Quinolines and quinazolines useful in therapy

Abstract: Compounds of formula I, wherein R 1 represents C 1-4 alkoxy optionally substituted by one or more fluorine atoms; R 2 and R 3 independently represent H or C 1-6 alkoxy (which is optionally substituted); R 4 represents a 4-, 5-, 6- or 7-membered heterocyclic ring, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic, the ring system as a whole being optionally substituted; X represents CH or N; and L is absent, or represents a cyclic group of formula Ia, or represents a chain of formula Ib, and pharmaceutically acceptable salts thereof; are useful in therapy, in particular in the treatment of benign prostatic hyperplasia.

Description: This invention relates to novel compounds useful in therapy, particularly in the treatment of benign prostatic hyperplasia. International Patent Application WO 89/05297 discloses a number of substituted quinazoline compounds that are indicated as inhibitors of gastric acid secretion. WO 95/25726 discloses derivatives of 4-amino-6,7-dimethoxyquinazoline having α-antagonist activity. EP 322133 discloses 2,4-diaminoquinazoline derivatives and their use as gastric acid secretion inhibitors. EP 308059 discloses 1,2,3,4-tetrahydroisoquinoline derivatives and their use as antiarrhythmic agents. EP 100200 discloses derivatives of 4-amino-6,7-dimethoxyquinoline and their use as antihypertensive agents. GB 2,171,997 discloses derivatives of 4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinazoline. Co-pending International Patent Application N° PCT/EP96/05609 discloses a number of quinoline and quinazoline compounds indicated in the treatment of benign prostatic hyperplasia, and discloses 4-amino-6-benzyloxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline as an intermediate [see Example 49, step (f), therein]. According to the present invention, there is provided a compound of formula I, wherein R 1 represents C 1-4 alkoxy optionally substituted by one or more fluorine atoms; R 2 represents H, C 1-6 alkoxy (optionally substituted by one or more fluorine atoms, or by phenyl which may in turn be substituted by one or more fluorine atoms), or cyclobutyloxy; R 3 represents cyclobutyloxy or CF 3 CH 2 O; R 4 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C 1-4 alkyl, C 1-4 alkoxy, halogen and NHSO 2 (C 1-4 alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms; X represents CH or N; and L is absent, or represents a cyclic group of formula Ia, in which A is attached to R 4 ; A represents CO or SO 2 ; Z represents CH or N; m represents 1 or 2, and in addition, when Z represents CH, it may represent 0; and n represents 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5; or a pharmaceutically acceptable salt thereof (referred to together herein as "the compounds of the invention"). Pharmaceutically acceptable salts include acid addition salts, such as hydrochloride and hydrobromide salts, and phosphate salts. Alkyl groups may be straight chain or branched. Similarly, the alkyl portion of alkoxy groups may be straight chain or branched. Preferably, heterocyclic rings represented or comprised by R 4 are saturated. Examples include morpholine, tetrahydrofuran and piperidine. The compounds of the invention may be optically active. The invention includes all optical isomers of the compounds of formula I, and all diastereoisomers thereof. Preferred groups of compounds that may be mentioned include those in which: (a) R 1 represents methoxy; (b) R 2 represents H or methoxy; (c) L is absent, in which case R 4 preferably represents a piperidine ring which is fused to a pyridine ring or to a benzene ring which is substituted by NHSO 2 (C 1-4 alkyl); and (d) L represents in which case R 4 preferably represents morpholinyl. According to the invention, there is also provided a process for the production of a compound of the invention, which comprises: (a) when X represents CH, cyclizing a compound of formula II, in which R 1-4 and L are as defined above; (b) when Z represents N, and L is present, reacting a compound of formula IIIa, in which R 1 , R 2 , R 3 , X, m and n are as defined above, with a compound of formula IV, Lg-A-R 4 IV in which R 4 and A are as defined above, and Lg represents a leaving group; (c) reacting a compound of formula V, in which R 1 , R 4 , X and L are as defined above, and R a and R b independently represent H or OH, provided that they do not both represent H, with a compound of formula VI, R c -Lg VI in which R c is alkyl (optionally substituted by one or more fluorine atoms, or by phenyl which may in turn be substituted by one or more fluorine atoms) or cyclobutyloxy, and Lg represents a leaving group, in the presence of a base; (d) when X represents N, reacting a compound of formula VII, in which R 1 , R 2 and R 3 are as defined above, with a compound of formula VIIIa or VIIIb, HR 4a VIIIb in which R 4 , A, Z, m and n and p are as defined above; and R 4a has the same significance as R 4 above except that it contains a nucleophilic nitrogen atom in the heterocyclic ring which is attached to the H in formula VIIIb; or (e) when A represents CO and R 4 comprises a nucleophilic nitrogen atom in the heterocyclic ring attached to L, reacting a compound of formula IXa, in which R 1-3 , X, Z, m and n are as defined above, and Lg is a leaving group, with a compound of formula VIIIb, as defined above; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable salt or vice versa. In process (a), the cyclization may be carried out in the presence of a strong base (for example lithium diisopropylamide) in a solvent that does not adversely affect the reaction (for example tetrahydrofuran), around room temperature. Alternatively, it may be performed using potassium hydroxide or potassium tert -butoxide in a solvent which does not adversely affect the reaction (for example dimethylsulphoxide or 1,2-dimethoxyethane), at an elevated temperature (for example 80°C). In addition, it may be performed using zinc chloride either without a solvent at an elevated temperature (for example 190°C), or in a solvent which does not adversely affect the reaction (for example dimethylformamide at the reflux temperature of the solvent). In process (b), suitable leaving groups are OH and Cl. When the compound of formula IV is a carboxylic acid, the reaction may be carried out in the presence of conventional coupling agents [for example 1-hydroxybenzotriazole monohydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-methylmorpholine] in a solvent which does not adversely affect the reaction (for example CH 2 Cl 2 ) at or around room temperature. When the leaving group is Cl, the reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH 2 Cl 2 or tetrahydrofuran), around 0°C or up to the reflux temperature of the solvent. In process (c), suitable leaving groups include halogens such as bromine or iodine, and suitable bases include sodium hydride. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example dimethylformamide) at room temperature or up to the reflux temperature of the solvent. In process (d), the reaction may be carried out in a solvent which does not adversely affect the reaction (for example n-butanol) in the presence of a base (for example triethylamine) at an elevated temperature (for example the reflux temperature of the solvent). In process (e), suitable leaving groups include Cl. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example THF) in the presence of a base (for example triethylamine) at room temperature. The reaction may also be carried out without isolating the compound of formula IXa, by reacting a compound of formula IIIa with triphosgene and a compound of formula VIIIb. In this case the leaving group is -Cl. