NL7807819A - Pharmaceutically active benzazepine cpds. - specifically, substd. 1-thienyl and furyl-2,34,5-tetra:hydro-1H-3-benzazepine(s) - Google Patents

Abstract

Thienyl or furyl 3-benzazepine derivs. of the formula (I) and their salts are new: (where R = H, phenethyl, benzyl, 1-5 C alkanoyl (incl. HCO-, CH3CO-, CF3CO-), 1-5 C alkyl, HOCH2CH2 or 3-5 C alkenyl; R1 = H, halo, CF3-, methylthio, CF3S-, CH3 or CH3O; R2 and R3 = H, 1-5 C alkyl or 2-5 C alkanoyl, or together form -CH2- or -CH2CH2-; R4 = H, halo, -CH2CN, -COOCH3 or CH3; X = O or S).

Description

/ - W "· 1¾ *: 'i VO 5490

Smithkline Corporation, PHILADELPHIA, Pennsylvania, United States of America

Substituted 1-thienyl and furyl-2,3,4t5-tetrahydro-1H-3-benzazepine compounds having, inter alia, cardiovascular activity.

The invention encompasses a new group of compounds characterized by that the 1-thienyl- and 1-furyl-2,3,4,5-t8-trahydro-1H-3-benzazepines which are 2 hydroxyl substituents in the benz ring of the benzazepine core. These new compounds are especially useful as cardiovascular agents because of their peripheral dopaminergic activity. They also show activity in animal experiments that serve to activity at the central dopamine receptors to predict anti-parkinsonism.

In general, therefore, it can be said that they have salient peripheral as central dopaminergic activity.

The structures of the compounds of the invention are specifically characterized by having a thienyl or furyl hetero ring in the 1-position of the 2,3,4,5-tetrahydro-1H-3-benzazepine system. Examples of these new group 15 compounds are those represented by formulas (1), wherein: R = hydrogen, phenethyl, benzyl, lower alkanoyl of 1-5 carbon atoms, such as formyl, acetyl or trifluoroacstyl, lower alkyl of 1-5 carbon atoms, hydroxyethyl or lower 20 alkenyl of 3-5 carbon atoms; R 2 = hydrogen, halogen, trifluoromethyl, lower alkyl thio, such as methylthio or ethylthio, trifluoromethylthio, methyl or methoxy; R 2 and R 3 are each hydrogen, lower alkyl of 1 to 5 carbon-25 atoms, lower alkanoyl of 2 to 5 carbon atoms or, taken together, methylene or ethylsen; R 2 is hydrogen, halogen such as F, Cl or Br, cyanomethyl, carbomethoxy or methyl and X = -O- or -S-.

V 7807819 <2

The above structural formulas show that the hetero ring is attached in its 2 '(alpha) or 3' (beta) position. The substituents on both hetero rings are limited only by the rules of furan or thiophene chemistry, but they are of course attached to C atoms.

The thienyl compounds are preferred, since dB furyl compounds of this type are sometimes less active and more toxic than the corresponding thienyl compounds.

A subset of compounds within the above main group includes the compounds of formula (1) u / aarin: R = hydrogen or methyl; R ^ = hydrogen or chlorine; R 2 and R 2 are the same and represent u / atoms, methyl or acetyl; 15 R ^ u / ater or methyl and X = S.

The compounds of the invention may also contain a fourth benzo substituent, e.g. in the 9th position, but it has never been found that these have any advantage from a biological point of view. The compounds [alpha] R <2> and R <1> are higher alkyl or alkanoyl groups or form an alkylene chain such as the methylenedioxy-containing compounds at the 7.8 positions, and the N-benzyl, phenethyl or alkanoyl-containing species are of great importance as intermediates . Flethylenedioxy-3-25 benzazepines of another group are disclosed in U.S. Pat. No. 3,795,683.

The pharmaceutically acceptable acid addition salts which are as useful as the free bases of the formula (1) and which are obtained in known manner, are prepared using inorganic or organic acids, such as, for example: maleic acid, fumaric acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, bismethylene-salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, itaconic acid 7807819

X

J * 3 * Benzenesulfonic Acid, Hydrogen Chloride and Water Bromide Acid, Sulfuric Acid, Cyclohexyl Sulfamic Acid, Phosphorus and Nitric Acid.

The quaternary salts include those prepared from organic halides such as methyl iodide, ethyl iodide or benzyl chloride, methyl tosylate or mesylate found at the basic 3 center or at a reactive thio center. While the 1-furylbenzazepines readily form salts with strong inorganic acids such as sulfuric acid or hydrochloric acid, such salts are less stable and difficult to purify, for each of which the furyl-containing compounds are best as the base or as the salt of an organic or organic inorganic acid can be used.

Certain 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines are described in U.S. Pat. No. 3,393,192, in British Pat. No. 1 11B 68B and in Swiss Pat. No. 15,555,831, including general preparation methods.

However, no 1-heteroge substituted compounds are described herein.

It will be apparent to those skilled in the art that the compounds of formula (1) may exist in the form of diastersoisomers which can be split into d or i optical isomers.

The cleavage of optical isomers can conveniently be effected by fractional crystallization of the salts of the base or of its solid derivatives with optically active acids from suitable solvents. Unless otherwise stated, in this description and claims all isomers, whether separated or mixed, are meant. When the isomers are separated, usually one of the isomers is most pharmacologically active, usually the d-isomer.

The compounds of formula (1) wherein R is a hydrogen atom are generally prepared from intermediates of formula (3) wherein R = hydrogen, lower alkyl, benzyl or lower alkenyl; R ^ and X meet the above description; R 2 ΒΠ R 3 * 39 θ alkyl 2 form together a lower alkylene group and R 3 = hydrogen or a chemically inert substituent from the above-described group, by means of an intramolular cyclization which is effected by reaction with a reaction component such as sulfuric acid alone or mixed with suitable solvents such as trifluoroacetic acid, polyphosphoric acid or the like dehydrating agent.

Mixed compounds substituted with alkoxygrospen are prepared by selecting the appropriate heteroarylethylamine starting material.

The cyclization is best carried out in such a way that the methylenedioxy or dimethoxy ethers are formed, after which these ether groups can be optionally treated by means of a mild cleavage agent such as boron trichloride for the methylenedioxy or tribromide for the dimethoxy ether are removed.

The heteroarylethylamines (4) used as starting materials for this method are known compounds or are prepared by similar methods as described in the illustrative examples.

The 6-substituted compounds are optionally prepared by a 7,8-dihydroxy-1- (furyl or trienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine with 2,3-dichloro-5,6- dicyano-1,4-20 benzoquinone or the like hydroquinone oxidizing agent to oxidize to 7,8-dione. This is then reacted with a quinone additive, a "neucleophic" reagent such as methyl mercaptan, trifluoromethyl mercaptan, hydrogen chloride or hydrogen bromide (in case there are no acid sensitive groups) in methanol at about room temperature, giving the desired 6- substituted compound is obtained.

The 6-bromine-containing compound can, if desired, in many cases be used as an intermediate for e.g. the preparation of 6-chloro or 6-iodine counterparts or the 6-lithium intermediates.

The latter lithium compounds can be reacted with a number of other conventional reactants to introduce 6-substituents such as with iodine or hexachloroethane to introduce iodine or chlorine.

