MXPA98003011A - New derivatives of naftilpiperac - Google Patents

Abstract

New derivatives of naphthylpiperazine of general formula (I) are described wherein R1 and R3 equal or different from each other can be hydrogen, a short chain alkyl group, halogen, a nitro group, an amino group, an acylamino group, and a short-chain alkoxy group, n can take values between 2 and 5, and R3 can be a methoxyl, a fluorine and hydrogen radical, as well as their pharmaceutically acceptable acid addition salts. The compounds have an affinity for serotonin 5HT1A and 5HT2 receptors, as well as dopamine D2 receptors and can be useful as antipsychotics. Its preparation is also described

Description

New derivatives of naft ± lp ± perac ± na.

Object of invention The present invention relates to a series of new derivatives of naphthylpiperazine and its addition salts, as well as to the process for its preparation. The new compounds exhibit central serotonergic and dopaminergic activity and are useful as antipsychotics.

BACKGROUND OF THE INVENTION The most widely accepted theory to explain the biochemical basis of schizophrenia holds that dopaminergic activity in the brain's esymbolic system is increased, and according to it, the pharmacological potency of classical antipsychotics correlates with its affinity for D2 receptors (Science 1976, 192, 481-483). On the other hand, it has been postulated (J. Pharm. Exp. Ther., 1989, 251, 238-246) that a high affinity for 5HT2 receptors, in atypical antipsychotics, would be responsible for the beneficial effects of the pharmacological profile of said atypical antipsychotics. It has also been found (J.? Eurol.Transia., 1983, 57, 255), that 5HT1A agonists are capable of reversing the haloperidol-induced catalepsy. Thus, it is possible that compounds with affinity for the 5HT1A, 5HT2, and D2 receptors may behave as atypical antipsychotics (Advances in Med. Chem., 3, 1995, 1-55). European Patent EP 0329168 describes a series of 1,4-disubstituted piperazines, in which the substituent in 1 is a bicyclic hetrocycle that incorporates an amide or imide function and the substituent in 4 is a heterocycle, with psychotropic activity. In US 4,983,606 a series of compounds carrying the phthalacinone group is collected which binds to a fragment of phenyl (benzoyl) piperazine or phenyl (benzoyl) piperidine through a carbon chain, endowed with platelet antiaggregant, antivaso-spastic and antiproliferative activity. J. Med. Chem. 1994, 37, 1060-1062 describes a series of new arylpiperazines endowed with high affinity for the D2, D3, 5-HT1A, and O11 receptors that confers them interesting antipsychotic properties, also presenting a low potential Finally, a series of arylpiperidines and arylpiperazines with antagonist properties on the D2 and 5-HT2 receptors, useful in the treatment of psychosis, are described in patent WO 93/16073. series of new derivatives of naphthylpiperazine, of formula (I), and their addition salts with pharmaceutically acceptable acids, where R x and R 2 (same or different from each other) can be hydrogen, a short chain alkyl group, halogen, a nitro group, an amino group, an acylamino group and a short chain alkoxy group; n can take values between 2 and 5, and R3 can be a methoxyl radical, a hydrogen atom, and a fluorine atom. The compounds described herein are essentially different, from those related in the aforementioned publications, by the presence of the naphthylpiperazine fragment, which characterizes them pharmacologically and confers them great affinity for the 5HT1A and 5HT2 receptors. These new compounds also have affinity for the D2 receptor, so they are useful as atypical antipsychotics.

Description of the invention The preparation of the compounds of formula (I) can be carried out by several synthetic routes, using conventional methods: a) Condensation of a compound of formula (II) where R x and R 2 have the meaning indicated for formula (I), and Z is chloro or bromo, with a piperazine of formula (III) The reaction takes place in an inert solvent, in the presence of a base, and at a temperature varying from ° C to the boiling temperature of the reaction mixture. Examples of solvents used are dichloromethane, chloroform, acetonitrile, dimethylformamide and tetrahydrofuran. The base used can be a carbonate or alkaline bicarbonate, such as K2C03, KHC03, Na2C03, NaHCO3 or a tertiary amine such as pyridine or triethylamine. The speed of the reaction can be increased by the addition, to the reaction mixture, of catalytic amounts of an alkaline iodide, such as Kl. - The piperazines of formula (III) are prepared by reaction of bis (2-chloroethyl) amine with the corresponding naphthylamine. The compounds of general formula (II), used as starting materials in the above condensation step, are prepared by reaction of a compound of general formula (IV) where R x and R 2, as defined above, with an alkyl dihalide in the presence of a strong base, such as NaH in an aprotic solvent such as dimethylformamide or tetrahydrofuran, or solid potassium hydroxide in dimethylformamide, at a temperature ranging from room temperature at 100 ° C. The compounds of general formula (IV) are prepared by reaction of the appropriate 2-formylbenzoic acids with hydrazine hydrate. Alternatively, the compounds of general formula (II) can be prepared by replacing the hydroxyl group of the compounds of formula (V) with chlorine or bromine.

