DD139850A5 - PREPARATION OF 4-AMINO-2- (PIPERAZIN-1-YL OR HOMOPIPERAZIN-1-YL) -CHINAZOLINE DERIVATIVES - Google Patents

Description

Field of application of the invention

The invention relates to therapeutic agents which 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 particularly in the treatment of hypertension.

Explanation of the essence of the invention

The new compounds according to the invention have the following general formula:

- (I)

in which mean:

(R) a 6,7-di (lower alkoxy) or 6,7,8-tri- (lower alkoxy) radical,

m = 1 or 2,

X is the radical -CHr " ¹ - or -CH ₂ CH ₂ -;

each of R, which may be the same or different, is a hydrogen atom or a lower alkyl group; and

R and R, which may be the same or different, each represents a hydrogen st offatom, a lower alkyl group, lower alkoxy group, a halogen atom, a lower alkanoyl group, lower alkoxycarbonyl group or a radical of formula

-CONR ⁴ R ⁵ or - £

4 5 wherein R and R, the same or

may each be a hydrogen atom or a lower alkyl group.

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

In the specification, "halogen" means fluorine, chlorine, bromine or iodine. The term "lower" used in connection with an alkyl or alkoxy radical means that such a straight-chain or branched radical contains from Λ to 6 carbon atoms and preferably from 1 to 4 carbon atoms. The term "lower" as used in connection with an alkanoyl radical means that such a straight-chain or branched radical contains from 2 to 6 carbon atoms and preferably from 2 to 4 carbon atoms.

Pharmaceutically acceptable acid addition salts of the compounds of this invention are salts formed from acids which form non-toxic acid addition salts with pharmaceutically acceptable anions, such as hydrochloride, hydrobromide,

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Sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate, pumarate, succinate, lactate, tartrate, citrate, gluconate, saccharate and p-toluenesulfonate salts.

A "preferred group of compounds according to the invention corresponds to the following formula:

(IA)

in which mean:

(H) a 6,7-di (lower alkoxy) or 6,7,8-tri (lower alkoxy) radical;

R is a hydrogen atom or a lower alkyl radical; and 2 3

R and R, which may be the same or different, each represents a hydrogen atom, a lower alkyl radical, lower alkoxy radical, a halogen atom, a lower alkanoyl radical,

or -GO ₀ NR R '

radical or a radical of the formula -CONR ₀

wherein R and R 1, which may be different, each represents a hydrogen atom or a lower alkyl group.

This preferred group also includes the pharmaceutically acceptable acid addition salts of compounds of formula (IA),

Another preferred group of compounds of the invention has the formula (I) wherein (R) _{n is} 6,7-dimethoxy, 6,7-satoxy or 6,7,8-trimethoxy, m is 1 or 2; each of R independently is H or CH; and R and R independently of one another are hydrogen, lower alkyl, lower alkoxy, halogen, lower alkanoyl,

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a lower Alkoxycärbonylrest, the remainder -00NH _p or

SO ₂ N (CH ₃ ) ε.

C.

The most preferred compounds correspond to the following formula:

.2

'(IB)

Y \ J

NH,

where R is H or CH, and R and R? is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a lower alkanoyl group. ,

The most preferred single compound is 4-amino-2- [4- (1, 1-benzodioxan-2-carbonyl) -piperazin-1-yl] -6,7-dimethoxy-quinazoline.

The 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 prepared by physical methods, e.g. B. by fractional crystallization of suitable salts are cleaved. The invention includes both the cleaved pairs and mixtures thereof, racemic mixtures or the cleaved d- and 1-optically active isomeric forms.

A A

When X has the meaning -CHR -, wherein R is a lower alkyl group, cis and trans isomerism is possible, and both isomers (and mixtures thereof) belong to the compounds of the invention.

-5-. 2 088 6

The compounds of the invention can be prepared in a number of ways, including the following:

(1) The compounds of the present invention can be prepared by reacting a suitably substituted quinazolines of the following formula:

- (ID

wherein Q represents a readily cleaving group such as a chlorine, bromine or iodine atom, a lower alkoxy radical or a (lower alkyl) thio radical, with a piperazine or homopiperazine of the following formula:

R ¹

HN N 2 m

with resultant cleavage of HQ. Q is preferably a chlorine or bromine atom. ,

The reaction is typically carried out by heating the reactants, e.g. B. to a temperature of 80 ⁰ C to 150 C, z. B. under reflux, in an inert, organic solvent, for. For example, n-butanol performed. After the practical completion of the reaction, the product can be isolated and purified by conventional procedures. For example, the reaction mixture becomes a typical procedure

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cooled, and the resulting, crude, solid product is collected, washed, z. B. with cold n-butanol, and dried. The crude product may be removed in a typical procedure by dissolving it in hot, aqueous dimethylformamide, filtering and concentrating the filtered solution, e.g. B. in a vacuum, to be cleaned. The solution is then cooled and ether is added to precipitate the pure product, the pure product 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 of the prior art. For example, the intermediates of formula (III) can be prepared according to the following reaction scheme:

NH + Cl

N-C \ / U

(IV)

(V)

(III)

The intermediates of formula (IV) and (V) are either known compounds or they can be prepared by conventional procedures. When X has the meaning of -CEH-, wherein R is a lower alkyl group, cis and trans isomers of the compound (V) are possible. A mixture of these isomers may be employed, but if the final cis or trans product is desired, the appropriate cis or trans starting material may generally be prepared by a suitable chromatographic procedure on the corresponding methyl or ethyl ester and conversion to the acid chloride become.

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(2) The compounds of the invention can also be prepared by reacting a quinazoline of the following formula:

(VI)

with a carboxylic acid of the following formula;

2

COOH

(VII)

or with their functional equivalent as acylating agent, e.g. An acid chloride or bromide, an "activated" ester or a mixed anhydride of the compound of formula (VII).

The acid chlorides or bromides can be prepared by conventional procedures, e.g. By reaction of the free acid with either thionyl chloride or bromide.

