DK162228B - Substituted 7-aminocarbonyloxy-2,3,4,5-tetrahydro-1H-3- benzazepines, their preparation and pharmaceutical preparations which comprise the compounds - Google Patents

Description

DK 162228B

The present invention relates to novel substituted 7-aminocarbonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepines of formula I according to claim 1 which are useful prodrugs in the treatment of mental disorders. As used herein, the term "prodrug" defines a derivative of a biologically active compound which, when absorbed into the bloodstream of animals and humans, is degraded in such a way that it releases the active compounds and allows them to obtain a higher bioavailability than that obtained if the active compound, per se, was administered orally, thus the active compound can be administered intravenously without problems, however, oral administration is usually preferred for obvious reasons. Oral administration of the active compound is often unsatisfactory; since it decomposes in the esophagus and at the first passage of the liver, but oral administration of prodrug provides both the advantages of easy administration and a high bioavailability.

European Patent Application No. 200455 discloses 2-, 3,4,5-tetrahydro-1H-3-benzazepines which are useful in the treatment of mental disorders. When these benzazepines are administered intravenously, they are very useful in the treatment of mental illnesses, as described in the European patent application; but if administered orally, they have the disadvantage of being administered in very large doses, e.g. from approx.

0.5 mg to approx. 150 mg to achieve the desired effect.

Thus, there is a need for a way in which the benzazepines described in European Patent Application 200455 can be administered orally in much smaller doses, but still produce the desired effect.

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It has been found that a selected group of the benzazepines disclosed in European Patent Application No. 200455, i.e. the group containing a hydroxy group at position no.

3 7 of the benzazepine nucleus (similar to the case where R is 5 hydroxy in the European patent application terminology) can be converted into useful prodrugs by reacting these benzazepines with specially selected carbamic acids to form the compounds of the invention.

10 As will be apparent from the following description, the bioavailability of the compounds of the present invention is significantly higher than the bioavailability of the compounds known from the European patent application by oral administration, which makes it clear to one skilled in the art that much smaller doses can be used in oral administration. of the compounds of formula I than of the known compounds, to obtain the same effect.

The compounds of the invention have the general formula I

/ CH \, / \ / CH2-CH2 \ 25 0 R -C CT \ 1 li i / -r? where c is halogen, R is benzufuran-7-yl or 2,3-dihydro-drobenzofuran-7-yl, R is H or C 1-4 alkyl R is H, alkyl, allyl, aralkyl, cycloalkyl or aryl R 3 is H, or 38 R together with R forms a pyrrolidinyl group or a 3

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pyrrolidinyl group of the formula

Cr 1 10 g or R may be alkyl or an alkoxycarbonyl group of formula, r 0 15 η

11 11 IS

- (GHRJ "L) - C - OR J; n = 0.1 where R11 is -H, -CHg, -CH (CH3) 2, CH2CH (CH3) 2, -CH - CH2 - CH3 CH3 -2- Or R is H, alkyl, cycloalkyl or aralkyl, or are pharmaceutically acceptable salts thereof.

In a preferred embodiment of the carbamic acid esters of the invention, R is chlorine or fluorine. The corresponding basic compound exhibits a very high affinity for the receptor.

In this specification, the basic compound corresponding to a particular prodrug is a compound akin to the prodrug, with the only difference being that position # 7 in the benzene pink core of the basic compound carries only one unesterified hydroxy group.

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In the carbamic acid esters of the invention, R is benzofuranyl or 2,3-dihydrobenzofuranyl. Due to the large 5 and lipophilic R moiety, the pharmacological effect is very potent.

In a preferred embodiment of the carbamic acid esters of the invention, R is hydrogen or methyl. Such carbamic acid esters exhibit a potent pharmacological effect.

In a preferred embodiment of the carbamic acid esters of the invention, R is H, alkyl, allyl, aralkyl or cycloalkyl and R is H, alkyl, or alkoxycarbonyl.

In a preferred embodiment of the carbamic acid esters of the invention, R and R together form a ring of formula I0 / v II.

Wherein R is alkyl, preferably C 1 -C 6 alkyl.

The invention also relates to pharmaceutical compositions, in particular for the treatment of mental illness, which are characterized in that they contain an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition is usually prepared as a tablet or capsule, preferably as an enteric coated tablet.

The invention also encompasses a pharmaceutical composition as a neuroleptic.

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The invention further includes a pharmaceutical composition for the treatment of schizophrenia, other psychoses and manic-depressive disorders.

The invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition according to the invention for the treatment of a mental illness.

