ANTIHYPERTENSIVE AGENTS

Abstract: 1,4,5,6,7,8-Hexahydro-2-alkyl-4-aryl-5-oxo-1, 7-naphthy­ ridine-3-carboxylic acid esters and pharmaceutically accept­ able salts thereof are useful antihypertensive agents.

Description: Pharmacological agents possessing the ability to block cellular tranamembrane influx of calcium are capable of suppressing that portion of myocardial or smooth muscle contractility which is dependent upon extracellular calcium. These pharmacological agents, termed calcium antagonists, have been proven to be useful in the treatment of hypertension, cardiac arrhythmias, angina pectoris, cardiac myopathy and coronary artery vasospasm (a possible cause of sudden cardiac death syndrome). Can 3. Physiol. Pharmacol., 57 443 (1979); Drugs, 15 169 (1978); Acta Pharmacol. Toxicol., 43, suppl. 1, 45 (1978). In theory, calcium antagonists are thought to act by blocking calcium influx through discrete calcium channels (slow channels) in cell membranes. Various tissues exhibit relative differences in sensivity toward the calcium blocking effect achieved by certain calcium antagonists, theoretically as a result of tissue specific differences in the calcium channels. Acta Pharmacol. Toxicol., 43, 5, (1978); loc. cit. 291 (1978); Microvascular Res., 6, 73 (1973); Am Rev. Pharmacol. Toxicol., 17 149 (1977). Calcium channels of tissue which are most sensitive to calcium antagonist blockade are those which allow calcium influx only when the cell membranes are electrically depolarised. a-adrenergic receptoractivated calcium channels are relatively unaffected by these agents. Circ. Res., 46 426 (1980). This observation provides basis for revaluation of calcium antagonism. Thus, vascular smooth muscle tissue from the rabbit aorta can be made to contract when exposed to a depolarising solution containing an elevated postassium ion concentration and normal amounts of calcium ions. Calcium antagonists added to the solution produce a dose dependent relaxation of the contracted rabbit aortic tissue. Normal contraction of the aortic tissue can then be induced in the presence of a calcium antagonist by subsequent addition of an a-adrenergic agonist, such as norepinephrine, to the solution. Eur. J. Pharmacol., 53, 281 (1979); Circ. Res., 46 426 (1980); 3.Exp. Pharmacol. Therap., 174 500 (1970). The normal contraction produced by an a-adrenergic agonist after maximal smooth muscle relaxation has been induced by a calcium antagonist, serves to distinguish the calcium blocking effect of an agent from a nonspecific depressant effect on the muscle. In accordance with this invention there is provided a group of 1,4,5,6,7,8-hexahydro-2-alkyl-4-aryl-5-oxo-1,7- naphthyridine-3-carboxylic acid esters and pharmaceutically acceptable salts thereof, which compounds are calcium antagonists useful in the treatment of hypertension, cardiac arrhythmias, angina pectoris, cardiac myopathy and coronary artery vasospasm. More specifically, the compounds of this invention are those of the formula: EMI2.1 in which R is hydrogen, alkyl of 1 to 6 carbon atoms or benzyl; R2 is alkyl of I to 6 carbon atoms; R 3 is alkyl of 1 to 6 carbon atoms, alkoxyalkyl in which each alkyl moiety has 1 to 6 carbon atoms, EMI2.2 where R9 is hydrogen or alkyl of 1 to 6 carbon atoms; and R10 is alkyl of 1 to 6 carbon atoms or arylalkyl of 7 to 10 carbon atoms and R9 and R10 taken with the nitrogen atom to which they are attached form a pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, 4-alkylpiperazinyl in which the alkyl group contains from 1 to 6 carbon atoms or morpholinyl heterocycle; and n is one of the integers 0, 1 or 2; R1 is pentafluorophenyl, tetrafluorophenyl or EMI3.1 wherein R6 and R8 are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, halo, trifluoromethyl, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, cyano or nitro; 7 R is hydrogen, alkyl of 1 to 6 carbon atoms, halo, trifluoromethyl, cyano or nitro; and R6 and R7 when in ortho position to each other and taken together are butadienylene, tetramethylene or trimethylene; or a pharmaceutically acceptable salt thereof. The compounds that are preferred because of production economics and availability of starting materials are those in which the aliphatic moieties are straight or branched chain containing from 1 to 4 carbon atoms, the arylalkyl group representing R10 is benzyl or phenethyl and n is 1 or 2. The compounds of this invention may be prepared by reacting a 3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine derivative (piperidine-3,5-dione), an aldehyde and a substituted or unsubstituted 3-aminocrotonate ester according to the reaction scheme EMI4.1 where R12 is alkyl of 1 to 6 carbon atoms or benzyl. The terms "unsubstituted" and "substituted" as used herein in respect of the 3-aminocrotonate esters denote that R2 is is alkyl of 1 carbon atom and alkyl of 2 to 6 carbon atoms respectively. The benzyl group of the compound of formula VII or a salt thereof may be removed by hydrogenolysis to afford the 7-unsubstituted products. If desired, the substituted or unsubstituted 3-aminocrotonate esters may be prepared, in situ, by ammonolysis of the alkanoylacetic acid having the formula R2COCH2CO2R3. The compounds of this invention may also be prepared by reaction of a benzylidine alkanoylacetic acid ester of the formula: EMI4.2 with a 3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine of the formula: EMI4.3 in the presence of ammonia. The ammonia may be supplied to the reaction medium as gaseous ammonia, ammonium hydroxide or an ammonium salt of a weak organic acid such as ammonium acetate. The benzylidene alkanoylacetic acid ester ractant may be prepared by reaction of an aldehyde having the formula R1CHO with an alkanoylacetic acid ester of the formula R2C0C142C02R3 The 3-oxo-5-hydroxy-1,2s3,6-tetrahydropyridines having formula IV may be prepared from N-substituted glycine esters by standard procedures. The N-methyl and N-benzyl 3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridines are literature compounds: Archiv. d-er