Process for producing azole-amides

New carbonylpiperazinylquinazolines and process for their preparation.

The present invention relates to new carbonylpiperazinylquinazolines in which the carbonyl radical carries a heterocyclic nitrogen radical which are potent antihypertensive agents generally exerting an a-adrenergic block activity lower than that of 4- (2-iuroyl) pine razine "l-yl / -^!4 ~ amino ~ ô, 7-diffiéthoxyqulnazoline which is a known powerful antihypertensive drug.

More specifically 5 the invention relates to comSY-1502 A posed of formula:

<img file="LU76802A1_D0001.tif" />

where Z represents an oxazole, isoxazole, thiazole, isothiazole or alkylthio-1,3,4-oxadiazole radical, substituted or not, as well as their pharmaceutically acceptable acid addition salts and methods for preparing them.

U.S. Patents 3,311,386, 3,635 * 979 and 3 * 663,706 describe various 4-amino-6,7-dimethoxy-2Z 4- (heterocyclic-2-carbonyl) piperazine-1-yl / Qu.inazolines.

One of these, namely 2- / ~ 4- (2-furoyl) piperazine-1-yl74-amino-6,7-dimethoxyquinazoline described in Example 72 of these patents, is an anti- hypertensive clinically useful and is sold as such in many countries under the name of prazosin. It is well established that the antihypertensive effect of prazosin results from two mechanisms of action, namely;

(1) a direct peripheral vasodilation effect on the vascular smooth muscle and (ii) a blockage of the functional peripheral a-adrenergic receptor, (see H. Adriaensen, The Practitioner, 214, 268 (1975);

Mroczek et al., Current Therapeutic Research, 16,769 (197½); Scriabin et al., Experientla, 24. 1150 (1968);

Constantine et al., Hypertension: Mechanisms and Management, ed. by Onesti, Kim and Moyer;

Grune and Stratton, 1973₅ pages 429-444; and

Zacest, Med, J. of Austral. Special Supplement. 1.4 (1975)).

Initial clinical trials of prazosin indicated an almost complete absence of side effects, but recent reports have

AB.MU.MDB. 8 - 2 - SY-1502 Revealed the existence as an adverse side reaction of hypotension when standing in some patients, see Bendall et al., Brit. Med. J., 727 (June 28, 1975); Bees, Brit, Med. J.,

593 (September 6, 1975); Gabriel et al., The Lancet. 1095 (10 nia 1975); and Bloom et al., Current Therapeutic Research, 18, 1¼½ (1975). It is generally considered that a side effect of this type results from the “-adrenergic blockage exerted by prazosin. Indeed, it was established by R. Zacest in Med.J. of Austral · ",., Special Supplement, 1, (1975) that if the α-energy blocking activity proves to be sensitive at high doses, it can lead to hypotension when standing,

The patents of the United States of America η ° 3 · 669.968 and 3.769.286 relate to trialkoxyquinazolines like those

<img file="LU76802A1_D0002.tif" />

where R can represent different radicals, in particular furyl and thienyl radicals. These patents mention that these compounds offer certain advantages over the corresponding 6,7-dialkoxylated compounds such as those described in the preceding patents. Thus, it is established that these compounds have a more favorable pharmacological profile (for example have no adrenolytic effect in dogs) and have a much better solubility (in particular in water) than the corresponding 6,7-dialkoxylated compounds. described previously. One of the compounds which is the subject of these patents is called trimazosin and corresponds to the formula:

AB.MJ.MDB.8

- 3 SY-I502 A ch₃o

<img file="LU76802A1_D0003.tif" />

Trimazosin has been shown to be an active antihypertensive agent in humans (see DeGuia et al., Current. Therapeutic Research,

15. 339 (1973); Vlachakis et al., Current Therapeutic Research, 17, 56h (1979)) However, this compound is a much less potent drug than prazosin since the daily clinical dose is approximately 150 to 900 mg for trimazosin and 1.9 15 mg for prazosin. Trimazosin is therefore ICO times less potent than prazosin at the lower end of the dose range.

Lesbrevets of the United States of America n ° 3 «9l7 · 0θ9₅3.59 ^. ^ 0 and 3.812.127 describe certain piperazinylquinazolines exerting both a bronchodilator and antihypertensive effect, for example compounds of formula:

<img file="LU76802A1_D0004.tif" />

where each of the symbols A and B can represent an alkoxy radical among others, R 'can represent a hydrogen atom or an alkyl radical and R can represent a hydrogen atom or a radical such as an alkyl, benzoyl radical and so right now.

United States Patent No. 3,920,636 indicates, as antihypertensive agents 5, homopiperazinoqulnazolines, for example the compound of formula;

- 1+ ~

AB.MJ.MDB.8

SY-1502 A

CH₃O ch₃where

Xo-cJU ''%.

U.S. Patent No. 3,780.0 ^ -0 describes compounds useful as antihypertensive agents, for example the compound of formula:

<img file="LU76802A1_D0005.tif" />

Netherlands patent application No. 72/0606 (CA, 78, 72180s) describes a process for preparing aminoquinazolines such as prazosin by reaction of the corresponding o-aminobenzonitrile in the presence of phenyllithiura according to the following scheme:

<img file="LU76802A1_D0006.tif" />

<img file="LU76802A1_D0007.tif" />

it being understood that, in the above formulas, the RgN group may represent the radical è— (2 ~ furoyl) -1-piperazinyl.

