LU82115A1 - NOVEL ANTI-HYPERTENSIVE QUINAZOLINES, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITION CONTAINING THEM - Google Patents

Description

OC 5o 948

A λ, V * GRAND-DUCHY OF LUXEMBOURG

Patent No .... 0 ... 2 ..... 1 ......... 1 · 3 of 31. January ... 198a ........... Mister Minister

Titrp delivers · from the National Economy and the Middle Classes

LUXEMBOURG Industrial Property Service

Patent Application I. Application ... M .. company .. ^ OTKPOBKTIOK, Calle 15½, AveM <^ Sa ^ ........ (1) ... OQDDN, .. : mana, ... a: ^ t..m .. £ tabli ^ ................................ .

... lQ2 ..,. Rus ... Leoo ....! J ^ egdQr.r ..... à .... lo9.Q..BRro ^^ Monsieur} .. Jacagues de. .Miiyser # acting as ..inamafcaire ........................................ .............................................

deposit ........ this ....... thirty-etrun ..... january ..... 19oo eighty ............... .............. (3) at ...... 15 ................. hours, at the Ministry of the Economy Nationale et des Classes Moyennes, in Luxembourg: 1. this request for obtaining a patent for an invention concerning: .. "Nouvelles ..... quinazolines ..... anti-hypertensives., ... .... len.P ..... prô.oédé ......................... (4) ....... pharmaceutical production and composition ......... ..... containing ..... ".

declares, assuming responsibility for this declaration, that the inventor (s) is (are): ... see ... on the back ................... .................................................. .................................................. .................................................. ................ (5) 2. the delegation of power, dated S.ANDWICÎ1, ïvônt .... 3.0 ..., η.0νβΙΠΟΓΘ 19 V.9 3 the description in French ..................... — ........ of the invention in two copies; 4 ...... // ............... ... drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office on .... January 31 ..... January ... 198o ................ .................................................. .................................................. .................................................. .......................................

claims for the above patent application the priority of one (or more) application (s) of (6) .......................... patent .......................................... filed) in (7) .. . Great Britain _____________________________________________________________ on ... 3.1 ..... January ..... 1.9.79 .......... (Nq ..,. „. 7.9..o3398) .... .................................................. ........................ ® on behalf of ...... PFIZER LIMITED .............. .................................................. .................................................. .................................................. ............ (9) elect domicile for him / her and, if appointed, for their proxy, in Luxembourg ................. .......................

... 35., ..... bld ....... Royal .............................. .................................................. .................................................. .................................................. .......................... (10) requests the grant of a patent for the invention for the subject described and represented in the abovementioned appendices , - with postponement of this issue to ............. /. / .......................... month.

\ ^ Le ..... ^ oanà ^ tai ^ e ........ | ........ £ ...... ^ j, II. Deposit Minutes

The above application for a patent for invention has been filed with the Ministry of National Economy and the Middle Classes, Industrial Property Service in Luxembourg, dated: January 31, 198o ....... Pr. The Minister at ....... 3 p.m. ^ National Economy ^ and the Middle Classes,

Co? D _ (1¾¾¾, -j · A /., _ \ J. -, Jl. Λ _i_L_ I / 1 / J 11V _____ A ___ ^ __________ _____________; ____ * __ / ____ J -___ D. 50.948

* CLAIM OF PRIORITY

of the patent application / di / fahé & é /

In GREAT BRITAIN From JANUARY 31, 1979 Description Brief filed in support of a request for

PATENT

at

Luxembourg on behalf of: Pfizer corporation for: "New anti-hypertensive quinazolines, their production process and pharmaceutical composition containing them".

1.

The present invention relates to therapeutic agents which are novel derivatives of 4-amino-2-piperidinoquinazoline, and it relates more particularly to derivatives carrying an alkoxy group substituted in position Ψ of the piperidino nucleus. These compounds are useful as regulators of the cardiovascular system and, in particular, in the treatment of hypertension.

The new compounds of the invention correspond to the general formula: 10 r1 ° v'v ^ \ x) —OX-OR2 7 YT \ _ / - (I, ') R0 y * 15 nh2 (in which R is a group C 1 -C 4 alkyl, benzyl or (C 1 -C 8 cyclo-alkyl) -methyl; R * is a C 1 -C alkyl group; X is a group substituted by a phenyl group and, where appropriate, by one or two methyl groups; and Λ R is a hydrogen atom, a C 1 to C alkyl group or a phenyl group optionally substituted by one or two substituents chosen from C 1 to C 4 alkyl, C 1 to C 4 alkoxy radicals, halogeno, CF ^> -CONR ^ R ^ and -SC ^ NR ^ R where R ^ and R each represent a hydrogen atom or an alkyl radical in C (to C ^) and are also present in the form of their salts addition of pharmaceutically acceptable acids.