To prepare the compounds of ds formula (1) in which R is hydroxy-35 ethyl, lower alkyl or lower alkenyl, the Q 7807819 - * 5 corresponding benzazepines in which R is a hydrogen atom according to known processes with ethylene oxide, are a reactive lower alkyl halide such as the bromide or chloride or a reactive alkenyl halide such as an allyl bromide or chloride alkylated.

To prepare the products in which R 2 and / or hydrogen are, the reaction with the alkylating agent with the corresponding methoxy-substituted benzazepines in an inert solvent such as methanol or acetone is preferably done, preferably at reflux temperature and in 1G absence of a basic condensing agent such as potassium hydroxide or potassium carbonate *. By the product thus obtained with e.g. to treat boron tribromide or other ether-splitting agents, the active hydroxyl-substituted benzazepines are obtained. When a reactive center such as a methylthio group is present, the quaternary sulfonium salt is obtained. If desired, this can be reconverted into the methylthio salt by heating it with a table salt solution, 1N hydrogen bromic acid or another source of halogen ion.

The 3-methyl species are an important part of the invention.

The compounds of formula (1) wherein R is a methyl group are conveniently prepared from 7,8-dimethoxy-substituted benzazepines in which R is a hydrogen atom by reacting them with formic acid / formaldehyde. Treatment of the product thus obtained with boron tribromide yields the corresponding 7,8-dihydroxy-substituted benzazepines. Another method for preparing the important N-methyl compounds is the conversion of the 3-hydrogen compound into the N-formyl classmate, after which it is converted by means of lithium aluminum hydride 30 u / d reduced; therefore a reaction in 2 steps.

The dialkanoyloxy derivatives such as the major 7,8-diacetoxy compounds can also be prepared by direct O-acylation of the dihydroxy compound whose N-position is blocked by protonation, such as using the 6-halo-7,8-dihydroxy- 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7807819/6 hydrobromide in trifluoroacetic acid at ambient temperature with the anhydride or halide. The N or 3-lower alkanoyl counterparts in the dihydroxy series are suitably prepared by N-acylation of the methoxy or methylenedioxy derivative followed by cleavage of the protecting group by boron tribromide or chloride.

Direct N-alkanoylation of the dihydroxy compounds under controlled conditions is also possible by allowing the appropriate amounts of reactants known in the art to act.

As noted in the illustrative examples, any 1G may require undesired Q acylation hydrolysis under mild conditions.

The intermediates of formula (3) are suitably prepared by heating equimolar amounts of an epoxyethylthiophene or furan with a 3,4-dialkoxyphenethylamine known or prepared in the art and each is appropriately substituted, which reaction may or may not proceed in an inert organic solvent such as tetrahydrofuran. It is preferably heated on a steam bath or at reflux temperature for 12-24 hours. The desired ethylene oxide is conveniently prepared by reacting the heteroaldehyde with sodium hydride / trimethylsulfonium iodide.

The compounds of the invention may conveniently be prepared in a reaction which the applicant considers to be original and hitherto unknown in the benzazepine chemistry (Reaction Scheme (A)).

The 1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepines of the formula (4) are reacted with compounds (5) in which R-R 1 and X meet the above description. It will be appreciated by those skilled in the art that certain compounds such as thiophene will react at the site adjacent to the hetero ring member until said site is present. The method is e.g. very suitable for preparing 2 * -thienyl compounds. The reaction can also be run so that mixtures of mono and polysubstituted products are formed which can be separated in known manner. If 1 or both 35 alpha sites are occupied in the hetero ring, then the reaction proceeds at the remaining alpha site or at the beta site.

The reaction can also be carried out by starting from the compound of the formula (4), but instead of using a heterocyclic compound (5) benzene which has activating groups such as phenol or anisole, the results are substituted by substituted 1-phenylbenzazepines. RR ^ meet the above description, but for convenience, the 1-hydroxy-benzazepines are used in the form of the diether (eg R2, R ^ = methyl or, together, methylene) with or without protected N or 3 position as in the art known N-protecting groups, e.g. benzyl or carbobenzoxy, but the 3-material compounds are formed.

leave the reaction at ambient temperature, e.g. at room temperature, for an appropriate time, e.g. 1-24 hours expired. A laboratory test at room temperature overnight is a suitable time course. As the solvent, (optionally an excess of) an inert organic solvent is chosen in which the reaction components are soluble, such as e.g. trifluoroacetic acid, methylene chloride, trichlorethylene, chloroform or tetrachloromethane. Also, at least 1 equivalent of an acidic catalyst such as trifluoroacetic acid, sulfuric acid, boron trifluoroetherate, etc. should be present. Certain 1-hydroxy or alkoxy-benzazepines are known in the art} see e.g. G, Hazebroucq,

Compt. Run. 257, 923 (1963) (C.A. 59 ', 12759) or 3. Likforman,

Compt. Run. 268, 2340 (1969) (C.A. 7J [, 6.1184). However, the specific 1-hydroxy-7,8-dihydroxy-benzazepine starting materials used herein are new and prepared according to the methods described in the examples.

The active dopaminergic compounds of the invention used herein stimulate peripheral dopamine receptors; they increase e.g. the flow of blood through the kidneys and ultimately lower blood pressure. This blood vessel-avoiding activity of the benzazepine compounds of formula (1) is determined in an anesthetized dog.

In this pharmacological test, 5-fold increments of 3 fold each time, starting from 0.1 mcg / kg / min to 810 mcg / kg / min, under anesthetic normo W 7807819 / / «8 Dogs are administered in accordance with the following parameters: arterial blood flow through the kidneys, arterial blood flow through the ileum, arterial blood pressure and number of heartbeats. The results were reported as percent change, increase or decrease, at peak response (compared to the u / s obtained before administration of the drugs u / s), with renal blood flow significantly increasing ( increase) and the resistance in the blood vessels of the kidneys (decrease) should be about $ 10 or more. The effect on resistance in the vessels of the kidneys can be calculated from the change in blood flow through the kidneys and blood pressure in the arteries. To determine the mechanism, the extent to which characteristic active renal dilatation compounds are blocked by bulbocapnine, which is a specific blocking agent for dopamine receptors of the kidneys, is investigated. Typical compounds of the formula (1) are, for example: 7,8-dihydroxy-1- (21-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide which has been administered in the manner described above at a dose of 30 mcg / kg reduced the resistance in the vessels of the kidneys by 30%; 7,8-dimethoxy-1- (5'-methyl-2'-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydroxide having an ED µg of 2.3 mcg / kg ; 7,8-dihydroxy-1- (3 * -thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide having an ED 4 g of 40; and the 5-methyl-2-thienyl by 50. ED / g is therefore the cumulative dose which upon administration decreases the resistance in the renal vessels by 15%. (R = - ‘•„ P ^ / ^ 9) x B.F. cm3 / min * * In addition to vasodilatory activity on the kidneys of the kidneys via a dopaminergic effect, certain benzazopine compounds of formula (1) are found to have weak diuretic activity. Such a diuretic activity is determined by the normalized rat salt loaded with table salt. A compound to be tested is injected i.p. administered in doses of 10 to 40 mg / kg and the parameters determined are urine volume (per hour for 3 hours), as well as sodium 35 and potassium content. You can also do usual diuretic V 7807819 9 4 '"" ΐ "Ψ * tests with dogs. 7,8-Dihydroxy-1- (2-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide tested in phosphate mannitol dogs caused a marked increase in renal plasma flow at a dose of only 5 10 and 20 µg / kg / min. i.v. Similar results were achieved at oral doses of 20 mg / kg.