The subject of the present invention is compounds of formula:

AB.MJ.MDB. 8

- 5 SY-1502 A

Q

<img file="LU76802A1_D0008.tif" />

or. Z represents a radical of formula:

<img file="LU76802A1_D0009.tif" />

where X represents the oxygen or sulfur atom, each of the symbols R and R, which are identical or different, represents a hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a lower alkoxy radical of 1 to 6 carbon atoms or a lower alkylthio radical of 1 to 6 carbon atoms and R ^ represents a lower alkyl radical of 1 to 6 carbon atoms, as well as their pharmaceutically acceptable acid addition salts, which manifest an antihypertensive power comparable to that of prazosin, but generally exert a peripheral α-adrenergic blocking effect lower than that of prazosin.

<img file="LU76802A1_D0010.tif" />

NN subject the compounds of formula:

S »R where R represents a lower alkyl radical of 1 to 6 carbon atoms and their pharmaceutically acceptable acid addition salts. These compounds have an antihypertensive effect comparable to that of prazosin, but have little or no effect on the peripheral α-adrenergic blocking of prazosin. These compounds are of AB .MJ.MDR.8 ~ 6 - SX-1 ^ 02 A powerful antihypertensive agents which have little or no side effect as shown by their absence of adrenolytic activity.

The preferred compound of the invention is h-amino ~ 6,7 dimethoxy-2- / 7 ^ "(5 ~^m®'foy¹''^vskd^o”¹5 3 >^-°^xadiazole “2-carbonyl) piperazine-1-yl / qulnazollne of formula:

<img file="LU76802A1_D0011.tif" />

AB.MJ.MDB. 8 and its acid addition salts and in particular its hydrochloride.

For the purposes of the invention, an acid addition salt of a compound of formula I, the anionic part of which is derived from a relatively non-toxic organic or inorganic acid, is considered to be pharmaceutically acceptable. The anion does not contribute appreciably to the toxicity of the salt, nor to its pharmacological activity. Examples of such salts are those formed with acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic , p-toluenesulfonic and related acids. The acid addition monosalts can be obtained in the conventional manner by reacting a solution or suspension of the free base in an inert organic solvent with 1 chemical equivalent of the acid, however that the addition salts of acids are obtained in the same way by reaction with at least 2 chemical equivalents of the acid. The salts are isolated using conventional concentration or crystallization techniques.

The subject of the invention is also a process for prepaSY-1502 A ration of compounds of formula:

<img file="LU76802A1_D0012.tif" />

where Z represents an oxazole, isoxazole, thiazole, isothia0 zole or alkylthio-1, β, ^ - οχαάίazole radical substituted or not, as well as their non-toxic pharmaceutically acceptable acid addition salts.

According to the invention, the compounds of formula I are prepared by a process, according to which a quinazoline of formula is reacted:

<img file="LU76802A1_D0013.tif" />

where A represents a NHg or NR'g radical, R'2 representing a conventional group which protects the amine function and B represents a chlorine atom or a piperazino or OR radical ”, R representing a radical F ^ CC (O) - , CH ^ SGg-, ^or- ^atlkylS0₂-, with a reagent of formula:

0 nn

Y - C «Z or Z - C - plperazine where Y represents a substituent activating the carbonyl function of the conventional type for amidation reactions, for example a halogen atom or an azido, ethoxy, carbonyloxy, 1-imidazo radical and so on, and Z represents a radical of formula;

AB.MJ.MDB.8

- 8 SY-1502 A

<img file="LU76802A1_D0014.tif" />

<img file="LU76802A1_D0015.tif" />

Nr where X represents an oxygen or sulfur atom, each of the R and R symholes, identical or different, represents a hydrogen atom, a lower alkyl radical - from 1 to 6 carbon atoms, a lower alkoxy radical from 1 has 6 carbon atoms or a lower alkylthio radical of 1 to 6 carbon atoms and R ^ represents a lower alkyl radical of 1 to 6 carbon atoms, then if necessary, the group R 'is eliminated._o protecting the amine function in a conventional manner and, if desired, the product is converted into a non-toxic pharmaceutically acceptable acid addition salt according to conventional techniques.

Equations 1 to p below illustrate the various possible modes of synthesis for the preparation of the compounds of the invention in accordance with the process described above.

Equation 1

<img file="LU76802A1_D0016.tif" />

AB.MJ.MDB.8

Sï-1502 A

According to a preferred embodiment of this process, in the formulas, Z represents a radical

<img file="LU76802A1_D0017.tif" />

where R represents a lower alkyl radical and the reaction is carried out in an inert solvent, such as dioxane, chloroform, methylene chloride, ethylene glycol dimethyl ether and so on, at room temperature and / or under heating at reflux 0 bringing the reaction to completion.

In a more preferred form, in the formulas, ï represents a chlorine atom and Z represents the N —— N radical and the reaction is carried out in dioxane.

