CA1193596A - Furobenzazepines, their production and pharmaceutical compositions containing them - Google Patents

Abstract

FUROBENZAZEPINES, THEIR PRODUCTION AND PHARMACEUTICAL
COMPOSITIONS CONTAINING THEM

Abstract of the Disclosure Furobenzazepine derivatives in free base form or in pharma-ceutically acceptable acid addition salt form are useful as neuroleptic, anti-depressant, sleep-inducing, sleep-promoting and sleep-prolonging agents.

Description

3~

~0-558 New furobenzazepines, their production and pharmaceutical compositions containing them The present invention relates to furobenzazepines, their production and pharmaceutical compositions containing them.
The present invention provides 4-piperazinyl-lOH-furo [3,2-c][l]benzazepines, hereinafter referred to as compounds of the invention. It is to be appreciated that a compound of the invention may be optionally substituted in any available posi-tion.
The present inventior, in particular provides compounds of formula I, ,R
r~
~ ~1

2 ~ R4 where-in Rl is hydrogen, (Cl 4)alky1, hydroxyalkyl with a maximum of 4 carbon atoms or a physiolo~ically acceptable and hydro-lyzable ester thereof, alkoxyalkyl with a maximum of 6 ~' ~9~ 6 carbon atQms, (C3 6)cycloalkylg (C4 7)cycloalkylalkyl or (C7 g)phenylal~yl~
R2 is hydrogen, halogen, trifluoromethyl, (Cl 4~alkyl, (Cl_4)alkoxy or (Cl 4)alkylthio, and ~3 and R4 are independently hydrogen or (Cl 4)al~yl.
~ ny alkyl, alkoxy or alkylthio radical of 1 to 4 carbon atoms is preferably of 1 to 3 carb~n atoms, especially 1 and 2 carbon atoms. Hydroxyalkyl has preferably 2 or 3 carbon atoms.
Preferably the hydroxy group in free f~rm or in esterified form is attached to a carbon atom other than the carbon atom adjacent to the nitrogen atom. The alkoxy m~iety in alkoxyalkyl is prefer-ably located in the terminal position of the alkylene chain which preferably has 2 or 3, especially 2 carbon atoms. The alkoxy radi~
cal in alkoxyalkyl is preferably methoxy. Cycloalkyl or the cycloalkyl moiety of cycloalkylalkyl is conveniently cyclopentyl and especially cyclopropyl. The alkyl moiety of cycloalkylalkyl is conveniently methyl. ~lalogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, especially chlorine.
Rl is preferably hydrogen or alkyl. R2 ;5 preferably hydrogen or halogen. R2 is preferably ;:n posit;on 7 or 8, es-pec;ally in position 7.
Physiologically acceptable and hydrolyzable esters are those esters which under physiological conditions are spli~t to the corresponding compounds having a hydroxyalkyl piperazinyl ; group. Such esters are particularly derived from (C2 18)alkanoic ~935~6

3 530-5588 and (C4 18)alkenoic acids.
The present invention in another aspect provides a pro-cess for the production of a compound of the present invention which comprises reacting an appropriate lOH-furo[3,2-c][l]
benzazepine derivative having a leaving group or a carbonyl group in the 4 position with an appropriate piperazine.
In particular a compound of formula I as defined above may be produced by a process which comprises reacting a compound of formula I I, Z Y
, I X

N- C/

R2 ~R4 II

wherein R2, R3 and R4 are as defined above, and either (i) Z and Y together form a single bond and X is a leaving group, or (ii) Z is hydrogen and Y and X together with the carbon atom to which they are bound are`C=0, with a compound of formula III, ,/ \
HN N-Rl III
\

wherein Rl is as defined above.