Pharmaceutically acceptable acid addition salts are the salts formed from acids which give non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochlorides, hydrobromides, sulfates, bisulfates , phosphates, acid phos-35 phates, acetates, maleates, fumarates, lactates, tartrates, citrates, gluconates, saccharates or p-toluenesulfonates.

The compounds of the invention having one or more centers of asymmetry exist in the form of one or more pairs of enantiomers and 2.

these pairs or the individual enantiomers can be separated by physical operations, for example by fractional crystallization of suitable salts. The invention covers separate pairs as well as their mixtures, racemic mixtures or the optically active isomeric forms d and 1 separated.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

Alkyl and alkoxy groups in and can be straight chain or branched chain groups.

According to one aspect of the invention, R is a C 1 -C 4 alkyl group. R is preferably a CH ^, C2Hy benzyl or cyclopropylmethyl group.

R1 is preferably a CH ^ group. R2 is preferably a hydrogen atom or a methyl, ethyl or phenyl group. X is preferably a -CH- (phenyl) -CHr, -CH2CH- (phenyl) - or -CH2C (CH3) - (phenyl) - group.

The preferred individual compounds are the compounds of Examples 1 and 3.

The compounds of the invention can be prepared by the following methods: (1) The compounds of the invention in the formula of which R is an alkyl group with or benzyl can be prepared according to the following scheme:

R1? O R * Q / \ Z

Κγ S / “Y, rY ^ f \ _ /

25 I + HN VO— · X-OIT f J

\ _y. KA ^ n f 'J + HQ.

RO NH2 'RO NH2 (II) (XII) (I) 30 1 o R, R, R and X have the definitions given above and Q represents an easily leaving group such as chloro, bromo, iodo, (Cj alkyl to C ^ -thio or (C 1 to C ^ 1-sulfonyl alkyl.

Q is preferably chlorine or bromine.

In a normal embodiment, the reactants are heated together, for example at a temperature of 70 to 130 ° C, preferably at reflux, in an inert organic solvent such as n-butanol, for periods reaching about 48 hours. The product can be isolated and purified by conventional operations.

3.

The intermediate compounds of formulas (II) and (III) are known compounds or can be prepared by methods analogous to those of the prior art. The preparation of many intermediate compounds of formula (III) is illustrated concretely in the Preparations given below.

(2) The compounds in the formula of which R is an alkyl group

Ci to or (C3 to C6 cyclo-alkyl) -methyl can be prepared according to the following reaction scheme: 10 Β? ° Τ *! 'ΊΓ n γ \ __ / ~ o "x r œ2

PhCH20 (IA), X2

! | hydrogenation. Pd / C

20 y ° γ ^ Μγ {_ / - ° ~ x -œ2 (IV) RQ (Q is an easily leaving group, preferably 25 Cl, Br or I) M Base - »r1 ° Ύγ- - X - OE2 R ° (IB) The hydrogenation can be carried out by conventional operations, for example by hydrogenation of the compound of formula (IA) in a suitable solvent such as ethanol on a palladium catalyst fixed on carbon, normally at room temperature and 1.05 bar pressure for a few hours.

The hydroxylic compound (IV) can then be reacted with the compound of formula R.Q in a suitable solvent such as j 4.

dimethylformamide, in the presence of a base such as sodium hydroxide and under a nitrogen atmosphere. In general, long reaction times are necessary, for example up to 24 hours. The product can be isolated and purified by conventional operations.

The starting substances of formula (IA) can be prepared according to the procedure (1) above.

(3) Pharmaceutically acceptable acid addition salts of the compounds of formula (I) can be prepared by conventional procedures, for example by mixing the free base with the corresponding acid in a suitable solvent such as isopropanol, by filtering and, if necessary, by recrystallizing the salt thus produced to purify it. Naturally, the products of procedure (1) are often in the form of an acid addition salt.

The antihypertensive activity of the compounds of the invention is illustrated by their ability to lower the blood pressure of non-anesthetized rats, in a state of spontaneous hypertension, and of non-anesthetized dogs, in a state of renal hypertension, when they are administered orally at doses up to 5 mg / kg.

The compounds of the invention may be administered alone, but they are generally administered in admixture with a pharmaceutical carrier selected taking into account the desired route of administration and normal pharmaceutical practice. For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules, alone or in mixtures with excipients, or in the form of elixirs or suspensions containing perfumes or dyes. They can be injected parenterally, for example intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other dissolved bodies, for example sufficient amounts of salts or glucose to make the solution isotonic.

