HU192242B - Process for production of derivatives of substituated dihydroxi-2/1/1/-quinoline and medical preparatives containing them - 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 novel substituted hydroxy-2 (1 H) -quinazolinone derivatives of the formula (I), to their acid addition, alkali metal or alkaline earth and quaternary salts and amino, aminoalcohol and amylic acid salts. In the general formula (I)

ΙΪ2 is hydrogen, (C1-C15) alkyl, (C3-C8) -cycloalkyl, (C3-C8) -cycloalkyl (C1-C4) -alkyl or (C1-C4) -trilialoalkyl,

Ra and R1 are independently hydrogen or C1-C4 alkyl,

R5 is the second valence bond of position 3-4 or, when there is one bond between position 3-4, C1-C4 alkyl,

X is benzyl, carboxylic (C 1 -C 6) alkoxy-carbonyl,

Y and 7 represent a hydroxy group, provided that the hydroxy groups are in the 5,6- or 6,7-position.

The alkali metal and alkaline earth metal salts of the compounds of the invention may be formed on the phenolic hydroxyl group and the Ni-hydroxy group; and amine salts such as noluminium, piperazine, N-methylpiperazine, morpholine and C 1-4 aliphatic amine salts; further derivatives can be formed with amino alcohols such as ethanolamine,

2-amino-1,3-propanediol or bis (hydroxyethyl-D-melylamine) and also ninino acids, arginine, lysine or ornithine.

Suitably, the compounds of the present invention are prepared wherein R 1 is hydrogen, C 1 -C 15 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 4 trihaloalkyl,

R 1 and R 1 are hydrogen or

C 1-4 alkyl,

X is carboxyl or C 1 -C 6 alkoxy-carbonyl,

R5 is a second bond or C1-C4 alkyl,

Y and Z are hydroxy.

Numerous 6,7-dialoxy-4-alkyl-2 (1H) -quinazoline derivatives are known in the literature (Budesinsky et al., Coll. Czeh. Commun., 37, 2779 (1972); Belgian Patent No. 765947/1971). ); however, none of the known substituted clnazoline compounds have a hydroxy substituent on the benzene ring. In addition, the known quinazolinone derivatives have substituent substituents at the Ni position.

The novel compounds of the present invention have a renal vasodilator effect, thereby increasing the amount of blood flowing through the kidneys and thus being useful cardiovascular agents. Some of the compounds of the invention also exhibit cardiotonic activity.

The novel compounds of the invention may be prepared according to Scheme A. In the formula, R 2, R 8, R 1, R 8, X and Y are as defined above.

That . Scheme II shows that the quinazoline derivative substituted at the Νι-position of formula II can be prepared by reacting an appropriately substituted quinazolinone with an olefin derivative. Examples include methyl acrylic acid, methyl crotonic acid, or methyl methacrylic acid.

The choice of the olefin derivative is based on the desired substituent of 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 hydroxides such as potassium ethoxide and sodium ethoxide, a hydroxide such as benzyltrimethylammonium hydroxide, a quaternary ammonium fluoride such as tetraethylammonium fluoride or a tertiary amine such as triethylamine. The reaction temperature may range from -10 ° C to 100 ° C. The preferred reaction temperature is 65 ° C. The Ni-substituted quinazolinone derivatives of formula (II) may be used to prepare other Ni-substituted quinazolinone derivatives according to the methods outlined in the Scheme below. For example, the Ni-substituted quinazolinone of formula (II) may be alkylated with an alkyl iodide such as methyl or ethyl iodide or reacted with iodobenzene such as ο-, m-, or p-fluoroiodobenzene, ο -, ιη or p-methyl iodobenzene and ο-, ni- or p-methoxy iodobenzene. The reaction yields a quaternary salt. The resulting salt may be hydrolyzed with an acid such as hydrobromic acid or hydrogen iodide to give the corresponding dihydroxy compound of formula (III). The Ni-substituted quinazolinone of formula II can be directly converted to the corresponding dihydroxy compound of formula V using an acid such as hydrobromic acid or hydrogen iodide. The dihydroxy compounds of formula (111) and (V) can then be partially saturated using hydrogen gas and a catalyst such as platinum, palladium, radium or nickel. The resulting saturated compounds can be represented by the formulas (IV) and (VI). We can use boranes for the reduction step,

-2192242 metal hydrides such as sodium borohydride.

Λ The starting compounds of formula (I) wherein the α-substituents are in the 6,7 position of the benzene ring can be prepared in two ways. Alternatively, an appropriately substituted alkoxyaniline can be converted to the corresponding isocyanate derivative. The conversion can be carried out with phosgene in the presence of a suitable solvent such as benzene, toluene or xylene. The isocyanate is then condensed with a suitable carboxamide derivative to form an adductun. The condensation can be carried out in an inert solvent such as xylene or toluene. The reaction is conveniently carried out at 100-150 ° C. The resulting adduct is then cyclized to the quinazolinone compound. As the cyclizing agent there may be used polyphosphoric acid, polyphosphoric acid ester and a mixture of phosphorus penloxide and inanesulfonic acid. The ratio of cyclizing agent to adduct may vary from 1: 1 to 25: 1. The preferred ratio is 5: 1. The reaction is preferably carried out at a temperature of 100 to 130 ° C under an inert atmosphere such as nitrogen. Alternatively, an appropriately substituted acetophenone is nitrated. The substituted o-nitroacetophenone isomers are separated and then reduced to the corresponding amine. The resulting compounds are not alkylated with an alkyl halogenated formic acid to give the corresponding urethane derivatives. The urethane derivative thus obtained is cyclized with ammonia to give the corresponding quinazoline derivative. The following examples illustrate these conversions.

Pharmaceutical compositions containing the active compounds of the present invention are prepared by intimately mixing the active ingredient with a pharmaceutical excipient in a known manner. A wide variety of excipients can be used, depending on whether the preparation is intravenous, oral or parenteral. Water, glycols, oils, alcohols, flavors, preservatives, coloring agents and the like may be used as adjuvants for the preparation of an oral liquid preparation. Suspensions, elixirs or solutions may be formulated as oral liquid preparations. When a solid oral preparation is a powder, capsule, tablet, starch, sugar, glidant, granulating agent, lubricant, binder, disintegrant may be used. Tablets and capsules are most preferred when solid carriers and excipients are used. If desired, α-tablets are sugar coated or enteric coated in a known manner. For parenteral preparations, the carrier will usually comprise sterile water and other ingredients, such as solubilizers or preservatives. Liquid carriers as well as suspending agents may be used to prepare suspensions for injection in the horseradish. The pharmaceutical compositions contain from 15 to 300 mg / kg, preferably from 30 to 200 mg / kg of active ingredient per unit dosage form, for example, in the form of a tablet, capsule, powder, injection, coffee spoon.

The following examples illustrate the present invention.

Example 1

6,7-dihydroxy-4-methyl-2 (lH) -quinazolinone-l- (3'-methyl) -propionic acid monohydrobromide monohydrate

Methyl ester of 6,7-dimethoxy-4-methyl-2 (111) -quinazolinone-1- (3'-methyl) -propionic acid (1.0 g, 3.2 mmol) in acetic acid (10 mL) and 48% aqueous hydrogen bromide. The solution was refluxed for 66 hours. The reaction mixture was then cooled; a green precipitate formed which was collected by filtration, washed with cold ether (20 mL) and dried in vacuo. Yield: 300 mg (25% yield) of the title compound. we get.

Mp: 220-222 ° C.

