GB1597911A - Benzazepines - Google Patents

Abstract

The 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diones of the general formula II <IMAGE> in which R1 denotes a hydrogen atom, a C1-5-alkyl, hydroxyethyl, C3-5-alkenyl, benzyl, phenethyl, carbobenzyloxy or C1-5-alkanoyl group and R2 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a trifluoromethyl, methyl, methoxy or hydroxyl group, and their salts with acids are useful as intermediates for the preparation of pharmacologically active compounds.

Description

(54) BENZAZEPINES (71) We, SMITHKLINE CORPORATION, of 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, United States of America, a Corporation organized under the laws of the Commonwealth of Pennylsvania, one of the United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention concerns I - phenyl - 2,3,4,5 - tetrahydro - 1H - 3 benzazepines having utility as dopaminergic agents with pronounced activity at central nervous system receptors.

According to the present invention there are provided compounds of the formula

in which: R and R3, which are the same or different, are hydrogen; lower alkylthio, sulfinyl or sulfonyl containing 1--5 carbon atoms; trifluoromethylthio, sulfinyl or sulfonyl; or dimethyl sulfonium salt (-(CH3)2SO2X where X is a pharmaceutically acceptable anion, e.g. chloride, bromide, iodide, tosylate or mesylate), at least one of R and R3 being other than hydrogen; R' is hydrogen, lower alkyl containing 1--5 carbons, hydroxyethyl, lower alkenyl containing 3-5 carbons, benzyl, phenethyl, carbobenzoxy or lower alkanoyl containing 1--5 carbons; and R2 is hydrogen, halo, for example fluoro, chloro, bromo or iodo, trifluoromethyl, methyl, methoxy or hydroxy; O-lower alkyl and O-lower alkanoyl derivatives thereof the alkyl and alkanoyl groups having 1--5 carbon atoms, and pharmaceutically acceptable non-toxic salts thereof.

The compounds in which R' is benzyl, phenethyl, carbobenzoxy or lower alkanoyl or the higher alkoxy or acyloxy containing compounds are of utility particularly as intermediates in the preparation of other more active compounds.

A subgeneric group of compounds of Formula I is that in which R is methylthio or trifluoromethylthio, and R' and R3 are both hydrogen. In this group, individual compounds of note are those in which R2 is hydrogen, chloro, methyl, trifluoromethyl, methoxy or hydroxy. The 9-methylthio containing compounds while less potent than the 6-methylthio compounds have fewer side effects.

The pharmaceutically acceptable acid addition salts which have similar utility to the free bases of Formula I can be prepared by methods known to the art, and they can be formed with either inorganic or organic acids, for example with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric or nitric acids. The invention also includes quaternary salts, including the sulfonium derivatives as defined above, and it includes those prepared from organic halides such as lower alkyl halides, for example methyl bromide, methyl iodide, ethyl iodide, benzyl chloride, as well as from methyl tosylate or mesylate.

Certain 1 - phenyl - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepines have been described in U.S. Patent Specifications 3,393,192 and 3,795,683; British Patent Specification 1,118,688; and Swiss Patent Specification 555,831, including general methods of preparation. However these references disclose no benztrisubstituted compounds of the type here claimed, no 6-methylthio substituted compounds of any kind and no advantage to such 6-methylthio substitution in the structures.

These references do disclose 7,8-dihydroxy substituted - 1 - phenyl - 3 benzazepines and various intermediates therefor, some of which serve as starting materials for preparing the compounds of the present invention.

The compounds of Formula I can exist as diastereo isomers which can be resolved into d or I optical isomers. Resolution of the optical isomers can be accomplished by factional crystallization of salts of the bases of Formula I with optically active acids from appropriate solvents. Unless otherwise specified herein or in the claims, it is intended to include all isomers, whether separated or not, and mixtures thereof. Where isomers are separated, the desired pharmacological activity will often predominate in one of the isomers, usually in the di-isomer.

The compounds of Formula I contain two hydroxy groups at positions 7 and 8, which can be converted into lower alkoxy derivatives with 1--5 carbons in each alkoxy group, for example methoxy, ethoxy, butoxy or isoamyloxy, or lower alkanoyloxy derivatives with 1--5 carbons, for example O-acetyl, O-propionyl or O-valeryl. The present invention includes such alkoxy and alkanoyloxy derivatives.

The dimethoxy or diacetoxy derivatives are most useful, but are of somewhat lower level of general biological activity than the corresponding hydroxy compounds.

The diacyloxy derivatives in general have substantial oral activity.

The lower alkyl and lower alkanoyl derivatives of the compounds of Formula I can be prepared by alkylation or acylation methods known to the art. However, the use of lower alkyl halides as alkylating agents in addition to O-alkylation would also form lower alkylsulfonium halides with sulphur atoms present during the alkylation. For example, dimethylsulfonium bromides would form during reaction with methyl bromide. These sulfonium salts can optionally be reconverted to the parent thio compound without affecting the O-alkyl groups by known methods, for example by heating in 1 N hydrobromic acid, in brine or another source of bromide or chloride ions.

