NZ205685A - Dihydroxy-2(1h)-quinazolinone-1-alkanoic acids and pharmaceutical compositions - Google Patents

Abstract

Cpds. of formula (I) and their quat. salts with alkyl halides, alkali (ne earth) metal salts and the amine salt, aminoalcohol salts and aminoacid salts are new. In (I) R1 is H, NH2 or N02; R2 is H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl or bicycloalkyl; R3 and R4 are H, lower alkyl, or aryl (opt. substd. by alkyl, lower alkoxy or OH); R5 is H, lower alkyl, or opt. substd. benzyl, provided that when R5 is other than H, the cpd. is a quat. salt; X is benzyl, COOH, alkoxycarbonyl, CN, CONH2, methane sulphonyl, formyl, alkanoyl, aroyl, heteroaroyl or heteroaryl; and Y and Z are H or OH, at least one being OH and when both are OH, they are in the 5,6- or 6,7- posn. Intermediates of formula (II) are also new. (R6 is lower alkyl; and R7 is H or is absent). Cpds. (I) are renal vasodilators and cardiovascular agents, and some intermediates in their prepn. are cardiotonic agents. Dose is 15-300 mg/kg.

Description

New Zealand Paient Spedficaiion for Paient Number £05685 2056 85 Priority Date(s): ,\Cr? Complete Specification Filed: Class: 4° ?.*?.•? ?.?/.??.... fo//U'/.» * t I^XR fssr* Publication Date: .... .V P.O. Journal. No: .

HO DRAW1N6S Patents Form No. 5 PATENTS ACT 1953 prp \ Number Dated COMPLETE SPECIFICATION Ortho Substituted Dihydroxy-2(1H)Quinazolinone-1-Alkanoic Acids ORTHO PHARMACEUTICAL CORPORATION a corporation organised under the laws of the State of New Jersey, United States of America of U.S. Route #202, Raritan, New Jersey 08869, United States of America do hereby declare the invention for which //we pray that a Patent may be granted to «K/us. and the method by which it is to be performed, to be particularly described in and by the following statement: l (Followed by page 1a) la 205685 The present invention relates to substituted quinazolinones having functionality at Nj.. The substituted quinazolinones which are the subject of this invention have the following wherein Ri is hydrogen, amino or nitro; R2 is hydrogen, alkyl having for example 1-20 carbon atoms, cycloalkyl having for example 4-8 carbon atoms, cycloalkylalkyl wherein the cycloalkyl group has for example 4-8 carbon atoms and the alkyl group has for example 1-3 carbon atoms, haloalkyl having for example 1-3 halogen atoms and 1-4 carbon atoms the halogen being chloro, bromo or fluoro, or bicycloalkyl such as norbornyl or norbornylmethyl; R3 and R4 may be the same or different and are hydrogen, lower alkyl, aryl or substituted aryl wherein the substituent(s) is/are independently selected from halo, alkyl, lower alkoxy and hydroxy (such as phenyl, 2-, 3- and 4-pyridyl, o-, m- and g-hydroxyphenyl, halophenyl such as £-chlorophenyl, j3—fluorophenyl, o-chlorophenyl and 2,4-difluorophenyl, lower alkoxyphenyl such as methoxy-, ethoxy- and butoxyphenyl, or alkylphenyl wherein the alkyl group contains 1-6 carbon atoms); X is benzyl, carboxy, carboalkoxy wherein the alkoxy group has for example 1-3 carbon atoms, cyano, carboxamido, methanesulfonyl, formyl, alkanoyl, aroyl (such as benzoyl or substituted benzoyl wherein the substituent is an alkyl group having 1-4 carbon atoms), heteroaryl such as 2-, 3- and 4-pyridyl, or 2-thienyl, or heteroaroyl such as 2-, 3- and 4-pyridoyl, 2-thienoyl, 2-furoyl or 3-(l,2,5-thiadiazolyl); R5 is hydrogen, lower alkyl, benzyl or substituted benzyl wherein the substituent(s) is/are independently selected from fluoro, chloro, bromo, alkyl or formula p 2 205685 alkoxy wherein the alkyl group has 1-6 carbon atoms, provided that when R5 is other than hydrogen the compound is a quaternary salt when the 3,4-imine linkage is unsaturated (the presence of an unsaturated imine linkage between N3 and C4 is optional and N3 may or may not be substituted); Y and Z are independently selected from hydrogen and hydroxy provided that at least one of Y and Z is hydroxy and when Y and Z are both hydroxy the hydroxyl groups are positioned adjacent to each other at either the 5,6- or the 6,7-position; and including the alkali metal and alkaline earth metal salts of the phenolic hydroxyls and the carboxy group at N-l and selected amine salts such as the salts of meglumine, piperazine, N-methylpiperazine, morpholine, aliphatic amines having 1-5 carbon atoms, salts of aminoalcohols (such as ethanolamine, 2-amino-l,3-propanediol or bis(hydroxymethyl)methylamine) and salts of amino acids such as arginine, lysine or ornithine.

The expression "lower alkyl" used herein refers to alkyl groups having from 1 to 6 carbon atoms unless otherwise specified.

The preferred compounds of the present invention are those wherein R^ is hydrogen; R2 is hydrogen, alkyl, cycloalkyl, bicycloalkyl or haloalkyl; R3 and R4 are hydrogen, lower alkyl, aryl or substituted aryl; X is carboxy, carbo-alkoxy, cyano, carboxamido or formyl; R5 is hydrogen, lower alkyl, benzyl, substituted benzyl, provided that when R5 is other than hydrogen the compound is a quaternary salt when the 3,4-imine linkage is unsaturated (the unsaturated imine linkage between N3 and C4 is optional and N3 may or may not be substitued); Y and Z are hydrogen or hydroxy, provided that at least one of Y and Z is hydroxy; and including the alkali metal and alkaline earth metal salts of the phenolic hydroxyls and the carboxy group at Nj and ted amine salts such as the salts of meglumine, A "M!987™ 3 205685 piperazine, N-methylpiperazine, morpholine, aliphatic amines having 1-5 carbon atoms, aminoalcohols (such as ethanolamine, 2-amino-l,3-propanediol or bis(hydroxymethyl)methylamine) or amino acids such as arginine, lysine or ornithine. When Y and Z are both hydroxy, the hydroxyl groups are positioned adjacent to each other and are located at either the 5,6- or the 6,7-position.

Several 6,7-dialkoxy-4-alkyl 2(lH)quinazolinones have been reported in the literature [Budesinsky et al., Coll. Czech. Chem. Commun., 37, 2779 (1972); British Patent No. 1317338]. None of the reported substituted quinazolinones have hydroxy groups substituted on the benzene ring. In addition, the known quinazolinones are not similarly substituted at Ni.

The novel quinazolinones of this invention are renal vasodilators. As such they increase renal blood flow and are therefore useful as cardiovascular agents. In addition, some of the compounds and some of the intermediates used to prepare the novel quinazolinones possess cardiotonic activity.

The substituted quinazolinones can be synthesized according to the following schematic diagram. 205685 205685 wherein Rj , R2, R3 , , R5 and X are as defined above and R is lower alkyl having 1-5 carbon atoms.

As can be seen from the diagram, the Nr substituted quin-5 azolinone (2) is prepared by reacting a substituted quina-zolinone with an appropriately substituted olefin, such as methyl cinnamate, methyl acrylate, methyl crotonate, acrylonitrile and methyl methacrylate, for example. The particular olefin employed will depend upon the type of 10 substitution desired in the end product. The reaction is carried out in the presence of a basic catalyst such as sodium carbonate, potassium carbonate, potassium fluoride, sodium fluoride, potassium hydroxide, sodium hydroxide, alkali metal alkoxides such as potassium ethoxide, and 15 sodium methoxide, quaternary ammonium hydroxides such as benzyltrimethylammonium hydroxide, quaternary ammonium fluorides such as tetraethylammonium fluoride and tertiary amines such as triethylamine. The reaction temperature employed can vary between -10aC and 100°C; the preferred 20 reaction temperature is about 65°C.

The N1 substituted quinazolinone (2) can be used to prepare the other Nj substituted quinazolinones by the routes shown in the diagram. For example, the N1 substituted 25 quinazolinone (2) can be conveniently alkylated with an alkyl iodide such as methyl or ethyl iodide or a benzyl iodide such as o-, m-, or p- fluorobenzyl, o-, m-, or £-methylbenzyl and o-, m-, or £- methoxybenzyl iodide to give the corresponding quaternary salt. The salt in turn 30 can be hydrolyzed with an acid such as hydrobromic acid or iodic acid, for example, to give the corresponding dni^lroxy compound (3). The Nx substituted quinazolinone W (2) lean be converted directly to the corresponding fl3JAN»8M •oxy compound (5) by reaction with an acid such as ipbrom-ic or hydriodic acid. The dihydroxy compounds 205685 (3 and 5) can then be partially saturated (4 and 6) by reaction with hydrogen in the presence of a catalyst such as platinum, palladium, rhodium or nickel. Ammonium formate, boranes and metallic hydrides such as sodium borohydride may-also be employed as reagents in the reduction step.