.~

~3~

The process may be effected in conventional manner for the production of similar compounds by condensation.
The reaction of lOH-furo[3,2-c][l]benzazepine derivative having a leaving group in the 4 position, in particular compound of formula II, wherein Z and Y together form a s;ngle bond and X is a leaving group, such as halogen, especially chlorine, sulfhydril, (Cl 4)alkoxy or (Cl 4)alkylthio, p-nitrobenzylthio or tosyloxy, is conveniently carried out in an inert organic solvent such as xylene, toluene or dioxane dt a temperature of from 50 to 170 C. When a lOH-furo[3,2-c][l]benzazepine deriva-tive having a carbonyl group in the 4 position, in particular compound of formula II, wherein 7 is hydrogen and Y and X to-gether with the carbon atom to which they are bound are ~C=0 is used as starting material then the compounds of formula III
are conveniently employed as metal complexes comprising a metal of the group IVb of the periodic system, or vanadium. The reac-tion is conveniently then carried out in the presence of an acid-binding agent, e.g. triethylamine, pyridine, dimethyl aniline, or an excess of the compound of formula III. Prefera-bly titanium is used as the metal. Conveniently the complex isobtained frorn the metal tetrachloride.
The starting material may be prepared in known manner, e.g. as described herein.
Insofar as the production of starting materials is not particularly described these compounds are known or may be `'i ~193~

- 5 - 500-5~8~

produced in ana1O9ous manner to known compounds or to pro-cesses described herein.
Free base forms of the compounds of the invention may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids are e.g. maleic acid, succinic acid, methane sulphonic acid, hydrochloric acid and hydrobromic acid.
In the following Examples the temperatures given are in degrees Centigrade and are uncorrected.

S~

Example 1: 4-(4-Methyl--l~piperazinyl)-10 _ uro[3,2~c][1]benza zepine 8 9 5~lo-Dihydro-4H-furoE3~2-c][l]benzazepin-4-on and 30.5 9 triethyloxonium tetrafluoroborate are heated 21 hours at 100. Thereafter 61 ml l-methylpiperazine are carefully added under ice cooling and the mixture is heated 3 hours at 100.
The mixture is fi~ltered, the organic phase separated and washed with water. The organic phase i~s extracted with 2N acetic acid, the acidic extracts made al~aline with conc. ammonia and extrac-ted with methylene chloride. The methylene chloride extract is washed with brine, dried, filtered and evaporated, whereby a brown, viscous oil is o~tained. The oil is filtered through aluminium oxide, eluted with methylene chloride and evaporated.
The colourless residue is crystallised from diethyl etherlhexane to yield the heading compound m.p. 103-105.
The starting material 5,10-dihydro-4H-furo[3,2-c][l]
benzazepin-4 one may be obtained as follows;;
a) 2-nitro-~-oxobenzenebutanoic acid etbXl este 10 g 2~nitro-~-oxobenzenebutanenitrile [prepared accor-ding to Ch.W. Muth et al., J.Org,Chem. 25, 736, 739 (1960)] are dissolved at room temperature in 700 ml acetic acid ethyl ester.
6.9 g abs. ethanol are added. At an internal temperature of 3 to 5 gaseous hydrogen chloride is introduced over a period of 1 hour. The reaction mixtllre is left for 20 hours at 5 and then is ~3~
- 7 - 500-~58~

brought to rQom temperature, whereby a part of the excess hydro-gen chloride emanates. 600 g o~ ice are added under ice cooling within few minutes and the mixture is vigorously stirred for 1 hours. 800 ml water are added and extracted wlth methylene chlo-ride. The organic phase is washed with brine, dried, filteredand evaporated. The cristalline residue is recrystallised from diisopropyl ether to give the heading compound, m.p. 55~56.
b) 2-[~2-nitroehen~l~methyl~-3-f_rane ca boxylic acid et~yl ester To a soluti~on of 1~ g of the product of step a) in 50 ml pyridine are added dropwise within 15 minutes at room tempè-rature 13.8 g of a 45% aqueous chloroacetaldehyde solution.
~he mixture is stirred at room temperature for 24 hours. The red-brown solution is treated with ice-water and methylene chlo-ride, thereafter acidified with conc. hydrochloric acid and ex-tracted with methylene chloride. The organic phase is washed withwater, dried, filtered and evaporated. The residue is chromato-graphed on silica gel (0.04-0.063 mm) using toluenelacetic acid ethyl ester (95:5) to give the heading compound as a light yellow G i 1 .
c) 2-C~2-amino~hen~yl~methyl~3~furane carbox~lic aci:d eth~l ester A solution of 5,1 g of the product of step ~) in 100 ml of acetic acid ethyl ester and 2-3 g oF Raney-Nickel . . ~ , 3~

