NO180193B - Intermediate in the preparation of aromatic amine compounds - Google Patents

Description

The aim of the present invention is to provide intermediate products to prepare new aromatic derivatives substituted with an amino group and with different ester, amine or amide functions, as well as their enantiomers as described in the main application, no. 90.4802.

The present invention relates to compounds which can be enantioselective and used in mixtures for therapeutic use, and more particularly for pathological phenomena which infect neurokinin systems such as: pain (D. Regoli et al., Life Scuences, 1987, 40, 109-117), allergy and inflammation (J.E. Morlay et al., Live Sciences, 1987, 41, 527-544), circulatory failure (J. Losay

et al., 1977, Substance P, Von Euler, U.S. and Pernow ed., 287-293, Raven Press, New York), gastrointestinal problems (D. Regoli et al., Trends Pharmacol. Sei., 1985, 6, 481-484), respiratory problems (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50).

Endogenous ligands or neurokinin receptors have been described, such as substance P (SP), neurokinin A (NKA) (S.J. Bailey et al., 1983, Substance P, P. Skrabanck ed., 16-17 Boole Press, Dublin) and neurokinin B (NKB) (S.P. Watson, Life Sciences, 1983, 25, 797-808).

The neurokinin receptors have been recognized in numerous preparations and are currently classified into 3 types: NK1, NK2 and NK3. While most of the preparations that have been studied so far have several types of receptors, such as guinea pig ileum (NK., NK2 and NK3),

some of them have only one, such as dog carotid artery (NK,) , rabbit pulmonary artery without endothelium (NK2) and rat portal vein (NK3) (D. Regoli et al., Trends Pharmacol. Sei., 1988 ,

9, 290-295 and Pharmacology, 1989, 38, 1-15).

A more accurate characterization of different receptors is made possible by the synthesis of selective antagonists. Thus [Sar<9>, Met-(02)<11>] SP, [Nie<10>] NK<A>4.10 and [Me Phe<7>] -NKB will present a selectivity respectively for the receptors NK1, NK2 and NK3 (cf.

D. Regoli, 1988 and 1989 mentioned above).

It has now been found that certain aminated aromatic compounds have interesting pharmacological properties, in the capacity of antagonists against neurokinin receptors and are particularly useful for the treatment of any substance P pathology and neurokinin dependence, and therefore the present invention relates to a compound for use in the preparation of compounds with formula (I) according to application no. 90.4802. Said connection has the following

formula:

where:

E0 0 represents a tetrahydropyranyloxy group, a

hydroxy group or a group

- X° ° represents hydrogen, a hydroxyl group which is free or protected by an O-protecting group or is united with X<11> below to form a carbon-carbon bond, or X and X°° together form an oxo group or dialkyl-aminoalkyloxyimino of the formula =N-0-(CH2)p-Am, where p is 2 or 3 and Am is a dialkylamino group, each alkyl

may contain from 1 to 4 carbon atoms;

Y represents a nitrogen atom or a group C(X" ) where X<1>' is hydrogen or forms with X°° a carbon-carbon bond;

R° ° represents hydrogen, a methyl group or a group (CH2)n-L°°, where n is an integer from 2 to 6 and L°° is hydrogen or an amino group which is free or protected by

an N-protecting group;

m is 2 or 3,

Ar and Ar' independently represent a thienyl group; a phenyl group, unsubstituted, mono- or disubstituted with a halogen atom, with C 1 -C 1 alkyl, with trifluoromethyl, with alkoxy, where alkyl is C 1 -C 3 , with hydroxyl, with methylenedioxy; an imidazolyl group; wherein Ar' can also be a benzothienyl group which is unsubstituted or substituted by halogen, a naphthyl group, unsubstituted or substituted by a halogen, a biphenyl group; an indolyl group, unsubstituted or substituted on the nitrogen with a benzyl group;

X represents hydrogen; and

Q represents hydrogen, an alkyl group C1-C4 or an aminoalkyl group of the formula -(CH2)-Am<1>, where q is 2 or 3 and Am' is a piperidine, 4-benzylpiperidine or dialkylamino group, each alkyl may contain from 1 to 4

carbon atoms;

when m = 2, E°° is a hydroxy group, R°° is hydrogen and Ar'

is unsubstituted phenyl, then Q is something other than hydrogen,

ethyl or propyl;

when m = 2, E°° is a hydroxy group, R<00> is hydrogen and

Q is hydrogen, then Ar' is something other than 3,4-dimethoxy-phenyl

or thienyl-2;

when m = 3, E°° is a hydroxy group, Ar' is unsubstituted

phenyl and Q is ethyl, then R°° is something other than hydrogen,

or one of their salts. Incidentally, reference is made to requirement 1.