The starting material (1) used in the preparation of the ... substituted hydroxyquinazolinones wherein the substituents on the benzene ring are in the 6,7-position can be prepared by two main routes. For the first, an appropriately substituted alkoxyaniline is converted to the corresponding isocyanate. The conversion is carried out with phosgene in a suitable solvent such as, for example, benzene, toluene or xylene. The isocyanate is then condensed with the appropriate carboxamide to form the corresponding adduct. The condensation can be carried out either neat or in an inert solvent such as xylene or toluene. It is preferred to carry out the reaction at a temperature between 100-150°C. The adduct is then cyclized to form a quinazolinone.

Suitable cyclizing agents which can be employed include polyphosphoric acid, polyphosphoric ester and a mixture of phosphorous pentoxide and methanesulfonic acid. The ratio of the cyclizing agent to the adduct may vary between 1:1 and 25:1; however, the preferred ratio is 5:1. The reaction is preferably carried out at a temperature between 100-130°C in an inert atmosphere such as nitrogen.

In the second route, an appropriately substituted acetophenone is nitrated. Arter separation of the isomers the substituted o-nitroacetophenone or an aictenyde-protected form thereof (eg 3 protected form in winicn the aldehyde group is protected by ketal formation with ethylene glycol) is reduced to the corresponding amine. This in turn is acylated with an alkylhaloformate to give the corresponding urethane. Cyclization of the urethane so obtained (if necessary on deprotection of the dehyde group) with ammonia gives the corresponding quinazolinone formula A H 205685 \ «/ in which R and R, are as defined above. The quinazolinone of formula 1 may then be obtained by a Grignard reaction to give an intermediate 3,4-saturated quinazolinone of formula N- H B which is then oxidized to the compound of formula 1.

Certain of the compounds of formulae A and B are novel and certain are known, for example in our published British Patent Applications 2039895A and 2088874A. A particular novel class of such compounds (which class as mentioned above also possesses pharmacological e.g. cardiotonic activity) may be defined by the general formula C in which R2 is hydrogen, lower alkyl, C4_8-cycloalkyl, C4_8-cycloalkyl-Ci_3-alkyl, Ci_4~haloalkyl having 1-3 halogen atoms, norbornyl or norbornylmethyl; Rg is lower and R7 is hydrogen; provided that R7 is hydrogen only wheri^^be 3,4-linkage is saturated. 205685 Pharmaceutical compositions containing a compound of the present invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compoundirtg tech-5 niques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for 10 example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, diluents, granulating agents, lubri-15 cants, binders,, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid 20 pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative pur-25 poses, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions will generally contain, dosage unit, e.g., tablet, capsule, powder, injection, teaspoon-30 ful and the like, from about 15 to about 300 mg/kg and preferably from about 30 to about 200 mg/kg of the active ingredient. llowing examples describe the invention in greater c—^.jJularity and are intended to be a way of illustrating ^ ^3 JAUl^not limiting the invention.

A 205685 Example 1 6,7-Dihydroxy-4-methyl-2(1H)quinazolinone-1-(31-methyl) propionic acid Monohydrobroraide Monohydrate A solution of methyl 6,7-dimethoxy-4-methyl-2(lH)quinazo-linone-l-(3'-methyl)propionate (1.0 g, 3.2 mM) in acetic acid (10 ml) and 48% aqueous hydrogen bromide (10 ml) is refluxed for 66 hours. The reaction mixture is cooled. A green precipitate results which is isolated by filtration, washed with cold ether (20 ml) and dried under vacuum to afford the product (300 mg, 25%). mp 220-222°C; 6™ 1.71-1.95 (d, 3H, 3'-CH3), 3.04 (S, 3H, 4-CH3) 3.18-3.53 (m, 1H, -C-CH,), 5.21-5.82 (m, 2H, I H -CH2-), 7.62 (s, 1H, Cs-H), 7.79 (s, 1H, C8-H); M+ 278. Example 2 6,7-Dihydroxy-3,4-dimethyl-2(lH)quinazolinonium-1-propionic acid Bromide A solution of methyl 6,7-dimethoxy-3,4-dimethyl-2(lH)-quinazolinonium-l-propionate iodide (1.5 g, 33 mM) in acetic acid (10.5 ml) and 48% aqueous hydrobromic acid (10.5 ml) is refluxed with stirring for 48 hours. The brown reaction mixture is cooled to room temperature and a yellow precipitate is isolated by filtration. After washing with cold ether (25 ml) and drying under vacuum, the product (650 mg, 55%) is isolated. mp 270-272°C; 6^ 3.22 (s, 3H, 4-CH3), 3.01-3.42 (m, 2H, 2'-CH2), 4.12 (s, 3H, =^CH3), 4.67-5.11 (t, 2H, 2'=CH2), 7.47 (S, 1H, C5-H), 7.93 (s, 1H, C8-H); M+ 278 (M-80). 2056 85 Example 3 6,7-Dihydroxy-4-methyl-2(IH)quinazolinone-1-(2'-methyl) propionic acid A solution of methyl 6,7-dimethoxy-4-methyl-2(lH)quinazo-1inone-l-(2'-methyl)propionate (2.40 g, 7.5 mM), acetic acid (25 ml) and 48% aqueous hydrogen bromide (25 ml) is refluxed for 48 hours under nitrogen. The reaction mixture is cooled in an ice bath, concentrated jLn vacuo to half volume and basified to pH 12 with IN sodium hydroxide (25 ml). The reaction is chilled again and acidified with glacial acetic acid to pH 5. A yellow precipitate results which is isolated by filtration, washed with cold ether and dried under vacuum to afford the product. (1.60 g, 76.9%); TFA mp 266-268°C; 1.38-1.65 (d, 3H, 2'-CH3), 2.99 (s, 3H- H -N- I I 4-CH3), 3.10-3.49 (m, 1H, -C-), 3.91-5.09 (m, 2H, CH2-C), 7.37 (s, IH, C5-H), 7.72 (s, 1H, C8-H); M+ 278.

When in the above procedure methyl 6-methoxy-4-methyl-2(IH)quinazolinone-l-propionate, methyl 7-methoxy-4-methyl-2(lH)quinazolinone-l-propionate, methyl 6-methoxy-2(IH)quinazolinone-l-propionate, methyl 7-methoxy-2(lH)-quinazolinone-l-propionate, methyl 6-nethoxy-4-trifluoromethyl-2 ( IH) quinazolinone-l-propionate and methyl 7-methoxy-4-trifluoromethyl-2(IH)quinazolinone-l-propionate are employed in place of methyl 6,7-dimethoxy-4-methyl-2(lH)quinazolinone-l-(2'-methyl)propionate the corresponding 6-hydroxy-4-methyl-2(IH)quinazolinone-l-propionic acid, 7-hydroxy-4-methyl-2(IH)quinazolinone-l-propionic acid, 6-hydroxy-2(lH)quinazolinone-l-propionic acid, 7-hydroxy-2(IH)quinazolinone-l-propionate, 6-hydroxy-4-trifluoromethyl-2(IH)quinazolinone-l-propionic acid and 7-hydroxy-4-trifluoromethyl-2(lH)quinazolinone-l-propionic acid are obtained. 205685 Example 4 6,7-Dihydroxy-4-methyl-2(IH)quinazolinone-1-(2'-methyl) propionic acid tripotassium salt monohydrate A suspension of 6,7-dihydroxy-4-methyl-2(IH)quinazolinone-l-(2'-methyl)propionic acid (1.5 g, 5.39 mM) in methanol (100 ml) is treated with 1.0N methanolic KOH (16.17 ml, 16.1 mM) with good stirring under nitrogen. The resulting dark solution is filtered under nitrogen and concentrated in vacuo to a yellow solid. The solid is triturated with acetone (40 ml) and isolated by filtration. After washing with ether (20 ml)/ the solid is dried in a dessicator under vacuum for 16 hours at room temperature to afford 6,7-dihydroxy-4-methyl-2(IH)quinazolinone-1-(2' -methyl) propionic acid tripotassium salt monohydrate (2.2 g, 100%); mp >300°C.

Example 5 6,7-Dihydroxy-4-methyl-l-(3'-phenylpropyl)-2(IH)quinazolinone Monohydrate A mixture of 6,7-dimethoxy-4-methyl-l-(3'-phenylpropyl)- ' 2(lH)quinazolinone (1.25 g, 3.6 mM) and 48% aqueous hydrogen bromide (10 ml) in glacial acetic acid (10 ml) is refluxed with stirring for 24 hours. After cooling to room temperature, the reaction mixture is quenched on ice (100 g). A yellow-brown solid deposits which is isolated, washed with water (2x20 ml) and then with ether (3x40 ml).

After drying in air, 1.21 g (100%) of the product is obtained.

TPA mp >275°C dec.; 6 2.00-2.70 (m, 2H, -CH2-), 2.75-3.30 (m, 2H, -CH2~0)i 3.00 (s, 3H, CH3 ), 4 .30-5.00 (t, 2H, -CH^N), 7.07 and 7.65 (2s, 2H, C5H, C8H), 7.25 (s, 5H,0-); M+ 310. 205685 -yC- When in the above procedure 6,7-dinethoxy-4-methyl-2{lH)-quinazolinone-1-(2-methanesulfonyl)ethane, 6,7-dimethoxy-4-methyl-2(lH)quinazolinone-l-(2-benzoyl)ethane, and 6,7-dimethoxy-4-methyl-2(lH)quinazolinone-l-2-(2'-pyridyl)-ethane, are employed in place of 6,7-dimethoxy-4-methyl-l-(3-phenylpropyl)-2(lH)quinazolinone the corresponding 6,7-dihydroxy-4-methyl-l-(2-methanesulfonyl)ethane-2(1H)-quinazolinone monohydrate, 6,7-dihydroxy-4-methyl-l-2(benzoyl)ethane-2(IH)quinazolinone monohydrate, and 6,7-dihydroxy-4-methyl-1-2(21-pyridyl)ethane-2(lH)quinazolinone monohydrate are obtained.

