GB1561305A - Benzazepine derivatives and pharmeceutical compositions containing them - Google Patents

Description

(54) BENZAZEPINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM (71) We, SMITHKLINE CORPORA TION, of 1500 Spring Garden Street, City of Philadelphia, Commonwealth of Penusyl vania, 19101, United States of America, a corporation organized under the laws of the Commonwealth of Pennsylvania, 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 relates to benzazepine derivatives and pharmaceutical compositions containing them.

Aocording to the present invention there are provided compounds of the formula:

where R is hydrogen, (C1 ) alkyl, hydroxy ethyl or (C86) alkenyl; Rl, and R2, which are the same or different, are (C2 < ) alkanoyloxy; R, is hydrogen, chlorine, bromine, fluorine, methyl, hydroxy, methoxy, or trifluorcr- methyl; and R4 is hydrogen or methyl.

The alkanoyl groups of the compounds of formula I are, for example, acetyl or pivaloyl groups. A particularly advantageous compound of formula I showing antiparkinsonism activity is 7,Sdipropionyloxy- 1 -phenyl- 2,3,4,5-tetrahydro- 1 H-3-benzazepine.

The compounds of this invention are stimulants of peripheral dopamine receptors. In particular, the compounds of formula I increase renal blood flow and have renal vasodilator activity. Stimulants of peripheral dopamine receptors are therefore useful, for example, in hypertension, shock, congestive cardiac failure and renal insufficiency. Due to the potential for dilating cerebral blood vessels, dopamine agonists may also be useful in the treatment of cerebral artery spasm as in migraine or after subarachnoid haemorrhage.

Evidence has been accumulating to suggest that there are specific peripheral dopamine receptors located in the renal, mesenteric, coronary and cerebral vasculatures that pnF duce vasodilation. The hypothesis is that localized renal vasodilation induced by dop aminergic receptor stimulation effectively lowers arterial blood pressure in hypertension.

The goal for vasodilators specific for the renal vasculature is, by lowering renal vasculature resistance, to increase renal blood flow and produce natriuresis thereby lowering blood pressure.

Parkinson's disease is a neurological disorder characterized by hypokinesia, akinesia, tremor and rigidity of the limbs. Parkinsonism is believed to be brought about by imbalance in the biochemical systems in the brain between the dopaminergic and cholinergic neural pathways. In patients suffering from parkinsonism, a depletion of dopamine in the brain is observed which is the result of progressive degeneration of nigro-striatal dopaminergic neurons.

There is a great need for compounds and compositions which produce anti-parkinsonism activity without having limiting side effects.

It is well known that L-dopa, a potential source of brain dopamine, has clinical utility in treating parkinsonism. LDopa is a precursor of dopamine, being decarboxylated in the brain, and it thereby raises the levels of dopamine in patients who are deficient in it.

However, L-dopa does not qualify as an ideal compound in the treatment of parkinsonism due in part to its limiting side effects, such as, for example, nausea, emesis and anorexia.

The compounds of formula I can exist as diastereoisomers which can be resolved into d, l-optical isomers. Resolution of the optical isomers can be conveniently accomplished by fractional crystallization of their salts with optically active adds from appropriate solvents. Unless otherwise specified herein all isomers are included, whether separated or as mixtures thereof. Where the isomers are separated, the desired pharmacological activity will usually predominate in one of the isomers.

The compounds of formula I can be prepared by reacting the corresponding 3-benzylhydroxy-substituted benzazepine (obtained by alkylation of the hydroxy benzazepine with benzyl bromide in the presence of potassium carbonate) with the appropriate alkanoic acid anhydride, for example acetic anhydride, and the resulting alkanoyloxy-substituted benzazepine is hydrogenated in the presence of palladium-on-carbon to remove the protective benzyl group. Alternatively, the hydroxysubstituted benzazepine hydrohalide salt can be reacted with an excess of an alkanoyl halide, for example propionyl chloride, in trifluoroacetic acid to give the desired alkanoyloxy derivative.

The compounds of formula I where R is hydrogen can be prepared from l-phenyl-2- oxo - 2,3,4,5 - tetrahydro - 1H - 3 - benz- azepine intermediates which can be obtained by heating an appropriate phenylalkylamine with an ester of mandelic acid to give the corresponding amide. The latter can be cyclized as described above to form the 2-oxo benzazepine intermediates which are chemically reduced, for example with borane in tetrahydrofuran, to the benzazepine products.

