DK157925B - 2,3,4,5-Tetrahydro-1H-3-benzazepine derivatives and pharmaceutical preparations comprising them - Google Patents

Description

, DK 157925B.

This invention relates to novel 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives or salts thereof which can be used in the treatment of mental disorders.

Within the last 10 years, intensive 5 pharmacological research has been conducted on benzazepines. The pharmacological properties of benzazepines depend largely on the nature of the substituents. It is known e.g. substituted benzazepines with neuroleptic, antiaggressive, antiparkinson and vascular effects.

In U.S. Patent No. 3,393,192 (Schering), derivatives of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine having been disclosed include hydroxy, lower alkoxy or halogen at the 7 and / or 8 position. In European patent applications with publication no. 5,298 and 5,299, corresponding to 15 7-hydroxy derivatives are disclosed. These compounds have been reported to have antipsychotic and antidepressant effects.

According to Life Sci. 31 (1982), 637 ff, are 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (designated SKF 38393) and 2,3,4,5- tetrahydro-9-chloro-7,8-dihydroxy-1- (4-hydroxyphenyl) -1H-3-benzazepine (designated SKF 82526) selective but partial D1-dopamine agonists, while 2,3,4,5-tetrahydro -7,8-dihydroxy-6-thiophenyl-1H-3-benzazepine (designated SKF 83742) is a selective D1-dopamine antagonist. Further it is stated in Eur. J. Pharmacol. 91 (1983), 153 et seq. That R-8-chloro-7-hydroxy-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine (designated SCH 23390) is a selective D1 dopamine antagonist (see also European Patent Application with Publication No. 5300).

U.S. Patent No. 4,187,314 (Smith Kline) discloses 1-thienyl or 1-furyl-2,3,4,5-tetrahydro-1H-3-benzazepines, which include contains hydroxy, lower alkoxy or lower alkanoyloxy at the 7- and 8-positions. In the specific examples therein of such benzazepines, the two substituents at the 7- and 8-positions are identical. These benzazepines are reported to have peripheral and central dopaminergic effects.

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It has now been found that novel 2,3,4,5-tetrahydro-1H-3-benzazepines of the general formula I

CHV

2 / X ^ CH2 "CH2x R -C Z \" II I n-r '(I)

r -c S

R 2 represents halogen, R represents hydroxy or alkoxy having not more than 4 carbon atoms, R 2 represents thienyl or phenyl ring systems orthocondensed with a benzene, cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring, in which rings one of the carbon atoms may be replaced by oxygen, and each of these ring systems may be substituted once by halogen, hydroxy or alkoxy of not more than 7 above 4 carbon atoms, and R represents hydrogen or alkyl of 20 not above 4 carbon atoms, or salts thereof, have useful pharmacological properties, in particular effects on the central nervous system, which are surprisingly superior to the effects of the known compounds. Benzazepines of formula I can be used as a drug, e.g. for the treatment of schizophrenia and manic depressive disorders.

In this specification, the term "" denotes alkyl having not more than 4 carbon atoms "", when used alone or in combinations, e.g. alkoxy, a branched or straight chain alkyl group, e.g. methyl, ethyl, propyl, isopropyl and tert-butyl. The term "alkoxy" is preferably meant methoxy and ethoxy. Halogen is chlorine, bromine, fluorine, and iodine, preferably chlorine and fluorine.

According to the above definition, the substituent R5 be a phenyl ring system orthocondensed with another ring, namely with a benzene ring, with a cyclohexane ring, with a cyclohexene ring, with a

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cyclopentane ring or with a cyclopentene ring, and in each of these rings one of the carbon atoms may be replaced by an oxygen atom and each of these ring systems may be substituted once by halogen, hydroxy or alkoxy having not more than 4 carbon atoms. Herein, the term "orthocondensed" means that the phenyl ring in question has one of its sides in common with another of the 5 specific rings listed above. The substituent R is preferably phenyl which is orthocondensed with one of the rings listed above.

