Derivatives naphthylamide and their pharmaceutically acceptable acid salt additive, a method of treating psychotic states

 

(57) Abstract:

Describes the new derivatives naphthylamide formula (I), where R1halogen, cyano, R2- nerasvetlena or branched alkyl with 1-6 carbon atoms, R3is phenyl, unsubstituted or substituted by 1-2 substituents selected from C1-6of alkyl, halogen, C1-6alkoxy or thio-C1-6alkoxy, 4-pyridinyl, 3-benzisothiazolin or 7-benzo[b] furanyl, and their pharmaceutically acceptable acid salt additive. The compounds of formula (I) are dopaminergic agents, useful as antipsychotic agents for the treatment of psychoses such as schizophrenia. 2 S. and 2 C.p. f-crystals, 1 PL.

The invention relates to new derivatives of naphthylamide possess biological properties, as well as to a method of treating psychotic States.

Antagonists of dopamine D2 are known antipsychotic agents. Recently discovered receptor dopamine D3, which is apparently responsible for some of the actions antipsihoticeskih agents (see Jean-Charles Schwartz and others, The Dopamine D3 Receptor as a Target for Antipsychotics, Novel Antipsychotic Drugs, edited by H. Y. Meltzer, publisher Raven Press, new York, 1992 , PP 135-144). Identification of MESTNAJA is more antipsychotic action of D2 receptors, however, do not have neurological side effects (see P. Sokoloff and others, Molecular Cloning and Characterization of a Novel Dopamine Receptor (D3) as a Target for Neuroleptics, Nature, 347: 146 (1990); P. Sokoloff and others, Localization and Function of the D3Dopamine Receptor, Arzneim.-Forsch./Drug Res., 42(1): 224 (1992 g)).

In published application EP N 539281 A1 describes derivatives of naphthylamide and their pharmaceutically acceptable acid additive salts that are useful as antipsychotic, antidepressant, stimulating, antiautisticskie agents, agents against Parkinson's disease and agents from and against hypertension.

Object of the invention is the expansion of the range of highly active derivative naphthylamide as with selectivity relative to the subtype of dopamine receptor D3 dopaminergic agents that can be used in the treatment of psychosis.

The problem is solved proposed derivatives naphthylamide General formula (I)

< / BR>
in which R1halogen, cyano,

R2is unbranched or branched alkyl with 1-6 carbon atoms,

R3is phenyl, unsubstituted or substituted by 1-2 substituents selected from C1-6of alkyl, halogen, C1-6alkoxy or thio-C1-6alcok the different salts.

Pharmaceutically acceptable acid additive salts of compounds of formula (I) are, for example, salts of non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, Hydrobromic acid, itestosterone acid, phosphoric acid, etc. and salts of non-toxic organic acids such as aliphatic mono - and dicarboxylic acids, hydroxyl alkanoyl acids, landiwiese acids, aromatic acids, aliphatic acids, aromatic sulfonic acids, etc. Thus, these salts include the sulfate, persulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, kaprilat, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, bansilalpet, toluensulfonate, phenyl acetate, citrate, lactate, tartrate, methanesulfonate, etc., Other possible salts are salts of amino acids, for example, Argent etc., gluconate, galacturonic.

Acid additive salts of these basic compounds get way the tsya salt in a known manner. Free basic form can again be obtained by casting salt into contact with the base and allocate the free base by a known method. Free base differ from their respective salt on certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base in the field of pharmaceutical use in accordance with the present invention.

Some members of the proposed compounds may be present in undissolved or dissolved form, including gidratirovannuyu form. In total dissolved forms, including gidratirovannuyu shape equivalent with undissolved forms, and they are also covered by the present invention.

Preferred are the compounds of formula (I) in which R1halogen or cyano, and R2is methyl or ethyl.