Consequently, the invention also relates to a pharmaceutical composition comprising a compound of formula (i) or a pharmaceutically acceptable acid addition salt of this compound, in combination with a diluent or carrier acceptable from the point of view of pharmaceutical view.

The compounds of the invention can be administered to humans for the treatment of oral or oral hypertension.

parenteral and can be administered orally in dosages approximately in the range of 1 to 50 mg / day for an average weight adult patient (70 kg) in a single dose or in divided doses of up to three. The intravenous dosage should be approximately between 5 and 1/10 of the daily oral dose. Thus, for an average adult patient, individual oral doses in the form of tablets or capsules are generally in the range of 1 to 50 mg of active compound. Variations naturally exist depending on the weight and condition of the subject being treated and the particular route of administration that is chosen, as is known to those skilled in the art.

The invention further relates to a method of treating an animal or human having hypertension, which comprises administering to the animal or human, an antihypertensive amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt of this compound, or a pharmaceutical composition of the type defined above.

The invention is illustrated by the following examples.

EXAMPLE 1

Preparation of 4-amino-6,7-dimethoxy-2- / 4- (2-ethoxy-l-20 phenylethoxy) -piperidino7-quinazoline hydrochloride 25 + \ · / ° ^ \ _ VJL ^ τ œ ^ oca NH - CH -OC-H- / ** ΊΓ 2 2 2 5 cHp HH2 30 Heated at reflux for 22 hours 2.6 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 3.0 g of 4- ( 2-ethoxy-1-phenylethoxy) -piperidine in 100 ml of n-butanol. The solution is then cooled, filtered and the filtrate is evaporated in vacuo. The residue is triturated with diethyl ether and recrystallized twice from isopropanol to give 2.0 g of 4-amino-6,7-dimethoxy-2 - // f- (2 --ethoxy-1-phenyl-ethoxy) -piperidino / -quinazoline, melting at 229-230 ° C.

Analysis: C,% H,% N,% calculated for C25H32N ^ 0 ^ .HC1 61.4 6.8 11.5 found 61.0 6.9 11.5.

6.

EXAMPLE 2

Preparation of hydrated hydrochloride of 4-amino-6,7-dimethoxy-2- / 4- (2- phenoxy-1-phenylethoxy) -piperidino7-quinazoline 5 \ _ / \ V / «cn2 10 ^ L ** i 2 - 3 HH_. \ _ Ö 15

1.44 g of 4-amino-2-chloro-ej7-dimethoxyquinazoline and 2.0 g of 4- (2-phenoxy-1-phenylethoxy) -20 piperidine in 100 ml of n-butanol are heated to reflux for 20 hours. . The solvent is then evaporated in vacuo, the residue is triturated with ether and it is crystallized from isopropanol. The solid is distributed between chloroform and an aqueous sodium carbonate solution, the chloroform extract is dried over magnesium sulfate and the solvent is evaporated in vacuo. The residue is chromatographed on 100 g of silica, eluting with chloroform, then with a mixture of chloroform and methanol at 20: 1. The fractions containing the product are combined, the solvent is evaporated in vacuo and the residue is transformed into hydrochloride by treatment of a chloroform solution with a solution of hydrochloric gas in ether.

The solid hydrochloride is collected and recrystallized from isopropanol to give 0.85 g of hydrated hydrochloride of 4-amino-6,7-dimethoxy-2 - / ^ - (2-phenoxy-1-phenylethoxy) -piperidino7- quinazoline melting at 202-204 ° C.

Analysis; C,% H,% N,% 35 calculated for C29H32N40 ^ .HC1.H20 62.8 6.4 10.1 found 62.8 6.1 10.0.

7.

EXAMPLES 3 to 6

The following compounds were prepared in the same manner as in the above examples, starting with 4-amino-2-chloro-6,7-dimethoxy-quinazoline and the corresponding pyridine; thus, the product of Example 3 was prepared in the same manner as in Example 1 'and the products of Examples Ψ, 5 and 6 were prepared in the same manner as in Example 2, but the product of Example 5 was not transformed into hydrochloride.

RS

10 <*. <,> V ... r ~ \ I * · Γ I ·

CH

15 kx 20 _ ^ _

Example R ^ Isolated form and Analysis,% n ° melting point (theoretical values (° C) in brackets)

25 C H N

3 HH Hydrochloride 59.7 6.3 12.0 241-243 ° C (59.9 6.3 12.2) 30 Ψ HC, Hc Hydrochloride 61.3 6.7 11.0 234-235 ° C (61 , (1 6.8 11.5) 8.

