GB2088874A - Substituted Quinazolines for the Treatment of Hypertension and Bradycardia and as Cardiotonic Agents - Google Patents

Substituted Quinazolines for the Treatment of Hypertension and Bradycardia and as Cardiotonic Agents Download PDF

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GB2088874A
GB2088874A GB8138698A GB8138698A GB2088874A GB 2088874 A GB2088874 A GB 2088874A GB 8138698 A GB8138698 A GB 8138698A GB 8138698 A GB8138698 A GB 8138698A GB 2088874 A GB2088874 A GB 2088874A
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bradycardia
hypertension
quinazolinone
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
    • C07C273/1827—X being H
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

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Abstract

Substituted quinazolines of the formula <IMAGE> wherein R1 is H, C4-20 alkyl, cycloalkyl, heterocycloalkyl, halo, COOC1-6 alkyl, CN, COOH, CH2OH, CH(OC1-6 alkyl)2 or NO2; and X and Y are each H, halo, NO2, C1-6 alkyl, C1-6 alkoxy, aryl, aralkyloxy, HO, acyloxy, aryloxy, amino, C1-6 alkylamino di C1-6 alkylamino, amido, C1-6 alkylamido, di C1-6 alkylamido, CN, COOH, COOC1-6 alkyl, CHO, CH2OH, CH2O acyl, or CH2O aryl and pharmaceutically acceptable acid addition salts thereof, provided that when X and Y are C1-6 alkoxy R1 is not H are useful for the treatment of hypertension and bradycardia and as cardiotonic agents.

Description

SPECIFICATION Substituted Pyrrolo (1,2-C) Quinazolines for the Treatment of Hypertension and Bradycardia and as Cardiotonic Agents The present invention relates to substiututed pyrrolo (1,2--C) quinazolines for the treatment of hypertension and bradycardia and as cardiotonic agents.
The broad class of such substituted quinozolines is represented by the formula:
wherein R1 is hydrogen; alkyl having 4-20 carbons; cycloalkyl, heterocycloalkyl; halo; COO loweralkyl; CN; C00H; 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; diloweralkylamido; cyano; C00H; COO loweralkyl; CHO; CH20H; CH20 acyl; or CH20 aryl; and pharmaceutically-acceptable acid addition salts thereof; provided that when X and Y are loweralkoxy R1 is not hydrogen.
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 "substitued 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 nbutyryl, and benzoyl, naphthoyl and 3,5-dichlorobenzoyl.
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 cardiotonic agents.
Some of the compounds of formula I are novel and as such are claimed in our co-pending Patent Application No. 7942289.
This invention provides the compounds of formula (I) for the treatment of hypertension and bradycardia and as cardiotonic agents.
The compounds of the invention possess cardiovascular activities and are useful in the treatment of hypertension and bradycardia and as cardiotonic agents, as 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 1 50 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 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 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 pharmaceutical compositions of the compounds 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 preparations such as for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, diluents, 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 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 with an appropriate acid, such as, for example, an inorganic acid, such as, a hydrohalic acid, e.g., hydrochloric, hydrobromic, hydroiodic 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, methane-sulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, p-aminosalicylic, 2-phenoxybenzoic, or 2acetoxybenzoic 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 R, is C420 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 (1952); Albert, J. Chem. Soc, 505(1954); Armarego, J. Chem. Soc., (C) 234 (1966); and "Part l-Quinazolines" by W. L. F. Armarego in "Fused Pyrimidines", D. J. Brown, ed., Interscience, 1967.
The novel compounds of formula I' may be prepared by cyclizing a compound of the formula
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 1000--1200C. 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 1550--1600C.
The intermediate used in the preparation of compound II may be prepared as indicated in the following chart:
Preferably, compound V together with the compound
in a suitable solvent such as xylene or benzene areffieated under nitrogen at about 1400C.
The intermediate used in the preparation of compound III may be prepared as indicated in the following chart:
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 present invention is illustrated by the following examples.
