DE2847623C2 - 4-Amino-2- (piperazin-1-yl or homopiperazin-1-yl) -quinazoline derivatives, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

NH-.

wherein

, 5

m = 1 or 2;

X = -CH ₂ -, -CH ₂ CH ₂ - or -CH (CH ₃ ) -; and R ¹ and R ² = independently of one another hydrogen,

lower-alkyl, lower-alkoxy, lower-alkanoyl or halogen

mean and their pharmaceutically acceptable acid addition salts.

2. 4-Amino-2- [4- (1,4-benzodioxane-2-carbonyl) -piperazine-1-yfj-öj -dimethoxy-quinazoline.

3. A process for the preparation of a compound of the formula (I) according to claim 1, characterized in that a quinazoline of the general formula

20th

25th

CH ₃ O

CH ₃ O

(Π)

NH ₂

30th

35

wherein Q is an easily leaving group such as a chlorine, bromine or iodine atom, a lower alkoxy group or a (lower alkyl) thio group,

with a piperazine or homopiperazine of the general formula

HN

N-C

R ¹

50 in which R ¹ , R ² , X and m have the meaning given in claim 1, or that a cinazoline of the general formula is reacted

CH ₃ O

CH ₃ O

NH

NH,

(VD

wherein m has the meaning given in claim 1 owns,

with a carboxylic acid of the general formula

(VII)

wherein R ', R ² and X have the meaning given in claim 1, or are reacted with a functional equivalent thereof as acylating agent.

4. Pharmaceutical composition, characterized by a content of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to one of Claims 1 or 2, optionally together with a pharmaceutically acceptable diluent or carrier.

The invention relates to therapeutic agents which new derivatives of 4-amino-2- (piperazin-l-yl or homopiperazin-l-yl) quinazoline. Such compounds are considered to be regulators of the cardiovascular system and particularly beneficial in the treatment of hypertension.

The compounds of the invention have the following general formula

CH, 0

CH ₁ O

(D

wherein

m = \ or2;

X = -CH ₂ -, - CH2CH2- or -CH (CH ₃ ) -round
R 'and R ² = independently of one another hydrogen, lower-alkyl, lower-alkoxy, lower-alkanoyl or halogen

mean.

The invention further relates to the pharmaceutically acceptable acid addition salts of compounds of formula (I).

In the description "halogen" means fluorine, chlorine, bromine or iodine. The one related to The term "lower" used for an alkyl or alkoxy radical means that such a straight-chain or branched radical 1 to 6 carbon atoms and

10 preferably contains J to 4 carbon atoms. The term "lower" used in connection with an alkanoyl radical means that such a straight-chain or branched radical contains 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms

Pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts which are an Acids are formed which contain non-toxic acid addition salts with pharmaceutically acceptable anion-n form like hydrochloride, hydrobromide, sulfate or Bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, succinate, lactate, tartrate, citrate, Gluconate, saccharate and p-toluene sulfonate salts.

Preferred compounds correspond to the general formula

CH ₃ O

CH ₃ O

wherein R has the meaning H or CH ₃ and R ¹ and R ^{2 are} a hydrogen atom, a lower alkyl radical, a lower alkoxy radical, a halogen atom or a lower alkanoyl radical.

The most preferred single compound is 4-amino-2- [4- (1,4-benzodioxan-2-carbo: yl) -pi; perazin-1 -yl] -6,7-dimethoxy-quinazoIine.

The compounds of the invention which contain one or more asymmetric centers exist as a pair or more pairs of enantiomers, and such pairs or individual isomers may be after physical methods, e.g. B. be split by fractional crystallization of suitable salts. The invention encompasses both the split pairs and mixtures thereof, racemic Mixtures or the split d- and 1-optically active isomeric forms.

When X is -CH (CH ₃ ) -, cis and trans isomerism is possible, and both isomers (and mixtures thereof) belong to the compounds according to the invention.

The compounds of the invention can be prepared by using a quinazoline general formula

in which R ¹ , R ² , X and m have the meaning given in claim 1, or that a cinazo-Hn of the general formula is reacted

CH ₁ O

CH ₃ O

NH

(VI)

wherein m has the meaning given in claim 1,

with a carboxylic acid of the general formula

CH ₁ O

CH ₃ O

(Π)

55

60

COOH

(VII)

NH ₂

> ■■ in which Q is an easily leaving group such as a chlorine, j: 'bromine or iodine atom, a lower alkoxy group or'; denotes a (lower alkyl) thio group,
Ε with a piperazine or homopiperazine through my formula

wherein R ¹ , R ² and X have the meaning given in claim I, or reacts with a functional equivalent thereof as acylating agent.