The compounds of formula I or salts thereof can be prepared by a process which is characterized by reacting a benzazepine compound of the general formula II

Where CH is halogen, R is benzofuran-7-yl, CH is a halogen, R is benzofuran-7-yl. or 2,3-dihy- 7

drobenzofuran-7-yl, and R is H or C 1-4 alkyl, with a reactive derivative of the carbamic acid of formula III

30

\ O

\ II

, N-C-OH (III) Å 35 Ry 6

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preferably the acid halide of formula IV

R \ 5 \ β .N-C-X (IV) / 10 o ...

wherein R is H, alkyl, allyl, aralkyl, cycloalkyl or 9,98 aryl, R is H, or R together with R forms a pyrrolidinyl group or a pyrrolidinyl group of formula 15

Λ II

r - C 'Njr13 20 - g or R may be alkyl or an alkoxycarbonyl group of the formula 25 0 11 M iq - (CHR2 "1) - C - OR °; n = 0.1 where R11 is -H, -CH , -CH (CH3) 2, CH2CH (CH3) 2, - | H - CH2 - CH3 CH3 35 13 7

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and R is H, alkyl, cycloalkyl or aralkyl, and X is halogen, preferably chlorine, or with an isocyanate V or V 5 R 8 -N = O0, (V) R 9-N = C = O (V) 8 9 where R and R has the meanings set forth above, after which the compound of formula I is isolated and, if desired, converted to a pharmaceutically acceptable salt thereof.

The compounds of formula I may contain several optically active centers and it is to be understood that the invention encompasses both racemic mixtures and all optical isomers.

In the synthesis of the compounds of formula I, various other novel compounds have also been synthesized according to methods published in the literature. Thus, carbamoyl chlorides of N-substituted amino moieties are prepared by reacting the current N-substituted amino compound in its basic form with phosgene in an appropriate organic solvent (see, e.g., J. Org.Chem., 51, 1986, 3494 -3498), and isocyanates of unsubstituted amino parts are generally prepared by reacting the amino compound in its basic form with the diphosgene reagent trichloromethyl chloroformate (TCF, e.g., J.Org.Chem. 41, 1976, 2070-71 ; Org.Synth., 59, 1979, 195-201). The identity of these partial intermediates has been confirmed by microanalysis, IR, and NMR spectroscopy. In European Patent Application No. 170 090, pages 4 and 5 show that it is not possible to accurately predict which prodrug structure will be suitable for one particular drug and that a derivative that works well for a drug may not do secondly, since differences in absorption, metabolism, distribution,

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s bution and excretion associated with drugs makes it impossible to generalize around prodrug design. Furthermore, on page 34 of this European Patent Application No. 170 090, it appears that different (but related) basic compounds with the same prodrug molecule exhibit very different relative bioavailability, confirming the above statement, that it is not possible to predict exactly which prodrug structure that will be appropriate for a particular drug, although it is known that a similar drug exhibits a satisfactory relative bioavailability with a specific prodrug structure.

Although US Patent No. 4,284,555 states that a particular class of benzazepines can be esterified with carbamic acid esters, thereby producing prodrugs with improved relative bioavailability, the basic compounds of the compounds of formula I according to the invention differ (the previously described subgroup of benzazepines described in Thus, European Patent Application No. 200455) is markedly 20 from the base compounds of the benzazepines disclosed in U.S. Patent No. 4,284,555, and thus there will be no exact way to predict what type of prodrug structure will be appropriate for the basic compound of the compounds. of formula 1.

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The prodrug effect is measured as the ratio of the area under the curve representing the concentration of the basic compound in the blood stream versus time in connection with oral administration of the prodrug and the corresponding area in connection with intravenous administration of an equimolar amount of the corresponding basic compound. It has been found that mainly the basic compound is present in the blood if the prodrug is administered orally.

35 For more detailed information related to prodrug definition, see A.A. Sinkula and S.H. Yalkowsky; J.Pharm.Sci., 64, 1975, 183-210, H. Bundgaard (ed.) (1985), 9

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Design of Prodrugs, Elsevier, Amsterdam, E.B. Roche (ed.) 1977, Design of Biopharmaceutical Properties through Pro-drugs and Analogs, American Pharmaceutical Association, Washington D.C.

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More precisely, the prodrug effect or bioavailability is measured as follows.

The prodrug is orally administered to an experimental animal and in a single dose designated "dose", expressed on a molar basis. Kon.p.o.

the concentration of the basic compound in the blood in mg of the basic compound / ml of plasma is measured at regular time intervals after administration, and a curve representing this concentration versus time, e.g. in hours, is recorded.

The area under the curve (AUC) for (mg / ml) x minutes is calculated.

Likewise, the basic compound is administered intravenously in a single dose designated "dose.", Expressed on a molar basis. An X · V · 20 similar curve is plotted and the area under this curve is corresponding to "AUC."

X · V ·

Now the bioavailability F is calculated according to the formula 25 AUC / dose_ p · O · β · 0 · F - -. 100% AUC. /dosage. .. i.v. i.v.

More specifically, in relation to this invention, the bioavailability of the prodrug is measured in dogs.

In a cross-over experiment, the basic compound is administered by a compound of formula I and the corresponding prodrug 35 at a one-week interval, the basic compound as an intravenous bolus and the corresponding prodrug as an oral solution.

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Using solid phase extraction of the plasma samples and HPLC, the plasma concentration of both the basic compound of a compound of formula 1 and the prodrug is determined up to 24 hours after administration.

