FI64366B - ANALOGIFICATION OF FRAMSTERING OF ANTIHYPERTENSIVE QUINAZOLINE DERIVATIVES - Google Patents

Description

j ra1. ,,. WHICH ISSUANCE SA-7S / · jtfjSfo ^ * UTLÄGG N1NGSSKRI FT 64 366 C Pot: i; Iti ry'i'r.r.V ‘1 ·· 1? il 1913 (45) n ... ί. , l ^ (51) Kv.lk. ^ InfcCI.3 C 07 D 405 / Ί2 FINLAND —FIN LAND (21) Pwenttlhtktmu * - P «t * ntin * ekplng 7033 ^ 7 (22) H» k * ml »pilrt - An »öknlng * dtg 02.11.78 (23) AlkupSlvl - Glltighetidig 02.11-78 (41) Become Public - Bllvlt offumllg 06.05.79

National Board of Patents and Registration NihtivUcipsnon j. month »» ™ date. -

Patent · och rcglsterstyrefsen Antiikin utlagd oeh utUkrlften publlcer »d 29.07.83 (32) (33) (31) Requested privilege —Begird prlorltet 05-11.77

English-English (GB) 16128/77 (71) Pfizer Corporation, Calle 15 1/2, Avenida Santa Isabel, Colon,

Panama (PA) (72) Simon Fraser Campbell, Kingsdovn, Deal Kent, England-England (GB) (7 * 0 Oy Kolster Ab (5M Analogue method for the preparation of antihypertensive quinazoline derivatives - Analogiförfarande för framställning av antihyper-tensiva .kinazolinderivat

The invention relates to an analogous process for the preparation of antihypertensive quinazoline derivatives of formula (I). (i) T T Ö XR3

1 N

nk 2 wherein m is 1 or 2, X is -CH 2 -, -CH 2 -C (H 2) - or -CH 2 -CH 2 -, R 1 is hydrogen or lower alkyl 23 and R and R, which may be the same or different, mean both to produce hydrogen, lower alkyl, lower alkoxy, halogen or lower alkanoyl, and pharmaceutically acceptable acid addition salts thereof.

2 64366

The compounds of formula I to be prepared are novel derivatives of 4-amino-2- (piperazin-1-yl or homopiperazin-1-yl) quinazoline. Such compounds are useful as regulators of the cardiovascular system and especially in the treatment of hyoertension.

In this patent, "halogen" means fluorine, chlorine, bromine or iodine The term "lower" when referring to an alkyl or alkoxy group indicates that such a straight or branched group contains from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. that such a straight-chain or branched group contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms.

Pharmaceutically acceptable acid addition salts of the compounds of the invention are those formed with acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or acid phosphate, acid phosphate, acid phosphate , fumarate, succinate, lactate, tartrate, citrate, gluconate, saccharate, and p-toluene sulfonate salts.

A preferred group of compounds are those compounds of formula I wherein m is 1, X is or -CH (CH 3) - is hydrogen.

The most preferred compound is 4-amino-2- [3- (1,4-benzodioxane-2-carbonyl) piperazin-1-yl] -6,7-dimethoxyquinazoline.

Compounds of the invention containing one or more asymmetric centers exist as one or more pairs of enantiomers, and such pairs or individual isomers may be separable by physical methods, e.g., by crystallization of appropriate salts and coconut. The novel compounds comprise both separated pairs and mixtures thereof as racemic mixtures or as separated d- and 1-optically active isomeric forms.

When X represents a group (CH 1 CH 2) - cis and trans isomers are possible.

The process according to the invention for the preparation of quinazoline derivatives of the formula I is characterized in that (A) quinazoline of the formula (II) 64 36-6 II di) ch30 nh2 in which Q represents a leaving group such as chlorine, bromine, iodine, lower alkoxy or lower alkylthio is reacted with piperazine or homopiperazine of formula (III)

Ri r2 x- <Γ X ΤΠ ««>

«N N-C -JL JL

(Yp, _ / '1 0 \ r3

im 0 R

Ί 2 3 wherein X, R "1", R, R and m are as defined above, or (B) a quinazoline of formula (VI) ^ R1 CH., 0 N x- <Γ (VI)

V-N NH

L. 1 N (CH2) m- ^ ch30 ^ NH2 wherein R1 and m are as defined above is reacted with a compound of formula (VII) R2 | (VII)

ys / / ^ x —— COOH

3

RJ

1 X 3 4 64366 wherein X, R and R are as defined above, or as an acylating agent with a functional equivalent, and if desired, methods (A) and (B) are followed by conversion of the resulting product of formula (I) into a pharmaceutically acceptable acid addition salt in reaction with a non-toxic acid.

