GB2107711A - Furobenzazepines, their production and pharmaceutical compositions containing them - Google Patents

Furobenzazepines, their production and pharmaceutical compositions containing them Download PDF

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Publication number
GB2107711A
GB2107711A GB08229098A GB8229098A GB2107711A GB 2107711 A GB2107711 A GB 2107711A GB 08229098 A GB08229098 A GB 08229098A GB 8229098 A GB8229098 A GB 8229098A GB 2107711 A GB2107711 A GB 2107711A
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Prior art keywords
compound
hydrogen
furo
alkyl
piperazinyl
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GB2107711B (en
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Robert Swoboda
Urs Stauss
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Sandoz AG
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Sandoz AG
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Priority claimed from CH662881A external-priority patent/CH646974A5/en
Priority claimed from CH207782A external-priority patent/CH650509A5/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

4-Piperazinyl-Furobenzazepine derivatives in free base form or in pharmaceutically acceptable acid addition salt form are useful as neuroleptic, anti-depressant, sleep-inducing, sleep- promoting and sleep-prolonging agents.

Description

SPECIFICATION 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-10H-furo [3,2-c][1]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 position.
The present invention in particular provides compounds of formula
wherein R1 is hydrogen, (C14)alkyl, hydroxyalkyl with a maximum of 4 carbon atoms or a physiologically acceptable and hydrolyzable 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, (C14)alkyl, (C1-4) alkoxy or (C1.4)alkylthio, and R3 and R4 are independently hydrogen or (C1.4)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 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 alkylene chain which preferably has 2 or 3, especially 2 carbon atoms. The alkoxy radical 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. Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, especially chlorine.
R1 is preferably hydrogen or alkyl. R2 is preferably hydrogen or halogen. R2 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 group. Such esters are particularly derived from (C2.18)alkanoic and (C4 18)alkenoic 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 1OH-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,
wherein R2, R3 and R4 are as defined above, and either (i) Z and Together form a single bond and Xis a leaving group, or (ii) Z is hydrogen and Y and X together with the carbon atom to which they are bound are C=O, with a compound of formula Ill,
wherein R1 is as defined above.
The process may be effected in conventional manner for the production of similar compounds by condensation.
The reaction of 1 OH-furo[3,2-c][l ]benzapine derivative having a leaving group in the 4 position, in particular compound of formula II, wherein Z and Ytogether form a single bond and X is a leaving group, such as halogen, especially chlorine, sulfhydril, (C1.4)alkoxy or (C1.4)alkylthio, p-nitrobenzylthio or tosyloxy, is conveniently carried out in an inert organic solvent such as xylene, toluene or dioxane at a temperature of from 50 to 170"C. When a 10H-furo[3,2-c][1]benzazepine derivative having a carbonyl group in the 4 position, in particular compound of formula II, wherein Z is hydrogen and Y and Xtogetherwith the carbon atom to which they are bound 0=0 is used as starting material then the compounds of formula lli 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 Ill. Preferably 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 particularly described these compounds are known or may be produced in analogous manner to known compounds orto processes 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.
EXAMPLE 1 4- (4-Methyl- 1-piperazinyl)- 1 OH-furof3,2-cjlijbenzazepine 8 g 5,1 O-Dihydro-4H-furo[3,2-cl[l ]benzazepin-4-on 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 1000. 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, viscous oil is obtained.The oil is filtered through aluminium oxide, eluted with methylene chloride and evaporated. The colourless residue is crystallised from diethyl ether/hexane to yield the heading compound m.p. 103-105".
The starting material 5,1 0-dihydro-4H4uro[3,2-cj[1 ]benzazepin-4-one may be obtained as follows:- a) 2-nitro-ss-oxobenzenebutanoic acid ethyl ester 10 g 2-nitro-p-oxobenzenebutanenitrile [prepared according to Ch.W. Muth et al., J. Org. Chem. 25,736, 739 (1960)1 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 mixture 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 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 cristalline residue is recrystallised from diisopropyl ether to give the heading compound, m.p. 55-56".
b) 2-f(2-nitrophen yl)m ethylj-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 (0.04-0.063 mm) using toluene/acetic acid ethyl ester (95:5) to give the heading compound as a light yellow oil.
