SE437265B - PROCEDURE FOR THE PREPARATION OF 1-PHENYL-2,3,4,5-TETRAHYDRO-1H-3-BENZZEPINES AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF - Google Patents

Description

7800455-3. l0 l5 2 of any kind and no advantage of such β-methylthio substitution in the structures. However, these references describe certain 7,8-dihydroxy-substituted-1-phenyl-β-benzazepines and various intermediates therefor, some of which serve as starting materials for the production process of the present invention.

It will be apparent to those skilled in the art that the compounds of formula I may exist as diastereoisomers, which may be divided into _c_1- or _1_- optical isomers. The division of the optical isomers can be easily carried out by fractional crystallization of their salts with optically active acids from suitable solvents. Unless otherwise stated herein or the Patent Claims, it is intended that all isomers be embraced, whether separated or present as mixtures thereof. Where isomers are separated, the desired pharmacological activity will often dominate for one of the isomers, usually the d-isomer.

According to the invention, the compounds of formula I are prepared by reacting N / II II a 7,8-dione of formula Û_ H 0 .._ with a mercaptan of formula R451-1, where R1; is lower alkyl 'having 1-5 carbon atoms, in a suitable inert organic solvent, such as an alcoholic solvent, at about room temperature.

The addition reaction also gives the 9-isomer, but the mixture is easily separated into the 6- and 9-isomers by the methods described below.

The compounds of formula I and their non-toxic pharmaceutically acceptable acid addition salts have a novel dopaminergic effect. It is well known that dopaminergic compounds have a dual effect on the dopamine receptors in the central nervous system, especially 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 successive administration of the compound by intravenous infusion at five minute intervals to an anesthetized normotenic dog with measurement of various cardiovascular parameters. The effect on renal vascular resistance can be calculated from each change in renal blood flow and arterial blood pressure. The effect is quantified as an ED 1 j value, which is the cumulative dose, which gives rise to a l966 reduction in renal vascular resistance (R - blood pressure in mm / h) "blood flow ml min The benzazepine compounds of formula I with G-lower alkylthio has particular antiparkinsonism activity due to the central dopaminergic activity, which is demonstrated using a modified standard pharmacological animal experiment reported by Ungerstedt et al., in Brain Research 24, 1970, 485- '493. This method is based on a drug-induced In short, the test includes quantitative registration of the rotational behavior of rats in which S-hydroxidopamine lesions have been produced in the nigrostriatal dopamine system. the caudate to become hypersensitive after the resulting degeneration of the nigral cell bodies. destroys the source of the neutrotransmitter dopamine in the caudate but leaves the caudate cell bodies and their dopamine receptors intact.

Activation of these receptors by the drug component, which causes contralateral rotation relative to the damaged side of the brain, is used as a measure of the drug's central dopaminergic activity.

Compounds which are known to be clinically active in the control of parkinsonism, such as e.g. L-dopa and apomorphine, are also active in this rat rotation model. These compounds directly activate the dopamine receptors and cause contralateral rotation of the injured rat.

Rotational activity is defined as the ability of a compound to produce 500 contralateral rotations over a two-hour period after administration, usually intraperitoneally. The dose corresponding to 500 counter-bilateral rotations in two hours is determined and is denoted by the RD joo value.

The unexpected nature of the biological spectrum of the dopaminergic compounds of formula I is a shift from activity at peripheral receptors to central activity. For example, 7,8-dihydroxy-6-methylthio-1-phenyl-Z, 3,4,5-tetrahydro-3-1H-benzazepine hydrobromide has an RD 500 of 0.18 (0.06-0.29) Ing / kg (0.4 mg / kg base) which is 8 times more potent than its β-hydrogen analogue with an activity with faster onset and longer duration. The ED 15 for this compound is 372, which is 10 times lower than the δ-hydrogen analogue. 7,8-Dihydroxy-9-methylthio-1-phenyl-2,3, / + J-tetrahydro-B-1H-benzazepine hydrobromide has an RD500 of 4.8 mg / kg (3.8 base), which is 3 times more powerful than the 6 ~ hydrogen analogue. The higher alkylthio analogs, i.e. other than methylthio, was weaker in the rotation test than the preferred compounds containing methylthio.

