U.S. patent application number 09/803621 was filed with the patent office on 2001-08-30 for use of substituted amino-methyl-chromans for the prevention of neuronal degeneration and for the promotion of neuronal regeneration.
Invention is credited to Fahrig, Thomas, Gerlach, Irene, Horvath, Ervin, Jork, Reinhard.
Application Number | 20010018530 09/803621 |
Document ID | / |
Family ID | 7849618 |
Filed Date | 2001-08-30 |
United States Patent
Application |
20010018530 |
Kind Code |
A1 |
Fahrig, Thomas ; et
al. |
August 30, 2001 |
Use of substituted amino-methyl-chromans for the prevention of
neuronal degeneration and for the promotion of neuronal
regeneration
Abstract
The invention relates to the use of substituted
aminomethyl-chromans for the treatment of neuronal degeneration and
for the promotion of neuronal regeneration in cerebral injuries and
chronic disorders of the nervous system.
Inventors: |
Fahrig, Thomas; (Leverkusen,
DE) ; Gerlach, Irene; (Leverkusen, DE) ;
Horvath, Ervin; (Leverkusen, DE) ; Jork,
Reinhard; (Leverkusen, DE) |
Correspondence
Address: |
Jeffrey M. Greenman
Vice president, Patents and Licensing
Bayer Corporation
400 Morgan Lane
West Haven
CT
06516
US
|
Family ID: |
7849618 |
Appl. No.: |
09/803621 |
Filed: |
March 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09803621 |
Mar 9, 2001 |
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09554971 |
May 23, 2000 |
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6235774 |
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Current U.S.
Class: |
549/385 ;
549/407 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 25/16 20180101; A61K 31/353 20130101; A61P 25/00 20180101 |
Class at
Publication: |
549/385 ;
549/407; 514/454; 514/456 |
International
Class: |
C07D 311/04; C07D
311/78; A61K 031/352 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 24, 1997 |
DE |
19751949.0 |
Claims
1. Use of substituted arninomethyl-chromans of the following
formula (I) 7in which R.sup.1 represents hydrogen, R.sup.2
represents hydrogen, hydroxyl or a radical of the formula
--OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2 or
--OCH.sub.2C(CH.sub.3).sub.2--Cl or R.sup.1 and R.sup.2 together
form a radical of the formula 8R.sup.3 represents cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl or o-benzenesulphirnidyl 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.
2. Use according to claim 1, characterized in that, in formula (I)
n=3, 4 or 5 and R.sup.3=o-benzenesulphimidyl.
3. Use according to claim 1 or 2, characterized in that, in formula
(1) R.sup.1 represents hydrogen, R.sup.2 represents hydrogen or a
radical of the formula --OCH.sub.3, --OCH(CH.sub.3).sub.2 or
--OCH.sub.2C(CH.sub.3).- sub.2--Cl, or R.sup.1 and R.sup.2 together
form a radical of the formula 9R.sup.3=o-benzenesulphimidyl and
n=4.
4. Use according to claim 1, characterized in that, in formula (1)
R.sup.1 represents hydrogen, R.sup.2 represents hydrogen,
--OCH.sub.3 or --OCH(CH.sub.3).sub.2, or R.sup.1 and R.sup.2
together form a radical of the formula 10R.sup.3 represents
cyclohexyl or cycloheptyl and n=1.
5. Use according to claim 4, characterized in that, in formula (I)
R.sup.1 represents hydrogen, R.sup.2 represents hydrogen or
-OCH.sub.3, R.sup.3 represents cycloheptyl and n=1.
6. Use according to claim 1, characterized in that, in formula (I)
R.sup.1 and R.sup.2 represent hydrogen, R.sup.3 represents
o-benzenesulphimidyl and n represents 4.
7. Use according to any of claims 1 to 6, characterized in that the
compounds of the formula (1) have the (-) enantiomer
configuration.
8. Use according to one or more of claims 1 to 7 for the
regenerative treatment of neurological conditions which are the
sequelae of damage due to surgical interventions, infections,
implantations, exposure to toxic agents, tumours, nutritional
deficits or metabolic disorders, Parkinson's disease, multiple
sclerosis, amyotrophic lateral sclerosis, epilepsy, drug abuse or
drug addiction, bone marrow disorders and/or injuries, dystrophy or
degeneration of the neural retina and peripheral neuropathies or
for the treatment of Alzheimer's disease in combination with
surgical implantations and/or prostheses.