The compounds of formula (XVI) which are particularly preferred are those in which E" represents a hydroxy group and R°° represents hydrogen.

The compounds (XVI), where

E<00> represents a tetrahydropyranyloxy group, a hydroxy group or a group

X<00> = X' and

R00 = R is as for formula (I) above,

and their salts have shown antagonistic properties against the binding of substance P in experiments carried out on membranes from rat cortex and lymphoblastic cells IM9, according to M.A. Cascieri et al., J. Biol. Chem., 1983, 258, 5158-5164 and D.D. Paya et al.,

J. Immunol. 1984, 133, 3260-3265.

The same compounds and their salts have shown antagonistic properties against binding of NKA in experiments performed on membranes from rat duodenum, according to L. Bergstom et al., Mol. Pharmacol., 1987, 32, 764-771.

The same compounds and their salts have shown antagonistic properties against specific antagonists for the receptors NK1, NK2, NK3 in experiments performed on different isolated organs, according to D. Regoli et al., Trends Pharmacol. Sci., 1988, 9, 290-295.

The same compounds and their salts have shown global antagonistic properties NK1, NK2, NK3 in experiments performed on different isolated organs, according to D. Regoli et al., Trends Pharmacol. Sci., 1988, 9, 290-295 and Pharmacology, 1989, 38, 1-15.

The same compounds and their salts have shown antagonistic properties against hypermotility induced in the rat by substance P in pharmacological experiments carried out according to Elliot et al., Brain Res., 1986, 381, 68-76.

Antagonistic properties against salivation induced in the rat by substance P or a specific antagonist NK1 ([Sar<9> Met (o2)<11>]SP) have been produced by pharmacological experiments carried out according to Y. Takeda and J.E. Krause, Proe. Nati. Acad. Pollock. USA, 1989, 86, 392-396.

Analgesic properties have been discovered in pharmacological experiments performed on the arthritic rat according to V. Kayser et al., Proceedings of the Vth World Congress on Pain, R. Dummer,

G.F. Gebhart and M.R. Bond et al., Elsevier Biomedical Division, 1988, 72-79.

The following examples illustrate the invention.

Example 1

N[4-(benzyl-piperidinyl)-2-(3,4-dichlorophenyl)butyl]-2,4-dichlorobenzamide hydrochloride. SR 45672 A

A) 1-amino(-4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butane dihydrochloride

14.5 g of 4-(benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyronitrile hydrochloride are brought into solution in 400 ml of ethanol 95°. A solution of 20 ml of concentrated ammonia in 40 ml of water and Raney nickel (10% by weight of the amount of amine) is added to the mixture which is then placed under a hydrogen atmosphere with vigorous stirring for 4 hours, during which time 1.67 liters of hydrogen consumed. After filtering the catalyst, the filtrate is concentrated under vacuum, the residue is taken up in ethyl acetate, washed with water, dried and concentrated under vacuum. The residue is taken up in a hydrochloric acid solution in methanol, filtered and recrystallized in a mixture of acetone/ether:3/7.

m = 10.2 g

sm.p. = 210°C

B) SR 45672 A

2.3 g of the product obtained above and 1 g of chloride of 2,4-dichlorobenzoic acid are brought into solution in 100 ml of dichloromethane in the presence of 0.03 g of triethylamine. The reaction mixture is stirred for 4 hours at room temperature, then concentrated under vacuum, taken up in water, extracted with ether, dried over magnesium sulfate and concentrated under vacuum. The residue is chromatographed on silica, eluent: dichloromethane/methanol: 97/3. The concentration of the pure fractions produces a residue which is taken up in hydrochloric acid ether.

m = 1 g

sm.p. = 86-87°C

Example 2

N-[5-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)pentyl]-2,4-dichlorobenzamide hydrochloride. SR 45083 A

By proceeding as in example 1, but using 5-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)pentylnitrile as starting product, SR 45083 A is obtained, recrystallized in a mixture dichloromethane, pentane.

sm.p. = 98-100°C.

Example 3

N-[4-(4-benzyl-1-piperidinyl)-2-(3,4-difluorophenyl)butyl]2,4-dimethylbenzamide hydrochloride hemihydrate. SR 46316 A.

