lowing nitrogen atom form the phthalimide radical or, including an imino group substituted by an acid radical, form a piperidine or pipcrazine radical, with A not being allowed to represent the methylene group when X, Z and R _{1 are} hydrogen, in acid and secondary amine. If a lower alkanoyl radical R _{4 is present, the} cleavage can be carried out by acidic or alkaline hydrolysis or by thermolysis and in the presence of a methanesulfonyl or p-toluenesulfonyl _{radical R 4} . z. B. by treatment with sodium in ammonia, done reductively.

The starting materials of the general formula VIII which can be used according to the invention are obtained by z. la. starts from the 11-acylamino-alkyl-9, 10-dihydro-9,10-ethano-anthracenes falling under the general formula II, in which A 'corresponds to A, Ri is hydrogen and R ₁ ' is an ayl radical. These connections are carried out e.g. B. into the sodium derivatives and alkylated them with a lower alkylation agent, such as methyl iodide. Dimethyl sulfate or n-butyl bromide.

Another production possibility for in accordance with the invention usable starting materials of the general formula VIII consists in the reaction of compounds of the general formula I in which R _{2 is} a lower alkyl group having 1 to 4 carbon atoms and the z. B. have been obtained by the first process, with an organic acid halide or anhydride, in particular a carbonic acid ester chloride (chloroformic acid ester), acetic anhydride. Acctyl bromide, benzoyl chloride or phosgene.

Furthermore, compounds of the general formula VIII are obtained by adding reactive esters of the Hydroxy compound of the general formula IX

(IX)

A - OH

in which X, Z and A have the meaning given under formula I, with carboxamides of the all-

my formula X

Η —Ν

in which R ₁ and R _{4 have} the meaning given under the general formula VIII, condensed in the presence of an acid-binding agent or with metal compounds of such amides.

As starting materials of the general formula VIII be z. B. der (S-Chlor- ^ 10-dihydro-QJO-ethanoanthracene-1 l-yl-methylj-methyl-carbamic acid c-ethyl ester and N-propyl-N- (4-chloro-9,10-dihydro-9.10-ethano-anlhracene-1 l-yl-ethyl) -acetamide called.

With inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, ethane disulphonic acid, fi- hydroxyethanesulphonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, and salicylic acid Mandelic acid form the new compounds of general formula I salts, some of which are water-soluble.

The substances of the general formula I represent racemates. These can be carried out in a manner known per se can be broken down into the optical antipodes. It has been shown that the biological activity of the Compounds of general formula I are mainly attributable to the levorotatory forms.

The following examples explain the preparation of the new compounds of the general Formula I closer. The temperatures are given in degrees Celsius.

example 1

a) 6.5 g of 35% formaldehyde solution are added at 25 to a solution of 7.5 g of 1 l-aminomethyl-9,10-dihydro-9,10-ethanoanthracene (melting point 116 to 117 ^r ) in 7.3 g of anhydrous formic acid and with this then refluxed for 12 hours. After cooling, the reaction mixture is mixed with 20 ml of 2N hydrochloric acid, extracted with 50 ml of chloroform and the chloroform extract is washed with water. The aqueous phase is made alkaline with concentrated ammonia, extracted with ether, the ethereal solution is washed with water, dried over sodium sulphate and evaporated in vacuo. The remaining oil crystallizes on standing and gives the crude 11-dimethylaminomethyl-9,10-dihydro-9.10-ethanoanthracene, melting point 70 to 78 °, yield 77% of theory, from which the hydrochloride is prepared with ethereal hydrochloric acid, melting point 248 to 250 ° (from methanol-acetone).

b) Starting from 11-aminomethyl-ll-methyl-9,10-dihydro-9,10-ethanoanthracene, 11-dimethylaminomethyl-11-methyl-9,10-dihydro-9,10-ethano-anthracene is produced in an analogous manner, Hydrochloride, melting point 251 to 255 °, obtained in 73.3% yield from methanol-acetone.

c) Starting from 1-chloro-11-aminomethyl-10-dihydro-9,10-ethano-anthracene, 1-chloro-1-dimethylaminomethyl-9,10-dihydro-9,10-ethano is also obtained in a similar manner -anthracene, hydrochloride, melting point 285 to 286 from methanol-acetone. Yield 72% of theory.

d) Starting from 4 - chloro - 11 - aminomelhyl-9,10-dihydro-9,10-ethano-an 4-chloro-l-dimethylaminomethyl-9 is obtained in an analogous manner. K) -dihydro-9,10-ethano-anthracene, hydrochloride. Melting point? 26 to 228. from methanol acetone. Yield 70% of theory.

