CH642634A5 - 1-Phenyl-2,3,4,5-tetrahydro-7,8-dihydroxy-1H-3-benzazepines - Google Patents

Abstract

The novel 1-phenyl-2,3,4,5-tetrahydro-7,8-dihydroxy-1H-3-benzazepines correspond to the general formula <IMAGE> in which R and R3 denote a hydrogen atom, an alkylthio, alkylsulphinyl, alkylsulphonyl, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl group, but the radicals R and R3 do not simultaneously represent hydrogen atoms, R1 denotes a hydrogen atom, an alkyl, C3-5-alkenyl, hydroxyethyl, benzyl, phenethyl, carbobenzyloxy or alkanoyl group and R2 denotes a hydrogen or halogen atom, a trifluoromethyl, methyl, methoxy or hydroxy group and X denotes a hydrogen atom or an alkyl or alkanoyl group, where all the alkyl and alkanoyl groups contain 1 to 5 carbon atoms, their salts with acids and their quaternary ammonium salts. The compounds of the formula (I) exhibit an antiparkinson activity. <IMAGE>

Description

The invention relates to the objects characterized in the claims.

Preference is given to compounds of the general formula I in which the radical R represents a C 1-5 alkylthio group. The invention also includes the S-oxidized derivatives of the compounds of general formula I, i.e. the 6- or 9-alkylsulfonyl, alkylsulfinyl, trifluoromethylsulfonyl and tri-fluoromethylsulfinyl compounds or the dimethylsulfonium halides. These are compounds of the general formula I in which at least one of the radicals R and R3 represents a methyl, trifluoromethylsulfoxide or sulfonyl group together with the sulfonium derivatives in which R or R3 denotes the group - (CH3) 2S02X, in which X is a Anion, for example a chloride, bromide, iodide, tosylate or mesylate anion.

In a subgroup of the compounds of the general formula I, R represents a methylthio or trifluoromethylthio group and Rj and R3 represent hydrogen atoms. The radical R2 in this subgroup specifically denotes a hydrogen or chlorine atom, a methyl, trifluoromethyl, methoxy or

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3rd

642634

Hydroxy group. The 9-methylthio compounds are preferred.

The salts of the compounds of the general formula I can be derived from inorganic or organic acids. Specific examples of the acids which can be used for salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedioic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid , Salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid and benzenesulfonic acid. The quaternary salts, including the sulfonium derivatives, are derived from organic halides, for example lower alkyl halides, such as methyl bromide, methyl iodide, ethyl iodide, benzyl chloride, methyl tosylate or methyl mesylate.

Certain l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepines are described in US Pat. Nos. 3,393,192 and 3,795,683, British Pat. No. 1,118,688 and Swiss Pat. No. 555,831. These documents also describe 7,8-dihydroxy-1-phenyl-3-benz-azepines and various intermediates, some of which can also serve as starting compounds for the preparation of the compounds of the general formula I.

The compounds of the general formula I can be in the form of diastereomers which can be split into the d- or 1-isomers. The optical isomers can be cleaved by fractional recrystallization of their salts with optically active acids from appropriate solvents. The invention encompasses all isomers and their mixtures. The d-isomers are usually more pharmacologically active.

The compounds of general formula I contain in the 7- and 8-position hydroxyl groups, which optionally in the corresponding C 1-4 alkyl ethers, for example the methoxy, ethoxy, butoxy or isoamyloxy compounds, or C2_5-alkanoyloxy compounds, for example the O Acetyl, O-propionyl or O-valeryl compounds can be converted. The dimethoxy and diacetoxy derivatives are particularly preferred, although their biological activity is somewhat lower. The diacyloxy derivatives are particularly suitable for oral administration.

The lower alkyl or alkanoyl derivatives of the compounds of the general formula I are prepared by customary methods. When using lower alkyl halides as alkylating agents, however, in addition to

0-alkylation also the formation of the lower alkyl sulfonium halides. For example, the reaction with methyl bromide gives dimethyl sulfonium bromide.

These sulfonium salts can be converted into the corresponding thio compounds without cleavage of the O-alkyl groups by conventional methods, for example by heating in hydrobromic acid or saline or another source of bromide or chloride ions.

The compounds of the general formula I can be prepared by the process described in US Pat. No. 3,393,192 from the corresponding 2-lower-alkylthio-3,4-dimethoxy-phenethylamines or the corresponding phenethylamino-methylbenzyl alcohols by cyclization. The N-substituted derivatives of the general formula I can also be prepared by cyclization of the corresponding tertiary amino alcohol. However, the compounds of the invention are preferably obtained by reacting

1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine-7,8-dions of the general formula II

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in which Rx and R2 are as defined above, with a mercaptan of the general formula R'-SH, in which R 'is an alkyl or trifluoromethyl group, preferably in an inert organic solvent, for example an alcohol, methanol or ethanol, at about room temperature to compounds of general formula III

R

obtained de 9 isomer. However, the mixture of these positional isomers can be easily separated into the 6- and 9-isomers in the manner described below. The 45 mixture of monosubstituted isomers can also be used to prepare the 6,9-disubstituted compounds.