Pharmaceutical compositions with dopaminergic activity are prepared in conventional 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 methods in a non-toxic amount sufficient for to achieve the desired pharmaco-. dynamic activity of a human or animal patient. Preferably, the composition contains the active ingredient in an active but non-toxic amount selected from about 2.5 mg to about 1000 mg of active ingredient per dosage unit form, but this amount depends on the specific desired biological activity and the condition of the patient. The most desirable purpose of the compositions is in the treatment of Parkinson's disease to alleviate or prevent the attacks which are common in patients suffering from this abnormality of the central nervous system. The pharmaceutical carrier used can e.g. be either solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Likewise, the carrier or diluent may comprise any time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate separately or with a wax.

A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or arranged in the form of a pill or lozenge.

The amount of solid carrier can vary widely, but should suitably be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, soft gelatin capsule, sterile injectable liquid, such as an ampoule, or a aqueous or non-aqueous liquid suspension.

The pharmaceutical preparations are prepared according to conventional procedures of the pharmaceutical chemist comprising mixing, granulating and pressing when required, or in various ways performed mixing and dissolving the ingredients as appropriate to give the desired end product.

The method of administering dopaminergic activity described above comprises administering to a patient in need of such activity internally a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, usually in combination with a pharmaceutical carrier, in a non-toxic amount. sufficient to accomplish this activity, as described above.

The route of administration can be any route which efficiently transports the active. the compound to the dopamine receptors to be stimulated, such as orally or parenterally, with the oral route being preferred. Advantageously, equal doses are administered several times such as two or three times a day with the daily dose range selected from about 150 mg to about 1.5 g. When the above-described method is performed, the antiparkinsonism activity is achieved with a minimum of side effects.

The following examples are intended to illustrate the invention. Other modifications of the synthetic procedures and of the possible structural variations become apparent in addition to what is taught in the examples. All temperatures are in ° c.

EXAMPLE 1 To a suspension of 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-β-benzazepine hydrobromide (34 g, 0.101 mol, 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, 0.1 μl mol) in methanol (125 ml). The addition was carried out rapidly with stirring at 0 ° under an argon atmosphere. After stirring at 0 ° C 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-dione hydrobromide (32.8 g, 0.98 mol, 9796) was obtained. , melting point 164-1650 (decomposition).

Calcd. H, 4.84; N, 4.11 Found: C, 56.02; H, 4.76; N, 4.01.

In a stirred solution of 1-phenyl-2,3,4,5-tetrahydro-11-1-3-benzazepine-7,8-dione (5 g, 0.015 mol, formed from the salt above) in methanol (150 ml) an excess of methyl mercaptan was rapidly bubbled. The orange canon was quickly resolved for Anal. 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 -tetra-hydro-1H-3-benzazepine hydrobromide. The 9-isomer could be directly crystallized by dissolving the residue in methanol and diluting to the point of grinding with ethyl acetate, but 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, 4.5 x 15 cm) and eluted with a linear gradient composed of chloroform containing an increasing concentration of methanol (1000 ml, 596 to 20% methanol). The δ-isomer was eluted first followed by a mixture of the 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 (0.0017 mol, 11%), mp 2580 (dec.). Calculated for C 19 H 19 NO 2 S.HBr: C, 53.41; H, 5.27; N, 3.66; S, 8.39 Found: C, 53.41; H, 5.10; N, 3.55; S, 8.6 μl.

Fractions containing the pure 9-isomer were evaporated to a residual Anal. and combined with the 2.2 g obtained by direct crystallization. Recrystallization from methanol-ethyl acetate gave the pure 9-isomer (1.25 g, 0.00% moi, 22%), mp 2700 (dec.).

