NO833541L - ORTHOS-SUBSTITUTED DIHYDROXY-2 (1H) CHINAZOLINON-1-ALKANIC ACIDS AND PROCEDURES FOR THEIR PREPARATION - Google Patents

Abstract

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

Description

The present invention relates to substituted quinazolinones with functionality at the N atom. The substituted quinazolinones according to the present invention have the following formula

where R 1 is hydrogen, amino or nitro; R? is hydrogen, an alkyl group with from 1-20 carbon atoms, cycloalkyl with from 4 to 8 carbon atoms, cycloalkylalkyl where the cycloalkyl group

has from 4 to 8 carbon atoms and the alkyl group has from 1 to

3 carbon atoms, haloalkyl with from 1 to 3 halogen atoms

and 1 to 4 carbon atoms, and wherein said halogen is chlorine, bromine or fluorine, and bicycloalkyl, such as norbornyl and norbornylmethyl; R, and R^ can be the same or different, and are hydrogen, lower alkyl having from 1 to 6 carbon atoms, aryl and substituted aryl, such as phenyl, 2-, 3- and 4-pyridyl, o-, m- or p-hydroxyphenyl, halogenyl such as p-chlorophenyl, p-fluorophenyl, o-chlorophenyl, 2,4-difluorophenyl, lower alkoxyphenyl such as methoxy, ethoxy and butoxyphenyl, alkyl-phenyl where the alkyl group has from 1 to 6 carbon atoms; X

is benzyl, carboxy, carboalkoxy where the alkoxy group has from 1 to 3 carbon atoms, cyano, carboxamido, methanesulfonyl, formyl, aroyl, such as benzoyl, substituted benzoyl where the substituent is an alkyl group with from 1 to 4 carbon atoms, heteroaryl such as 2-, 3 -, and 4-pyridyl, and 2-thienyl; heteroaroyl, such as 2-, 3-, and 4-pyridoyl, 2-thienoyl, 2-furoyl, and 3-(1,2,5)-thiadiazolyl; R 1 - is hydrogen, lower alkyl having from 1 to 6 carbon atoms; benzyl or substituted benzyl where the substituent is fluorine, chlorine, bromine, alkyl or alkoxy, where the alkyl group has from 1 to 6 carbon atoms;

provided that when R 1 is different from hydrogen, then the compound is a quaternary salt when the 3,4-imine bond is unsaturated; (the presence of an unsaturated imine bond mellon and may be present or absent, and may be substituted or unsubstituted); Y and Z are hydrogen or hydroxy, provided that at least one of Y and Z is hydroxy (when Y and Z are both hydroxy, then the hydroxyl groups will be placed next to each other and either be in the 5,6- or 6,7-position); and includes alkali metal and alkaline earth metal salts of the phenolic hydroxyl groups and the carboxy group at N-1, and selected amine salts such as salts of meglumine, piperazine, N-methylpiperazine, morpholine and aliphatic amines having from 1 to 5 carbon atoms; amino alcohols, such as ethanolamine, 2-amino-1,3-propanediol and bis(hydroxymethyl)methylamine; and amino acids such as arginine, lysine and ornithine.

The preferred compounds according to the present invention are those where R 1 is hydrogen, R 2 is hydrogen, alkyl, cycloalkyl, bicycloalkyl and haloalkyl; R 1 and R 2 are hydrogen, lower alkyl, aryl or substituted aryl; X is carboxy, carboalkoxy, cyano, carboxamido and formyl; R^ is hydrogen, lower alkyl, benzyl, substituted benzyl, provided that when R^- is other than hydrogen, then the compound is a

quaternary salt when the 3,4-imine bond is unsaturated (the unsaturated imine bond between N-, and C. may be<*>present or absent, and N, may be substituted or unsubstituted); Y and Z are hydrogen or hydroxy, provided that at least one of the groups Y and Z is hydroxy; and includes alkali metal and alkaline earth metal salts of the phenolic hydroxyl groups and of the carboxyl group on N^, besides selected amine salts, such as salts of meglumine, piperazine, N-methylpiperazine, morpholine and aliphatic amines with from 1 to 5 carbon atoms; amino alcohols, such as ethanolamine, 2-amino-1,3-propanediol and bis(hydroxymethyl)methylamine, and amino acids, such as arginine, lysine and ornithine. When Y and Z are both hydroxy, the hydroxy groups are placed next to each other and placed either in the 5,6 or 6,7 position. ;Several 6,7-dialkoxy-4-alkyl 2(1H)quinazolinones are reported in the literature (Budesinsky et al., Coll. Czech. Chem. Commun., 37, 2779 (1972); Belgian Patent No. 765947 (1971 )). None of the indicated substituted quinazolinones have hydroxy groups substituted on the benzene ring. Moreover, none of the known quinazolinones are correspondingly substituted at N 2 . The new quinazolinones according to the present invention are newer vasodilators. As such, they increase the flow of blood in the kidneys and can therefore be used as cardiovascular agents. In addition to this, some of the compounds and some of the intermediates used to prepare the new quinazolinones will have cardiotonic activity. The substituted quinazolinones can be synthesized using the following schematic diagram. ; ; where R 1 , R 2 /R 2 , R 4 1 R- and X are as defined above, and R is a lower alkyl group with from 1 to 5 carbon atoms. It appears from the diagram that the N, substituted quinazolinone (2) can be prepared by reacting a substituted quinazolinone with a suitable substituted olefin, such as methyl cinnamate, methyl acrylate, methyl crotonate, acrylonitrile, and methyl acrylate e.g. The particular olefin that will be used will depend on the type of substitution that is desired in the final product. The reaction is carried out in the presence of a basic catalyst such as sodium carbonate, potassium carbonate, potassium fluoride, sodium fluoride, potassium hydroxide, sodium hydroxide, alkali metal alkoxides such as potassium ethoxide, and sodium methoxide, quaternary ammonium hydroxides, such as benzyltrimethylammonium hydroxide, quaternary. ammonium fluorides such as tetraethylammonium fluoride and tertiary amines such as triethylamine. The reaction temperature will be between -10 and 100°C, preferably around approx. 65°C. The substituted quinazolinones (2) can be used to prepare other N-substituted quinazolinones by means of the pathways shown in the diagram. E.g. the N, substituted quinazolinone (2) can be conveniently alkylated with an alkyl iodide, such as methyl or ethyl iodide, or a benzyl iodide such as o-, m- or p-fluorobenzyl, o-, m-; or p-methylbenzyl and o-, m- or p-methoxybenzyl iodide, whereby the corresponding quaternary salt is produced. This salt can then be hydrolysed again with an acid such as hydrobromic acid or hydroiodic acid, whereby the corresponding dihydroxy compound (3) is obtained. The N, substituted quinazolinone (2) can be converted directly to the corresponding dihydroxy compound (5) by reaction with an acid, such as hydrobromic acid or hydroiodic acid. The dihydroxy compounds (3 and 5) can then be partially saturated (4 and 6) by a reaction with hydrogen in the presence of a catalyst such as platinum, palladium, rhodium or nickel. Ammonium formate, boranes and metal hydrides, such as sodium borohydride, can also be used as reagents during the reduction step. The starting compound (1) used for the preparation of the substituted hydroxyquinazolinones where the substituents on the benzene ring are in the 6,7-position can be prepared using two different synthesis routes. In the first, an appropriately substituted alkoxyaniline is converted to the corresponding isocyanate. The conversion is carried out with phosgene in a suitable solvent, such as benzene, toluene or xylene. The isocyanate can then be condensed with a suitable carboxamide to produce the corresponding adduct. The condensation can be carried out as such without solvent or in an inert solvent such as xylene or toluene. It is preferred to carry out the reaction at temperatures between 100 and 150°C. The adduct can then be cyclized to produce a quinazolinone. Suitable cyclizing agents which can be used include polyphosphoric acid, polyphosphoric acid esters or a mixture of phosphorus pentaoxide and methanesulfonic acid. The ratio of cyclizing agent to adduct can vary between 1.1 and 25:1, but the preferred ratio is 5:1. The reaction is preferably carried out at temperatures between ;100 and 130°C in an inert atmosphere, such as nitrogen. In the second synthetic route, a suitably substituted acetophenone is nitrated. After separation of the isomers, the substituted o-nitroacetophenone can be reduced to the corresponding -amine. This can then be alkylated with an alkyl halogen formate to the corresponding urethane. Cyclization of the urethane using ammonia gives the corresponding quinazolinone. Examples of these transformations are illustrated in what follows. Pharmaceutical preparations containing a compound according to the present invention as active ingredient in intimate mixture with a pharmaceutical diluent or carrier can be prepared using commonly known pharmaceutical techniques. The carrier or diluent can have a number of different forms, all depending on the preparation you want to add, e.g. an intravenous preparation, an oral or parenteral preparation. When preparing preparations in oral dosage form, different pharmaceutical media can be used, e.g. water, glycols, oils, alcohols, flavourings, conferring agents, dyes etc., in connection with oral liquid preparations, such as e.g. suspensions, elixirs and solutions. You can also use diluents, such as starch, sugar, granulating agents, lubricants, binding agents, disintegrants etc. when you want to make solid preparations such as e.g. powders, capsules and tablets. Due to their ease of administration, tablets and capsules will usually represent the most convenient dosage form, and in such cases solid pharmaceutical diluents are used. If desired, the tablets can be coated with sugar in a commonly known manner. For parenteral administration, the diluent will usually include sterile water, but may also include other ingredients to facilitate solubility or to protect the active ingredients. Injectable suspensions can also be prepared and in this case suitable liquid diluents, suspending agents etc. will be used. The pharmaceutical preparations will usually per dosage unit such as in a tablet, a capsule, a powder, or for injection etc., contain from 15 to 300 mg/kg body weight, preferably from approx. 30 to 200 mg/kg body weight of the active ingredient. The following examples illustrate the invention without it being limited to these examples. Example 1: 6, 7-dihydroxy-4-methyl-2(1H)quinazolinone-1-(3'-methyl)propionic acid monohydrobromide monohydrate. A solution of 1.0 g (3.2 mM) 6,7-dimethoxy-4-methyl-2(1H)-quinazolinone-1-(3'-methyl)propionate in 10 ml acetic acid and 10 ml 48% aqueous hydrogen bromide was refluxed for 66 hours. The reaction mixture was then cooled. A green precipitate was obtained which was filtered off, washed with 20 ml of cold ether and dried under vacuum, whereby 300 mg of product was obtained (25% yield). ;TFA ;Smp. 220-222°C; &^£t1.71-1.95 (d, 3H, 3 '-CH3) , 3.04 (s, 3H, 4-CH3) 3.18-3.53 (m. 1H, -C-CH- j), 5.21-5.82 (m, 2H, ;H ;-CH2-), 7.62 (s, 1H, C5-H), 7.79 (s. 1H, CglH); M<+>278. ;Example 2. ;6,7-dihydroxy-3,4-dimethyl-2(1H)k inazolinonium-1-propionic acid bromide. A solution of 1.5 g (33 mM) 6,7-dimethoxy-3,4-dimethyl-2(1H)-quinazolinonium-1-propionate iodide in 10.5 ml acetic acid and 10.5 ml 48% aqueous hydrobromic acid was boiled under reflux and stirring for 48 hours. The brown reaction mixture was cooled to room temperature and the yellow precipitate was isolated by filtration. After washing with 25 ml of cold ether and drying under vacuum, 650 mg of product was obtained (300 mg, 25% yield. ;Mp. 270-272°C; 3.22 (s, 3H, 4-CH3), 3 .01-3.42 ;(m, 2H, 2'-CH2), 4.12 (s, 3H, =NCH3), 4.67-5.11 (t, 2H, ;2'=CH2), 7 .47 (s, 1H, C5"H), 7.93 (s. 1H, Cg-H); M<+>278 (M-80). ;Example 3.;6, 7-dihydroxy-4-methyl - 2(1H)quinazolinone-1-(2'-methyl)propionic acid. ;A solution of 2.4 g (7.5 mM) methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1- (2<1->methyl)propionate, 25 ml of acetic acid and 25 ml of 48% aqueous hydrogen bromide were refluxed for 48 hours under nitrogen. The reaction mixture was cooled in an ice bath, concentrated in vacuo to half its original volume and then basified to pH 12 with 25 mL of 1N sodium hydroxide solution. The mixture was again cooled and acidified with glacial acetic acid to pH 5. A yellow precipitate was obtained which was filtered off, washed with cold ether and dried under vacuum to give the desired product in a amount of 1.6 g (76.9% yield);