This is described below.

The compounds of general formula I are valuable medicinal substances with a novel dopaminergic Ef-50 effect. It is known that dopaminergic compounds have a different effect both on dopamine receptors in the central nervous system and on peripheral dopamine receptors, in particular of the cardiovascular system. The effect on peripheral dopamine receptors leads to increased blood flow to the kidneys, which results in a drop in blood pressure. To determine this effect, anesthetized dogs with normal blood pressure are given the compound to be examined intravenously and in portions at 5-minute intervals. The effect on renal vascular resistance can be calculated from the change in renal blood flow and arterial blood pressure. The effect is expressed by the ED1S value, i.e. the cumulative dose that causes a 15 percent decrease in renal vascular resistance

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Blood pressure in mm Hg

(R =).

Blood flow in ml / min.

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The 6-alkylthio derivatives of the compounds of the general formula I show anti-Parkinson activity due to their central dopaminergic activity. This effect can according to the von Ungerstedt u. Mitarb., Brain Research, Vol. 24 (1970), pp. 485 to 493. The method is based on drug-induced rotation in rats with extensive unilateral lesions of the substantia nigra. The rotational behavior of the rats in which 6-hydroxydopamine lesions of the nigrostriatal dopamine system were generated was recorded. A unilateral brain lesion in the left substantia nigra causes the dopamine receptor in the left caudate to become hypersensitive due to the degeneration of the Nigerian cell bodies. These lesions destroy the source of the neurotransmitter dopamine in the caudate, but leave the caudate cell bodies and their dopamine receptors intact. Activation of these receptors by drugs that cause contralateral rotation relative to the injured side of the brain is used as a measure of the drug's central dopaminergic activity.

Compounds that can be used effectively for the treatment of Par-Kinson's disease, such as L-dopa or apomorphine, also show an effect in these rotation attempts on the rat. These compounds immediately activate the dopamine receptors and cause contralateral rotation in the brain-injured rat.

The activity to generate rotational motions is defined by the ability of a compound to produce 500 contralateral rotations over a period of 2 hours after intraperitoneal administration of the compound. The dose corresponding to 500 contralateral turns per 2 hours is called the RD500 value.

The surprising nature of the pharmacological spectrum of the compounds of the general formula I consists in a shift from the activity towards the peripheral receptors to a central effect. For example, l-phenyl-2,3,4,5-tetrahydro-7,8-dihydroxy-6-methylthio-lH-3-benzazepine hydrobromide has an RD500 of 0.18 (0.06 to 0.29) mg / kg (0.14 mg / kg free base). This compound is 8 times more effective than the corresponding compound with a hydrogen atom in the 6-position, the effect being quicker and taking longer. The EDIS of this connection is 372, i.e. the compound is 10 times less active than the corresponding compound with a hydrogen atom in the 6-position. l-Phenyl-2,3,4,5-tetra-hydro-7,8-dihydroxy-9-methylthio-1H-benzazepine hydro-bromide has an RD500 of 4.8 mg / kg (3.8 mg / kg the free base). This compound is 3 times more active than the corresponding compound with a hydrogen atom in the 6-position. The higher alkylthio compounds as well as the corresponding 6,9-disubstituted compounds are less active in the spin test than the preferred compounds with a methylthio group.

The examples illustrate the invention.

example 1

A suspension of 34 g (0.101 mol) of l-phenyl-2,3,4,5-tetrahydro-7,8-dihydroxy-1H-3-benzazepine hydrobromide in 275 ml of methanol is mixed with a solution of 25.2 g (0.111 mol) 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone in 125 ml of methanol were added rapidly at 0 ° C. with stirring and under argon as a protective gas. After stirring for 1 hour at 0 ° C., the reaction mixture is filtered and the orange precipitate is washed with 75 ml of cold methanol, then 100 ml of ethyl acetate and then 100 ml of diethyl ether. The product is then dried under reduced pressure at room temperature. There are 32.8 g (0.89 mol; 97% of theory) of 1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine-7,8-dione hydrobromide obtained from F. 164 to 165 ° C (dec.).

