CS214797B2 - Method of making the new derivatives of 4-amino-2-piperidinochinazoline - Google Patents

Description

Ph represents a phenyl group,

R ⁴ is hydrogen and R ² is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl substituted with phenyl, monosubstituted or disubstituted phenyl. C 3 -C 7 cycloalkyl, halogen, hydroxy, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxycarbonyl alkoxy moieties or phenoxy, wherein the substituents of the above-mentioned phenyl group are selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, alkoxy groups of 1 to 6 carbon atoms and halogen atoms, or a radical of the formula -NR ³ R ⁴ , wherein each R is ³ and R ⁴ are hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl or C 1 -C 6 alkylsulfonyl, with any of the oxygen, nitrogen or halogen atoms in the radical R being ² is separated by at least 2 carbon atoms from the nitrogen atom to which R ² is attached; or

R ¹ and R ² together with the nitrogen atom to which they are attached form a morpholino group or a 1,2,3,4-tetrahydroisoquinolyl group optionally substituted on the benzene ring with two C 1 -C 6 alkoxy groups.

Also included within the scope of the invention are pharmaceutically acceptable bleach precursors of these compounds and pharmaceutically acceptable acid addition salts of these compounds.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine. By alkyl alkoxy, alkanoyl, alkenyl or alkynyl groups is meant the abovementioned groups containing up to 6 carbon atoms, preferably up to 4 carbon atoms, which groups may optionally be straight or branched.

The term "phenyl" as used in, this text [including fenylpvé groups in Z ^ Open - OCH (Ph) CQNRlR ^2] refers fenýrová group which may optionally be substituted with 1 or 2 substituents vybranýn) and from alkyl groups C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy and halogen.

By pharmaceutically acceptable s-acid addition salts is meant a salt formed with acids forming non-toxic addition salts containing pharmaceutically acceptable anions such as hydrochlorides, hydrobromides, sulfates or bisulfates, phosphates or hydrogenphosphates. acetates, nialeates, fumarates, lactates, tartrates, citrates, glucowates, saccharates or β-tolueusulfonates.

e., _n; 4jiqjj, čpniny invention containing jednebo several asymmetric centers may oxistoyat in the form of one or more enantionierů, said vapor or indiΛ [Ρύ £ 1ηί isomers may be, separating the physio; methods, "for example f..fcřys; | AII cípyďpdiiýc ^ ,, ^ salts invention comprise from 4 ^ i _j YY ané.pá _1, and mixtures thereof, as well, jalta JMF ^ jnicke sinesl worry separated optically kJasomerní _OLV fej i ^ b | _date; The compounds of formula 1 are those of Mora in formula 1 in which ///,

(a) the radical of the formula - CONR ¹ R ² , wherein R ¹ represents a hydrogen atom and R ² represents an alkyl group having from 1 to 6 carbon atoms, cyclo; or a C 1 -C 4 alkyl group or a C 1 -C 4 allyl group substituted with a phenyl group (as defined above), a cycloalkyl group, M 1, diatomic or biphenyl. is alkoxy having 1 or 2 carbon atoms, —CH = CH2, —C = CH2, —C = CH,

CH3 alkoxycarbonyl having 1 or 2 carbon atoms in the alkoxy moiety, phenoxy, -N (CH3) 2, -NHCOCH3, -NHSO2CH3 or halogen provided that any of the oxygen, nitrogen or halogen atoms in R ² is separated by at least 2 the carbon atoms from the nitrogen atom to which R ² or R ¹ and R ² are attached together with the nitrogen atom to which they are attached form a morpholino group or a 1,2,3,4-tetrahydroisoquinolyl group optionally substituted on the benzene ring by two methoxy, [bj -CH2CONHR residue of formula ² wherein R ² represents an alkyl group having 1 to 6 carbon atoms, benzyl, cyclopropylmethyl group or a group -CH2CH = CH2, [cj -CH2CH2CONHR residue of formula ² wherein R ² is an alkyl group C 1 to 6 carbon atoms or a benzyl group;

- OCHCONH ² Z wherein R ² represents a C 1-6 alkyl group, a benzyl group or a cyclopropylmethyl group.

The most preferred compounds produced by the process of the present invention correspond to the above formula (I) wherein X represents a group, r-C () bWa, i.

, -UONHíCHzjaCtU ', _; -CQMIC1k, cyclopropyl, -CONH. _{benzyl:, w} ,, -UOfMi. UH 2 CH 2 UH 2, —Cl 12 CONH (CH 2) 2 UH 2, -, _B h - CH 2 CONHCH 2. cyclopropyl.

