CH622770A5 - Process for the preparation of heterocyclic aminoalcohol derivatives - Google Patents

Description

The present invention relates to processes for the preparation of heterocyclic amino alcohol derivatives comprising substituted amino alcohols, esters of these amino alcohols and salts thereof.

The compounds according to the methods of the invention correspond to the following general formula:

R.

R

5

X

(CH)

.2 11

30

—CHOH — CH — Z or

I

R2

/ ° \

-CH — CH — R2

in which:

a) R 1 represents hydrogen, one or two linear or branched alkyl radicals (C1-C3), a phenyl radical or a carboxyl radical;

B) R2 represents a linear or branched (C1-C3) alkyl radical; c) R3 represents:

- a mono or polyunsaturated alkenyl radical (C3-C18);

- a mono or polyunsaturated alkenyl radical (C3-Ci2) substituted by oxygen, sulfur or a phenyl radical;

- a mono or polyunsaturated (C3-C18) alkynyl radical;

- a mono or polyunsaturated (C3-C12) alkynyl radical substituted by oxygen, sulfur or a phenyl radical;

- a cycloalkyl radical (C3-C10);

55 - a linear or branched (C2-C2o) alkyl radidcal;

A linear or branched (C2-C18) alkyl radical substituted by at least one atom and / or radical chosen from the group formed by:

1) oxygen or sulfur;

2) alkoxycarbonyl (C1-C3), Pyrrolidine, pyr-60 rolidinone or imidazolidone radicals;

3) phenyl, phenoxy, phenylthio, benzoyl, indanyloxy, naphthyloxy radicals;

4) phenyl, phenoxy, phenylthio, benzoyl radicals substituted by one or two alkyl radicals (C1-C4) or alkoxy

"S (C1-C4), by one or two halogen atoms, by a nitrile, hydroxy, amino, alkanoyl (C2-C6), acylamino (C2-C4), alkoxycarbonyl (C1-C4) or alkylsulfonamido (C1) radical -C4);

3

622,770

d) R4 represents a hydrogen atom or forms with R3 and the neighboring nitrogen atom a morpholine radical, Pyrrolidine,

piperidine, piperidine substituted by one or two alkyl radicals (C1-C4), phenyl or phenylalkyl (C1-C4), or a piperazine radical substituted in position 4 by a phenyl radical or by a phenyl radical substituted 1) by a or two alkyl radicals (C1-C4)

or alkoxy (C1-C4), 2) by one or two halogen atoms or 3) by a trifluoromethyl radical;

e) R5 represents a hydrogen atom or an alkyl radical (C1-C3); 10

f) R6 represents hydrogen or a linear or branched (Ci-Ci ") alkanoyl radical or a cycloalkanoyl radical (C3-C8);

g) n has the value of 1,2 or 3;

h) X represents sulfur, oxygen, a CH2 radical or an NH radical; 15

i) Y represents a CH2 radical or sulfur;

j) when simultaneously X is oxygen, Y a CH2 group, has the value of 2, Rt and Rs of hydrogen, R2 a methyl radical, and R6 is hydrogen or an alkanoyl radical, R4 does not form not with R3 and the neighboring nitrogen atom a substituted piperazine radical. 20

The present invention advantageously covers processes for preparing the derivatives corresponding to formula I in which:

a) Ri represents hydrogen or one or two alkyl radicals (Ci-C3);

b) R2 represents an alkyl radical (C1-C3); 25

c) R3 represents:

- a mono or polyunsaturated alkenyl radical (C3-Ci8);

- a mono or polyunsaturated (C3-C18) alkynyl radical;

- a cycloalkyl radical (C3-C8);

- an alkyl radical (C2-Ci8); 30

- an alkyl radical (C2-Ci6) substituted 1) by a phenylthio radical, by an alkoxy radical (Ci-C6) by an alkylthio radical (Ci-C6), by a phenoxy radical, by a benzoyl radical, by one or two phenyl radicals, 2) with a phenyl, benzoyl, phenylthio or phenoxy radical each substituted by an alkyl (Cj-C3) or halogen, 3) by a phenoxy radical substituted by a nitrile or an alkanoyl (C2-C3) ;

d) R4 represents a hydrogen atom or forms with R3 and the neighboring nitrogen atom 1) a piperazine radical substituted by a phenyl radical itself substituted by an alkyl radical (Ci-C3), 40 2) a radical piperidine substituted by an alkyl radical (Ci-C3), itself substituted by a phenyl radical;

e) R5 represents hydrogen or an alkyl radical (Ci-C3); i) Rö represents hydrogen, a linear or branched alkanoyl radical (Ci-C8) or a cycloalkanoyl radical (C3-C6); 45

g) n has the value of 1,2 or 3;

h) X represents sulfur, oxygen, a CH2 radical or an NH radical;

i) Y represents a CH2 radical or sulfur.

A preferred class of compounds according to formula I is that in which Rt represents hydrogen or a methyl radical; R2 represents a methyl or ethyl radical; R3 represents an alkyl radical (C2-Ci8), an alkyl radical (C2-Cio) substituted 1) by a phenyl, phenylthio, phenoxy or benzoyl radical, or 2) by a phenyl, phenylthio, phenoxy or benzoyl radical each substituted 55 by one or two alkyl radicals (C1-C3) or with halogen; R4 and Rs represent hydrogen, n has a value of 1,2 or 3;

X is a sulfur atom and Y is a CH2 radical. The compounds excluded by the definition under j) above are already known.

Examples of derivatives according to the invention are: 60

l- (6-thiochromannyl) -2-n.-octylamino-l-propanol, l- (6-thiochromannyl) -2- (4-phenylbutylamino) -l-propanol, l- (6-thiochromannyl) -2- [ 2- (phenoxy) ethylamino] -1-propanol, 1- (2,3-dihydro-5-benzo- [b] -thienyl) -2-n.-octylamino-1-propanol, l- (2,3- dihydro-5-benzo- [b] -thienyl) -2- (4-phenylbutylamino) -l- 65 propanol,

1- (2,3-dihydro-5-benzo- [b] -thienyl) -2- [4- (p.-chlorophenyl) -buty lamino] -1-propanol,

l- (2-methyl-2,3-dihydro-5-benzo- [b] -thienyl) -2- (4-phenyl-

buty lamino) -1-propanol, l- (2-methyl-2,3-dihydro-5-benzo- [b] -furannyl) -2-n.-octylamino-1-propanol,

l- (2,3,4,5-tetrahydrobenzo- [b] -thiepin-7-yl) -2- (4-phenylbutyl-

amino) -1 -propanol,, l- (2,3-dihydro-5-indolyl) -2-n.-octylamino-l-propanol, l- (2,3-dihydro-5-benzo- [b] - thienyl) -2- (4-phenylbutylamino) -l-

propionyloxypropane, 1- (2,3-dihydro-5-benzo- [b] -thienyl) -2- (4-phenylbutylamino) -l-

cyclohexanoyloxypropane, 1 - (5-indanyl) -2- (4-phenylbutylamino) -1 -propanol,

1 - (5-indanyl) -2- [2- (4-chlorophenoxy) ethy lamino] -1 -propanol, l- (5-indanyl) -2- [2- (4-fluorobenzoyl) propylamino] -l-propanol .

