NL2020792B1 - Cantharidinimides for treating a demyelinating disease - Google Patents

Cantharidinimides for treating a demyelinating disease Download PDF

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NL2020792B1
NL2020792B1 NL2020792A NL2020792A NL2020792B1 NL 2020792 B1 NL2020792 B1 NL 2020792B1 NL 2020792 A NL2020792 A NL 2020792A NL 2020792 A NL2020792 A NL 2020792A NL 2020792 B1 NL2020792 B1 NL 2020792B1
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cantharidinimides
cantharidinimide
formula
hydrogen
group
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NL2020792A
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Julianus Maria Martens Gerardus
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Neurodrug Res B V
Johannes Hubertus Jozef Maria Kelders
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

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Abstract

The present invention relates to cantharidinimides for treating a demyelinating disease. In particular, cantharidinimides for treating a demyelinating disease selected from the group consisting of demyelinating myelinoclastic diseases and demyelinating leukodystrophic diseases, such as multiple sclerosis, clinically isolated syndrome, Devic's disease, Neuromyelitis optica, anti-MOG autoimmune encephalomyelitis, Chronic relapsing inflammatory optic neuritis, Acute disseminated encephalomyelitis, Acute hemorrhagic leukoencephalitis, Balo concentric sclerosis, diffuse myelinoclastic sclerosis (Schilder diffuse sclerosis), Marburg multiple sclerosis, Tumefactive multiple sclerosis and Solitary sclerosis.

Description

DESCRIPTION
The present invention relates to cantharidinimides for treating a demyelinating disease.
Demyelinating diseases are diseases of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency in sensation, movement, cognition, or other functions depending on which nerves are involved. Some demyelinating diseases are caused by genetics, some by infectious agents, some by autoimmune reactions, some by unknown factors, and some by a combination of (some of) these factors.
Demyelinating diseases are traditionally classified in two kinds: demyelinating myelinoclastic diseases and demyelinating leukodystrophic diseases. In the first group a normal and healthy myelin is destroyed by a toxic, chemical or autoimmune substance. In the second group (also denominated as dysmyelinating diseases), myelin is abnormal and degenerates.
The best-known example of a demyelinating disease is multiple sclerosis (MS). MS is a chronic inflammatory and degenerative disease of the central nervous system (CNS) with a highly heterogeneous course of disease progression, and caused by a complex interplay of genetic and environmental factors. The inflammatory and neurodegenerative processes cause damage to nerve cells (neurons), which eventually leads to a loss of the electrically isolating myelin sheet around the axons, the neuronal extensions that transmit brain signals. This loss of myelin and hence neuronal functionality gives rise to a variety of neurological symptoms and impairments, depending on the brain region where the demyelination occurs.
MS symptoms are diverse with large heterogeneity among patients, making an accurate diagnosis and prognosis cumbersome. Effective MS treatments reduce the number and severity of relapses, and disease burden.
Despite the broadening range of available treatments, the response of MS patients to medication remains unpredictable and heterogeneous. Furthermore, it has been suggested in the art that genetic heterogeneity influences the pathogenesis of disease, and is involved in the disease progression, i.e. the number of relapses, the rate of disease progression and the overall disease burden.
In MS (and most other demyelinating diseases), the myelin sheath surrounding neurons is gradually degraded and/or not repaired anymore, a process that together with the autoimmune reaction characterizes MS and causes the neurological symptoms of the disease.
In order to improve the patient’s quality of life and slow down the rate of demyelination, there is a need for a therapy to treat demyelinating diseases by stopping the demyelination process and/or inducing a remyelination mechanism of the affected nerves.
The present invention provides hereto cantharidinimides for treating a demyelinating disease, wherein the cantharidinimides are selected from compounds of formula (A):
Figure NL2020792B1_D0001
N~(CH2)n
Ar ch3q (A), wherein:
n is independently selected from 0, 1, 2, 3, 4 or 5; and
Ar is independently selected from the group consisting of compounds of formula (B-G):
Figure NL2020792B1_D0002
wherein:
R represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C1.4 alkyl, C14 alkoxy, C1-4 alkylamino, C1-4 alkylthio, aryl, benzyl, phenoxy or benzoxy;
formula C is selected from the group consisting of R-substituted 1-naphthyl and R-substituted 2-naphthyl;
formula E is selected from the group consisting of R-substituted 2-pyridyl, R-substituted 3-pyridyl and R-substituted 4-pyridyl;
formula F is selected from the group consisting of R-substituted 2-pyrimidinyl, R-substituted 4-pyrimidinyl and R-substituted 5-pyrimidinyl; and formula G is selected from the group consisting of R-substituted 2-indolyl and R-substituted 3-indolyl.
It was found that the cantharidinimides of the present invention stop the demyelination process and/or induce a remyelination mechanism. Thus, the cantharidinimides of the present invention are good drug candidates for treating demyelinating diseases. Demyelinating diseases may be selected from the group consisting of demyelinating myelinoclastic diseases and demyelinating leukodystrophic diseases.
It is noted that the cantharidinimides of the present invention are good drug candidates for treating inflammatory demyelinating diseases in particular. Examples of inflammatory demyelinating diseases include, but are not limited to, multiple sclerosis, clinically isolated syndrome, Devic's disease, Neuromyelitis optica, anti-MOG autoimmune encephalomyelitis, Chronic relapsing inflammatory optic neuritis, Acute disseminated encephalomyelitis, Acute hemorrhagic leukoencephalitis, Balo concentric sclerosis, diffuse myelinoclastic sclerosis (Schilder diffuse sclerosis), Marburg multiple sclerosis, Tumefactive multiple sclerosis and Solitary sclerosis.