The term 'pharmaceutically usable pha-precursor' used above requires some clarification. In pharmaceutical chemistry, it is common practice to overcome certain undesirable physical or chemical properties of drugs by converting the drug into a chemical derivative that does not have such undesirable property, but which is converted back to the parent drug upon administration to the animal or human.

For example, when a drug is orally administered to an animal or a human being well absorbed, a well-absorbed derivative that is well absorbed and which is converted back to the parent drug in serum or tissue. Alternatively, if the solution is unstable in solution, it can be converted to a chemical derivative that is stable and which can be administered, but which is converted into the parent drug in the body. Those skilled in pharmaceutical chemistry are d, ^e QBRs known possibilities _for ^their gjjgkppéWLW ^ ňPhb properties of drugs of chemical modifications which are only temporary and after application to an animal or human reverslbilní.

For the purposes of this invention, the term " pharmaceutically acceptable biopresor " of a compound of formula (I) refers to a compound of a structural formula different from that of formula (I).

The present invention provides a process for the preparation of novel 4-amino-2-piperidinylquinazoline derivatives of the formula I and their pharmaceutically acceptable acid addition salts, characterized in that the amine of the formula

R ¹ R ² NH, in which R ¹ and R ² are as defined above, is reacted with

IV CKO • 3 in which íiv) X ‘represents a residue or formulas (CH 2) _m COCH

Ph

OCHCOOH, wherein m and Ph are as hereinbefore defined, or with a functional equivalent of the acylating agent, and the product of formula (I) is optionally converted by reaction with a non-toxic acid to a pharmaceutically acceptable acid addition salt.

Suitable functional equivalents of compounds of formula IV acting as acylating agents include, for example, chlorides, bromides, activated esters, mixed anhydrides or imidazolides of compounds of formula IV.

When the free acid of formula (IV) is used, the reaction is generally carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.

Acid chlorides and bromides can be prepared by conventional methods, for example by reaction of the free acid with thionyl chloride and the like. thionyl bromide.

Preferred activated esters are succinimido and phthalimido esters, which may also be prepared by conventional methods, for example by reacting the free acid with N-hydroxysuccinimide or N-hydroxyphthalimide in the presence of a dehydrating agent, for example dicyclohexylcarbodiimide.

Suitable mixed anhydrides correspond to the general formula V

X 'is a radical of formula (CH ² ) _m CO.O.CO.Alk or

OCHJPhjCO.O.CO.Alk, where

Alk is C 1 -C 6 alkyl, and m and Ph are as defined above.

These compounds can be prepared in a conventional manner, for example by reacting the free acid with an appropriate alkanoyl chloride (e.g. pivaloyl chloride) in the presence of a base such as triethylamine.

Imidazoles of Formula VI CH ₃ o

CHjO

in which

X '' represents the remainder of the formula ^{, C} W ^ON, or

Ph I

OCHCO 'wherein m and Ph are as defined above may be prepared in a conventional manner by reacting the free acid of the above formula (IV) in a suitable solvent, for example dimethylformamide, with N, N‘-carbonyldiimidazole.

According to a typical embodiment, N, N'-carbonyldiimidazole is added to a solution of the free acid of formula IV in a suitable solvent, for example dimethylformamide, optionally in the presence of a molecular sieve, at a temperature of 50 to 100 ° C. After stirring the solution for two to four hours at this temperature, an amine of formula R ⁴ R ² NH is added and the solution is allowed to react at a temperature in the above range for up to 10 hours. After cooling, the molecular sieve can be filtered off and thoroughly washed with chloroform. The chloroform from the washings can be combined with the filtrate, washed with water and, after drying, evaporated in vacuo. In this way a crude product is obtained which can be purified in a conventional manner.

The acid addition salt may be prepared by taking up the crude product with a minimum amount of a suitable solvent, such as chloroform, and adding a solution of the appropriate acid in a suitable solvent, such as ethereal hydrogen chloride, to the solution. The precipitated acid addition salt formed can be filtered off and, if necessary, recrystallized from a suitable solvent, for example a mixture of isopropanol and methanol.

The free acids of the above formula (IV) can be prepared by conventional methods, for example by reacting the corresponding 4-amino-6,7-di (lower) alkoxy-2-chloroquinazoline with the corresponding substituted piperidine.