The reaction of method (A) results in the elimination of HQ. Q is preferably chlorine or bromine. This reaction is typically carried out by heating the reactants, e.g. at a temperature between 80 and 150 ° C, e.g. under reflux in an inert organic solvent, e.g. n-butanol. When the reaction is substantially complete, the product can be isolated and purified by conventional methods. For example, in a typical procedure, the reaction mixture is cooled and the crude product obtained is collected, washed with e.g. cold n-butanol and dried. The crude product can be purified by a typical procedure by dissolving it in hot aqueous dimethylformamide, filtering and concentrating the filtered solution, e.g. in vacuo. The solution is then cooled and ether is added to the Duhta to precipitate a product which can be filtered and washed with ether.

The intermediates of formulas (II) and (III) are either known compounds or can be prepared by methods analogous to those previously known in the art. For example, intermediates of formula (III) can be prepared according to the following reaction procedure: 2 HN MW 1 I -> HN Nc — L Λ \ Nh + Cl - c— \ / 8, «ay * /» (CH2) m- / o R3 ( IV) (V) (III)

The intermediates of formulas (IV) and (V) are either known compounds or can be prepared by conventional methods. When X is a group -CH (CH 2) -, the cis and trans isomers of compound (V) are possible. A mixture of these isomers may be used, but if a predominantly cis or trans end product is desired, the appropriate cis or trans starting material may generally be prepared by suitable chromatographic treatment of the corresponding methyl or ethyl ester followed by conversion to the acid chloride.

Il i 64366

In process (B), the functional equivalent of the acylating agent with the carboxylic acid of formula (VII) is, for example, the acid chloride or bromide of the compound of formula (VII), an "activated" ester or a mixed anhydride.

Acid chlorides or bromides can be prepared by conventional methods, e.g. by reacting the free acid with thionyl chloride or bromide, respectively.

The preferred "activated" ester is of formula (VIII)

Vr0 ^ »y,, I JLc-o-h (viii>

y L

A succinic imido ester according to R 0 ', which can again be prepared by conventional methods, e.g. by reacting the free acid with N-hydroxysuccinimide in the presence of a dehydrating agent, e.g. in the presence of dicyclohexylcarbodiimide. Another preferred "activated" ester is a phthalimido ester.

Suitable mixed anhydrides have the formula (IX) R 2%; ° <ix) - o - C - x R 3 / wherein Y is a lower alkyl or lower alkoxy group, most preferably a t-butyl or iso-butoxy group. They can be prepared by conventional methods, e.g. by reacting the free acid with a suitable lower alkanoyl chloride or lower alkyl chloroformate, e.g. pivaloyl chloride or iso-butyl chloroformate, in the presence of a base such as triethylamine.

64366

When the free acid form of the compound (VII) is used, the reaction should generally be carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.

The compounds of formula (VII) are preferably reacted in the form of their acid chlorides or bromides.

In a typical procedure using the acid chloride of compound (VII), the acid chloride in a suitable solvent, e.g. methylene chloride, is added dropwise to a stirred suspension of quinazoline (VII) in a suitable solvent, e.g. methylene chloride. The mixture can then be stirred for a few hours at room temperature and the resulting solid is then filtered off and purified by conventional means.

When X is a group -CH (CH 2) -, the cis-trans isomer is possible, as in method (A).

The intermediates of formula (VI) and (VII) can be prepared by conventional methods.

The pharmaceutically acceptable acid addition salts of the compounds of formula I may be prepared by conventional methods, e.g. by reacting the free base with a suitable acid in an inert organic solvent and recovering the resulting salt precipitate by filtration. If necessary, the product can then be recrystallized for purification. Often, however, the product obtained in methods (A) and (B) is already in the form of an acid addition salt.

The invention also includes pharmaceutically acceptable bio-precursors of the compounds of formula (I) and said salts thereof.

The term "pharmaceutically acceptable bio-precursor" requires some explanation. In pharmaceutical chemistry, of course, it is common practice to determine a detrimental physical or chemical property of a drug by converting the drug to a chemical derivative that does not have that detrimental property, but which, upon administration to an animal or human, is converted back to the parent compound. For example, if the drug is not well absorbed when administered orally to an animal or patient, it may be possible to convert the drug to a chemical derivative that is well absorbed and converted back to the parent compound in serum or tissues. Again, if the drug is unstable in solution, it may be possible to prepare a chemical derivative of the drug that is stable and can be administered in solution but that changes in the body to produce the parent substance. The pharmaceutical chemist is well aware of the possibility of overcoming the inherent disadvantages of a drug with chemical modifications that are only temporary and reversible when administered to an animal or patient.

64366 For purposes of this patent, the term "pharmaceutically acceptable bio-precursor" for a compound of formula (I) means a compound having a structural formula different from that of the compounds of formula (I) but which nevertheless becomes a compound of formula (I) when administered to an animal or human.

The antihypertensive activity of the compounds of the invention is demonstrated by their ability to lower the blood pressure of conscious spontaneously hypertensive rats and conscious renally hypertensive dogs when administered orally at doses up to 5 mg / kg.

