MXPA96006289A - New 2-naftamide derivatives and their therapeutic applications - Google Patents

Abstract

The invention is concerned with the 2-naphthamide derivatives, in the form of bases or salts, which are represented by the following general formula (I): wherein: the entity ZY represents a group N-CH2, C = CH or CH -CH2; R1 represents a hydrogen, fluorine, bromine or iodine atom or a hydroxy, methoxy, nitrile or nitro group, R2 represents a hydrogen or bromine atom or a hydroxy, methoxy, nitrile or nitro group; and R2 are both located in the same nucleus of the naphtamide portion or each on one of the nuclei, R3 and R4 may be identical or different and each independently represents a hydrogen atom or chlorine atom or a methoxy or methyl group or an electrophilic group. The invention also concerns its therapeutic applications as partial dopamine D3 receptor agonists. The invention applies more particularly to the treatment of neuropsychiatric infections involving the D3 receptor of dopamine, particularly psychotic and depressive states, to the treatment of drug dependence states or to the treatment of problems of the sexual sphere.

Description

NEW 2-NAFTAMIDE DERIVATIVES AND THEIR THERAPEUTIC APPLICATIONS Description of the invention The present invention is concerned with the new chemical compounds derived from the 2-naphthamides. as well as its therapeutic applications, particularly as selective dopaminergic agents. Numerous derivatives of phenylpiperazines are known and used for their activity on the central nervous system, in particular for their neuroleptic properties. Phenylpiperazines are essentially known as serotonergic agents. With respect to dopamine receptors, it has been shown that certain arylpiperazine derivatives have a higher affinity for the D3 receptor of dopamine, in relation to the other receptors of the same, (MURRAY PJ et al., Bioorganic &Medicinal Chemistry Letters, vol 5 No. 3, pp 219-222 (1995)). According to this document, these compounds, which exhibit a certain selectivity towards the D3 receptor of dopamine in relation to the other receptors, could be used to verify the hypothesis that a selective dopamine D3 receptor antagonist could provide an agent effective antipsychotic free of extrapyramidal side effects. On the other hand, it has been shown that certain derivatives of the paftamides behave as pure antagonists of the D3 receptor and could REF: 23702 this way be used for the preparation of dopamine antagonist drugs by the biological blockade of the D3 receptor (French Patent Application No. 91 13103). Recently, naphthamide derivatives of arylpiperazines have also been described in US patent 5 395 835 as selective dopamine D3 receptor antagonists. These compounds are useful as antipsychotic agents and are useful in the treatment of problems linked to dopaminergic block. It is in this state of knowledge that it has been evidenced, quite surprisingly and unexpectedly, that the 2-naphthamide derivatives of formula (I) given below have a strong affinity for dopaminergic receptors and particularly for the receptor D3 and selectively behave as potent partial agonists of dopamine to the D3 receptor. Thus, the subject of the present invention is the derivatives of 2-paftamides, in the form of bases or salts, which are represented by the general formula (I): wherein the Z-Y entity represents a group N-CH, C = CH or CH-CH2; R1 represents a hydrogen, fluorine, bromine or iodine atom or a hydroxy, methoxy, nitrile or nitro group; R 2 represents a hydrogen or bromine atom or a hydroxy, methoxy, nitrile or nitro group; the substituents Ri and R2 are both located in the same nucleus of the naphtamide portion or each on one of the nuclei; R3 and R4 may be identical or different and each independently represents a hydrogen or chlorine atom or a methoxy or methyl group or an electron-withdrawing or electrophilic group. The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one derivative of the formula (I) mentioned above, in the form of a base or a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable carrier or excipient. It is still concerned with medicaments acting as partial agonists of the dopamine D3 receptor, comprising as an active principle, at least one derivative of formula (I) mentioned above, as well as the use of the derivatives for the preparation of such medications. The derivatives according to the invention are represented by the general formula (I). These compounds are new.