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

Specific values of this activity for representative compounds of the invention are given in the following overview. The decrease in blood pressure in% caused by oral administration of the test compound is calculated according to the following formula:

blood pressure drop in% maximum drop control blood pressure - 130 x 100

Product of Example No. Maximum Blood Drop Measured after the following v / _o pressure following oral administration of hours to rats at 5 mg / kg

1 73 4 2 83 6 3 62 2 4 57 4 5 64 4 6 31 1 7 44 6 8 39 6 9 34 4 10 36 1 11 38 4 12 63 4 13 30 6 14 43 4 15 Dec 23 4 16 90 6 17 27 Mar: 6 18 23 4 19 Dec 42 6 20 May 78 2 21 42 2 22nd 82 1 23 46 2 24 41 6 25 53 4 26 59 6 27 Mar: 78 6 28 62 4 29 42 4 30 47 6 31 55 4 32 49 6 33 45 6 34 33 6 35 64 6 36 33 6 37 27 Mar: 6 38 40 4 39 45 4 40 69 4

G

The compounds of the invention may be administered alone, but are generally administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing, for example, starch or lactose as carriers, or in the form of capsules containing either alone or in admixture with carriers, or in the form of elixirs or suspensions containing flavoring or coloring agents. They can also be administered parenterally by injection, for example, intramuscularly, intravenously or subcutaneously.

For parenteral administration, the compounds of the invention are most preferably used in the form of a sterile aqueous solution which may contain other soluble substances, for example sodium chloride or glucose, in an amount sufficient to render the solution isotonic.

Accordingly, the present invention also provides pharmaceutical compositions comprising the compounds of formula (I) or pharmaceutically acceptable acid addition salts thereof, together with a pharmaceutically acceptable diluent or carrier.

The compounds of the invention may be administered to humans either orally or parenterally for the treatment of hypertension, usually in unit dosage form. Orally, they can be administered in an amount ranging from about 0.5 to 50 mg / day for an average adult patient (70 kg), the total dose being administered either as a single dose or as up to three divided doses. Dosage for intravenous administration is expected to range from 1/5 to 1/10 of the daily dose used for oral administration. Thus, a tablet or capsule for individual oral administration to an average adult patient will contain from about 0.25 to 25 mg of active ingredient. Of course, in practice, variations from the above dosage will occur depending upon the weight and condition of the patient being treated and the route of administration chosen, as is well known in the art.

The invention also provides a method of treating an animal, including a human, suffering from hypertension, comprising administering to the animal an antihypertensively effective amount of a compound of formula I, a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition as defined above.

The invention is illustrated by the following non-limiting examples. In these examples, all temperatures are given in degrees Celsius.

Example 1

Preparation of 4-amino-6,7-dimethoxy-2- (4- (N-phenylcarbamoyl) piperidino] quinazoline hydrochloride

To 2.0 g of 4-amino-2- (4-carboxypiperidino) -6,7-dimethoxyquinazoline in 100 ml of dimethylformamide, in the presence of a molecular sieve (3.10 < 10 &gt; , N'-carbonyldiimidazole. The solution was stirred at 70 ° for 2 hours, 1.0 g of 2-phenylethylamine was added thereto, the reaction mixture was heated at 70 ° for a further 5 hours, then allowed to stand overnight at room temperature. The mixture was stirred at 70 ° C for a further 3 hours. After cooling, the molecular sieve is filtered off and washed thoroughly with chloroform. The filtrate was combined with the chloroform washings, washed with water and dried over sodium sulfate and concentrated in vacuo. The residue is taken up in a minimum volume of chloroform, ethereal hydrogen chloride is added to the solution, the precipitated solid product is filtered off and, after washing with ether, crystallized from a mixture of isopropanol and methanol. 0.81 g of 4-amino-6,7-dimethoxy-2- (4- (N-ethylcarbamoyl) piperidino] quinazoline hydrochloride, m.p. 284 DEG-285 DEG, is obtained.

Analysis: for C 24 H 29 N 5 O 3. HCl calculated:

% C, 61.1;% H, 6.4;% N, 14.8.

61.0% C, 6.5% H, 14.5% N. Examples 2 to 25

Using the same procedure as in Example 1, using the appropriate carboxyl-containing quinazoline, N, N'-carbonyldiimidazole and the corresponding amine of the formula R ^X R ² NH as the starting materials, the following compounds are obtained as starting materials. In Examples 2 to 4, 7, 9 to 12, 16 and 22 to 25, the crude product is purified by silica gel chromatography using a mixture of chloroform and methanol as eluent.