Example 2

a) A solution of 23 g of 1 l-aminomethyl-9,10-dihydro-9.10-äthano-anlhraccn in 60 g of methyl formate is refluxed for 24 hours. The cooled reaction mixture is diluted with Ether, the ethereal solution washes with 2N hydrochloric acid and water, dry them over sodium sulfate and evaporate them in a vacuum. The residue ran after crystallization from acetone, the 11-formylaminomethyl-9,10-dihydio-9,10-ethano-anthracene, Melting point 127 to 128. Yield 100% of theory.

b) A solution of 26 g of the formylamine obtained according to a) in 100 ml of absolute tetrahydrofuran is in a suspension of 3.8 g of lithium aluminum hydride in 250 ml of absolute ether within a Dripped in for an hour. After refluxing for 15 hours, 3.8 ml are added successively at 20 Water. 3.9 ml of 15% sodium hydroxide solution and 11.4 ml of water are added. The resulting granular precipitate is suctioned off and washed with ether. The combined filtrates are evaporated in vacuo, the residue taken up in ether and the ethereal solution extracted with 2N hydrochloric acid. Hieraul the acidic extracts are made alkaline with concentrated ammonia and extracted with ether. After washing the essential solution with water and drying over sodium sulfate, the Solvent evaporated. The remaining crude 11 -Methylaminornethyl ^ .lO-dihydro ^ .lO-ethanoanthraccn is converted into the hydrochloride with ethereal hydrochloric acid. Melting point 309 to 311 (Decomposition) (from methanol-acetone). Yield 76% of theory.

el In an analogous way one obtains. starting from 11 - amino - methyl - 11 - methyl - 9.10 - dihydro-9.10-ethano-anthracene. via 11-formylaminomethyl-II-methyl-9.10-dihydro-9,10-ethano-anthracene. Melting point 170. The 11-methylaminomethyl-11 - methyl - 9.10 - dihydro - 9.10 - ethano - anthracene. Hydrochloride, m.p. 179 to 181 °, from methanol Acetone. Yield 73% of theory.

d) In an analogous manner, starting from 4-chloro-II-aminomethyl-9,10-dihydro-9,10-ethano, one obtains anthracene, via 4-chloro-ll-formylaminomethyl 9,10-dihydro-9,10-ethano-anthracene, m.p. 148 to 149 °, 4-chloro-II-methylaminomethyl-9,10-di hydro-9,10-ethano-anthracene, hydrochloride, m.p. 280 to 283 °, from methanol-acetone. Yield 72 ° / i the theory.

e) In a similar manner , starting from 1 -chloro-II-aminomethyl-9,10-dihydro 9,10-ethano-anthracene, via the 1 -chloro-11-formyl aminomethyl - 9,10 - dihydro - 9,10-ethano-anthracene 1 -chloro-II-methylaminomethyl-9,10-dihydro 9,10-ethano-anthracene, hydrochloride, melting point 28 ° to 292 °, from methanol-acetone. Yield 72% of theory.

ίο

Example 3

a) 25 g of 9,10-dihydro-9.10-ethano-anthracene-11-carboxylic acid are introduced into 150 ml of thionyl chloride over the course of 20 minutes with stirring at 10 ° and refluxed with this for 1 hour. The reaction mixture is then concentrated in vacuo, the crude carboxylic acid chloride that remains is dissolved in 80 ml of benzene and the benzene solution is added dropwise to a mixture of 53.5 g of 1-piperazine-1-ethanol and 50 ml of water over the course of 15 minutes with vigorous stirring at 40-50 . The reaction mixture is then stirred for 1 hour at 70 ^{° C.} , then diluted with benzene and the phases are separated. The organic phase is washed with 2N sodium carbonate solution and water and extracted with 2N hydrochloric acid. The hydrochloric acid extract is made alkaline with concentrated ammonia and extracted with chloroform. The chloroform extract washed with water gives, after drying over sodium sulfate and evaporation in vacuo, amorphous 9,10-dihydro-9,10-ethanoanthracene-11-carboxylic acid [4- (T -hydroxy-ethyl) -piperazide]. The hydrochloride prepared with ethereal hydrochloric acid crystallizes from acetone ether, melting point 238 ° to 240 °. Yield 100% of theory.

b) A solution of 35.5 g of the piperazide prepared according to a) in 150 ml of absolute tetrahydrofuran is added dropwise to a suspension of 4.7 lithium aluminum hydride in 400 ml of absolute ether. Man heated under reflux for 15 hours, then added successively at 20 with 4.7 ml of water, 4.7 ml of 15% Sodium hydroxide solution and 14.1 ml of water, sucks off the resulting precipitate and washes it with ether. The combined filtrates are evaporated in vacuo, the remaining oil is dissolved in methanol taken up and this solution acidified with essential hydrochloric acid. The separating raw 4- (9, 10'-dihydro-9 ', 10'-ethano-anthracene-11 -ylmethyl) - Piperazine -1 - ethanol - dihydrochloride is recrystallized from water-methanol, melting point 240 up to 250 ° or 268 to 270 ° in the sealed capillary tube. Yield 75% of theory.