<img file="LU76802A1_D0018.tif" />

Equation 2

<img file="LU76802A1_D0019.tif" />

AB.MJ. MDB.8

- 10 Sï-1502 A

Equation 3

<img file="LU76802A1_D0020.tif" />

<img file="LU76802A1_D0021.tif" />

<img file="LU76802A1_D0022.tif" />

Γ ~ \

Μ N v_ /

The group R '₂ protecting the amine function can then be removed from compound 1 (a) according to conventional techniques for obtaining the corresponding compound I.

AB.MJ.MDB. 8 -11SY-1502 A

Equation 4

<img file="LU76802A1_D0023.tif" />

As for equation 3, the group protecting the amine function can be removed from compound 1 (a) according to conventional techniques for the preparation of the corresponding compound I.

Equation 5

<img file="LU76802A1_D0024.tif" />

+ R «0H (or R Cl) ->

AB.MJ.MDB. 8

- 12 SY-1502 A

GOLD"

<img file="LU76802A1_D0025.tif" />

It is possible to invent the invention also in the manner of obtaining the compounds of the diagram below:

<img file="LU76802A1_D0026.tif" />

<img file="LU76802A1_D0027.tif" />

ab.mj, MDB.8

- 13 SY-1502 A

COgCHo

<img file="LU76802A1_D0028.tif" />

EXAMPLE 1 '+ -ataino-6 hydrochloride_s? "Dlniéthoxy-'2- / ~ⁱ4- (ß ~ ~ the taéthylthio, 3d

4-oxadlazole-2-carbonyl) pipera2lne-l-yl7quinazoline

A solution of 0.601 g (3.36 millimoles) of 5 “methylthio-1,3 d chloride is added.¹+ -oxaâiazole-2-carbonyl in 10 ml of dioxane with a solution of 0.972 g (3.36 millimoles) of ^ -amino-6,7 ~ dimethoxy-2- (1-piperazinyl) quinazoline in 100 ml of dioxane. The resulting mixture was stirred at room temperature for 65 hours, then heated to reflux for 30 minutes. By filtration, 1.56 g of the desired compound are isolated. AB.MJ.MDB.8 - 1> + - SY-1502 A

By recrystallization from methanol, the product melting is obtained at 28O ~ 285 ° C with decomposition.

Analysis for C ^ gHgjN ^ O ^ S.HCl calculated C, 46.20; III, 4.74; Cl, 7.58; N, 20.96; S, 6.85% found C, 46.34; H, 4.89; Cl, 7.59; N, 20.38; S, 6.58%

EXAMPLE 2 4-amino-6,7 hydrochloride ~ dimethoxy-2- / 4- (5-ethylthio-1,3₅4oxadiazole-2-carbonyl) piperazine ~ l-yl / quinazoline

The desired compound is prepared from 0.79 g (4.1 millimoles) of 5 ”ethylthio-1,3,4-oxadiazole-2-carbonyl chloride and 1.19 g (4.1 millimoles) of 4 - &amp; mlno ~ 6,7-dimethoxy-2 ~ (l-piperazinyl) quinazoline by applying the procedure of Example 1. The product melts at 2b6 ~ 248.5 ° C.

Analysis for¹ C ^ K ^ N ^ O ^ S.HOl calculated C, 47.34; H, 5.02; N, 20.34; S, 6.65% found C, 47.37? H, 4.76; N, 20.15; S, 6.71% (corrected for an HgO content of 4.11%)

EXAMPLE 3 4-amino-6,7-dimethoxy-2 - / ”4— (5-isopropylthio1,3,4-oxadiazole-2-carbonyl) piperazine-1-yl / quinazoline hydrochloride

The desired compound is prepared from 1.54 g (7.5 millimoles) of 5-isopropylthio-1,3,4-oxadiazole2-carbonyl chloride and from 2.1 g (7.5 millimoles) of 4-amino ~ 6,7-dimetho ~ xy-2- (l-piperazinyl) quinazoline by applying the procedure of Example 1. The product melts at 260-263 ° C with decomposition. Analysis for CæHg ^ NrjO ^ S.HÇl calculated C, 48.43; H, 5.28; N, 19.77% found C, 48.05; H, 5.20; N, 19.61%

EXAMPLE 4 4-aminO hydrochloride “6,7 ~ eimethoxy-2 - /” 4 - (5-n-propylthio-1,3,

AB.MJ.MDB.8

- 15 SY-1502 A

4-oxadiazole-2-carbonyl) piperazine-l-yl / quinazoline

The desired compound is prepared from 1.68 g (8.16 millimoles) of 5-nP chloride^ropyltbi ° * -l, 3,4-oxaâiazole2-carbonyl and 2.36 g (8.16 millimoles) of 4-amino-6,7-dimethoxy-2- (1-piperazinyl) quinazoline by applying the procedure of Example 1. The product melts at 230-245 ° C with decomposition.

Analysis for CggHg ^ NyO ^ S.HCl calculated C, 48.43; H, 5.25; N, 19.77fi found c, 1 + 8.11; H, 5.35; N, 19.65%

EXAMPLE 5 4-amino-6,7-dimethoxy-2- hydrochloride_j/ ~ 4- (5-n-butylthio-l, 3,

4-oxadiazole-2-carbonyl) pipérasine-l-yl / quinazoline

The desired compound is prepared from 5-n-butylthio-1,3,4-oxadiazole-2-carbonyl chloride and 4-amino-6,7dimethoxy-2- (1-piperazinyl) quinazoline by applying the procedure. from example 1.

