EP0589973A1

EP0589973A1 - Medicaments

Info

Publication number: EP0589973A1
Application number: EP92912293A
Authority: EP
Inventors: John Gerard Ward; Rodney Christopher Young; Alberto Julio Kaumann
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 1991-06-21
Filing date: 1992-06-17
Publication date: 1994-04-06
Also published as: MX9203012A; IE921990A1; PT100602A; WO1993000094A3; CA2110575A1; JPH06508352A; AU1927992A; WO1993000094A2; KR940701258A

Abstract

L'invention se rapporte à des dérivés de tétrahydrobenzazépine utilisés comme médicaments.The invention relates to tetrahydrobenzazepine derivatives used as medicaments.

Description

MEDICAMENTS The present invention relates to certain tetrahydrobenzazepine derivatives for use in the treatment of disorder characterised by excessive vasodilatation, in particular the treatment of portal hypertension and the treatment and prophylaxis of migraine, and more generally to the use of 5-HT₂ and 5-HT₁-like receptor agonists in the treatment of portal hypertension and to the use of 5-HT₂ agonists in the treatment and prophylaxis of migraine.

Portal hypertension, which is commonly associated with cirrhosis of the liver is characterised by increased portal venous blood flow, (which is caused by dilatation of

mesenteric arterioles), and increased portal vascular

resistance. A serious complication of this condition is rupture of esophageal varices or paraesophageal collaterals, which develop to reduce portal pressure.

It has now been found that certain tetrahydrobenzazepines known in the art for the treatment of

gastrointestinal motility disorders are agonists at 5-HT₂ and/or 5-HT₁-like-receptors and are expected to have utility in the treatment of portal hypertension.

Migraine is a non-lethal disease suffered by one in ten individuals. The main symptom is headache; other symptoms include vomiting and photophobia. Currently, the most widely used treatment for migraine involves administration of ergotamine, dihydroergotamine or methysergide. All these drugs are inter alia agonists of 5HT₁-like receptors but also have other actions; treatment with them is associated with a number of adverse side effects. In addition, some patients experience a "withdrawal headache" following the cessation of treatment with an ergot product, such as ergotamine, causing them to repeat the treatment and resulting in a form of addiction. In view of the foregoing, there is clearly a need for the provision of effective and safe medicaments for the treatment of migraine. It has now been found that certain tetrahydrobenzazepines known in the art for the treatment of

gastrointestinal motility disorders are agonists at 5HT₁-like and/or 5HT₂-receptors and are expected to have utility in the treatment of migraine.

The present invention therefore provides compounds of structure (I):

in which:

R is hydrogen, C_1-6alkyl or C_3-5alkenyl;

R¹ is NO₂, cyano, halo, COR³, SO_nR⁴ or

SO_nNR⁵R⁶;

R² is hydrogen, hydroxy or C_1-4alkoxy;

R³ is hydrogen, C_1-4alkyl, OR⁵ or NR⁵R⁶;

R⁴ is C_1-6alkyl or halo C_1-6 alkyl;

R⁵ and R⁶ are hydrogen, C_1-6alkyl or C_3-6 cycloalkyl; and n is 1 or 2;

and pharmaceutically acceptable salts thereof for use in the manufacture of a medicament for the treatment of portal hypertension and/or migraine.

Suitably R is hydrogen, C_1-6alkyl or C_3-5alkenyl;

preferably R is hydrogen. Suitably R¹ is nitro, cyano, halo, COR³, SO_nR⁴ or

SO_nNR⁵R⁶; preferably R¹ is SO_nR⁴, nitro or halo; most preferably R¹ is SO_nR⁴. Suitably n is 1 or 2; preferably n is 2.

Suitably R² is hydrogen, hydroxy or C_1-4alkoxy;

preferably R² is C_1-4alkoxy or hydroxy.

Suitably R³ is hydrogen, C_1-4alkyl, OR⁵ or NR⁵R⁶;

preferably R³ is C_1-4alkyl, in particular methyl.

Preferably the group R¹ is at the 8-position and the group R² is at the 7-position of the ring of the compound of structure (I).

Suitably R⁴ is C_1-6alkyl or halo C_1-6 alkyl;

preferably R⁴ is C_1-6alkyl, or C_1-6 alkyl substituted by 1 to 6 halogen atoms (eg. CF₃) and most preferably R⁴ is methyl.

