CS207672B2 - Method of making the piperazinylchinazoline derivatives - Google Patents

Description

(54) A method for producing piperazinylquinazoline derivatives

The invention relates to a process for the preparation of therapeutically effective novel 4-amino-2- (1-piperazinyl or 1-homopiperazinyl) quinazoline derivatives. Said compounds are useful as regulators of the cardiovascular system and in particular for the treatment of hypertension.

The novel compounds of the invention correspond to the general formula I,

wherein (R) represents a 6,7-dialkoxy group wherein each alkoxy group contains 1 to 6 carbon atoms, or a 6,7,8-trialkoxy group wherein each alkoxy group contains 1 to 6 carbon atoms, m is 1 or 2,

X is -CHR ¹ '- or -CH-CH 2 -,

11 C. C.

each of R, R and R, which may be the same or different, represents a hydrogen atom or a C 1 -C 6 alkyl group, and each of R ² and R ³ , which may be the same or different, represents a hydrogen atom, an alkyl (C 1 -C 6) alkoxy, (C 1 -C 6) alkoxy, halogen, (C 2 -C 6) alkanoyl, (C 1 -C 6) alkoxycarbonyl, or -SO-NR 6 R 6;

A K 'wherein each of R and R, which may be the same or different, represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

The invention also includes pharmaceutically acceptable acid addition salts of these compounds.

Halogen atoms are fluorine, chlorine, bromine and iodine atoms. All alkyl, alkoxy and alkanoyl groups may be straight or branched chain and preferably contain up to 4 carbon atoms.

Pharmaceutically useful acid addition salts of the compounds of the invention are those derived from non-toxic acid addition salts comprising pharmaceutically acceptable anions such as hydrohalides, hydrobromides, sulfates or bisulfates, phosphates or acid phosphates, acetates, maleates, fumarates, succinates, lactates, tartrates, citrates, gluconates, saccharates and p-toluenesulfonates.

One preferred group of compounds of the present invention are compounds of formula IA,

(IA) wherein (R) _n represents a 6,7-dialkoxy group in which each alkoxy group contains 1 to 6 carbon atoms, or a 6,7,8-trialkoxy group in which each alkoxy group contains 1 to 6 carbon atoms,

R ¹ represents a hydrogen atom or a C 1 -C 6 alkyl group and each of R ⁸ and R ⁷ , which may be the same or different, represents a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a radical of from 2 to 6 carbon atoms or a radical of the formula -SOgNR R, where each of R ⁴ and R ⁴ , which may be the same or different, each represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; And pharmaceutically acceptable acid addition salts thereof.

Another preferred group of compounds of the invention are those compounds of formula (I) wherein (R) _n is 6,7-dimethoxy, 6,7-diethoxy, or 6,7,8-trimethoxy, m is 1 or 2; R @ ¹ , R @ ¹ and R @ ¹¹ are each independently hydrogen or methyl and

3, each of R and R, which may be the same or different, represents a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a C 2 -C 6 alkanoyl group, an alkoxycarbonyl group containing in the alkoxy moiety of 1 to 6 carbon atoms or the moiety -SOgNCCH3)

The most preferred compounds of the invention correspond to the general formula IB,

(IB) in which

R ¹ represents a hydrogen atom or a methyl group and p * 5, each of R and R ^j is hydrogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, a halogen atom or an alkanoyl group having 2-6 carbon atoms .

The most preferred individual compound of the invention is 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) -1-piperazinyl] -6,7-dimethoxyquinazoline.

Compounds of the invention containing one or more centers of asymmetry may exist in one or more pairs of enantiomers and these pairs as well as individual isomers may be separated by physical methods, for example, fractional crystallization of suitable salts. The invention includes separate pairs as well as mixtures thereof, racemic mixtures, and separated optically active d- and 1-isomeric forms.

If X is ~ CHR3 ^! where R ¹ is C 1 -C 6 alkyl, cis- and trans-isomerism is possible and both isomeric forms as well as mixtures thereof are within the scope of the invention.

One possible process for the preparation of the compounds of the above general formula (I) is described in our related Czechoslovak patent specification No. 207 671.

In accordance with the invention, the compounds of formula (I) and their salts are prepared by quinazoline of formula (II),

wherein the individual symbols are as defined above, reacted with a carboxylic acid of formula III,

(III)

COOH in which the individual symbols are as defined above, or with a functional qualiant thereof as an acylating agent, for example with a chloride or bromide, an activated ester or a mixed anhydride of a compound of the formula III, and optionally obtained by the reaction of a non-toxic acid for its pharmaceutically acceptable acid addition salt.

The chlorides or bromides of the aforementioned acid may be prepared in a conventional manner, for example by reaction of the free acid with thionyl chloride, respectively. thionyl bromide.

The preferred activated ester is the succinimido formula IV ° - _X ⁰ Y ~ O4

C-O-N .1 (IV) wherein each general symbol is as defined above. This ester can be prepared in a conventional manner, for example by reacting the corresponding free acid with N-hydroxysuccinimide in the presence of a dehydrating agent, for example dicyclohexylcarbodiimide. Another preferred activated ester is phthalimidoester.

