MEDICAMENTS

Abstract: Tetrahydrobenzazepine derivatives are disclosed as medicaments.

Description: MEDICAMENTS fc The present invention relates to certain tetrahydro- 5 benzazepine 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-H 2 and 5-HTι-like receptor agonists in the treatment of 10 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 15 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. 20 It has now been found that certain tetrahydro- benzazepines known in the art for the treatment of gastrointestinal motility disorders are agonists at 5-HT2 and/or 5-HTι-like-receptors and are expected to have utility 25 in the treatment of portal hypertension. Migraine is a non-lethal disease suffered by one in te individuals. The main symptom is headache; other symptoms include vomiting and photophobia. Currently, the most 30 widely used treatment for migraine involves administration o ergotamine, dihydroergotamine or methysergide. All these drugs are inter alia agonists of 5HTι~like receptors but als * have other actions; .treatment with them is associated with a number of adverse side effects. In addition, some patients 35 experience a "withdrawal headache" following the cessation o 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 tetrahydro- benzazepines known in the art for the treatment of gastrointestinal motility disorders are agonists at 5HTχ-lik and/or 5HT2~receptors and are expected to have utility in th treatment of migraine. The present invention therefore provides compounds of structure (I) : Structure (I) in which: R is hydrogen, C^-galkyl or C3_5alken l; R 1 is NO2, cyano, halo, COR 3 , SO n R 4 or SO n NR 5 R 6 ; R2 is hydrogen, hydroxy or Cχ_4alkoxy; R 3 is hydrogen, Cι_4alkyl, OR 5 or NR 5 R 6 ; R 4 is Ci-galkyl or halo C^-g alkyl; R 5 and R> are hydrogen, C^-galkyl or C^-ζ 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^-galkyl or C3_5alke yl; preferably R is hydrogen. Suitably R 1 is nitro, cyano, halo, COR 3 , SO n R 4 or SO n NR 5 R 6 ; preferably R 1 is SO n R 4 , nitro or halo; most preferably R 1 is SO n R 4 . Suitably n is 1 or 2; preferably n is 2. Suitably R^ is hydrogen, hydroxy or Cι_4alko y; preferably R^ is Cι_4alkoxy or hydroxy. Suitably R 3 is hydrogen, OR 5 or NR 5 R 6 ; preferably R 3 is Cι_4alkyl, in particular methyl. Preferably the group R 1 is at the 8-position and the group R^ is at the 7-position of the ring of the compound of structure (I) . Suitably R 4 is Cι_galkyl or halo C^- alkyl; preferably R 4 is Cι_galkyl, or C^- alkyl substituted by 1 t 6 halogen atoms (eg. CF3) . and most preferably R 4 is methyl. Suitably R^ and R> are hydrogen or Cι_galkyl, or C3_ cycloalkyl. Preferably, when both groups represent Cι_g alkyl, they are the same. Cι_galkyl 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-lH-benzazepine, an 7-hydroxy-8-(N,N-dimethylsulphamoyl)-2,3,4,5-tetrahydro-lH- benzazepine. In particular the present invention relates to the use of a compound in which R is hydrogen, R^ is methylsulphonyl and R^ is hydroxy, namely, 7-hydroxy-8- methylsulphonyl-2,3,4,5-tetrahydro-lH-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-lH- benzazepine oxalate; 7-methoxy-8-nitro-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride; 7-hydroxy-8-nitro-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride; 7-methoxy-8-bromo-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride; 7-hydroxy-8-bromo-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride; 7-methoxy-6-nitro-2,3, ,5-tetrahydro-lH-benzazepine hydrochloride; 6-bromo-7-methoxy-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride; 8-acetyl-7-hydroxy-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride; 7-hydroxy-8-methylsulphin l-2,3,4,5-tetrahydro-lH- benzazepine; and 7-hydroxy-8-trifluoromethylsulphonyl-2,3,4,5-tetrahydro-lH- 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 R^ represents -SO n R 4 , the reaction of a compound of structure (ID : R Structure (II) (wherein R^ and R 4 are as hereinbefore defined and R 7 is an N-protecting group) with an oxidising agent, in the presence of titanium trichloride; b) to prepare a compound of structure (I) wherein R 1 represents -COR 3 , NO2 or halogen, the reaction of a compound of structure (III) : Structure (III) (wherein R^, R 3 and R 7 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 R 7 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 equivalen 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 gro R 3 CO-. The reaction is desirably effected in the presence 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 an 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 fo 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-HTι-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-HTχ-like receptors. It is believed that the use of 5-HT2 and 5-HTι-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-HT -like-agonists for use in the treatment of portal hypertension. The invention also provides the use of 5-HT2 receptor agonists and 5-HT -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-HTι_ like-agonist. For use according to the present invention a 5-HT2~agonist or 5-HTι-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-HT^-like receptors. The compounds of structure (I) have been found to be agonists at 5HTι~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 5HTι-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 5HTι~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 thereo which is active when administered in this way, with a bindin 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 o the formula (I) or a pharmaceutically acceptable salt thereo 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-HT^-like Receptor Screen Dog Saphenous Vein Helicoids of dog saphenous vein were set up at 37°C i modified Krebs solution at a resting force of 10 mN. The solution also contained 1 μmol/1 each of ketanserin prazosi atropine and mepyramine, 6 μmol/1 cocaine and 200 μmol/1 ascorbate. Nearly isomeric contractions were measured wit force transducers on a polygraph. The tissues were expose twice to 5-hydroxytryρtamine (5-HT) 2 μmol/1 followed by washes. A cumulative concentration-effect curve to the tes 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 f 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-lH-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); Ca 2+ (2.25); Mg 2+ (0.5); Cl ~ (98.5); SθJ ~ (1); EDTA (0.04), equilibrated with 95% 02 5% Cθ2- 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) ; Na 2+ (20); fumarate (10); pyruvate (5); L-glutamate (5 and glucose (10) . The arteries were then placed under a resting force of 3-4 N maintained at 37°C and the solution bubbled with 95% 02/5% CO2. After tests for initial reactivity with 90 mM KC1 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-methylsulρhonyl-2,3,4,5-tetrahydro-lH- 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-lH-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-lH-benzazepine in the drinking water and another period of 4 days without 7-hydroxy-8-methylsulphony1-2,3,4,5 tetrahydro-lH-benzazepine in the drinking water. 7-hydroxy- 8-methylsulphonyl-2,3,4,5-tetrahydro-lH-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- methylsulphon l-2,3,4,5-tetrahydro-lH-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-methylsulphon l-2,3,4,5-tetrahydro- lH-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-lH- benzazepine monooxalate 3-Acetyl-7-methoxy-8-methylthio-2,3,4,5-tetrahydro- IH-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.Og), 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-lH-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 vaπuo. and the remaining solution was diluted with water, and extracted with chloroform. The extracts were combined, dried (MgSθ4) and evaporated to give 