When in the above procedure 6,7-dimethoxy-4-methyl-2(IH)-quinazolinone-1-propionaldehyde, 6,7-dimethoxy-4-methyl-2(lH)quinazolinone-l-propionitrile and methyl 6,7-dimethoxy-4-methyl-2(lH)quinazolinone-l-(1-phenyl)propionate are employed in place of 6,7-dimethoxy-4-methyl-l-(3-phenylpropyl)-2(lH)quinazolinone the corresponding 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionaldehyde, 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid and 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-(l-phenyl) propionic acid are obtained.

The following compounds are prepared by the procedure of Examples 3, 4 or 5 using an appropriately substituted quinazolinone as the starting material. ch2ch2co2r6 wherein R6 is potassium or hydrogen and R2 is as defined. 205685 -X- Hydrobromide mp/Yield % Salt IS Free Acid mp/Yield % Tripotassium Salt mp/Yield % H CH ■ CF ■ 231-232°C/57.8 257-259°C/82.5 264-266°C/42.8 222-224°C/79.2 ethyl propyl isopropyl jv-pentyl ri-hexyl n-heptyl in-octyl ji-decyl :H2-CH2 276-278°C/88.0 I Ho-iii- CH 2 -CH 2 | CH- CH2-CH2/ CH2-CH2w | ^CH-CH 2- CH2-CH2^ 125-130° C/22.2 308-310° C/84.5 328-329° C/71.4 310-312°C/73.3 275-277°C/72.3 242-246°C/64.3 248-250° C/91.6 238-240°C/55.1 164-166° C/71. 6 228-230°C/8.9 >300°C/96.9 >310° C/76.6 30 5-306°C/73.8 310-312°C/97.2 Dec.>300°C/74.0 Dec. 220°C/68.2 302-304°C/80.0 259-261°C/100.0 276-278° C/74.6 298-300°C/91.5 262-264°C/79.0 Example 6 Ethyl 6 ,7-dihydroxy-4-methyl-2(lH)quinazolin6ne-l-propionate A suspension of 6,7-dihydroxy-4-methyl-2(lH)quinazolinone -1-propionic acid (2.0 g, 6.5 mM) in absolute ethanol (35 ml) containing methanesulfonic acid (1.0 ml) is refluxed with stirring for 3 days. The reaction mixture is cooled to room temperature and quenched on ice (200 g). A yellow-green precipitate forms which is isolated/ washed with water, acetone, and ether and then dried _in vacuo to afford the product. (1.75 g, 92.2%); mp >308°C (dec.); O ,TFA [, CH2H-) ' -TMS 1.35-1.60 (t, 3H, CH2CH3), 2.95-3.30 (m, 2H, 3.10 (s, 3H, CH3), 4.20-4.60 (q, 2H, CH2-0), 4.65-5.00 (t, 2Hf CH2-N), 7.35 (sf IH, Cs-H), 7.75 (s, IH, C8-H); M+ 292 X 2056 \Hr Example 7 6 ,7-Dihydroxy-3 ,4-dimethyl-3 ,4-dihydro-2(lH)quinazolinone -1-propionic acid A solution of the quaternary salt 6,7-dihydroxy-3,4-di-methyl-2(lH)quinazolinonium-l-propionic acid bromide (1 meq) in glacial acetic acid (15 ml) is treated with 5% Pd/C (0.1 g) and the reaction mixture is hydrogenated at 45 psi for 12 hours. The catalyst is filtered and the 10 mother liquor is poured into water (100 ml). The precipitate of 6,7-dihydroxy-3,4-dimethyl-3,4-dihydro-2(lH)quin-azolinone-l-propionic acid is filtered, washed with water and dried jLn vacuo.

Example 8 6, 7-Dihydroxy-3,4-d ihydro-4-methyl-2(IH)quinazolinone-1-propionic acid monohydrate A slurry of 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-20 propionic acid monohydrate (5.0 g, 17.7 mM) in methanol (270 ml) is treated with Pd/C (10%, 2.5 g) and the mixture hydrogenated at 45 psi for 16 hours. Filtration, removal of the solvent in vacuo and titration of the residue with acetone gives the product as a tan solid (4.3 g, 91.4%); ? ^ TPA " mp 202-204°C; 6.86 (s, IH, 5-H) , 6.83 (s, IH, 8-H) , 4.78 (d, IH, J=7.0 Hz, 4-H), 4.36 (t, 2H, J=10 Hz, 2'-H), 3.03 (t, 2H, J=10 Hz, l'-H), 1.55 (d, 3H, J=7 Hz, 4-CH3); 30 M+ 266.

Example 9 6,7-Dihydroxy-3-benzyl-4-methyl-2(lH)quinazolinonium-1-propionic acid bromide A solution of methyl 6,7-dimethoxy-4-methyl-2(IH) quinazolinone-l-propionate (10 g) in acetone (100 ml) is treated with benzyl bromide (10 eq) and the solution aged ORTH-388 205685 if overnight at room temperature. The resulting crystalline precipitate is isolated and dried in vacuo. The crude quaternary salt is then dissolved in a mixture of glacial acetic acid (70 ml) and 48% aqueous HBr (70 ml) and the reaction mixture refluxed with stirring for three days. Upon cooling to room temperature 6,7-dihydroxy-3-benzyl-4-methyl-2(lH)quinazolinonium-l-propionic acid bromide is isolated as a crystalline precipitate.

Identical conditions are utilized employing £-fluorobenzyl bromide and j>-chlorobenzyl bromide to give the corresponding substituted benzyl quaternary salts.

Example 10 6,7-Dihydroxy-4-norbornylmethyl-2(IH)quinazolinone-1-propionic acid hydrobromide A mixture of methyl 6,7-dimethoxy-4-norbornylmethyl-2(1H)-quinazolinone-l-propionate (5 g) , 48% aqueous HBr (40 ml) 20 and glacial acetic acid (40 ml) is refluxed with stirring for three days. The solution is then cooled and the resulting gold precipitate isolated by filtration, washed with acetone (25 ml) and dried in vacuo to afford the title compound.

When in the above procedure methyl 6,7-dimethoxy-5-amino-4-methyl-2(lH)quinazolinone-l-propionate and methyl 6,7-dimethoxy-5-nitro-4-methyl-2(lH)quinazolinone-l-propionate are employed in place of methyl 6,7-dimethoxy-4-nor-30 bornylmethyl-2(IH)quinazolinone-l-propionate, the corres-^ ponding hydrobromides 6,7-dihydroxy-5-amino-4-methyl- 2(IH)quinazolinone-l-propionic acid dihydrobromide and 6,7-dimethoxy-5-nitro-4-methyl-2(lH)quinazolinone-l-propionic acid hydrobromide are obtained. The propionate 35 starting materials are prepared according to the procedure outlined in Example G.

ORTH-388 205685 tC -y- Exanple 11 6 ,7-Dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid monopotassium salt A suspension of 6,7-dihydroxy-4-methyl-2(IH)quinazolinone-1-propionic acid (9.97 g, 37.10 mM) in methanol (30 ml) under nitrogen, is treated with IN KOH in methanol (37.10 ml, 37.10 mM). The resulting yellow slurry is stirred at room temperature, under nitrogen, for 22 hours. The reaction mixture is cooled in an ice-water bath and filtered. The resulting yellow solid is washed with cold methanol (3x17 ml) and dried _in vacuo at 120°C for 336 hours (14 days). The product (10.41 g) is obtained as a yellow solid, mp = 303-305°C.

Example 12 6,7-Dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid dipotassium salt A suspension of 6,7-dihydroxy-4-methyl-2(IH)quinazolinone-l-propionic acid (45.0 g 167.47 mM) in methanol (600 ml) is treated with IN KOH in methanol (334.94 ml, 334.94 mM) at room temperature under nitrogen; a large amount of yellow solid is present after addition of the KOH. Additional methanol (200 ml) is added. Water is then added until the solid dissolves. The total amount of water added is 300 ml. The reaction mixture is then stirred at room temperature, under nitrogen for 30 minutes. The slightly cloudy solution is then filtered and concentrated to dryness in vacuo to give a yellowish-brown semi-solid. This is triturated with acetone (300 ml) and the resulting yellow solid filtered and dried to afford the dipotassium salt (54.26 g, mp >325°C). \1 -yd- 20568 Example 13 6,7-Dihydroxy-4-methyI-2(lH)quinazolinone-l-propionic acid monoarqinine salt monohydrate A mixture of 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid (4.0 g, 14.6 mM) and L-arginine (2.34 g, 14.6 mM) in water (150 ml) is aged at room temperature for 3 hours. After 15 minutes the initial solution clears and then a yellow precipitate begins to form. After 3 hours, this precipitate is isolated, washed with water (15 ml), acetone (20 ml), and then ether (2 x 20 ml). The precipitate is dried in vacuo at 60°C. for 3 hours to give the amino acid salt (5.81 g, 93.8%).