In a suspension of 5 g (0.015 mol) of l-phenyl-2,3,4,5-5-tetrahydro-lH-3-benzazepine-7,8-dione (prepared from the salt) in 150 ml of methanol is stirred methyl mercaptan initiated in a strong current. The orange colored quinoni quickly dissolves. A light yellow solution is obtained which is evaporated. 5.5 g of an io residue are obtained, which consists of a mixture of the hydrobromides of l-phenyl-2,3,4,5-tetrahydro-6-methylthio-7,8-dihydroxy-lH-3-benzazepine and l-phenyl-2,3,4,5-tetrahydro-7,8-dihydroxy-9-methylthio-lH-3-benzazepine. The 9-isomer can be crystallized immediately by dissolving the residue in methanol 15 and diluting the solution with ethyl acetate to the cloud point. 2.2 g of a product are obtained which still contain small amounts of the 6-isomer. Complete separation is achieved by chromatography on silica gel. For this purpose, 20 3.3 g of the mixture of the isomers are dissolved in 3.2 ml of methanol and diluted to 80 ml with chloroform. This solution is placed on a column filled with 100 g of silica gel with the dimensions 4.5 × 15 cm and eluted with a linear gradient of chloroform with increasing concentration of methanol (1000 ml, 5% to 20% methanol). First the 6-isomer is isolated, then a mixture of the 6- and 9-isomers, and then the 9-isomer. The fractions with the pure 6-isomer are combined and evaporated. 1.4 g of a residue are obtained, which is recrystallized from a mixture of ethanol and ethyl acetate. Yield 0.64 g (0.0017 mol; 11% of theory) of melting point 258 ° C (dec.).

The fractions with the pure 9 isomer are also combined and evaporated. The residue is combined with 35 to 2.2 g of the product obtained by direct crystallization. After recrystallization from a mixture of methanol and ethyl acetate, 1.25 g (0.0034 mol; 22% of theory) of pure 9-isomer of melting point 270 ° C. (decomp.) Are obtained.

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Example 2

Preparation of 6- and 9-lower-alkylthio-7,8-dih.ydroxy - 2,3,4,5-tetrahydro-1-phenyl-l H-3-benzazepìn en

45 A 1 liter three-necked flask is equipped with a magnetic stirrer, a gas inlet tube and an outlet tube for argon and an addition funnel. The outlet pipe is connected to a gas bottle filled with a sodium hypochlorite solution in order to separate entrained 50 mercaptan. A solution of 3 to 3.7 ml (0.041 to 0.07 mol) of the corresponding alkyl mercaptan in 300 ml of methanol is passed through the addition funnel with 10 g (0.03 mol) of l-phenyl-2,3,4,5-tetrahydro -lH-3-benzazepine - 7,8-dione hydrobromide added. The addition is made in portions such that the initially intense brick-red color of the solution changes to light orange before each subsequent addition. In this way, the addition is complete within about 10 minutes. The yellowish solution thus obtained is stirred for a further 15 to 30 minutes and then evaporated under 60 reduced pressure. The oily residue is chromatographed on silica gel and eluted with a gradient of 5 to 15% methanol in chloroform. The quantitative ratio of the 6- and 9-isomers is about 1: 2 and the 6-isomer is eluted first. However, further chromatography is usually required to complete separation. Although the raw yield is relatively high, the yield of the pure isomers is relatively low.

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The melting points, analytical values and yields of the isomers obtained in the form of the hydrobromides are summarized below.

Connection o

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found

Exploit

9-n BuS

191-192

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56.60

56.42

14.9%

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6.18

6.31

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3.30

3.22

6-n BuS

197

C.

56.60

56.94

9.6%

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6.18

6.29

N

3.30

3.45

9-i-PrS-

245-246

C.

55.07

54.72

25.6%

H

5.95

5.79

N

3.38

3.30

6-i-PrS-

269-270

C.

55.61

55.38

18.7%

H

5.89

6.16

N

3.41

3.34

9-EtS-

287

C.

54.55

54.32

13.4%

(Dec.)

H

5.59

5.71

N

3.53

3.20

6-EtS

215-217

C.

54.44

54.42

15.1%

(Dec.)

H

5.59

5.72

N

3.53

3.21

A mixture of 10 g trifluoromethyl disulfide and a stoichiometric amount of dithioerythritol in methanol is left at room temperature until the reaction is complete. The reaction mixture is then used as a source of a trifluoromethylthio compound in the process described above for the preparation of l-phenyl-2,3,4,5-tetrahydro-6-trifluoromethylthio-7,8-dihydroxy-lH-3-benz-azepine hydrobromide used.

The bases of the salts listed above are prepared by treating the salts in a mixture of sodium bicarbonate solution and methylene dichloride, separating the organic phase and evaporating the organic solution under reduced pressure.