To prepare the compounds of formula I where R is lower alkyl, hydroxyethyl or lower alkenyl as defined above, the corresponding benzazepines wherein R is hydrogen are alkylated with ethylene oxide, or a lower alkyl or lower alkenyl bromide.

The compounds of formula I where R is methyl are conveniently prepared from methoxy substituted benzazepines wherein R is hydrogen by reaction with formic acid/ formaldehyde. Treatment of the resulting product with boron tribromide gives the corresponding hydroxy-substituted benzazepines which thereafter can be alkanoylated.

The compounds of formula I can be used not only as the free bases but as acid addition salts or quatemary salts thereof, and where reference is made herein to the free bases it is to be understood that it includes the salts.

The acid addition salts can be prepared by methods well known to the art, and they can be formed with 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, and nitric acids. Similarly the quaternary salts of the free bases of formula I include those prepared from organic halides such as methyl iodide, ethyl iodide and benzyl chloride.

The present invention further provides pharmaceutical compositions in dosage unit form comprising a compound invention and a non-toxic pharmaceutically acceptable carrier.

The active ingredients of the compositions of the invention stimulate peripheral dopamine receptors, for example they increase renal blood flow. This renal vasodilator activity of the benzazepine compounds of formula I is me sured in an anesthetized dog. In this pharmacological procedure, a test compound is administered either by rapid i.v. injection at doses of 1, 100 and 1000 mcg/kg, or by infusion of 10 mcg/kg/min up to a maximum of 60 minutes to anesthetized normotensive dogs and the following parameters are measured: renal artery blood flow, femoral artery blood flow, arterial blood pressure and heart rate. Results are reported as a percent change, increase or decrease, at the time of peak response (from controls) and for a significant effect renal blood flow (increase) and renal vascular resistance (decrease) should be approximately 10% or greater. The effect on renal vascular resistance can be calculated from any change in renal blood flow and arterial blood pressure. To confirm the mechanism of action, representative active renal vasodilator compounds are checked for blockade by bulbocapnine which is known to be a specific blocker of renal dopamine receptors.

The anti-parkinsonism activity of the benzazepine compounds of formula I used in the compositions of this invention is 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 6hydroxydopamine lesions of the nigrostriatal dopamine system have been produced. A unilateral 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 nerotransmitter 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, L-dopa and apomorphine, are also effective in this rat 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. 7,8-Dipropionyloxy-l- phenyl - 2,3,4,5 - tetrahydro - 1H - 3benzazepine produced an RD,,,, i.p. of 0.9 mg/kg.

The compositions of this invention are in dosage unit form, and in general they can be prepared by incorporating a compound of formula I or a pharmaceutically acceptable salt thereof, in a non-toxic amount sufficient to produce the desired activity in an animal, with a non-toxic pharmaceutically acceptable carrier according to accepted procedures.

Preferably, the compositions for stimulating peripheral dopamine receptors will contain an active ingredient of formula I in an active but non-toxic amount of from 20 mg. to 1000 mg. of active ingredient per dosage unit.

The compositions for producing anti-parkinsonism activity will contain preferably the active ingredient of formula I in an active but non-toxic amount of from 25 mg. to 100 mg.

of active ingredient per dosage unit.

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 enteric absorption delaying material well known to the art, such as 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, an emulsion, a soft gelatin cap sule, a sterile injectable liquid, for example in an ampoule or for i.v. infusion, or as an aqueous or non-aqueous liquid suspension.

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

In order to stimulate peripheral dopamine receptors the compositions of this invention will in general be administered internally to an animal requiring stimulation of said peripheral dopamine receptors in a non-toxic amount sufficient to stimulate said peripheral dopamine receptors. The active ingredient is preferably administered in a dosage unit containing an active, non-toxic quantity of from 20 mg. to 1000 mg. of the compound of formula I or its salt. The route of administration can be oral or parenteral, the oral route being preferred. Advantageously, equal doses are administered three times a day with the daily dosage regimen being selected from 60 mg. to 3000 mg. For administration by i.v.

infusion, for example over a ten to thirty minute period, a total dose of from 0.5 mg.

to 50 mg. will usually be administered. When the compositions are administered in such manner, stimulation of peripheral dopamine receptors is produced with a minimum of side effects.