The preferred "activated" ester is the succinimido ester of the following formula:

XO

J C-O-N

(VIII)

which in turn can be produced according to conventional working methods, e.g. B. by reaction of the free acid with H-hydroxysuccinimide in the presence of a dehydrating agent, for. B. of dicyclohexylcarbodiimide. Another preferred "activated ester" is the phthalimido ester.

Suitable mixed anhydrides have the following formula:

- (ix)

wherein Y is a lower alkyl or lower alkoxy, more preferably a t-butyl or isobutoxy. They can be prepared by conventional methods, s. 3. by reaction of the free acid with the appropriate lower alkanoyl chloride or lower alkyl chloroformate, e.g. B. with Pivaloylciilorid or Isobutylchlorformiat, in the presence of a base such as triethylamine.

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

Preferably, the. Compounds of formula (VII) reacted in the form of their acid chlorides or bromides.

In a typical procedure using an acid chloride of compound (VII), the acid chloride is dissolved in a suitable solvent, e.g. As methylene chloride, dropwise to a stirred suspension of quinazolines (VI) in a suitable solvent, eg. For example, methylene chloride added.

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The mixture can then be stirred for a few hours at room temperature and then the resulting pellet is filtered off and purified by conventional procedures.

When X has the meaning of -CHR -, wherein R is a lower alkyl group, cis-trans isomerism is possible as mentioned in the route (1).

The intermediates of formulas (YI) and (VII) can be prepared by conventional procedures.

(3) The pharmaceutically acceptable acid addition salts of compounds of the invention may be prepared by conventional procedures, e.g. Example by reacting the free base with the appropriate acid in an inert organic solvent and collecting the resulting precipitate of the salt by filtration. If necessary, the product can then be recrystallized for purification. However, the product obtained by routes (1) and (2) is often already present in the form of the acid addition salt.

The invention further includes the pharmaceutically acceptable bioprecursors of compounds of formula (I) and the salts thereof.

The term "pharmaceutically-acceptable bioprecursor" is illustrated as follows: In pharmaceutical chemistry, it is common practice to overcome some undesirable physical or chemical properties of an active ingredient by converting the active ingredient into a chemical derivative that does not have this undesirable property Derivative, however, is converted back to the starting drug in the application in an animal or in a human.

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For example, if the active ingredient is not well absorbed orally in an animal or in a patient, it is possible to convert the active ingredient to a chemical derivative which is well absorbed and which is reconverted to the parent drug in the serum or tissues becomes. On the other hand, if an active ingredient is unstable in solution, it may be possible to produce a chemical derivative of the active ingredient which is stable and can be applied in solution, but which is reconverted in the body to form the starting drug. The pharmaceutical chemist is well aware of the possibilities of overcoming these inherent drawbacks by chemical modifications that are only temporary and reversible in animal or patient administration.

For the purposes of this specification, the term "pharmaceutically acceptable bioprecursor" of a compound of formula (I) means a compound having a structural formula different from that of the compounds of formula (I) but which is administered to an animal or a human People in the body of the patient is converted back to a compound of formula (I).

The antihypertensive activity of the compounds of this invention is demonstrated by their ability to lower the blood pressure of conscious, spontaneously hypertensive rats and conscious kidney-hypertensive dogs. oral administration in doses up to 5 mg / kg.

The compounds of the invention may be administered alone, but in general they will be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be taken orally

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in the form of tablets containing such diluents as starch or lactose, or in capsules either alone or in admixture with diluents or in the form of elixirs or suspensions containing flavoring and coloring agents. You can parenteral, ζ. Β. administered intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, e.g. For example, enough salt or glucose to render the solution isotonic.

The invention therefore relates to a pharmaceutical composition or a medicament which comprises a compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier.

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 approximately within the range of 1 to 20 mg / day for an average adult patient (70 k.sup.-1). where the dose is given as a single dose or in up to three divided doses. The dose levels for intravenous administration are expected to be about 1/5 to 1/10 of the daily oral dose. Therefore, the oral unit doses in tablet or capsule form are approximately in the range of 1 to 50% of active compound for an average adult patient. Of course, deviations are required depending on the weight and the condition of the patient to be treated and the particular, chosen route of administration, as known in the art.

The invention further relates to a method of treating an animal including a human suffering from hypertension, which method comprises administering an antihypertensive effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof or a pharmaceutical composition as above defined in which animal or human comprises

Exemplary embodiments .

The invention will be explained in more detail with reference to the following examples.

Example 1 4-amino-2

j4-benzodioxan-2-

6 ^ 2-dimethoxvchinazolin

/ ~ Λ

.r ~ \ Γ T> L I J. ° ⁺

NH,

HCl

g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 150 g of K- (1,4-benzodioxan-2-carbonyl) -piperazine were stirred at reflux in 2 liters of n-butanol for 3 hours and 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 (80 ° C) 550 ml dimethylformamide and 130 ml of water, filtered, concentrated in vacuo to about 300 ml and then cooled, then 1.8 l of ether was added. The resulting gum was collected and washed with ether to give 215 g of 4-amino-2- [4- (1,4-benzodioxan-2-carbonyl) -piperazin-1-yl] -6,7-dimethoxyquinazoline hydrochloride with mp 289-290C.

