DK163993B - 5,7,8-Substituted 2,3,4,5-tetrahydro-1H-3-benzadepines, preparing these compounds, and pharmaceutical preparations which comprise them - Google Patents

Description

in

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The present invention relates to novel 2,3,4,5-tetrahydro-1H-3-benzazepines and pharmaceutically acceptable acid addition salts thereof, a process for their preparation, pharmaceutical compositions containing the compounds, and their use in the preparation of pharmaceutical compositions for treatment of central nervous system disorders that are sensitive to the dopamine D1 receptor.

10 Intensive pharmacological research into benzazepines has been conducted over the last decade. The pharmacological properties of benzazepines depend largely on the substituents. For example, substituted benzazepines with neuroleptic, antiaggressive, antiparkinson 15 and certain vascular effects are known.

In U.S. Pat. 3,393,192 (Schering) discloses derivatives of 5-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze-pin having inter alia hydroxy, lower alkoxy or halogen in 7- and / or 8- position. j In European patent application no. 5.298 and 5.299 (ScherΙσο) describe the corresponding 7-hydroxy derivatives.

25 In European patent application no. 200,455 (NOVO) (U.S. Patent 4,751,222) discloses 2,3,4,5-tetrahydro-1H-3-benzazepines, with a heterocyclic or ortho-condensed heterocyclic ring system at the 5-position. These compounds are said to exhibit antidopaminergic activity.

The compounds of the invention, which differ in particular from the known compounds of the nitro substitution at the 8-position, have surprisingly been found to have a very favorable bioavailability after oral administration, as will be apparent from the compounds of the present invention. Tables II and III provided data.

From German Publication No. 26 29 887 2 is known

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substituted 5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines, with stimulatory effect on peripheral dopamine receptors. Contrary to the known compounds, the compounds of the invention carry a nitro group in the 5-position, which substituent is not included in German writing. The chemically most closely related compounds (Examples 5-10 and 18) disclosed in the specification further differ from the compounds of the invention in the absence of methyl substitution in the 3-position.

Danish Patent Application No. 4790/87 discloses trans-6,7,7a, 8,9,13b-hexahydro-2-hydroxy-7-methyl-5H-benzo- [d] naphtho [2,1b] azepine and the corresponding 2-methoxy compound. The compounds are stated to have analgesic, anticholinergic and antiagressive properties. In the known compounds, unlike the compounds of the invention, there is no nitro group at the 8-position, and there is no suggestion that the compounds known from the above-mentioned properties may comprise such a substituent at the 8-position.

It is also reported 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 No. 5,300 (Scherico)).

A general disadvantage which greatly limits the use of the above-known known benzazepines is their, in comparison with the compounds of this invention, low bioavailability after oral administration.

Thus, an object of the present invention is to provide compounds which are dopamine antagonists.

Another object of the present invention is to provide 3

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bring compounds that are useful as neuroleptics.

A third object of the present invention is to provide compounds which can be used in the treatment 5 of various mental disorders, e.g. manic-depressive conditions.

A fourth object of the present invention is to provide substituted benzazepines with favorable bioavailability after oral ingestion.

It has now been found that the novel 2,3,4,5-tetrahydro-3-benzazepines according to the invention of the general formula I C 13 alkyl, 4 10 R is hydrogen or together with R forms a bridge connecting 4 10 to the positions to which R and R are bonded, and wherein this bridge is -CE ^ -CH 2 - or -CH = CH- , 11 11 R, R and R are each hydrogen, halogen, or alkyl, or R 1 is trifluoromethyl, or wherein R 1 together with R 4 forms a bridge as described in connection with the definition of R, or where R together with 11 12 R forms a bridge or where R together with R forms 4

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a bridge, in which case the bridge is in both cases selected from -O-CH2-CH2- and -CH2-CH2-CH2-5, as well as pharmaceutically acceptable acid addition salts thereof, exhibit useful pharmacological properties, especially on the central nervous system, and, in contrast to The known compounds have a surprisingly favorable bioavailability after oral administration, as will be seen in 10 of the pharmacological tests listed below.