EXAMPLE 6 4-Amino-6 hydrochloride_}7 ~ dimethoxy-2- / 4- (isoxazole-5-carbonyl) piperazine-l-yl7Quinazoline

A solution of 1.33 g (0.01 mole) of isoxazole-5-carbonyl chloride in dioxane is added to a solution at 30 ° θ of 2.94 g (0.01 mole) of ^l+ -amino ~ 6,7-dimethoxy ~ 2- (1 »piperazinyl) quinazoline in dioxane. The mixture is stirred at reflux for 3 minutes, then at room temperature for 16 hours. By filtration, 4.02 g (94% yield) of the desired compound are obtained. Through. recrystallization from aqueous methanol, the product melting at 270 ° C. is obtained with decomposition.

Analysis for Ο - ^^ θΝ ^ Ο ^ .ΗΟΙ calculated c, 51.37; h, '5.03; Cl, 8.42; n, 19.97% found C, 50.86; H, 4.65; Cl, 8.52; N, 19.81%

AB.MJ.MDB.8 - 16 - SY-1502 A (corrected for an HgO content of $ 4.30)

EXAMPLE 7 4-amino-6,7-dimethoxy-2- ^ 4- hydrochloride (isoxazole-3-carbony 1) p ip er azine -1-y TJ quinaz oline

A solution of 0.753 g (5.7 millimoles) of isoxazoie-3-carbonyl chloride in 20 ml of dioxane is added to a solution of 1.66 g (5.7 millimoles) of 4-amino-6,7- dimethoxy-2- (1 piperazinyl) quinazoline in 60 ml of dioxane. The mixture is stirred at reflux for 3 minutes, then at room temperature for 6½ hours. By filtration, 1.81 g of the desired compound is obtained (yield of $ 75) which is recrystallized from methanol. The product melts at 268-273 ° C with decomposition.

Analysis for Ο ^ Η ^ Ν ^ Ο ^ .ΚΟΙ calculated C, 51.37; H, 5.03; ci, 8.42; N, $ 19.97 found C, 50.04; ïï, 4.86; Cl, 8.66; N, $ 19.57 (corrected for an H ^ O content of $ 3.11)

EXAMPLE 8 4-AminO hydrochloride 6,7-diniethoxy-2- / 4- (isoxazole-4-carbo nyl) piperazine-1-yl7quinazoline

A solution of 1.06 g (8.08 millimoles) of isoxazole-4-carbonyl chloride in 8 ml of dioxane is added to a solution of 2.34 g (8.08 moles) of 4-amino ~ 6, 7 ~ dimethoxy-2- (l-piperazinyl) quinazoline in 200 ml of dioxane. The mixture is stirred at room temperature for 20 hours. By filtration, the desired compound is obtained which, after recrystallization in methanol, melts at 255-260 ° C with decomposition.

Analysis for ^vs18^H20^NOT6⁰4-^HG1 calculated c, 51.37; H, 5.03; ci, 8.42; N, $ 19.97 found C, 51.37; H, 4.95; Cl, 8.34; N, 19.95? ^ (Corrected for a Hgû content of $ 1.63)

AB.MJ.mDB.8

- 17 SY-1502 A

EXAMPLE 9 Wamino-6,7 hydrochloride ~ dimethoxy-2- / ”^li - (5-methylisoxazole ~

3-carbonyl) piperazine-l ~ yl7quinazoline

A solution of 0.4l g (2.83 millimoles) of chloride 5 ~ ôréthyllsoxazole ~ 3 ~ carbonyl in dioxane is added to a solution of 0.82 g (2.83 millimoles) of U-amino-6,7 ~ 2-dimethoxy (1-piperazinyl) quinasoline in dioxane. The mixture is treated as described in the previous example to obtain the desired compound, melting at 271-273 ° ^ with decomposition.

Analysis for calculated C, 50.38; H, 5.56; N, 18.56; HgO, 3.92% found C, 50.58; H, 5Λθ; N, 18.86; H₂0, 3,72%

EXAMPLE 10 h-amino-6,7-dimethoxy-2 - / ^ - (3 ~ methyli soxazolecarbonyl) hydrochloride piperazine-1-yl / qulnazoline

A solution of 1.01 g (6.9 millimoles) of 3-methylisoxazole chloride is stirred at reflux for 15 hours.¹-i— carbonyl in dioxane and a solution of 2.00 g (6.9 millimoles) of! {~ aniino-6,7-dimethoxy ~ 2- (1-piperazinyl) quinazoline in dioxane, then the mixture is treated as described in Example 6. After recrystallization from methanol, the desired compound melts at 3CO-3O1 ° C with decomposition.

