FR2514767A1 - NOVEL FUROBENZAZEPINE DERIVATIVES, THEIR PREPARATION AND MEDICAMENTS CONTAINING THESE DERIVATIVES - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS 4-PIPERAZINYL-10H-FURO3,2-C1BENZAZEPINES AND THEIR PREPARATION. THE COMPOUNDS MAY BE USED THERAPEUALLY AS NEUROLEPTIC AGENTS, ANTIDEPRESSANT AGENTS AND AGENTS THAT INDUCE, PROMOTE AND PROLONG SLEEP.

Description

The present invention aims to

  new derivatives of furobenzazepine, their preparation

  and the drugs containing these derivatives.

  The invention relates in particular to 4-piperazinyl-1-OH-furol 3,2-cll 1 benzazepines, hereinafter referred to as compounds of the invention. It should be noted that a compound of the invention may optionally be substituted on any of the free positions. The invention relates more particularly to the compounds of formula I (I) R 2 in which R 1 represents hydrogen, a C 1 -C 4 alkyl group, hydroxyalkyl having at most 4 carbon atoms or one of its esters physiologically acceptable and hydrolysable, alkoxyalkyl having at most 6 carbon atoms, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl or phenylalkyl

C 7-C 9,

  R 2 represents hydrogen, a halogen, a tricyclic group,

  fluoromethyl, C 1 -C 4 alkyl, C 4 -C 4 alkoxy or C 1 -C 4 alkylthio, and R 3 and R 4 each independently represent one of

  the other, hydrogen or a C 1 -C 4 alkyl group.

  The alkyl, alkoxy or alkylthio groups preferably contain from 1 to 3 carbon atoms, especially 1 or 2 carbon atoms. The hydroxyalkyl group preferably contains 2 or 3 carbon atoms; the hydroxy group is preferably attached to

  a carbon atom other than the adjacent carbon atom

  In the alkoxyalkyl group, the alkoxy radical is preferably located in the

  end of the alkylene chain, the latter contains

  preferably 2 or 3 carbon atoms, especially

  The alkoxy group of the alkoxyalkyl group is preferably a methoxy group. The cycloalkyl group or the cycloalkyl group of the cycloalkylalkyl group is preferably a cyclopentyl group and especially a cyclopropyl group. The alkyl group of the cycloalkylalkyl group is preferably a methyl group per halogen, fluorine, chlorine, bromine or iodine, preferably fluorine

  or chlorine, especially chlorine.

  R 1 preferably means hydrogen or an alkyl group R 2 preferably means hydrogen or a halogen R 2 is preferably located in position

  7 or 8, especially in position 7.

  The term "physiologically acceptable and hydrolysable esters of the hydroxyalkyl group" means those esters which, under physiological conditions, are split into the corresponding compounds containing a hydroxyalkylpiperazinyl group. Such esters are in particular derived from alkanolecic acids.

  C 2 -C 18 and alkenol C 4 -C 18.

  The invention also relates to a process for the preparation of the compounds of the invention, in which a suitable derivative of 1H-furo E 3,2-cllllbenzazepine having a removable group or a carbonyl group in the form of a compound is reacted.

  position 4, with an appropriate piperazine.

  In particular, the compounds of formula I as defined above can be prepared by reacting a compound of formula II

Z Y X

zy R 3

0 R 4

in which

  R 2, R 3 and R 4 have the meanings given above.

  and i) Z and Y together form a double bond and X signifies a group that can be eliminated, or ii) Z stands for hydrogen and Y and X together with the carbon atom to which they are attached , a group C = O, with a compound of formula III

N N-R (III)

/ -

  in which R 1 has the meaning given above

is lying.