Description
[0001] 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.
[0002] 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.
[0003] 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, immnunological,
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.
[0004] 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.
[0005] 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, arnyotrophic lateral sclerosis or
bone marrow disorders and/or injuries.
[0006] 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
[0007] 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.
[0008] 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.
[0009] The object is achieved according to the invention by the use
of substituted aminomethyl-chromans of the following formula (I)
1
[0010] in which
[0011] R.sup.1 represents hydrogen,
[0012] R.sup.2 represents hydrogen, hydroxyl or a radical of the
formula --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2 or
--OCH.sub.2C(CH.sub.3).sub.2--Cl, or
[0013] R.sup.1 and R.sup.2 together form a radical of the formula
2
[0014] R.sup.3 represents cyclopentyl, cyclohexyl, cycloheptyl, or
the following radical, designated as o-benzenesulphimidyl: 3
[0015] and
[0016] n is selected from 1, 2, 3, 4 or 5,
[0017] 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.
[0018] 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.sup.1 and R.sup.2=hydrogen,
R.sup.3=o-benzenesulphimidyl and n=4.
[0019] 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, fumaric acid, maleic acid or
benzoic acid.
[0020] 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 thc 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.
[0021] Preferred compounds in the context of the invention are
those of the general formula (I),
[0022] where
[0023] R.sup.1 represents hydrogen,
[0024] R.sup.2 represents hydrogen, hydroxyl or a radical of the
formula --OCH.sub.3, --OH(CH.sub.3).sub.2 or
--OCH.sub.2C(CH.sub.3).sub.2--Cl or,
[0025] R.sup.1 and R.sup.2 together form a radical of the formula
4
[0026] R.sup.3 represents o-benzenesulphimidyl
[0027] n=3 or 4;
[0028] and aminomethyl-chromans of the general formula (1)
[0029] in which
[0030] R.sup.1 represents hydrogen,
[0031] R.sup.2 represents hydrogen, hydroxyl or a radical of the
formula --OCH.sub.3 or --OCH(CH.sub.3).sub.2, or
[0032] R.sup.1 and R.sup.2 together form a radical of the formula
5
[0033] n=1 and
[0034] R.sup.3 represents cyclohexyl or cycloheptyl.
[0035] Particularly preferred compounds are those of the general
formula (I),
[0036] where
[0037] R.sup.1 represents hydrogen, and
[0038] R.sup.2 represents hydrogen or a radical of the formula
--OCH.sub.3, --OCH(CH.sub.3).sub.2 or
--OCH.sub.2C(CH.sub.3).sub.2--Cl, or
[0039] R.sup.1 and R.sup.2 together form a radical of the formula
6
[0040] R.sup.3 represents o-benzenesulphimidyl, and
[0041] n=4;
[0042] and aminomethyl-chromans of the general formula (1)
[0043] in which
[0044] R.sup.1 represents hydrogen,
[0045] R.sup.2 represents hydrogen or --OCH.sub.3,
[0046] n=1,
[0047] and
[0048] R.sup.3 represents cyclopentyl.
[0049] It is generally preferred that if
R.sup.3=o-benzenesulphimidyl, n=3, 4 or 5, particularly preferably
3 or 4.
[0050] The active compounds can be converted in a known manner into
the customary formulations; such as tablets, coated tablets, pills,
granules, aerosols, syrups, emulsions, suspensions and solutions,
using inert, non-toxic, pharmaceutically suitable excipients or
solvents. In this connection, the therapeutically active compound
should in each case be present in a concentration from
approximately 0.1 to 95% by weight, preferably from approximately
0.5 to 90% by weight, of the total mixture, i.e. in amounts which
are sufficient in order to achieve the dose range indicated.
[0051] The formulations are prepared, for example, by extending the
active compounds using solvents and/or excipients, if appropriate
using emulsifying agents and/or dispersing agents, where, for
example, if the diluent used is water, organic solvents can
optionally be used as auxiliary solvents.
[0052] The auxiliaries can be selected, for example, from the group
comprising water, non-toxic organic solvents, such as paraffin
(e.g. petroleum fractions), vegetable oils (e.g. peanut/sesame
oil), alcohols (e.g. ethyl alcohol, glycerol), excipients, such as,
for example ground natural minerals (e.g. kaolins, argillaceous
earths, talc, chalk), ground synthetic minerals (e.g. highly
dispersed silicic acid, silicate), sugars (e.g. cane sugar, lactose
and dextrose), emulsifying agents (e.g. polyoxyethylene fatty acid
esters, polyoxyethylene fatty alcohol ethers), dispersing agents
(e.g. lignin sulphite waste liquors, methylcellulose, starch and
polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate,
talc, stearic acid and sodium sulphate).