The derivatives according to formula I which may be in the form of salts are in particular salts of inorganic acids,

such as hydrochlorides, hydrobromides, phosphates, sulfates, or organic acids, such as oxalates, lactates, tartrates, acetates, citrates, maleates, gluconates, glucuronates.

Since the most active products of the invention have two centers of asymmetry, two racemates can be obtained corresponding respectively to the erythro and threo configurations; these two racemates can be resolved by conventional methods, for example by the formation of diastereomeric salts by the action of optically active acids such as tartaric, diacetyltartaric, tartranic, dibenzoyltartaric, ditoluoyltartaric acids and separation of the mixture of diastereoisomers by crystallization, distillation, chromatography then release of the optically active bases from these salts.

The same methods can be used if the compounds of the invention contain more than two centers of asymmetry.

The most active derivatives of the invention can therefore be used either in the form of racemates of erythro or threo configuration, or in the form of a mixture of these two forms, or also in the form of optically active compounds of each of these two forms .

In general, the amino alcohol derivatives according to the invention are endowed with activities on the cardiovascular system, for example antihypertensive and / or antispasmodic, peripheral vasodilator, protective against myocardial anoxia, lipid-lowering, antithrombotic, ß-lytic, inhibitor of platelet aggregation, and / or activities on the central nervous system, for example a tranquilization.

These properties make it possible to envisage the use of the products of the invention in the treatment of hypertension and of cardiovascular conditions, such as atherosclerosis.

More particularly, it has been discovered that the derivatives according to the invention are endowed, among other properties, with significant antihypertensive, lipid-lowering and antithrombotic activities.

The active compounds of the invention can be administered in combination with various pharmaceutical excipients and this orally or parenterally.

For oral administration, dragees, granules, tablets, capsules, solutions, syrups, emulsions or suspensions containing conventional additives or excipients in galenic pharmacy will be used. For parenteral administration, sterile water or an oil such as peanut oil or ethyl oleate will be used.

These active compounds can be used alone or in combination with other active products having a similar or different activity.

The new compounds according to formula I are prepared according to the methods of the invention as follows:

1. The process for preparing the compounds of formula I, in which R6 represents hydrogen, is characterized in that a compound corresponding to formula I is reacted

622,770

4

(ch

\ ^ q in which Q represents a group —CHOH— CH — Zou

I

r2

/ ° \

—CH — CH — R2 with an amine of the R3R4NH type, Z being a halogen Rx to R5, X, Y and n having the values given above.

2. The process for preparing the compounds of formula I, in which Rs represents a linear or branched C1-C10 alkanoyl radical or a C3-C8 cycloalkanoyl radical, is characterized in that a compound of formula I or a salt thereof is prepared by the process according to claim 1 and then reacted with an excess or an equimolecular amount of a corresponding acid or anhydride.

According to the process according to the invention, a compound of general formula I is reacted, in which Q represents a —CHOH — CH — Z group with an amine of the R3R4NH type, formulas

I

r2

in which R2 to R4 and Z have the meaning given above.

This reaction is carried out in a solvent, such as alcohols, chloroform, dioxane, carbon tetrachloride, and most easily in the presence of a product fixing the halogenated hydracid formed, such as inorganic or tertiary organic bases, or still in the presence of 'an excess of amine. It is well known that in these cases the group

—CHOH — CH — Z first gives a typed oxirane

I

r2

o

/ \

- CH — CH — R2, which reacts with the amine compound.

The present process therefore also includes the preparation of amino alcohols from oxiranes; this process can be advantageously used for the preparation of amino alcohol derivatives of threo configuration.

The salts of the amino alcohols according to formula (I) can be formed, according to the invention, as indicated previously by the general method described above.

This process includes various variants. In general, these salts can be formed by methods well known to the above general process, such as for example the reaction in equimolecular amount of the amino alcohol with an acid in an adequate solvent, such as an alcohol for example, then precipitation of the salt. by adding another solvent miscible with the first solvent and in which the salt is insoluble, ether, for example; or again by neutralizing an ethereal solution of the acid or the base with the base or the acid. The acids used are either organic acids or inorganic acids. As inorganic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc. are preferably used.

Organic acids are either carboxylic acids or sulfonic acids, such as formic, acetic, propionic, glycolic, lactic, citric, ascorbic, fumaric, maleic, pamoic, succinic, tartaric, phenylacetic, benzoic, p- acids. aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic, methanesulfonic, ethanedisulfonic, glucuronic, etc.

The esters of amino alcohols according to general formula I, in which R 6 is an alkanoyl or cycloalkanoyl radical are prepared by reacting an amino alcohol or a salt thereof with an excess of adequate acid chloride or anhydride and preferably with a temperature between 50 ° C and the reflux temperature of the acid chloride or anhydride.

5 Below are given detailed examples of the preparation of some amino alcohol derivatives according to the invention. These examples are mainly intended to further illustrate the particular characteristics of the process according to the invention.

Example 1:

10

l- (2,3-dihydro-5-benzo- \ J>] - thienyl) -2- (4-phenylbutylamino) -l-propanot (threo form)

4 g of l - (2,3-dihydro-5-benzo- [b] -thienyl) -2-bromo-l-propanol, 100 ml of ethanol and 20 g of 4-phenylbutylamine are brought to reflux

15 during 5 h. The solvent and the excess amine are evaporated under vacuum and the residue obtained is treated with ether. The solid is recrystallized from a mixture of methanol and ether and the corresponding free base is obtained by treatment with a dilute solution of sodium hydroxide and recrystallized from acetone. 1.05 g of final product is thus obtained.

20 M.P. (° C): 85-87.

Centesimal analysis:

Calculated: C 73.80 H 7.95 N 4.10%

Found: C 73.40 H 7.90 N 4.20%.