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example CH 2 Cl 2 ) in the presence of a base (for example triethylamine) at or around room temperature. Compounds of formula II [see process (a)] may be prepared by reaction of a compound of formula X, in which R 1 , R 2 and R 3 are as defined above, with a combination of a compound of formula XI, in which R 4 and L are as defined above, and phosphorous oxychloride in dichloromethane at the reflux temperature of the solvent. Compounds of formula X may be prepared from compounds of formula XII, in which R 1-3 are as defined above, by reaction with Na 2 S 2 O 4 . The reaction may be carried out in a vigorously stirred mixture of dichloromethane and water, at room temperature. Compounds of formula XII may be prepared from compounds of formula XIII, in which R 1-3 are as defined above, by reaction with NO 2 BF 4 . The reaction may be carried out in acetonitrile at around 0°C. Alternatively, compounds of formula X may be prepared from compounds of formula XIV, in which R 1-3 are as defined above, by reaction with (a) magnesium turnings in methanol at room temperature; or (b) triphenylphosphine in tetrahydrofuran at room temperature in the presence of water to form a phosphonimide, followed by acidic hydrolysis. Compounds of formula XIV may be prepared from compounds of formula XV, in which R 1-3 are as defined above, by reaction with sodium azide in dimethylformamide, at an elevated temperature (for example 115°C). Compounds of formula IIIa [see process (b)] in which X represents CH may be prepared from compounds of formula XVIa, in which R 1-3 , m and n are as defined above, by bubbling HCl gas through a solution of the compound in dichloromethane. Compounds of formula XVIa may be prepared from compounds of formula XVIIa, in which R 1-3 , m and n are as defined above, by cyclization using potassium hydroxide at an elevated temperature (such as 90°C) in DMSO, quenching with water, or lithium diisopropylamide at room temperature in THF, quenching with water. Compounds of formula XVIIa may be prepared by reacting a compound of formula X, as defined above, with a compound of formula XVIIIa, in which m and n are as defined above, by the method described above for producing compounds of formula II. Compounds of formula IIIa [(see process (b)] in which X represents N may be prepared by reacting a compound of formula VII, as defined above, with a compound of formula XIXa, in which m and n are as defined above, using the conditions mentioned for process (d) above. Compounds of formula VII may be prepared by conventional means from known compounds (or compounds available using known techniques) according to Scheme 1 below (see also Example 1), in which R 1-3 are as defined above: Compounds of formula V [see process (c)] in which X represents CH may be prepared by cyclization of a compound of formula XX, in which R 1 , R 4 , R a , R b and L are as defined above, using the reaction conditions mentioned in process (a) above. Compounds of formula XX may be prepared by conventional means from known compounds (or compounds available using known techniques) according to Scheme 2 below, in which R 1 , R 4 , R a , R b and L are as defined above: Compounds of formula V in which X represents N may be prepared from compounds of formula XXI, in which R 1 , R a and R b are as defined above, by reaction with a compound of formula VIIIa, or VIIIb, as defined above, as appropriate, using the conditions described in process (d). Compounds of formula XXI may be prepared by methods analogous to those set out in scheme 1 above for the preparation of compounds of formula VII. The preparation of compounds of formula VII [see process (d)] has already been described above. Compounds of formula VIIIa may be prepared by reaction of a compound of formula IV, as defined above, with a compound of formula XIXa, as defined above, using the conditions indicated for process (d) above. Compounds of formula IXa [see process (e)] in which Lg represents Cl may be prepared from compounds of formula IIIa, as defined above, by reaction with triphosgene. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH 2 Cl 2 ) in the presence of a base (for example triethylamine) at around -10°C. Compounds of formulae IV, VI, VIIIb, XI, XIII, XV, XVIIIa and XIXa are either known or are available using known techniques. The intermediate compounds of formulae II, IIIa, V, VII and IXa form a further aspect of the invention. It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional techniques, for example as described in 'Protective Groups in Organic Synthesis' by T W Greene and P G M Wuts, John Wiley and Sons Inc, 1991. The compounds of the invention are useful because they possess pharmacological activity in animals. In particular, the compounds are useful in the treatment of a number of conditions including hypertension, myocardial infarction, male erectile dysfunction, hyperlipidaemia, cardiac arrhythmia and benign prostatic hyperplasia. The latter condition is of particular interest. Thus, according to another aspect of the invention, there is provided a method of treatment of benign prostatic hyperplasia which comprises administering a therapeutically effective amount of a compound of the invention to a patient suffering from such a disorder. The use of the compounds of the invention as pharmaceuticals, and the use of the compounds of the invention in the manufacture of a medicament for the treatment of benign prostatic hyperplasia, are also provided. The compounds of the invention may be administered by any convenient route, for example orally, parenterally ( e.g. intravenously, transdermally) or rectally. The daily dose required will of course vary with the particular compound used, the particular condition being treated and with the severity of that condition. However, in general a total daily dose of from about 0.01 to 10mg/kg of body weight, and preferably about 0.05 to 1mg/kg, is suitable, administered from 1 to 4 times a day. The compounds of the invention will generally be administered in the form of a suitable pharmaceutical formulation. Thus, according to another aspect of the invention, there is provided a pharmaceutical formulation including preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The pharmaceutical formulation is preferably in unit dose form. Such forms include solid dosage forms, for example tablets, pills, capsules, powders, granules, and suppositories for oral, parenteral or rectal administration; and liquid dosage forms, for example sterile parenteral solutions or suspensions, suitably flavoured syrups, flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil and peanut oil, and elixirs and similar pharmaceutical vehicles. Solid formulations may be prepared by mixing the active ingredient with pharmaceutical carriers, for example conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other diluents, for example water, to form a homogeneous preformulation formulation in which the active ingredient is uniformly dispersed so that it may be readily subdivided into equally effective unit dosage forms containing typically from 0.1 to about 500mg of the active ingredient. The solid dosage forms may be coated or otherwise compounded to prolong the action of the formulation. The formulations of the invention may also contain a human 5-α reductase inhibitory compound [see International Patent