DE3236937A1 - NEW FUROBENZAZEPINES, THEIR PRODUCTION AND USE - Google Patents

Description

500-5588

The present invention relates to furobenzazepines, their manufacture and medicaments containing them.

The present invention relates to 4-piperazinyl-10H-furo [3,2-c] [!!! benzazepine, hereinafter referred to as "compounds according to the invention". The compounds of the invention can be used in any be substituted in any position.

In particular, the present invention relates to compounds of the formula I »

wherein

R _{1 stands} for hydrogen, (C _1-4 ) alkyl, hydroxyalkyl with a maximum of 4 carbon atoms or its physiologically acceptable and hydrolyzable esters, alkoxyalkyl with a maximum of 6 carbon atoms, (C _3-6 ) cycloalkyl, (C _4-7 ) cycloa! kylalkyl or (C _7-g ) phenylalkyl,

R _{2 is} hydrogen, halogen, trifluoromethyl 1, (C _1-4 ) alkyl, (C _1-4 ) alkoxy or (C _1-4 ) alkylthio, and

R ₃ and R ₄ independently of one another are hydrogen or (C _1-4 ) alkyl,

and their acid addition salts.

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Each alkyl, alkoxy or alkylthio containing 1 to 4 carbon atoms preferably has 1 to 3 carbon atoms, in particular 1 and 2 carbon atoms. Hydroxyalkyl preferably contains 2 or 3 carbon atoms. The hydroxyl group in free or esterified form is preferably not on the carbon atom bonded to the nitrogen atom. The alkoxy radical in the alkoxyalkyl is preferably in the end position of the alkylene chain, which preferably has 2 or 3 carbon atoms, in particular 2 carbon atoms. The alkoxy radical in alkoxyalkyl is preferably methoxy. Cycloalkyl or the cycloalkyl part of cycloalkyl alkyl is expediently meaning cyclopentyl and in particular cyclopropyl. The alkyl part of cycloalkyl alkyl conveniently represents methyl. Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, in particular chlorine. R- preferably represents hydrogen or alkyl. R ₂ preferably denotes hydrogen or halogen. R ₂ is preferably in position 7 or 8 in particular in _S position. 7

Physiologically acceptable and hydrolyzable esters are those esters which are saponified under physiological conditions to give corresponding derivatives with a hydroxyalkyl ρiperazinyl group. Such esters are derived in particular from C _2-18 alkanecarboxylic acids and (C * ·, g) alkenecarboxylic acids.

The compounds of the invention are prepared by a corresponding 10H-furo [3,2-c] [l] benzazepine derivative, the is substituted in position 4 by a removable group or by carbonyl, with a corresponding piperazine derivative implements.

In particular, compounds of the formula Ϊ can be prepared by adding compounds of the formula H ₅

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ZYy
N - Γ X ^R 3 L Jl J | ^R 4 "O

II

wherein R ₂ , R ₃ and R _{4 have the} above meanings, and either Z and Y together mean a second bond between the nitrogen and the carbon atom, and X means a removable group, or Z is hydrogen and Y and X together with the carbon atom to which they are bound represent the group C = O, with compounds of the formula III,

III

wherein R- has the above meaning.

The process can be used in a for the preparation of analogous compounds known manner.

The implementation of a 10H-furo [3,2-c] [l] benzazepine derivative, which has a removable group in position 4, in particular a compound of the formula II in which Z and Y together form one mean second bond and X means a group which can be split off, for example halogen, in particular chlorine, sulfhydryl, alkoxy or alkylthio each having 1 to 4 carbon atoms, p-nitrobenzylthio or tosyloxy, is conveniently carried out in one inert organic solvents such as xylene, toluene or dioxane at temperatures between 50 and 170 ° C. Get 10H-Furo [3,2-c] [l] benzazepine derivatives which carry the carbonyl group in position 4, in particular compounds of the formula II in which Z is Hydrogen and Y and Z together with the carbon atom to which they are bonded represent the group ^ C = O,

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so the compounds of formula III are conveniently in Form of their complexes with a chloride of a metal of Group IVb of the Periodic Table or vanadium is used. The implementation is then conveniently carried out in the presence of an acid-binding agent, for example triethylamine, pyridine, dimethylaniline or an excess of the compound of the formula III. Titanium is preferably used as the metal. Appropriately the complex is made from the metal tetrachloride.

The starting compounds can be prepared in a manner known per se, for example as described here.

If the preparation of the starting compounds is not described, these are known or analogous to known compounds or process can be produced.

The compounds according to the invention can be known per se Ways to be converted into their acid addition salts and vice versa. The acids are e.g. maleic acid, fumaric acid, methanesulf onic acid, hydrochloric acid and hydrobromic acid are suitable.

The compounds according to the invention are distinguished by pharmacological ones Effects and can therefore be used as a remedy. They have a neuroleptic, antidepressant, sleep-inducing effect, sleep-promoting and sleep-inducing.