TFA

Temp. 266-268°C; 6^ 1.38-1.65 (d, 3H, 2 1-CH3) , 2.99 (s,

H

3H-4-CH3), 3.10-3.49 (m, 1H, -C-), 3.91-5.09 (m, 2H,

-N-

CH2-C), 7.37 (s, 1H, C5-H), 7.72 (s, 1H, C8-H); M<+>278.

When using methyl 6-methoxy-4-methyl-2(1H)quinazolinone-1-propionate, methyl 7-methoxy-4-methyl-2(1H)quinazolinone-1-propionate, methyl 6-methoxy- 2(1H)quinazolinone-1-propionate, methyl 7-methoxy-2(1H)-quinazolinone-1-propionate, methyl 6-methoxy-4-trifluoromethyl-2(1H)quinazolinone-1-propionate and methyl 7-methoxy- 4-trifluoro-methyl-2(1H)quinazolinone-1-propionate instead of methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(2<1->methyl)propionate is obtained corresponding to 6-hydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid, 7-hydroxy-4-methyl-2(1H)-quinazolinone-1-propionic acid, 6-hydroxy-2(1H)quinazolinone-1- propionic acid, 7-hydroxy-2(1H)quinazolinone-l-propionate, 6-hydroxy-4-trifluoromethyl-2(1H)quinazolinone-l-propionic acid and 7-hydroxy-4-trifluoromethyl-2(1H)quinazolinone-l- propionic acid.

Example 4.

6, 7-dihydroxy-4-methyl-2(1H)quinazolinone-1-(2'-methyl)propionic acid tripotassium salt monohydrate.

A suspension of 1.5 g (5.39 mM) 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-(2<1->methyl)propionic acid in 100 ml methanol b '.€■ treated with 16.17 mL (16.1 mM) of a 1.ON methanolic KOH solution with good stirring and under nitrogen. The resulting dark solution was filtered under nitrogen and concentrated in vacuo to a yellow solid. This was treated with 40 ml of acetone and filtered off. After washing with 20 ml of ether, the product was dried in a drying chamber under vacuum for 16 hours at room temperature, whereby 2.2

g (100% yield) of 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-(2'-methyl)propionic acid tripotassium salt monohydrate (2.2 g, 100%). Temp. above 300°C.

Example 5.

6, 7-dihydroxy-4-methyl-1-(3'-phenylpropyl)-2(1H)-quinazolinone monohydrate.

A mixture of 1.25 g (3.6 mM) 6,7-dimethoxy-4-methyl-1-(3'-phenylpropyl)-2(1H)quinazolinone and 10 ml of 48% aqueous hydrogen bromide in 10 ml of glacial acetic acid was boiled under reflux and under stirring for 24 hours. After cooling to room temperature, 100 g of ice was added to the reaction mixture. A yellowish-brown precipitate was obtained which was filtered off, washed with 2 x 20 ml of water and then with 3 x 40 ml of ether. After drying in air, 1.21 g of product was obtained (100% yield).

TF A

Temp. above 275°C dek • <" 2.00-2.70 (m, 2H, -CH2~), 2.75-3.30 (m, 2H, -CH2~0), 3.00 (s. 3H , CH3), 4.30-5.00 (t, 2H, -CH2N), 7.07 and 7.65 (2s, 2H, C5H, CgH), 7.25 (s, 5H,0-); M <+>310.

When using 6,7-dimethoxy-4-methyl-2(1H)-quinazolinone-1-(2-methanesulfonyl)ethane in the above method, 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1 - (2-benzoyl)ethane, and 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-2-(2'-pyridy1)-ethane instead of 6,7-dimethoxy-4-methyl-1 -(3-phenylpropyl)-2(1H)-quinazolinone then the corresponding 6,7-dihydroxy-4-methyl-1-(2-methanesulfonyl)ethane-2(1H)-quinazolinone monohydrate is produced, 6,7- dihydroxy-4-methyl-1-2(benzoyl)ethane-2(1H)-quinazolinone monohydrate and 6,7-dihydroxy-4-methyl-1-2(21-pyridy1)ethane-2(1H)quinazolinone monohydrate.