The compounds of Formula I can be prepared by the cyclization reactions analogous to those described in U.S. Patent Specification No. 3,393,192 using as starting materials an appropriate 2-lower alkylthio - 3,4 dimethoxyphenethylamine or the corresponding phenethylaminomethylbenzyl alcohol. The N-substituted derivatives of Formula I can also be prepared using the appropriate tertiary amino alcohol in the cyclization reaction. A preferred method of preparation of compounds of Formula I where R is a lower alkylthio group is to react a 7,8-dione of the formula:

(where R1 and R2 are as defined for Formula I) with an appropriate mercaptan R4SH in a suitable inert organic solvent for example an alcoholic solvent, e.g.

methanol or ethanol, at about room temperature to give a compound of the formula:

(where R' and R2 are as defined for formula I and R is a lower alkylthio group).

The diones of formula II are described and claimed in British Patent Application 20952/80 (Serial No. 1,597,912).

In this addition reaction, the analogous 9-position isomer is also obtained.

However, the mixture of isomers is easily separated into the 6 and 9-isomers by methods described hereafter. Also the mixture of monosubstituted isomers can be used to prepare the 6,9-disubstituted congeners as described immediately hereafter.

A second lower alkylthio substituent can optionally be introduced into the 9position of a compound of Formula III by oxidation (or into the 6-position of the 9substituted, 6-unsubstituted isomer) by reaction with 2,3 - dichloro - 5,6 dicyano - 1,4 - benzoquinone followed by reaction once more with the desired mercaptan.

The 7,8-dialkoxy derivatives of the compounds of Formula I can be prepared by reacting a 6-lithium analogue of the desired compound of Formula I (R=Li) with the appropriate lower alkyl or trifluoromethyldisulfide in an inert organic solvent in which the reactants are soluble, for example ether or tetrahydrofuran, at ambient or elevated temperature under anhydrous conditions. The 7,8-dimethoxy derivatives can also be prepared by reaction of the 7,8-dihydroxy congener with diazomethane. Of course the dialkoxy derivatives can also be prepared directly by the cyclization reaction mentioned above.

The sulfonyl derivatives of the compounds of formula I in which R and/or R3 are lower alkyl or trifluoromethyl sulfonyl (alkSO2- or CF3SO2-) can be prepared by oxidizing the corresponding sulfide, the N or 3-position being optionally protected by an inert group for example trifluoroacetyl or carbobenzoxy, using a sulfonyl-producing oxidizing agent, for example excess hydrogen peroxide, mchloroperbenzoic acid, peracetic acid or perbenzoic acid. The 6- and/or 9-position sulfinyl compounds of Formula I in which R and/or R3 are lower alkyl or trifluoromethyl sulfinyl (alkSO-- or CF3SO-) can be prepared using a sulfoxideproducing oxidizing agent, for example sodium periodate usually in neutral solution or one equivalent of hydrogen peroxide or m-chlorobenzoic acid at low temperatures.

The compounds of formula I, their lower alkyl ethers or esters and their nontoxic pharmaceutically acceptable addition salts have a novel dopaminergic effect.

It is well known that dopaminergic compounds have a dual effect on dopamine receptors in the central nervous system notably the brain as well as on peripheral dopamine receptors such as those affecting the peripheral cardiovascular system.

The latter effect results in increased renal blood flow with a resulting hypotensive effect. It is often measured by administering compounds by incremental infusion i.v. at five minute intervals to the anesthetized normotensive dog with measurement of various cardiovascular parameters. The effect on renal vasculator resistance can be calculated from any change in renal blood flow and arterial blood pressure. The effect is quantified as an ED15 values which is the cumulative dose which produces a 15% decrease in renal vascular resistance B.P. in mm/Hg.

(R= ) B.F. ml/min.

The 6-lower alkylthio compounds of formula I especially have antiparkinsonism activity due to central dopaminergic activity as demonstrated by employing a modified standard animal pharmacological test procedure reported by Ungerstedt et al., in Brain Research 24, 1970, 485493. This procedure is based on a drug-induced rotation of rats having extensive unilateral lesions of the substantia nigra. Briefly, the test comprises the quantitative recording of rotational behaviour in rats in which 6-hydroxydopamine lesions of the nigrostriatal dopamine system have been produced. A unilaterial brain lesion in the left substantia nigra causes the dopamine receptor in the left caudate to become hypersensitive following the resulting degeneration of the nigral cell bodies. These lesions destroy the source of the neutrotransmitter dopamine in the caudate but leave the caudate cell bodies and their dopamine receptors intact. Activation of these receptors by drugs which produce contralateral rotation, with respect to the lesioned side of the brain, is used as a measure of central dopaminergic activity of the drug.

Compounds which are known to be clinically effective in controlling parkinsonism, such as, for example, Ldopa and apomorphine, are also effective in this rate turning model. These compounds directly activate the dopamine receptors and cause contralateral rotation of the lesioned rat.

Rotational activity is defined as the ability of a compound to produce 500 contralateral rotations during a two-hour period after administration, usually intraperitoneally. The dose corresponding to 500 contralateral rotations per two hours is obtained and assigned as the RID,, value.

