NZ202170A - 4-(piperazin-1-yl)-10h-furo(3,2-c)(1)benzazepines - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £02170 Priority Date(s): ~?J,. .-£'.*7 $?..

Complete Specification Filed: Class: Publication Date: P.O. Journal, No: )2r?~i No.: Date: ill m NEW ZEALAND PATENTS ACT, i 953 J COMPLETE SPECIFICATION u°CTm new fuR0BENZAZEPINES, theie pboddction phaemacedtical compositions containing them M We, sandoz ltd ^ r- Switzerland- a St" ' r tStr3SSe' CH-4002 Basle, -Land, a Swiss Body Corporate hereby declare the invention for which i / we prav ^hat be granted to m#/us and th u ' Patent may to be particullr ' "" meth°d by " «o <« P«fo™d, ».cularly d8scrioed in and by [he foUowing statemen( _ J (followed by. 1^ 203170 - la - New furobenzazepines, their production and pharaaceutical compositioris containing them The present invention relates to furobenzazepines, their production and pharmaceutical compositions containing them.

The present invention provides 4-(piperazin-l-yl)-10H-furo [3,2-c][l]benzazepines, hereinafter referred to as the compounds of the invention. It is to be appreciated that a compound of /the invention may be optionally substituted in any available position.

The present invention iri particular provides compounds of formula I, >-v r 12 SEP 1985 wherein R-j is hydrogen, (C-j_^)alkyl, hydroxyalkyl with a maximum of 4 carbon atoms or a physiologically acceptable and hydro-lyzable ester thereof, alkoxyalkyl with a maximum of 6 w // .j y 2 - "500=5568- carbon atoms, (C^gHycloalkyl, (C^_y)cycloalkylalkyl or (C7_g)phenylalkyl, R2 is hydrogen, halogen, trifluoromethyl, (C-j_^)alkyl, (C-|_^) alkoxy or (C^_^)alkylthio, and 5 R^ and R^ are independently hydrogen or (C^_^)alkyl.

Any alkyl, alkoxy or alkylthio radical of 1 to 4 carbon atoms is preferably of 1 to 3 carbon atoms, especially 1 and 2 carbon atoms. Hydroxyalkyl has preferably 2 or 3 carbon atoms. Preferably the hydroxy group in free form or in esterified form 10 is attached to a carbon atom other than the carbon atom adjacent to the nitrogen atom. The alkoxy moiety in alkoxyalkyl is preferably located in the terminal position of the alkyl erie chain which preferably has 2 or 3, especially 2 carbon atoms. The alkoxy radical in alkoxyalkyl is preferably methoxy. Cycloalkyl or the cycloalkyl 15 moiety of cycloalkylalkyl is conveniently cyclopentyl and especially cyclopropyl. The alkyl moiety of cycloalkylalkyl is conveniently methyl. Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, especially chlorine. R-| is preferably hydrogen or alkyl. R£ is preferably 20 hydrogen or halogen.R9 is preferably in position 7 or 8, especially in position 7.

Physiologically acceptable and hydrolyzable esters are those esters which under physiological conditions are split to the corresponding compounds having a hydroxyalkyl piperazinyl 25 group. Such esters are particularly derived from (C^gjalkanoic 202 1 "500-5508— and (C^_-jg)a1 kenoic acids.

The present invention in another aspect provides a process for the production of a compound of the present invention which comprises reacting an appropriate 10H-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 II, II wherein R^, R^ and R^ 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-'R i in wherein R-j is as defined above. 4 ? rt ^ f t The process may be effected in conventional manner for the production of similar compounds by condensation.