When using 6,7-dimethoxy-4-methyl-2(1H)-quinazolinone-l-propionaldehyde, 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-l-propionitrile and methyl 6 in the above method, 7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(1-phenyl)propionate instead of 6,7-dimethoxy-4-methyl-1-(3-phenylpropyl)-2(1H)quinazolinone, then get the corresponding 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionaldehyde, 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid and 6,7-dihydroxy- 4-Methyl-2(1H)quinazolinone-1-(1-phenyl)propionic acid.

The following compounds were prepared by the procedure of Examples 3, 4 or 5, using an appropriately substituted quinazolinone as starting material: where R 8 is potassium or hydrogen and R 2 is as defined above.

Example 6.

Ethyl 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionate.

A suspension of 2.0 g (6.5 mM) 6,7-dihydroxy-4-methyl-2(1H)-quinazolinone-1-propionic acid in 35 ml of absolute ethanol containing 1.0 ml of ethanesulfonic acid was refluxed for 3 day and night. The reaction mixture was cooled to room temperature and 200 ml of ice was added. A yellow-green precipitate was obtained which was filtered off, washed with water, acetone and with ether and then dried in vacuum, whereby 1.75 g of product was obtained (92.2% yield); m.p. above 3 08°C (dec.);

6^g 1.35-1.60 (t, 3H, CH2CH3), 2.95-3.30 (m. 2H,

31.0 (s, 3H, CH3), 4.20-4.60 (q, 2H, CH2-0), 4.65-5.00 (t,

2H, CH2-N), 7.35 (s, 1H, Cg-H), 7.75 (s, 1H, Cg-H); M<+>292.

Example 7.

6,7-dihydroxy-3,4-dimethyl-3,4-dihydro-2(1H)-inazolinone-1-propionic acid.

A solution of the quaternary salt 6,7-dihydroxy-3,4-dimethyl-2(1H)quinazolinonium-1-propionic acid bromide (1 meq.)

in 15 ml of glacial acetic acid was treated with 0.1 g of 5% Pd/C, and the reaction mixture was hydrogenated at approx. 3 kg/cm 2 for 12 hours. The catalyst was filtered off, and the mother liquor poured in

100 ml of water. The precipitate of 6,7-dihydroxy-3,4-dimethyl-3,4-dihydro-2(1H)quinazolinone-1-propionic acid was filtered off, washed with water and dried in vacuo.

Example 8.

6, 7- dihydroxy- 3, 4- dihydro- 4- methyl- 2( 1H) quinazolinone- l- propionic acid monohydrate.

A suspension of 5.0 g (17.7 mM) 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid monohydrate in 270 ml methanol was treated with 2.5 g (10%) Pd/ C, and the mixture was hydrogenated at approx. 3 kg/cm 2 for 16 hours. Filtration, removal of the solvent in vacuo and titration of the residue with acetone gave the product as a pale brown solid (4.3 g, 91.4%);

Temp. 202-204°C; 6.86 (s, 1H, 5-H), 6.83 (s, 1H, 8-H), 4.78 (d, 1H, J=7.0 Hs, 4-H ), 4.36 (t, 2H, J=10 Hz, 2'-H),

3.03 (t, 2H, J=10 Hz, 1'-H), 1.55 (d, 3H, J=1 Hz, 4-CH 3 );

M<+>2 66.

Example 9.

6, 7- dihydroxy- 3- benzyl- 4- methyl- 2( 1H) quinazolinone-1- propionic acid bromide.

A solution of 10 g of methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-propionate in 100 ml of acetone was treated with 10 equivalents of benzyl bromide, and the solution aged overnight at room temperature. The crystalline precipitates were isolated and dried in vacuo. The impure quaternary salt was then dissolved in a mixture of 70 ml of glacial acetic acid and 70 ml of 48% aqueous HBr, after which the mixture was boiled under reflux for 3 days. On cooling to room temperature, 6,7-dihydroxy-3-benzyl-4-methyl-2(1H)quinazolinone-1-propionic acid bromide was precipitated as a crystalline product.

If identical conditions are used and p-fluorobenzyl bromide and p-chlorobenzyl bromide are used, the corresponding substituted benzyl quaternary salts are produced.

Example 10.

6, 7-dihydroxy-4-norbornylmethyl-2(1H)quinazolinone-1-propionic acid hydrobromide.

A mixture of 5 g of methyl 6,7-dimethoxy-4-norbornylmethyl-2(1H)quinazolinone-1-propionate, 40 ml of 48% aqueous HBr and 40 ml of glacial acetic acid was boiled under reflux and stirring for 3 days. The solution was then cooled and the resulting golden precipitate was filtered off, washed with 25 ml of acetone and dried in vacuo to give the title compound.

When using methyl 6,7-dimethoxy-5-amino-4-methyl-2(1H)quinazolinone-1-propionate and methyl 6,7-dimethoxy-5-nitro-4-methyl-2(1H) in the above method quinazolinone-l-propionate instead of methyl 6,7-dimethoxy-4-norbornylmethyl-2(1H)quinazolinone-l-propionate, the corresponding hydrobromides 6,7-dihydroxy-5-amino-4-methyl-2 (1H)quinazolinone-1-propionic acid dihydrobromide and 6,7-dimethoxy-5-nitro-4-methyl-2(1H)quinazolinone-1-propionic acid hydrobromide. The starting propionate compounds were prepared using the procedure set forth in Example G.

Example 11.

6, 7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid monopotassium salt.

A suspension of 9.97 g (37.10 mM), 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid in 30 ml of methanol under nitrogen was treated with 37.10 ml (37.10 mM) IN KOH in methanol. The resulting yellow suspension was stirred at room temperature under nitrogen for 22 hours. It was then cooled in an ice water bath and filtered. The resulting yellow product was washed with 3 x 17 ml of cold methanol and then dried in vacuo at 120°C

for 336 hours (14 days). 10.41 g of product was obtained as a yellow solid with m.p. at 303-305°C.

Example 12.

6, 7- dihydroxy- 4- methyl- 2( 1H) quinazolinone- 1- propionic acid dipotassium salt.

A suspension of 45.0 g (167.47 mM) 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid in 600 mL methanol was treated with 334.94 mL (334.94 mM) IN KOH in methanol at room temperature under nitrogen. A larger amount of a yellow solid was precipitated after the addition of KOH. A further 200 ml of methanol was then added. Water was added until the product dissolved. The total amount of water was 300 ml. The reaction mixture was then stirred at room temperature under nitrogen for h hour. The slightly cloudy solution was then filtered and concentrated to dryness in vacuo to give a tan, semi-solid product. This was treated with 300 ml of acetone, and the resulting yellow solid was filtered off and dried to give the dipotassium salt: 54.26 g, m.p. above 325°C.

Example 13.

6, 7-dihydroxy-4-methyl-2(1H)quinazolinone-l-propionic acid monoarginine salt monohydrate.

A mixture of 4.0 g (14.6 mM) 6,7-dihydroxy-4-methyl-2(1H)-quinazolinone-l-propionic acid and 2.34 g (13.6 mM) L-arginine in 150 ml water was aged at room temperature for 3 hours. After 15 minutes, the original solution became clear and a yellow precipitate began to form. After 3 hours, the precipitate was filtered off, washed with 15 ml of water, 20 ml of acetone and then with 2 x 20 ml of ether. The precipitate was dried in vacuum at 60° for 3 hours, whereby the amino acid salt was obtained in an amount of 5.81 g (93.8% yield).

Example 14.

6, 7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid N-methylglucamine salt.

A mixture of 0.79 g (3 mM) 6,7-dihydroxy-4-methyl-2(1H)-quinazolinone-1-propionic acid, 0.59 g (3 mM) meglumine and 40

ml of methanol and 4 ml of water were mixed and left at room temperature overnight. The resulting suspension was filtered and the precipitate washed with 2 x 20 ml of ether. After drying in air for 3 hours, the amine salt was isolated as a yellow solid (0.88 g, 62.51%, mp = decomp. 197-198°C).

The salts of monoethanolamine, piperazine, N-methylpiperazine and morpholine were prepared in a similar manner.

Example 15.