Specific examples of the substituent designated R 1 hydroxy or alkoxy having not more than 4 carbon atoms, e.g. chlorochromanyl, methoxychromanyl, hydroxychromanyl and hydroxybenzofurany1.

It has never before been described that there is a particular biological benefit to the specific substitution pattern in the structures of the benzazepines of this invention.

Compounds of formula I exhibit a strong anti-dopaminergic effect. Thus, they strongly inhibit stereotyped bites in mice induced by methylphenidate (eg, using 60 mg / kg body weight, subcutaneously, one hour before the observation, which was performed analogously to that of Acta Pharmacol. Toxicol. 31.

25 (1972), 488, described method). In addition, compounds of formula I inhibit the conditional aversion response and the accumulation of amphetamine in rats.

Compounds of formula I surprisingly work a lot

* D

stronger on dopamine D1 receptors labeled with H-SCH 30 23390 than on dopamine D2 receptors labeled with ^ H-spiperone.

Compounds of formula I are surprisingly better than the previously described dopamine D1 antagonists, especially SCH 23390. Thus, compounds of formula I inhibit better dopamine-stimulated adenylate cyclase in rat striatum homogenates than SCH 23390, see Example 7.

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Furthermore, SCH 23390 has been reported to have poor, oral absorption and a short effect (cf. Life Sci.

34 (1984), 1529). Compounds of formula I exhibit better properties than SCH 23390 does, cf. Table I of Example 5 below.

Compounds of formula I also blocked the dopamine-mediated behavior (eg, stereotyped bites in rodents caused by dopamine releasing agents).

The compounds of formula I may be present as 10 enantiomeric forms which can be split into R or S forms. This cleavage may conveniently be obtained by fractional crystallization from relevant solutions of the salts of the compounds of formula I with optically active acids. When the enantiomers are cleaved, the desired pharmacological activity will predominate in one of the enantiomeric forms, mostly in the R form. Therefore, this invention includes all isomers, whether they are cleaved or are mixtures thereof.

Particularly valuable embodiments of this invention are nontoxic, pharmaceutically acceptable salts of 20 benzazepines of formula I. Such salts include salts of inorganic and organic acids such as salt, hydrocarbon, sulfur, phosphorus, methanesulfone, vinegar, milk. -, maleic, phthalic and tartaric acids. These can be prepared by standard procedures such as mixing an acetone solution of the base with the stoichiometric amount of the acid in a solution such as acetone and evaporation of the solvent to precipitate the desired salt as residue.

In a first group of preferred benzazepines of Formula I, R is chlorine or fluorine.

5

In another group of benzazepines of formula I, R is

phenyl which is orthocondensed with a benzene, cyclohexane, cyclohexene, cyclopentane or cyclopenten ring which may be substituted once by halogen, hydroxy or methoxy.

In a third group of preferred benzazepines of formula I, R is benzofuranyl, 2,3-dihydrobenzofuranyl, thienyl or chromanyl.

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.1 a fourth group of preferred benzazepines of formula I is R hydrogen or methyl.

Examples of representative and preferred benzazepines of formula I are the following: 5 1) 8-Chloro-7-hydroxy-3-methyl-5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3 -benzazepine, 2) 8-chloro-7-hydroxy-3-methyl-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 3) 8-chloro-7 -hydroxy-3-methyl-5- (3-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 4) 8-chloro-7-hydroxy-3-methyl-5 (2,3-dihydrobenzofuran-4-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 5) 8-chloro-7-hydroxy-5- (3-thienyl) -2,3,4,5 tetrahydro-1H-3-benzazepine, 6) 8-chloro-7-hydroxy-5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 7) 8-chloro-7 -methoxy-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 8) 8-chloro-7-hydroxy-3-methyl-5- (5-indanyl) -2 3,4,5-tetrahydro-1H-3-benzazepine, 9) 8-chloro-7-methoxy-3-methyl-5- (5-indanyl) -2,3,4,5-tetra hydro-1H-3-benzazepine, 10) 8-chloro-7-hydroxy-5- (4-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 11) 8-chloro-7 -hydroxy-3-methyl-5- (5-indenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 12) 8-chloro-7-hydroxy -3-methyl-5- (7-chromanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 13) 8-chloro-7-hydroxy-5- (1,2,3, 4-tetrahydronaphth-6-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 14) 8-chloro-7-hydroxy-3-methyl-5- (2,3-dihydronaphth-4) -yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 15) 8-chloro-7-hydroxy-3-methyl-5- (7-benzothienyl) -2,3,4,5-tetrahydro-1H 3-benzazepine.