Pharmazie, 300 91 (1967); J.A.C.S. 95 7458 (1973); Tet. Lett., 4075 (1977). The preparatory technique generally follows the equations: EMI5.1 The aldehyde and substituted or unsubstituted 3-aminocrotonate reactants are either commercially available or may be prepared by standard procedures. The pharmaceutically acceptable salts of the antihypertensive agents of this invention may be prepared directly by neutralisation of the free base or by metathetical displacement. The physiologically acceptable salts may be formed with organic or inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, sulphonic, nitric-, methylsulphonic, acetic, maleic, succinic, fumaric, tartaric, citric, salicylic, lactic, naphthalenedisulphonic acid, and the like. The free bases may be prepared by neutralizing the acid addition salts by treatment with a base. The N-benzyl 1,4,5,6,7,8-hexahydro-2-alkyl-4-aryl-5- oxo-1,7-naphthyridine-3-carboxylic acid esters form an additional intermediate compound aspect of the invention useful in the preparation of the N-unsubstituted analogues referred to supra. The N-benzyl intermediates are depicted by the structural formula: EMI6.1 where PhCH2 is benzyl and the R1 ¯ R3 groups are defined supra. These compounds, although categorised as intermediates herein, are very potent in vitro Ca+2 antagonists. The N-benzyl derivatives generally lack sufficient bioavailability in vivo (because of their insolubility, protein binding propensity or analogous functional deactivating property) to qualify as meaningful antihypertensive agents. Derivitisation of the 7-benzyl intermediates to afford in vivo antihypertensive activity is achieved by preparing compounds that are functionalised to provide solubility and avoid physical deactivation in the animal. Thus, preparation of the aminoalkyl esters (where R3 has formula II) illustrates one method for improving the bioavailability of the 7-benzyl derivatives such that they afford excellent antihypertensive agents without removal of the 7-benzyl substituent. The in vitro Ca+2 antagonist level and the in vivo blood pressure reduction obtained, where applicable, for these intermediates, is presented in the following examples. The compounds of this invention were initially shown to exhibit Ca+2 antagonism in rabbit aortic strips wherein the strips were contracted in an organ bath containing a modified physiological salt solution (Broekaert et al., Europ. J. Pharmacol. 53 281 (1979) in which 100 millimoles potassium ion had been substituted on an equimolar basis for sodium ion. After a stable active tension has developed in the strip, as measured by Statham UC-2 force transducers and rscorded on an eight channel Beckman Dynograph Polygraphic Recorder, an amount of the antagonist -was added to the organ bath to make a 10 molar concentration of antagonist. The depressant effect, expressed as percent relaxtion, was taken from the mean of at least two experiments. After maximum Ca+2 antagonist induced relaxation was obtained, a maximal dose of norepinephrine (10 5 moles) was added to the organ bath to determine whether normal a-adrenergic responses were still effected and show that the compound being tested was not a general depressant. A Ca+2 antagonist producing a 20 per cent relaxation of aortic tissue in this test procedure at a 1D 5 molar bath concentration of the antagonist, generally produces a significant reduction blood pressure when a sufficient amount is given to the spontaneously hypertensive rat. The in vivo blood pressure lowering ability of the compounds of this invention was established by measuring the systolic pressure of spontaneously hypertensive rats with a Decker Caudal Plethysmograph or similar sensor device. The compound tEing tested is administered to groups of four rats and their blood pressure is read prior to compound administration and at 1.5 and 4 hours after compound administration. Depending upon the behaviour of the compound being tested, the schedule of blood pressure readings and route of administration is modified. Initially the compounds are administered orally but where compound solubility is a factor, the compounds may be administered parenterally (i.e. i.p., i.m., s.c., i.v., etc.) as desired. The compounds of this invention were initially administered orally at a standard testing dose of 50 mg/kg. Based upon the activity profile elicited by the compounds of this invention in the above-described standard scientifically recognised test models, the compounds are established as hypotensive agents useful in the treatment of hypertension and conditions characterised by constrictive blood flow in coronary arteries. For that purpose, the compounds may be administered orally or parenterally in suitable dosage forms compatable with the route of administration, whether oral, intraperitoneal, intramuscular, intravenous, intranasal, buccal, etc. The effective dose range determined in the animal test models has been established at from 1 to about 50 milligrams per kilogram host body weight to be administered in single or plural doses as needed to obtain the desired hypotensive response. The specific dosage regimen for a given patient will depend upon age, pathological state, severity of dysfunction, size of the patient, etc. Oral administration is performed with either a liquid or solid dosage unit in any conventional form such as tablets, capsules, solutions, etc., which comprise a unit dose (e.g. from about 25 milligrams to about 4 grams) of the active ingredient alone or in combination with adjuvants needed for conventional coating, tableting, solubilising, flavour or colouring. Parenteral administration with liquid unit dosage forms may be via sterile solutions or suspensions in aqueous or oleagenous medium. Isotonic aqueous vehicle for injection is preferred with or without stabilisers, preservatives and emulsifiers. Thus the invention also provides a pharmaceutical composition comprising a compound having formula I or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier. The composition may be prepared by