Suitably R⁵ and R⁶ are hydrogen or C_1-6alkyl, or C_3-6 cycloalkyl. Preferably, when both groups represent C_1-6 alkyl, they are the same. C_1-6alkyl groups, either alone or as part of another group, can be straight or branched.

Suitable salts will be apparent to those skilled in th art, and include, for example, acid addition salts such as the hydrochloride, or the oxalate.

Suitable examples of compounds for use in the present invention are as described in EP-0229510-B, for example : 7-hydroxy-8-sulphamoyl-2,3,4,5-tetrahydro-1H-benzazepine, an 7-hydroxy-8-(N,N-dimethylsulphamoyl)-2,3,4,5-tetrahydro-1H-benzazepine. In particular the present invention relates to the use of a compound in which R is hydrogen, R¹ is methylsulphonyl and R² is hydroxy, namely, 7-hydroxy-8- methylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of migraine.

Certain compounds falling within the scope of structur (I) are themselves novel and as such form a further aspect o the invention. These compounds are in particular:

7-methoxy-8-methylsulphinyl-2, 3, 4, 5-tetrahydro-1H- benzazepine oxalate;

7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride;

7-hydroxy-8-nitro-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride;

7-methoxy-8-bromo-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride;

7-hydroxy-8-bromo-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride;

7-methoxy-6-nitro-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride;

6-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride;

8-acetyl-7-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride;

7-hydroxy-8-methylsulphinyl-2,3,4,5-tetrahydro-1H-benzazepine; and

7-hydroxy-8-trifluoromethylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepine.

Compounds of structure (I) may be prepared by the methods described in EP 0229510-B, or by the following methods : a) to prepare a compound of structure (I) where R¹ represents -SO_nR⁴, the reaction of a compound of structure (II) :

(wherein R² and R⁴ are as hereinbefore defined and R⁷ is an N-protecting group) with an oxidising agent, in the presence of titanium trichloride; b) to prepare a compound of structure (I) wherein R¹ represents -COR³, NO₂ or halogen, the reaction of a compound of structure (III) :

(wherein R², R³ and R⁷ are as hereinbefore defined) with an appropriate acylating, nitrating or halogenating agent respectively; followed in each case by removal of the N-protecting group, and if desired salt formation. Suitable N-protecting groups R⁷ are well known in the art and include acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, and benzyloxycarbonyl. N-deprotection may be carried out by conventional methods. In process (a) the oxidising agent may be for example hydrogen peroxide or a peracid such as 3-chloroperbenzoic acid, in a solvent such as acetic acid. It will be appreciated that one equivalent of the oxidising agent will produce a compound wherein n is 1 and two or more equivalents will give a compound wherein n is 2. In process (b) the acylating agent may be for example an acid chloride or acid anhydride corresponding to the group R³CO-. The reaction is desirably effected in the presence of tin tetrachloride. Nitration may be effected using

concentrated nitric acid in admixture with acetic anhydride, followed by neutralisation with e.g. sodium bicarbonate.

Halogenation may be carried out with an acidic solution of halogen e.g. Br₂ in acetic acid, followed by neutralisation with e.g. sodium bicarbonate. In general the nitration and halogenation reactions will result in a mixture of isomeric compounds, substituted respectively at the 7,8 and 6,7 positions of the benzazepine ring, which may be separated for example by chromatography, or crystallisation.

The compounds of structure (I) have been found to be agonists at 5-HT₂ and/or 5-HT^-like receptors and are

expected to have utility in medicine in the treatment or prophylaxis of portal hypertension. Whilst not wishing to be bound by theory, it is believed that 5-HT₁-like agonists and 5-HT₂-agonists are effective in portal hypertension through constriction of mesenteric arterioles, and partial constriction of paraesophageal collaterals with consequent reduction of portal flow and portal pressure. Preferred compounds for use according to the present invention are partial agonists at 5-HT₂ receptors and/or 5-HT₁-like

receptors.