The prior art does not in any way suggest that a particular pharmacological benefit can be expected as a result of the specific substitution pattern in the structures of the benzazepines of the present invention.

The compounds of formula I exhibit strong antidopaminergic activity. Therefore, they greatly inhibit stereotypic rodence in mice given methylphenidate (Experiment 20, as described in Acta Pharmacol. Toxicol. 31 (1972) 488), and also inhibit conditional escape response and amphetamine accumulation in rats.

The benzazepine derivative SCH 23390 is reported to exhibit poor bioavailability after oral administration and a short duration of action (vide Life Sci. 34 (1984) 1529). The compounds of formula I exhibit favorable bioavailability.

The compounds of formula I may exist as a mixture of optical isomers which can be resolved into the various pure isomers. This resolution can be conveniently achieved by fractional crystallization, of appropriate solvents, of salts of the compounds of formula 35 I with optically active acids. When the optical isomers are resolved, the desired pharmacological action will usually be strongest in one of them. Therefore, about 5

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the present invention encompasses all isomers, whether resolved or present as mixtures.

In the present specification, where the term alkyl 5 is used, either alone or in a compound such as alkoxy, this is a straight or branched chain having no more than four carbon atoms, e.g. methyl, ethyl, propyl, isopropyl and tert-butyl. Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

10

According to the above definitions, the substituents may be

A ΊΑ 11 1 O

mentioned R, Rx, Rx, and RA are included in the formation of bridges.

Thus, when R forms a bridge together with R, a tetracyclic ortho-condensed ring system is obtained, except 11 12 15 when R simultaneously forms a bridge with R such that a pentacyclic system of ortho-condensed rings is formed.

Particularly advantageous are non-toxic, pharmaceutically acceptable acid addition salts of benzazepines of formula I.

Such salts include those derived from inorganic and organic acids such as hydrochloric, hydrochloric, sulfuric, phosphorus, methanesulfonic, acetic, lactic, maleic, phthalic and tartaric acids. They can be prepared by standard procedures such as mixing a solution of the base in acetone or in a lower alcohol with the stoichiometric amount of the acid in a solvent such as acetone or a lower alcohol and evaporation of the solvent to give the desired salt as £ t residue.

30 I

In a group of preferred benzazepines of formula I, R is methyl.

In another group of preferred benzazepines of formula I, R is hydrogen or together with R forms a bridge of formula 6

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In a fourth group of preferred benzazepines of formula I, R 1 together with R 11 forms a bridge of the formula -O-Cl 2 -CE 2 - wherein the group comprises both possible orientations of the bridges.

In a fifth group of preferred benzazepines of formula I, together with R11 is a bridge of the formula -ch2-ch2-ch2-.

In a sixth group of preferred benzazepines of formula I, R is hydrogen.

In a seventh group of preferred benzazepines of formula I, R is hydrogen.

In an eighth group of preferred benzazepines of Formula 12, R, together with R, forms a bridge of the formula -O-Cl 2 -CEL -, -, or -CE 2 -Cl 2 -CEL 2 - wherein the group comprises both possible orientations of the asymmetric bridges.

20

The process according to the invention for the preparation of the compounds of the general formula I is characterized by the characterizing part of claim 9 *.

Moreover, the 2,3,4,5-tetrahydrobenzazepines of general formula I may be prepared by one or more of the following procedures A-D.

The starting compounds, the preparation of which is not described herein, are either known compounds or compounds which can be prepared in accordance with the preparation of known compounds or analogous to known methods.

Method A

7

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Compounds of general formula III

«FoT- * 10 (iii) io l12

O Λ IO * | i * IO

wherein R, R, R, Rj "1 and Rx are as defined for the compounds of general formula I and R are al-8v alkoxy and R is hydrogen or chlorine or bromine, can be converted to benzazepines of formula IV by ring closure in an acidic medium such as sulfuric acid, mixtures of trifluoroacetic acid and sulfuric acid (1-10%) or methanesulfonic acid at temperatures from -10 ° C to 50 ° C, depending on the reaction medium.