In an embodiment of the present invention, the cantharidinimides of the present invention are good drug candidates for treating demyelinating diseases selected from the group consisting of standard multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis and benign multiple sclerosis.
The present invention also relates to a formulation for treating a demyelinating disease, wherein the formulation comprises at least one cantharidinimide of the present invention. Such formulation may comprise any suitable form for administration of at least one cantharidinimide to a subject suffering from the demyelinating disease. The subject may be a mammal including human beings.
The present invention also relates to a method of treating a subject suffering from a demyelinating disease by administration of a pharmacologically effective amount of at least one cantharidinimide of the present invention.
The present invention further relates to the use of at least one cantharidinimide of the present invention in the treatment of a subject suffering from a demyelinating disease.
Given the cantharidinimides of the present invention as defined above, it is noted that the C-i-4 alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. Further, the C1-4 alkoxy may be selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy. Methoxy is the preferred C1-4 alkoxy. With regard to the C1-4 alkylamino it was found that the Ci4 alkylamino may be selected from the group consisting of monomethylamino, dimethylamino, monoethylamino and diethylamino. Dimethylamino and diethylamino are preferred substituents. Further, C1-4 alkylthio may be selected from the group consisting of methylthio, ethylthio, propylthio, isopropylthio, butylthio and tertbutylthio.
With regard to the aryl substituent it is noted that the aryl may be selected from the group consisting of phenyl, tolyl, and xylyl. Preferably the aryl substituent comprises a phenyl.
With regard to the formulas C, F and G it is noted that the cantharidinimides of the present invention may have different configurations. However, for formula C an Rsubstituted 2-naphthyl is preferred, for formula F an R-substituted 2-pyrimidinyl is preferred and for formula G an R-substituted 3-indolyl is preferred.
In an embodiment of the present invention, the cantharidinimides for treating a demyelinating disease may be selected from compounds of formula (AB):
Figure NL2020792B1_D0003
(AB), wherein n is independently selected from 0, 1, 2, 3, 4 or 5; and
R1 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C1.4 alkyl, C1.4 alkoxy, C1-4 alkylamino, C1.4 alkylthio, aryl, benzyl, phenoxy or benzoxy in the ortho, meta and/or para position.
Preferred cantharidinimides selected from compounds of formula AB may include cantharidinimides wherein R1 is selected from hydrogen, amino, hydroxy, methoxy, benzoxy, nitro or phenyl in the ortho, meta and/or para position. More specifically, even further preferred cantharidinimides selected from compounds of formula AB may include cantharidinimides wherein R1 is selected from hydrogen, ortho-, meta- or paraamino, ortho- or para-hydroxy, para-nitro, para-phenyl, para-methoxy, meta-paradimethoxy, meta-benzoxy-para-methoxy or meta-methoxy-para-benzoxy.
In an embodiment of the present invention, the cantharidinimides selected from compounds of formula AB may include cantharidinimides wherein n is independently selected from 0, 1,2, or 4 and R1 is selected from hydrogen, ortho-amino, meta-amino, para-amino, meta-hydroxy, para-hydroxy, meta-para-dimethoxy, para-methoxy, metabenzoxy-para-methoxy, meta-methoxy-para-benzoxy, para-nitro or para-phenyl.
In a further embodiment of the present invention, the cantharidinimides for treating a demyelinating disease may be selected from compounds of formula (I):
Figure NL2020792B1_D0004
wherein
O),
R7 represents one or more substituents independently selected from hydrogen, hydroxy, preferably meta- and/or para-hydroxy, nitro, preferably para-nitro, and/or phenyl, preferably para-phenyl.
In another embodiment of the present invention, the cantharidinimides for treating a demyelinating disease may be selected from compounds of formula (II):
Figure NL2020792B1_D0005
wherein
R8 represents one or more substituents independently selected from hydrogen, hydroxy, preferably para-hydroxy, and/or amino, preferably ortho-, meta- and/or paraamino.
In an embodiment of the present invention, the cantharidinimides for treating a demyelinating disease may be selected from compounds of formula (III):
Figure NL2020792B1_D0006
(HI).
wherein
R9 represents one or more substituents independently selected from hydrogen, hydroxy, preferably para-hydroxy, methoxy, preferably meta- and/or para-methoxy, and/or benzoxy, preferably meta- and/or para-benzoxy.
Further, in an embodiment of the present invention, the cantharidinimides for treating a demyelinating disease may be selected from a compound of formula (IV):
Figure NL2020792B1_D0007
(IV).
In an embodiment of the present invention, the cantharidinimides for treating a demyelinating disease may be selected from compounds of formula (AC):
Figure NL2020792B1_D0008
(AC), wherein n is independently selected from 0, 1, 2, 3, 4 or 5; and
R2 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C1-4 alkyl, C1.4 alkoxy, C1.4 alkylamino, C1.4 alkylthio, aryl, benzyl, phenoxy or benzoxy in the 5, 6, 7 and/or 8 position.
Preferred cantharidinimides selected from compounds of formula AC may include cantharidinimides wherein R2 is selected from hydrogen, hydroxy, methoxy, in the 5, 6, 7 and/or 8 position.
The cantharidinimides for treating a demyelinating disease may be selected from a compound of formula (V):
Figure NL2020792B1_D0009
(V).
In an embodiment of the present invention, the cantharidinimides for treating a demyelinating disease may be selected from compounds of formula (AD):
Figure NL2020792B1_D0010
(AD), wherein n is independently selected from 0, 1, 2, 3, 4 or 5; and
R3 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C1-4 alkyl, C1-4 alkoxy, C1.4 alkylamino, C1.4 alkylthio, aryl, benzyl, phenoxy or benzoxy in the 4, 5, 6 and/or 7 position.