25

Example 2

15 g of 1- (2,3-dihydro-5-benzo- [b] -thienyl) -2- (4-phenyl-butylamino) -l -propanol are dissolved in 750 ml of toluene and 150 ml of chloroform and bubbled a stream of HCl gas 30 sec for 2 h. The mixture is then stirred for a further 2 hours at room temperature, the precipitate obtained is filtered, it is washed with ice-cold pentane and dried.

15 g of hydrochloride are thus obtained. M.P. (° C): 208-209.

35

Centesimal analysis:

Calculated: C 66.72 H 7.40 N 3.70% Found: C 66.70 H 7.50 N 3.65%.

Example 3

40 16 g of I- (6-thiochromannyl) -2-n.-octylamino-1-propanol are dissolved in 600 ml of toluene and a stream of anhydrous HCl is passed through during VA h. The precipitate obtained is filtered, washed with ice cold pentane and dried. 17 g of hydrochloride are obtained. M.p. (° C): 227.

Centesimal analysis:

Calculated: C 64.60 H 9.15 Found: C 64.60 H 9.15

N 3.77% N 3.65%.

50 Example 4

2 g of 1- (6-thiochromannyl) -2- (4-phenylbutylamino) -l-propanol are dissolved in 100 ml of anhydrous ether. A stream of dry HCl gas is passed for 15 min, the precipitate obtained 55 is filtered and dried. 2.1 g of hydrochloride are thus obtained. M.p. (° C): 204-205.

Example 5:

28.0 g (0.144 M) of D-glucuronic acid are dissolved in 340 ml 60 of water heated to 50 ° C. and 34.1 g (0.1 M) of l- (2, 3-dihydro-5-benzo- [b] -thienyl) -2- (4-phenylbutyl-amino) - 1-propanol with vigorous stirring. Stirring is continued until complete dissolution which requires approximately 20 minutes. A clear solution is thus obtained, dilutable at will with distilled water 65.

The melting points of the compounds given in the examples as well as of other compounds prepared according to the invention are listed in Table 1 appended.

5

622,770

Pharmacological results of a large number of compounds according to the invention are given in Tables 2 and 3 also annexed. The results given in Table 2 should be interpreted as set out below:

1) Acute toxicity is determined in fasting male mice. 5 The test substances are administered orally and the LD 50 (lethal dose for 50% of the animals) are calculated according to the method of Litchfield and Wilcoxon ("J. Pharmacol. Exp. Ther.", 96, 99-113.1949) . These LD50s are expressed in mg / kg and given, where possible, with their confidence limits for p = 95%. io

2) The antihypertensive activity is measured in the spontaneously hypertensive non-anesthetized rat. The test substances are administered orally at a dose of 60 mg / kg. The systolic blood pressure is measured every 30 min for 2 h before and 3 h after taking the test product. The results are expressed as follows:

0: no reduction in blood pressure;

4-: reduction less than 10 mm Hg;

+ +: reduction from 10 to 20 mm Hg;

+ + +: reduction greater than 20 mm Hg. 20

3) The vasodilator activity is measured at the level of the femoral artery in the anesthetized dog (technique of the perfused paw). The test substances are administered intraarterially at a dose of 30 mg / kg. The results are expressed relative to papaverine, 2J tested at the same dose:

0: no action;

+: slight activity;

+ +: effect equal to half that of papaverine;

+ + +: effect equal to that of papaverine; 30

+ + + +: effect superior to that of papaverine.

4) The antispasmodic activity is measured in vitro, on guinea pig ileum whose contractions are caused by histamine (Hist.), Acetylcholine (Achol.) Or barium chloride (BaCl2). The tested products are added to the infusion bath 15 min 35 before the spasmogens.

The dose is given in micrograms (| ig) per ml of bath causing total inhibition of the spasm.

The results given in Table 3 should be interpreted on the basis of the following information:

1) The method of Campbell and Richter ("Acta Pharmacol. Toxicol.", 25, 345, 1967) is used. The test substances are administered intraperitoneally to 25 g male mice, 30 min before the observation. The purpose of this test is to determine the LD5 0 intraperitoneally, to define the modifications in the behavior of the animals and to determine the minimum active dose by this route (DMA). The DLS0 and DMA are expressed in mg / kg. The main signs observed in this case indicate a central nervous system depression qualitatively comparable to the effect of tranquilizers. In Tables 2 and 3 the numbers given in column 1 correspond to the numbers in column 1 of Table 1. The same numbers relate to the same compounds.

The products of the invention can be used in various forms.

The galenical formulations such as solutions for i.m. injections, solutions for oral administration, capsules, suppositories, tablets, can be formulated containing as active product, hereinafter designated by the reference A, one of the following compounds:

1- (2,3-dihydro-5-benzo- [b] -thienyl) -2- (4-phenylbutylamino) -1-propanol;

1- (6-thiochromannyl) -2- (4-phenylbutylamino) -1-propanol; l- (2,3,4,5-tetrahydrobenzo- [b] -thiepin-7-yl) -2- (4-phenylbutyl-

amino) -1 -propanol; 1- (2,3-dihydro-5-benzo- [b] -thienyl) -2- (4-phenylbutylamino) -1-cyclohexanoyloxypropane.

Among the products of the invention, the compounds endowed with antihypertensive activity can be used in humans, orally, at daily doses of 50 to 3000 mgr.

In various animal species studied, the side effects observed for these compounds are characterized by sedation. This is obtained at doses far greater than the therapeutic doses; the ratio between active and sedative dose is clearly in favor of the products of the present invention compared to those observed for reference products such as a-methydopa and propanolol.

Table 1

N ° X Y n R,

R, -N

/ v

1 s ch2 2 h

2 S CH, 2 H

CH3 -NHnC 0H _ o 17

CH3 _OTI_ (CH2) 4 ~ VJ ^

3 s ch2 1 h ch3 —nhnc0h _

8 I /

4 s ch2 2 2ch3 ch3 —nf-inc h

8 X7

5 S CH2 2 2CH3 CH3 -NH- (CH_)

6 S

7 S

9 S

10 s

CH2 1 CH2 1

CH2 2 CH2 2

H H

8 S CH, 2 H

ch3 -nh- (ch2) 2-

ch3 -NH- (CH2) 4 - / _ ^

CH3 -NH- (CH „) _ 2 o

2CH3 CH3 ~ NH- (CH2) 2 - <^)

2CH, CH3 -N

11S

12 S

CH2 3 CH2 3

H H

13 S CH, 2 H

14 S CH, 3 H

ch3 —nhncqh o 1 /

ch3 -nh- (ch2) 4 - <^>

ch3 -nh- (ch2) 2 - <^> ch3 -nï-î- (ch2) 2 ~ Vy>

r5 r6

m.p. (° c) (1) (4)