R * CH3Q / \ I ± 5 TJf 2 Ί NH2 [) 10

Example R5 R2 Isolated form and Analysis,% dd n ° melting point (theoretical values (° C) in parentheses)

C H N

20 5 CH3 H Mono-free base 63.0 6.8 12.2 hydrated (63.1 7.1 12.3)

146-m ° C

6 CH., C ^ Hc Hydrochloride 61.9 7.0 11.1 25 231-233 ° C (62.1 7.0 11.1) EXAMPLE 7

Preparation of 4-amino-6-cyclopropylmethoxy-2- / 4- (2-ethoxy-1-phenylethoxy) -piperidino7-7-methoxyquinazoline D - (+) tartrate The mixture is stirred at room temperature under a nitrogen atmosphere for ¢ 0 minutes in the dark 0.75 g of 4-amino-2- / 5- (2-ethoxy-1-phenylethoxy) -piperidingf-6-hydroxy-7-methoxyquinazoline hydrochloride in 50 ml of dimethylformamide and 1 ml of 5N sodium hydroxide solution. 0.27 g of cyclopropylmethyl bromide is then added and the solution is stirred under a nitrogen atmosphere for 20 hours. 5 mg of potassium iodide are added, followed by 0.27 g of cyclopropylmethyl bromide and the stirring is continued for 2 hours at room temperature. The solvent is evaporated in vacuo and the residue is taken up in 50 ml of water, it is made alkaline at pH 12 by addition of 2N sodium hydroxide and it is extracted with chloroform (3 x 100 ml). The combined chloroform phases are dried over sodium sulfate and the solvent is evaporated in vacuo to give a semi-solid substance. The product is chromatographed on 7 g of silica, the elution being carried out with chloroform. The fractions containing the product are 9.

collected and the solvent is evaporated under vacuum. The residue is converted to tartrate by treatment of a chloroform solution with a solution of D - (+) - tartaric acid in ether. The resulting solid is filtered off, washed with ether and dried under reduced pressure to give 115 mg of 5 D - (+) - 4-amino-6-cyclopropylnethethoxy-2- / 4- (2-ethoxy) tartrate -l-phenyl-ethoxy) -piperidinQ7-7-methoxyquinazoline melting at 142-145 ° C.

Analysis: C,% H,% N,% calculated for C28H36N404‘C4H6 ° 6 59.8 6.6 8.7 found 59.8 6.5 8.9.

10 EXAMPLE 8

Preparation of 4-amino-6-ethoxy-2- / 4 - (2-ethoxy-1-phenyl-ethoxy) -piperidino7-7-methoxyquinazoline hydroiodide

The compound indicated in the title is prepared by following the procedure of Example 7, starting from 4-amino-2- / 4- (2-ethoxy-1-phenylethoxy) -15 piperidinq7-6-hydroxy-7- methoxyquinazoline and ethyl iodide, in the presence of sodium hydroxide, and it melts at 227-228 ° C.

Analysis: C,% H,% N,% calculated for C26H3404 ° 4 * HI 52.5 5.9 9.4 found 52.1 5.8 9.4.

20 EXAMPLE 9

Preparation of 4-amino-6-benzyloxy-2- / 4- (2-ethoxy-1-phenyl-ethoxy) -pararidinQ7-7-methoxyquinazoline hydrochloride

0.72 g of 4-amino-6-benzyloxy-2-chloro-7-methoxyquinazoline is heated at reflux for 30 hours ["Z. Med. Chem.", 1977, 20, 146? and 0.57 g of 4- (2-ethoxy-1-phenylethoxy) -piperidine in 50 ml of n-butanol. The solvent is evaporated in vacuo and the residue is triturated with ether to obtain a solid which is recrystallized from a mixture of isopropanol and diisopropyl ether, which gives 740 mg of 4-amino hydrochloride. 6-benzyloxy-2- / 4- (2-ethoxy-1-phenylethoxy) -piperidinQ7-7-methoxyquinazoline.

A sample recrystallized from ethanol has a melting point of 238-240 ° C. Analysis: C,% H, 96 N, 96 calculated for C ^ h ^ N ^ .HCl 65.9 6.6 9.9 found 65.5 6.5 10.0.

The following Preparations illustrate how to obtain some of the starting materials: 10.