- 8 - 500-558~

is hydrogenated at room temperature and normal pressure. After completion of the reduction the catalyst is filtered off and the filtrate is evaporated to give the heading compound as an colourless viscous oil.

d~ 5,10-dihydro-4H-furo[3,2-c][l]benzazepin-4-one 36.1 9 of the product of step c), 720 ml toluene and 10.1 g lithium amide are refluxed for 5 hours. The dark suspen-sion is treated with 1 liter acetic acid ethyl ester, ice-water and 2N acetic acid. The organic phase is washed with water, dried and filtered. The filtrate is filtered through neutral aluminium oxide, eluated with acetic acid ethyl ester and eva-porated. The crystalline residue is treated with a small amount of diethyl ether, filtered and dried to yield the heading com-pound, m.p. 192-194.

Example 2: 7-Chloro-3-methyl-4-(4-methyl-1-piperazinyl~-lOH
furo[3,2-c][l]benzazepine 5.9 9 7-chloro-5,10-dihydro-3-methyl-4H-furo[3,2-c][l]
benzazepin-4-thione and 60 ml 1 methylpiperazine are heated ~ hours at 100. To the dark solution toluene and water are added and filtered through a charcoal filter. The filtrate is washed with water. The organic phase is extracted with 2N
acetic acid, the acidic extracts made alkaline with conc.
ammonia and extracted with methylene chloride. The methylene '~f chloride extract is washed with ~rine, dried, filtered and evaporated. The brown resin is dissolved in acetic acid ethyl ester and filtered throwgh basic aluminium oxide. After eva-poration a yellow resin is obtained, which crystallises from methylene chlorideldiethyl ether to yield the heading compound m.p. 203-206.
The starting material 7~chloro-5,10 dihydro-3-methyl-4H-furo[3,2-c]~l]benzazepin-4-thione may be obtained as follows:-a) 2-[(4-chloro-2-nitroehenyl~methyl]-4-methyl-3-furane 1 0 _ ~
ca_bQxylic aci~ _thYl ester 20 g 4-chloro-2-nitro-~-oxobenzenebutanoic acid ethyl ester, 20 ml hydroxyacetone and 10 9 zinc chloride are heated 3 hours at 100. Thereatter 5 ml hydroxyacetone and 5 g zinc chlo-ride are added and the mixture is heated further 3 hours at 100.The brown-red solution is poured into ice-water and extraced with ether. The organic phase is treated with 2N sodium hydroxide, washed with water, dried, filtered and evaporated. The residue i~
chromatographed on silica gel (~.04-0.063 mm) using toluene, whereby the heading compound is obtained as an yellow oil.

3~ 6 - 10 - 500~5588 b) 2-[~2-amino-4-chloroehen~l)meth~ 4-methx1~3-furane carboxylic acid ethyl ester In manner analogous to that described in Example lc) the headi~ng compound, m.p. 67-71 is obtatned.
c) 7-chloro-5,10-dihydro-3-meth~1-4H-furo[3,2-c]benzaze~in~

4-one 21 9 of the product of step b), 275 ml tQluene and 6.5 9 lithium amide are refluxed for 3 h~urs, The brown suspension is poored into ice-water and acidifted with acetic acid. The precipitate is filtered off, washed with water, dried and re-crystallised from tetrahydrofuranelmethanol to give the heading compound, m.p. 260-262 (sublimation).
d) 7-chloro-5,10-dih~dro-3-meth~1_4H-furo53,2~c][1]benzazeein-4-thlone A suspension of 8 g of the product of step c) in 150 ml benzene is treated with 7.2 9 2,4-bis-C4-methoxyphenyl)-1,3 dithia~2,4~diphosphetan-2,4-di:sulfide and refluxed for 2 hours.
The yellow suspension is evaporated jn vacuo, treated with methylene chloride and filtered through 100 g silica gel 60 (0.040-0.063 mm) to obtain after evaporation -the heading com~
pound as yellowish crystals.