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16) 8-chloro-7-hydroxy-3-methyl-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 17) 8-chloro-7-hydroxy-3 methyl-5- (2,3-dihydrobenzofuran-6-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 18) 8-chloro-7-hydroxy-3-methyl-5- (2,3- dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 19) 8-chloro-7-hydroxy-3-methyl-5- (2,3-dihydrobenzothien-7-yl) - 2.3.4.5 - tetrahydro-1H-3-benzazepine, 20) 8-chloro-7-hydroxy-3-methyl-5- (5-chloro-chromoman-8-yl) -2,3,4,5-tetrahydro-1H-3 benzazepine, 21) 8-chloro-7-hydroxy-3-methyl-5- (8-chromanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 22) 8-chloro-7- hydroxy-3-methyl-5- (6-hydroxychroman-8-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 23) 8-chloro-7-hydroxy-3-methyl-5- (5- hydroxybenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 24) 8-chloro-7-hydroxy-3-methyl-5- (4-hydroxybenzofuran-6-yl) -2,3,4,5-tetrahydro -1H-3-benzazepine, 25) 8-chloro-7-hydroxy-3-methyl-5- (4-hydroxybenzothien-6-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, and physiologically acceptable salts thereof .

In general, the present 5-substituted 2,3,4,5-tetrahydro-1H-3-benzazepines of formula I can be prepared from 2- (phenethylamino) ethanols of the general formula IV

25. CH.

2 / X

R '-C C-CH - CH_-N-CH -CH-OH (IV) 3 II I 1 I 7 I 5 R' -C CH R 'R' \ /

30 CH

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2 3 5 7 wherein R1, R ', R' and R 'are each identical to 2 3 5 7 respectively

R, R, R r and R or represent groups convertible thereto. These alcohol intermediates of formula IV can be prepared by heating equimolar amounts of an oxirane of the general formula III

0 / Λ 5 H2C-CH-R, J (III) 5

wherein R 'is as described above, with a β-phenethylamine of general formula II

2 / CH \ R '-C C-CHO-CH -NH-R' 3 II I 2 2 (II) 15 R '-C CH 1 3 7 wherein R', R 'and R' are each as described above. The condensation is preferably carried out at temperatures of approx. 100 ° C.

However, the reaction can take place within the range of room temperature to approx. 105 ° C. The alcohol intermediates of formula IV can be isolated by ordinary operations such as crystallization or distillation.

2- (phenethylamino) ethanols of formula IV are converted to the desired benzazepines of formula I by an intra-molecular cyclization obtained by reacting the 2- (phenethylamino) ethanol of formula IV with reagents such as polyphosphoric acid, sulfuric acid, trifluoroacetic acid or mixtures thereof or other reagents having similar effect. Cyclization 30 is preferably carried out in sulfuric acid or in a mixture of sulfuric acid (1-20%) and trifluoroacetic acid at temperatures between -10 and + 20 ° C.

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Benzazepines substituted at the 3-position can be readily formed, either by the use of suitable N-substituted phenethylamines or preferably by alkylation of the benzazepine of formula I, x which R represents hydrogen.