(IN)

Suitable mixed anhydrides correspond to the general formula V, 2

II

C-Y in which

Y is lower alkyl or lower alkoxy, most preferably tert-butyl or isobutyloxy, and the remaining general symbols are as defined above.

These mixed anhydrides may be prepared in a conventional manner, for example by reacting the free acid with an appropriate lower alkanoyl chloride or lower alkyl chloroformate, for example with pivaloyl chloride or isobutyl chloroformate, in the presence of a base such as triethylamine.

When the free acid of formula III is used, the reaction is generally to be carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.

Preferably, the compounds of formula III are used in the reaction in the form of their chlorides or bromides. *

According to a typical embodiment using an acid chloride of formula III, the acid chloride in a suitable solvent, for example methylene chloride, is added dropwise to a stirred suspension of the quinazoline of formula II in a suitable solvent, for example methylene chloride. The reaction mixture can then be stirred at room temperature for several hours, the resulting solid product filtered off and purified in the usual manner.

If X represents a radical -CHR ¹ '- in which R ¹¹ represents an alkyl group having 1 to 6 carbon atoms, the cis- and trans-isomerism mentioned above is possible.

The starting materials of formulas II and III can be prepared in a conventional manner.

The pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared in a conventional manner, for example by reacting the free base with the appropriate acid in an inert organic solvent, and filtering out the precipitated salt. If desired, the product obtained can be purified by recrystallization. The products prepared according to the process of the invention often result in the form of acid addition salts.

The antihypertensive activity of the compounds of the invention demonstrates their ability to reduce the blood pressure of awake, spontaneously hypertensive rats and awake, renally hypertensive dogs when administered orally at doses up to 5 mg / kg.

The results of the antihypertensive activity assays of a number of compounds of the invention are presented below. · '

In these tests, the compounds of the invention were administered orally (usually in a mixture of dimethylacetamide and water) at a dose of 5 mg / kg to spontaneously hypertensive rats. Blood pressure was recorded and measured using an animal's tail cuff. The results were calculated using the following formula:

blood pressure drop in% = actual blood pressure drop (Pa) x 100 blood pressure before administration of test substance (Pa) - 17 392

the results are summarized in the following tables: compound maximum decrease time needed to from example no. blood pressure («) reduction of maximum decrease (h) 1 119 1 2 81 6 3 22nd 1 4 67 6 5 116 2 6 58 1 7 100 ALIGN! 1 8 33 6 9 83 6 10 109 2 1 1 102 6 12 72 1 13 90 6 14 40 4 15 Dec 92 1 16 85 4 17 40 1 18 79 1 19 Dec 56 1 20 May 47 6 21 30 4

The compounds produced by the method of the invention may be administered alone, but are generally administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing, for example, starch or lactose as carriers, or in the form of capsules containing the active substances either alone or in admixture with carriers and / or excipients, or elixirs or suspensions containing additives or dyes. The compounds produced by the method of the invention may further be administered parenterally in the form of injections, for example, intramuscular, intravenous or subcutaneous injections.

For parenteral administration, the disclosed compounds are best used in the form of sterile aqueous solutions which may contain other soluble substances, for example, an appropriate amount of sodium chloride or glucose to ensure the isotonic nature of the solution.

Accordingly, the invention also provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The compounds produced by the method of the invention may be administered orally or parenterally to humans for the treatment of hypertension. For oral administration, an average adult patient (70 kg) is administered a dose ranging from about 1 to 20 mg / day, in a single dose or divided into three divided doses. Intravenous administration is expected to be a gross 1/5 to 1/10 daily oral dose. Thus, for an average adult patient, an individual oral dosage in the form of a tablet or capsule will range from about 1 to 50 mg of the active ingredient. Of course, variations will necessarily occur in the present case depending on the weight and condition of the subject being treated and the route of administration chosen, as is common in the art.

The invention further provides a method of treating hypertensive animals, including humans, comprising administering to said animal an antihypertensively effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition as defined above.

The invention is illustrated by the following non-limiting examples.

Example 1

4-Amino-2- [4- (6-methoxy-1,4-benzodioxane-2-carbonyl) -1-piperazinyl] -6,7-dimethoxyquinazo-

To a suspension of 2.48 g of 4-amino-2-piperazin-1-yl-6,7-dimethoxyquinazoline in 60 ml of methylene chloride is added dropwise a solution of 2.17 g of 6-methoxy-1,4-benzodioxan-2 with stirring at room temperature. -carbonyl chloride (prepared from acid and thionyl chloride) in 25 ml of dichloromethane. After the addition was complete, the mixture was stirred at room temperature for 4 hours, then filtered, the solid material was suspended in aqueous potassium carbonate solution and extracted with chloroform. The combined extracts were washed with water, dried over sodium sulfate and evaporated in vacuo to give a solid residue (4.15 g) which was chromatographed on 160 g of silica gel using chloroform first and then chloroform with 2.5% methanol as eluent. Fractions which are identical by thin layer chromatography are combined, concentrated in vacuo, taken up in ethyl acetate / methanol, and ethereal hydrogen chloride is added to the solution. Addition of additional ether followed by cooling gave a solid material which was filtered and recrystallized from methanol to give 0.95 g of 4-amino-2- [4- (6-methoxy-1,4-benzodioxane-2-carbonyl) -1- piperazinyl] -6,7-dimethoxyquinazoline hydrochloride hydrate, m.p. 220-222 ° C.

