IE49470B1 - Substituted quinazolines for the treatment of hypertension and bradycardia and as cardiotonic agents - Google Patents

Description

The present invention relates to pharmaceutical ccmpositions containing substituted quinazolines for the treatment of hypertension and bradycardia and as cardiotonic agents.

The broad class of such substituted quinazolines 5 is represented by the formula: wherein is alkyl having 4-20 carbons, cycloalkyl, heterocycloalkyl; COO loweralkyl; CN; COOH, CH20H; CH(0-loweralkyl)2 or nitro; or when X and/or Y are hydr10 oxy, loweralkoxy or arylalkyloxy amy also be hydrogen or halo; and X and Y are each hydrogen; halo; nitro; loweralkyl, loweralkoxy, aryl; arylalkyloxy; hydroxy, acyloxy, aryloxy, amino; loweralkyl-amino; diloweralkylamino; amido; loweralkylamido; diloweralkylamido, cyano COOH: COO loweralkyl; CHO: CH2OH; CHjO acyl; or CH20 aryl; and pharmaceutically-acceptable acid addition salts thereof; provided that (a) when X and Y are both lower49470 - 3 alkoxy R^ is not hydrogen and (b) that the compound is not 4-(ethoxycarbonylmethyl)-6-methoxy-2(1H)guinazoiinone, 4-(γ-piperidinopropyl)-6-chloro-2(1H)guinazoiinone, 4—(γ— 4'-phenylpiperidinopropyl)-2(1H)guinazoiinone or 4-(γmorpholinopropyl)-6-chloro-2(1H)guinazoiinone.

By the terms loweralkyl and loweralkoxy as used herein are meant straight or branched chain aliphatic hydrocarbons having from 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl and pentyl, and respectively, methoxy, ethoxy, isopropoxy and pentoxy. By the term halogen is meant fluoro, chloro, bromo, and iodo. By the term aryl is meant aromatic hydrocarbons such as naphthyl and phenyl, and substituted aromatic hydrocarbons such as phenyl substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, halo and methylenedioxy provided that only one such member is methylenedioxy (called herein substituted phenyl). By the term acyl is meant loweralkanoyl and aroyl radicals derived from carboxylic acids having the formula HCOOH, loweralkyl-COOH, and aryl-COOH. Examples of these acyl groups are acetyl, propionyl and n-butyryl, and benzoyl, naphthoyl and 3,5-dichlorobenzoyl.

The quinazolines having the formula I possess cardiovascular activity and are also useful in the treatment of hypertension and bradycardia and as cardiotonic agents.

Some of the compounds of formula I are novel and as such are claimed in our σο-pending Patent Application no.

This invention provides pharmaceutical ccepositions containing the compounds of formula (I) for the treatment of hypertension or bradycardia or as cardiotonic agents.

The compounds of the formula I possess cardiovascular activities and are useful in the treatment of hypertension and bradycardia and as cardiotonic agents, as - 4 shown by their activity in the spontaneous hypertensive rat test at dosages from about 50 mg/kg to about 100 mg/ kg body weight. They have also been found to inhibit cyclic AMP phosphodiesterase at dosages from about 10 to about 900 mg/kg/day, thereby providing an increase in the intracellular concentration of adenosine-3',5'-cyclic monophosphate, and are, therefore, useful as antiasthmatic agents. A preferred dosage range is from about 200 to about 250 mg/kg/day. The compounds of the invention are also useful for treatment of cardiac arrythmia as shown by their activity in eliminating chloroform-induced arrythmia in the mouse at dosages from about 30 to about 150 mg/kg.

In view of the activities of the compounds of formula I, they are suitable for use in a method for treating a patient or subject having an ailment selected from hypertension, bradycardia, and cardiac arrythmia which method comprises systematically administering to said patient or subject an effective amount of said compounds for treatment of said ailment in base or acid addit ion salt form, preferably in admixture with a pharmaceutic ally-acceptable carrier. These compounds are particularly suitable for use in treating warm-blooded animals.

To prepare the pharmaceutical compositions of this invention, a compound of formula I or salt thereof is combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparat35 ions such as for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, diluents, - 5 granulating agents, lubricants, 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 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 purposes 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 herein will generally contain, per dosage unit, e.g., tablet, capsule, powder, injections, teaspoonful and the like, from about 5 to about 500 mg. and preferably from about 10 to about 250 mg.