Example 1 7-Ethoxy-6-methoxy-4-methyl-2(1 H, quinazolinone Hemihydrate Dry ammonia gas is passed for three hours through a solution of 2-(n-carbethoxyamino)-4ethoxy-5-methoxy acetophenone (12.0 g, 42,6 mM) and ammonium acetate (118.9 g) maintained at 155--160 C. 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-methyl2(1 H)quinazolinone hemihydrate as a tan solid; 8.5 g (85.2%); m.p.262--264 C: FMAS 7.46 (s,1 H, 5-H), 7.15 (5, 1 H, 8-H), 4.56 (q, 2H, J=7.0 Hz, 7-0-CH2-OH3) 4.16 (s,3H,6-OCH3),3.13 (s,3H,4-CH3),1.65 (t, 3H, J=7.0 Hz, 7-0-OH2-CH3);M+234.
Example 2 7-Benzyloxy-6-methoxy-4-methyl-2(1 H)quinazolinone A stream of dry ammonia gas is passed for 3 hours through a solution of 4-benzyloxy-2-(Ncarbethoxyamino)-5-methoxy acetophenone (16.7 g, 0.0486 m) and ammonium acetate (140 g) in dimethylformamide (75 ml) maintained at 155160 C. The reaction mixture is cooled and poured into an ice water mixture (1000 mi). The greyish precipitate is filtered and crystallized from methanol (after treatment with charcoal) to give 7-benzyloxy-6-methoxy-4-methyl-2( 1 H)quinazolinone as an offwhite solid; 11.4 g (80.0%); m.p.250--252 C; 8$X00H 7.46 (s, 5H. 2', 3', 4', 5', 6'-H), 7.43 (s, 1H, 5-H), 7.23 (s, 1H, 8-H), 5.46 (s,2H,7-0- OK2-), 4.11(s,3H,6-OCH3),3.13(s,3H,4-OH3).
Example 3 7-n-Butoxy-6-methoxy-4-methyl-2(1H)quinazolinone Hydrate A stream of dry ammonia gas is passed for three hours through a solution of 4-n-butoxy-2-(Mcarbethoxyamino)-5-methoxy acetophenone (21.97 g, 71 mM) and ammonium acetate (196 g) maintained at 155--160 C. 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-n-Butoxy-6methoxy-4-methyl-2(1 H)quinazolinone hydrate as a tan solid, 15.77 g (79.2%); m.p.=138--140 C; COOH 7.40 (s, 1 H, 5-H), 7.10 (5, 1 H, 8-H), 4.40 (t, 2H, J=6.0 Hz, 1 '-H), 4.13 (s,3H,6-OCH3), 3.10 (s, 3H, 4-OH3), 0.80-2.38 (m, 7H2'-H, 3'-H, 4'-H); M+ 262.
Example 4 7-(2',6'-Dichlorobenzyloxy)-6-methoxy-4-methyl-2(1 H)quinazolinone A stream of dry ammonia gas is passed for three hours through a solution of 2-(Ncarbethoxyamino)-4-(2',6'-dichlorobenzyloxy)-5-methoxy acetophenone and ammonium acetate (200 g) in dimethylformamide (125 ml) maintained at 160--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( 1 H)quinazolinone as a tan solid; 15.33 g (76.3%); m.p.=286--288 C.
8WOOH 7.55 (s,1 H,5-H),7.30--7.65 (M, 4H, 8-H, 3'H, 4'H, 5'H, 5.80 (s, 2H, CH2-O-),4.15 (s, 3H, 6-OCH3),3.15 (s,3H 4-CH3) M+ 365.
Example 5 4-n-Decyl-6,7-dimethoxy-2(1 H)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 13500. The suspension is maintained at 13500 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 8.0. The resulting precipitate is isolated, washed with water and dried in air to give 4-n-decyl-6,7-dimethoxy2(1 H)quinazolinone (6.1 g; 63.2%). Upon recrystallisation from ethanol (200 ml) yellow flakes are obtained; m.p. 166--167 C).
