CA1125170A - Quinazol in -2-ones - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Compounds of the formula wherein R1 is hydrogen; alkyl having 4-20 carbons; cyclo-alkyl, heterocycloalkyl; halo; COO loweralkyl; CN; COOH;
CH2OH; CH (O-loweralkyl)2 or nitro; and X and Y are each hydrogen; halo; nitro; loweralkyl; loweralkoxy; aryl;
arylalkyloxy; hydroxy; acyloxy; aryloxy; amino; loweralkyl-amino; diloweralkylamino; amido; loweralkylamido; diloweralkyl-amido; cyano; COOH; COO loweralkyl; CHO; CH2OH; CH2O acyl;
or CH2O aryl. The compounds find use in the treatment of hypertension and bradycardia and as a cardiotonic agent.

Description

'5~'7~

Description of the Invention The present invention relates to the use in the treat-ment of hypertension and bradycardia and as a card10tonic agent, of a compound of the formula X CH2Rl ~ y~O
H
I
`
wherein Rl is hydrogen; alkyl having 4-20 carbons; cyclo-alkyl, heterocycloalkyl; halo; COO loweralkyl; CN; COOH;
CH20H; CH(O-loweralkyl)2 or nitro; and X and Y are each hydrogen; halo; nitro; loweralkyl; loweralkoxy; aryl;

arylalkyloxy; hydroxy; acyloxy; aryloxy; amino; loweralkyl-amino; diloweralkylamino; amido; loweralkylamido; diloweralkyl-amido; cyano; COOH; COO loweralkyl; CHO; CH20H; CH20 acyl; or CH20 aryl; and pharmaceutically-acceptable acid .

r ., w~ ~

addition salts thereof; providecl that when X and Y are loweralkoxy Rl is not hydrogen.
As used herein, the terms ~loweralkyl~ and ~loweralkoxy"
mean straight or branched chain aliphatic hydrocarbons having from 1 to about 6 carbon atoms, such as for example methyl, ethyl, ~sopropyl, pentyl, and the like loweralkyls, and respectively, methoxy, ethoxy, isopropoxy, pentoxy, and the like loweralkoxys. The term "halo" includes fluoro, chloro, bromo, and iodo. The term ~aryl~ includes aromatic hydro-carbons such as naphthyl, phenyl and the l~ke and subst~tuted aromatic hydrocarbons such as phenyl substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, halo and methylenedioxy, prov~ded that only one such member is methylenedioxy (called herein "substituted phenyl"); and the like. The term "acyl"
includes loweralkanoyl and aroyl radicals derived from carboxylic acids having the formula HCOOH, loweralkyl-COOH, and aryl-COOH. Examples of the acyl groups included herein are acetyl, propionyl, n-butyryl, and the like loweralkanoyls and benzoyl, naphthoyl, 3,5-dichlorobenzoyl, and the like aroyls.
The quinazolines of this invention having the formula I, possess cardiovascular activity and are also useful in the treatment of hypertension and bradycardia and as cartiotonic agents.
Some of the instant compounds are novel and as such are included as part of this invention. The novel substituted quinazolinones include those compounds having the following formula:

CH2Rl ~ N ~ 0 Y
H I' wherein Rl is alkyl having 4-20 carbons or cycloalkyl; and X and Y are each hydrogen; halo; nitro; loweralkyl; lower-alkoxy; aryl; arylalkyloxy; hydroxy; acyloxy; aryloxy;
amino; loweralkylamino; diloweralkylamino; amido, loweralkyl-amido; diloweralkylam~do; cyano; COOH; C00 loweralkyl; CH0;
CH20H; CH20 acyl; or CH20 aryl; and pharmaceutically-acceptable acid addition salts thereof.
The compounds of the invent~on possess cardiovascular activities and are useful ~n the treatment of hypertension and bradycardia and as cardiotonic agents, as shown by the,r 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 activ1ty in eliminating chloroform-~nduced arrythmia in the mouse at dosages from about 30 to about 150 mg/kg.
In view of the activities of the subject 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 whichmethod comprises systematically administering to said patient or subject an effective amount of said compounds for treatment of said ailment in base or acid addition salt form, preferably in admixture with a pharmaceutically-acceptable carrier. The present 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 phar-maceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatlves, 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, lubricants, binders, disintegrating agents and the ltke in the case of oral solid preparations such as, for example, powders, capsules and tablets. 8ecause of their ease in administration, tablets and capsules represent the most atvantageous 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 ingre-dients, for example, to aid solubil1ty or for preservatlve ,:

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, iniections, teaspoonful and the like, from about 5 to about 500 mg and preferably from about 10 to about 250 mg.
The instant compounds 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 w1th an appropriate acid, such as, for example, an inorganic acid, such as, a hydrohalic acid, e.g., hydrochloric, hydrobromic, hydro-iodic acid; sulfuric or nitric acid; a phosphoric acid;
an organlc acid, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methane-sulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, p-aminosalicylic, 2-phenoxybenzoic, or 2-acetoxy-benzoic acid. Conversely, the salt form can be converted in the usual manner into the free base.
Most of the substituted quinazolines of the invention, with the exception of those wherein Rl is C4-20 alkyl or cycloalkyl, are generally known per se or can be prepared by known procedures, as taught in the following articles and book: Schoefield, J. Chem. Soc., 1927 tl952);
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., _5_ ;
~1 ~ 5 Interscience, 1967.
The novel compounds of formula I' may be prepared by cyclizing a compound of the formula X

NH - C - NH - C - CH2-~
O O

in the presence of a polyphosphoric acid. Preferably, said reactlon is carr~ed out by heat~ng compound II in polyphosphiric acit under nitrogen to about 135C., the suspension being maintained at this temperature for about ;~ 3 hours. After cooling, the product ~s neutralized with a suitable base, preferably ammonium hydroxide. Im-proved yields have also been obtained by preheating the polyphosphoric acid to about 100-120C. before adding compound II.
An alternative method of preparing novel compounds of formula I' consists in reacting a compound of the formula O
X
~ ~ C -- CH2-; - ~ NHC02Et Y

I I I
^6-., with ammonia in the presence of ammonium acetate.
Preferably, dry ammonia gas is passed for about3 hours through a solutlon of compound III with ammonium acetate in a suitable solvent such as dimethyl formamide.
: The temperature is preferably maintained at about 155-160C.
The intermediate used in the preparation of compound II may be prepared as indicated in the following chart:

O
; ~ Phosgene ~ ~ ~ 2 ~ :l ,~ IY Y

Preferably, compound Y together with the compound O

RlC-NH2 in a suitable solvent such as xylene or benzene are heated under nitrogen at about 140C.

The intermediate used in the preparation of compound III may be prepared as indicated in the following chart:

CT.~O ~Et > III

VI

~ 5~

Preferably, the above reaction is carried out at room temperature in a suitable solvent such as tetrahydrofuran.
The present invention is lllustrated by the following examples.

7-Ethoxy-6-methoxy-4-methyl-2(lH)quinazolinone hemihydrate Dry ammonia gas is passed for three hours through a sol-ution of 2-(N-carbethoxyamino)-4-ethoxy-5-methoxy acetophenone (12.0 g, 42.6 mM) and ammonium acetate (118.9 g) maintained at 155-160C. The reaction mixture is cooled and poured into an ice-water mixture (500 ml). The crude product is collected and washed well with acetone to give 7-ethoxy-6-methoxy-4-methyl-2(1H)quinazolinone hemihydrate as a tan solid; 8.5 g TFA
(85.2%); m.p. 262-264C;~ TMS 7.46 (s,lH,5-H), 7.15 (s,lH,8-H), 4.56 (q,2H, J= 7.0Hz,7-0-CH~-CH3), 4.16 (s,3H,6-OCH3), 3.13 (s,3H,4-CH3~, 1.65 (t,3H,J = 7.OHz,7-0-CH2-CH3); M+ 234.