/ 'Vi— * 10 (IV) (oT ^ I »30

This method is analogous to that described in European Patent Application No. 200,455. All compounds of formula IV can be used as intermediates in the synthesis 35 of benzazepines of formula I.

8

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Method B

8 *

Compounds of general formula IV wherein R is 7 'halogen and R is hydroxy or alkoxy and the other substituents are as defined above can be dehalogenated in the 8-position by catalytic hydrogenation e.g. palladium on coal, both at atmospheric pressure and at elevated pressure. Other halogens optionally present in the starting material may be simultaneously substituted by hydrogen depending on the single compound and the reaction conditions.

Preferred solvents are water of high pH (pH 9- 13), dimethylformamide or acetic acid and sodium acetate,

15 but other solvents may also be used. The dehalo-generated compounds have the general formula V

rof ^? * r3 20, (V) i12 "

25 R

3 4 7 'wherein the substituents R, R and R are as defined 10' 'in 12' 'above and the substituents R, R and R are each identical and independently are hydrogen, alkyl or alkoxy except that where any additional halogen atom in the starting material has been replaced by hydrogen, the corresponding double-labeled substituent of formula V indicates hydrogen.

Process C

7 '

Compounds of general formula V where R is hy 9

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droxy or alkoxy, may be nitrated by commonly known methods (see, e.g., Jerry March; Advanced Organic Chemistry 3rd ed., McGraw-Hill, New York, 1985) e.g. by treating a solution of a compound of general formula V in acetic acid or in a mixture of acetic acid and methylene chloride with fuming nitric acid at temperatures of -10 ° C to 10 ° C. The resulting products will be predominantly mononitrated with the nitro group at the 8-position.

10

The nitrated compounds can be used as such for therapeutic purposes or as intermediates in the synthesis of other benzazepines.

Method D

Compounds of general formula IV or V wherein the 7 'substituent R is alkoxy may be O-dealkylated according to commonly known methods to obtain the corresponding 20 7-hydroxy compounds, for example, by treating a solution of the substrate in methylene chloride with boron tribroamide at low temperature, e.g. -70 ° C to 30 ° C, preferably -25 ° C to 0 ° C (see, for example, Theodora W. Greene: Protective Groups in Organic Synthesis, John Wiley, New York, 1981).

In some cases, the order of reactions may be different from that described here. For example, the O-de-alkylation can be performed before the nitration.

30

The benzazepines of formula I are useful because of their pharmacological action. In particular, compounds of formula I may be useful as antipsychotics. Benzazepines of formula I are administered in an effective amount to an individual in need of treatment.

Compounds of formula I were tested for their binding

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Ding to doparain D1 receptor in rat striatum homogenates using the one in Life Science vol. 37, p. 1971 (1985) by P. Andersen et al. and the results are shown in Table I where the tested compounds of formula I are (+) enantiomeric or racemic mixtures. is the affinity of the tested compounds for the dopamine D1 receptor.

TABLE I

Test compound nM

Dopamine D1 receptor 15

Example 1 42

Example 3 28

Example 4 13

Example 5 11 20 Example 6 88

Example 7 169

As already mentioned, the known benzazepines of general formula I wherein the 8-position comprises halogen have a low oral bioavailability. The increased bioavailability of the benzazepines of this invention, in comparison with the corresponding benzazepines wherein the 8-position comprises halogen, can be shown either by comparing foil to 30 ED5o vec * Peroral ° 9 intravenous administration in inhibitory amphetamines in rats, or by comparing the absolute oral bioavailability of the current compounds measured on bastard dogs. Some test results are given below.

35 11

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PHARMACOLOGICAL EXPERIMENTS

Using the method of Pedersen, V. and Christensen, A.V .: "Antagonism of methylphenidate-induced stereotyped gnawing in mice", Acta Pharmacol, et Toxicol.

31: 488-496, 1972, antagonism of dopamine-dependent, methyl-phenidate-enhanced rodent behavior in mice was used to determine the effects of the mentioned D-1 antagonists. Furthermore, the ratio of ED ^ Q values was reached by i.v. administration and oral administration taken as an index for the bioavailability of the test compounds. It was found that the presence of a nitro group at the 8-position plays an important role for the p.o./i.v.-effect ratio and thus for the bioavailability.