E. * Calculated for CUHUNOZSHBr: 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-phen-ZI-B-1H-benzazepines A 1 liter round bottom B-neck flask was equipped with a magnetic transducer, argon gas inlet and outlet pipe, and a powder addition funnel. The outlet pipe was arranged so that the exhaust gas bubbled through a solution of sodium hypochlorite (CLORO to remove entrained mercaptan. To a stirred solution of 3- 3.7 ml (0.0 # l-0.07 mol) of the appropriate alkyl mercaptan in 300 ml of methanol 10 g (0.03 mol) of 1-phenyl-7,8-dione-2,3,4,5-tetrahydro-3-1H-benzazepine hydrobromide were added by means of the powder addition funnel. the original brick red color of the solution was changed to light orange before each subsequent addition, this procedure takes about 10 minutes to perform, the resulting yellowish solution was stirred for a further 515-30 minutes and then evaporated under reduced pressure. The oily residue was chromatographed on silica gel, and The products were eluted with a gradient of 5% methanol in chloroform, the ratio of the 6- and 9-isomers is about 1: 2 and the oe isomer is eluted first, however, repeated chromatography is usually required to obtain complete sep. aration. Thus, although the crude yield is rather 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 given in the table below. 7800455-3 7 Compounds Melting point Calculated Found Yield 9-5-ßus- 191-2 ° C 56.60 56.42 14.996 H, 6.18 6.31 N, 3.30 3.22 6-5-ßus- 197 ° C 56.60 56.94 9.696 H 6.18 6.29 N 3.30 3.45 9-: 1-PrS- 245-60 C 55.07 54.72 25.696 H 5.95 5.79 N 3.38 3.30 δ-PrS- 269-700 C 55.61 55.38 18.796 H 5.89 6.16 N 3.41 3.34 s-ßrs- zs7 ° (Sun.) c 54.55 54 13,496 H 5.59 5.71 N 3.53 3.20 6-EtS-215-70 (Sun.) C 54.44 54.42 - 15.196 H 5.59 5.72 N 3.53 3, EXAMPLE 3 Ingredients Mg gives kagsel 6-methylthio-LS-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-β-benzazepine 125 (free base) (as acid addition salt) Magnesium stearate 2 Lactose 200 The above ingredients mix well and place in hard gelatin capsules.

Such capsules are administered orally to patients in need of treatment from 1-5 times daily to induce dopaminergic or antiparkinsonism activity.

EXAMPLE 4 Ingredients Mg gives tablet 9-methylthio-LS-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-β-benzazepine 200 (free base) (as acid addition salt) Maize starch Polyvinylpyrrolidone 12 Maize starch 16 Magnesium stearate 3 7800455-3. 8 Mix the first two ingredients and mix well. The resulting granules are dried, mixed with the remaining corn starch and magnesium stearate, and compressed into tablets.

The capsules or tablets thus prepared are administered orally to an animal or human which requires stimulation of central dopamine receptors, e.g. to treat symptoms of Parkinson's disease, within the above dose ranges. Similarly, other compounds of formula I and according to the illustrative examples may be formulated in the same manner to give useful pharmaceutical compositions based on the chemical properties and relative biological activity using the test methods described.

Claims (1)

A process for the preparation of a compound of the structural formula: I wherein R and RB are hydrogen or lower alkylthio having 1 to 5 carbon atoms, wherein one of R 1 and R 3 is lower alkylthio having 1-5 carbon atoms and the other is hydrogen, or a non-toxic pharmaceutically acceptable acid addition salt thereof, characterized in that a compound of the structural formula: \ NH O_ 0 "; - / \ is reacted with a mercaptan of the formula R4SH where 124 is lower alkyl of 1 -5 carbon atoms, optionally separating a resulting mixture of 6- and 9-isomers into the individual isomers, and optionally reacting with an acid to form a non-toxic pharmaceutically acceptable acid addition salt.