The reaction of 10H-furo[3,2-c][l]benzazepine derivative having a leaving group in the 4 position, in particular compound 5 of formula II, wherein Z and Y together form a single bond and X is a leaving group, such as halogen, especially chlorine, sulfhydril, (C^_^)alkoxy or (C-j_^)alkylthio, p-nitrobenzylthio or tosyloxy, is conveniently carried out in an inert organic-solvent such as xylene, toluene or dioxane at a temperature of 10 from 50 to 170° C. When a l0H-furo[3,2-c][13benzazepine derivative having a carbonyl group in the 4 position, in particular compound of formula II, wherein Z is hydrogen and Y and X together with the carbon atom to which they are bound are ^C=0 is used as starting material then the compounds of formula III 15 are conveniently employed as metal complexes comprising a metal of the group IVb of the periodic system, or vanadium. The reaction 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-20 bly titanium is used as the metal. Conveniently the complex is obtained from 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 25 particularly described these compounds are known or may be 2.021 70 - 5 - °500 DGOQ. produced in analogous manner to known compounds or to processes described herein.

Free base forms of the compounds of the invention may be converted into acid addition salt forms in conventional 5 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. 202170 Example 1: 4-(4-Methyl -piperazin-1 -yl)-1 OH-furo{3,2-c] [1 ]- 8 g 5,10-Dihydro-4H-furc[3»2-c3[13benzazepin-4-one and 30.5 g triethyloxonium tetrafluoroborate are heated 21 hours at 100°. Thereafter 61 ml 1 -methylpiperazine are carefully added under ice cooling and the mixture is heated 3 hours at 100°. The mixture is filtered, the organic phase separated and 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 chloride extract is washed with brine^ dried, filtered and evaporated, whereby a brown, vi5c0'js oil is obtained. The oil is filtered through aluminium oxide, eluded with methylene chloride ana evaporated. The colourless residue is crystallised from diethyl ether/hexane to yield the heading compound m.p. 103-105°.