Tables I and II show the therapeutic test results obtained for the compounds of the invention using the following test method:

Test compounds were administered orally at 5.0 mg / kg to six hypertensive rats in each group. Systolic pressure and heart rate were obtained using a blood pressure monitor attached to the tail and an adjustable capacitance transducer connected to oscilloscopes. Rats were kept in a warm cage at 33 ° C for 20-30 minutes before measuring blood pressure. Blood pressure and heart rate were measured before test compound administration and then 1, 2, 4, and 6 hours after test compound administration when test compound was administered orally to rats by gavage. Prior to test compound administration, the reference value for systolic pressure in all experimental animals was greater than 160 mmHg. Normal blood pressure in the rat is 130 mmHg.

The tables show the maximum percentage reduction in blood pressure (mmHg) and are calculated as follows: / maximum actual / blood pressure reduction / „* V x 100%

Reference blood pressure - 130 8

Table I

64366 and CH30 n / ^ - c - ^ ^ J (ch2v; NH2

Maximum percentage m reduction in blood pressure (mtnHg) 1 77 2 72

II

64366

Table II R1 / \ 7) T - N N —c _ z ^ I r v_y n nh2

Maximum percent- R1 z tual reduction in blood pressure (mmHg) n ^ OCH ^ H f VV 119> sx)! o x! f V \) 6 (8- and 5- {H JL J! CH3; '- saT, eer;' - different 81! I mixture! 8

- JOCC

CCH 3

YEAH

- ^ - 1_i 64 36 6 10

Table II (continued)

Maximum prosen- r1 tual reduction in blood pressure (mmHg) HXI 58 och3 H r ° V ^ 16 (mixture of 6 and ΤΙ JJ - Cl isome- 100 7 rien) * 'X ° X> h jC (+) 109 Y ° · HI f cis, trans- 102 ^ O mixture CH _ V ° y \ H jtrans ^ 1_j_

Table II (continued) 11 64366

Maximum percentage- R1 Z tual reduction in blood pressure (mmHg) H] Il cis 90 Λθ coch3

iXT

<€ 0

xliO

--------- ----------- ------------, j 64 36 6

The compounds of the invention may be administered alone, but will generally be 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 excipients such as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salt or glucose to make the solution isotonic.

The compounds of the invention may be administered to humans for the treatment of hypertension, either orally or parenterally, and may be administered orally at dose levels in the range of about 1 to 20 mg / day to the average adult patient (70 kg) in a single dose or up to three divided doses. Intravenous dose levels would be expected to be between 1/5 and 1/10 of the daily oral dose. Thus, for the average adult patient, a single oral dose in the form of a tablet or capsule will be in the range of about 1 to 50 mg of active compound. Depending on the weight and condition of the subject being treated and the route of administration chosen, these dosage amounts may be varied.

The preparation of the starting materials used in the process is described below: II: 13 64366

Preparation 1 (A) N- (1,4-Benzodioxane-2-carbonyl) piperazine "\ _Τ + IVJ1 γ ^ Ο - ^

O

A suspension of piperazine (11.88 g) and sodium acetate (29.30 g) in a mixture of water (70 ml) and acetone (95 ml) was stirred at 10-15 ° C, then concentrated hydrochloric acid (about 35 ml) was added until the pH of the solution was 1.5. 1,4-Benzodioxane-2-carbonyl chloride (31.0 g) and sodium hydroxide (5N, about 45 ml) were then added portionwise keeping the temperature between 10 and 15 ° C, with sodium hydroxide maintaining the pH between 1.7 and 2. 2. When the addition was complete, the pH was adjusted to 2.0 by the addition of sodium hydroxide and the suspension was stirred for an additional 30 minutes. Water was added until a homogeneous solution was obtained, the acetone was removed in vacuo, and the remaining aqueous solution was extracted with chloroform (3 x 200 mL). The aqueous phase was basified with pH 8-9 sodium hydroxide (5N), re-extracted with chloroform (3 x 200 ml) and the extracts washed with water, dried (MgSO4) and evaporated in vacuo, the oily residue dissolved in ethyl acetate, treated with ethereal hydrogen chloride and evaporated. the solid residue was triturated with ether followed by recrystallization from methanol to give N- (1,4-benzodioxane-2-carbonyl) piperazine hydrochloride (4.85 g), m.p. 265-267 ° C.

Analysis%.

Found: C, 54.6; H, 5.5; N, 9.7

Calcd for C 13 H 16 N 2 O 3 .HCl C, 54.8; H, 6.0; N, 9.8.