The benzazepine compounds of formula (1) also exhibit some anti-parkinsonism activity due to central dopaminergic activity, as shown in an altered standard pharmacological animal test by Ungerstedt et al., In Brain Research 24, 1970, 485-. 493, described.

The method relies on drug induced rotation of rats that have major lesions on one side of the substantia nigra. Briefly, the test relies on the quantitative determination of rotational behavior in rats causing 6-hydroxydopamine injuries of the nigrostriatal dopamine system. A brain injury in the left substantia nigra results in the dopamine receptor in the left part of the tail becoming hypersensitive due to the degeneration of the nigral cell bodies caused. These injuries 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 to the injured side of the brain is used as a measure of the central dopaminergic activity of the drug.

Compounds that are known to be clinically effective in fighting parkinsonism, such as L-dopa and apomorphine, are also effective in rat rotation.

These compounds directly activate the dopamine receptors and cause rotation of the injured rat to the other side.

Rotational activity is defined as the ability of a compound to effect 500 rotations to the tsgen-35 side for 2 hours after, usually intraperitoneally (i.p.) administration. The dose required for this is called the RDggg earth.

Characteristic compounds of the formula (1) such as 7,8-dihydroxy-1- (2'-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, the 3'-thienyl and the 5 ' -methyl-3'-thienyl species-5 nuts are shown to show activity in animal experiments with rats, ip at 5.5 (ED / µg), 5 (active) and 1.5 (ED / µg) mg / kg, respectively. Furthermore, the compounds cause only minor emesis or stsrotyp behavior at doses that prove to be effective in rat rat experiments.

The pharmaceutical compositions of the invention having dopaminergic activity are prepared in conventional dosage units by a compound of the formula (1), an isomer or a pharmaceutically acceptable addition salt thereof in a non-toxic amount sufficient to treat in a patient who has man or an animal may be to produce the aforementioned pharmacodynamic activity, to be mixed with a non-toxic pharmaceutical carrier in known manner. The compositions preferably contain the active ingredient in an active but non-toxic amount comprised between about 25 mg and about 500 mg of the active ingredient per dosage unit, but this amount depends on the mild specific biological activity and the condition of the patient. Generally, smaller doses are required to stimulate central dopamine receptors than for peripheral receptors. The dosing units are administered 1-5 times per day.

The pharmaceutical vehicle can e.g. be a solid or a liquid. Examples of suitable solid vehicles are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, etc. Examples of liquid vehicles are syrup, peanut oil, olive oil, etc. The vehicle or excipient can also be a known material that delay the release of the active compound, such as glyceryl monostearate or glyceryl distearate, which may be added as such or together with mas or paraffin.

35 (KIen can administer a wide variety of pharmaceutical forms

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y \

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11 i fit: Will be e.g. If a vehicle for oral administration is used, the composition may be formulated into tablets, placed in powder or granular form into a hard gelatin capsule, or in the form of a medicament tablet or lozenge. The amount of solid vehicle can be very different, but is preferably 25 mg - 1 g. If a liquid vehicle is used, a syrup, emulsion soft gelatin capsule, sterile injection liquid, e.g. an ampoule or an aqueous or non-aqueous liquid suspension.

The pharmaceutical preparations are prepared in the usual manner by mixing, granulating and, if necessary, compressing, or mixing and dissolving the ingredients, whereby the final product is obtained.

The method of inducing dopaminergic activity according to the invention comprises administering to a patient in need of this activity internally a compound of the formula (1) or a pharmaceutically acceptable acid addition salt thereof, usually in combination with a pharmaceutical vehicle, in a non-toxic amount sufficient to develop the above-described activity, fflen may administer the compositions in any manner which results in the active compound reaching the dopamine receptors to be stimulated, such as eg Orally or paranterally, although oral administration is preferred, fflen does well to administer equal doses 25 times, such as 9 e.g. 2 or 3 times a day with about 50 mg - about 2 g being administered per day. When using the method described above, blood pressure-lowering, diuretic or Parkinson's disease-fighting activity is deployed with a minimum of side effects.

The examples below serve only to illustrate preparation and use of the phenomena of the invention. Experts can come up with variations of these examples for themselves.

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7807819

12> EXAMPLE I

11flen stirred 4.84 g of sodium hydride (57% dispersion in mineral oil) after it had been washed with hexane to give the oil 3 hours, stirred in 70 cm of dry dimethyl sulfoxide and stirred at 65 for 1 h under an argon atmosphere. - 68 C heated. Thereby a clear greenish solution is obtained. The source of heat 3 was removed and 75 cm of dry tetrahydrofuran was added. The solution thus obtained was uddered in a methanol / ice bath cooled to 5 ° C, then 19 g (93 mol) of trimethyl-3-fulsonium iodide in 100 cm of dry dimethylsulfoxide was added in about 5 minutes, after all was added, the reaction mixture was added for another 5 minutes. stirred, limes slowly added a solution of 10.4 g (93 mmol) of 3 2-thiophene carboxaldehyde in 120 cm of tetrahydrofuran while the reaction mixture was kept at 0 ° to -5 ° C. When everything is added, the mixture is stirred for an additional 5 minutes and then stirred at room temperature for 1 hour, then diluted with 500 ml of iced water and extracted 4 times with ether. The combined extracts fumigated with saturated table salt solution and dried. 10.1 g of rutu 2-epoxyethylthiophene (a yellowish liquid) obtained by drying the drying agent and solvent yielded 8.1 g (69%) of a pale yellow liquid (boiling point 0.15 mm, 43-5 ° C) on vacuum distillation.

A mixture of 11.6 g (64 mmol) of horaoveratrylamine and 8.1 g (64 mmol) of 2-epoxyethylthiol or a mixture stirred at 100 ° C overnight under stirring under argon. The reaction mixture was cooled to room temperature and subjected to chromatography in a silica column (700 g) and eluted with benzene / ethyl acetate. In this way the witnessed product tuer'd separated from its isomer.

Recrystallization from ethyl acetate / hexane tuerd 3.6 g (18.4 $) of pure N- (beta-hydroxy-beta-2-thienyl) ethyl homoatatrylamine, m.p. of 102 ° C.

C16H21NO3S

Calculated $ 62.51; 6.89 $ H; 4.56 $ N ‘35 Found: 62.36 $ C; 6.69 $ H; 4.51 $ N

CL

780 7 8 1 9 13 '' ψ * 3.5 g (11.8 mmol) N- (beta-hydroxy-beta-2-thienyl) -3 ethyl homoatatrylamine was dissolved in a mixture of 36 cm 3 of acetic acid and 18 cm of conc . hydrochloric acid. The solution thus obtained was refluxed for 3 hours.

The reaction mixture is evaporated under reduced pressure to a brown residue, which is then suspended in 5% sodium carbonate solution and extracted thoroughly with ethyl acetate.