7-Benzyloxy-6-methoxy-4-methyl-2(lH)quinazolinone 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, 0.0486 m) and ammonium acetate (140g) in dimethylformamide (75 ml) maintained at 155-160C. The reaction mixture is cooled and poured into an ice water mix-ture (1000 ml). The greyish precipitate is filtered and crystallized from methanol (after treatment with charcoal) to give 7-benzyloxy-6-methoxy-4-methyl-2(1H)qu-inazolinone as an off-white solid; 11.4 g (80.0%); m.p. 250-252C; CF-COOH
TMS
7.46 (s,5H, 2', 3', 4', 5'~ 6~-H), 7.43 (s, lH/ 5-H), 7.23 (s, lH, 8-H~, 5.46 (s,2H, 7-0-CH2-), 4.11 (s,3H, 6-OCH3), 3.13 (s,3H, 4-CH3~.

_ g -"
,, ., v~ ~

7-n-Butoxy-6-methoxy-4-methyl-2(lH)quinazolinone hydrate A stream of dry ammonia gas is passed for three hours through a solution of 4-_-butoxy-2-(N-carbethoxyamino)-5-methoxy acetophenone (21.97 g, 71 mM) and ammonia acetate(196 g) maintained at 155-160C. The reaction mixture is cooled and poured into an ice-water mixture (500 ml). A tan solid forms. Filtration, washing with water (50 ml), and drying affords 7-_-Butoxy-6-methoxy-4-methyl-2(lH)quinazolinone hydrate as a tan solid, 15.77 g (79.2~); m.p. 138-140C, CF3COOH 7.40 (s,lH,5-H), 7.10 (s,lH,8-H), 4.40 (t,2H,J=
6.0Hz,l'-H), 4.13 (s,3H~6-OCH3), 3.10 (s,3H,4-CH3), 0.80-2.38 (m,7H2'-H~3'-H,4'-H); M+ 262.

7-(2',6'-Dichlorobenzyloxy)-6-methoxy-4-methyl-2(lH) quinazolinone A stream of dry ammonia gas is passed for three hours through a solution of 2-(N-carbethoxyamino-4-(2',6'-dichloro-benzyloxy)-5-methoxy acetophenone and ammonium acetate (200 g) 2Q in dimethylformamide (125 ml) maintained at 160-165C. 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(lH)quinazoli-none as a tan solid; 15.33 g (76.3%); m.p.= 286-288 C.

CF COOH
53 7.55 (s,lH,5-H), 7.30-7.65 (M,4H,8-H,3'H,4'H,5'H), TMS
5.80 (s,2H,C_2-0-), 4.15 (s,3H,6 OCH3), 3.15 (s,3H,4-CH3) M 365.

~, ~ 52 ~ ~

4-n-Decyl-6,7-dimethoxy-2(:LH)quinazolinone A suspension of N-(3,4-dimethoxyphenyl)-N'-undecanoyl urea (10.0 g, 0.024 m) in excess polyphosphoric acid (80 g) is heated under nitrogen to 135C. The suspension is main-tained at 135C 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 neutralized with conc.
ammonium hydroxide to ~ pH 8Ø 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 re-crystallization from ethanol (200 ml) yellow flakes are obtained (M.P. 166-167C).

6,7-Dimethoxy-4-n-hexyl-2(lH)quinazolinone A mixture of N-(3,4-dimethoxyphenyl)-N'-heptanoyl urea (21.1 g, 68.8 mM) and polyphosphdric acid (254.4 g, 753 mM) is heated to 130C for three hours under nitrogen. After cooling, ice water ( -200 ml) is added followed by the addi-tion of conc. ammonium hydroxide until the pH is ~ 7Ø Theprecipitate is isolated, washed with water, and dried to give a light green solid (4.4 g). Recrystallization from ethyl acetate/isopropanol (1:1) gives 6,7-dimethoxy-4-n-hexyl-2(lH)-TMS
quinazolinone (1.6 g, 8.0%); m.p. 120-123 C; NMR DMSO-6 ~ 0.60-

2.00 (m,llH-(CH2)4-CH3), 2.80-3.20 (m,2H-CH2-C=N-), 3.87 (s,6H,-OCH3s), 6.80 and 7.30 (2-s, 2H, C5-C8-H's); M~290.