S spectrum birds:

TEA δ 1.71-1.95 (d, 311, 3'-Cl 3), 3.04 (s, 3H,

TMS

4-Clb), 3.18-3.53 (m, III, -C-Clb), 5.21-5.82

II (in, 211, -C1-12-), 7.62 (s, 111? Cs-H), 7.79 (s, III, Ce-11); M '278

Example 2

6,7-Dihydroxy-3,4-dimethyl-2 (1H) -quinazolithiomine-1-propionic acid, Bronide

1.5 g (33 mmol) of 6,7-dimethoxy-3,4-dinethyl-2 (1H) -quinazolinonium-1-propionic acid methyl-6Z-1-iodide in 10.5 ml acetic acid and 10.5 ml 48% aqueous hydrogen bromide. The solution was refluxed for 48 hours with stirring. The brown reaction mixture was cooled to room temperature and the resulting yellow precipitate was collected by filtration. The precipitate was washed with cold ether (25 mL), dried in vacuo to give 650 mg (55% yield).

270-272 ° C.

Spec Data:

TEA

3.22 (s, 3H, 4-CH 3), 3.01-3.42 (m, 2H,

TMS

2'-CH 2), 4.12 (s, 311, = NCH 3), 4.67-5.11 (t, 2H, 2 '= CH 2), 7.47 (s, H 1, C 5 -H), 7 , 93 (s, 111, Ceti); M * 278 (M-80).

Example 3

6,7-Dihydroxy-4-methyl-2 (1H) -quinazolinone-1- (2'-methyl) propionate

Methyl 6,7-dimethoxy-4-methyl-2 (III) -quinazolipone-1- (2'-methyl) -propionic acid (2.40 g, 7.5 mmol) in acetic acid (25 ml) and aqueous hydrogen bromide was added and the mixture was refluxed for 48 hours. The reaction mixture was cooled in an ice bath, concentrated in vacuo to half volume and then basified to pH 12 with 25 mL of n sodium hydroxide solution. The reaction mixture was re-cooled and then acidified to 5 P with glacial acetic acid. A yellow precipitate was obtained which was collected by filtration; the resulting material was washed with cold ether and dried in vacuo. 1.60 g of the expected product are obtained.

Yield: 76.9%.

266-268 ° C.

Spec Data:

TFA δ 1.38-1.65 (d, 311, 2'-Cl), 2.99

TMS

II (s, 3H-4-Cib), 3.10 -3.49 (m, 1H, -C-), 3.91-N-5.09 (in, 211, CH2-C), 7.37. (s, 111, Cs-H), 7.72 (s, 1H, Cs-H); M * 278.

In the case where the starting material is 6-methoxy-4-methyl-2 (1H) -quinazolinone-1-propionic acid methyl ester, 7-methoxy-4-methyl-2 (III) -quinazolinone-1-propionic acid methyl ester,

6-methoxy-2 (1H) -quinazolinone-1-propionic acid methyl ester, 7-methoxy-2 (1H) -quinazolinone-1-propionic acid methyl ester, 6-methoxy-4-trifluoromethyl-2 ( 1H) - N -azolinone-1-propionic acid methyl ester and 7-methoxy-4-trifluoromethyl-2 (1H) -quinazolinone-1-propionic acid methyl ester, 6,7-dimethoxy-4- instead of methyl 2 (III) -quinazolinone-1- (2'-methyl) -propionic acid methyl ester, 6-hydroxy-4-methyl-2 (1H) -quinazolinone-1-propionic acid, 7-hydroxy-4 -methyl-2 (III) -quinazolinone-1-propionic acid, 6-hydroxy-2 (1H) -quinazolinone-1-propionic acid, 7-hydroxy-2 (1H) -quinazolinone-1-propionic acid, 6-hydroxy-4 trifluoro-ethyl-2 (1H) -quinazolinone-1-propionic acid and 7-hydroxy-4-trifluoromethyl-2 (1H) -quinazolinone-1-propionic acid.

Example 4

6,7-dihydroxy-4-inelH-2 (III) -kinazolinoii-l- (2'-methylimino) -piopionsav-Lrik (íliuni salt monohidröl

A suspension of 1.5 g (5.39 mmol) of G, 7-dihydroxy-4-methyl-2 (1H) -quinazoline-1- (2'-methyl) -propionic acid in 100 ml of methanol was added.

Treat with 16.17 mL (16.1 mmol) of melanolic potassium hydroxide solution while stirring with a stream of nitrogen. The resulting solution was filtered through a stream of nitrogen inlet and concentrated in vacuo. A yellow solid is obtained. The resulting material was triturated with acetone (40 mL) and collected by filtration. The resulting material was washed with ether (20 mL) and the solid dried in a vacuum oven for 16 hours at room temperature; 2.2 g (100% yield) of the title compound are obtained.

M.p.> 300 ° C

Example 5

6,7-Dihydroxy-4-niellyl-1- (3 ^, -1'-phenylpropyl) -2 (III) -quinazolinone nonionic hydrate

1.25 g (3.6 mmol) of 6,7-diethylethoxy-4-methyl-1- (3-phenylpropyl) -2 (1H) -quinazolinone were added with 10 ml of 48% aqueous hydrobromic acid and 10 ml. the ice-cream mixture was heated to reflux for 24 hours with stirring. After cooling to room temperature, the reaction mixture was poured onto 100 g of ice. A brownish-yellow solid precipitated and was separated, washed with water (20-20 ml) and ether (3 x 40-40 ml). The resulting material is air-dried; 1.21 g (100% yield) of the title product are obtained.

M.p. 275 ° C.

S Baker Lrum Data:

TFA ά 2.00-2.70 (m, 2, C1Cl2-), 2.75-3.30 TMS (in, 211, -Cl2-O), 3.00 (s, 311, Clb), δ , 30-5.00 (L, 211, -C11zN), 7.07 and 7.65 (2s, 211, Cili, Cell), 7.25 (s, 5II, 10-); M '310.

In the case where the starting material is 6,7-dinethoxy-4-diethyl-2 (III) -quinazolinone-1- (2-methanesulfonyl (-elane), 6,7-dimethoxy-4-methyl-2 (II) -quinazolinone -1- (2-benzoyl) ethane, and

6,7-Dimethoxy-4-methyl-1-2 (1H) -quinazolinone-1- (2- (2'-pyridyl) -1-yl) is used 6,7-dimethoxy-4-methyl-1- ( Instead of 3 * -phenylpropyl) -2 (111 J-quinazolinone, the corresponding 6,7-dihydroxy-4-methyl-1- (2-methanesulfonyl) ethane-2 (1H) -quinazolinone monohydrate, 6.7 -dihydroxy-4-methyl-1- (2-benzoyl) -ethane-2 (1H) -quinazolinone monohydrate and

6,7-Dioxide roxy-4-methyl-1- (2- / 2'-pyridyl / ethane) -2 (III) -quinazolinone monohydrate is obtained.

In the case where the starting material is 6,7-dimethoxy-4-diethyl-2 (1H) -quinazolinone-1-propionaldehyde, 6,7-dlmethoxy-4-methyl-2 (1H) -quinazolinone-1-propionitrile and 6 7,7-Dimethoxy-4-methyl-2 (1H) -quinazolinone-1- (1-phenyl) -propioneava-methyl ester 6,7-dimethoxy-4-methyl-1- (3'-phenyl-propyl) is used Instead of -2 (1H) -quinazolinone, the corresponding 6,7-dhydroxy-4-methyl-2 (1H) -quinazolinone-1-propionaldehyde, 6,7-dihydroxy-4-roethyl-2 (1H) -quinazolinone-1 6,7-Dihydroxy-4-methyl-2 (1H) -quinazol-5-one non-1- (1-phenyl) -piperidone is obtained.