c) 2-f(2-aminophen yl)methylj-3-furan e carb oxylic acid ethyl ester A solution of 5.1 g of the product of step b) in 100 ml I ml acetic acid ethyl ester and 9 of Raney-Nickel 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-dEhydro-4H-furo[3,2-cl[11benzazepin-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, 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 compound, m.p. 192-194'.
EXAMPLE 2 7-Chloro-3-methyl-4-(4-methyl- 1-piperazinyl)- 10H-furo[3,2-cl[11benzazepine 5.9 g 7-chloro-5,10-dihydro-3-methyl-4H-furo[3,2-c][1]benzazepin-4-thione and 60 ml 1-methylpiperazine are heated 8 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 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 methylene chloride/diethyl ether to yield the heading compound m.p. 203-206".
The starting material 7-chloro-5,1 0-dihydro-3-methyl-4H4uro[3,2-cj[1 jbenzazepin-4-thione may be obtained as follows:a) 2-f(4-chloro-2-nitrophenyl)meth yl]-4-methyl-3-furane carboxylic acid ethyl ester 20 g 4-chloro-2-nitro--oxobenzenebutanoic acid ethyl ester, 20 ml hydroxyacetone 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 1000. 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 and evaporated. The residue is chromatographed on silica gel (0,04-0,063 mm) using toluene, whereby the heading compound is obtained as an yellow oil.
b) 2-[62-amino-4chlorophenyl)methyll-4methyl-3-furane carboxylic acid ethyl ester In manner analogous to that described in Example 1 c) the heading compound, m.p. 67-71" is obtained.
c) 7-chloro-5, 1 0-dih ydro-3-m eth yl-4ll-furol3, 2-cjjljbenzazepin-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 poored into ice-water and acidified with acetic acid. The precipitate is filtered off, washed with water, dried and recrystallised from tetrahydrofurane/methanol to give the heading compound, m.p.
260-262" (sublimation).
d) 7-chloro-5, 1 0-dih ydro-3-m eth yl-4H-furof3,2-c][ 1J-benzazepin-4-thion e 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 methoxyphenyl)-1 ,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 crystals.
EXAMPLE 3 In analogous manner to that described in Example 1 or 2, the following compounds of formula I are obtained: Example RI R2 R3 R4 m.p. C a H H H H 126-130 b CH3 7-CI H H 144-146 c CH3 H H CH3 100-103 d CH3 7-F H H 159-161 e CH3 7-CI H CH3 141-143 f CH3 7-CI CH3 CH3 175-177 g CH3 7-F CH3 H 208 (dec.)* h CH3 7-F H CH3 CH3 7-F CH3 CH3 234 (dec.)* * dihydrochloride 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 (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 a strong affinity to 3H-Clozapine binding sites in vitro [modified method of D. Hauser et al., Life Science 23, 557 (1978)]. The test was performed as follows: Fresh calf cortex was homogenized in a 19 fold volume 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 tissue weight, 0.65 nM 3H-Clozapine and 1 FM unlabelled Clozapine for the determination of non-specific binding. To determine the inhibition of the specific binding of 3H-Clozapine the test drugs were added to give 5 to 9 different concentrations between 1 nM and 10 cm, each in duplicate. After incubation for 40 minutes at room temperature, the assay mixtures were rapidly filtered through Whatman (RTM) GF/B filter, the filters washed twice with 5 ml of ice cold Tris buffer and scintillation-counted.
The compounds of the invention bind further on 3H-Spiperone binding sites in the brain [modified method of J. 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 suspended in a 22 fold volume of Tris buffer, incubated for 15 minutes at 37"C and centrifuged. The pellets were suspended in a 300 fold volume of Tris buffer.The composition of the assay mixtures 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-Spiperone, 5 x 10-7 M Cinanserin to eliminate the contribution of 5-HT2 receptors and 1 I1M unlabelled Spiperone for the determination of non-specific binding. To determine the inhibition of the specific binding of 3H-Spiperone the test drugs were added to give 5 to 9 different concentrations between 1 nM and 10 M, each in duplicate. After incubation 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 neuroleptic 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 males, 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 administration of 10 mglkg 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 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, 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 tetrabenazine administration.
The compounds are therefore indicated for use as anti-depressant 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 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 sleepprolonging 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.
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 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 pharmaceutical composition comprising a compound of the invention, in free base form or in pharmaceutically 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 R1 is hydrogen or (C1 4)alkyl, R2 is hydrogen or halogen, R3 is hydrogen or (C1.4)alkyl and R4 is hydrogen or (C1.4)alkyl.