The extracts were combined, washed once with saturated saline and dried. By removing desiccant and dissolving sirtg, 3.3 g of a thick oily residue (96% yield) were obtained; 1- (2'-thiethyl) -7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.

The above described method is the basic method of preparing the compound of the invention. Others may be prepared by replacing equivalent amounts of the 2'-thienyl reactants used in said reaction with the appropriate heterocyclic carboxaldehyde or ethyl epoxide.

This compound can also be prepared by adding 8.9 g of 20 (40 mmol) 1-hydroxy-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-3-3 benzazepine with 5 cm thiophene in 45 cm Treat tri-fluoroacetic acid overnight at room temperature under argon. After the volatile components. by means of A stripping treatment was removed for 3 days, the residue was dissolved in 250 ml of 3N u / hydrogen chloride acid 25. This acidic solution was thoroughly extracted with ether, with conc. ammonia made alkaline and extracted 3 times with ethyl acetate. The extracts were combined 1 time with conc. saline solution and dried with u / anhydrous potassium carbonate. Removal of desiccant and solvent gave 9.2 g of the desired base in the form of an oily residue (81%).

A sample of this oily residue was dissolved in ethyl ether and a solution of hydrogen bromide in ether was added. An off-white precipitate was obtained. By recrystallization from methanol / ethyl acetate, the pure hydrobromide was m.p. of 215 ° C.

C16H19S02S * HBr

Calculated: 51.90% C; 5.44 $ H; 3.78 $ N Found: 52.10 $ C; 5.58 $ H; 3.65 $ N

EXAMPLE II

3.5 g (12 mmol) of 1- (2'-thienyl) -7,8-dimethoxy-2,3,4,5-3-tetrahydro-1H-3-benzazepine dissolved in 60 ml of methylene chloride were dissolved by means of a methanol / ice bath cooled to -12 ° C then dropwise 6 cm (62 mmol) boron tribromide added. The solution thus obtained was stirred at room temperature for 1.5 hours and was then evaporated under reduced pressure to a brown residue. The residue was cooled in ice and slowly treated with methanol. The methanol was evaporated under reduced pressure at room temperature. The residue was again treated with methanol and stripped in a 50 ° C warm water bath or other reduced pressure. This treatment is repeated 3 times. The final residue was udder on a silica column which was eluted with a 9: 1 mixture of chloroform / ethanol, chromatographed or dissolved in water, any undissolved material was filtered off and the aqueous filtrate was lyophilized to give pure 1- (2 1'-thienyl) -7,8-dihydroxy-2,3,4,5-tetrahydro-3-1H-benzazepine hydrobromide salt, m.p. 239-40 ° (decomposition) yielded about 70 $.

25C14H15NO2s * HBr

Calculated: 49.13 $ C; 4.71 $ H; 4.09 $ N; 9.37 $ S Found: 48.91 $ C; 4.59 $ H; 4.10 $ N; 9.10 $ 5 Nlen obtains the free base by dissolving the salt in a minimal amount of water and slowly adding a 5 $ 30 sodium bicarbonate solution until the base separates.

r 7807819 15

EXAMPLE III

3-Thiophene carboxaldehyde was prepared from 3-thenyl bromide according to the method known from the literature (Org. Syn. Call. Vol. IV p. 918-9) which in turn was prepared according to the method known from the literature (Org. Syn. Coll Vol IV IV 921-3) was obtained from 3-methylthiophene.

fflen stirred 11.7 g (0.28 mol) sodium hydride (57% dispersion in mineral oil which had been washed with hexane to remove the oil) for 2 hours at 50 - 65 ° C under an argon atmosphere with dry dimethyl sulfoxide (196 cm). The mix

was diluted with 196 ml dry tetrahydrofuran and to -5 ° C

cooled, then 57.12 g of trimethylsulfonium iodide (0.28 mol) 3 in 196 to add dry dimethyl sulfoxide at such a rate that the temperature of the reaction mixture is not above

O

15 0 C came. After all was added, stirring was continued for 1 minute, then 3 added 13.4 g (0.12 mol) of 3-thiophene carboxaldehyde in 84 cm of tetrahydrofuran. The methanol / ice bath was removed and the reaction mixture was kept at room temperature for 1.5 hours, then diluted with 1.1 ice water and extracted with ether 20 '. The extracts were combined, washed with a saturated sodium chloride solution and dried with anhydrous sodium sulfate. By removing the drying agent and solvent, 16.5 g of crude 3-epoxyethylthiophene were obtained. Since the spectral values (infrared = ir and nuclear magnetic resonance = 25 nmr) were satisfactory, the epoxy compound was used without further purification.

(KIen heated a mixture of 39.8 g (0.22 mol) of homo-veratrylamine and 24.8 g (0.195 mol) of 3-epoxyethylthiophene with stirring overnight at 100 ° C. The reaction mixture was stirred into room temperature. The temperature was cooled and stirred with 5% ethyl acetate in petrolsumether The solution was decanted and the crystals were washed 2 more times with the same solvent mixture to give N-ibeta-hydroxy-beta-S'-thienyl) ethyl homoveratrylamine was obtained. After recrystallization from ethyl acetate, 21.5 g of pure product, m.p. of 113 - 4 ° C (yield 36 $) 780 7 8 1 9 "16 obtained.

C16H21NO3S

Calculated: 62.51 ° C 6.89 $ H; 4.56 $ N

Found: 61.87 $ C; 6.92 $ Η; 4.65 $ N

9.2 g (30 mmol) of N- (beta-hydroxy-beta-3-3-thienyl) -ethylhomoveratrylamine were dissolved in 92 cm of acetic acid and 46 cm of concentrated hydrogen chloride. The mixture was refluxed for 3 hours and stripped under reduced pressure to a brown residue, which was then treated with 5% carbonate solution and extracted with ethyl acetate. The organic extracts were combined, rinsed twice with sodium chloride solution and dried over anhydrous sodium sulfate. By removing desiccant and solvent, 8.7 g thick oily residue (yield 99 $) 1- (3'-thienyl) -7,8-dimethoxy-2,3,4,5-15-tetrahydro-1H -3-Benzazepine obtained.

A sample of this free base was dissolved in methanol and ethereal hydrochloric acid was added until it was acidic. This acidic solution was evaporated to dryness.

The pure hydrochloride salt (mp 178 °) is obtained by recrystallization from raethanol-ethyl acetate.

5.25 g (18 mmol) of 1- (3'-thienyl) -7,8-3-dimethoxy-2,3,4,5-tetrahydro-3-1H-benzazepine, dissolved in 90 cm methylene chloride, was cooled by means of a methanol / ice bath to -12 ° and 3 added 9 cm of boron tribromide (93 mmol) dropwise. Onions 25 allowed the resulting solution to reach room temperature for 1 hour.

The solvent was stripped to yield a brown residue, which became. cooled and carefully treated with methanol. The methanol was evaporated under reduced pressure and the resulting residue was again treated with methanol and stripped at 50 °. This treatment was repeated three times to obtain 4.2 g of crude 1- (3'-thienyl) -7,8-dihydroxy-2,3,4,5-tetrahydro-3-1H-benzazepine hydrobromide. This was further purified by chromatography on silica, eluted with 9: 1 chloroform: methanol and dissolved in water, treated with charcoal and filtered. Freeze-drying the filtrate <\\ 780 78 1 9 f.