The compounds of formula I may be isolated as the free base or in the form of an acid addition salt by the synthetic process normally employed. These compounds, in base form, are convertible to therapeutically active acid addition salts by treatment with an appropriate acid such as, for example, an inorganic acid, such as, a hydrohalic acid, e.g., hydrochloric, hydrobromic, hydroiodie acid; sulfuric or nitric acid; a phosphoric acid; an organic acid, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, £-toluenesulfonic, cyclohexanesulfamic, salicylic, £-aminosalicylic, 2-phenoxybenzoic, or 2-acetoxybenzoic acid. Conversely, the salt form can be converted in the usual manner into the free base.

Most of the substituted quinazolines of the formula I, with the exception of those wherein R^ is C^-20 alkyl or cycloalkyl, are generally known per se or can be pre49470 - 6 pared by known procedures, as taught in the following articles and book: Schoefield, J. Chem. Soc., 1927 (1952); Albert, J. Chem. Soc., 505 (1954); Armarego, J. Chem. Soc., (C) 234 (1966); and Part I-Quinazolines by W. L. F. Armarego in Fused Pyrimidines, D. J. Brown, ed., Interscience, 1967.

The novel compounds of formula 11 may be prepared by cyclizing a compound of the formula: II NH - C - NH - C - CH2 - R in the presence of a polyphosphoric acid. Preferably, said reaction is carried out by heating compound II in polyphosphoric acid under nitrogen to about 135°C., the suspension being maintained at this temperature for about 3 hours. After cooling, the product is neutralized with a suitable base, preferably ammonium hydroxide. Improved yields have also been obtained by preheating the polyphosphoric acid to about 100°-120°C. before adding compound II.

An alternative method of preparing novel compounds of formula I' consists in reacting a compound of the formula: with ammonia in the presence of ammonium acetate.

Preferably, dry ammonia gas is passed for about 3 hours through a solution of compound III with ammonium acetate in a suitable solvent such as dimethyl formamide. The temperature is preferably maintained at about 155°16O°C.

The intermediate used in the preparation of compound II may be prepared as indicated in the following chart: V IV II c - nh2 —> II Preferably, compound V together with the compound R3C-NH2 in a suitable solvent such as xylene or benzene are heated under nitrogen at about 14O°C.

The intermediate used in the preparation of compound III may be prepared as indicated in the following chart: 48470 C - CH- - R. 1 CLCO2Et III nh2 VI Preferably, the above reaction is carried out at room temperature in a suitable solvent such as tetrahydrofuran.

The preparation and use of the compounds of the fonnula I is illustrated by the following examples.

EXAMPLE 1 7-Benzyloxy-6-methoxy-4-methy1-2(IH)guinazolinone A stream of dry ammonia gas is passed for 3 hours through a solution of 4-benzyloxy-2-(N-carbethoxyamino) -5-methoxy acetophenone (16.7 g. 0,486 m) and ammonium acetate (140 g) in dimethylformamide (75 ml) maintained at 155-16O°C. The reaction mixture is cooled and poured into an ice water mixture (1000 ml). The greyish precipi15 tate is filtered and crystallized from methanol (after treatment with charcoal) to give 7-benzyloxy-6-methoxy~4methyl-2(IH)quinazolinone as an off-white solid; 11.4 g. (80.0%); m.p. 25O-252°C; CF,-COOH 7.46 (s, SH, 2',3', JTMS 4', 5', 6'-H), 7.43 (s. IH, 5-H), 7.23 (s, IH, 8-H), 5.46 (s, 2H, 7.0-CH2-), 4.11 (s, 3H, 6-00¾) 3.13 (s, 3H, 4-0¾).

EXAMPLE 2 7-(21,6'-Dichlorobenzyloxy)-6-methoxy-4-methyl-2(IH)quinazolinone. - 9 A stream of dry ammonia gas is passed for three hours through a solution of 2-(N-carbethoxyamino)-(2’,6’dichlorobenzyloxy)-5-methoxy acetophenone and ammonium acetate (200 g) in dimethylformamide (125 ml) maintained at 16O-165°C. The reaction mixture is cooled and poured into methanol-water (500 ml.). The tan precipitate which forms is filtered, washed with cold water (50 ml) and triturated with acetone (250 ml) to give 7-(2',6'-dichlorobenzyloxy) -6-methoxy-4-methyl-2(1H)quinazolinone as a tan solid; 15.55 g. (76.5%); m.p. = 286-288°C. CF-COOH δ-3 TMS 7.55 (S, 3H, 5-H), 7.50-7,65 (Μ, 4M, 8-H, 3Ή, 4Ή, 5'K), 5.80 (β, 2H, q^-O), 4.15 (β, 5H, 6-0¾), 5.15 (s, 5H, 4¾) M+565.