Application WO 95/28397], or a compound of the invention could be presented in a pharmaceutical pack also containing a human 5-α reductase inhibitory compound as a combined preparation for simultaneous, separate or sequential use. The compounds of the invention may be tested in the screens set out below. Contractile responses of human prostate Prostatic tissue was cut into longitudinal strips (approximately 3×2×10 mm) and suspended in organ baths under a resting tension of 1 g in Krebs Ringer bicarbonate of the following composition (mM): NaCl (119), KCI (4.7), CaCl 2 (2.5), KH 2 PO 4 (1.2), MgSO 4 (1.2), NaHCO 3 (25), glucose (11), and gassed with 95% O 2 /5% CO 2 . The solution also contained 10 mM cocaine and 10 mM corticosterone. Tissues were exposed to a sensitising dose of (-)-noradrenaline (100 mM) and washed over a 45 minute period. Isometric contractions were obtained in response to cumulative additions of (-)-noradrenaline to obtain control curves.in all tissues. A further curve was then generated in the presence or absence of antagonist (incubated for 2 hours). Antagonist affinity estimates (pA 2 ) were determined using a single concentration of competing antagonist, pA 2 = -log [A]/(DR-1) where the dose ratio (DR), relative to corresponding controls, was produced by a single concentration of antagonist [A], assuming competitive antagonism and Schild regression close to unity. Anaesthetised dog model of prostatic pressure and blood pressure Mature male beagles (12-15 kg body weight) were anaesthetised with sodium pentobarbitone (30-50 mg/kg i.v.) and a tracheal cannula was inserted. Subsequent anaesthesia was maintained using pentobarbitone infusion. The animals were respirated with air using a Bird Mk8 respirator (Bird Corp., Palm Springs, CA, USA) adjusted to maintain blood gasses in the range pO 2 90-110 mm Hg, pCO 2 35-45 mm Hg, pH 7.35-7.45. Body temperature was maintained at 36-37.5°C using a heated operating table. Catheters were placed into the left femoral artery for recording blood pressure and into the left femoral vein for compound administration. Heart rate was recorded via the lead II E.C.G. A laparotomy was performed to cannulate both ureters to prevent change of fluid volume within the bladder. A 7F cardiac catheter (with a 1.5 ml capacity balloon tip) was inserted into the bladder via the urethra. The balloon was filled with air and the catheter withdrawn until the balloon became lodged in the prostate, which was confirmed by digital pressure. Balloon pressure was recorded via a Druck transducer. Prostatic pressure and haemodynamic parameters were made on a Grass Polygraph (Grass Instruments, Quincy, Mass, U.S.A.) and the data measured on line using a Motorola 68000-based microcomputer system (Motorola Inc., Temple, AZ, U.S.A.). Compounds were made up in PEG 300 and administered i.v. through a catheter in the femoral vein. Responses to phenylephrine (1-16 µg/kg i.v. in saline) were obtained to generate control dose-response curves (two control curves for each experiment). Compounds were administered (in terms of compound base) at 10-300 µg/kg i.v. 5 min before construction of phenylephrine curves (constructed up to a maximum dose of 128 µg/kg in the presence of test compound). Due to α 1 -related dysrhythymic properties of phenylephrine, absolute maximal responses were not obtained but were taken as 10 % greater than the control response obtained with 16 µg/kg phenylephrine. Drug concentrations were calculated on the basis of molar weight of compound/kg body weight thus allowing a "pseudo pA 2 " calculation by Schild analysis using dose ratios derived from shifts in the phenylephrine dose-response curves. The compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective (in particular they may have beneficial effects in benign prostatic hyperplasia without causing undesirable cardiovascular effects, for example because they are able to selectively antagonise prostatic receptor subtypes of the α 1 -adrenoceptor), or have other more useful properties than the compounds of the prior art. The invention is illustrated by the following examples, in which the following abbreviations may be used: 2xm = two overlapping multiplets DMF = dimethylformamide DMSO = dimethylsulphoxide EtOAc = ethyl acetate EtOH = ethanol h = hour MeOH = methanol min = minute n-BuOH = n-butanol THF = tetrahydrofuran Intermediate 1 1-(4-Morpholinecarbonyl)-1,4-diazepane hydrochloride (a) 1-(t-Butyloxycarbonyl)-1,4-diazepane To a solution of homopiperazine (100g, 1.0 mol) and triethylamine (210ml, 152g, 1.5mol) in dichloromethane (500ml) at 0"C was added a solution of di-(t-butyl) dicarbonate (195g, 0.89mol) in dichloromethane (300ml). The mixture was allowed to warm to room temperature and stirred for 18 hours after which time the dichloromethane was evaporated under reduced pressure. The resulting residue was partitioned between diethyl ether and 2N citric acid and the aqueous layer was extracted with diethyl ether (4×200ml). The aqueous layer was basified with 2N aqueous sodium hydroxide and then extracted with dichloromethane (4×400ml). The combined dichloromethane extracts were washed with water (2x), saturated brine (1x) and dried over MgSO 4 . Evaporation under reduced pressure followed by azeotroping with dichloromethane (4x) gave the subtitle compound as a yellow waxy solid (94.3g, 53%). R f 0.25 (0.880 aqueous ammonia:methanol:dichloromethane 1:10:90, v/v). MS m/z 201 (MH) + . Found: C,58.86; H,10.03; N,13.58; C 10 H 20 N 2 O 2 0.05CH 2 Cl 2 requires C, 59.02; H, 9.91; N,13.70%. (b) 1-(t-Butyloxycarbonyl)-4-(4-morpholinecarbonyl)-1,4-diazepane A solution of 1-(t-butyloxycarbonyl)-1,4-diazepane (92.0g, 0.46mol) and triethylamine (96.0ml, 69.7g, 0.69mol) in dichloromethane (500ml) at 0°C was treated dropwise with a solution of 4-morpholinecarbonyl chloride (64.0ml, 82.0g, 0.55mol) in dichloromethane (100ml) and the reaction was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was then diluted with dichloromethane (400ml) and washed with 2N citric acid (3×400ml), saturated brine (1×500ml), dried over MgSO 4 and evaporated to give the subtitle compound as an off-white solid (141.7g, 98%). R f 0.80 (0.880 aqueous ammonia:methanol:dichloromethane 1:10:90, v/v). MS m/z 314 (MH) + . Found: C,57.50; H,8.69; N,13.41; C 15 H 27 N 3 O 4 requires C, 57.50; H, 8.69; N,13.41%. (c) 1-(4-Morpholinecarbonyl)-1,4-diazepane hydrochloride A solution of 1-(t-butyloxycarbonyl)-4-(4-morpholinecarbonyl)-1,4-diazepane (140.0g, 0.44mol) in dichloromethane:methanol (1:1, v/v, 600ml) at 0°C was saturated with hydrogen chloride gas and the reaction mixture was stirred at room temperature under nitrogen for 18 hours after which time the reaction mixture was evaporated under reduced pressure and slurried in ethyl acetate to give, after filtration, a white hygroscopic solid. This was further purified by slurrying in acetone, filtering, washing with diethyl ether and drying in vacuo at 60°C to give the title compound as a colourless solid (99.0g, 90%). R f 0.41 (0.880 aqueous ammonia:methanol:dichloromethane 2:14:84, v/v). MS m/z 214 (MH) + . Found: C,47.50; H,8.10; N,16.55; C 10 H 19 N 3 O 2 HCl 0.2H 2 O requires C, 47.41; H, 8.12; N,16.59%. Intermediate 2 1-Acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane To a solution of 1-(4-morpholinecarbonyl)-1,4-diazepane hydrochloride (50g, 0.2mol) and triethylamine (42ml, 30.5g, 0.3mol) in dichloromethane (400ml) at 5°C was added acetic anhydride (23ml, 24.9g, 0.24mol) dropwise over 15 minutes and the reaction was then stirred for a further 