Analysis for calculated:

found:

^C 24 ^H 27 ^N 5 ° 6 - ^HCl - ^H 2 °

C 53.8%, C 53.3%,

H 5.6 «, H 5.5%,

N 13.1% and N 13.4%.

In analogy to Example 1, the following compounds were prepared from 4-amino-2-piperazin-1-yl (or 2- [3-methyl-1-piperazinyl)) - 6,7-dimethoxyquinazoline and the corresponding carbonyl chloride:

In ch ₃ o.

CH ₃ O '

NH, example Z number

isolated form and melting point (° C) analysis (%) found (calculated) C H N hydrochloride- 56.2 5.4 13, -Hemihydrate (56.4 5.7 13, 238 ° to 240 °

example ZR ¹ number

(mixture of 8- and 5-isomers)

mixture of cis, trans

isolated form and melting point (° C) analysis (%) found (calculated) C H N hydrochloride- 58.0 6.2 13.3 -Hemihydrate 225-230 ° (57.9 6.2 13.0) hydrochloride- 57.5 5.8 13.3 -Hemihydrate 286 DEG-288 DEG (57.2 6.0 13.3) hydrochloride- 54.1 5.5 13.9 -Hemihydrate 268 to 270 ° (54.7 5.5 13.3) hydrochloride- 53.4 5.3 12.8 -hydrate 230 ° (decomposition) (53.8 5.6 13.1) hydrochloride- 52.3 4.8 12.8 hydrate 280 to 281 (52.0 4.9 13.2) hemihydrate 52.5 4.3 ’3.2 242 DEG-243 DEG (52.2 4.6 13.2) hydrochloride 279-280 ° 56.5 5.6 14.1 % = -99.3 (0.4 v in dimethylformamide) (56.6 5.4 14.4) hydrochloride 284-286 ° 56.2 5.4 14.5 rf _D = + 95 ° (0.4% in dimethylformamide) (56.6 5.4 14.4) hydrochloride- 55.0 5.5 13.6 -hydrate 237 DEG-240 DEG (55.4 5.8 13,5) hydrochloride- 55.8 5.7 13.1 -hydrate 242 DEG-243 DEG (55.4 5.8 13,5)

trance

example number OF R 13 'It cis H 14 ch ₃ H 15 Dec H 16 ^ch 3 Q H 17 / ° VAi: CH, XXj- ^s ° < ^x CH ₃ (mixture of 6- and 7-isomers) H 18 xn H

isolated form and melting point (° C) analysis (%) found (calculated) C H N hydro- chloride- 54.0 5.5 12.7 -dihydrate 214-215 ° (53.6 6.0 13.0) hydrochloride- 55.6 5.4 13.3 -hydrate 234-237 ° (55.4 5.8 13,5) hydrochloride- 55.6 5.2 13.0 -Hemihydrate 272 ° (55.7 5.4 13.0) hydrochloride- 54.4 5.2 12.8 -hydrate 230 ° (54.8 5.5 12.8) hydrochloride- 48.6 5.3 13.5 -hydrate 232-234 ° (rozkled) (49.0 5.4 13.7) -hydrochlorid- 55.3 6.1 12.9 - sesquimethanolate 205-207 ° (55.7 6.2 12.7)

CH 2 oxalate sesquihydrate 176-179 °

H hydrochloride dihydrate 208-210 ° (hygroscopic

53.8 5.4 11.6 (53.6 5.5 12.0)

52.2 5.2 11.4 (52.4 5.8 11.8)

4-Amino-6,7-dimethoxy-2- [4- (6- and 7-carbamoyl-1,4-benzodioxane-2-carbonyl) piperazino] quinazoline hydrochloride

To a solution of 2.23 g of a mixture of 6- and 7-carbamoyl-1,4-benzodioxane-2-carboxylic acid in 70 ml of dimethylformamide at 0 ° C is added 2.06 g of dicyclohexylcarbodiimide and 1.15 g of N-hydroxysuccinimide at 0 ° C. .

The mixture is stirred at 0 ° C for 1 hour, then 2.8 g of 4-amino-6,7-dimethoxy-2-piperazinoquinazoline are added, the reaction mixture is stirred at room temperature overnight, then filtered, the filtrate is filtered. Dilute with 500 mL of ether and collect the precipitated oil. The product was partitioned between chloroform, isopropanol and sodium bicarbonate solution, the chloroform layer was separated, washed with water and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform containing 3% methanol as eluent. The crude product was treated with ethereal hydrogen chloride solution. Subsequent recrystallization first from a mixture of methanol, water, ether and dimethylformamide and then from a mixture of methanol, water and dimethylformamide affords 4-amino-6,7-dimethoxy-2- [4- (6- and 7-carbamoyl-1,4- benzodioxane-2-carbonyl) piperazinoquinazoline hydrochloride hydrate, melting at 228-235 ° C with decomposition.

After further recrystallization, an analytical sample with a melting point of 245-248 ° C is obtained.