By following the procedure described in Examples 3, 4, and 5, the compounds of formula 11a listed in Table 1 can be prepared. Starting material10 as sulfur. u use appropriate quinazolinone stools. Ite in the formula is potassium or hydrogen.

Table 1 (IIa) is general. compounds

RZ Hydrogen bromide salt op / yield% Free acid op / yield% Tricalsium salt op / yield% 11 231-232 ”0 / 57.8 Clb 257-259 ”0 / 82.5 > 300 ”0 / 96.9 CF3 125-130 ”0 / 22.2 > 310 ”0 / 76.6 ethyl 308-310 ”0 / 84.5 305-306 ”0 / 73.8 propyl 264-266 C / 42.8 328-329 "0 / 71.4 310-312 ”0 / 97.2 isopropyl 310-312 ° C / 73.3 decomposition> 300 ”0 / 74.0 n-pentyl 222-224 ° C / 79.2 275-277 "0 / 72.3 n-hexyl 242-246 ”0 / 64.3 decomposition 220 ”0 / 68.2 n-heptyl 248-250 "0 / 91.6 n-octyl 238-240 ”0 / 55.1 302-304 ”0 / 80.0 n-decyl 164-166 ”0 / 71.6 259-261 ”0/100, Oh CH2-CH2 I I 276-278 ° C / 88.0 228-230 ”0 / 8.9 1 1 CH-CH CII2-CII2. 1> H- CH-CH 276-278 "0 / 74.6 298-300 ”0 / 91.5 CH2-CH2 | = CH-CH2- Clk, Clk ^ 262-264 ”0 / 79.0

Example 6

6,7-Dihydroxy-4-methyl-2 (1H) -quinazolinone- ₅₀

-1-propionic acid ethyl ester

To a suspension of 2.0 g (6.5 mmol) of 6,7-dihydroxy-4-methyl-2 (1H) -quinazolinone-1-propionic acid in 35 ml of absolute ethanol was added 1 ml of ₅₅ methanesulfonic acid, and the mixture was refluxed for 3 days. while stirring. The reaction mixture was then cooled to room temperature and then

Pour into 200 g of ice. A yellowish-green precipitate formed qq, which was collected, washed with water, acetone, then ether and then dried in vacuo. 1.75 g of the expected product are obtained; yield: 92.2%.

M.p.> 308 (dec.) 65

Speklrumadatok:

TFA i 1.35-1.60 (L, 311, ClkClb), 2.95 -3.30 TMS

II (ni, 211, CH 2 Cl 2), 3.10 (s, 311, Clb), 4.20-4, G0 (q, 2H, C / ft-O), 4.65-5.00 (l, 211, C / ft-N), 7.35 (s, 111, Cs-11), 7.75 (s, 111, Ce-11); M '292.

Example 7

6,7-Dihydroxy-3,4-dimethyl-3,4-dihydro-2 (1H) -quinazolinone-1-propionic acid mmol 6,7-dihydroxy-3,4-dimethyl-2 (III) -quinazolinone-1 propionic acid bromides in 15 ml of glacial acetic acid

-511

After treatment with 0.1 g of activated charcoal containing 5% palladium on carbon, the reaction mixture was hydrogenated at ^3.1 DEG C. for 12 hours. The catalyst is filtered off and the mother liquor is poured into 100 ml of water. The precipitated compound is filtered off, washed with water and dried in vacuo.

Example 8

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

5.0 g (17.7 mmol) of 6,7-dihydroxy-4-methyl-2 (1H) -quinazoline non-1-propionate monohydrate is suspended in 270 ml of methanol. The slurry was treated with activated charcoal (2.5 g, 10% palladium) and hydrogenated at 3 nin for 16 hours. The mixture was filtered and the solvent removed in vacuo; the residue is taken up in acetone; 4.3 g (91.4% yield) of a brownish product are obtained.

Mp 202-204 ° C.

S pe k tru madat:

TFA δ 6.86 (s, 1H, 5-H), 6.83 (s, 1H, 8-H),

TMS

4.78 (d, 111, J = 7.0 Hz, 4-H), 4.36 (t, 2H, J = 10 Hz, 2'-H), 3.03 (t, 2H, J = 10 Hz, 1'-II), 1.55 (d, 311, J = 7 Hz, 4-CH5); M * 266.

Example 9

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

A suspension of 9.97 g (37.10 mmol) of 6,7-dihydroxy-4-methyl-2 (1H) -quinazolinone-1-propionic acid in 30 ml of methanol under a stream of nitrogen was 37.10 ml (37.10 mmol) of potassium hydroxide solution. The resulting yellow slurry was stirred at room temperature under a stream of nitrogen for 22 hours. The reaction mixture was cooled in an ice-water bath and filtered. The resulting yellow material was washed with cold methanol (3 x 17 mL), dried in vacuo at 120 ° C for 336 hours (14 days); 10.41 g of a yellow product are obtained; mp 303-305 ° C.

Example 10

G, 7-Dihydroxy-4-methyl-2 (1H) -quinazolinone-1-propionic acid dipotassium salt

A suspension of 45.0 g (167.47 mmol) of 6,7-dihydroxy-4-methyl-2 (1H) -quinazolinone-1-propionic acid (600 mL of methanol) in 334.94 mL (334.94 mmol) of methanolic IN After addition of potassium hydroxide solution, a large amount of yellow solid thermos was formed, an additional 200 ml of methanol was added and a total of 300 ml of water was added until the solid dissolved. The reaction mixture was then stirred at room temperature under a stream of nitrogen for 30 minutes, then the slightly opalescent solution was filtered and concentrated in vacuo to give a tan solid which was triturated with acetone (300 mL) to give a yellow solid. This gave the dipotassium salt, 54.26 g, mp> 325 ° C.

Example 11

6,7-dihydroxy-4-nieíil-2 (lH) quinazolinone-l-propionic acid-nionoargininsó monoliidrát

A mixture of 4.0 g (14.6 mmol) of 6,7-dihydroxy-4-methyl-2 (1H) -quinazolinone-1-propionic acid and 2.34 g (14.6 mmol) of L-arginine in 150 ml of water is added. and leave to stand at room temperature for 3 hours. After 15 minutes, the stock solution clears and a yellow precipitate slowly forms. After 3 hours, the precipitate was collected, washed with water (15 mL), acetone (20 mL), and ether (2 x 20 mL). The precipitate was dried at 60 ° C under vacuum for 3 hours. 5.81 g (93.8% yield) of the title product are obtained.

Example 12

6,7-dihydroxy-4-methyl-2 (lH) quinazolinone-l-propionic acid N-methylglucamine salt

0.79 g (3 mmol) of 6,7-dihydroxy-4-methyl-2 (1H) -quinazolinone-1-propionic acid, 0.59 (3 mmol) of noluml, 40 mL of methanol and 4 mL of water were added and overnight at room temperature. The resulting suspension was filtered and the precipitate was washed with ether (2 x 20 mL). The resulting material was air-dried for 3 hours to give the amine as yellow-colored thermos.

0.88 g (62.51% yield)

197-198 ° C (dec)

The monoethanolamine, piperazine, N-methylpiperazine and morpholine salts can be prepared as described above.