bringing the compound having formula I or a pharmaceutically acceptable salt thereof into association with the said carrier, for example, by mixing the ingredients. The following examples illustrate the preparation of a representative number of compounds of this invention. After each example, the Caf antagonist activity of the compound is presented in terms of per cent relaxation (P.R.) at the stated concentration. Similarly, the anti-hypertensive activity is reported in terms of millimetres mercury (mmHg) blood pressure (B.P.) reduction at the stated time post 50 mg/kg oral dosing unless otherwise indicated. Example 1 1,4,5,6,7,8-Hexahydro-2,7-Dimethyl-2,7-Dimethyl-4-(2- Nitrophenyl)-6-Oxo-1 , 7-Naphthyridine-3-Carboxylic Acid Methyl Ester 1-Methyl-3-oxo-5-hydroxy-1,2,3p6-tetrahydropyridine (6.36 g.), 5.93 g. of methyl 3-aminocrotonate (97%), 7.56 g. of o-nitrobenzaldehyds and 100 ml. of ethanol were heated at reflux for 1.4 hours. The mixture was cooled to room temperature and the precipitated solid was separated by filration. The solid, m.p. 233-235 C., was suspended in ethanol and saturated with hydrogen chloride. The solid dissolved, then repracipitated. The mixture was cooled and the solid was separated by filtration. The solid was recrystallised from 95% ethanol with charcoal treatment to obtain the title compound as the hydrochloride, m.p. 227-229O C. dec. Analysis for: C18H19N3G5 . HCl Calculated: C, 54.90; H, 5.12; N, 10.67; Cl, 9.00 Found: C, 54.87; H, 5.20; N, 10.74; Cl, 8.96 P.R. = 14 at B.P. = -27 at 1.5 hours; - 21 at 4 hours. Example 2 1,4,5,6,7,8-Hexahydro-2,7-Dimethyl-4-(2-Methylphenyl)-5- Oxo-1 , 7-Naphthyridine-3-Carboxylic Acid Methyl Ester A mixture of 7.65 g. of 1-methyl-3-oxo-6-hydroxy-1,2,3, 6-tetrahydropyridine, 7.29. of o-tolualdehyde, 6.9 g. of methyl 3-aminocrotonate (97%), 110 ml. of ethanol and 35 ml. of acetic acid was refluxed for 3 hours. The mixture was evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and extracted with saturated sodium carbonate solution. The dichloromethane solution was evaporated to dryness. The residue was slurried with diethyl ether and the solid was separated by filtration. Recrystallisation from ethanol afforded the title compound, m.p. 249-252O C. dec. Analysis for: C19H22N203 Calculated: C, 69.91; H, 6.80; N, 8.58 Found: C, 70.07; H, 6.81; N, 8.73 The solid was suspended in ethanol and saturated with hydrogen chloride. The solvent was removed in vacuo. The residue was recrystallised twice from ethanol-diethyl ether to obtain the hydrochloride, m.p. 245-247 C. dec. Analysis for: C19H22N203 . HCl Calculated: C, 62.89; H, 6.39; N, 7.72; Cl, 9.77 Found: C, 62.48; H, 6.36; N, 7.72; Cl 9.75 P.R. = 31 at B.P. = -57 at 1.5 hours; -28 at 4 hours. Example 3 1,4,5,6,7,a-Hexahydro-2-Methyl-4-(2-Methylphenyl)-5-ûXo-7- (Phenylmethyl)-1,7-Naphthyridine-3-Carboxylic Acid Methyl Ester A mixture of 6.1 g. of 1"benzyl-3-oxo-5-hydroxy-1,2,3, 6-tetrahydropyridine, 3.6 g. of methyl 3-aminocrotonate (97%), 3.6 g of o-tolualdehyde, 55 ml. of ethanol and 18 ml. of acetic acid was refluxed for 7 hours. The solution was evaporated to dryness in vacuo. The residue was triturated with diethyl ether and the solid was separated by filtration. Recrystallisation from ethanol afforded the fitle compound, m.p. 201-2040C. Analysis for: C25H26N203 Calculated: C, 74.60; H, 6.51; N, 6.96 Found: C, 74.42; H, 6.57; N, 6.87 P.R. = 90 at 8.P. = -23 at 1.5 hours; - 41 at 4 hours. Example 4 1,4,s,6,7,8-Hexahydro-2,7-oimethyl-6-oxo-4-[2-(Trifluoro- methyl) Phenylj-1 ,7-Naphthyridine-3-Carboxylic Acid Methyl Ester 1-Methyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine (6.36 g;) 5.93 g. of methyl 3-aminocrotonate, 8.70 g. of o-trifluoromethylbenzaldehyde and 100 ml. of ethanol were refluxed for 2 hours. The reaction mixture was filtered and allowed to cool to room temperature. The solid was separated by filtration. The solid, m.p. 250-252 C. dec., was suspended in ethanol and saturated with hydrogen chloride. The solution was evaporated to dryness in vacuo. The residue was slurried with diethyl ether and filtered. Recrystallisation from ethanol-di-ethyl etcher afforded the title compound as the hydrochloride, m.p. 234-2370 C. dec. Analysis for: C19H19N2F303 . HCl Calculated: C, 54.74; H, 4.84; N, 6.72; Cl, 8.50 Found: C, 54.42; H, 4.90; N, 6.64; Cl, 8.46 P.R. = 48 at B.P. = -68 at 1.5 hours; -70 at 4 hours. Example 5 1,4,5,6,7,8-Hexahydro-2-Methyl-5-Oxo-7-(Phenylmethyl)-4- [2-(Triflurormethyl)Phenyl]-1 , 7-Naphthyridine-3Carboxylic Acid Methyl Ester A mixture of 8.5 g. of 1-benzyl-3-oxo-5-hydroxy-1,2,3, 6-tetrahydropyridine, 4.75 g. of methyl 3-aminocrotonate (97%), 6.96 g. of o-triflurormethylbenzaldehyde and 125 ml. of ethanol was refluxed for 2 hours. The mixture was filtered while hot and the filtrate was allowed to cool to room temperature. The solid was separated by filtration. Recrystallisation from ethanol afforded the title compound, m.p. 2262270 C. Analysis for: C25H23N2F303 Calculated: C, 65.78; H, 5.08; N, 6.14 Found: C, 65.68; H, 5.18; N, 6.04 P.R. = 40 at 10 6M Example 6 1,4,5,6,7,8-Hexahydro-2,7-Dimethyl-4-(3-Nitrophenyl)-5-Oxo-1, 7-Naphthyridine-3-Carboxylic Acid Methyl Ester 1-Methyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine (5.10 g.), 4.75 g. of methyl 3-aminocrotonate (97%), 6.05 g. of m-nitrobenzaldehyde and 100 ml. of ethanol were refluxed for 1.5 hours. The mixture was filtered while hot and allowed to cool to room temperature. The solid was separated by filtration. The solid, m.p. 2100 C. dec., was suspended in ethanol and saturated with hydrogen chloride. The solution was filtered and evaporated to dryness. The residue was slurried with diethyl ether and filtered. Two recrystallisations from ethanol afforded the title compound as the hydrochloride, m.p. 2200 C. dec. Analysis for: C18H19N3O5 . HCl Calculated: C, 54.90; H, 5.12; N, 10.67; Cl, 9.00 Found: C, 54.89; H, 5.19; N, 10.76; Cl, 8.95 P.R. = 35 at 10'5M B.P. = -85 at 1.5 hours; -47 at 4 hours. Example 7 1,4,5,6,7,8-Hexahydro-2-Methyl-4-(2-Methylphenyl)-5-Oxo-1,7- Naphthyridine-3-Carboxylic