The following values were obtained: 20 25.

30 35 12

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TABLE II

X ^ 0 "CH3

5 J

R

10 ED ^ q values (mg / kg) Ratio p.o. i.v. p.o./i.v.

X = C1 R = 0.14 6.5 0.017 382 (1) X = NO2 R = /?% 13 11.9 5.4 2.2 (2) 20 X-Cl R- (^) 0.2 4.5 0.06 75 (3) 25 x = no2 R- όώ 4.6 1.9 0.11 17.3 (4) 30 (1) Reference substance SCH 23390 (2) Compound of Example 4 (3) Reference substance , compound g) of Example 5 35 of US Patent 4,751,222 (NOVO) (4) Compound of Example 5 13

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Study on absolute bioavailability

The benzazepines are administered orally to dogs after which samples of their blood plasma are analyzed for compound 5 by a special HPLC method. The area under the curve showing the oral plasma concentration versus time is calculated. This area is called AUC i.v.

The absolute oral bioavailability, F, is calculated as the ratio of the area representing the oral dose to the area of the intravenous dose of the formula AUC p.o./dose p.o. x 100 15 F «- AUC i.v./dose i.v.

The results are shown in Table III.

20

TABLE III

Absolute bioavailability, F (%) Compound F (%) 8-Chloro-7-hydroxy-3-methyl-5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro -1H-3-benzazepine (note 1) a 5.5 - (+) + - 7-hydroxy-3-methyl-8-nitro-5- (2,3-dihydro-benzofuran-7-yl) -2,3, 4,5-Tetrahydro-1H-3-benzazepine (note 2) 65 note 1: reference substance, compound g) in Example 5 of US Patent 4,751,222 (NOVO) 14

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Note 2: The compound of Example 5 in this specification 5 The acute toxicity of the compounds tested is low.

The dosage of the compounds of the invention, when used in therapy, will depend on the particular benzazepine of formula I, the mode of administration and the desired therapy. However, generally satisfactory results can be obtained with a daily dose of from 0.005 mg to about 5 mg per kg body weight, conveniently in single doses 2 to 5 times daily, or in the form of retard tablets. Generally, suitable dosage units for oral administration are from about 0.5 mg to about 250 mg of the benzazepines of formula I mixed with a pharmaceutically acceptable carrier or diluent.

The benzazepines of formula I may be administered in the form of a pharmaceutically acceptable acid addition salt. The invention also relates to pharmaceutical compositions containing a benzazepine of formula I or a pharmaceutically acceptable salt thereof, in particular in an amount of 0.1 mg - 250 mg per unit dose. Usually, such preparations also contain a pharmaceutical carrier or diluent. The compositions of the present invention can be prepared by conventional techniques in known forms, e.g. capsules or tablets.

The pharmaceutical carriers used may be conventional solid or liquid carriers. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid 35 carriers are syrup, peanut oil, olive oil and water. Also, the carrier or diluent may contain any known delayed release material.

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such as glyceryl monostearate or glyceryl distearate, alone or together with a wax.

If a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatin powder or pellet form, or in the form of a dulcible tablet or a lozenge. The amount of solid carrier will vary widely, but will usually be from about 25 mg to about 1 g. For example, if a liquid carrier is used, the composition may be in the form of a syrup, an emulsion, a soft gelatin capsule, a sterile injectable. solution or an aqueous or non-aqueous suspension.

The pharmaceutical compositions of the present invention can be prepared according to conventional techniques in the pharmacy comprising blending, granulating and compression or variously blending and dissolving the most suitable ingredients to obtain the desired final product.

Method of administration may be any manner that effectively transports the active compound to the desired site, e.g. orally or parenterally, with the oral route being preferred.