-613

Example 13

6,7-Dihydroxy-4-methyl-2 (1H) -quinazolinone-J-propionazole (2-methyl-2-amino-1,3-propanediol salt monohydrate)

6,7-Dihydroxy-4-methyl-2 (III) -quinazolinone-1-propionic acid (1.0 g, 3.6 mmol) was suspended in a mixture of 40 mL of methanol and 10 mL of water and then 0.38 g (3.6 mmol) of ) Treated with 2-methyl-2-amino-1,3-propanediol-III. It's your mixture! allow to stand at room temperature for 16 hours. The resulting pale yellow precipitate was collected and washed with methanol (10 mL) and ether (2 x 10 mL). The mixture was dried in vacuo at 60 ° C for 6 hours; 1.18 g (85.5%) of the amine salt are obtained; mp: 212213 «C.

I4. example

6,7-Dihydroxy-4-methyl-2 (II) -quinazolinone-J-propionic acid mono (1-amino-2,3-propanediol) salt hemihydrate

0.84 g (3.0 mmol) of 6,7-dihydroxy-4-methyl-2 (III) -quinazolinone-1-propionic acid, 0.27 g (3-fused 1-amino-2,3-propanediol, 40 mL) methanol and water (10 mL) were added and the mixture was allowed to stand overnight at room temperature and the resulting precipitate was collected, washed with methanol (10 mL) and ether (20 mL) and dried under nitrogen for 3 hours to give 0.94 g (84.7). %) of the amine salt is obtained.

Example 15

5,6-Dihydroxy-4-methyl-2 (1H-quinazolinone-1-propionoyl monohydroiodide

1.173 g of 5,6-dimethoxy-4-methyl-2 (1H) -quinazolinone-1-propionic acid methyl ester (3.83 mmol) were treated with 50% aqueous hydrogen iodide at room temperature, An orange solution is obtained which is refluxed under a stream of nitrogen for 11 hours. The mixture was then stirred at room temperature for one hour. The orange crystalline material was collected by filtration, washed with acetone and dried. 0.972 g (65% yield).

240-241 ° C.

Infrared spectrum: (KBr) μ, 3.23 (broad, OH),

5.78 (0 = 0).

If α in the above process is 5,6-dimethoxy-4-trifluoromethyl-2 (III) -quinazolinone-1-propionic acid-methyl ester, 5,6-dimethoxy-4-isopropyl-2 (III) -quinazolinone-1 methyl propionic acid, 4-cyclopentyl-5,6-dimethoxy-2 (III) -quinazolinone-1-propionic acid methyl ester, and the like. Methyl 4-cyclohexylmethyl-5,6-dimethoxy-2 (1H) -quinazolinone-1-propionic acid is used 5,6-dimethoxy-4-methyl-2 (1H) -quinazolinone-1-piperonic acid acid methyl 5,6-dihydroxy-4-trifluoromethyl-2 (1H) -quinazolinone-1-propionic acid monohydroiodide, 5,6-dihydroxy-4-isopropyl-2 (1H) -quinazoHnone-1-propionic acid monohydroiodide, 4-cyclopentyl-5,6-dihydroxy-2 (III) -quinazolinone-1-propionic acid monohydroiodide; 4-Cyclohexylmethyl-5,6-dihydroxy-2 (1H) -quinazolinone-1-propionic acid monohydroiod time is obtained.

The preparation of the ester compounds used as starting materials is described in Example G.

Example 16

6,7-Dihydroxy-4-methyl-2 (1H-quinazolinone-1-propionazole monohydrate

6,7-Dimethoxy-4-methyl-2 (111) -quinazolinone-1-propionic acid methyl ester (1.53 g, 5 mmol), acetic acid (20 ml) and aqueous hydrobromic acid (15 ml) Reflux under nitrogen for 120 hours. The solvent was removed in vacuo to give 1.5 g (88.2%) of the green hydrobromide salt. M.p. 292-295 ° C.

A solution of the resulting salt in methanol (5 mL) was added to the solution until saturated aqueous sodium bicarbonate was added until the pH was neutral. The precipitated free base was collected by filtration and washed with steel to give 1.0 g (76.9%) of the title compound as a light green product.

308-310 ° C.

Spec Data:

TFA i 7.80 (s, 111, 5-11), 7.46 (s, 1H, 8-11),

TMS 4.66-5.08 (ni, 211, 2'-II), 3.13 (in, 511, 1'-H, 4-Clb) M '264.

Further dihydroxy-2 (1H) -quinazolinone derivatives can be prepared using the appropriately substituted starting materials as described above.

The biological activity of the novel quinazolinone derivatives of the invention can be assayed according to Goldberg (Goldberg, b. 1, Sonneville, P. F. and McNay, J.L. (1968)). The dopamine-like renal vasodilator activity was assayed against phenethylamine and apomorphine (J. Pharmacol. Exp. Ther. 163).

Adult dogs are anesthetized and the animals are prepared for electromagnetic measurement of the renal artery blood flow. A cannula is inserted into the carolid artery to measure the blood pressure of the dog. The test substance is administered intravenously. Heart rate is measured with a cardiothachometer. Renal vascular resistance is defined as the ratio of the mean arterial blood pressure to the renal arterial blood flow. intravenously at a dose of three pg / kg / min dopamine

-715 was administered intravenously for 10 minutes (1 ml / min) to determine the response of the animals to dopamine receptor stimulation. Cumulative dose / response values may be measured by infusion of the test substance in progressive increments (usually three times). Each dose value was infused for 5 minutes. The maximum% increase in renal arterial flow or decrease in renal vascular resistance was determined at each infusion dose. .

Production of starting materials and intermediate products

The example

An equimolar amount of 3,1-dimethoxyphenyl isocyanate was passed through a medium of a solution of 1 equimolar of 3,4-dimethoxyaniline in 2 L of benzene. The solution is contained in a three-necked flask. The contents of the vessel were cooled in an ice bath for about 15 minutes and then the solution was refluxed for 1 and 3/4 hours while excess phosgene was flushed. The reaction mixture was then refluxed overnight and the solvent was evaporated in vacuo. After the addition of acetone, the solvent is removed in vacuo; a dark brown oily residue is obtained. It is distilled at 132-134 ° C / 79 Pa. Yield: 22.5 g.

Example P

N- (3,4-dimethyloxyphenyl) -N'-propionylurea

26.0 g (145 mmol) of 3,4-dimethyloxyphenyl isocyanate, 10.61 g (145 mmol) of propionic acid amine.

The mixture was heated at 160-165 ° C for 1.5 hours. A homogeneous pale yellow solution was obtained which solidified after 15 minutes. Stop the heat treatment and allow the contents of the pan to cool slowly; triturate with acetone and filter the resulting white solid to dry. Yield: 32.45 g.

M.p. 193-197 ° C.

Example C

6,7-Dimethoxy-4-ethyl-2 (1H) -quinazolinone 15

A suspension of 32.45 g (128 mmol) of N- (3,4-dimethoxyphenyl) -N'-propionylcarbamide and 375.12 g (1109 mmol) of polyphosphoric acid is stirred vigorously at ΐ3θ135 CC for 3.5 hours under a stream of nitrogen. . The mixture was poured into 500 g of ice water and stirred further. The solution was adjusted to pH 5.5 with concentrated ammonium hydroxide solution and allowed to stand at room temperature overnight. A brown precipitate formed and the resulting solid was filtered and dried to give 7.4 g of a white precipitate. The filtrate was extracted with chloroform (5 x 250-250 mL), the organic extract was dried over MgSO4 and the solvent was evaporated in vacuo. A tan solid is obtained. The resulting material was triturated with tin and filtered to give 4.98 g of a solid ( _3r) . The resulting material is slurried in water and then dried again for further addition.