Example 6 6,7-Dimethoxy-4-n-hexyl-2(1 H)quinazolinone A mixture of N-(3,4-dimethoxyphenyl)-N'-heptanoyl urea (21.1 g, 68.8 mM) and polyphosphoric acid (254.4 g, 753 mM) is heated to 130 C for three hours under nitrogen. After cooling, ice water (y200 ml) is added followed by the addition of conc. ammonium hydroxide until the pH is y7.0. The precipitate is isolated, washed with water, and dried to give a light green solid (4.4 g).Recrystallisation from ethyl acetate/isopropanol (1:1) gives 6,7-dimethoxy-4-n-hexyl-2(1 H)quinazolinone (1.6 g,8.0%); m.p. 120--123 C:
Example 7 4-Cylcopentylmethyl-6,7-dimethoxy-2(1 H)quinazolinone A suspension of N-(3,4-dimethoxyphenyl)-N'-cyclopentylacetyl urea (6.95 g 0.024 m) in polyphosphoric acid (200 g) is heated for 3 hours under nitrogen at 130--140 C. 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-6,7dimethoxy-2(1 H)-quinazolinone (0.97 g, 15.4%) as a dark solid; m.p. > 2400C dec.
Example 8 4-n-Butoxy-3-methoxyacetophenone A solution of acetovanillone (40.0 9,241 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. Crystallization from methanol/water affords 4-n-butoxy-3-methoxyacetophenone as an off-white solid; (47.61 9,88.9%); m.p.=46-4700; bTClasl3 7.58 (dd, 1 H, J6.5=9 Hz, J62=2 Hz, 6-H, 7.50 (d, 1 H, J26=2 Hz, 2-H), 6.85 (d, 1 H, J56=9 Hz, 5-H), 4.10 (t, 2H, J=6 Hz, 1 '-H), 3.95 (s, 3H, 3-OCH3),
0.75-2.10 (m, 7H, 2'-H, 3'-H, 4'-H), M+ 222.
Example 9 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 90--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 precipipated solid is filtered. Crysallization from ethanol (150 ml) and subsequent recrystallization from the methanol (200 ml) gives 6-amino-3-methoxy-4-benzyloxyacetophenone as a light brown solid; (15.5 g, 70.8%); m.p. 124--126 C; MMSSO 6.6-7.6 (m, 9H, 2, 5, 2', 3', 4', 5', 6'-H and NH2), 5.06 (5, 2H OH2-0-), 3.73 (s, 3H, -OCH3),
Example 10 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). Recrystallization from isopropanol affords 4-benzyloxy-2- (N-carbethoxyamino)-5-methoxyacetophenon as an off-white solid; (18.1 9,70.0%); m.p. 88--90 C; bTCMcl311.33 (broad s, 1 H, NH), 8.23 (s,1H,6-H),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-CH2-CH3),3.83 (s,3H,5-OCH3),
1.32 (t, 3H, J=7.0 Hz, -O-CH2-CH3).
Example 11 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 OOC, the precipitate which forms is isolated, washed with water and dried in air to give undecanoylamide (61.0 g, 61%), m.p. 88--890C Example 12 N-3,4-Dimethoxyphenyl-N'-undecanoyl Urea A mixture of 3,4-dimethoxyphenylisocyanate (19.69 g,0.1 1 m) and undecanoylamide (18.5 g, 0.1 m) in xylene (15 ml) is heated to 1400C under nitrogen.After 2.5 hours, the reaction mixture is cooled to 700C and acetone is added (50 ml). After cooling to about 1 OOC, 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--1130C.