The pharmaceutically acceptable acid addition salts of compounds of the invention can according to conventional procedures are produced, e.g. B. by reacting the free base with the appropriate one

Acid in an inert organic solvent and Collect the resulting precipitate of the salt by filtration. If necessary, the product can then recrystallized for purification.

The antihypertensive activity of the invention Compounds are recognized by their ability to lower blood pressure spontaneously hypertensive rats and conscious kidney hypertensive dogs shown for oral administration in doses of up to 5 mg / kg

The compounds according to the invention can be administered alone, but in general they are applied in admixture with a pharmaceutical carrier, which in view of the intended Application route and is selected according to standard pharmaceutical practice. For example, they can be taken orally in the form of tablets containing such diluents as starch or lactose, or in capsules either alone or in mixtures with diluents or in the form of elixirs or suspensions, which contain aromatics and dyes, applied will. You can parenterally, e.g. B. be administered intramuscularly, intravenously or subcutaneously. For the For parenteral administration, they are best used in the form of a sterile aqueous solution, soft may contain other solutes, e.g. B. Sufficient salt or glucose to make the solution isotonic.

The invention therefore relates to a pharmaceutical one

Composition or, a drug, which a

Compound of formula (I) or a pharmaceutical

acceptable acid addition salt thereof, optionally together with a pharmaceutically acceptable one Contains diluents or carriers

The compounds of the invention can be used in humans to treat hypertension either

ίο be administered orally or parenterally, and they can be administered orally at dose levels approximately within the range of 1 to 20 mg / day for one average, adult patient (70 kg), the dose as a single dose or in

is given up to three divided doses. The dose values for intravenous administration are As expected, about Ά to Vio of the daily oral Dose. Therefore, the single oral doses in tablet or capsule form are for an average adult

for patients approximately in the range of 1 to 50 mg of active compound. Deviations are of course possible depending on this, Vv <m weight and the condition of the patient to be treated and the particular, chosen route of application required,

as known per se to the person skilled in the art

The connection is from BE-PS 7 66 444

OCH ₃ ^ ".

CH ₃ ONN —C-4 )

CH ₃ O

NH ₂

known to have an antihypertensive activity of 30% at a dosage of 10 mg / kg p. o. in the rat. The compounds according to the invention are significantly more effective. The following calculation formula is used as a basis:

Activity (in%)

Maximum actual drop in blood pressure

Hypertensive rat blood pressure *) - Normotensive rat blood pressure *) Before administration of the test compound.

The closest prior art, however, is US Pat. No. 3,663,706. The most relevant compounds of US Pat. No. 3,663,706 are

100%.

_M NN —C — Ii )

(B) ("Prazosin")

CH ₃ O

NH ₂

which has an antihypertensive activity of 100% at a dosage of 5 mg / kg p. 0. in the rat and

CH ₁ O

CH ₃ O

N-C

which had an antihypertensive activity of 33% at a dosage of 5 mg / kg p. o. in the rat.

Compound B is the well-known prazosin, a top-quality antihypertensive drug, which is on the market worldwide.

Of all these prior art connections, connection C comes to the subject of the application closest, which is about twice as active as compound A from BE-PS 7 66 444. On the other hand, are abtfr the compounds according to the invention about twice as active as connection C.

If the skilled artisan compares the activities of compounds B and C of the prior art, he must

come to the result that the condensation of a benzene ring (see. C versus B) to a Must lead to a decrease in effectiveness (C is only about Vj as effective as B).

The prior art does not suggest the condensation of a benzene ring, on the contrary, it does leads away from it, but precisely that is the essential feature by which the invention Connection class differs from the closest known connection class.

A detailed test report is laid out.

The invention win. ' explained in more detail using the following examples.

example 1 4-Amino-2- [4- (1,4-benzodioxane-2-carbony [) -pipera / .in-1-ylJ-b, 7-dimethoxyquin / oline

CH ₃ O

CH ₃ O

HCI

CH ₃ O

NH ₂

140 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 150 g of N- (1,4-benzodioxane-2-carbonyl) piperazine were stirred under reflux in 2 liters of n-butanol for 3.5 hours. The mixture was then ^{cooled to 80 °} C., the solid product was collected, washed with cold n-butanol (2 × 250 ml) and dried. The crude product was dissolved in hot (8O ⁰ C) 530 ml of dimethylformamide and 130 ml of water, filtered, concentrated in vacuo to about 300 ml and then cooled.

then 1.81 ether was added. The solid obtained was collected and washed with ether, whereby 215 g of 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) -piperazin-1-yI] -6,7-dimethoxyquinazoline hydrochloride with F 289-290 ⁰ C. were obtained.