5

Following the synthesis of prodrugs illustrated in the examples, results for the bioavailability of some of the exemplified prodrugs of formula I will be shown.

The present invention is further illustrated by the following examples.

EXAMPLE 1 (+) - 8-chloro-7 [(N, N-dimethylamino) carbonylloxy] -5- (7-benzo-furanyl) -2,3,4,5-tetrahydro-1H-3-methyl-3 -benzazepine, HCl.

1.0 g (3.04 mmol) of the basic compound (+) - 8-chloro-7-hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl - 3-benzazepine) was dissolved in 20 ml of dry pyridine. To this solution was added 0.56 ml (6.08 mmol) of Ν, Ν-dimethylcarbamoyl chloride in a single operation. The resulting mixture was placed in an oil bath and refluxed for 24 hours.

Pyridine was evaporated in vacuo along with excess reagent. The residual material was dissolved in 30.0 ml of dry ether and precipitated with a 1.0 N HCl solution in ether. The white precipitate was washed with 2 x 10 ml dry ether. Drying in the presence of ^ 2 ^ 5 performed for 24 hours at 0.2 mm Hg.

30

The purity of the product in this example and in Examples 2-6 was determined using the HP-LC method set forth below.

The synthesized compound was chromatographed on a column with a Nucleosil RP C-18 silica support (average particle size 5 µm) by a step gradient.

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method. The elution program was initiated with a mixture of 25% acetonitrile and 75% of a 0.1M ammonium sulfate buffer of pH 3.0. By two steps, the acetonitrile volume fraction of the eluent was raised to 55%. Column effluent detection was performed by UV absorption measurement.

Purity by HPLC> 98%. Product maximum corresponds to a retention time of 16.0 minutes.

1 H-NMR, ppm. (CDCl 3, TMS): 2.36 3H (s); 3.00 6H (s); 2.70-3.30 6H (m); 4.60 lH (t); 6.10 1H (s); 6.70-7.55 6H (m); EXAMPLE 2 (+) - 8-chloro-7 - [(N, N-diethylamino) carbonylloxy] -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl 3-benzazepine, HCl.

0.5 g (1.52 mmol) of (+) - 8-chloro-7-hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3 (benzazepine) was dissolved in 20 ml of dry pyridine. To this solution was added 0.39 ml (3.04 mmol) of Ν, Ν-diethylcarbamoyl chloride in one step. The resulting mixture was placed in an oil bath and refluxed for 24 hours. Pyridine was evaporated in vacuo along with excess reagent. The residue was dissolved in 20 ml dry ether 25 and separated with a 10% excess of 1N HCl solution in ether. The white precipitate was washed with 2x10 ml dry ether. Drying with P2 ° 5 was performed for 24 hours at 0.2 mmHg.

Purity by HPLC> 98%. Product maximum corresponds to a retention time of 24.0 minutes.

1 H-NMR, ppm. (CDCl 3, TMS): 1.15 6H (m); 2.84 3H (s): 2.9-4.2 6H (m); 3.30 4H (m); 5.48 lH (s); 6.30 lH (s); 6.84-7.70 6H (m); 2.9-4.2 6H (m).

(+) - 8-chloro-7 - [(N-methyl-N-ethoxycarbonyl) aminocarbonyloxy] -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-5 3-benzazepine, HCl.

EXAMPLE 3 12

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0.98 g (3.0 mmol) of (+) - 8-chloro-7-hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3 -benzazepine was dissolved in 10 ml of dry pyridine. This solution was added dropwise at room temperature to a solution of 1.5 g (9 mmol) of N-methyl-N-chloroformylethylcarbamate in 5 ml of dry pyridine.

The resulting mixture was placed in an oil bath and refluxed for 16 hours. Pyridine was evaporated in vacuo together with excess reagent. The residue was dissolved in 20 ml of 15 dry ether and precipitated with 10% excess of 1N HCl dissolved in ether. The white precipitate was washed twice with 10 ml of dry ether.

Purity by HPLC> 98%. Product maximum corresponds to a 20 retention time of 15.8 minutes.

1 H-NMR, ppm. (CDCl 3, TMS): 1.30 3H (t); 2.96 3H (s); 3.28 3H (s); 4.25 2H (q); 2.9-4.2 6H (m); 5.50 1H (s); 6.30 lH (s); 6.85-7.70 6H (m).

EXAMPLE 4 (+) - 8-Chloro-7- [(R, S) -N- (1-methoxycarbonyl-1-ethyl) amino-carbonylloxy] -5- (7-benzofuranyl) -2,3,4, 5-tetrahydro-1H-3-30 methyl-3-benzazepine.

0.40 g (3.05 mmol) of N-carbonyl D, L-alanine methyl ester was dissolved in 5 ml of acetonitrile. This solution was added dropwise to a refluxing solution of 0.50 g (1.52 mmol) (+) - 8-35 chloro-7-hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-hydrochloride. 1H-3-methyl-3-benzazepine in 20 ml of acetonitrile and continued to reflux for an additional 8 hours. Acetonitrile and excess of 13

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the reagent was evaporated in vacuo, leaving a yellow oil which was readily purified using flash chromatography on a silica gel column and evaporated in vacuo to a white crystallized compound.