Example 3

3.7 g (0.0145 mol) of l-phenyl-2,3,4,5-tetrahydro-7,8-di-hydroxy-1H-3-benzazepine are slurried in 25 ml of acetone and mixed with 0.07 g ( 0.016 mol; 10% excess) of ethylene oxide. The mixture is placed in a pressure bottle and stirred at room temperature for 40 hours. The reaction mixture is then heated to 60 to 80 ° C. for 30 minutes, then cooled and filtered. The filtrate is evaporated. 4.5 g of a crystalline solid are obtained. This solid is taken up in ethyl acetate, precipitated by adding diethyl ether and converted into the hydrochloride in ethanol by means of a solution of hydrogen chloride in diethyl ether. The hydrochloride is precipitated by adding diethyl ether. After filtering off and drying, 3.0 g (60% of theory) of l-phenylene-2,3,4,5-tetrahydro-3- (β-hydroxyethyl) -7,8-dihydroxy-1H-3 -benzazepine hydrochloride obtained. After recrystallization from a mixture of ethanol and diethyl ether, 1.9 g (38% of theory) of the compound of mp 136 to 137 ° C. are obtained.

1.5 g of the β-hydroxyethyl compound thus obtained are reacted according to Example 1 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in methanol. The l-phenyl-2,3,4,5-tetrahydro-3- (β-hydroxyethyl) -lH-3-benzazepine-7,8-dione-

-hydrobromide obtained. 1 g of this compound is converted according to Example 1 with methyl mercaptan in methanol to 1-phenyl-2,3,4,5-tetrahydro-3- (ß-hydroxyethyl) -6-methylthio-7,8 - dihydroxy-1H-3- implemented benzazepine hydrobromide.

Example 4

A mixture of 25 g (0.0874 mol) of 2-methoxy-2- (m-trifluoromethylphenyl) ethyl bromide and 75 ml of 2- (3,4-di-methoxyphenyl) ethylamine are used as protective gas for 2 hours with stirring and under nitrogen heated to 93 to 95 ° C. After cooling, the 2- (3,4-dimethoxyphenyl) ethylamine hydrobromide crystallizes out. The product is filtered off. Yield 21.3 g. The filtrate is fractionally distilled under reduced pressure. The fraction boiling at 207 to 232 ° C (1.3 to 2.0 torr) is collected and converted into the hydrochloride in diethyl ether. The hydrochloride thus obtained is recrystallized from a mixture of acetonitrile and diethyl ether. There are 14.5 g (40% of theory) of N- [2-methoxy-2- (m-trifluoromethylphenyl) ethyl] -N-2- (3 ', 4'-dimethoxyphenyl) ethylamine hydrochloride from F. 157 to 160 ° C.

A 1.0 g sample (0.00238 mol) of this compound is added to 20 ml of 48 percent hydrobromic acid. The mixture is heated under reflux for 1 hour with stirring and under nitrogen as a protective gas. The solution is then cooled, evaporated to dryness under reduced pressure and the residue digested with diethyl ether. 1.0 g of a crystalline solid are obtained. Yield 89% of theory. The product is recrystallized from a mixture of ethanol and diethyl ether. The l- (m-trifluoromethylphenyl) -2,3,4,5-tetrahydro-7,8-dihydroxy-1H-3-benzazepine hydrobromide of mp 153 ° C. is obtained. The connection forms a glass.

1 g of the base are reacted with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in methanol to form the dione. Yield 0.5 g. The compound thus obtained is reacted with methyl mercaptan to give l- (m-trifluoromethylphenyl) -2,3,4,5-tetrahydro-6-methylthio-7,8-dihydroxy-lH-3-benzazepine hydrobromide.

Example 5

4.84 g (0.115 mol) of 57 percent sodium hydride are washed with hexane and then stirred with 70 ml of anhydrous dimethyl sulfoxide at 65 to 70 ° C. for 2 hours under argon as protective gas. The mixture is then diluted with 70 ml of anhydrous tetrahydrofuran, then cooled to -5 ° C and within 3 minutes with a solution of. 23.5 g (0.115 mol) of trimethylsulfonium iodide in 100 ml of anhydrous dimethyl sulfoxide. After stirring for 1 minute, 11.5 g (0.0926 mol) of o-tolualdehyde are introduced at a moderate rate, the temperature of the reaction mixture being adjusted to 0 to -5 ° C. The mixture is stirred for 5 minutes at 0 ° C. and for a further hour at room temperature, then diluted with 500 ml of ice water and extracted 3 times with diethyl ether. The ether solution is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The oily residue is distilled under reduced pressure (0.25 to 0.5 torr). 10.25 g (83% of theory) of o-methylstyrene oxide are obtained as a bright liquid with a boiling point of 35 to 38 ° C.