Particularly preferred compounds selected from the group including

4-bromo-N-{ 2-[4-(2,3-dichlorophenyl)-1-piperazinil] ethyl}-1-methoxy-2 - naphthaleneboronic;

4-bromo-1-methoxy-N-[2-(4-phenyl-1-piperazinil)ethyl] -2 - naphthaleneboronic;

4-bromo-1-methoxy-N-[2-(4-pyridin-2-yl-1-piperazinil)this is d;

4-bromo-1-methoxy-N-{ 2-[4-(2-propylsulfonyl-phenyl)-1 - piperazinil]ethyl} -2-naphthaleneboronic;

4-bromo-1-methoxy-N-[2-(4-o-tolyl-1-piperazinil)ethyl] -2 - naphthaleneboronic;

4-bromo-N-{ 2-[4-(2,3-dimetilfenil)-1-piperazinil]ethyl}-1-methoxy-2 - naphthaleneboronic;

4-bromo-N-{ 2-[4-(2-chlorophenyl)-1-piperazinil]ethyl}-1-methoxy-2 - naphthaleneboronic;

4-bromo-N-{ 2-[4-(3-chlorophenyl)-1-piperazinil]ethyl}-1-methoxy-2 - naphthaleneboronic;

4-bromo-N-{ 2-[4-(4-chlorophenyl)-1-piperazinil]ethyl}-1-methoxy-2 - naphthaleneboronic;

4-bromo-N-{ 2-[4-(3-chloro-2-were)-1-piperazinil]ethyl}-1 - methoxy-2-naphthaleneboronic;

4-bromo-1-ethoxy-N-{ 2-[4-(2-methoxyphenyl)-1-piperazinil] ethyl}-2 - naphthaleneboronic;

4-bromo-1-ethoxy-N-[2-(4-pyridin-2-yl-1-piperazinil)ethyl]-2 - naphthaleneboronic;

4-cyano-1-methoxy-N-[2-(4-phenyl-1-piperazinil)ethyl] -2 - naphthaleneboronic;

N-{ 2-[4-(3-benzisothiazolin)-1-piperazinil] ethyl} -4-bromo-1 - methoxy-2-naphthaleneboronic;

N-{ 2-[4-(7-benzo[b] furanyl)-1-piperazinil] ethyl}-4-bromo-1 - methoxy-2-naphthaleneboronic;

and their pharmaceutically acceptable acid additive salt.

The ability of compounds of the formula (I) selective binding with the receptor dopamine D3 was detected by determining the ing the zie and other (see Characterization of the human dopamine D3 receptor expressed in transfected cell lines, Eur. J. Pharmacol. 266: 79 (1994)) and the ability to reversibly caused by amphetamine stimulation of the engine system in the rat according to the method described by R. C. Parker (see Life Sci., 22: 1067-1076 (1978 )). This technique is a traditional experience to predict antipsychotic actions of dopamine antagonists. It is known that amphetamines increase the release of dopamine in the brain, which leads to similar psychosim phenomena in man. Giving amphetamine rodents leads to a painful condition, which is manifested in increased motor activity. Removing this motor activity in rodents by a reduced level of dopamine indicates antipsychotic activity in man. Data presented in table show receptor binding activity and antipsychotic activity of the compounds of formula (I) (see the end of the description).

A similar activity and other compounds according to the invention.

Taking into account the above biological data further object of the invention is a method of treating psychotic States by introducing the patient a therapeutically effective amount derived by Neftyanoi formula (I) or its pharmaceutically acceptable acid additive salt in the form of a suitable drug.

Compounds of the above formula (I) can be obtained by known methods, for example by reacting the compounds of formula (II)

< / BR>
in which R1and R2have the above values,

with the compound of the formula (III)

< / BR>
in which R3have the above values. in the presence of a binding agent, for example isobutyl-chloroformate, and bases, such as triethylamine or similar , or dicyclohexylcarbodiimide or etc., in the environment of a solvent, such as tetrahydrofuran, dichloromethane or etc., at a temperature of about 0oC.

The compound of formula (III) are obtained from the compounds of formula (IV)

< / BR>
in which R3have the above values,

in the presence of a reducing agent such as lithium aluminum hydride or similar , in the environment of a solvent, such as tetrahydrofuran or etc., at a temperature of about 0oC. Preferably the reaction is carried out in the presence of lithium aluminum hydride in an environment of tetrahydrofuran at a temperature of about 0oC.