The starting material 5,10-dihydro-4H-furo[3,2-c][l] ' a)' 2-nitro-|i-oxobenzenebutanoic_acid_ethyl_ester ' g 2-nitro-ft-oxobenzenebutanenitrile [prepared • according to Ch.W. Huth et al., J. Org. Chem. 25, 736, 739 (1950)]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° caseous hydrogen chloride is introduced over a period of 1 hour. The reaction mixlure is left for 20 hours at 5°.and then is brought to room temperature, whereby a part of the excess hydrogen chloride emanates. 600 g of benzazepine benzazepin-4-om may be obtained as follows:- •v-' 'w ice are added under ice cooling within few minutes and the mixture is vigorously stirred for 1 hour. 800 ml water are added and extracted with methylene chloride. The organic phase is washed with brine, dried, filtered and evaporated. The cri-stalline residue is recrystallised from diisopropyl ether to give the heading compound, m.p. 55-56°. b) 2-[[2-nitroghenyl}methyl]-3-furane_carboxylic_acid ethyl ester To a solution of 10 g of the product of step a) in 50 ml pyridine are added dropwise within 15 minutes at room temperature 13.8 g of a 45 % aqueous chloroacetaldehyde solution. The mixture is stirred at room temperature for 24 hours. The red-brown solution is treated with ice-water and methylene chloride, thereafter acidified with conc. hydrochloric acid, and extracted with methylene chloride. The organic phase is washed with water, dried, filtered and evaporated. The residue is chromatographed on silica gel (0.04-0.C63 mm) using toluene/ acetic acid ethyl ester (95:5) to give the heading compound as a light yellow oil. c) ?-[ (.2-ami nognenvl_[methv 1_]-3-furaneIcaTboxyl_i c_aci cf_ethy1 ester A solution of 5.1 g of the product of step b) in 100 ml of acetic acid ethyl ester and 2-3 g of Rar.ey-Nickel 202170 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 g of the product of step c), 720 ml toluene and 10.1 g lithium amide are refluxed for 5 hours. The dark suspension is treated with 1 liter acetic acid ethyl ester, ice-water and 2N acetic acid. The organic phase is washed with water, 10 dried and filtered. The filtrate is filtered through neutral aluminium oxide, eluated with-acetic acid ethyl ester and evaporated. The crystalline residue is treated with a small amount of diethyl ether, filtered and dried to yield the heading com- Example 2: 7-Chloro-3-methyl-4-(4-methyl-piperazin-l-y 1)-10H- .9 g 7-chloro-5,10-dihydro-3-roethyl-4H-furo[3,2-cj[l] benzazepin-4-thione and 60 ml 1-methylpiperazine are heated 8 hours at 100°. To the dark solution toluene and water are 20 added and filtered through a charcoal filter. The filtrate is washed with water. The organic phase is extracted with 2!1 acetic acid, the acidic extracts made alkaline with conc. ammonia and extracted with methylene chloride. The methylene pound, m.p. 192-194°. furo[3,2-c][l]benzazepine chloride extract is washed with brine, dried, filtered and evaporated. The brown resin is dissolved in acetic acid ethyl ester and filtered through basic aluminium oxide. After evaporation a yellow resin is obtained, which crystallises from 5 methylene chloride/diethyl 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-L £.4-chl oro-2-ni trophenyl )niethyl li^methvl^-furane _ester g 4-chloro-2-nitro-p>-oxobenzenebutanoic acid ethyl ester, 20 ml hydroxyacetorie and 10 g zinc chloride are heated 3 hours at 100°. Thereafter 5 ml hydroxyacetone and 5 g zinc chloride are added and the mixture is heated further 3 hours at 100°. The brown- red" solution is poured into' ice-water and extracted with ether. The organic phase is treated with 2 N sodium hydroxide., washed with water, dried, filtered arid evaporated. The residue is chromatographed on silica gel (0,04-0.063 mrn) using toluene, whereby the heading compound is obtained as an yellow oil. 1 70 -5©a-55S8- k) 2-C ^2-ami no-4-c hloroghen ^l^me t h^ll-4-me th^l^-3-^ura ne £5!C^2^Yii9_ac"'c' ethyl ester In manner analogous to that described in Example 1c) the heading compound,m.p. 67-71° is obtained. ^ c) hydro-3-methyl-4H-furo[3,2-c][[]ben2azeDir)3 4-one 21 g of the product of step b), 275 ml toluene and 6.5 g lithium amide are refluxed for 3 hours. The brown suspension is pcored into ice-water and acidified with acetic acid. The precipitate is filtered off, washed with water, dried and recrystal1ised 10 from tetrahydrofurane/methanol to give the heading compound, m.p. 250-262°(sublimation). d) Zl2bl2r2l§2lQ:dihYdro33-methyl_34H2furo[3,2-c][l]benzazegin-4^thione A suspension of 8 g of the product of step c) in 150 ml benzene is treated with 7.2 g 2,4-bis-[4-niethoxyphenyl)-l,3-dithia- 2,4-diphosphetan-2,4-disulfide and refluxed for 2 hours. The yellow suspension is evaporated in vacuo, treated with methylene chloride and filtered through 100 g silica gel 60 (0.040-0.063 mm) to obtain after evaporation the heading compound as yellowish 20 crystals. 202170 - ii - Example 3: In analogous manner to that described in Example 1 or 2, the following compounds of formula 1, and their respective starting materials, are obtained Example' R2 - R3 R^ m.p. ° C a H H H H 126-130 b ch3 7-c1 H H 144-146 c ch3 H H ch3 100-103 d ch3 7-F H H 159-161 e ch. 3 7-c1 H ch3 141-143 f ch3 7-c1 ch3 ch3 175-177 g ch3 7-f ch3 H 208 (dec.) h ch3 7-f H ch3 i ch3 7-f ch3 ck3 234 (dec.) 2C21T0 The compounds of the invention (i.e. the 4-(piperazin--1-yl )-10H-furo[3,2-c] [1 ] benzazepines)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, 5 e.g. by an inhibition of locomotion in mice. In this test groups of 3 male mice (18-24 g OF-1, Sandoz Basle) received 3.2, 10, 32, 100 and 320 mg p.o. of the test drug. 1 hour after drug administration the mice were observed individually and their locomotion compared with that of controls.