Example 13 4-n-Decyl-6,7-dimethoxy-2(1 H)quinazolinone A suspension of N-3,4-dimethoxyphenyl-N'-undecanoyl urea (10.0 g,0.024 m) in potypliosphoric acid (80 9, x's) is heated under nitrogen for 3 hours at 1350C. The reaction is quenched on ice water (200 9) and adjusted to pH 8 with conc. ammonium hydroxide. The yellow precipitate is isolated, washed with water and air dried to give 4-n-decyl-6,7-dimethoxy-2(1 H)quinazolinone (6.1 g, 64%). The product is recrystallized from ethanol; m.p. 166--670C.
When in the above procedures heptadecanamide is employed in place of undecanoylamide, 4hexadecyl-6,7-dimethoxy-2(1 H)quinazolinone is obtained.
When in the above procedures 3-piperidylpropionamide is employed in place of undecanoylamide, 4-(3-piperidylethyl)-6,7-dimethoxy-2(1 H)quinazolinone is obtained.
When in the above procedures 2-chloroacetamide is employed in place of undecanoylamide, 4 chloromethyl-6,7-dimethoxy-2( 1 H)quinazolinone is obtained.
Example 14 Heptanamide A mixture of heptanoyl chloride (52 9, 0.3514 m) and tetrahydrofuran (100 ml) is cooled to OOC 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 in vacuo over phosphorous pentoxide to give heptanamide (13.68g,30.1%); m.p. 87--1 100C, M+ 129.
Example 15 N-(3,4-Dimethoxyphenyl)-N'-heptanoyl Urea A mixture of 3,4-dimethoxyphenyl isocyanate (18.98 9, 0.106 m) and heptanamide (13.68 9, 0.106 m) is fused under nitrogen at 12500 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-dimethoxyphenyl)-Nt-heptanoyl urea (31.2 g, 95.5%); m.p.
168--1 720C, M+308.
Example 16 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 refluxed with stirring for 1 6 hours. The reaction mixture is then concentrated in vacuo to a tan oil. The oil is dissolved in tetrahydrofuran (200 ml) and cooled to 000. 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 OOC for 12 hours. The resulting precipitate is isolated, washed with water and dried in vacuo to give cyclopentylacetamide (21.7 9, 28%) as a colorless solid; m.p. 1 37390O).
Example 17 N-(3,4-dimethoxyphenyl)-N'-cyclopentylacetyl Urea A mixture of 3,4-dimethoxyphenylisocyanate (5.0 9, 0.028 m) and cyclopentylacetamide (3,81 9 0.028 m) is fused neat at 130--1400C for 3 hours. The solid mass is cooled and triturated with acetone (30 ml) to give N(3,4-dimethoxyphenyl-N'-cyclopentylacetyl urea (6.95 g, 78.9%); m.p. 1 80- 21000 dec.
Example 18 3-Methoxy-4-n-butoxynitrobenzene Sodium hydride (mineral oil) (50%, 1.44 9, 0.03 m) is added to a solution of 3-methoxy-4hydroxynitrobenzene (3.78 g; 0.02 m) in anhydrous dimethylformamide (25 ml) at --50C. After aging for 1 5 minutes at room temperature, n-butylbromide (4.11 9) is added all at once and the mixture is aged for 2 hours at room temperature and then 2.5 hours at 800 0. After cooling, the reaction is quenched on ice (1009) 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 3-methoxy-4-n-butoxynitrobenzene (1.72 9, 38.5%); m.p. 53--540C.
Example 19 3-Methoxy-4-n-butoxyaniline Hydrochloride A solution of 3-methoxy-4-n-butoxynitrobenzene (1.1 9,0.004 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-nbutoxyaniline hydrochloride (1.0 g, 88%) as a grey solid; m.p. dec 2500C.
Example 20 4-Ethoxy-3-methoxy-2-nitroacetophenone Nitric acid (180 ml) is cooled in ice water. 4-Ethoxy-3-methoxy-acetophenone (30 9, 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. 105- 10900.
Example 21 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--950C 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. Recrystallization from isopropanol give 2-amino-4-ethoxy-5 methoxyacetophenone as a yellow solid (13.5 9, 76.8%); m.p. 154--1560C.