The unexpected nature of the biological spectrum of the dopaminergic compounds of the present invention is a shift from activity at peripheral receptors to central activity. For example, 7,8 - dihydroxy - 6 - methylthio - 1 - phenyl 2,3,4,5 - tetrahydro - 3 - 1H - benzazepine hydrobromide has an RD500 of 0.18 (0.06-0.29) mm/Kg (0.14 mg/Kg base] which is 8 times more potent than is its 6hydrogen analog with a faster onset and longer duration of activity. The ED15 of this compound is 372 which is 10 times less potent than the 6-hydrogen analog.

7,8 - Dihydroxy - 9 - methylthio - 1 - phenyl - 2,3,4,5 - tetrahydro - 3 - lH - benzazepine hydrobromide has an RD500 of 4.8 mg/Kg [3.8 base] which is 3 times more potent than the 6-hydrogen analog. The higher alkylthio, i.e. those other than methylthio as well as the 6,9-disubstituted, congeners were less potent in the rotation test than the preferred methylthio-containing compounds.

The invention also provides pharmaceutical compositions which comprise a compound according to the invention and a pharmaceutically acceptable carrier.

In general they will be prepared in dosage unit forms by incorporating a compound of formula I, an isomer or a pharmaceutically acceptable acid addition salt thereof, with a non-toxic pharmaceutical carrier according to accepted procedures in a non-toxic amount sufficient to produce the desired pharmacodynamic activity in a subject, animal or human. Preferably the dosage units will contain the active ingredient in an active but non-toxic amount selected from 2.5 mg to 1000 mg of active ingredient but this quantity depends on the specific biological activity desired and the conditions of patient. A most desirable use of the compositions is in the treatment of Parkinson's disease to ameliorate or prevent the attacks common with patients suffering from this central nervous system abnormality.

The pharmaceutical carrier employed can be solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Similarly the carrier or diluent can include any time delay material well known to the art, for example glyceryl monostearate or glyceryl distearate, alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used the compositions can be tableted, placed in a hard gelatin capsule in powder or pellet form, or be in the form of a troche or lozenge. The amount of solid carrier can be varied widely but preferably it will be from 25 mg to 1 g per dosage unit. If a liquid carrier is used, the compositions can be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as in an ampoule, or be as an aqueous or non-aqueous liquid suspension.

The pharmaceutical compositions can be made following conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to give the desired end product.

A dopaminergic effect can be achieved by administering internally to a subject in need of such treatment a compound of the invention usually combined with a pharmaceutical carrier, in a non-toxic amount sufficient to produce the desired effect, as described above. The route of administration can be any route which effectively transports the active compound to the dopamine receptors which are to be stimulated, for example orally or parenterally, the oral route being preferred.

Advantageously, equal doses will be administered several times such as two or three times a day with the daily dosage regimen being from 150 mg to 1.5 g. When the method described above is carried out anti-parkinsonism activity is produced with a minimum of side effects.

The following Examples illustrate the invention. All temperatures are in degrees Centigrade.

EXAMPLE 1 To a suspension of 7,8 - dihydroxy - 1 - phenyl - 2,3,4,5 - tetrahydro - 1H 3 - benzazepine hydrobromide (34 g, .101 mole, U.S. Patent No. 3,393,192) in methanol (275 ml) was added a solution of 2,3 - dichloro - 5,6 - dicyano - 1,4 benzoquinone (25.2 g, .111 mole) in methanol (125 ml). The addition was carried out rapidly with stirring at 0 under an argon atmosphere. After stirring at 0 for 1 hour the reaction mixture was filtered and the orange precipitate was washed with cold methanol (75 ml), ethyl acetate (100 ml) and then diethyl ether (100 ml). After drying at room temperature under vacuum, 1 - phenyl - 2,3,4,5 - tetrahydro 1H - 3 - benzazepine - 7,8 - diene hydrobromide (32.8 g, 0.98 mole, 97%) was obtained, mp 164165 (dec.).

Anal. Calc'd for C,6H,5NO2- HBr. 1/4 H2O: C, 56.34; H, 4.84; N, 4.11 Found: C, 56.02; H, 4.76; N, 4.01.

In a stirred suspension of 1 - phenyl - 2,3,4,5 - tetrahydro - 1H - 3 benzazepine - 7,8 - dione (5 g, .015 mole, generated from the salt above) in methanol (150 ml) was rapidly bubbled an excess of methyl mercaptan. The orange quinone quickly dissolved to give a pale yellow solution which was evaporated to a residue (5.5 g) which was a mixture of 7,8 - dihydroxy - 6 - methylthio and 9 methylthio - 1 - phenyl - 2,3,4,5 - tetrahydro - lH - 3 - benzazepine hydrobromides. The 9-isomer could be directly crystallized by dissolving the residue in methanol and diluting to the cloud point with ethyl acetate; however, this material (2.2 g) contained a small amount of the 6-isomer. A more efficient separation was achieved by chromatography on silica gel. A mixture of the isomers (3.3 g) was dissolved in 3.2 ml of methanol and diluted to 80 ml with chloroform.