It is believed that the use of 5-HT₂ and 5-HT₁-like-receptor agonists in the treatment of portal hypertension ha not previously beeen described and hence represents a novel use for these classes of compounds. In a further aspect

therefore the present invention provides 5-HT₂ receptor agonists and 5-HT₁-like-agonists for use in the treatment of portal hypertension. The invention also provides the use of 5-HT₂ receptor agonists and 5-HT₁-like-agonists in the

manufacture of a medicament for the treatment of portal hypertension. Also provided is a method of treating portal hypertension which comprises administering to a subject in need thereof an effective amount of a 5-HT₂-agonist or 5-HT₁-like-agonist. For use according to the present invention a 5-HT₂-agonist or 5-HT₁-like-agonist is preferably a partial agonist at the said receptor. Most preferably, a compound for use according to this invention is a partial agonist at both 5-HT₂ and 5-HT₁-like receptors. The compounds of structure (I) have been found to be agonists at 5HT₁-like and/or 5HT2 receptors and are expected to have utility in medicine in the treatment or prophylaxis of migraine. Whilst not wishing to be bound by theory, it is believed that 5HT₁-like agonists are effective in migrain through constriction of cerebral arteries and that 5HT₂ agonists constrict the superficial temporal artery.

Preferred compounds for use according to the present

invention are partial agonists at 5HT₁-like and/or 5HT₂ receptors.

It is believed that the use of 5-HT₂-receptor agonists in the treatment of migraine has not previously been

described and hence represents a novel use for this class of compound. In a further aspect therefore the present

invention provides 5-HT₂-receptor agonists for use in the treatment of migraine. The invention also provides the use of 5-HT₂-receptor agonists in the manufacture of a medicamen for the treatment of migraine. Also provided is a method of treating migraine which comprises administering to a subject in need thereof an effective amount of a 5-HT₂ agonist. For use according to the present invention a 5-HT₂-agonist is preferably a partial agonist at this receptor.

In therapeutic use the compounds are incorporated into standard pharmaceutical compositions. They can be

administered orally, parenterally, rectally or transdermally

The compounds of structure (I) and their

pharmaceutically acceptable salts which are active when give orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for

example, ethanol, glycerine, non-aqueous solvent, for exampl polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carrier include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier (s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

The compounds of structure (I) and their

pharmaceutically acceptable salts which are active when administered parenterally (i.e. by injection or infusion) can be formulated as solutions or suspensions.

A composition for parenteral administration will generally consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, for example polyethyleneglycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.

Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to

administration. A typical suppository composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.

A typical transdermal formulation comprises a

conventional aqueous or non-aqueous vehicle, for example, a cream, ointment lotion or paste or in the form of a

medicated plaster, patch or membrane.

Preferably the composition is in unit dose form. Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 150 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base. The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 400 mg, for example between 10 and 400 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 30 mg, for example between 1 and 30 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be

administered for a period of continuous therapy.

BIOLOGICAL DATA 5-HT₁-like Receptor Screen Dog Saphenous Vein

Helicoids of dog saphenous vein were set up at 37°C in modified Krebs solution at a resting force of 10 mN. The solution also contained 1 μmol/1 each of ketanserin prazosin, atropine and mepyramine, 6 μmol/1 cocaine and 200 μmol/1 ascorbate. Nearly isomeric contractions were measured with force transducers on a polygraph. The tissues were exposed twice to 5-hydroxytryptamine (5-HT) 2 μmol/1 followed by washes. A cumulative concentration-effect curve to the test compound was determined, followed by a curve to 5-HT in the presence of the highest used concentration of test compound. Contractions caused by the test compound were compared with those caused by 5-HT. The intrinsic activity of the test compound was calculated as the ratio of the maximum test compound-induced effect over the effect caused by 2 μmol/1 5-HT. The EC₅₀ of the test compound was estimated from the corresponding effect curve. When appropriate equilibrium dissociation constraints Kp were estimated by the method of Marano & Kaumann (1976, J. Pharmacol. Exp. Ther. 198, 518-525).

The compounds of structure (I) have been found to demonstrate activity in this screen, for example:

7-hydroxy-8-methylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepin (prepared according to the procedures described in EP 229510-B), was found to have an EC₅₀ of 0.2 μM, and the compound of Example 1 an EC₅₀ of 20 μM.

RABBIT BASILAR ARTERY

METHODS

Experiments were performed in intracranial arteries from rabbit isolated basilar artery in a similar method to one described previously (Parsons and Whalley, 1989. Eur J Pharmacol 174, 189-196.).