The above designation "group which can be converted there" refers, for example, to the corresponding protected groups such as protected hydroxy, e.g. lower alkyl protected, e.g. methoxy or ethoxy, or benzyloxy. The protecting groups can be removed in a manner known per se, e.g. by hydrolysis 10 or hydrogenation.

The starting materials for which the preparation is not described herein are either known compounds or compounds which can be made analogous to the preparation of known compounds or analogous to known methods.

Benzazepines of formula I are useful because they have pharmacological effects on animals, e.g. on humans. In particular, compounds of formula I may be useful as psychopharmaceuticals. Benzazepines of formula I are administered in an effective amount to the host in need of treatment.

For the above use, the dosage will vary depending on the benzazepine of formula I used, the manner of administration and the desired therapy. In general, however, satisfactory results can be obtained with a daily dose of from 0.005 mg to approx. 2 mg per 25 kg of body weight, which may conveniently be given in sub-doses from 2 to 5 times a day or in retarded form. Generally, the dosage forms useful for oral administration contain from ca.

0.5 mg to approx. 150 mg of benzazepine of formula I mixed with a pharmaceutical carrier or diluent.

Benzazepines of formula I can be administered in the form of a pharmaceutically acceptable acid addition salt. This invention also relates to pharmaceutical compositions containing a benzazepine derivative of formula I or a pharmaceutically acceptable salt thereof, and usually such compositions also contain a pharmaceutical carrier or one. diluent. The compositions

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according to this invention can be produced by conventional methods in conventional forms, e.g. capsules or tablets.

The pharmaceutical carrier used may be conventional, solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Likewise, the carrier or diluent may contain any known material which delays the uptake such as glyceryl monostearate or glyceryl distearate alone or together with a wax.

If a solid carrier is used for oral administration, the composition may be in tablet form, placed in a hard gelatin capsule in powder form or as small beads or in the form of a lozenge or cup. The amount of solid carrier may vary considerably, but generally it will be from about 1 25 mg to approx. If a liquid carrier is used, the composition may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule or an aqueous or non-aqueous liquid suspension.

The pharmaceutical compositions of this invention can be prepared by conventional methods by a pharmacist, which includes mixing, granulating and compressing or alternating mixing and dissolving the ingredients appropriate to provide the desired final product.

The mode of administration may be any manner in which the active compound is effectively transported to the appropriate or desired site, such as oral or parenteral administration, with oral administration being preferred.

The nomenclature used herein is in accordance with the IUPAC nomenclature, with the proviso that in an attempt to facilitate the reading of this description, the position of sub

i ° DK 157925 B

the stituent denoted R is always number 5. According to the IUPAC nomenclature, this position is number 1 or 5, depending on how the benzazepine is substituted.

The characteristics set forth in the foregoing description and in the following Examples and Claims may be both individually and in any combination thereof relevant to the practice of the invention in various ways.

The invention is further illustrated in the following examples. Examples 1 and 2 illustrate the preparation of starting materials which can be used to prepare the subject compounds of formula I, Examples 3-6 illustrate the preparation of the compounds of the invention, Examples 7 and 8 illustrate the effect of the compounds of the invention, and Examples 9 and 10. illustrates the preparation of pharmaceutical compositions containing the compounds of the present invention.

Example 1

To a solution of 4.9 g of sodium hydride in 115 ml of dimethylsulfoxide was added 26.2 g of trimethylsulfoxonium iodide over a period of approx. 30 minutes. 15.0 g of 5-indanyl-20 carboxaldehyde was then added over a period of 5 minutes and the reaction mixture was stirred for 15 minutes at room temperature and then for 30 minutes at 50 ° C. The reaction mixture was poured into ice water and extracted twice with 200 ml ether. The mixed extracts were washed with water and dried over Na 2 SO 4 (anhydrous).

Evaporation of the solvent gave an oil which was fractionated in vacuo to give a colorless liquid, namely 5-indanyloxirane with a boiling point (hereafter kp.) Of 66 ° C at 0.3 mm Hg.