5

Purity by HPLC> 98%. Product maximum corresponds to a retention time of 14.3 minutes.

1 H-NMR, ppm. (CD ^SO-CDg, TMS): 1.25 3H (8d); 2.28 3H (s); 2.80-4.20 8H (m); 3.56 3H (s); 4.80 lH (d); 6.30 lH (s); 7.0 - 8.0 6H (m).

EXAMPLE 5 (+) - 8-Chloro-7 - [(S) (2-methoxycarbonyl) -1-pyrrolidinyl-carbonyloxy] -5- (7-benzofuranyl) -2,3,4,5-tetrahydroalkyl 1H-3-methyl-3-benzazepine.

A solution of 0.58 g (3.05 mmol) of N-chlorocarbonyl-L-proline methyl ester in 10 ml of dry pyridine was added dropwise to 0.5 g (1.52 mmol) of (+) - 8-chloro 7-Hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine in 10 ml of dry pyridine. After completion of the addition, the mixture was placed in an oil bath for 16 hours with reflux. Pyridine and excess reagent were evaporated in vacuo and the residue was taken up in 50 ml of ether and washed with 5% NaHCO 3, saturated NaCl and 2 O. The ether phase was dried over MgSO4 and evaporated to an oil. The residual oil was purified on a silica gel column using flash chromatography and, after vacuum evaporation of the solution, a white crystallized compound was obtained.

Purity by HPLC> 98%. Product maximum corresponds to a retention time of 18, * 6 minutes.

1 H-NMR, ppm. (CDCl3, TMS): 1.50-4.50 19H (m, complex); 4.80 lH (d); 6.40 lH (d); 6.80-7.70 6H (m).

EXAMPLE 6 14

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(+) - 8-chloro-7- (isopropylaminocarbonyloxy) -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine 5

To a refluxing mixture of 0.5 g (1.52 mmol) (+) - 8-chloro-7-hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-me -thyl-3-benzazepine in 20 ml of acetonitrile was added dropwise 0.30 ml (3.04 mmol) of isopropyl isocyanate. The mixture was refluxed for an additional 6 hours and then acetonitrile was removed by evaporation in vacuo. The residual material appeared as analytically pure crystals from hot isopropanol.

Purity by HPLC> 98%. Product maximum corresponds to a retention time of 17.5 minutes.

1 H-NMR, ppm. (CD 3 SO 3, TMS): 1.00 6H (d); 2.20 3H (s); 2.10 - 3.50 8H (m); 4.80 lH (s); 6.25 lH (s); 6.8-7.9 6H (m).

Analogously to the preparation described in Example 6, the following compounds were synthesized: EXAMPLE 7 (+) - 8-chloro-7- (allylaminocarbonyloxy) -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl 3-benzazepine 1 H-NMR, ppm. (CDCl3, TMS): 2.35, 3H (s); 2.4-3.3 6H (m); 3.8 2H (t); 4.8 lH (t)? 5.0-5.2 3H (m); 5.8 lH (m); 6.4 lH (s); 6.78 1H (s); 7.05 1H (d); 7.25 2H (m); 7.55 2H (m).

Example 8 (+) - 8-chloro-7- (benzylaminocarbonyloxy) -5- (7-benzofuranyl) -35 2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine on heating to 70 ° C in toluene with 0.5 equivalent of N-methyl-15

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piperidine as a catalyst.

1 H-NMR, ppm. (CDCl 3, TMS): 2.3 3H (s); 2.4-3.4 6H (m); 4.85 lH (d); 5.1-5.3 3H (m); 6.5 lH (s); 6.8 IH (s); 7.0-7.6 10H (m).

EXAMPLE 9 (+) - 8-Chloro-7- (n-butylaminocarbonyloxy) -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine 10 on heating to 70 ° C in toluene with 0.2 equivalent of N-methylpiperidine as catalyst.

1 H-NMR, ppm. (CDCl 3, TMS): 1.27H (m); 2.3 3H (s); 2.4-3.3 δ 6H (m); 4.7 lH (d); 5.0-5.2 3H (m); 6.4 lH (s); 6.8 lH (d); 7.05 1H (d); 7.25 2H (m); 7.6 2H (m).

EXAMPLE 10 (+) - 8-Chloro-7- (cyclohexylaminocarbonyloxy) -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine at reflux for 24 hours hours in methylene chloride with 1 equivalent of triethylamine as catalyst.

1 H NMR, ppm. (CD3 SOCD3, TMS): 1.0-1.8 10H (m); 2.15 lH (m); 2.25 3H (s); 2.6-3.2 5H (m); 3.7 lH (m); 4.6 1H (d); 6.2 lH (s); 6.8 2H (m); 7.15 2H (m); 7.6 2H (m).