Preparation A

Preparation of 4- (2-hydroxyphenethyloxy) -piperidine

5.0 g of N-acetyl-4-hydroxypiperidine in 50 ml of tetrahydrofuran (THF) are added to a stirred suspension of sodium hydride 5 (1.84 g, 50% dispersion in mineral oil) in 25 ml of tetrahydro furan (THF) under a nitrogen atmosphere. When the effervescence has stopped, 4.6 g of styrene oxide are added in 25 ml of THF, then the reaction mixture is diluted with 25 ml of dimethylformamide (DMF) and the mixture is stirred at 60 ° C. for 18 hours . After adding isopropanol to the cooled solution, the solvent is removed in vacuo, the residue is treated with water, its pH is adjusted to 4 by addition of 2N hydrochloric acid and it is extracted with chloroform. The chloroform extract is dried over sodium sulfate and the solvent is evaporated in vacuo to give N-acetyl-4- (2-hydroxyphenethyloxy) -piperidine. This product in 50 ml of ethanol and 100 ml of 5N sodium hydroxide solution is heated at reflux for 3 hours. The solvent is then removed under vacuum, the residue is taken up in water, it is extracted with chloroform, dehydrated, and the solvent is evaporated under vacuum. The product in chloroform is converted to the hydrochloride by treatment with a solution of hydrogen chloride in ether, then evaporation of the solvent. The residue is taken up in methanol, treated with ether, the precipitated solid is separated, then it is recrystallized from isopropanol, giving 0.6 g of fonding 4- (2-hydroxyphenethyloxy) -piperidine hydrochloride at 174-175 ° C.

Analysis: C,% H,% N,% calculated for C13H19N02.HC1 60.6 7.8 5.4 25 found 60.1 7.8 5.2.

Preparation B

Preparation of 4- (2-ethoxyphenethyloxy) -piperidine

8.0 g of N-acetyl-4- (2-hydroxy-phenethyloxy) -piperidine, prepared as in Preparation A, and 0.3 g of 1,2-dimethoxyethane in 50 ml are added dropwise. of anhydrous DMF, to a suspension with stirring of sodium hydride (2.96 g, 50% dispersion in mineral oil) in 50 ml of anhydrous DMF. The suspension is stirred at room temperature for 3.5 hours, cooled to 0-5 ° C, then a solution of 9.6 g of ethyl iodide in 25 ml of DMF is added dropwise. The mixture is allowed to warm to room temperature (20 ° C), then stirred at room temperature for 2 hours. 75 ml of isopropanol are added, the solvent is removed in vacuo and the residue is partitioned between chloroform and water. The chloroform phase is dehydrated and the solvent is evaporated in vacuo giving 11.

5.2 g of N-acetyl-4- (2-ethoxyphenethyloxy} -piperidine. This product is heated under reflux for 3.5 hours in 50 ml of ethanol and 50 ml of 5N sodium hydroxide solution. the organic solvent in vacuo and the aqueous residue is extracted with chloroform The organic extract is dried over sodium sulfate, evaporated in vacuo, then the residue is partitioned between a solution of 2N hydrochloric acid and ether. The aqueous phase is then basified with sodium carbonate solution and extracted with chloroform The chloroform extract is dried over sodium sulfate, the solvent is evaporated in vacuo, then the residue is taken up in ether and 10 converted to oxalate, by recrystallization from isopropanol, 1.6 g of 4- (2-ethoxyphenethyloxy) piperidine oxalate, melting at 136-137 ° C., is obtained.

Analysis: C,% H,% N,% calculated for C ^ f ^ NC ^. C ^ C ^ 60.2 7.4 ¢, 1 found 60.3 7.4 4.1.

15 12.

Preparation C

Preparation of 4- (2-ethoxy-1-phenylethoxy) -piperidine 5 1. Natt oh 2- O) r ÔNS / pCHC02C2H5

BrCHCOoH. v 3- "* · H © 'k ..

t I

Γ0 a = o

CH

3 CH3 15 LiBH.

4 1

I I

V V

OCHCH OC H- OCHCH-OH

A ‘·“ X.

j 2- w r ^ ^ N / 3. NaOH / CH ^ OH t | ^

25 H T

C = O

CH3

Alpha- (N-acetyl-fr-piperidinoxy) -phenylacetic acid ethyl ester 27.5 g of N-acetyl-4-hydroxypiperidine in 100 ml of anhydrous DMF are slowly added to a suspension with hydride stirring sodium (25 g, 50% dispersion in mineral oil) in 150 ml of DMF and 10 ml of 1,2-dimethoxyethane. The suspension is stirred at room temperature for 3 hours. Then slowly add Ψ5 g of alpha-bromo-35 phenylacetic acid in 250 ml of DMF, cooling with a mixture of ice and water. The reaction mixture is stirred at room temperature for 20 hours, then isopropanol is added and the solvent is evaporated in vacuo. The residue is taken up in water and acidified to pH 1 with hydrochloric acid 13.