In brief, rabbits were killed by overdose with

anaesthetic (sodium pentobarbitone). The whole brain was quickly removed and immersed in ice cold modified Kreb's solution and the basilar artery removed with the aid of a dissecting microscope. The Krebs solution was of the following composition (mM) Na⁺ (120); K⁺ (5); Ca²⁺ (2.25); Mg²⁺ (0.5); Cl- (98.5); SO₄ ^2- (1); EDTA (0.04), equilibrated with 95% 02/5% CO₂. The endothelium was removed by a gentle rubbing of the lumen with a fine metal wire. Arteries were then cut into ring segments (ca 4-5 mm wide) and set up for recording of isometric tension in 50 ml tissue baths in modified Krebs solution with the additional supplement of

(mM) ; Na²⁺ (20); fumarate (10); pyruvate (5); L-glutamate (5 and glucose (10). The arteries were then placed under a resting force of 3-4 mN maintained at 37°C and the solution bubbled with 95% 02/5% CO₂.

After tests for initial reactivity with 90 mM KCl depolarising solution and for lack of acetylcholine-induced relaxation of 5-HT (10 mM) precontraction, cumulative concentration-effect curves (2 nM-60 mM) to 5-HT were constructed in the presence of ascorbate 200 mM, cocaine 6 mM, indomethacin 2.8 mM, ketanserin 1 mM and prazosin 1 mM.

Following a 45-60 min wash period, cumulative

concentration-effect curves to the test compounds or 5-HT (a a time match control) were constructed in the presence of ascorbate, indomethacin, cocaine, ketanserin and prazosin.

5-HT₂-Receptor Screen Rat Tail Artery (Kaumann A.J. & Frenken M. 1988, J.

Pharmacol. Exp. Pharmacol. 245, 1010-1015)

The ventral caudal artery was used from rats pretreate with reserpine 7mg/kg ip (20 h). Five interconnected arterial rings were prepared and set up to contract in modified Krebs solution at 32.5°C as follows. Resting for of the rings was set to be 4 mN and the rings allowed to relax thereafter without further readjustment. Three cumulative concentration-effect curves were determined, the first to 5-HT followed by washout, the second to the test compound and the third to 5-HT in the presence of the highe used concentration of test compound. The intrinsic activi of the test compound was calculated as the ratio of the maximum test compound-induced effect over maximum 5-HT- induced effect. The EC₅₀ of the test compound was estimat from the corresponding concentration-effect curve.

Equilibrium dissociation constants Kp were estimated by the method of Marano & Kaumann (1976, J. Pharmacol. Exp. Ther., 198, 518-525).

The compounds of structure (I) have been found to demonstrate activity in this screen, for example, 7-hydroxy- 8-methylsulphonyl-2,3,4,5-tetrahydro-1H- benzazepine was found to have an EC₅₀ of 2 μM, and the compound of Example 2 an EC₅₀ of 1 μM.

Portal Hypertension - In vivo

The effect of 7-hydroxy-8-methylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepine was investigated on superior mesenteric arterial flow in conscious normal and portal vein ligated rats (Sprague-Dawley). Portal hypertension in porta vein-ligated rats was produced as described (Groszmann et al 1982). A Doppler flowmeter probe was implanted into the superior mesenteric artery for chronic studies. Superior mesenteric flow changes were observed during 4 days, followe by 4 days' exposure to 7-hydroxy-8-methylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepine in the drinking water and another period of 4 days without 7-hydroxy-8-methylsulphony1-2,3,4,5tetrahydro-1H-benzazepine in the drinking water. 7-hydroxy- 8-methylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepine

significantly reduced superior mesenteric flow in both sham-operated and portal vein-ligated rats. The effect was reversible during the last 4 day period without 7-hydroxy-8- methylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepine in the drinking water.

Groszmann R J, Vorobioff J and Riley E (1982). Splachnic hemodynamics in portal hypertensive rats: measurement with gamma-labelled microspheres. Am J Physiol 242: G156-G160.

PHARMACEUTICAL FORMULATIONS

1. Formulation for intravenous infusion

Compound of structure (I) 0.1 - 150 mg

Sodium hydroxide/hydrochloric acid to pH ca 7 polyethylene glycol 0 - 30 ml propylene glycol 0 - 30 ml alcohol 0 - 10 ml water to 100 ml

2. Formulation for bolus injection

Compound of structure (I) 0.1 - 150 mg sodium hydroxide or hydrochloric acid to pH ca 7 polyethylene glycol 0 - 2.5 ml alcohol 0 - 2.5 ml water to 5 ml

A toxicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added.