A mixture of 13.6 g (0.0753 mol) of homoveratrylamine and 10.1 g (0.0753 mol) of o-methylstyrene oxide is heated and stirred at 100 ° C. under argon as a protective gas for 16 hours. The reaction mixture is then diluted with benzene and hexane and cooled in an ice bath. The precipitated crystals are filtered off and recrystallized from a mixture of benzene and hexane. 8.6 g (36%

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That is, 2-methyl-a- [N- (3,4-dimethoxyphenethyl) aminomethyl] -benzyl alcohol of melting point 91 to 94 ° C.

A mixture of 8.5 g (0.0269 mol) of 2-methyl-a- [N- (3,4-dimethoxyphenethyl) aminomethyl] benzyl alcohol in 58 ml of 48 percent hydrobromic acid is heated under reflux under argon as a protective gas for 2 hours . After cooling, the product formed is filtered off and recrystallized once from a mixture of ethanol and ethyl acetate. 6.7 g (69% of theory) of l- (2-methylphenyl) -7.8-dihydroxy-2,3,4,5-tetrahydro-lH-3-benzazepine hydrobromide as a hemihydrate of F Obtained 232 to 233 ° C.

5 g of the compound obtained are oxidized according to Example 1 with 1,4-benzoquinone. The l- (2-methylphenyl) -2,3,4,5-tetrahydro-lH-3-benzazepine-7,8-dione is obtained.

2 g of this compound are reacted with methyl mercaptan in methanol to give 1- (2-methylphenyl) -2,3,4,5-tetrahydro-6-methyl-thio-7,8-dihydroxy-1H-3-benzazepine hydrobromide.

If m-methylstyrene oxide is used, the corresponding 7,8-dihydroxycer bond is from 108 ° to 110 ° C., then the 7,8-dione and finally the l- (3-methylphenyl) - 2,3,4,5- tetrahydro-6-methylthio-7,8-dihydroxy-1H-3-benz-azepine hydrobromide obtained.

Using m-methoxystyrene oxide, the 7,8-dihydroxy-m-hydroxyphenyl compound (F. of hydrobromide 285 ° C), then the 7,8-dione and finally the l- (3-hydroxyphenyl) -2,3 , 4,5-tetrahydro-6-methylthio-7,8-dihydroxy-1H-3-benzazepine.

Using p-chlorostyrene oxide, the corresponding 7,8-dihydroxy-p-chlorophenyl compound is melting at 156-164 ° C, then the 7,8-dione and finally the l- (pl-chlorophenyl) -2,3,4,5 -tetrahydro-6-methylthio-7,8-dihy-droxy-lH-3-benzazepine hydrobromide.

Using p-trifluoromethylstyrene oxide, the corresponding 7,8-dihydroxy-p-trifluoromethylphenyl compound, then the dione and finally the l- (p-trifluoromethylphenyl) -2,3,4,5-tetrahydro-6-methylthio -7,8-dihy-droxy-lH-3-benzazepine hydrobromide obtained.

Example 6

A slurry of 3.3 g (0.019 mol) of 1-phenyl-2,3,4,5-tetrahydro-7,8-dihydroxy-1H-3-benzazepine in 40 ml of anhydrous acetone is mixed with 4.0 g of anhydrous potassium -carbonate added. The mixture is stirred under nitrogen, mixed with a small amount of ascorbic acid as an antioxidant, then cooled to 0 ° C. and mixed with 1.57 g (0.0129 mol) of allyl bromide. The mixture becomes 2 to

Stirred in the cold for 3 hours, then warmed to room temperature and stirred for a further 12 hours. The mixture is then heated under reflux for 30 minutes and then cooled, poured into water and extracted 3 times with ethyl acetate. The ethyl acetate extracts are combined and evaporated. 2.7 g (71% crude yield) of a solid are obtained. The solid is taken up in boiling ether and the solution obtained is left to stand for several hours. The solution is then filtered off from a small amount of a precipitate. An ether solution of hydrogen chloride is added to the filtrate, and the precipitated hydrochloride is filtered off and dried. 2.0 g of an amorphous but not hygroscopic residue are obtained. The solid is digested with hot ethyl acetate and then recrystallized from a mixture of ethanol and ethyl acetate. 0.85 g of crystalline l-phenyl-2,3,4,5-tetrahydro-3-allyl-7,8-dihydroxy-1H- -3-benzazepine hydrochloride obtained from F. 232 to 234 ° C (dec.).

This compound is reacted with quinone to the corresponding 7,8-dione. After reacting this compound with methyl mercaptan in methanol, the l-phenyl-2,3,4,5-

-tetrahydro-3-allyl-6-methylthio-7,8-dihydroxy-1H-3-benz-azepine obtained.