The compounds prepared in this way are summarized in the following overview and correspond to the general formula

Example X number

Isolated form and melting point (° C)

Analysis (%) found (calculated)

C H N 2 —CONHC2H5 hydrochloride- 53.7 6.7 17.4 -Hemihydrate (53.4 6.7 17.3) 287 to 288 3 —CONHCH (CH5) 2 hydrochloride- 54.6 6.9 16.9 -Hemihydrate (54.5 7.0 16.7) 281 to 282 4 —CONH.cyclopentyl hydrochloride- 55.5 6.8 15.4 -hydrate 263 to 264 (55.6 7.1 15.4) 5 r- \ hydrochloride 54.6 6.3 16.0 -CON _x 0 > 300 ° (54.9 6.4 16.0) 6 —CONHCH2CH2N (CH3) 2 dihydrochloride-1 1/2 47.5 6.4 16.5 0 hydrate (48.0 6.7 16.8) 11 244 to 245 7 —CH2CH2CNHCH2CH3 hydrochloride 56.7 7.2 16.9 0 242 to 243 (56.7 7.1 16.5) 8 0 hydrochloride 238 to 239 61.8 (61.8 6.3 6.6 14.1 14.4) 9 11 —CH2CH2CNH (CH2) 3CH3 hydrochloride 58.1 7.5 15.6 0 219 to 220 (58.5 7.6 15,5} 10 —CH2CNHCH2CH3 hydrochloride- 54.6 7.0 16.5 -Hemihydrate (54.5 7.0 16.7) 11 238-239 hydrochloride 59.6 6.3 14.8 0 -Hemihydrate (59.9 6.5 14,6) 12 254 to 255 hydrochloride- 56.6 7.0 15.6 0 0 -Hemihydrate (56.7 7.0 15.7) II II —CNH (CH2) 3 NHCCH3 247 to 249 13 hydrochloride- 53.3 6.6 18.0 Q -Hemihydrate (53.0 6.8 17.7) 14 -CNHCH ^ C ^ O ^ y 0 0 II II -CNH _(CH2) 2NHCCH3 256-257 free base 210 to 212 63.4 (63.8 6.7 6.5 15.3 15.5) 15 Dec free hemihydrate 56.8 6.7 19.5 0 II 1 —CH2CNHCH2CH = CH2 bases 252 to 255 (56.5 6.9 19.8) 16 hydrochloride- 56.0 6.6 16.7 -Hemihydrate (55.7 6.8 16.3) 239 to 241

Example number

O O — CNHCH 2 COC 2 H 5 O

II — CNHCH2CH2NSO2CH3

-OCH-CONHC 1 H 5

-OCHCONHCHfrHf

-OCHCONHiCH2CH3

-OCHCONHCH2. — 4 — CONH (CH2) 5C1 — CONHCH2CH2OC2H5

Isolated form Analysis (%) and melting point (° C) found (calculated)

C H N hydrochloride- 51.8 6.0 15.2 -Hemihydrate (51.9 6.3 15.1) 250 to 251 hydrochloride- 59.6 6.5 14.2 -Hemihydrate (59.8 6.4 13.9) 256 to 258 hydrochloride- 58.3 7.3 14.6 -Hemihydrate (58.4 7.5 14.8) 242 to 243 hydrochloride 59.6 6.5 14.2 256 to 258 (59.8 6.4 13.9) hydrochloride- 61,2, 6.1 11.8 -hydrate (61.9 6.2 12.0) 175 to 180 hydrochloride- 60.1 6.7 13.0 -Hemihydrate (60.2 6.9 13.0) 195 to 198 hydrochloride 61.0 6.6 13.7 210 to 213 (61.4 6.5 13.3) free base hydrate 53.6 6.4 16.7 251 to 253 (53.6 6.6 16.4) hydrochloride- 53.6 6.8 15.8 -Hemihydrate (53.5 7.0 15.6)

255 to 258

Example 26

Preparation of 4-amino-2- [4- (N-allylcarbamoyl) piperidino] -6,7-dimethoxyquinazoline hydrochloride

COOH

i) dicyclohexylcarbodiirnide, N-hydroxysuccinimide

-------- 5 ii) allylamine

1β

2.3 g of 4-amino-2- [4-carboxypiperidino] -6,7-dimethoxyquinazoline, 1.4 g of dicyclohexylcarbodiimide and 0.8 g of N-hydroxysuccinimide were stirred at 60 DEG C. in dry dimethylformamide for 2 hours. To the resulting suspension was added 0.4 g of allylamine and heating at 60 ° C was continued for 6 hours. To the cooled mixture was first added 50 ml of 5 N hydrochloric acid and then 50 ml of chloroform. The resulting mixture was shaken and the phases separated. The aqueous phase was basified to pH 12 with 5 N sodium hydroxide solution and extracted twice with 50 ml of chloroform each. The chloroform extract was dried over magnesium sulfate and evaporated in vacuo. 1.4 g of a yellow gum residue are obtained, which is taken up with a minimum amount of isopropanol and treated with a little excess of hydrogen chloride gas until a slight excess is obtained. Recrystallization of the product from ethyl acetate / methanol gave 0.6 g of pure 4-amino-2- [4- (N-allylcarbamoyl) piperidino] -6,7-dimethoxy quinazoline hydrochloride hemihydrate, m.p. 277 °.