Example 22 2-(N-Carbethoxyamino)-4-ethoxy-5-methoxyacetophenone Ethyl chloroformate (12 9,117 mM) is added with stirring to 2-amino-4-ethoxy-5methoxyacetophenone (11.4 9, 59.5 mM) is dissolved in tetrahydrofuran (200 ml). A solution of sodium hydroxide in water (3.7 9 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 (2x 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)-4-ethoxy-5methoxyacetophenone (14.5g,94.7%); m.p.91--93 C.
Example 23 4-n-Butoxy-5-methoxy-2-nitroacetophenone 4-n-Butoxy-5-methoxyacetophenone (45.33 9,204 mM) is added during five minutes to nitric acid (280 ml, specific gravity 1.42) at 00. 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 methanol (200 ml) affords 4-n-butoxy-5-methoxy-2-nitroacetophenone as a yellow solid, (32.76g,60.1%); m.p.76--77 C.
Example 24 2-Amino-4-n-butoxy-5-methoxyacetophenone A mixture of 4-n-butoxy-5-methoxy-2-nitroacetophenone (30.66 9,115 mM) in glacial acetic acid (205 ml) and water (205 ml) is treated at 90--950C 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--950C, 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 (Na2SO4), 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 9) from isopropanol (30 ml) affords 2-amino-4-n-butoxy-5-methoxyacetophenone as a yellow solid (1.90 9); m.p. 88--890C.
Example 25 4-n-Butoxy-2-(N-carbethoxya mino)-5-methoxyacetophenone Ethyl chloroformate (23.6 ml, 0.247 m) is added cautiously with stirring to 2-amino-4-n-butoxy5-methoxyacetophenone (23.109,0.097 m) dissolved in tetrahydrofuran (500 ml). A solution of sodium hydroxide (7.84 9, 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 (4x 1 50 ml), dried (NaSO4) 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-ca rbethoxyamino)-5-methoxyacetophenone as a pale yellow solid; m.p. 64--660C.
Example 26 4(2,6,-Dichlornbenzyloxy)5methoxy2nitrnacetophenone To HNO3 (specific gravity 1.42, 285 ml) cooled in ice water is added portion wise 4-(2',6' dichlorobenzyloxy)-5-methoxyacetophenone (56.27 9, 0.173 m). A red solid forms. The reaction mixture is removed from the ice bath and heated to 300C in an oil bath. The temperature is maintained at 300C 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 27 2-Amino-4-(2',6'-dichlorobenzyloxy)-5-methoxyacetophenone A mixture of 4-(2',6'-dichlorobenzyloxy)-5-methoxy-2-nitroacetophenone (60.98 9, 0.165 m) in glacial acetic acid (428.5 ml) and water (428.5 ml at 9095 C OC is treated with iron powder (134.4 g) added in 1012 portions over 0.5 hours with vigorous stirring. When the addition is complete, the suspension is heated at 90--950C for two hours. The reaction mixture is then heated at 90--950C 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.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--880C.
Example 28 2-( N-Carbethoxyamino)-4(2',6'-dichlorobenzyloxy)-5-methoxyacetophenone Ethyl chloroformate (16.28 9, 0.150 m) is added cautiously with stirring to 2-amino-4-(2',6'dichlorobenzyloxy)-5-methoxyacetophenone (20.41 9, 0.058 m) dissolved in tetrahydrofuran (500 ml).
A solution of sodium hydroxide (4.849,0.121 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 (3x 1 50 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 9.
Example 29 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 00--200C. 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 recrystallizatons from methanol give 4-benzyloxy-3-methoxy-6-nitroacetophenone as a pale yellow solid (40.0 57.3%); m.p. 141--143 C.