In the literature, naphthamide derivatives of arylpiperazines can be found (US patent 5 395 835 cited above) but in these compounds, the piperazine portion is separated from the naphthamide portion by a chain of 2 carbon atoms when, according to the invention, the chain has 4 carbon atoms. The derivatives according to the invention can be in the form of free bases or in the form of salts, in particular in the form of addition salts with physiologically acceptable acids and the invention also extends to these different forms. According to the invention, the derivatives for which the entity Z-Y represents a group N-CH2 constitute the preferred derivatives. As the particularly preferred derivatives according to the invention, mention may be made of the following compounds: N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-4-nitro-2-naphthamide; N- [4- (4-phenol-1, 2,3,6-tetrahydropyridinyl) butyl] -2-naphthamide; N- [4- (4-phenyl-piperidinyl) butyl] -2-naphthamide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-4-cyano-2-naphthamide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -2-naphthamide; N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -3-methoxy-2-naphthamide; N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -2-naphthamide; N- [4- (4- (3-chlorophenii) piperazinyl) butyl] -2-naphthamide; N- [4- (4- pheny1 -DiDeraz i n i l) but i ll - ^ - naftamide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-2-naphthamide oxalate; The derivatives of formula (I) according to the present invention can be prepared by known methods (W. Adcock et al., Aust. J. Chem., 1965, 18 1351). The acid part (2-naphthoic acid) suitably substituted is converted to mixed anhydride by isobutyl chloroformate in acetone or any other solvent, in basic medium and reacted with the desired amine as indicated in the following reaction scheme: B Z-Y N-CH. C Z - Y = C = CH D Z - Y = CH-CH.

Other methods of activation of the carboxylic function can also be used; in fact all suitable amide preparation methods 20 and comprise the use of the corresponding acid chlorides. Amino-piperazines of type B are obtained by conventional methods frequently from commercially available phenylpiperazines, by alkylation to the bosom of chlorobutyronite in basic medium in an alcoholic solvent. Then, the nitrop function is reduced in amine pnmary, either by L1AIH4 or by catalytic hydrogenated in the presence of palladium (Pd) on carbon The C-type aminobutylphenyltetrahydropindines or the C-type aminobutylphenylpipepines are also obtained by conventional methods from either commercial products, either N-Boc-4-pipepdone (where Boc means tert-butoxycarbonyl) which is reacted with a phenyl magnesium, then dehydrated to obtain the corresponding tetrahydropipdin. The corresponding pipendine is obtained by catalytic hydrogenation. The t-butoxycarbonyl (Boc) protection is hydrolyzed in an acidic medium and the nitrogen is alkylated by means of bromobutyronitop in basic medium, in the same manner as mentioned above. The preparation scheme for compounds C and D is given below: The invention will be described in greater detail below with the help of the following examples given by way of non-limiting illustration.

EXAMPLES Example 1: Preparation of N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-4-nitro-2-naphtamide (Do 885) In a recent 25 ml, 120 are dissolved mg of 1-methoxy-4-nitro-naphthalene-2-carboxylic acid A (prepared as hereinafter in (a)) in 15 ml of anhydrous acetone. 2.5 equivalents of triethylamine are added, the medium is cooled to -15 ° C in a dry ice-acetone bath. Immediately add 1.05 equivalents of isobutyl chloroformate to the mixture and allow it to react for 1 hour at -15 ° C. 1.05 equivalents of N-4-aminobutyl-N '- (2-methoxyphenyl) -piperazine B (prepared as hereinafter in (b)) are added and left to react for 2 hours at room temperature under inert atmosphere. The triethylamine hydrochloride is filtered and the filtrate is evaporated to dryness. The residue is taken up in a little ethyl acetate and the naphthamide is purified by chromatography on a column of silica (eluent: AcOEt-MeOH 90/10). The naphthamide is crystallized from diethyl ether. 85 mg of yellow crystals are obtained. R = 37%. TF = 109 ° C. 1 H NMR (CDCl 3): 1 59-1.73 (m, 2H, -CH 2 -), 2.47-2.66 (m, 6H, -H 2 C -CH 2 -CH 2 -), 3.02-3.20 (m, 4H, -CH 2 -CH 2) 3.58-3.61 (m, 4H, -H2C-CH2-), 3.86 (s, 3H, OCH3, phenyl), 4.08 (s, 3H, OCH3, naphthyl), 6.79-7.03 (m, 4H, -HC-CH -CH-CH-, phenyl), 7.68-7.85 (m, 2H, -HC-CH-), 8.27-8.31 (d, 1 H, -CH-), 8.62-8.66 (d, 1 H, - CH-), 8.87 (s, 1H, -CH). Analysis of C27H32N? 5. Cal.% C 65.84; % H 6.55; % N 1 1.37 Jan.% C 66.25; % H 6.43; % N 1 1.12 (a) Preparation of 1-methoxy-4-nitro-2-naphthoic acid (A) - 1-Methoxy-2-naphthoic acid methyl ester 1.88 g (10 mmol) of 1-hydroxy-2- acid are suspended. Naphthoic in 50 ml of methyl ethyl ketone. 2.76 g (2 equivalents) of anhydrous potassium carbonate are added, then 2.51 g (2 equivalents) of dimethyl sulfate in solution in the solvent dropwise. The mixture is refluxed with stirring for 1 night, then, after cooling, the excess potassium carbonate is filtered and the filtrate is concentrated. The evaporation residue is taken up in water and extracted several times with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and then evaporated. Purify by chromatography on a column of silica (eluent: hexane-ethyl acetate 90/10). You get a golden oil. R = 82%. 1 H NMR (CDCl 3): 4.00 (3H, s, C02CH3), 4.08 (3H, s, OCH3), 7.55-7.63 (3H, m, HC-CH-CH), 7.83-7.90 (2H, m, HC-CH ), 8.27-8.32 (1H, m, CH). 13 C NMR (CDCl 3): 52.1 (OCH 3), 58.3 (OCH 3), 166.4 (C = 0), 158.1 (CO, a), 119.0 (CC = 0, ß), 126.3 (CH, ß), 123.4 (CH, a), 128.2 (CH, a), 128.4 (CH, ß), 127.7 (CH, ß), 127.6 (CH,), 128.6 (CC,?), 136.6 (CC,?).