Analysis for C ₂₃ H ₂₅ N ₅ O ₅ HCI:
found: C 56.9 H 5.4 N 14.4%

calculated: C 56.6 H 5.4 N 14.4%

Example 2 4-Amino-2- [4-M, 4-benzodioxane-2-carbonyl) homopiperazin-1-yl] -6,7-dimethoxyquinazoline

1.58 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 2.0 g of N- (1,4-benzodioxane-2-carbonyl) homopiperazine were refluxed in 114 ml of n-butanol for 60 hours. The mixture was then cooled, the butanol was removed in vacuo, and the solid residue was 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 was dissolved in added hot isopropanol, cooled, filtered and then evaporated again in vacuo. The residue was combined with the original, solid product, treated with cold methanol and recrystallized from ethanol, whereby 0.57 g of 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) -homopiperazine-1- yl] -6.7-dimethoxyquinazoline hydrochloride was obtained with F. 250 -251 ⁰ C.

ί> 5 analysis for C ₂₄ H ₂₇ N ₃ O ₅ ■ HC !:

found: C 57.2 H 5.4 N 13.8%

calculated: C 57.4 H 5.6 N 14.0%

9 10

Example 3

4-Amino-2- [4- (6-methoxy-1,4-benzodioxane-2-carbonyl) -piperazin-1-yl] -6,7-dimethoxyquinazoline

CH ₁ O

Γ H ₃ O

N NH

+ Cl

OCH ₃

Nile,

CH ₁ O

NH ₂

HCI

A solution of 2.17 g of 6-methoxy-1,4-benzodioxane-2-carbonyl chloride (prepared from the acid and thionyl chloride) in 25 ml of dichloromethane was added dropwise to a stirred suspension of 2.48 g of 4-amino-2piperazin-l-yI-6,7-dimethoxyquinazoline in Given 50 ml of methylene chloride at room temperature. Upon completion of the addition, the mixture became at Stirred at room temperature for 4 hours, then filtered and the solid dissolved in aqueous potassium carbonate solution suspended and extracted with chloroform. The combined extracts were washed with water, dried over Na2SO4 and evaporated in vacuo, leaving 4.15 g of a solid residue. These were eluted over 160 g of silica gel chromatographed with chloroform and then with chloroform-methanol (2.5%).

Comparable fractions (identified by thin layer chromatography which contained the desired product) were combined and evaporated in vacuo. The residue was then taken up in ethyl acetate-methanol and treated with ethereal hydrogen chloride. Addition of more ether and subsequent cooling gave a solid which was collected and recrystallized from methanol to give 0.95 g of 4-amino-2- [4- (6-methoxy-1,4-benzodioxane-2-carbonyl) - piperazin-1-yl] -6,7-dimethoxyquinazoline hydrochloride hydrate obtained with F. 220-222 ⁰ C.

Analysis for C24H27N5O6
found: C 533

calculated: C, 53.8

HCI · H ₂ O:

H 5.5 N 13.4%
H 5.6 N 13.1%

Examples 4-18

The following compounds were prepared in a manner similar to that in Example 3, using from 4-Amino-2-piperazin-1 -yl- (or 2- [3-methyl-piperazine l-yl]) - 6,7-dimethoxy-quinazoline and the correspondingly suitable carbonyl chloride was assumed.

CH ₃ O

CH ₃ O

E.g. Z

Isolated form and F. ( ⁰ C) analysis values in%

(theoretical values in brackets)
C HN

I -4 -CH ₃ Hydrochloride 56.2 5.4 13.9 / '- O ^/ \ y ^ hemihydrate (56.4 5.7 13.7) 238-240 Mixture ion 8 and 5-isomers

11th

12th

continuation

Ex. Z isolated form and F.