Example 14 6,7-Dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid N-methylglucamine salt A mixture of 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid (0.79 g, 3 mM), meglumine (0.59 g, 3 mM), methanol (40 ml) and water (4 ml) is aged at ambient temperature overnight. The resulting slurry is filtered and the precipitate washed with ether (2 x 20 ml). After drying in air for 3 hours, the amine salt is isolated as a yellow solid, (0.88 g, 62.51%, mp = dec. 197-8°C).

The salts from monoethanolamine, piperazine, N-methylpi-perazine and morpholine are prepared in a similar fashion.

Example 15 6,7-Dihydroxy-4-methyl-2(lH)guinazolinone-l-propionic acid mono(2-methyl-2-amino-l,3-propandiol) salt monohydrate A suspension of 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-1-propiortic acid (1.0 g, 3.6 mM) in methanol (40 ml) and 205685 -X- water (10 ml) is treated with mono(2-methyl-2-amino-l,3-propandiol) (0.38 g, 3.6 mM) and the mixture aged at ambient temperature for 16 hours. The resulting pale-yellow precipitate is isolated, washed with methanol 5 (10 ml) and ether (2 x 10 ml). After drying in vacuo for 6 hours at 60°C, the amine salt (1.18 g, 85.5%) is isolated, mp » 212-13°C.

Example 16 6 ,7-Dihydroxy-4-methyl-2(IH)quinazolinone-l-propionic acid mono(l-amino-2,3-propandiol) salt hemihydrate A mixture of 6,7-dihydroxy-4-methyl-2(IH)quinazolinone-l-propionic acid (0.84 g, 3 mM), mono (l-amino-2,3-propan-15 diol) (0.27 g, 3 mM), methanol (40 ml) and water (10 ml) is aged overnight at room temperature. The resulting precipitate is isolated and washed with methanol (10 ml) and ether (1 x 20 ml). After drying under a stream of nitrogen for 3 hours, the amine salt (0.94 g, 84.7%) is 20 obtained.

Example 17 /6-Dihydroxy-4-methvl-2(IH)quinazolinone-l-propionic acid Monohydroiodide Methyl 5,6-dimethoxy-4-methyl-2(lH)quinazolinone-l-propionate (1.173g, 3.83mM) is treated with 50% aq HI (13 ml) at room temperature to give a clear orange solution which is refluxed under nitrogen for 11 hr. and 30 then allowed to stir at room temperature overnight. The orange crystalline solid which precipitates is collected by filtration, washed with acetone and dried to give the product; yield 0.972 g, (65%), mp. 240-241°C(d) IR (KBr)u, 3.23 (broad, OH), 5.78 (C=0).

ORTH-388 205685 -jrf- When in the above procedure methyl 5,6-dinethoxy-4-tri-fluoromethyl-2(lH)quinazolinone-l-propionate, methyl 5,6-dimethoxy-4-isopropyl-2(IH)quinazolinone-l-propionate methyl 4-cyclopentyl-5,6-dimethoxy-2(lH)quinazolinone 1-propionate, and methyl 4-cyclohexylmethyl-5,6-dimethoxy-2(lH)quinazolinone-l-propionate are employed in place of methyl 5,6-dimethoxy-4-methyl-2(IH)quinazolinone-l-pro-pionate the corresponding 5,6-dihydroxy-4-trifluoromethyl-2(lH)quinazolinone-l-propionic acid monohydroiodide, 5,6-dihydroxy-4-isopropyl-2(IH)quinazolinone-l-propionic acid monohydroiodide, 4-cyclopentyl-5,6-dihydroxy-2(IH)quinazolinone-l-propionic acid monohydroiodide and 4-cyclo-hexylmethyl-5,6-dihydroxy-2(IH)quinazolinone-l-propionic acid monohydroiodide are obtained. The ester starting materials are prepared according to the method outlined in Example G.

Example 18 6,7-Dihydroxy-4-roethyl-2(IH)quinazolinone-l-propionic acid Monohydrate A suspension of methyl 6,7-dimethoxy-4-methyl-2(IH)quina-zolinone-l-propionate (1.53 g, 5 mM), acetic acid (20 ml) and 48% aqueous HBr (15 ml) is refluxed for 120 hours under nitrogen. The solvent is removed _in vacuo to yield a greenish hydrobromide salt (yield 1.5 g, 88.2%); mp 292-295°C. A solution of the salt in methanol (5 ml) is treated with saturated aqueous NaHC03 until the pH is neutral. The precipitated free base is collected by filtration and washed with acetone to obtain the product (yield 1.0 g, 76.9%) as a pale green solid, mp 308-310°C; NMR: ^TMS 7,80 (S' 1H' 5~H)' 7,46 (s' lH' 8~H>' 4.66-5.08 (m, 2H, 2'-H), 3.13 (m, 5H, l'-H, 4-CH3) M+ 264. 205685 ^o -y- The various other substituted mono- and dihydroxy-2(1H)-quinazolinones encompassed by the present invention can be prepared by any of the above methods using an appropriately substituted mono- or dialkoxy-2(lH)quinazolinone prepared according to the examples utilizing the various starting materials described below.

The biological activity of the novel quinazolinones was determined according to the method of Goldberg, L.I., Sonneville, P. F. and McNay, J. L. (1968). An investigation of the structural requirements for dopamine-like renal vasodilation; phenethylamines and aponorphine, J. Pharmacol. Exp. Ther. 163.

Adult mongrel dogs are anesthetized and surgically prepared for electromagnetic measurements of renal artery blood flow. A carotid artery is cannulated for measuring arterial blood pressure and drugs are administered intravenously. Heart rate is monitored by a cardiotachometer.

Renal vascular resistance is calculated as the ratio of mean arterial blood pressure/renal artery blood flow.

Dopamine is infused intravenously at 3 pg/kg/min for ten minutes (1 ml/min) to determine responsiveness of each dog to renal dopamine receptor stimulation. Cumulative dose-response data are obtained by infusing the test drug at progressively increasing (usually three fold) infusion rates, each dose being infused five minutes. The maximum percent increase from pre-drug control in renal artery blood flow (or decrease in renal vascular resistance) is quantitated for each infusion dose. 205685 ■20- preparation of Starting Materials Example A 3,4-Dimethoxyphenylisocyanate Phosgene (4 eq) is bubbled at a moderate rate into a 3-neck flask containing a solution of 3,4-dimethoxyaniline (1 eq.), in benzene (2 liters). The flask is cooled in an ice bath for 15 minutes and then the solution is refluxed for 1 3/4 hours while excess phosgene is added. The reaction mixture is then refluxed overnight and the solvent removed under vacuum. Acetone is added and the solvent is again removed under vacuum leaving a dark brown oily residue which is distilled at 132-134°C/0.6 ram. Yield: 22.5 g.

Example B N-(3 ,4-Dimethoxyphenyl)-N'-propionylurea A mixture of 3,4-dimethoxyphenylisocyanate (26.0 g, 145 mM) and propionamide (10.61 g, 145 mM) is heated at 160-165°C for 1 1/2 hours. A homogeneous pale yellow solution forms which after 15 minutes solidifies. The heating is discontinued and the flask is allowed to cool slowly. The mixture is triturated with acetone and this resulting white solid is filtered and dried. Yield: 32.45 g, mp 193-197°C.

Example C 6,7-Dimethoxy-4-ethyl-2(IH)quinazolinone A suspension of N-(3,4-dimethoxyphenyl)-N'-propionylurea (32.45 g, 128 mM) in polyphosphoric acid (375.12 g, 1109 mM) is heated at 130-135°C under nitrogen with vigorous stirring for 3.5 hours. The mixture is then poured onto 500 g ice-H20 and stirred. The solution is brought to pH 5.5 with concentrated NHkOH and allowed to stand at room temperature overnight. A brown precipitate 205685 -yir forms. The resulting solid is filtered and dried to yield 7.40 g of a white solid. This filtrate is extracted with CHC13 (5x 250 ml), the organic extract is dried (MgS0H) and the solvent removed in vacuo to give a tan solid. The solid is triturated with acetone and filtered to give a tan solid (4.98 g). A sample is slurried in water and redried for additional purification, in.p. 263-265°C. 6^* 7.50 (s, IH, 5—H) , 7.23 (s, IH, 8-H), 4.30 (s, 3H, 6 TMS or 7-OCH3) 4.17 (s, 3H, 6 or 7-OCH3), 3.50 (q, 2H, J«8.0H2, CHj^CH 3) , 1.70 (t, 3H, J«8.0Hz, CH,CH,) .