5~ ~

4-Cyclopentylmethyl-6,7-dimethoxy-2(1H)quinazolinone A suspension of N-(3,4-dimethoxyphenyl)-N'-cyclopentyl-acetyl urea (6.95 g,0.024 m) in polyphosphoric acid (200 g) is heated for 3 hours under nitrogen at 130-140C. After cooling, the reaction mixture is quenched on 1000 g ice and brought to ~ pH 10 with conc. ammonium hydroxide~ The precipitate which forms is isolated, washed with water and dried to give 4-cyclopentylmethyl-6,7-dimethoxy-2(lH)quinazolinone (0.97 g, 15.4~) as a dark solid, m.p.~ 240C. dec.

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 mr~) 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. Crystallization from methanol/water affords 4-_-butoxy-3-methoxy-acetophenone as an off-white solidi (47.61 g, 88.9~); m.p.= 46-47 C; ~TMS 7.58 (dd,lH, 2Q J6 5 =9; Hz, J6 2 =2 Hz,6-H), 7.50 (d,lH,J2 6=2 Hz,2-H), 6.85 (d,lH,J5 6 =9 Hz,5-H), 4.10 (t,2H,J =6 Hz,l'-H), 3.95 (s,3H,3-OCH3), 2.55 (s,3H,-C-CH3), 0.75-2.10 (m,7H,2'-H,

3'-H, 4'-H), M+222.

,:

., ,, 6-Amino-3-methoxy-4-benzyloxyacetophenone A solution of 4-benzyloxy-3-methoxy-6-nitroacetophenone (24.5 g, 0.0183 m) in glacial acetic acid (140 ml) and water (140 ml) is treated at 90-95C 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/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 subse-quent recrystallization from methanol (200 ml~ gives 6-amino-3-methoxy-4-benzyloxy-acetophenone as a light brown solid;
DMSO
(L5.5 g, 70.8%); m.p. 124-126C; TMS 6.6-7.6 (m, 9H, 2, 5, 2~, 3~, 4~, 5'r 61-H and N_2), 5.06 (s, 2H~ ~-C_2-0-), 3.73 (s, 3H, -OCH3), 2.46 (s, 3H, -Cl-C_3).
,!,.~ EXAMPLE 10 ` 4-Benz lox -2-(N-carbethoxyamino)-5-methoxyacetophenone ~, Y Y

Ethyl chloroformate (18.5 g, 0.125 m) is added cautiously with stirring to 6-amino-3-methoxy-4-benzyloxy-acetophenone (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). Recrystalliza-; tion from isopropanol affords 4-benzyloxy-2-(N-carbethoxyamino)-5-methoxyacetophenone as an off-white solid, (18.1 g, 70.0%) m.p88-90 C; ~ TMS 3 11.33 (broad s, lH, NH), 8.23 (s, lH, 6H), ~i .

., "
s 7.20-7.40 (m, 6H, 2', 3', 4', 5', 6', 3-H), 5.16 (s, 2H,

4-O-CH2), 4.16 (q, 2H, J=7.0 Hz, -O-C_2-CH3), 3.83 (s, 3H,

5-OCH3), 2.53 (s, 3H, -,C,-C_3), 1.32 (t, 3H, J=7.0 Hz, -O-CH -CH ).

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 eoncentrated ln vacuo to a dark oil. The oil is dissolved in tetrahydrofuran (150 ml), eooled to 0 C and coneentrated ammonium hydroxide (150 ml) is added dropwise with stirring. After aging for 1 hour at 0 C, the precipitate whieh forms is isolated, washed with water and dried in air to give undeeanoylamide (61.0 g, 61%) m.p.
88-89C.

