MXPA00005054A - Application of substituted aminomethyl chromans in order to prevent neural degeneration and to promote neural regeneration - Google Patents

Abstract

The invention relates to the application of substituted aminomethyl chromans in order to treat neural degeneration and to promote neural regeneration in cases of cerebral injuries and chronic diseases of the nervous system.

Description

Use of substituted aminomethylchromans for the prevention of neuronal degeneration and the promotion of neuronal regeneration The invention relates to the use of substituted aminomethylchromans for the preparation of medicaments for the prevention of the degeneration of nerve cells (neurodegeneration) and for the promotion of neuronal regeneration (neuroregeneration) in the post-acute phase of brain lesions or diseases. Chronicles of the nervous system.

The nervous system of mammals consists essentially of two distinct classes of cells: (a) nerve cells (neurons) and (b) neurogliales cells, which are divided into oligodendrocytes, Schwann cells, microglia and astrocytes.

After any disturbance of the integrity of the nervous system, the astrocytes react in a stereotypical manner which is termed reactive astrogliosa. This glial response can be triggered by a series of injuries or diseases, such as surgical interventions, traumatic, immunological, chemical or ischemic injuries or neurological diseases, such as Alzheimer's disease or Parkinson's disease. The reactive glial is REF .: 120229 characterized by the proliferation and hypertrophy of the cell body and the cytoplasmic extension of astrocytes. With the reaction of astrocytes increases the expression of the specific component of astrocytes of the cellular skeleton, the glial fibrillary acidic protein (GFAP). During later phases, GFAP produces the major component of the glial scar tissue as a result of the glial reaction. Currently the increased expression of GFAP is the only consistent signal of the reactive glial.

The formation and persistence of glial scar tissue seems to be a major obstacle to the regeneration of nerve cells, as it inhibits the formation and growth of neuronal extensions, both in vitro and in vivo (Reier and Houle, in Advances in Neurology, vol 47: Functional Recovery in Neurological Diseases, Raven Press, New York (1988), pages 87-138). The inhibition of glial tissue formation for the therapeutic treatment of different neurodegenerative and neurological diseases could therefore represent a new therapeutic principle.

Surprisingly, it has now been observed that aminomethylchromans can reduce the expression of GFAP. The experiments carried out were performed on animals whose mean cerebral arteries (MCA) were occluded, which are used as an animal model of apoplectic attack. These experiments lead us to suppose that aminomethylchromans can reduce the formation of glial scar tissue in vivo and therefore can be therapeutically significant for the treatment of neurodegenerative diseases characterized by the formation of glial scar tissue or reactive glial tissue, for example Parkinson's disease, lateral amyotrophic sclerosis or diseases and / or spinal cord injuries.

EP-A-0352613, EP-A-0540914 and EP-A-0749970 describe derivatives of aminomethylchromans which are suitable for the prophylaxis, neuroprotection and treatment of cerebral infarction (cerebral apoplexy) as apoplectic attack and cerebral ischemia.

The therapeutic activity of the compounds described therein, however, refers to neuroprotection in the acute phase of the development of the disease. The acute consequences of cerebral ischemia, such as after an apoplectic attack, are reduced by the use of neuroprotective drugs containing the aminomethylchromans described as active pharmacological components.

In contrast, however, it was an object of the present invention to provide regenerative substances that were suitable for the treatment of the post-acute phase of brain injuries or for the treatment of various chronic diseases of the nervous system.

The object was achieved, according to the invention, by the use of substituted aminomethylchromans of the following formula (I) in which R1 is hydrogen R2 is hydrogen, hydroxy or a moiety of formula -OCH3, -OCH2CH3, -OCH (CH3) 2 or -OCH2C (CH,) 2-Cl, or R1 and R2 together form a remainder of formula R3 is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the following residue called ortho-benzosulfimidyl: Y n is selected from 1, 2, 3, 4 or 5, as well as its optical isomers and pharmaceutically acceptable salts, for the preparation of a medicine for the treatment of neurodegenerative diseases and for the promotion of neuronal regeneration.

The principle of the preparation of the aminomethylchromans used according to the invention is known from EP-A-0352613, EP-A-0540914 or EP-A-0749970.

In the context of the present invention, the compounds can be present in different stereoisomeric forms, that is, in the form of their (+) or (-) enantiomer or as mixtures (racemate). For the separation of the racemates into the enantiomeric forms, reference is made to the corresponding specialized literature. A preferred compound is the (-) enantiomer of the compound of formula (I) wherein R 1 and R 2 = hydrogen, R 3 = ortho-benzylsulfimidyl and n = 4.