-13- 20386

Analysis on C ₂ , H ₂ CNcO ₅ .HCl:

found: C = 56.9 H = 5.4 N = calculated: C = 56.6 H = 5.4 N = 14.4 %

Example 2

1 g of 4-amino-2-chloro-6,7,8-trimethoxyquinazoline and 1.168 g of N- (1,4-benzodioxan-2-carbonyl) -piperazine were dissolved in 67 ml of n-butanol together with 1.87 g of triethylamine Heated under reflux for 24 hours. Then another 0.026 g of N- (1,4-benzodioxan-2-carbonyl) -piperazine was added and the mixture refluxed for a further $ 0 hours. The butanol was then removed in vacuo and the residue was partitioned between aqueous sodium carbonate solution and chloroform. The combined chloroform extracts were washed with water, dried over Na ₂ SO ₄ and evaporated in vacuo to leave 3.4 g of solid. These were taken up in the minimum amount of dimethylformamide and then allowed to stand at 0 ^° C. overnight. Then ether was added and the cloudy solution. further cooled to give 0.58 g of 4-amino-2- [4- (1,4-benzodioxan-2-carbonyl) -piperazin-1-yl] -6,7,8-trimethoxyquinazoline with mp 26 (] -271 ⁰ C were obtained.

Analysis on ^C 24 ^H 27 ^N 5 ° 6 ^:

Found: C = 59.3 H = 5.6 N = 14.1 %

calculated: C = 59.9 H = 5.7 N = 14.6 %.

Example 3

0.33 g of 4-amino-2-chloro-6,7-cliethoxyquinazoline and 0.32 g of N- (1,4-benzodioxan-2-carbonyl) -piperazine were refluxed in 30 ml of n-butanol overnight. The mixture was

2 0886 8

then evaporated in vacuo and the residue was partitioned between sodium carbonate solution and chloroform. The combined chloroform extracts were washed with water, over Na ₂ SO ₄ . dried and evaporated in vacuo. The residue was chromatographed over 70 g of silica gel using chloroform / ethanol (0-5%) as eluent. The appropriate fractions were combined, evaporated in vacuo, then redissolved in chloroform / ethanol and treated with ethereal hydrogen chloride. The solution was then evaporated in vacuo and the residue recrystallized from isopropanol to give 0.19 g of 4-amino-2-C4- (1,4-benzodioxan-2-carbonyl) -piperazin-1-yl] -6, 7-diäthoxychinazolinhydrochlorid-2,5-hydrate with P. 180-184- ⁰ C (dec.) were obtained.

Analysis on C ₂₅ H ₂ QlT ₅ O ₅ .HCl.2.5H ₂ O: Found: C = 53.3 H = 5.6 N = 12.2% Calculated: C = 53.5 H = 6.3 N = 12.5%

Example 4

1.58 g of α-amino-2-chloro-6,7-dimethoxyquinazoline and 2.0 g of N- (1,4-benzodioxan-2-carbonyl) -homopiperazine were refluxed in 114 ml of n-butanol 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 and then re-evaporated in vacuo. The residue was combined with the original, solid product, treated with cold ethanol and from ethanol

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recrystallized to give 0.57 S 4-Amino-2- [4- (1,4-benzodioxan-2-carbonyl) homopiperazine-1-yl] -6,7-din ⁱ etlioxychina2olinhydrochlorid with F., 250-251 ⁰ C. were obtained.

Analysis on

found: calculated:

O, - HCl:

C = 57.2 H = 5.4 N C = 57.4 H = 5.6 N

13.8 % 14.0 %

Example 5

A solution of 2.17S 6-methoxy-1,4-benzodioxan-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-2 -piperazin-1-yl-6,7-dimetho>: ychinazoline in 50 ml of liethylenchlorid at room temperature. After completion of the addition, the mixture was stirred at room temperature for 4 hours, then filtered, and the solid was suspended in aqueous potassium carbonate solution and extracted with chloroform. The combined extracts were washed with water, dried over N 2 SO 4 and evaporated in vacuo to leave 4.15 g of a solid residue. These were chromatographed over 160 g of silica gel eluting with chloroform and then with chloroform-methanol (2.5%). ·

- 16 - 2 0 8 8 6

Comparable fractions (analyzed by TLC, containing the desired product) were combined and evaporated in vacuo. The residue was taken up in ethyl acetate-methanol and treated with ethereal hydrogen chloride. The addition of more ether followed by cooling gave a solid which was collected and recrystallized from methanol to give 0.95 S 4-Amino-2- [4- (6-methoxy-1 ^/ <~ benzodioxan-2-carbonyl) -piperai; ini-yll-ÖJV-dimethoxyquinazoline hydrochloride hydrate with F. 220-222 ⁰ C were obtained.

Analysis on ^C 24 ^H 27 ^N 5 ° 6 ' ^{HC1 # H} 2 ^0:

Found: c C = 53.3 H = 5.5 N = 13.4 %. calculated:. C = 53.8 H = 5.6 N = 13.1%

Examples 6 to 24

The following compounds were prepared in a similar manner to Example 5 using 4-amino-2-piperazin-1-yl (or 2- [3-methylpiperazin-1-yl]) -6,7-dimethoxy- quinazoline and the corresponding suitable carbonyl chloride

has been.

CH

Ex,

isolxerte Porn and F. ( ⁰ C) ^Ί

Analytical values in % (theor. Values in brackets) C HN

Hydrochloride

hemihydrate

238-240

56.2 (56.4

5.4 5.7

13.9 13.7)

Mixture of 8 and isomers

Mixture of 8- and isomers

hydrochloride

iiemihydrat

225-23Ο

58.0 (57.9

6.2 6.2

13.3 13.0)

Hydrochloride

hemihydrate

286-288

57.5 (57.2

5.8 6.0

13.3 13.3)

CH

isolated form and F. ( ⁰ C)

Analytical values in % (theor.values in brackets)

C H N

OCH.

