Substituted 1,2,3,4-tetrahydro-2-naphthalenamine, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new substituted 1,2,3,4-tetrahydro-2-naphthalenamine formula I, where R1and R2independently represent hydrogen, C1-4alkyl, C1-4alkoxy, halogen, trifluoromethyl; R3represents hydrogen, hydroxyl, C1-4alkoxyl, cyano, carbarnoyl; R4and R5independently represent hydrogen, C1-4alkyl, hydroxy2-4alkyl, or form together with the nitrogen atom to which they are attached, piperidine; in the form of free bases or salts obtained by joining acids. The method of obtaining the compounds of formula I by reacting the compounds of formula II with the compound of the formula III and the compound obtained is isolated in the form of free bases or salts obtained by joining acids. Pharmaceutical composition having anticonvulsive activity, activity during ischemia induced neuronal damage and activity in conditions involving the release of glutamate containing the compound of formula I in free base form or pharmaceutically acceptable salt, in therapeutically effective amounts. 3 c. and 5 C.p. f-crystals, 1 PL.

m), their receipt, their use as pharmaceuticals, and to the containing pharmaceutical compositions.

In the first aspect in accordance with the invention offers 1,2,3,4-tetrahydro-2-naphthalenamine, bearing a phenyl substituent in the aromatic ring, and their salts obtained by the accession acid.

Phenyl substituent is preferably in position 5 2 naphthalenamine.

A phenyl substituent may bear additional substituents, for example, as in the case of formula I, below.

Additional substituents may also be represented conveniently, but not exclusively, on the aromatic ring, for example, in position 8 2 naphthalenamine, when the phenyl group is in position 5.

In particular, the present invention features a compound of formula I

< / BR>
where R1and R2independently represent hydrogen, (C1-4)alkyl, (C1-4)alkoxy, (C1-4)allylthiourea, halogen, trifluoromethyl, trifluromethyl, cyano, (C2-5)alkanoyl, (C1-4)alkylsulfonyl or sulfamoyl,

R3represents hydrogen, hydroxyl, (C1-4)alkyl, (C1-4)alkoxy, halogen, -

R4and R5independently represent hydrogen, (C1-4)alkyl, hydroxy(C2-4)alkyl or phenyl(C1-4)alkyl, or form together with the nitrogen atom to which they are attached, pyrrolidinyl, piperidino or piperazinil,

in free base form or salt obtained by the accession acid.

Halogen represents fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

Any alkyl, CNS, alkylthio radicals, preferably radicals are straight chain. They preferably have from 1 to 3 carbon atoms, more preferably they are stands, metaxylem and methylthioribose.

Preferred the following values and their combinations:

R1and R2independently represent hydrogen, (C1-4)alkyl, (C1-4)alkoxy, halogen or trifluoromethyl,

R3represents hydrogen, hydroxyl, (C1-4)alkoxyl, cyano or carbarnoyl,

R4and R5independently represent hydrogen or (C1-4)alkyl, or form together with the nitrogen to which they are included, piperidinium.

In a private group of compounds of formula I, R1and R2nezavisimyi, the cyano or (C2-5)alkanoyl, R3such as described above, and R4and R5independently represent hydrogen, (C1-4)alkyl or phenyl(C1-4)alkyl, or form together with the nitrogen atom to which they are attached, pyrrolidinyl, piperidino or piperazinil.

Compounds according to the invention have an asymmetric carbon atom in position 2. Therefore, they can exist in optically active form or in the form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures, including racemic mixtures, form part of this invention.

If the connection according to the invention is in optically active form, it is preferable R configuration.

In another aspect of the invention proposes a method of producing compounds according to the invention, in which 1,2,3,4-tetrahydro-2-naphthalenamine carrying the halogen in the aromatic ring, is subjected to the interaction with the possibly substituted phenylboronic acid and the compound obtained is isolated in free base form or salt obtained by the accession acid.

In particular, the invention proposes a method of obtaining compounds from the above, and Hal represents halogen, is subjected to the interaction with the compound of the formula III

< / BR>
where R1and R2such as defined above, and the compound obtained is isolated in free base form or salt obtained by the accession acid.

The reaction can be carried out in a known manner, preferably by implementing catalyzed by transition metal aryl-aryl combinations, for example, as described in example 1. As preferred halogen is bromine or iodine, especially bromine.

The treatment of the reaction mixtures obtained according to the above method, and purification of the thus obtained compounds can be performed in accordance with known procedures.

Salts obtained by attaching acid, can be produced in a known manner from the form of the free bases and Vice versa. Suitable pharmaceutically acceptable salts obtained by the accession acid, for use in accordance with the present invention include, for example, hydrochloride, gidromolot, gidrofumarat and gidromolot.