In the context of the present invention, the physiologically acceptable salts can also be used. The physiologically acceptable salts of the substituted 2 -aminomethylchromans can be salts of the compounds according to the invention with suitable organic or inorganic acids, especially mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

The compounds of general formula (I), as well as the pharmaceutical compositions derived from these compounds, can be used for the post-acute therapeutic treatment of various neurological states in which different types of cells of the nervous system degenerate and / or were damaged as a consequence of diseases, interventions or neurodegenerative exposures. In particular, compounds of general formula (I) can be used for the treatment of conditions in which damage to cells of the nervous system occurs due to surgical interventions, infections, exposures to toxic agents, tumors, food deficits or metabolic diseases. In addition, the compounds of general formula (I) can be used for the treatment of the sequelae of neurodegenerative diseases, such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, drug abuse or drug addiction. (alcohol, ***e, heroin, amphetamines or similar), diseases and / or spinal cord injuries, dystrophy or degeneration of the neural retina (retinopathies) and peripheral neuropathies, such as diabetic neuropathies and / or peripheral neuropathies induced by toxins. In addition, the compounds of general formula (I) can be used in combination with surgical tissue implants and / or prostheses for the treatment of Alzheimer's disease and other neurological diseases and / or dysfunctions in which implants are indicated.

The compounds of formula (I) are preferred in the context of the invention.

R1 is hydrogen R2 is hydrogen, hydroxy or a moiety of formula -OCH3, -0 (CH2CH3) or -0CH2C (CH3) 2-C1, or R 'and R2 together form a remainder of formula R3 is ortho-benzylsulfimidyl, n = 3 or 4, and aminomethylchromans of general formula (I) in which R1 is hydrogen R2 is hydrogen, hydroxy or a moiety of formula -0CH3 or -0 (CH2CH3) 2, O R1 and R2 together form a remainder of formula n = 1 and R3 is cyclohexyl or cycloheptyl.

Especially preferred are compounds of general formula (I) in which R1 is hydrogen, and R2 is hydrogen or a moiety of formula -0CH3, -OCH (CH3) 2 or 0CH2C (CH3) 2-C1, or R1 and R2 together form a remainder of formula R3 is ortho-benzosulfimidyl n = and aminomethylchromans of general formula (I) in which R1 is hydrogen, and R2 is hydrogen or -OCH ,, n = 1 Y R3 is cyclopentyl.

It is generally preferred that when R3 = ortho-benzylsulfimidyl, n = 3, 4 or 5, particularly preferably 3 or 4.

The active substance can be incorporated in known manner into conventional formulations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inert, non-toxic and pharmaceutically suitable vehicles or solvents. At the same time the therapeutically active compound should be provided in a concentration of from about 0.1 to 95% by weight, preferably from about 0.5 to 90% by weight of the total mixture, ie, in an amount that is sufficient to reach the given dosage interval.

The formulations are prepared, for example, by diluting the active substance with solvents and / or vehicles, where appropriate using emulsifiers and / or suspending agents, for example in the case of the use of water as a diluent; where appropriate, organic solvents can be used as coadjuvant solvents.

The adjuvants can be selected, for example, from the group comprising water, non-toxic organic solvents such as paraffins (for example, petroleum fractions), vegetable oils (for example, peanut / sesame oil), alcohols. (for example ethyl alcohol, glycerin), vehicles, such as, for example, natural rock powder (for example kaolin, clay, talc, chalk), synthetic rock powder (for example finely dispersed silica, silicates), sugars (for example sugar) of cane, lactose and glucose), emulsifiers (for example polyoxyethylene esters of fatty acids, polyoxyethylene ethers of fatty alcohols), suspending agents (for example lignin, sulphite bleach, methylcellulose, starch or polyvinylpyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid and sodium sulphate) ).

The administration is carried out conventionally, preferably subcutaneously, especially intramuscularly or intravenously. In case of oral use, tablets can be used, it is understood that in addition to the mentioned vehicles, with additives such as sodium citrate, sodium carbonate or dicalcium phosphate, together with different filling materials such as starch, preferably potato starch, gelatin and Similar. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used together for the preparation of tablets. In case of aqueous suspensions, the active substance can be used, in addition to the aforementioned coadjuvants, with different flavor improvers 0 colorants.

In general, the intravenous administration of amounts of between about 0.001 is indicated as advantageous. 1 mg / kg, preferably around 0.01 to 0.5 mg / kg of body weight every 24 hours to obtain an effective result. In oral administration the dosage amounts to about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg of body weight every 24 hours. The administration can be carried out in each case in the form of a single shot.