Analysis: for Cj ^HpgNNgOgHHClíO O

calculated: C 52.5%, H 5.3%, N 15.3%; found: C 52.6%, H 5.5%, N, 14.6%. According to high pressure liquid chromatography is a product consisting of a mixture of 6- and 7-isomers 7: : 3.

The following preparations illustrate the preparation of certain starting materials.

Preparation 1

6-Methoxy-1,4-benzodioxane-2-carboxylic acid

To a suspension of 4.52 g of 2-hydroxymethyl-6-methoxy-1,4-benzodioxane in a solution of potassium hydroxide (1.47 g of hydroxide in 42 mL) of water) is added in 4 portions of 5.02 with stirring at 5 ° C. g finely divided potassium permanganate. During the reaction, the temperature was maintained at 5 to 15 ° C, after completion of the addition, the reaction mixture was stirred at room temperature for 4 hours, then allowed to stand overnight.

The manganese dioxide is filtered off, the solid residue is washed with water, the combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid and, after cooling, extracted with chloroform. The combined chloroform extracts are washed twice with 40 ml of 5N sodium hydroxide solution each time, the alkaline phase is further washed with chloroform, cooled, acidified to pH 1 with concentrated hydrochloric acid and extracted again with chloroform. The latter chloroform solution was washed with water, dried over sodium sulfate and evaporated to a residue of 2.33 g of crude 6-methoxy-1,4-benzodioxane-2-carboxylic acid.

The product sample melts 120-121 ° C after recrystallization from water.

Analysis: Calculated: C 57.1%, H 4.8%;

Found: C 57.1%, H 4.8%.

Preparation 2

A mixture of 8- and 5-isopropyl-1,4-benzodioxane-2-carboxylic acid (A) A solution of 3-isopropylcatechol (23 g) in acetone (250 ml) was heated to reflux and potassium carbonate (28 g) was added. The heterogeneous mixture was refluxed for 15 minutes, then 10 g of methyl 2,3-dibromopropionate was added dropwise. 3 more portions of potassium carbonate (28 g) and methyl 2,3-dibromopropionate (10 g) were added in a similar manner, the resulting mixture was refluxed for 12 hours, then evaporated, the residue was diluted with 700 ml of water, It is extracted with chloroform, the combined extracts are washed with water and, after drying over magnesium sulphate, evaporated. Distillation of the oily residue yielded 29.3 g of methyl 8 (S) -a-propyl-1,4-benzodioxane-2-carboxylate, b.p. 115-120 ° C. According to NMR spectroscopy ⁽¹³ C) product is a mixture of 8- and 5-isomers (71% A29 ").

(B) 29.0 g of the above product was heated to 100 ° C in 160 ml of 2.5N sodium hydroxide solution for 0.5 hour, the resulting solution was cooled and acidified with concentrated hydrochloric acid. The mixture was extracted with chloroform (3 x 200 ml), the combined extracts dried (MgSO4) and evaporated in vacuo to give an oil (18g) which solidified on standing. Recrystallization from methanol gave a mixture of 8- and 5-isopropyl-1,4-benzodioxane-2-carboxylic acid, m.p. 86-88 ° C.

H, 6.3; Found: C, 64.7; H, 6.3;

According to high pressure liquid chromatography, the product is a mixture of the 8-isomer (86%) and the 5-isomer (13%).

Preparation 3

A mixture of 8- and 5-methyl-1,4-benzodioxane-2-carboxylic acid

To a suspension of 20 g of a mixture of 8- and 5-methyl-2-hydroxymethyl-1,4-benzodioxane in a solution of potassium hydroxide (6.5 g of potassium hydroxide in 187 ml of water) is added in 3 portions with stirring at 5 ° C. , 15 g of potassium permanganate. During the addition, the reaction temperature was kept below 15 ° C and after completion of the addition, the reaction mixture was stirred at room temperature for 4 hours. The manganese dioxide is filtered off, the filtrate is cooled, acidified with concentrated hydrochloric acid and the oily product which precipitates after further cooling is extracted with chloroform. The chloroform extracts were washed with 5N sodium hydroxide solution, the basic layer was washed with chloroform and then acidified to pH 1 with concentrated hydrochloric acid. The acidic solution was extracted with chloroform, the combined extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo.

7.3 g of a mixture of 8- and 5-methyl-1,4-benzodioxane-2-carboxylic acid are obtained in the form of a syrupy residue with corresponding spectroscopic characteristics. A small sample of the product is esterified with diazomethane and the resulting product is a 5: 2 mixture of the above isomers according to gas chromatography.

Preparation 4

6,7-Dimethyl-1,4-benzodioxane-2-carboxylic acid

OH

OH

Br

Br (a)

(b) ch ₃ ch ₃

every ₂ h (A) A solution of 7.0 g of 4,5-dimethylcatechol in 45 ml of dry acetone is heated to reflux with stirring, after which 5 g of potassium carbonate are first added thereto, followed by the dropwise addition of 3.5 g. g of ethyl dibromopropionate.