The nomenclature used here is broadly in line with the IUPAC nomenclature, but one of the major differences is that, in an attempt to facilitate the reading of this specification, one always refers to the position of the benzazepine nucleus to which the phenyl group bearing the substituents R 1 -R 2 is bonded, as number 5. According to the IUPAC nomenclature, this position has the number 1 or 5, depending on the other substituents in the benzazepine nucleus. In addition, the substituents are not always arranged alphabetically in the compound names, which should facilitate comparison of the different series of sub-16

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stitutionsmønstre.

The invention is further illustrated by the following examples.

5

Starting material for which preparation is not disclosed herein is disclosed in European Patent Application No. 200,455 (NOVO) and in European Patent Application No.

023 0270.

EXAMPLE 1 5- (2-Fluorophenyl) -7-hydroxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine A) 5- (2-fluorophenyl) -7 -hydroxy-3-methyl-2,3,4-5-tetrahydro-1H-3-benzazepine: 10.0 g of 8-chloro-5- (2-fluorophenyl) -7-hydroxy-3-methyl 2.3.4.5-Tetrahydro-1H-3-benzazepine was dissolved in 500 ml of acetic acid containing sodium acetate. Palladium-on-charcoal was added and the solution heated to 60 ° C.

With vigorous stirring, hydrogen was passed through the solution to give 7.9 g of crystalline compound after 48 hours. Yield 72%.

NMR:> CH-OH: 4.45 dd, Cg H: 5.95 d, Cg H: 6.4j> d, C 10 H: 30.75 s ppm. respectively.

This compound was used in the next step without further purification.

B) 5- (2-Fluorophenyl) -7-hydroxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-5-benzazepine: 17

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5.0 g of 5- (2-fluorophenyl) -7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazeplin was dissolved in 90 ml of a mixture of acetic acid and 10% water. and cooled in an ice water bath 0 ° C. With stirring, 1.7 ml of fuming nitric acid was added and the mixture was stirred cold for 1 hour. The reaction mixture was neutralized (pH 7.9) and the precipitate was extracted with ethyl acetate, dried and evaporated.

After column chromatography (silica gel / C ^C ^: CHgOH 95: 5), yellow crystals were isolated. Mp. 90-94 ° C (decomposition). NMR: CgH: 4.61 d; CgH: C [41% 6 s and CgH: 7.88 s ppm. respectively.

EXAMPLE 2 7-Hydroxy-3-methyl-8-nitro-5- (3-trifluoromethylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine A) 7-hydroxy-3-methyl-5- (3-trif 2,3,4,5-tetrahydro-1H-3-benzazepine was prepared analogously to Method A of Example 1. Yield 2.5 g, 81%.

NMR: CgH: 4.25 dd, CgH: 5.9 d, CgH: 6.5 dd, CgH: 7.0 d ppm. respectively.

This compound was used in the next step without further purification.

B) 7-Hydroxy-3-methyl-8-nitro- (3-trifluoromethylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine is prepared analogously to Method B of Example 1 to give 0.4 g (14%) . Mp.

205 - 210 ° C (dec.). NMR: CgH: 5.08 d, CgH: 6.5 s, CgH: 7.88 s ppm. respectively.

35

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EXAMPLE 3 7-Hydroxy-3-methyl-8-nitro-5 (2-methylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine 5 --- A) 1 g of 7-methoxy-3 -Methyl-5- (2-methylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in a mixture of acetic acid (5 ml) and acetic anhydride (5 ml). This mixture was added fuming nitric acid and the reaction mixture was stirred at room temperature for 2 hours. Crushed ice was added to the reaction mixture and sodium hydroxide solution (6 N) was slowly added to pH 7.5. This mixture was extracted with ethyl acetate, the organic layer was dried and evaporated to give a solid which was purified by column chromatography (silica gel: CH3 OH 98/2). Yield: 300 mg (27%). NMR: CgH: 4.58 d,

CgH: 6.11 s, CgH: 7.64 s ppm. respectively.