Hydrochloride

heinihydrat

268-270 54.1 (54.7

5.5 5.5

13.9 13.3)

OCH,

H-

Hydrochloride hydrate 230 (Zers.) 53.4 (53.8

5.3 5.6

12.8 13.1)

Mixture of 6- and 7 "isomers

Hydrochloride hydrate 1280-281

52nd 3 4 .8th 12 .8th (52nd 0 4 .9 13 .2)

CH

isolated form and E. ( ⁰ C)

Analytical values in % (theor.values in brackets)

C H N

Hemihydrate 242-243

52.5 X52.2

4.3 4.6

13.2 13.2)

• Cl

279 - 280 C < _D = -99.3 °

(0.4% in DMF)

56.5 (56.6

5.6

5.4

14.1 14.4)

Hydrochloric! 284 - 286 OC _D = + 95 °

(0.4% in DMF)

56.2 (56.6

5.4 5.4

14.5 14.4)

CH

..Bsp.

isolated form and E. ( ⁰ C)

Analytical values in% (theor. Values in brackets) C H N

CH.

ice, trans-Medley

Hydrochloride ·

hydrate 237-240

55.0 (55.4

5.5 5.8

13.6 13.5)

trans

Hydrochloride

hydrate 242 - 243

55.8 (55.4

5.? 5.8

13.1 13.5)

Hydrochloride

dihydrate

214-215 '

54.0 (53.6

5.5

6.0

12.7 13.0)

Bsp.-

isolated form and V. ( ⁰ C)

Analytical values in% (theor.values in brackets)

CH.,

Hydro chior id-

hydrate 234 - 237

55.6 (55.4

5.4 5.8

13.3 13.5)

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)

Mixture of 6- and 7-isomers

CH ₃

isolated form and F. ( ⁰ C)

Hydrochloride

hydrate 232 - 234 (Ze.rs.)

Hydrochloridsesqui-methano

Lat 205 - 207 '

Analytical values in% (theor.values in brackets)

48.6 (49.0

5.3 5.4

13.5 13.7)

55.3 (55.7

6.1 6.2

12.9 12.7)

Oxalate - sesqui-

hydrate 176 - 179

53.8 (53.6

5.4 5.5

11.6 12.0)

Ex. Z R ¹ isolated form and F. ( ⁰ C) Analytical values in % (theor.values in brackets) CH N 24 Η _L COOC ₂ H ₅ ~~ ^ O ^ v ^ ⁷ Mixture of β- and 7-isomers. H Hydrochloride dihydrate 208-210 (hygroscopic) 52.2 5.2 11.4 (52.4 5.8 11.8)

2 088 6 8

Example 25

2.06 s of dicyclohexylcarbodiimide and 1.15 S of N-hydroxysuccinimide were added to a stirred solution of a mixture of 2,23S-6- and V-carbamoyl-1,4-benzodioxane-2-carboxylic acid in 70% dimethylformamide at 0 ^° C. The mixture was stirred for 1 hour at 0 ⁰ C, then 2.8 g 4-Amino-6,7-dimethoxy-2-piperazino-quinazoline was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then filtered, the filtrate was diluted with 500 ml of ether, and the resulting oily precipitate was collected. The product was partitioned between chloroform / isopropanol / sodium bicarbonate solution, the chloroform layer was separated, washed with water and evaporated in vacuo. The Kickstand was chromatographed over silica gel, and elution with chloroform-methanol (3%) gave a crude product, which in the treatment with ethereal hydrogen chloride solution and recrystallization from methanolA'asser / ether / dimethylformamide and then from Hethanol / v / asser / dimethylformamide 4-Amino-6,7-dimethoxy-2- [V- (6- and 7- (mixture) -carbamoyl-1,4-benzodioxan-2-carbonyl) -piperazine-q] -quinazoline hydrochloride hydrate with m.p. 228-235 ⁰ C (Zers.) Yielded. Further recrystallization gave an analytical sample with F. 24-5-248 ⁰ C.

Analysis on C ₂ H ₂₆ N ₆ O ₆ HCLH ₂ O:

found:. C = 52.6 H = 5.5 N = 14.6% calculated: C = 52.5 H = 5.3 N = 15.3%

Analysis by high pressure liquid chromatography showed that the product was a mixture of the 6 and 7 isomers in the ratio of 7: 3.

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The following shows the preparation of certain starting materials;

Preparation 1

+ HCl

A suspension of 11.88 g of piperazine and 20.30 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 Had reached 1.5. Subsequently, 31.0 g of 1,4-benzodioxan-2-carbonyl chloride and about 4-5 ml of 5N sodium hydroxide solution were added portionwise while maintaining the temperature at 10-15 ° C and the sodium hydroxide brought the pH to 1.7-2 , 2 stopped. After the completion of the addition, the pH was adjusted to 2.0 by adding sodium hydroxide solution, and the suspension was stirred for a further 30 minutes. Then, water was added until a homogeneous solution was obtained, the acetone was removed in vacuo, and the aqueous residue was extracted with chloroform (3 × 200 ml). The aqueous phase was basified to pH = 8-9 with 5N sodium hydroxide solution back-extracted with chloroform (3x200ml) and the extracts were washed with water, dried over MgSO4, and evaporated in vacuo.

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The oily residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride, evaporated in vacuo, and the solid residue triturated with ether. It was then recrystallised from methanol to give 4.85 g of N- (1,4-benzodioxan-2-carbonyl) -piperazine hydrochloride with mp.

267 ° C were obtained. Analysis on C

Found: calculated

Preparation 2

.HCl:

C = 54 , 6 H = 5 , 5 N = 9 , 7 % C = 54 ,8th H = 6 , 0 N = 9 ,8th %

CH ₂ OH

5.02 g of finely ground potassium permanganate were added in four. Add portions to a stirred suspension of 4.52 g of 2-hydroxymethyl-6-methoxy-1,4-benzodioxane in a potassium hydroxide solution of 1.47 g in 42 ml of water at 5 ° C. During the reaction, the temperature was maintained at 5 - 15 ° C, after completion of the addition, stirring was continued at room temperature for 4 hours, then the reaction mixture was set aside overnight.

The hangania 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 (2 × 40 ml), then the basic phase was further co-precipitated

2 008

Chloroform washed, cooled, acidified to pH = 1 with concentrated hydrochloric acid and back-extracted with chloroform. This latter chloroform solution was washed with water, dried over Na 2 SCL and evaporated to leave 2.33 g of a crude residue of 6-methoxy-1,4-benzodioxan-2-carboxylic acid. A sample was recrystallized from water, m.p. 120-121 ⁰ C.