The substitution reaction can be carried out by treatment with hydrogen chloride, hydrogen bromide, or by treatment with halides of organic or inorganic acids, such as thionyl chloride, oxalyl chloride, in an inert solvent such as chloroform, dichloromethane, or toluene, or by using the acid chloride as the solvent, at a temperature which may vary between 0 ° C to the boiling temperature of the reaction mixture. In turn, the compounds of the general formula (V) can be prepared as indicated in Chimie Thérapeutique, 1967, 2, 250-253. As already indicated above, the novel compounds of general formula (I), according to the present invention, show activity on the CNS, particularly at the level of 5HT1A, 5HT2 and D2 receptors.

STUDIES OF UNION TO PHARMACOLOGICAL RECEPTORS. Studies of binding to the SHTm, 5HT2 and D2 receptors have been carried out to determine the affinity of the compounds object of the present invention for said receptors.

RECEIVER 5HT1A Cerebral cortex obtained from Wistar rats of both sexes, was homogenized in 0.32 M sucrose buffer (1:10 g / mL) and centrifuged at 900 g (10 min, 4 ° C). The supernatant was collected and centrifuged at 48,000 g (25 min, 4 ° C). The sediment thus obtained was resuspended in 50 mM TRIS buffer (pH 7.5) cold (1:10, g / mL), homogenized, incubated at 37 ° C for 15 min and centrifuged again at 48000 g (25 min, 4 ° C). The final pellet was resuspended in cold SNAYDER buffer (1: 4, g / mL), homogenized and stored at -70 ° C in 5 mL capacity containers. For the displacement experience, 100 μL of radioligand (2 nM, final conc.), 100 μL of the different tested concentrations of the displacer product and 750 μL of a membrane suspension 1:32 in SNAYDER with pargyline were used. The volume was completed to 1 mL, with 50 μL of SNAYDER. To define the non-specific binding, 10 μM serotonin (5HT) was used.

RECEIVER 5HT2A Pre-frontal cortex obtained from Wistar rats of both sexes, was homogenized in 0.25 M sucrose buffer (1:10 g / mL) and centrifuged at 1080 g (10 min, 4 ° C). The supernatant was reserved and the pellet resuspended in the same buffer (1: 5, g / mL), and centrifuged again under the same conditions. The mixture of the two supernatants was completed to 1:40 (g / mL) with 50 mM TRIS buffer (pH 7.7) and centrifuged at 35,000 g (10 min, 4 ° C). The sediment thus obtained was resuspended in cold TRIS buffer (1:40, g / mL) and centrifuged again at 35000 g (10 min, 4 ° C). The final pellet was resuspended in cold TRIS buffer (1:10, g / mL), homogenized and stored at -70 ° C in 5 mL capacity containers. For the displacement experience, 100 μL of radioligand (0.5-1 nM, final concentration), 100 μL of the different tested concentrations of the displacer product and 750 μL of a membrane suspension 1:50 were used. (0.54 mg / mL, 15 mg fresh tissue) in TRIS. The volume was completed to 1 mL, with 50 μL of TRIS / 10% ethanol. To define the non-specific binding, Metisergida 1 uM was used. All dilutions of the displacer, radioligand and Metysergide, were made with TRIS buffer with 10% ethanol (v / v).

RECEIVER D2 Striated obtained from Wistar rats of both sexes, was homogenized in 50 mM TRIS buffer pH 7.7 (1:50 g / mL) and centrifuged at 47800 g (10 min, 4 ° C). The supernatant was removed and the pellet resuspended in the same buffer (1:50, g / mL), incubated at 37 ° C for 10 min and centrifuged again under the same conditions. The final pellet thus obtained was resuspended in TRIS buffer cold 50 mM (pH 7.4) (1:10, g / mL) containing 120 mM NaCl + 5 mM KCl + 2 mM CaCl2 + 1 mM MgCl 2 + 0.01% g / mL ascorbic acid and stored at -70 ° C in 2.5 mL aliquots. Subsequently dilutions of the membranes were made (1: 100-1: 300) and the amount of proteins was assessed by the Lowry method. For the displacement experience, 100 μL of radioligand (1-2 nM, final conc.), 100 μL of the different tested concentrations of the displacer product and 750 μL of a membrane suspension 1: 150 (0.39-0 , 43 mg protein / mL) in the above TRIS (saline) + 10 μM pargyline. The volume was completed to 1 mL, with 50 μL of the previous TRIS. To define the non-specific binding, 1 μM Butaclamol was used, which was added (100 μL) to the blank series. All dilutions of the displacer, radioligand and Butaclamol, were performed with TRIS buffer (saline) + pargyline. The samples were incubated for 60 min at 25 ° C.