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

115-116 (acetone)

131-133 (acetone)

118-120 (acetone)

116-117 (CH3OH)

118-119 (CH3OH)

134-137 (acetone)

113-115 (acetone)

119-120 (CH3OH)

125-126 (CH3OH)

149-151 (acetone)

221-223 (CH30H-Et20) 87-89 (acetone)

118-120 (acetone)

115-117 (acetone)

.r3

n °

X

Y

not

Rx

R2

15

S

ch2

2

h ch3

16

s ch2

2

h ch3

17

s ch2

2

h ch3

18

s ch2

1

2ch3

ch3

19

s ch2

1

2ch3

ch3

20

s ch2

2

h ch3

21

s ch2

2

h ch3

22

s ch2

2

h ch3

23

s ch2

2

h ch3

24

s ch2

2

h ch3

25

s ch2

2

h ch3

26

s ch2

2

h ch3

<

R *

/ - \

-U- <r

.W

ci-i ch3 -nh- (ch2) 2 "ch t

2 3: 8hi7

/ \

'2> 4-0

r5 r6

M.p. (° C) (1) (4)

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

165-166 (acetone)

119-120 (acetone)

110-111 (MeOH) 70-72 (MeOH)

89-90 (MeOH)

117-118 (acetone)

119-121 (CH3OH)

131-133 (acetone)

106-107 (acetone) 141-144 (AcOEt)

141-142 (CHCI3) 126-127 (acetone)

R,

N ° X Y n R, R2 -N

/ \

R *

27 S CH2 2 H

28 S CH2 1 H

29 S CH, 1 H

ch3 -NHcycloC0H_ „

8 b

CH3 -NHcycloC gH. ' ^ CH3 -NH- (CIi2) 4 ^^ - 01

30 S CH, 3 H

ch3 _nh- (cn2; 4 - // _ \ v cm3

31 S CH, 1 H

ch3 -nh- (ch2) 4s - //

32 S CH2 1 H

CH3 -NH- (CH2) 4- ^ 7-ÇH3

33 S CH2 1 H CH3 -NH ^ SOC ^ H

3 7

34 S CH2 2 H CH3 -nh- (ch-)

2 '4 \ -

ch.

35 O CH, 1 H CH3 -NH- (ÇH „)

2 '4

7 \\

36 S CH, 3 H

CH3 -NH- (CH2) 2 ° \ _ \

37 S CH, 2 H

CH3 -NH- (CH2) 3S -o

38 S CH2 3 H

CH3 -NHisoC3H7

39 S CH, 3 H

CH3 -NH - (CH2) 3S-

// \NOT

88-89 (C6H6-petroleum ether 97-99 (acetone)

120-122 (acetone) 90-92 (acetone)

146-148 (MeOH-CHCl3)

128-130 (MeOH)

127-129 (acetone)

126-127 (MeOH —CHÇ13)

131-133 (acetone)

90-92 (MeOH)

95-96 (acetone)

107-109 (acetone)

102-104 (acetone)

/ Ra

N ° X Y n Ri R2 -W

\

r.

• 4

40 S CH2 2 H CH3 -nii- (CH2) 20 - ^ \ ycl

41 S CH, 2 H

CH3 -NH- ^ TT ^)

42 S CH2 2 H CH.

ch

3 -nhçk- (ch) - / ^)

PH \ = _ /

3

43 S CH2 2 3CH3 CH3 -NHnC H

8 T /

<jh3

44 S CH2 2 H CH3 -NH-Ç-ChCH

f ch3

45 S CH2 2 3CH3 CH3 -NH (CH2) 4

46 S CH2 2 H CH3 -NH- (CH2) 2OCH2- {3

47 S CH2 1 H CH3 -NR- (CH2) 2 ° - ^ 3

48 S CH2 2 3CH3 CH3 -nh- (ch) \

49 S CH2 2 3CH3 CH3 -nh- (ch2) 20 "" V

50 S CH2 2 H CH3 -nh (ch2) 30 (ch2) "3ch

123-124 (acetone) 97-98 (hexane-Et20) 94-95 (Et20)

70-72 (acetone)

226-227 (Et20 — MeOH)

108-110 (acetone) 96-98 (acetone)

131-132 (acetone)

100-102 (acetone)

85-87 (acetone) 89.0 (hexane)

Rs

N ° X Y n Ri R2 -N;

\

R4

51 s ch2 2 h ch3 -NHcycloC_H_

J D

52 S ch2 2 h ch3 -NHadama ntyl- (t)

53 S CH2 2 H CH3 -Mi- (CH2) 20 - {^^) - 0CH3

54 S CH2 2 H CH3 -NH-fCH2) 20 - <^^) - CH3

55 O CH2 1 2CH3 CH3 -NHnC_H

o T 7

56 S CH2 2 H CH3 -NH- (CH-) -l / |

57 S CH2 1 H CH3 -NH (CH ^ - ^)

58 S CH2 1 2CH3 CH3 - NH - (CH) 0

V

59 S CH2 2 H CH3 -NH- (CH2) 3N ^]

60 S CH2 1 H CH3 -NH- (CH2) 3S

-o

61 S CH2 1 2CH3 CH3 -NH- (CH2) 20 -O

62 O CH2 1 2CH3 CH3 -NH- (CH2) 3 ~ N

63 S CH2 1 H CH3 -NH (j: H- (CH2)

CH „

96-97 (acetone)

114-115 (acetone)

109-110 (acetone)

132-133 (acetone)

94.5 (acetonitrile)

101-102 (acetone)

128-129 (acetone)

108-109 (acetone)

258.5 (M ^ OH — Et20) (3)

109-110 (acetone)

109-111 (MeOH)

250.8 (EtOH) <3)

175-178 (Me0H-Et20) <2>

r3

/

N ° X Y n Rj R2 -W

\

r.