EXAMPLE 3 4-n-Decyl-6,7-dimethoxy-2(1H)quinazolinone A suspension of N-(3,4-dimethoxyphenyl)-N'undecanoyl urea (10.0 g, 0.024 m) in excess polyphosphoric acid (80g.) is heated under nitrogen to 135°C. The suspension is maintained at 135°C for three hours with stirring. The reaction mixture is cooled and quenched on ice water (200 g) and the resulting gummy mixture is warmed and neutralised with cone, ammonium hydroxide to pH 8.0. The resulting precipitate is isolated, washed with water and dried in air to give 4-n-decyl-6,7-dimethoxy-2(1H)quinazolinone (6.1 g; 63.2%). Upon recrystallization from ethanol (200 ml) yellow flakes are obtained (M.P. 166-167°C).

EXAMPLE 4 6,7-Dimethoxy-4-n-hexyl-2(1H)quinazolinone A mixture of N-(3,4-dimethoxyphenyl)-N'-heptanoyl urea (21.lh, 68.8 nM) and polyphosphoric acid (254.4 g, 753 mM) is heated to 130°C for three hours under nitrogen. 48470 - 10 After cooling, ice water (200 ml) is added followed by the addition of cone, ammonium hydroxide until the pH is 7.0. The precipitate is isolated, washed with water, and dried to give a light green solid (4.4 g). Recrysta5 llization from ethyl acetate/isopropanol (1:1) gives 6,7-dimethoxy-4-n-hexyl-2(IH)quinazolinone (1.6 g, 8.0%); m.p. 12O-125°C; NMR 0.60-2.00 (m, 11H) , -CH2) χCHj), 2.80 - 5.20 (m, 2H-C&2-C=N), 5.87 (s, 6H, -OCH^s), 6.80 and 7.30 (2-s, 2H, Cg-Cg-H's); M+29O.

EXAMPLE 5 4-Cyclopentylmethyl-6,7-dimethoxy-2(IH)quinazolinone A suspension of N-(3,4-dimethoxyphenyl)-Ν'cyclopentylacetyl urea (6.95 g, 0.024 m) in polyphosphoric acid (200 g) is heated for 3 hours under nitrogen at 13O-14O°C. After cooling, the reaction mixture is quenched on 1000 g ice and brought to ~pH 10 with cone, ammonium hydroxide. The precipitate which forms is isolated, washed with water and dried to give 4-cyclopentylmethyl-6,7-dimethoxy-2(IH)quinazolinone (0.97 g, .4%) as a dark solid, m.p. >24O°C dec.

EXAMPLE 6 4-n-Butoxy-3-methoxyacetophenone A solution of acetovanillone (40.0 g, 241 mM), sodium hydroxide (10.12 g, 253 mM) and iodobutane (56. 60 g, 308 mM) in ethanol (800 ml) is heated at reflux for 16 hours. The reaction mixture is cooled and the solvent removed in vacuo to give a brown syrup. Cryatallization from methanol/water affords 4-n-butoxy-3methoxyacetophenone as an off-white solid; (47.61 g, 88.9%); m.p. = 46-47°C; δ^13 7.58 (dd, IH, Jg 5 = Hz, J, ,= 2 Hz, 6-H), 7.50 (d, IH, J- , = 2 Hz, 2-H), O f £ & / b 6.85 (d, IH, J. _ = 9 Hz, 5-H), 4.10 (t, 2H, J=6 Hz, O f J l'-H), 3.95 (s, 3H, 3-OCH3), 2.55 (s, 3H, _$_CH O>75_ - 11 2.10 (m, 7H, 2'-H, 3'-H, 4'-H), M+ 222.

EXAMPLE 7 6-Amino-3-methoxy-4-benzyloxyacetophenone A solution of 4-benzyloxy-3-methoxy-6-nitroacetophenone (24.5 g, 0.0813 m) in glacial acetic acid (140 ml) and water (140 ml) is treated at 9O-95°C with iron powder (19.5 g), added in portions during 1 hour; water is added at the start of the reaction and at successive quarter hour intervals (total of 5 times/5 ml each). After a further 30 minutes, the mixture is diluted with water and the precipitated solid is filtered. Crystallization from ethanol (150 ml) and subsequent recrystailization from methanol (200 ml) gives 6-amino-3-methoxy-4-benzyloxyacetophenone as a light brown solid; (15.5 g, 70.8%); m.p. 124-125°C; 6.6-7.6 (m, 9H, 2, 5, 2', 3·, 4', ', 6'-H and NH2), 5.06 (s, 2H, 0-CH2-O-), 3.73 (s, 3H, -0CH3), 2.46 (s, 3H, -£-CH3).