The products described in the present invention have shown high affinity (of the nanomolar range) for the three receptors tested, which makes them potentially useful as antipsychotics.

The following examples give more details about the invention, without this being limited in any way to them.

Example 1. 2- (4-Bromobutyl) -1 (2H) -phthalacinone. On a solution of 7.3 g. (50 mmol) of 1 (2H) -phthalacinone, in 100 mL. of dimethylformamide, cooled to 0 ° C, 2.5 g are added in small portions. (60 mol) of a 60% dispersion of NaH in mineral oil. The reaction mixture is allowed to reach room temperature, and is maintained with stirring for one hour. Then, 18 mL (150 mmol) of 1,4-dibromobutane are added at once and the reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is poured onto crushed ice, extracted with ethyl ether (2 times) and the organic extracts are dried over anhydrous Na2SO4 and concentrated to dryness. The excess dibro-obutan is removed by distillation and the residue obtained is purified by a "flash" column (CH2C12) to obtain 11.6 g. (yield: 83%) of an oil identified based on its spectroscopic data as the product of the title.

Example 2. 2- Í4- (4-naphthylDiperacin-1-yl) -butyl -1 (2H) -phthalacinone.

A mixture of 1.7 g. (6 mmol) of 2- (4-bromobutyl) -1 (2H) -phthalacinone, 1.3 g. (6 mol) of 1-naphthylpiperazine, 0.84 g. (6 mmol) of K2C03 and 10 mg. of Kl in 50 mL of acetonitrile, is heated to reflux for 4 hours. After heating, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and water; The aqueous phase is extracted with dichloromethane (2 times). The organic extracts are combined, dried over anhydrous Na2SO4 and concentrated to dryness. The obtained residue is purified by flash column (CH2Cl2 / MeOH 97: 3) obtaining 1.7 g of 2- [4- (4-naphthylpiperazin-1-yl) -butyl] -1 (2H) -phthalacinone. Treatment with hydrochloric ethanol gives a white solid, which is recrystallized from methanol, to give the monohydrochloride of the title compound having a P.F. above 260 ° C.

Example 3. 2- (2-hydroxyethyl) -6,7-dimethoxy-l (2H) -phthalacinone.

To a solution of 10.5 g (50 mmol) of 6-formyl-3,4-di-ethoxy-benzoic acid in 100 mL of ethanol is added 4.2 g (55 mmol) of 2-hydroxyethylhydrazine. The reaction mixture is heated to reflux for 3 hours; after which the solvent is removed under reduced pressure. The resulting residue is treated with ethyl ether to give a white solid which is collected by filtration, yielding 9.2 g of 2- (2-hydroxy) -6,7-dimethoxy (2 H) -t. to the acinone (yield: 76%). P. F. = 176-179 ° C.

Example 4. 2- (2-Chloroethyl) 1-6,7-dimethoxy-l (2H) -phthalacinone.

On a solution of 2.5 g (10 mmol) of 2- [2- (hydroxyethyl)] -6,7-dimethoxy-l (2H) -phthalacinone in 50 mL of chloroform, (15 mmol) of sodium chloride is added. Thionyl and the mixture is kept under stirring at room temperature overnight. The solvent is removed, under reduced pressure; the solid obtained is treated with hexane, filtered and purified by flash column (CH2C12) obtaining 2.2 g (yield: 81%) of 2- (2-chloroethyl) -6,7-dimethoxy-1 (2H ) -ftalacinone. P.F. 178-181 ° C.

Example 5. 2- 2 - (4-naphthylpiperazin-1-yl) -ethyl-6,7-dimethoxy-l (2H) -phthalacinone. A mixture of 1.6 g. (6 mmol) of 2- (2-chloroethyl) -6,7-dimethoxy-1 (2H) -phthalacinone, 1.3 g. (6 mmol) of 1-naphthylpiperazine, 0.84 g. (6 mmol) of K2C03 and 10 mg. of Kl in 50 mL of acetonitrile, heated to reflux for 7 hours. After heating, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and water; The aqueous phase is extracted with dichloromethane (2 times). The organic extracts are combined, dried over anhydrous Na2SO4 and concentrated to dryness. The obtained residue is purified by flash column (CH2Cl2 / MeOH 97: 3) obtaining 1.5 g of 2- [2- (4-naphthylpiperazin-1-yl) -ethyl] -6,7-dimethoxy-l (2H) -ftalacinone. Treatment with hydrochloric ethanol gives a white solid, which is recrystallized from methanol, to give the monohydrochloride of the title compound having a P.F. above 260 ° C.