Analysis: for C 19 H 25 N 5 O 3 .HCl. 1/2 H2O calculated:

H, 6.6%; N, 16.8%; found:

% C, 54.9%;% H, 6.5%; N. 16.9%.

Examples 27 to 37

In the same manner as in the previous example, the following compounds are always obtained from the corresponding carboxylic acid-containing piperidinequinazoline, N-hydroxysuccinimide, dicyclohexylcarbodiimide and the corresponding amine of formula RWNH:

Analysis (%)

Example X Isolated form found (calculated) number and melting point (° C) C H N 27 Mar: -CNPCH 2 - < hydrochloride- 55.5 6.6 16.3 -Hemihydrate (55.7 6.8 16.3) n 270 to 272 28 CHa oxalate monohydrate 53.5 5.8 14.4 242 ° (53.5 6.3 14.2) —CNHCHaC II \ O CH3 29 —CNHCHaC = CH oxalate. 1/4 H2O 54.3 5.5 14.7 II O -CN H CH3 - ^ - - OCH3 249 to 250 (54.4 5.5 15.1) 30 hydrochloride- -monohydrate 260 ° 57.4 (57.0 6.2 6.4 13.6 13.8)

O

-CNHCHi

OC ^ Hg

-CNHCH ^ OCH ^ OCH $ CH,

-CNHC_u

-CNHCHg ^ ^ ^Ct II

O

-CNHCH? O hydrochloride- 57.8 6.3 13.8

monohydrate (57.7 6.6 13.5)

241 to 242 hydrochloride 54.9 5.9 13.0

-Squihydrate (55.1 6.5 12.9)

250 to 251 (south at 180 °) hydrochloride-56.8 6.2 13.8

-dihydrate (56.7 6.8 13.8]

250 to 251 hydrochloride 53.2 5.9 13.6

-Squihydrate (53.2 5.8 13.5)

215 to 216 hydrochloride-59.6 6.6 14.7

-Hihydrate (59.9 6.5 14.6)

290-292

Example X number

Isolated form and melting point (° C)

Analysis (%) found (calculated) C Η N

Preparation of 4-amino-2- [4- (N-n-butylcarbamoylmethyl) piperidino] -6,7-dimethoxyquinazoline hydrochloride

3.0 g of 4-amino-2- [4-carboxymethylpiperidino] -6,7-dimethoxyquinazoline, 1.83 g of N, N'-dicyclohexylcarbodiimide and 1.0 g of N-hydroxysuccinimide were stirred in 50 ml of dry dimethylformamide for 2 hours. at 70 [deg.], then 10 ml of n-butylamine is added, the reaction mixture is stirred at 50 [deg.] for 4 hours, then cooled and filtered. To the filtrate was added 50 ml of 5 N hydrochloric acid solution, and the mixture was extracted three times with 50 ml of chloroform each. The chloroform extract was dried over sodium sulfate and the solvent was evaporated in vacuo. The oily residue is taken up in 10 ml of 2 N hydrochloric acid and shaken with ethyl acetate. The aqueous phase was separated, basified to pH 11 by addition of sodium hydroxide solution and extracted three times with 20 ml of chloroform each. The chloroform extract was dried and the solvent was evaporated in vacuo. The residue was stirred with dioxane, filtered and the filtrate evaporated in vacuo. The product obtained is chromatographed on 100 g of silica gel, eluting first with chloroform and then with a 30: 1 mixture of chloroform and methanol. The fractions containing the desired product are combined, concentrated, dissolved in chloroform and converted to the hydrochloride by addition of ethereal hydrogen chloride. recrystallization from methanol-dioxane gave 0.25 g of 4-amino-2- [4- (N-butylcarbamoylmethyl) piperidino] -6,7-dimethoxyquinazoline hydrochloride hemihydrate, m.p. 238-239 °.

Analysis: for C 21 H 31 N 5 O 3 .HCl. 1/2 H2O calculated:

56.4% C, 7.4% H, 15.7% N, hydrochloride dihydrate 210-212 hydrochloride hemihydrate 266-267

56.3 6.2 12.3 (55.9 6.6 12.1)

57.1 6.3 13.6 (57.0 6.3 13.3) carbamoylmethyl) piperidino] quinazoline hydrochloride