Analysis for C ^ Hg ^ O ^. BCl calculated C, 52, h-7; H, 5.33; N, 19.33% found C, 52.62; H, 5.31; N, 19.12% (corrected for an H ^ O content of 1.13%)

EXAMPLE 11 Hydrochloride of ¹i-amino-6,7-dimethoxy-2-_i/ "The_i- (3 ~ méthylisoxazole5-carbonyl) piperazine-l ~ yl / quinazoline

A solution of 0.73 g (5.02 millimoles) of

AB.MJ.MDB »8 - 18 - SY-1502 A 3-iaethylisc (xazole-5-carbony] e chloride in dioxane to a solution of 1.45 g (5> 02 millimoles) of 4-amino-6 , 7-dimethoxy-2- (1-piperaziny) quinazoline in dioxane The mixture is briefly heated and then stirred at 20 ° C for 2 hours and 30 minutes.

The operations are continued as in Example 6 to obtain the desired compound melting at 263-261 + 00 with decomposition.

Analysis for C ^ HggN ^ O ^ .HCl calculated c, 52.1 + 7; H, 5.33; Cl, 8.15; -N, 19.33 # found C, 51.82; H, 5.04; Cl, 8.36; N, 19, W (corrected for H content₂0 4.82%)

EXAMPLE 12 4-Amino ~ 6 hydrochloride_s7-dimethoxy-2- / f4- (oxazole “4 ~ carbO“ nyl) piperazine-1-yl / quinazoline

A solution of 0.73 g (5.53 millimoles) of oxazole-4-carbonyl chloride in dioxane is added to a solution of 1.60 g (5.53 millimoles) of 4-amino-6,7- dimethoxy-2- (1-piperazinyl) quinazoline in dioxane. The mixture is heated at reflux for 3 minutes, then stirred at 20 ° C for 64 hours. By filtration, the desired compound is obtained, melting at 291-294 ° C with decomposition after recrystallization from aqueous ethanol. Analysis for C₁gH₂o^ÎI6°4'^,^¹‘®2⁰ calculated C, 49.26; H, 5.28; Cl, 8.08; N, 19.15 # found C, 48.92; H, 4.83; Cl, 8.33; N, 18.94%

EXAMPLE 13 4-amino-6,7-dimethoxy-2- ^ ~ 4- (2-methyloxazole-4carbonyl) piperazine-1-yl / quinazoline hydrochloride

A solution of 1.01 g (6.9 millimoles) of 2-methyloxazole-4 ~ carbonyl chloride in dioxane is added to a solution of 2.00 g (6.9 millimoles) of 4-amino-6.7 -dimethoxy-2- (lpiperazinyl) quinazoline in dioxane. The mixture is heated at reflux for 2 hours. By filtration, the compound is obtained - 19 ΛΡ VT Τ'ΤΊΡ

SY-1502 A sought melting at 278-230 ° C with decomposition after recrystallization from methanol.

Analysis for C ^ HggügO ^ .HCl calculated C, 52.47; H, 5.33; N, $ 19.33 found c, 52.08; H, 5Λ3; N, 18.89% (corrected for HgO content)

EXAMPLE 14 4-AminO hydrochloride 6,7-dimethoxy-2- / ~ 4- (4-methyloxazole-5 carbonyl) piperazine-1-yl / quinazoline

The desired compound is prepared by applying the procedure of Example 6 from 0.85 g of 4-methyloxasole-5-carbonyl chloride and 1.68 g of 4-amino-6,7dimethoxy ”2 (1 piperazinyl) quinazoline. The product melts at 283.5 "288 ° C with decomposition.

Analysis for C ^ Hggtl ^ .HCl calculated C, 52.48; H, 5.33; Cl, 8.15; N, $ 19.33 found C, 52.19; H, 4.94; Cl, 8.13; N, $ 19.05 (corrected for H content₂0 $ 1.59)

EXAMPLE 15 4-amino-6,7-dimethoxy-2- / ~ 4- hydrochloride (isothiazole-4-car bonyl) piperazine-1-yl / quinazoline

The desired compound is prepared by applying the procedure described above from 1.01 g of isothiazole-4-carbonyl chloride and 1.99 g of 4 “amlno-6,7-dimethoxy ~ 2 (1-piperazinyl ) quinazoline, The product melts at 286-2S7 ° C with decomposition.

Analysis for C ^ gHgQN ^ O ^ S.HCl calculated C, 49.48; H, 4.84; Cl, 8.11; N, 19.23; S, 7.3¹^ found C, 49.20; H, 4.81; Cl, 8.19; N, 19.27; S, $ 7.23 (corrected for H content₂0 $ 0.93)

AB.MJ.MDB.4

SY-1502 A

EXAMPLE 16 4-Amino-6,7dlmethoxy-2 ~ 24 ~ (t hiazole-2-carbonyl) piperazine-1-yl / quinazoline hydrochloride

The desired compound is prepared by applying the procedure already described from 0.79 g of thiazole2-carbonyl chloride and 1.54 g of 4-amino-6,7-dimethoxy-2- (1-piperazinyl) quinazoline. . The product melts at 273-276 ° C with decomposition.

Analysis for Ο ^ βΗρθΝ ^ Ο ^ δ.ΗΟΙ calculated C, 49.48; H, 4.84; N, 19.23% found C, 48.68; H, 4.62; K, 18.87% (corrected for an E ^ O content of 4.19%) '

EXAMPLE 17. 4-amino-6,7-dimethoxy-2- ^ 4- hydrochloride (4-thiazole carbonyl) piperazine-1-yl / quinazoline

The desired compound is prepared by applying the procedure already described from 1.02 g of thiazole4-carbonyl chloride and 2.00 g of 4-amino-6,7-d.imethoxy-2- (l ~ piperazinyl ) quinazoline. The product melts at 274-277 ° C with decomposition.