Analogously to the preparation described in Example 4, the following compounds were synthesized: 35 (+) - 8-chloro-7 - [(S) -N- (1-methoxycarbonyl-phenethyl) amino-carbonyloxy] -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3- methyl-3-benzazepine Example 11 16

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1 H-NMR, ppm. (CDCl3, TMS): 2.25 3H (s); 2.4-3.2 6H (m); 3.8 - 4.1 4H (s, m); 4.55 lH (d); 5.1 2H (m); 6.3 lH (s); 6.75 2H (m); 7.15 2H (m); 7.55 2H (m).

Example 12 (+) - 8-Chloro-7 - [(S) -N- (1-methoxycarbonyl-2-methylbutyl) amino-carbonylloxy] -5- (7-benzofuranyl) -2,3,4,5- tetrahydro-1H-3-methyl-3-benzazepine 1 H-NMR, ppm. (CDCl 3, TMS): 1.2-1.5 9H (m); 2.3 3H (s); 2.4-3.2 6H (m); 3.8-4.3 4H (s, m); 4.55 lH (d); 5.2 2H (m); 6.3 IH (s); 6.7 2H (m); 7.3 2H (m); 7.6 2H (m).

EXAMPLE 13 (+) + - 8-Chloro-7- [(R, S) -N- (1-methoxycarbonyl-3-methylbutyl) aminocarbonyloxy] -5- (7-benzofuranyl) -2,3,4, 5-tetrahydro-1H-3-methyl-3-benzazepine 1 H-NMR, ρρπκ (CDCl 3, TMS): 1.2-1.5 9H (m); 2,3J3H (s); 2.4 - 3.2 6H (m); 3.8-4.3 4H (s, m); 4.6 1H (d); 5.3 2H (m); 6.5 lH (s); 6.7 2H (m); 7.3 2H (m); 7.7 2H (m).

30

Analogously to the preparation described in Example 2, the following compounds were synthesized: 35 (+) - 8-chloro-7 - [(N, N-dimethylamino) carbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) - 2,3,4,5-tetrahydro-1H-3-methyl-3- benzazepine, HCl EXAMPLE 14 17

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1 H-NMR, ppm. free base (CDgSOCDg, TMS): 2.2 lH (t); 2.3 3H (s); 2.85 3H (s); 3.0 3H (s); 2.6-3.3 7H (m); 4.35 lH (d); 4.4 2H (t); 6.38 lH (s); 6.95 2H (m); 7.2 2H (m).

EXAMPLE 15 (+) - 8-Chloro-7 - [(N, N-diethylamino) carbonylloxy] -5- (2,3-dihydro-benzofuran-7-yl) -2,3,4,5- tetrahydro-1H-3-methyl-3-benzazepine, HCl 1 H-NMR, ppm. (CD3SOCD3, TMS): 1.15 6H (double t); 2.85 3H (s); 3.0-3.8 12H (m); 4.5 2H (m); 4.85 lH (d); 6.3 lH (s); 7.0 2H (m); 7.3 2H (d); Example 16 (+) - 8-Chloro-7 - [(N-methyl-N-cyclohexyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydroxy 1H-3-25 methyl-3-benzazepine, HCl at reflux for 4 hours in pyridine-1-NMR, ppm. free base (CD3SOCD3, TMS): 1.0-1.8 10H (m); 2.15 1H (t); 2.2 3H (s); 2.7-3.7 HH (m); 4.35 lH (d); 4.45 2H (t); 6.35 lH (s); 6.9 2H (m); 7.2 lH (d); 7.35 lH (s).

EXAMPLE 17 (+) - 8-Chloro-7 - [(N-methyl-N-ethyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydroxy 1H-3-methyl-3-benzazepine, HCl 18

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by reflux for 8 hours in pyridine.

1 H-NMR, ppm. free base (CD2 OCDg, TMS): 1.0-1.15 3H (double t, after heating to 90 ° C it appears as a t); 2.15 δ 1H (t); 2.25 3H (s); 2.7-3.4 12H (m); 4.4 lH (d); 4.45 2H (t); 6.35 IH (broad s); 6.9 2H (m); 7.2 2H (d).

Example 18 (+) - 8-Chloro-7 - [(N-methyl-N-isopropyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydroxy 1H-3-methyl-3-benzazepine, HCl at reflux for 8 hours in pyridine.

1 H-NMR, ppm. free base (CD3 SOCD3, TMS): 1.0-1.2 6H (double d); 2.15 1H (t); 2.25 3H (s); 2.7-3.25 lH (m); 4.4 IH (d); 4.45 2H (t); 6.3 lH (s)? 6.9 2H (m); 7.2 IH (d); 7.4 lH (s).

EXAMPLE 19 (+) - 8-Chloro-7 - [(N-methyl-N-benzyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydroxy 1 H-3-methyl-3-benzazepine, HCl 25 H-NMR, ppm. free base (CD3 SOCD3, TMS): 2.25 lH (t); 2.3 3H (s); 2.7-3.3 10H (m)? 4.3-4.6 5H (m); 6.3 lH (d); 6.9 2H (m); 7.2-7.5 7H (m).