Acid Methyl Ester Twelve grams of 1,4,5,6,7,8-hexahydro-2-methyl-4-(2- methylphenyl)-5-oxo-7-(phenylmethyl)-1,7-naphthyriding-3- carboxylic acid methyl ester (Example 3) were suspended in 150 ml. of 95% ethanol and 2.5 ml of concentrated hydrochloric acid. One half gram of 10% palladium on carbon uas added and the mixture was shaken with hydrogen at an initial pressure of 50 psi. After 7.5 hours, the mixture was filtered to remove the catalyst. The filtrate was evaporated to dryness in vacuo. The residue was slurried with ethanol and filtered. Recrystallisation from 95% ethanol afforded the title compound as the hydrochloride, m.p. 278-2B0 C. dec. Analysis for: Cl8H20N203 ' HCl Calculated: C, 61.97; H, 6.07; N, 8.03; Cl, 10.18 Found: C, 62.02; H, 6.19; N, 8.23; Cl, 9.96 P.R. = 46 at 10'5M B.P. = -77 at 1.5 hours; -64 at 4 hours. Example 8 4-(2-Chlorophenyl)-1,4,5,6,7,8-Hexahydro-2,7-Dimethyl-5- Oxo-1,7-Naphthyridine-3-Carboxylic Acid Methyl Ester 1-Methyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine (5.10 o.), 4.75 g. of methyl 3-aminocrotonate, 5.62 g. of o-chlorobenzaldehyde and 85 ml. of ethanol were heated to reflux. Solid began to precipitate after 15 minutes. Refluxing was continued for 45 minutes. The mixture was cooled and the solid was separated by filtration. The solid, m.p. 253-255 C. dec., was suspended in ethanol and saturated with hydrogen chloride. The solution was evaporated in vacuo. The residue was slurried with diethyl ether and filtered. Two recrystallisations from ethanol-diethyl ether afforded the title compound as the hydrochloride, m.p. 2412430 C. dec. Analysis for: C18H19N2Cl03 . HCl Calculated: C, 56.40; H, 5.26; N, 7.31; Cl, 18.46 Found: C, 56.21; H, 5.30; N, 7.19; Cl, 18.17 P.R. = 28.3 at B.P. = -54 at 1.5 hours; -30 at 4 hours. Example 9 4-(2,6-Dichlorophenyl)-1 ,4,6,6,7, 8-Hexahydro-2,7-Dimethyl-5 Oxo-1,7-Naphthyridine-3- Carboxylic Acid Methyl Ester A mixture of 7.25 g. of 1-methyl-3-oxo-5-hydroxy-1,2, 3,6-tetrahydropyridine, 8.75 g. of 2,6-dichlorobenzaldehyde, 5.94 g. of methyl 3-aminocrotonate (97%) and 135 ml. of ethanol were heated at reflux for 3 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was slurried with ethanol and the solid was separated by filtration. The solid, m.p. 258-260 C. dec., was suspended in ethanol and saturated with hydrogen chloride. The solution was evaporated to dryness. The residue was triturated with a samll volume of ethanol and filtered. The solid was recrystallised from 96% ethanol to obtain the title compound as the hydrochloride, m.p. 260-2620 C. dec. Analysis for: C18H18Cl2N203 HCl Calculated: C, 51.75; H, 4.58; N, 6.71; Cl, 25.66 Found: C, 51.71; H, 4.67; N, 7.06; Cl, 24.77 P.R. = 41.5 at B.P. = -22 at 1.5 hours; -43 at 4 hours. Example 10 1,4,5,6,7,8-Hexahydro-2-methyl-4-(3-nitrophenyl)-5-oxo-7- (phenylmethyl )-1 , 7-naphthyridine-3-carboxylic acid methyl ester 1-Benzyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine (10.6 g.), 5.45 g. of methyl 3-aminocrotonate, 7.55 g. of m-nitrobenzaldehyde and 120 ml. of ethanol were heated at reflux for 3 hours. The mixture was filtered and the filtrate was cooled in an ice bath. The precipitated solid was separated by filtration. The solid, m.p. 189-191 C dec., was suspended in ethanol and saturated with hydrogen chloride. The salt was separated and recrystallised from aqueous ethanol to obtain the title compound as the hydrochloride, m.p. 211-214 C dec. Analysis for: C24H23N305 Calculated: C, 61.34; H, 5.15; N, 8.94; Cl, 7.54 Found: C, 60.99; H, 5.32; N, 8.71; Cl, 7.56 P.R. = 89.7 at 10 6M Example 11 4-(2,5-Dimethylphenyl)-1,4,5,6,7,8-hexahydro-2,7-dimethyl-5- oxo-1,7-naphthyridine-3-carboxylic acid methyl ester A mixture of 5.10 g. of 1-methyl-3-oxo-5-hydroxy-1,2, 3,6-tetrahydropyridine, 4.75 g. of methyl 3-aminocrotonate, 5.38 g. of 2,5-dimethylbenzaldehyde and 100 ml. of ethanol was refluxed for 1.5 hours. The mixture was filtered and allowed to cool to room temperature. The solid was separated by filtration. The solid, m.p. 2700 C dec, was suspended in ethanol and saturated with hydrogen chloride. The solution was evaporated to dryness in vacuo. The residue was recrystallised from 95% ethanol to obtain the title compound as the hydrochloride, m.p. 243-2460 C dec. Analysis for: C20H24N203 Calculated: C, 63.73; H, 6.68; N, 7.43; Cl, 9.41 Found: C, 63.52; H, 6.60; N, 7.46; C1, 9.39 P.R. = 22 at Example 12 1,4,5,6,7,8-Hexahydro-2-methyl-5-oxo-4-[2-(trifluoromethyl) phenyl i-i, 7-naphthyridine-3-carboxylic acid methyl ester The hydrochloride prepared from 11.5 g. of 1,4,5,6,7, 8-hexahydro-2-methyl-5-oxo-7-(phenylmethyl)-4-[2-(trifluoro methyl)phenyl]-1,7-naphthyridine-3-carboxylic acid methyl ester (Example 5) was dissolved in 150 ml. of 90% methanol. One gram of 10% palladium on carbon was added and the mixture was shaken with hydrogen at an initial pressure of 50 psi.. After 3 hours, the mixture was filtered to remove the catalyst. The filtrate was evaporated to dryness. The residue was slurried with diethyl ether and filtered. Recrystallisation from methanol-diethyl ether afforded the title compound as the hydrochloride, m.p. 272-27S C dec. Analysis for: C18H17N2F303 HCl Calculated: C, 53.67; H, 4.50; N, 6.95; Cl, 8.80 Found: C, 53.