* 17 2.8 g of reddish-yellow-colored amorphous powder were obtained (mp. 254-6 ° dec.).

C14H15N02SH8r * V * Hz0

Calculated: 46.105 ° C; 5.11% Hj 3.845¾ N; 8.735¾ S

Found: 45.84% C; 4.89% H} 3.68% Nj 8.39% S

HOUR IMAGE IV

Hlen adds 117 g (1.1 mol) of benzaldehyde to 181 g (1 mol) of homoveratrylamine in 1 liter of ethanol. The mixture was stirred at room temperature for 15 minutes. Then, a solution of 100 g of potassium borohydride in 500 cm of cold material was slowly added, while the solution was kept near room temperature by external cooling. When the hydride solution was completely added, the reaction mixture was stirred for 5 hours, then cooled and acidified with 6.N hydrochloric acid. By cooling further to 0 °, the 1-benzyl homoveratrylamine hydrochloride salt precipitated, which was collected by filtration. The crude product was recrystallized from ethanol (mp 204-6 °).

Iflen suspended 44 grams (0.143 mol) of the N-benzyl-3 homoveratrylamine hydrochloride salt in 440 cm of dry dimethylformamide. To this was added 100 g (0.725 mol) of powdered anhydrous potassium carbonate and 29 g (0.17 mol) of bromoacetaldehyde dimethyl acetal. Liles refluxed the reaction mixture with stirring for 20-24 hours under argon. Then the salts were removed by filtration and the filtrate was evaporated under reduced pressure to give a dark brown oil. It was dissolved in a mixture of water and ethyl acetate and the layers were separated. The water layer was thoroughly extracted with ethyl acetate. The combined organic layers were further washed with brine, dried and the solvent was evaporated, yielding 46 g of crude product (brown syrup, yield 90%). Chromatography gave 64% pure N-benzyl-N- (beta-3,4-dimethoxyphenyl) ethylaminoacetaldehyde dimethyl acetal.

3 µl of dissolved 24 g of dimethylacetal in 240 ml of concentrated HCl / OHAr] (ratio 3: 2: 1) and left overnight at room temperature. It was then poured into 1 liter of ice-ujater, made basic by adding concentrated ammonia 5 to pH 8 and extracted with ethyl acetate. The extracts were uddered together, again washed with saturated saline and dried over sodium-free sodium sulfate. Removal of the desiccant and solvent gave 19.5 g of rum product (92% yield).

Chromatography on a silica column gave pure N-benzyl-1-hydroxy-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in a yield of 51%. The oily product could be recrystallized from ethyl acetate-hexane.

The "dimethylacetal" -15 reaction described in detail above is another general method which can be used for preparing various 1-hydroxybenzazepine intermediates according to the invention, with various substituted N-lower alkyl or phenylalkyl homovera-trylamines as starting materials, in particular the N-methyl, N-benzyl or N-phenethyl homoveratrylamines. The reaction apparently does not proceed with the N-H amines. The N-benzyl compounds are most commonly used because the protecting group can be easily avoided, which is described below.

Liles dissolved 1.1 grams of the pure N-benzyl-1-hydroxyl benzazepine in 50 cm methanol and added 220 mg of 10% palladium on charcoal moistened with butanol. The solution was left under material at 2.8 atm for 4 hours. shaken. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure to yield a slightly gelled syrup which crystallized from ethyl acetate.

Recrystallization from acetonitrile (mp 153-4 °) gave pure 1-hydroxy-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine a minimal key compound.

liles dissolved 8.9 grams (40 mmol) of 1-hydroxy-7,8-dimethoxy-3, 2,3,4,5-tetrahydro-1H-3-benzazepine and 2.5 cm 2-methyl-thiophene. : \ 7807819 ♦ 3 19 in 45 cm of trifluoroacetic acid. The reaction mixture was allowed to stand overnight at room temperature, evaporated under reduced pressure to an oily residue, which was dissolved in 250 ml of 3N2 hydrochloric acid. The acid solution was thoroughly uddered with ether, made basic with concentrated ammonia and finally extracted with ethyl acetate. The organic extracts were combined, washed with ββη saturated saline and dried over anhydrous sodium sulfate. Removal of desiccant and solvent gave 10.1 g of 10 1 "(5 * methyl-2, -thienyl) -7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in the form of an oil (83.3 / 6); amp. (HCl) 227-228 °.

Similarly, 1- (2 * -thienyl) -7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine and 1- (2 * -furyl ') - 7,8- dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine with thiophene, 2-bromothiophene and furan.

EXAMPLE V

liles dissolved 4.6 grams (15 mmol) of 1- (5'-methyl-2'-thienyl) -3.

7,8-dimethoxy-2,3,4,5-tetrahydro-3-1H-benzazepine in 45 cm methylene chloride under argon, the solution was cooled to -12 by an o 3 methanol ice bath, then slowly 78 cm 1 7807819 20

At the same time, the 7,8-dihydroxy-1- (2'-thienyl), (5, -bromo-2'-thienyl) and (2'-furyl) congeners from the 7,8-dimethoxy compounds . of Example IV.

EXAMPLE VI

A mixture of 10.2 g (0.056 mole) of homoveratrylamine and 5.9 g (0.053 mole) of 2-epoxyethyl furanur was prepared, heated on a steam bath overnight and treated in the manner described in Example 1, whereby N - (beta-hydroxy-beta-2'-furyl) ethyl homoveratrylamine in the form of a crystalline solid material was obtained which was recrystallized from ethyl acetate-petroleum ether (mp 90 °).

The furylaminoalcohol (2.9 g) was cycled in 30 cm trifluoroacetic acid at room temperature overnight. The black 3 3 3 mixture was poured into 20 cm ammonium hydroxide / 300 cm ice and 40 cm ethyl acetate, after which more ammonia was added until the pH was 9. The combined organic layer and subsequent extracts were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo after the desiccant was removed gave 2.51 g of 20 'of an oleaginous product of 1- (2 * -furyl) -7, B-dimethoxy-2,3,4,5-tetrahydro-1H -3-benzazepine. This material is similar to the same product obtained by catalytic hydrogenation of the N-benzyl derivative (Examples VII and VIII) with palladium-on-charcoal in methanol at 50 °.

EXAMPLE VII

A solution of 20.1 g (64 mmol) of 1-hydroxy-N-benzyl-3 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 130 ml of methylene chloride was added with 14 g (0.2 mol) furan and 16 cm ethereal boron trifluoride. After the reaction mixture had stood at room temperature overnight, it was stirred with concentrated ammonium hydroxide and ice. The methylene chloride phase was separated and extracted with 1 m phosphoric acid. The acidic extracts were made neutral and extracted with ethyl acetate 780 7 8 1 9 21. The dried extracts marden to 19.8 g of rum product JJ - {2'-furyl) -3-benzyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine7, which is evaporated by chromatography on silica was purified.

EXAMPLE VIII

The N-benzyl product 3 prepared in Example 7 (14.2 g, 0.12 mol) in methylene chloride was reacted with 145 ml of boron tribromide methylene chloride (1 g / 5 cm) at room temperature for 1.25 hours. The desired 1- (2 * -furyl) -3-benzyl-10,8,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine was isolated in the manner described above. This compound was treated in the manner described in Example 6 by hydrogenolysis, debenzylated, but by 1- (2'-furyl) -3-benzyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine. merd isolated above. This compound was debenzylated by hydrogenolysis in the manner described in Example 6 to give 1- (21-furyl) -7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine. The hemi-fumarate salt was prepared in methanol and recrystallized from material (mp, 267 DEG).