  The process can be carried out according to the

  conventional methods for the preparation of similar compounds by condensation. The reaction of the derivative of 1H-furo E 3; 2-cl lllbenzazepine having a group capable of being removed in the 4-position, in particular a compound of the formula II in which Z and Y together form a double bond and X signifies a group capable of being eliminated, such as a halogen, especially chlorine, or a mercapto group, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, p-nitrobenzylthio or tosyloxy, is advantageously carried out in an inert organic solvent such as xylene, toluene or dioxane, a temperature of between 50 and 170 When a starting material is used containing a 4-carbonyl-benzazepine-3-fluorobenzene having a carbonyl group at the 4-position, in particular a compound of the formula II in which Z is hydrogen and Y and X are form, together with the carbon atom to which they are bonded, a group> C = 0, the compound of formula III is advantageously used in the form of a metal complex comprising a metal of group I Vb of the periodic system,

  or vanadium The reaction is carried out advantageously

  in the presence of an acid-accepting agent, such as triethylamine, pyridine,

  dimethylaniline, or an excess of the compound of formula III.

  As metal, titanium is preferably used.

  complex is obtained advantageously from the tetra-

metal chloride.

  The starting materials can be prepared according to known methods, for example as described below. When the preparation of a particular starting material is not specifically described, it will be a known compound or may be prepared analogously to the compounds

  known or according to the procedures described below.

  The free bases of the compounds of the invention can be converted into acid addition salts according to the known methods, and vice versa. Suitable acids for the formation of salts include, for example, maleic acid, succinic acid, methanesulfonic acid, hydrochloric acid

and hydrobromic acid.

  The following examples illustrate this invention.

  without limiting the range All temperatures

  are given in degrees Celsius and not corrected.

Example 1

  4- (4-methyl-1-piperazinyl) -10 H-furol 3,2-cllllbenzazepine 8 g of 10-dihydro-4H-furol 3,2-clllllbenzazepine-4-one are heated to 100 for 21 hours. and 5 g of triethyloxonium tetrafluoroborate. While cooling with ice, 61 ml of 1-methylpiperazine are then added cautiously and the reaction mixture is heated for 3 hours at 100 ° C. The reaction mixture is filtered off and the organic phase is separated off. and washed with water The organic phase is extracted with 2 N acetic acid, the extracts are alkalized

  acids with concentrated ammonia and they are

  The methylene chloride extract is washed with sodium chloride solution, dried, filtered and evaporated to give a viscous brown oil. The colorless residue is recrystallized from a mixture of diethyl ether and hexane, which gives

  the title compound; Mp 103-105.

  5,10-Dihydro-4H-furol 3,2-cllllbenzazepine-

  4-one, used as a starting material, can be obtained in the following manner: a) 4 (2-nitro: 2-phenyl-3-oxo-butanoate) 10 g of 4- ( 2-nitro-phenyl) -3-oxo-butyronitrile prepared as described by Ch W Muth et al, in Org Chem., 736-739 0960) in 700 ml of ethyl acetate and 6.9 g of absolute ethanol at an internal temperature of 3 to 5, gaseous hydrochloric acid is introduced within one hour. The reaction mixture is maintained for 20 hours at 5 and is warmed to room temperature. which gives off a portion of the excess hydrochloric acid. While cooling with ice, 600 g of ice are added over a period of a few minutes and the mixture is stirred vigorously for one hour. ml of water and extracted with methylene chloride The organic phase is washed with a chloride solution

  of sodium, dried, filtered and evaporated.

  The crystalline residue is recrystallized from diisopropyl ether to give the title compound;

F = 55-560.

  b) 2: Ethyl-2-nitrophenyl-methyl-furan-3-carboxylate To a solution of 10 g of the product obtained under a) in 50 ml of pyridine is added dropwise at room temperature and at room temperature. 15 minutes, 13.8 g of a 45% aqueous solution

  chloroacetaldehyde and the reaction mixture is stirred

  for 24 hours at room temperature.

  The red-brown solution is treated with a mixture of water and ice and methylene chloride,

  then acidify with concentrated hydrochloric acid

  extracted and extracted with methylene chloride.