This solution was applied to a silica gel column (100 g, 4.5x 15 cm) and eluted with a linear gradient composed of chloroform containing an increasing concentration of methanol (1000 ml, 5% to 20% methanol). The 6-isomer was eluted first followed by a mixture of 6- and 9-isomers and then the 9-isomer. Fractions containing the pure 6-isomer were combined and evaporated to a residue (1.4 g) which was crystallized from ethanol-ethyl acetate to give 0.64 g (.0017 mole, 11%), mp 258 (dec.).

Anal. Calc'd for C,7H19NO2S HBr: C, 53.41; H, 5.27; N, 3.66; S, 8.39 Found: C, 53.41; H, 5.10; N, 3.55; S, 8.64.

Fractions containing the pure 9-isomer were evaporated to a residue and combined with the 2.2 g obtained by direct crystallization. Recrystallization from methanol-ethyl acetate gave the pure 9-isomer (1.25 g, .0034 mole, 22%), mp 270 (dec.).

Anal. Calc'd for Ca7HagNO2S HBr: C, 53.41; H, 5.27; N, 3.66; S, 8.39 Found: C, 53.15; H, 5.33; N, 3.58; S, 8.24.

EXAMPLE 2 Preparation of 6- and 9-lower Alkylthio-7,8-dihydroxy-2,3,4,5 tetrahydro- 1 -phenyl-3- 1 H-benzazepines A 1 1 3-necked, round bottom flask was equipped with a magnetic stirrer, argon gas inlet and outlet tubes, and a powder addition funnel. The outlet tube was arranged so the exit gas bubbled through a solution of sodium hypochlorite (Clorox) to remove entrained mercaptan. To a stirred solution of 3-3.7 ml (0.041-0.07 moles) of the appropriate alkylmercaptan in 300 ml of methanol was added 10 grams (0.03 moles) of 1 - phenyl - 7,8 - dione - 2,3,4,5 - tetrahydro - 3 lH - benzazepine hydrobromide by means of the powder addition funnel. Addition was carried out in portions at such a rate that the initial intensity brick red color of the solution changed to light orange before each subsequent addition. This process normally takes about 10 minutes to complete. The resulting yellowish solution was stirred for an additional 15-30 minutes and was then evaporated under reduced pressure. The oily residue was chromatographed on silica gel, the products being eluted with a gradient of 515% methanol in chloroform. The ratio of 6- and r- isomers is about 1:2 and the 6-isomer is eluted first. However, repeated chromatography is usually necessary in order to obtain a complete separation.

Thus, although the crude yield is quite high, the isolated yields of pure isomers are relatively low.

The melting points, analytical values and isolated yields of the separated isomers as the hydrobromide salts are tabulated below.

Compounds m.p. Calcd. Found Yield 9--nn-BuuS- 1912 C 56.60 56.42 14.9% H 6.18 6.31 N 3.30 3.22 6-n-BuS- 197 C 56.60 56.94 9.6% H 6.18 6.29 N 3.30 3.45 9-i-PrS- 245--60 C 55.07 54.72 25.6% H 5.95 5.79 N 3.38 3.30 6--ii-PrS 26970 C 55.61 55.38 18.7% H 5.89 6.16 N 3.41 3.34 9--EtSS- 287"C(d) C 54.55 54.32 13 4ox H 5.59 5.71 N 3.53 3.20 6--EtSS- 215--7"(d) C 54.44 54.42 15.1% H 5.59 5.72 N 3.53 3.21 A mixture of 10 g of trifluoromethyldisulfide, a stoichiometric quantity of dithioerythritol in methanol is allowed to stand at room temperature until the reaction is complete. The mixture is then used as the source of trifluoromethylthio in the general procedure outlined above to produce 6 - trifluoromethylthio - 7,8 dihydroxy - 1 - phenyl - 2,3,4,5 - tetrahydro - 3 - 1H - benzazepine hydrobromide.

The bases of the noted salts are obtained by shaking each salt in a bicarbonatemethylene dichloride mixture, separating the organic layer and evaporating the dried organic extract in vao.

EXAMPLE 3 A 3.7 g (0.0145 mole) sample of 7,8 - dihydroxy - 1 - phenyl - 2,3,4,5 tetrahydro - 1 H - 3 - benzazepine free base was slurried in 25 ml of acetone and 0.07 g (.016 mole, 10% excess) of ethylene oxide was added and the mixture placed in a pressure bottle and stirred at ambient temperature for ca. 40 hours. The reaction mixture was heated to 6080 for thirty minutes, cooled and filtered.

Concentration of the filtrate gave 4.5 g of crystalline solid. This was taken up in ethyl acetate, reprecipitated by the addition of ether and converted to its hydrochloride salt by solution in ethanol, addition of ethereal hydrogen chloride and precipitation of the salt by additional ether to give 3.0 g (yield 60%) on drying.

Recrystallization from ethanol-ether gave 1.9 g (yield 38%), mp 136-1 37C of 7,8 dihydroxy - 3 - (2 - hydroxyethyl) - 1 - phenyl - 2,3,4,5 - tetrahydro - I H - 3 benzazepine hydrochloride.