Tabulated below are selected examples of 2(IH)quinazolinones prepared by the route described above. 205685 R2 M.p./°C % Yield H 247-248 67.5 CH3 269-271 65.0 CF3 280-282 46.3 propyl 208-210 53.8 isopropyl 238-240 86.0 n-pentyl 152-154 21.9 ^h3 -CH2-CH^ 199-202 14.4 3 n-hexyl 120-123 8.0 n-heptyl 184-186 78.2 n-octyl 130-132 24.4 n-decyl 166-167 37.4 -CH 2-Q 262-264 79.0 CH.-CH chz-<j:h2 ch2-ch— ch2-ch2 CH0 ifl- • 0 \/ CH 253-255 12.6 196-197 37.0 298-302 16.6 Example D 3 ,4-Dimethoxy-6-nitroacetophenone 3,4-Dimethoxyacetophenone (1.8 eq) is added during 0.5 hour to nitric acid (18 eq), at 0°. After a further 1 hour at 20°C., the dark brown solution is poured onto ice water. The crude product is collected by filtration. Recrystallization from ethyl alcohol affords the purified product, mp = 124-126°C; S^g"1"3 2.50 (s, 3H, CH3), 4.00 (s, 6H, OCH3's), 6.80, 7.59 (2s, IH ea., C2H, CSH). 20568 Example E 6-Am ino-3,4-dimethoxyacetophenone A slurry of 1 equivalent of 3,4-dimethoxy-6-nitroaceto-5 phenone in methanol is treated with Pd/C (10%) and the mixture is hydrogenated at 45 psi for 24 hours. The residue after filtration and removal of solvent is crystallized from ethyl alcohol to afford purified product, mp = 98-l00°C; 2 5Q (g^ 3H# 3.80-3 .85 (2s, 3H ea. , OCH3); 6.05, 7.05 (2s, IH ea., C2H, CSH).

Example F 2-(N-Carbethoxyam ino)-4,5-dimethoxyacetophenone Ethyl chloroformate (1 eq) is added cautiously with stirring to 6-amino-3,4-dimethoxyacetophenone (0.3 eq) at room temperature. The dark brown reaction mixture is stirred 20 at room temperature for 1/2 hour. Aqueous sodium hydroxide is added and the reaction mixture stirred at room temperature for an additional hour. The reaction mixture is extracted with chloroform. Removal of chloroform gives an oily residue. Recrystallization from ether affords the product, mp = 97-99°C; 6£„gl3 1.10-1.50 (t, 3H, CH3), 2.60 (s, 3H, CH3), 3.85 and 3.95 (2s, 3H ea., OCH3's), 4.0-4.4 (q, 2H, CH2), 7.15 and 8.20 (2s, IH ea., C2H, CSH).

Example G General preparation of methyl 2(lH)guinazolinone-l-propionates R, iH2CH2COOCH3 ORTH-388 ■-)A- 2056 An appropriately substituted 2(lH)quinazolinone (5 g) is placed in a mixture of methanol (75 mol), chloroform (100 ml), methyl acrylate (125 ml) and excess Triton B (40% methanol) and the mixture is refluxed with stirring 5 for 4-16 hours. The solution is then cooled and after evaporation of the solvent, the ester is obtained by chromatography on silica gel.

The following compounds are made by the above general 10 procedure: R2 M.P/°C H 186-188 CH3 155-157 CF3 140-143 ethyl 132-134 propyl 120-122 isopropyl 112-114 £-pentyl oil n-hexyl 122-124 n-heptyl 107-110 n-octyl 100-104 n-decyl oil ch2-ch.

I I 140-142 -ch2 -ch- ch2-ch2 L L 103-105 \ / ch2 ch2-ch2*»^ I ^1CH-CH2- 92-95 CH2-CH2^^ When in the above procedure 6-methoxy-4-methyl-2(IH)quinazolinone, 4-methyl-7-methoxy-2(lH)quinazolinone, 6-methoxy-2(IH)quinazolinone, 7-methoxy-2(IH)quinazolinone, 6-methoxy-4-trifluoromethyl-2(lH)quinazolinone and -388 2056B5 -yi- 7-methoxy-4-trifluoromethyl-2(lH)quinazolinone are employed as the starting materials, the corresponding 1-propionic acid esters are obtained.

When in the above procedure 3,4-dihydro-5,6-dimethoxy-4-methyl-2(lH)quinazolinone, 5,6-dimethoxy-4-methyl-2(1H)-quinazolinone, 5,6-dimethoxy-4-trifluoromethyl-2(IH)-quinazolinone are employed as the substituted quinazolinone the corresponding 1-propionic acid esters are obtained.

Example H 6,7-Dimethoxy-4-methyl-2(IH)quinazolinone-1-(2-methanesulfonyl) ethane A solution of 6,7-dimethoxy-4-methyl-2(lH)quinazolinone (10 g) in chloroform (100 ml), methanol (100 ml) and methylvinyl sulfone (40 eq) is treated with Triton B (benzyltrimethylammonium hydroxide, 40% in methanol, 1.1 eq) and the solution refluxed, with stirring, for 24 hours. The solution is then cooled to room temperature and the solvent removed by concentration in vacuo. The residue is chromatographed on silica gel to afford purified 6,7-dimethoxy-4-methyl-2(IH)quinazolinone-1-(2-methanesulfonyl) ethane.

Example I 6,7-Dimethoxy-4-methyl-2(IH)quinazolinone-1-(2-benzoyl) ethane A solution of 6,7-dimethoxy-6-methyl-2(lH)quinazolinone (10 g) in chloroform (100 ml), methanol (100 ml) and phenylvinyl ketone (40 eq) is treated with Triton B (40% in methanol, 1.1 eq) and the solution refluxed with stirring for 24 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue chromato-graphed on silica gel. Purified 6,7-dimethoxy-4-methyl-2(lH)quinazolinone-l-(2-benzoyl) ethane is obtained. 205685 Example J 6,7-Dimethoxy-4-methyl-2(IH)quinazolinone-1-I2-(2'-pyridy1)ethane] A solution of 6,7-dimethoxy-4-methyl-2(lH)quinazolinone (10 g) in chloroform (100 ml), methanol (100 ml and 2-vinylpyridine (25 eq) is treated with Triton B (40% in methanol, 1.1 eq), and the solution refluxed with stirring for 24 hours. The resulting solution is cooled to room temperature and the solvent removed by concentration in vacuo. The residue is chromatographed on silica gel to give purified 6,7-dimethoxy-4-methyl-2(IH )quinazolinone-l-[2-(2'-pyridyl)ethane] .

When in the above procedure 4-vinylpyridine is employed in place of 2-vinylpyridine the corresponding 4'-pyridyl derivative is obtained.

Example K 6,7-Dimethoxy-4-methyl-2(IH)quinazolinone-l-propionaldehyde A solution of 6,7-dimethoxy-4-methyl-2(lH)quinazolinone (10 g) in methanol (100 ml), chloroform (100 ml) and acrolein (40 eq) is treated with Triton B (40% in methanol, 1.1 eq). The resulting mixture is concentrated in vacuo and the residue is chromatographed on silica gel to afford purified 6,7-dimethoxy-4-methyl-2 (lH)quinazolinone-l-propionaldehyde.

Example L 6,7-Dimethoxy-4-methyl-2(IH)quinazolinone-l-propionitrile A solution of 6,7-dimethoxy-4-methyl-2(lH)quinazolinone (10 g) in chloroform (100 ml), methanol (100 ml) and acrylonitrile (excess) is treated with Triton B (40% in methanol, x's). The solution is refluxed with stirring for 24 hours. The resulting solution is cooled to room 205685 -?*- temperature and the solvent is removed by evaporation in vacuo. The resulting residue is chromatographed on silica gel to give purified 6,7-dimethoxy-4-methyl-2(IH) quinazolinone-l-propionitrile.

Example M Methyl 6,7-dimethoxy-4-methyl-2(lH)quinazolinone-l-(l-pheny1) prop ionate A solution of 6,7-dimethoxy-4-methyl-2(lH)quinazolinone (10 g) in chloroform (100 ml), methanol (100 ml) and methyl a-phenylacrylate (excess) is treated with Triton B (40% in methanol, 1.1 eq) and the resulting solution refluxed with stirring for 24 hours. After 15 cooling to room temperature, the solvent is removed in vacuo and the residue purified by chromatography on silica gel to give purified methyl 6,7-dimethoxy-4-methyl-2(IH)quinazolinone-1-(1-phenyl)propionate.

When in the above procedure methyl (2,4-difluorophenyl) acrylate, methyl (4-chlorophenyl)acrylate and methyl (4-methoxyphenyl acrylate are employed in place of methyl o-phenylacrylate, the corresponding quinazolinones methyl 6,7-d imethoxy-4-methyl-2(lH)quinazolinone-l-[l-(2,4-25 difluorophenyl)propionate]; methyl 6,7-dimethoxy-4-methyl-2(lH)quinazolinone-l-(l-(4-chlorophenyl) propionate]; and methyl 6,7-dimethoxy-4-methyl-2(lH)quinazolinone-l-[l-(4-methoxyphenyl) propionate] are obtained.

Example N Methyl 6 ,7-dimethoxy-4-methyl-2(IH)quinazolinone-1-(2-phenyl propionate) A solution of 6,7-dimethoxy-4-methyl-2(lH)quinazolinone 35 (10 g) iri chloroform (100 ml), methanol (100 ml), and methyl cinnamate (excess) is treated with Triton B (50% in methanol, 1.1 eq) and the resulting solution refluxed with 388 20568 stirring for 24 hours. The solution is concentrated in vacuo to remove the solvent and the residue is purified by chromatography on silica gel. In this manner, purified methyl 6,7-dimethoxy-4-methyl-2(IH)quinazolinone-1-(2-phenyl propionate) is obtained.