The compound of formula (IV) are obtained by reacting the compounds of formula (V)

< / BR>
in which R3have the above values,

with the compound of the formula (VI)

Hal-CH2 the Christmas metal for example potassium carbonate or similar, or a carbonate or hydroxide of alkaline earth metal in the environment of the solvent, for example acetonitrile, or etc., at a temperature from about room temperature up to the temperature phlegmy solvent. Preferably the reaction is carried out in the presence of potassium carbonate in an environment of acetonitrile at about the temperature phlegmy.

Compounds of formula (II), (V) and (VI), or known, or they can be obtained with known methods.

Compounds according to the invention can be given in the form of various preparations intended for oral or parenteral villas. For example, the proposed connection can be given by intravenous, intramuscular, intradermal, subcutaneous, vnutribolnychnoy or intraperitoneal injection, or they can be given by inhalation, for example, through the nose. Further, the proposed connection can be given transdermal.

To obtain pharmaceutical compositions using compounds of formula (I) can be used, or a solid or liquid pharmaceutically acceptable carriers. Solid preparations may be in the form of powder, tablets, pills, capsules, suppositories, or capable of dispersing granules. As a solid novtel azmoudeh agent, preservative agent, contributing to the dissolution of the tablets of the agent or material of the capsule.

In powders, the carrier is malorasprostranennoe solid is mixed with melkorazdroblennym active substance.

In tablets, the active substance in a suitable ratio is mixed with carrier having the necessary binding properties, and the mixture is transferred into a compact tablet of desired shape and size.

In powders and tablets active substance has preferably a number from 5 or 10 to about 70 percent. Suitable carriers are, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, carboxymethylcellulose sodium, wax with a low melting point, coconut oil, etc. In this context, the term "drug" in the case of capsules, you should understand the totality of the active substance with the enclosing material as a carrier, forming a capsule in which the total of the active substance with further carriers or without them. Tablets, powders, capsules, pills, cachets, and lozenges can be used in the form of individual doses, available in solid form and is capable of oral is an example of a mixture of glycerides of fatty acids or coconut oil, then, while stirring in him is homogeneous dispersed active substance. The molten homogeneous mixture is then poured into molds of suitable size and cool, and suppositories harden.

As preparations in liquid form can be called solutions, suspensions and emulsions, such as solutions in water or water and propylene glycol. Liquid preparations intended for parenteral injection may be present as a solution in water and glycol.

Aqueous solutions suitable for oral villas, can be obtained by dissolving the active substance in water and adding, if necessary, suitable colorants, flavoring agents, stabilizers and thickeners.

Next, intended for giving oral suspension can be obtained by dispersing melkodispersnogo active substances in water containing a viscous material such as natural or synthetic rubbers, resins, methylcellulose, carboxymethylcellulose sodium, or other known suspendresume agents.

It is also possible solid dosage forms intended for cooking liquid preparations for oral villas directly before use. As did the CSOs substances, dyes, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, dissolving agents, etc.

Preferably, the pharmaceutical preparation is available in the form of individual doses. This means that the preparation is subdivided into individual doses, containing suitable quantities of the active substance. Individual doses can be Packed, with one unit, for example a box contains a certain amount of the drug, such as packaged tablets, capsules, and powders in vials or ampoules. Single dose may constitute the capsule, a tablet, or a certain number of these units in Packed form.

The amount of active substance per dose can vary and can be 1 to 1000 mg, preferably 10 to 100 mg depending on the specific form of villas and power of action of the active substance. If necessary, the composition may contain other compatible agents, has a therapeutic effect.

In the case of use in the framework of the proposed method of treatment of psychosis connections give in an amount of about 1 to 50 mg per 1 kg of body weight per day as a starting dose. Prepost what I depending on the needs of the patient, the severity of the disease, and specifically used for the connection. The person skilled in the art can determine the appropriate dose in each case. In General, the treatment is started with the dose, the smaller the optimal dose and then the dose is increased slowly to achieve the optimal result. If desired, for the sake of convenience, the total daily dose can be divided into separate doses that yield multiple servings a day.