2 hours at room temperature under nitrogen. Dilution with dichloromethane (600ml) was followed by washing with saturated aqueous sodium bicarbonate (2×200ml) and the combined aqueous layers extracted with dichloromethane (1×100ml). The dichloromethane layers were combined and washed with saturated brine, dried over MgSO 4 and evaporated to give a light brown oil. This was dissolved in dichloromethane (300ml) and treated with triethylamine (8ml, 5.8g, 0.06mol) and ethanol (5ml), stirred for 1 hour at room temperature then washed with saturated sodium bicarbonate and the aqueous layer extracted with dichloromethane (5x). The combined dichloromethane layers were dried over MgSO 4 and evaporated under reduced pressure to give a yellow oil which was then azeotroped with dichloromethane (4x) to give the title compound as a yellow oil (47.1g, 92%). R f 0.45 (0.880 aqueous ammonia: methanol:dichloromethane 1:10:90, v/v). MS m/z 256 (MH) + . Found: C,52.62; H,8.18; N,15.02; C 12 H 21 N 3 O 3 0.3CH 2 Cl 2 requires C, 52.61; H, 7.75; N,14.96%. Intermediate 3 6-Acetyl-5,6,7,8-tetrahydro-1,6-naphthyridine To a solution of 5,6,7,8-tetrahydro-1,6-naphthyridine [Shiozawa et al Chem. Pharm. Bull., 32 , 2522 (1984)] (4.9g, 0.037mol) in dichloromethane at 0°C was added triethylamine (6.1ml, 0.044mol) and acetyl chloride (3.11ml, 0.044mol) dropwise and the reaction was allowed to warm to room temperature and stirred for a further 18 hours. The reaction mixture was partitioned between water and dichloromethane, the layers were separated and the aqueous layer was extracted twice more with dichloromethane. The combined organic layers were dried over MgSO 4 and evaporated under reduced pressure to afford a residue which was purified on silica gel, eluting with 0.880 aqueous ammonia:methanol:dichloromethane (0.5:3.5:96, v/v). This afforded the title compound (58%) as an oil. R f 0.60 (0.880 aqueous ammonia:methanol:dichloromethane, 2:14:84, v/v). 1 H NMR (CDCl 3 ): δ = 2.15 (3H, s), 3.04 (2H, m), 3.75 and 3.90 (2H, 2xm), 4.60 and 4.70 (2H, 2xs), 7.10 (1H, m), 7.42 (1H, m), 8.42 (1H, m). Intermediate 4 2-Acetyl-5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline (a) 5-Methanesulfonamidoisoquinoline Methanesulfonyl chloride (3.2ml, 0.042mol) was added to a solution of 5-aminoisoquinoline (5.0g, 0.035mol) in pyridine (40ml) and the mixture was allowed to stand for 72 hours. The reaction mixture was then poured into aqueous citric acid (10%, 400ml) and extracted with ethyl acetate (2×230ml). The organic layer was evaporated to give a residue which was purified on silica gel, eluting with dichloromethane:methanol (95:5, v/v), to afford the subtitle compound as a solid (3.55g, 46%). R f 0.03 (CH 2 Cl 2 :diethyl ether 4:1, v/v). 1 H NMR (D 6 -DMSO) δ: 3.07 (3H, s), 7.68 (1H, t), 7.75 (1H, d), 8.03 (1H, d), 8.10 (1H, d), 8.54 (1H, d), 9.32 (1H, s), 9. 79 (1H, bs). (b) 5-Methanesulfonamido-1,2,3,4-tetrahydroisoquinoline hydrochloride A solution of 5-methanesulfonamidoisoquinoline (3.50g, 0.0156mol) in ethanol (250ml) was treated with platinum dioxide (1.5g) and 1N aqueous hydrochloric acid (15.7ml). The mixture was hydrogenated at a pressure of 414 kPa (60 psi) for 16 hours, after which time the reaction mixture was filtered. The filtrate was evaporated under reduced pressure and triturated with dichloromethane to afford the subtitle compound as a colourless solid. The solid residue from the filtration was taken up into methanol:water (1:2, v/v), and the suspension filtered, washing with dichloromethane (3x). This filtrate was evaporated to afford a second crop of the subtitle compound (total yield 3.45g, 84%). R f 0.21 (0.880 aqueous ammonia:methanol:dichloromethane, 1:10:90, v/v). 1 H NMR (D 6 -DMSO) δ: 2.96-3.10 (2H, m), 3.31 (3H, m), 4.21 (2H, s), 7.12 (1H, m), 7.26 (2H, m), 9.24 (1H, s), 9.61 (2H, bs). (c) 2-Acetyl-5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline To a solution of 5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.87g, 0.011mol) in dichloromethane at 0°C was added acetic anhydride (1.2ml, 0.013mol) and triethylamine (3.4ml, 0.024mol), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between ethyl acetate and aqueous sodium bicarbonate solution and the aqueous phase extracted with further portions of ethyl acetate. The combined organic extracts were dried (MgSO 4 ) and evaporated to afford an oil. This was dissolved in methanol (15ml) and treated with aqueous sodium carbonate solution (7%, w/w, 15ml) and the mixture stirred for 16 hours at room temperature, after which time the methanol was removed under reduced pressure, the pH was adjusted to pH 8 with 2N hydrochloric acid and the product was extracted with ethyl acetate (2x). The combined organic extracts were dried (MgSO 4 ) and evaporated to give an oil which was purified on silica gel, eluting with dichloromethane:methanol (95:5, v/v) to give the title compound as an oil (2.0g, 68%). R f 0.20 (dichloromethane:methanol 95:5, v/v). MS m/z 269 (MH) + . Example 1 4-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline (a) Methyl 3,4-dimethoxy-2-hydroxybenzoate A solution of diazomethane in diethyl ether (30ml, 0.25M, 0.0075mol) was added to a solution of 3,4-dimethoxy-2-hydroxybenzoic acid (1.5g, 0.0075mol) in diethyl ether (50ml) and the reaction stirred at room temperature for 10 minutes. Glacial acetic acid was then added and stirring continued for a further 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (40ml) and aqueous sodium hydrogen carbonate solution (40ml). The aqueous phase was further extracted with dichloromethane (100ml), the combined organic extracts dried (MgSO 4 ), filtered and evaporated under reduced pressure to give the subtitle compound as a white crystalline solid (1.5g, 94%). 1 H-NMR (CDCl 3 ): δ = 3.82 (9H, m), 6.48 (1H, d), 7.58 (1H, d), 10.84 (1H, s). (b) Methyl 3,4-dimethoxy-2-methanesulfonyloxybenzoate Methanesulfonyl chloride (634µl, 0.008mol) was added dropwise to an ice-cooled solution of methyl 3,4-dimethoxy-2-hydroxybenzoate (1.58g, 0.0075mol) and triethylamine (1.27ml, 0.009mol) in dichloromethane (30ml) and the reaction then allowed to warm to room temperature, with stirring. The reaction mixture was washed with water (2×25ml) and the organic layer dried (MgSO 4 ), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of diethyl ether:hexane (60:40 to 100:0, v/v) to give the subtitle compound as a colourless oil that crystallised on standing (1.94g, 90%). MS m/z 308 (MNH 4 ) + . (c) Methyl 3,4-dimethoxy-2-methylsulfonyloxy-6-nitrobenzoate Concentrated nitric acid (0.62ml) was added dropwise to an ice cooled solution of methyl 3,4-dimethoxy-2-methanesulfonyloxybenzoate (1.94g, 0.0067mol) in acetic anhydride (3ml) and the reaction stirred for 1 hour. Water (20ml) was carefully added, and the resulting precipitate filtered and washed with further water. Drying under suction filtration gave the subtitle compound as a white solid (1.94g, 86%). 1 H-NMR (CDCl 3 ): δ = 3.34 (3H, s), 3.94 (3H, s), 4.00 (3H, s), 4.18 (3H, s), 7.68 (1H, s). (d) Methyl 3,4-dimethoxy-2-hydroxy-6-nitrobenzoate 4N aqueous sodium hydroxide solution (17ml) was added to an ice cooled suspension of methyl 3,4-dimethoxy-2-methanesulfonyloxy-6-nitrobenzoate (1.74g, 0.0052mol) in dioxane (9ml) and the resulting orange solution stirred for 1 hour. The reaction mixture was acidified with 2N aqueous hydrochloric acid and extracted with dichloromethane (2×50ml). The combined organic extracts were dried (MgSO 4 ), filtered and evaporated under reduced pressure to give the subtitle compound as a white solid (1.23g, 92%). MS m/z 275 (MNH 4 ) + . 