7- methoxy-8-methylsulphinyl-,3,4,5-tetrahydro-lH-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-lH-benzazepine hydrochloride Concentrated nitric acid (0.6ml, 70% w/w) was added a stirred, ice-cooled solution of 3-acet l-7-methoxy- 2,3,4,5-tetrahydro-lH-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 chro atography (Siθ2/ CgH^/EtOAc) to give 3-acetyl-7- methoxy-8-nitro-2,3,4,5-tetrahydro-lH-benzazepine (0.93g) , m.p. 127-132°C and 3-acetyl-6-nitro-7-methoxy-2,3,4,5- tetrahydro-lH-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-lH-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 _?2 0 5 and recrystallised from methanol to give 7-methoxy-8- nitro-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride (0.74g), m.p. 234-7°C. Example 3 7-Hydroxy-8-nitro-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride 7-Methoxy-8-nitro-2,3,4,5-tetrahydro-lH-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 chro atography (Siθ2; CHCl3/MeOH) , then recrystallised from methanol/conc. hydrochloric acid to give 7-hydroxy-8-nitro- 2,3,4,5-tetrahydro-lH-benzazepine hydrochloride (O.llg), m.p 251-5°C. Example 4 7-Methoxy-8-bromo-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride 3-Acetyl-7-methoxy-2,3,4,5-tetrahydro-lH-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 (Siθ2; CH2Cl2/EtOAc) , followed by crystallisation from ethyl acetate/ether to give 3-acetyl-7- methoxy-8-bromo-2,3, ,5-tetrahydro-lH-benzazepine (1.55g) , m.p. 123-125°C, and 3-acetyl-6-bromo-7-methoxy-2,3,4,5- tetrahydro-lH-benzazepine, m.p. 99-101°C. The above product (3-acetyl-7-methoxy-8-bromo- 2,3,4,5-tetrahydro-lH-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-lH-benzazepine hydrochloride as a white solid (0.25g), m.p. 268-272°C. Example 5 7-Hydroxy-8-bromo-2,3,4,5-tetrahydro-lH-benzazepine hydrochloride A solution of 3-acetyl-7-methoxy-8-bromo-2,3,4,5- tetrahydro-lH-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 ( gSθ4) and evaporated to a solid, which was purified by chromatography (Siθ2," CHCl3/MeOH) to give 3-acetyl-7-hydroxy-8-bromo -2,3,4,5- tetrahydro-lH-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-lH-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-lH-benzazepine hydrochloride (0.15g) in 3N.HC1 (9mL) at reflux. The product, 7-methoxy-6-nitro-2,3,4,5-tetrahydro-lH-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-lH-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-lH-benzazepine (0.20g) in 3N.HC1 (11 L) at reflux. The product, 6-bromo-7-methoxy- 2,3,4,5-tetrahydro-lH-benzazeρine 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, ,5-tetrahydro-lH-benzazepine hydrochloride Tin tetrachloride (2.4 mL) was added dropwise, with stirring to a solution of acetyl chloride (1.46 mL) in CH2CI (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-lH-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.HC1 and CH2CI2. The aqueous layer was re- extracted and the combined organic layers were washed with saturated sodium bicarbonate solution and then H2O, dried (MgSθ4) 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-lH- 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-lH- benzazepine (0.20g) was dissolved in CH2CI2 (5 mL) and coole 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 (MgSθ ) . Evaporation gave a gum which was purified b flash chromatography (Siθ2; CHCl3 MeOH) . The product, 3,8- diacetyl-7-hydroxy-2,3,4,5-tetrahydro-lH-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-lH-benzazepine hydrochloride, a small orange crystals (0.064g), m.p. 241-7°C decomp. Example 9 7-Hydroxy-8-methylsulphiny1-2,3,4,5-tetrahydro-lH-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- lH-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 (MgSθ4) , evaporated to an oil, and purified by chromatography (Siθ2," MeOH/CH2Cl2) to give 3- acetyl-7-hydroxy-8-_tιethylsulphinyl-2,3,4,5-tetrahydro-lH- 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 "1" ) 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° Example 