Preferred cantharidinimides selected from compounds of formula AD may include cantharidinimides wherein R3 is selected from hydrogen, hydroxy or methoxy, in the 5, 6, 7 and/or 8 position, preferably selected from hydrogen or 5-methoxy.
The cantharidinimides for treating a demyelinating disease may be selected from a compound of formula (VI):
Figure NL2020792B1_D0011
(VI), wherein
R10 represents one or more substituents independently selected from hydrogen, and/or methoxy, preferably 5-methoxy.
In an embodiment of the present invention, the cantharidinimides for treating a demyelinating disease may be selected from compounds of formula (AE):
Figure NL2020792B1_D0012
wherein n is independently selected from 0, 1, 2, 3, 4 or 5; and
R4 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, aryl, benzyl, phenoxy or benzoxy.
Preferred cantharidinimides selected from compounds of formula AE may include cantharidinimides wherein R4 is hydrogen.
The cantharidinimides for treating a demyelinating disease may be selected from the compounds of formulas (VII, VIII, IX):
Figure NL2020792B1_D0013
Figure NL2020792B1_D0014
(VIII); and (IX).
In an embodiment of the present invention, the cantharidinimides for treating a demyelinating disease may be selected from compounds of formula (AF):
Figure NL2020792B1_D0015
(AF), n is independently selected from 0, 1, 2, 3, 4 or 5; and
R5 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C1-4 alkyl, C1.4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, aryl, benzyl, phenoxy or benzoxy.
Preferred cantharidinimides selected from compounds of formula AF may include cantharidinimides wherein R5 is hydrogen.
In an embodiment of the present invention, the cantharidinimides for treating a demyelinating disease may be selected from compounds of formula (AG):
Figure NL2020792B1_D0016
(AG), wherein n is independently selected from 0, 1, 2, 3, 4 or 5; and
R6 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, aryl, benzyl, phenoxy or benzoxy.
Preferred cantharidinimides selected from compounds of formula AG may include cantharidinimides wherein R6 is hydrogen.
The cantharidinimides for treating a demyelinating disease may be selected from the compounds of formulas (X):
Figure NL2020792B1_D0017
(X).
The cantharidinimides are preferably selected from the group consisting of NBenzylcantharidinimide, N-(2-Aminobenzyl)cantharidinimide, N-(3Aminobenzyl)cantharidinimide, N-(4-Aminobenzyl)cantharidinimide, N-[2-(4’Hydroxyphenyl)ethyl] cantharidinimide, N-(4-Phenylbutyl)cantharidinimide, N-[2-(3’,4’Dimethoxyphenyl)ethyl] cantharidinimide, N-[2-(p-Methoxyphenyl)ethyl] cantharidinimide, N-[2-(3’-Methoxy-4’-benzyloxyphenyl)ethyl]cantharidinimide, N-[2(3’-Benzyloxy-4’-methoxyphenyl)ethyl]cantharidinimide, N-(4Hydroxyphenyl)cantharidinimide, N-(3-Hydroxyphenyl)cantharidinimide, N-4-(1Nitro)phenylcantharidinimde, N-(4-Biphenyl)cantharidinimide, N-[2-(2Naphthyl)ethyl]cantharidinimide, N-[2-(3’-lndolyl)ethyl]cantharidinimide, N-[2-(5’Methoxy-3’-lndolyl)ethyl] cantharidinimide, N-[2-(2’-Pyridyl)ethyl]cantharidinimide and N-[2-(3’,4’-Methylenedioxyphenyl)ethyl] cantharidinimide.
EXAMPLES
Synthesis of cantharidinimides
Cantharidinimides were prepared by heating cantharidin and primary amines, aniline derivatives or aminopyridines according to the following general reaction scheme:
Figure NL2020792B1_D0018
H2NR, Et3N toluene, reflux
Figure NL2020792B1_D0019
The reactants were heated to a temperature of about 200°C with 3 mL of dry toluene and about 1.5 mL of trimethylamine in a high-pressure sealed tube (Buchi glasuster 0032). After 2 hours and recrystallization from methanol the cantharidinimides listed in table 1 were obtained.
Table 1. Overview of synthesized compounds
Ex Structure Chemical name
1 CHsy o I N—\ θΗ=ο ΛΛ N-Benzylcantharidinimide
2 ο Ί-Ι θ lX N---v NH2 ζΧ XX -1-I3 0 c y N-(2-Aminobenzyl)cantharidinimide
3 o •>|_l O -3 // N--\ DH3 0 y--NH2 N-(3-Aminobenzyl)cantharidinimide
4 o Ί-Ι ° N—\ ζΧ -¾ 0 <7 y nh2 N-(4-Aminobenzyl)cantharidinimide
5 o ~>i_i ° _ 3 // n—\ Γ/—λ ---\ /--OH DH3 O \=/ N-[2-(4’-Hydroxyphenyl)ethyl] cantharidinimide
6 o Ί-Ι θ ; 3// N--\ iX \_v=\ 3 ° λ \\ /7 N-(4-Phenylbutyl)cantharidinimide
7 ch3/? N-[2-(3’,4’-Dimethoxyphenyl)ethyl] cantharidinimide
o JJ OMe
N--\ ^h 3'q --ς —OMe
?H3//
o N—\ .---------------------.
8 // \\ N-[2-(2-Naphthyl)ethyl]cantharidinimide
\ / \\
θΗ3/°
q o N—\ N-[2-(3’,4’-Methylenedioxyphenyl)ethyl]
\ /^° cantharidinimide
θΗ3 Q '---------\ I
O·^
ch3/°
10 o N---v N-[2-(p-Methoxyphenyl)ethyl]
u / \ cantharidinimide
-—OMe
θΗ3*Ο
?H3/?