1.2 g of BOP is added to a solution of 1 g of 1-amino-3-(4-benzyl-1-piperidinyl)-2-(3,4-difluorophenyl)butane, 0.34 g of 2,4-di- methylbenzoic acid and 1 g of triethylamine in 50 ml of dichloromethane. The reaction mixture is stirred for 1 hour at room temperature and concentrated under vacuum. The residue is taken up in water, extracted with ether, washed with water, then with a solution of sodium bicarbonate, dried over magnesium sulfate, then concentrated under vacuum. The residue is taken up in methylene chloride, in which hydrogen chloride is produced, which is filtered and washed with ether.

m - 0.4 g

sm.p. = 99-103°C.

The compounds described in Tables 1 and 2 are prepared according to Examples 1, 2 or 3.

In the formula below, group Z in formula I denotes a phenyl group which is unsubstituted, mono-, di- or tri-substituted by A,

A', A''.

Example 87

N'-[4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyl]-N-1-naphthylurea hydrochloride. SR 45924 A.

2.52 g of 1-amino-4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butane is brought into solution in 30 ml of anhydrous benzene, then 1.09 g of 1-naphthyl isocyanate is added and allow the reaction mixture to stand under stirring overnight at room temperature. The excess of isocyanate is decomposed by adding 10 ml of methanol and heating the mixture by boiling for 30 minutes.

The mixture is concentrated under vacuum, and the residue is taken up in a mixture of ethyl acetate-water, washed with a solution of 10% sodium hydroxide, then with water, decanted, dried over magnesium sulfate and concentrated under vacuum. The residue is taken up in acetone, then hydrochloric acid ether is added, the hydrogen chloride is filtered and transferred to solid form in ether.

m = 3.3 g

sm.p. = 174°C

The compounds described in Table 3 are prepared according to Example 87.

Example 9 6

N1 -[4-(4-benzyl-i-piperidinyl)-2-(3,4-dichlorophenyl)butyl]-N-1-benzylcarbamate hydrochloride. SR 45940 A.

2.26 g of 1-amino-r-(4-benzyl-1-piperidinyl)2-(3,4-dichlorophenyl)butane hydroxide and 0.89 g of benzyl chloroformate are brought into solution in 30 ml of dichloromethane. The mixture is cooled to 0°C, then 1.52 g of triethylamine in solution in 10 ml of dichloromethane is added. The reaction mixture is allowed to stand for 1 hour at room temperature, then is concentrated under vacuum. The residue is taken up in water, extracted with ethyl acetate, washed with a 10% solution of sodium hydroxide, then with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel, eluent: dichloromethane/methanol: 96/4. After concentration under vacuum of the pure fractions, the residue is taken up in ether, hydrochloric acid ether is added and the hydrogen chloride is filtered.

m = 1.7 g

sm.p. = 130°C

Example 97

N' - [4-(4-Benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyl]carbamate hydrochloride.

9.8 g of 1-amino-4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butane dihydrochloride and 6.7 g of triethylamine are brought into solution in 200 ml of dichloromethane. 2.28 g of ethyl chloroformate is added drop by drop at room temperature to this solution and the reaction mixture is left for 1 hour at room temperature while stirring. The reaction mixture is concentrated under vacuum, the residue is taken up in ethyl acetate/water and washed successively with a 5% sodium hydroxide solution, with water and with a saturated sodium chloride solution.

The organic phase is dried over Na 2 SO 4 and concentrated under vacuum to provide a residue which is chromatographed on silica gel, eluent dichloromethane/methanol: 94/6. The concentration of the pure fractions gives a residue which is taken up in ethyl acetate. Hydrochloric ether is added to the solution and the hydrogen chloride is filtered.

m = 6.5 g

sm.p. = 108-110°C

Example 98

N'-methyl-N-[4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyl]-2,4-dichlorobenzamide hydrochloride. SR 46650 A. a) 4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)-N-1-methyl-aminobutane hydrochloride.