3. Tablet for oral administration

mg/tablet

Compound of structure (I) 50 lacatose 153 starch 33 crospovidone 12 microcrystalline cellulose 30 magnesium stearate 2

280 Examples

Compounds within the scope of the present invention (e.g. 7-hydroxy-8-methylsulphonyl-2,3,4,5-tetrahydro-1H-3-benzazepine) can be prepared using the methods describ in EP-229510-B or the methods disclosed hereinbefore.

Example 1 7-Methoxy-8-methylsulphinyl-,3,4,5-tetrahydro-1H-benzazepine monooxalate

3-Acetyl-7-methoxy-8-methylthio-2,3,4,5-tetrahydro-1H-benzazepine (3.04g) was dissolved in methanol (500 ml) a treated with a 15% solution of titanium trichloride (11.8g), followed by 6% hydrogen peroxide solution (18.0g), dropwise, with stirring, over 10 minutes at room temperature. After stirring for a further 30 minutes, the reaction mixture was filtered, diluted with water and extracted with chloroform. The latter extract was washed with aqueous sodium sulphite, then water, dried, filtered, and evaporated to dryness leaving 3-acetyl-7-methoxy-8-methylsulphinyl-,3,4,5-tetrahydro-1H-benzazepine (3.21g) as a solid, m.p. 130-2°C. The above product (20mg) was hydrolyzed by refluxing solution in isopropanol (1ml) with 40% aqueous sodium hydroxide (1ml) for 60 hours. Most of the isopropanol was evaporated in vacuo, and the remaining solution was diluted with water, and extracted with chloroform. The extracts were combined, dried (MgSO₄) and evaporated to give 7-methoxy-8-methylsulphinyl-,3,4,5-tetrahydro-1H-benzazepine (17mg) which was converted to the monooxalate salt, m.p. 21 4°C. Example 2

7-Methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride

Concentrated nitric acid (0.6ml, 70% w/w) was added a stirred, ice-cooled solution of 3-acetyl-7-methoxy- 2,3,4,5-tetrahydro-1H-benzazepine (1.98g) in acetic anhydr (30ml) over 5-6 hours. The solution was allowed to warm room temperature and, after standing overnight, was added saturated aqueous sodium bicarbonate. When all of the excess acetic anhydride had reacted, the resulting mixture was saturated with sodium chloride and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgS04) and evaporated to a gum, which was purified b chromatography (SiO₂/ C₆H₁₄/EtOAc) to give 3-acetyl-7- methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzazepine (0.93g), m.p. 127-132°C and 3-acetyl-6-nitro-7-methoxy-2,3,4,5- tetrahydro-1H-benzazepine which was recrystallised from benzene (0.16g), m.p. 143-149°C.

The above product (3-acetyl-7-methoxy-8-nitro- 2,3,4,5-tetrahydro-1H-benzazepine) (0.90g) was heated at reflux in 3N.HC1 (54ml) for 16 hours. The resulting solution was evaporated to dryness to leave a yellow solid which was triturated with acetone and collected by

filtration. The beige solid thus obtained was dried over P₂O₅ and recrystallised from methanol to give 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride

(0.74g), m.p. 234-7°C.

Example 3

7-Hydroxy-8-nitro-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride

7-Methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (0.40g) was dissolved in 48% aqueous

hydrobromic acid, and the solution was heated to reflux for 24 hours. The solution was evaporated to dryness to leave crude yellow solid which was basified and purified by chromatography (SiO₂; CHCl₃/MeOH), then recrystallised from methanol/conc. hydrochloric acid to give 7-hydroxy-8-nitro-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (0.11g), m.p 251-5°C.