11 O N—\ N-[2-(3’-Methoxy-4’-
— benzyloxyphenyl)ethyl]cantharidinimide
CH3^ \---/
OMe
12 CH^ I O Γ N---\ r--λ '--</ —oMe ch3 o O N-[2-(3’-Benzyloxy-4’- methoxyphenyl)ethyl]cantharidinimide
13 O ->|_l O HH3// N—\ f/—X lX \ / -m3 o N—/ N-[2-(2’-Pyridyl)ethyl]cantharidinimide
14 CH^ CDd^^h ch3\\ N-[2-(3’-lndolyl)ethyl]cantharidinimide
15 O ~LJ O jj iH\\ VI -ns 0 / MeO N-[2-(5’-Methoxy-3’-lndolyl)ethyl] cantharidinimide
16 CHs^ —C —oh CH3^ N-(4-Hydroxyphenyl)cantharidinimide
17 ch3/° N-(3-Hydroxyphenyl)cantharidinimide
o N---((
CH3^O oh
18 ChJ? --N O 2 N-4-(1-Nitro)phenylcantharidinimde
19 o ~|_| O ;3// N---(( J)---(( J) Xï -H3 o N-(4-Biphenyl)cantharidinimde
Cultures of cell lines
The neuroblastoma cell line SH-SY5Y was purchased from ATCC (Manassas, VA, USA). Human oligodendroglial HOG cells were kindly provided by Prof. Dr. José Antonio López Guerrero (Univeristy of Madrid, Spain). The MO3.13 cell line was kindly provided by Prof. Dr. Neil Cashman (University of Vancouver, Canada).
All cell lines were cultured in growth medium (GM) containing Earl’s Modified Eagle Medium (EMEM, Lonza) supplemented with 15% heat-inactivated fetal bovine serum (hiFBS, Gibco), 1% antibiotic-antimycotic (Gibco) and 1% Glutamax (Gibco) in a humidified 5% CO2 incubator at 37°C. Regular mycoplasm tests (MycoAlert Detection Kit, Lonza) were performed in order to assure the bacteria-free status of the cells.
Differentiation of cell lines
SH-SY5Y
At 0 days in vitro (DIV), SH-SY5Y cells were plated at a confluency of 5.0*104 cells/cm2 in a plate or on a glass coverslip coated with Matrigel (1 : 100; Corning) diluted in Dulbecco’s Modified Eagle Medium (DMEM) for 1 hour at 37°C.
To induce differentiation, the cells were subjected for 6 DIV to differentiation medium 1 (DM1), consisting of EMEM, 2.5% hiFBS and 1% antibiotic-antimycotic, freshly supplemented at each medium change with 10 pm all-trans retinoic acid (ATRA, Sigma). Medium of the cells was changed every 48 hours.
At 7 DIV, the cells were split 1 : 1 onto a new plate coated with Matrigel (1 : 100) diluted in DMEM for 1 hour at 37°C.
At 8 DIV, the cells were subjected to differentiation medium 2 (DM2), consisting of EMEM, 1% hiFBS and 1% antibiotic-antimycotic, freshly supplemented at each medium change with 10 pm ATRA.
At 10 DIV, the cells were split 1 : 1 onto a new plate coated with Matrigel (1 : 100) diluted in DMEM for 1 hour at 37°C.
To induce final differentiation, differentiation medium 3 (DM3) was added at 11, 14 and 17 DIV. DM3 consists of Neurobasal Medium (Gibco) supplemented with 20 mM KCI (Merck), 20 mM B-27 supplement (Gibco), 1% antibiotic-antimycotic, culture-one supplement (1 : 100, Gibco), 50 ng/ml brain-derived neurotrophic factor (BDNF, Sigma), 2mM adenosine-3',5'-cyclic monophosphate (cAMP, Sigma) and 10 μΜ ATRA added freshly at each medium change.
HOG and MO3.13
At 0 DIV, the HOG cells as well as the MO3.13 cells were plated at a confluency of 1.5*104 cells/cm2 in a plate or on a glass coverslip coated with Matrigel (1:100) diluted in DMEM for 1 hour at 37°C.
To induce differentiation, the HOG and MO3.13 cells were subjected for 5 DIV to differentiation medium 4 (DM4), consisting of EMEM supplemented with 50 pg/ml apotransferrin (Sigma), 16 pg/ml putrescine (Sigma), 0.5 pg/ml human-derived insulin (Sigma), 30 nM sodium selenite (Sigma), 30 nM triiodo-L-thyronine (T3, Sigma), 500 μΜ 3-isobutyl-1-methylxanthine (IBMX, Sigma), 500 μΜ cAMP and 1% antibioticantimycotic.
Oxidative stress-exposed cell lines
Undifferentiated SH-SY5Y cells were exposed to oxidative insult of hydrogen peroxide (H2O2, Sigma) at a concentration of 100 μΜ for 18 h.
Undifferentiated HOG cells were exposed to oxidative insult of H2O2 at a concentration of 100 μΜ for 18 h.
Undifferentiated MO3.13 cells were exposed to oxidative insult of H2O2 at a concentration of 500 μΜ for 18 h.
The optimal concentrations of H2O2 were determined by dose-response experiments. Cell viability following oxidative insult experiments was determined by quantification of fluorescent cell signals with the NucBlue/NucGreen Cell Viability kit (Thermo Fisher) and fluorescence-activated cell sorting (FACS) of NucGreen-positive cells and Propidium Iodide (Sigma)-positive cells.