Analogously to the preparation described in Example 5, the following compounds were synthesized: EXAMPLE 20 (+) - 8-chloro-7 - [(S) - (2-benzyloxycarbonyl) -1-pyrrolidinylcarbonyloxy] -5- (2.3) -dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine

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19 by reflux for 4 hours in pyridine.

ppm. (CD3SOCD3, TMS): 1.8-2.0 3H (m); 2.2 2H (s); 2.3 3H (s); 2.8-3.7 10H (m); 4.4-4.55 3H (m); 4.95-5.2 2H (m); Δ 6.45 lH (d); 6.7 1H (s); 6.9 2H (m); 7.2 lH (m); 7.25-7.4 5H (m).

Example 21 (+) - 8-chloro-7 - [(R) - (2-benzyloxycarbonyl) -1-pyrrolidinylcarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4 , 5-Tetra-hydro-1H-3-methyl-3-benzazepine at reflux for 4 hours in pyridine.

1 H-NMR, ppm. (CD3 SOCD3, D20, TMS) in 1.8-2.0 3H (m); 2.2 2H (s); 2.3 3H (s); 2.8-3.7 10H (m); 4.4-4.55 3H (m); 4.95 - 5.2 2H (m); 6.45 lH (d); 6.7 1H (s); 6.9 2H (m); 7.2 lH (m); 7.25-7.4 5H (m).

EXAMPLE 22 (+) - 8-Chloro-7 - [(S) - (2-N, N-diethylaminocarbonyl-methyloxy-carbonyl) -1-pyrrolidinyl-carbonylloxy] -5- (2,3-dihydrobenzo-furan) (7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine at reflux for 4 hours in pyridine.

1 H-NMR, ppm. (CD3SOCD3, D20, TMS): 1.0-1.1 6H (double t, 30 after heating to 90 ° C appears as a t); 1.9 2H (m); 2.1-2.36H (s, m); 2.6-3.6 13H (m); 4.3-4.55 4H (m); 4.6-4.85 2H (m); 6.35 lH (d); 6.9 2H (m); 7.2 2H (m); 7.4 lH (d).

EXAMPLE 23 (+) - 8-Chloro-7 - [(R) - (2-N, N-diethylaminocarbonyl-methyloxy-carbonyl) -1-pyrrolidinyl-carbonylloxy] -5- (2,3-dihydrobenzoic acid)

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(Furan-7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine by reflux for 4 hours in pyridine.

1 H NMR / ppm. (CDgSOCDg, TMS). 1.0-1.1 6H (double t, after heating to 90 ° C it appears as a t); 1.9 2H (m); 2.1-2.36H (s, m); 2.6-3.6 13H (m); 4.3-4.55 4H (m); 4.6-4.85 2H (m); 6.35 lH (d); 6.9 2H (m); 7.2 2H (m); 7.4 lH (d).

EXAMPLE 24 (+) - 8-Chloro-7 - [(S) - (2-carboxy) -1-pyrrolidinyl-carbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4 5-Tetrahydro-1H-3-methyl-3-benzazepine 15 - 113 mg (0.2 mmol) (+) - 8-chloro-7 - [(S) - (2-benzyloxycarbonyl) -1-pyrrolidinyl] carbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine (Example 20 22) was dissolved in 20 ml of tetrahydrofuran. 10 mg of palladium / cellite (10%) was added and the slurry was hydrogenated at room temperature and 1 atm. for 45 minutes. Further, 20 mg of palladium / carbon (10%) was added and the mixture was hydrogenated for 3 hours. The catalyst was removed by filtration and the solvent was evaporated in vacuo.

The residue was dissolved in few ml of methanol / tetrahydrofuran, water was added and the product obtained by lyophilization.

1 H-NMR, ppm. (CDgSOCDg, D₂O, TMS): 1.8-2.0 3H (m); 2.1-2.3 1H (m); 2.25 3H (s); 2.9-4.6 22H (m); 6.45 lH (s); 6.9 2H (d); 7.2 H (broad s); 7.4 lH (d).

Example 25 (+) - 8-chloro-7 - [(R) - (2-carboxy) -1-pyrrolidinyl-carbonyloxy] 5- (2,3-dihydrobenzofuran-7-yl) -2,3,4 , 5-tetrahydro-lH-3-methyl-3-benzazepine

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21

The compound was prepared analogously to the preparation described in Example 24.

1 NMR, ppm. (CD3SOCD3, H2O, TMS): 1.8-2.0 3H (m); 2.1-2.3 δ 1H (m); 2.25 3H (s); 2.9-4.6 22H (m); 6.45 lH (s); 6.9 2H (d); 7.2 IH (broad s); 7.4 lH (d).