M.p .: 263-265 'C.

Speklrumadalok:

^TFA δ 7.50 (s, 111, 5-11), 7.23 (s, 1H, 8-H), 4.30 TMS (s, 3il, 6 or 7-OCH3), 4.17 (β, 3H, 6 or 7-OCHa), 3.50 (q, 2H, J = 8.0 Hz,

CH 2 Cl 2), 1.70 (t, 311, J = 8.0 Hz, CH 2 CH 3).

Proceeding as above, we can obtain a

2 (1H) -quinazolinone derivatives of formula (Ia) listed in Table 2.

Table Ia Compounds of formula (Ia)

112

Op. ('C)

Yield (%)

ll 247-248 67.5 Clb 269-271 65.0 Clb 280-282 46.3 propyl 208-210 53.8 isopropyl 238-240 86.0 n penlil ^ Clb 152-154 21.9 -ab-ENJ ^ '' Cila 199-202 14.4

-817 192242

ib Mp (° C) Yield (%) n-hexyl 120-123 8.0 n-heptyl 184-186 78.2 n-octyl 130-132 24.4 n-decyl 166-167 37.4 -c.bO 262-264 79.0 Clb-Cliz 253-255 12.6 Cllz-CII --- Clb-Cllz 196-197 37.0 Clb Cll- V Cllz

Example D

3.4-dinieLoxy-6-nitroaceLofetion

3.4-Dimethoxyacetophenone (1.8 equimolar volume) was added over half an hour to 0 ° C nitric acid (18 equimolar volume). After an additional hour, the brown solution was poured into ice water at 20 ° C. Λ isolating the crude product by filtration; The resulting material is recrystallized from ethyl alcohol to give a pure product.

124-120 ° C

Spec Data:

CDCI

A 2.00 (s, 311, Clb), 4.00 (s, 611,

TMS OCib’s), 6.80, 7.59 (2s, 111, ea., Czli,

CSLL).

EXAMPLE A suspension of equivalents of 3,4-dimethoxy-6-nylacetophenone-phenyamino-3,1-dimethoxy-acetophenone in methanol is treated with 10% palladium on activated carbon and the mixture is stirred for 24 hours. Hydrogenate at a pressure of 3.10 Pa. The solution is filtered, the solvent is removed from the filtrate, and the product is recrystallized from ethyl alcohol.

98-100 ° C.

Spekl.ru Pendants: 65

CDí'ki

2.50 (?, 311, CH?), 3.80-3.85 (2s, 311,

TMS ea., OCII.a); 6.05, 7.05 (2s, III ea.,

Czll, Cr.ll).

M i> heaven

The equivalent of 2- (N-non-carbonyl-H-allino) -4,5-dinoethoxy-aeto-phenone is mixed carefully with 0.3 equivalents of 6-amino-3,4-dimethyl-oxo-acetorenone. mixing is carried out at room temperature; the dark brown reaction mixture was stirred at room temperature for half an hour. Aqueous sodium hydroxide solution was added to the reaction mixture and the mixture was stirred at room temperature for an additional hour. The reaction mixture is extracted with chloroform and then the chloroform is distilled off. An oily residue is obtained which is recrystallized from ether. Λ melting point 9740 ™ C of the product ·

Spec Data:

CDCI

? 1.10-1.50 (t, 311, Clb), 2.60 (s, 3H,

TMS Clb), 3.85 and 3.95 (2s, 311 ea, 45 OCib's), 4.0-4.4 (q, 211, Clb), 7.15 and 8.20 (2s, III ea). , CzII, Csll).

<7 Example

Preparation of 2 (11) -Inazole Inone-J-Propionic Acid Esters (Formula 6) g is dissolved in a mixture of 75 ml of methanol, 100 ml of chloroform and 125 ml of acrylic acid methyl ester, then an excess of Triton D in 40% methanol was added. The mixture was refluxed for 4-16 hours

Boil for -919 with stirring. The solution was then cooled and the solvent was distilled off; Chromatography on silica gel gives the corresponding ester.

Proceeding as above, we can obtain a

Compounds of formula 6 listed in Table 3:

Table 3

R2 op. C

ii 186-188 CIFO 155-157 CFj 140-143 ethyl 132-134 propyl 120-122 isopropyl 112-114 n-pentyl oil n-hexyl 122-124 n-heptyl 107-110 n-octyl 100-104 n-decyl oil CH2-CII2 I I 140-142 CIlz-CII- CH2-CH2 I I 103-105 CH2 Cll \ / CH2 CH2-CH2 | '' CH Cífo- 92-95 0112-0112 ^

In the case of 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-inethoxy-4-trifluoromethyl-2 (III) -quinazolinone, and the like. 7-Methoxy-4-trifluoro-ethyl-2 (III) -quilazolinone is used as starting material to give the corresponding 1-propionic acid ester.

In the case of 3,4-dihydro-5,6-dimethoxy-4-methyl-2 (1H) -quinazolinone, 5,6-dimethoxy-4-methyl-2 (III) -quinazolinone, respectively. 5,6-Dinieloxy-4-trifluoromethyl-2 (1H) -quinazolinone is used as the substituted quinazolinone derivative to give the corresponding 1-propionic acid ester.

example

6,7-Dimethoxy-4-methyl-2 (1U) -quinazolinone-1- (2-netonsulfonyl) -ethane g 6,7-dimethoxy-4-methyl-2 (ii) -quinazolinone 100 ml chloroform, 100 ml methanol and 40 equivalents of methyl vinyl sulfone. To the solution was added 1.1 equimolar Triton B (40% methanol in benzyltrimethylammonium hydroxide); the mixture was refluxed for 24 hours with stirring. The solution was then cooled to room temperature and the solvent was evaporated in vacuo; the residue is chromatographed on silica gel; This gives G, 7-dimethoxy-4-methyl-2 (LH) -quinazolinone-1- (2-methanesulfonyl) -ethane.

Example I

6,7-Dimetelox1-4-methyl-2 (1H) -quinazolinone-150- (2-benzoyl) -ethane g 6,7-Dinethoxy-4-methyl-2 (1H) -quinazolinone 100 ml chloroform, 100 ml methanol and dissolved in 40 equimolar amounts of phenyl vinyl ketone; a solution of 1.1 equimolar Triton B in 40% methanol was added. The mixture is then refluxed for 24 hours with stirring. The solution was cooled to room temperature, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel. Pure title compound is obtained.

-1021 <7 Example

6,7-Dimethoxy-4-methyl-2 (1H) -quinazolinone-1 ~

- (2- (2'-Pyridyl) -ethane) 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 dissolved. The solution was heated to reflux for 24 hours using a reflux condenser. The resulting solution was cooled to room temperature, the solvent concentrated in vacuo and the residue chromatographed on silica gel; pure title compound is obtained.

When 4-vinylpyridine is used in place of the 2-vinylpyridine, the corresponding 4'-pyridyl derivative is obtained.

Example K,

6,7-Dimethoxy-4-methyl-2 (1H) -quinazolinone-1-propionaldehyde. 10 g 6,7-dimethoxy-4-methyl-2 (1H) -quinazolinone in 100 ml methanol, 100 ml chloroform and 40 g equimolar The solution was treated with 1.1 equimolar of 40% Triton B in methanol, and the resulting mixture was concentrated in vacuo to give a residue which was chromatographed on silica gel to give the pure title compound.