6, 7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid mono(2-methyl-2-amino-1,3-propanediol) salt monohydrate.

A suspension of 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid (1.0 g, 3.6 mM) in 40 mL methanol and 10 mL water was treated with 0.38 g ( 3.6 mM) mono(2-methyl-2-amino-1,3-propanediol) and the mixture left at room temperature for 16 hours. The resulting pale yellow precipitate was filtered off, washed with 10 ml of methanol and then with 2 x 10 ml of ether. After drying in vacuum for 6 hours at 60°, 1.18 was isolated

g of the amine salt (85.5%), m.p. 212-213°C.

Example 16.

6, 7- 4- methyl1- 2( 1H) quinazolinone- l- propionic acid mono( l- amino- 2, 3- propanediol) salt hemihydrate.

A mixture of 0.84 g (3 mM) 6,7-dihydroxy-4-methyl-2(1H)-quinazolinone-1-propionic acid, 0.27 g (3 mM) mono (1-amino-2,3-propane -diol), 40 ml of methanol and 10 ml of water were left overnight at room temperature. The precipitate was isolated and washed with 10 ml of methanol and 1 x 20 ml of ether. After drying under a stream of nitrogen for 3 hours, the amine salt was prepared in an amount of 0.94 g (84.7% yield).

Example 17.

5, 6-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid monohydroiodide.

1.173 g (3.83 mM) methyl 5,6-dimethoxy-4-methyl-2(1H)quinazolinone-1-propionate was treated with 13 ml of 50% aqueous HI at room temperature, whereby a clear orange solution was obtained which was boiled under reflux and under nitrogen for 11 hours

and then stirred at room temperature overnight. The orange crystalline precipitate was filtered off, washed with acetone and dried to a product of 0.972 g (65%), mp 240-241°C(d) IR (KBr)u, 3.23 (broad, OH), 5, 78 (C=0).

When using methyl 5,6-dimethoxy-4-trifluoromethyl-2(1H)quinazolinone-1-propionate in the above-mentioned method, methyl 5,6-dimethoxy-4-isopropyl-2(1H)quinazolinone-1-propionate methyl 4-cyclopentyl- 5,6-dimethoxy-2(1H)quinazolinone 1-propionate,

and methyl 4-cyclohexylmethyl-5,6-dimethoxy-2(1H)quinazolinone-1-propionate instead of methyl 5,6-dimethoxy-4-methyl-2(1H)-quinazolinone-1-propionate, the corresponding 5,6-dihydroxy-4-trifluoromethyl-2(1H)quinazolinone-l-propionic acid monohydroiodide, 5,6-dihydroxy-4-isopropyl-2(1H)quinazolinone-l-propionic acid monohydroiodide, 4-cyclopentyl-5,6- dihydroxy-2(1H)quinazolinone-1-propionic acid monohydroiodide and 4-cyclohexylmethyl-5,6-dihydroxy-2(1H)quinazolinone-1-propionic acid monohydroiodide. The starting ester compounds were prepared using the method described in Example G.

Example 18.

6, 7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid monohydrate.

A suspension of 1.53 g (5 mM) 6,7-dimethoxy-4-methyl-2(1H)-quinazolinone-1-propionate, 20 ml acetic acid and 15 ml 48% aqueous HBr was refluxed for 120 h under nitrogen. The solvent was removed in vacuo to give

a greenish hydrobromide salt (yield 1.5 g, 88.2%), m.p. 292-295°C. A solution of the salt in 5 ml of methanol was treated with a saturated aqueous NaHCO 3 solution until pH

was neutral. The precipitated free base was filtered off and washed with acetone to give 1.0 g of product (76.9% yield) as a pale green solid, mp 308-310°C.

TFA

NMR 6TMS 7.80 (s, 1H, 5-H), 7.46 (s, 1H, 8-H), 4.66-5.08

(m, 2H, 2'H), 3.13 (m, 5H, 1'-H, 4-CH 3 ) M<+>264.

Various other substituted mono- and dihydroxy-2(1H)-quinazolinones which form part of the present invention can be prepared by any of the above-mentioned methods using the appropriate mono- or dihydroxy-2(1H)quinazolinones prepared by means of the following examples where different output connections have been used.

The biological activity of the new quinazolinones was determined using the method described by Goldberg, L.I., Sonneville, P.F. and McNay, J.L. (1968).

An investigation of the structural requirements for dopamine-like renal vasodilation; phenethylamines and apomorphine,

J. Pharmacol. Exp. Ther. 163.

Adult bastard dogs were anesthetized and surgically operated for electromagnetic measurement of renal artery blood flow. A carotid artery was punctured for the insertion of a cannula for measuring the arterial blood pressure, and the active ingredients were administered intravenously. Heart rate was measured using a cardiotachometer. Renal vascular resistance was calculated as the ratio between the mean arterial blood pressure/. arterial blood flow in the kidney. Dopamine was infused intravenously in an amount of 3 ug/kg body weight per min for 10 minutes (1 ml/min) to determine the response of each individual dog to a renal dopamine receptor stimulation. Cumulative dose-related data were obtained by infusing the active ingredient in progressively increasing amounts (usually 3 times) with each dose infused for 5 minutes. The maximum percentage increase from the control before administration of the active ingredient on renal blood flow (or decreased renal vascular resistance) was quantified for each infusion dose.

Production of output connections.

Example A.

3, 4- dimethoxyphenyl isocyanate.

4 equivalents of phosgene were bubbled at a moderate rate into a 3-neck flask containing a solution of 1 equivalent of 3,4-dimethoxyaniline in 2 liters of benzene. The flask was cooled in an ice bath for 15 minutes, after which the solution was refluxed for 1 hour and 35 minutes while additional phosgene was added. The mixture was then refluxed overnight, after which the solvent was removed under vacuum. Acetone was added and the solvent was again removed under vacuum to give a dark brown, oily residue which was distilled at 132-134°C/0.6 mm. Yield 22.5 g.

Example B.

N-(3,4-dimethoxyphenyl)-N'-propionylurea.

A mixture of 26.0 g (145 mM) 3,4-dimethoxyphenyl isocyanate and 10.61 g (145 mM) propionamide was held at 160-165°C for 1 hour. A homogeneous, pale yellow solution was obtained which solidified after 15 minutes. The heating was stopped and the flask cooled to room temperature. The mixture was treated with acetone, and a white solid was obtained which was filtered off and dried. Yield 32.45 g, m.p. 192-197°.

Example C.

6, 7-dimethoxy-4-ethyl-2(1H)quinazolinone.

A suspension of 32.45 g (128 mM) N-(3,4-dimethoxyphenyl)-N'-propionylurea in 375.12 g (1109 mM) polyphosphoric acid was kept at 130-135°C under nitrogen and vigorous stirring for 3 .5 hours. The mixture was then poured into 500 g of ice water and stirred. It was then adjusted to pH 5.5 using concentrated NH 2 OH and then left at room temperature overnight. The brown precipitate was filtered off and dried to give 7.40 g of a white solid. The filtrate was extracted with 5 x 250 mL chloroform, and the organic extract was dried over magnesium sulfate and the solvent removed in vacuo to give a pale brown solid. This was treated with acetone and filtered, whereby 4.98 g of product was obtained.

A sample was stirred in water and dried again for further purification, and then had a melting point of 263-265°C.

TF A

6TMS 7.50 (S' 1H' 5_H)' 7.23 (S' 1H' 8_H)' 4.30 {S' 3H' 6 or 7-OCH3) 4.17 (s, 3H, 6 or 7-OCH3 ), 3.50 (q, 2H, J=8.0 Hz, CH2CH3), 1.70 (t, 3H, J=8.0 Hz, CH2CH3).

Some examples of 2(1H) quinazolinones prepared in the manner described above are given below.

Example D.

3, 4- dimethoxy- 6- nitroacetophenone.

1.8 equivalents of 3,4-dimethoxyacetophenone were added to 18 equivalents of nitric acid at 0° over the course of h hour. After a further 1 hour at 20°C, the dark brown solution was poured into ice water. The crude product was filtered off. Recrystallization from ethyl alcohol gives the purified product,

CDC1 mp 124-126°C; STRS3 2.50 (s, 3H, CH3), 4.00 (s, 6H, OCH3's), 6.80, 7.59 (2s, 1H ea., C2H, CgH). ,

Example E.