By analogy with the preparation described in Example 5, the following compounds were synthesized: EXAMPLE 26 (+) - 8-chloro-7 - [(S) - (N-methyl-N- (1-methoxycarbonyl-1-phenethyl)) aminocarbonyloxy ] -5- (2,3-dihydrobenzofuran-7-yl) -15 2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine at reflux for 4 hours in pyridine.

1 H-NMR, ppm. (CD ^OCDg, D₂O, TMS): 2.1-2.2 4H (s, t); 2.6-20 3.2 12H (m); 3.6 3H (d, after heating to 90 ° C it appears as s); 4.3-4.5 3H (m); 4.8 lH (m); 6.4 lH (d, after heating to 90 ° C it appears as a single spectral line); 6.85 2H (m); 7.15-7.35 7H (m).

EXAMPLE 27 (+) - 8-chloro-7 - [(S) -N-methyl-N- (1-N ', N1-diethylaminocarbonyl-methyloxycarbonyl-1-phenethyl) aminocarbonyloxy] -5- (2,3- dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-30-benzazepine by reflux for 5 hours in pyridine.

1 H-NMR, ppm. (CD 3 SO 3, TMS): 0.9-1.1 6H (double t); 2.7-5.1 26H (m); 6.1 1H (s); 6.9-7.5 9H (m).

EXAMPLE 28 22

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(+) - 8-chloro-7 - [(S) -N-methyl-N- (1-methoxycarbonyl-1-ethyl) -aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2, 3,4,5-5 tetrahydro-1H-3-methyl-3-benzazepine at reflux for 6 hours in pyridine.

1 H-NMR, ppm. (CDgSOCDg, TMS): 1.4 3H (double d); 2.2 lH (t); 2.25 3H (s); 2.7-3.3 10H (m); 3.6 3H (double s); 4.4 IH (d); 4.5 2H (t); 4.6 lH (m); 6.4 lH (d); 6.9 2H (m); 7.2 lH (d); 7.4 lH (d).

EXAMPLE 29 (+) - 8-Chloro-7- [N-methyl-N- (benzyloxycarbonylmethyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5- tetrahydro-1H-3-methyl-3-benzazepine 20 H-NMR, ppm. (CD ^OCDg, TMS): 2.1 IH (t); 2.15 3H (s); 2.7-3.49H (m); 4.1-4.3 2H (d, after heating to 90 ° C it appears as a single spectral line); 4.4 lH (t); 4.5 2H (t); 5.15 2H (m); 6.4 lH (d); 6.85 2H (m); 7.15 lH (t); 7.35 6H (m).

EXAMPLE 30 (+) - 8-Chloro-7- [N-methyl-N- (methoxycarbonylmethyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5 -tetra-hydro-1H-3-methyl-3-benzazepine 1 H NMR, ppm. (CD 3 SO 3, TMS): 2.2 lH (t); 2.3 3H (s); 2.8 - 3.3 10H (m); 3.65 3H (d); 4.15 2H (d); 4.4 lH (t); 4.5 2H (t); 6.4 lH (d); 6.9 2H (m); 7.2 lH (d); 7.4 lH (d).

EXAMPLE 31 23

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(+) - 8-Chloro-7- [(R, S) -N-methyl-N- (1-methoxycarbonyl-1-ethyl) -aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) - 2,3,4,5-5 tetrahydro-1H-3-methyl-3-benzazepine at reflux for 6 hours in pyridine.

1 H-NMR, ppm. (CD3SOCD3, TMS): 1.4 3H (double d); 2.2 lH (t); 2.3 3H (s); 2.8-3.4 10H (m); 3.6 3H (t); 4.4 lH (d); 4.5 2H (t); 4.6 lH (m); 6.4 lH (d); 6.9 2H (m); 7.2 lH (d); 7.4 lH (d).

EXAMPLE 32 (+) - 8-Chloro-7 - [(N-methyl-N-carboxymethyl) aminocarbonyloxy] 5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-hydroxy 1H-3-methyl-3-benzazepine, HCl

The compound was prepared analogously to the preparation 20 described in Example 26 by hydrogenation for 10 hours using the hydrochloride salt of (+) - 8-chloro-7- [N- methyl-N- (benzyloxycarbonylmethyl) aminocarbonyloxy] -5- (2) (3-Dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine 1 H-NMR, ppm. (CD 3 SO 3, TMS): -2.75 3H (s); 2.8-3.0 3H (2s); 3.1-3.6 8H (m); 3.9-4.1 2H (2s); 4.5 2H (m); 4.8 lH (s); 6.35 lH (s); 6.9 2H (d); 7.3 lH (d); 7.5 lH (d).

EXAMPLE 33

Tablets are prepared by techniques known to those skilled in the art, and the composition of each tablet is as follows: 24

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Formulation, mg / tablet tablets

Benzazepine 50 5 Lactose 120

Avicel (PH 101) 40

Kollidon K25 5

Talc 4

Magnesium stearate 1 - 10 ----: -

Tablet weight 220

Bioavailability of prodrugs described in Examples 1-15 32, measured in bastard dogs according to the method previously described, is shown in the table below.