⁰ C) analysis values in%

(Iheor. Values in brackets) C Il N

CH (CH ₃ J ₂ hydrochloride

Mixture of 8- and 5-isomers hemihydrate
225-230

58.0 (57.9

6.2 6.2

O ^CH '

Hydrochloride hemihydrate

CH, 286-288

57.5 (57.2

5.8 6.0

OCH ₃

Hydrochloride

hemihydrate

268-270

54.1 (54.7

5.5

5.5

OCH ₃ hydrochloride hydrate
230 (decomp.)

53.4 (53.8

5.3 5.6

Mixture of 6- and 7-isomers hydrochloride

hydrate

280-281

52.3 (52.0

4.8 4.9

10

Hemihydrate
242-243

52.5 (52.2

4.3 4.6

12th

279-280
a _D = -99.3
(0.4% in DMF)

Hydrochloride
284-286
a _D = +95
(0.4% in DMF)

56.5 (56.6

56.2 (56.6

5.6 5.4

5.4 5.4

13th

CH ₃

ice cream. trans mixture

Hydrochloride

hydrate

537-240

55.0 (55.4

5.5 5.8

Port setting

E.g. Z

CH,

14th

15th

16

17th

CH,

CH ₃

Isolated form and F. ( ⁰ C) analysis values in%

(thcor values in brackets)
C HN

Hydrochloride

hydrate

242-243 55.8
(55.4

5.7 5.8

18th

The production of certain starting materials is shown below:

Preparation 1 (A) N- (1,4-Benzodioxane-2-carbonyI) -piperazine

13.1
13.5)

Hydrochloride 54.0 5.5 12.7 dihydrate (53.6 6.0 13.0) 214-215

Hydrochloride
hemihydrate
272 55.6
(55.7 5.2
5.4 13.0
13.0) Hydrochloride
hydrate
230 54.4
(54.8 5.2
5.5 12.8
12.8) llydrochloride
sesqui methanolate
205-207 55.3
(55.7 6.1
6.2 12.9
12.7)

HN

NH + Cl

HN

+ HCl

A suspension of 11.88 g of piperazine and 2030 g of sodium acetate in a mixture of 70 ml of water and 95 ml of acetone was stirred at 10 - 15 ° C, then about 35 ml of concentrated hydrochloric acid were added until the pH of the solution was 1, 5 reached. Subsequently, 31,0g l, 4-benzodioxan-2-carbonyl chloride, and about 45 ml of 5N sodium hydroxide was added portionwise while maintaining the temperature at 10-15 ⁰ CeO was maintained and the sodium hydroxide to pH 1.7 - 2.2 gave . After the addition was complete, the pH was adjusted to 2.0 with the addition of sodium hydroxide solution and the suspension was stirred for an additional 30 minutes. Then water was added until a homogeneous solution was obtained, the acetone was removed -m VaI- and the aqueous residue was dissolved in; C uniformly (3 × 200 ml) extracted. The aqueous phase was made basic to pH = 8-9 with 5N sodium hydroxide solution, back-extracted with chloroform (3 × 200 ml), and the extracts were washed with water, dried over MgSCtt and evaporated in vacuo. The oily residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride, evaporated in vacuo, and the solid residue was triturated with ether. It was then recrystallized from methanol, whereby 4.85 g of N- (1,4-ber.zodioxan-2-carbonyl) piperazine hydrochloride with a melting point of 265-267 ° C. were obtained.

Analysis for CuH ₁₆ N ₂ O ₃ ■ HCl:

found: C 54.6 H 5.5 N 9.7%

calculated: C 54.8 H 6.0 N 9.8%

Preparation 2 ö-methoxy-1 ^ -benzodjoxane ^ -carboxylic acid

CHjO

CH ₃ OH

KMnO ₄

CO ₂ H

5.02 g of finely ground potassium permanganate was in four portions to a stirred suspension of 432 g of 2-hydroxymethyl-6-methoxy-l, 4 ^ -benzodioxane in a potassium hydroxide solution of 1.47 g in 42 ml of water at 5 ° C was added. During the reaction, the Maintained temperature at 5-15 ° C after completion After the addition, stirring was continued at room temperature for 4 hours, then the reaction mixture was added Set aside overnight.

The manganese dioxide was removed by filtration, the solid was washed with water and the combined aqueous phase was acidified to pH = 1 with concentrated hydrochloric acid, cooled and then extracted with chloroform. The combined chloroform extracts were washed with 5N sodium hydroxide solution 12 × 40 ml), then the basic phase was washed further with chloroform, cooled, acidified to pH = 1 with concentrated hydrochloric acid and back-extracted with chloroform. This latter chloroform solution was washed with water, dried over NazSO4 and evaporated to leave 233 g of a crude residue of 6-methoxy-1,4-benzodioxane-2-carboxylic acid. A sample was recrystallized from water, F. 120 -12 Γ C.