4

64 S CH2 1 2CH3 CH3 -NH- (CH2) 30 - ^^

65 O CH2 1 2CH3 CH3 -NH- (CH2) 4-Ç ^ -CL

66 S CH2 1 2CH3 CH3 -NH- (CH2) 20 - <^^ - 0CH3

67 S CH2 1 2CH3 CH3 -NH- (CH2) 3 "(/ _ S)

S CH2 1 2CH3 CH3 -NH- (CH2) 4_ ^ Cl

69 O CH2 1 2CH3 CH3 -NH- (CPI2) 3 ~ ^^

70 O CH2 1 2CH3 CH3 -NH- (CH2) 4 - <[3

71 S CH2 1 2CH3 CH3 -MH- (CH2) 4 "^^ - CH3

72 S CH2 2 H CH3 -NH- (CH2) 30 (CH2) 20nC4Hg

73 S CH2 2 H CH3 -NH- (CH2) IOCOOCH3

74 O CH2 1 2CH3 CH3 -NIÎ- (CH2) 30- (CH2) 3CH3

75 S CH2 2 H CH3 -NH- (CH2) 30- ^)

M.p. (° C) (1) (4)

177-179 (MeOH — Et20) (2) 107.8 (cyclohexane)

O

121-122 (acetone)

85-8 (Et20)

88-90 (EtzO)

96.9 (iso-PrOH-hexane) 110.7 (cyclohexane)

86-88 (acetone)

82.0 (pentanecyclohexane) 108-109 (MeOH)

152.3 (C6H6-cyclohexane) <2) 113-114 (acetone)

N ° X Y n Ri R2 -N

/ \

Ri

76 S CH, 2 H CH3 -NHnC „H

77 S CH, 2 H

14 29 CH3 -NI-i- (CIÏ) _- / i

3_p o

78 S CH2 2 H CH3 -NH- (CH2) 3- ^ J ^ -C1

79 S CH2 1 2CH3 CH3 -NH- (CH2) 20 - ^) - CH3

80 S CH2 2 H CH3 -.KH- (CH2) 3S (CH2) 3CH3

81 S CH2 2 H CH3 -NH- (CH2) 30 (CH2) 20CH3

82 o CH2 1

2CH3 CH3 -tlHCH (CII2) 3-

CH.

83 S CH, 2

H CH3 -NH- (CH) O-

84 O CH, 1

2CH3 CH3 -NH- (CH2) 20 - <^) - C 1

85 S CH2 1 H CH3 -NH- (CH2) 20

o

CN

86 S CH2 1 H CH3 -NH- (CH2) 2O {} ™ 3

110-112 (MeOH)

102-104 (acetone)

84-86 (acetone)

129-130 (acetone) 93.6 (hexane)

79.0 (cyclohexane) 195 (iso-PrOH) <2)

208.9 (CH2C12) 74 (toluenepentane) 86-88 (acetone)

119-121 (MeOH-acetone)

r3

/

N ° X Y n Ri R2 -N ^

R4

87 S CH2 2 H CH3 -NH- (CH2) 20 - <^) - NHC0CH,

s ch2 2 h ch3 -nh- (ch2) 2 ° ~ r ✓jl 1

"G

89 o ch2 1 2ch3 ch3 -NH- (CH_) _ 0

90 O CH2 1 2CH3 CH3 -NH- (CIi2) 4 - </ _> CH3

91 S CH, 2 H CH3

92 s ch2 1 h ch3 -nh- (ch2) g-ch = ch2

93 s ch2 2 h ch3 -nhncghi7

94 s ch2 2 h ch3 -nh (ch2) 4-ç ^>

95 s ch2 2 h ch3 -m {eh2) 2 ° ~ ^)

96 s ch2 2 h ch3 -nh (ch2) 3s - ^^)

97 s ch2 1 h ch3 -nhncgh ^^

98 s ch2 1 h ch3 -nh (ch2) 4 - ^^)

99 s ch2 1 h ch3 "nh (ch2)

r5 r6

M.p. (° C) (l) (4)

H H 120-121 (MeOH — Et20)

H H 185.4 (H20)

H H 99.1 (cyclohexane)

H H 108.9 (cyclohexane)

H H 116.1 (cyclohexane)

H H 107-109 (methanol)

8CH3 H 129-130 (CHC13)

8CH3 H 131-132 (CHC13)

8CH3 H 136-137 (CHC13-Et20)

8CH3 H 121-122 (CHC13-Et20)

H H 81-83 (acetone) (5)

H H 85-87 (acetone) (5)

H COC (CH3) 3 177-179 (iso-PrOH) <2)

r3

/

N ° X Y n Ri r2 _nss r4

100 S S 2 H CH3 -NH (CH2) 4- ^)

101 S S 2 H CH3 -NlInC 8HI7

102 S CH2 2 H CH3 -NH (CH2) 3CO - ^^ - F

103 S CH2 1 H CH3 -NH (CH2) 20 - ^^ - NHS02CH3

104 S S 2 H CH3 -NH (CH2) 20 - ^^

105 O CH2 1 2CH3 CH, -NH (CH2) 3CQ-Ç ^ -F

106 S CH2 1 2CH3 CH3 -NH (CH2) 2S -o

107 S CH2 2 H CH3 -NH (GH2) 20 - ^^ - C (CH3) 3

108 S CH2 1 H CH3 -NH (CH2) 20 - ^^ - CCX: 2H5

109 S CH2 1 3CH3 CH3 -NH (CH2) 4-Ç ^

/ - \

110 S CH2 2 H CH, -r

"u

CH- C.H.

3 6 5

111 S CH2 1 H CH3 -NH (CH2) 3CO- ^ F

Rs RÖ

m.p. (° C) (1) w

H H 138-140 (MeOH)

H H 108-109 (acetone)

H H 181.6 (MeOH / iso-PrOH) (2)

H H 160-161 (MeOH)

H H 130-132 (CHC13)

H H - 184.9 (MeOH / iso-PrOH) (2)

H H 100-101 (MeOH)

H H 138.0 (hexane)

H H 176-177 (Me0H-Et20) (2)

H H 102-103 (MeOH)

H H 200.3 (MeOH / AcOEt)

H H 178-179 (MeOH) (2)

r3

/

N ° X Y n Ri R2 -N ^

R

4

112 S CH2 1 H CH3 -NH (CH2) 4 ~ \ 7 ^)

113 S CH2 1 H CH3 -NH (CH2) 4 - ^^

114 S CH2 2 H CH3 -èîH (CH2) 2O-Ç ^ -C00CH3

115 S CH2 1 H C2Hj -NH (CH2) 4- (3

116 S CH2 1 2CH3 CH3 -NH (CH2) 2 ° - ^) - COC2H5

117 S CH2 1 H CH3 -NH (ch2) 4 ~ ^ ~ ^

118 S CH2 1 H CH3 -NH (CH2) 4 - {^)

119 S CH2 1 H C2H5 -NHnC0H__

O J. /

120 S CH2 1 2CH3 CH3 -NH (CH2) 20CH2 - ^^

121 O S 2 H CH3 -NHnC QH

o X /

122 O S 2 H CH3 -NH (CH2) 4 O

123 O S 2 H CH3 -NH (CH

VÎ0 "®

R5 Rs

M.p. (° C) (1> (4)

H COCH3 159.1 (acetonitrile) <2)