c) In an analogous manner, starting from 9,10-dihydro-9,10-ethano-anthracene-11-acetic acid, 9,10-dihydro-9,10-ethanoanihracene-11-acetyl chloride, 9,10-dihydro-9,10-ethanoane-11-acetyl chloride, is obtained -Dihydro-9,10-ethanoanthracene-11-acetic acid [4- (2'-hydroxyethyl) piperazide], m.p. 159 to 161 °, the 4 [2 '(9 ".IO' -dihydro - 9", 10th "- ethano - anthracene -11" - yl) -1 '- ethyl] -piperazine-1-ethanol, melting point 101 to 104 ^c , from diethyl ether-petroleum ether. Yield 71% of theory.

d) Starting from 9,10 - dihydro - 9,10 - ethanoanthracene-11-carboxylic acid is obtained in an analogous manner via the intermediate 9,10-difaydro-9,10 - ethano - anthracene - 11 - carboxylic acid piperazide the l- (9 ', 10' - dihydro - 9 ', 10' - ethano - anthracene-1 T-yl-methyl) piperazine difumarate, melting point 183 to 186 ° C. from methanol. Yield 72% of theory

e) In a similar manner, starting from 9,10-dihydro-9,10-ethano-anthracene-11 -carboxylic acid, the intermediates 9,10-dihydro-9,10-ethano-anthracene -11-carboxylic acid chloride and 9.10 - dihydro - 9.10 - ethano - anthracene -11 - carboxylic acid (4'-methyl-piperazide), m.p. 165 to 166 ⁵ C, the 1-methyl-4- (9 ', 10'-dihydro -9 ', 10'-ethano-anthracene-1 (r, -yl-methyl) piperazine, dihydrochloride, melting point 238 to 242 ° C. from ethanol. Yield 71% of theory.

f) In an analogous manner, starting from 9,10-dihydro-älhano-anthracene-11-carboxylic acid, via the intermediates 9,10-dihydro-9,10-ethanoanthracene-11 -carboxylic acid chloride and 9,10-dihydro-9, 'iO-ethano-anthracene-11 -carboxylic acid diälhylamid, m.p. 99 to 100, 11-diethylamino-methyl-9,! 0-dib.ydr <i-9,10-iithano-anthracene. Hydrochloride, Mp. 244 to 247 ° from methanol-acetone. Yield 80% of theory.

Example 4

a) 20 g of 11-acetyl-9,10-dihydro-9,10-ethanoanthracene are with 20 g of hydroxylamine hydrochloride. 20 ml of pyridine and 200 ml of ethanol for 2 hours heated to reflux. The reaction mixture is evaporated in vacuo, the residue in chloroform added, the chloroform solution with 2N hydrochloric acid, 2N sodium bicarbonate solution and water washed, dried over sodium sulfate and evaporated in vacuo. The 11-acetyl-9,10-dihydro-9,10-ethano-anthracene-oxime obtained crystallized from ether-petroleum ether, m.p. 159 to 160. yield 88% of theory.

b) 9.3 g of the oxime prepared according to a) are dissolved in 80 ml of absolute n-butanol and placed under nitrogen heated to the boil. 6.3 g of sodium are added in small amounts to this solution over the course of 20 minutes Pieces and reflux the reaction mixture for a further 2 hours. Then it will be

- \ o cools and dilutes with 200 ml of ice water and 100 ml of ether. After the organic phase has been separated off, it is evaporated in vacuo and the residue is taken up in ether. The ethereal solution is extracted with 2η hydrochloric acid, the hydrochloric acid extract is made alkaline with concentrated ammonia and extracted with ether. The ether solution is washed with water, dried over sodium sulfate, evaporated in vacuo and the residue is crystallized from petroleum ether. The 11 - (Γ - amino - ethyl) - 9,10 - dihydro - 9,10 - ethanoanihracene is obtained. M.p. 76 to 84 °. The hydrochloride prepared with ethereal hydrochloric acid crystallizes from methanol-acetone. Mp. 258 °, or 287 to 290 in the fused capillary tube. Yield 87% of the theory.

Example 5

12 g of H- (T- amino - ethyl) ■ 9.10 - dihydro-9.10-ethano-anthracene are refluxed with 50 ml of methyl formate for 24 hours. Then the reaction mixture is evaporated in vacuo, the residue is taken up in chloroform, the chloroform solution washed with 2N hydrochloric acid and water, dried over sodium sulfate and im Evaporated in vacuo. The obtained II- (T-formylamino-ethyl) -9,10-ethano-anthracene is, dissolved in 35 ml of absolute tetrahydrofuran, to a suspension of 2 g of lithium aluminum hydride in 100 ml of absolute Ether added dropwise. The reaction mixture is then refluxed for 20 hours and mixed then at 20 ° one after the other with 2 ml of water, 2 ml of 15% sodium hydroxide solution and 6 ml of v / ater, sucks the resulting precipitate and washes it with ether. The combined filtrates are in vacuo evaporated, the residue taken up in ether and extracted with 2η hydrochloric acid. The hydrochloric acid extract is made alkaline with concentrated ammonia and then extracted with chloroform. Man

the chloroform solution was washed with water, dried over sodium sulfate and evaporated in vacuo. The remaining H- (I'- methyl-amino-ethyl) -9.10-dihydro-9.10-ethano-anthracene is also supplied ethereal hydrochloric acid the hydrochloride, Schrnp. 258 to 260 '(from methanol-acetone). Yield 67% of the Theory.