2N and extracted four times with 300 ml of chloroform. The combined chloroform extracts are washed with water and brine, dried over magnesium sulfate and the solvent is evaporated in vacuo. The residue in ¢ 50 ml of anhydrous ethanol, supplemented with 9 ml of concentrated sulfuric acid, is heated at reflux for δ hours. The cooled solution is carefully neutralized by adding an aqueous solution of sodium carbonate and the organic solvent is evaporated in vacuo. The aqueous residue is adjusted to pH 10 by addition of a sodium carbonate solution and it is extracted twice with chloroform. The combined chloroform extracts are dried over magnesium sulfate and evaporated in vacuo. By distillation of the residue, 37.2 g of ethyl ester of alpha- (N-acetyl-4-piperidinoxy) -phenyl-acetic acid boiling at 190-19 ^ 0 / 0.18 mm are obtained.

Analysis: C,% H,% N,% calculated for 66.9 7.6 ¢, 6 15 found 66 ^ 7.8 ¢, 5.

(ii) N-acetyl-M2-hydroxy-1-phenylethoxy) -piperidine

3.2 k g of lithium borohydride are added in portions to a solution of 11.2 g of ethyl ester of alpha- (N-acetyl-4-piperidinoxy) -phenylacetic acid in 200 ml of anhydrous THF. When the evolution of hydrogen has ceased, the reaction mixture is heated under reflux for ¢ hours. Water is added to the cooled solution, the solvent is evaporated in vacuo then the residue is taken up in 200 ml of chloroform and washed with dilute hydrochloric acid, water and brine. The chloroform extract is dried over magnesium sulfate and the solvent is evaporated in vacuo. Analysis of the product by thin layer chromatography indicates that the reduction is incomplete; therefore, the product in 100 ml of THF is treated with an added amount of 3.2 kg of lithium borohydride and it is heated under reflux for ¢ hours. The reaction mixture is treated as above, yielding 9.5 g of N-acetyl-M2-hydroxy-1-phenylethoxy) -piper-dine in the form of an oil which solidifies on standing. A sample crystallized from ether has a melting point of 92-9k ° C.

Analysis: C,% H,% N,% calculated for C15H21N03 68 ^ 8.1 5.3 found 68.1 8.1 5.7.

(Iii) M2-ethoxy-1-phenylethoxy) -piperidine

This compound is prepared by following the procedure of Preparation B starting with N-acetyM- (2-hydroxy-1-phenylethoxy) -piperidine (prepared as indicated in part (ii) above) and iodide d ethyl, in 14.

then carrying out the hydrolysis of the N-acetyl group. A sample characterized in the form of the oxalic acid salt melts at 137-139 ° C.

Analysis: C,% H, 96 N,% calculated for Cj ^ H ^ NC ^ .C 2H20 ^ 60.2 7.4 4.1 5 found 59.9 7.4 4.0.

Preparation D

4- (2-phenoxy-1-phenylethoxy) -piperidine

Stirred at 0 ° C for 2 hours, then allowed to stand at room temperature for 48 hours, a mixture of 5.25 g of N-acetyl-4-10 (2-hydroxy-1-phenylethoxy) -piperidine (prepared as indicated in (ii) in * Preparation C), 4.2 g of diethyl azodicarboxylate, 6.3 g of triphenylphosphine and 2.25 g of phenol in 100 ml of anhydrous tetrahydrofuran. The solvent is evaporated in vacuo, the residue is taken up in 50 ml of diethyl ether at reflux and kept in the refrigerator for about 18 hours. The precipitated by-products are removed by filtration and the filtrate is evaporated to dryness. The residue is again taken up in ether, it is allowed to cool and the solid precipitate is separated by filtration. The ether filtrate is evaporated to dryness and the residue in 50 ml of methanol and 30 ml of 5N sodium hydroxide solution is heated under reflux for 5 hours. The organic solvent is removed in vacuo, the aqueous residue is acidified to pH 3 by addition of 2N hydrochloric acid, then it is extracted twice with ether, the organic extracts being discarded. The aqueous phase is adjusted to pH 12 with a sodium hydroxide solution, it is extracted with ether (three times 100 ml), the extraction phases with ether are combined, dried over magnesium sulfate and the solvent is evaporated in vacuo giving 3.55 g of 4- (2-phenoxy-1-phenyl-ethoxyj-piperidine in the form of an oil. A sample is converted to the oxalate which is recrystallized from isopropanol; it has a melting point of 170 to 172 ° C.