However, it may be advisable to deviate from the aforementioned amounts depending on the body weight, or the type of route of administration, the individual behavior towards the medication, the type of formulation and the time or interval in which the procedure is performed. administration. In some cases, quantities lower than the aforementioned minimum quantity may suffice, while in other cases the aforementioned upper limit must be exceeded. In case of administration of a larger amount, it is advisable to divide it into several unique shots throughout the day.

The invention is illustrated in more detail with the following example.

Example; In the present example, the test substance was administered during the acute phase of the lesion to obtain the optimum effect. However, the effect of the substance on the chronic phase of the development of the disease was evaluated so that full results on the potential of the test substance for the treatment of chronic damage were observed.

Occlusion of the middle cerebral artery (MCA-O) Unilateral brain ischemia was induced in mice anesthetized with tribromoethanol by permanent occlusion of the middle cerebral artery (MCA). The operation was performed by the corresponding known procedures (Elsh, et al., J. Neurochem, 49, pp. 846-851 (1987)) and produced an infarction in the cortical and subcortical regions of the ipsilateral cerebral hemisphere, which was maintained by middle of the left MCA.

Determination of GFAP immunoreactivity Seven days after the operation, the animals were sacrificed by decapitation, the brain was taken, the protein fractions were obtained and the immunoreactivity of GFAP in the "soluble" protein fraction was determined as described in (Fahrig, Neurochem. P. 1796-1801 (1994)). The GFAP content determined in the contralateral cerebral hemisphere was established as 100% (control) and the GFAP content of the ipsilateral cerebral hemisphere (that is, the hemisphere that includes the infarct area) was calculated in relation to that.

Treatment with test substance In this example the (-) enantiomer of the compound of general formula (I) was used, with R1 and R2 = hydrogen, R3 = ortho-benzosulfimidyl, as well as n = 4. The compound was dissolved in a physiological solution of buffered sodium chloride with citrate (citric acid / sodium citrate) and was administered by means of several intravenous injections, immediately, 2 and 4 hours after the operation. Under these conditions, the compound reduced the immunoreactivity of GFAP induced by ischemia (and therefore the formation of glial scar) depending on the dose (Table 1). Table 1: Reduction of the immunoreactivity of GFAP by an aminomethylchroman of general formula (I) with R 'and R 2 = H, R 3 = ortho-benzylsulphidimidyl, n = 4 * Standard deviation the value --- It is stated 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 or products to which it refers.

Claims (1)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: . Use of substituted aminomethylchromans of the following formula (I), in which R1 is hydrogen R2 is hydrogen, hydroxy or a moiety of formula -OCH3, -OCH2CH3, -OCH (CH3) 2 or -OCH2C (CH3) 2-Cl, or R1 and R2 together form a remainder of formula R3 represents cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or ortho-benzylsulfimidyl, n is selected from 1, 2, 3, 4 or 5, as well as its optical isomers and pharmaceutically acceptable salts, for the preparation of a medicine for the treatment of neurodegenerative diseases and for the promotion of neuronal regeneration. Use according to claim 1, characterized in that in formula (I) n = 3, 4, or 5 and R3 = ortho-benzylsulfimidyl. Use according to claim 1 or 2, characterized in that in the formula (I) R1 is hydrogen, R2 is hydrogen or a residue of the formula -OCH ,, -OCH (CH3) 2 or -0CH2C (CH3) 2-C1, or R1 and R2 together form a remainder of formula R3 is ortho-benzosulfimidyl and n = 4. Use according to claim 1, characterized in that in the formula (I) R1 is hydrogen R2 is hydrogen, -0CH3 or -OCH (CH3) R1 and R2 together form a remainder of formula R3 is cyclohexyl or cycloheptyl and n = 1 Use according to. claim 4, characterized in that in formula (I) R1 is hydrogen R2 is hydrogen or -OCH3, R3 is cycloheptyl and n = 1 Use according to claim 1, characterized in that in the formula (I) R1 and R2 are hydrogen R3 is ortho-benzosulfimidyl and n is 4. Use according to any of claims 1 to 6, characterized in that the compounds of formula (I) show the enantiomeric configuration (-). Use according to one or more of claims 1 to 7 for the regenerative treatment of neurological conditions as a consequence of damage by surgical interventions, infections, implants, exposure to toxic agents, tumors, food deficits or metabolic diseases, Parkinson's disease, multiple sclerosis , lateral amyotrophic sclerosis, epilepsy, drug abuse or drug addiction, diseases and / or spinal cord injuries, neuronal retina dystrophy or degeneration and peripheral neuropathies or for the treatment of Alzheimer's disease in combination with surgical implants and / or prostheses .