35~
- 1l - 500-5588 Example 3:
.
In analogous manner to that described in Example 1 or 2, the following compounds of formula I are obtained:-Example Rl R2 R3 R4 m.p. C

a H H H H 126-130 b CH3 7-Cl H H 144-146 c CH3 H H CH3 100-103 d CH3 7-F H H 159-161 e CH3 7-Cl H CH3 141-143 f CH3 7-Cl CH3 CH3 175-177 CH3 7-F CH H 208 (dec.)*

CH3 7-F CH3 CH3 234 (dec.)*

* dihydrochloride S~6 - l2 - 500-5588 The compounds of the invention exhibit pharmacological activity and are therefore indicated for use as pharmaceuticals, e.g. for therapy. In particular, the compounds of the invention exhibit neuroleptic activity, as indicated in standard tests, e.g. by an inhibition of locomotion in mice. In this test groups of 3 male mice (l8-24 9 OF-l, Sandoz Basle) received 3.2, lO, 32, lOO and 320 mg p.o. of the test drug. l hour after drug ad-ministration the mice were observed individually and their loco-motion compared with that of controls.
lo The cornpounds of the invention possess a strong affin;ty to 3H-Clozapine binding sites ;n vitro [modified method of D.
Hauser et al.g Life Science 23, 557 (1978)]. The test was per-formed as follows:-Fresh calf cortex was homogenized in a- l~ fold Vo1ume of Tris buffer (50 mM, pH 7.4) and centrifuged. The pellets were suspended in a 400 fold volume of Tr;s buffer, and the suspension used for the binding study. The composition of the assay mixtures (end volume 2 ml) was as ~ollows: 50 mM Tris buffer pH 7.4, membranes corresponding to 4.5 mg of original tissue weight, 0.65 nM 3H-Clozapine and l ,uM unlabelled Cloza-

5~6 pine for the determination of non-specific b;nding. To deter-mine the inhibit;on of the specific binding of 3H-Clozapine the test drugs were added tn give 5 to 9 different concentra-tions between 1 nM and 10 ~Mg each in dupl;cate. After incuba-tion for 40 minutes at room temperature, the assay mixtures were rapidly filtered through Whatman GF/B filter, the filters washed twice with 5 ml of ice cold Tris buffer and scintilla-tion-counted.
The compounds of the in~ention bind further on 3H-Spiperone binding sites in the brain Cmodified method of J. Leysen et al., Biochem. Pharmac. 27, 307 (1978)]. The test was per-formed as follows: fresh calf brain str;atal tissue was homo-genized in the 25 fold volume of Tris buffer (pH 7.4, 50 mM, 120 mM sodium chloride) and centrifuged. The pellets were suspended in a 22 fold volume of Tris buffer, incubated for 15 minutes at 37 C and centrifuged. The pellets were suspended u~ a 300 fold volume of Tris buffer. The composition of the assay mixtur~ was as follows: 45 mM Tris buffer pH 7.7, 108 mM
sodium chloride, membranes corresponding to 6 mg of original tissue weight, 0.1 nM 3H-Spiperbne, 5 x 10 7 M Cinanserin to eli-minate the contribution of 5-HT2 receptors and 1 ~M unlabelled Spi-perone for the determination of non-specific binding. To deter-mine the inhibition of the specific binding of 3H-Spiperone the test drugs were added to g;ve 5 to 9 different concentra-tions between 1 nM and 10 ~M, each in duplicate. After incuba-- 14 - 500-~588 tion for 40 minutes at room temperature, the assay mixtures were rapidly filtered through Whatm~n GF/B filter, the filters washed twice with 5 ml of ice cold Tris buffer and scintilla-tion-counted.