Similar administration as described above will produce renal vasodilator activity. In order to produce anti-parkinsonism activity the compositions of this invention will in general be administered internally to an animal requiring treatment of parkinsonism in a non-toxic amount sufficient to produce said activity. The active ingredient is preferably administered in a dosage unit containing an active. nontoxic quantity of from 25 mg. to 100 mg. of the compound of formula I or its salt. The route of administration can be oral or parenteral, the oral route being preferred. Advantageously, equal doses will be administered two or three times a day with the daily dosage regimen being from 50 mg to 300 mg. When the compositions are administered in such manner, antiparkinsonism activity is produced with a minimum of side effects.

The following Examples illustrate the invention.

EXAMPLE 1.

A 3.78 g. (0.009 mol) sample of 3-benzvl- 7,8 - dihydroxy - 1 - phenyl - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepine (prepared from the 3-unsubstituted benzazepine bv reaction with benzyl bromide in the presence of potassium carbonate' is dissolved in 50 ml. of acetic anhydride, and 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 dIyness. The residue is triturated with ethyl acetate, the solution washed with water, dried, and the solvent is removed in vacua to leave an oil.

The latter is dissolved in ether, and ethereal hydrogen chloride is added to precipitate 3benzyl - 7,8 - diacetoxy - 1 - phenyl - 2,3,4,5 tetrahydro- 1H-benzazepine hydrochloride, m.p.

145--1SO"C.

The diacetoxy compound prepared above, 3.5 g. (0.007 mol), is dissolved in 100 ml.

of ethanol and 1 g. of 10% palladium-oncarbon is added. The mixture is hydrogenated in a Parr apparatus at 50"C. under 50 psi of hydrogen for one hour. The reaction mixture is filtered, and the filtrate is evaporated to give 7,8 - diacetoxy - 1 - phenyl - 2,3,4,5tetrahydro - 1H - 3 - benzazepine hydrochloride, m.p. 17e180"C.

EXAMPLE 2.

A solution of 4.2 g. (0.01 mol) of 3-benzyl- 7,8 - dihydroxy - 1 - phenyl - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepine in 20 ml.

of pivalic anhydride is heated on a steam bath for four hours. The reaction mixture is cooled, and excess etheral hydrogen chloride is added followed by 200 ml. of ether to precipitate 3benzyl - 7,8 - di(pivaloyloxy) - 1 - phenyl2,3,4,5 - tetrahydro- 1H- 3 - benzazepine hydrochloride, m.p. 248--2500C.

This compound (2.68 g.) is dissolved in 100 ml. of ethanol and 1.0 g. of 10% palladium-on-carbon is added. The mixture is hydrogenated in a Parr apparatus at 37"C under 50 psi of hydrogen for four hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness to yield 7,8-di(pivaloyloxy) - 1 - phenyl - 2,3,4,5 - tetrahydro lH-3-benzazepine hydrochloride, m.p.

2752760 C.

EXAMPLE 3.

A 10.0 g. (0.0343 mol) quantity of 7,8dihydroxy - 1 - phenyl - 2,3,4,3 - tetrahydro lH-3-benzazepine hydrochloride is slurried in 200 ml. of anhydrous trifluoroacetic acid under nitrogen, and 9.52 g. (0.1029 mol) of plo- pionyl chloride are added dropwise with stirring. After several hours stirring at ambient temperature the reaction mixture is concentrated under reduced pressure. The residual oil is taken up in ethyl acetate, ethereal hydro gen chloride is added, and the solution is concentrated again. The oil is taken up in ethyl acetate, and crystallization is induced with ether and cooling. The solid is recrystallized from ethyl acetate to yield 7,8-dipropionyloxy - 1 - phenyl - 2,3,4,5 - tetrahydro lH-3-benzazepine hydrochloride, m.p.

153-1570C.

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

where R is hydrogen, (C, < ) alkyl, hydroxy ethyl or (Ca < ) alkenyl; Rl, and R2, which are the same or different, are both (C2 < ) alkanoyloxy; R, is hydrogen, chloride, bromine, fluorine, methyl, hydroxy, methoxy or trifluoromethyl; and x is hydrogen or methyl.

2. A compound according to claim 1, in which R3 and R4 are both hydrogen.

3. A compound according to claim 1 or claim 2, in which Rl and R2 are both acetoxy.

4. A compound according to claim 1 or claim 2, in which R, and R2 are both propionyloxy.

5. A compound according to any of claims 1 to 4, in the form of a pharmaceutically acceptable acid addition salt or quaternary salt thereof.