Example 4

7-Methoxy-8-bromo-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride

3-Acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-benzazepine (5.0g) was dissolved in glacial acetic acid (70ml) and heate to 70°C. A 1.0M solution of bromine in acetic acid was added over 20-30 minutes, and the resulting solution was heated at 70°C for a further hour. The solution was allowe to cool overnight, during which a mass of beige crystals was obtained. These were collected by filtration, basified and purified by chromatography (SiO₂; CH₂Cl₂/EtOAc), followed by crystallisation from ethyl acetate/ether to give 3-acetyl-7-methoxy-8-bromo-2,3,4,5-tetrahydro-1H-benzazepine (1.55g), m.p. 123-125°C, and 3-acetyl-6-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-benzazepine, m.p. 99-101°C. The above product (3-acetyl-7-methoxy-8-bromo- 2,3,4,5-tetrahydro-1H-benzazepine) (0.30g) was heated under reflux in 3M HC1 (16.5ml) for 20 hours. The solution was evaporated to dryness in vacuo and triturated with acetone t give 7-bromo-8-methoxy-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride as a white solid (0.25g), m.p. 268-272°C.

Example 5 7-Hydroxy-8-bromo-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride

A solution of 3-acetyl-7-methoxy-8-bromo-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) in dichloromethane (12 ml) was cooled in an acetone/dry ice bath. Boron tribromide (0.32 ml) was added to the stirred solution in one portion, and the mixture was allowed to warm to room temperature over 1 hour. Stirring was continued for a further 30 minutes, then water was added. The mixture was partitioned between water and dichloromethane, and the aqueous layer was re- extracted with dichloro-methane. The combined extracts wer washed with water and brine, dried (MgSO₄) and evaporated to a solid, which was purified by chromatography (SiO₂;

CHCl₃/MeOH) to give 3-acetyl-7-hydroxy-8-bromo -2,3,4,5- tetrahydro-1H-benzazepine as a white solid (0.37 g).

The above product (0.30 g) was heated in 3H HCl (50 ml) to reflux overnight. The resulting solution was evaporated to dryness and triturated with acetone to give a white solid. This was recrystallised from n-propanol/ HCl to give the title compound as white crystals (0.21 g), m.p. 277-281°C.

Example 6 7-Methoxy-6-nitro-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride

The title compound was prepared following the

procedures described in Example 2, by heating 3-acetyl-7-methoxy-6-nitro-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride (0.15g) in 3N.HCl (9mL) at reflux. The product, 7-methoxy-6-nitro-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride, was isolated as described, and recrystallised from n-propanol to give small yellow crystals (0.077g), m.p. 258-61°C decomp.

Example 7

6-Bromo-7-methoxy-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride

The title compound was prepared following the

procedures described in Example 2, by heating 3-acetyl-6-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-benzazepine (0.20g) in 3N.HCl (11 mL) at reflux. The product, 6-bromo-7-methoxy- 2,3,4,5-tetrahydro-1H-benzazepine hydrochloride, was isolate as described and recrystallised from n-propanol to give whit needles (0.12g), m.p. 255-60°C. Example 8

8-Acetyl-7-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine

hydrochloride Tin tetrachloride (2.4 mL) was added dropwise, with stirring to a solution of acetyl chloride (1.46 mL) in CH₂CI₂ (15 mL), at room temperature. Stirring was continued for a further 1 hour, and then a solution of 7-methoxy-3-acetyl-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (3.0g) in CH₂CI₂ (15 mL) was added over a period of 20 minutes. The mixture was left to stir for 16 hours, and then partitioned between 3N.HCl and CH₂CI₂. The aqueous layer was re-extracted and the combined organic layers were washed with saturated sodium bicarbonate solution and then H₂O, dried (MgSO₄) and evaporated. The residue was dissolved in methanol and treated with charcoal. The filtrate was evaporated to dryness and the residue extracted twice with boiling benzene, the extracts decanted combined and

evaporated to give a solid which was triturated with ether. The product, 3,8-diacetyl-7-methoxy-2,3,4,5-tetrahydro-1H-benzazepine, was obtained as an off-white solid (1.7g), m.p. 142-6°C.