This addition was repeated three more times for 1 1/4 hour, after which the reaction mixture was stirred at reflux for a further 3/4 hours. After cooling, the mixture was filtered, the solids were washed thoroughly with acetone, and the combined filtrates were concentrated in vacuo. Water (35 ml) was added to the residue and the precipitated solid was collected, washed with petroleum ether and taken up in ether. The ether solution was washed with water and dried over sodium sulfate and evaporated in vacuo. 10.17 g of ethyl 6,7-dimethyl-1,4-benzodioxane-2-carboxylate are obtained, m.p. 70-71 ° C.

Analysis: Calculated: C 66.1%, H 6.8%. Found: C 65.7%, H 6.8%.

(B) Hydrolysis of 5.0 g of the above ester of 13 ml of 10% sodium hydroxide in 125 ml of ethanol as described for related compounds [see JACS, 77. 5374 (1956)] afforded 4.04 g of crude 6,7-dimethyl- 1,4-benzodioxane-2-carboxylic acid. A sample of the product melts after recrystallization from water at 150-151 ° C.

Analysis: calculated for C 11 H ₁₂ O ₄ ; C 63.5%, H 5.8%;

Found: C 63.9%, H 6.0%.

Preparation 5

6,7-Dichloro-1,4-benzodioxane-2-carboxylic acid

Hydrolysis of 5.0 g of ethyl 6,7-dichloro-1,4-benzodioxane-2-carboxylate with 10.9 ml of 0% sodium hydroxide in 50 ml of ethanol gave 3.4 g of 6,7-dichloro-1,4 -benzodioxane-2-carboxylic acid having a melting point of 155-158 ° C, which has the corresponding NMR spectrum and has the same Rf value as the authentic sample in thin layer chromatography.

Preparation 6

8-Methoxy-1,4-benzodioxane-2-carboxylic acid

2.41 g of 8-methoxy-1,4-benzodioxane-2-carboxamide in 35 ml of 50% hydrochloric acid was stirred at 100 ° C for 1 hour. The solution was cooled, diluted with water (200 ml), extracted with chloroform (3.times.100 ml), dried (MgSO4) and evaporated in vacuo. The solid residue (1.8 g) was recrystallized from water (m.p. 75-78 ° C) and then ethyl acetate / hexane to give 8-methoxy-1,4-benzodioxane-2-carboxylic acid, m.p. to 132 ° C.

Analysis: Calculated: C 57.1%, H 4.8%;

Found: C 56.9%, H 4.8%.

Preparation 7 *

5-Methoxy-1,4-benzodioxane-2-carboxylic acid

This compound was prepared according to the procedure described in Preparation 6, starting from 5-methoxy-1,4-benzodioxane-2-carboxamide. The product was crystallized first from water (m.p. 85-87 ° C) and then from ethyl acetate-hexane to give 5-methoxy-1,4-benzodioxane-2-carboxylic acid, mp 139-41 ° C.

Analysis calculated for: CΟΟ ΗΗΟΟ: C 57.1%, H 4.8%;

Found: C 56.9%, H 4.8%.

Preparation 8

6-Acetyl-1,4-benzodioxane-2-carboxylic acid

To a solution of 4.0 g of 6-acetyl-2-hydroxymethyl-1,4-benzodioxane in 70 ml of acetone was added dropwise 11.6 ml of Jones reagent while stirring at 10-15 ° C. The reaction mixture was stirred at room temperature for 18 hours, then diluted with a mixture of isopropanol, water and chloroform, the organic layer was separated and evaporated in vacuo. The residue was redissolved in chloroform, extracted twice with 30 ml of saturated sodium carbonate solution each time, the basic phases were washed with chloroform, cooled and acidified to pH 1 with concentrated hydrochloric acid.

The acidic solution is extracted with chloroform, the combined extracts are washed with saturated sodium chloride solution and, after drying over sodium sulfate, evaporated in vacuo. 1.56 g of 6-acetyl-1,4-benzodioxane-2-carboxylic acid of melting point 159 DEG-162 DEG C. are obtained. A sample of the product melts after recrystallization from ethanol-ethyl acetate at 174-175 ° C.

Analysis calculated: C 59.5%, H 4.5%;

Found: C 59.0%, H 4.8%.

Preparation 9

7-Acetyl-1,4-benzodioxane-2-carboxylic acid (A) To a suspension of 15.1 g of 3,4-dihydroxyacetophenone and 28 g of anhydrous potassium carbonate in 100 ml of acetone is added dropwise while stirring and refluxing at 0, A solution of 13 ml of methyl 1,3-dibromopropionate in 50 ml of acetone for 5 hours. The reaction mixture was refluxed under stirring for 4 hours, then evaporated in vacuo and the residue partitioned between chloroform and water. The chloroform extracts were washed with water and, after drying over magnesium sulfate, evaporated. The 18 g residue is a 2: 1 mixture of 6- and 7-acetyl-1,4-benzodioxane-2-carboxylic acid methyl esters (as shown by NMR spectroscopy (C ¹³ )). A sample of this crude product was recrystallized from isopropanol 68-80 ⁶ C. Analysis for θ] 2 ^Η, 2θ5 calculated: C 61.0%, H 5.1%;

Found: C 60.7%, H 4.9% · (Β) To a solution of 7 g of the product prepared in (A) in 25 ml of ethanol is added aqueous sodium hydroxide solution (1.2 g) with stirring at 15 ° C. sodium hydroxide in 5 ml of water). The reaction temperature was kept below 25 ° C for 0.5 h, then the mixture was evaporated in vacuo. The residue was triturated with water, acidified with concentrated hydrochloric acid and extracted with chloroform. The combined chloroform extracts were dried over magnesium sulphate, evaporated in vacuo and the 1.46 g residue was recrystallized from ethyl acetate-methanol. 7-Acetyl-1,4-benzodioxane-2-carboxylic acid is obtained, m.p. 167-168 ° C.