The 2-hydroxyethyl compound (1.5 g) is reacted with 2,3 - dichloro - 5,6 dicyano - 1,4 - benzoquinone in methanol as in Example 1 to give 3 - (2 hydroxyethyl) - 1 - phenyl - 2,3,4,5 - tetrahydro - lH - 3 - benzazepine - 7,8 dione hydrobromide. The (1 g) is reacted with methylmercaptan in methanol as in Example 1 to give 6 - methylthio - 7,8 - dihydroxy - 3 - (2 - hydroxyethyl) - 1 phenyl - 2,3,4,5 - tetrahydro - IH - 3 - benzazepine hydrobromide.

EXAMPLE 4 A 25 g (0.0874 mole) quantity of 2- methoxy - 2- (m trifluoromethylphenyl)ethyl bromide (U.S. Patent 3,226,440) and 75 ml of 2 - (3,4 dimethoxyphenyl)ethylamine were heated at 9095 for two hours with stirring under nitrogen. Cooling caused crystallization of 21.3 g of 2 - (3,4 dimethoxyphenyl)ethylamine hydrobromide. This was filtered and the filtrate fractionally distilled under vacuum. The fraction boiling at 207-2320C (1.3-2.0 mm) was collected and thehydrochloride salt formed in ether. This was recrystallized from acetonitrile/ether to give 14.5 g (40% yield) of N - [2 methoxy - 2- (m - trifluoromethylphenyl)ethyll - N - 2- (3',4' dimethoxyphenyl) - ethylamine hydrochloride, m.p. 157160 .

A 1.0 g (0.00238 mole) sample of this material was added to 20 ml 48% hydrobromic acid and the mixture heated at reflux for one hour with stirring under nitrogen. The solution was cooled, concentrated to dryness under reduced pressure and the residue triturated with ether to give 1.0 g of crystalline solid (yield, 89%).

This was recrystallized from ethanol/ether to give 7,8 - dihydroxy - 1 - (m trifluoromethylphenyl) - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepine hydrobromide of mp 1530 (forms glass).

Ihe base (1 g) is reacted with ~ 2,3 - dichloro - 5,6 - dicyano - 1,4 benzoquinone in methanol to give the dione which (0.5 g) is reacted with methyl mercaptan to give 6- methylthio - 7,8 - dihydroxy - 1 - (m - trifluoromethylphenyl) - 2,3,4,5 - tetrahydro - lH - 3- benzazepine hydrobromide.

EXAMPLE 5 Sodium hydride (57%) (4.84 g, 0.115 mole) previously washed with hexane was stirred with dry dimethylsulfoxide (70 ml) at 6570 for 2 hours under argon. The mixture was diluted with dry THF (70 ml), cooled to --50 and trimethylsulfonium iodide (23.5 g, 0.115 mole) in 100 ml of dry DMSO was added over a period of 3 minutes. After stirring for one minute o-tolualdehyde (11.5 g, 0.0926 mole) was added at a moderate rate while keeping the reaction mixture at 0 to -5 . The mixture was stirred at 0 for 5 minutes and at room temperature for 1 hour, diluted with 500 ml of ice water and extracted three times with ether. The ether solution was washed with saturated sodium chloride, dried with sodium sulfate and evaporated to an oil which was distilled under reduced pressure (.25-.50 mm) to give 10.25 g (83%) of o-methylstyrene oxide as a clear liquid (b.p. 3538 ).

Homoveratrylamine (13.6 g, 0.0753 mole) and o-methylstyrene oxide (10.1 g, 0.0753 mole) were stirred at 1000 under argon for 16 hours and then diluted with benzene and hexane and cooled in ice. The solid which precipitated was filtered and recrystallized from benzene-hexane to give 8.6 g (36%) of 2 - methyl - a - [N - (3,4 - dimethoxyphenethyl)aminomethyl]benzyl alcohol, mp 9194 .

2 - Methyl - a- [N- (3,4- dimethoxyphenethyl)aminomethyl] - benzyl alcohol, (8.5 g, 0.0269 mole), was refluxed in 48% HBr (58 ml) for 2 hours under argon. After cooling the product was filtered off and recrystallized once from ethanol-ethyl acetate to give 6.7 g (69%) of 1 - (2 - methylphenyl)- 7,8 dihydroxy - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepine hydrobromide which analyzed for a 1/2 hydrate, mp 232-2330C.

This compound (5 g) is oxidized using the l,4-benzoquinone as in Example 1 to give 1 - (2 - methylphenyl) - 2,3,4,5 - tetrahydro - lH - 3 - benzazepine - 7,8 dione which (2 g) is reacted with methylmercaptan in methanol to give 6 methylthio - 7,8 - dihydroxy - 1 - (2 - methylphenyl) - 2,3,4,5 - tetrahydro 1H - 3 - benzazepine hydrobromide.

Using m-methylstyrene oxide gives the 7,8-dihydroxy compound (mp 108 110 ), the 7,8-dione and finally 6 - methylthio - 7,8 - dihydroxy - I - (3 methylphenyl) - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepine hydrobromide.

Using m-methoxystyrene oxide gives the 7,8 - dihydroxy - m - hydroxyphenyl compound (mp 285 as the hydrobromide), the 7,8-dione and finally 6methylthio - 7,8 - dihydroxy - 1 - (3 - hydroxyphenyl) - 2,3,4,5 - tetrahydro 1H - 3 - benzazepine.