6- amino- 3, 4- dimethoxyacetophenone.

A suspension of one equivalent of 3,4-dimethoxy-6-nitroacetophenone in methanol was treated with Pd/C 10%, and the mixture was hydrogenated at ca. 3 kg/cm 2 in 24 hours. After filtration and removal of the solvent, the residue was recrystallized from ethyl alcohol to give the purified product, CDCl m.p. 98-100°C; «^MS 2.50 (s' 3H' CH 3 )' 3'80-3'85 (2s' 3H ea-. OCH 3 ); 6.05, 7.05 (2s, 1H ea-. C2H, C5H).

Example F.

2-(N-carbethoxyamino)-4,5-dimethoxyacetophenone.

1 equivalent of ethyl chloroformate was carefully added with stirring to 0.3 equivalents of 6-amino-3,4-dimethoxyacetophenone at room temperature. A dark brown reaction mixture was obtained which was stirred at room temperature for h hour. Aqueous sodium hydroxide was added and the reaction mixture stirred at room temperature for an additional 1 hour. It was then extracted with chloroform, after which the chloroform was removed and an oily residue was obtained. Recrystallization from ether gives pro-rnr i

in the duct, m.p. 97-99°C; 6TMS i'10-1'50 (t'3H'€H3)'2'60

(s, 3H, CH3), 3.85 and 3.95 (2s, 3H ea., OCH3's), 4.0-4.4 (q, 2H, CH2), 7.15 and 8.20 (2s, 1H ea., C2H, C5H).

Example G.

)

General preparation of methyl 2(1H)quinazolinone-1-propionates.

An appropriately substituted 2(1H)quinazolinone (5g) was placed

in a mixture of 75 ml of methanol, 100 ml of chloroform, 125 ml of methyl acrylate and an excess of triton B (40% methanol),

and the mixture was refluxed with stirring for from 4 to 16 hours. The solution was then cooled, and after evaporation of the solvent, the ester was obtained by chromatography on silica gel.

The following compounds were prepared using the above general procedure:

i When using in the above procedure 6-methoxy-4-methyl-2(1H)quinazolinone, 4-methyl-7-methoxy-2(1H)quinazolinone, 6-methoxy-2(1H)quinazolinone, 7-methoxy-2 (1H)quinazolinone, 6-

methoxy-2(1H)quinazolinone, 7-methoxy-2(1H)quinazolinone, 6-methoxy-4-trifluoromethyl-2(1H)quinazolinone and 7-methoxy-4-trifluoromethyl-2(1H)quinazolinone as starting compounds,

then the corresponding 1-propionic acid esters are produced.

When using 3,4-dihydro-5,6-dimethoxy-4-methyl-2(1H)quinazolinone, 5,6-dimethoxy-4-methyl-2(1H)quinazolinone, 5,6-dimethoxy- 4-trifluoromethyl-2(1H)quinazolinone as the substituted quinazolinone, the corresponding 1-propionic acid esters are produced.

Example H.

6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(2-methanesulfonyl)ethane.

A solution of 10 g of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone

in 100 ml of chloroform, 100 ml of methanol and 40 equivalents of methyl vinyl sulfone, was treated with 1.1 equivalents of Triton B (benzyltrimethylammonium hydroxide, 40% in methanol), after which the solution was refluxed and stirred for 24 hours. The solution was then cooled to room temperature, and the solvent removed by concentration in vacuo. The residue was chromatographed on silica gel, whereby a purified 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-12-methanesulfonyl)ethane was obtained.

Example I.

6,7-Dimethoxy-4-methyl-2(1H)quinazolinone-1-(2-benzoyl)ethane.

A solution of 10 g of 6,7-dimethoxy-6-methyl-2(1H)quinazolinone in 100 ml of chloroform, 100 ml of methanol and 40 equivalents of phenyl vinyl ketone was treated with 1.1 equivalents of Triton B (40% in methanol), after which the solution was boiled under reflux and stirring for 24 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue chromatographed on silica gel. Purified 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(2-benzoyl)ethane was produced.

Example J.

6, 7-dimethoxy-4-methyl-2(1H)quinazolinone-1-[2-(2'-pyridyl)ethane].

A solution of 10 g of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone in 100 ml of chloroform, 100 ml of methanol and 25 equivalents of 2-vinylpyridine was treated with 1.1 equivalents of Triton B (40% in methanol), and the solution was then refluxed for 24 hours. The resulting solution was cooled to room temperature, after which the solvent was removed in vacuo. The residue was purified by chromatography on silica gel, whereby a purified 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-[2-(2'-pyridyl)ethane] was obtained.

When in the above-mentioned method 4-vinylpyridine is used instead of 2-vinylpyridine, the corresponding 4<1->pyridyl derivative is produced.

Example K.

6, 7-dimethoxy-4-methyl-2(1H)quinazolinone-1-propionaldehyde.

i A solution of 10 g of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone in 100 ml of methanol, 100 ml of chloroform and 40 equivalents of acrolein was treated with 1.1 equivalents of Triton B (40% in methanol). The resulting mixture was concentrated in

vacuum, and the residue chromatographed on silica gel to give purified 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-propionaldehyde.

Example L.

6, 7-dimethoxy-4-methyl-2(1H)quinazolinone-1-propionitrile.

A solution of 10 g of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone in 100 ml of chloroform, 100 ml of methanol and an excess of acrylonitrile was treated with Triton B (40% in methanol). The solution was boiled under reflux for 24 hours. The resulting solution was then cooled to room temperature and the solvent removed by evaporation in vacuo. The residue was chromatographed on silica gel to give a purified 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-propionitrile.

Example M.

Methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(1-phenyl)propionate.

A solution of 10 g of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone in 100 ml of chloroform, 100 ml of methanol and an excess of methyl α-phenyl acrylate was treated with 1.1 equivalents of Triton B (40% in methanol ), and the solution was then refluxed for 24 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue purified by chromatography on silica gel, which gave a purified methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(1-phenyl)-propionate.

When in the above-mentioned method methyl (2,4-difluorophenyl)acrylate, methyl (4-chlorophenyl)acrylate and methyl (4-methoxyphenyl)acrylate are used instead of methyl α-phenylacrylate, then

the corresponding quinazolinones are produced, namely methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-[1-(2,4-difluorophenyl)propionate]; methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-[1-(4-chlorophenyl)propionate]; and methyl 6,7-dimethoxy-

4-methyl-2(1H)quinazolinone-1-1-(4-chlorophenyl)propionate; and methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-[1-(4-methoxy-phenyl)propionate].

Example N.

Methyl 6, 7- dimethoxy- 4- methyl 1- 2( 1H) quinazolinone- 1-( 2- phenyl propionate).

A solution of 10 g of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone in 100 ml of chloroform, 100 ml of methanol and methyl cinnamate in excess was treated with 1.1 equivalents of Triton B (50%

in methanol), after which the solution was refluxed and stirred for 24 hours. It was then concentrated in vacuo to remove the solvent and the residue was purified by chromatography on silica gel. Pure methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(2-phenylpropionate) was produced in this way.

When in the above-mentioned method methyl, 2,4-difluoro-cinnamate, methyl 4-chlorocinnamate and methyl 4-methoxycinnamate are used instead of methyl cinnamate, the corresponding quinazolinones are produced, namely methyl 6,7-dimethoxy-4-methyl- 2(1H)-quinazolinone-1-[2-(2,4-difluorophenyl)propionate]; methyl 6,7-

in dimethoxy-4-methyl-2-(1H)quinazolinone-1-[2-(4-chlorophenyl)-propionate] and methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-[2- (4-methoxyphenyl)propionate].

Example 0.

)

6, 7- dimethoxy- 4-( 2- norbornylmethyl)- 2( 1H) quinazolinone

A solution of 25.0 g (16 m) of norborny1-2-acetic acid in 50

ml of benzene was treated with 75 l of thionyl chloride, after which

in the mixture was refluxed for 12 hours. The volatile compounds were removed in a rotary evaporator at 50°. The resulting acid chloride was dissolved

in 150 ml of tetrahydrofuran, after which 200 ml of aqueous concentrated ammonia was slowly added while stirring. A precipitate formed during the following half hour. The product was isolated by filtration and washed with cold water. After drying, 15.3 g (62.5%) were obtained, m.p. 144-146°C of norbornyl-2-acetamide.