Example 6

7.5 g of 11 - (Y - amino - ethyl) - 9,10 - dihydro-9,10-ethano-anthracene are dissolved in 6.1 ml of anhydrous formic acid with cooling and mixed with 6.5 g of 35% strength (; r The mixture is heated under reflux for 12 hours, cooled, 20 ml of 2N hydrochloric acid are added and it is evaporated in vacuo. The residue is taken up in benzene and water, the aqueous phase is separated off and the organic phase is with it 2N hydrochloric acid. The acidic extract is made alkaline with concentrated ammonia and extracted with chloroform. After washing with water, drying over sodium sulfate and evaporation of the solvent in vacuo, 11 - < I -Di methyl - amino - ethyl) - 9.10 - dihydro - 9.10 - ethanoanthracine. Mp. 127 to 130 '(from petroleum ether). Yield 98% of theory. With essential maleic acid, the acidic maleal is obtained, melting point 198 to 199 (from methanol-ethyl acetate).

Example 7

a) In a solution of 47 g of 9.10 - Dihydro-9.10 - ethano - anthracene - 11 - methanol (m.p. 109 to 111) in 200 ml of absolute pyridine, 39 g of p-toluenesulfonic acid chloride are entered at 10 to 15. The reaction mixture is stirred for 15 hours at 20 to 25 hours and then the pyridine is distilled in Vacuum below 30. The residue solidifies when rubbed with ice water. He is sucked off washed with dilute hydrochloric acid and with water and dried. P-Toluene-sulfonic acid- (9.10 - dihydro - 9.10 - ethano - anthracene - 11 - yl) methyl ester, Melting point 143 to 144 '(from chloroform ether). Yield 85% of theory.

b) 98 g of the toluenesulfonate obtained according to a) are at 20 'within 20 minutes in a Suspension of 31 g of sodium cyanide in 400 ml of dimethyl sulfoxide entered and the mixture heated under reflux for 3 hours. After cooling it will the reaction mixture diluted with ice water and extracted with ether, the ether extract with water washed, dried over sodium sulfate and evaporated in vacuo, the residue being crystalline stiffens. The suction filtered crystals are washed with pentane. The crude product obtained delivers after recrystallization from acetone-petroleum ether pure 9.10 - dihydro - 9.10 - ethano - anthracene-11-acetonitrile, 123 to 124 °. Yield 92% of theory.

c) 10.5 g of the ¹ nitrile obtained according to b), dissolved in 20 ml of absolute tetrahydrofuran, are added within 30 minutes to a suspension of 1.3 g of lithium aluminum hydride in 70 ml of absolute ether. The reaction mixture is then refluxed for 15 hours, and 1.3 ml of water, 1.3 ml of 15% strength sodium hydroxide solution and 4.2 ml of water are added in succession at 20 °. The resulting granular precipitate is filtered off with suction and washed with ether. The combined filtrates are evaporated in vacuo, the residue is dissolved in ether and extracted with 2η hydrochloric acid. The hydrochloric acid extract is made alkaline with concentrated ammonia and extracted with ether, the Älhcrextrakt washed with water, dried over sodium sulfate and evaporated in vacuo. With ethereal hydrochloric acid, the residue gives 1 l- (2'-amino-ethyl) -9,10-dihydro-9,10-ethano-anthracene hydrochloride, melting point 240 to 246 (from methanol-acetone). Yield 68% of theory.

Example 8

7.5 g of the 11-aminoethyl compound obtained according to 8c) are dissolved in 7.3 g of formic acid (100%) with cooling and with 6.5 g of 35% formaldehyde solution 1 heated under reflux for 2 hours. The cooled reaction mixture is then mixed with 20 ml of 2N hydrochloric acid added and concentrated in vacuo. The residue is dissolved in water and the solution is extracted with Ether, then alkalizes them with concentrated ammonia and extracts them with chloroform. E> he Chloroform extract is washed with water, dried over sodium sulfate and the solvent is im Vacuum evaporated. The remaining 11- (2'-dimethylamino - ethyl) - 9.10 - dihydro - 9.10 - ethanoanthracn supplies the hydrochloride with ethereal hydrochloric acid. M.p. 259 to 261 (from methanol-acetone). Yield 78% of theory.