H, 4.5; found: C, 59.0; H, 4.5;

According to HPLC, the purity of the isomers is about 96%.

The acidic aqueous phase is evaporated in vacuo, the residue is extracted with methanol, the combined extracts are evaporated in vacuo and the product (5.5 g) is recrystallized from a mixture of ethyl acetate and methanol. 6-Acetyl-1,4-benzodioxane-2-carboxylic acid is obtained. According to high pressure liquid chromatography, the product contains only a single component corresponding to an authentic sample prepared as described in Preparation 8.

Preparation 10 (A) (+) - 1,4-Benzodioxane-2-carboxylic acid

21.6 g of 1,4-benzodioxane-2-carboxylic acid and 34.26 g of (+) - dehydroabietylamine are mixed in 1000 ml of hot ethanol denatured with methanol and the mixture is allowed to stand at room temperature for 24 hours. The precipitate formed (20 g) was collected, the filtrate was concentrated to a volume of 600 ml and left to stand for 48 hours, leaving an additional 4 g of solid product. The combined products (24 g, m.p. 204-210 ° C) were repeatedly crystallized from a mixture of denatured ethanol and methanol to a constant melting point of 229-230 ° C to give 3.0 g of a product of this melting point. The mother liquors from the last two crystallizations were combined, concentrated and the resulting 4.6 g solid collected. The salt obtained is converted in a standard manner to a free carboxylic acid of 5.5 g and optical rotation [alpha] _D = + 60.1 [deg.] (1% solution in chloroform). After recrystallization twice from toluene, this product yields 0.23 g of (+) - 1,4-benzodioxane-2-carboxylic acid, m.p. 98 DEG-99 DEG C. and optical rotation .alpha. = + 62.1 DEG (1% v / v solution). chloroform).

For C 8 H 8 O 4 calculated: C 60.0%, H 4.5%;

Found: C 60.3%, H 4.4%.

(B) (-) - 1,4-Benzodioxane-2-carboxylic acid

The first mother liquor from the previous experiment (610 ml) was evaporated in vacuo, the oily residue was taken up in 250 ml of acetone and the solution was allowed to stand until crystallization was complete. 10.0 g of solid are isolated, which is recrystallized from acetone. 6.0 g of salt are obtained, which is converted to the free acid by standard procedure using dilute sulfuric acid. The crude product was taken up in chloroform and chromatographed on a silica gel column (10 x 50 mm column) using chloroform as eluent. The eluate was evaporated in vacuo and the residue was crystallized from toluene to give 0.90 g of (-) - 1,4-benzodioxane-2-carboxylic acid, mp 98-99 ° C and optical rotation = -66.1 ° (1% solution in chloroform).

Analysis: calculated for: C 60.0%, H 4.5%;

Found: C 59.9%, H 4.5 56.

Preparation 11

A mixture of 6- and 7-chloro-1,4-benzodioxane-2-carboxylic acid (A) To an ice-cold solution of 10 g of methyl 1,4-benzodioxane-2-carboxylate in 100 ml of chloroform in the presence of 0.06 g of chloride Alumina lists chlorine gas. The reaction was stopped after 20 minutes, the solution was purged with nitrogen, washed with water, sodium bicarbonate solution and water again, dried over sodium sulfate and evaporated in vacuo. 12.0 g of a mixture of 6- and 7-chloro-1,4-benzodioxane-2-carboxylic acid methyl esters [1: 1 by NMR spectroscopy (c ' ³ )] are obtained.

(Β) To 1.4 g of the above product in 20 ml of ethanol at room temperature was added a solution of 0.25 g of sodium hydroxide in 1 ml of water, the reaction mixture turning black.

The mixture was allowed to react at room temperature for 48 hours, then concentrated in vacuo, the residue diluted with water, extracted with chloroform and the chloroform layer discarded. The aqueous phase was acidified with concentrated hydrochloric acid, extracted with chloroform, the combined extracts were dried over magnesium sulphate and evaporated in vacuo. 1.0 g of a mixture of 6- and 7-chloro-1,4-benzodioxane-2-carboxylic acid, melting at 145 DEG -146 DEG C., having corresponding spectroscopic characteristics is obtained.

Preparation 12

2-Methyl-1,4-benzodioxane-2-carboxylic acid

To a solution of 5 g of 2-hydroxymethyl-2-methyl-1,4-benzodioxane with 300 ml of acetone, 33.3 ml of Jones reagent is added dropwise with stirring at 5 [deg.] C., the reaction mixture is allowed to warm to room temperature. first add 10 ml isopropanol and then 200 ml water. The resulting solution is extracted with chloroform, the extracts are evaporated in vacuo, the oily residue is taken up in 200 ml of chloroform, the solution is extracted with 2-dilute sodium bicarbonate solution and the aqueous phase is washed with chloroform. The aqueous phase was then acidified with hydrochloric acid and extracted with chloroform. The combined extracts were washed with water and, after drying over magnesium sulfate, evaporated in vacuo to give 1.7 g of 2-methyl-1,4-benzodioxane-2-carboxylic acid. A sample of the product melts after recrystallization from toluene at 133-134 ° C.