Usingp-chlorostyrene oxide gives the 7,8-dihydroxy (mp 156--164"), the dione and finally 6 - methylthio - 7,8 - dihydroxy - 1 - (p - chlorophenyl) - 2,3,4,5 tetrahydro - 1 H - 3 - benzazepine hydrobromide.

Using p-trifluoromethylstyrene oxide gives the 7,8-dihydroxy, the dione and finally 6- methylthio - 7,8 - dihydroxy - 1 - (p - trifluoromethylphenyl) - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepine hydrobromide.

EXAMPLE 6 A 3.3 g (0.019 mole) quantity of 7,8 - dihydroxy - 1 - phenyl - 2,3,4,5 tetrahydro - 1H - 3 - benzazepine (free base) was slurried in 40 ml of dry acetone and 4.0 g of anhydrous potassium carbonate was added. The mixture was sti with water, 6 - methylthio - 7,8 - dimethoxy - 1 - phenyl - 2,3,4,5 - tetrahydro 1H - 3 - benzazepine is obtained. Other disulfides especially di(trifluoromethyl)disulfide may be substituted as well as other N-alkylated or Nacylated benzazepines.

EXAMPLE 9 2 - (2 - Methylthio - 3,4 - dimethoxyphenyl) - ethylamine was prepared from 2-chloroveratraldehyde [L. C. Raiford and R. P. Perry, J. Org. Chem., 7, 354 (1942)] by first forming the ethylene acetal (from ethylene glycol with acid catalysis and azeotropic removal of water) and then the Grignard reagent (magnesium and dibromoethane in refluxing benzene) which was reacted with dimethyldisulfide in refluxing benzene. Hydrolysis of the acetal (refluxing aqueous acetic acid) gave 2methylthioveratraldehyde which was condensed with nitromethane and then reduced with lithium aluminum hydride to give the desired phenethylamine.

2 - (2 - Methylthio - 3,4 - dimethoxyphenyl)ethylamine (26 g) is heated to 1150 in an oil bath. Styrene oxide (14.4 g) is added and the reaction is heated for 1 hour. After cooling to 300, hexane-ethyl acetate is used to produce - N - [(2 hydroxy - 2 - phenylethyl)] - N - [2 - (2' - methylthio - 3',4 dimethoxyphenyl)ethyl]amine.

The methylthio containing hydroxyphenethylamine (15 g) is dissolved in a 2:1 mixture of acetic acid/conc. hydrochloric acid. The reaction is - refluxed 2 hours.

After cooling most of the volatiles are stripped off and the residue is poured into water. It is made basic with 50% sodium bicarbonate and extracted with ethyl acetate twice. The extracts are washed with brine, dried and evaporated to give 6 methylthio - 7,8 - dimethoxy - 1 - phenyl - 2,3,4,5 - tetrahydro - lH - 3benzazepine.

EXAMPLE 10 7,8 - Dihydroxy - 6 - methylthio - 1 - phenyl - 2,3,4,5 - tetrahydro - lH - 3 - benzazepine (5.0 g) is suspended in 50 ml of benzene. Trifluoroacetic anhydride (15 g) is added dropwise rapidly. The solution is stirred an additional hour and then the volatiles are stripped off, leaving the N,Q,O-tris-trifluoroacetyl derivatives.

This is added directly to 50 ml of methanol and hydrogen chloride gas is bubbled in for a few minutes. The reaction is stirred for 2 hours and the solvent stripped off, leaving a residue of 7,8 - dihydroxy - 6 - methylthio - 1 - phenyl - 3 trifluoroacetyl - 2,3,4,5 - tetrahydro - lH - 3 - benzazepine.

The N-trifluoroacetyldihydroxy compound (3 g) is reacted with an excess of methyl iodide in the presence of sodium carbonate in aqueous ethanol at room temperature. The crude 7,8 - dimethoxy - 6 - dimethyl sulfonium iodide is isolated by evaporation then heated at reflux in brine solution for 2 hours. The folatiles are evaporated and the residue recrystallized to give 7,8 - dimethoxy - 6methylthio - 1 - phenyl - 3 - trifluoroacetyl - 2,3,4,5 - tetrahydro - 1H - 3 benzazepine. The N-acyl group is removed by treatment with 5% sodium hydroxide in aqueous methanol at room temperature to give 7,8 - dimethoxy - 6 methylthio - 1 - phenyl - 2,3,4,5 - tetrahydro - lH - 3 - benzazepine.

EXAMPLE 11 7,8 - Dihydroxy - 6 - methylthio - I - phenyl - 2,3,4,5 - tetra - lH - 3 - benzazepine hydrobromide (5 g) is dissolved in trifluoroacetic acid and reacted with a stoichiometric quantity of acetyl chloride in the cold. The reaction mixture is quenched in brine and extracted with ethyl acetate to give the desired 7,8diacetoxy derivative. Substituting other alkanoyl anhydrides or chlorides gives various 7,8-dialkanoyl derivative.