EXAMPLE 8 4-Benzyloxy-2-(N-carbethoxyamino)-5-methoxyacetophenone Ethyl chloroformate (18.5 g, 0.125 m) is added cautiously with stirring to 6-amino-3-methoxy-4-benzyloxyacetophenone (20.5 g, 0.0755 m) in tetrahydrofuran (200 ml). A solution of sodium hydroxide in water (5.0 g in 25 ml) is added slowly. Removal of the solvent in vacuo yields a light brown semi-solid. The crude product is extracted with chloroform (3X200 ml), dried (sodium sulfate), filtered, and the solvent removed in vacuo to give a pale brown residue (19.2 g). Recrystailization from isopropanol affords 4-benzyloxy-2-(N-carbethoxyamino) -5-methoxyacetophenone as an off-white solid; (18.1 g, 70.0%) m.p. 88-9O°C; δ^13 11.33 (broad s, 1H, NH), 8.23 (s, 1H, 6-H), 7.20-7.40 (m, 6H, 2', 3', 4', 5', 6', - 12 3-H), 5.16 (s, 2H, 4-O-CH2), 4.16 (q, 2H, J=7.0Hz, -O-CH2-CH3), 3.83 (s, 3H, S-OCHf) , 2.53 (s, 3H, -^-¾). 1.32 (t, 3H, J=7.0 Hz, -0-CH2-CH3).

EXAMPLE 9 Undecanoylamide A mixture of undecanoic acid (150 g), thionyl chloride (100 g) and benzene (150 ml) is refluxed with stirring for 6 hours. The reaction mixture is concentrated in vacuo to a dark oil. The oil is dissolved in tetrahydrofuran (150 ml), cooled to 0°C and concentrated ammonium hydroxide (150 ml) is added dropwise with stirring. After aging for 1 hour at 0°C, the precipitate which forms is isolated, washed with water and dried in air to give undecanoylamide (61.0 g, 61%), m.p. 88-89°C.

EXAMPLE 10 N-3,4-Dimethoxyphenyl-N *-undecanoyl urea A mixture of 3,4-dimethoxyphenylisocyanate (19. 69 g, 0.11 m) and undecanoylamide (18.5 g, 0.1 m) in xylene (15 ml) is heated to 140°C under nitrogen. After 2.5 hours, the reaction mixture is cooled to 70°C and acetone is added (50 ml). After cooling to about 10°C, the crystalline product which forms is isolated and dried in vacuo to give N-3,4-dimethoxyphenyl-N'-undecanoyl urea (22.5 g, 55.2%), m.p. 112-113°C.

EXAMPLE 11 4-n-Decyl-6,7-dimethoxy-2(IH)quinazolinone A suspension of N-3,4-dimethoxyphenyl-N'-undecanoyl urea (10.0 g, 0.024 m) in polyphosphoric acid (80 g, X's) is heated under nitrogen for 3 hours at 135°C. The - 13 reaction is quenched on ice water (200 g) and adjusted to -pH 8 with cone, ammonium hydroxide. The yellow precipitate is isolated, washed with water and air dried to give 4-n-decyl-6,7-dimethoxy-2(1H)quinazolinone (6.1 g, 64%).

The product is recrystallized from ethanol (m.p. 166-67°C).

When in the above procedures heptadecanamide is employed in place of undecanoylamide, 4-hexadecyl-6,7dimethoxy-2(1H)quinazolinone is obtained.

When in the above procedures 3-piperidylpropion10 amide is employed in place of undecanoylamide, 4-(3piperidylethyl)-6,7-dimethoxy-2(1H)quinazolinone is obtained.

EXAMPLE 12 Heptanamide A mixture of heptanoyl chloride (52 g, 0.3514 m) and tetrahydrofuran (100 ml) is cooled to 0°C and stirred under nitrogen. After cooling, the reaction mixture is made basic by adding cone, ammonium hydroxide dropwise.

A tan solid precipitates and is collected by filtration and dried in vacuo over phosphorous pentoxide to give heptanamide (13.68 g, 30.1%), m.p. 87-110°C, M+ 129.