20 This connection was used directly in the next step.

B) 300 mg of 7-methoxy-3-methyl-8-nitro-5 (2-methylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in MeOH and cooled to -70 ° C. 1 g of BBr 2 was added slowly and the mixture was stirred for 1 hour at -70 ° C and stirring continued for 1 hour. Methanol was added slowly to destroy excess BBr 2 and the mixture evaporated to dryness. The crude product was purified by column chromatography (silica gel, C ^C ^ / CHgOH: 98/2) to give 110 mg of the desired compound. Mp. 59-61 ° C. NMR:

CgH: 5.10 d, CgH: 6.20 s, CgH: 8.05 s ppm. respectively.

35 19

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Example 4 (R) -7-hydroxy-3-methyl-8-nitro-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine 5 -: - (R) -7-hydroxy -3-methyl-5-phenyl-2,3,4,5-tetrahydro-ΙΗ-3-benzazepine was prepared analogously to the method described in Example 1B to give 1.5 g (42%). Mp.

90-92 ° C. NMR: CgH: 4.37 d, CgH: 6.46 s, CgH: 7.88 s ppm. respectively.

EXAMPLE 5 (+) -5- (2,3-dihydrobenzofuran-7-yl) -7-hydroxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine A ) (+) - 5- (2,3-dihydrobenzofuran-7-yl) -7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 6.55 g, (0.020 mole) (+) - 5- (benzofuran-7-yl) -8-chloro-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 1.0 N sodium hydroxide (100 ml, 0.100 mol) and water (100 ml). 10% palladium-on-charcoal (3.0 g) was added and the resulting solution was stirred under hydrogen at 20 ° C and 100 kPa for 5 days. The reaction mixture was filtered and the filter cake was carefully washed with 0.3 N hydrochloric acid (70 ml) and methanol (135 ml). The pH of 3r, 30 of the total filtrate and washes was adjusted to 8.0 and the resulting solution was filtered. The filter cake was washed with water / methanol (1/1) and dried in vacuo at 40 ° C to give 3.45 g (76% of theoretical yield) of the desired compound as white crystals). Mp. 227-30 ° C.

20

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B) 3.0 g (3.03 mmol) (+) -5- (2,3-dihydrobenzofuran-7-yl) -7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H 3-Benzazepine 5 was dissolved in a mixture of methylene chloride (25 ml) and acetic acid (75 ml) at 10 ° C and fuming nitric acid (0.5 ml) was added. The reaction mixture was stirred for 2 hours at 10- 15 ° C. Then the reaction mixture was evaporated to ca. 20 ml and diluted with water (100 ml).

The pH was adjusted to 8.5 and the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried and evaporated to give 2.1 g of the crude product.

Purification by column chromatography (methylene chloride / methanol 9/1) gave 1.9 g of (+) - 5- (2,3-dihydrobenzosuran-7-yl) -7-hydroxy-3-methyl-8-nitro -2,3,4,5-tetrahydro-1H-3-benzazepine as white crystals. Mp. 122-3 ° C.

Calculated: 67.0% C, 5.9% H, 8.2% N Found: 66.8% C, 6.1% H, 8.1% N

Example 6 7-hydroxy-5- (5-indanyl) -3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine A) 7-hydroxy-5- (5) -indanyl) -3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was prepared analogously to Example 1 A. Yield: 1.05 g (92%). Mp. 213-22 ° C (dec.). NMR: CgH: 4.6 d, CgH: 5.65 d, CgH: 6.4 dd,

CgH: 6.9 d ppm. respectively.

B) 7-Hydroxy-5- (5-indanyl) -3-methyl-8-nitro-2,3,4,5- tetrahydro-1H-3-benzazepine was prepared analogously to Example 1B. Yield: 0.45 g (39%). Mp. 58-63 ° C. NMR:

CgH: 4.66 d, CgH: 6.06 s, CgH: 7.8 s ppm. respectively.