C14H15NO3-1 / 2C4H404.1 / 4H20

Calculated $ 62.43; 5.73 ^ H; 4.56 $ N Found: 62.78? C; 6.14% H; 4.52% N

EXAMPLE IX

Three solutions, each consisting of 0.31 g of 25 (1 molar) of 2-hydroxy-3-benzyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 2 methylene chloride containing boron trifluoride etherate react overnight with an excess of furan, 2-methylfuran and 2-cyanomethylfuran at room temperature. Each solution was quenched in an ammonia solution, isolated and transferred to silica gel. In thin layer chromatography on silica gel with cyclohexane ethyl acetate (7: 3), Rp values of resp. 0.68, 0.70 and 0.43 were found, while that of the starting material was 0.14 mas. These are the 2 * -furyl-, 5f-methyl-2'-furyl-

G

[7807819] An 5'-cyanomethyl-2'-furyl congeners optionally in the described manner can be de-benzylated and demethylated, but by 1- (2-furyl) -7,8-dihydroxy-2,3,4, 5-Tetrahydro-1H-3-benzazepine, the methyl furyl and cyanomethyl furyl congeners are obtained.

When this reaction is prepared with 1-hydroxy-3-methyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (prepared in the manner described in Example IV from N-methyl homoveratrylamine) and 2 - methylthiophene is repeated, 1- (5 * -methyl-2 * -thienyl) -10 3-methyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine is obtained. By demethylation in the above-described mine, 1- (51-methyl-2'-thienyl) -3-methyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide is obtained.

EXAMPLE X

15 lills left a mixture of 7.9g (25.2mmol) 1-hydroxy-3-benzyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, 3 5.35 g (50.4 mmol) methyl furoate and 6.2 cm (50.4 mmol) boron trifluoride etherate react for 1½ hours at room temperature. Wen 3 added another 3.1 cm of trifluoride but Ben and others were left overnight at room temperature. The product 1- (5'-carbo-methoxy-2'-furyl) -benzyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine was mixed according to the methods used in the previous examples isolated and purified. This material was demethylated to the 7,8-dihydroxy compound and debenzylated as described above to give 1- (5'-carbomethoxy-2'-furyl) -7,8-dihydroxy-2,3,4,5-tetrahydro-1H -3-benzazepine hemifumarate hydrate, m.p. 198-200 ° (dec.).

EXAMPLE XI

By 2-chloro-3,4-30 dimethoxyphenylethylamine, 2-fluoro-3,4-dimethoxyphenylethylamine or 2-trifluoromethyl-3,4-dimethoxyphenylethylamine (prepared via 2-trifluoromethyl-3,4-dimethoxytoluene) described in Example 1 ) reacting in a stoichiometric amount with 2-epoxyethylthiophene gives v * 780 7 8 1 9 - "* 23 2-chloro-1- (2'-thienyl) -7,8-dihydroxy-2,3,4, 5-tetrahydro-1H-3-benzazepine, 6-fluoro-1- (2'-thienyl) -7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine and 6-trifluoromethyl-1 - (2'-thienyl) - 7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazapine via its 7,8-5 dimethylathers.

EXAMPLE XII

KIen dissolves a mixture of 4.5 g of 6-chloro-7,8-dimethoxy-3 1- (2, -thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, 0.02 cm 3 i-butyl bromide and 0.02 mole of potassium hydroxide in 120 cm of dry methanol and reflux for 48 hours.

The reaction mixture is evaporated to dryness, taken up in ethyl acetate and filtered to remove inorganic salts. The filtrate is washed with water, dried and evaporated to give 3-n-butyl-6-chloro-7,8-dimethoxy-1- (21-thienyl) -2,3,4,5-tetra-15 hydro-1H- 3-benzazepine.

3

The 3-i-butyl benzazepine (0.01 mol) is dissolved in 120 cm of dry methylene chloride and 0.032 mol of boron tribromide is added dropwise at -10 °. The solution is warmed to room temperature and stirred for 2 hours. The excess of boron tribromide is destroyed by the dropwise addition of methanol with cooling under ice-cooling, and the cold solution is refluxed to remove the hydrogen bromide and evaporated. The residue is refluxed with brine for 2 hours to give 3-ri-butyl-6-chloro-7,8-dihydroxy-1 - (2'-thienyl) -2,3,4,5-tetra-hy dro-1 H-3-benzazepine hydrobromide is obtained.

Liles uses the N-alkylation method described above, but uses 7,8-dimethoxy-1- (5 * -methyl-2 * -thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine as starting compound and obtains the N-allyl, N-phenethyl, N-butyl, N-amyl or N-2,2-dimethylallyl derivatives. Hydrolysis of the methoxy groups as described above yields the active 7,8-dihydroxy compounds.

(H 'H, l 780 78 1 9 24

EXAMPLE XIII

(KIen suspends 3.9 g of 7,8-dihydroxy-1- (3'-thienyl) -3 2.3.4.5-tetrahydro-1H-3-benzazepine in 25 cm acetone and adds 0.7 g (0.016 mol, 10 (excess) ethylene oxide The mixture is transferred to a pressure flask and stirred at ambient temperature for about 40 hours, then the reaction mixture is heated at 60 DEG-8 DEG C. for 30 minutes, cooled and filtered By evaporation of the filtrate, a solid is obtained material which is taken up in ethyl acetate and precipitated again with ether.

The solid material thus obtained is dissolved in ethanol and treated with ethereal hydrogen chloride to give 7,8-dihydroxy- 3- (2-hydroxyethyl) -1- (3'-thienyl) -2,3,4,5- tetrahydro-1H-3-benzazepine hydrochloride.

EXAMPLE XIV

4.0 g of 3-benzyl-7,8-dihydroxy-1- (2'-thienyl) -2,3.4,5-tetrahydro-1H-3-benzazepine (prepared from the 3-unsubstituted benzazepine are dissolved by reaction) with benzyl bromide in the presence of potassium carbonate) in 50 cm of acetic anhydride, after which the solution is heated on a steam bath for one hour. The reaction mixture is cooled, ice water is added and the solution is evaporated to dryness. The residue is triturated with ethyl acetate, the solution is washed with water, dried and the solvent is removed in vacuo to leave an oil.

This is dissolved in ether, then ethereal hydrogen chloride 25 is added and 3-benzyl-7,8-diacetoxy-1- (2 * -thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride precipitates.

7.8-Dihydroxy-1- (21-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (10 g) is dissolved in trifluoroacetic acid, followed by 1-2 Leave to agitate with a stoichiometric amount of acetyl bromide for 1 hour at room temperature. The reaction mixture is evaporated and the residue is triturated in ether-i-propanol to give the desired diacetoxy derivative.

When using other alkanoyl hydrides or chlorides x 7807819, different 7,8-alkanoyl derivatives such as the diacetoxy derivatives of 2'-furyl, ö'-methyl-1'-furyl, 5'-cyanomethyl, 3 * -thienyl are obtained -, 5'-methyl-2'-thienyl, and 5'-bromo-21-thienyl compounds.