EXAMPLE 13 N-(3,4-Dimethoxyphenyl)-N'-heptanoyl urea A mixture of 3,4-dimethoxyphenyl isocyanate 25 (18.98 g, 0.106 m) and heptanamide (13.68 g, 0.106 m) is fused under nitrogen at 125°C for 3 hours. After cooling to room temperature, acetone is added and the solid which forms is filtered, washed with acetone and dried in vacuo over phosphorous pentoxide to give N-(3,4-dimethoxy30 phenyl)-N'-heptanoyl urea (31.2 g, 95.5%); m.p. 168-172°C, M+ 308. - 14 EXAMPLE 14 Cyclopentylacetand.de A solution of cyclopentyl acetic acid (50 g, 0.38 m) in benzene (100 ml) is treated with thionyl chloride (100 ml) and the resulting mixture is refluxed with stirring for 16 hours. The reaction mixture is then concentrated in vacuo to a tan oil. The oil is dissolved in tetrahydrofuran (200 ml) and cooled to 0°C. Concentrated ammonium hydroxide (200 ml) is added over 1 hour with stirring. After aging at room temperature overnight, the reaction mixture is concentrated in vacuo to 100 ml and chilled at 0°C for 12 hours. The resulting precipitate is isolated, washed with water and dried in vacuo to give cyclopentylacetamide (21.7 g, 28%) as a colorless solid (m.p. 137-39°C).

EXAMPLE 15 N-(3,4-dimethoxyphenyl)-N‘-cyclopentylacety1 urea A mixture of 3,4-dimethoxyphenylisocyanate (5.0 g, 0.028 m) and cyclopentylacetamide (3.81 g, 0.028 m) is fused neat at 13O-14O°C for 3 hours. The solid mass is cooled and triturated with acetone (30 ml) to give N-(3,4dimethoxyphenyl)-N1-cyclopentylacetyl urea (6.95 g, 78.9%), m.p. 180-210°C dec.

EXAMPLE 16 3-Methoxy-4-n-butoxyn itrobenz ene Sodium hydride (mineral oil) (50%, 1.44 g, 0.03 m) is added to a solution of 3-methoxy-4-hydroxynitrobenzene (3.78 g; 0.02 m) in anhydrous dimethylformamide (25 ml) at ~5°C. After aging for 15 minutes at room temperature, n-butylbromide (4.11 g) is added all at once and the mixture is aged for 2 hours at room temperature and then • 49470 - 15 2.5 hours at 8O°C. After cooling, the reaction is quenched on ice (100 g) and extracted with ether (3X100 ml). The ether is washed with water (2X75 ml) and dried over magnesium sulfate. Evaporation of the ether yields a tan oil which is crystallized from hot hexane to give 3methoxy-4-n-butoxynitrobenzene (1.72 g, 38.5%), m.p. 53-54°C.

EXAMPLE 17 3-Methoxy-4-n-butoxyaniline hydrochloride IO A solution of 3-methoxy-4-n-butoxynitrobenzene (1.1 g, 0.004 m) in ethanol (50 ml) and cone, aqueous hydrochloric acid (2 ml) is treated with 10% Pd/C (0.2 g). The mixture is shaken with hydrogen for 2 hours at about 45 psi., filtered through celite and cone, in vacuo to give 3-methoxy-4-n-butoxyaniline hydrochloride (1.0 g, 88%) as a gray solid, (m.p. dec 250°C).

EXAMPLE 18 4-Ethoxy-3-methoxy-2-nitroacetophenone Nitric acid (180 ml) is cooled in ice water. 420 Ethoxy-3-methoxy-acetophenone (30 g, 0.154 m) is added portion wise and a light brown solution forms. After standing for 10 minutes, the reaction mixture is poured over ice water. The solid yellow product which forms is filtered and crystallized from isopropyl alcohol to yield 4-ethoxy-3-methoxy-2-nitroacetophenone (30.1 g, 81.9%), m.p. 1O5-1O9°C).

EXAMPLE 19 2-Amino-4-ethoxy-5-methoxyacetophenone A mixture of 4-ethoxy-5-methoxy-2-nitroacetophenone (20.1 g, 84 mM) in glacial acetic acid (144.2 ml) - 16 and water (144.2 ml) is treated at 9O-95°C with iron powder (20.1 g) (added in portions over one hour). Water is added at the start of the reaction and at successive quarter hour intervals (five times/5 ml each). After two hours, the mixture is diluted with water and the light green precipitate which forms is filtered. Recrystallizat ion from isopropanol gives 2-amino-4-ethoxy~5-methoxyaceto phenone as a yellow solid (13.5 g, 76.8%), m.p. 154-156°C.

EXAMPLE 20 2-(N-Carbethoxyamino)-4-ethoxy-5-methoxyacetophenone Ethyl chloroformate (12 g, 117 mM) is added with stirring to 2-amino-4-ethoxy-5-methoxyacetophenone (11.4 g, 59.5 mM) dissolved in tetrahydrofuran (200 ml).