6. A compound according to claim 1, as herein specifically described in any of the Examples.

7. A pharmaceutical composition in dosage unit form comprising a compound according to any of the preceding claims and a nontoxic pharmaceutically acceptable carrier.

8. A pharmaceutical composition according to claim 7, substantially as herein described.

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

Claims (8)

**WARNING** start of CLMS field may overlap end of DESC **. solution washed with water, dried, and the solvent is removed in vacua to leave an oil. The latter is dissolved in ether, and ethereal hydrogen chloride is added to precipitate 3benzyl - 7,8 - diacetoxy - 1 - phenyl - 2,3,4,5 tetrahydro- 1H-benzazepine hydrochloride, m.p. 145--1SO"C. The diacetoxy compound prepared above, 3.5 g. (0.007 mol), is dissolved in 100 ml. of ethanol and 1 g. of 10% palladium-oncarbon is added. The mixture is hydrogenated in a Parr apparatus at 50"C. under 50 psi of hydrogen for one hour. The reaction mixture is filtered, and the filtrate is evaporated to give 7,8 - diacetoxy - 1 - phenyl - 2,3,4,5tetrahydro - 1H - 3 - benzazepine hydrochloride, m.p. 17e180"C. EXAMPLE 2. A solution of 4.2 g. (0.01 mol) of 3-benzyl- 7,8 - dihydroxy - 1 - phenyl - 2,3,4,5 - tetrahydro - 1H - 3 - benzazepine in 20 ml. of pivalic anhydride is heated on a steam bath for four hours. The reaction mixture is cooled, and excess etheral hydrogen chloride is added followed by 200 ml. of ether to precipitate 3benzyl - 7,8 - di(pivaloyloxy) - 1 - phenyl2,3,4,5 - tetrahydro- 1H- 3 - benzazepine hydrochloride, m.p. 248--2500C. This compound (2.68 g.) is dissolved in 100 ml. of ethanol and 1.0 g. of 10% palladium-on-carbon is added. The mixture is hydrogenated in a Parr apparatus at 37"C under 50 psi of hydrogen for four hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness to yield 7,8-di(pivaloyloxy) - 1 - phenyl - 2,3,4,5 - tetrahydro lH-3-benzazepine hydrochloride, m.p. 2752760 C. EXAMPLE 3. A 10.0 g. (0.0343 mol) quantity of 7,8dihydroxy - 1 - phenyl - 2,3,4,3 - tetrahydro lH-3-benzazepine hydrochloride is slurried in 200 ml. of anhydrous trifluoroacetic acid under nitrogen, and 9.52 g. (0.1029 mol) of plo- pionyl chloride are added dropwise with stirring. After several hours stirring at ambient temperature the reaction mixture is concentrated under reduced pressure. The residual oil is taken up in ethyl acetate, ethereal hydro gen chloride is added, and the solution is concentrated again. The oil is taken up in ethyl acetate, and crystallization is induced with ether and cooling. The solid is recrystallized from ethyl acetate to yield 7,8-dipropionyloxy - 1 - phenyl - 2,3,4,5 - tetrahydro lH-3-benzazepine hydrochloride, m.p. 153-1570C. WHAT WE CLAIM IS:

1. A compound of the formula:

where R is hydrogen, (C, < ) alkyl, hydroxy ethyl or (Ca < ) alkenyl; Rl, and R2, which are the same or different, are both (C2 < ) alkanoyloxy; R, is hydrogen, chloride, bromine, fluorine, methyl, hydroxy, methoxy or trifluoromethyl; and x is hydrogen or methyl.

2. A compound according to claim 1, in which R3 and R4 are both hydrogen.

3. A compound according to claim 1 or claim 2, in which Rl and R2 are both acetoxy.

4. A compound according to claim 1 or claim 2, in which R, and R2 are both propionyloxy.

5. A compound according to any of claims 1 to 4, in the form of a pharmaceutically acceptable acid addition salt or quaternary salt thereof.

6. A compound according to claim 1, as herein specifically described in any of the Examples.

7. A pharmaceutical composition in dosage unit form comprising a compound according to any of the preceding claims and a nontoxic pharmaceutically acceptable carrier.

8. A pharmaceutical composition according to claim 7, substantially as herein described.