Racemic compounds according to the invention can be obtained from racemic starting materials. Optically active tolucan from the racemate known methods, for example by fractional crystallization diastereoisomeric salts, for example their salts with (+)-di-O,O'-p-toluoyl-D-tartaric acid or (-)-di-O,O'-p-toluoyl-L-tartaric acid.

Starting materials of formula II can be obtained by halogenosilanes compounds of formula IV

< / BR>
where R3, R4and R5such as defined above, in accordance with known procedures, for example as described in example 1.

Starting materials of formulas III and IV are known or can be produced in a similar manner by known methods.

Compounds according to the invention, for example the compounds of formula I and their pharmaceutically acceptable salts obtained by the accession acid, hereinafter referred to as the agents according to the invention exhibit pharmacological activity, therefore successfully be used as pharmaceuticals.

The agents according to the invention provides lasting protection against maximum convulsions in mice induced by electroshock, in doses of from about 1 to 100 mg/kg orally and from about 0.32 to 32 mg/kg intraperitoneally [cf. E. A. Swinyard, J. Am. Pharm. Assoc. Scient. Ed. 38, 201 (1949); J. Pharmacol. Exptl. Therap. 106, 319 (1952)].

The agents according to the invention is therefore suitable for the treatment of epilepsy and other su is retenu reduce neurological damage caused by ischemia, and related symptoms in models of occlusion of the middle cerebral artery in rats at a dose of from 1 to 30 mg/kg intraperitoneally, intravenously and orally [cf. A. Tamura et al., J. Cereb. Blood Flow Metabol. 1, 53-60 (1981)), A. Sauter, M. Rudin, Stroke IZ, 1228-1234 (1986)).

Therefore, the agents according to the invention are suitable for treating any medical conditions, including component cerebral anoxia, hypoxia and/or ischemia, such as in ischemic damage to gray and white matter, stroke, subarachnoid hemorrhage, injuries, and traumatic brain and spinal cord, high intracranial pressure, dementia due to multiple infarcts and vascular dementia, in any surgical interventions, potentially related to cerebral anoxia, hypoxia and/or ischemia (for example, when the artificial circulation, operations on extracerebral vessels).

The agents according to the invention show the property to contact sensitive veratridine sodium channel IR50constituting from about 0.1 to about 100 microns. The procedure of binding known (J. B. Braun, Journal of Neuroscience 6, 2064-2070 (1986). They block veratridine-induced release of glutamate in the drugs slices of rat hippocampus in concentric is 24, 1063-1067 (1993)], using exogenous glutamate.

As a result, agents izobreteniya indicated for the treatment of any diseases, disorders or clinical condition, the etiology of which includes the release of glutamate, including mental disorders (such as schizophrenia, depression, anxiety, panic attacks, attention deficit disorder, cognitive abilities, social exclusion); hormonal disorders (excess secretion of growth hormone (GH) [for example, in the treatment of diabetes mellitus, angiopathy and acromegaly] or excess secretion of luteinizing hormone (LH) [hypertrophy of prostate cancer, menopausal syndrome], excess secretion of corticosterone in stress); metabolically induced brain damage (hypoglycemia, acetaminophe hyperglycinemia [glycine encephalopathy] , the deficit sulfadoxine, hepatic encephalopathy associated with liver failure), vomiting, cramps, tinnitus, pain (cancer, arthritis) and the misuse of drugs (ethanol, opiates [including synthetic epitopically action, such as pethidine, methadone], cocaine, amphetamine, barbiturates, and other sedatives; benzodiazepines) and abst neurological damage for example neurodegenerative disorders (such as Alzheimer's disease (Aizheimer's), Huntington (Huntington's), Parkinson's (PA s)), neurodegeneration induced by viruses (including HIV), amyotrophic lateral sclerosis (ALS), supranuclear palsy, oligometastases atrophy (OPCA), environmental, exogenous neurotoxins.

For the above indications, the appropriate dosage will, of course, vary depending on, for example, used the connection recipient, the route of administration and the nature and severity of the condition to be treated. However, in General, satisfactory results in animals are at a daily dose of from about 0.1 to about 100, preferably from about 0.5 to about 100 mg/kg animal body weight. For the larger mammals, for example humans, an indicated daily dosage is in the range from about 1 to about 500, preferably from about 1 to about 300 mg of the agent according to the invention, with appropriate introduction, for example in divided doses up to 4 times a day, or in the form of a supported release.