EXAMPLE 12 A solution of 7.10 g (18.6 mmoles) of 7,8 - dihydroxy - 1 - phenyl - 6 methylthio - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepine, hydrobromide in 120 ml of aqueous dimethyl-formamide at 0 under an argon atmosphere is basified to pH 10.0 with 10% sodium hydroxide solution. To this cold mixture is added 13.0 g (76 mmoles) of carbobenzoxy chloride in small portions over 15 minutes with concomitant addition of 10% alkali so as to maintain a pH of 10 to 10.5. The reaction is allowed to warm to room temperature after stirring at 0 for 1-1/2 hours.

The mixture is diluted with saturated salt and extracted with three portions of ethyl acetate. The combined organic extract is backwashed twice with saturated salt.

The dried extract is concentrated in vacuo and heated at 750/0.1 mm Hg to remove any benzyl alcohol.

The residue is taken up in 50 ml of glacial acetic acid, cooled to 15 and treated with 14 ml of 40% peracetic acid over 5 minutes at 1e-150. The solution is allowed to warm to room temperature. Further treatment with portions of 40% peracetic acid to complete conversion to the sulfone are often needed. The reaction is quenched in 800 ml of water and extracted with three portions of ethyl acetate. The combined organic layers are washed with two portions of saturated salt, three portions of 5% bicarbonate and two portions of saturated salt. The extracts are dried, treated with decolorizing charcoal, concentrated in vacuo and pumped free of solvent to give 12 g of N-carbobenz Jxy 6-methylsulfonyl compound.

This protected sulfone is treated with 70 ml of 38% hydrobromic acid in glacial acetic acid at room temperature for 2 hours. The solution is added dropwise into 11 of rapidly stirred anhydrous diethyl ether over 40 minutes. The solids are allowed to settle and the supernatant decanted. The precipitate is washed several times with fresh ether and dried under a nitrogen stream to give the hydrobromide salt of 7,8 dihydroxy- 6 - methylsulfonyl - 1 - phenyl - 2,3,4,5 - tetrahydro - 1H - 3 benzazepine.

Using variations of this method with other starting materials the 6trifluoromethylsulfonyl containing compound and other products of this invention can be prepared.

EXAMPLE 13 A solution of 8.6 g (20 mm) of 3 - acetyl - 7,8 - diacetoxy - 1 - phenyl - 6 methylthio - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepine (prepared by reacting the hydroxy parent with an excess of acetic an hydride in pyridine at room temperature) in 40 ml of methanol at --50 is treated with 40 ml of 0.52 M sodium periodate (20.8 mm) dropwise over 15 minutes at 00. The mixture is cooled overnight, then filtered to give a solid which is washed with methylene chloride.

The organic extracts are combined, dried and evaporated in vacuo. The residue is heated at reflux in ethanolic hydrochloric acid overnight. The volatiles are removed and the residue taken up in water. Neutralization with ammonia and extraction with ethyl acetate gives the desired 7,8- dihydroxy - 6methylsulfinyl - 1 - phenyl - 2,3,4,5 - tetrahydro - IH - 3 - benzazepine. The hydrochloride salt is formed by treatment with ethereal hydrogen chloride.

EXAMPLE 14 Mg. per Ingredients Capsule 6 - Methylthio - 7,8 - dihydroxy - 1 - phenyl - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepine (as an acid addition salt) 125 (free base) Magnesium stearate 2 Lactose 200 The above ingredients are thoroughly mixed and placed into hard gelatin capsules. Such capsules are administered orally to subjects in need of treatment from 1--5 times daily to induce dopaminergic or antiparkinsonism activity.

EXAMPLE 15 Mg. per Ingredients Tablet 9 - Methylthio - 7,8 - dihydroxy - 1 - phenyl) - 2,3,4,5 - tetrahydro - 1 H - 3 - benzazepine (as an acid addition salt) 200 (free base) Corn starch 30 Polyvinyl pyrrolidone 12 Corn starch 16 Magnesium stearate 3 The first two ingredients are thoroughly mixed and granulated. The granules obtained are dried, mixed with the remaining corn starch and magnesium stearate, and compressed into tablets.

The capsules or tablets thusly prepared are administered orally to an animal or human requiring stimulation of central dopamine receptors such as to treat the symptom of Parkinson's disease within the dose ranges set forth hereinabove.

Similarly other compounds of Formula I and the illustrative examples can be formulated in the same manner to give pharmaceutical compositions useful in this invention based on the chemical characteristics and relative biological activity using the test methods outlined.

WHAT WE CLAIM IS: 1. A compound of the formula:

in which: R and R3, which are the same or different, are hydrogen; lower alkylthio, sulfinyl or sulfonyl containing 1--5 carbon atoms; trifluoromethylthio, sulfinyl or sulfonyl; or dimethyl sulfonium salt ( < CH3)2SO2X where X is a pharmaceutically acceptable anion), at least one of R and R3 being other than hydrogen R' is hydrogen, lower alkyl containing 1-5 carbons, hydroxyethyl, lower alkyl containing 3-5 carbons, benzyl, phenethyl, carbobenzoxy or lower alkanoyl containing 1-5 carbons; and R2 is hydrogen, halo, trifluoromethyl, methyl, methoxy or hydroxy; O-lower alkyl and O-lower alkanoyl derivatives thereof, the alkyl and alkanoyl groups having 1--5 carbon atoms, and pharmaceutically acceptable non-toxic salts thereof.