A mixture of 0.95 g (0.05 m) of 3,4-dimethoxyphenyl isocyanate

and 6.12 g (0.04 m) of norbornyl-2-acetamide was melted under nitrogen at 130-140°C over 1 hour. After cooling, 100 ml of acetone was added, and the mixture broken up by hand. After 1 hour aging at room temperature, the precipitate was isolated and dried in vacuum. A solution of this adduct, 9.0 g (0.027 m) in 200 g of polyphosphoric acid was held at 130-140° for 3 hours with stirring. After cooling, the reaction mixture was added to 1500 g of ice and stirred. The pale green solution was adjusted to a pH of approx. 8.0 using concentrated ammonia. The resulting precipitate was isolated, washed with 2 x 50 mL of distilled water and then dried to give 6,7-dimethoxy-4-(2-norbornylmethyl)-2-(1H)quinazolinone as a pale brown solid. After recrystallization from 95% ethanol, pale yellow crystals were obtained, 2.0 g, m.p. 231-232°C.

Example P.

Methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(3'-methyl)propionate.

Into 26.0 ml of Triton B (40% in methanol) was added slowly and with stirring a solution of 20.0 g (91 mM) 6,7-dimethoxy-4-methyl-2(1H)quinazolinone in 90.0 g (900 mM) methyl crotonate,

in 80 ml of methanol and 126 ml of chloroform cooled to 0°C. The reaction mixture was stirred and refluxed for 18 h

in hours. It was then cooled to room temperature and the suspension was isolated by filtration. The filtrate was concentrated in vacuo, after which an airy, solid substance was obtained which remained

chromatographed on SilicAR CC-7, 125 m, prepared in 1:1 CH 2 Cl 2 /ethyl acetate. Elution with 5-20% methanol/CH2Cl2 gives the product as an orange solid in a yield of 560 mg (1.9%);

m.p. 5 5-5 6°C.

Example Q.

Methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(2'-methyl)propionate.

26.0 ml Triton B (40% in methanol) was added slowly and with stirring to a solution of 20.0 g (91 mM) 6,7-dimethoxy-4-methyl-2(1H)quinazolinone in 206 ml methyl methacrylate, 79 ml of methanol and 127.5 ml of chloroform cooled to 0°C. The mixture was stirred at room temperature for 18 hours and then held at 50°C for 66 hours. The suspension was cooled in an ice bath, and the precipitate was filtered off. 75 ml of water was added to the filtrate, and the solution was extracted with 4 x 100 ml of methylene chloride. The extract was dried over magnesium sulfate, filtered and concentrated in vacuo to a reddish oil which was chromatographed on SilicAR CC-7 preparation in ethyl acetate. Elution with 5-10% ethyl acetate/ethanol gives an oil. Treatment of this oil with cold ethyl acetate/ether 1:1 gives a precipitate

of white crystals which were filtered off, washed with 25 ml

in ether and dried in vacuo to give methyl t>, 7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(2'-methyl)propionate.

Example R.

)Methyl 6,7-dimethoxy-4-norbornylmethyl-2(1H)quinazolinone-1-(2'-methyl)propionate.

A solution of 10 g of 6,7-dimethoxy-4-norbornylmethyl-2(1H)-quinazolinone in 50 ml of chloroform, 50 ml of methanol and 50 ml of methyl

acrylate was treated with Triton B (benzyltrimethylammonium hydroxide, 40% in methanol, 20 mL, excess), and the mixture was refluxed for 24 hours. After processing

and purification via chromatography produced the purified product.

Example S.

Methyl 6,7-dimethoxy-3,4-dihydro-3,4-dimethyl-2(1H)-quinazolinone-1-propionate.

A solution of 1 equivalent of methyl 6,7-dimethoxy-3,4-dimethyl-2(1H)quinazolinone-1-propionate bromide in 700 ml

ethanol was treated with 10 g of 10% Pd/C. The mixture was hydrogenated at approx. 3 kg/cm 2 for 16 hours until the hydrogen absorption stopped. The solution was filtered off the catalyst, and the filtrate was concentrated in vacuo.

The resulting product was recrystallized from acetone, whereby a 60-70% yield of purified methyl 6,7-dimethoxy-3,4-dihydro-3,4-dimethyl-2(1H)quinazolinone-1-propionate was obtained.

Example T.

6, 7-dimethoxy-5-nitro-4-methyl-2(1H)quinazolinone.

One equivalent of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone was

during three quarters of an hour added a 5:1 mixture of 6 equivalents of concentrated nitric acid (70%) and concentrated sulfuric acid at 0° t 3°C. After 1 hour at the same temperature, the solution was poured over 1000 ml of crushed ice. The crude product was filtered off, worked up with boiling alcohol after which the suspension was filtered. Crystallization from ethyl alcohol gives 6,7-dimethoxy-5-nitro-4-methyl-2(1H)quinazolinone.

Example U.

6, 7- dimethoxy- 5- amino- 4- methyl- 2(1H) quinazolinone.

A solution of 13 equivalents of FeSO4.7H2O in 6 parts of water was heated to 95°C. A suspension of 1 equivalent of 6,7-dimethoxy-5-nitro-4-methyl-2(1H)quinazolinone in 800 ml of water at 80° was added and the resulting yellow mixture was kept at 98-100°C for a quarter . 13 equivalents of ammonium hydroxide were added dropwise over fifteen minutes while the temperature was maintained at 98-100°C. A black reaction mixture was obtained which was stirred at the aforementioned temperature for h hour, after which it was filtered and the black residue washed with hot water. The brown filtrate was extracted with chloroform. The solvent was removed in vacuo to give a dark brown semi-solid crude product which was chromatographed on silica. Recrystallization of the crude product from ethyl alcohol gives the purified product.

Example V.

6, 7- dimethoxy- 3, 4- dimethyl- 2( 1H) quinazolinone propionic acid methyl ester iodide hemihydrate.

A large excess of 20 mL of CH 2 I was added to a solution of 2.0 g (6.53 mM) of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone propionate in 300 mL of acetone, and the mixture was boiled under reflux for 3 days. Removal of the solvent in vacuo and subsequent treatment with ether gives 2.4 g of a dark brown solid. Recrystallization from isopropyl alcohol and then from methanol gives the product as a yellow solid, yield 1.2 g (41.3%).

Starting compounds for the compounds where the hydroxyl groups for the aromatic ring are in the 5-, 6- or 7-positions can be prepared using the methods described in the following examples.

Example W.

2- hydroxy- 3- methoxybenzaldehyde- 2- benzenesulfonate.

A suspension of 45.6 g (299 mM) 3-methoxysalicylic aldehyde

in 138 mL of NaOH (15% aqueous solution) was treated with 66 g (373 mM) of benzenesulfonyl chloride, and the mixture was vigorously stirred for 1 hour. It was then poured into 500 mL of ice water and the resulting solid product was filtered off, washed with cold water and then recrystallized from acetic acid to give the product as a white solid, yield 72.2 g (85%), m.p. . 119-120°C.

Example X.

2- hydroxy- 3- methoxy- 6- nitrobenzaldehyde- 2-benzenesulfonate. 50 g (171 mM) of 2-hydroxy-3-methoxybenzaldehyde-2-benzenesulfonate was added to 500 ml of nitric acid at 0-5°C, and the solution was kept for 5 minutes at 5°C and then completely over for 1.5 liters of ice water. The crude product which had a pale brown color was filtered off, washed with cold water, alcohol and then recrystallized from 650 ml of acetic acid, which gave the product as a white solid in a yield of 30.3 g -(52.6%).

m.p. 152-154°C.

Example Y.

2- hydroxy- 3- methoxy- 6- nitrobenzaldehyde.

A suspension of 10.12 g (30 mM) of 2-hydroxy-3-methoxy-6-nitrobenzaldehyde-2-benzenesulfonate in 120 ml of methanol was heated to reflux. A solution of 6 g of KOH in 24 ml of water and 12 ml of methanol was then added, and the two-phase mixture was boiled under reflux for 1 hour.