Analysis: C,% H,% N,% 30 calculated for C19H23N02.C2H20 ^ 65.1 '6.5 3.6 found 64.9 6.6 3.8.

15.

Preparation E

Preparation of 4- (2-hydroxy-2-phenyl-n-propoxy) -piperidine 5, _ ^ Ά Λ2 '“^ O XT) ^ X? N> [J-—> Γ j 10 ^ ^ IsiX CH3OH k "/ 1

. C = O C = O H

I I

ch3 ch3 15 N-acetyl-4- (2-phenylallyloxy) -piperidine

13.6 g of N-acetyl-4-hydroxypiper-20 dine in 50 ml of DMF are added dropwise to a stirred suspension of sodium hydride (10 g, 50% dispersion in mineral oil) in 50 ml of DMF under nitrogen atmosphere. The mixture is stirred at room temperature for 3 hours, then 20 g of alpha- (bromomethyl) -styrene are added dropwise in 50 ml of DMF. The mixture is stirred at room temperature for 4 hours, then diluted with water and extracted with three times 200 ml of chloroform. The combined chloroform extracts are dried over sodium sulfate, evaporated in vacuo and distilled to give 25 g of N-acetyl-4- (2-phenylallyloxy) -piperidine boiling at 170-180 ° C / 0.3 mm; the nuclear magnetic resonance spectrum agrees with this structure.

(Ii) 4- (2-hydroxy-2-phenyl-n-propoxy) -piperidine

4.0 g of N-acetyl-4- (2-phenylallyloxy) -piperidine in 60 ml of anhydrous THF are added dropwise to a stirred solution of 6.35 g of mercuric acetate in 60 ml of water and the solution is stirred at room temperature for 1 hour. 40 ml of 3N sodium hydroxide solution and 0.75 g of sodium borohydride in 40 ml of 3N sodium hydroxide solution are then added dropwise to the solution with stirring at 0 ° C. The gray suspension is stirred at 0 ° C for one hour, supplemented with acetic acid crystallizable to pH 6, then the suspension is filtered and the »16.

filtrate is extracted with chloroform (three times 150 ml). The combined chloroform extracts are dried over sodium sulfate and evaporated in vacuo to give 2.1 g of N-acetyl-4- (2-hydroxy-2-phenyl-n-propoxy) -piperidine. This product in 30 ml of methanol and 20 ml of 5N sodium hydroxide solution is heated at reflux for 4 hours. The organic solvent is evaporated and the aqueous solution is extracted with three times 20 ml of chloroform, dried over sodium sulfate, then the solvent is evaporated in vacuo giving 1.8 g of 4- (2-hydroxy-2-phenyl -n-propoxy) -piperidine in the form of an oil. A sample is characterized in the form of the oxalate which is recrystallized from ethyl acetate; it melts at 132-134 ° C.

Analysis ·. C,% H,% N,% calculated for C14H2jlN02.C2H20 ^ 59.1 7.1 4.3 found 58.8 7.1 4.8.

Preparation F

15 Preparation of 4- (2-ethoxy-2-phenyl-n-propoxy) -piperidine

7.0 g of N-acetyl-4- (2-phenylallyloxy) -piperidine (prepared as indicated in Preparation E) in 10 ml of ethanol are added to a stirred suspension of 9.2 g of mercuric acetate in 50 ml of ethanol at room temperature. The mixture is stirred at room temperature for one hour, then cooled to 0 ° C. 20 ml of 5N sodium hydroxide solution are added, then 1.03 g of sodium borohydride in 20 ml of 5N sodium hydroxide solution to the suspension with stirring and, 10 minutes later, water is added. acetic acid crystallizable to pH 6. The suspension is filtered, the filtrate is concentrated and the residue is partitioned between chloroform and water. The organic phase is dried over sodium sulfate and the solvent is evaporated in vacuo. Analysis by gas chromatography of the product indicates incomplete conversion to the desired product; therefore, the oxymercuration process is repeated as above, yielding 7.4 g of N-acetyl-4- (2-ethoxy-2-phenyl-n-propoxy) -piperidine of purity equal to 84% d 'after thin layer chromatography. The product in 100 ml of ethanol and 30 ml of sodium hydroxide solution is heated at reflux for 11 hours. The organic solvent is evaporated and the aqueous solution is extracted with three times 30 ml of chloroform. The combined chloroform extracts are dried over sodium sulfate and the solvent is evaporated in vacuo to give 4- (2-ethoxy-2-phenyl-n-propoxy) -piperidine as an oil (3.8 g). A sample converted to the oxalate is recrystallized twice from ethyl acetate and then from acetone. It melts at 126-127 ° C.