Following visual confirmation of the differentiated phenotype, differentiated cell lines SH-SY5Y, HOG and MO3.13 were exposed to oxidative insult of H2O2. The optimal concentrations to induce oxidative insult in differentiated SH-SY5Y cells, HOG cells and MO3.13 cells were 500 μΜ, 50 μΜ and 100 μΜ, respectively. Quantification of cell viability was performed by quantification of fluorescent cell signals with the NucBlue/NucGreen Cell Viability kit and FACS of NucGreen-positive cells and Propidium Iodide-positive cells.
Co-cultures of SH-SY5Y and HOG
Co-culture of differentiated SH-SY5Y cells with undifferentiated HOG cells
In order to generate a co-culture of differentiated SH-SY5Y cells with undifferentiated HOG cells, the protocol to generate differentiated SH-SY5Y cells was used until 10 DIV.
At 10 DIV, the differentiating SH-SY5Y cells were split 1 : 1 onto a new plate coated with Matrigel (1 : 100) diluted in DMEM for 1 hour at 37°C. SH-SY5Y cell density was determined by cell counting by hand and undifferentiated HOG cells were added at various cell densities relative to the number of SH-SY5Y cells, at a ratio of HOG : SHSY5Y cells of 1 : 2, 1 : 4, 1 : 6 and 1 : 8.
Co-culture of differentiated SH-SY5Y cells with differentiated HOG cells
First, a co-culture of differentiated SH-SY5Y cells with undifferentiated HOG cells was generated using the above protocol.
Next, in order to generate a co-culture of differentiated SH-SY5Y cells with differentiated HOG cells, differentiation medium 5 (DM5) was added at 11, 14 and 17 DIV. DM5 consists of DM3 supplemented with 50 pg/ml apo-transferrin, 16 pg/ml putrescine, 0.5 pg/ml human-derived insulin, 30 nM sodium selenite, 30 nM T3 and 500 pM IBMX.
Oxidative stress-exposed co-cultures of SH-SY5Y and HOG
To elicit oxidative stress, the above obtained co-cultures of differentiated SH-SY5Y cells and undifferentiated HOG cells and differentiated SH-SY5Y cells and differentiated HOG cells were exposed to various concentrations of H2O2 in order to determine the optimal concentrations.
Co-cultures of SH-SY5Y and MO3.13
Co-culture of differentiated SH-SY5Y cells with undifferentiated MO3.13 cells
In order to generate a co-culture of differentiated SH-SY5Y cells with undifferentiated MO3.13 cells, the protocol to generate differentiated SH-SY5Y cells was used until 10 DIV.
At 10 DIV, the differentiating SH-SY5Y cells were split 1 : 1 onto a new plate coated with Matrigel (1 : 100) diluted in DMEM for 1 hour at 37°C. SH-SY5Y cell density was determined by cell counting by hand and undifferentiated MO3.13 cells were added at various cell densities relative to the number of SH-SY5Y cells, at a ratio of MO3.13 : SH-SY5Y cells of 1 : 2, 1 : 4, 1 : 6 and 1 : 8.
Co-culture of differentiated SH-SY5Y cells with differentiated MO3.13 cells
First, a co-culture of differentiated SH-SY5Y cells with undifferentiated MO3.13 cells was generated using the above protocol.
Next, in order to generate a co-culture of differentiated SH-SY5Y cells with differentiated MO3.13 cells, DM5 was added at 11, 14 and 17 DIV.
Oxidative stress-exposed co-cultures of SH-SY5Y and MO3.13
To elicit oxidative stress, the above obtained co-cultures of differentiated SH-SY5Y cells and undifferentiated MO3.13 cells and differentiated SH-SY5Y cells and differentiated MO3.13 cells were exposed to various concentrations of H2O2 in order to determine the optimal concentrations.
Myelin-inducing activity of cantharidinimides
The cantharidinimides of table 1 were tested in the above-obtained cell cultures.
Hereto various concentrations of cantharidinimides (1 to 20 μΜ) were added to: cultures of undifferentiated and differentiated SH-SY5Y cells; cultures of undifferentiated and differentiated HOG cells; cultures of undifferentiated and differentiated MO3.13 cells;
cultures of oxidative stress-exposed undifferentiated and
differentiated SH-SY5Y cells;
cultures of oxidative stress-exposed undifferentiated and
differentiated HOG cells;
cultures of oxidative stress-exposed undifferentiated and
differentiated MO3.13 cells;
co-culture of differentiated SH-SY5Y cells with undifferentiated
HOG cells;
co-culture of differentiated SH-SY5Y cells with differentiated
HOG cells;
co-culture of differentiated SH-SY5Y cells with undifferentiated
MO3.13 cells;
co-culture of differentiated SH-SY5Y cells with differentiated
MO3.13 cells;
oxidative stress-exposed co-culture of differentiated
SH-SY5Y cells with undifferentiated HOG cells;
oxidative stress-exposed co-culture of differentiated
SH-SY5Y cells with differentiated HOG cells;
oxidative stress-exposed co-culture of differentiated
SH-SY5Y cells with undifferentiated MO3.13 cells; and oxidative stress-exposed co-culture of differentiated
SH-SY5Y cells with differentiated MO3.13 cells.