Methyl ester of 1-methoxy-4-nitro-2-naphthoic acid 2 g of methyl ester of 1-methoxy-2-naphthoic acid are dissolved in ml of crystallizable acetic acid. 1.2 equivalents of concentrated nitric acid in solution in crystallizable acetic acid are added dropwise and they are allowed to react for 4 hours at room temperature with good agitation. The reaction medium is slowly hydrolysed on ice. The methyl ester of 1-methoxy-4-nitro-2-naphthoic acid precipitates. The precipitate is filtered, washed several times with ice water, then redissolved in ethyl acetate, washed with water, then with a saturated solution of potassium carbonate (note 1) to remove residual acetic acid and finally, wash with water. Dry in sodium sulfate and concentrate the medium. It is purified by chromatography on a silica column (eluent: hexane-CH2Cl2 60/40). Yellow crystals are obtained. R = 89%. Melting T 110 ° C. 1 H NMR (CDCl 3): 4.02 (3H, s, -C02CH3), 4.14 (3H, s, -OCH3), 7.65-7.86 (2H, m, -HC-CH-), 8.39-8.43 (1H, dd, - CH), 8.62-8.66 (1H, dd, -CH) 8.74 (1H, s, -CH). 13 C NMR (CDCl 3): 52.7 (-OCH 3), 64.0 (-OCH 3), 164.5 (> C = 0), 162.9 (> C-0,), 116.9 (> CC = 0, ß), 124.4 ( > CH, ß), 129.5 (> C-N02, a), 141.5 (> CC,?), 123.6 (> CH, a), 131.8 (> CH, ß), 127.9 (> CH , ß), 126.6 (> CH, a), 128.2 (> CC,?).

Note 1. It is preferable not to use sodium hydroxide because a very colored complex is formed which is difficult to remove. It is important to thoroughly wash the precipitate beforehand to eliminate as much acid as possible, since the neutralization of acetic acid by K2C03 liberates carbon dioxide. 1-methoxy-4-nitro-2-naphthoic acid (A) 750 mg of 1-methoxy-4-nitro-2-naphthoic acid methyl ester are dissolved in 20 ml of methanol. 1.5 equivalents of sodium hydrogencarbonate are added and the mixture is heated at reflux for 10 hours. The medium is concentrated and the residue is taken up with water. It is extracted with ether to remove the organic impurities and the aqueous phase is acidified to pH = 2 with 5 N hydrochloric acid. A yellowish-white precipitate is obtained. It is extracted with ethyl acetate, washed three times with water, dried over sodium sulfate and the medium is concentrated. The acid is crystallized in pentane. It is purified by hot crystallization in water and by adding activated carbon to remove the impurities. White-yellowish crystals are obtained. R = 94%. (b) Preparation of N-4-aminobutyl-N '- (2-methoxyphenyl) -piperazine (B) N- (2-methoxyphenyl) -N' - (3-cyanopropyl) -piperazine 8 g of suspension are suspended. N '- (2-methoxyphenyl) -piperazine hydrochloride in 150 ml of acetonitrile. 2.5 equivalents of anhydrous potassium carbonate are added, then 1.05 equivalents of 4-bromobutyronitrile dropwise in acetopitrile solution. The mixture is heated under reflux for 10 hours, then filtered and the filtrate is concentrated. The residue is taken up in ethyl acetate and washed 3 times with water. The organic phase is extracted with a 1 M hydrochloric acid solution and the acid phase is washed with ethyl acetate. The acid phase is neutralized with 28% ammonia until pH >; 11. Extract with ethyl acetate, wash the organic phase with water, dry in anhydrous sodium sulfate and concentrate the medium. The nitrile is crystallized from hexane and recrystallized hot in this same solvent. 6.8 g of nitrile are obtained. R = 75%. TF = 74 ° C. 1 H NMR (CDCl 3): 1 80-1.94 (m, 2 H, -CH 2 -), 2.43-2.57 (m, 4 H, -CH 2 CH 2 -), 2.62-2.67 (broad t, 4 H, -CH 2 -N <), 3.09 (broad s, 4H, > N-CH2-), 3.87 (s, 3H, -OCH3), 6.85-7.04 (m, 4H, -CH-CH-CH-CH). 13 C NMR (CDCl 3): 14.9 (-CH 2 -CH 2 -C, N), 22.7 (-CH 2 -C, N), 50.5 (-CH 2 -N- (CH 2) 2-), 53.2 (> CN- (CH 2) ) 2-), 55.3 (-OCH3), 56.3 (> N-CH2), 111.1 (-CH-C-OCH3), 118.1 (-CH-CH-C-OCH3), 119.8 (-CN), 120.9 ( -CH-CN <), 122.9 (-CH-CHC-N <), 141.1 (> CN <), 152.2 (-C-OCH3).