ΐ4 64366

Preparation 2; ί 6-methoxy-1,4-benzodioxane-2-carboxylic acid CH? ° H ° 'ν' co? "ΛΧ j juu C h3o c: h3o v

Finely ground potassium permanganate (5.02 g) was added in four portions to a stirred suspension of 2-hydroxymethyl-6-methoxy-1,4-benzodioxane (4.52 g) in potassium hydroxide solution (1.47 g, 42 mL water) at 5 ° C: in. During the reaction, the temperature was maintained between 5 and 15 ° C, after the addition was complete, stirring was continued at room temperature for 4 hours, then the reaction mixture was left to stand overnight.

The manganese dioxide was removed by filtration, the solid was washed with water and the combined aqueous phase was acidified (pH 1) with concentrated hydrochloric acid, cooled, then extracted with chloroform. The combined chloroform extracts were washed with sodium hydroxide solution (5N, 2 x 40 mL), then the basic phase was further washed with chloroform, cooled, acidified (pH 1) with concentrated hydrochloric acid and re-extracted with chloroform. The latter chloroform solution was washed with water, dried (Na 2 SO 4) and evaporated to leave a crude residue of 6-methoxy-1,4-benzodioxane-2-carboxylic acid (2.33 g). The sample was recrystallized from water, m.p. 120-121 ° C.

Analysis%;

Found C, 57.1; H, 4.8

Calculated for C 18 H 10 O 5: He C, 57.1; H, 4.8.

Preparation 3 64366 8- and 5- (Mixture) -isopropyl-1,4-benzodioxane-2-carboxylic acid (A) A stirred solution of 3-isopropylcatechol (23 g) in acetone (250 ml) was heated to reflux, then potassium carbonate was added. (28 g). The heterogeneous mixture was further refluxed for 15 minutes, followed by dropwise addition of methyl 2,3-dibromopropionate (10 g). Three more portions of potassium carbonate (28 g) and methyl 2,3-dibromopropionate (10 g) were added in the same manner. , the mixture was stirred at reflux for 12 hours. The mixture was then evaporated, the residue was diluted with water (700 ml), extracted with chloroform and the combined extracts were washed with water, dried (MgSO 4) and evaporated. The residual oil was distilled off. Methyl 3 (5) -isopropyl-1,4-benzodioxane-2-carboxylate (29.3 g) was obtained, b.p. 115-120 ° C / 0.07 kPa. nmr spectroscopy confirmed the product as a mixture of 8- (71%) and 5- (29%) isomers.

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

Analysis%:

Found: C, 64.7; H, 6.3

Calcd for C 12 H 14 O 4 c, 64.9; H, 6.3.

High performance liquid chromatography showed that the product was a mixture of 8- (86%) and 5- (13%) isomers [spectrum Physics 3,500 cs instrument; column, 25.4 mm x 6.35 mm (1 'x 1/4 ") OO ^ a Bondapak C-18; eluent, acetonitrile (1) / 0.15 M potassium hydrogen phosphate buffer pH 3.5 (2); flow rate, 14 ml / min, pressure 4139 kPaT] i6 64366

Preparation 4 Mixture of 8- and 5-methyl-1,4-benzodioxane-2-carboxylic acids

Potassium permanganate (23.15 g) was added in three portions to a stirred suspension of a mixture of 8- and 5-methyl-2-hydroxymethyl-1,4-benzodioxanes (20 g) in potassium hydroxide solution (6.5 g in 187 ml H 2 O). ° C. The reaction temperature was kept below 15 ° C, and when the addition was complete, the reaction mixture was stirred at room temperature for 4 hours. The manganese dioxide was removed by filtration, the filtrate was cooled, acidified with concentrated hydrochloric acid, and the oily product which separated on further cooling was extracted with chloroform. The chloroform extracts were washed with 5N sodium hydroxide solution, the basic layer was washed with chloroform and then acidified with concentrated hydrogen chloride to give 1. The acidic solution was extracted with chloroform, the combined extracts were washed with brine, dried (MgSO 4) and evaporated in vacuo. A mixture of 4-benzodioxane-2-carboxylic acids (7.3 g) as a syrupy residue with uniform spectroscopic properties. A small sample was esterified with diazomethane and turned out to be a mixture of isomers by gas chromatography (5: 2).

Preparation 5 6,7-Dimethyl-1,4-benzodioxane-2-carboxylic acid α'3ΥΥ "'Ύ“ ^ νγ Υ ^ ΥϊΤ a.3 ^ 0 ,, ^' ci, ^ (A) A mixture of 4,5-dimethylcatechol (7.9 g) in dry acetone (45 ml) was heated to reflux, then potassium carbonate (5 g) was added, followed by dropwise addition of ethyl dibromopropionate (3.5 g), then the addition was repeated three more times over 1 1/4 hours. , then the reaction mixture was stirred at reflux with further cooling for 3 3/4 hours.After cooling the mixture was filtered »the solids were washed well with acetone, then the combined filtrate was concentrated in vacuo.Water (35 ml) was added, the resulting solid was collected, washed with petrol, taken up. then to ether. The ether solution was washed with water, dried (Na 2 SO 4) and evaporated in vacuo to give ethyl 6,7-dimethyl-1,4-benzodioxane-2-carboxylate (10.17 g), m.p.