When in the above procedure methyl 2,4-difluorocinnamate, methyl 4-chlorocinnamate and methyl 4-methoxycinnamate are employed in place of methyl cinnamate, the corresponding 10 quinazolinones methyl 6,7-dimethoxy-4-methyl-2(lH)quinazo-linone-1-[2-(2,4-difluorophenyl)propionate]; methyl 6,7-d imethoxy-4-methyl-2-(IH)quinazolinone-1-[2-(4-chloro-phenyl) propionate] and methyl 6,7-dimethoxy-4-methyl-2(IH)quinazolinone-1-[2-(4-methoxyphenyl)propionate] are 15 obtained.

Example 0 6,7-Dimethoxy-4-(2-norbornylmethyl)-2(IH)quinazolinone A solution of norbornyl-2-acetic acid (25.0 g, 0.16 m) in benzene (50 ml) is treated with thionyl chloride (75 ml) and the mixture refluxed with stirring for 12 hours. The volatiles are removed on a rotary evaporator at about 50°C. The resulting acid chloride is dissolved in 25 tetrahydrofuran (150 ml) and then aqueous concentrated ammonia (200 ml) is slowly introduced with stirring. A precipitate forms during the subsequent 30 minute aging period. It is isolated by filtration and washed well with cold water. After drying, 15.3 g (62.5%), mp = 144-6°C, 30 of norbornyl-2-acetamide are obtained.

A mixture of 3,4-dimethoxyphenylisocyanate (8.95 g, 0.05 m) and norbornyl-2-acetamide (6.12 g, 0.04 m) is fused under nitrogen at 130-140°C with stirring for one 35 hour. After cooling, acetone (100 ml) is introduced and the mixture broken-up manually. After one hour aging at room temperature, the precipitate is isolated and dried 3RTH-388 2 0 5 6 8 io •&- in vacuo. A solution of the adduct (9.0 g, 0.027 m) in polyphosphoric acid (200 g) is heated at 130-140°C for three hours with stirring. After cooling, the reaction mixture is quenched on ice (1500 g) and stirred well.

This pale green solution is brought to pH~ 8.0 with concentrated ammonia. The resulting precipitate is isolated, washed with distilled water (2x50 ml) and dried to yield 6,7-dimethoxy-4-(2-norbornylmethyl)-2-(lH)-quinazoline as a tan solid. After recrystallization from 10 95% ethanol, pale yellow crystals are obtained, 2.0 g, M.P. 231-2°C. o w Example P Methyl 6 ,7-dimethoxy-4-methyl-2(IH)quinazolinone-1-(3' -15 methyl)propionate Triton B (26.0 ml, 40% in methanol) is added as a slow stream with stirring to a solution of 6,7-dimethoxy-4-methyl-2(IH)quinazolinone (20.0 g, 91 mM) in methyl 20 crotonate (90.0 g, 900 mM), methanol (80 ml), and chloroform (126 ml) precooled to 0°C. The reaction is stirred at reflux for 18 hours. The reaction mixture is then cooled to room temperature and the suspension is isolated by filtration. The filtrate is concentrated _in 25 vacuo to give a fluffy solid which is chromatographed on SilicAR CC-7 (125 g) prepared in 1:1 CH2Cl2/ethyl acetate. Elution with 5-20% methanol/CH2Cl2 affords the product as an orange solid (560 mg, 1.9%); mp 55—56°C.

Example Q Methyl 6,7-dimethoxy-4-methyl-2(IH)quinazolinone-1-(2'-methyl)propionate Triton B (26.0 ml, 40% in methanol) is added as a slow 35 stream with stirring to a solution of 6,7-dimethoxy-4-methyl-2(lH)quinazolinone (20.0 g, 91 mM) in methyl methacrylate (206 ml), methanol (79 ml), and chloroform ORTH-388 5 6 8 5 -xf-3' (127.5 ml) precooled to 0°C. The reaction is stirred at room temperature for 18 hours and then heated at 50°C for 66 hours. The suspension is cooled in an ice bath and the resulting precipitate is isolated by filtration. Water 5 (75 ml) is added to the filtrate and this solution is extracted with methylene chloride (4x100 ml). The extract is dried (MgSOH), filtered and concentrated in vacuo to give a reddish oil which is chromatographed on SilicAR CC-7 prepared in ethyl acetate. Elution with 5-10% ethyl 10 acetate/ethanol gives an oil. Trituration of this oil with cold ethyl acetate/ether (1:1) deposits white crystals which are filtered, washed with ether (25 ml), and dried in vacuo to afford methyl 6,7-dimettioxy-4-methy1-2(IH)-quinazolinone-1-(2'-methyl)propionate.

Example R Methyl 6,7-d imethoxy-4-norbornylmethyl-2(IH) quinazolinone-l-(2'-methyl)propionate A solution of 6,7-dimethoxy-4-norbornylmethyl-2(lH)quin-azolinone (10 g) in chloroform (50 ml), methanol (50 ml) and methylacrylate (50 ml) is treated with Triton B (benzyltrimethylammonium hydroxide, 40% in methanol, 20 ml, excess) and the reaction is refluxed with stirring 25 for 24 hours. After work-up and purification via chromatography, the purified product is obtained.

Example S Methyl 6,7-dimethoxy-3,4-dihydro-3 ,4-dimethyl-2(IH) 30 quinazolinone-l-propionate A solution of methyl 6,7-dimethoxy-3,4-dimethyl-2(lH)quin-azolinonium-l-propionate bromide (1 eq) in ethanol (700 ml) is treated with 10 g 10% Pd/C. The mixture is 35 hydrogenated at ~45 psi for 16 hours until uptake ceases. The solution is filtered free of catalyst and the filtrate is concentrated in vacuo. The resulting solid is H-388 m sv 2056 8 recrystalli2ed from acetone to give a 60-70% yield of purified methyl-6,7-dimethoxy-3,4-dihydro-3,4-dimethyl-2(IH)quinazolinone-l-propionate.

Example T 6,7-Dimethoxy-5-nitro-4-methyl-2(IH)quinazolinone One equivalent of 6,7-dimethoxy-4-methyl-2(lH)quinazoli-none is added during 3/4 hr. to a mixture (5:1) of 6 equi-10 valents of concentrated nitric acid (70%) and concentrated f^SOi, at 0° t 39C. After one hour at the same temperature the solution is poured onto crushed ice (1000 ml). The crude product is collected by filtration, digested with boiling alcohol and the suspension is filtered. Crystal-15 lization from ethyl alcohol affords 6,7-dimethoxy-5-nitro-4-methyl-2(IH)quinazolinone.

Example U 6,7-Dimethoxy-5-amino-4-methyl-2(IH)quinazolinone A solution of 13 equivalents of FeS01+ .7H20 in water (6 parts) is heated to 95°C. A slurry of 1 equivalent of 6,7-dimethoxy-5-nitro-4-methyl-2(lH)quinazolinone in water (800 ml) at 804C. is added and the resulting yellow 25 mixture is heated at 98-100°C. for 15 minutes. Ammonium hydroxide (13 eq) is added to the mixture dropwise over a 15 minute period, maintaining the temperature at 98-100°C. The resulting black reaction mixture is stirred at 98-100°C. for 30 minutes, the hot mixture is filtered and the 30 insoluble black residue is washed with hot water. The brownish filtrate is extracted with chloroform. The solvent is removed in vacuo to give a dark brown semisolid crude product, which is chromatographed on a silica gel column. Recrystallization of the crude product from 35 ethyl alcohol affords purified product.

RTH-388 205685 -y£- Example V 6,7-Dimethoxy-3/4-dimethyl-2(IH)quinazolinonium propionic acid methyl ester Iodide Hemihydrate A large excess of CH3I (20 ml) is added to a solution of methyl 6,7-dimethoxy-4-methyl-2(lH)quinazolinone propionate (2.0 g, 6.53 mM) in acetone (300 ml) and the mixture is refluxed for 3 days. Removal of the solvent _in vacuo and subsequent trituration with ether yields a dark brownish solid (2.4 g). Crystallization from isopropyl alcohol and then from methanol affords the product as a yellow solid; yield 1.2 g (41.3%).

The starting materials for those compounds wherein the hydroxyl groups on the aromatic ring are in the 5-, 6- or 7-positions are prepared according to the following examples.

Example W 2-Hydroxy-3-methoxybenzaldehyde-2-benzenesulfonate A slurry of 3-methoxysalicylaldehyde (45.6 g, 299 mM) in NaOH (138 ml, 15% aqueous solution) is treated with benzenesulfonyl chloride (66 g, 373 mM) and the mixture vigorously stirred for 1 hour. The reaction mixture is then poured into ice-water (500 ml) and the resulting white solid filtered, washed with cold water, and then recrystallized from acetic acid to afford the product as a white solid; yield 72.2 g (85%); m.p. 119-120°C.

Example X 2-Hydroxy-3-methoxy-6-nitrobenzaldehyde-2-benzenesulfonate 2-Hydroxy-3-methoxybenzaldehyde-2-benzenesulfonate (50 g, 171 mM) is added to nitric acid (500 ml) at 0°C - 5°C. 205685 -y{- The solution is kept five minutes at 5°C and then poured into ice-water (1.5 L). The crude product, a tan solid, is filtered, washed with cold water, alcohol, and then recrystallized from acetic acid (650 ml) to afford the product as a white solid; yield 30.3 g (52.6%); m.p. 152-154°C.