H COCH3 179.1 (Me0H / Et20) (5> (2)

H H 113-115 (acetone)

H H 72-73 (MeOH)

H H 191-192 (MeOH-Et20) (2>

H COCH (CH3) 2 167.4 (acetonitrile) (2>

H - COC2H5 169.9 (acetonitrile) (2)

H H 78-80 (MeOH)

H H 144-145 (MeOH-Et20) <2)

H H 170-172 (MeOH) (2>

H H 95-97 (MeOH)

ts>

H H 116-118 (MeOH) ^

o

r3

/

N ° X Y n Ri R2 -N ^

r4

124 O S 2 H CH3 -NH (CH2) 3S tlC4Hg

125 S CH2 1 H CH3 -NH (CH) _S nC H

2 3 4 9

126 S CH2 1 H C2H5 -NH (CH2) 20 - </ N,

127 S CH2 2 H CII3 -NHnC H

8 17

128 S CH2 2 II C2H5 -NHnCJH _

o 17

129 S CH2 1 H CH3 -NH (CH) O (CH) OCH.

130 S CH2 1 H CHS -NH (CH2) 4-0

131 S CH2 2 H CH3 -NHnC H _

8 17

132 S CH2 1 H CH3 "NH (CH2) 4 ~ ^" ^

133 S CH2 1 H CH3 -NH (CH2) 4- <Q

134 S CH2 2 H CH3 -NHnC_H

8 17

135 S CH2 2 H C2H5 -NH (CH_)

2 '4 W

136 S CH2 2 H CH3 -NH.nC H

137 S CH2 1 H CH3 -NH (CH2) 4 ~ r S

WE

If * "4

R5 R6 RF. (° C) (1) W O

H H 64-65 (Et20-hexane)

H H 196.2 (acetonitrile / EtOH) '2)

H H 86-88 (acetone)

H H 52-53 (hexane) (5)

H H 167-168 (Et20 —MeOH) (2)

H H 152.2 (acetonitrile) (2)

H COnC3H7 151.4 (acetonitrile) (2)

H COC2H5 139.4 (AcOEt) (2)

H CO-cyclo-C4H7 131.7 (AcOEt) (2>

H COnC7Hi5 145.2 (acetonitrile / iso-PrOH) <2)

H COnC3H7 156.2 (AcOEt) (2)

H H 72-73 (MeOH)

H COnC7Hi5 151.5 (AcOEt) <2>

H CO-cyclo-CsHg 158-160 (AcOEt) (2)

/ Ra

N "X Y n Ri R2 -NT

\

R4

138 S CH2 1 H CH3 -NH (CH2)

139 S CH2 2 H CH3 -rome h o 17

140 S CH2 2 H CH3 —NHnC 0H _

o I /

141 S CH2 2 H CH3 -NH (CH -) QCH = CH-nC H

2 o o X 7

142 S CHZ 2 H CH3 -NHnC_H

o 17

143 S CH2 2 H CH3 -ffiiCH CH = Ç- (CH2) 2CH =

2 CH

144 S CH2 2 H CH3 -NJ-InC H

o X /

145 S CH2 2 H CH3 -NHnC _H

o X /

146 S CH2 2 H CH3 -NHnCgHl7

147 S CH2 2 H CH3 -NHnC I8H37

3 c (ch3) 2

C 1

148 S CH2 1 H CH3 -NH (CH2) 2 ° / C 1

149 S CH2 2 H CH3 —NHnC „H„ c

12. 2.b

150 S CH2 3 H CH3 -NH (CH2)

T3

151 S CH2 1 H CH3 -NH- (CH-), 0-C-CHCH

2 3 |

CH3

R5 R6 P.F. (° c) <1, <4>

H CO-cyclo-C6Hn 148-150 (acetonitrile) (2)

H COCH (CH3) 2 126.6 (AcOEt) (2)

H COCH3 148.5 (AcOEt) (2)

H H 97-98 (acetone)

H CO-cyclo-CsHg 156.5 (AcOEt) (2)

H H 75-77 (Et20)

H COC (CH3) 3 149.4 (AcOEt) (2>

H CO-cyclo-C4H7 144.6 (AcOEt) (2)

H CO-cyclo-C6Hn 182.9 (AcOEt) <2)

H H 122-123 (CHC13) •

H H 118.1 (iso-PrOH-hexane)

H H 93-101 (MeOH-CHC13)

H COC2H5 150-152 (MeOH-EtzO)

(2)

H H 107.1 (hexane) B

• g o

N ° X Y n Ri r3

r2 -n;

/ \

R4

152 S CH2 2 H

153 S CH2 2 H

154 NH CH2 1 H

ch3 -nh- (ch_) -c = ch 2 b ch3 -nh- (ch2) 4-v3

CH3 -NHnC

^ 17

155 S CH2 1

156 S CH2 2

157 S CH2 2

158 S CH2 2

159 NH CH2 1

160 NH CH2 1

161 S • CH2 2

162 S CH2 2

163 CH2 CH2 1

164 CH2 CH2 1

165 CH2 CH2 1

166 CH2 CH2 1

H CH3 -NH- (CH „) rC = CH

2.6

ch

H CH3 -nh (ch -ch = c-ch) -ch -ch = j:

2 ch3 2

\ "=

ch

3

2 (CH3) 2 CH3 -NH- (CH?) 4

2 (CH3) 2 GH3 -nh "(ch2) 20

7 \\

H CH3 -nh- (ch2) 2

O "-Q

H

ch3 -nh- (ch2) 4 -o

4 9

2COOH CH3 -NH-nC H

8 X 7

H CH3 -NH- (CH2) 6C = C-nC ^ H

H CH3 -NH- (CH2) 4 - (^>

H CH3 -NHnCgHi7

H CH3 -NH- (CI12)

H CH3 -NH- (CH.2)

CH.

105-107 (MeOH)

128-130 (Me0H-Et20) 84-85 (acetone-H20) 113-115 (MeOH)

52-55 (Et20)

121.8 (CH3CN)

12.5.5 (CH3CN) 90-91 (CH3CN-H20)

78-80 (CHsCN)

125-127 (MeOH —Et20)

86-88 (MeOH)

108-110 (acetone)

98-100 (acetone)

111.9 (acetonitrile)

126.6 (hexane)

r3

n °

x y

not

Ri

R2

167

ch2

ch2

1

h ch:

168

ch2

ch2

1

h ch-

169

ch2

ch2

1

h ch;

170

ch2

ch2

2

h ch:

171

ch2

ch2

2

h ch;

172

ch2

ch2

1

h ch:

173

ch2

ch2

1

h ch:

174

ch2

ch2

1

h ch;

175

ch2

ch2

1

h ch:

176

ch2

ch2

1

h ch:

177

ch2

ch2

1

h ch:

178

ch2

ch2

1

h ch:

179

ch2

ch2

1

h ch:

180

ch2

ch2

1

h ch:

181

ch2

ch2

1

h ch:

<

R4

CH3 -NH- (CH2) 4QC1 CH3 -NH- (CH2) 20 Q »

-o in: ch2) 4

-Q-ch2-Q

CH.