Example L

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

Dissolve 10 g of 6,7-dimethoxy-4-methyl-2 (1H) -quinazolinone in 100 ml of chloroform, 100 ml of methanol and excess acrylonitrile; the solution was treated with 40% Triton B in methanol. The solution was heated to reflux with stirring for 24 hours. The resulting solution was cooled to room temperature and the solvent was evaporated in vacuo. The residue was chromatographed on silica gel to give the pure title compound.

Example M

6,7-Dimethoxy-4-methyl-2 (1H) -quinazolinone-1- (2-phenyl) -propionic acid methyl ester 6,7-dimethoxy-4-methyl-2 (1H) -quinazolinone in 100 ml of chloroform (100 mL of methanol in excess of? -Phenylacrylic acid methyl ester) was treated with 1.1 equimolar of 40% Triton B in methanol. The resulting solution was refluxed with stirring for 24 hours. After cooling to room temperature, the solvent was distilled off in vacuo and the residue was chromatographed on silica gel; pure title compound is obtained.

ff example

6,7-Dimethoxy-4-methyl-2 (1H) -quinazolinone-1- (3-phenylpropionic acid) -methyl ester 6,7-dimethoxy-4-methyl-2 (1H) -quinazolinone in 100 ml of chloroform and 100 ml of methanol are added, and excess cinnamic acid methyl ester is added. The solution was then treated with 1.1 equimolar Triton B in 50% methanol. The resulting solution was stirred at reflux for 24 hours. The solution was concentrated in vacuo and the solvent was distilled off and the residue was chromatographed on a silica gel column. This affords the pure title compound.

In the case of methyl 2,4-difluoro-cinnamic acid, methyl 4-chloro-cinnamic acid sits. Instead of methyl 4-methoxy-cinnamic acid, the corresponding 6,7-dimethoxy-4-methylethyl-2 (III) -quinazolinone-1- (3- / 2,4-difluorophenyl) is used. methyl propionic acid, 6,7-dimethoxy-4-methyl-2 (1H) -quinazolinone-1- (3- (4-chlorophenyl) -propionic acid methyl ester, and 6,7-dimethoxy-4 methyl-2 (1H) -quinazolinone-1- (3- (4-methoxyphenyl) -propionic acid) methyl ester is obtained.

Example P

6,7-Dimethoxy-4-methyl-2 (1H) -quinazolinone-1- (d-methylpropionic acid methyl ester g, 91 mmol) 6,7-dimethoxy-4-methyl-2 (1H) - To a solution of clnazolinone and 90 g (900 mmol) of crotonic acid methyl ester in a mixture of 80 ml of methanol and 126 ml of chloroform was added 26 ml of 40% Triton B in methanol with stirring, and the mixture was cooled to 0 ° C. Subsequently, the mixture was heated under reflux for 18 hours with stirring, then the reaction mixture was cooled to room temperature and the suspension was filtered. using a 1: 1 mixture of ethylene dichloride and ethyl acetate. Eluting with 5-20% methanol in dichloromethane.

An orange colored compound is obtained. Yield: 560 mg (1.9%).

Mp: 55-56 C.

-1 123

Example Q.

PREPARATION OF 6.7-Dimethoxy-4-methyl-2 (1H) -quinazolinone-1- (2'-naphthyl) -propionic acid methyl ester

6,7-Dimethoxy-4-methyl-2 (111) -quinazolinone (20.0 g, 91 mmol) was dissolved in a mixture of methacrylic acid methyl ester (206 ml), methanol (79 ml) and chloroform (127.5 ml), then gently stirring. 0 ml of 40% Triton B1 in methanol was added. The reaction mixture was stirred at room temperature for 18 hours and then at 50 ° C for 66 hours. The resulting slurry was cooled in an ice bath and the precipitate was collected by filtration. Water (75 mL) was added to the filtrate and the solution was extracted four times with 100 mL of methylene chloride. The extract was dried over magnesium sulfate, filtered, and concentrated in vacuo; a red oily product is obtained which is chromatographed on SILICAR CC 7; ethyl acetate was used as the liquid phase for column preparation. Ethanol containing 5-10% ethyl acetate was used for the elution; yielding an oily product. The resulting oil was triturated with ethyl acetate: ether (1: 1), the white crystals which precipitated were filtered off, washed with 25 ml of ether and dried in vacuo; This affords 6,7-dimethoxy-4-methyl-2 (III) -quinazolinone-1- (2'-methyl-propionic acid methyl ester).

Example S

6.7-Dimethoxy-3,4-dihydro-3,4-dimethyl-2 (1H) -quinazolinone-1-propionic acid methyl ester equivalent to 6,7-dimethoxy-3,4-dimethyl-2 (III) -quinazole A solution of methylnonium-1-propionic acid methyl ether bromide in ethanol (700 mL) was treated with activated carbon (10 g, 10% palladium). The mixture is hydrogenated for 16 hours at ^{3 bar} until hydrogen uptake is complete. The solution was filtered to remove the catalyst and the filtrate was concentrated in vacuo. The resulting solid is reassumed from acetone; In this way, 6,7-dinoxy-3,4-dihydro-3,4-dimethyl-2 (1H) -quinazolinone-1-propionic acid methyl ester is obtained in 60-70% yield.

Example 7 '(1,7-dimethoxy-5-nitro-4-methyl-2 (1H) -quinazolinothiol)

An equivalent of 6,7-dimethoxy-4-methyl-2 (III) -quinazolinone was added over about 3/4 hour to a 5: 1 mixture of 6 equivalents of concentrated nitric acid (70%) and concentrated sulfuric acid at 0 ± 3 ° C. After one hour at the same temperature, the solution is poured onto 1000 ml of crushed ice. The crude product was isolated by filtration, taken up in hot alcohol and the suspension filtered. The resulting material was recrystallized from ethyl alcohol to give the title compound.

Example U

6,7-Dimethoxy-5-amyl-o-4-methyl-2'-yl) -quinazolinone is dissolved in 6 parts of water and the solution is kept at 95 ° C. An equivalent amount of 6,7-dimethoxy-5-nitro-4-methyl-2 (1H-quinazolirion) l (800 ml) was suspended in 80 ml of water and added to the above solution at 80 ° C for 15 minutes at 98-100 ° C. 13 equivalents of ammonium hydroxide were added dropwise over about 15 minutes while maintaining the temperature at 98-100 C. The resulting black reaction product was stirred at 98-100 ° C for 30 minutes; The insoluble black residue was washed with hot water and the brown filtrate was extracted with chloroform to remove the solvent in vacuo to give a dark brown semi-solid crude product which was chromatographed on a silica gel column to give the crude product as an alcohol.

Example 1 '

6,7-Dimethoxy-3,4-dimethyl-2 (1H) -quinazolinonium-propionic acid methyl ester iodide hemihydrate ml of excess methyl iodide was added 2.0 g (6.53 mmol) 6.7- Dimethoxy-4-methyl-2 (1H) -quinazolinone-propionic acid methyl ester in 300 ml of acetone and refluxed for 3 days. The solvent was evaporated in vacuo and the residue was triturated with ether; 2.4 g of a dark brown solid are obtained. Recrystallization from isopropyl alcohol followed by methanol gave a yellow product. Yield: 1.2 g (41.3%).

The starting compounds for which the hydroxyl groups are in the 5th, 6th, 6th and 6th and 7th positions of the aromatic group can be prepared as follows.