^ ₀ example 9

a) 24.5 g of 9,10-dihydro-9.10-ethano-anlhracene-11-acetonitrile are with 14.5 g potassium hydroxide, 5 m! Water and 200 ml isoamyl alcohol for 24 hours heated to reflux. After cooling, the reaction mixture is diluted with ice water and extracted it with ether. The aqueous phase is treated with concentrated hydrochloric acid until a Congo acidic reaction is obtained added and extracted with ether. The ether extract is washed with water and dried over sodium sulfate and. narrows him. After adding petroleum ether, the 9,10-dihydro crystallizes from the concentrated solution - 9,10 - ethano - anthracene - 11 - acetic acid. 167-172. Yield 95% of theory.

b) 8.5 g of the carboxylic acid obtained according to a) are refluxed with 25 ml of thionyl chloride for 1 hour heated. Then the excess thionyl chloride evaporated in vacuo, the oily residue dissolved in 20 ml of benzene and the benzene solution within 15 minutes at 20 to 25 with stirring in a solution of 12 g of diethylamine in 12 ml of water. The reaction mixture is heated to 70 ° for 1 hour, then cooled and diluted with benzene separates the aqueous phase. The organic phase is treated with 2N hydrochloric acid and 2N sodium carbonate solution and washed with water, dried over sodium sulfate and evaporated in vacuo. The remaining Crude diethylamide, dissolved in 50 ml of absolute ether, is dissolved in a suspension of 1.5 g of lithium aluminum hydride dripped into 100 ml of absolute ether. The reaction mixture is then refluxed for 15 hours and then added Cool down successively at 20 ° with 1.5 ml of water, 1.5 ml of 15% sodium hydroxide solution and 4.5 ml of water. Dei Resulting precipitate is sucked off, with Äthei washed and the ethereal filtrate with 2N hydrochloric acid moved out. The separated, acidic, aqueous phase is made alkaline with concentrated ammonia. and undressed with ether. The ether extract is mii

Washed water, dried over sodium sulfate and the solvent evaporated. With ethereal hydrochloric acid, the residue gives I l- (2'-diethylamino-ethyl) -9, IO-dihydro-9,10-älhano-anthraene hydrochloride, melting point 221 to 22? (from acetone
Ether). Yield 88% of theory.

c) In an analogous manner, starting from 9,10-dihydro - 9,10 - ethano - anlhracene - 1 I - acetic acid according to process b) via the intermediate products 9.K) -dihydro - 9.10 - alhano - anlhracene - 11 - acetyl - chloride. 9.IO-Dihydro-9.K) -ethano-anthracene-11-acetic acid methyl - amide, 11 - (2 '- methylamino - ethyl) -9, K) -dihydro-9.10-ethano-anthracene obtained, which with essential oxalic acid supplies the acidic oxalate, M.p. 226 to 228 (from methanol).

d) Starting from 9.10 - dihydro - 9.10 - ethanoanthracene-11-acetic acid is also in an analogous manner via the intermediates 9.10-dihydro-9,10-ethano-anlhracene 1! acetyl chloride. 9,10-dihydro-9.10 - ethano-anthracene-11-acetic acid piperidide, the 11 - (2 '- piperidinoethyl) - 9,10 - dihydro-9,10-ethano-anthracene, Hydrochloride. M.p. 248-252, obtained from methanol-acetone. yield 80% of theory.

Example MO

a) To a suspension of 11.5g sodium hydride (50% in paraffin oil) in 100 ml of absolute dimethylformamide are 38.5 g of malonic acid diethyl ester within of 30 minutes, and then 75 g ρ - toluenesulfonic acid - (9.10 - dihydro - 9.10 - ethanoanthracene-1 l-yl) methyl ester in 200 ml of absolute dimethylformamide, also within 30 minutes, dripped in. The reaction mixture is then refluxed for 20 hours, cooled and diluted with 1 l of water, mixed it with concentrated hydrochloric acid until the Congo acid reaction and extracted it with Ether. The ether extract is washed with water, dried over sodium sulfate and evaporated in vacuo, the residue was dissolved in 48% ethanol and refluxed with 20 g of potassium hydroxide for 15 hours heated. The ethanol is then evaporated off in vacuo. extracts the aqueous, alkaline Distillation residue with ether, mixed with concentrated hydrochloric acid until the Congo acidic reaction and strips it off with chloroform. The chloroform extract is washed with water over sodium sulfate dried and evaporated in vacuo. The residue is heated in a stream of nitrogen for 2 hours to 160 to 180 ', then cools it down and absorbs it into ether. The ethereal solution becomes n; it is 2N sodium carbonate solution shaken out. The aqueous phase is separated off and 2N hydrochloric acid is added to it to the Congo acid reaction and extracted it with ether. The ethereal solution is washed with water, dried over sodium sulfate, concentrated and mixed with petroleum ether. 9.10-dihydro-9,10-ethano-anthracene-II-propionic acid crystallizes off, m.p. 149 to 151 °. Yield 47% of theory.