-64; H, 4.54; N, 6.85; Cl, 8.74 P.R. = 89.1 at 10 5M B.P. = -88 at 1.5 hours Example 13 1,4,5,6,7,8-Hexahydro-2-methyl-4-(3-nitrophenyl)-5-oXo-1,7- naphthyridine-3-carboxylic acid methyl ester 1,4,5,6,7, 8-Hexahydro-2-methyl-4-(3-nitrophenyl)-5- oxo-7-(phenylmethyl)-1,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (8.5 g.) (Example 10) was dissolved in 250 ml. of 90% methanol. One-half gram of 10% palladium on carbon was added and the mixture was shaken with hydrogen at atmospheric pressure. Hydrogen uptake ceased after 45 minutes. The mixture was filtered to remove the catalyst and the filtrate was concentrated to dryness in vacuo. The residue was crystallised from isopropanol. Recrystallisation from ethanol afforded the title compound as the hydrochloride, hemihydrate, m.p. 2440 C dec. analysis for: C17H17N305 . HCl. /2 H20 Calculated: C, 52.52; H, 4.92; N, 10.81; Cl, 9.12 Found: C, 52.46; H, 4.82; N, 11.06; Cl, 9.68 P.R. = 86.5 at 10-5M B.P. = (Dose 25 mg/kg) -58 at 1.5 hours. Example 14 1,4,5,6,7,8-Hexahydro-2-methyl-5-oxo-4-[3-(triflurormethyl) phenylJ1,7-naphthyridine-3-carboxylic acid methyl ester A mixture of 10.5 g. of 1-benzyl-3-oxo-5-hydroxy-1,2, 3,6-tetrahydropyridine, 5.95 g. of methyl 3-aminocrotonate (97%), 8.7 g. of 3-trifluoromethylbenzaldehyde and 120 ml. of ethanol was refluxed for 3 hours. The solution was concentrated to dryness. The residue was triturated with ethanol and the solid was separated by filtration. The solid was suspended in methanol and saturated with hydrogen chloride. The solid was separated and recrystallised from ethanol to obtain 1,4,5,6,7,8hexahydro-2-methyl-5-oxo-7-(phenylmethyl)-4-[3-(trifluor methyl)phenyl]-1,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride, m.p. 2250 C dec. Analysis for: C25H23N2F303 HCl Calculated: C, 60.92; H, 4.91; N, 5.68; Cl, 7.19 Found: C, 60.76; H, 5.07; N, 5.58; Cl, 7.52 P.R. = 46.2 at 10'6M Nine grams of the above hydrochloride, 0.5 g. of 10% palladium on carbon and 250 ml. of methanol were shaken with hydrogen at an initial pressure of 40 psi. After 2 hours, the mixture was filtered to remove the catalyst. The filtrate was evaporated to dryness in vacuo and the residue crystallised on standing overnight. Recrystallisation from ethyl acetate - diethyl ether afforded the title compound as the hydrochloride, m.p. 232-2340C dec. Analysis for: C18H17N2F303 HCl Calculated: C, 53.67; H, 4.50; N, 6.95; Cl, 8.80 Found: C, 53.65; H, 4.67; N, 6.99; Cl, 8.83 P.R. = 84.0 at P.B. = -S1 at 1.5 hours; -43 at 4 hours. Example 15 4-(2-Fluorophenyl)-1,4,5,6,7,8-hexahydro-2-methyl-6-oxo-1, 7-naphthyridine-3-carboxylic acid methyl ester A mixture of 10.5 g. of 1-benzyl-3-oxo-5-hydroxy-1,2,3, 6-tetrahydropyridine, 5.95 g. of methyl 3-aminocrotonate (97%), 6,2 g. of 2-fluorobenzaldehyde and 125 ml. of ethanol was refluxed for 3 hours. The precipitated solid was separatad by filtration. The solid was suspended in methanol and saturated with hydrogen chloride. The solid was separated and recrystallised from 95% ethanol to obtain 4-(2-fluorophenyl)-1,4,5,6,7,8-hexahydro-2-methyl-5- oXo-7-(phenylmethyl)-1,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride, m.p. 237O C dec. Analysis for: C24H23N2F03 . HCl Calculated: C, 65.08; H, 5.46; N, 6.32; Cl, 8.00 Found: C, 64.97; H, 5.57; N, 6.31; Cl, 8.05 P.R. = 48 at 10 6M. Ten grams of the above hydrochloride, 0.5 g. of 10% palladium on carbon, 200 ml. of methanol and 15 ml. of water were shaken with hydrogen at an initial pressure of 40 psi. After 2 hours, the catalyst was separated by filtration and the filtrate was evaporated to dryness in vacuo. The solid residue was slurried with acetonitrile, filtered, and dried in vacuo. Recrystallisation from 95% ethanol afforded the title compound as the hydrochloride, m.p. 262-263 C dec. Analysis for: C17H17N2F 3 HCl Calculated: C, 57.88; H, 5.14; N, 7.94; Cl, 10.05 Found: C, 57.58; H, 5.15; N, 7.41; Cl, 10.05 P.R. = 54 at 10-5M B.P. = -45 at 1.5 hours. Example 16 4-(3-Cyanopheny1)-1,4,5,6,7,8-hexahydro-2,7-dimethyl-5- oxo-1,7-naphthyridine-3-carboxylic acid methyl ester. 1-Methyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine (6.6 9.),5.95 g. of methyl 3-aminocrotonate (97%), 6.5 g. of 3-cyanobenzaldehyde and 125 ml. of ethanol were refluxed for 3 hours. The solvent was removed in vacuo and the residue was crystallised from a small volume of ethanol. The solid was suspended in methanol and saturated with hydrogen chloride. The solution was evaporated to dryness. The residue crystallised on standing in a small volume of ethanol. The solid was recrystallised from ethanol to obtain the title compound as the hydrochloride, m.p. 226-229 C dec. Analysis for: C19H19N303 HCl Calculated: C, 61.05; H, 5.39; N, 11.24; Cl, 9.48 Found: C, 60.09; H, 5.66; N, 11.16; Cl, 9.36 Example 17 4(2,3oimethylphenyl)-1,4,5,6,7,B-hexahydro-2,7-dimethyl-5 oxo-1,7-naphthyridine-3-carboxylic acid methyl ester 1-Methyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine (6.36 g.), 5.93 g. of methyl 3-aminocrotonate (97%), 11 g. of 2,3-dimethylbenzaldehyde and 100 ml. of ethanol were refluxed for 3 hours. The mixture was filtered while hot and then left standing overnight. The precipitated solid was separated by filtration. The solid was suspended in methanol and saturated with hydrogen, chloride. The solvent removed in vacuo. The residue was crystallised from ethanol to obtain the title compound as tha hydrochloride, m.p. 244-247 C dec. Analysis for: C20H24N203 HCl Calculated: C, 63.73; H, 6.68; N, 7.43; Cl, 9.41 Found; C, 63.85; H, 6.77; N, 7.38; Cl, 9.33 P.R. = 54 at 10 B.P. = -40 at 4 hours. Example 18 4-[2-(n-Butyl)phenyl]-1,4,6,6,7,8-hexahydro-2-methyl-5-oxo-7- (phenylmethyl)-1,7-naphthyridine-3-carboxylic acid methyl ester A mixture of 10.6 g. of 1-benzyl-3-oxo-5-hydroxy-1,2, 3,6-tetrahydropyridine, 5.95 g. of methyl 3-aminocrotonate (97%), 8.1 g. of 2-(n-butyl)benzaldehyde and 125 ml. of ethanol was refluxed for 3 hours. The solvent was removed in vacuo. The viscous residue was crystallised by dissolving in ethanol and cooling in an ice bath. The solid was dissolved in methanol and saturated with hydrogen chloride. The solution was evaporated to a solid residue. Recrystallisation from 95% ethanol afforded the title compound as the hydrochloride, m.p. 220-223 C dec. Analysis for: C28H32N203 H Calculated: C, 69.91; H, 6.91; N, 5.82; Cl, 7.37 Found: C, 69.42; H, 7.09; N, 5.61; Cl, 7.42 P.R. = 61 at 106iv1. Example 19 4-[2-(n-Butyl)phenyl]-1,4,5,6,7,8-hexahydro-2-methyl -5-oxo- 1,7-naphthyridine-3-carboxylic acid methyl ester 4-[2-(n-butyl)phenyl]-1,4,5,6,7,8-hexahydro-2-methyl- 6-oxo-7- (phenylmethyl)-1 , 7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (9.5 g), 0.5 g. of 10% palladium on carbon, 200 ml. of methanol and 50 ml. of water were shaken with hydrogen at an initial pressure of 40 psi. After 2 hours, the