-1225 h ^r example

2-hydroxy-3-n-loxybenzaldelated d-2-benzenesulfanate

A suspension of 3-methoxysalicylaldehyde (45.6 g, 299 mmol) in 15% aqueous sodium hydroxide (138 mL) was treated with benzenesulfonyl chloride (66 g, 373 mmol) and stirred vigorously for one hour. The reaction mixture was poured into ice water (500 mL) and the resulting white solid was filtered, washed with cold water and recrystallized from acetic acid. A white solid is obtained. Yield: 72.2 g. (85%). 119-120 ° C.

A solution of middat is added dropwise at a temperature such that the temperature does not rise above 35 ° C. After 1 hour at room temperature, methyl iodide (100 mL) was added dropwise. A slight exothermic reaction begins. The mixture was stirred vigorously at room temperature for 19 hours, after which excess methyl iodide was distilled off, the reaction mixture was poured into 1 liter of ice water. We obtain a brown crude product which is filtered off; The product was washed with cold water and recrystallized from isopropyl alcohol (700 mL). This gave a brown solid. Yield: 27.9 (53.3%)

Mp: 106-108 ° C.

Example X.

2-Hydroxy-3-methoxy-6-nitrobenzaldehyde-2-benzenesulfonate 2-hydroxy-3-methoxybenzaldehyde-2-benzenesulfonate (50 g, 171 mmol) was added to 500 mL of nitric acid at 0-5 ° C. After 5 minutes at 5 ° C, the solution was poured into 1-5 liters of ice water. The brownish crude product was filtered off, washed with cold water and then alcohol, and recrystallized from 650 mL of acetic acid. A white solid is obtained; Yield: 30.3 g (52.6%).

152-154 ° C.

Example J '

2-hydroxy-3-methoxy-6-nitro-benz & ldehid

A suspension of 2.12-hydroxy-3-methoxy-6-nitrobenzaldehyde-2-benzenesulfonate (10.12 g, 30 mmol) in methanol (120 mL) was heated to reflux. Dissolve 6 g of potassium hydroxidol in 24 ml of water and 12 ml of methanol; the biphasic mixture was refluxed for 30 minutes. The light reddish precipitate was filtered off and dissolved in 120 ml of hot water. The hot aqueous solution was acidified to 4 µl with 10% hydrochloric acid; 5.0 g of a yellow precipitate are obtained. This was recrystallized from isopropyl alcohol to give a yellow product. Yield: 4.5 g (76.2%). 102-104 ° C.

Example 7

2,3-Dimethoxy-6-nitrobenzaldehyde

A 50% oily suspension of 16.0 g (337 mmol) of sodium hydride in 200 mL of dimethylformamide was treated with 49.0 g (248 mmol) of 2-hydroxy-3-methoxy-6-nitrobenzaldehyde. ml of dimethyl phosphorus14

Example AA

2,3-dimethoxy-G-nitrobenzaldehyde ethylene ketal,

A mixture of 2,3-dimethoxy-6-nitrobenzaldehyde (16.0 g, 75 mmol), ethylene glycol (64 g) and p-toluenesulfonic acid monohydrate (64 g) in benzene (750 mL) was refluxed in a Dean-Stark apparatus. hours. The solution is then poured into 1 liter of water. The organic layer was saturated with saturated aqueous sodium bicarbonate solution (2 x 20 mL); the organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product was recrystallized from n-hexane (2 L); yield:

15.2 g (78.2%).

74-76 ° C.

sitting example

2-aii> amino-5 _t 6-dimethoxy-benzaldehyde ethylene ketal

2,3-Dinethoxy-6-nitrobenzaldehyde-ethylone ketal (12.1 g, 62.7 mmol) was dissolved in ethyl acetate (0.5 g, 0.5 g sodium sodium acetate). The solution was treated with 1.0 g of platinum oxide. The mixture was hydrogenated for 24 hours at ^{3 bar} . The solvent was removed in vacuo and the catalyst was filtered off; a pale brown oil is obtained. The material was recrystallized from n-hexane to give a brown product. Yield: 12.8 g (85.1%).

M.p. 78-80 ° C.

CC example

2- (N-ethoxy-kavbonil-amino) -G, 6-dimethoxy-ethyl-benzaldehyde ketal

Ethyl chloroformate (1.9 g, 17.5 mmol) was added with stirring (1.6 g, 7.1 g).

To a solution of 2-amino-5,6-dimethoxybenzaldehyde ethylene (-1327 mmol) in tetrahydrofuran (50 mL) was added. A solution of sodium hydroxide (0.72 g) in water (3.5 ml) was added to the above mixture and the mixture was stirred at room temperature for 2 hours. The tetrahydrofuran was evaporated in vacuo and the residue was extracted with chloroform (2 x 100 mL). The extract was dried over sodium sulfate and filtered; evaporation of the solvent in vacuo. The crude product is co-crystallized from n-hexane. Yield: 1.2 g (57.1%)

95-96 ° C.

DD example

2- (N-Ethoxy-carbonyl] amino) -5,6-dimethoxy-benzaldehyde

2- (N-Eloxycarbonylamino) -5,6-dimethoxybenzaldehyde ethylene ketal (5.0 g, 16.8 mmol) was dissolved in acetone (36 mL) and aqueous 1N hydrochloric acid (3 mL) was added. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo;

3.9 g of a yellow product are obtained. The resulting material was recrystallized from n-hexane to give a yellow crude product. Yield: 3.6 g (84.7%)

M.p. 86-88 ° C.

Example EE

6,6-dimethoxy-2 (1H-quinazolinone

A solution of 12.4 g (48.9 mmol) of 2- (N-ethoxycarbonylamino) -5,6-dimethoxybenzaldehyde and 95 g of ammonium acetate was bubbled through anhydrous ammonia gas at 155-160 ° C for 3 hours. . The reaction mixture was cooled and poured into ice-water. A tan solid is formed. The aqueous mixture was treated with 50 g of sodium chloride and extracted with 3 x 200 ml of chloroform. The organic extracts were combined and the solvent was evaporated in vacuo; 9.2 g of a pale yellow oil are obtained. The resulting oil was triturated with hot acetone; yellow product. Yield: 2.1 g (20.8%).

Mp 242-244 ° C.

FE example

3,4-dihydro-5,6-dimethoxy-4-methylpyridin-2 (III) -quinazolinone

10.0 g (48.5 mmol) of 5,6-dimethoxy-2 (1H) -quinazolinone are dissolved in 1100 ml of anhydrous telrahydrofuran; 62.60 ml of methyl magnesium bromide are added to the solution under a stream of nitrogen gas at 0 ° C for 20 minutes.

A solution of 3.1 M in ether (194.06 mmol) was added. The reaction mixture was then removed from the ice bath, allowed to cool to room temperature, and stirred for 16 hours. An additional 15.65 mL of methyl magnesium bromide (3.1 N ether solution, 48.52 mmol) was added to the above mixture and the reaction mixture was refluxed for 2 hours. The mixture was cooled in an ice-water bath and aqueous ammonium chloride solution was added with stirring. (100 mL of saturated ammonium chloride and 100 mL of water.) After addition was complete, the pI was adjusted to about 6.0 with 10% aqueous hydrochloric acid. The phases are separated and the aqueous phase is extracted three times with 250 ml each of 250 ml of chloroform. The chloroform extract was combined with the previously separated tetrahydrofuran phase, washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. During filtration, the solution was concentrated to 250 inl: an off-white precipitate was obtained which was filtered off and recrystallized from 200 ml of isopropanol; a colorless solid is obtained.