Example 30 6,7-Dihydroxy-4-methyl-2-( 1 H )quinazolinone Hydrate A solution of 6,7-dimethoxy-4-methyl-2(1 H)quinazolinone (12.49, 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 hydrobromide salt (8.0 9) 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 collected by filtration and washed with acetone to yield 6,7-dihydroxy-4-methyl-2(1 H)quinazolinone hydrate (4.5 9,41.0%) as a pale yellow solid; m.p. 3200C dec.
Example 31 7-Hydroxy-6-methoxy-4-methyl-2(1 H)quinazoline Hydrobromide A solution of 7-benzyloxy-6-methoxy-4-methyl-2( 1 H)quinazolinone (20.0 9, 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 9) which precipitates is collected by filtration, washed with hot methanol and then recrystallized from water (150 ml) to afford pure 7-hydroxy-6-methoxy-4methyl-2(1 H)quinazolinone hydrobromide as a yellowish-green solid (9.0 9,46.4%); m.p. 303- 305CC.
Example 32 6-Hydroxy-7-methoxy-4-methyl-2(1 H)quinazolinone Hydrobromide Hemihydrate 6,7-Dimethoxy-4-methyl-2(1 H)quinazolinone (6.2 9,0.0285 m) in acetic acid (150 ml) and hydrobromic acid (120 ml, 48% aqueous) is refluxed for 1 9 hours. The solution is cooled in an icewater bath and the solid (5.1 9) which precipitates is collected by filtration. Removal of the solvent from the filtrate gives an oily residue (1.95 9) which is crystallized from water and then twice from methanol to afford pure 6-hydroxy-7-methoxy-4-3(1 H) quinazolinone hydrobromide hemihydrate as a yellowish-green solid (0.6 9,7.1%); m.p. 230--2320C.
Example 33 Certain of the compounds of the invention 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 SH rats with systolic pressures greater than 1 70 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 procedures 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 in renal blood flow was measured in dogs by the following method. Adult mongrel dogs were anaesthetized 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 predrug control in renal artery blood flow (or decrease in renal vacular resistance) was quantified for each infusion dose. Reference Goldbert and coworkers, Journal of Pharmacology and Experimental Terapeutics, 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:
Table I BP (SHR) R R' R" lowering (mum) Dose {mg/Kg) n-C10H21 CH3 CH3 12 100 n-C6Ha3 CH3 CH3 18 100 CH3 02H5 CH3 27.5 40 CH3 n-C4Hg CH3 17 10 CH3 H CH3 6 100 CH3 H H 12 100 CH3 CH3 H 12 100 Table II R R' R" Increase Dose mg/Kg n-C,OH2, CH3 CH3 NA 13.9 n-C6H,3 CH3 CH3 +44 13.9 CH3 02H5 CH3 NA 13.9 CH3 n-C4H9 CH3 +26 13.9 CH3 H CH3 +16 13.9 CH3 H H +49 13.9 CH3 CH3 H +29 13.9 *NA means not active in test.

Claims (8)

Claims
1. For the treatment of hypertension and bradycardia and as a cardiotonic agent a compound of the formula:
wherein R, is a hydrogen or halogen atom, and alkyl group containing from 4 to 20 carbon atoms, a cycloalkyl heterocycloalkyl, COO loweralkyl, CN, COOH OH20H CH (O-loweralkyl)2 or nitro group; and X and Y are each independently a hydrogen or halogen atom, a nitro, loweralkyl, loweralkyl, loweralkoxy, aryl, arylalkyloxy, hydroxy, acyloxy, aryloxy, amino, loweralkylamino, diloweralkylamino, amido, loweralkylamido, diloweralkylamido, cyano, COOH, COO loweralkyl, CHO, CH20H, CH2O acyl or CH20 aryl group, or a pharmaceutically acceptable acid addition salt thereof, provided that when X and Y are each loweralkoxy R, is not a hydrogen atom.
2. 4-n-Decyl-6,7-dimethoxy-2(1 H)quinazolinone for the treatment of hypertension and bradycardia and as a cardiotonic agent.