The 3,8-diacetyl-7-methoxy-2,3,4,5-tetrahydro-1H-benzazepine (0.20g) was dissolved in CH₂CI₂ (5 mL) and cooled to ca -70°C (acetone/solid CO₂ bath). Boron trichloride (1.0M solution in CH₂CI₂; 1.53 mL) was added from a syringe over 10 minutes. The mixture was allowed to warm slowly to room temperature (1 hour) and then stirred for a further 30 minutes. The reaction was quenched by the addition of H₂O and the mixture was partitioned between water and CH₂CI₂- The aqueous layer was re-extracted with CH₂CI₂ and the combined organic layers washed with water and brine, and dried (MgSO₄). Evaporation gave a gum which was purified b flash chromatography (SiO₂; CHCl₃/MeOH). The product, 3,8- diacetyl-7-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine, crystallised from ether as an off-white solid (0.129g), m.p. 131-4°C. The above diacetyl compound (0.121g) was heated at reflux in 3M.HC1 (3.7 mL) for 16 hours. The solution was then evaporated to dryness, giving a yellow-orange

crystalline solid. This was recrystallised from n-propanol containing dissolved HCl gas, to yield the product, 8-acetyl- 7-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride, as small orange crystals (0.064g), m.p. 241-7°C decomp.

Example 9 7-Hydroxy-8-methylsulphiny1-2,3,4,5-tetrahydro-1H-benzazepin

Aluminium chloride (1.71 g) was added to

dichloromethane (50 ml) at room temperature, and a solution of 3-acetyl-7-methoxy-8-methylsulphinyl-2,3,4,5-tetrahydro- 1H-benzazepine (0.90 g) in dichloromethane was added dropwis with stirring over 3h. After leaving the mixture to stir overnight at room temperature, the dichloromethane solution was decanted from the precipitated gum. The latter was digested with IM sodium hydroxide solution, and the resultin aqueous solution was washed with dichloromethane, acidified to pH2 with cone. HCl and extracted (3x) with chloroform.

The extract was dried (MgSO₄), evaporated to an oil, and purified by chromatography (SiO₂; MeOH/CH₂Cl₂) to give 3-acetyl-7-hydroxy-8-methylsulphinyl-2,3,4,5-tetrahydro-1H-benzazepine (0.72 g).

The above product (0.64 g) was heated with IM sodium hydroxide solution (10 ml) at 100°C overnight. After

cooling, the mixture was passed down an ion exchange column (Amberlite CG50; NH4⁺) and eluted with water. The resulting eluate was evaporated to dryness, extracted with hot

methanol, treated with activated charcoal, filtered and evaporated to a green gum. This crystallized on addition of acetonitrile to give the title compound (0.45 g), mp 175-8°C.

Example 10

7-Hydroxy-8-trifluoromethylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepine

3-Acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-benzazepine (7.0 g) was dissolved in dry dichloromethane (100 ml), cooled in an ice bath, and treated dropwise with chlorosulphonic acid (13.9 g), with stirring. The mixture was stirred for a further 2 1/2 h at room temperature and then poured carefully onto ice. The resulting brown oil was partitioned between dichloromethane and water, and the aqueous layer was

extracted further with dichloromethane. Combined organic extracts were dried (MgS04> and evaporated to give 3-acetyl-7-methoxy-8-chlorosulphonyl-2,3,4,5-tetrahydro-1H-benzazepin (4.5 g).

The above product (3.95 g) was dissolved in acetic aci (75 ml), and stannous chloride dihydrate (11.2 g) and cone. HCl (15 ml) were added. The mixture was stirred at 75°C for 1 h then poured into ice water and shaken with ethyl acetate The solid thus produced was combined with the ethyl acetate extracts and evaporated to dryness in vacuo. This crude product was shaken with dry ethanol (200 ml) and filtered. The resulting solid was stirred with 1M NaOH solution (100 ml) for 30 min., filtered, acidified with cone. HCl and extracted with chloroform. The extracts were combined, dried (MgSO₄) and evaporated to dryness to give 3-acetyl-7-methoxy-8-mercapto-2,3,4,5-tetrahydro-1H-benzazepine (1.86 g).

This product (1.22 g) was dissolved in dry DMF (50 ml) and potassium carbonate (1.33 g) added. Trifluoromethyl iodide was bubbled through the solution, while irradiating with U.V. light, with cooling, for 5 h. Most of the DMF was removed under vacuum, and the residue was partitioned between chloroform and 1M NaOH solution. The organic phase was drie (MgSO4) and evaporated to dryness. The residue was purified by chromatography (SiO₂; CHCl₃/MeOH) to give 3-acetyl-7- methoxy-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzazepine (0.33 g).