A solution of sodium hydroxide in water (3.7 g in 10 ml water) is added and the solution is refluxed for two hours and then concentrated in vacuo. The light brown residue which forms is extracted with chloroform (2 x 125 ml), dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude product is recrystallized from n-hexane (200 ml) to afford 2-(N-carbethoxyamino)-4ethoxy-5-methoxyacetophenone (14.5 g, 94.7%), m.p. 91-93°C) EXAMPLE 21 4-n-Butoxy-5-methoxy-2-nitroacetophenone 4-n-Butoxy-5-methoxyacetophenone (45.33 g, 204 25 mM) is added during five minutes to nitric acid (280 ml, specific gravity 1.42) at 0°. After an additional ten minutes at the same temperature, the dark brown solution is poured into ice water (1 liter). The crude product is collected by filtration. Recrystallization from metha30 nol (200 ml) affords 4-n-butoxy-5-methoxy-2-nitroacetophenone as a yellow solid, (32.76 g, 60.1%); m.p. 76-77°C. - 17 EXAMPLE 22 2-Amino-4-n-butoxy-5-methoxyacetophenone A mixture of 4-n-butoxy-5-methoxy-2-nitroacetophenone (30.66 g, 115 mM) in glacial acetic acid (205 ml) and water (205 ml) is treated at 90-95°C with iron powder (64.4 g, 40 mesh), added in portions over one hour; water is added at the start of the reaction and at successive quarter hour Intervals (total of five times/5 ml each). After two hours at 90-95°C, the mixture is diluted with water (1000 ml) and the precipitate filtered. The dark brown solid which forms is washed with chloroform (2 liters). The chloroform is dried (Na2S04), filtered, and the solvent removed in vacuo to give the product as a light brown syrup that crystallizes on standing. Recrystallization of a portion (3.10 g) from isopropanol (30 ml) affords 2-amino-4-n-butoxy-5-methoxyacetophenone as a yellow solid (1.90 g); m.p. 88-89°C.

EXAMPLE 23 4-n-Butoxy-2-(N-carbethoxyamino)-5-methoxyacetophenone Ethyl chloroformate (23.6 ml, 0.247 m) is added cautiously with stirring to 2-amino-4-n-butoxy-5-methoxyacetophenone (23.10 g, 0.097 m) dissolved in tetrahydrofuran (500 ml). A solution of sodium hydroxide (7.84 g, 0.196 m) in water (24 ml) is added slowly and the resulting solution is heated at reflux for two hours. The tetrahydrofuran is removed in vacuo from the reaction mixture and the resulting brown aqueous mixture is extracted with chloroform (4 x 150 ml), dried (Na2SO4) and the chloroform is removed in vacuo to give a brown syrup that crystallizes on standing. Recrystallization from hexane yields 4-nbutoxy-2-(N-carbethoxyamino)-5-methoxyacetophenone as a pale yellow solid (m.p. 64-66°C). - 18 EXAMPLE 24 4-(2',6’-Dichlorobenzyloxy)-5-methoxy-2-nitroacetophenone To HNO3 (specific gravity 1.42, 285 ml) cooled in ice water is added portion wise 4-(21,6'-dichlorobenzyl5 oxy)-5-methoxyacetophenone (56.27 g, 0.173 m). A red solid forms. The reaction mixture is removed from the ice bath and heated to 30°C in an oil bath. The temperature is maintained at 30°C for ten minutes. During this time, the red solid turns yellow. The reaction mixture is then poured over ice water (1 liter) and the resulting yellow solid is filtered, washed with water (100 ml), and dried to give 4-(2',6'-dichlorobenzyloxy)-5-methoxy-2-nitroacetophenone as a yellow solid (m.p. 148-151°C).

EXAMPLE 25 2_5 2-Amino-4- (21,6 '-dichlorcbenzylaxy) -5-methoxyaoetcphencne A mixture of 4-(2',6'-dichlorobenzyloxy)-5methoxy-2-nitroacetophenone (60.98 g, 0.165 m) in glacial acetic acid (428.5 ml) and water (428.5 ml) at 90-95°C is treated iron powder (134.4 g) added in 10-12 portions over 2o 0.5 hours with vigorous stirring. When the addition is complete, the suspension is heated at 90-95°C for two hours. The reaction mixture is then heated at 9O-95°C for an additional four hours and then cooled. Water (1 liter) is added and the dark brown solid material is filtered and washed with chloroform (2 liters). The chloroform is dried (Na^SO^), filtered, and the solvent removed in vacuo to give a brown solid. Recrystallization from methanol (500 ml) treated with charcoal gives 2-amino-4-(2',6'dichlorobenzyloxy)-5-methoxyacetophenone as a yellow solid (22.71 g); m.p. 86-88°C.