Analysis for CioH I ₀ O ₅ :

found: C 57.1 H 4.8%

calculated: C 57.1 H 4.8%

Preparation 3

Mixture of 8- and 5-isopropyl-1,4-benzodioxane-2-carboxylic acid

(A) A stirred solution of 23 g of 3-isopropylcatechol in 250 ml of acetone was refluxed, then 28 g of potassium carbonate were added, Das heterogeneous mixture was refluxed for an additional 15 minutes, then 10 g Methyl 2,3'-dibromopropionate was added dropwise. Three more batches of 28 g of potassium carbonate and 10 g of methyl 23-dibromopropionate were made in the same way added, then the mixture was stirred under reflux for 12 hours. The mixture was then evaporated, the residue was diluted with 700 ml of water, extracted with chloroform, and the combined Extracts were washed with water over MgSO < dried and evaporated. The remaining oil was distilled, giving 29.3 g of methyl 8 (5) isopropyl 1,4-benzodioxane-2-carboxylate with K.

115-10 ° C / 0.5 mm Hg. The C ¹³ NMR spectroscopy confirmed that the product was a mixture of the 8-isomer (71%) and the 5-isomer (29%).

(B) 29.0 g of this product in 160 ml of 24 N sodium hydroxide solution were ^{heated to 100 °} C. for 04 hours, then the solution obtained was cooled and acidified with concentrated hydrochloric acid. The mixture was extracted with chloroform (3>: 200 ml), the combined extracts were dried over MgSO4 and evaporated in vacuo, leaving 18 g of an oil which solidified on standing. Recrystallization from methanol gave a mixture of 8- and 5-isopropyl-1,4-benzodioxane-2-carboxylic acids with a melting point of 86-88 ° C.

Analysis for C12H14O4:
found: C 64.7 H 63%
calculated: C 643 H 63%

High pressure liquid chromatography showed that the product was a mixture of the 8-isomer (86%) and the 5-isomer (13%). An Commercially available device (Spectra Physics 3500 es Machine) with a column of 30 cm χ 6.35 mm outer Diameter, μ Bondapak C-18, eluent = acetonitrile (l) / 0.15M potassium hydrogen phosphate buffer, pH = 34 (2); flow rate = 14 ml / min; Pressure 41.6 bar applied.

Preparation 4

Mixture of 8- and 5-methyll, 4-benzodioxane-2-carboxylic acid

23.15 g of potassium permanganate were made in three servings

4i to a stirred suspension of 20 g of a mixture of 8- and S-methyl ^ -hydroxymethyl-M-benzodioxane in a potassium hydroxide solution of 6.5 g in 187 ml HjO added at 5 ° C. The reaction temperature was kept below 15 ° C, and after the addition was complete, the reaction mixture was at for 4 hours Stirred at room temperature. The manganese dioxide was removed by filtration, the filtrate was cooled, acidified with concentrated hydrochloric acid, and that The oily product separating on further cooling was extracted with chloroform. The chloroform extracts were washed with 5N sodium hydroxide solution, the basic layer was washed with chloroform washed, then acidified to pH = 1 with concentrated hydrochloric acid. The acidic solution was with

extracted in chloroform, the combined extracts were washed with brine, dried over MgSO4 and evaporated in vacuo, with 7.3 g of a mixture of 8- and 5-methyl-1,4-benzodioxane-2-carboxylic acid as a syrup-like residue with matching, spec-

m> troscopic properties remained. A small Sample was esterified with diazomethane and shown to be a Mixture of isomers (5: 2) acted.

308 122 / Ü44

ϊ. ~ -Γ ft. T ** -

CH ₃

CHj

Preparation 5 6,7-Dimethyl-1,4-benzodioxane-2-carboxylic acid

OH Br C ₂ OC ₂ H ₅ CH ₃

OH

Br

CO ₂ C ₂ Hs

(b)

CH ₃

(A) A stirred solution of 7.0 g of 4,5-dimethylcatechol in 45 ml of dry acetone was refluxed heated, then 5 g of potassium carbonate was added, followed by the dropwise addition of 3.5 g ethydibromopropionate.