3.0 g of 4-amino-2- [4- (carboxymethyl) piperidino] -6,7-dimethoxyquinazoline, 1.83 g of N, N'-dicyclohexylcarbodiimide and 1.04 g of N-hydroxysuccinimide in dry dimethyl formamide 2.5 The mixture was stirred at 70 ° C for 1 hour, then 0.78 g of 2,2-dimethylpropylamine was added and stirred at 50 ° C for 4 hours. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue is taken up in 50 ml of chloroform, extracted with sodium bicarbonate solution, the organic layer is dried over sodium sulphate and the solvent is evaporated off under vacuum. The residue is chromatographed on 120 g of silica gel, eluting first with chloroform and then with a 20: 1 mixture of chloroform and methanol. The fractions containing the desired product were combined, concentrated, the residue dissolved in chloroform and converted to the hydrochloride by addition of ethereal hydrogen chloride. Recrystallization of the solid material first from a mixture of methanol and dioxane and then from a mixture of methanol and acetonitrile gave 0.45 g of 4-amino-6,7-dimethoxy-2- [4- (N- (2,2-dimethylpropyl) carbamoylmethyl) piperidino] quinazoline hydrochloride hemihydrate, m.p. 228-231 °.

Analysis: for C 22 H 33 N 5 O 3 .HCl. 1/2 H2O calculated:

57.3% C, 7.7% H, 15.2% N, found:

57.3% C, 7.8% H, 15.3% N. Example 40

Preparation of 4-amino-6,7-dimethoxy-2- (4- (N-n-propylcarbamoyl) piperidino] quinazoline hydrochloride found:

56.5% C, 7.3% H, 15.4% N. Example 39

Preparation of 4-amino-6,7-dimethoxy-2- [4- (N- (2,2-dimethylpropyl)] This product is prepared from 4-amino-2- (4-carboxypiperidino) -6,7-dimethoxyquinazoline and n. The desired hydrochloride hemihydrate is recrystallized first from a mixture of methanol and isopropanol, then from ethanol, and has a melting point of 263-264 °.

Analysis: for C19H27N5O3.HCl. 1/2 H2O calculated:

H, 7.0%; N, 16.7%; found:

C, 54.4; H, 6.6; N, 16.8.

The following preparations, in which all temperatures are given in degrees Celsius, illustrate the preparation of some of the starting materials used in the preceding examples. Preparation

Preparation of 4-amino-2- (4-carboxypiperidino) -6,7-dimethoxyquinazoline monohydrate

The above compound, melting at 295 °, was prepared by reacting 4-amino-2-chloro-6,7-dimethoxyquinazoline with 4-carboxypiperidine. Analysis: for C16H20N4O4. H2O calculated:

54.8% C, 6.4% H, 16.0 0/0 N, found:

54.9% C, 6.0% H, 16.1 θ / ο N. Preparation B

Preparation of 4-amino-2- (4-carboxymethylpiperidino) -6,7-dimethoxyquinazoline hydrochloride

17.3 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 12.0 g of piperidine-4-acetic acid hydrochloride and 200 ml of triethylamine are heated under reflux in 500 ml of n-butanol for 20 hours. The reaction mixture is cooled to 0-4 °, the precipitated product is filtered off, stirred with 100 ml of acetone, filtered, the solid is stirred with 100 ml of chloroform, then filtered off and washed with ether. 19.0 g of 4-amino-2- (4-carboxymethylpiperidino) -6,7-dimethoxyquinazoline hydrochloride are obtained. A sample of the product melts after recrystallization from acetic acid at 250-252 °. Analysis: for C17H22N4O4. HCl calculated:

53.3% C, 6.1% H, 14.6% N, found:

53.1% C, 6.4% H, 14.2% N. Preparation C

Preparation of 4-amino-2- [4- (2-carboxyethylpiperidino) -6,7-dimethoxyquinazoline hydrochloride

24.9 g of 4-amino-2-chloro-6,7-dimethoxyquinoline 20 zoline and 20 g of 3- (4-piperidinyl) propionic acid hydrochloride are heated to reflux in 1000 ml of n-butanol for 20 hours with stirring. insoluble material is discarded The filtrate is cooled in ice-water, the precipitated solid product is filtered off and the filtrate is evaporated in vacuo, the solid residue combined with the precipitated solid product and crystallized from isopropanol to give 27.0 g of 4-amino-2- [4- (2- (n-butoxycarbonyl) ethyl] piperidino] -6,7-dimethoxyquinazoline hydrochloride, m.p. 250 DEG-252 DEG.

Analysis: for C 22 H 32 N 4 O 4. HCl calculated:

H, 7.3%; N, 12.4%;

58.0% C, 7.3% H, 12.5% N.

g of this n-butyl ester is refluxed in 50 ml of methanol and 50 ml of 5N sodium hydroxide solution for 4 hours. The organic solvent was evaporated, the aqueous residue was acidified with 2N hydrochloric acid and cooled. The precipitated solid material was filtered off, dried, stirred with ether and filtered again. 17.9 g of 4-amino-2- [4- (2-carboxyethyl) piperidino] -6,7-dimethoxyquinazoline hydrochloride are obtained. After recrystallization, a sample of the product melts first from water and then from dimethylformamide at 238-241 °.