N-4-aminobutyl-N '- (2-methoxyphenyl) -piperazine (B) 1.2 g of double lithium aluminum hydride are suspended in 50 ml of anhydrous diethyl ether (freshly distilled in sodium) in small portions (solution exothermic). 5 g of N '- (2-methoxyphenyl) -N- (3-cyanopropyl) -piperazine in anhydrous tetrahydrofuran (THF) solution are added dropwise, then heated under reflux for 2 hours. The medium is hydrolysed with a mixture of 5 ml of water in 25 ml of THF and allowed to stand overnight to allow the precipitate to agglomerate. The precipitate is filtered over zeolite, the filtrate is dried over anhydrous sodium sulfate and the filtrate is concentrated. R = 81%. 13 C NMR (CDCl 3): 24.3 (-CH 2 -CH 2 -CH 2 -NH 2), 31.9 (-CH 2 -CH 2 -NH 2), 42.2 (C_H 2 -NH 2), 50.6 (-CH 2 -N- (CH 2) 2), 53.4 ( > CN- (CH2) 2), 55.3 (-OCH3), 58.6 (> N-CH2), 111.1 (-CH-C-OCHs), 118.1 (-CH-CH-COCH3), 120.9 < -CH-C-N < ), 122.8 (-CH-CH-C-N <), 141.3 (> C-N <), 152.2 (-C-OCH3).

