Use of substituted amino-methyl-chromans for the prevention...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S454000

Reexamination Certificate

active

06331561

ABSTRACT:

The invention relates to the use of substituted aminomethyl-chromans for the production of medicaments for the prevention of degeneration of nerve cells (neurodegeneration) and for the promotion of neuronal regeneration (neuroregeneration) in the post-acute phase of cerebral injuries or in chronic disorders of the nervous system.
The nervous system of mammals consists essentially of two different cell classes: (a) the nerve cells (neurons) and (b) the glia cells, which for their part are divided again into oligodendrocytes, Schwann's cells, microglia and astrocytes.
After each disturbance of the integrity of the nervous system, astrocytes react in a stereotyped manner, which is described as reactive astrogliosis. This glial response can be triggered by a series of different injuries or disorders, such as, for example, surgical interventions, traumatic, immunological, chemical or ischaemic injuries or neurological disorders, such as Alzheimer's disease or Parkinson's disease. Reactive gliosis is characterized by the proliferation and hypertrophy of the cell bodies and cytoplasmic processes of astrocytes. The reaction of the astrocytes increases the expression of the astrocyte-specific constituent of the cell skeleton, glial fibrillary acidic protein (GFAP). During later phases, GFAP is the main constituent of the gliotic scar tissue, which results from the glial reaction. At present, the increased expression of GFAP is the only consistent characteristic of reactive gliosis.
The formation and persistence of glial scar tissue appears to be a main obstacle to the regeneration of nerve cells, since it inhibits the formation and the growth of neuronal processes 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 the formation of the glial scar for the therapeutic treatment of various neurodegenerative and neurological disorders could therefore be a novel therapeutic principle.
Surprisingly, it appears that aminomethyl-chromans can reduce GFAP expression. The experiments were carried out in animals whose middle cerebral artery (MCA) was occluded and which are used as an animal model of stroke. These experiments indicated that aminomethyl-chromans can prevent the formation of glial scar tissue in vivo and thus can be therapeutically important for the treatment of neurodegenerative disorders which are characterized by the formation of glial scar tissue or by reactive gliosis, such as, for example, Parkinson's disease, amyotrophic lateral sclerosis or bone marrow disorders and/or injuries.
EP-A-0 352 613, EP-A-0 540 914 and EP-A-0 749 970 describe aminomethyl-chroman derivatives which are suitable for the prophylaxis, neuroprotection and treatment of formation of cerebral infarcts (cerebral apoplexy) such as stroke and cerebral ischaemia.
The therapeutic efficacy of the compounds described in these documents relates, however, to neuroprotection in the acute phase of the course of the disease. The acute sequelae of cerebral ischaemia, such as occurs, for example, after stroke, are reduced by use of neuroprotective drugs which contain the described aminomethyl-chromans as pharmacologically active constituents.
In contrast to this, however, it was an object of the present invention to make available compounds with regenerative potential which are suitable for the treatment of the post-acute phase of cerebral injuries or for the treatment of various chronic disorders of the nervous system.
The object is achieved according to the invention by the use of substituted aminomethyl-chromans of the following formula (I)
in which
R
1
represents hydrogen,
R
2
represents hydrogen, hydroxyl or a radical of the formula —OCH
3
, —OCH
2
CH
3
, —OCH(CH
3
)
2
or —OCH
2
C(CH
3
)
2
—Cl, or
R
1
and R
2
together form a radical of the formula
R
3
represents cyclopentyl, cyclohexyl, cycloheptyl, or the following radical, designated as o-benzenesulphimidyl:
and
n is selected from 1, 2, 3, 4 or 5,
and their optical isomers and pharmaceutically acceptable salts, for the production of a medicament for the treatment of neurodegenerative disorders and for the promotion of neuronal regeneration.
The principle of the preparation of the aminomethyl-chromans to be used according to the invention is disclosed in EP-A-0 352 613, EP-A-0 540 914 or EP-A-0 749 970. In the context of the present invention the compounds can be present in various stereoisomeric forms, i.e. in the form of their (+) or (−) enantiomers or as a mixture of these enantiomers (racemate). For the separation of the racemates into the enantiomeric forms, reference is made to the relevant, known specialist literature. A preferred compound is the (−) enantiomer of the compound of the formula (I) in which R
1
and R
2
=hydrogen, R
3
=o-benzenesulphimidyl and n=4.
In the context of the present invention, the physiologically acceptable salts can also be employed. Physiologically acceptable salts of the substituted 2-aminomethyl-chromans can be salts of the compounds according to the invention with suitable organic or inorganic acids, in particular mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalene-disulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, furnaric acid, maleic acid or benzoic acid.
Compounds of the general formula (I) and the pharmaceutical compositions derived from these compounds can be used for the post-acute therapeutic treatment of a variety of neurological conditions in which various cell types of the nervous system are degenerated and/or have been damaged as a result of neurodegenerative disorders or injuries or exposures. In particular, compounds of the general formula (I) can be used for the treatment of resulting conditions, in which damage to cells of the nervous system has occurred due to surgical interventions, infections, exposure to toxic agents, tumours, nutritional deficits or metabolic disorders. In addition, compounds of the general formula (I) can be used for the treatment of the sequelae of neurodegenerative disorders, such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, drug abuse or drug addiction (alcohol, cocaine, heroin, amphetamine or the like), bone marrow disorders and/or injuries, dystrophy or degeneration of the neural retina (retinopathies) and peripheral neuropathies, such as diabetic neuropathy and/or the peripheral neuropathies induced by toxins. In addition, compounds of the general formula (I) can be used in combination with surgical implantations of tissues and/or prostheses for the treatment of Alzheimer's disease or other neurological disorders and/or malfunctions in which implantation is indicated.
Preferred compounds in the context of the invention are those of the general formula (I),
where
R
1
represents hydrogen,
R
2
represents hydrogen, hydroxyl or a radical of the formula —OCH
3
, —OH(CH
3
)
2
or —OCH
2
C(CH
3
)
2
—Cl or,
R
1
and R
2
together form a radical of the formula
R
3
represents o-benzenesulphimidyl,
n=3 or 4;
and aminomethyl-chromans of the general formula (I)
in which
R
1
represents hydrogen,
R
2
represents hydrogen, hydroxyl or a radical of the formula —OCH
3
or —OCH(CH
3
)
2
, or
R
1
and R
2
together form a radical of the formula
n=land
R
3
represents cyclohexyl or cycloheptyl.
Particularly preferred compounds are those of the general formula (I),
where
R
1
represents hydrogen, and
R
2
represents hydrogen or a radical of the formula —OCH
3
, —OCH(CH
3
)
2
or —OCH
2
C(CH
3
)
2
—Cl, or
R
1
and R
2
together form a radical of the formula
R
3
represents o-benzenesulphimidyl, and
n=4;
and aminomethyl-chromans of the general formula (I)

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