Analysis: for C 18 H 24 N 4 O 4. HCl calculated:

54.5% C, 6.4 θ / ο H, 14.1% N, found:

H, 6.3; N, 14.3.

Example 1 d

A. Preparation of ethyl 2- (1-acetylpiperidine-4-oxy) phenylacetate

To a suspension of 25 g of sodium hydride (50% dispersion in mineral oil) in 150 ml of dimethylformamide and 10 ml of dimethoxyethane was slowly added with stirring 27.5 g of N-acetyl-4-hydroxypiperidine in 100 ml of dry dimethylformamide. 45 g of 2-bromophenylacetic acid in 250 ml of dimethylformamide are slowly added thereto under cooling with ice-water, and the reaction mixture is stirred at room temperature for 20 hours, isopropanol is added and the solvent is evaporated off under vacuum. The residue is taken up in water, acidified with 2N hydrochloric acid to pH 1 and extracted four times with 300 ml of chloroform.

The combined chloroform extracts were washed with water and brine, dried (MgSO 4) and the solvent evaporated in vacuo. The rest was at 450

2Ί4797 milliliters of anhydrous ethanol are heated to reflux with 9 ml of concentrated sulfuric acid for 8 hours. The cooled solution was carefully neutralized with aqueous sodium carbonate solution and the organic solvent was evaporated in vacuo. The aqueous residue was adjusted to pH 10 with sodium carbonate solution and extracted twice with chloroform. The combined chloroform extracts were dried (MgSO 4) and evaporated in vacuo. Distillation of the residue yielded 37.2 g of ethyl 2- (1-acetylpiperidine-4-oxy) phenylacetate boiling at 190 to 194724 Pa.

66.9 _0/0 C, 7.6% H, 4.6% N,

Πίΐ1θ7ΟΠΠ '

66.4% C, 7.8% H, 4.5% N.

B. Preparation of 2- [piperidin-4-oxy] phenyioetic acid hydrochloride

Ethyl 2- [1-acetylpiperidine-4-oxy] phenylacetate (10.0 g) was refluxed in 50 ml of methanol and 30 ml of 5N sodium hydroxide solution for 5 hours. The organic solvent was evaporated in vacuo, the aqueous residue acidified to pH 2 with hydrochloric acid solution and filtered. The filtrate was evaporated in vacuo, the residue was stirred with toluene and evaporated again in vacuo. 50 ml of isopropanol are added to the residue, the mixture is filtered and the solid material is washed with isopropanol. The filtrate was combined with the washings and the solvent was evaporated in vacuo. The residue was triturated with acetone, the white solid product was filtered off and crystallized from isopropanol. 5.05 g of 2- [piperidin-4-oxy] phenyioetic acid hydrochloride of melting point 180 DEG-182 DEG are obtained.

Analysis: for C 13 H 17 NO 3. HCl calculated:

% C, 57.5%;% H, 6.7%;% N%;

57.4% C, 6.8% H, 5.5% N.

C. Preparation of 4-amino-2- [4- (1-carboxy-1-phenylmethoxy) piperidino] -6,7-trimethoxyquinazoline

4.8 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 4.9 g of 2- (piperidine-4-oxy) phenyioetic acid hydrochloride and 5 ml of triethylamine are heated under reflux in 100 ml of n-butanol for 20 hours. The mixture was cooled, the precipitated solid was filtered off and washed with ether and a sample of this solid (0.7 gj) was recrystallized from acetic acid and the resulting solid was washed with ether to give 0.56 g.

4-amino-2- [4- (1-carboxy-1-phenylmethoxy) piperidino] -6,7-dimethoxyquinazoline acetate melting at 271-274 °.

Analysis: for C 23 H 26 N 4 O 5. CH3CO2H calculated:

H, 6.1; N, 11.2. Found:

H, 6.0; H, 11.3.

The residual product is suspended in hot isopropanol, the mixture is filtered and the solid product is washed with isopropanol and ether. 6.46 g of 4-amino-2- [4- (1-carboxy-1-phenylmethoxy) piperidino] -6,7-dimethoxyquinazoline are obtained.