6.5 g of the product obtained in Example 97 and 1.6 g of lithium aluminum hydride are brought into solution in 150 ml of tetrahydrofuran and heated under reflux for 3 hours. The reaction mixture is hydrolysed by adding a 2N sodium hydroxide solution, then filtered on celite. The filtrate is concentrated under vacuum, the residue is taken up in ethyl acetate, and addition of hydrochloric acid ether makes it possible to obtain the hydrogen chloride.

m = 4.3 g

sm.p. = 234-236°C

b) SR 46650 A

By reacting the 2,4-dichlorobenzoic acid chloride with

the product obtained above according to the working method described in example 1, you get SR 46650 A.

sm.p. = 140-142°C

Example 99

N-(amino-1-hexyl)-N-[4-(4-benzylpiperidinyl)-2-(3,4-dichlorophenyl)-butyl]2,4-dichlorobenzamide dihydrochloride hemihydrate. SR 46510 A.

a) 4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)-N-1-(trityl-aminopentylamido)butane. 3 g of 1-amino-4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)-butane hydrochloride are suspended in 60 ml of methylene chloride in the presence of 3.2 ml of triethylamine. After dissolving the diamine, add 2.5 g of tritylaminocaproic acid, then 3.2 g of BOP. The reaction mixture is stirred at room temperature for 30 minutes, washed with water, with a dilute sodium hydroxide solution, then with water, decanted, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is chromatographed on silica gel, eluent: methylene chloride/methanol: 95/5. The concentration of the pure fractions allows obtaining 3.6 g of the expected product. b) 4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)-N-1-(1-tritylaminohexylamino)butane.

3.6 g of the product obtained above is brought into solution in 40 ml of tetrahydrofuran and added drop by drop to a suspension of 600 mg of lithium aluminum hydride in 20 ml of tetrahydrofuran. The reaction mixture is heated under reflux for 18 hours, then cooled, hydrolyzed, filtered and concentrated under vacuum. The residue is chromatographed on silicon dioxide gel, eluent methylene chloride/methanol 80/20.

The concentration of the pure fractions yields 1.9 g of the expected product. c) N-[4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)-N-(1-tritylaminohexylamino)butyl]-2,4-dichlorobenzamide.

1.9 g of the product obtained above is brought into solution in 30 ml of methylene chloride. The solution is cooled to -20°C, then 0.57 g of 2,4-dichlorobenzoyl chloride in 10 ml of methylene chloride is added. The mixture is allowed to return to room temperature, washed twice with water, decanted, dried over magnesium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel, eluent: methylene chloride/methanol: 95/5. The concentration of pure fractions provides 1.5 g of the expected amide.

d) SR 46510 A

1.5 g of the tritylated derivative obtained above are brought in

solution in 15 ml of 50% formic acid in water and stirred at 60 °C for 1 hour. The mixture is cooled and filtered, and the filtrate is concentrated under vacuum. The residue is taken up in water, washed with ether, made alkaline with sodium hydroxide, extracted with methylene chloride, decanted, dried over magnesium sulfate and concentrated under vacuum. The obtained residue is taken up in 5 ml of methylene chloride, and hydrochloric acid ether is added to pH = 1.

m = 1 g

sm.p. = 100°C (decomposition).

Example 107

N-[4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)-2-isobutyl-butyl]-3,4-dichlorobenzamide hydrochloride. SR 46753 A.

a) 4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)-2-isobutyl-butyronitrile. 6 g of 4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)-butyronitrile are brought into solution in 70 ml of anhydrous ether in the presence of 0.62 g of sodium amide. The reaction mixture is heated under reflux for 2 hours, then it is allowed to return to room temperature and 2.12 g of 1-bromo-2-methylpropane is added. The reaction mixture is heated under reflux for 24 hours and concentrated under vacuum. The residue is taken up in water, extracted with ethyl acetate, decanted, dried over magnesium sulphate, filtered and concentrated under vacuum.

The expected product is obtained after purification by chromatography on silica gel, eluent: hexane/ethyl acetate: 90/10. b) 1-amino-4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)-2-isobutylbutane. 2.6 g of the product obtained above is brought into solution in a mixture of 30 ml of ammonia and 20 ml of water. A catalytic amount of Raney nickel is added and hydrogenated at atmospheric pressure at room temperature. The catalyst is separated by filtration, and the filtrate is concentrated under vacuum. The remainder is taken up in methanol, and the addition of hydrochloric acid ether enables the hydrogen chloride to be obtained. c) SR 46753 A.

By reacting the product obtained above with 2,4-dichlorobenzoic acid chloride as described in Example 1, SR 46753 A is obtained.

sm.p. = 126°C.

The compounds described in Table 5 have been synthesized according to Example 107.

In the formula below, group Ar' indicated in formula I is a 3,4-dichlorophenyl group and group Z has a 2,4-dichlorophenyl group.