1 H-NMR (CDCl 3 ): δ = 3.92 (9H, m), 6.86 (1H, s), 9.66 (1H, s). (e) Methyl 2-cyclobutyloxy-3,4-dimethoxy-6-nitrobenzoate Cyclobutyl bromide (0.44ml, 0.0047mol) was added to a suspension of methyl 3,4-dimethoxy-2-hydroxy-6-nitrobenzoate (1g, 0.0039mol) and potassium carbonate (1.2g, 0.0086mol) in dimethylformamide (10ml) and the reaction stirred at 100°C for 4 hours. On cooling, aqueous sodium carbonate solution was added and the mixture extracted with ethyl acetate (2×40ml). The combined organic extracts were washed with water, dried (MgSO 4 ), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with diethyl ether to give the subtitle compound as a colourless oil (511mg, 42%). R f 0.89 (diethyl ether). MS m/z 312 (MH) + . 1 H-NMR (CDCl 3 ): δ = 1.48 (1H, m), 1.76 (1H, m), 2.27 (4H, m), 2.94 (9H, m), 4.70 (1H, m), 7.51 (1H, s). (f) Methyl 6-amino-2-cyclobutyloxy-3,4-dimethoxybenzoate A solution of sodium dithionite (3g, 0.017mol) in water (6ml) was added to a solution of methyl 2-cyclobutyloxy-3,4-dimethoxy-6-nitrobenzoate (511mg, 0.00164mol) and tetra-n-butylammonium chloride (280mg, 0.001mol) in dichloromethane (15ml) and the reaction stirred vigorously for 1 hour at room temperature. The mixture was basified with 2N aqueous sodium hydroxide solution (10ml) and extracted with dichloromethane (3×20ml). The combined organic extracts were washed with water (30ml), dried (MgSO 4 ), filtered and evaporated under reduced pressure. The residue was dissolved in a minimum volume of dichloromethane and an excess of ethereal hydrogen chloride added. The resulting precipitate was filtered and partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was evaporated under reduced pressure to give the subtitle compound (500mg). R f 0.70 (diethyl ether). 1 H-NMR (CDCl 3 ): δ = 1.46 (1H, m), 1.70 (1H, m), 2.28 (4H, m), 3.72 (3H, s), 3.83 (3H, s), 3.90 (3H, s), 4.52 (1H, m), 5.20 (2H, bs), 5.82 (1H, s). (g) 5-Cyclobutyloxy-2,4-dihydroxy-6,7-dimethoxyquinazoline Methyl 6-amino-2-cyclobutyloxy-3,4-dimethoxybenzoate (500mg, 0.00177mol) was added to a solution of sodium cyanate (462mg, 0.00708mol) and trifluoroacetic acid (0.55ml, 0.00708mol) in dichloromethane (15ml) and the reaction stirred at room temperature for 1 hour. Water (25ml) was then added and the mixture extracted with dichloromethane (3×25ml). The combined organic extracts were washed again with water (40ml), dried (MgSO 4 ), filtered and evaporated under reduced pressure. The residue was suspended in a solution of sodium hydroxide (750mg) in water (30ml) and heated to 60°C for 1 hour. On cooling, the mixture was acidified with concentrated hydrochloric acid, the resulting precipitate filtered and washed with water (20ml) and diethyl ether (10ml). Drying under air suction gave the subtitle compound as a solid (300mg, 58%). 1 H-NMR (DMSO-d 6 ): δ = 1.40 (1H, m), 1.67 (1H, m), 2.16 (4H, m), 3.68 (3H, s), 3.83 (3H, s), 4.58 (1H, m), 6.50 (1H, s). (h) 5-Cyclobutyloxy-2,4-dichloro-6,7-dimethoxyquinazoline 1 drop of dimethylformamide was added to a solution of 5-cyclobutyloxy-2,4-dihydroxy-6,7-dimethoxyquinazoline (300mg, 0.001mol) in oxalyl chloride (1.5ml) and the reaction stirred under a nitrogen atmosphere at 50°C for 90 minutes. The reaction was cooled in ice, water was added and the solution basified with 2N aqueous sodium hydroxide solution. The mixture was extracted with dichloromethane (3×10ml) and the combined organic extracts dried (MgSO 4 ), filtered and evaporated under reduced pressure to give the subtitle compound as a white solid (300mg, 89%). R f 0.96 (diethyl ether). 1 H-NMR (CDCl 3 ): δ = 1.52 (1H, m), 1.80 (1H, m), 2.40 (4H, m), 3.92 (3H, s), 4.02 (3H, s), 4.78 (1H, m), 7.13 (1H, s). (i) 4-Amino-2-chloro-5-cyclobutyloxy-6,7-dimethoxyquinazoline 5-Cyclobutyloxy-2,4-dichloro-6,7-dimethoxyquinazoline (300mg, 0.0009mol) was suspended in a saturated ethanolic ammonia solution (10ml) and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, resuspended in a minimum volume of diethyl ether and the resulting solid filtered off. Drying under suction gave the subtitle compound as a white solid (189mg, 68%). R f 0.69 (diethyl ether). 1 H-NMR (CDCl 3 ): δ = 1.56 (1H, m), 1.82 (1H, m), 2.26 (2H, m), 2.42 (2H, m), 3.85 (3H, s), 3 .94 (3H, s), 4.92 (1H, m), 5.82 (1H, bs), 6.94 (1H, s), 7.72 (1H, bs). (j) 4-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline 4-Amino-2-chloro-5-cyclobutyloxy-6,7-dimethoxyquinazoline (184mg, 0.00059mol) was added to a solution of 1-(4-morpholinecarbonyl)-1,4-diazepane hydrochloride (163mg, 0.00065mol) and triethylamine (184µl, 0.0013mol) in n-butanol (6ml) and the reaction stirred at reflux for 2 hours. On cooling, the reaction was concentrated under reduced pressure and the residue partitioned between ethyl acetate (20ml) and water (20ml). The aqueous layer was further extracted with ethyl acetate (2×20ml), the combined organic extracts dried (MgSO 4 ), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of methanol:dichloromethane (0:100 to 7:93 v/v) to give the title compound as a white foam (110mg, 38%). MS m/z = 487 (MH) + . 1 H-NMR (CDCl 3 ): δ = 1.53 (1H, m), 1.76 (1H, m), 2.04 (2H, m), 2.25 (2H, m), 2.38 (2H, m), 3.20 (4H, t), 3,36 (2H, t), 3.55 (2H, t), 3.66 (4H, t), 3.80 (3H, s), 3.85 (3H, m), 3.94 (6H, m), 4.86 (1H, m), 6.62 (1H, s). Found: C, 58.09; H, 6.96; N, 16.69; C 24 H 34 N 6 O 5 0.15CH 2 Cl 2 , requires C, 58.09; H, 6.92; N, 16.83% Example 2 4-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinoline (a) 2-Benzyloxy-3,4-dimethoxybenzaldehyde Benzyl bromide (12.9ml, 0.108mol) was added to a suspension of 2-hydroxy-3,4-dimethoxybenzaldehyde (19g, 0.104mol) and potassium carbonate (14.41g, 0.104mol) in acetone (200ml) and the reaction stirred at reflux for 3 hours. On cooling, the mixture was concentrated under reduced pressure and the residue partitioned between water (150ml) and dichloromethane (150ml). The organic layer was filtered through silica, washing through with hexane and then ethyl acetate. Evaporation of the filtrate under reduced pressure gave a yellow gum. The crude product was purified on silica gel eluting with ethyl acetate:hexane (30:70 v/v) to give the subtitle compound (25.9g, 88%). R f 0.82 (ethyl acetate:hexane 1:1, v/v). MS m/z 273 (MH) + . (b) 2-Benzyloxy-3,4-dimethoxybenzonitrile A slurry of sodium acetate (17.06g, 0.208mol) and hydroxylamine (14.45g, 0.208mol) in glacial acetic acid (120ml) was added to 2-benzyloxy-3,4-dimethoxybenzaldehyde (28.3g, 0.104mol) and the resulting suspension stirred at reflux for 18 hours. On cooling, water (250ml) was added and the mixture extracted with dichloromethane (500ml). The combined organic extracts were dried (MgSO 4 ), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with hexane:ethyl acetate (80:20 v/v) to give the subtitle compound as an oil that crystallised on standing (21.06g, 75%). R f 0.52 (ethyl acetate:hexane, 1:1, v/v). MS m/z 270 (MH) + . (c) 2-Hydroxy-3,4-dimethoxybenzonitrile 10% palladium on charcoal (2.0g) was added to a solution of 2-benzyloxy-3,4-dimethoxybenzonitrile (20.8g, 0.077mol) in ethanol (250ml) and the reaction stirred under a hydrogen atmosphere of 414 kPa (60 p.s.i.) for 4 hours. On cooling, the mixture was filtered through Arbocel™, washing with further ethanol. The filtrate was evaporated under reduced pressure to give the subtitle compound as a yellow solid (13.37g, 97%). R f 0.19 (dichloromethane). MS m/z 197 (MNH 4 ) + . (d) 2-Cyclobutyloxy-3,4-dimethoxybenzonitrile 2-Hydroxy-3,4-dimethoxybenzonitrile (6.65g, 0.037mol) was