The compounds of the invention possess 3 strong affinity 3 to h'-Clozapine binding sites in vitro [modified method of D. Hauser et al., Life Science 22, 557 (1978)]. The test was performed as follcws:- Fresh calf cortex was homogenized in a: 19 fold volume 15 of Tris buffer (50 mM, pH 7.4) and centrifuged. The pellets were suspended in a 400 fold volume of Tris buffer, and the suspension used for the binding study. The composition of the . assay mixtures (end volume 2 ml) was as follows: 50 mM Tris buffer pH 7.4, membranes corresponding to 4.5 mg of original 3 tissue weight, 0.65 nM H-Clozapine and 1 pH unlabellea Cloza- 102170 pine for the determination of non-specific binding. To deter- 3 mine the inhibition of the specific binding of H-Clozapine the test drugs were added to give 5 to 9 different concentrations between 1 nM and 10 pM, each in duplicate. After incuba-5 tion for 40 minutes at room temperature, the assay mixtures were rapidly filtered through Whatman 6F/B filter, the filters washed twice with 5 ml of ice cold Tris buffer and scintillation-counted. 3 The compounds of the invention bind further on H-10 Spiperone binding sites in the brain [modified method of 0. Leysen et al., Biochem. Pharmac. 27, 307 (1978)]. The test was performed as follows: fresh calf brain striatal tissue was homogenized in the 25 fold volume of Tris buffer (pH 7.4, 50 mM, 120 mM sodium chloride) and centrifuged. The pellets were 15 suspended in a 22 fold volume of Tris buffer, incubated for minutes at 37° C and centrifuged. The pellets were suspended in • a.. 300 fold volume of Tris buffer. The composition of the assay mixtureswas as follows: 45 mM Tris buffer pH 7.7, 108 mM sodium chloride, membranes corresponding to 6 mg of original 3 -7 tissue weight, 0.1 nM H-Spiperone, 5 x 10 M Cinanserin to eliminate the contribution of 5-HT2 receptors and 1 pM unlabelled Spi perone for the determination of non-specific binding. To deter- 3 mine the inhibition of the specific binding of H-Spiperone the test drugs were added to give 5 to 9 different concentrations between 1 nM and 10 jjM, each in duplicate. 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 scintillation-counted.

The compounds are therefore indicated for use as neuro leptic agents. For this use an indicated daily dosage is from about 25 rng 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 10 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. Stilie, Arzneimittelforschung 14_, 534 15 (1964)]. The test was performed as follows:- Groups of 6 rats (Sprague-Dawley derivation, females and males, 120-160 g, Siiddeutsche Tierfarm, Tuttlingen, West Germany) received the test substance in a dosage of ca. 5 to 20 mg/kg i.p. 30 minutes before administration 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 block. The time for which the animal remained in this unnatural position was measured up to a maximum of ?a-2.1 70' - 15 - -5©©=5568— 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 separately scored eyes were added, 5 so that the maximum score possible was 8. If a catalepsy of 30 seconds or less was observed, the tetrabenazine-induced catalepsy was said 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 10 tetrabenazine administration.

'The compounds are therefore indicated for use as antidepressant agents. For this use an indicated daily dosage is from about 25 to about 500 mg of the compounds conveniently administered in divided doses 2 to 4 times a day in unit dosage 15 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 20 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 SO mg/kg p.o. animal body weight of the compounds. ,n 16- I The compounds are therefore indicated as sleep-inducing, sleep-promoting and sleep-prolonging agents, e.g. for insomnia. For this use an indicated daily dose is from about 1 to about 100 mg of the compounds, conveniently given shortly 5 before retiring to sleep.