2. A compound according to Claim 1, in which R3 is hydrogen and R is methylthio or trifluoromethylthio.

3. A compound according to Claim 1, in which R3 is methylthio and R and R' are both hydrogen.

4. A compound according to Claim 3, in which R2 is hydrogen.

5. A compound according to Claim 1, in which R' and R3 are both hydrogen, R is methylthio or trifluoromethylthio, and R2 is hydrogen, chloro, methyl, trifluoromethyl, methoxy or hydroxy.

6. A compound according to Claim 1, in which one of R and R3 is methylthio and the other is hydrogen, and R' and R2 are both hydrogen.

7. A compound according to Claim 1, in which one of R and R3 is methylthio and the other is hydrogen, R1 is methyl, and R2 is hydrogen.

8. A compound according to Claim 1, in which R is methylthio, R2 and R3 are both hydrogen, and R1 is methyl.

9. A compound according to Claim 1, in which R3 is methylthio, R and R2 are both hydrogen, and R1 is methyl.

10. A compound according to any of the preceding claims, in the form of a non-toxic, pharmaceutically acceptable acid addition salt thereof.

11. A compound according to any of the preceding claims in the form of a hydrobromide thereof.

12. A compound according to any of Claims 1--9, in the form of a base.

13. A compound according to Claim 1, as herein specifically described in any of Examples 1 to 13.

14. A process for preparing a compound as claimed in Claim 1 where R is a lower alkylthio group, which comprises reacting a compound of formula

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (19)

**WARNING** start of CLMS field may overlap end of DESC **. human requiring stimulation of central dopamine receptors such as to treat the symptom of Parkinson's disease within the dose ranges set forth hereinabove. Similarly other compounds of Formula I and the illustrative examples can be formulated in the same manner to give pharmaceutical compositions useful in this invention based on the chemical characteristics and relative biological activity using the test methods outlined. WHAT WE CLAIM IS:

1. A compound of the formula:

in which: R and R3, which are the same or different, are hydrogen; lower alkylthio, sulfinyl or sulfonyl containing 1--5 carbon atoms; trifluoromethylthio, sulfinyl or sulfonyl; or dimethyl sulfonium salt ( < CH3)2SO2X where X is a pharmaceutically acceptable anion), at least one of R and R3 being other than hydrogen R' is hydrogen, lower alkyl containing 1-5 carbons, hydroxyethyl, lower alkyl containing 3-5 carbons, benzyl, phenethyl, carbobenzoxy or lower alkanoyl containing 1-5 carbons; and R2 is hydrogen, halo, trifluoromethyl, methyl, methoxy or hydroxy; O-lower alkyl and O-lower alkanoyl derivatives thereof, the alkyl and alkanoyl groups having 1--5 carbon atoms, and pharmaceutically acceptable non-toxic salts thereof.

2. A compound according to Claim 1, in which R3 is hydrogen and R is methylthio or trifluoromethylthio.

3. A compound according to Claim 1, in which R3 is methylthio and R and R' are both hydrogen.

4. A compound according to Claim 3, in which R2 is hydrogen.

5. A compound according to Claim 1, in which R' and R3 are both hydrogen, R is methylthio or trifluoromethylthio, and R2 is hydrogen, chloro, methyl, trifluoromethyl, methoxy or hydroxy.

6. A compound according to Claim 1, in which one of R and R3 is methylthio and the other is hydrogen, and R' and R2 are both hydrogen.

7. A compound according to Claim 1, in which one of R and R3 is methylthio and the other is hydrogen, R1 is methyl, and R2 is hydrogen.

8. A compound according to Claim 1, in which R is methylthio, R2 and R3 are both hydrogen, and R1 is methyl.

9. A compound according to Claim 1, in which R3 is methylthio, R and R2 are both hydrogen, and R1 is methyl.

10. A compound according to any of the preceding claims, in the form of a non-toxic, pharmaceutically acceptable acid addition salt thereof.

11. A compound according to any of the preceding claims in the form of a hydrobromide thereof.

12. A compound according to any of Claims 1--9, in the form of a base.

13. A compound according to Claim 1, as herein specifically described in any of Examples 1 to 13.

14. A process for preparing a compound as claimed in Claim 1 where R is a lower alkylthio group, which comprises reacting a compound of formula

(in which R' and R2 are as defined in Claim 1) with a mercaptan of the formula RSH (in which R4 is a lower alkyl group) and thereafter optionally acylating, alkylating or oxidising the compound of formula I produced, with a subsequent optional reaction with an acid to form an acid addition salt.

15. A process according to Claim 14, in which R4 is methyl.

16. A process for preparing a compound according to Claim 1, substantially as herein described in any of Examples I to 13.

17. A compound according to Claim 1, when prepared by a process according to any of Claims 14 to 16.

18. A pharmaceutical composition having antiparkinsonism activity comprising a compound according to Claim 1, and a pharmaceutically acceptable carrier.

19. A composition according to Claim 15, in which the compound is 6 methylthio - 7,8 - dihydroxy - 1 - phenyl - 2,3,4,5 - tetrahydro - I H - 3 benzazepine or a non-toxic, pharmaceutically acceptable acid addition salt thereof.