Analysis for ^VS18^H2O^NOT6°3^S-^HC1 calculated c, 49.48; H, 4.84; II, 19.23% found C, 49.11; H, 4.69; N, 19.31% (corrected for an IgO content of 4.47%)

EXAMPLE 18 4-AminO hydrochloride 6,7-dimethoxy-2- / 4- (2-methylthiazole4 ~ carbonyl) piperazine-1-yl / quinazoline

The desired compound is prepared by applying the procedure already described from 0.49 g of 2-methylthiazole-4-carbonyl chloride and 0.87 g of 4-amino-6,7-dimethoxy-2 ~ (lpiperazinyl ) quinazoline. The product melts at 260-263 ° C with decomposition.

AB.MJ.MDB. 8 - 21 SY-1502 A

Analysis for C ^ Hp ^ O ^ S.HCl calculated C, 50.60; H, 5.14; N, $ 18.64 found C, 50.88; H, 4.96; K, $ 18.67 (corrected for an H ^ O content of $ 2.88)

EXAMPLE 19 4-amino-6,7-dimethoxy hydrochloride ~ 2-_&lt;/^-4- (thiazol-5 "darbonyl) piperazine-l-yl / quinazoline

The desired compound is prepared by applying the procedure already described from 0.77 g of thiazole5-carbonyl chloride and 1.51 g of 4-amino-6,7-dimethoxy-2 ~ (l-piperazinyl) quinazoline . The product melts at 280-281 ° C with decomposition.

Analysis for ^vs18^H20^NOT6°3^S-^HC1 calculated C, 49.48; H, 4.84; Cl, 8.11; N, 19.23; S, $ 7.34 found C, 49.22; H, 5.19; Cl, 8.31; N, 19.49; S, 6.79 # (corrected for an HgO content of $ 2.63)

EXAMPLE 20 4-amino-6,7-dimethoxy-2- / 4- (2-methylthiazole-5carbonyl) piperazine-1-yl7quinazoline hydrochloride

The desired compound is prepared by applying the procedure already described from 0.42 g of 2-methylthiazole-5-carbonyl chloride and 0.75 g of 4 ~ amino ~ 6.7 ~ dimethoxy-2- (l -pi ~ perazinyl) quinazoline. The product melts at 294-297 ° C with decomposition.

Analysis for C ^ HggH ^ O ^ S.HCl calculated C, 50.60; H, 5.14; N, $ 18.64 found C, 50.60; H, 4.95; N, 18.5-0 $ (corrected for H content₂0 $ 1.96)

EXAMPLE 21 4-amino-6,7-dimethoxy-2- hydrochloride₂/ ~ 4- (4-methylthiazole5-c arbony1) pip erazine-1-y1 / quinaz oline

AB.MJ. MDB.8 - 22 -

SY-I502 A

The desired compound is prepared by applying the procedure already described, starting with 1.1 g of 4-methylthiazole-5-carbonyl chloride and 2.0 g of * t-oino-6,7-âiniethoxy-2- ( l-piperazinyl) quinazoline. The product melts at 293-29 ^ ° C with decomposition.

Analysis for C- ^ Hg ^ O ^ S.HCl calculated C, 50.60; H, 18.6 * $ 1 found C, 5θΛ7?^H? ^1d-?7^S5 (corrected for an HgO content of * i-, $ 72)

To determine the effectiveness of the compounds of the invention as antihypertensive agents, tests are carried out by comparing these compounds with prazosin.

Table I below establishes the comparison between the product of Example 1 and prazosin. As can be seen from Table I, the product obtained in Example 1, which is hereinafter called compound BL-511l, has an antihypertensive power comparable to that of prazosin, but exerts little or no a-adrenergic blocking peripheral of prazosin. The development of this compound therefore constitutes progress in the constant search for potent antihypertensive drugs having little or no side effect demonstrated by the absence of a-adrenergic blocking activity.

The antihypertensive activity listed in Table I is determined by oral administration to spontaneously hypertensive rats and the blocking effect of α-adrenergic receptors in vitro and in vivo is evaluated during the tests described after Table I. In the in vitro test, the inhibition exerted by the compound BL-5111 on the contractions induced by norepinephrine on the rat seminal vesicles is measured, however, in the in vivo test, the inhibition is measured. exerted by the compound BL-5111 on the variation of arterial pressure induced by norepinephrine on anesthetized dogs. The in vivo tests are carried out by intravenous administration of each of the compounds to h-dogs with 2 doses for each dog.

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SY-1502 A

Seminal vesicle test isolated from rats

It has been shown by Dangan et al, Int.J. Neuropharmacol._}J +: 219 (1965) read the seminal vesicle of the rat is a tissue which responds well to the compounds activating the receptors but which is relatively insensitive to the compounds activating the receptors ß.