  The organic phase is washed with water, dried, filtered and evaporated.

  the evaporation residue on silica gel (0.04 -

  0.063 mm) using a mixture of toluene and ethyl acetate 95: 5 to give the title compound as an oil

pale yellow.

  c) 2-: 1 2 aminophenyl-methyl-furan-3-carboxylate

ethyl-

  A solution of 5.1 g of the product obtained under b) in 100 ml of ethyl acetate and in the presence of 2 to 3 g of Raney nickel is hydrogenated at ambient temperature and under normal pressure. After completion, the catalyst is filtered off and the filtrate is evaporated. The title compound is thus obtained in the form of a viscous oil.

colorless.

  d) 5,10-Dihydro-4H-furol 3,2-clElll-benzazeine-4-one 36.1 g of the product obtained under c), 720 ml of toluene and 10.1 g are heated under reflux for 5 hours. The dark suspension is treated with 1 liter of ethyl acetate, a mixture of water and ice, and 2 N acetic acid. The organic phase is washed with water, and the mixture is washed with water. The filtrate is passed through neutral alumina, eluted with ethyl acetate and evaporated. The crystalline residue is treated with a small amount of diethyl ether, filtered and dried. which gives the title compound;

F, 192-194.

Example 2

  7-Chloro-3-methyl-4- (4-methyl-1-piperazinyl) -1H-OH

  furol 3,2-cl Ellbenzazepine 5.9 g of 7-chloro-5,10-dihydro-3-methyl-4H-furol 3,2-cllll is heated at 100 for 8 hours.

  benzazepine-4-thione and 60 ml of 1-methylpiperazine.

  Toluene and water are added to the dark solution, and filtered through active charcoal. The filtrate is washed with water, the organic phase is extracted with 2N acetic acid and the acidic extracts are rendered alkaline. with concentrated ammonia and extracted with methylene chloride The methylene chloride extract is washed with a chloride solution

  of sodium, dried, filtered and evaporated.

  The brown resin is dissolved in ethyl acetate and filtered through basic alumina. After evaporation, a yellow residue is obtained which crystallizes from a mixture of methylene chloride and diethyl ether to give the title compound;

Mp 203-206.

  7-Chloro-5,10-dihydro-3-methyl-4H-furo [3,2-clll] benzazepine-4thione, used as a product

  starting point, can be prepared as follows.

  a) 2: lt 4: chloro-2-nitrophenylmethyl-4-methyl furan

  3-ethyl carboxylate 100 g of ethyl 4- (4-chloro-2-nitro-phenyl) -3-oxo-butanoate, ml of hydroxyacetone and 10 g of zinc chloride are heated for 3 hours. 5 ml of hydroxyacetone and 5 g of zinc chloride are then added and the reaction mixture is heated for a further 3 hours at 100 ° C. The red-brown solution is poured into a mixture of water and ice and the mixture is extracted with water. The organic phase is treated with a 2N solution of sodium hydroxide, washed with water, dried, filtered and evaporated. The residue is chromatographed on silica gel. (0.04-0.033 mm) using toluene as eluent. The title compound is thus obtained.

in the form of a yellow oil.

  b) 2: 1 2: 4 amino-4-chloropehenylmethyl-4-methyl-furan-3

  ethyl carboxylate The title compound is obtained by proceeding

  in a similar manner to that described in Example 1c.

  The product melts at 67-71 c) 7-chloro-5,10: dihydr: o-3-methyl-4H-furol 3,2-cllIl 9 enzazeine-4-one 21 g of the mixture are heated under reflux for 21 hours. product obtained under b), 275 ml of toluene and 6.5 g of lithium amide The brown suspension is poured into a mixture of water and ice and acidified with water.

  acetic acid. The precipitate is separated by filtration.

  The mixture is washed with water, dried and recrystallized from a mixture of tetrahydrofuran and methanol.

title; F = 260-262 (sublimation).

  d) 7-chloro-5,10-dihydro-3-methyl-4H-furol 3,2-cll 3 benzazine-4-ebione A suspension of 8 g of the product obtained under c) in 150 ml of benzene is treated with 7.2 g

  2,4-bisl-4-methoxyphenyl-1,3-dithia-2,4-diphos-

  Phetane-2,4-dithione and heated under reflux for 2 hours. The yellow suspension is evaporated under reduced pressure, treated with methylene chloride and filtered over 100 g of silica gel 60 (0.040-0.063 mm). After evaporation we get the

  composed of the title in the form of yellowish crystals.