70-71 ° C.

Analysis%

Found C, 65.7; H, 6.8

Calculated: - C, 66.1; H, 6.8.

(B) Hydrolysis of the ester prepared above (5.0 g) with sodium hydroxide (10%, 13 mL) in ethanol (125 mL) as described for analogous compounds (JACS, 77, (1 → 56), 5374 afforded crude 6, 7-Dimethyl-1,4-benzodioxane-2-carboxylic acid (4.04 g) The sample was recrystallized from water, mp 150-151 ° C.

Found: C, 63.9; H, 6.0

Calcd for C 18 H 18 N 2 O 2 C, 63.5; H, 5.8.

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

Hydrolysis of ethyl 6,7-dichloro-1,4-benzodioxane-2-carboxylate (5.0 g) with sodium hydroxide (10%, 10.9 mL) in ethanol (50 mL) afforded 6,7-dichloro-1,4 -benzodioxane-2-carboxylic acid (3.4 g), mp 155-158 ° C, with a nmr spectrum consistent with the authentic sample and an identical Rf (in thin layer chromatography).

Preparation 7 8-Methoxy-1,4-benzodioxane-2-carboxylic acid 8-Methoxy-1,4-benzodioxane-2-carboxamide (2.41 g) in 50% hydrochloric acid (35 ml) was stirred at 100 ° C for 1 hour. . The resulting solution was cooled, diluted with water (200 ml), extracted with chloroform (3 x 100 ml), then the extracts dried (MgSO 4) and evaporated in vacuo. The solid residue (1.8 g) was recrystallized from water (m.p. 75-78 ° C), then ethyl acetate / hexane to give 8-methoxy-1,4-benzodioxane-2-carboxylic acid, m.p. 131-132 ° C.

Analysis%

Found: C, 56.9; H, 4.8

Calcd for C 11 H 11 qO 5 C, 57.1; H, 4.8.

i8 64 3 6 6

Preparation 8 5-Methoxy-1,4-benzodioxane-2-carboxylic acid This compound was prepared by the method of Preparation 7 starting from 5-methoxy-1,4-benzodioxane-2-carboxamide. The product was crystallized from water, m.p. 85-87 ° C, then from ethyl acetate-hexane to give 5-methoxy-1,4-benzodioxane-2-carboxylic acid, m.p. 139-141 ° C.

Analysis%:

Found: C, 56.9; H, 4.8

Calculated for C 10 H 10 O 5: He C, 57.1; H, 4.8.

Preparation 9 6-Acetyl-1,4-benzodioxane-2-carboxylic acid

Jones' reagent (11.6 mL) was added dropwise to a stirred solution of 6-acetyl-2-hydroxymethyl-1,4-benzodioxane (4.0 g) in acetone (70 mL) at 10-15 ° C. The reaction mixture was stirred at room temperature for 18 hours, then diluted with isopropanol / water / chloroform, the organic layer separated and evaporated in vacuo. The residue was redissolved in chloroform, extracted with saturated sodium carbonate solution (2 x 30 mL), then the basic phase was washed with chloroform, cooled and acidified to pH 1 with concentrated hydrochloric acid. The acidic solution was extracted with chloroform, the combined extracts washed with saturated brine, dried (Na 2 SO 4) and evaporated in vacuo to give 6-acetyl-1,4-benzodioxane-2-carboxylic acid (1.56 g) mp 159-162 ° C. The sample was recrystallized from ethanol / ethyl acetate, m.p. 174-175 ° C.

Analysis%:

Found: C, 59.0; H, 4.8

Calcd for C 18 H 18 N 2 O 3 C, 59.5; H, 4.5.

Preparation 10 7-Acetyl-1,4-benzodioxane-2-carboxylic acid (A) A solution of methyl 2,3-dibromopropionate (13 ml) in acetone (50 ml) was added dropwise over 1/2 hour with stirring of 3,4-dihydroxy acetophenone ( 15.1 g) and a suspension of anhydrous potassium carbonate (28 g) in acetone (100 ml) which was heated to reflux. The mixture was stirred at reflux for 4 hours, then evaporated in vacuo and the residue partitioned between chloroform and water. The chloroform extracts were washed with water, dried (MgSO 4) and evaporated to leave a 2: 1 mixture of methyl esters of 6- and 7-acetyl-1,4-benzodioxane-2-carboxylic acids in a 2: 1 ratio as determined by C-nmr spectroscopy. A sample of this crude product was recrystallized from isopropanol, m.p. 68-80 ° C.

Analysis%:

Found: C, 60.7; H, 4.9

Calculated for C 12 H 12 O 5 C, 61.0; H, 5.1.