The addition procedure was repeated an additional three times over 1.25 hours, then the reaction mixture was stirred at reflux for an additional 3.75 hours. After cooling, the mixture was filtered, the solids washed well with acetone, and then the combined The filtrate was concentrated in vacuo. 35 ml of water were added, the solid obtained was collected, washed with petroleum jelly and then taken up in ether. The ethereal solution was washed with water, _{dried over Na 2} SO ₄ and evaporated in vacuo, 10.17 g of ethyl-6-dimethyl-M-benzodioxane-carboxylate with a temperature of 70-7 ° C. were obtained.

Analysis for CnH ^ O «: found: C 65.7 H 6.8%

calculated: C 66.1 H 6.8%

(B) The hydrolysis of 5.0 g of the previously obtained ester with 13 ml of 10% sodium hydroxide solution in 125 ml of ethanol as described for related compounds in J.A.C. S, 77 (1956), 5374 gave 4.04 g of tube Ö ^ -Dimethyl-i ^ -benzodioxane ^ -carboxylic acid. A sample was recrystallized from water; 150-151 ° C.

Analysis for CnHi ₂ O ₄ : found: C 63.9 H 6.0%

calculated: C 63.5 H 5.8%

Preparation 6 6,7-dichloro-1,4-benzodioxane * 2-carboxylic acid

The hydrolysis of 5.0 g of ethyl 6,7-dichloro-1,4-benzodioxane-2-carboxylate with 10.9 ml of 10% sodium hydroxide solution in 50 ml of ethanol gave 3.4 g of 6,7-dichloro 1,4-Benzodioxane-2-carboxylic acid with a temperature of 155-158 ° C with a matching NMR spectrum and identical Rf values (thin layer chromatography) with an authentic sample.

45

so

Preparation 7 e-Methoxy-1 ^ -benzodioxane ^ -carboxylic acid

2.41 g of e-methoxy-M-benzodioxane ^ -carboxamide in t> 5 35 ml of 50% hydrochloric acid was stirred at 100 ° C. for 1 hour. The resulting solution was cooled, diluted with 200 ml of water, with chloroform (3 × 100 ml), and then the extracts were _{dried over MgSO 4} and evaporated in vacuo. The solid residue of 1.8 g was recrystallized from water; M.p. 75-78 ° C, then from ethyl acetate / hexane, 8-methoxy-1,4-benzodioxane-2-carboxylic acid having a mp of 131-132 ° C was obtained.

Analysis on C10H10O5: found: C 563 H 4.8% calculated: C 57.1 H 4.8%

Preparation 8 5-methoxy-1,4-benzodioxane-2-carboxylic acid

This compound was prepared according to the procedure of Preparation 7 using 5-Methoxy-1,4-benzodioxane-2-carboxamide prepared as starting material The product was made from Recrystallized water, mp 85-87 ° C, then from Ä thylacetat-hexane, whereby 5-methoxy-1,4-benzodioxane-2-carboxylic acid with mp 139-141 ° C was obtained.

Analysis for C ₁₀ H10O5: found: C 563 H 4.8% calculated: C 57.1 H 4.8%

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

11.6 ml of Jones reagent was added dropwise to one stirred solution of 4.0 g of δ-acetyl ^ -hydroxymethyl-1,4-benzodioxane in 70 ml of acetone at 10-15 ° C was added. The reaction mixture was stirred at room temperature for 18 hours, then with isopropanol / water / Diluted chloroform. The organic layer was separated and evaporated in vacuo. The residue was redissolved in chloroform, with Saturated sodium carbonate solution (2 χ 30 ml) extracted, and then the basic phase was with Washed chloroform, cooled and acidified to pH = 1 with concentrated hydrochloric acid.

The acidic solution was extracted with chloroform, the combined extracts were washed with saturated saline solution, _{dried over Na 2} SO ₄ and evaporated in vacuo, 1.56 g of 6-acetyl-1,4-benzo · dioxane-2-carboxylic acid with F 159-162 ° C. A sample was recrystallized from ethanol / ethyl acetate; F. 174-175 ⁰ C.