Example 3

  By proceeding in a manner analogous to that described in Example I or 2, the following compounds of formula I are obtained: Example R 1 R 2 P 3 R 4 Melting point a HHHH 126-130 b CH 3 7-CI HH ## STR2 ## ## STR1 ##

  of the invention are of interest

  pharmacological properties and can by

  therefore be used therapeutically as medicinal

  In particular, the compounds of the invention exert a neuroleptic action, as is apparent from standard tests, for example inhibition of locomotion in mice. In this test, male mice (OF-1, Sandoz Basel) are used. The animals are divided into groups of 3 and are administered orally a dose of 3.2, 10, 32, 100 and 320 mg.

  of the substance to be tested One hour after administration of -

  the substance to be tested, the animals are observed individually and their locomotion is compared with that of the control animals The values obtained for the DMA (minimum active dose) are reported

in the table below.

  The compounds of the invention possess

  high affinity to the 3 H-Clozac binding sites

  pine in vitro lmodification of the method of D Hauser

  et al., described in Life Science 23, 557 (1978) 1.

  The test is performed as follows.

  Calf fresh cortex is homogenized in 19 times its volume of Tris buffer (50 mM, pH 7.4) and centrifuged. Centrifugal pellets are suspended in 400 times their volume of Tris buffer and the suspension is used. for the measurement of the affinity to the binding sites The test mixtures (final volume 2 ml) are constituted by: 50 m M of Tris buffer p H 7.4, corresponding membranes

  at 4.5 mg of the original tissue weight, 0.65 n M of 3 H-Cloza-

  pine and 11 pM Clozapine unmarked for the determination of

  nonspecific affinity to binding sites.

  To determine the specific competitive effect at the 3-Clozapine binding sites, the test substances are added at 5 to 9 different concentrations between 1 nM and 10 μM, each in duplicate After incubation for 40 minutes at room temperature, the test mixtures are rapidly filtered through Whatman GF / B filters. The filters are washed twice.

  with 5 ml ice-cold Tris buffer and determine the

  dioactivity of the filters in a scintillation counter

  IC 50 values are summarized in the table below.

  The compounds of the invention also possess

  an affinity for the binding sites of 3 H-Spipene

  In the brain, modification of the method of J. Leysen et al., described in Biochem Pharmac. 27, 307 (1978). The procedure is as follows: homogenization of fresh calf striatum tissues in 25 times their volume of Tris buffer (p H 7.4, 50 mM, 120 mM sodium chloride) and centrifuged The centrifugation pellets are suspended in 22 times their volume of Tris buffer,

  incubated for 15 minutes at 37 and centrifuged.

  The centrifugation pellets are suspended in 300 times their volume of Tris buffer. The test mixtures consist of: 45 mM of Tris buffer p H 7.7,

  108 m M sodium chloride, membranes corresponding to

  spanning 6 mg original tissue weight, 0.1 nM 3 H-Spiperone, 5 x 10 7 M Cinanserin to eliminate the contribution of 5-HT 2 and 1 μM binding sites.

  Unmarked spiperone for determining affinity

  nonspecific binding sites To determine the specific competitive effect at the 3 H-Spiperone binding sites, we add

  substances to be tested at 5-9 different concentrations

  between 1 n M and 10 ju M, each in duplicate After incubation for 40 minutes at

  ambient temperature, the test mixtures are rapidly

  Filtered on Whatman GF / B filters The filters are washed twice with 5 ml of ice-cold Tris buffer and the radioactivity of the filters.

  is determined in a scintillation counter.

  The values obtained for the IC 50 are collected

in the following table.

BOARD

  Thanks to these properties, the compounds of the invention can therefore be used in therapy as neuroleptic agents, for example for the treatment of psychotic disorders such as schizophrenia. For this indication, the appropriate daily dose is between about 25 mg and about 600 mg of active substance, advantageously administered in fractional doses 2 to 4 times per day in the form of unit doses each containing between about 6 and

  about 300 mg of active substance, or in retard form.