3. 4-Cyclopentylmethyl-6,7-dimethoxy-2( 1 H)quinazolinone for the treatment of hypertension and bradycardia and as a cardiotonic agent.
4. 6,7-Dimethoxy-4-n-hexyl-2(1 H)quinazolinone for the treatment of hypertension and bradycardia and as a cardiotonic agent.
5. 7-n-Butyoxy-6-methoxy-4-methyl-2(1 H)quinazolinone for the treatment of hypertension and bradycardia and as a cardiotonic agent.
6. 6,7-Dimethoxy-4-n-hexadecyl-2(1 H)quinazolinone for the treatment of hypertension and bradycardia and as a cardiotonic agent.
7. 6,7-Dihydroxy-4-methyl-2(1 H)quinazolinone hydrate for the treatment of hypertension and bradycardia and as a cardiotonic agent.
8. 6-Hyd roxy-7-m ethoxy-4-methyl-2( 1 H)quinazolinone hydrobromide hemihydrate for the treatment of hypertension and bradycardia and as a cardiontonic agent.
GB8138698A 1978-12-07 1979-12-07 Substituted quinazolones for the treatment of hypertension and bradycardia and as cardiotonic agents Expired GB2088874B (en)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
GB2127823A (en) * 1982-09-30 1984-04-18 Ortho Pharma Corp Quinazolines
US4631283A (en) * 1982-09-30 1986-12-23 Ortho Pharmaceutical Corporation Ortho substituted dihydroxy-2(1H)quinazolinone-1-alkanoic acids
WO2001098250A1 (en) * 2000-06-21 2001-12-27 Portela & Ca Sa Substituted nitrated catechols, their use in the treatment of some central and peripheral nervous system disorders and pharmaceutical compositions containing them

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US4751304A (en) * 1984-09-26 1988-06-14 Ortho Pharmaceutical Corporation Process for preparing 5,6-dialkoxy-4-alkyl-2(1H)-quinazolinones
USD966133S1 (en) * 2020-09-21 2022-10-11 Aileen Martin Sanitizer dispenser

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DE2118315C3 (en) * 1970-04-20 1975-04-03 Sumitomo Chemical Co., Ltd., Osaka (Japan) 2- (1H) -quinazolinone derivatives, processes for their preparation and pharmaceuticals containing these compounds
US4129653A (en) * 1977-01-05 1978-12-12 Ortho Pharmaceutical Corporation Substituted pyrrolo [1,2-c] quinazolines and pharmaceutical compositions and methods employing them

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2127823A (en) * 1982-09-30 1984-04-18 Ortho Pharma Corp Quinazolines
EP0107398A1 (en) * 1982-09-30 1984-05-02 Ortho Pharmaceutical Corporation Ortho substituted dihydroxy-2(1H)quinazolinone-1-alkanoic acids
US4490374A (en) * 1982-09-30 1984-12-25 Ortho Pharmaceutical Corporation 5,6-Dialkoxy-3,4-optionally substituted-2(1H)quinazolinones, composition and method of use
US4631283A (en) * 1982-09-30 1986-12-23 Ortho Pharmaceutical Corporation Ortho substituted dihydroxy-2(1H)quinazolinone-1-alkanoic acids
EP0220786A2 (en) * 1982-09-30 1987-05-06 Ortho Pharmaceutical Corporation Substituted quinazolinones
EP0220786A3 (en) * 1982-09-30 1988-02-24 Ortho Pharma Corp Substituted quinazolinones
WO2001098250A1 (en) * 2000-06-21 2001-12-27 Portela & Ca Sa Substituted nitrated catechols, their use in the treatment of some central and peripheral nervous system disorders and pharmaceutical compositions containing them
EP1167341A1 (en) * 2000-06-21 2002-01-02 Portela &amp; Ca., S.A. Substituted nitrated catechols, their use in the treatment of some central and peripheral nervous system disorders and pharmaceutical compositions containing them

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