Example Y 2-Hydroxy-3-methoxy-6-nitrobenzaldehyde A slurry of 2-hydroxy-3-methoxy-6-nitrobenzaldehyde-2-benzenesulfonate (10.12 g, 30 mM) in methanol (120 ml) is heated to reflux. A solution of KOH (6 g) in water (24 ml) and methanol (12 ml) is added and the two phase 15 mixture refluxed for 30 minutes. The light reddish precipitate which forms is filtered and then dissolved in boiling water (120 ml). Acidification of the hot aqueous solution with 10% aqueous HC1 to pH~ 4 gives a yellow precipitate (5.0 g) . Recrystallization from isopropyl 20 alcohol affords the product as a yellow solid; yield 4.5 g (76.2%); m.p. 102-104°C.

Example Z 2,3-Dimethoxy-6-nitrobenzaldehyde A slurry of NaH (16.0 g, 50% oily dispersion, 337 mM) in dimethylformamide (200 ml) was treated dropwise with a solution of 2-hydroxy-3-methoxy-6-nitrobenzaldehyde (49.0 g, 248 mM) in DMF (300 ml) at such a rate that the 30 temperature did not exceed .35°C. The mixture is aged at room temperature for 1 hour and then a large excess of methyl iodide (100 ml) is added dropwise. A slight exothermic reaction occurs. The mixture is then stirred vigorously for 19 hours at room temperature. After the 35 removal of excess methyl iodide, the reaction mixture is poured into ice-water (1 1). The crude product, a brown 205685 -K- solid, is filtered, washed with cold water, and then recrystallized from isopropyl alcohol (700 ml) to afford the product as a tan solid; yield 27.9 g (53.3%); m.p. 106-108°C.

Example AA 2,3-Dimethoxy-6-nitrobenzaldehyde-ethyleneketal A mixture of 2,3-dimethoxy-6-nitrobenzaldehyde (16.0 g, 75 mM), ethylene glycol (64 g, 103 mM), and jj-toluenesul-fonic acid monohydrate (0.2 g) in benzene (750 ml) is refluxed in a Dean-Stark apparatus for 48 hours. The solution is then poured into water (1 1.). The organic phase is washed with saturated aqueous NaHC03 (2x20 ml), dried over Na2S(\, filtered, and the solvent removed in vacuo. The crude product is recrystallized from j}-hexane (2 1.); yield 15.2 g (78.2%); m.p. 74-76°C.

Example BB 2-Amino-5 ,6-dimethoxybenzaldehyde ethyleneketal A solution of 2,3-dimethoxy-6-nitrobenzaldehyde-ethylene-ketal (12.1 g, 62.7 mM) in ethyl acetate (350 ml) containing sodium acetate (0.5 g) is treated with platinum oxide (1.0 g) and the mixture hydrogenated for 24 hours at ~50 psi. The solvent is removed in vacuo after filtering off the catalyst to give a pale brown oil. After crystallization from ri-hexane, the product is obtained as a tan solid; yield 12.8 g (85.1%); m.p. 78-80°C.

Example CC 2-(N-Carbethoxyamino)-5,6-dimethoxybenzaldehyde ethyleneketal Ethylchloroformate (1.9 g, 17.5 mM) is added with stirring to 2-amino-5,6-dimethoxybenzaldehyde-ethyleneketal 205685 (1.6 g, 7.1 mM) dissolved in tetrahydrof uran (50 ml). A solution of sodium hydroxide in H20 (0.72 g in 3.5 ml H20) is added and the resulting solution is stirred for 2 hours at room temperature. The tetrahydrofuran is removed 5 in vacuo and the residue extracted with CHC13 (2x100 ml). The extracts are dried over Na2SOit/ filtered, and the solvent removed _in vacuo. The crude product is recrystallized from n-hexanej yield 1.2 g (57.1%); m.p. 95-96°C.

Example DP 2-(N-Carbethoxyamino)-5,6-d imethoxybenzaldehyde 2-(N-Carbethoxyamino)-5,6-d imethoxybenzaldehyde-ethylene-ketal (5.0 g, 16.8 mM) is dissolved in acetone (36 ml) and 15 aqueous HC1 (3 ml of IN solution). The mixture is stirred at room temperature for 4 hours. The solvent is removed in vacuo to give a yellow solid (3.9 g) . Recrystallization from ji-hexane gives the pure product as a yellow solid; yield 3.6 g (84.7%); m.p. 86-88°C.

Example EE ,6-Dimethoxy-2(lH)-quinazolinone A stream of dry ammonia gas is passed through a solution 25 of 2-(N-carbethoxyamino)-5 ,6-dimethoxybenzaldehyde (12.4 g, 48.9 mM) and ammonium acetate (95 g) maintained at 155-160°C for 3 hours. The reaction mixture is cooled and poured into an ice-water mixture. A tan solid forms. The aqueous mixture is treated with NaCl (50 g) and then 30 extracted with CHC13 (3x200 ml). The organic extracts are combined and the solvent is removed _in vacuo to yield 9.2 g of a pale brown oil. Trituration of the oil with hot acetone gives the product as a yellow solid; yield 2.1 g (20.8%); m.p. 242-244°C.

ORTH-388 s -388 2056 -x-i7 Example FF 3 ,4-Dihydro-5,6-dimethoxy-4-methyl-2(IH)quinazolinone To a partial solution of 5,6-dimethoxy-2(lH)quinazolinone (10.0 g, 48.5 mM) in dry tetrahydrofuran (1100 ml) under nitrogen, is added at 0°C over 20 minutes, an excess of methyl magnesium bromide in ether (62.60 ml of a 3.1 M solution in ether, 194.06 mM). The reaction mixture is then removed from the cooling bath, allowed to reach room temperature and is stirred at room temperature for 16 hours. Additional methyl magnesium bromide is added (15.65 nl of a 3.1 M solution in ether; 48.52 mM) and the reaction mixture is heated at reflux for 2 hours, cooled in an ice-water bath and an aqueous solution of NH^Cl (100 ml of saturated Nl^Cl and 100 ml H20) is added with stirring. After the addition is complete, 10% aqueous HC1 is added until a pH of ~6.0 is reached. The layers are separated and the aqueous layer is extracted with CHC13 (3x250 ml) . The CHC13 extract is combined with the previously separated tetrahydrofuran layer, and the combined organic layers are washed with a saturated aqueous solution of NaCl (200 ml) and dried (Na2S04). Filtration followed by concentration to ~250 ml affords an off-white precipitate which is filtered and recrystallized from isopropanol (200 ml) to give the product as a colorless solid; yield 9.7 g (87.8%), m.p. 210-212°C.

Eample GG ,6-Dimethoxy-4-methyl-2(IH)quinazolinone Potassium permanganate (25.6 g, 162.38 mM) is added to a solution of 3,4-dihydro-5,6-dimethoxy-4-methyl-2(lH)quinazolinone (18.04 g, 81.19 mM) in acetone (5.0 liters) and the mixture is stirred at room temperature (under nitrogen, protected from light with aluminum foil) for 96 hours. The brown precipitate which forms is filtered and washed with acetone (500 ml) and is partially dissolved in 10S685 boiling water (1000 ml). The hot, aqueous solution (after filtration) is neutralized with 10% aqueous HC1 and then extracted with CHC13 (4x250 ml) and 10% isopropyl alcohol/ethyl acetate (4x250 ml). The CHC13 extracts are dried (MgSO,,), filtered, and concentrated to 500 ml at which point a solid forms. The solid is filtered off and the filtrate is further concentrated _in vacuo to give 3.25 g of a tan solid which is chromatographed on a 350 g SilicAR column that has been prepared in CHC13 (500 ml fractions). Elution with 1/2% methanol/chloroform affords a yellow solid (1.92 g) which upon recrystallization from isopropanol (75 ml) affords the product as a yellow solid; yield 0.940 g (5.3%); mp 230-232°C.

When in the above procedure 3,4-dihydro-5,6-dimethoxy-4-trifluoromethyl-2(lH)quinazolinone, 3,4-dihydro-5,6-dimethoxy-4-isopropyl-2(lH)quinazolinone and 3,4-dihydro-4-cyclohexyl-5,6-dimethoxy-2(lH)quinazolinone are employed in place of 3,4-dihydro-5,6-dimethoxy-4-methyl-2(lH)quina-zolinone the corresponding 5,6-dimethoxy-4-trifluoromethyl-2 ( lH)quinazolinone, 5,6-dimethoxy-4-isopropyl-2(lH)quinazolinone and 4-cyclohexyl-5,6-dimethoxy-2(1H)-quinazolinone are obtained.

Example HH 2-(N-Carbethoxyamino)-5-methoxy-acetophenone Ethyl chloroformate (8.6 g, 080 m) is added cautiously with stirring to 2-amino-5-methoxyacetophenone (8.0 g, 0.0479 m) while cooling the reaction mixture. A solution of sodium hydroxide in H20 (3.2 g in 15 ml) is added slowly. The reaction becomes exothermic and all of the solids dissolve. The yellow reaction mixture is removed from the ice bath and allowed to stir at room temperature for 2 hours. The reaction mixture is then extracted with CHC13 (3X100 ml) dried over Na2S04, filtered, and the solvent is removed in vacuo to give a yellow solid. 205685 Crystallization from hexane affords the product as a yellow solid; yield 7.4 g (65%); mp 90-92°C.