Analysis on C11H10O5: found: C 59.0 H 4.8%

calculated: C 59.5 114.5%

Preparation 10
7-acetyl-1,4-ben? O4ioxsn-2-carboxylic acid

(A) A solution of 13 ml of methyl 23-dibromopropionate in 50 ml of acetone was added dropwise over 0.5 hour to a stirred suspension of 15.1 g of 3,4-dihydroxyacetophenone and 28 g of anhydrous potassium carbonate in 100 ml of acetone, which under Reflux boiled, given. The mixture was stirred under reflux for 4 hours, then it was evaporated in vacuo and the residue partitioned between chloroform / water. The chloroform extracts were washed with water, dried over MgSC> 4 and evaporated, whereby 18 g of a mixture of 6- and 7-acetyl-1,4-benzodioxane-2-carboxylic acid methyl ester in a ratio of 2: 1, determined by C ' ³ NMR spectroscopy. A sample of this crude product was recrystallized from isopropanol; F. 68-80 ⁰ C

Analysis for C12H12O-:
found: C 50.7 H 4.9%
calculated: C 61.0 H 5.1%

(B) An aqueous sodium hydroxide solution of 1.2 g in 5 ml of water became a stirred solution of 7 g of the product from step (A) in 25 ml of ethanol at 15 ° C admitted. The reaction temperature was kept below 25 ° C for 0.5 hour, then that was Mixture evaporated in vacuo, the residue triturated with water, concentrated with Hydrochloric acid acidified and extracted with chloroform. The combined choroform extracts were over MgSOt dried, evaporated in vacuo and the residue of 1.46 g recrystallized from ethyl acetate / methanol, wherein 7-acetyl - !, 4-benzodioxane-2-carboxylic acid with m.p. 167-168 "C was obtained.

Analysis for CnH _t o0 ₅ :
found: C 59.0 H 4.5%
calculated: C 59.5 H 4.5%

High pressure liquid chromatography (HPLC) showed the isomer purity of ~ 96% (commercial device Spectra Physics 3500 es Machine; column 30 cm 635 mm outer diameter, μ Bondapak C-18; Eluant = acetonitrile (l) / 0.05 M potassium hydrogen phosphate buffer pH = 4.5 (2); Flow rate = 0.6 ml / min; Pressure -54.1 bar).

The acidic, aqueous phase was evaporated in vacuo, the residue was washed with methanol extracted, the combined extracts evaporated in vacuo and the 53 g of product from ethyl acetate / methanol umkrislallisieri, where ö-acetyl-l ^ -benzodioxane-2-carboxylic acid was obtained. The HPLC showed only one component, which is an authentic sample, manufactured in preparation 9, corresponds

Preparation 11
(A) (+) - 1 / ♦ -Benzodioxan ^ -carboxylic acid

21.6 g of 1,4-benzodioxane-2-carboxylic acid and 34.26 g of (+) -Dehydroabietvlamin were mixed together in 1000 ml of hot, technical, denatured ethyl alcohol and then left to stand at room temperature for 24 hours. The 20 g of precipitate formed were collected, the filtrate was concentrated to 600 ml and allowed to stand for 48 hours, during which time a further 4 g of solid product formed. The combined product in the form of 24g with F. 2O4-21O ° C was repeated from technical, denatured ethyl alcohol, methanol up to a constant melting point of 229-23O ⁰ C recrystallized (3.0 g), the mother liquors from the two were last recrystallizations combined, reduced in volume and collected 5.6 g of solid product. This salt was converted in the usual way to 5.5 g of free carboxylic acid with «o = + 60.1 ° (1% in chloroform). It was then recrystallized twice from toluene, giving 0.23 g of (-t -) - 1,4-benzodioxane-2-carboxylic acid with a melting point of 89-99 ° C. and « _D = + 62.1 ° (1% solution in Chloroform).

Analysis for CgHeO *:
found: C 603 H 4.4% calculated: C 60.0 H4.5%

(B) (-) - 1 ^ -Benzodioxane ^ -carboxylic acid

The 600 ml of initial mother liquors from the previous experiment were evaporated in vacuo, and the oily residue was taken up in 250 ml of acetone and set aside until the Crystallization was complete. It was 10.0 g solid product collected and recrystallized from acetone. Then 6.0 g of the salt were added to the free acid in The crude product was converted conventionally using dilute sulfuric acid taken up in chloroform, over silica gel (10 50 mm column size) after elution with chloroform chromatography «, evaporated in vacuo and then recrystallized from toluene, whereby 0.90 g of (-) - 1,4-benzodioxane-2-carboxylic acid mi »F 98-99 ° C and ad = -66.1 ° (1% solution in chloroform).