When using the 3-methyl, 3-butyl (F. of hydrobromide 231 to 234 ° C) and the 3-benzyl compound, the l-phenyl-2,3,4,5-tetrahydro-3-methyl 6-methylthio, l-phenyl-2,3,4,5-tetrahydro-3-butyl-6-methylthio and the l-phenyl-2,3,4,5-tetrahydro-3-benzyl-6-methylthio 7,8-dihy-droxy-lH-3-benzazepine obtained. When using phen-ethyl bromide, the corresponding 3-phenethyl-6-methyl-thio compound is obtained.

Example 7

5 g of l-phenyl-2,3,4,5-tetrahydro-6-methylthio-7,8-dihydroxy-lH-3-benzazepine are, according to Example 1, at room temperature with 2,3-dichloro-4,5- Dicyano-l, 4-benzoquinone oxidized in methanol. There are 1 g of l-phenyl-2,3,4,5-tetra-hydro-6-methylthio-lH-3-benzazepine-7,8-dione obtained, which with methyl mercaptan in methanol to l-phenyl-2,3 , 4,5 - tetrahydro-6,9-dimethylthio-7,8-dihydroxy-1H-3-benzazepine is reacted.

Example 8

In a solution of 280 g (0.75 mol) of l-phenyl-2,3,4,5-tetrahydro-7,8-dimethoxy-1H-3-benzazepine in 1700 ml of acetic acid, 280 g (1.75 mol ) Bromine introduced into thin stream. The reaction mixture is stirred for 2 hours. The precipitate formed after 1 hour is filtered off and washed with diethyl ether. This precipitate is dissolved in boiling methanol and acetone is added to remove the excess bromine. The resulting 1-phenyl - 2,3,4,5-tetrahydro-6-bromo-7,8-dimethoxy-1H-3-benzazepine - hydrobromide crystallizes out of the methanol solution. A second crop is obtained after adding diethyl ether to the mother liquor. The total yield is 298 g (77% of theory). The compound melts at 236 to 238 ° C. This bromination can be applied to any 7,8-dialkoxy or -Al-kanoyloxybenzazepine which has a free 6-position.

The hydrobromide is shaken in a mixture of excess 10% sodium hydroxide solution and methyl chloride. The organic phase is separated off, dried and evaporated. The base remains as a solid, which is recrystallized from a mixture of toluene and hexane. Yield 238 g (97% of theory) of melting point 125 to 128 ° C.

5 g of l-phenyl-3-trifluoroacetyl-2,3,4,5-tetrahydro-6-bromo-7,8-dimethyloxy-lH-3-benzazepine (prepared by reacting the compound described above with trifluoroacetic anhydride in benzene ) is reacted with excess butyllithium in diethyl ether at -78 ° C. The 6-lithium salt of the 3-trifluoroacetylbutyl lithium adduct is obtained. This intermediate product is heated under reflux with excess dimethyl disulfide in diethyl ether for 15 to 18 hours without isolation. After hydrolysis with water, the l-phenyl-2,3,4,5-tetrahydro-6-methylthio-7,8-dimethoxy-lH-3-benzazepine is obtained. Other disulfides can also be used, especially di (tri-fluoromethyl) disulfide, as well as other N-alkylated or N-acylated benzazepines.

Example 9

2- (2-Methylthio-3,4-dimethoxyphenyl) ethylamine is prepared from 2-chloro-veratrum aldehyde (cf. LC Raiford and RP Perry, J. Org. Chem., Vol. 7 (1942), p. 354), that first the ethylene acetal (from ethylene glycol by acid catalysis and azeotropic separation of the water) is produced, which is then processed with the Grignard

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Compound of magnesium and dibromoethane is reacted in refluxing benzene. The compound obtained is then reacted with dimethyl sulfide. Hydrolysis of the acetal with refluxing aqueous acetic acid gives the 2-methylthioveratrumaldehyde, which is condensed with nitromethane. The product obtained is reduced with lithium aluminum hydride to phenethylamine.

26 g of 2- (2-methylthio-3,4-dimethoxyphenyl) ethylamine are heated to 115 ° C. in an oil bath. Then 14.4 g of styrene oxide are added and the mixture is heated for a further hour. After cooling to 30 ° C, a mixture of hexane and ethyl acetate is added. The N- (2-hydroxy-2-phenylethyl) -N- [2- (2'-methylthio-3 ', 4' - dimethoxyphenyl) ethyl] amine is precipitated.

15 g of this compound are dissolved in a 2: 1 mixture of acetic acid and concentrated hydrochloric acid and heated under reflux for 2 hours. After cooling, most of the volatile compounds are distilled off and the residue is poured into water. The aqueous mixture is made alkaline with 50 percent sodium bicarbonate solution and extracted twice with ethyl acetate. The ethyl acetate extracts are combined, washed with brine, dried and evaporated. The 1-phenyl-2,3,4,5-tetrahydro-6-methylthio-7,8-dimethoxy-1H-3-benzazepine is obtained.