Analysis: calculated: C 61.9%, H 5.2%;

Found: C 61.8%, H 5.2%.

Preparation 13

Mixture of 6- and 7-N, N-dimethylsulfamoyl-1,4-benzodioxane-2-carboxylic acid (A) To 138.5 ml of sulfuric acid, 180 g of catechol are added in portions with stirring at such a rate that the reaction temperature is kept below Deň: 18 ° C. After the addition was complete, the semi-solid mixture was heated at 45 ° C for 60 minutes, then cooled to room temperature and poured into 700 ml of ice water. The solution is neutralized with solid barium carbonate, the precipitated barium sulfate is filtered off, the filtrate is acidified with concentrated sulfuric acid to pH 1 and filtered again. Evaporation of this second filtrate gave 182.40 g of crude 3,4-dihydroxybenzenesulfonic acid which was used without further purification.

(B) 182.40 g of the above product was acetylated in a standard manner using 300 ml of acetic anhydride in 800 ml of pyridine and the resulting crude diacetoxy derivative weighing 302.49 g was used directly.

(C) To a solution of 3,4-diacetoxybenzenesulfonic acid pyridine salt (302.49 g) in 1000 mL chloroform cooled to 0 ° C was added portionwise 378 g of phosphorus pentachloride with stirring at such a rate that the temperature of the reaction mixture did not exceed 15 ° C. After complete addition, the mixture was stirred at room temperature overnight, then filtered, the chloroform solution was evaporated in vacuo and the oily residue was poured into ice water.

The aqueous phase is extracted with chloroform, the combined extracts are dried over sodium sulphate and evaporated in vacuo to a semi-solid residue which is recrystallized from carbon tetrachloride.

To 26.74 g of the product thus obtained was added 265 ml of a 15% aqueous dimethylamine solution at 20 ° C, the reaction mixture was allowed to stand overnight at room temperature, then evaporated in vacuo. The dark colored residue was diluted with 250 ml of acetone, the solution was decanted off, evaporated in vacuo and the oily residue stirred for 2 hours at room temperature with an equal volume of sodium hydroxide solution. The solution was acidified with concentrated hydrochloric acid and the product crystallized from water. N, N-dimethyl-3,4-dihydroxybenzenesulfonamide, melting at 142 ° C, is obtained.

(D) To a suspension of 3.0 g of the above product and 1.43 ml of epichlorohydrin in 15 ml of water was added dropwise with stirring a solution of 0.61 g of sodium hydroxide in 5 ml of water, and the reaction mixture was heated at 80 ° C for 1.5 hours. , then cooled and extracted with methylene chloride. The combined extracts were washed with water and dried over sodium sulfate and evaporated.

2.84 g of a mixture of 6- and 7-N, N-dimethylsulfamoyl-2-hydroxyiaethyl-1,4-benzodioxane are obtained in the form of a thick oil with corresponding spectroscopic characteristics.

(E) To a suspension of 2.8 g of the above alcohol in a solution of potassium hydroxide (0.59 g of potassium hydroxide in 20 ml of water) and 10 ml of acetone cooled to 5 ° C was added 2.15 g with stirring in 3 portions. potassium permanganate such that the temperature of the reaction mixture does not exceed 10 ° C. The mixture was allowed to stand at room temperature for 3 hours, then the acetone was evaporated, an additional 1.5 g of potassium permanganate was added to the residue, stirred overnight, then an additional 3.0 g of potassium permanganate was added and the reaction mixture was stirred at room temperature. was stirred at 35-40 ° C overnight. The precipitated manganese dioxide is filtered off, washed with water, the combined filtrates are acidified with concentrated hydrochloric acid and extracted with chloroform.

201612

The combined extracts are washed twice with 40 ml of 5N sodium hydroxide solution each time, the alkaline phase is acidified with concentrated hydrochloric acid and extracted with chloroform. The combined extracts were washed with water, dried over sodium sulfate and evaporated in vacuo. 0.46 g of crude product was combined with 0.21 g of analogous material obtained by repeated extraction of the initially precipitated manganese dioxide to give 0.67 g of a mixture of 6- and 7-N, N-dimethylsulfamoyl-1,4-benzodioxane-2- 156 DEG-62 DEG.

H, 4.6%; N, 4.9. Found: C, 45.5%; H, 4.6%; N, 4.90%.

Preparation 14 cis-o trans-ethyl-3-methyl-1,4-benzodioxane-2-carboxylate

The above compounds are separated from each other by preparative high pressure liquid chromatography and in accordance with published data (see, for example, J. Med. Chem., 10.

880, 1967) were identified by NMR spectroscopy. Each of the isolated isomers was hydrolyzed to the corresponding acid, which was converted to the acid chloride without further characterization.