Analogous to the method described above, the following compounds were prepared:

DK 157925B

11 b) (5-Chlorochroman-8-yl) oxirane, b.p. 114 ° C at 0.3 mm Hg, c) (3-thienyl) oxirane, b.p. 218 ° C, d) (7-benzofuranyl) oxirane, b.p. 76 - 78 ° C at 0.1 mm Hg, e) (2,3-dihydrobenzofuran-7-yl) oxirane, b.p. 78 ° C at 0.4 mm Hg 5 and f) (1,2,3,4-tetrahydronaphth-6-yl) oxirane, b.p. 83 ° C at 0.1 mm Hg.

Example 2 a) A mixture of 3.0 g of α-3-chloro-4-methoxyphenethyl-10 amine and 2.5 g of 5-indanyloxirane was stirred at 100 ° C for 18 hours.

20 ml of acetonitrile was added to the still warm reaction mixture and crystallization started immediately. The crystallization was terminated by cooling the mixture in ice water. The product was isolated by filtration, washed with cold acetonitrile and dried. Recrystallization from acetonitrile afforded N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (5-indanyl) -2-aminoethanol with a melting point (hereinafter, m.p.) of 138-139 ° C.

Analogous to the method described above, the following compounds were prepared: b) N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (2-naphthyl) -2-amino-ethanol, m.p. 150.5 - 151 ° C, c) N- (α- (3-Chloro-4-methoxyphenethyl)) - 1- (1-naphthyl) -2-amino-ethanol, m.p. 121.5 - 124.5 ° C.

d) N- (α- (3-Chloro-4-methoxyphenethyl)) - 1- (1,2,3,4-tetrahydro-naphth-6-yl) -2-aminoethanol, m.p. 148 - 150 ° C.

e) N- (α- (3-Chloro-4-methoxyphenethyl)) - 1- (3-thienyl) -2-amino-ethanol, m.p. 68 - 71 ° C.

By analogous condensation of N-methyl-3-chloro-4-methoxyphenethylamine and oxirane, the following compounds were prepared:

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f) N-methyl-N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (7-benzo-furanyl) -2-aminoethanol, m.p. 89 ° C, g) N-methyl-N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (2,3-dihydro-benzofuran-7-yl) -2-aminoethanol, oil, purified by column chromatography on silica gel; h) N-methyl-N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (5-chloro-chroman-8-yl) -2-aminoethanol, oil, purified by column chromatography on silica gel; j) N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (8-chromanyl) -2-amino-ethanol, k) N- (α- (3-chloro) -4-methoxyphenethyl) -1- (6-methoxychroman-8-yl) -2-aminoethanol and l) N- (α- (3-chloro-4-methoxyphenethyl)) - 1- (5-methoxybenzofuran-7 -yl) -2-aminoethanol.

Example 3 a) 2.7 g of N- (ot- (3-chloro-4-methoxyphenethyl)) -1- (5-20 indanyl) -2-aminoethanol were dissolved in a mixture of 100 ml of trifluoroacetic acid (TFA) and 2 , 5 ml of concentrated E ^ SO ^. The reaction mixture was allowed to stand for 1 hour at room temperature. Most TFA was removed by evaporation in vacuo (about 10 mm Hg) and the residue was mixed with an excess of dilute NaOH (2.25 N). The basic suspension thus obtained was extracted twice with 50 ml of dichloromethane. The organic extract was washed with a saturated brine solution and dried over Na 2 SO 4

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(Anhydrous). Evaporation of the dichloromethane gave the desired product as an oil. This oil was dissolved in ether and precipitated as hydrochloride salt by the addition of HCl. After filtration and recrystallization from methanol / water, 5 8-chloro-7-methoxy-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 150 - 146 ° C.