EXAMPLE 26 2-(N-Carbethoxyamino)-4-(2',61-dichlorobenzyloxy)-5methoxyacetophenone - 19 Ethyl chloroformate (16.28 g, 0.150 m) is added cautiously with stirring to 2-amino-4-(2',6'-dichlorobenzyloxy) -5-methoxyacetophenone (20.41 g, 0.058 m) dissolved in tetrahydrofuran (500 ml). A solution of sodium hydroxide (4.84 g, 0.121 m) in water (20 ml) is added slowly and the resulting solution is heated at reflux for two and one half hours. The tetrahydrofuran is removed in vacuo from the reaction mixture to give a light brown solid. Water (50 ml) is added and the resulting mixture is extracted with chloroform (3 x 150 ml) and dried (NajSO^). The chloroform is then removed in vacuo to give a yellow solid. Recrystallization from isopropanol gives 2-(N-carbethoxyamino)-4-(2',6'-dichlorobenzyloxy) -5-methoxyacetophenone as an off-white solid (m.p. 160162°C), 7.80 g.

EXAMPLE 27 4-Benzyloxy-3-methoxy-6-nitroacetophenone 4-Benzyloxy-3-methoxyacetophenone (61.Og, 0.234 m) is added to nitric acid (110 ml, specific gravity 1.42) at 0°-20°C. After 2-5 minutes, a vigorous reaction occurs dissolving all solids. The dark brown solution which forms is poured onto ice water (1 liter) and the crude product is collected by filtration. Two recrystallizations from methanol give 4-benzyloxy-3-methoxy-6-nitroacetophenone as a pale yellow solid (40.0 g, 57.3%); m.p. 141-143°C.

EXAMPLE 28 6,7-Dihydroxy-4-methyl-2(lH)quinazolinone hydrate A solution of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone (12.4 g, 0,057 M) in acetic acid (300 ml) and hydrobromic acid (240 ml, 48% aqueous) is refluxed for 19 hours. The solution is cooled in an ice-water bath and - 20 the precipitated hydrobronide salt (5.0 g) is collected by filtration and then washed with excess acetone. The salt is dissolved in water (75 ml) and saturated aqueous sodium bicarbonate is added until the pH is neutral. The precipi5 tated free base is collected by filtration and washed with acetone to yield 6,7-dihydroxy-4-methyl-2(IH)quinazolinone hydrate (4.5 g, 41.0%) as a pale yellow solid, m.p. 32O°C dec.

EXAMPLE 29 7-Hydroxy-6-methoxy-4-raethyl-2(1H)quinazolinone hydrobromide A solution of 7-benzyloxy-6-methoxy-4-methyl-2(1H)quinazolinone (20.0 g, 0.0675 m) in acetic acid (350 ml) and hydrobromic acid (325 ml, 48% aqueous) is refluxed for 4 hours. The solution is cooled in an ice-water bath and the solid (10.1 g) which precipitates is collected by filtration, washed with hot methanol and then recrystallized from water (150 ml) to afford pure 7-hydroxy-6-methoxy4-methyl-2(IH)quinazolinone hydrobromide as a yellowish20 green solid (9.0 g, 46.4%); m.p. 3O3-3O5°C.

EXAMPLE 30 6-Hydroxy-7-methoxy-4-methyl-2(IH)quinazolinone hydrobromide hemihydrate 6,7-Dimethoxy-4-methyl-2(IH)quinazolinone (6.2 g, 0.0285 m) in acetic acid (150 ml) and hydrobromic acid (120 ml, 48% aqueous) is refluxed for 19 hours. The solution is cooled in an ice-water bath and the solid (5.1 g) which precipitates is collected by filtration. Removal of the solvent from the filtrate gives an oily residue (1.95 g) which is crystallized from water and then twice from methanol to afford pure 6-hydroxy-7-methoxy-42 (IH)quinazolinone hydrobromide hemihydrate as a yellowishgreen solid (0.6 g, 7.1%); m.p. 230-232°C. ' 49470 - 21 EXAMPLE 31 Certain of the compounds of the formula I were subjected to certain tests to determine their effects on lowering blood pressure and increasing renal blood flow.

The blood pressure lowering effects of the compounds tested was measured by their activity in the spontaneous hypertensive rat test (SHR).

The procedure of the SHR (spontaneously hypertensive rats) was as follows: Groups of 4 male SHR rats with systolic pressures greater than 170 mm. mercury were used to evaluate compounds for antihypertensive activity. Systolic blood pressure is recorded via the tail-cuff method (which is indirect). Compounds were administered by various routes in graded doses. Blood pressure was recorded at various time intervals following each dose. There are two references regarding this procedure—Okamoto and his co-author Aoki. Japanese Circulation Journal Volume 27, Page 282 (1963); and Roper Laboratory of Animal Science, Volume 26, 305 (1976).