17.

Analysis; C,% H,% N,% calculated for α16Η25Ν02.02Η20ψ.1 / 4Η2Ο 60.4 7.3 3.9 found 60.4 7.6 4.1.

Preparation G

5 Preparation of 4-amino-2- / 4- (2-ethoxy-1-phenyl-ethoxy) -piperidino / -6-hydroxy-7-methoxyquinazoline hydrochloride hydrochloride

0.9 g of 4-amino-6-benzyloxy-2- / 4- hydrochloride is hydrogenated on 5% palladium fixed on carbon, at room temperature and under pressure of 1.05 bar for 2 hours. 2-ethoxy-1-phenylethoxy) -piper-10 dinç ^ -Z-methoxyquinazoline in 150 ml of anhydrous ethanol. The catalyst is removed by filtration and the filtrate is evaporated to dryness under vacuum. The residue is triturated with ether to give 0.55 g of a white solid. A 200 mg sample is recrystallized from isopropanol to obtain 71 mg of hydrated hydrochloride of 4-amino-2- / 4- (2-ethoxy-1-phenylethoxy) -15 piperidino7-6-hydroxy-7-methoxyquinazoline at 141-144 ° C.

Analysis: C,% H,% N,% calculated for C24H30N ^ O4.HCl.H2O 58.5 6.8 11.4 found 58.0 6.5 11.5.

Claims (9)

1. Compounds of formula: 5 RW-γ. χ. or2 RO -NV Jv ^ N --- (I) NH2 10 (in which R is C 1 -C 4 alkyl, benzyl or (C3-C 3 -C cyclo-alkyl) - methyl; 1 0 R is a C1 to C5 alkyl group; 15. is a -CH2CH2- group substituted by a phenyl group and, where appropriate, by one or two methyl groups; and R is a hydrogen atom, a Cj alkyl group or a group phenyl optionally substituted with one or two substituents chosen from C 1 -C 4 alkyl, C 1 -C 20 alkoxy, halo, CF3, -CONrV and -SO2NrV where R3 and R4 each represent a hydrogen atom or a radical C1-C6 alkyl) also in the form of their pharmaceutically acceptable acid addition salts. 2. - Compound according to claim 1, characterized in that R is a CH3, C2H3, benzyl or cyclopropylmethyl group; R ^ is a CH3 group; X is a group -CH- (phenyl) -CH2-, -CH2CH- (phenyl) - or -CH2C- (CH3) - (phenyl) ~; and is a hydrogen atom or a methyl, ethyl or phenyl group. 3. The 4-amino-6,7-dimethoxy-2- / 5- (2-ethoxy-1 ~ phenylethoxy) - piperidino7-quinazoline according to claim 1. 4. The 4-amino-6,7-dimethoxy-2- / 4- (2-hydroxy-2-phenylethoxy) -piperidinc ^ -quinazoline according to claim 1. 5. A compound according to claim 1, characterized in that R 35 is a C ^ to C ^ alkyl group. 6. Process for the production of a compound of formula (I) according to claim 1, in which R is a C 1 -C 4 alkyl or benzyl group, characterized in that it consists in reacting a compound of formula: * 19. i '- ✓s. M y δ I I I. - (II) 5 aoA ^ / k ^ · 11 ™ 2 (in which R is a C 1 to alkyl or benzyl group, R1 has the definition given in claim 1 and Q is an easily leaving group) with a piperidine of formula: ,, Y-0 - x 'or2 - (III) 15 \ _ (• y (in which R ^ and X have the definitions given in claim 1). 7. A process for the production of a compound of formula 1 according to claim 1, in which R is an alkyl group or (C3-C8 cycloalkyl) -nethyl group, characterized in that it consists in reacting a compound of formula: 25 N <S | ^ N \ O - X - OR2 Js. ~~, (IV) HO N / NH2 30 1 O (in which R, R and X have the definitions given in claim 1) with a compound of formula RQ in the presence of a base, formula in which R is a C1-alkyl or (C6-cycloalkyl) ) -methyl and Q is an easily leaving group. 8. A compound of formula (I) according to claim 1, prepared by a process according to one of claims 6 and 7. 9. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of the claims 20. cations 1 to 5 and S in mixture with a diluent or carrier acceptable from the pharmaceutical point of view.