Analogous to the method described above, the following compounds were prepared: b) 8-chloro-7-methoxy-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 245.5 - 248.5 ° C; c) 8-Chloro-7-methoxy-5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 200 ° C.

d) 8-Chloro-7-methoxy-5- (1,2,3,4-tetrahydronaphth-6-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 185 - 195 ° C (dec.), E) 8-chloro-7-methoxy-5- (3-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, oil, purified by column chromatography on silica gel, NMR: CKH: 4.32; C.H: 6.42; C.H: 7.12; C_H-thienyl: 7.34; CH Joy 2. 4 and C 1 H -thienyl: 6.95 ppm (CDCl 3), 20 f) 8-Chloro-7-methoxy-5- (7-benzofuranyl) -3-methyl-2,3,4, 5-tetrahydro-1H-3-benzazepine, m.p. 141 - 142 ° C, g) 8-Chloro-7-methoxy-5- (2,3-dihydrobenzofuran-7-yl) -3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, oil, purified by column chromatography on silica gel, NMR: C 5 H: 4.74; CgH: 6.32; CgH: 7.20; C2H-dihydrobenzofuran: 4.52; C ^H-dihydrobenzofuran: 3.24 ppm (CDCl ^ Jr h) 8-chloro-7-methoxy-5- (5-chlorochroman-8-yl) -3-methyl-2,3,4,5-tetrahydro-hydroxy 1H-3-benzazepine hydrochloride, m.p. 181 ° C,

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j) 8-chloro-7-methoxy-5- (3-thienyl) -3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, oil, and k) 8-chloro-7 -methoxy-3-methyl-5- (8-chromanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 165 ° C.

Example 4 a) To a mixture of 40 ml formic acid and 30 ml 35% formaldehyde is added 2.0 g of 8-chloro-7-methoxy-5- (5-indanyl) - 2,3,4,5-tetrahydro-1H -3-benzazepine. The reaction mixture is refluxed for 4 hours and the solvent is evaporated. To the crude residue, a dilute sodium hydroxide solution (2 N) is added in excess and the mixture is extracted with ether. The organic phase is washed with water and with brine and dried over anhydrous sodium sulfate. The ether is evaporated in vacuo to give the desired product as a syrup. The free base is dissolved in dry ether by addition of a solution of hydrobromic acid in ether and the hydrobromide salt precipitates. This is recrystallized from trifluoroacetic acid / ether to give 8-chloro-7-methoxy-3-methyl-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. .

217 - 222 ° C (dec.).

The following compounds are prepared analogously to the method described above: b) 8-chloro-7-methoxy-3-methyl-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide , m.p. 251 - 253 ° C; and c) 8-chloro-7-methoxy-3-methyl-5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 200 ° C (dec.).

Example 5

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a) 1.1 g of 8-chloro-7-methoxy-3-methyl-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine is dissolved in 10 ml of dichloromethane. The solution is cooled to -10 ° C and 5 ml of boron tribromide is added. The reaction mixture is stirred while heated to room temperature. After standing for 4 hours, the volatiles are removed by evaporation in vacuo and the residue is diluted with methanol at -10 ° C. Striping with methanol gives 8-chloro-7-hydroxy-3-methyl-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 190 DEG-200 DEG C. (decomposition).

The following compounds are prepared analogously to the method described above: b) 8-chloro-7-hydroxy-3-methyl-5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; mp. 260 ° C (dec.).

C) 8-Chloro-7-hydroxy-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 180 ° C (dec.).

d) 8-chloro-7-hydroxy-3-methyl-5- (3-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 200 - 209 ° C, e) 8-Chloro-7-hydroxy-5- (3-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 190 ° C (dec.), F) 8-Chloro-7-hydroxy-3-methyl-5- (5-chlorochroman-8-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. . 230 - 232 ° C, g) 8-chloro-7-hydroxy-3-methyl-5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, mp. 225 ° C (dec.), H) 8-chloro-7-hydroxy-3-methyl-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, mp. 245 ° C,

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j) 8-Chloro-7-hydroxy-5- (1,2,3,4-tetrahydronaphth-6-yl) -3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p.