Analysis on C ₁₀ H ₁₀ Oc:

found: C = 57.1 H = 4.8% calculated: C = 57.1 H = 4.8%

Preparation 3

(A) heated to a stirred solution of 23 g 3-I ^s opropylcatechin was dissolved in ml of acetone under reflux, then 28 g of potassium carbonate were added. The heterogeneous mixture was refluxed for a further 15 minutes, then 10 g of ethyl 2,3-dibromopropionate was added dropwise. Three more batches of 28 g of potassium carbonate and 10 g of methyl 2,3-dibromopropionate were added in the same manner, then The mixture was stirred at 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, dried over MgSO4 and evaporated. The residual oil was distilled to give 29.3 g Kethyl-8 (5) -isopropyl-1 _r 4-benzpdioxan-2-carboxylate with K. 115-120 ° C / o, 5 ™ a Hg

1-5 were received. The C - UMR spectroscopy confirmed that the product was a mixture of the 8-isomer (71%) and the 5-isomer (29 %) .

(B) 29, Og of this product in 160 ml 2.5N sodium hydroxide solution was heated 0.5 hours at 100 ⁰ C, then the resulting solution cooled Wurd Vind with concentrated

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Hydrochloric acid acidified. The mixture was extracted with chloroform (5x200ml), the combined extracts were dried over MgSO4 and evaporated in vacuo leaving 18g of an oil which solidified on standing. The Umkristallisatiön from methanol gave a mixture of 8- and 5-isopropyl-1,4-benzodioxan-2-carboxylic acid with P. 86-88 ⁰ C..

Analysis on G ^^ R ^^ O ^:

found: C = 64.7 H = 6.3% calculated: C = 64.9 H = 6.3 %

High pressure liquid chromatography showed that the product was a mixture of the 8-isomer (86%) and the 5-isomer (13 %) . For analysis, a commercially available instrument (Spectra Physics 3500 es Machine) with a column of 30 cm χ 6.35 nmi outer diameter, ^ Bondapak C-18, eluent = acetonitrile (1) / O, 15I1 potassium hydrogen phosphate buffer, pH = 3 »5 (2); Flow rate = 14 ml / min; Pressure 41.6 bar applied.

Preparation 4

23 »15 S potassium permanganate was added in three portions to a stirred suspension of 20 g of a mixture of 8- and 5-methyl-2-hydroxymethyl-1,4-benzodioxane in a potassium hydroxide solution of 6.5 g in 187 1 H 2 O at 5 ⁰ C added. 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 was removed by filtration, the filtrate was cooled, acidified with concentrated hydrochloric acid, and the oily product 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, then acidified to pH = 1 with concentrated hydrochloric acid. The acid solution was extracted with chloroform, the combined extracts were washed with brine, over MgSO4. dried and evaporated in vacuo, leaving 7 »3 S of a mixture of 8- and 5-methyl-1, ^ - benzodioxane - ^ - carboxylic acid as syrup-like residue with consistent, spectroscopic properties. A small sample was esterified with diazomethane and it was shown by gas chromatography to be a mixture of isomers (5: 2).

Preparation 5

(A) A stirred solution of 7 »0 g of 4,5-dimethylcatechin in ⁷ ^ ^r " *

heated to reflux with dry acetone, then distilled

5 g Kaliujncarbonat added, followed by the dropwise addition of 3.5 g ethyldibronrpropionate.

The operation of the addition was repeated a further three times for 1.25 hours, then the reaction mixture was stirred at reflux for a further 3.75 hours. After cooling, the mixture was filtered, the solids were washed well with acetone and then the combined filtrate was concentrated in vacuo. 35 ml of water was added, the resulting solid was collected, washed with petroleum ether and then taken up in ether. The ethereal solution was washed with water, dried over Na 2 SCv and evaporated in vacuo, whereby

10.17 g of ethyl-6,7-dimethyl-1, with F. 7O-71 ⁰ C were obtained.

Analysis on Cj ^ H ^ gO ^: found: C = 65.7 H = 6.8% calculated: C = 66.1 H = 6.8 %

(B) Hydrolysis of 5> 0 g of the previously obtained ester with 13 parts of 10% sodium hydroxide solution in 125 ml of ethanol as described for related compounds in JACS, 22. (1956), 537, gave 4.04 g of crude 6 , 7-dimethyl-i, 4-benzodioxan-2-carboxylic acid. A sample was recrystallized from water; F. ⁰

Analysis on Cy, Al ^ pO ₁ .:

found: C = 63.9 H = 6.0% calculated: C = 63.5 H = 5.8%

Preparation 6

Hydrolysis of 5 »0 g of ethyl-6,7-dichloro-1,4-benzodioxan-2-carboxylate with 10.9 ml of 10% sodium hydroxide solution in 0 ml of ethanol gave 3.4 g of 6,7-dichloro -1,4-benzodioxan-2-carbonsä \ ^u> e with F. 155-158 ⁰ C with a matching NMR spectrum and identical Rf values (thin-layer chromatography) with an authentic sample.

Preparation 7

2.41 g of 8-methoxy-1,4-benzodioxan-2-carboxamide in 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, extracted with chloroform (3 x 100 ml), and then the extracts were dried over MgSO4 and evaporated in vacuo. The solid

Residue of 1.8 g was recrystallized from water; F. 75-78 ⁰ C., then from ethyl acetate / hexane to give 8-methoxy-1,4-benzodioxan-2-carboxylic acid was obtained with F. 131-132 ⁰ C.

Analysis on

found: C = 56.9 H = 4.8 % "calculated: C = 57.1 H = 4.8%

Preparation 8

This compound was prepared according to the procedure of Preparation 7 using 5-methoxy-1,4-benzodioxan-2-carboxamide as a starting material. The product was recrystallized from water, m.p. 85-87 C, then from ethyl acetate-hexane to give 5-Hethoxy-1 ^ ^ -carboxylic acid -bensodioxan with F. 139-141 ⁰ C was obtained.