Example 2: Preparation of N- [4- (4-phenyl-1, 2,3,6-tetrahydropyridinyl) butyl] -2-naphthamide (Do 911) 250 mg of naphthalene-2-carboxylic acid A are suspended (2-naphthoic acid) in 20 ml of anhydrous dichloromethane (freshly distilled over CaH2). 1.2 equivalents of oxalyl chloride are added at 0 ° C, then 2 drops of anhydrous dimethylformamide (to catalyze the chlorination reaction) then allowed to react at room temperature for 1 hour in an inert atmosphere (argon) and vigorous stirring. The medium is concentrated to remove the solvent and excess oxalyl chloride, then the acid chloride formed is redissolved in 20 ml of dichloromethane. 1.05 equivalents of N-4-aminobutyl-4-phenyl-1, 2,3,6-tetrahydropyridine C (prepared as follows in (c)) are added and left to react for 2 hours at room temperature in an inert atmosphere. (argon). The medium is concentrated and the residue is taken up in an aqueous solution of 3 M hydrochloric acid. The acid phase is washed with ethyl acetate, then the aqueous phase is neutralized with a 32% ammonia solution to a pH> 0. 11. i? > Extract with ethyl acetate, wash the organic phase several times with water, dry in sodium sulfate and concentrate the medium. The residue is crystallized from a 50/50 hexane ether mixture. 280 mg of white crystals are obtained. R = 50%. TF = 172 ° C. 1 H NMR (CDCl 3): 1 73-1.83 (m, 4H, -H 2 C -CH 2 -), 2.51-2.58 (t, 4H, -H 2 C -CH 2 -), 2.69-2.75 (t, 2H, -CH2-), 3.11-3.16 (q, 2H, -CH2-), 3.52-3.58 (2H, q, -CH2-), 6.01- 6.04 (1 H, t, - CH =), 7.24-7.35 (5H, m, - (CH) 5 <phenyl), 7.39-7.55 (m, 2H, > HC-CH < naphthyl), 7.78-7.85 (4H, m, > HC-CH-CH-CH < naphthyl), 8.24 (1H, s, > CH-, naphthyl). 0 (c) Preparation of N-4-aminobutyl-4-phenyl-1, 2,3,6-tetrahydropyridine (C) 4- (4-phenyl-1, 2,3,6-tetrahydropyridinyl) butyronitrile In a flask of 250 ml, 5 g of 4-phenyl-1, 2,3,6-tetrahydropyridine hydrochloride (highly toxic compound: New Engl. J. Med., 1983, 309, 310; Science, 1983, 219, 979) are introduced.; Psychiatry Res. 1979, 1, 249) then 100 ml of acetonitrile. 2.5 equivalents of anhydrous potassium carbonate are added, then 1.05 equivalents of 4-bromobutyronitrile dropwise in acetonitrile solution. The mixture is heated at reflux for 16 hours, then filtered, the precipitate is washed with acetone and the filtrate is concentrated. The residue is taken up in ethyl acetate and washed 3 times with water. The organic phase is extracted with a 3M hydrochloric acid solution and the acid phase is washed with ethyl acetate. The acidulated phase is neutralized with 28% ammonia to a pH> 11. Extract with ethyl acetate, wash the organic phase with water, dry in sulfate r '". of anhydrous sodium and the medium is concentrated. The nitrile is purified by chromatography on a column of silica (eluent: ethyl acetate-hexane 80/20). White crystals are obtained. TF = 57-59 ° C. R = 79%. 1 H-NMR (CDCl 3, 330 ° K): 1.81-1.95 (m, 2 H, -CH 2 -), 2.40-2.48 (t, 2 H, -CH 2 -), 2.54-2.60 (t, 4 H, -H 2 C -CH 2 -) , 2.67-2.72 (t, 2H, -CH2-), 3.12-3.17 (q, 2H, -CH2-), 6.06-6.09 (m, 1 H, -CH =), 7.24- 15 7.44 (m, 5H, phenyl). 13 C NMR (CDCl 3): 14.7 (-CH 2 -CH 2 -CN), 22.8 (-CH 2 -NC), 27.7 (> C-CH 2 -CH 2 -N < pyrid), 50.0 (-CH 2 -CH 2 -N < pyrid), 52.9 (= CH-CH2-N <, pyrid), 55.9 (> N-CH2-), 119.6 (-CN), 121.3 (> CH), 124.6 (= CH-, piri), 126.8 (> (CH) 2-), 128.1 (> CH2-), 134.7 (> C = C-, piri), 140.4 (> C <). 0 N-4-aminobutyl-4-phenyl-1, 2,3,6-tetrahydropyridine (C) 1.8 g of double lithium aluminum hydride are suspended in 50 ml of anhydrous THF (freshly distilled in sodium) in small portions (exothermic solution). 4.5 g of 4- (4-phenyl-1, 2,3,6-tetrahydropyridinyl) butyronitrile in THF solution are added dropwise at 0 ° C, then allowed to react at 0 ° C for 3 hours with good agitation. The medium is hydrolyzed with a mixture of 5 ml of water in THF solution and allowed to stand overnight to agglomerate the precipitate. The precipitate is filtered in zeolite, the filtrate is dried in anhydrous sodium sulfate and the filtrate is concentrated. The residue is distilled in vacuo. A colorless oil is obtained. R = 86%. 1 H NMR (CDCl 3): 1.26 (broad s, 2H, -NH 2 -), 1.43-1.66 (m, 4H, -H 2 C -CH 2 -), 2.44-2.51 (t, 2H, -CH 2 -), 2.59 (s broad , 2H, -CH2-), 2.68-2.76 (m, 4H, -CH2-CH2-), 3.15-3.19 (d, 2H, -CH2-), 3.72-3.78 (q, 2H, -CH2-), 6.06 (q, 1H, -CH =), 7.22-7.41 (m, 5H, phenyl). 13 C NMR (CDCl 3): 24.6 i '"(-CH 2 -CH 2 -CH 2 -NH 2), 28.1 (-CH 2 -CH 2 -NH 2), 31.9 (-CH 2 -CH 2 -N < pyrid), 42.2 (-CH 2 -NH 2 ), 50.4 (CH2-CH2-N < pirid), 53.3 (= CH-CH2-N <), 58.3 (> N-CH2-) "121.9 (> CH-), 124.9 (> ) 2-), 126.9 (> (CH)), 128.2 (> C = CH- pyrid), 135.0 (> C = CH-, pyrid), 140.9 (> C <).