catalyst was separated by filtration. The filtrate was evaporated in vacuo to a solid residue. Recrystallisation from ethanol afforded the title compound as the hydrochloride, m.p. 259-260 C. Analysis for: C21H26N203 . HCl Calculated: C, 64.52; H, 6.96; N, 7.16; Cl, 9.07 Found: C, 64.41; H, 7.01; N, 7.31; Cl, 9.18 P.R. = 49.2 at 10 5M B.P. = -24 at 1.5 hours. Example 20 4-(2,3-Dimethylphenyl)-1,4,5,6,7,8-hexahydro-2-methyl¯5¯ oxo-7- (phenylmethyl)- 1, 7-naphthyridine-3-carboxylic acid methyl ester A mixture of 16.2 g. of 1-benzyl-3-oxo-6-hydroxy-1,2, 3,6-tetrahydropyridine, 9.2 g. of methyl 3-aminocrotonate, 11,6 g. of 2,3-dimethylbenzaldehydr and 180 ml. of ethanol was heated at reflux for 3 hours. The solvent was removed in vacuo and the residue was recrystallised from ethanol to obtain 14 9. of solis, m.p. 208-211 C. The solid was suspended in methanol and saturated with hydrogen chloride. The solvent was removed in vacuo. The residue was recrystallised from'methanol to obtain the title compound as the hydrochloride, m.p. 238-2390 d. Analysis for: C26H28N203 .HCl Calculated: C, 68.94; H, 6.45; N, 6.18; Cl, 7.83 Found: C, 68.78; H, 6.51; N, 6.41; Cl, 7.77 P.R. = 33.3 at 106M; 80.4 at B.P. = -24 at 1.5 hours; -39 at 4 hours. Example 21 4-(2j3-Dimethylphenyl)-1,4,5,6,7,8-hexahydro-2-methyl-5- oxo-1 , 7-naphthyridine-3-carboxylic acid methyl ester Eight grams of the compound produced in Example 20, 0.5 g. of 10% palladium on carbon, 200 ml. of methanol, 50 ml. of water and 3 drops of concentrated hydrochloric acid were shaken with hydrogen at an initial pressure of 40 p.s.i. After two hours, the catalyst was separated by filtration. The filtrate was evaporated to dryness in vacuo. The residue was triturated with ethanol end separated to obtain the title compound as the hydrochloride, m.p. 254-2550 C, dec. Analysis for: C19H22N203 HCl Calculated: C, 62.89; H, 6.39; N, 7.72; Cl, 9.77 Found: C, 62.51; H, 6.58; N, 7.76; Cl, 9.46 P.R. = 76.7 at 10-5M B.P. = -44 at 1.5 hours; -45 at 4 hours. Example 22 1,4,6,6,7, 8-Hexahydro-2-methyl-6-oxo-7-phenylmethyl-4-L2 (trifluoromethyl)phenyl -1,7-naphthyridine-3-carboxylic acid, 2-(N-benzyl-N-methylamino)ethyl ester A mixture of 15.2 g. of 1-benzyl-3-oxo-5-hydroxy-1, 2,3,6-tetrahydropyridine, 13.1 g. of o-trifluoromethylbenzaldehyde, 18.7 g. of 2-(N-benzyl-N-methylamino)ethyl acetoacetate, 6 ml. of 28% ammonium hydroxide and 200 ml. of isopropanol was heated at reflux for 3 hours. The solution was evaporated to dryness. The residue was dissolved in 100 ml. of methylenechloride and extracted with 150 ml. of 15% hydrochloric acid. The acid extract was cooled and made basic with saturated sodium carbonate solution. The mixture was extracted with methylenechloride. The methylenechloride solution was dried over magnesium sulphate,then evaporated in vacuo to a solid residue. The residue was recrystallised from ethanol to obtain the title compound, m.p. 183-1850C. Analysis for: C34H34N3F303 Calculated: C, 69.2'; H, 5.81; N, 7.12 Found: C, 68.90; H, 6.02; N, 7.27 P.R. = 65.6 at 10-6M B.P. = -74 at 1.5 hours; -68 at 4 hours. Example 23 1,4,5,6,7,8-Hexahydro-2,7-dimethyl-4-[2,3,4,5,6-pentafluoro¯ phenyl -5-oxo-1,7-naphthyridine-3-carboxylic Acid Methyl Ester 1-Methyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine (6.36 g.), 5.92 g. of methyl 3-aminocrotonate, 9.8 g. of pentafluorobenzaldehyde and 125 ml. of methanol were refluxed for 4 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was slurried with ethanol and filtered. Recrystallisation from methanol afforded the title compound; m.p. 250-253 C. dec. Analysis for: C18H15N2F503 Calculated: C, 53.74; H, 3.76; N, 6.96 Found: C, S3.42; H, 4.02; N, 6.85 Hydrochloride, m.p. 240-243 C. dec. (recrystallised from methanol). Analysis for: C18H16N2F603 . HCl Calculated: C, 49.27; H, 3.68; N, 6.38; Cl, 8.08. Found: C, 49.12; H, 3.59; N, 6.38; Cl, 8.07 P.R. = 22.9 (10 5M) B.P. = 50 mg/kg -95 at 1.5 hours; -89 at 4 hours. 25 mg/kg -71 at 1.5 hours; -49 at 4 hours. 10 mg/kg -63 at 1.5 hours; -31 at 4 hours. 5 mg/kg -21 at 1.5 hours; -10 at 4 hours. Example 24 1,4,5,6,7,8-Hexahydro-2-methyl-5-oxo-4-(2,3,4,5,6-penta- fluorophenyl)-7-(phenylmethyl)-1,7-naphthyridine-3-carboxylic Acid Methyl Ester. A mixture of 10.2 g. of 1-benzyl-3-oxo-5-hydroxy-1,2, 3,6-tetrahydropyridine, 5.93 g. of methyl 3-aminocrotonate, 10 g. of pentafluorobenzaldehyde and 125 ml. of methanol was refluxed for 4 hours. The solution was allowed to cool to room temperature. The solid was separated by filtration. The solid, m.p. 258-260 C. dec., was suspended in methanol and saturated with hydrogen chloride. The solution was evaporated to dryness in vacuo. Recrystallisation of the residue from methanol afforded the title compound as the hydrochloride, m.p. 198-200 C. dec. Analysis for: C24H19N2F503 HCl Calculated: C, 55.97; H, 3.91; N, 5.44; Cl, 6.88 Found: C, 55.53; H, 4.12; N, 5.30; Cl, 7.08 P.R. = 56 (10 6M) B.P. = 50 mg/kg -20 at 1.5 hours; -23 at 4 hours. Example 25 1,4,5,6,7,8-Hexahydro-2-methyl-5-oxo-4-(2,3,4,5,6- pentafluorophenyl)-1,7-naphthyridine-3-carboxylic Acid Methyl Ester Six grams of 1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-4- (2,3,4,5,6-pentafluorophenyl)-7-(phenylmethyl)-1,7- naphthyridine-3-carboxylic acid methyl ester hydrochloride (Exampla 24), 200 ml. of methanol, 15 ml. of water and 0.5 g. of 10% palladium on carbon were shaken with hydrogen at an initial pressure of 50 psi. After 3 hours, the catalyst was separated and the filtrate was evaporated to dryness in vacuo. The residue was slurried with ethanol and filtered. Recrystallisation from methanoldiethyl ether afforded the title compound as the hydrochloride, m.p. 268-2700 C. dec. Analysis for: C17H13N2F503 HCl Calculated: C, 48.07; H, 3.32; N, 6.59; Cl, 8.34 Found: C, 48.36; H, 3.53; N, 6.69; Cl, 7.94 P.R. = 65.2 (10-6 M); 78.7 (10-5M). B.P. = 50 mg/kg -64 at 1.5 hours; -88 at 4 hours. 25 mg/kg -76 at 1.5 hours 10 mg/kg -79 at 1.5 hours; - 24 at 4 hours. 5 mg/kg -48 at 1.5 hours; -36 at 4 hours. 2.5 mg/kg -34 at 1.5 hours; -30 at 4 hours.