195 - 200 ° C (decomposition), k) 8-Chloro-7-hydroxy-3-methyl-5- (5-hydroxychroman-8-yl) - 2,3,4,5-tetrahydro-1H-3- benzazepine hemimaleate, 1) 8-chloro-7-hydroxy-3-methyl-5- (5-hydroxybenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine hemimaleate and m) 8-chloro 7-hydroxy-3-methyl-5- (8-chromanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 190 DEG-200 DEG C. (decomposition).

Example 6 a) 0.4 g of 8-chloro-7-methoxy-3-methyl-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine is dissolved in 20 ml of 47% hydrochloric acid and the solution is refluxed for 1 hour. The reaction mixture is diluted with water and neutralized to a pH of 8.5 by the addition of sodium bicarbonate. The resulting suspension is extracted with ethyl acetate and dried over anhydrous sodium sulfate. Evaporation of the solvent gives the product in the form of an oil. This is dissolved in dry ether and after the addition of gaseous hydrochloric acid, 8-chloro-7-hydroxy-3-methyl-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide is isolated. with m.p. 260 ° C (dec.).

The following compound is prepared analogously to the method described above: b) 8-chloro-7-hydroxy-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

17 DK 157925B

Example 7

Compounds of formula I and SCH 23390 were tested for their ability to inhibit dopamine-stimulated adenylate cyclase in rat striatum homogenates using it in Life Sci. 37 5 (1985), 1971 et al., And the result is shown in Table I in which the tested compounds of formula I are racemic mixtures, whereas SCH 23390 was tested as the pure R - (+) - isomer. is the affinity of the tested compounds for dopamine D1 receptors, as determined by the Schild assay.

Table I _ Κ ± (nM)

Test compound_dopamine-stimulated adenylate cyclase

Example No. 5j 21

Example # 5h 6 15 Example # 5f 10 SCH 23390_40_

Example 8 8-Chloro-7-hydroxy-3-methyl-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine is atoxic when administered to rats and mice at a dose of 100 mg / kg intraperitoneally.

Example 9

18 DK 157925 B

Capsule Preparation_

Ingredients_ mg per Capsule 8-Chloro-7-hydroxy-3-methyl-5- (5-indanyl) -5 2,3,4,5-tetrahydro-1H-3-benzazepine-HBr 125

Magnesium stearate 2

Lactose_ 200_

The above ingredients are thoroughly mixed and placed in hard gelatin capsules. Such capsules are administered orally to 10 individuals in need of treatment 1-5 times daily to provide dopaminergic activity.

Example 10

Preparation of Tablets_

Ingredients_mg per tablet 15 8-chloro-7 "hydroxy-3-methyl-5- (5-indanyl) - 2,3,4,5-tetrahydro-1H-3-benzazepine-HBr 200

May starch 46

Polyvinylpyrrolidone 12

Magnesium stearate_1_ 20 The benzazepine is thoroughly mixed with two thirds of the corn starch and granulated. The obtained granules are dried, mixed with the remaining ingredients and turned into tablets. The capsules or tablets thus prepared can be administered orally. Similarly, other benzazepines of formula I may be used.

Claims (7)