10 7-Hydroxy-8-trifluoromethylsulphonyl-2,3,4,5-tetrahydro-lH- benzazepine 3-Acetyl-7-methoxy-2,3,4,5-tetrahydro-lH-benzazepine (7.0 g) was dissolved in dry dichloromethane (100 ml), coole 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 carefull 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 (MgS0 > and evaporated to give 3-acetyl- 7-methoxy-8-chlorosulphonyl-2,3,4,5-tetrahydro-lH-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 IM NaOH solution (100 ml) for 30 min., filtered, acidified with cone. HCl and extracted with chloroform. The extracts were combined, drie (MgSθ ) and evaporated to dryness to give 3-acetyl-7-methoxy 8-mercapto-2,3,4,5-tetrahydro-lH-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 betwee chloroform and IM NaOH solution. The organic phase was drie (MgSθ4) and evaporated to dryness. The residue was purified by chromatography (Siθ2; CHCl3/MeOH) to give 3-acetyl-7- methoxy-8-trifluoromethyl-2,3,4,5-tetrahydro-lH-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 (MgSθ4) and evaporated to dryness leaving 3- acetyl-7-methoxy-8-trifluoromethylsulphonyl-2,3,4,5- tetrahydro-lH-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 IM 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 (Siθ2; CHCl3/ eOH MH4θH) 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) Structure (I) in which: R is hydrogen, Cι_galkyl ' or C3_5alkenyl; R 1 is NO2, cyano, halo, COR 3 , SO n R 4 or SO n NR 5 R 6 ; R 2 is hydrogen, hydroxy or Cι_4alkoxy; R 3 is hydrogen, C _ alkyl, OR 5 or NR 5 R 6 ; R 4 is Cι_galkyl or halo C]__galkyl; R5 and R^ are hydrogen or C^-galkyl or C3_g 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 whic R 1 is at the 8-position and R 2 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 clai 2 in which R-*- is SO2R , R 2 is hydrogen, alkoxy or hydroxy an R is hydrogen. 4. The use of a compound according to any of claims 1 to 3 in which R 3 is methyl and R 2 is hydroxy. 5. The use of a compound according to claim 1 which i 7-hydroxy-8-methylsulphonyl-2,3,4,5-tetrahydro-lH- benzazepine. 6. A compound according to claim 1 which is: 7-methoxy-8-methylsulphin 1-,3, ,5-tetrahydro-lH-benzazepine 7-methoxy-8-nitro-2,3,4,5-tetrahydro-lH-benzazepine; 7-hydroxy-8-nitro-2,3,4,5-tetrahydro-lH-benzazepine; 7-methoxy-8-bromo-2,3,4,5-tetrahydro-lH-benzazepine; 7-bromo-8-hydroxy-2,3,4,5-tetrahydro-lH-benzazepine; 7-methoxy-6-nitro-2,3,4,5-tetrahydro-lH-benzazepine; 6-bromo-7-methoxy-2,3,4,5-tetrahydro-lH-benzazepine; 8-acetyl-7-hydroxy-2,3,4,5-tetrahydro-lH-benzazepine; 7-hydroxy-8-methylsulphinyl-2,3,4,5-tetrahydro-lH- benzazepine; and 7-hydroxy-8-trifluoromethylsulphonyl-2,3,4,5-tetrahydro-lH- 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, R 2 , R 3 , R 4 , R^ and n are as defined in claim 1 an R 1 represents SO n R 4 , -COR 3 , NO2 or halogen, which comprises : a) to prepare a compound of structure (I) where R 1 represents -SO n R 4 , the reaction of a compound of structure (ID : Structure (II) (wherein R 2 and R 4 are as hereinbefore defined and R 7 is an N-protecting group) with an oxidising agent, in the presence of titanium trichloride; b) to prepare a compound of structure (I) wherein R 1 represents -COR 3 , NO2 or halogen, the reaction of a compound of structure (III) : Structure (III) wherein R 2 , R 3 and R 7 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-HTχ-like-receptor agonist in the treatment of portal hypertension. 11. Use of a compound which is an agonist at both 5-HT2 and 5-HTι~like-receptors in the treatment of portal hypertension. 12. Use of a 5-HT2 receptor agonist in the treatment and prophylaxis of migraine.

Inventors: KAUMANN ALBERTO JULIO, WARD JOHN GERARD, YOUNG RODNEY CHRISTOPHER, KAUMANN, ALBERTO, JULIO, WARD, JOHN, GERARD, YOUNG, RODNEY, CHRISTOPHER
Applicants: SMITHKLINE BEECHAM PLC
Application year: 1992
Main classification: A61K31
IPC codes: A61K31, A61P9, A61P25, A61P43, C07B61, C07D223