A bright red precipitate was formed which was filtered off and then dissolved in 120 ml of boiling water. Acidification of the hot aqueous solution with 10% HCl to pH 4 gives 5.0

g of a yellow precipitate. Recrystallization from isopropyl alcohol gives the product as a yellow solid, yield 4.5 g, (76.2%), m.p. 102-104°C.

Example Z.

2, 3- dimethoxy- 6- nitrobenzaldehyde.

A suspension of 16.0 g NaH (50% oily dispersion, 337 mM) in 200 ml dimethylformamide was treated dropwise with a solution of 49.0 g (248 mM) 2-hydroxy-3-methoxy-6-nitrobenzaldehyde in 300 ml DMF so that the temperature never exceeded 35°C. The mixture was aged at room temperature for 1 hour, after which a large excess of 100 ml of methyl iodide was added dropwise. A weak exothermic reaction was obtained. The mixture was then stirred vigorously for 19 hours at room temperature. After removing the excess of methyl iodide, the reaction mixture was poured into 1 liter of ice water. The crude product, a brown solid, was filtered off, washed with cold water and then recrystallized from 700 mL of isopropyl alcohol, yielding 27.9 g (53.5%) of the product as a pale brown solid, m.p. 106-108°C:

Example AA.

2, 3- dimethoxy- 6- nitrobenzaldehyde- ethylene ketal.

A mixture of 16.0 g (75 mM) 2,3-dimethoxy-6-nitrobenzaldehyde, 64 g (103 mM) ethylene glycol and 0.2 g p-toluenesulfonic acid monohydrate in 750 ml benzene was refluxed in a Dean-Stark device for 48 hours. The solution was then poured into 1 liter of water, and the organic phase washed with 2

x 20 ml saturated aqueous NaHCO 3 , dried over sodium sulfate, filtered, after which the solvent was removed in vacuo. The crude product was recrystallized from 2 liters of n-hexane, yield 15.2 g (78.2%), m.p. 74-76°C.

Example BB.

2- amino- 5, 6- dimethoxybenzaldehyde ethylene ketal.

A solution of 12.1 g (62.7 mM) of 2,3-dimethoxy-6-nitrobenzaldehyde ethylene ketal in 350 ml of ethyl acetate containing 0.5 g of sodium acetate was treated with 1.0 g of platinum oxide, and the mixture was hydrogenated for 24 hours at approx. 3.5 kg/cm 2 . The solvent was removed in vacuo after removal of the catalyst, whereby a pale brown oil was obtained.

After recrystallization from n-hexane, the product was obtained as a pale brown solid, yield 12.8 g (85.1%).

m.p. 78-80°C.

Example CC.

2-( N-carbethoxyamino)- 5, 6- dimethoxybenzaldehyde ethylene ketal.

1.9 g (17.5 mM) of ethyl chloroformate was added with stirring to 1.6 g (7.1 mM) of 2-amino-5,6-dimethoxybenzaldehyde-ethylene ketal dissolved in 50 ml of tetrahydrofuran. A resolution of 0.72

g of sodium hydroxide in 3.5 ml of water was added, and the solution

was stirred for 2 hours at room temperature. The tetrahydrofuran was removed in vacuo and the residue extracted with 2 x 100

ml of chloroform. The extracts were dried over sodium sulphate, filtered and the solvent removed in vacuo. The crude product was recrystallized from n-hexane to give 1.2 g (57.1%), m.p. 95-96°C: Example DD.

2-(N-carbethoxyamino)-5,6-dimethoxybenzaldehyde.

5.0 g (16.8 mM) of 2-(N-carbethoxyamino)-5,6-dimethoxybenzaldehyde-ethylene-ketal was dissolved in 36 ml of acetone and 3 ml of a 1N solution of HCl. The mixture was stirred at room temp.

erature for 4 hours. The solvent was removed in vacuo to give 3.9 g of a yellow solid. Recrystallization from n-hexane gives the pure product as a yellow solid in a yield of 3.6 g (84.7%), m.p. 86-88°C.

Example EE.

5, 6-dimethoxy-2(1H)quinazolinone.

A stream of dry ammonia gas was passed through a solution of 12.4 g (48.9 mM) 2-(N-carbethoxyamino)-5,6-dimethoxybenzaldehyde and 95 g ammonium acetate held at 155-160°C for 3 hours. The reaction mixture was cooled and poured into

an ice water mixture. A pale brown solid was formed. The aqueous mixture was treated with 50 g of sodium chloride and then extracted with 3 x 200 ml of chloroform. The organic extracts were combined and the solvent removed in vacuo to give 9.2 g of a pale brown oil. Treatment

of this with hot acetone gives the product as a yellow solid

in substance, yield 2.1 g (20.8%), m.p. 242-244°C:

Example FF.

3,4-dihydro-5,6-dimethoxy-4-methyl-2(1H)quinazolinone.

An excess of

) 62.6 ml of methyl magnesium bromide in a 3.1 M solution in ether (194.06 mM). The reaction mixture was removed from the cooling bath, warmed to room temperature and stirred for 16 hours. Additional methylmagnesium bromide was added to 15.65 ml of

a 3.1 M solution in ether (48.52 mM), and the mixture became

in boiled under reflux for 2 hours, cooled in an ice water bath, after which 100 ml of a saturated NH 2 Cl solution in 100 ml of water was added. Then 10% aqueous was added

hydrochloric acid until a pH of approx. 6.0. The layers were separated and the aqueous layer extracted with 3 x 250 ml chloroform. The chloroform extract was combined with the previously separated tetrahydrofuran layer, and the combined organic layers were washed with 200 ml of a saturated aqueous sodium chloride solution and dried over sodium sulfate. Filtration followed by concentration to approx. 250 ml gives a loose, white precipitate which was filtered off and recrystallized from 200

ml of isopropanol, whereby 9.7 g of product was obtained as a colorless solid (87.8%), m.p. 210-212°C.

Example GG.

5, 6-dimethoxy-4-methyl-2(1H)quinazolinone.

26.5 g (162.38 mM) potassium permanganate was added to a solution of 18.04 g (81.19 mM) 3,4-dihydro-5,6-dimethoxy-4-methyl-2(1H)quinazolinone in 5 liters of acetone, and the mixture was stirred at room temperature under nitrogen and protected from light by an aluminum foil for 96 hours. The brown precipitate formed was filtered off and washed with 500 ml of acetone and then partially dissolved in 1000 ml of boiling water. The hot, aqueous solution was after filtration neutralized with 10% aqueous HCl and then extracted with 4 x 250 ml chloroform,

and 4 x 250 ml 10% isopropyl alcohol/ethyl acetate. The chloroform extracts were dried over magnesium sulfate, filtered and concentrated to 500 mL, at which point a solid began to form. This was filtered off, and the filtrate further concentrated in vacuo to 3.25 g of a pale brown solid which was chromatographed on a 350 SilicAR column prepared in CHCl 2 (500 ml fractions). Elution with a \% methanol/chloroform mixture gives a yellow solid in a yield of 1.92 g which on recrystallization from 75

ml of isopropanol gives the product as a yellow solid, yield 0.940 g (5.3%), m.p. 230-232°C.

If 3,4-dihydro-5,6-dimethoxy-4-trifluoromethyl-2(1H)quinazolinone, 3,4-dihydro-5,6-dimethoxy-4-isopropyl-2(1H)quinazolinone and 3,4-dihydro-4-cyclohexyl-5,6-dimethoxy-2(1H)quinazolinone instead of 3,4-dihydro-5,6-dimethoxy-4-methyl-2(1H)quinazolinone, then the corresponding to 5,6-dimethoxy-4-trifluoromethyl-2(1H)quinazolinone, 5,6-dimethoxy-4-isopropyl-2(1H)quinazolinone and 4-cyclohexyl-5,6-dimethoxy-2(1H)quinazolinones.

Example HH.

2-(N-carbethoxyamino)-5-methoxy-acetophenone.

8.6 g (0.80 m) of ethyl chloroformate was carefully added with stirring to 8.0 g (0.0479 m) of 2-amino-5-methoxyacetophenone while cooling. A solution of 3.2 was then slowly added

g of sodium hydroxide in 50 ml of water. The reaction became exothermic, and all solids dissolved. The yellow reaction mixture was removed from the ice bath and stirred at room temperature for 2 hours. It was then extracted with 3 times 100 ml of chloroform, dried over sodium sulfate, filtered, after which the solvent was removed in vacuo, and a yellow solid was obtained. Recrystallization from hexane gives the product as a yellow solid, yield 7.4 g (65%), m.p. 90-92°C.

in Example II.