Example 10

A suspension of 5.0 g of 1-phenyl-2,3,4,5-tetrahydro-6-methylthio-7,8-dihydroxy-1H-3-benzazepine in 50 ml of benzene is rapidly added dropwise with 15 g of trifluoroacetic anhydride transferred. The solution obtained is stirred for a further hour. Volatile compounds are then distilled off. The N, 0,0-tris-trifluoroacetyl derivative is left behind. This product is taken up in 50 ml of methanol and hydrogen chloride gas is bubbled into the solution for a few minutes. The mixture is stirred for 2 hours. The solvent is then distilled off. The l-phenyl-3-trifluoroacetyl-2,3,4,5-tetrahydro-6-methylthio - 7,8-dihydroxy-lH-3-benzazepine remains.

3 g of the compound obtained are reacted with excess methyl iodide in the presence of sodium carbonate in aqueous ethanol at room temperature. The resulting crude 7,8-dimethoxy-6-dimethylsulfonium iodide is isolated by evaporation and then heated under reflux in saline for 2 hours. The volatile compounds are then distilled off, and the residue is recrystallized. The l-phenyl-3-trifluoroacetyl-2,3,4,5-tetrahydro-6-methylthio-7,8-dimethoxy-lH-3-benz-azepine is obtained. The N-acyl group is removed by treatment with a 5 percent solution of sodium hydroxide in aqueous methanol at room temperature. The l-phenyl-2,3,4,5-tetrahydro-6-methylthio-7,8-dimethoxy-lH-3-benzazepine is obtained.

Example 11

A solution of 5 g of l-phenyl-2,3,4,5-tetrahydro-6-methylthio-7,8-dihydroxy-lH-3-benzazepine hydrobromide in trifluoroacetic acid is mixed with a stoichiometric amount of acetyl chloride in the Cold implemented. The reaction mixture is poured into brine and extracted with ethyl acetate. The ethyl acetate extract is evaporated. The corresponding 7,8-diacetoxy derivative is obtained. If other alkanoyl hydrides or chlorides are used, the corresponding 7,8-dialkanoyl derivatives are obtained.

Example 12

A solution of 7.10 g (18.6 mmol) of 7,8-dihydroxy-1-phenyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine - hydrobromide in 120 ml of aqueous Dimethylformamide is adjusted to a pH of 10.0 at 0 ° C. under argon as a protective gas with 10% sodium hydroxide solution. The cold mixture is then mixed in small portions with 13.0 g (76 mmol) of carbobenzyloxychloride within 15 minutes with the simultaneous addition of 10% sodium hydroxide solution, so that the pH remains at 10 to 10.5. The mixture is then stirred at 0 ° C for 1% hours and. then warmed to room temperature. The reaction mixture is then diluted with saturated sodium chloride solution and extracted 3 times with ethyl acetate. The ethyl acetate extracts are combined and extracted back twice with saturated sodium chloride solution. The ethyl acetate extract is dried and evaporated under reduced pressure and heated to 75 ° C./0.1 torr to remove residual benzyl alcohol.

The residue is taken up in 50 ml of glacial acetic acid, cooled to 15 ° C. and 14 ml of 40 percent peracetic acid are added at 10 to 15 ° C. in the course of 5 minutes. The solution obtained is warmed to room temperature and further portions of 40 percent peracetic acid are added to complete the oxidation to the sulfone. The reaction mixture is then poured into 800 ml of water and extracted 3 times with ethyl acetate. The ethyl acetate extracts are combined, washed twice with saturated saline, three times with 5 percent sodium bicarbonate solution and twice with saturated saline. Then the ethyl-30 acetate extract is dried, decolorized with activated carbon and evaporated under reduced pressure until the solvent is separated off. 12 g of the N-carbobenzyloxy-6-methylsulfonyl compound are obtained.

The protected sulfone is treated with 70 ml of 38 percent 35 hydrobromic acid in glacial acetic acid for 2 hours at room temperature (then the solution is added dropwise in 1 liter of strongly stirred anhydrous diethyl ether within 40 minutes. The supernatant solution is decanted from the precipitate formed washed with fresh diethyl ether and dried in a stream of nitrogen. l-Phenyl-2,3,4,5-tetrahydro-6-methyl-sulfonyl-7,8-dihydroxy-1H-3-benzazepine is obtained.

The corresponding 6-45 trifluoromethylsulfonyl compounds can be prepared from other starting compounds by the process described above.