b) 11.5 g of the carboxylic acid obtained according to a) are heated under reflux with 30 ml of thionyl chloride for 1 hour. Then the excess thionyl chloride distilled off in vacuo, the residue dissolved in 20 ml of benzene and at 20 to 25 ° with stirring added dropwise to 25 ml of a 40% strength aqueous dimethylamine solution. ' The reaction mixture is heated 1 hour at 70 °, then cools it down and dilutes it with benzene. After separating the aqueous Phase, the organic phase is washed with 2N hydrochloric acid, 2N sodium carbonate solution and water, dried over sodium sulfate and evaporated in vacuo. A solution of the Residue in 35 ml of absolute ether to a suspension of 1.0 g of lithium aluminum hydride in KK) ml of absolute ether. This reaction mixture is refluxed for 24 hours and cooled and then at 20 in succession with 1 ml of water.

ίο 1 ml 15% sodium hydroxide solution and 3 ml water added, the precipitate formed is filtered off with suction and washed with ether. The combined filtrates are with 2N hydrochloric acid extracted. The hydrochloric acid phase is mixed with concentrated ammonia up to the alkaline

see reaction and extract it with ether. The ether extract is washed with water over sodium sulfate dried and evaporated. The 11 - (3 '- dimethylaminopropy!) - 9,10 - dihydro-9.10-ethano-anthracene obtained supplies with essential hydrochloric acid

ze the hydrochloride. M.p. 191 to 192 (from ethyl acetate). Dent removal 37% of theory.

c) In an analogous manner, 9.10-Dihulro-9, K) -ethano-anthracene-1! propionic acid according to process b) via the intermediates. 9.10-dihydro-9.10 - ethano - anthracene - 11 - propionyl chloride. 9,10-dihydro-9,10-ethano-anthracene-11-propionic acid methylamide. 11 - (3'-methylamino-propy!) - 9.10-dihydro-9.10-ethano-anthracene. Hydrochloride. Mp. 213 to 215 obtained from methanol acetone.

d) From 9.10 - Dihydro - 9.10 - ethano - anthr.uvn-

I! -Propionic acid is also processed analogously via the intermediates 9.lü-dihydro-9.10-ethano-anthr; ice;: -

I1 - propionyl chloride, 9.10 - dihydro - 9.10 - ütlv.no anthracene-11 -propionic acid amide, the 11- (3'-AnIi ¹ I 'propyl) - 9.10 - dihydro - 9.10 - ethano - anthnuci hydrochloride. Melting point 244 to 252, obtained from ethane and ethylacelate. Yield 36% of theory

Example 11 178 anthracene are refluxed in 900 ml of Acctanhu '. N 'is added dropwise to this solution. 150 g Ni within 1.5 hours with stirring. acrylonitrile and then heated the mixture to reflux for 48 hours. After cooling, the precipitated crystals were filtered off with suction. You get 65 ρ unreacted anthracene. The filtrate is freed <vacuum of acetic anhydride. The residue 1: is extracted with 1.51 hot methanol. From delimit animal charcoal treated methanol extract knsia ^; lisicren on cooling 130g 11-cyano-! l-meih \! ■

9,10-dihydro-9,10-ethano-anthracine, m.p. 116 to

117 ', after recrystallization from acetone - dieth> I.

ether m.p. 118 to 119 °. Yield 53% of theory In an analogous manner, starting from

1-chloroanthracene, a mixture with acrylonitrile of 1-chloro- and 4-chloro-II-cyano-9,10-dihydro-9 10-ethano-anthracene.

Example 12

Mar is added dropwise to a suspension of 15 g of lithium aluminum hydride in 800 ml of absolute diethyl ether a solution of 123 s within 45 minutes 11 - cyano -11 - methyl - 9.10 - dihydro - 9.10 - ethano " anthracene, then heated to reflux for 15 hours, cooled and 15 ml of water are added dropwise one after the other 15 ml of 15% sodium hydroxide solution and 45 ml of water are added. The resulting precipitate is filtered off and mi Washed diethyl ether. The combined filtrates who

i 793 6! 2

vien evaporated in vacuo. Maci receives 123 g raw Π - aminomethyl - 11 - methyl - 9,10 - dihydro-9,10-ethano-anthracene. The hydrochloride prepared in methanol with ethereal hydrochloric acid crystallizes from methanol-diethyl ether. 123 g are obtained II - aminomethyl - 1Γ- methyl - 9,10 - dihydro-9,10-ethano-anthracene, Hydrochloride, melting point 266 ° to 282 °, after recrystallization from methanol-acetone M.p. 280 to 283 °.