For all these indications, the preferred compound is (R)-1,2,3,4-tetrahydro-8-methoxy-N, N-dimethyl-5-[4-trifloromethyl)phenyl] -2 - naftol is rosocha this connection provides the maximum protection against induced by electroshock seizures in the threshold dose of 10 mg/kg orally for a period of up to 8 hours after injection. In the model of MCA occlusion was established that connection, introduced intraperitoneally immediately after occlusion, a dose-dependent manner reduces the size of the infarct in the 3.2, 10 and 32 mg/kg (19, 43, and 53%, respectively). In the test with veratridine-induced release of glutamate was found that the combination lock release IR50constituting 0.5 Ám, which is consistent with its affinity for the binding site veratridine (IR50= 125 nm).

The compound of example 21, for example, exceeds the standard limuzin in the model of MCA occlusion (reduction of heart attack by 43% vs. 25% after a dose of 10 mg/kg, introduced intraperitoneally). In the test with veratridine-induced release of glutamate was found that it is approximately equal potency limuzina, but exceeds the standards riluzole and lamotrigine (IR50= 0.5 Ám to 5 Ám and 20 Ám, respectively).

Preferred indications include epilepsy, stroke, traumatic brain injury and spinal injury.

The agent according to the invention may be introduced by any conventional method, in particular enterline, preferably orally, e.g. in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or plants for use as pharmaceuticals, for example, for the treatment of epilepsy, stroke, brain injury and spinal cord injury.

The present invention further provides a pharmaceutical composition comprising the agent according to the invention in combination with at least one pharmaceutical carrier or diluent. Such compositions can be manufactured in the traditional way. Standard doses contain, for example, from about 0.25 to about 150, preferably from 0.25 to about 25 mg of the compounds according to the invention.

In addition, the present invention provides the use of the agent according to the invention for the manufacture of a medicinal product for the treatment of any of the above conditions, such as epilepsy, stroke, brain injury and spinal cord injury.

In another aspect of the present invention proposes a method of treatment of any of the above conditions, such as epilepsy, stroke, brain injury and spinal cord injury, subject, if necessary, in such treatment, in which the specified subject act therapeutically effective amount of an agent according to the invention.

The following examples illustrate the invention. Temperatures are given in degrees Clinamen

0,57 g (2 mmol) of (+/-)-1,2,3,4-tetrahydro-5-bromo-8-methoxy-N,N - dimethyl-2-naphthalenamine dissolved in 8 ml of toluene. Added 0.55 g (3.54 mmol) of 4-Chlorfenvinphos acid, 0.07 g (0.23 mmol) three(orthotopic)phosphine, 3 ml of 2N aqueous sodium carbonate and 0.7 ml of methyl alcohol. After degassing and filling the system with argon add 0,031 g (0.14 mmol) of palladium (II) acetate and the mixture is stirred overnight at a temperature of 80 degrees. The aqueous phase is separated and extracted with ethyl acetate. The combined organic phases are extracted with 2N acetic acid, acidic extracts alkalinized with an aqueous solution of ammonia and again extracted with ethyl acetate. After drying with sodium sulfate, filtration and evaporation of the organic phase obtained is a light brown oil is treated with fumaric acid in methyl-tert.-butylamine. The obtained salt is recrystallized from isopropanol, getting white crystals of hydrofolate the connection specified in the header, with a melting point 213-216o.

The source material can be obtained in the following way:

4.1 g (20 mmol) of (+/-)-1,2,3,4-tetrahydro-8-methoxy-N,N-dimethyl-2 - naphthalenamine dissolved in 50 ml of acetic acid and add 1.8 g (22 mmol) of sodium acetate. A solution of 1.02 ml (20 mmol) minutes. Formed colorless precipitate. After stirring overnight the solvent is distilled off under vacuum, the residue is collected with water and extracted with ethyl acetate. The remaining aqueous phase is alkalinized with an aqueous solution of ammonia and extracted with ethyl acetate. The organic phase is dried with sodium sulfate, filtered and evaporated to a dry residue. The remaining oil is distilled in apparatus for distilling flask in flask", receiving a light yellow oil with a boiling temperature of 170-180owhen 0,04 mbar.

The following connections get analogously to example (see table).

Gelatin capsules can be obtained in the usual way and is suitable for use in the treatment of epilepsy and cerebral strokes.

Gelatin capsules

The compound of formula I, for example, example 21 in the form of a free base - 10.0 mg

Lactose - 165,5 mg

Silicon dioxide (Aerosil) 1.5 mg

Corn starch - to 120.0 mg

Magnesium stearate - 3.0 mg

All of 300.0 mg

Blank caps. - 77.0 mg

Result. weight - 377,0 and

1. Substituted 1,2,3,4-tetrahydro-2-naphthalenamine General formula I

< / BR>
R1and R2independently represent hydrogen, C1-4alkyl, C1-4alkoxyl, halogen, triforma is B>4and R5independently represent hydrogen, C1-4alkyl, hydroxy-C2-4alkyl, or form together with the nitrogen atom to which they are attached, piperidine group

in the form of free bases or salts obtained by joining acids.