9.7 g (87.8%).

Mp 210-212 ° C.

GG example

5,6-d. Loxi-4-niel, γ-2 (1H) -quinazolinone

25.6 g (162.38 mmol) of potassium pentanenalenal are added to a solution of 18.04 g (81.19 mmol) of 3,4-dihydro-5,6-dimethyloxy-4-methyl-2 (1'-clnazolinone in 5 L of acetone), the mixture was stirred at room temperature under nitrogen for 96 hours, protected from light, covered with aluminum foil Λ The brown precipitate was filtered off, washed with 500 ml of acetone, partially dissolved in 1000 ml of hot water. Extract four times with chloroform (250 ml), extract with 10% isopropyl alcohol / ethyl acelate (250 ml), dry the chloroform extract, filter, concentrate to 500 ml to give a solid. The solid precipitate was filtered off and the filtrate was further concentrated in vacuo to give a brownish precipitate (3.25 g) which was chromatographed on a column of 350 g of SILICAU in chloroform. Chloroform (2% methanol) was used to obtain 1.92 g of a yellow solid which was recrystallized from 75 ml of isopropanol. A yellow product is obtained; Yield: 0.940 g (5.3%).

230-232 ° C.

In the above process, if 3,4-dihydro-5,6-dimethoxy-4-trifluoromethyl-2 (1H) -quinazolinone, 3,4-dihydro-5,6-dimethoxy-4-isopropyl-2 (II) -quinazolinone respectively. 3,4-Dihydro-4-cyclohexyl-5,6-dimethoxy-2 (1H, -quinazolone)

-1429 instead of 3,4-dihydro-5,6-dimethoxy-4-methyl-2 (1H) -quinazolinone, the corresponding 5,6-dimethoxy-4-trifluoromethyl-2 (1H) -quinazolinone, 6-Dimethoxy-4-isopropyl-2 (1H) -quinazolinone and 4-cyclohexyl-5,6-dimethoxy-2 (1H) -quinazolinone are obtained.

Example HH

2- (N-ethoxycarbonyl-kafbonil-ylamino) -5-methoxyacetophenone

Ethyl chloroformate (8.6 g, 0.80 mol) was added gently with stirring to 2-amino-5-methoxyacetophenone (8.0 g, 0.0479 mol) while cooling the reaction mixture.

Dissolve 3.2 g of sodium hydroxide in 15 ml of water and add slowly to the above mixture. An exothermic reaction is initiated and all solids dissolve. The yellow reaction mixture was removed from the ice bath and stirred at room temperature for 2 hours. The reaction mixture was then extracted with chloroform (3 x 100 mL), dried over sodium sulfate, filtered; evaporation of the solvent in vacuo gave yellow products. Recrystallization from hexane gave a yellow solid. Yield: 7.4 g (65%).

90-92 ° C.

II. example

6 ineloxi-4-i> trichloro--2 (LHI-quinazolinone

A solution of 14.0 g (0.058 mol) of 2- (N-ethoxycarbonylamino) -5-methoxyacetophenone and ammonium acetate was bubbled through anhydrous ammonia gas at 155-160 ° C for 3 hours. The reaction mixture was cooled and poured into 750 ml of ice water. This gives a dark orange solution. The solution was extracted with methylene chloride (500 mL), twice with ethyl acetate (3 x 500 mL), and n-butanol (500 mL). The combined organic extracts were dried over sodium sulfate and the solvent removed to give a brown residue. The residue is suspended in acetone, the insoluble material is filtered off to give a pale yellow product. 3.25 g (25%) mp 232-236 ° C (dec).

JJ. example

4-methyl-7-methoxy-2 (lH) quinazolinone ~

A mixture of 32.5 g (0.156 mmol) of 1-acetyl-3- (3-methoxyphenyl) urea and 912.5 g of polyphosphoric acid was heated at 120-130 ° C for 2 hours. The melt was cooled to 50 ° C, poured into 2 J ice water, and the solution was made slightly basic with ammonia and allowed to stand overnight. A brownish-red precipitate formed, which was filtered, washed with cold water, then hot acetone, and recrystallized from ethanol. (Activated charcoal is used for this step.) A pale yellow color is obtained; Yield: 11.5 g (39.1%).

M.p. 251-254 ° C.

Claims (5)

PATENT IGftNYI'ONT A process for the preparation of the substituted hydroxy-2 (III) -quinazolinone derivatives of the formula (I) and the acid addition, alkaline, alkaline earth metal and quaternary salts thereof, as well as the anino, amino alcohol and amino acid salts thereof, Hz is hydrogen, C1-C15 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl; C 1 -C 4 alkyl or 1 to 3-membered tri-haloalkyl, U3 and R1 are independently hydrogen or C1-C4 alkyl, R5 is a second valence bond at the 3-4 position or, when there is a bond at the 3-4 position, a C1-C4 alkyl group, X is benzyl, carboxyl or (C 1-6 alkoxy) carbonyl; Y and Z are bidroxiceoporl, provided that the hydroxy groups are in the 5,6- or 6,7-position, characterized in that a) for the preparation of the substituted quinolinone derivatives of the formula (I) wherein Rz, Ra, R1 and Y are as defined herein and R5 is the second bond of the 3-4 position; reacting a compound of formula (II) wherein Π2 is as defined above and R is methyl, with an olefin of formula (K) in the presence of a base, and the resulting compound of formula (II) wherein R2, R1, FU and X are above treated with acid, or b) for the preparation of the substituted quinazolinone derivatives of the formula (I) wherein R 2, R a, R 4 and X are as defined above, R 5 is a C 1 -C 4 alkyl group of the general formula (I); reacting a compound of formula wherein Rz is as defined above and R is lower alkyl, with an olefin of formula X In formula -1531, Rs and R1 are the same as in the subject stone, then α-kapotL (II) is reacted with an iodide compound of the formula RsJ - Rs is a C1-C4 alkyl group and the resulting compound of formula IIa is obtained. reacting a compound of the formula wherein Rz, Rs, R1 and R5 are as defined above and X 'is J with hydrogen halide, then hydrogenating the resulting salt and optionally obtaining the compound of formula (I) wherein X is carboxyl. The compound of formula (X) is esterified to a compound containing a (C1 -C6) alkoxy-carbonyl group in X and, if desired, the compound obtained by any of the above processes is converted to a salt thereof. Process (a) according to claim 1 for the preparation of compounds of general formula (V) having the formula: wherein R 1 is hydrogen or methyl, R 1 is hydrogen and X is carboxyl or methoxycarbopylceoport. acrylic acid methyl ester or crotonic acid methyl ester. Method b) according to claim 1 5 for the preparation of compounds of formula (IV) having a methyl group, wherein the iodide compound is methyl iodidol. Process b) according to claim 1, wherein the horse has the formula (IV) wherein R3 is hydrogen or methyl, R1 is hydrogen and X is carboxyl or methoxycarbonyl. 15, wherein the olefin is an acrylic acid methyl ester or a crotonic acid methyl ester. 5. A process for the preparation of a medicament for the treatment of hypertension and other cardiovascular disorders, which comprises as an active ingredient a compound of the formula I according to claim 1, wherein Y, Z, R2, R5, R1, R5 and X represents 2) as defined in claim 1, mixed with pharmaceutically acceptable excipients and carriers, to form a pharmaceutical composition. 3 drawings