added to a suspension of cyclobutyl bromide (5.01g, 0.037mol) and potassium carbonate (5.11g, 0.037mol) in dimethylformamide (65ml) and the reaction stirred at 80°C for 4 hours. On cooling, the mixture was concentrated under reduced pressure and the residue partitioned between water (50ml) and ethyl acetate (50ml). The aqueous layer was extracted with further ethyl acetate (100ml) and the combined organic extracts dried (MgSO 4 ), filtered and evaporated under reduced pressure to give the subtitle compound as a brown oil (6.50g, 75%). R f 0.63 (dichloromethane). MS m/z 251 (MNH 4 ) + . (e) 2-Cyano-3-cyclobutyloxy-4,5-dimethoxynitrobenzene Nitronium tetrafluoroborate (4.64g, 0.035mol) was added portionwise to an ice cooled solution of 2-cyclobutyloxy-3,4-dimethoxybenzonitrile (6.28g, 0.027mol) in acetonitrile (150ml) and the reaction stirred for 1 hour. Saturated aqueous sodium bicarbonate solution (150ml) was added and the mixture extracted with ethyl acetate (400ml). The combined organic extracts were washed with water (150ml), dried (MgSO 4 ), filtered and evaporated under reduced pressure to give a dark brown oil. The crude product was purified on silica gel eluting with dichloromethane to give the subtitle compound as a pale yellow solid (4.01g, 53%). R f 0.23 (hexane:isopropyl alcohol:0.880 aqueous ammonia 90:10:0.75, v/v). MS m/z 296 (MNH 4 ) + . (f) 2-Cyano-3-cyclobutyloxy-4,5-dimethoxyaniline A solution of sodium dithionite (27.6g, 0.144mol) in water (100ml) was added to a solution of 2-cyano-3-cyclobutyloxy-4,5-dimethoxynitrobenzene (4.0g, 0.0143mol) and tetra-n-butylammonium chloride (2.33g, 0.0084mol) in dichloromethane (100ml) and the reaction stirred vigorously for 90 minutes. 2N aqueous sodium hydroxide solution (100ml) and dichloromethane (100ml) were then added and stirring continued for 5 minutes. The aqueous phase was extracted with further dichloromethane (400ml) and the combined organic extracts dried (MgSO 4 ), filtered and concentrated under reduced pressure to a volume of 50ml. Ethereal hydrogen chloride was added and the resulting precipitate filtered and washed with diethyl ether. The solid was then partitioned between 2N aqueous sodium hydroxide (50ml) and dichloromethane (100ml) and the organic layer dried (MgSO 4 ), filtered and evaporated under reduced pressure to give the subtitle compound as a yellow oil (2.99g, 86%). R f 0.75 (ethyl acetate). MS m/z 266 (MNH 4 ) + . (g) 2-Cyclobutyloxy-3,4-dimethoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}benzonitrile Phosphorous oxychloride (210µl, 0.0022mol) was added to a solution of 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane (1.02g, 0.0040mol) in dichloromethane (10ml) and the solution stirred at room temperature for 1 hour. 2-Cyano-3-cyclobutyloxy-4,5-dimethoxyaniline (500mg, 0.002mol) was then added and the reaction stirred at reflux under a nitrogen atmosphere for 18 hours. On cooling, water (30ml) and aqueous sodium hydroxide solution were added and the mixture extracted with dichloromethane (2×100ml). The combined organic extracts were dried (MgSO 4 ), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with dichloromethane:methanol:0.880 aqueous ammonia solution (96:3.5:0.5 v/v) to give the subtitle compound as a gum (950mg, 97%). R f 0.62 (dichloromethane:methanol:0.880 aqueous ammonia 92:7:1, v/v). MS m/z 486 (MH) + . (h) 4-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinoline A solution of lithium diisopropylamide in tetrahydrofuran (10ml, 0.5M, 0.005mol) was added to a solution of 2-cyclobutyloxy-3,4-dimethoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}benzonitrile (950mg, 0.002mol) in tetrahydrofuran (25ml) at -70°C and the reaction allowed to warm to room temperature under a nitrogen atmosphere. 1N aqueous citric acid solution (25ml) was then added and the mixture extracted once with ethyl acetate (25ml). The aqueous phase was basified using 1N aqueous sodium hydroxide solution and the mixture extracted with further ethyl acetate (60ml) and these combined organic extracts dried (MgSO 4 ), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with dichloromethane:methanol:0.880 aqueous ammonia (97:3:1 v/v) and trituration with diethyl ether gave the title compound as a foam (680mg, 67%). R f 0.31 (dichloromethane:methanol:0.880 aqueous ammonia, 97:3:1, v/v). MS m/z 486 (MH) + . 1 H-NMR (CDCl 3 ): δ = 1.45 (1H, m), 1.70 (1H, m), 2.03 (2H, m), 2.30 (4H, m), 3.30 (4H, m), 3.35 (2H, m), 3.60 (8H, m), 3.80 (3H, s), 3.92 (5H, br.s), 4.80 (1H, m), 5.60 (2H, m), 5.70 (1H, s), 6.73 (1H, s). Found : C, 61.27; H, 7.39; N, 13.92; C 25 H 35 N 5 O 5 0.1(C 2 H 5 ) 2 O 0.3 H 2 O requires C, 61.21; H, 7.40; N, 14.05%. Example 3 4-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)quinoline hydrochloride (a) 2-Cyclobutyloxy-3,4-dimethoxy-6-[1-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethylideneamino]benzonitrile The subtitle compound was prepared from 2-cyano-3-cyclobutyloxy-4,5-dimethoxyaniline and 6-acetyl-5,6,7,8-tetrahydro-1,6-naphthyridine following the procedure described in Example 2(g), allowing the reaction to reflux for 3 hours. The crude product was purified on silica gel eluting with ethyl acetate:methanol:0.880 aqueous ammonia solution (95:5:1, v/v) to give the subtitle compound as a gum (382mg, 48%). R f 0.53 (dichloromethane: methanol:0.880 aqueous ammonia 90:10:1, v/v). MS m/z 407 (MH) + . (b) 4-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)quinoline hydrochloride The title compound was prepared from 2-cyclobutyloxy-3,4-dimethoxy-6-[1-(5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)ethylideneamino]benzonitrile following a similar procedure to that described in Example 2(h). The crude product was purified on silica gel eluting with dichloromethane:methanol:0.880 aqueous ammonia (96:3.5:0.5 v/v) followed by suspension in ethereal hydrogen chloride to give the title compound as a sand-coloured solid (18%). MS m/z 407 (MH) + . 1 H-NMR (DMSO-d 6 ): δ = 1.45 (1H, m), 1.66 (1H, m), 2.23 (4H, m), 3.30 (2H, m), 3.70 (3H, s), 3.84 (3H, s), 4.04 (2H, m), 4.78 (1H, m), 4.95 (2H, s), 6.18 (1H, s), 7.64 (1H, s), 7.75 (2H, m), 8.10 (1H, bs), 8.18 (1H, m), 8.64 (1H, s), 12.47 (1H, s). Found: C, 55.32; H, 6.29; N, 10.56; C 23 H 26 N 4 O 3 HCl 1.5H 2 O 0.5CH 2 Cl 2 , requires C, 55.08; H, 6.10; N, 10.93%. Example 4 4-Amino-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]-5-(2,2,2-trifluoroethoxy)quinoline hydrochloride (a) 4-Cyano-3-fluoro-5-(2,2,2-trifluoroethoxy)anisole Sodium hydride (1.6g, 60%, 0.040mol) was added to a solution of trifluoroethanol (4.0g, 0.040mol) in dimethylformamide (50ml) and the solution stirred for 90 minutes. This solution was then added to 4-cyano-3,5-difluoroanisole [Grey et al , Mol Cryst Liq Cryst, 172 , 165-189 (1989)] (6.30g, 0.037mol) in tetrahydrofuran (50ml) and the reaction stirred at room temperature for 2 hours. The reaction mixture was poured into diethyl ether (250ml) washed with water (2×150ml) and then brine (50ml). The organic layer was dried (MgSO 4 ), filtered and evaporated under reduced pressure, then triturated with diethyl ether:hexane to give the subtitle compound as white crystals (5.92g, 59%). R f 0.14 (dichloromethane:hexane, 1:2, v/v). MS m/z 267 (MNH 4 ) + . (b) 3-Azido-4-cyano-5-(2,2,2-trifluoroethoxy)anisole Sodium azide (1.77g, 0.027mol) was added to a solution of 4-cyano-3-fluoro-5-(2,2,2-trifluoroethoxy)anisole (5.66g, 0.0227mol) in dimethylformamide and the reaction stirred under a nitrogen atmosphere at 115°C for 2 hours. On cooling, the reaction mixture was poured