Claims (17)

1. CLAIMS 1.- New naphthylpiperazine derivatives, characterized by comprising compounds of general formula (I) where R1 and R2, equal or different from each other, can be hydrogen, a short chain alkyl, halogen, a nitro group, an amino group, an acylamino group and a short chain alkoxy group; n can take values between 2 and 5; and and R3 may be a methoxyl radical, a fluorine atom and hydrogen.
2. 2.- New naphthylpiperazine derivatives according to claim 1, characterized in that it comprises a compound consisting of a 2- [4- (4-naphthylpiperazin-1-yl) -butyl] -1 (2H) -phthalacinone.
3. 3.- New derivatives of naph ilpiperazine, according to claim 1, characterized in that it comprises a compound consisting of a 2- [3- (4-naphthylpiperazin-1-yl) -propyl] -1 (2H) -phthalacinone.
4. 4.- New naphthylpiperazine derivatives according to claim 1, characterized in that it comprises a compound consisting of a 2- [2- (4-naphthylpiperazin-1-yl) -ethyl] -1 (2H) -phthalacinone.
5. 5.- New naphthylpiperazine derivatives according to claim 1, characterized in that it comprises a compound consisting of a 2- [4- (4-naphthylpiperazin-1-yl) -butyl] -6,7-dimethoxy-l (2H) - phthalacinone
6. 6.- New naphthylpiperazine derivatives according to claim 1, characterized in that it comprises a compound consisting of a 2- [2- (4-naphthylpiperazin-1-yl) -ethyl] -6,7-dimethoxy-l (2H) - phthalacinone
7. 7. - New naphthylpiperazine derivatives according to claim 1, characterized in that they comprise a compound consisting of a 2- [4- (4-naphthylpiperazin-1-yl) -butyl] -7-nitro-l (2H) -phthalacinone.
8. 8.- New naphthylpiperazine derivatives according to claim 1, characterized in that it comprises a compound consisting of a 2- [4- (4-naphthylpiperazin-1-yl) -butyl] -7-amino-1 (2H) -phthalacinone.
9. 9.- New naphthylpiperazine derivatives according to claim 1, characterized in that it comprises a compound consisting of a 2- [4- (4-naphthylpiperazin-1-yl) -butyl] -7-acetylamino-l (2H) -phthalacinone.
10. 10.- New naphthylpiperazine derivatives according to claim 1, characterized in that it comprises a compound consisting of a 2- [3- (4-naph il-piperazin-1-yl) -propyl] -7-nitro-l (2H) -phthalacinone .
11. 11.- New naph ilpiperazine derivatives according to claim 1, characterized in comprising a compound consisting of a 2- [4- (4- (7-methoxynaphthyl) -piperazin-1-yl) -butyl] -1 (2H) -ftalacinone.
12. 12.- New naphthylpiperazine derivatives according to claim 1, characterized in that it comprises a compound consisting of a 2- [3- [4- (7-methoxynaphthyl) -piperazin-1-yl) -propyl] -1 (2H) - phthalacinone
13. 13.- New naphthylpiperazine derivatives according to claim 1, characterized in that it comprises a compound consisting of a 2- [4- [4- (7-methoxynaphthyl) -piperazin-1-yl) -butyl] -7-nitro-1 (2H) -ftalacinone.
14. 14. - New derivatives of naph ilpiperazine, according to claim 1, characterized in that it comprises a compound consisting of a 2- [3- [4- (7-methoxynaphthyl) -piperazin-1-yl) -propyl] -7-nitro-1 ( 2H) -f-alacinone.
15. 15.- New naph ilpiperazine derivatives according to claim 1, characterized in that it comprises a compound consisting of a 2- [4- [4- (7-methoxynaphthyl) -piperazin-1-yl) -butyl] -6, 7- dimethoxy-1 (2H) -phthalacinone.
16. 16.- New naphthylpierazine derivatives according to claims 1 to 15, characterized in that they comprise addition salts with pharmaceutically acceptable acids of the compounds of formula (I).
17. 17.- New naphthylpiperazine derivatives according to claims 1 to 15, characterized by the use of the compounds of formula (I) as antipsychotics.