'2'3-0

-O-O

-NH (CH2)

-NH (CH2) 20 - ^^ - C (CH3)

CH „C _H

6 5

; CH2 »3SnC4H9

2 '3

w

! 2 * 4

2 2

o "o

R5 RO

M.p. (° C) (1) <4>

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

H H

H COCH3 H CO (CH2) 6CH3

109-110 (acetone)

122.2 (hexane)

132.4 (acetone)

97.2 (acetone)

99.7

112.9 (acetone)

213 (iso-PrOH) (2)

vo

210.8 (iso-PrOH) (2)

180.7 (MeOH / iso-PrOH) <2>

102.2 (hexane)

177.1 (MeOH / AcOEt) <2)

82.1 (acetone)

134.9 (benzenecyclohexane) (2)

129-131 (acetonitrile) (2)

Q \

ts>

oil ^ 4

N ° X Y n Rj r3

/

R2 -N ^

R4

Rs

R6

M.p. (° C) (1, (4)

182 CH2 CH2 1 H

CH3 -nh (ch2) 20- (2>

H

COCH3

140-141 (acetonitrile) (2) (5>

(1) The recrystallization solvent is given in parentheses; the melting point entered is that of the free base, unless otherwise indicated. The melting points were noted either on a Tottoli device or a Mettler FP5.

(2) Melting point of the hydrochloride;

<3) Melting point of the dihydrochloride;

(4> The elementary analyzes were carried out for the elements C, H, N, and conform to the theoretical values.

<5) Threo form.

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

21 Table 2

622,770

acute toxicity

(1) Activity

antihypertensive (2)

Activity

vasodilator (3)

Antispasmodic activity (4) Hist. Achol. BaCl2

> 4000 ++

> 4000 + + -

4450 (3903-5073) + + •

4000 (3138-4280) 0

3600 (3068-4212) ++

<500 +

860 (754-980) + + ■ 0

± 2750 0

> 4000 + + -

3300 (3113-3498) + ±

5200 (2789-10880) + + -

> 4000> 4000

3350 (223 -5025) 1550 (1130-2108)> 4000

3700 (3458-3959) ± 2100> 4000> 4000

580 (411-818) 0

1750 (1336-2292) + + +

> 4000 0

4000 (3419-4680) + + +

355 (317-398) 0

± 4000 + + +

430 (187-989) + + +

> 4000 +++

> 4000 + + + 240 (210-274)

> 4000 ++

> 4000 • + + +

3300 (2062-5280)> 4000

4000 (3418-4680)

> 4000

> 4000

± 3700

900 (818-990)

> 4000> 4000 350 (226-543)

> 2000> 4000

1125 (986-1282)> 2000

+ + +

+ + +

+ + +

+ + +

+ + +

+ + +

+ +

3.3

3.3

1.7

1.7

8.3

16.7

8.3

• 16.7

8.3

3.3 3.3

> 16.7

1.7

1.7

0.8

1.7

0.8

3.3

3.3

0.8

0.33

16.7

8.3

0.8

1.7

3.3

0.33

0.8

0.8

3.3

0.8

3.3

1.7

3.3

1.7

0.8

3.3

> 16.7

0.3

0.8

0.33

0.8

1.7

1.7

0.8

0.33

0.8

1.7

0.8

8.3

3.3

8.3

0.33

0.33

1.7

3.3

8.3

8.3

0.8

1.7

0.8

0.33

1.7

1.7

0.8

0.8

0.8

0.017

1.7

0.8

1.7

1.7

1.7

0.8

1.7

1.7

1.7

1.7

1.7

0.8

0.17

1.7

0.8

1.7

16.7

16.7

0.8

0.8

0.8

1.7

3.3

1.7

1.7

1.7

3.3

8.3

1.7

0.8

1.7

1.7

8.3

8.3

1.7

1.7

0.8

1.7

16.7

8.3

0.8

0.8

8.3

3.3

1.7

1.7

0.8

1.7

3.3

1.7

1.7

1.7

8.3

16.7

1.7

1.7

3.3

1.7

3.3

3.3

3.3

8.3

> 16.7

> 16.7

1.7

1.7

1.7

1.7

3.3

3.3

3.3

1.7

No.

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

22

Acute toxicity (1) Activity Activity Antispasmodic activity (4)

antihypertensive (2) vasodilator (3)

Hist. Achol.

± 4000

+ + +

+ +

3.3

3.3

885 (799-991)

0

0

> 16.7

> 16.7

1850 (1480-2312)

+ ±

+ +

0.8

0.8

+ + +

+ + +

1.7

1.7

160 (124-206)

+ + +

+ + +

0.8

1.7

0

+ +

1.7

3.3

+ + +

+ + +

1.7

1.7

<500

+ + +

+ + +

3.3

0.8

+ + +

+ +.

8.3

16.7

285 (247-327)

+ + +

+ +

1.7

1.7

+ + +

+ + +

0.8

0.8

880 (628-1232)

0

+ +

1.7

1.7

> 4000

0

+ + +

3.3

1.7

+

+ +

8.3

8.3

> 4000

+ + +

+ + +

0.8

1.7

> 4000

+

235 (97-564)

0

0

0.8

1.7

725 (671-783)

+ + +

+ + + +

0.8

1.7

0

1.7

0.8

5000 (4065-6150)

+ + +

'+ 4-

0.8

1.7

+ + +

+ +

16.7

16.7

0

+ +

0.3

1.7

> 4000

0

+ + +

1.7

0.8

1200 (952-1518)

+ + +

+ + +

8.3

3.3

+ + +

. + + +

8.3

16.7

1425 (1319-1539)

+ ±

+ + +

1.7

16.7

0

+ + +

8.3

16.7

> 4000

0

+ + +:

1.7

1.7

550 (500-605)

+ + +

+ + +

8.3

8.3

+ + +

+ + + +

0.8

1.7

+ ±

+ + +

0.8

1.7

> 4000

+ +

16.7

16.7

> 4000

0

0.8

0.8

> 4000

+ + +

+ + +

0.8

0.8

> 4000

+ + +

> 4000

+ + + ±

+

0.8

1.7

0

8.3

1.7

> 2000

+ + +

+ + + +

8.3

1.7

+ +

+ + +

0.8

0.8

> 4000

+ + +

- + + +

0.8

0.3

0

3.3

16.7

> 4000

+ + +

8.3

16.7

± 360

+ + +

+ + +

3.3

3.3

> 4000

+ +

+ + +

1.7

1.7

> 4000

0

+ + +.