  The compounds of the invention also exert an anti-depressive action as is apparent from standard tests, for example inhibition of

  catalepsy and ptosis caused by tetra-

  benazine in the rat according to a modification of the method described by G Stille, in Arzneimittelforschung Example Inhibition of affinity at sites DMA binding locomotion in mg / kg CI 50 in n M

CLOZAPIWE SPIPERONE

1 3,2 335 2,771

2 10 19 1 600

  3 c 32 94> 10 000 3 d 10 34 4 400 3 e 10-32 6 736 3 f> 32- <320 59 5 256 3 g 10-100 20> 10 000 3 i 10-> 320 30 3,500 Clozapine 3 The test is carried out as follows: Groups of 6 male and female rats from the Sprague Dawley strain, weighing between 120 and 160 g are used (S Uddeutsche Tierfarm, US Pat. Tuttlingen, FRG). The test substance is administered intraperitoneally at a dose of about 5 to 20 mg / kg and 30 minutes later tetrabenazine is administered.

  at a dose of 10 mg / kg intraperitoneally.

  40 minutes after the administration of tetrabenazine, the catalepsy of each rat is evaluated by placing

  front legs on a block of wood 7 cm high.

  The time during which the animal remains in this unnatural position is measured up to a maximum of 45 seconds. Immediately after determining the catalepsy, the degree of ptosis is evaluated on a 4-point scale, with 1 meaning no ptosis and 4

  indicating a complete closure of the eyelids

  The values obtained for each eye evaluated separately, so that the measurable maternal assessment is 8 Tetrazenazine-induced catalepsy is considered to be inhibited when catalepsy of 30 seconds or less is observed. Rats are considered to be protected against ptosis. caused by tetrabenazine, when the value obtained for the determination of the ptosis is lower

  at 3 This test is repeated 60 minutes after the administration

tetrabenazine.

  Owing to this property, the compounds of the invention can therefore be used therapeutically as anti-depressant agents. For this use, the appropriate daily dose is between about 25 and about 500 mg of active substance, advantageously administered in divided doses. at 4 times per day in unit doses each containing between about 6 and about 250 mg of active substance,

or in delay form.

  Moreover, the compounds of the invention are distinguished by an activity inducing, promoting and prolonging sleep as has been demonstrated by standard tests. For example, in a test carried out according to the method described by H. Kleinlogel. and coll in European J Pharmacol. 33, 159-163 (1975), the compounds of the invention, administered orally to rats at a dose of between 2 and 80 mg / kg, increase the duration of

  Phase II sleep and decrease the waking phase.

  Thanks to this property, the compounds of the invention can therefore be used in therapeutics as agents inducing, promoting and prolonging sleep, for example for the treatment of insomnia. For this indication, they will be prescribed at a daily dose of between approximately

  1 and 100 mg of active substance, to be administered advantageously

just before bedtime.

  The compounds of the invention can be administered in the form of pharmaceutically acceptable acid addition salts. The activity of these acid addition salts is of the same order as

  that of the corresponding free bases.

  The invention also relates to a medicament containing, as an active substance, a compound of the invention in free base form or in the form of a pharmaceutically acceptable acid addition salt.

pharmaceutical view.

  The compounds of the invention may be administered in the form of suitable pharmaceutical compositions containing, in addition to the active substance, the pharmaceutically acceptable diluents and carriers. Such compositions also form part of the invention. example in the form of

solutions or tablets.

  In a group of compounds, R 1 is hydrogen or C 1 -C 4 alkyl, R 2 is hydrogen or halogen, R 3 is hydrogen, or C 1 -C 4 alkyl. and R 4 means hydrogen

or a C 1 -C 4 alkyl group.