Example 3. Preparation of N- [4- (4-phenyl-piperidinyl) butyl] -2-naphthamide (Do 912) In a flask of 100 ml PARR, 120 mg of N- [4- (4 - phenyl-1, 2,3,6-tetrahydropyridinyl) butyl] -2-naphthamide obtained according to example 2, in 20 ml of methanol. A spatula tip of Pd / C (palladium on carbon) is added and hydrogenated in the PARR apparatus for 6 hours at a pressure of 4.2 Kg / cm2 (60 pounds per square inch). The catalyst is filtered, the catalyst is rinsed with methanol and the filtrate is concentrated. Purify by chromatography on a column of silica (eluent: ethyl acetate-methanol 90/10). It is crystallized from hexane. 110 mg of white crystals are obtained. R = 91%. TF = 143-144 ° C. 1 H NMR (CDCl 3, 330 ° K): 1.76-1.86 (m, 7H, -H 2 C -CH 2 -CH 2 -CH <), 2.06-2.14 (m, 2H, -CHr), 2.48-2.54 (m, 4H, -H2C-CH2), 3.07-3.13 (m, 2H, -CH2-), 3.56-3.60 (q, 2H, -CH2-), 6.94 (broad s, 1H, -NH), 7.12-7.29 (m, 5H , > (CH) 5-, phenyl), 7.51-7.55 (m, 2H, > HC-CH <), 7.84-7.93 (m, 4H, > HC-CH-CH-CH <), 8.30 5 (s, 1H, > CH-). Analysis of C26H3oN20 Cale. % C 80.79,% H 7.82,% N 7.25 Jan.% C 80.66,% H 7.89,% N 7.22 \F. Example 4: Preparation of N- [4- (4- (2-methoxyphenyl) -piperazinyl) butyl] butyl-1-methoxy-4-cyano-2-naphtamide (883) 120 mg of 1-methoxy acid are dissolved -cyano-naphthalene-2-carboxylic acid (prepared as in example 1 (a)) in 20 ml of anhydrous acetone. 2.5 equivalents of triethylamine are added and the medium is cooled to -15 ° C to the a dry ice-acetone bath. 1.05 equivalents of isobutyl chloroformate are added and left to react for 1 hour at -15 ° C. Then, 1.05 equivalents of N-4-aminobutyl-N '- (2-methoxyphenyl) piperazine (prepared as in Example 1 (b)) are added and left to react for 2 hours at room temperature under inert atmosphere. The triethylamine hydrochloride is filtered and the filtrate is evaporated to dryness. The evaporation residue is taken up in a little ethyl acetate and the naphthamide is purified by chromatography on a silica column (eluent: ethyl acetate-methanol 90/10). The naphthamide is crystallized from diethyl ether. 76 mg of white crystals are obtained. R = 23%. TF = 128 ° C. 13 C NMR (CDCl 3): 24.4 (-CH 2 -CH 2 -CH 2 -NH-), 27.5 (-CH 2 -CH 2 -NH-), 39.9 (-CH 2 -NH-), 50.4 (-CH N- ( CH2) 2), 53.3 (> CN- (CH2) 2-), 55.1 (-OCH3, phenyl), 58.0 (> N-CH2-), 63.4 (-OCH3, naphthyl), 106.7 (CH-C N ,), 111.0 (-CH-C-OCH3, phenyl), 116.9 (CN), 117.9 (-CH-CH-C-OCH3, phenyl), 120.8 (-CH-CN < phenyl), 122.5 (> CC = 0, ß), 122.8 (-CH-CH-CN <, phenyl), 123.6 (-CH-CH-CC-OCH3, ß), 125.5 (-CH-CC-OCH3, a), 127.5 (-CC -OCH3,?), 128.0 (-CH-CC N, a), 130.1 (-CH-CC = 0, ß), 134.4 (-CH-CH-CCCN, ß), 134.7 (-CC N,?), 141.1 (>; C-N < phenyl), 152.1 (C-OCH3, phenyl), 158.4 (-C-OCH3, a), 163.8 (> C = 0). Example 5 N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -2-naphthamide TF = 121 ° C, C26H31N302 (OD 897) Example 6 N- [4- (4- (2-chlorophenyl) piperazinyl ) butyl] -3-methoxy-2-naphthamide TF = 86 ° C, C26H30N3O2CI (OD 917) Example 7 N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -2-naphthamide TF = 107-109 ° C, C25H28CIN30 (OD 910) Example 8 N- [4- (4- (3-chlorophenyl) piperazinyl) butyl] -2-naphthamide TF = 150-152 ° C, C25H28CIN30 (OD 908) Example 9 N- [4 - (4- (4-phenyl-piperazinyl) butyl] -2-naphthamide TF = 164 ° C, C25H29N30 (OD 905) Example 10 N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] oxalate 1-methoxy-2-naphthamide TF = 164 ° C, C27H34N3? 3, C2H20 (OD 897a) Biological activity The activity of the derivatives of formula (I) according to the invention has been evaluated in cells expressing recombinant human dopaminergic receptors of which the degree of stimulation can be determined by the measurement of thymidine incorporation [3H] : CHO cells expressing the D2s receptor and NG 108-15 cells expressing the D3 receptor (Pilón et al., Eur. J. Pharmacol.Mol.Pharmacol.Sect. 1994, 268: 129-139; Sautel et al., Neuroreport , 1995, 6: 329-332). Among these derivatives, certain have a much higher affinity for the D3 receptor compared to the D2 receptor. When compounds of the nafadotride type (French patent application No. 91 13103 cited above) behave as pure antagonists of the D3 receptor, it has been discovered that, unexpectedly, the compounds of the present invention behave as powerful partial agonists of the Dopamine in the D3 receptor, its intrinsic activity varies between 50% and 80% (dopamine = 100%). Thus, the compound of Example 5 has an intrinsic activity of 60% and its effective concentration at 50% is 3 nM. This same compound has an apparent affinity 25 times weaker at the level of the D2 receptor against the D3 receptor: it is therefore an agonist (partial) very selective of the latter. Furthermore, it has also been shown that the minimal structural differences between the compounds described herein, can cause significant variations in the selectivity and intrinsic activity of the molecules. For example, when R3 and R each represent a methoxy group, this distribution causes the receptor selectivity D3 / receptor D2 to be lost in r., Relative to a monosubstitution. On the other hand, the presence of a chlorinated substituent (R3 or R4) considerably decreases the affinity of the derivative (I) for the D3 receptor. These properties lead to therapeutic applications not yet conceivable with the existing dopaminergic agents. In effect, the high selectivity of the molecules allows a selective activation of the dopaminergic transmissions of the limbic regions involved in the emotional and cognitive processes (which express the D3 receptor) without interference with the dopaminergic transmissions of the extrapyramidal, antehipphysial or vegetative systems. (postrema area). They should therefore avoid the secondary effects of the existing compounds, linked to the effect of the latter in the extrapyramidal, antihypophysial and vegetative spheres. In addition, the partial D3 antagonist character is by nature to normalize dopaminergic transmissions without risk of excessive activation.