Analysis on C ^ qH ^ qOc-:

found: C = 56.9 H = 4.8% calculated: C = 57 »1- H = 4.8 ° / a

Preparation 9

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

20886

The acid solution was extracted with chloroform, the combined extracts were washed with saturated brine, dried over Na ₂ SO ₄ , and evaporated in vacuo to give 1.56 g of 6-acetyl-1,4-benzodioxane-2-carboxylic acid with Ϊ , 159-162 ⁰ C were obtained. A sample was recrystallized from ethanol / ethyl acetate; p. 174-175 · ° o.

Analysis on C ^ H ^ qOc:

found: C = 59.0 H = 4.8 % calculated: C = 59.5 H = 4.5 %

Preparation 10

(A) A solution of 13 ml of diethyl 2,3-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 Acetone, which refluxed, was added. The mixture was stirred at reflux for 4 hours, then it was evaporated in vacuo and the residue partitioned between chloroform / water. The chloroforin extracts were washed with water, dried over HgS (X) and evaporated to give 18 g of a mixture of methyl 6- and 7-acetyl-1,4-benzodioxan-2-carboxylate in a ratio of 2: 1, determined by C 1 A sample of this crude product was recrystallized from isopropanol, mp 68-80 ⁰ C,

Analysis on ^c ^ 2 ^ 12 '^ 5 ^:.

found: C = 60.7 H = 4.9 % calculated: 0 = 61.0 H = 5.1%

(B) An aqueous sodium hydroxide solution of 1.2 g in 5 hlL of water was added to a stirred solution of 7 g of the product of step (A) in 25 ml of ethanol at 15 ⁰ . The heatsealing temperature was below 25 ° C for 0.5 hours

33 - 2 0 88 6

The mixture was then 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 MgSO 4. dried, evaporated in vacuo and the residue of 1.86 g of ethyl acetate / methanol recrystallized to give 7-acetyl-1,4-benzodioxane-2-carboxylic acid with mp 167-168 ⁰ C.

Analysis on C ^ H ^ O ^:

found: C = 59.0 H = 4.5 % calculated: C = 59.5 H- = 4.5 %

Column pressure liquid chromatography (HPLC) showed the isomeric purity of * »96% (commercial Spectra Physics 3500 es Machine, column 30 cm χ 6.35 nm outer diameter, u Bondapak C-18, eluent = acetonitrile (0 / 0.05M Potassium hydrogen phosphate buffer pK = 4.5 (2), flow rate = 0.6 ml / min, pressure = 54.1 bar).

The acidic aqueous phase was evaporated in vacuo, the residue was extracted with methanol, the combined extracts were evaporated in vacuo, and the 5.5 g of product was recrystallized from ethyl acetate / methanol to give 6-acetyl-1,4-benzodioxan-2-one. carboxylic acid was obtained. The HPLC showed only one component corresponding to an authentic sample prepared in Preparation 9.

Preparation 11

21.6 g of 1,4-benzodioxan-2-carboxylic acid and 34.26 g of (+) - dehydroabietylamine were mixed together in 1000 ml of hot, technical, denatured ethyl alcohol and then allowed to stand at room temperature for hours. The 20 g of precipitate formed

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were collected, the filtrate was concentrated to 600 ml and allowed to stand for 48 hours, forming an additional ⁴ g of solid product. The combined product in the form of 24 g with F. 204-210 ° C. was repeated from technical grade methylated alcohol to methanol to a constant melting point of 229-230 ⁰ C recrystallized (3.0 g), then the mother liquors were combined from the last two recrystallizations, reduced in volume and collected 5 »6 g solid product. This salt was added to 5i5 g of free carboxylic acid with _α Ώ = + 60.1 ° (1% in chloroform) was converted in the usual manner then was recrystallized twice from toluene to give 0.23 g of C +) -. 1,4-benzodioxane-2-carboxylic acid with 98-99 ⁰ F. C and α = + 62.1 (1% solution in chloroform).

Analysis on CqHqO ^:

found: C = 60.3 H = 4.4% calculated: C = 60.0 H = 4.5 %

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 crystallization was complete. 10.0 g of solid product were collected and recrystallized from acetone. Then, 6.0 g of the salt was converted to the free acid in a conventional manner using dilute sulfuric acid. The crude product was taken up in chloroform, chromatographed over silica gel (10χ50 mm column size) eluting with chloroform, evaporated in vacuo and then recrystallised from toluene to give 0.90 g of (-) - 1,4-benzodioxan-2-carboxylic acid with P. 98-99 ° C and ^a _D = - 66.1 ° (1% solution in chloroform) were obtained.

20 88 6

Analysis on CqHqO ·

found: C = 59.9 H. = 4.5 % calculated: C = 60., 0 H = 4.5 %

Preparation 12 .

This compound was prepared according to the procedure of Preparation 1 using homopiperazine instead of piperazine. A sample of the hydrochloride salt was recrystallized from methanol; I *. 189 ⁰ C.

Analysis on C ₁₄ H ₁₈ N ₂ O ₃ .HCl:

found: C = 56.2 H = 6.2 N = 9.3% calculated: 'C = 56.3 H = 6.4 N = 9.4%

Preparation 13

Mixture. von_6 ~ _und_2 ~ Chloro-1 ^^ benzodioxane - ^ - carboxylic acid

(A) Chlorine gas was introduced into a stirred, ice-cooled solution of 10 g of ethyl-1- ^L- benzodioxan-2-carboxylate in 100 ml of chloroform in the presence of 0.06 g of aluminum chloride. The reaction was stopped after 20 minutes, then the solution was purged with nitrogen, washed with water, with sodium bicarbonate solution and again with water, dried over Na ₅ SO 4, dried and evaporated in vacuo to give 12.0 g of a mixture (1: 1 according to C ^ NMR spectroscopy) of Kethy1-6 and -7-chloro-1,4-benzodioxan-2-carboxylate.