21

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Calculated: 70.99% C, 6.55% H, 7.67% N Found: 70.43% C, 6.94% H, 7.77% N

EXAMPLE 7 trans- [6,7,7a, 8,9,13b] -hexahydro-2-hydroxy-7-methyl-3-nitro-5H-benz [d] naphtho [2,1b] azepine 10 trans- 6,7,7a, 8,9,13b] -hexahydro-2-hydroxy-7-methyl-5H-benzo [d] naphtho [2,1b] azepine (642 mg) was dissolved in a mixture of 40 ml of acetic acid and 4 ml of water, cooled to about 5 ° C and treated with 0.5 ml of concentrated nitric acid. After 1 hour, the reaction mixture was neutralized to pH 7.8. The precipitate was collected and purified by column chromatography (silica gel; THF + 1% TEA) to give 95 mg (15% th). Mp. 115-20 ° C. NMR: CjH: 6.06 s, C ^H: 7.8s, C ^^ HH: 4.75 d ppm. respectively.

EXAMPLE 8

Manufacture of capsules

Ingredients mg per capsule 25 - (+) - 7-hydroxy-3-methyl-8-nitro-5- (2,3-dihydrobenzofuran-7-yl) - 2,3,4,5-tetrahydro-1H-3- benzazepine hydrobromide a 125 30 magnesium stearate 2 lactose 200 The above ingredients were thoroughly mixed and placed in hard gelatin capsules. Such capsules were administered orally once or more daily to individuals there

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needed treatment.

EXAMPLE 9 5 Preparation of Tablets

Ingredients mg per tablet (+) - 7-hydroxy-3-methyl-8-nitro-δ-ΙΟ (2,3-dihydrobenzofuran-7-yl) - 2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide 200 corn starch 46 15 polyvinylpyrrolidone 12 magnesium stearate 1 20

The benzazepine was thoroughly mixed with two thirds of the corn starch and granulated. The resulting granulate was dried, mixed with the other ingredients and compressed into tablets.

25 30 35

Claims (8)

231 163993 B 1. 2,3,4,5-tetrahydro-1H-3-benzazepines of the general formula I 5 TqT n-r310 (I) (or * 10) where R3 is C1-3 alkyl, R R is hydrogen or together with R®® forms a bridge which connects the positions to which R and R are bonded and wherein this bridge is -CH₂-CH₂- or -CH = CH-, R1®, R11 og and R 12 each is hydrogen, halogen or alkyl, or R1 * is trifluoromethyl, or where R * ® 4 together with R forms a bridge, as described in connection with the definition of R, or wherein R together with 11 11 12 R forms a bridge, or where R together with R forms a bridge, in which case the bridge is in both cases selected from 30-O-CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 - and pharmaceutically acceptable acid addition salts thereof. 35 24 DK 163993 B 2. Benzazepines according to claim 1, characterized in that R4 together with R1 2 3 forms a bridge wherein the bridge is -CH2-CH2-or -CH-CH-. Benzazepines according to claim 1, characterized in that R 4 is hydrogen and R 1 and R 4 form a bridge wherein the bridge is -O-CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -. 4. A compound according to claim 1, characterized in that it is (+) - 7-hydroxy-3-methyl-8-nitro-5- (2,3-dihydro-benzofuran-7-yl) -2. 3,4,5-tetrahydro-1H-3-benzazepine. A pharmaceutical composition, characterized in that it contains a benzazepine according to claims 1-4 or a pharmaceutically acceptable acid addition salt thereof. Pharmaceutical composition according to claim 5, characterized in that it contains between 0.1 mg and 250 mg of the active substance or a pharmaceutically acceptable acid addition salt thereof per unit dose. A pharmaceutical composition for the treatment of a central nervous system disease sensitive to the dopamine D1 receptor, particularly schizophrenia or a manic depressive state, characterized in that it contains an effective amount of a benzazepine according to claims 1-4 or a pharmaceutically acceptable acid addition salt thereof. Use of a benzazepine according to claims 1-4 or 30, a pharmaceutically acceptable acid addition salt thereof 2 for the preparation of a pharmaceutical composition for the treatment of central nervous system disorders sensitive to the dopamine D1 receptor. DK 163993 B A process for the preparation of the benzazepines according to claims 1-4, characterized by nitration of a compound of formula II wherein: R3, R4 , R10, R11 and R12 have the meanings defined in claim 1. 20 25 30 35