Claims: CLAIMS 1. A compound of the formula EMI28.1 in which R is hydrogen, alkyl of 1 to 6 carbon 2 atoms or benzyl; R2 is alkyl of 1 to 6 carbon atoms; R3 is alkyl of 1 to 6 carbon atoms, alkoxyalkyl in which each alkyl moiety has 1 to 6 carbon atoms, -CH2CF3, -CH2CH2CF3 or EMI28.2 where R9 is hydrogen or alkyl of 1 to 6 carbon atoms; and R10 is'alkyl of 1 to 6 carbon atoms or arylalkyl of 7 to 10 carbon atoms and R9 and R10 taken with the nitrogen atom to which they are attached form a pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, 4-alkylpiperazinyl in which the alkyl group contains from 1 to 6 carbon atoms or morpholinyl heterocycle; and n is one of the integers 0, 1 or 2; R1 is pentafluorophenyl, tetrafluorophenyl or EMI28.3 wherein R6 and R8 are, independently, hydrogen, alkyl Qf 1 to 6 carbon atoms, halo, trifluoromethyl, alkcxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, cyano or nitro; R7 is hydrogen, alkyl of 1 to 6 carbon atoms, halo, trifluoromethyl, cyano or nitro; and R6 and R7 when in ortho position to each other and taken together are butadienylene, tetramethylene or trimethylene; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in Claim 1, wherein R1 is pentafluorophenyl or a group having the formula EMI29.1 wherein R6 and R7 are as defined in Claim 1 and R8 is hydrogen. 3. A compound as claimed in Claim 1 or 2 wherein R3 is alkyl of 1 to 6 carbon atoms or EMI29.2 wherein n is 1 or 2, R10 is benzyl or phenethyl and R9 is as defined in Claim 1. 4. 1,4,6,6,7,8-Hexahydro-2,7-dimethyl-4-[2,3,4, 6,6- pentafluorophenyl3-5-oxo-1,7-naphthyridine-3- carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof. 5. 1,4,5,6,7,8-Hexahydro-2-methyl-5-oxo-4-(2,3,4,5,6- pentafluorophenyl)-1 ,7-naphthyridine-3-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof. 6. A compound selected from 1,4,5,6,7,8-hexahydro -2-methyl-5-oxo-4-[2-(trifluoromsthyl)phenyl]-1,7- naphthyridine-3-carboxylic acid methyl ester; its 7-methyl substitution product; 1,4,5,6,7,8-hexahydro- 2-methyl-5-oxo-7-phenylmethyl-4-[2-(triflùoromethyl) phenyl]-1 , 7-naphthyridine-3-carboxylic acid 2-(N benzyl-N-methylamino)ethyl ester and their pharmaceutically acceptable salts. 7. A compound selected from 1,4,5,6,7,8-hexahydro-2- methyl-4-(2-methylphenyl or 3-nitrophenyl)-5-oxo 1,7-naphthyridine-3-carboxylic acid methyl ester, the 7-(methyl or benzyl) substitution product thereof and their pharmaceutically acceptable salts. 8. 4-Aryl-1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-1,7- 'naphthyridine-3-carboxylic acid methyl ester (wherein the aryl group is 3-(trifluoromethy2)phenyl, 2 fluorophenyl, 2-(n-butyl)phenyl or 2,3-dimethylphenyl); or 4-aryl-1,4,5,6,7,8-hexahydro-2,7-dimethyl-5-oXo-1, 7-naphthyridine-3-carboxylic acid methyl esterfwhereinthe aryl group is 2-nitrophenyl, 2-chlorophenyl, 2,- dichlorophenyl, 2, 5-dimethylphenyl, 3-cyanophenyl or 2,3-dimethylphenyl); or 4-aryl-1,4,5,6,7,8-hexahydro -2-methyl-5-oxo-7-(phenylmethyl)-1,7-naphthyridine- 3-carboxylic acid methyl ester (wherein the aryl group is 2-(trifluoromethyl)phenyl, 2-(n-butyl)phenyl, 2, 3-dimethylphenyl, 2-fluorophenyl, 3- (trifluoromethyl) phenyl or pentafluorophenyl); or a pharmaceutically acceptable salt thereof. 9. A compound as claimed in any one of claims 1 to 8 for use as an antihypertensive agent. 10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 8 in association with a pharmaceutically acceptable carrier. 11. A pharmaceutical composition as claimed in claim 10 in the form of a tablet or capsule. 12. A process for the preparation of a compound having the formula EMI31.1 (wherein R, R1, R2 and R3 are as defined in claim 1) or a pharmaceutically acceptable salt thereof, comprising (a) reacting a compound having formula IV EMI31.2 12 (wherein R12 is alkyl of 1 to 6 carbon atoms or benzyl), an aldehyde having formula R1CH0 (wherein 1. R is as defined above) and a substituted or unsubstituted 3-aminocrotonate ester having formula VI EMI32.1 2 3 (wherein R and R are as defined above); or (b) reacting a compound having formula VIII EMI32.2 (wherein R1, R2 and R3 are as defined above) with a compound having the formula IV EMI32.3 (wherein R12 is as defined above) in the presence of ammonia; or (c) subjecting a compound having formula VII EMI32.4 (wherein R1, R2 and R3 are as defined above and R12 is benzyl) or a salt thereof to hydrogenolysis; and, if desired, forming a free base form of the compound having formula I by neutralising an acid addition salt thereof with an acid or forming a pharmaceutically acceptable salt by neutralising the free base with an acid or by subjecting another salt to metathetic displacement. 