The isolated rat seminal vesicle was used by Lietch et al, Brit.J. Pharmacol .. £: 236 (195 * 0 in a comparative study of a receptor blocking drugs and the Applicant's research was carried out according to a variant of this procedure.

They are sacrificed by knocking out male rats of the Long Evans strain weighing approximately 3θΟ g. The seminal vesicles are removed and placed in a shallow box containing modified Tyrode solution. The vesicles are emptied of their contents by gently pressing them using forceps. A silk thread (^ -0) is attached to the two ends of the vesicle which is then suspended in a 20mL muscle test chamber containing modified oxygenated solution of Tyrode (that is to say comprising per liter 8 g NaCl, 0.2 g KC1, 0.26 g CaCl₂, 1 g NaHCO ^, 0.0575 g ïïa ^ HPO ^, 0.5 g glucose and 0.02 g MgCl₂). The liquid is maintained at 37 ° C. by means of a thermostatic bath for isolated organs. The contractions are measured by isometry using a force displacement transducer and the recordings are made using the Beckman BP Dynograph device. Norepinephrine is introduced into the chamber in volumes ranging from 0.1 to 0, U ml using a 1 ml syringe carrying a needle No. 20 of

- 25 7) 6 cm in length. The norepinephrine and the test compounds are dissolved in deionized water.

The response curves are noted for norepinephrine alone as well as in the presence of the compounds tested. The norepinephrine is left in contact with the vesicle until maximum contraction. It is then washed with the infusion liquid for

AB.MJ. MDB.8 - 25 - SY-1502 At 30 seconds, then it is allowed to return to its baseline before being subjected again to the effect of a dose of norepinephrine. Cn injects increasing amounts of norepinephrine into the bath in the same manner until a complete response curve is obtained.

The seminal vesicles used to obtain the control response to the doses of norepinephrine are discarded and new preparations are introduced into the bath for the evaluation of the test compound. The test compound is added directly to the infusion liquid (at the rate of 10 nanograms / ml) and the vesicles are left in contact with the medium for at least 10 minutes before determining the response to the dose of norepinephrine.

DE ^ q for norepinephrine are determined by regression analysis as described by Finney in Probit, Analysis, 2nd ed., Cambridge (196 * 1-). We take a minimum of 4 vesicles and at least * 4 · doses to calculate the regression curves. We define the DE ^_Q as the concentration of norepinephrine which provides a contraction equal to $ 50 of the maximum contraction.

The ratio of the “-adrenergic blocking activity of compound BL-5111 to that of prazosin is calculated by applying the following relationship;

DDepending_not (NE + Med) - DE, - ,, (NE only) yar. $ = —22 ------ 22 ~ —--_{x 100}

OF ^₀ (NE alone) where Var. $ is the variation in $ with respect to norepinephrine NE = norepinephrine - Med = drug;

and then making the ratio of the value obtained for compound BL-5111 to that obtained for prazosin:

Activity report - ..? $ £ “..„ ffù- ^ ill

Activity Report - _{Var for NE} _ p_ra20sin

AB.MjT. MDB. 8

- 26 SY-1502 A

Table II collates the results obtained for norepinephrine, prazosin and the compound BL-5111.

TABLE II

Effect of prazosin and BL-5H1 on the response to norepinephrine in seminal vesicles isolated from rats

<td>Treatment</td><td>Number of vesicles</td><td>OF_?0 (RE) (/ Ug / ml)</td><td>Variation $ compared to witness</td><td>Activity report Ψ4 ·</td>

<td>Witness</td><td> 32</td><td> 0,89 (0,8^-0,9^-)</td><td> -</td><td> -</td>

<td>prazosin</td><td></td><td></td><td></td><td></td>

<td>10 nanog / ml</td><td> 8</td><td> 6,03 (5,30-6,81)</td><td> 578</td><td> 1,0</td>

<td>BL-5111</td><td> 7</td><td> 0,93 (0,80-1,08)</td><td></td><td> 0,008</td>

<td>10 nanog / ml</td><td></td><td></td><td></td><td></td>

<td>+ DE ^ q for</td><td colspan="2">norepinephrine with</td><td>limits of</td><td>95 ^ reliability</td>

<td colspan="3">++ compared to prazosin.</td><td></td><td></td>

These results clearly show that at a concentration of 10 nanograms / ml, prazosin decreases by almost six times the sensitivity of the isolated seminal vesicles of rats to the stimulating activity of norepinephrine, while the compound BL-5111 is essentially inactive. in this respect. It can be concluded that compound BL-5111 exerts less than 1 ^ of the a-adrenergic blocking activity of prazosin.

“Adrenergic blocking agents test on anesthetized dogs

It has been shown by Nash CB, Pharmacological Research Communications, ί ±: Μ-23, (1969) and Maxwell RA, Drill's Pharmacology in Medicine, (1971) page 683. that a-adrenergic blocking agents are opposed in dogs anesthetized by the elevated blood pressure caused by intravenous norepinephrine. Thus, as a criterion for the blocking effect of the α-adrenergic receptors of drugs, a variation in blood pressure after injection of norepinephrine into anesthetized dogs.