Preparation

Preparation of mono-N- (methanesulfonyl) ethylenediamine A solution of 15 g of mono-N-acetyiethylenediamine and 15 ml of triethylamine in 25 ml of dry chloroform was added dropwise while stirring at 0 ° with 16.8 g of methanesulfonyl chloride in 25 ml of dry chloroform. The resulting solution was stirred at room temperature for 60 hours. The reaction mixture was extracted three times with 50 ml of water each time. The combined aqueous fractions were shaken with chloroform, separated, the aqueous was evaporated in vacuo, the residue was dissolved in 100 mL of methanol and 50 mL of concentrated hydrochloric acid, and the mixture was heated under reflux for 12 hours. The solvent is dissolved in vacuo and the residue is refluxed with methanol. Insoluble solid material is filtered off and discarded. The filtrate was evaporated in vacuo and the residue was heated to reflux with chloroform. After decanting off the solvent, N-monomethanesulfonylethylenediamine hydrochloride is obtained in the form of a semi-solid which also contains triethylamine hydrochloride. The product was used without further purification to prepare the product as in Example 18.

The amines used in the previous examples are known, with the exception of the amine used in Example 18, the preparation of which is described above.

Claims (4)

OBJECT OF INVENTION A process for the preparation of the novel 4-amino-2-piperidinoquinazoline derivatives of the general formula I R ⁴ R ² NH wherein R ¹ and R ² have the above meanings, is reacted with a compound of formula IV by CH ₃ CH 3 in which X is - (CH 2) _m CONR ⁴ R ² or wherein X ‘represents a radical of formula (CH 2 Cl COOH or Ph — OCHCONR ¹ R ² , Ph f OCHCOOH where m is 0, 1 or 2, Ph represents a phenyl group, R ¹ represents hydrogen and R ² represents a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group or a C 1 -C 6 alkyl group substituted with a phenyl group, a monosubstituted or disubstituted phenyl group, a C 3 -C 7 cycloalkyl group, a halogen , hydroxy, (C 1 -C 6) alkoxy, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, (C 1 -C 6) alkoxycarbonyl, or phenoxy, wherein the substituents of the above-mentioned phenyl group are selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, alkoxy groups of 1 to 6 carbon atoms and halogen atoms, or a radical of the formula -NR ³ R ⁴ , wherein each of R ³ and R ⁴ represents a hydrogen atom; (C 1 -C 6) alkanoyl, (C 1 -C 6) alkanoyl or (C 1 -C 6) alkylsulfonyl group; e any of oxygen, nitrogen or halogen atoms in R ² is separated by at least 2 carbon atoms from the nitrogen atom which is bonded to radical R ^2, or R ¹ and R ² together with the nitrogen atom to which they are attached form a morpholino group, or a 1,2,3,4-tetrahydroisoquinolyl group optionally substituted on the benzene ring with two C 1 -C 6 alkoxy groups, and pharmaceutically acceptable edible salts thereof with acids, characterized in that the amine of the formula wherein m and p are as defined above, or with a functional equivalent of the acylating agent, and the product of the formula I is optionally converted by reaction with a nontoxic acid into a pharmaceutically acceptable acid addition salt. . 2. A process according to claim 1, wherein the functional equivalent of the acylating agent is a chloride or bromide, an activated ester, a mixed anhydride or an imidazolide of the acid of formula IV. 3. The process of item 1, for producing compounds of formula IA X _A stands for UA) - (CH 2) _m CONR ⁴ R ² , wherein m is 0, 1 or 2, R @ ¹ represents a hydrogen atom and R @ ² represents an alkyl group having from 1 to 2 (C uhlíku-C cyk) cycloalkyl, (C až-C 7) cycloalkyl or (C až-C alky) alkyl group substituted by phenyl, mono- or di-substituted-phenyl, (C cyk-C cyk) cycloalkyl, halogen, hydroxy, (C alko-C alko) alkoxy; the substituents of the above-mentioned phenyl group are selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, alkoxy groups of 1 to 6 carbon atoms and halogen atoms, or a radical of the formula -NR ³ R ⁴ , wherein each of the symbols R ³ and R ⁴ are hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl or C 1 -C 6 alkylsulfonyl, with any of the oxygen, nitrogen or halogen atoms in R 3 ² is separated by at least 2 carbon atoms from the nitrogen atom to which R ² is attached; or R ¹ and R ² together with the nitrogen atom to which they are attached form a morpholino or 1,2,3,4-tetrahydroisoquinolyl group optionally substituted on the benzene ring with two C 1 -C 6 alkoxy groups, and pharmaceutically acceptable addition salts thereof acids, characterized in that the amine of the general formula (I) is used R ⁴ R ² NH wherein R ¹ and R ² are known at this point and react with a compound of formula IVA X _A 'represents a group of the formula (CH 2) _m COOH, wherein m is as defined above, or with a functional equivalent of this compound acting as an acylating agent, and the product of formula IA obtained is optionally converted by reaction with a nontoxic acid into its pharmaceutically acceptable addition salt with acid. 4. A process according to claim 3, wherein the functional equivalent of the acylating agent is a chloride, bromide, activated ester, mixed anhydride or imidazolide of the compound of formula IVA.