The compounds according to the invention can also be in the form of whose pharmaceutically acceptable acid addition salts are administered which have the same level of activity as the free bases.

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The compounds according to the invention or their salts can be administered orally in the form of tablets, granules, Capsules or dragees, or parenterally in the form of injection solutions.

In the examples below, the temperatures are in degrees Celsius and are uncorrected.

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Example 1: 4- (4-Methyl-1-piperazinyl) -10H-furoi: 3,2-c; n; i] benzazepine

8 g of 5,10-dihydro-4H ~ furo [3,2-c] [l] benzazefh "n-4-one are mixed with 30.5 g of triethyloxonium tetrafluoroborate at 100 ° C. for 21 "hours warmed up. Then 6Π ml of N-methylpiperazine are cooled with ice added carefully and heated to 100 ° C. for 3 hours. The dark solution is added to a mixture of ice water and toluene poured. Insoluble flakes are filtered off, the organic phase is separated off and washed with water.

The organic phase is extracted with 2N acetic acid, the acidic extracts with conc. Ammonia and alkalized with methylene chloride extracted. The methylene chloride extract is washed with brine, dried, filtered and in a vacuum to dryness evaporated to give a brown, viscous oil.

The latter is filtered neutral through Alox with methylene chloride eluted and evaporated in vacuo. The colorless residue is crystallized in diethyl ether / hexane, whereby one the title compound of m.p. 103-105 ° C is obtained.

Das.as starting compound used 5,10-dihydro-4H-furo [3,2-c] [l] benzazepin-4-one can be prepared as described below:

10 g of 2-nitro-ß-oxobenzenebutyronitrile (preparation according to literature: Ch. W. Muth et al., J. Org. Chem. 25_, 736, 739 [1950] are dissolved in 700 ml of ethyl acetate at room temperature. Now 6.9 g * abs'. "Ethane oil is added / At ~~~ ~ _ '~~~~ _"[' an internal temperature of 3 to 5 ° C, hydrogen chloride gas is passed in for 1 hour and at 5 ° C for 20 hours It is now brought to room temperature, some of the excess dissolved hydrogen chloride gas escaping.

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With ice cooling, 600 g of ice are introduced within a few minutes and stirred intensively for 1 hour. SOO ml of water are added and the mixture is extracted with methylene chloride. The organic Phase is washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered and evaporated to dryness in vacuo. The crystalline residue is made from diisopropyl ether recrystallized, the title compound having a melting point of 55 ° to 56 ° C.

-3; for ^^

10 g of the reaction product described under a) are dissolved in 50 ml of pyridine. Thereupon 13.8 g of a 45% strength aqueous solution of chloroacetaldehyde within 15 minutes Added dropwise to room temperature and stirred for 24 hours at room temperature. The red-brown solution is mixed with ice water and methylene chloride added, whereupon it is acidified with concentrated hydrochloric acid. It is extracted with methylene chloride, which organic phase washed with water, dried with sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is chromatographed on silica gel 60 (0.040 to 0.063 mm) with toluene-ethyl acetate 95: 5, the Title compound is obtained as a light yellow oil.

^c ) 2 - [(2-AmingBhenyJ) methyl] 23-fura

5.1 g of the reaction product described under b) mixed with 100 ml of ethyl acetate; on this 2 to 3 g

Raney nickel added and with 'hydrogen ""' ".'_".

hydrogenated at room temperature and normal pressure. After the calculated amount of hydrogen has been taken up, the catalyst is sucked off, Washed with a little ethyl acetate and evaporated in vacuo, the title compound as a colorless viscous OeI is obtained.

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36.1 g of the reaction product described under c) are mixed with 720 ml of toluene and 10.1 g of lithium amide and 5 hours boiled on reflux. The dark suspension is stirred with 1 liter of ethyl acetate, ice water and 2N acetic acid, which separated organic phase, washed with water, dried with sodium sulfate and filtered. This solution is through Alox filtered neutral, eluted with ethyl acetate and in vacuo evaporated. The crystals obtained are stirred with a little diethyl ether, filtered off with suction and dried, whereby one the title compound with a melting point of 192-194 ° C. is obtained.

Example 2: 7-Chloro-3-methyl-4- (4-methyl-1-piperazinyl) -10H-furo [3,2-c] [1] benzazepine

5.9 g of 7-chloro-5,10-dihydro-3-methyl-4H-furo [3,2-e] [I] benzazepine-4-thione and 60 ml of N-methylpiperazine are heated to 100 ° C. for 8 hours warmed up. The dark solution is mixed with toluene and water and filtered through an activated charcoal filter. The filtrate is with Water washed. The organic phase is extracted with 2N acetic acid, the acid extracts with conc. Ammonia alkalizes and extracted with methylene chloride. The methylene chloride extract is washed with brine, dried with sodium sulfate and filtered and evaporated to dryness in vacuo. The brown resin obtained is dissolved in ethyl acetate and filtered through basic alox. After evaporation, a yellow resin is obtained which, crystallized from methylene chloride-diethyl ether, the title compound of m.p. 203-206 ° C results.