[0053] Administration is carried out in a customary manner,
preferably orally or subcutaneously, in particular intramuscularly
or intravenously. In the case of oral administration, apart from
the excipients mentioned tablets can, of course, also contain
additions, such as sodium citrate, calcium carbonate or dicalcium
phosphate together with various additives, such as starch,
preferably potato starch, gelatine and the like. Furthermore,
lubricants, such as magnesium stearate, sodium lauryl sulphate and
talc can additionally be used for tableting. In the case of aqueous
suspensions, apart from the above-mentioned auxiliaries, the active
compounds can be treated with various flavour enhancers or
colorants.
[0054] In general, it has proven advantageous in the case of
intravenous administration to administer amounts from approximately
0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg, of
body weight every 24 hours to achieve efficacious results. In the
case of oral administration, the dose is approximately 0.01 to 20
mg/kg, preferably 0.1 to 10 mg/kg, of body weight every 24 hours.
Administration can in each case be carried out in the form of
individual doses.
[0055] Despite this, where appropriate it may be necessary to
deviate from the amounts mentioned, namely depending on the body
weight or the type of administration route, on individual behaviour
towards the medicament, the manner of its formulation and the time
or interval at which administration takes place. Thus in some cases
it may be adequate to manage with less than the above-mentioned
minimum amount, while in other cases the upper limits mentioned
have to be exceeded. In the case of the administration of
relatively large amounts, it may be advisable to divide these into
several individual doses over the course of the day.
[0056] The invention is illustrated in greater detail by the
following example.
EXAMPLE
[0057] In the present example, the test substance was administered
during the acute phase of the injury process in order to achieve
its optimum action. However, the substance effect on the chronic
phase of the course of the illness was assessed, so that the
results definitely point to the potential of the test substance for
the treatment of chronic damage.
[0058] Occlusion of the Middle Cerebral Artery (MCA-O)
[0059] Unilateral cerebral ischaemia was induced in
tribromoethanol-anaesthetized mice by permanent occlusion of the
middle cerebral artery (MCA). The operation was carried out
according to known methods (Welsh et al., J. Neurochem. 49, pages
846-851 [1987]) and leads to infarction of cortical and subcortical
regions of the ipsilateral cerebral hemisphere which is supplied by
the left MCA.
[0060] Determination of the GFAP Immunoreactivity
[0061] Seven days after operation, the animals were sacrificed by
decapitation, the brains were removed, protein fractions were
prepared and the GFAP immunoreactivity in the "soluble" protein
fraction was determined as described (Fahrig, J. Neurochem. 63,
pages 1796-1801 [1994]). The determined GFAP content of the
contalateral cerebral hemisphere was set equal to 100% (control)
and the GFAP content of the ipsilateral cerebral hemisphere (i.e.
the hemisphere which includes the infarct region) was calculated in
relation thereto.
[0062] Treatment with Test Substance
[0063] In this example, the (-) enantiomer of the compound of the
general formula (I) was used, where R.sup.1 and R.sup.2=hydrogen,
R.sup.3=o-benzenesuiphimidyl and n=4. The compound was dissolved in
a citrate-buffered (citric acid/sodium citrate) physiological
saline solution and administered by multiple i.v. injections
immediately, 2 and 4 hours after the operation. Under these
conditions, the compound reduced the ischaemia-induced GFAP
immunoreactivity (and thus the glial scar formation) in a
dose-dependent manner (Table 1).
1TABLE 1 Reduction of the GFAP immunoreactivity by an
aminomethyl-chroman of the general formula (I) where R.sup.1 and
R.sup.2 = H, R.sup.3 = o-benzenesulphimidyl, n = 4 Dose 1 .mu.g/kg
10 .mu.g/kg 30 .mu.g/kg 100 .mu.g/kg GFAP immunoreactivity [% of
94.0 79.7 62.3 59.5 the control] S.E.M. *[%] 3.2 9.2 8.5 3.4
Reduction of the GFAP immuno- -6.0 -20.3 -37.7 -40.5 reactivity [%]
*Standard error of the mean
* * * * *