EXAMPLE XV

7,8-Dihydroxy-1- (2 * -thienyl) -2,3,4,5-tetrahydro-1H-3-. . 3 benzazepine (5 g) is suspended in 500 cm benzene. ITIen quickly adds droplets of 15 g of trifluoroacetic anhydride.

The solution is stirred for an additional hour and the volatiles are removed by stripping to leave the N, 0,0-tris-trifluoro-acetyl derivative. This is added directly to 500 ml of methanol, after which hydrogen chloride gas is bubbled through for a few minutes. The reaction mixture is stirred for 2 hours, after which the solvent is removed by stripping to give 7,8-dihydroxy-15 1- (2'-thienyl) -3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3- benzazepine remains.

EXAMPLE XVI

3

Dry dimethyl formamide (50 cm) is deoxygenated four times by drawing a vacuum and refilling the evacuated flask 20 with argon. 5 g of 7,8-dihydroxy-1- (21-thienyl) -3-trifluoroacetyl-2,3 are added. 4,5-tetrahydro-1H-3-benzazepine which dissolves while deoxygenating the solution again. 11 ml add 5.3 g methylene chloride, 5 g [potassium carbonate and 0.13 g copper oxide, after which the solution is deoxygenated for the last time. The reaction mixture is heated to 150 ° under argon for 2 hours.

It is worked up by pouring it into 2 liters of ice water with stirring. The aqueous suspension is extracted four times with 300-400 cm. Of ether, and the ether is extracted another three times three times with 1.5 liters of water. The ether is dried and evaporated. The residue is dissolved in chloroform and chromatographed on silica gel to give 7.8-methylenedioxy-1- (2-thienyl) -3-trifluoroacetyl-2,3,4,5-780 78 1 9 26 tetrahydro-1H -3-benzazepine.

EXAMPLE XVII

A suspension of 7,8-dihydroxy-1- (2 * -thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3.4 g) in methanol 3 (40 cm) is allowed react with 2.5 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in methanol for 1 hour at 0 °. The 1- (2'-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione hydrobromide is collected by filtration and washed with ether. The dionhydro bromide salt is added to an excess of methyl mercaptan in methanol. The solution is evaporated after 1 hour to give a residue of the 6-methylthio and 9-methylthio isomers. Separation on a column of silica gel gives 6-methylthio-1- (2'-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide salt.

Similarly, the 6-methylthio-3'-thienyl and 2'-furyl congeners are prepared.

EXAMPLE XVIII

5.5 grams (18 mmol) of 7,8-dimethoxy-1- (5 * -methyl-3 2'-thienyl-2,3,4,5-tetrahydro-1H-3-benzazepine were dissolved in 120 cm 3 of ethyl- 20 formate and refluxed for 24 hours.

3

After 50 cm 3 of ethyl ether was added, the reaction mixture was washed 3 times with 30 cm 3N hydrochloric acid, twice with 3 20 cm 5 / d's sodium bicarbonate and then with brine. After drying over sodium sulfate and removing the desiccant, the solvent was evaporated to yield 4.8 g of the oil-containing N-formyl derivative.

EXAMPLE XIX

3

2.15 g of lithium aluminum hydride and then 4.7 g (14.2 mmol) of the 3 N-formyl derivative in 80 cm benzene were added to 120 ml of ethyl ether under argon. The resulting slurry was refluxed gently for 5 hours. Then, the mixture was cooled and the excess hydride was added by successively adding 6 cm @ 3 methanol in 25 cm ether, 2.15 cm h / meter, 3 3 2.15 cm @ 10 alkali and 6.45 cm of water decomposed The solid obtained was removed by filtration The filtrate was evaporated to an oil, which was taken up in ethyl acetate and extracted thoroughly with 3 J hydrochloric acid The acidic extracts were combined, washed with ether, until Basic made pH 8 and extracted thoroughly with ethyl acetate The organic extracts were added and dried over anhydrous sodium carbonate Removing the desiccant and solvent 1G gave 3.6 g of 1- (5-methyl-2-thienyl) -3 methyl 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.

This was dissolved in methanol and ethereal hydrogen chloride was added. The solution was stripped to dryness under reduced pressure to yield T 10 -dimethoxy-1-C 3 -methyl-15-thienyl) -3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, which was from methanol- ethyl acetate hydrochloride was recrystallized. (Mp 227-8 °).

By using the 1 (2'-thienyl), 1- (3'-thienyl) or 1- (2'-furyl) congeners in the methods of Examples XIX-XX by 20 obvious variations replacement gives 7.8-dimethoxy-1- (2, -thienyl) -3-methyl-3,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, 7,8-dimethoxy-1- (3 ' -thiethyl) -3-methyl- 2.3.4.5-tetrahydro-1H-3-benzazepine hydrochloride or 7,8-dimethoxy-1- (2'-furyl) -3-methyl-2,3,4,5 - * - tetrahydro-1H-3-benzazepine hemifumarate. Cleaving the ethers as described above gives the three dihydroxy congeners.

EXAMPLE XX

If the dion hydrobromide salt is treated with anhydrous hydrogen bromide in methylene chloride or with dilute hydrogen bromic acid, 6-bromo-1- (2'-thienyl) -2,3.4,5-tetrahydro-1H-3-benzazepine hydrobromide salt is obtained. The 6-bromo-1- (5r-methyl-2 * -thienyl) -, 6-bromo-1- (2'-furyl) -, 6-bromo-3'-thienyl analogs are prepared in a similar manner.

780 7 8 1 9 i 28

Ingredients 11 mg per capsule 7.8- Dihydroxy-1- (5, -methyl-2, -thienyl) - 125 (free base) 2,3,4,5-tetrahydro-1H-3-benzazepine (as acid addition salt) 5 Magnesium stearate 2

Lactose 200

The above ingredients are thoroughly mixed together and transferred to hard gelatin capsules. »These capsules are administered orally to patients to be treated 1-5 times a day to elicit dopaminergic activity.

EXAMPLE XXI

Ingredients Mg per tablet 7.8- Dihydroxy-1- (2'-thienyl) -2,3,4,5-200 (free base) 15 tetrahydro-1H-3-benzazepine (as acid addition salt)

Corn flour 30

Polyvinylpyrrolidone 12

Corn meal 16 20 Magnesium stearate 3

The first two components were thoroughly mixed together and granulated. The granules obtained were dried, mixed with the remaining starch and magnesium stearate and pressed into tablets.

The capsules or tablets thus prepared are to be administered orally to humans or animals but stimulation of either the peripheral or central dopamine receptors is necessary to lower blood pressure or to treat the symptoms of Parkinson's disease, within the above dosages.

Likewise, other compounds of the formula (1) can market typical examples thereof on the same mine, but obtain pharmaceutical preparations which, on the basis of the chemical properties and associated biological activity, according to the described test methods according to the invention. invention may be used.

\

Ct 7807819 * 29

A subset of compounds within the group of formula (1) consists of compounds wherein: R is phenethyl, benzyl, lower alkyl of 1-5 C atoms, hydroxyethyl or lower alkenyl of 3-5 C atoms; R 1 is hydrogen, halogen, trifluoromethyl, lower alkylthio, trifluoromethylthio, methyl or methoxy; R 1 and R 2 are any hydrogen, lower alkyl of 1-5 C atoms, lower alkanoyl of 2-5 C atoms or, together, methyl B or ethylene; R 1 is material, halogen or methyl; and X is -O- or -S-.