The 7-chloro-5,10-dihydro-3-methyl-4H-furo [3,2-c] [l] benzazepine-4-thione used as the starting compound can be produced as described below:

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^a ) ^

20 g of ethyl 4-chloro-2-nitro-β-oxobenzenebutanoate, 20 ml of hydroxyacetone and 10 g of tines! on d are at 100 ° for 3 hours warmed up. Then 5 ml of hydroxyacetone and 5 g of zinc chloride are added and the mixture is heated to 100 ° for a further 3 hours. Then will the brown-red solution poured onto ice water, extracted with ether, the organic phase washed with 2N sodium hydroxide solution and with water, dried, filtered and evaporated. The evaporation residue is chromatographed on silica gel 60 (0.040 to 0.063 mm) with toluene, the titanium compound being a yellow oil is obtained.

Analogous to example Ic) one arrives at the title connection from the smp. 67-71 °.

^c ) ZzCbloL'Z ^ lQz ^ iÜl '^ Ql ^ niethYl- ^ H-furoCSj ^ cDCllbenzazegin-4 ₌ on

21 g of the reaction product described under b), 275 ml of toluene and 6.5 g of lithium amide are refluxed for 3 hours. The brown suspension is then poured onto ice water and acidified with acetic acid. The precipitate is removed soaks, washed with water and dried. After recrystallization the title compound of melting point 260-262 ° (sublimation) is obtained from a mixture of tetrahydrofuran-methanol.

^d) ZlQbl2: i5 _{i 10:} dihYdrg-3 _{:: meti2Yl:;} 4H _:: fun3 [3 ,, 2 ^ c] Q] benzazep_in _z 4-thione

8 g of the reaction product described under c) are suspended in 150 ml of benzene. 7.2 g of 2,4-bis- (4-methoxy

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phenyl) -l, 3-dithia-2,4-diphosphetane-2,4-disulfide was added and the mixture was refluxed for 2 hours. Then, the yellow suspension is evaporated in vacuo, taken up in methylene chloride and filtered (0.040-0.063 mm) by 100 g silica gel 60, wherein after evaporation Jm _- vacuum the title compound in the form of gel crystals Blicher ⁵ "is obtained.

Example 3:

Analogously to Example 1 or 2 and using appropriate starting compounds, the following compounds are obtained Formula I, in which:

Example R ₁ R ₂ R ₃ R ₄ Mp ° C

a H H HH 126-130

b CH ₃ 7-Cl HH 144-146

c CH ₃ H .H-CH ₃ 100-103

d CH ₃ 7-F HH 159-161

e CH ₃ 7-Cl H CH ₃ 141-143

f CH ₃ 7-Cl CH ₃ CH ₃ 175-177

g CH, 7-F CHo H h CH, 7-F R. CHo "131-133 i CH ₃ 7-F CH ₃ CH ₃ 234 (dec.) *

"*) Dihydrochloride

Claims (6)

SANDOZ-PATENT-GMBH
7850 Loerrach Case 500-5588 New furobenzazepines, their manufacture and uses Claims .) 4-Piperazinyl-10-furo [3,2-c] [l! Benzazepine and their acid addition salts. 2. Compounds according to claim 1 of the formula I, wherein is hydrogen, (C- | _ ₄₎ alkyl, hydroxyalkyl with a maximum of 4 carbon atoms or its physiologically acceptable and hydro isierbare esters, alkoxyalkyl having at most 6 carbon atoms, (C ₃ _ ₆₎ cycloalkyl, (C _4-7) cycloalkyl alkyl or! (Cy_g) phenylalkyl, 500-5588 Hydrogen, halogen, trifluoromethyl, alkoxy or (C -, _ ») alkylthio, and R- and R. independently of one another are hydrogen or (C-. *) Alkyl mean, and their acid addition salts. 3. Process for the preparation of the compounds according to claim 1 characterized in that a corresponding IOH-furo [3,2-c] [l] benzazepine derivative, which is abspal in position 4 table group or is substituted by carbonyl, reacted with a corresponding piperazine derivative. 4. Process for the preparation of the compounds of the formula I according to claim 2, characterized in that one compounds of formula II, II wherein R ^, R ^ and R, have the above meaning, and either Z and Y together represent a second bond between the nitrogen and the carbon atom, and X a leaving group represents, or Z represents hydrogen and Y and X together with the carbon atom to which they are attached represent the group ^ C = O, with compounds of the formula III, NR ₁ III wherein R, has the above meaning, converts. - 3 - 500-5588 5. Medicinal products, characterized by a content of compounds according to claim 1 or their pharmaceutically acceptable use Acid addition salts. 6. Compounds of the formula H ₅ II wherein Rp ₅ R ₃ > R ^ s Z, Y and X have the meaning given in claim 4.