In an analogous manner, the mixture of 1-chloro and 1-chloro prepared according to Example 12 is obtained 4 - chlorine - 11 - cyano - 9.10 - dihydro - 9.10 - ethanoanthracene a mixture of 1-chloro- and 4-chloro-11-aminomethyl-9.10-dihydro-9.10-ethanoanthracene, which can be separated by fractional crystallization of the hydrochloride. The hydrochloride of 1 -Chlor-11 -aminomethyl ^ 10-dihydro ^ 10-ethanoanthracene crystallized from acetone-diethyl ether, m.p. 282 to 287 ', yield 40% of theory, while the hydrochloride of the 4-chlorine derivative remains in the mother liquor and from it through further Fractionation can be obtained.

Example 13

50 g of (±) - 11 - methylaminomethyl - 9,10 - dihydro-9,10-ethano-anthracene are dissolved in 200 ml of ethyl acetate and a hot solution of 36 g of dibenzoyl-D-tartaric acid in 100 ml of ethyl acetate is added. Cooling, suction of the precipitated crystals, repeated concentration of the mother liquors and suction of the further crystal fractions gives a total of 80 g of the neutral salt as a mixture of the two diastereomers. This mixture is separated by fractional crystallization from methanol. After repeated recrystallization of the top fraction up to constant specific rotation, 16 g of (-) - II-methylaminomelhyl-9,10-dihydro-9,10-ethano-anthracene-dibcnzoyl-D-tartrate, melting point 177 to 180 ", [a ] S ³ - 55, c = 1.00 in methanol.

The distribution of this salt between aqueous ammonia and diethyl ether, separation of the ethereal phase, washing until neutral with water, drying over sodium sulfate and evaporation in vacuo yields 9.0 g (-) - l 1-methylaminomethyl 1-9,10-dihydro-9,10 -ethano-anthracene as oil, [«] ?, '-14.5, c = 1.04 in chloroform, yield 18% of theory. The hydrochloride prepared therefrom with ethereal hydrochloric acid crystallizes from methanol-acetone, melting point 269 to 270 °, [a] | ³ -9, 1 ", c = 0.98 in methanol. As a control, this salt was converted into the acidic D-tartrate, melting point 126 ° / 159 to 161 °, from methanol-acetone, [α]? +3, 2 ^o , 'c = 1.10 in methanol, on further recrystallization from methanol-acetone the melting point and specific rotation remain constant.

In an analogous manner, the (+) - 11 - methylaminomethyl - 9,10 - dihydro-9,10-ethano-anthracene-dibenzoyl-n-tartrate is obtained from the mother liquor of the (±) - 11 - methylaminomethyl - 9.10 - dihydro-9.10 - ethano - anthracene - dibcnzoyl - π - tartral, m.p. 157 to 160 ", [«]? -45.3 ", c = 0.98 in methanol and from this the (+) -11-methylaminomethyl-9,10-dihydro-9,10-ethano-anlhraccine. Hydrochloride, m.p. 266 to 270 from methanol acetone, [«]" +6.2 ", c = 1.04 in methanol. Yield 17% of theory.

Example 14

3.5 g of 4- (9 ', l ()' - dihydro-9 ', 10'-äthano-anthracenll'-yl-methyl) -piperazine-l-ethanol are dissolved in 25 ml of absolute pyridine, cooled to 0 C and ^u mixed with 1 ml of acetic anhydride. The mixture is then left to stand for 15 hours at room temperature, then evaporated in a water jet vacuum, the residue is taken up in benzene and evaporated again in a vacuum. The residue is dissolved in methanol and mixed with methanolic hydrochloric acid. After the addition of acetone, 4.1 g of 4- (9 ', 10'-dihydro - 9', 10 '- ethano - anthracene - 11' - yl - methyl) -1 - [ß - acetoxyethyl) - piperazine, dihydrochloride, Mp. 250 to 254 after recrystallization from methanol acetone. Yield 87% of theory.

Example 15

2.6 g of 11-dimethylaminomyl-9, (0-dihydro-9.10-ethano-anthracene are dissolved in 30 ml of benzene and heated to 50 ° C. A solution of 2.1 g of ethyl chloramcisenate is added dropwise to this solution over a period of 30 minutes 15 ml of benzene and then heated to reflux for 6 hours. The cooled benzoic solution is then washed with 2 η-hydrochloric acid and water, dried over sodium sulfate and evaporated in a vacuum in a water jet. 2.9 g of 11 (N - carbethoxy - N - methylamino) - methyl-9,10-dihydro-9.1 () - ethano-anthracene as an oil. This oil is refluxed with 2.1 g of potassium hydroxide in 30 ml of diethylene glycol ethyl ether for 6 hours, then cooled, and then diluted with 200 ml of water and extracted with diethyl ether. The ether extract is exhaustively extracted with 2N hydrochloric acid. The hydrochloric acid extracts are made alkaline with concentrated ammonia and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate and extracted Evaporation in vacuo ¹ 1.9 g of crude 11-methylamino-methyl-9.10-dihydro-9.10-ethano-anthracene. Yield 77% of theory. The hydrochloride prepared therefrom with ethereal hydrochloric acid crystallizes from methanol - acetone, melting point 309 to 31Γ.