Example II 6-Methoxy-4-methyl-2(IH)quinazolinone A stream of dry ammonia gas is passed for 3 hours through a solution of 2-(N-carbethoxyamino)-5-methoxy-acetophenone (14.0 g, 0.058 ro) and ammonium acetate maintained at 155-10 160°C. The reaction mixture is cooled and poured into ice-water (750 ml) to give a dark orange solution. The solution is extracted with CH2C12 (3X500 ml) followed by ethyl acetate (2X500 ml) and jv-butanol (2X500 ml); the combined organic extracts are dried over Na2SOlt and the 15 solvent is removed to give a brownish residue. The residue is slurried in acetone and the insoluble portion is filtered to give the product as a pale yellow solid; yield 3.25 g, (25%); mp 232-236°C dec.

Example JJ 4-Methyl-7-methoxy-2(IH)quinazolinone A mixture of l-acetyl-3(3-methoxyphenyl)urea (32.5 g, 0.156 m) and polyphosphoric acid (912.5 g) is heated at 25 120-130°C for 2 hours. After cooling to 50°C the melt is poured on ice-water (2 liters), and the solution is made weakly basic with ammonia and left standing overnight. The brownish-red precipitate which forms is filtered off, washed with cold water followed by hot acetone, and 30 crystallized from ethanol (after treatment with charcoal) to give the product as a pale yellow solid; yield 11.5 g (39.1%); mp 251-254°C.

The 5,6-2(IH)quinazolinones having a substituent other 35 than the methoxy group at C6 and C7 and a substituent other than lower alkyl at ^ are prepared according to the methods described for the preparation of the corresponding ORTH-388 6,7-2(IH)quinazolinones. 40 205685

Claims (1)

1. WHAT WE CLAIM IS: 1. A compound of the formula alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl or bicycloalkyl; and R^ are the same or different and are hydrogen, lower (C ^ ) alkyl, aryl or substituted aryl wherein the substituent(s) is/are independently selected from halo, alkyl, lower (C^ g) alkoxy and hydroxy; Rg is hydrogen, lower (C.j_g) alkyl, benzyl or substituted benzyl wherein the substituent(s) is/are independently selected from fluoro, chloro, bromo, alkyl and alkoxy wherein the alkyl group has 1-6 carbon atoms, provided that when R^ is other than hydrogen the compound is a quaternary salt when the 3,4-imine linkage is unsaturated; X is benzyl, carboxy, carboalkoxy, cyano, carboxamido, methanesulfonyl, formyl, alkanoyl, aroyl, heteroaroyl or heteroaryl; Y and Z are independently selected from hydroxy and hydrogen provided that at least one of Y and Z is hydroxy and when Y and Z are both hydroxy the hydroxy groups are positioned at either the 5,6- or the 6,7-position; including the quaternary salts at made from lower (C.j_g) alkyl halides; and the alkali metal and alkaline earth metal salts of the phenolic hydroxyls and the carboxy group at N1 as well as the amine salts, aminoalcohol salts and the amino acid salts. A compound of Claim 1 which is 6,7-dihydroxy-4-ethyl-2(lH)quinazolinone-1-propionic acid. M3JM^987/ CP. o 205685 41 3. A compound of Claim 1 which is 6,7-dihydroxy-4-trifluoromethyl-2(1H)quinazolinone-1-propionic acid. 4. A compound of Claim 1 which is 6,7-dihydroxy-4-octyl-2(1H)quinazolinone-1-propionic acid - 5. A compound of Claim 1 which is 6,7-dihydroxy-4-cyclopentyl-2(1H)quinazolinone-1-propionic acid. 6. A compound of Claim 1 which is 5,6-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid monohydro-iodide. 7. A compound of Claim 1 which is 6,7-dihydroxy-2(lH)-quinazolinone-l-(2'-methyl)propionic acid. G, A compound of Claim 1 which is 6,7-dihydroxy-4-methyl-2(IH)quinazolinone-l-propionic acid N-methylglucanine salt. 9. A compound of Claim 1 which is 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid mono(2-methyl-2-amino-1,3-propandiol)salt. 10. A compound of Claim 1 which is 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid mono(1-amino-2,3-propandiol)salt. 11. A compound of Claim 1 which is 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid monoarginine salt. A compound of Claim 1 which is 5,6-dihydroxy-2(lH)-quilj^zolinone-l-propionic acid. L ■ $ jf(13JANt9S7 ^ * r ' 42 205685 13. A compound of Claim 1 which is 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid monoethylamine salt. 14. A compound of Claim 1 which is 6, 7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid piperazine salt. 15. A compound of Claim 1 which is 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic • acid N-methylpiper-azine salt. 16. A compound of Claim 1 which is 6,7-dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid morpholine salt. 17. A compound of the formula wherein R2 is hydrogen, lower (C.,_6) alkyl, cycloalkyl, cyclo-alkylalkyl, haloalkyl or bicycloalkyl; R6 is lower (C^_g) alkyl and R7 is hydrogen, provided that R7 is hydrogen only when the 3,4-imine linkage is saturated. 18. A compound of Claim 17 which is 5,6-dimethoxy-4-methyl-2(lH)quinazolinone. 19. A compound of Claim 17 which is 3,4-dihydro-5,6-fcN j-^<^^inethoxy-4-methyl-2 (IH) quinazolinone. 26. A compound of Claim 17 which is 5,6-dimethoxy-13 ) quinazol inone. OR,. R H \ * 43 205685 21. Compounds according to claim 1 or claim 17, with the exception of compounds claimed in any one of claims 2 to 16 and 18 to 20, as herein specifically described. 22. Compounds according to claim 1 or claim 17, with the exception of compounds claimed in any one of claims 2 to 16 and 18 to 20, as herein specifically described with reference to one or more of the Examples. 23. The process for preparing a compound of the formula R, R R 4 which comprises reacting a compound of the formula H" with an olefin of the formula X. R '4 in the presence of a base form a compound of the formula (V 3 JAN 1937' 44 '4 and if necessary reacting the product with acid; wherein R is hydrogen or lower (C1-6) alkyl; R1 is hydrogen, amino or nitro; R2 is hydrogen, alkyl, cycloalkylalkyl, ~ cycloalkyl, haloalkyl or bicycloalkyl; R3 and R4 are the same or different and are hydrogen, lower (C.j_g) alkyl, aryl or substituted aryl; and X is benzyl, carboxy, carboalkoxy, cyano, carboxamido, methanesulfonyl, formyl, alkanoyl, aroyl, heteroaroyl or heteroaryl. 24. The process of Claim 23 wherein the olefin is selected from methyl cinnamate, methyl acrylate, methyl crotonate and acrylonitrile. 25. The process of Claim 23 or claim 24 wherein the acid is hydrobromic acid. 26. The process for the preparation of a compound of the formula which comprises reacting a compound of the formula 45 205685 with an iodide of the formula V and reacting the product formed with a hydrohalic acid;wherein R is lower (C,^) alkyl; R1 is hydrogen, amino or nitro; R2 is hydrogen, cycloalkylalkyl, alkyl, cycloalkyl, haloalkyl or bicycloalkyl; R3 and R4 are the same or different and are hydrogen, lower {C1 _6) alkyl, aryl, or substituted aryl; R5 is lower (C-|_g) alkyl, benzyl or substituted benzyl; Hal" is a halide ion; and X is benzyl, carboxy, carboalkoxy, cyano, carboxamido, methanesulfonyl, formyl, alkanoyl, aroyl, heteroaryl or heteroaryl. 27. The process of Claim 26 wherein R5 is benzyl. 28. The process of Claim 26 or 27, wherein the acid is hydrobromic acid. 29. The process for the preparation of a compound of the formula R '4 which comprises reacting a compound of the formula "H 46 206685 with an olefin of the formula ,R. »r~ to form a compound of the formula RO* reacting the product formed with an iodide of the formula R^, reacting the product formed with a hydrohalic acid to form a salt of the formula HO> N'-Rr Hal' and hydrogenating the salt; wherein R is lower (C.j_g) alkyl; is hydrogen, amino or nitro; R2 is hydrogen, cycloalkylalkyl, alkyl, cycloalkyl, haloalkyl or bicycloalkyl; R3 and R4 are the same or different and are hydrogen, lower (C7_6) alkyl, aryl or substituted aryl; R5 is lower (C.j _g) alkyl, benzyl or substituted benzyl; X is benzyl, carboxy, carboalkoxy, cyano, carboxamido, methanesulfonyl, o 47 205685" formyl, alkanoyl, aroyl, heteroaroyl or heteroaryl and Hal" represents a halide ion. 30. The process of Claim 29 wherein the hydrohalic acid is ' hydrogen bromide. 31. The process of Claim 29 or Claim 30 wherein the iodide is methyl iodide. 32. The process of any one of Claims 29 to 31 wherein the olefin is selected from methyl cinnamate, methyl acrylate, methyl crotonate and acrylonitrile. 33. A process for the preparation of compounds according to Claim 1 substantially as herein desribed. 34. A process for the preparation of compounds according to claim 1 substantially as herein described with reference to one or more of the Examples. 35. A pharmaceutical composition useful in the treatment of cardiovascular disorders in unit dosage form comprising from 15 mg/kg to 3 00 mg/kg of a compound of Claim 1 in admixture with a pharmaceutically acceptable carrier. 36. Pharmaceutical compositions substantially as herein desribed. N z