Example 111

N[4-(4-benzoyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyl] 2,4-dichlorobenzamide hydrochloride. SR 46159 A.

a) 3-(3,4-dichlorophenyl)-1-(2-tetrahydropyranyloxy)-3-nitrile-propane. 20 g of 55-60% sodium hydride in oil are suspended in 200 ml of dry tetrahydrofuran. A solution of 85 g of 3,4-dichlorophenylacetonitrile in 500 ml of tetrahydrofuran is added drop by drop at 20°C over the course of 30 minutes, and the reaction mixture is stirred at room temperature for 2 hours. The mixture is cooled to -20°C, and a solution of 98 g of 1-bromo-2-tetrahydropyranyloxyethane in 100 ml of tetrahydrofuran is added, the mixture is allowed to return to room temperature, and after 2 hours a solution of 50 g is added ammonium chloride in 3 liters of water. It is extracted with 1.5 liters of ether, washed with a saturated solution of sodium chloride, decanted, dried over magnesium sulfate and concentrated under vacuum.

The residue is chromatographed on silica gel, eluent: dichloromethane. The fractions of pure product are concentrated under vacuum to provide 83.6 g of an oil. b) 1-amino-2-(3,4-dichlorophenyl)-4-(2-tetrahydropyranyloxy)-butane. 83.6 g of the nitrile obtained above are brought into solution in 100 ml of absolute ethanol. 350 ml of concentrated ammonia is added, then Raney nickel (10% of the initial amount of amine) is added under nitrogen treatment. Hydrogenation is then carried out under a hydrogen atmosphere at room temperature and normal pressure. 11.9 liters of hydrogen are absorbed within 3 hours. The catalyst is separated by filtration on celite, the filtrate is concentrated under vacuum, the residue is taken up in a saturated sodium chloride solution. After extraction with ether and drying over magnesium sulfate, 82.5 g of an oil are obtained. c) 1-(2,4-dichlorobenzoylamino)-2-(3,4-dichlorophenyl)-4-(2-tetrahydropyranyloxy)butane. 80 g of the amine obtained above are brought into solution in 800 ml of dichloromethane. The solution is cooled to 0°C, 38.4 ml of triethylamine are added, then 55 g of 2,4-dichlorobenzoic acid chloride. The reaction mixture is then stirred at room temperature for 1 hour, then washed with water. The organic phase is decanted, dried over magnesium sulfate and concentrated under vacuum to provide 120 g of an oil.

d) 1-(2,4-dichlorobenzoylamine)-2-(3,4-dichlorophenyl)butanol.

120 g of the product obtained above is brought into solution in 1

liter of methanol in the presence of 12 g of paratoluenesulfonic acid. The reaction mixture is stirred for 18 hours at room temperature and then concentrated under vacuum. The residue is taken up in dichloromethane and washed with a 10% sodium carbonate solution. The organic phase is decanted and dried over magnesium sulfate to provide 106 g of an oil. e) 1-(2,4-dichlorobenzoylamino)-2-(3,4-dichlorophenyl)-4-mesyloxy-butane.

106 g of the alcohol obtained above are brought into solution in

1 liter of dichloromethane, then 44 ml of triethylamine and 24.2 ml of mesyl chloride are added to the solution cooled to 0°C. The reaction mixture is stirred at 0°C for 45 minutes, washed three times with ice water, decanted, dried over magnesium sulfate and concentrated under vacuum.

The residue is recrystallized with isopropyl ether.

m = 95 g.

f) SR 46159 A.

3 g of the mesylate obtained above and 3.1 g of 4-benzoylpiperidine

is brought into solution in 7 ml of dichloromethane, and the reaction mixture is heated under reflux for 24 hours. The mixture is diluted in dichloromethane, washed with water, then with a dilute sodium hydroxide solution, then once more with water. The organic phase is decanted, dried over magnesium sulphate and concentrated under vacuum. The residue is chromatographed on silica gel, eluent: dichloromethane/methanol: 70/30.

The fractions of the pure product are concentrated under vacuum, the residue is diluted in dichloromethane and addition of hydrochloric acid ether enables the hydrogen chloride to be obtained.

m = 930 mg.

The compounds from the examples listed in Table 6 (I, Ar' = 3,4-dichlorophenyl; Z = 2,4-dichlorophenyl) are prepared according to Example 111.

The compounds from the examples set out in Table 7 (I, Ar' = 3,4-dichlorophenyl) and Table 8 (I, Ar' = 3,4-dichlorophenyl or 3-trifluoromethylphenyl) are prepared according to Examples 1, 2 or 3 .