Analysis for CgHaO. »:

found: C 59.9 H 4.5% calculated: C 60.0 H 4.5%

Preparation 12 N- (1,4-Benzodioxane-2-carbonyl) homopiperazine

This compound was prepared following the procedure of Preparation 1 using Homopiperazine made instead of piperazine. A sample the hydrochloride salt was recrystallized from methanol; 189 ° C.

Analysis for CuHi ₈ N ₂ O ₃ HCI:
found: C 56.2 H 6.2

Calculated: C 563 H 6.4

N 93% N 9.4

Preparation 13

Mixture of 6 and 7-chloro-1,4-benzodioxane-2-carboxylic acid

(A) Chlorine gas was passed into a stirred, 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 aluminum chloride. The reaction was terminated after 20 minutes, then the solution was flushed with nitrogen, washed with water, with sodium bicarbonate solution and again with water, _{dried over Na 2} SQ * and evaporated in vacuo, 12.0 g of a mixture (I: 1 according to C ^l3 -NMR spectroscopy) of methyl-6 and - / - chloro-M-benzodioxane ^ -carboxy-IaI were obtained.

(B) A sample of 1.4 g of the product obtained above in 20 ml of ethanol was mixed with a solution of Treated 0.25 g of sodium hydroxide in 1 ml of water at room temperature, turning a black color

developed. After 48 hours at room temperature the mixture was concentrated in vacuo with Diluted water, extracted with chloroform, and the chloroform layer was discarded. The watery one Phase was acidified with concentrated hydrochloric acid, extracted with chloroform, then the combined Extracts dried over MgSO4 and in vacuo evaporated, 1.0 g of a mixture of 6- and 7-chloro-l, 4-benzodioxane-2-carboxylic acid with F, 145 to 146 ° C with matching, spectroscopic ι ο Properties were obtained.

Preparation 14
2-methyl-1,4-benzodioxane-2-carboxylic acid ¹ ^

33.3 ml of Jones reagent was added dropwise to a stirred solution of 5 g of 2-hydroxymethyl-2-methyl-1,4-benzodioxane in 300 ml of acetone at 5 ° C. then the reaction mixture was allowed to warm to room temperature. 10 ml of isopropanol were then added, followed by 200 ml of water, the solution was extracted with chloroform and the extracts were evaporated in vacuo. The remaining oil was taken up in 200 ml of chloroform, then extracted with dilute sodium bicarbonate solution and the aqueous phase was further extracted with chloroform washed. The aqueous phase was then acidified with hydrochloric acid and extracted with chloroform, the combined extracts were washed with water, dried over MgSO4 and evaporated in vacuo, 1.7 g of 2-methyl- ^{1,4-benzene; c J} > oxane-2- carboxylic acid were obtained. A sample was recrystallized from toluene; F. 133-134 ° C. Analysis for CiqHioOi:
found: C 61.8 H 53b
calculated: C 61.9 H 5.2%

Preparation 15

cis and trans ethyl 3-methyl-1,4-benzodioxane-2-carboxylate

These compounds were separated from one another by preparative HPLC and by NMR spectroscopy according to published values, see, e.g., J. Med. Chem, 10 (1967), 880, each identified Isomer was hydrolyzed to the corresponding acid; this was converted into the acid chloride without further action Characterization converted

Preparation 16

4-Amino-6,7-dimethoxy-2- (3-methyIpiperazin-1 -yl) quinazoline

8.05 g of 4-amino-2-chloro-6,7-dime: ~ oxychinazoline and 10 g of 2-methylpiperazine were heated under reflux in butanol for t5 hours. The reaction mixture was then evaporated in vacuo and the remaining oil was in 200 ml Chloroform was taken up, washed with water (4 × 50 ml), _{dried over Na 2} SO 4 and evaporated in vacuo. The remaining oil, 13 g, was recrystallized from isopropanol, with 3.0 g of 4-amino-6,7-dimethoxy-2 - (3-methylpiperazin-1-yl) -quinazoline-hfcmihydrate with mp 185-187 ° C were obtained.

Analysis on Ci 5H ₂₁ N ₅ O ₂ · '/ ₂ H ₂ O: N 22.8o / o found: C 58.1 H 6.8 N 22.40 / o calculated: C 57.7 H 7.1

Claims (1)

Patent claims: 1. 4-Amino-2- (piperazin-l-yl or homopiperazin-l-ylj-quinazoline derivatives of the general formula O R ' CH ₃ O CH ₃ O N-C