into diethyl ether (400ml), washed with water (2×100ml) and then brine (50ml). The organic phase was dried (MgSO 4 ), filtered and evaporated under reduced pressure to give an off-white foam (5.66g, 91%). R f 0.10 (dichloromethane:hexane, 1:2, v/v). MS m/z 273 (MH) + . (c) 3-Amino-4-cyano-5-(2,2,2-trifluoroethoxy)anisole 3-Azido-4-cyano-5-(2,2,2-trifluoroethoxy)anisole (5.66g, 0.0208mol) was added to a suspension of magnesium turnings (1.86g, 0.0775mol) in methanol (150ml) and the reaction stirred at room temperature for 40 hours. The reaction was concentrated under reduced pressure to a minimum volume and ethyl acetate (200ml) added. The mixture was washed with saturated aqueous ammonium chloride solution (75ml) and brine (75ml) and then dried (MgSO 4 ), filtered and evaporated under reduced pressure. Trituration with diethyl ether:hexane gave the subtitle compound as a brown solid (4.51g, 88%). R f 0.46 (ethyl acetate:hexane, 1:1, v/v). MS m/z 247 (MH) + . (d) 2-(2,2,2-Trifluoroethoxy)-4-methoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}benzonitrile The subtitle compound was prepared from 3-amino-4-cyano-5-(2,2,2-trifluoroethoxy)-anisole and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following a similar procedure to that described in Example 2(g) allowing the reaction to stir for 60 hours at room temperature. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 to 95:5, v/v). The product was dissolved in a minimum volume of dichloromethane and an excess of ethereal hydrogen chloride added. The resulting precipitate was filtered off and partitioned between saturated aqueous sodium hydroxide solution (100ml) and dichloromethane (200ml). The organic layer was dried (MgSO 4 ) and evaporated under reduced pressure to give the subtitle compound (1.83g, 95%). R f 0.58 (dichloromethane:methanol:0.880 aqueous ammonia 92:7:1, v/v). MS m/z 484 (MH) + . (e) 4-Amino-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]-5-(2,2,2-trifluoroethoxy)quinoline hydrochloride Zinc chloride (3.0g, 0.022mol) was added to a solution of 4-methoxy-2-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}-6-(2,2,2-trifluoroethoxy)-benzonitrile (900mg, 0.00186mol) in tetrahydrofuran (50ml) and the mixture concentrated under reduced pressure. The residue was then heated at 190°C under vacuum for 30 minutes. On cooling, the residue was dissolved in ethyl acetate (100ml), ethylenediaminetetraacetic acid disodium salt (10g, 0.027mol) was added and the mixture basified with 2N aqueous sodium hydroxide solution. The organic phase was separated, washed with brine (50ml), dried (MgSO 4 ), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane:methanol:0.880 aqueous ammonia (100:0:0 to 93:7:1, v/v), followed by crystallisation from acetone/ethereal hydrogen chloride to give the title compound as a solid (66mg, 7%). MS m/z 484 (MH) + . 1 H-NMR (CDCl 3 ): δ = 2.07 (2H, m), 3.04 (4H, m), 3.26 (2H, t), 3.52 (4H, m), 3.60 (2H, t), 3.78 (2H, t), 3.88 (3H, s), 4.09 (2H, m), 4.42 (2H, q), 5.73 (1H, s), 6.19 (1H, s), 6.80 (2H, bs), 8.38 (1H, s), 12.4 (1H, s). Found: C, 47.02; H, 5.93; N, 12.41; C 22 H 28 F 3 N 5 O 4 HCl, requires C, 47.02; H, 5.57; N, 12.08%. Example 5 4-Amino-5-cyclobutyloxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinoline (a) 4-Cyano-3-fluoro-5-cyclobutyloxyanisole The subtitle compound was prepared from 4-cyano-3,5-difluoroanisole and cyclobutanol following the procedure described in Example 4(a). The crude product was purified on silica gel eluting with dichloromethane:hexane (60:40 v/v) to give the subtitle compound as a white solid (92%). R f 0.26 (dichloromethane:hexane 1:2, v/v). MS m/z 239 (MNH 4 ) + . (b) 3-Azido-4-cyano-5-cyclobutyloxyanisole The subtitle compound was prepared from the product of step (a) following the procedure described in Example 4(b). The crude product was purified on silica gel eluting with dichloromethane:hexane (60:40 v/v) to give the subtitle compound as a colourless oil that crystallised on standing (1.33g, 54%). R f 0.29 (dichloromethane:hexane 1:1, v/v). MS m/z 262 (MNH 4 ) + . (c) N-(2-Cyano-3-cyclobutyloxy-5-methoxy)-P,P,P-triphenylphosphine imide Triphenylphosphine (1.42g, 0.0054mol) was added to a solution of 3-azido-4-cyano-5-cyclobutyloxyanisole (1.32g, 0.0054mol) in tetrahydrofuran (20ml) and the solution stirred at room temperature for 1 hour. Water (1ml) was added and the reaction stirred for a further 18 hours and the reaction then concentrated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane: methanol (100:0 to 97:3 v/v) to give the subtitle compound as a white solid (2.17g, 84%). R f 0.07 (dichloromethane). MS m/z 479 (MH) + . (d) 3-Amino-4-cyano-5-cyclobutyloxyanisole N-(2-Cyano-3-cyclobutyloxy-5-methoxy)-P,P,P-triphenylphosphine imide (2.17g, 0.00453mol) was added to a solution of 2N aqueous hydrochloric acid (5ml), water (50ml), methanol (50ml) and dichloromethane (50ml) and the reaction stirred at reflux for 16 hours. On cooling, the mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (100ml) and 0.5N aqueous sodium hydroxide (50ml). The phases were separated and the organic, washed with brine (50ml), dried (MgSO 4 ), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 to 98:2 v/v) to give the subtitle compound as a white solid (866mg, 88%). R f 0.64 (ethyl acetate:hexane, 1:1, v/v). MS m/z 219 (MH) + . (e) 2-Cyclobutyloxy-4-methoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}benzonitrile The subtitle compound was prepared from 3-amino-4-cyano-5-cyclobutyloxyanisole and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following the procedure described in Example 4(d) (93%). R f 0.52 (dichloromethane:methanol:0.880 aqueous ammonia, 92:7:1, v/v). MS m/z 456 (MH) + . (f) 4-Amino-5-cyclobutyloxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinoline Potassium tert -butoxide (810mg, 0.00725mol) was added to a solution of 2-cyclobutyloxy-4-methoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylidene-amino}benzonitrile (1.65g, 0.00363mol) in 1,2-dimethoxyethane (250ml) and the reaction stirred at 90°C under a nitrogen atmosphere for 1 hour. On cooling, the reaction mixture was washed with 1N aqueous citric acid solution (100ml) and extracted with ethyl acetate (100ml). The aqueous layer was then basified with 2N aqueous sodium hydroxide solution and extracted with dichloromethane (2× 100ml). These combined organic extracts were dried (MgSO 4 ), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane:methanol:0.880 aqueous ammonia (100:0:0 to 91:9:1 v/v) gave the title compound as a foam (0.93g, 56%). R f 0.27 (dichloromethane:methanol:0.880 aqueous ammonia, 97:2:1, v/v). MS m/z 456 (MH) + . 