Following treatment with cantharidinimides, the exposed cells were analysed with:
microscopy on cells stained with antibodies directed towards the myelin-related proteins myelin-basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), myelin proteolipid protein (PLP1) and myelin-associated glycoprotein (MAG), and quantification of the signals with Cellomics software (Thermo Fisher), wherein an increase in the amount of staining reflects myelin-inducing activity of the cantharidinimides;
live-cell imaging of living cells using the fluorescent myelin stain FluoroMyelin Red (Thermo Fisher) and quantification of the signals with Cellomics, wherein an increase in the amount of fluorescent staining reflects myelin-inducing activity of the cantharidinimides;
mutli-electrode arrays (MEAs) to quantify electrical activity of the living cells as a measure of the degree and quality of myelination induced by the cantharidinimides;
imaging cellular Ca2+ signals with organic fluorescent Ca2+ indicators for functional analysis of the neuronal circuits induced by the cantharidinimides;
western blot protein analyses of protein lysates of the cells using antibodies against MBP, MOG, PLP1, MAG and the “housekeeping gene” glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and quantification of protein bands by an Odyssey imaging system to collect data in digital form, wherein an increase in the amount of myelin-related proteins reflects myelin-inducing activity of the cantharidinimides; and quantitative polymerase chain reaction (qPCR) analysis of RNA extracted from the cells and using primers specific for MBP, MOG, PLP1, MAG and the “housekeeping genes” GAPDH, peptidylprolyl isomerase A (PPIA), tyrosine 3monooxygenase/tryptophan 5-monooxygenase activation protein zeta polypeptide (YWHAZ), and eukaryotic translation initiation factor 4a2 (EIF4A2), wherein an increase in the amount of myelin-related RNAs reflects myelin-inducing activity of the cantharidinimides.
The results of the above tests show myelin-inducing activity of the cantharidinimides tested.

Claims (22)

CONCLUSIESCONCLUSIONS 1.1. Cantharidinimiden voor het behandelen van een demyeliniserende ziekte, met het kenmerk dat de cantharidinimiden zijn gekozen uit verbindingen met formule (A):Cantharidinimides for treating a demyelinating disease, characterized in that the cantharidinimides are selected from compounds of formula (A):
Figure NL2020792B1_C0001
Figure NL2020792B1_C0001
 (A), waarbij:(A), wherein: n onafhankelijk is gekozen uit 0, 1, 2, 3, 4 of 5; enn is independently selected from 0, 1, 2, 3, 4 or 5; and Ar onafhankelijk is gekozen uit de groep bestaande uit verbindingen met formule (B-G):Ar is independently selected from the group consisting of compounds of formula (B-G):
Figure NL2020792B1_C0002
Figure NL2020792B1_C0002
Figure NL2020792B1_C0003
Figure NL2020792B1_C0003
 (F);(F); (G), waarbij:(G), wherein: R staat voor één of meer substituenten onafhankelijk gekozen uit waterstof, fluor, chloor, broom, jood, hydroxy, nitro, cyano, amino, Cm alkyl, Cm alkoxy, Cm alkylamino, Cm alkylthio, aryl, benzyl, fenoxy of benzoxy;R represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C 1 alkyl, C 1 alkoxy, C 1 alkylamino, C 1 alkylthio, aryl, benzyl, phenoxy or benzoxy; formule C is gekozen uit de groep bestaande uit Rgesubstitueerde 1-nafthyl en R-gesubstitueerde 2-naphthyl;formula C is selected from the group consisting of R-substituted 1-naphthyl and R-substituted 2-naphthyl; formule E is gekozen uit de groep bestaande uit Rgesubstitueerde 2-pyridyl, R-gesubstitueerde 3-pyridyl en R-gesubstitueerde 4-pyridyl;formula E is selected from the group consisting of R-substituted 2-pyridyl, R-substituted 3-pyridyl and R-substituted 4-pyridyl; formule F is gekozen uit de groep bestaande uit Rgesubstitueerde 2-pyrimidinyl, R-gesubstitueerde 4-pyrimidinyl en R-gesubstitueerdeformula F is selected from the group consisting of R-substituted 2-pyrimidinyl, R-substituted 4-pyrimidinyl and R-substituted 5-pyrimidinyl; en formule G is gekozen uit de groep bestaande uit Rgesubstitueerde 2-indolyl en R-gesubstitueerde 3-indolyl.5-pyrimidinyl; and formula G is selected from the group consisting of R-substituted 2-indolyl and R-substituted 3-indolyl. 2. Cantharidinimiden volgens conclusie 1, met het kenmerk dat de:Cantharidinimides according to claim 1, characterized in that the: Cm alkyl is gekozen uit de groep bestaande uit methyl, ethyl, propyl, isopropyl, butyl en tert-butyl;C 1 alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl; Cm alkoxy is gekozen uit d groep bestaande uit methoxy, ethoxy, propoxy, isopropoxy, butoxy en tert-butoxy;C 1 alkoxy is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy; Cm alkylamino is gekozen uit de groep bestaande uit monomethylamino, dimethylamino, monoethylamino en diethylamino;Cm alkylamino is selected from the group consisting of monomethylamino, dimethylamino, monoethylamino and diethylamino; Cm alkylthio is gekozen uit de groep bestaande uit methylthio, ethylthio, propylthio, isopropylthio, butylthio en tert-butyIthio; en/of aryl is gekozen uit de groep bestaande uit fenyl, tolyl, en xylyl.C 1-6 alkylthio is selected from the group consisting of methylthio, ethylthio, propylthio, isopropylthio, butylthio and tert-butythio; and / or aryl is selected from the group consisting of phenyl, tolyl, and xylyl. 