(B) An aqueous solution of sodium hydroxide (1.2 g, in 5 ml of water) was added to a stirred solution of the product of (A) (7 g) in ethanol (25 ml) at 15 ° C. The reaction temperature was kept below 25 ° C for 1/2 hour, 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 (MgSO 4), evaporated in vacuo and the residue (1.46 g) recrystallised from ethyl acetate / methanol to give 7-acetyl-1,4-benzodioxane-2-carboxylic acid, m.p. 167-168 ° C.

Analysis%:

Found: C, 59.0; H, 4.5

Calcd for C 18 H 18 N 2 O 2 C, 59.5; H, 4.5.

High performance liquid chromatography (HPLC) showed <"'-' 96% isomeric purity / Spectrum Physics 3,500 CS instrument; column 25.4 x 6.4 mm 0.D.yU-Bondapak C-18; eluent, acetonitrile (1) / 0.05M potassium phosphate buffer pH 4.5 (2), flow rate 0.6 ml / min pressure 5381 kPa_.7 The acidic aqueous phase was evaporated in vacuo, the residue was extracted with methanol, the combined extracts were evaporated in vacuo and the product.

(5.5 g) was recrystallized from ethyl acetate / methanol to give 6-acetyl-1,4-benzodioxane-2-carboxylic acid. HPLC showed only one component to correspond to the authentic sample prepared according to Preparation 9.

Preparation 11 (A) (+) 1,4-Benzodioxane-2-carboxylic acid 1,4-Benzodioxane-2-carboxylic acid (21.6 g) and (+) dehydroabietylamine (34.26 g) were mixed together in hot industrial methylated in spirits (1000 ml), then allowed to stand at room temperature for 24 hours. The precipitate formed 6464366 2 O (20 g) was collected, the filtrate was concentrated to 600 ml and left for 48 hours to form more solid (4 g). The combined product (24 g, mp 204-210 ° C) was recrystallized from industrial concentrate-methanol to a constant mp 229-230 ° C (3.0 g), then the mother liquors from the last two recrystallizations were combined, reduced in volume and the solid product (5 g). , 6 g) was recovered. This salt was converted to the free carboxylic acid (5.5 g), <+ 1 + 60.1 ° (1% in chloroform) in the usual manner, then recrystallized twice from tdylene to give (+) 1,4-benzodioxane-2- carboxylic acid (0.23 g), m.p. 98-99 ° C, λmax = + 62.1 ° (1% solution in chloroform).

Analysis%:

Found: C, 60.3; H, 4.4

Calculated for C 9 H 9 O 4 C, 60.0; H, 4.5.

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

The original mother liquors (600 ml) from the previous experiment were evaporated in vacuo and the oily residue was taken up in acetone (250 ml), then set aside until crystallization was complete.

The solid product (10.0 g) was collected, crystallized from acetone, then the salt (6.0 g) was converted to the free acid in the usual manner using dilute sulfuric acid. The crude product was taken up in chloroform, chromatographed on silica gel (10 x 50 mm column size), eluted with chloroform, evaporated in vacuo, then crystallized from toluene to give (-) - 1,4-benzodioxane-2-carboxylic acid (0.90 g), m.p. 98-99 ° C, 6 D = -66.1 ° (1% solution in chloroform.

Analysis%:

Found: C, 59.9; H, 4.5

Calculated for C 9 H 9 O 2 C, 60.0; H, 4.5.

Preparation 12 N- (1,4-Benzodioxane-2-carbonyl) homopiperazine This compound was prepared as in Preparation 1 using homo-piperazine instead of piperazine. A sample of the hydrochloride salt was recrystallized from methanol, m.p. 189 ° C.

Analysis%:

Found: C, 56.2; H, 6.2; N, 9.3

Calculated for cy4H], gN2O 3:

Ile C, 56.3; H, 6.4; N, 9.4.

n 2i 64366

Preparation 13 6- and 7- (Mixture) Chloro-1,4-benzodioxane-2-carboxylic acid (A) Chlorine gas was introduced into a stirred ice-cold solution of methyl 1,4-benzodioxane-2-carboxylate (10 g) in chloroform (100 ml) of aluminum chloride. in the presence of (0.06 g). After 20 minutes the reaction was quenched with nitrogen, washed with water, sodium bicarbonate solution, then again with water, dried (Ν32δΟ ^) and evaporated in vacuo to leave methyl 6- and 7-chloro-1,4-benzodioxane-2- a mixture of carboxyl plates (12 g) (1: 1 mixture by C-nmr spectroscopy).