1 H-NMR (CDCl 3 ): δ = 1.75 (1H, m), 1.92 (1H, m), 2.05 (2H, m), 2.24 (2H, m), 2.54 (2H, m), 3.14 (4H, t), 3.34 (2H, t), 3.57 (2H, t), 3.64 (4H, t), 3.70 (2H, t), 3.88 (3H, s), 3.94 (2H, bm), 4.62 (1H, m), 5.55 (2H, bs), 5.70 (1H, s) 5.96 (1H, s), 6.56 (1H, bs). Found: C, 60.87; H, 7.45; N, 14.79; C 24 H 33 N 5 O 4 H 2 O, requires C, 60.67; H, 7.08; N, 14.51%. Example 6 4-Amino-6,7-dimethoxy-5-(2,2,2-trifluoroethoxy)-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinoline (a) 3,4-Dimethoxy-2-(2,2,2,-trifluoroethoxy)benzonitrile Potassium carbonate (6.91g, 0.05mol) was added to a stirred solution of 2-hydroxy-3,4-dimethoxybenzonitrile (from Example 2(c), 5.61 g, 0.031mol) in dimethylformarnide (30ml). This was followed by the addition of a solution of 2,2,2-trifluoroethyl triflate (23.2g, 0.10mol) in dichloromethane (100ml) and the reaction was stirred at room temperature for 18 hours. The reaction was partitioned between 2N hydrochloric acid and ethyl acetate, the organic layer separated, washed sequentially with saturated aqueous brine and water, dried (MgSO 4 ) and evaporated under reduced pressure. Trituration with diethyl ether followed by filtration afforded the subtitle compound as a colourless solid (7.67g, 94%). R f 0.76 (dichloromethane:methanol 95:5, v/v). MS m/z 279 (MNH 4 ) + (b) 2-Cyano-4,5-dimethoxy-3-(2,2,2-trifluoroethoxy)nitrobenzene Ammonium nitrate (2.82g, 0.035mol) and trifluoroacetic anhydride (12.4ml, 0.088mol) were added to a solution of 3,4-dimethoxy-2-(2,2,2,-trifluorethoxy)benzonitrile in dichloromethane. The temperature was maintained between 20°C and 30°C for 2 hours, after which time the reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried (MgSO 4 ) and evaporated under reduced pressure. Trituration with diethyl ether followed by filtration afforded a first crop of product. The filtrate was purified on silica gel, eluting with dichloromethane to afford the subtitle compound as a colourless solid (combined yield 6.56g, 73%). R f 0.31 (ethyl acetate:hexane 20:80, v/v). MS m/z 324 (MNH 4 ) + (c) 2-Cyano-4,5-dimethoxy-3-(2,2,2-trifluoroethoxy)aniline The subtitle compound was prepared from 2-cyano-4,5-dimethoxy-3-(2,2,2-trifluoroethoxy)nitrobenzene using Na 2 S 2 O 4 following the procedure described in Example 10(f) (87%). R f 0.27 (dichloromethane). MS m/z 294 (MNH 4 ) + (d) 3,4-Dimethoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}-2-(2,2,2-trifluoroethoxy)benzonitrile The subtitle compound was prepared from 2-cyano-4,5-dimethoxy-3-(2,2,2-trifluoroethoxy)aniline and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following the procedure described in Example 2(g) (73%). R f 0.16 (dichloromethane:methanol 95:5, v/v). MS m/z 514 (MH) + (e) 4-Amino-6,7-dimethoxy-5-(2,2,2-trifluoroethoxy)-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinoline The title compound was prepared from 3,4-dimethoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}-2-(2,2,2-trifluoroethoxy)benzonitrile following the method of Example 4(e). Purification on silica gel, eluting with dichloromethane: methanol (95:5, v/v) afforded the title compound as a colourless foam (7%). R f 0.25 (dichloromethane:methanol:0.880 aqueous ammonia, 90:10:1, v/v). MS m/z 514 (MH) + . 1 H-NMR (CDCl 3 ): δ = 2.05 (2H, m), 3.15 (4H, t), 3.34 (2H, t), 3.58 (2H, m), 3.64 (4H, t), 3.70 (2H, m), 3.86 (3H, s), 3.95 (5H, m), 4.60 (2H, q), 5.37 (2H, bs), 5.78 (1H, s) 6.83 (1H, bs). Example 7 4-Amino-5-cyclobutyloxy-6,7-methoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline (a) 6-Cyclobutyloxy-3,4-dimethoxy-[1-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)ethylideneamino]benzonitrile The subtitle compound was prepared from 2-cyano-3-cyclobutyloxy-4,5-dimethoxyaniline and 2-acetyl-5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline following the procedure described in Example 2(g). Trituration with diethyl ether afforded the subtitle compound as a colourless solid (85%). R f 0.14 (ethyl acetate:hexane 1:1, v/v). (b) 4-Amino-5-cyclobutyloxy-6,7-methoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline The title compound was prepared from 6-cyclobutyloxy-3,4-dimethoxy-[1-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)ethylideneamino]benzonitrile following the procedure described in Example 5(f). The title compound was obtained as a light brown foam (100%). R f 0.09 (ethyl acetate). 1 H-NMR (CDCl 3 ): δ = 1.50 (1H, m), 1.76 (1H, m), 2.15-2.40 (3H, m), 2.87 (2H, m), 3.00 (3H, s), 3.81 (3H, s), 3.88 (2H, m), 3.97 (3H, s), 4.78 (2H, s,), 4.81 (1H, m), 5.78 (2H, bs), 5.88 (1H, s), 6.92 (2H, s), 7.10 (1H, s), 7.21 (1H, t), 7.28 (2H, m).

Claims: A compound of formula I, wherein R 1 represents C 1-4 alkoxy optionally substituted by one or more fluorine atoms; R 2 represents H, C 1-6 alkoxy (optionally substituted by one or more fluorine atoms, or by phenyl which may in turn be substituted by one or more fluorine atoms), or cyclobutyloxy; R 3 represents cyclobutyloxy or CF 3 CH 2 O; R 4 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C 1-4 alkyl, C 1-4 alkoxy, halogen and NHSO 2 (C 1-4 alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms; X represents CH or N; and L is absent, or represents a cyclic group of formula Ia, in which A is attached to R 4 ; A represents CO or SO 2 ; Z represents CH or N; m represents 1 or 2, and in addition, when Z represents CH, it may represent 0; and n represents 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5; or a pharmaceutically acceptable salt thereof. A compound as claimed in claim 1, wherein R 1 represents methoxy. A compound as claimed in claim 1 or claim 2, wherein R 2 represents H or methoxy. A compound as claimed in any preceding claim, wherein L is absent. A compound as claimed in claim 4, wherein R 4 represents a piperidine ring which is fused to a pyridine ring or to a benzene ring which is substituted by NHSO 2 (C 1-4 alkyl). A compound as claimed in any one of claims 1-3, wherein L represents A compound as claimed in claim 6, wherein R 4 represents morpholinyl. A pharmaceutical formulation including a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. A compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. A pharmaceutical formulation as claimed in claim 9, including a 5-α reductase inhibitory compound. The use of a compound of formula I, as defined in claim 1, or a pharmaceutiically acceptable salt thereof, in the manufacture of a medicament for the treatment of benign prostatic hyperplasia. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, which comprises: (a) when X represents CH, cyclizing a compound of formula II, in which R 1-4 and L are as defined in claim 1; (b) when Z represents N, and L is present, reacting a compound of formula IIIa, in which R 1 , R 2 , R 3 , X, m and n are as defined in claim 1, with a compound of formula IV, Lg-A-R 4 IV in which R 4 and A are as defined in claim 1, and Lg represents a leaving group; (c) reacting a compound of formula V, in which R 1 , R 4 , X and L are as defined in claim 1, and R a and R b independently represent H or OH, provided that they do not both represent H, with a compound of formula VI, R c -Lg VI in which R c is alkyl (optionally substituted by one or more fluorine atoms, or by phenyl which may in turn be substituted by one or more fluorine atoms) or cyclobutyloxy, and Lg represents a leaving group, in the presence of a base; (d) when X represents N, reacting a compound of formula VII, in which R 1 , R 2 and R 3 are as defined in claim 1, with a compound of formula VIIIa or VIIIb, as appropriate, HR 4a VIIIb in which R 4 , A, Z, m and n are as defined in claim 1; and R 4a has the same significance as R 4 in claim 1 except that it contains a nucleophilic nitrogen atom in the heterocyclic ring which is attached to the H in formula VIIIb; or (e) when A represents CO and R 4 comprises a nucleophilic nitrogen atom in the heterocyclic ring attached to L, reacting a compound of formula IXa, in which R 1-3 , X, Z, m and n, are as defined in claim 1, and Lg is a leaving group, with a compound of formula VIIIb, as defined above. Compounds of formulae II, IIIa, V, VII, and IXa as defined in claim 12.

Inventors: COLLIS ALAN JOHN, FOX DAVID NATHAN ABRAHAM, MANTELL SIMON JOHN, COLLIS, ALAN JOHN, FOX, DAVID NATHAN ABRAHAM, MANTELL, SIMON JOHN
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER LIMITED
Application year: 1998
Main classification: C07D215
IPC codes: A61K31, C07D471, A61P15, C07D403, A61P13, C07D405, C07D401