The compounds are therefore indicated for use as neuro-leptic agents. For this use an indicated daily dosage is from about 25 mg to about 600 mg of the compounds, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 6 to about 300 mg or in sustained release form.
Furthermore, the compounds exhibit anti-depressant activity as indicated in standard tests, for example, by an inhibition of tetrabenazine-induced catalepsy and ptosis in rats [modified method of G. Stille, Arzneimittelforschung 14, 534 (1964)]. The test was performed as follows:-Groups of 6 rats (Sprague-Dawley derivation, females _._ and ma1es, 120-160 g, SUddeutsche Tierfarm, Tuttlingen, West Germany) received the test substance in a dosage of ca. 5 to 20 mg/kg i.p. 30 minutes before administratlon of 10 mg/kg i.p.
tetrabenazine. 40 minutes after tetrabenazine administration the catalepsy of each rat was estimated by placing the forepaws on a 7 cm high wooden b10ck. The time for which the animal remained in this unnatural position was measured up to a maximum of '';~.~

S9~i 500-55~

45 seconds. Immediately after determining the catalepsy, the degree of ptosis was scored on a 4-point scale. No ptosis was represented by 1 whereas a score of 4 indicated complete eye-closure. The values from the separàtely scored eyes were added, so tha~ the maximum score poss;ble was 8. I~ a catalepsy of 30 seconds or less was observed, the tetrabenaz;ne-;nduced cata-lepsy was sa;d to be antagonised. Rats with a ptosis score of less than 3 were said to be protected against the ptotic effect of tetrabenazine. This procedure was repeated 60 minutes after tetrabenazine administration.
The compounds are therefore indicated for use as anti-depressant agents. For this use an indicated daily dosage is fronl about 25 to about 500 mg of the compounds conveniently ad-ministered in divided doses 2 to 4 times a day in unit dosage form containing from about 6 to about 250 mg or in sustained release form.
Additionally the compounds of the invention exhibit sleep-inducing, sleep-promoting and sleep-prolonging activity as indicated in standard tests. For example, in the sleep/wake cycle test carried out in accordance with the principles of H. Kleinlogel et al., European J. Pharmacol. 33, 159-163 (1975), in increase in the sleep phase II and a decrease of the wake phase is observed after administration to rats of from 2 to 80 mg/kg p.o. animal body weight of the compounds.

1" ~i 5~;
- 16 - 500-558~

The compounds are therefore indicated as sleep-inducing, sleep-promoting and sleep-prolonging agents, e.g. for in-somnia. For this use an indicated daily dose is from about 1 to about 100 mg of the compounds, conveniently given shortly before retiring to sleep.
The compounds of the invention may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms. The present invention also provides a pharma-ceutical composition comprising a compound of the invention, in free base form or in pharmaceutically acceptable acid addi-tion salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.
In one group of compounds Rl is hydrogen or (Cl 4)alkyl, R2 is hydrogen or halogen, R3 is hydrogen or (Cl 4)alkyl and is hydrogen or (Cl ~)alkyl.

Claims (4)

Claims:

1. A process for the production of a 4-piperazinyl-1OH-furo[3,2-c][1]benzazepine or pharmaceutically acceptable salts thereof which comprises reacting an appropriate 1OH-furo[3,2-c][1]benzazepine derivative having a leaving group or a carbonyl group in the 4-position with an appropriate piperazine and when a salt is required, reacting the free base obtained with a corresponding acid.

2. A process according to claim 1 for the production of a compound of formula I, I

or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, (C1-4)alkyl, hydroxyalkyl with a maximum of 4 carbon atoms or a physiologically acceptable and hydro-lyzable ester thereof, alkoxyalkyl with a maximum of 6 carbon atoms, (C3-6)cycloalkyl, (C4-7)cycloalkylalkyl or (C7-9)phenylalkyl, R2 is hydrogen, halogen, trifluoromethyl, (C1-4)alkyl, (C1-4)alkoxy or (C1-4)alkylthio, and R3 and R4 are independently hydrogen or (C1-4)alkyl, which comprises reacting a compound of formula II, II

wherein R2, R3 and R4 are as defined above, and either (i) Z and Y together form a single bond and X is a leaving group, or (ii) Z is hydrogen and Y and X together with the carbon atom to which they are bound are C=0, with a compound of formula III, III

wherein R1 is as defined above, and when the salt is required, reacting the free base obtained with a corresponding acid.

3. A 4-piperazinyl-10H-furo[3,2-c][1]benzazepine or a pharmaceutically acceptable salt thereof whenever produced by a process of claim 1, or an obvious chemical equivalent.

4. A compound of formula I as defined in claim 2 or a pharmaceutically acceptable salt thereof, whenever produced by a process of claim 2, or an obvious chemical equivalent.