The results are given in Table I, the lowering of the blood pressure being given in mm. relative to the controls.

The increase ih renal blood flow was measured in dogs by the following-method. Adult mongrel dogs were anaesthesized and surgically prepared for electromagnetic measurement of renal artery blood flow. A carotid artery was cannulated for measuring arterial blood pressure and drugs were administered intravenously. Heart rate was monitored by a cardio tachometer. Renal vascular resistance was calculated as the ratio of the mean-arterial blood pressure over renal artery blood flow. Cumulative dose response data was obtained by infusing the test drug at progressively increasing infusion rates, each dose being infused for five minutes. The maximum percentage increase from pre-drug control in renal artery blood flow (or - 22 decrease in renal vascular resistance) was quantified for each infusion dose. Reference Goldberg and co-workers, Journal of Pharmacology and Experimental Therapeutics, Vol. 163 (1968).

Active renal vascodilators cause an increase in renal blood flow (RBF). The results are given in Table II, the increase being given as a percentage relative to the controls.

The compounds tested had the formula: - 23 TABLE I R R' R BP (SHR) Dose (mg/Kg) lowering (mm)n-C10H21 ch3 ch3 12 100n-C6H13 ch3 ch3 18 100 ch3 H ch3 6 100 ch3 H H 12 100 ch3CH3 H 12 100 TABLE II R R' R Increase Dose mg/Kgn_C10H21 ch3 ch3 NA 13.9n_C6H13 ch3 ch3 +44 13.9 ch3 H ch3 +16 13.9 gh3 H H +49 13.9 ch3CH3 H +29 13.9 *NA means not active in the test

Claims (8)

1. A pharmaceutical composition for the treatment of hypertension or bradycardia or for use as a cardiotonic agent comprising a compound of the formula: wherein R^ is alkyl having 4-20 carbons, cycloalkyl, heterocycloalkyl; COO loweralkyl; CN; COOH, CH 2 OH; CH(O-loweralkyl) 2 or nitro; or when X and/or Y are hydroxy, loweralkoxy or arylalkyloxy R^ may also be hydro10 gen or halo; and X and Y are each hydrogen; halo; nitro; loweralkyl, loweralkoxy, aryl; arylalkyloxy; hydroxy, acyloxy, aryloxy, amino; loweralkyl-amino; diloweralkylamino; amido; loweralkylamido; diloweralkylamido, cyano; COOH: COO loweralkyl; CHO: CHjOH; CH 2 O acyl; 15 or CH 2 0 aryl; and pharmaceutically-acceptable acid addition salts thereof; provided that (a) when X and Y are both loweralkoxy R^ is not hydrogen and (b) that the compound is not 4-(ethoxycarbonylmethyl)-6-methoxy-2(1H)quinazolinone, 4-(γ-piperidinopropyl)-6-chloro-2(IH)quina20 zolinone, 4-(γ—4 1 -phenylpiperidinopropyl)-2(1H)quinazolinone or 4-(γ-morpholinopropyl)-6-chloro-2(1H)quinazolinone.

2. . A pharmaceutical composition for the treatment of hypertension and bradycardia and as a cardiotonic agent comprising 4-n-decy1-6,7-dimethoxy-2(lH) quinazolinone.

3. A pharmaceutical composition for the treatment of hypertension and bradycardia and as a cardiotonic agent comprising

4. -cyclopentylmethy 1-6,7-dinethoxy-2(1H)quinazolinone. 4947 - 25 4. A pharmaceutical composition for the treatment of hypertension and bradycardia and as a cardiotonic agent comprising 6,7-dimethoxy-4-n-hexyl-2(IH)quinazolinone.

5. A pharmaceutical composition for the treatment 5 of hypertension and bradycardia and as a cardiotonic agent comprising 6,7-dimethoxy-4-ri-hexadecyl-2(IH)quinazolinone.

6. A pharmaceutical composition for the treatment of hypertension and bradycardia and as a cardiotonic agent comprising 6,

7. -dihydroxy-4-methy1-2(1H)quinazolinone hydrate. 10 7. A pharmaceutical composition for the treatment of hypertension and bradycardia and as a cardiotonic agent comprising 6-hydroxy-7-methoxy-4-methyl-2(lH)quinazolin· one hydrobromide hemihydrate.

8. A pharmaceutical composition according to 15 Claim 1, substantially as hereinbefore described.