The derivatives of the invention can thus be used for the preparation of pharmaceutical compositions and medicaments for the treatment of neuropsychiatric conditions that bring into play the D3 receptor such as psychotic or depressive states. In addition, taking into account the role of the D3 receptor in the states of drug dependence, pharmaceutical compositions or drugs based on these derivatives could be usefully administered in states linked to abstinence and / or facilitate the detoxification of cocaine dependent subjects, heroin, alcohol, nicotine, etc. The derivatives according to the invention also have effects on the erection of the penis and can thus be used for the preparation of pharmaceutical compositions and medicaments for the treatment of problems of the sexual sphere, particularly male impotence. The derivatives according to the invention, as well as, in general, the D3 receptor agonists, can also be used for a complementary treatment of the treatment of Parkinson's disease by L. DOPA. The invention is therefore concerned with such complementary medicaments as well as the use of the D3 receptor agonists and comprises the novel products of the present invention for the preparation of a medicament for the complementary treatment of the Parkinson's disease. This activity could be explained by the discovery, in an animal model of Parkinson's disease, that the treatment of L. DOPA induces the expression, in the stpatum cells, of D3 receptors that underline sensitization to the motor effects of L-DOPA. The derivatives of formula (I) according to the invention can be administered particularly orally in the form of a pharmaceutical composition. The therapeutically useful doses vary with the different derivatives but, for the compound of example 5, it can be specified that they are between 0.05 and 5 mg / kg orally. It is noted that in relation to this date, the best method <• 'known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it refers. Having described the invention as above, property is claimed as contained in the following fifteen 0