N-3,4-Dimethoxyphenyl-N'--undeeanoyl urea A mixture of 3,4-dimethoxyphenylisoeyanate (19.69 g, 0.11 m) and undeeanoylamide (18.5 g, 0.1 m) in xylene (15 ml) is heated to 140C under nitrogen. After 2.5 hours, the reaction mixture is cooled to 70C and aeetone is added (50 ml).
; After eooling to about 10C, the erystalline produet whieh forms is isolated and dried in vaeuo to give N-3,4-dimethoxy-phenyl-N'-undeeanoyl urea (22.5 g, 55.2%), m.p. 112-113 C.

,.~i u' 4-n-Decyl-6,7-dimethoxy-2(lH)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 135C. The reaction is quenched on ice water (200 g) and adjusted to ~JpH 8 with conc. ammonium hydroxide. The yellow precipitate is isolated, washed with water and air dried to give 4-n-decyl-6,7-di-methoxy-2(lH)quinazolinone (6.1 g, 64%). The product is re-crystallized from ethanol (m.p. 166-67C).
When in the above procedure heptadecanamide is employed in place of undecanoylamide, 4-hexadecyl-6,7-dimethoxy-2-(lH)quinazolinone is obtained.
When in the above procedures 3-piperidylpropionamide is employed in place of undecanoylamide, 4-(3-piperidylethyl)-

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

7-dimethoxy-2(1H)quinazolinone is obtained.

1`

~ 25 .

:
~; - 15 -,: . j., .; ", I
.`. .

;~ .

:;
:~

~ ~2~7~

-Heptanamide A mixture of heptanoyl chloride (52 g, 0.3514 m) and tetrahydrofuran (100 ml) is cooled to 0C and stirred under nitrogen. After cooling, the reaction mixture is made basic by adding conc. ammonium hydroxide dropwise. A tan solid precipitates and is collected by filtration and dried ln vacuo over phosphorus pentoxide to give heptanamide (13.68 g, 30.1~), m.p. 87-110 C, M 129.

N-(3,4-Dimethoxylphenyl)-N'-heptanoyl urea A mixture of 3,4-dimethoxyphenyl isocyanate (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 tem-perature, acetone is added and the solid which forms is filtered, washed with acetone and dried ln vacuo over phos-phorus pentoxide to give N-(3,4-dimethoxy-phenyl)-N'-heptanoyl urea (31.2 g, 95.5~); m.p. 168-172C, M 308.

Cyclopentylacetamide 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 reflxued with stirring for 16 hours. The reaction mixture is then concentrated ln vacuo to a tan oil. The oil is dissolved in tetrahydrofuran (200 ml) and cooled to 0C.

-, .

~-p~

concentrated ammonium hydroxide (200 ml) is added over 1 hour with stirring. After aging at room temperature overnight, the réaction mixture is concentrated ln vacuo to 100 ml and chilled at 0C for 12 hours. The resulting precipitate is isolated, washed with water and dried in vacuo to give cyclo-pentylacetamide (21.7 g, 28%) as a colorless solid (m.p.
137-39C).

N-(3,4-dimethoxyphenyl)-N'-cyclopentylacetyl urea A mixture of 3,4-dimethoxyphenyl-isocyanate (5.0 g, 0.028 m) and cyclopentylacetamide (3.81 g, 0.028 m) is fused neat at 130-140C for 3 hours. The solid mass is cooled and triturated with acetone (30 ml) to give N-(3,4-dimethoxy-phenyl)-N'-cyclopentylacetyl urea (6.95 g, 78.9%), m.p.
180-210C dec.

-3-Methoxy-4-n-bu*oxynitrobenzene 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-butyl-bromide (4.11 g) is added all at once and the mixture is aged for 2 hours at room temperature and then 2.5 hours at 80C.
After cooling, the reaction is ~uenched on ice (100 g) and extracted with either (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 3-methoxy-4-n-butoxynitrobenzene (1.72 g, 38.5%), m.p. 53-54C.

~,'2~~

EXA~IPLE 19 3-Methoxy-4-n-butoxyaniline hydrochloride A solution of 3-methoxy-4-n-butoxynitrobenzene (1.1 g, 0.004 m) in ethanol (50 ml) and conc. 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 conc. in vacuo to give 3-methoxy-4-_-butoxyaniline hydrochloride (1.0 g, 88%) as a gray solid, (m.p. dec 250C~.