(B) A sample of the product prepared above (1.4 g) in ethanol (20 ml) was treated with a solution of sodium hydroxide (0.25 g) in water (1 ml) at room temperature to give a black color. After standing for 48 hours at room temperature, the mixture was concentrated in vacuo, diluted with water, extracted with chloroform and the chloroform layer was discarded. The aqueous phase was acidified with concentrated hydrochloric acid, extracted with chloroform, then the combined extracts dried (MgSO 4) and evaporated in vacuo to give a mixture of 6- and 7-chloro-1,4-benzodioxane-2-carboxylic acids (1.0 g), m.p. . 145-146 ° C with uniform spectroscopic properties.

Preparation 14 2-Methyl-1,4-benzodioxane-1-carboxylic acid

Jones' reagent (33.3 mL) was added dropwise to a stirred solution of 2-hydroxymethyl-2-methyl-1,4-benzodioxane (5 g) in acetone (300 mL) at 5 ° C, then the reaction mixture was allowed to warm to room temperature. . Isopropanol (10 ml) was then added, followed by water (200 ml), then extracted with dilute sodium bicarbonate solution, and the aqueous phase was further washed with chloroform. The aqueous phase was then acidified with hydrochloric acid, extracted with chloroform, the combined extracts washed with water, dried (MgSO 4) and evaporated in vacuo to give 2-methyl-1,4-benzodioxane-2-carboxylic acid (1.7 g). The sample was recrystallized from toluene, m.p. 133-134 ° C.

Analysis%:

Found C, 61.8; H, 5.2

Calcd for C 18 H 18 N 2 O 2 C, 61.9; H, 5.2.

22 64366

Preparation 15 cis- and trans-ethyl-3-methyl-1,4-benzodioxane-2-carboxylate These compounds were separated by preparative HPLC and identified by NMR spectroscopy according to published data (see e.g. J. Med. Chem., 10, (1967), 880. Each isomer was hydrolyzed to the corresponding acid, which was converted to the acid chloride without further identification.

Preparation 16 4-Amino-6,7-dimethoxy-2- (3-methylpiperazin-1-yl) quinazoline 4-Amino-2-chloro-6,7-dimethoxyquinazoline (8.05 g) and 2-methylpiperazine (10 g ) was heated at reflux in butanol for 15 hours. The reaction mixture was then evaporated in vacuo and the residual oil was taken up in chloroform (200 ml), washed with water (4 x 50 ml), dried (Na 2 SO 4) and evaporated in vacuo. The residual oil (13 g) was recrystallized from isopropanol to give 4-amino-6,7-dimethoxy-2- (3-methylpiperazin-1-yl) quinazoline hemihydrate (3.0 g), m.p. 185-187 ° C.

Analysis%:

Found: C, 58.1; H, 6.8; N, 22.8

Calcd. H, 7.1; N, 22.4.

The following examples illustrate the invention.

Example 1 23 64366 4-Amino-2- [4- (1,4-benzodioxane-2-carbonyl) piperazin-1-yl] -6,7-dimethoxyquinazoline Cha / -λ r vsriv> λ r V> Vy 1 '^ ° 4-Amino-2-chloro-6,7-dimethoxyquinazoline (140 g) and N- (1,4-benzodioxane-2-carbonyl) piperazine (150 g) were stirred at reflux. in n-butanol (2 L) for 3 1/2 hours. The mixture was then cooled to 80 ° C, the solid product was collected, washed with cold n-butanol (2 x 250 ml) and dried. The crude product was dissolved in hot (80 ° C) dimethylformamide (530 mL) and water (130 mL), filtered, concentrated in vacuo to about 300 mL, then cooled and ether (1.8 L) was added. The solid product thus obtained was collected and washed with ether to give 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) piperazin-1-yl] -6,7-dimethoxyquinazoline hydrochloride (215 g), m.p.

289-290 ° C.

Analysis%:

Found C, 56.9} H, 5.4; N, 14.4

Calculated for C23H25N5 ° 5'HClC '56'6f H' 5'4 * N '14'4 * 24 64366

Example 2 4-Amino-2- [4- (1,4-benzodioxane-2-carbonyl) homopiperazin-1-yl] -6,7-dimethoxyquinazoline 4-Amino-2-chloro-6,7-dimethoxyquinazoline (1, 58 g) and N- (1,4-benzodioxane-2-carbonyl) homopipertazine (2.0 g) were heated at reflux in n-butanol (114 ml) for 60 hours. The mixture was then cooled, the butanol removed in vacuo and the solid residue triturated with ether, taken up in hot methanol, filtered and cooled. The solid product was collected, then the remaining solution was evaporated in vacuo and the residue taken up in hot isopropanol, cooled, filtered, then re-evaporated in vacuo. The residue was combined with the original solid, treated with cold methanol and recrystallized from ethanol to give 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) homopiperazin-1-yl] -6,7-dimethoxyquinazoline. hydrochloride (0.57 g), m.p. 250-251 ° C.