The experiments are carried out on anesthetized mongrel dogs using 30 mg / kg of sodium pentobarbital administered intravenously. A cannula is introduced into the artery

AB.MJ.MDB.8 - 27 SY-1502 A left femoral for measuring aortic arterial pressure as well as in a femoral vein for the administration of drugs. All animals undergo bilateral vagotomy. A response curve as a function of the dose of norepinephrine is obtained by intravenously administering increasing doses of norepinephrine, namely doses of 0.01 to 1 µg / kg. The drug tested, namely prazosin or the compound BL-5111, is then administered intravenously at a rate of 3 mg / kg. After approximately 30 minutes, a response curve is again established as a function of the dose of norepinephrine administered by intravenously at 0.01 to 10 yug / kg. The dose of nor epinephrine (with reliability of $ 95) which increases blood pressure by 50 mm Hg is determined based on an analysis of the dose response curve before and after administration of prazosin or of compound BL-5111 · The ratio of α-adrenergic blocking activity of compound BL-5111 is determined on the basis of prazosin by the following relation:

OF_?0 (BL-5111) - (NE)

Activity report ----- DIS ^₀ (Prazosin) - ϋΞ ^ θ (NE) where ~ DEj₀

Table III summarizes the results obtained with norepinephrine, prazosin and the compound BL-5111. The results show that compound BL-5111 has an a-adrenergic blocking activity, at a dose of 3 mg / kg intravenously, which is approximately 30 times lower than that of prazosin.

AB-MTMPB. 8

SY-1502 A

TABLE III

Effect of prazosin and compound BL-5111 on the increase in blood pressure during the intravenous injection of norepinephrine

<td>Treatment</td><td>W</td><td>^OF5o</td><td>(Wk) 4 *</td><td>Activity report + *</td>

<td>Witness</td><td> 20</td><td> 0,23</td><td> (0,19-0,28)</td><td> -</td>

<td>prazosin,</td><td> 1+</td><td> 6,90</td><td> (^,80-10,7)</td><td> 1,00</td>

<td>3 mg / kg</td><td></td><td></td><td></td><td></td>

<td>BL-5111</td><td>h-</td><td>0Λ7</td><td> (0,^0-0,55)</td><td> 0,036</td>

<td>⁺ mm H</td><td colspan="3">for norepinephrine</td><td>with reliability limits</td>

++ compared to prazosin.

Table IV below collates the results of comparison tests carried out with the products of Examples 6 to 21 and prazosin. As this table shows, the products obtained in examples 6 to 21 above have an antihypertensive activity comparable to that of prazosin, but generally less alpha-adrenergic blocking than prazosin.

These compounds therefore constitute significant and unexpected progress in the development of powerful antihypertensive drugs.

TABLE IV

Antihypertensive activity '

Dose mg / kg

Voltage variation ar Blocking of g-adrenergic receptors

Activity report - In vitro activity report in vivo activity

Prazosin 10 reference 3

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SY-1502 A

TABLE IV (continued)

Antihypertensive activity

<td></td><td>Do mg / kg</td><td>Variation in blood pressure. %</td>

<td> 4</td><td> 10</td><td> -41</td>

<td></td><td> 3</td><td> -18</td>

<td></td><td> 1</td><td> -14</td>

<td> 5</td><td> 10</td><td> -33</td>

<td></td><td> 3</td><td> -29</td>

<td></td><td> 1</td><td> -17</td>

<td> 6</td><td> 10</td><td> “37</td>

<td></td><td> 3</td><td> -21</td>

<td></td><td> 1</td><td> -18</td>

<td> 7</td><td> 10</td><td> -45</td>

<td></td><td> 3</td><td> «29</td>

<td></td><td> •1</td><td> -15</td>

<td> 8</td><td> 10</td><td> -35</td>

<td></td><td> 3</td><td> “31</td>

<td></td><td> 1</td><td> “13</td>

<td> 9</td><td> 10</td><td> -41</td>

<td></td><td> 3</td><td> -26</td>

<td></td><td> 1</td><td> -14</td>

<td> 10</td><td> 10</td><td> -25</td>

<td></td><td> 3</td><td> -23</td>

<td></td><td> 1</td><td> -14</td>

<td> 11</td><td> 10</td><td> -33</td>

<td></td><td> 3</td><td> “27</td>

<td></td><td> 1</td><td> -14</td>

<td> 12</td><td> 10</td><td> -32</td>

<td></td><td> 3</td><td> -24</td>

<td></td><td> 1</td><td> -20</td>

<td> 13</td><td> 10</td><td> -28</td>

<td></td><td> 3</td><td> -28</td>

<td></td><td> 1</td><td> “19</td>

<td> 14</td><td> 10</td><td> -33</td>

<td></td><td> 3</td><td> -22</td>

<td></td><td> 1</td><td> -12</td>

<td> 15</td><td> 10</td><td> “37</td>

<td></td><td> 3</td><td> -25</td>

<td></td><td> 1</td><td> -20</td>

<td> 16</td><td> 10</td><td> -28</td>

<td></td><td> 3</td><td> -22</td>

<td></td><td> 1</td><td> - 4</td>

Blocking of “adrenergic” receptors

Activity report - In vitro activity report in vivo activity

0,24

0,30 0,18

0,25

0,6 1,22

0,17

0,19

0,12

0.02. ί

0,10 ·/

0,19 0,09

0,35