In comparison, the absolute bioavailability of the basic compounds, also measured in bastard dogs, is on average about 5%.

25 '30 35 25

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TABLE

CH.

5 / \ / CH2-CH2 \ O Cl-C c \ \\ II I / -ch3 \ / Xch-ch2 / 10 Λ CH7 Λ.

R8 R9 15

Absolute bioavailability, F (%) 5 8 9 20 Example No. R R R F (%)

Example 1 -CH 2

Example 4 1 -H -CH-C-OCH

Example 6 -H CH 3

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26

EXAMPLE 7 (3) = CH2_CH = CH2_H24

Example 8 iCH2 -o. - «5

Example 10 6 H 6 10 CH -CH-c-och3

Example 11 “H I II 7? H2 0 15

20 O

«I -CH-C-0CHo T 3

Example 12 Γ JT \ -H | 11 HC-CHo 25 I -? H2 ch3

30 I

Example 13 \ -H -CH-C-OCHQ

I I 3 7 9H2 o

35 CH

Xch3 27

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Example 14 "CH3" CH3 30 Example 15 "C2H5" C2H5 14

Example 28 "CH3" 9H £ C> CH3 IJJ I II 18 10 ch3 o 15 20 25 30 35

Claims (14)

28 DK 162228 B 1. Substituted 7-aminocarbonyloxy-2,3,4,5-tetrahydro-ΙΗ-3-benzazepines, CHARACTERIZED IN THEIR GENERAL FORMULA I, - / CH2-CH2 10. R -CC \ \\ II I / -r7 c- ° -c \ / K / (I> \ / c »-c <N CH '15 / \, R8 R9 2 5 where R is halogen, R is benzofuran-7-yl or 2,3-dihydrobenzofuran-7-yl, R is H or C4-4 alkyl R is H, alkyl, allyl, aralkyl, cycloalkyl or aryl R is H, or 9 8 R together with R form a pyrrolidinyl group or a pyrrolidinyl group of formula 25 io> NV 11 30 g or R may be alkyl or an alkoxycarbonyl group of formula 35 11 (CHR) n-C - OR; n = 0.1 where R11 is -H, -CH3 / -CH (CH3) 2, CH2CH (CH3) 2.5 - j - - ch2 - CH3 CH3 And -R 2 are H, alkyl, cycloalkyl or aralkyl, or are pharmaceutically acceptable salts thereof. 15 A compound according to claim 1, characterized in that it is (+) - 8-chloro-7 [(N, N-dimethylamino) carbonyloxy] -5- (7-benzo-furanyl) - 2,3,4,5 tetrahydro-lH-3-methyl-3-benzazepine. A compound according to claim 1, characterized in that it is (+) - 8-chloro-7 - [(R, S) -N- (1-methoxycarbonyl-1-ethyl) amino-carbonyloxy] -5- ( 7-benzofuranyl) -2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine. A compound according to claim 1, characterized in that it is (+) - 8-chloro-7 - [(S) -N- (1-methoxycarbonyl-2-methyl-butyl) -aminocarbonyloxy] -5- (7-benzofuranyl ) -2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine. A compound according to claim 1, characterized in that it is (+) - 8-chloro-7- (allylaminocarbonyloxy) -5- (7-benzofuranyl) - 2,3,4,5-tetrahydro-1H-3- methyl-3-benzazepine. A compound according to claim 1, characterized in that it is 35 (+) - 8-chloro-7- (isopropylaminocarbonyloxy) -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3 -methyl-3-benzazepine. DK 162228B 30 A compound according to claim 1, characterized in that it is (+) - 8-chloro-7- [(N, N-dimethylamino) carbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2, 3,4,5-tetrahydro-1H-3-methyl-3-benzazepine, HCl 5 A pharmaceutical composition, characterized in that it contains as an active ingredient a compound according to claims 1-7 and a pharmaceutically acceptable carrier or diluent. 10 Pharmaceutical composition according to claim 8 suitable for use in the treatment of mental illness, characterized in that it contains an effective amount of a compound according to claims 1-7 for the relief of such a disease, together with a pharmaceutically acceptable carrier or diluent. Use of a compound according to claims 1-7 for the preparation of a pharmaceutical composition according to claim 8 for the treatment of a mental illness. 20 A process for the preparation of the compounds of formula I according to claim 1, or pharmaceutically acceptable salts thereof, characterized in that a benzene-pin compound of the general formula II 2 / R-C C is reacted. N-R7 (II) HO-C C / X / Hc-CH 2 Cn R5 wherein R2, R5 and R7 have the meanings mentioned in claim 1. With a reactive derivative of the carbamic acid of formula R? 0 '5 \ I) n-C-OH (III) R 10 10 9 wherein R and R have the meanings referred to in claim 1, or with an isocyanate V or V' R 8 -N = C = O (V) r 9-N = C = O (V 1) 8 9 wherein R and R have the meanings mentioned in claim 1, after which the compound of formula I is isolated and, if desired, converted to a pharmaceutically acceptable salt thereof. 25 30 35