Claims (2)

1. Compound, useful for the preparation of a compound of formula (I): where: - m is 2 or 3; the carbon atom bonded to Q and Ar may have a specific (+) or (-) configuration, Ar and Ar' independently represent a thienyl group; a phenyl group , unsubstituted, mono- or disubstituted with a halogen atom, with C 1 -C 1 alkyl, with trifluoromethyl, with alkoxy, in which the alkyl is C 1 -C 3 , with hydroxyl, with methylenedioxy; an imidazolyl group; wherein Ar' can also be a benzothienyl group, unsubstituted or substituted by halogen; a naphthyl group, unsubstituted or substituted by halogen; a biphenyl group; an indolyl group, unsubstituted or substituted on the nitrogen with a benzyl group; X represents hydrogen; X' represents hydrogen, a hydroxyl group or is joined to X<11> below to form a carbon-carbon bond; or X and X' together form an oxo- or dialkylaminoalkyloxyimino group with the formula =N-0-(CH2) p-Am, where p is 2 or 3 and Am is a dialkylamino group, each alkyl can contain from 1 to 4 carbon atoms; Y represents a nitrogen atom or a group Z(X,<!>) where X<1>' is hydrogen or together with X<1> forms a carbon-carbon bond; Q represents hydrogen, a C1-C4 alkyl group or an amino alkyl group of formula -(CH 2 ) -Am', where q is 2 or 3 and Am' is a piperidine, 4-benzylpiperidine or dialkylamino group, each alkyl may contain from 1 to 4 carbon atoms; R represents hydrogen, a methyl group or a group (CH2)n-L, where n is an integer from 2 to 6 and L is hydrogen or an amino group, T represents a group chosen from where W is an oxygen or sulfur atom, and Z represents either hydrogen or M or OM when T represents the group or M when T represents the group M represents hydrogen or straight or branched C 1 -C 4 -alkyl; phenylalkyl in which the alkyl group comprises from 1 to 3 carbon atoms, unsubstituted, mono- or polysubstituted on the aromatic ring with halogen, hydroxy, alkoxy with from 1 to 4 carbon atoms, alkyl with from 1 to 4 carbon atoms; pyridylalkyl in which the alkyl group comprises from 1 to 3 carbon atoms; naphthylalkyl in which the alkyl group comprises from 1 to 3 carbon atoms; pyridylthioalkyl in which the alkyl group comprises from 1 to 3 carbon atoms; styryl; (1-methyl)-2-imidazolylthioalkyl in which the alkyl group comprises from 1 to 3 carbon atoms; 1-oxy-3-phenylindan-2-yl; an aromatic or heteroaromatic group, unsubstituted, mono- or polysubstituted; or one of their salts with inorganic or organic acids, characterized in that it has formula (XVI): where: E°° represents a tetrahydropyranyloxy group, a hydroxy group or a group - X°° represents hydrogen, a hydroxyl group which is free or protected by an O-protecting group or is joined to X<1>' below to form a carbon-carbon bond, or X and X"° together form an oxo group or dialkylamino-alkyloxyimino with the formula =N-0-(CH2)-Am, where p is 2 or 3 and Am is a dialkylamino group, as each alkyl can contain contain from 1 to 4 carbon atoms; Y represents a nitrogen atom or a group C(X'') where X'<1> is hydrogen or forms with X°° a carbon-carbon bond; R°° represents hydrogen, a methyl group or a group (CH2)n-L°°, where n is an integer from 2 to 6 and L°<0> is hydrogen or an amino group; m is 2 or 3, Ar and Ar' are as indicated above; - X represents hydrogen; and Q represents hydrogen, an alkyl group C1-CA or an amino alkyl group of formula -(CH 2 ) -Am', where q is 2 or 3 and Am' is a piperidine, 4-benzylpiperidine or dialkylamino group, each alkyl may contain from 1 to 4 carbon atoms; when m = 2, E°° is a hydroxy group, R°° is hydrogen and Ar' is unsubstituted phenyl, then Q is other than hydrogen, ethyl or propyl; when m = 2, E°° is a hydroxy group, R" is hydrogen and Q is hydrogen, then Ar' is something other than 3,4-dimethoxy-phenyl or thienyl-2; when m = 3, E°° is a hydroxy group, Ar' is unsubstituted phenyl and Q is ethyl, then R°° is something other than hydrogen, or one of their salts. 2. Compound according to claim 1, characterized in that: - E°° represents a hydroxy group, R" represents hydrogen, and m, Q and Ar' are as defined in claim 1.