DE1084267B - Process for the preparation of 1-aza- [2, 3: 5, 6] -dibenzocycloheptadiene derivatives, their salts and quaternary ammonium compounds - Google Patents

Description

GERMAN

It was found that 1-aza- [2.3: 5.6] -dibenzocycloheptadiene derivatives the general formula

CH ₂ .

in which R is a lower, branched or unbranched alkylene group having 2 to 4 carbon atoms, Am is a lower dialkylarhino, pyrrolidino, piperidino, morpholino or 4'-alkylpiperazino group or R —Am together mean a l-alkylpyrrolidyl - ^ - methyl group, as well as their sake and quaternary ammonium compounds are very effective antihistamines, which also have psychotropic properties.

They are already aminoalkyl derivatives of iminodib / enzyl (10.1 L-dihydro-5-dibenzo- [b ,, f] -azepines) (W, Schindler and F. Häfligeiy HeIv.Chim.Acta, Vol. 37 [1954], pp. 472 to 483). These are according to the investigations of the authors mentioned the known N-dimethylaminoethyl-N-benzylanüin with respect to antihistamine action in the best case equal, "but usually inferior by 10 to 50 times.

Thanks to W. Wenner, 6-sübstituiette 6,7-Dl - hydro - 5 - H - dibenz - [c, e] - azepine (J. Org. Chem., Vol. 16 [1951], pp. 1475 to 1480). These In addition to a pronounced adrenaline-antagonistic effect, compounds show according to the investigations of L. O. Randall and T. H. Smith (J. Pharm. And JExptl. Therap., Vol. 103 [1951], pp. 10 to 23) practically none or only very low antihistamine effectiveness.

It was all the more surprising to find that the invention 1-aminoalkyl-1-aza-dibenz.ocycloheptadiene very effective, N-Dimethylaminoätjiyl-N-ben-'zylänilin are antihistamines that are one to three powers of ten. Incidentally, they show next to one good tolerance nor a pronounced narcosis-potentiating Effect.

The invention relates to a process for the preparation of l-aza- [2,3: 5,6] -dibenzocycloheptadiene derivatives of the general formula I, their salts and quaternary ammonium compounds, which is characterized by is that you have either a l-aza- [2,3: 5,6] -dibenzocycloheptadiene the general formula

CH ₉

II method of manufacture

of l-aza- [2,3: 5,6] -dibenzocycloheptadiene derivatives, their salts and quaternaries

Ammonium compounds

Applicant:

Cilag-Chemie Aktiengesellschaft, Schaffhausen (Switzerland)

Representative: Dipl.-Chem. Dr. A. Ullrich, patent attorney, Heidelberg, Bismarckstrasse 17th

¹ S Claimed priority:

Switzerland from December 28, 1955

Dr. Henry Martin, Zurich, and Dr Ernst Habicht, Schaffhausen (Switzerland), have been named as inventors

in which X represents a hydrogen or a "metal atom, in a manner known per se with a reactive ester of an amino alcohol of the general formula

Am- ^ R-OH

or a corresponding 1-aminoacyl-l-aza- [2,3: S.oJ-dibenzocycloheptadiene with lithium aluminum hydride reduced and the base obtained optionally with an acid, an acidic compound or treated with a quaterhizing agent.

Hydrohalic acid esters are preferably used as esters of amino alcohols of the formula III, for example the chlorides or bromides, such as dirnethylaminoethyl chloride, .. Diethylaminoethyl chloride, 2-dim. thylaminopropyl chloride, 3-dimethylanimopropyl chloride, Piperidinoethylchlorid, PyrroUdinoäthylchlorid, Morpholinoäthykhloridj ^ Methyl-piperazino-ethyl-chloride, 1-methyl-3-bromomethyl-pyrrolidine.

, One can proceed in such a way that one either has the azadibenzocycloheptadiene of formula II (X = hydrogen atom) with a hydrohalic acid ester Amino alcohol of the formula III reacts in the presence of a hydrogen halide binding agent or else initially a metal salt of azadibenzocycloheptadiene. of the formula II (X = metal atom) and this with a Reacts hydrogen halide ester of an amino alcohol of the formula III.