The advantageous properties of the compounds according to the invention are illustrated with the aid of the following Compounds obtained pharmacological test data set out:

a) Checked connections

111 - melhylaminomethyl - 9,10 - dihydro-9,10-ethano-anthracene as the hydrochloride (produced according to the invention);

II II - dimelhylaminomethyl - 9,10 - dihydro-9,10-ethano-anthracene as the hydrochloride (prepared according to the invention);

III 1 - chlorine - 11 - aminomethyl - 9,10 - dihydro-9,10-ethano-anthracene as the hydrochloride (produced according to the invention);

IV 4-chloro-l 1 -methylaminomethyl ^ 10-dihydro-9,10-ethano-anthracene as hydrochloride · (produced according to the invention);

V 1 - chlorine - 11 - dimethylaminomethyl - 9,10 - dihydro-9, K) -älhano-anthracine as hydrochloride (prepared according to the invention);
VI 1 - hydroxyaryl - 4 - (9 ', 1O' - dihydro-9 ', K)' - ethano - II '- anthracnyl ■■ methyl) - piperazine - dihydrochloride (prepared according to the invention);

309 609/306

VII 5 - (y-Dimethylaminopropyiiden) - 5Η - dibenzo- [a, d] - [1,4] -cycloheptadiene ["Amilriplyline"] (known).

Rcserpin antagonistic effect

b) method

Male white rats weighing 120 to 150 g are injected subcutaneously with 2 mg kg of reserpine. The reverse injection leads to a Decrease in spontaneous motivation, typical changes in posture, diarrhea, miosis and a narrowing the cleft eyelids. Since the width of the eyelid fissures can best be assessed quantitatively from these symptoms leaves, this is used in the present test as a measure of an antagonistic effect on the reserpine effect used.

The test substance is injected intraperitoneally in doses of 25 mg / kg 30 minutes before the administration of reserpine. At least 10 animals are treated per dose. In order to obtain the maximum gap between the eyelids, this is visually assessed at intervals of 30 minutes for 2 1/2 to 6 hours. The average value is visually assessed for 3 'hours (2', ₂ to 6 hours after the reserpine injection) in the absence of 30 minutes and the average value is calculated from the Finzel values from the 3 to 6 hours. The change compared to the reserpine controls is given in%

dose Ver mg leg am inlra- fertilize peri- toneal I. 25th II 25th III 25th IV 25th V 25th VI 25th VII 25th

Change in reserpine-related eyelid constriction "in%

average - 65

average -52

average - 100

on average -100

average -100

average - 39

on average —22

DL ₅₁

(Mouse)

intravenous.)

mg / V, a

42 35 45 45 45 41 52

Conclusion

Based on the comparison of the results *: the reserpine antagonistic effect at approximately same toxicity (same order of magnitude) it can be shown that the compounds I to VI which can be prepared according to the invention are significantly more effective are as the previously known compound of the formula VIl

Also the others that fall under the general formula Compounds have one thing in common: comparable reserpine antagonistic activity.

Claims (1)

Claim: Ethanoanthracene derivatives of the general formula Z A —N in which X is hydrogen or chlorine and Z is hydrogen or the methyl group, A is an untrusted or branched alkyl group having 1 to 3 carbon atoms. R ₁ and R _{2 are} hydrogen or a lower alkyl group with 1 to 4 carbon atoms, or R ₁ and R ₂ together with the nitrogen atom represent a piperidine or optionally a 1-methyl, l - (/ (- acetoxyethyl) or l - (/ i-Hydroxyethyl) group-substituted piperazine radical and where R ₁ and R ₂ can not both be hydrogen, if X and Z are hydrogen and A is the methylene group, as well as their salts with inorganic or organic acids. full pharmacological properties, in particular antagonize reserpine, 2-oxo-3-isobutyl-9,10-dimethoxy-U, 3,4,5,6,7-hexahydro-llbH-benzo [a] -diinolizine and l, 4-Dipyrrolidinobutin- (2), potentiate norepinephrine and have a spasmolytic, antiemetic, as well as anesthetically. Compounds of the general formula I in which A denotes the methylene radical, predominantly have a central effect and compounds in which A is an alkylene radical with 2 to 3 carbon atoms means predominantly peripheral effect. . In the compounds of general formula 1, X can occupy the 1-, 2-, 3- or 4-position. A is z. B. the methylene, ethylene, propylene radical. R ₁ and R ₁ , apart from hydrogen, denote the methyl, ethyl, n-propyl, isopropyl or n-butyl radical. The new compounds of general formula I are obtained by converting into compounds of general Formula Il