The compounds of the invention may be administered in pharmaceutical!}' 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-10 ceutical composition comprising a compound of the invention, in free base form or in pharmaceutical^ acceptable acid addition 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 is hydrogen or (C-j_^)aTky 1 s R2 is hydrogen or halogen, R^ is hydrogen or (C-j_^)a 1 kyl and R^ is hydrogen or (C-j_^)alkyl. 202170

Claims (2)

WHAT WE CLAIM IS:

1. A process for the production of 5 4-(piperazin-l-yl)-10H- furo[3,2-c][l]benzazepine which comprises reacting an appropriate 10H-furo[3,2-cD[ljbenzazepine derivative having a leaving group or a carbonyl group in the 4-position v/ith an appropriate piperazine. 10 15

2. A process according to claim 1 for the production of a compound of formula I, wherein R-j is hydrogen, (C-j_^)alkyl, hydroxyalkyl with a maximum of 4 carbon ato:ns or a physiologically acceptable and hydro-lyzable ester thereof, alkoxyalkyl with a maximum of 6 carbon atoms, (C^^cycloalkyl, (C/,_y)cycloalkylalkyl cr (C7_9)phenylalkyl, is hydrogen, halogen, trif luorcmethyl, (Cj^)alkyl, (C-j_^) alkoxy or (C^_^}alkylthio, and R^ and are independently hydrogen or (C^ )al kyl, which comprises reacting a compound of formula II, 202170 - 18 - wherein R£» and R^ are as defined above, and either (i) Z and Y together fora a single bond and X is a leaving group, 5 or (ii) Z is hydrogen and Y and X together with the carbon atom to which they are -bound are^C-0, v/ith a compound of formula I J. I, HN U-R, III v_y 1 wherein Rj is as defined above.

3. A process for the production of a 4-(piperazin-l-yl)-10H-10 furo[3,2-c][l]benzazepine substantially as hereinafter described with reference to any one of the Examples.

4. A 4-(piperazin-l-yl)-10H-furo[3,2-c][l]benzazepine whenever produced by a process of claim 1, 2 or 3. 202170 - 19 -

6. A compound of formula I es defined in claim 2.

7. A compound of claim 6 wherein R^ is hydrogen or (C-,) alkyl, is hydrogen or halogen, is hydrogen or (C^_,)alkyl and R^ is hydrogen or XC-j)alkyl. 5 8. A compound of claim 6 which is 4-(4-methyVpi perazi n-1 - yl)-lCH-furo[3,2-c][1]benzazepine. S. A compound of claim 6 which is 7-ch1oro-3-methyl-4- (4-methyl-piperazin-1-yl )-10H-furo[3,2-c] [1 ]benzazepine.

10. A compound of claim 6 wherein R-j, R-j and R^, are 10 respectively H, H, H and H.

11. A compound of claim 5 wherein R-j, Ro, R^ and are respectively CHV 7-C1, H and H.

12. A compound of claim 6 wherein R-j, R£, R^ and R^ are respectively CH^, H, H and CH^. 15 13. A compound of claim 6 wherein R^, R^, R^ and R^ are respectively CH^, 7-F, M and H. </ ^ v <: t; u, V»' 202170 - 20 -

14. A compound of claim 6 wherein R-j, R^, and R^ are respectively CH^, 7-C1, H and CH^.

15. A compound of claim 6 wherein R-j, R^, and R^, are respectively CH^, 7-C1>-CH3 and CFL. 5 16. A compound of claim 6 wherein R-j, R2, R-j and R^ are respectively CH^, 7-F, CH^ and H.

17. A compound of claim 6 wherein R-|, R2, R^ ana R^, are respectively CH_, 7-F, H and CH9.

13. A compound of claim 6 wherein R-j, R^, and are 10 respectively CH^. 7-F, CH^ and CH^.

19. A compound according to any one of claims 4 to 18 in acid addition salt form.

20. A compound according to any one of claims 4 to 18 in a form suitable for use as a pharmaceutical.

21. A compound according to any one of claims 4 to 18 in a form suitable for use as a neuroleptic, anti-depressant, sleep-inducing, sleep-promoting or sleep-prolonging agent. 'O/ ■J 202170 - 21

22. A pharmaceutical composition comprising a compound of any one of claims 4 to 18 in free base form or in pharmaceutical^ acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.

23. A compound of formula II, II wherein R^, R3, R^, Z, Y and X are defined in claim 2. BATED THtt I'I ©AY Of |» S A. J. PARK 1 SON AGENTS POft IMC APfUCAMTS /,