4-Ethoxy-3-methoxy-2-nitroacetophenone Nitric acid (180 ml) is cooled in ice water. 4-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-nitro-acetophenone (30.1 g, 81.9~), m.p. 105-109C.

,/, 20 !.

5~'^L''V

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) and water (144.2 ml) is treated at 90-95C with iron powder (20.1 g) (added in portions over one hour). Water is added at the start of the reaction and at successive auarter hour intervals (five times/5 ml each). After two hours, the mixture is di-luted with water and the light green precipitate which forms is filtered. Recrystallization from isopropanol gives 2-amino-4-ethoxy-5-methoxyacetophenone as a yellow solid (13.5 g, 76.8%), m.p. 154-156C.

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 ln 2~ 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 re-crystallized from _-hexane (200 ml) to afford 2-(N-carbethoxy-amino)-4-ethoxy-5-methoxyacetophenone (14.5 g, 94.7%),(m.p.
` 25 91-93C).

_ lg --:~ ~ 2~

_ 4-n-Butoxy-5-methoxy-2-nitroacetophenone 4-n-Butoxy-5-methoxyacetophenone (45.33 g, 204 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 filtra-tion. Recrystallization from methanol (200 ml) affords 4-n-butoxy-5-methoxy-2-nitroacetophenone as a yellow solid, (32.76 g, 60.1~); m.p. 76-77C.

2-Amino-4-n-butoxy-5-methoxyacetophenone A mixture of 4-_-butoxy-5-methoxy-2-nitroacetophenone (30.66 g, 115 mM) in glacial acetic acid (205 ml) and water (205 ml) is treated at 90-95C 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 90-95C, the mixture is diluted with water (1000 ml) and the precipi-tate filtered. The dark brown solid which forms is washedwith chloroform (2 liters). The chloroform is dried (Na2SO4), filtered, and the solvent removed in vacuo to give the product ` as a light brown syrup that crystallizes on standing. Re-crystallization of a portion (3.10 g) from isopropanol (30 ml) affords 2-amino-4-n-butoxy-5-methoxy-acetophenone as a yellow solid (1.90 gl~ m.p. 88-89C.

, ., . .

!, 7~

4-n-sutoxy-2-(N-carbethoxyamino)-5-methoxyacetophenone Ethyl chloroformate (23.6 ml, 0.247 m) is added cautious-ly with stirring to 2-amino-4-_-butoxy-5-methoxy-acetophenone (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 ln 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-n-butoxy-2-(N~carbethoxyamino)-5-methoxyacetophenone as a pale yellow solid (m.p. 64-66C).

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-(2',6'-dichlorobenzyloxy)-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
~.:
i~ 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. 148-151C).

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5~.'70 2-Amino-4-(2~,6'-dichlorobenzyloxy)-5-methoxyacetophenone A mixture of 4-(2',6'-dichlorobenzyloxy)-5-methoxy-2-nitroacetophenone (60.98 g, 0.165 m) in glacial acetic acid (428.5 ml) and water (428.5 ml) at 90-95C is treated with iron powder (134.4 g) added in 10-12 portions over 0.5 hours with vigorous stirring. When the addition is complete, the suspension is heated at 90-95C for two hours. The reaction mixture is then heated at 90-95C 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 (Na2SO4), filtered, and the solvent removed in vacuo to give a brown solid. Recrystal-lization from methanol (500 ml) treated with charcoal gives 15 2-amino-4-(2~,6~-dichlorobenzyloxy)-5-methoxyacetophenone as a yellow solid (22.71 g); m.p. 86-88C.

2-(N-Carbethoxyamino)-4-(2',6'-dichlorobenzyloxy)-5-methoxy-acetophenone Ethyl chloroformate (16.28 g, 0.150 m) is added cautious-ly with stirring to 2-amino-4-(2',6'-dichlorobenzyloxy)-5-methoxyacetophenone (20.41 g, 0.058 m) dissolved in tetra-hydrofuran (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 m vacuo from the reaction mixture .