The above product (1.0 g) was dissolved in 1,2- dichloro-ethane (75 ml) and meta-chloro perbenzoic acid (2.26 g) was added. The mixture was heated under reflux for 2 h. The resulting cooled solution was washed with IM NaOH

solution, dried (MgSO4) and evaporated to dryness leaving 3- acetyl-7-methoxy-8-trifluoromethylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepine (0.95 g). This product (0.50 g) was dissolved in dichloromethane (100 ml) and boron tribromide (0.71 g) was added dropwise with stirring at room temperature overnight. Methanol was added cautiously, dropwise, and the solvents were removed in vacuo. The residual green oil consisting of the 7-hydroxy compound was dissolved in chloroform and washed with 1M NaOH solution.

The aqueous phase was separated and heated at 100°C for 40 h, cooled, and passed down an ion exchange column

(Amberlite CG-50(H). The relevant fractions were combined and evaporated to dryness to leave a residue which was chromatographed (SiO₂: CHCl₃/MeOH/MH₄OH) to give a product which was crystallized under acetonitrile to give the title compound (0.12 g), mp >273°C.

Claims

CLAIMS :

1. The use of a compound of structure (I)

in which:

R is hydrogen, C_1-6alkyl or C_3-5alkenyl;

R¹ is NO₂, cyano, halo, COR³, SO_nR⁴ or

SO_nNR⁵R⁶;

R² is hydrogen, hydroxy or C_1-4alkoxy;

R³ is hydrogen, C_1-4alkyl, OR⁵ or NR⁵R⁶;

R⁴ is C_1-6alkyl or halo C_1-6alkyl;

R⁵ and R⁶ are hydrogen or C_1-6alkyl or C_3-6 cycloalkyl; and n is 1 or 2;

or a pharmaceutically acceptable salt thereof in the

manufacture of a medicament for the treatment of portal hypertension and/or migraine.

2. The use of a compound according to claim 1 in which R¹ is at the 8-position and R² is at the 7-position of the ring of the compound of structure (I).

3. The use of a compound according to claim 1 or claim 2 in which R¹ is SO₂R³, R² is hydrogen, alkoxy or hydroxy and R is hydrogen.

4. The use of a compound according to any of claims 1 to 3 in which R³ is methyl and R² is hydroxy.

5. The use of a compound according to claim 1 which is 7-hydroxy-8-methylsulphonyl-2, 3, 4, 5-tetrahydro-1H- benzazepine.

6. A compound according to claim 1 which is:

7-methoxy-8-methylsulphinyl-,3,4,5-tetrahydro-1H-benzazepine

7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzazepine;

7-hydroxy-8-nitro-2,3,4,5-tetrahydro-1H-benzazepine;

7-methoxy-8-bromo-2,3,4,5-tetrahydro-1H-benzazepine;

7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine;

7-methoxy-6-nitro-2,3,4,5-tetrahydro-1H-benzazepine;

6-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-benzazepine;

8-acetyl-7-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine;

7-hydroxy-8-methylsulphinyl-2,3,4,5-tetrahydro-1H-benzazepine; and

7-hydroxy-8-trifluoromethylsulphonyl-2,3,4,5-tetrahydro-1H-benzazepine;

or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition comprising a compound according to claim 6 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient therefor. 8. A process for preparing a compound of Structure (I) wherein R, R², R³, R⁴, R⁵ and n are as defined in claim 1 and R¹ represents SO_nR⁴, -COR³, NO2 or halogen, which comprises : a) to prepare a compound of structure (I) where R¹ represents -SO_nR⁴, the reaction of a compound of structure (II) :

Structure (II)

(wherein R² and R⁴ are as hereinbefore defined and R⁷ is an N-protecting group) with an oxidising agent, in the presence of titanium trichloride; b) to prepare a compound of structure (I) wherein R¹ represents -COR³, NO2 or halogen, the reaction of a compound of structure (III) :

wherein R², R³ and R⁷ are as hereinbefore defined) with an appropriate acylating, nitrating or halogenating agent respectively; followed in each case by removal of the N-protecting group, and if desired salt formation.

9. Use of a 5-HT₂ receptor agonist in the treatment of portal hypertension.

10. Use of a 5-HT₁-like-receptor agonist in the

treatment of portal hypertension.

11. Use of a compound which is an agonist at both 5-HT₂ and 5-HT₁-like-receptors in the treatment of portal

hypertension.

12. Use of a 5-HT₂ receptor agonist in the treatment and prophylaxis of migraine.