The following acids or acidic compounds that are suitable for salt formation may be mentioned: sulfuric acid, Hydrochloric acid, hydrobromic acid, phos-

009 548/429

1 UÖ4 ZO /

phosphoric acid, citric acid, tartaric acid, methanesulfonic acid, Ethane disulphonic acid, oxyethane sulphonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, p-aminobenzoic acid, p-aminosalicylic acid or haloxanthines, like 8-chloro-theophylline.

example 1

100 g of l-aza- [2,3: S.oJ-dibenzocycloheptadiene are dissolved in 600 cm ^{3 of} absolute xylene. 31 g of sodium amide in chips are added to this solution while stirring. After 4 hours, a solution of 122 g of 3-dimethylaminopropyl chloride in 400 cm ^{3 of} absolute xylene is added dropwise over the course of one hour while stirring. After a further 3 hours, the mixture is cooled and ^{stirred with 400 cm 3 of} 2N sodium hydroxide solution. The xylene layer is separated and evaporated. The residue is taken up in 800 cm ^{3 of} 1 n-acetic acid, little undissolved material is filtered off, the filtrate is made alkaline and extracted with ether. After drying and evaporation of the ether, it is distilled in a high vacuum. 49 g of a colorless oil boiling below 0.01 mm at 141 to 143 ° C. are obtained. The 1 - (3 '- dimethylaminopropyl) -1 - aza - [2.3: 5.6] - dibenzocycloheptadiene obtained can be converted into the hydrochloride, which melts at 176 to 178 ° C., with ethereal hydrochloric acid. The methoiodide of the compound melts at 189-190 ° C.

Example 2

In the same way as in Example 1, 1- (2'-diethylaminoethyl) -1-aza- [2.3: 5.6] - dibenzocycloheptadiene is obtained when the azadibenzocycloheptadiene is reacted with diethylaminoethyl chloride in the presence of sodium amide in xylene. The base boils below 0.01 mm at 140 to 145 ⁰ C. The dihydrochloride of the base melts at 162 to 164 ° C, which Monomethojodid at 209 to 210 ° C.

Example 3

From l-aza- [2,3: S.oj-dibenzocycloheptadiene and 3-pyr-

crude dinopropyl chloride in the presence of sodium amide gives l- (3'-pyrrolidinopropyl) -l-aza- [2,3: 5,6] -dibenzocycloheptadiene, that boils below 0.01 mm at 151 to 153 ° C.

Example 4

10 g Diäthylaminoacetyl-l-aza- [2,3: 5,6] -dibenzocycloheptadien (. Kp _{0, 03 MRA} 180-181 ° C) are reduced in tetrahydrofuran using 3.1 g LitMumaluminiumhydrid. After working up, 7.5 g of l- (diethylaminoethyl) aza- [2.3: 5.6] -dibenzocycloheptadiene, which boils below 0.01 mm at 140 to 145 ° C., are obtained.

In the same manner as indicated in the previous examples, the following l-aza- [2,3: 5,6] -dibenzocycloheptadiene derivatives can be used produce:

At the > N : R properties 195 to 198 ⁰ C
171 to 172 ° C
221 to 222 ° C H ₃ C,
H ₃ C ^y ) N - ^V N - - CH ₂ - CH ₂ - Bp 0.01 / 147-153 ° C
M.p. of the hydrochloride
Mp of picrates
Of Methojodides 208 to 210 ⁰ C
200 to 201 ° C \ ^H ^ N- -N H N - Bp 0.01 / 145 to 148 ^° C
Melting point of the dihydrochloride
Of Methojodides 225 ° C N-- - CH ₂ - CH ₂ - Bp 0.03 / 161 to 164 ^° C
Schmp des Methojodides H N - -CH-CH ₂ - Bp 0.01 / 152 to 153 ° C CH ₃ H ₅ C _{2 N}
H ₅ C ₂ PfT PfT PfT Bp 0.015 / 161 to 162 ° C 199 to 201 ⁰ C \H - CH ₂ - CH ₂ - CH ₂ - Bp 0.02 / 165 to 166 ° C
Melting point of the dihydrochloride CH ₃ - - CH ₂ - CH ₂ - Bp 0.01 / 160 to 163 ° C -CH ₂ - Bp 0.02 / 152 to 154 ^° C Hj
I. CH ₃ -CH ₂ - Bp 0.01 / 165 to 168 ° C C ₂ H ₅

Claims (1)

ί \ J UT Claim: Process for the preparation of l-aza- [2,3: 5,6] -dibenzocycloheptadiene derivatives the general formula At the in which R is a lower, branched or unbranched alkylene group with 2 to 4 carbon atoms, Am is a lower dialkylamino, pyrrolidino, piperidino, morpholino or 4'-alkylpiperazino group or R - Am together is a 1-alkylpyrrolidyl- (3) -methyl group mean, as well as their salts and quaternary ammonium compounds, characterized in that either a l-aza- [2,3: 5,6] - dibenzocycloheptadiene of the general formula
CH ₂ N-CH. in which X represents a hydrogen or metal atom, in a manner known per se with a reactive one Esters of an amino alcohol of the general formula Am - R - OH converts or a corresponding 1-aminoacyl-l-aza- [2,3: 5,6] -dibenzocycloheptadiene reduced with LitMumaluminiumhydrid and the base obtained if necessary treated with an acid, an acidic compound or a quaternizing agent. Considered publications:
German Patent No. 829 167;
Helvetica Chimica Acta, 37: 472-483 (1954).