Obtaining compounds of formula (I) is illustrated by the following examples.

Example 1. 4-Bromo-N-{ 2-[4-(2,3-dichlorophenyl)-1-piperazinil]ethyl}-1 - methoxy-2-naphthaleneboronic

Stage A: Obtain 4-(2,3-dichlorophenyl)-1-piperidinecarbonitrile

0.5 g (0,0216 mol) of 2,3-dichloronitrobenzene, to 1.37 ml (0,0216 mol) of chloroacetonitrile and 14.95 g (0,0108 mol) of potassium carbonate are served in acetonitrile and heated at a temperature of phlegmy for 18 hours, the Reaction mixture was concentrated in vacuo and the resulting residue partitioned between water and dichloromethane. The organic layer is dried over sodium sulfate and concentrated, resulting in a gain of 5.45 g of the target compound as a yellow solid: melting point: 89-92oC.

Stage B: Obtain 4-(2,3-dichlorophenyl)-1-piperazineethanol 0oC drops added to a suspension of 0.84 g (0,210 mol) of lithium aluminum hydride in 50 ml of dry tetrahydrofuran. The suspension is stirred at 0oC for 3 h, then add 2 drops of n sodium hydroxide.

The resulting mixture was filtered through silica trademark Celite and concentrated in vacuum, and obtain 5.7 g of the target compound as a yellow oil.

Stage: Obtain 4-bromo-N-{ 2-[4-(2,3-dichlorophenyl)-1 - piperazinil] ethyl}-1-methoxy-2-naphthaleneboronic

1,24 ml (8,87 mmol) of triethylamine and 0.50 ml (3.9 mmol) of isobutylacetate at 0oC is added to 1.0 g (3,55 mmol) of 1-methoxy-4-bromo-2-naftalofos acid in 20 ml dry tetrahydrofuran and stirred for 1 h To the resulting mixed anhydride added 0.97 g (3,55 mmol) of 4-(2,3-dichlorophenyl)-1-piperazinecarboxamide in 5 ml of dry tetrahydrofuran and continue to stir for 18 h, and the mixture is allowed to slowly warm to room temperature. The reaction mixture is washed with saturated sodium chloride, dried over sodium sulfate and concentrated, resulting in a gain of 0.27 g of the target compound as a white solid: melting point: 137oC.

Analogously to example 1 are the following compounds.

Example 2. 4-Bromo-1-is 3. 4-Bromo-1-methoxy-N-[2-(4-pyridin-2-yl-1 - piperazinil)ethyl]-2-naphthaleneboronic; melting point: 201oC.

Example 4. 4-Bromo-1-methoxy-N-{2-[4-(2-methoxyphenyl)-1 - piperazinil]ethyl} -2-naphthaleneboronic; melting point: 198oC.

Example 5. 4-Bromo-1-methoxy-N-{2-[4-(2-propylsulfonyl)-1 - piperazinil]ethyl}-2-naphthaleneboronic; melting point: 206oC.

Example 6. 4-Bromo-1-methoxy-N-[2-(4-o-tolyl-1-piperazinil)ethyl]-2 - naphthaleneboronic; melting point: 190oC.

Example 7. 4-Bromo-N-{2-[4-(2,3-dimetilfenil)-1-piperazinil]ethyl}-1 - methoxy-2-naphthaleneboronic; melting point: 192oC.

Example 8. 4-Bromo-N-{2-[4-(2-chlorophenyl)-1-piperazinil]ethyl}-1 - methoxy-2-naphthaleneboronic; melting point: 158oC.

Example 9. 4-Bromo-N-{2-[4-(3-chlorophenyl)-1-piperazinil]ethyl-1 - methoxy-2-naphthaleneboronic; melting point: 113-114oC.

Example 10. 4-Bromo-N-{ 2-[4-(4-chlorophenyl)-1-piperazinil]ethyl)-1 - methoxy-2-naphthaleneboronic; melting point: 153oC.

Example 11. 4-Bromo-N-{2-[4-(3-chloro-2-were)-1 - piperazinil]ethyl}-1-methoxy-2-naphthaleneboronic; melting point 143oC.