6-Methoxy-4-methyl-2(1H)quinazolinone.

A stream of dry ammonia gas was passed over the course of 3 hours

I through a solution of 14.0 g (0.058 m) of 2-(N-carbethoxy-amino)-5-methoxy-acetof enone and ammonium acetate maintained at 155-165°C. The reaction mixture was cooled and poured into 700 ml of ice water, whereby a dark orange solution was obtained.

This was extracted with 3 x 500 ml Cr^C^ followed by

in 2 x 500 ml ethyl acetate and 2 x 500 ml n-butanol, after which

the combined organic extracts were dried over sodium sulfate and the solvent removed to give a brown residue.

This was stirred in acetone and the insoluble portion filtered off to give the product as a pale yellow solid, yield 3.25 g (25%), m.p. 232-236°C (decomp.)

Example JJ.

4- methyl- 7- methoxy- 2(1H) quinazolinone.

A mixture of 32.5 g (0.156 m) of 1-acetyl-3(3-methoxyphenyl)-urea and 912.5 g of polyphosphoric acid was held at 120-130°C for 2 hours. After cooling to 50°, the melting was completely over

in 2 liters of ice water, and the solution was made weakly basic with ammonia and left overnight. The brown-red precipitate was filtered off, washed with cold water and then with hot acetone, and then the product was crystallized from ethanol (after treatment with charcoal) to give the product as a pale yellow solid, yield 11.5 g (39, 1%), m.p. 251-254°C.

i The 5,6-2(1H)quinazolinones having a substituent different from the methoxy group at Cg and C^ and a substituent different from a lower alkyl group at C^ can be prepared by means of the methods described for the preparation of the corresponding 6,7-2(1H)quinazolinones.

in

Claims (33)

1. Chemical compound, characterized by the formula where is hydrogen, amino and nitro; R 2 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl and bicycloalkyl; R 1 and R 2 are the same or different, and may be hydrogen, lower alkyl, aryl, substituted aryl, where the substituent is alkyl, lower alkoxy and hydroxy; R 1 - can be hydrogen, lower alkyl, benzyl or substituted benzyl, provided that when R 1 is different from hydrogen, the compound is a quaternary salt; X is benzyl, carboxy, carboalkoxy, cyano, carboxamido, methanesulfonyl, formyl, alkanoyl, aroyl or heteroaroyl; Y and Z are hydroxy and hydrogen, provided that at least one of the groups Y and Z is hydroxy, and when Y and Z are both hydroxy, then the hydroxy groups are located either in the 5,6 or 6,7 position; and wherein said compounds include quaternary salts prepared by means of lower alkyl halides; as well as the alkali metal and alkaline earth metal salts of the phenol and the carboxy group at N-^ as well as the amine salts, amine alcohol salts and amino acid salts. 2. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid. 3. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-trifluoromethyl-2(1H)quinazolinone-1-propionic acid. 4. Chemical compound according to claim 1. characterized by being 6,7-dihydroxy-4-octyl-2(1H)quinazolinone-1-propionic acid. 5. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-cyclopentyl-2(1H)quinazolinone-1-propionic acid. 6. Chemical compound according to claim 1, characterized by being 5,6-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid monohydroiodide. 7. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-2(1H)-quinazolinone-1-(2'-methyl)propionic acid. 8. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid N-methylglucamine salt. 9. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid mono(2-methyl-2-amino-1,3-propanediol) salt. 10. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid mono(1-amino-2,3-propanediol) salt. 11. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-propionic acid monoarginine salt. 12. Chemical compound according to claim 1, characterized by being 5,6-dihydroxy-2(1H)quinazolinone-1-propionic acid. 13. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-methyl-2(1H)-quinazolinone-1-propionic acid monoethylamine salt. 14. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-methyl-2(1H)-quinazolinone-1-propionic acid piperazine salt. 15. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-methyl-2 (1H) quinazolinone-1-propionic acid N-methylpiperazine salt. 16. Chemical compound according to claim 1, characterized by being 6,7-dihydroxy-4-methyl-2(1H)-quinazolinone-1-propionic acid morpholine salt. 17. Chemical compound, characterized by the formula where R~ is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl or bicycloalkyl; Rg is lower alkyl and R^ is hydrogen, provided that R^ is hydrogen only when the R^ -imine bond is saturated. L 18. Chemical compound according to claim 17, characterized by being 5,6-dimethoxy-4-methyl-2(1H)quinazolinone. 19. Chemical compound according to claim 17, characterized by being 3,4-dihydro-5,6-dimethoxy-4-methyl-2(1H)quinazolinone. 20. Chemical compound according to claim 17, characterized by being 5,6-dimethoxy-2(1H)quinazolinone. 21. Method for making a compound with the formula characterized by reacting a compound else with the formula with an olefin of the following formula in the presence of a base so that an intermediate with the following formula is produced after which the product is reacted with acid; where R is hydrogen or methyl; R 1 is hydrogen, amino and nitro; R 2 is hydrogen, alkyl, cycloalkylalkyl, cycloalkyl, haloalkyl and bicycloalkyl; R 1 and R 4 are the same or different; and is hydrogen, lower alkyl, aryl and substituted aryl; and X is benzyl, carboxy, carboalkoxy, cyano, carboxamido, methanesulfonyl, formyl alkanoyl, aroyl and heteroaroyl and heteroaryl. 22. Method according to claim 21, characterized in that the olefin is selected from the group consisting of methyl cinnamate, methyl acrylate, methyl crotonate and alkyl nitrile. 23. Method according to claim 21, characterized in that the acid is hydrobromic acid. 24. Method for preparing a compound of the formula characterized by reacting a compound with the following formula with an iodide of the formula after which the prepared product is reacted with an acid, where R is lower alkyl, R 1 is hydrogen, amino or nitro; R 2 is hydrogen, cycloalkylalkyl, alkyl, cycloalkyl, haloalkyl or bicycloalkyl; R 1 and R 2 are the same or different and are hydrogen, lower alkyl, aryl, substituted aryl; R 1 is lower alkyl, benzyl or substituted benzyl; and X is benzyl, carboxy, carboalkoxy, cyano, carboxamido, methanesulfonyl, formyl alkanoyl, aroyl, heteroaryl and heteroaryl. 25. Process according to claim 24, characterized in that Rj is benzyl. 26. Method according to claim 24, characterized in that the acid is hydrobromic acid. 27. Method of making a compound with the following formula characterized by reacting a compound with the formula with an olefin with the following formula for the preparation of a compound of the formula after which the prepared product is reacted with an iodide of the formula after which the produced product is reacted with a hydrohalic acid to produce a salt of the formula after which this salt is hydrogenated, and wherein R is lower alkyl; R 1 is hydrogen, amino or nitro; R 2 is hydrogen, cycloalkylalkyl, alkyl, cycloalkyl, haloalkyl or bicycloalkyl; R 1 and R 4 are the same or different and are hydrogen, lower alkyl, aryl or substituted aryl; R 1 is lower alkyl, benzyl or substituted benzyl; and X is benzyl, carboxy, carboalkoxy, cyano, carboxamido, methanesulfonyl, formyl, alkanoyl, aroyl, heteroaroyl and heteroaryl. 28. Method according to claim 27, characterized in that the hydrohalic acid is hydrogen bromide. 29. Method according to claim 27, characterized in that the iodide is methyl iodide. 30. Method according to claim 27, characterized in that the olefin is selected from the group consisting of methyl cinnamate, methyl acrylate, methyl protanate and acrylonitrile. 31. Pharmaceutical preparation that can be used for the treatment of cardiovascular disorders in unit dose form, characterized by containing from approx. 15 mg/kg body weight to approx. 300 mg/kg body weight of a compound according to claim 1 in admixture with a pharmaceutically acceptable diluent or carrier. 32. Method for treating patients with hypertension or other cardiovascular disorders characterized by poor blood flow in the kidneys, characterized in that said patient is administered an effective antihypertensive amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent. 33. Method for treating a patient with cardiotonic disorders, characterized in that said patient is administered an effective amount of a compound according to claim 17, together with a pharmaceutically acceptable carrier or diluent.