Claims (25)

1. A process for the production of a 4-piperazinyl-10H-furo[3,2-c][1]benzazepine which comprises reacting an appropriate 10H-furo[3,2-c][1]benzazepine derivative having a leaving group or a carbonyl group in the 4-position with an appropriate piperazine.
2. A process according to claim 1 for the production of a compound of formula I,
wherein R1 is hydrogen, (C1.4)alkyl, hydroxyalkyl with a maximum of 4 carbon atoms or a physiologically acceptable and hydrolyzable ester thereof, alkoxyalkyl with a maximum of 6 carbon atoms, (C3.6)cycloalkyl, (C47)cycloalkylalkyl or (C79)phenylalkyl, R2 is hydrogen, halogen, trifluoromethyl, (C1.4)alkyl, (C1-4) alkoxy or (C14)alkyIthio, and R3 and R4 are independently hydrogen or (C1.4)alkyl, which comprises reacting a compound of formula 11,
wherein R2, R3 and R4 are as defined above, and either (i) Z and Y together form a single bond and Xis a leaving group, or (ii) Z is hydrogen and Y and X together with the carbon atom to which they are bound are C=O, with a compound of formula Ill,
wherein R1 is as defined above.
3. A process for the production of a 4-piperazinyl-1 OH-furo[3,2-c] [1]benzazepine substantially as hereinafter described with reference to any one of the Examples.
4. A4-piperazinyl-10H-furo[3,2-c][1]benzazepinewhenever produced by a process of claim 1,2 or 3.
5. A 4-piperazinyl-1 0H-furo[3,2-c] [1 ]benzazepine.
6. A compound of formula I as defined in claim 2.
7. A compound of claim 6 wherein R1 is hydrogen or (C1-4) alkyl, R2 is hydrogen or halogen, R3 is hydrogen or (C1.4)alkyl and R4 is hydrogen or (C1.4)alkyl.
8. A compound of claim 6 which is 4-(4-methyl-1 -piperazinyl)-1 0H-furo[3,2-c][1]benzazepine.
9. A compound of claim 6 which is 7-chloro-3-methyl-4-(4-methyl-1 -piperazinyl)-1 OH-furo[3,2 c][1 ]benzazepine.
10. A compound of claim 6 wherein R1, R2, R3 and R4 are respectively H, H, H and H.
11. A compound of claim 6 wherein Ra, R2, R3 and R4 are respectively CH3, 6-Cl, H and H.
12. A compound of claim 6 wherein R1, R2, R3 and R4 are respectively CH3, H, H and CH3.
13. A compound of claim 6 wherein R1, R2, R3 and R4 are respectively CH3, 7-F, H and H.
14. A compound of claim 6 wherein R1, R2, R3 and R4 are respectively CH3, 7-Cl, H and CH3.
15. A compound of claim 6 wherein R1, R2, R3 and R4 are respectively CH3, 7-Cl, CH3 and CH3.
16. A compound of claim 6 wherein R1, R2, R3 and R4 are respectively CH3, 7-F, CH3 and H.
17. A compound of claim 6 wherein R1, R2, R3 and R4 are respectively CH3, 7-F, H and CH3.
18. A compound of claim 6 wherein R1, R2, R3 and R4 are respectively CH3, 7-F, CH3 and CH3.
19. A compound according to any one of claims 4to 18 in free base form.
20. A compound according to any one of claims 4to 18 in acid addition salt form.
21. A compound according to any one of claims 4 to 18 for use as a pharmaceutical.
22. A compound according to any one of claims 4 to 18 for use as a neuroleptic, anti-depressant, sleep-inducing, sleep-promoting or sleep-prolonging agent.
23. A pharmaceutical composition comprising a compound of any one of claims 4to 18 in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
24. A method of treating schizophrenia, depression or insomnia, which comprises administering a compound of any one of claims 4 to 18 to a subject in need of such treatment.
25. A compound of formula II,
wherein R2, R3, R4, Z, Y and X are defined in claim 2.
GB08229098A 1981-10-16 1982-10-12 Furobenzazepines their production and pharmaceutical compositions containing them Expired GB2107711B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH662881A CH646974A5 (en) 1981-10-16 1981-10-16 Furobenzazepines, their preparation and use
CH207782A CH650509A5 (en) 1982-04-05 1982-04-05 Furobenzazepines, their preparation and use

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GB2107711A true GB2107711A (en) 1983-05-05
GB2107711B GB2107711B (en) 1985-04-17

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AU (1) AU8936982A (en)
BE (1) BE894623A (en)
CA (1) CA1193596A (en)
DE (1) DE3236937A1 (en)
DK (1) DK457082A (en)
ES (1) ES516489A0 (en)
FI (1) FI823437L (en)
FR (1) FR2514767A1 (en)
GB (1) GB2107711B (en)
HU (1) HU189184B (en)
IT (1) IT1189389B (en)
NL (1) NL8203954A (en)
NZ (1) NZ202170A (en)
PH (1) PH20263A (en)
PT (1) PT75677A (en)
SE (1) SE8205849L (en)

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EP0001401A1 (en) * 1977-09-29 1979-04-18 Sandoz Ag Thienobenzazepine derivatives, processes for their production and pharmaceutical compositions containing them

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DE3236937A1 (en) 1983-05-05
BE894623A (en) 1983-04-07
FI823437A0 (en) 1982-10-08
FR2514767B1 (en) 1984-01-27
IT8249285A0 (en) 1982-10-15
SE8205849D0 (en) 1982-10-14
SE8205849L (en) 1983-04-17
IT1189389B (en) 1988-02-04
PT75677A (en) 1982-11-01
DK457082A (en) 1983-04-17
ES8401483A1 (en) 1983-12-16
CA1193596A (en) 1985-09-17
FI823437L (en) 1983-04-17
PH20263A (en) 1986-11-14
ES516489A0 (en) 1983-12-16
AU8936982A (en) 1983-04-21
HU189184B (en) 1986-06-30
NL8203954A (en) 1983-05-16
FR2514767A1 (en) 1983-04-22
GB2107711B (en) 1985-04-17

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