Example 12. 4-Bromo-1-ethoxy-N-{2-[4-(2-methoxyphenyl)-1 - piperazinil]ethyl} -2-naphtalen the]-2-naphthaleneboronic; the melting point 100-104oC.

Example 14. 4-Cyano-1-methoxy-N-[2-(4-phenyl-1-piperazinil)ethyl]-2 - naphthaleneboronic: melting point: 128-129oC

Example 15. N-{2-[4-(3-Benzisothiazolin)-1-piperazinil]ethyl}-4 - bromo-1-methoxy-2-naphthaleneboronic; melting point 125-126oC.

Example 16. N-{2-[4-(7-Benzo[b]furanyl)-1-piperazinil]ethyl}-4 - bromo-1-methoxy-2-naphthaleneboronic; melting point: 136oC.

1. Derivatives naphthylamide formula (I)

< / BR>
in which R1- halogen, cyano;

R2is unbranched or branched alkyl with 1 to 6 carbon atoms;

R3is phenyl unsubstituted or substituted by 1 to 2 substituents selected from C1-6of alkyl, halogen, C1-6alkoxy or thio-C1-6alkoxy, 4-pyridinyl, 3-benzisothiazolin or 7-benzo[b]furanyl,

and their pharmaceutically acceptable acid additive salt.

2. Derivatives naphthylamide formula (I) under item 1, in which R1halogen or cyano, and R2is methyl or ethyl.

3. Derivatives naphthylamide formula (I) under item 1, representing

4-bromo-N-{ 2-[4-(2,3-dichlorophenyl)-1-piperazinil)] ethyl}-1-methoxy-2-naphthaleneboronic;

4-bromo-1-methoxy-N-[2-(4-phenyl-1-piperazinil)ethyl] -2-NAF is-1-methoxy-N-{ 2-[4-(2-methoxyphenyl)-1-piperazinil] ethyl}-2-naphthaleneboronic;

4-bromo-1-methoxy-N-{ 2-[4-(2-propylsulfonyl-phenyl)-1-piperazinil]-ethyl} -2-naphthaleneboronic;

4-bromo-1-methoxy-N-[2-(4-o-tolyl-1-piperazinil)ethyl] -2-naphthaleneboronic;

4-bromo-N-{ 2-[4-(2,3-dimetilfenil)-1-piperazinil)-1-piperazinil] ethyl}-1-methoxy-2-naphthaleneboronic;

4-bromo-N-{ 2-[4-(2-chlorophenyl)-1-piperazinil] ethyl}-1-methoxy-2-naphthaleneboronic;

4-bromo-N-{ 2-[4-(3-chlorophenyl)-1-piperazinil] ethyl}-1-methoxy-2-naphthaleneboronic;

4-bromo-N-{ 2-[4-(4-chlorophenyl)-1-piperazinil] ethyl}-1-methoxy-2-naphthaleneboronic;

4-bromo-N-{ 2-[4-(3-chloro-2-were)-1-piperazinil] ethyl}-1-methoxy-2-naphthaleneboronic;

4-bromo-1-ethoxy-N-{ 2-[4-(2-methoxyphenyl)-1-piperazinil] ethyl} -2-naphthaleneboronic;

4-bromo-1-ethoxy-N-[2-(4-pyridin-2-yl-1-piperazinil)ethyl] -2-naphthaleneboronic;

4-cyano-1-methoxy-N-[2-(4-phenyl-1-piperazinil)ethyl] -2-naphthaleneboronic;

N-{ 2-[4-3-(benzisothiazolin)-1-piperazinil] ethyl} -4-bromo-1-methoxy-2-naphthaleneboronic and N-{ 2-[4-(7-benzo[b]furanyl)-1-piperazinil]ethyl}-4-bromo-1-methoxy-2-naphthaleneboronic.

4. A method of treating psychotic States by introducing the patient a therapeutically effective amount of a derivative naphthylamide, characterized in that as a function of ol in the form of a suitable drug.

 

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< / BR>
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