In this subgroup, particular compounds are those wherein R is methyl or allyl; R1 is hydrogen, chlorine, bromine or methylthio; R 1 and R 3 are the same and hydrogen, methyl or acetyl; 15 R hydrogen or 5 * methyl and X is -S-.

The compounds of the above subgroup have a particularly useful antihypertensive activity, since they cause arterial hypotension and accompanying bradycardia. This activity has been demonstrated in anesthetized rats with spontaneously elevated blood pressure (SHR). In this pharmacological method, adult male SHR weighing approximately 350-400 g are anesthetized with pentobarbital sodium (65 mg / kg i.p.). The trachea is cannulated and the rats are allowed to breathe spontaneously. The carotid artery with Ben cannula is used to measure pulsatile arterial blood pressure by means of a Stathamin device (P23AA) measured. The mean arterial blood pressure is calculated as diastolic blood pressure plus 1/3 pulse pressure. The heart rate is monitored by means of a cardiotachometer that is turned on by the systolic blood pressure. The phasic arterial blood pressure and heart rate are measured by means of a multi-channel oscillograph registered. Solutions of the drug are administered through a cannulated tail vein. Ilflen elapses approximately 10 minutes after administration to allow the preparation to equilibrate. The immediately measurable parameters are then determined. Subsequently, each rat is administered an initial dose of 1 mcg / kg of the prosf compound.

Arterial blood pressure and heart rate responses are recorded and expressed as an absolute change from the respective comparison value established just prior to injection.

These successive operations must be repeated at approximately 5-10 minute intervals, with the doses of the test compound increasing, until each rat has received individual doses of 1, 3, 10, 30, 100, 300 and 1000 mcg / kg .

In the table below, the responses of the mean arterial blood pressure and heart rate induced in the anesthetized SHR according to the method described above are evoked at i.v. administration to three rats of 7,8-dimethoxy-3-methyl-t- (5 * -methyl-2'-thienyl) -2,3,4,5-tetrahydro-1H-3-benzazepine in the form of the hydrochloride salt (dose in mcg / kg of the free base).

Change of the qemid. blood pressure (mmHg) 1 mcg / 3 mcg / 10 mcg / 30 mcg / 100 mcg / 300 mcg / 1000mcg / kg kg kg kg kg kg kg + 5.6 + 1.3 + 10.0 + 1.1 +7, 3 + 1.7 -21.6 + 11.3 -88.0 + 7.9 -75.0 + 7.2 -67.2 + 4.4 20 Change of heart rate (slaq / minute) 1 mcg / 3 mcg / 10 mcg / 30 mcg / 100 mcg / 300 mcg / 1000 mcg / kg kg kg kg kg kg kg -4.6 + 1.7 -1.0 + 1.5 -0.6 + 2.8 - 73.6 + 25.4 -174 + 29.7 -144 ^ 20.8 -98. + 25.2

Thus, the compound produced mean maximum changes in arterial blood pressure of -88 mmHg and heart rate of -174 beats / minute, with dose-dependent blood pressure reduction at 30-1000 mcg / kg and bradycardia over the entire dose range. occurred.

- \ \ f- £} 7807819

Claims (20)

31 - A compound of the formula (1), characterized in that R u / atoms, benzyl, phenethyl, lower alkanoyl with 1-5 C atoms, lower alkyl with 1-5 C atoms, hydroxyethyl or lower alkenyl with 3-5 C atoms; 2. A compound according to claim 1, characterized in that 15 X -S- and R is methyl. A compound according to claim 1, characterized in that R 1 is methyl, R 1 is hydrogen, R 2 and R 1 are both methyl, R 1 is hydrogen or methyl and X is -S-. A compound according to claim 3, characterized in that R 20 is ö'-methyl and X -S- and the thienyl ring is attached at 2 '. Compound according to claim 4, characterized in that the salt is the hydrochloride. R 1 is hydrogen, halogen, trifluoromethyl, methylthio, trifluoromethylthio, methyl or methoxy; R 2 and R 1 are each hydrogen, lower alkyl of 1-5 C atoms, lower alkanoyl of 2-5 C atoms, or together, methylene or ethylene; 6. A compound according to claim 1, characterized in that R is methyl and R, R2, R3 and R1 are hydrogen 7. A compound according to claim 6, characterized in that a thienyl ring is attached at the 2 'position. A compound according to claim 6, characterized in that the thienyl ring is attached at the 3 * position. A compound according to claim 1, characterized in that 3G R is methyl and X -O-. A pharmaceutical composition with dopaminergic or blood pressure-lowering activity, characterized in that it comprises an effective and non-toxic amount of a compound according to claim 1 and an excipient for it. 7807819 * R 1 is hydrogen, halogen, cyanomethyl, methyl or carbonethoxy; and X is -O- or -S-; or its pharmaceutically acceptable non-toxic salts, A process for preparing a compound of the formula (1), characterized in that a compound of the formula (4) in which R is lower alkyl, benzyl or phenethyl, R 2 hydrogen, halogen, trifluoromethyl, methylthio, trifluoromethylthio, methyl or methoxy; and R 1 and R 1 are lower alkyl and together are methylene or ethylene; reacting in the presence of at least one equivalent of an acidic catalyst, with a compound of the formula (5), wherein R 1 is hydrogen, halogen, methyl, cyanomethyl or carbomethoxy, and optionally N- according to methods known in the art alkylation, O-dealkylation or alkylation and salt formation takes place. Marking method according to claim 11, characterized in that R is methyl and X is -S-. 13. Process according to claim 11, characterized in that R 15 is methyl, R 1 is hydrogen, R 1 and R 3 are methyl, R 1 is 5 * -methyl, X is -S- and the thienyl ring on the 2'- place is attached. Method according to claim 13, characterized in that a non-toxic salt is formed. 15. Process according to claim 14, characterized in that the hydrochloride or methanesulfonate salt is formed. A compound of the formula (4), characterized in that R is hydrogen, lower alkyl, benzyl or phenethyl, R 1 is hydrogen, halogen, trifluoromethyl, methylthio, trifluoromethylthio, methyl or methoxy; and R 1 and R 1 are lower alkyl and together are methylene or ethylene; and the acid addition salts thereof. A compound according to claim 16, characterized in that R 2 and R 1 are methyl and R is methyl, benzyl or hydrogen. A compound according to claim 16, characterized in that R is methyl, R 1 is hydrogen and R 2 and R 1 are both methyl. Process for the preparation of a pharmaceutical composition with dopaminergic and antihypertensive activity, characterized in that a compound prepared according to claims 11 to 15 is brought into a form suitable for medical purposes. 20, Molded preparations, such as tablets, capsules, etc., obtained according to claim 19. 780 7 8 1 9 1 R R o 5 Λ 3N — R R 3 ° lAj 2 / X - ¾ 2> 1 r, o — r ^ C ^ HR ¥. Jh X --R4 REACTION SCHEDULE A R1 R3 — 1s ^ k __ / \ J OH 780 78 1 9 Smithkline Gorp.