~.25~ 7~) 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 (Na2SO4). 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. 160-162 C), 7.80 g.

4-Benzyloxy-3-methoxy-6-nitroacetophenone 4-Benzyloxy-3-methoxyacetophenone (61.0 g, 0.234 m) is added to nitric acid (110 ml, specific gravity 1.42)at 0-20C. After 2-5 minutes, a vigorous reaction occurs dis-solving all solids. The dark brown solution which forms is poured onto ice water (1 liter) and the crude product is col-lected 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. 141-143C.

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 the precipitated hydro-bromide salt (8.Q 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 precipitated free base is ,:

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collected by filtration and washed with acetone to yield 6,7-dihydroxy-4-methyl-2(1H)quinazolinone hydrate (4.5 g, 41.0%) as a pale yellow solid; m.p. 320C dec.

7-Hydroxy-6-methoxy-4-methyl-2(1H)quinazolinone hydrobromide A solution of 7-benzyloxy-6-methoxy-4-methyl-2(lH) 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-methoxy-4-methyl-2(1H)quinazolinone - hydrobromide as a yellowish-green solid (9.0 g, 46.4~); m.p.
303-305C.
EXAMP~E 32 6 Hyd ox 7 methox -4-meth 1-2(1H) inazolinone hydrobromide - r y- - y y qu hemihydrate 6,7-Dimethoxy-4-methyl-2(1H)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 tw-ice from methanol to afford pure 6-hy-droxy-7-methoxy-4-2(lH)quinazolinone hydrobromide hemihydrate as a yellowish-green solid (0.6 g, 7.1~); m.p. 230-232 C.

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The following pharmacological data is provided:

TABLE I

R' ~ ~ O
H
~ ¦ B.~.~S~R) R R' ~" I ORF I lowcring (mm)Dose (!/
_._ n-ClOH21 CH3 CH3 15757 12 100 .
CH3 . C2H5 CH3 15710 27.5 40 CH3 n-C4HgCH3 15724 17 10 :
.^ CH3 H H 15615 12 100 I

. I

TABLE II
Increase in -; ~RF RBF (%) Dose (MPK) : 15757 NA 13.9 . 15643 +44 13.9 : 15710 NA 13.9 15724 +26 13.9 15417 +16 13.9 . 15615 +49 13.9 5403 +29 13.9 .

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, OR~'.-I 3 5 0 ~ 2 exa e ~
The following procedure of the SHR (spontaneously hypertensive rats) is 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 Vid the tail-cuff method (which is indirect). Compounds are administered by various routes in graded doses. Blood pressure is 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).

Roper Laboratory of Animal Science, Volume 26, 305 (1976).

The Renal Vasodilator Procedure Adult mongrel dogs are anesthesized and surgically prepared for electromagnetic measurement 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 cardio tachometer. Renal vascular resistance is calculated as the ratio of the mean-arterial blood pressure over renal artery blood flow. Cumulative dose response data is 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 decrease in renal vascular resistance) is quantitated for each infusion dose.
Reference Goldberg and coworkers, Journal of Pharmacology and Experimental Therapeutics, Vol. 163 (1968).

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Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. For use in the treatment of hypertension and bradycardia and as a cardiotonic agent a composition comprising a compound of the formula I
wherein R1 is hydrogen;
heterocycloalkyl; halo; C00 loweralkyl; CN; C00H; CH20H;
CH (O-loweralkyl)2 or nitro; and X and Y are each hydrogen;
halo; nitro; loweralkyl; aryl; arylalkyloxy;
hydroxy; acyloxy; aryloxy; amino; loweralkylamino; dilower-alkylamino; amido; loweralkylamido; diloweralkylamido; cyano;
C00H; C00 loweralkyl; CH0; CH20H; CH20 acyl; or CH20 aryl;
and pharmaceutically-acceptable acid addition salts thereof, together with a pharmaceutically acceptable carrier.