0.8

0.8

> 4000

+ +

+ + +

0.8

3.3

± 2750

+ + +

+ +: +

0.17

0.8

+

0

0.8

3.3

± 700

+ +

+. + +

0.3

0.8

+ + +

. + + +

0.3

3.3

+

> 2000

0

+ + +

0.8

3.3

± 2500

+ + +

+ + +

0.8

1.7

> 4000

+ +

+ +

0.17

3.3

2200 (1294-3740)

+ + +

+ + + +

1.7

0.8

2020 (1897-2151)

+ + +

+ +

0.8

1.7

1800 (1171-2790)

0

+ + + +

0.3

± 1450

+ +

+ + +

0.8

0

+ + +

0.8

1650 (1375-1980)

+ + +

+ + + +

0.3

> 4000

+ + +

+ + + +

0.8

No.

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

149

147

153

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

23-

622,770

Acute toxicity <1) Activity Activity

antihypertensive <2) - vasodilator (3)

Antispasmodic activity (4) Hist. Achol.

BaCl,

3400 (3063-3774)> 4000

> 4000 250 (176-355) 3700 (2242-6105)> 4000

1900 (1496-2413)

2600 (1926-3510)

> 4000

> 4000

> 4000

± 1750

> 4000

800 (533-1200) 1750 (1129-2713) 3800 (3699-3914)

± 270> 2000> 4000 ± 2300

1900 (1310-2755) 2600 (1838-3692) 2150 (1720-2687)

> 4000

870 (833-909) 250 (179-350)

0

+ +

1.7

0

+ +

1.7

+ + +

0

+ + +

,

+ + +

+

+ + +

+ + +

+ + +

+ + +

0

+ + +

+ + +

+ + +

0

0

±

+ + +

+ +

1.7

0.8

+ +

+ + +

0.8

0.8

+ + +

+ ± +

1.7

1.7

+ +

+ + +

0.8

0.8

+ + +

+ + +

0.8

0.8

+ + +

+ + + +

3.3

3.3

+ + +

+ + +

3.3

0.8

0

+ + +

1.7

0.8

+

+ + +

0.8

0.8

+ + +

+ + + +

0.08

1.7

0

+ +

0.8

0.8

+ ±

+ + +

0.8

+ + +

+ +

0.8

0.8

0

+ + +

0.17

0.8

+ +

±

1.7

1.7

+ +

+ + + +

1.7

+ + +

Table 3

N ° Activity on the central nervous system

DL50 DMA

1

1780

200

2

2910

400

3

728

400

4

300

100

5

1600

100

6

110

50

7

880

100

8

> 1600

800

9

> 400

200

10

> 1600

200

11

91

25

12

600

50

13

46

50

Claims (4)

622,770 2 1. Process for the preparation of amino alcohol derivatives corresponding to formula (I): in which Q is a CH - CH — N group I \ OR6 R4. a) R 1 represents hydrogen, one or two linear or branched alkyl radicals (C1-C3), a phenyl radical or a carboxyl radical; b) R2 represents a linear or branched (C1-C3) alkyl radical; c) R3-represents: - a mono or polyunsaturated alkenyl radical (C3-Ci8); - a monken or polyunsaturated alkenyl radical (C3-C12) substituted by oxygen, sulfur or a phenyl radical; - a mono or polyunsaturated (C3-C18) alkynyl radical; - a mono or polyunsaturated (C3-C12) alkynyl radical substituted by oxygen, sulfur or a phenyl radical; - a cycloalkyl radical (C3-C10); - an alkyl radical (C2-C20), linear or branched; A linear or branched (C2-C18) alkyl radical substituted by at least one atom and / or radical chosen from the group formed by: 1) oxygen or sulfur; 2) alkoxycarbonyl radicals (C1-C3) Pyrrolidine, pyrro-lidinone or imidazolidone; 3) phenyl, phenoxy, phenylthio, benzoyl, indanyloxy, naphthyloxy radicals; 4) phenyl, phenoxy, phenylthio, benzoyl radicals substituted by one or two alkyl (C1-C4) or alkoxy (C1-C4) radicals, by one or two halogen atoms, by a nitrile, hydroxy, amino, alkanoyl radical (C2-C6) acylamino (C2-C4), alkoxycarbonyl (C1-C4) or alkylsulfonamido (Ci-C *); d) R4. represents a hydrogen atom or forms with R3 and the neighboring nitrogen atom a morpholine, pyrrolidine, pipé-ridine, piperidine radical substituted by one or two alkyl radicals (C1-C4.), phenyl or phenylalkyl (C1-C4) , or a piperazine radical substituted in position 4 by a phenyl radical or by a phenyl radical substituted 1) by one or two alkyl (C1-C4) or alkoxy (C1-C4) radicals, 2) by one or two halogen atoms or 3) with a trifluoromethyl radical; e) R5 represents a hydrogen atom or an alkyl radical (C1-C3); f) R6 represents hydrogen; g) n has the value of 1,2 or 3; h) X represents sulfur, oxygen, a CH2 radical or an NH radical; i) Y represents a CH2 radical or sulfur; j) when simultaneously X is oxygen, Y a CH2 group, has the value of 2, Ri and R5 of hydrogen, R2 a methyl radical, and R6 is hydrogen, R4 does not form with R3 and the neighboring nitrogen atom a substituted piperazine radical, characterized in that a compound corresponding to formula I is reacted, in which Q represents a group with an amine of the R3R4NH type, Z being a halogen R 1 to R 5, X , Y and n having the values given above. 2. Method according to claim 1, characterized in that it consists in carrying out the reaction in the presence of a fixing product 5 the hydracid formed, such as a mineral or organic base or an excess of amine. 3. Method according to claim 1, characterized in that the reaction is carried out in a solvent chosen from the group comprising alcohols, chloroform, dioxane and tetrachloride. 10 carbon. 4. Process for the preparation of a compound of formula I, in which R6 represents a linear or branched C1-C10 alkanoyl radical or a C3-Cs cycloalkanoyl radical, characterized in that a compound of formula I or one of its compounds is prepared salts by the process 15 according to claim 1 and then reacted with an excess or an equimolecular amount of a corresponding acid or anhydride.