Claims (12)

1. Claims 1 Derivatives of 2-naphthamides, in the form of bases or salts, which are represented by the following general formula (I): characterized in that the entity Z-Y represents a group N-CH2, C = CH or CH-CH2; R1 represents a hydrogen, fluorine, bromine or iodine atom or a hydroxy, methoxy, nitrile or nitro group; R 2 represents a hydrogen or bromine atom or a hydroxy, methoxy, nitrile or nitro group; the substituents Ri and R2 are both located in the same nucleus of the naphtamide portion or each on one of the nuclei; R3 and R4 may be identical or different and each independently represents a hydrogen or chlorine atom or a methoxy or methyl group or an electron-withdrawing or electrophilic group.
2. 2. The derivatives according to claim 1, characterized in that the entity Z-Y represents a group N-CH23.
3. The derivatives according to claim 1, characterized in that they are chosen from the following compounds: N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-4-nitro-2-naphthamide; N- [4- (4-phenyl-1, 2,3,6-tetrahydropyridinyl) butyl] -2-naphthamide; N- [4- (4-phenyl-piperidinyl) butyl] -2-naphthamide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-4-cyano-2-naphth: amide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -2-naphthamide; N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -3-methoxy-2-naphthamide; N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -2-naphthamide; N- [4- (4- (3-chlorophenyl) piperazinyl) butyl] -2-naphthamide; N- [4- (4-phen i -Di Derazin i l) butyl II -2-naphthamide; and N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-2-naphthamide oxalate.
4. 4. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of at least one derivative according to any of claims 1 to 3, in base or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable carrier or excipient.
5. 5. The use of a derivative according to any of claims 1 to 3 for the preparation of a medicament that acts as a partial agonist of the dopamine D3 receptor.
6. 6. The use according to claim 5, for the preparation of a medicament for the treatment of neuropsychiatric conditions involving the D3 receptor of dopamine, particularly for the treatment of psychotic and depressive states, for the treatment of drug dependence states, particularly the states linked to abstinence and / or to the detoxification of subjects dependent on cocaine, heroin, alcohol, nicotine, etc., or for the treatment of problems of the sexual sphere, particularly sexual impotence.
7. 7. The use according to claim 5 for the preparation of a medicament for a complementary treatment of the disease of Parkinson.
8. 8. A medicine that acts as a partial agonist of the dopamine D3 receptor, characterized in that it comprises, as an active ingredient, at least one derivative according to any of claims 1 to 3,
9. 9. The medicament according to claim 8, for the treatment of neuropsychiatric conditions involving the D3 receptor of dopamine, particularly for the treatment of psychotic and depressive states, for the treatment of drug dependence states, particularly the states linked to abstinence. and / or the detoxification of subjects dependent on cocaine, heroin, alcohol, nicotine, etc., or for the treatment of problems of the sexual sphere, particularly male impotence.
10. 10. The medicament according to claim 8, for the complementary treatment of Parkinson's disease.
11. 11 The use of a compound that acts as an agonist of the D3 receptor of dopamine for the preparation of a drug intended for a complementary treatment of Parkinson's disease.
12. 12. A medicine that contains as an active ingredient, a compound that acts as an agonist of the D3 receptor of dopamine, intended for a complementary treatment of Parkinson's disease. SUMMARY OF THE INVENTION The invention is concerned with the 2-naphthamide derivatives, in the form of bases or salts, which are represented by the following general formula (I): wherein: the entity Z-Y represents a group N-CH2, C = CH or CH-CH2; R1 represents a hydrogen, fluorine, bromine or iodine atom or a hydroxy, methoxy, nitrile or nitro group; R 2 represents a hydrogen or bromine atom or a hydroxy, methoxy, nitrile or nitro group; the substituents Ri and R2 are both located in the same nucleus of the naphtamide portion or each on one of the nuclei; R3 and R4 may be identical or different and each independently represents a hydrogen or chlorine atom or a methoxy or methyl group or an electrophilic group. The invention is equally concerned with its therapeutic applications as the partial agonists of the dopamine D3 receptor. The invention applies more particularly to the treatment of neuropsychiatric infections involving the D3 receptor of dopamine, particularly psychotic and depressive states, to the treatment of drug dependency states or to the treatment of problems of the sexual sphere.