Preparation 15

A mixture of 6- and 7-ethoxycarbonyl-1,4-benzodioxane-2-carboxylic acid (A) To a suspension of 4.6 ml of epichlorohydrin and 8 g of ethyl 3,4-dihydroxybenzoate is added dropwise a solution of 1.94 g with stirring at room temperature. sodium hydroxide in 16 ml of water, the suspension becoming a solution. The reaction mixture was heated at 80 ° C for 1.5 hours, then cooled, extracted with dichloromethane, the extracts washed with water and dried over sodium sulfate and evaporated in vacuo. 10.87 g of a mixture of 6- and 7-ethoxycarbonyl-2-hydroxymethyl-1,4-benzodioxane as a thick oil with corresponding spectroscopic characteristics are obtained as a residue.

(B) 5.0 g of the above alcohol were oxidized with 12.3 ml of Jones reagent in 70 ml of acetone as described in Preparation 9. 1.78 g of a mixture of 6- and 7-ethoxycarbonyl-1,4-benzodioxane-2-carboxylic acid (2: 1) according to high pressure liquid chromatography with corresponding spectroscopic characteristics are obtained.

Preparation, 6

A mixture of 6- and 7-carbamoyl-1,4-benzodioxane-2-carboxylic acid (A) A suspension of 5.6 g of potassium carbonate and 2.7 g of 4-cyanocatechol in 50 ml of acetone is heated to boiling under stirring for 1/4 hour. 4.9 g of methyl 2,3-dibromopropionate are added dropwise. The resulting mixture was refluxed for 48 hours, then evaporated in vacuo, diluted with water and extracted with chloroform. The combined extracts were washed with water, dried (MgSO4) and evaporated in vacuo to give 1.0 g of a mixture of methyl 6- and -7-cyano-1,4-benzodioxane-2-carboxylate. A sample of the product melts after recrystallization from isopropanol at 95-96 ° C.

Analysis: calculated for: C 60.25%, H 4.2%;

Found: C 60.2%, H 4.2%.

According to high pressure liquid chromatography, this crude product is a 5: 2 mixture of the above two components.

Π (Β) Κ suspension of 0.5 g of the above cyanester in 4 ml of ethanol is added dropwise with stirring at 15 ° C with 0.7 ml of 6N sodium hydroxide solution and 1 ml of 30% hydrogen peroxide. The resulting mixture was heated at 40-50 ° C for 2 hours, then cooled and acidified with concentrated hydrochloric acid. The precipitated product is filtered off and recrystallized from methanol-ethanol-water to give a mixture of 6- and 7-carbamoyl-1,4-benzodioxane-2-carboxylic acid, m.p. 258 DEG-260 DEG.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of piperazinylquinazoline derivatives of the general formula I in which (R) _n represents a 6,7-dialkoxy group in which each alkoxy group contains 1 to 6 carbon atoms or a 6,7,8-trialkoxy group in which each alkoxy group contains 1 to 6 carbon atoms, having a value of 1 or 2, X is a radical -CHR '- or -CH "CH _O -, Each of R, R and R, which may be the same or different, represents a hydrogen atom or a C 1 -C 6 alkoxy group and 23 each of the R and R ^j symbols which may be the same or different, is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl or the radical of the formula -SOgNR 6; R '', wherein each of R ⁴ and R '', which may be the same or different, represents a hydrogen atom or a C 1 -C 6 alkyl group, and pharmaceutically acceptable acid addition salts thereof, characterized in that: a quinazoline of formula II, i (R), NH,. N NH IY IC _"2Fe / (II) wherein the various symbols are as hereinbefore defined, is reacted with a carboxylic acid of formula III by * -COOH (UL) R ^y '' R ¹ in which the various symbols are as hereinbefore defined, or with its functional equivalent as an acylating agent, and the resulting product of formula I is optionally converted with an acid into its non-toxic pharmaceutically-acceptable acid addition salt thereof. 2. A process according to claim 1, wherein the functional equivalent of the acid of formula (III) is its chloride, bromide or succinimido ester. 3. The process of item 1 for producing compounds of formula IA wherein (R) _n is a 6,7-dialkoxy group wherein each alkoxy group contains 1 to 6 carbon atoms or a 6,7,8-trialkoxy group wherein each alkoxy group contains 1 to 6 carbon atoms, R ¹ represents a hydrogen atom or a C 1 -C 6 alkyl group and each of R 1 and R 2, which may be the same or partial, represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a radical of 2-6 carbon atoms or a radical of the formula -SOR R wherein each of R-and R ^, which may be the same or different, each represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; carbon atoms, and pharmaceutically acceptable acid addition salts thereof, characterized in that the quinazoline of formula (IIA), (IIA) nh ₂ in which (R) _n is as defined herein, is reacted with a carboxylic acid of formula (IIIA), R ⁶ R ⁷ (IIIA) COOH in which R ¹ , R ® and R? are as defined herein, or with a functional equivalent thereof as acylating agent, and the product of formula (IA) obtained is optionally converted by reaction with a nontoxic acid into its pharmaceutically acceptable acid addition salt. ^{4 *} 4. A process according to claim 3, wherein the functional equivalent of the acid of formula (IIIA) is chloride, bromide or succinimido ester.