19 DK 157925B 1. 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives of the general formula I CHV 5 Η * - «/ \ - CH2-CX? ? II I n-r '(I) R -C C. S \ X ^ ch-ch / CE represents c halogen, R represents halogen, R represents hydroxy or alkoxy having not more than 4 carbon atoms, R represents thienyl or ring systems consisting of phenyl orthocondensed with a benzene, cyclohexane, cyclohexene, cyclopentane or cyclopentene ring in which rings one of the carbon atoms may be replaced by oxygen and each of these ring systems may be substituted once by halogen, hydroxy or alkoxy of not more than 4 7 20 carbon atoms, and R represents hydrogen or alkyl by not more than 4 carbon atoms, or salts thereof, preferably physiologically tolerable salts thereof. Benzazepine derivatives according to claim 1, characterized in that R is chlorine or fluorine. Benzazepine derivatives according to claim 1 or 2, characterized in that R is phenyl which is orthocondensed with a benzene, cyclohexane, cyclohexene, cyclopentane or cyclopentene ring which may be substituted once with halogen, hydroxy or methoxy. Benzazepine derivatives according to claim 1 or 2, characterized in that R is benzofuranyl, 2,3-dihydrobenzofuranyl, thienyl or chromanyl. 20 DK 157925 B Benzazepine derivatives according to any one of the preceding claims, characterized in that R is hydrogen or methyl. Benzazepine derivative according to claim 1, characterized in that it is 8-chloro-7-methoxy-5- (5-indanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, 8-chloro 7-Methoxy-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, 8-chloro-7-methoxy-5- (1-naphthyl) -2,3,4,5-tetrahydro-hydroxy 1H-3-benzazepine hydrochloride, 8-chloro-7-methoxy-5- (1,2,3,4-tetrahydronaphth-6-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine , 8-Chloro-7-methoxy-5- (3-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 8-chloro-7-methoxy-5- (7-benzofuranyl) -3 -methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 8-chloro-7-methoxy-5- (2,3-dihydrobenzofuran-7-yl) -3-methyl-2,3,4 5-Tetrahydro-1H-3-benzazepine, 8-chloro-7-methoxy-5- (5-chloro-chromoman-8-yl) -3-methyl-2,3,4,5-tetrahydro-ΙΗ-3- benzazepine hydrochloride, 8-chloro-7-methoxy-5- (3-thienyl) -3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 8-chloro-7-methoxy-3-methyl 5- (8-chromanyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, 8-chloro-7-methoxy-3-methyl-5- (5-indanonyl) -2,3 , 4,5-tetrahydro-lH-3-benzazepine inhydrobromide, 8-chloro-7-methoxy-3-methyl-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, 8-chloro-7-methoxy-3- methyl 5- (1-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, 8-chloro-7-hydroxy-3-methyl-5- (5-indanyl) -2,3,4,5 tetrahydro-ΙΗ-3-benzazepine hydrobromide, 8-chloro-7-hydroxy-3-methyl-5- (1-naphthyl) - 2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, 8-chloro-7-hy -Droxy-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, 8-chloro-7-hydroxy-3-methyl-5- (3-thienyl) - 2.3 4,5-tetrahydro-1H-3-benzazepine, 8-chloro-7-hydroxy-5- (3-30 thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, 8-chloro-7- hydroxy-3-methyl-5- (5-chlorochroman-8-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 8-chloro-7-hydroxy-3-methyl-5- (2 (3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 8-chloro-7-hydroxy-3-methyl-5- (7-benzofuranyl) -2,3, 4,5-tetra-hydro-1H-3-benzazepine, 8-chloro-7-hydroxy-5- (1,2,3,4-tetra-1 B (hydronaphth-6-yl) -3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, 8-chloro-7-hydroxy-3-methyl-5- (5- hydroxy-chroman-8-yl) -2,3,4,5-tetrahydro-1H-3-benzazepine hemimaleate, 8-chloro-7-hydroxy-3-methyl-5- (5-hydroxybenzofuran-7-yl) -5 2,3,4,5-tetrahydro-1H-3-benzazepine hemimaleate, 8-chloro-7-hydroxy-3-methyl-5- (8-chromanyl) -2,3,4,5-tetrahydro-1H-3 benzazepine, 8-chloro-7-hydroxy-3-methyl-5- (2-naphthyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide or 8-chloro-7-hydroxy 5- (5-indanyl) -2,3,4,5-tetrahydro-lH-3-benzazepinhydrobromid. Pharmaceutical composition characterized in that it contains a benzazepine derivative of formula I according to any one of the preceding claims or a physiologically tolerable salt thereof.