2. Connection on p. 1, wherein R1and R2independently represent hydrogen, C1-4alkyl, C1-4alkoxy, halogen, trifluoromethyl; R3represents hydrogen, hydroxyl, C1-4alkoxyl, cyano, carbarnoyl R4and R5independently represent hydrogen, C1-4alkyl, or form together with the nitrogen atom to which they are attached, piperidine group, in the form of free bases or salts obtained by joining acids.

3. Connection on p. 1, characterized in that it is a compound of formula I, in optically active or racemic form, where

R1=4-Cl, R2=H, R3=OMe, R4=Me, R5=Me,

R1=H, R2=H, R3=OMe, R4=Me, R5=Me,

R1=2-Cl, R2=H, R3=OMe, R4=Me, R5=Me,

R1=2-Me, R2=H, R3=OMe, R4=Me, R5=Me,

R1=2-OMe, R2=H, R3=OMe, R4=Me, R5=Me5=Me,

R1=4-Me, R2=H, R3=OMe, R4=Me, R5-Me,

R1=4-CF3, R2=H, R3=OMe, R4=Me, R5=Me,

R1=2-Cl, R2=4-Cl, R3=OMe, R4=Me, R5=Me,

R1=2-F, R2H, R3=OMe, R4=Me, R5=Me,

R1=3-Cl, R2=H, R3=OMe, R4=Me, R5=Me,

R1=2-Cl, R2=H, R3=OMe, R4=Me, R5=H

R1=H, R2=H, R3=OMe, R4+R5=piperidino,

R1=2-Cl, R2=H, R3=OMe, R4+R5=piperidino,

R1=H, R2=H, R3=OMe, R4=n-Pr, R5=n-Pr,

R1=4-CF3, R2=H, R3=OH, R4=Me, R5=Me,

R1=2-Et, R2=H, R3=OMe, R4=Me, R5=Me,

R1=2-Cl, R2=H, R3=CN, R4=Me, R5=Me,

R1=2-Cl, R2=4-F, R3=OMe, R4=Me, R5=Me,

R1=2-F, R2=4-F, R3=OMe, R4=Me, R5=Me,

R1=2-OMe, R2=4-OMe, R3=OMe, R4=Me, R5=Me,

R1=2-F, R2=3-F, R3=OMe, R4=Me, R5=Me,

R1=2-OMe, R2=3-OMe, R3=OMe, R4=Me, R5=Me,

R1=2-Me, R2=5-Me, R3=OMe, R4=Me, R5=Me,

R1=2-Cl, R2=3-Cl, R3=OMe, R4 R3=OMe, R4=Me, R5=Me,

R1=2-Cl, R2=H, R3=CONH2, R4=Me, R5=Me,

R1=4-CF3, R2-H, R3=OMe, R4=Me, R5=H

R1=4-OMe, R2=H, R3=OMe, R4=Me, R5=Me,

R1=4-F, R2=H, R3=OMe, R4=Me, R5=Me,

R1=4-CF3, R2=H, R3=OMe, R4=Et-OH, R5=Me, and

R1=4-CF3, R2=H, R3=H, R4=Me, R5=Me

Me is methyl, Et is ethyl and Pr is propyl, in the form of free bases or salts obtained by joining acids.

4. Connection on p. 1, which is (R)-1,2,3,4-tetrahydro-8-methoxy-N, N-dimethyl-5-[4-(trifluoromethyl)phenyl] -2-naphthalenamine in the form of free bases or salts obtained by joining acids.

5. Connection under item 1 in the form of free base or pharmaceutically acceptable salts obtained by the accession acid, for use in a pharmaceutical facility.

6. Connection under item 1 in the form of free base or pharmaceutically acceptable salts obtained by the accession acid with anticonvulsive activity, activity in the neuronal damage caused by ischemia, and activity conditions, including the formula I under item 1 in the form of free base or salt, received by the accession acid, characterized in that the compound of formula II,

< / BR>
where R3, R4and R5such, as defined in paragraph 1;

Hal represents halogen, is subjected to the interaction with the compound of the formula III

< / BR>
where R1and R2such, as defined in paragraph 1, and the compound obtained is isolated in the form of free bases or salts obtained by joining acids.

8. Pharmaceutical composition having anticonvulsive activity, activity during ischemia induced neuronal damage and activity in conditions involving the release of glutamate containing the active agent in combination with a pharmaceutical excipient or diluent, wherein the active agent it contains compound I under item 1 of the formula in free base form or pharmaceutically acceptable salts obtained by the accession acid, in therapeutically effective amounts.

 

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