Example 13

A 5 ° C cold solution of 8.6 g (20 mmol) of 1-phenyl-3-acetyl-2,3,4,5-tetrahydro-6-methylthio-7,8-diacetoxy-lH-50 -3- benzazepine (prepared by reacting the dihydroxy compound with excess acetic anhydride in pyridine at room temperature) in 40 ml of methanol is added dropwise within 40 minutes at 0 ° C. with 40 ml of a 0.52M sodium periodate solution (20.8 mmol). The mixture 55 is left in the cold for 15 to 18 hours. The precipitate formed is then filtered off and washed with methylene chloride. The organic extracts are combined, dried and evaporated under reduced pressure. The residue is refluxed in a solution of chlorine-60 hydrogen in ethanol for 15 to 18 hours. The volatile compounds are then distilled off and the residue is taken up in water. After neutralization with ammonia and extraction with ethyl acetate, the l-phenyl-2,3,4,5-tetrahydro-6-me-65 thylsulfinyl-7,8-dihydroxy-1H-3-benzazepine is obtained. The hydrochloride is produced by treatment with a solution of hydrogen chloride in diethyl ether.

v

Claims (12)

642 634 2. Compounds according to claim 1 of the general formula I, in which R3 denotes a hydrogen atom and R denotes a methylthio or trifluoromethylthio group. 2nd PATENT CLAIMS 1. l-phenyl-2,3,4,5-tetrahydro-7,8-dihydroxy-lH-3-benz-azepines of the general formula I R XO ' NO- in which R and R3 represent a hydrogen atom, an alkylthio, alkylsulfinyl, alkylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl or trifuormethylslufonyl group, but the radicals R and R3 do not simultaneously represent hydrogen atoms, Rt is a hydrogen atom, an alkyl , C3_5-alkenyl, hydroxyethyl, benzyl, phenethyl, carbobenzyloxy or alkanoyl group, R2 is a hydrogen or halogen atom, a trifluoromethyl, methyl, methoxy or hydroxyl group and X is a hydrogen atom or an alkyl or alkanoyl group, where all alkyl and alkanoyl groups contain 1 to 5 carbon atoms, their salts with acids and their quaternary ammonium salts. 3. Compounds according to claim 1 of the general formula I, in which R3 is a methylthio group and R and Rj are hydrogen atoms. 4. Compounds according to claim 3 of the general formula I, in which R ^ represents a hydrogen atom. 5. Compounds according to claim 1 of the general formula I, in which Rx and R3 are hydrogen atoms, R is a methylthio or trifluoromethylthio group and R2 is a hydrogen or chlorine atom, a methyl, trifluoromethyl, methoxy or hydroxyl group. 6. Compounds according to claim 1 of the general formula I, in which one of the radicals R and R3 is a methylthio group and the other radical is a hydrogen atom and Ri and R2 are hydrogen atoms. 7. Compounds according to claim 1 of the general formula I, in which one of the radicals R and R3 is a methylthio group and the other radical is a hydrogen atom, Rt is a methyl group and R2 is a hydrogen atom. 8. Compounds according to claim 6 in the form of the hydrobromides. 9. Compounds according to claim 6 in the form of the free bases. 10. A process for the preparation of the compounds of the general formula I as claimed in claim 1, in which X denotes a hydrogen atom and one of the symbols R and R3 denotes an alkylthio or trifluoromethylthio group and the other symbol denotes a hydrogen atom, characterized in that an l- Phenyl-2,3,4,5-tetrahydro-lH-3-benz-azepine-7,8-dione of the general formula II YY \ O — I ^ n-R ^ / (II) O"** in which Rj and R2 have the meaning given in claim 1, with a mercaptan of the general formula R'-SH, in which R 'is alkyl or trifluoromethyl, and optionally converting the compound obtained with an acid into a salt. 11. A process for the preparation of the compounds of general formula I according to claim 1, in which X denotes an alkyl group containing 1 to 5 carbon atoms and one of the symbols R and R3 denotes an alkylthio or trifluoromethylthio group and the other symbol denotes a hydrogen atom, characterized in that a compound of the general formula I in which X, R and R3 have the meanings given in claim 10 is prepared by the process according to claim 10 and the compound thus obtained is reacted with an alkylating agent containing 1 to 5 carbon atoms and optionally the compound obtained with an acid is converted into a salt. 12. A process for the preparation of the compounds of the general formula I according to claim 1, in which X denotes an alkanoyl group containing 1 to 5 carbon atoms and one of the symbols R and R3 denotes an alkylthio or trifluoromethylthio group and the other symbol denotes a hydrogen atom, characterized in that a compound of the general formula I in which X, R and R3 have the meanings given in claim 10 is prepared by the process according to claim 10 and the compound thus obtained is reacted with an acylating agent containing 1 to 5 carbon atoms and, if appropriate, the compound obtained converted into a salt with an acid.