Claims (13)

  1. The 4-piperazinyl-1 OH-furo E 3,2-clElllbenza- zépines.   2. The derivatives of furobenzazepine in formula I R t N À (I) 1.9 R 3   R 2 in which R 1 represents hydrogen, a C 1 -C 4 alkyl group, hydroxyalkyl having at most 4 carbon atoms or one of its physiologically acceptable and hydrolysable esters, alkoxyalkyl having at most 6 carbon atoms, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or phenylalkyl C 7-C 9,   R 2 represents hydrogen, a halogen, a tr-i group,   fluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 1 -C 4 alkylthio, and R 3 and R 4 each independently represent one of   the other, hydrogen or a C 1 -C 4 alkyl group.   3. The furobenzazepine derivatives according to claim 2, characterized in that R 1 denotes hydrogen or a C 1 -C 4 alkyl group, R 2 denotes hydrogen or a halogen, R 3 denotes hydrogen or a C 1 -C 4 alkyl group and R 4 means hydrogen or a C 1 -C 4 alkyl group.   4. Derivatives of furo-benzazepine, characterized in that they are selected from   4- (4-methyl-1-piperazinyl) -10 H-furol 3,2-clll'lbenzaze   pine, 7-chloro-3-methyl-4- (4-methyl-1-piperazinyl) -   IOH-furol 3,2-cllIlbenzazepine, 4- (1-piperazinyl) -OH-   furol 3,2-cylbenzazepine, 6-chloro-4- (4-methyl-1-yl)   piperazinyl) -10 H-furol 3,2-c) lIbenzazepine, the 2-methyl-   4- (4-methyl-1-piperylinyl) -10 H-furol 3,2-cilbenzazepine,   7-chloro-2-methyl-4- (4-methyl-1-piperazinyl) -1-OH-   furol 3,2-clllIbenzazepine and 7-fluoro-2-methyl-4 (4-   methyl-1-piperazinyl) -10 H-furol 3,2-clllbenzazepine.   5. 7-Fluoro-4- (4-methyl-1-piperazinyl) - 1H-furol 3,2-cllIlbenzazepine.   6. 7-Chloro-2,3-dimethyl-4- <4-methyl-1-   piperazinyl) -10H-furol 3,2-cllIbenzazepine.   7-Fluoro-3-methyl-4- (4-methyl-1-piperyl)   razinyl) -10 H-furo-1,3,2-cllllbenzazepine.   8. 7-Fluoro-2,3-dimethyl-4- (4-methyl-1-   piperazinyl) -OH-furol 3.2 c Rllbenzazepine.   9 Derivatives of furobenzazepine according to   any of claims 1 to 8, characterized   in that they are in free base form   or as an acid addition salt.   10. A process for the preparation of a 4-piper   razinyl-IOH-broth 3,2-cllllbenzazepine, characterized in that an appropriate derivative of 1 OH-furol 3,2-c EllIbenzazepine having a removable group or a carbonyl group in the 4-position is reacted. with a suitable derivative of piperazine 11 A process for the preparation of the furobenzazepine derivatives of formula I as claimed in claim 2, wherein a compound of formula II is reacted 1 4767 Z Y He X l-C / O / (R 4   wherein R 2, R 3 and R 4 have the meanings given in claim 2, and i) Z and Y together form a double bond and X signifies a group which can be eliminated, or ii) Z means hydrogen and Y and X together with the carbon atom to which they are attached form a group> C = O with a compound of formula III HN N-R (III)   in which R 1 has the meaning given to the 2.   12. A derivative of frobenzazepine according to   any of claims 1 to 8, in the form of   free base or as an acceptable acid addition salt.   from a pharmaceutical point of view, for use as a medicament 13. A derivative of furobenzazepine according to   any of claims 1 to 8, in the form of   free base or as an acid addition salt   acceptable from the pharmaceutical point of view, for the   as a neuroleptic agent, as an anti-   depressant or as an inducing, promoting or prolonging sleep   14. A medicament, characterized in that it contains, as active substance, a furobenzazapine derivative specified in any one of the   Claims 1 to 8, in free base form or   in the form of an accpetable acid addition salt from the pharmaceutical point of view.   15. A pharmaceutical composition, characterized   in that it contains a derivative of furo   benzazepine specified in any one of the claims   1 to 8, in free base form or in the form of a pharmaceutically acceptable acid addition salt, in combination with a diluent.   or a pharmaceutically acceptable carrier.   16. The derivatives of frobenzazepine having the formula II z y N-f R 3 (II) R 2 Ii I O R 4   wherein R 2, R 3 and R 4 have the meanings given in claim 2, and X, Y and Z have the same   meanings given in claim 11.