13. A process as claimed in claim 12, wherein step (a) is carried out and the substituted or unsubstituted 3-aminocrotonate ester is prepared in situ by ammonolysis of the alkanoylacetic acid ester having the formula R2CDCH2CO2R3 (in which R2 and R3 are as defined in claim 1). CLAIMS FOR AUSTRIA 1. A process for the preparation of a compound of the formula EMI34.1 in which R is hydrogen, alkyl of 1 to 6 carbon atoms or benzyl; R2is alkyl of 1 to 6 carbon atoms; R3 is alkyl of 1 to 6 carbon atoms, alkoxyalkyl in which each alkyl moiety has 1 to 6 carbon atoms, -CH2CF3, EMI34.2 where 10 R is alkyl of 1 to 6 carbon atoms or arylalkyl of 7 to 10 carbon atoms and R9 and R10 taken with the nitrogen atom to which they are attached form a pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, 4-alkylpiperazinyl in which the alkyl group contains from 1 tp 6 carbon atoms or morpholinyl heterocycle; and n is one of the integers 0,1 or 2; R1 is pentafluorophenyl, tetrafluorophenyl or EMI35.1 wherein R6 and R8 are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, halo, trifluoromethyl alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, cyano or nitro; R7is hydrogen, alkyl of 1 to 6 carbon atoms, halo, trifluoromethyl, cyano or nitro; and R6 and R7 when in ortho position to each other and taken together are butadienylene, tetramethy lene or trimethylehe; ; or a pharmaceutically acceptable salt thereof, characterised by (a) reacting a compound having formula IV EMI35.2 (wherein R12 is alkyl of 1 to 6 carbon atoms or benzyl), an aldehyde having formula R10HO (wherein R is as defined above) and a substituted or unsubstituted 3-aminocrotonate ester having formula VI EMI35.3 (wherein R2 and R3 are as defined above); or (b) reacting a compound having formula VIII EMI36.1 (wherein R1, R2 and R3 are as defined above) with a compound having the formula IV EMI36.2 (wherein R12 is as defined above) in the presence of ammonia; or (c) subjecting a compound having formula EMI36.3 (wherein R1 R2 and R3 are as defined above and R12 is benzyl) or a salt thereof to hydrogenolysis; and, if desired, forming a free base form of the compound having formula I by neutralising an acid addition salt thereof with a base or forming a pharmaceutically acceptable salt by neutralising the free base with an acid or by subjecting another salt to metathetic displacement. 2. A process as claimed in claim 1, wherein step (a) is carried out and the substituted or unsubstituted 3-aminocrotonate ester is prepared in situ by ammonolysis of the alkanoylacetic acid ester having the formula R2COCH2C02R3 (in which R2 and R3 are as defined in claim 1). 3. A process for the preparation of a compound having formula I EMI37.1 (wherein R, R1, R2 and R3 are as defined in claim 1), characterised in that an acid addition salt thereof is neutralised with a base. 4. A process for the preparation of a pharmaceutically acceptable salt of a compound having formula I EMI37.2 (wherein R, R1, R2 and R3 are as defined in claim 1), characterised in that (a) a compound having formula I as defined above is neutralised with an acid; or (b) another salt of the compound having formula I is subjected to metathetic displacement. 5. A process according to claim 4, characterised in that R1 is tetrafluorophenyl. 6. A process according to claim 4, characterised in that R1 is EMI38.1 wherein RB wherein , R7, and R are as defined in claim 1. 7. A process for the preparation of a compound having the formula I EMI38.2 (wherein R1 is pentafluorophenyl and R, R2 and R3 are as defined in claim 1) or a pharmaceutically acceptable salt thereof characterised by (a) subjecting a compound having the formula XII EMI39.1 (wherein PhCH2 is benzyl and R1, R2. and R3 are as defined above) or a salt thereof to hydrogenolysis; or (b) reacting together a compound having the formula IV EMI39.2 (wherein R12 is alkyl of 1 to 6 carbon atoms or benzyl), an aldehyde having the formula R1CH0 (wherein R1 is as defined above) and a substituted or unsubstituted 3-aminocrotonate ester having the formula V.I EMI39.3 (wherein R2 and R3 are as defined above) and, if desired, converting a compound having formula I into a pharmaceutically acceptable salt thereof by neutralization with an acid. 8. A process for the preparation of a compound having the formula I EMI40.1 (wherein R, R2 and R are as defined in claim 1 and R1 is a group having the formula EMI40.2 wherein R6, R7 and RB are as defined in claim 1) or a pharmaceutically acceptable salt thereof, characterised by (a) subjecting a compound having the formula XII EMI40.3 (wherein PhCH2 is benzyl and R1, R2 and R3 are as defined above) or a salt thereof to hydrogenolysis; or (b) reacting together a compound having the formula IV EMI41.1 (wherein R12 is alkyl of 1 to 6 carbon atoms or benzyl), an aldehyde having the formula 1 (wherein 1. R CHO (wherein R is as defined above) and a substituted or unsubstituted 3-aminocrotonate ester having the formula VI EMI41.2 (wherein R2 and R3 are as defined above) and, if desired, converting a compound having formula I into a pharmaceutically acceptable salt thereof by neutralisation with an acid. 9. A process for the preparation of a pharmaceutical composition characterised by bringing a compound having the formula I EMI41.3 (wherein R, R1, R2 and R3 are as defined in claim 1) into association with a pharmaceutically acceptable carrier. 10. A process according to claim 9, characterised in that the composition is prepared in the form of a tablet or capsule. 11. A process according to claim 9 or 10, therein R1 is a group having the formula EMI42.1 wherein R6, R7 and R8 are as defined in claim 1. 12. A process according to claim 9 or 10, wherein R is pentafluorophenyl.

Inventors: BERGEY, JAMES LAVERNE, MASCITTI, ALBERT ANGELO, SULKOWSKI, THEODORE SYLVESTER
Applicants: AMERICAN HOME PRODUCTS CORPORATION
Application year: 1981
Main classification: C07D471
IPC codes: C07D471