3.3. Cantharidinimiden volgens conclusie 1 of 2, met het kenmerk dat: formule C is een R-gesubstitueerde 2-naphthyl; formule F is een R-gesubstitueerde 2-pyrimidinyl; of formule G is een R-gesubstitueerde 3-indolyl.Cantharidinimides according to claim 1 or 2, characterized in that: formula C is an R-substituted 2-naphthyl; formula F is an R-substituted 2-pyrimidinyl; or formula G is an R-substituted 3-indolyl. 4. Cantharidinimiden volgens conclusie 1 of 2, met het kenmerk dat de cantharidinimiden zijn gekozen uit verbindingen met formule (AB):Cantharidinimides according to claim 1 or 2, characterized in that the cantharidinimides are selected from compounds of formula (AB): o ch3 o ch 3
Figure NL2020792B1_C0004
Figure NL2020792B1_C0004
 o ch3 o ch 3 N-(CH2)N- (CH 2 )
Figure NL2020792B1_C0005
Figure NL2020792B1_C0005
 R1 (AB).R 1 (AB). waarbij:at which: n onafhankelijk is gekozen uit 0, 1,2, 3, 4 of 5; enn is independently selected from 0, 1.2, 3, 4 or 5; and R1 staat voor één of meer substituenten onafhankelijk gekozen uit waterstof, fluor, chloor, broom, jood, hydroxy, nitro, cyano, amino, Ch alkyl, C1-4 alkoxy, C1-4 alkylamino, C1.4 alkylthio, aryl, benzyl, fenoxy of benzoxy in de ortho, meta en/of para positie.R 1 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C 1 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, aryl, benzyl , phenoxy or benzoxy in the ortho, meta and / or para position. 5. Cantharidinimiden volgens conclusie 4, met het kenmerk dat R1 is gekozen uit waterstof, amino, hydroxy, methoxy, benzoxy, nitro of fenyl in de ortho, meta en/of para positie.Cantharidinimides according to claim 4, characterized in that R 1 is selected from hydrogen, amino, hydroxy, methoxy, benzoxy, nitro or phenyl in the ortho, meta and / or para position. 6. Cantharidinimiden volgens conclusie 4 of 5, met het kenmerk dat R1 is gekozen uit waterstof, ortho-, meta- of para-amino, ortho- of para-hydroxy, para-nitro, para-fenyl, para-methoxy, meta-para-dimethoxy, meta-benzoxy-para-methoxy of metamethoxy-para-benzoxy.Cantharidinimides according to claim 4 or 5, characterized in that R 1 is selected from hydrogen, ortho, meta or para-amino, ortho or para-hydroxy, para-nitro, para-phenyl, para-methoxy, meta para-dimethoxy, meta-benzoxy-para-methoxy or metamethoxy-para-benzoxy. 7. Cantharidinimiden volgens één der conclusies 1 -3, met het kenmerk dat de cantharidinimiden zijn gekozen uit verbindingen met formule (AC):Cantharidinimides according to any one of claims 1 to 3, characterized in that the cantharidinimides are selected from compounds of formula (AC):
Figure NL2020792B1_C0006
Figure NL2020792B1_C0006
 waarbij n onafhankelijk is gekozen uit 0, 1,2, 3, 4 of 5; enwherein n is independently selected from 0, 1.2, 3, 4 or 5; and R2 staat voor één of meer substituenten onafhankelijk gekozen uit waterstof, fluor, chloor, broom, jood, hydroxy, nitro, cyano, amino, Ch alkyl, C1-4 alkoxy, C1-4 alkylamino, C1.4 alkylthio, aryl, benzyl, fenoxy of benzoxy in de 5, 6, 7 en/of 8 positie.R 2 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, jew, hydroxy, nitro, cyano, amino, Ch alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, aryl, benzyl , phenoxy or benzoxy in the 5, 6, 7 and / or 8 position. 8. Cantharidinimiden volgens conclusie 7, met het kenmerk dat R2 is gekozen uit waterstof, hydroxy, methoxy, in de 5, 6, 7 en/of 8 positie.Cantharidinimides according to claim 7, characterized in that R 2 is selected from hydrogen, hydroxy, methoxy, in the 5, 6, 7 and / or 8 position. 9. Cantharidinimiden volgens conclusie 1 of 2, met het kenmerk dat de cantharidinimiden zijn gekozen uit verbindingen met formule (AD):Cantharidinimides according to claim 1 or 2, characterized in that the cantharidinimides are selected from compounds of formula (AD):
Figure NL2020792B1_C0007
Figure NL2020792B1_C0007
 (AD), n onafhankelijk is gekozen uit 0, 1, 2, 3, 4 of 5; en(AD), n is independently selected from 0, 1, 2, 3, 4 or 5; and R3 staat voor één of meer substituenten onafhankelijk gekozen uit waterstof, fluoor, chloor, broom, jood, hydroxy, nitro, cyano, amino, C1.4 alkyl, C1.4 alkoxy, C1.4 alkylamino,R 3 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C1-4 alkylthio, aryl, benzyl, fenoxy of benzoxy in de 4, 5, 6 en/of 7 positie.C1-4 alkylthio, aryl, benzyl, phenoxy or benzoxy in the 4, 5, 6 and / or 7 position. 10. Cantharidinimiden volgens conclusie 9, met het kenmerk dat R3 is gekozen uit waterstof, hydroxy of methoxy, in de 5, 6, 7 en/of 8 positie, bij voorkeur gekozen uit waterstof of 5-methoxy.Cantharidinimides according to claim 9, characterized in that R 3 is selected from hydrogen, hydroxy or methoxy, in the 5, 6, 7 and / or 8 position, preferably selected from hydrogen or 5-methoxy. 11. Cantharidinimiden volgens conclusie 1 of 2, met het kenmerk dat de cantharidinimiden zijn gekozen uit verbindingen met formule (AE):Cantharidinimides according to claim 1 or 2, characterized in that the cantharidinimides are selected from compounds of formula (AE):