(B) A sample of 1.4 g of the previously obtained product in 20 ml of ethanol was treated with a solution of 0.25 g of sodium hydroxide in 1 ml of water at room temperature to give a black color. After 48 hours at room temperature, the mixture was concentrated in vacuo, diluted with water, extruded with chloroform, and

-56 -. 2 0886

Chloroform layer was discarded. The aqueous phase was acidified with concentrated hydrochloric acid, extracted with chloroform, then the combined extracts were dried over MgSCL and evaporated in vacuo to give 1.0 g of a mixture of 6- and? -Chloro-1,4-benzodioxan-2-carboxylic acid F. 14-5-146 ⁰ C with consistent spectroscopic properties.

Preparation 14-

33 ml of Jones reagent was added dropwise to a stirred solution of 5S 2-hydroxymethyl-2-methyl-1,4-benzodioxane in 300 ml of acetone at 5 ° C, then the reaction mixture was allowed to come to room temperature. Then 10 ml of isopropanol and then 200 ml of water were added, the solution was extracted with chloroform and the extracts were evaporated in vacuo. The residual O1 was taken up in 200 ml of chloroform, then extracted with dilute ITatriuribicarbonatlösung, and the aqueous phase was washed much ter with chloroform. The aqueous phase was then acidified with hydrochloric acid, extracted with chloroform, the combined extracts were washed with water, I ⁷ IGSG ,; dried and evaporated in vacuo to give 1.7 g of 2-methyl-1,4-benzodioxan-2-carboxylic acid. A sample was recrystallized from toluene; Έ. 133-134 ⁰ C.

Analysis on C ₁₀ H ₁₀ O ₄ : Found: C = 61.8 H = 5.2 % calculated: C = 61.9 H = 5.2%

Preparation 15

(A) 180 g of catechol were added in portions to 138.5 ml of stirred sulfuric acid so that the reaction temperature

 After completion of the addition, the semi-solid mixture was heated to 45 ° C for 60 minutes, then cooled to room temperature and poured into 700 ml of ice-water The solution was neutralized with solid barium carbonate, and the barium sulfate was collected The filtrate was acidified to pH = 1 with concentrated sulfuric acid and then filtered again The filtrate was evaporated to leave 182.40 g of crude 3,4-dihydroxybenzenesulfonic acid, which was used without further purification.

(B) 182.40 g of the previously obtained product was acetylated in the usual manner using 300 ml of acetic anhydride in ml of pyridine and the resulting 302.49 g of crude diacetoxy product were used directly.

(C) 378 g of phosphorus pentachloride were added portionwise to a stirred solution of the pyridinium salt of 3i4-diacetoxybenzenesulfonic acid (302.49 g) in 1000 ml of chloroform at G ⁰ C so that the heat of the reaction did not rise above 15 ° C. After completion of the addition, the reaction mixture was stirred at room temperature overnight, then filtered: the chloroform solution was evaporated in vacuo and the residual oil was poured into ice-water. The aqueous phase was extracted with chloroform, the combined extracts were added via NapSO. dried and evaporated in vacuo to give a semi-solid residue, which was recrystallized from carbon tetrachloride. This product, 26,74- S "was treated with 265 ml of 15% aqueous dimethylamine solution at 20 ⁰ C, the reaction mixture was allowed to stand overnight at room temperature, and then the solution was evaporated in vacuo. The dark residue was diluted with 250 ml of acetone, then decanted, the solution was evaporated in vacuo and the residual

Oil was stirred with an equal volume of sodium hydroxide solution at room temperature for 2 hours.

The solution was then acidified with concentrated hydrochloric acid and the product obtained was recrystallized from water to give, N-DijEethyl-3,4-dihydrosQrbenzolsulfonamid was obtained with P. 142 ⁰ C N.

(D) A solution of 0.61 g of sodium hydroxide in 5 ml of water was added dropwise to a stirred suspension of 3.0 g of the previously obtained product and 1.43 ml of epichlorohydrin in 15 ml of water, then the reaction mixture was stirred for 1.5 Heated to 80 ⁰ C hours. After cooling, the reaction mixture was extracted with methylene chloride, the combined extracts were washed with water, dried over NapSO4 and evaporated to give 2.84 g of a mixture of 6- and 7 "-N, N-dimethylsulfamovl-2-hydroxymethyl-1 , 4-benzodioxane as a sticky oil with consistent, spectroscopic properties were obtained.

(E) 2.15 g of potassium permanganate were added in three portions to a stirred suspension of 2.8 g of the previously obtained alcohol in potassium hydroxide solution of. 0.59 g in 20 ml of water and 10 ml of acetone at 5 ° C was added so that the reaction temperature did not rise above 10 C. The reaction mixture was allowed to stand at room temperature for 3 hours, then the acetone was evaporated and another 1.5 S potassium permanganate was added and then stirred overnight. Finally, a further 3 g of potassium permanganate was added and the reaction mixture was stirred under nitrogen at 35-40 ° C overnight. The resulting hangand dioxide was then collected, washed with water, the combined filtrates were acidified with concentrated hydrochloric acid and extracted with chloroform.

39- 2 0886

The combined extracts were washed with 5N sodium hydroxide solution (2 x 40 ml), the alkaline phase acidified with concentrated hydrochloric acid, extracted with chloroform, and the combined extracts washed with water, dried over NapSO4 and evaporated in vacuo. The crude product, 0.46 g, was combined with 0.21 g of similar material obtained from the reextraction of the original manganese dioxide, with 0.6? S of a mixture of 6- and 7-N, N-dimethylsulfamoyl-1,4-benzodioxan-2-carboxylic acid having P. 156-162 ⁰ C were obtained.

Analysis on C ^ H ₁ g

found: C = 45.5 H = 4.6 N = 4.90% calculated: C = 46.0 H = 4.6 N = 4.9% ..