Analysis%;

Found C, 57.2; H, 5.4; N, 13.8

Calculated for C24H27N5O5'HCl C'57'4; H '5'6j N' 14 '°

II

Example 3 64366 4-Amino-2- [4- (6-methoxy-1,4-benzodioxane-2-carbonyl) piperazin-1-yl] -6,7-dimethoxyquinazoline? '3 Γιί -tlf [“Ί Ν-7 £ ϊ * -Hei Π o I Jj ^ 0 CH_0 NH. A solution of N, N-methoxy-1,4-benzodioxane-2-carbonyl chloride (2.17 g) (prepared from acid and thionyl chloride) in dichloromethane (25 ml) was added dropwise to a stirred 4-amino-2-piperazin-1-yl mixture. To a suspension of 6,7-dimethoxyquinazoline (2.48 g) in methylene chloride (50 ml) at room temperature. After the addition was complete, the mixture was stirred at room temperature for 4 hours, then filtered and the solid suspended in aqueous potassium carbonate and extracted with chloroform. The combined extracts were washed with water, dried (Na 2 SO 4) and evaporated in vacuo to give a solid residue (4.15 g) which was chromatographed on silica (160 g) and eluted with chloroform, then chloroform-methanol (2 1/2%). . Similar fractions (from thin layer chromatography) were combined, evaporated in vacuo, then the residue taken up in ethyl acetate-methanol and treated with ethereal hydrogen chloride. Addition of ether followed by cooling afforded a solid which was collected and crystallized from methanol to give 4-amino-2- / 4- (6-methoxy-1,4-benzodioxane-2-carbonyl) piperazin-1-yl Β-6,7-dimethoxyquinazoline hydrochloride hydrate (0.95 g), m.p. 220-222 ° C.

Analysis%:

Found C, 53.3; H, 5.5; N, 13.4

Calcd for C 24 H 27 N 5 O 6 .HCl.H 2 O; He C, 53.8; H, 5.6; N, 13.1.

Examples 4-19 26 64366

The following compounds were prepared as described in Example 3 starting from 4-amino-2-piperazin-1-yl (or 2- (3-methylpiperazin-1-yl)) - 6,7-dimethoxyquinazoline and the appropriate carbonyl chloride.

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Claims (2)

33 64 36 6 1. An analogous method for the preparation of antihypertensive quinazoline derivatives of the formula (I) ^ r1 / - <! T ai CH..0. N N N-C _i \ Λ '' yv v ^ 2) mv s 3 j | 2 m 3 CH 3 O nh 2 where m is 1 or 2, X is -CH 2 -, -CH (CH 3) - or -CH 2 -CH 2 -, R is hydrogen or lower alkyl 2 3 and R and R, which may be the same or different , both represent hydrogen, lower alkyl, lower alkoxy, halogen or lower alkanoyl, and for the preparation of their pharmaceutically acceptable acid addition salts, characterized in that (A) a quinazoline of formula (II) CH., 0 NQ γγν ch30 nh2 wherein Q is easily a leaving group such as chlorine, bromine, iodine, lower alkoxy or lower alkylthio is reacted with piperazine or homopiperazine of formula (III) * 34 '64366 R2 R1 / ° \ /' \ I HN NC-1 Jl (III) '2'm R 12 3 wherein X, R, R, R and m are as defined above, or (B) quinazoline of formula (VI) R 1 CH 3 O / -C -N NH (VI) i Ix / L. N (σΐ2ν - CH30 nh2 wherein R1 and m are as defined above is reacted with a compound of formula (VII) R2 R1 ov X (VII) ixA0 ^ -COOH R3 2 3 wherein X, R and R are as defined above above, or with it as an acylating agent with a functional equivalent, and if desired, methods (A) and (B) are followed by conversion of the product of formula (I) obtained into a pharmaceutically acceptable acid addition salt by reaction with a non-toxic acid. (B) The functional equivalent is an acid chloride or bromide or a succinic acid imido ester of a compound of formula (VII) A process according to claim 1 or 2, characterized in that m is 1 and R, R and R are hydrogen and X is -CH 2 - · 35 Patentkrav 64 3 6 6 1. Analogous formulation for antihypertensive quinazoline derivatives of formula (I) / r1 r ~ \ f i l 111 | ^ Zrrr7 o * CH30 N nh2 color m är 1 eller 2, X is -CH 2 ~ f-CH (CH 2) - or R 1 is a residue or a alkyl group and R 2 and R 3, which may be identical to an alkyl group, but the base is a alkyl group, a alkoxy group, a halogen or a alkanoyl group, and a pharmaceutical form of a syrup addition, which is described in Fig. (A) and quinazoline in the form of (II) CH3O / QI II I (II) JL / N NH2 color Q in the formulation. a group of chlorine, bromine, iodine, alkoxy or alkylation, a mixture of pioerazine or homo-piperazine with formula (III) R2 / r1 / / \ 1 1 J (m) ° * 12 3 color X, R, R, R and m in the same invention as in (B) and quinazoline in formula (VI)