Preparation 16

These compounds were separated from each other by preparative HPLG and analyzed by δδ spectroscopy according to the published values, see e.g. BJMed. Chem., 10: ₁ (1967), 880. Each isomer was hydrolyzed to the corresponding acid, which was converted to the acid chloride without further characterization.

Preparation 17

8.05 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 10 g of 2-methylpiperazine were heated under reflux in butahoi for 15 hours. The reaction mixture was then evaporated in vacuo and the residual oil was taken up in 200 ml of chloroform, washed with water (4 × 50 ml), over Napso. dried and evaporated in vacuo. The residual oil, 13 g., Was recrystallized from isopropanol to give 3> 0 g of 4-amino-6,7-dimethoxy-2- (3-methylpiperazin-1-yl) quinazoline hemihydrate with Έ. 185-187 ⁰ C were obtained.

-Ki-

20886

Analysis on C ^^ H ^ N ^. 1/2 H ₂ O: found: C = 58.1 H = 6.8 N = 22.8 % calculated: C = 57.7 H = 7.1 N = 22.4 %

Preparation 18

(A) Sodium hydroxide solution, 1.94 g in 16 ml of water, was added dropwise at room temperature to a stirred suspension of 4.6 ml of epichlorohydrin and 8 g of ethyl-3,4-dihydroxybenzoic acid until a solution was obtained. The reaction mixture was then heated to 80 ^° C. for 1.5 hours, cooled and extracted with dichloromethane. The extracts were washed with water over NapSO. dried and evaporated in vacuo to give 10.87 g of a mixture of 6- and 7-carbethoxy-2-hydroxy-methyl-1,4-benzodioxane as a sticky oil with consistent spectroscopic properties.

(B) 5% of the previously obtained alcohol was mixed with 12.3 ml of Jones reagent in 70 ml of acetone as previously described in Preparation. described oxidized to give 1.78 g of a mixture {.2 .: ^Λ according to HPLC) of 6- and 7-Carbethoxy-1,4-benzodioxane-2-carboxylic acid with consistent, spectroscopic properties.

Preparation 19

(A) A stirred suspension of 5j6 g of potassium carbonate and 2.7 e of 4-cyanocatechol in 50 ml of acetone was refluxed for 0.25 hours, then 4.9 g of ethyl 2,3-dibromopropionate was added dropwise. The resulting mixture was refluxed for 48 hours, then was evaporated in vacuo, the residue was diluted with water and extracted with chloroform. The combined extracts were

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washed with water, dried over MgSO 4 and evaporated in vacuo to give 1.0 g of a mixture of methyl 7-6 and 7-cyano-1,4-benzodioxan-2-carboxylate. A sample was recrystallized from isopropanol; P. 95-96 ⁰ G.

Analysis on C ^^ Έ

found: C = 60.2 H = 4.2% "calculated: C = 60.25 H = 4.2 %

HPLC analysis of the crude product mixture showed a mixture of two components in the ratio of 5: 2.

(B) 0.7 ml of 6N sodium hydroxide solution and 1 ml of 30% hydrogen peroxide were added dropwise to a stirred suspension of 0.5S of the previously obtained cyanoester in 4 ml of ethanol at 15G. The mixture was then warmed to 40-50 ° C for 2 hours, cooled, acidified with concentrated hydrochloric acid, the product was collected and recrystallized from ethanol / ethanol / water to give a mixture. 6- and 7-carbamoyl-1,4-benzodioxan-2-csrbonsäure with?. 258-260 ⁰ G was obtained.

Analysis on C ^ H

found: C = 53.2 H = 4.1 N = 6.4 % calculated: C = 53.8 H = 4.1 IT = 6.3 %

Claims (5)

Invention claim: 1 '
each of R, which may be the same or different = 1 or 2, the rest -CHR ¹ - or 1. A process for the preparation of 4-amino-2- (piperazin-1-yl or homopiperazine-i-yli-quinazoline derivatives of the following general formula: NH ₁ in which mean: (R) a 6,7-di (lower alkoxy) or 6,7,8-tri- (lower alkoxy) -rast; 2 3 and R and R are hydrogen, lower alkyl, lower alkoxy, halo, lower alkanoyl, lower alkoxy carbonyl, -CONHp or SO ₂ N (CHJ ₂ . 2. A process for the preparation of a compound of formula (J) according to item 1 or a pharmaceutically acceptable acid addition salt thereof, characterized in that-a quinazoline of the following formula: , R ⁴ in which (R), R and m have the meaning given in point 1, with a carboxylic acid of the following formula: -W- 12 3 · wherein R, R, R and X have the meaning given in point 1, or is reacted with a functional equivalent thereof as Acylierungsraittel. 2 3 hydrogen atom or a lower alkyl radical; and R and R, which may be the same or different, each represent a hydrogen atom, a lower alkyl radical, lower alkoxy radical, a halogen atom, a lower alkanoyl radical, lower alkoxycarbonyl radical or a radical of the formula -CONR R * ⁵ or -SOpNR R- ⁵ , wherein R and R 1, which may be the same or different, each represents a hydrogen atom or a lower alkyl group; and the pharmaceutically acceptable acid addition salts thereof, characterized in that a quinazoline of the following formula: NH x wherein Q represents a readily 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 following formula: 12 4 wherein R, R, R, X and m have the meaning given in point 1, is reacted. 3. The method according to item 2, characterized in that the functional equivalent of an acid chloride or bromide, an activated ester 'or a mixed anhydride of the compound • of the formula (VII). · ' 4. Process according to items 1 to 3, characterized in that (R) 6,7-dimethoxy, 6,7-diethoxy or 6,7,8-trimethoxy, m 1 or 2, R ^ is hydrogen or methyl, 5. Method according to item 4, characterized by dap (R) _{n is} 6,7-dimethoxy, m is 1 and R ¹ , R ² and R ^{3 is} hydrogen.