Figure NL2020792B1_C0008
Figure NL2020792B1_C0008
 n onafhankelijk is gekozen uit 0, 1, 2, 3, 4 of 5; enn is independently selected from 0, 1, 2, 3, 4 or 5; and R4 staat voor één of meer substituenten onafhankelijk gekozen uit waterstof, fluor, chloor, broom, jood, hydroxy, nitro, cyano, amino, Cm alkyl, C1-4 alkoxy, C1-4 alkylamino, Cm alkylthio, aryl, benzyl, fenoxy of benzoxy.R 4 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C 8 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, aryl, benzyl, phenoxy or benzoxy. 12. Cantharidinimiden volgens conclusie 11, met het kenmerk dat R4 waterstof is.Cantharidinimides according to claim 11, characterized in that R 4 is hydrogen. 13. Cantharidinimiden volgens één der conclusies 1 -3, met het kenmerk dat de cantharidinimiden zijn gekozen uit verbindingen met formule (AF):Cantharidinimides according to any one of claims 1 to 3, characterized in that the cantharidinimides are selected from compounds of formula (AF):
Figure NL2020792B1_C0009
Figure NL2020792B1_C0009
 n onafhankelijk is gekozen uit 0, 1,2, 3, 4 of 5; enn is independently selected from 0, 1.2, 3, 4 or 5; and R5 staat voor één of meer substituenten onafhankelijke gekozen uit waterstof, fluor, chloor, broom, jood, hydroxy, nitro, cyano, amino, Cm alkyl, Cm alkoxy, Cm alkylamino, Cm alkylthio, aryl, benzyl, fenoxy of benzoxy.R 5 represents one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, cyano, amino, C 1 alkyl, C 1 alkoxy, C 1 alkylamino, C 1 alkylthio, aryl, benzyl, phenoxy or benzoxy. 14. Cantharidinimiden volgens conclusie 13, met het kenmerk dat R5 waterstof is.Cantharidinimides according to claim 13, characterized in that R 5 is hydrogen. 15. Cantharidinimiden volgens één der conclusies 1 -3, met het kenmerk dat de cantharidinimiden zijn gekozen uit verbindingen met formule (AG):Cantharidinimides according to any one of claims 1 to 3, characterized in that the cantharidinimides are selected from compounds of formula (AG):
Figure NL2020792B1_C0010
Figure NL2020792B1_C0010
 n onafhankelijk is gekozen uit 0, 1,2, 3, 4 of 5; enn is independently selected from 0, 1.2, 3, 4 or 5; and R6 staat voor één of meer substituenten onafhankelijk gekozen uit waterstof, fluor, chloor, broom, jood, hydroxy, nitro, cyano, amino, Cm alkyl, Cm alkoxy, Cm alkylamino, Cm alkylthio, aryl, benzyl, fenoxy of benzoxy.R 6 represents one or more substituents independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino, C 1 alkyl, C 1 alkoxy, C 1 alkylamino, C 1 alkylthio, aryl, benzyl, phenoxy or benzoxy. 16. Cantharidinimiden volgens conclusie 13, met het kenmerk dat R6 waterstof is.Cantharidinimides according to claim 13, characterized in that R 6 is hydrogen. 17. Cantharidinimiden voor het behandelen van de demyeliniserende ziekte, met het kenmerk dat de cantharidinimiden zijn gekozen uit de groep bestaande uit:17. Cantharidinimides for treating the demyelinating disease, characterized in that the cantharidinimides are selected from the group consisting of: N-Benzylcantharidinimide;N-Benzyl cantharidinimide; N-(2-Aminobenzyl)cantharidinimide;N- (2-Aminobenzyl) cantharidinimide; N-(3-Aminobenzyl)cantharidinimide;N- (3-Aminobenzyl) cantharidinimide; N-(4-Aminobenzyl)cantharidinimide; N-[2-(4’-Hydroxyfenyl)ethyl]cantharidinimide; N-(4-fenylbutyl)cantharidinimide;N- (4-Aminobenzyl) cantharidinimide; N- [2- (4'-Hydroxyphenyl) ethyl] cantharidinimide; N- (4-phenylbutyl) cantharidinimide; N-[2-(3’,4’-Dimethoxyfenyl)ethyl]cantharidinimide; N-[2-(p-Methoxyfenyl)ethyl]cantharidinimide; N-[2-(3’-Methoxy-4’-benzyloxyfenyl)ethyl]cantharidinimide; N-[2-(3’-Benzyloxy-4’-methoxyfenyl)ethyl]cantharidinimide; N-(4-Hydroxyfenyl)cantharidinimide;N- [2- (3 ', 4'-Dimethoxyphenyl) ethyl] cantharidinimide; N- [2- (p-Methoxyphenyl) ethyl] cantharidinimide; N- [2- (3'-Methoxy-4'-benzyloxyphenyl) ethyl] cantharidinimide; N- [2- (3'-Benzyloxy-4'-methoxyphenyl) ethyl] cantharidinimide; N- (4-Hydroxyphenyl) cantharidinimide; N-(3-Hydroxyfenyl)cantharidinimide;N- (3-Hydroxyphenyl) cantharidinimide; N-4-(1 -Nitro)fenylcantharidinimde;N-4- (1-Nitro) phenylcantharidinimide; N-(4-Bifenyl)cantharidinimide; N-[2-(2-Nafthyl)ethyl]cantharidinimide; N-[2-(3’-lndolyl)ethyl]cantharidinimide;N- (4-Biphenyl) cantharidinimide; N- [2- (2-Naphthyl) ethyl] cantharidinimide; N- [2- (3'-indolyl) ethyl] cantharidinimide; N-[2-(5’-Methoxy-3’-lndolyl)ethyl]cantharidinimide N-[2-(2’-Pyridyl)ethyl]cantharidinimide; enN- [2- (5'-Methoxy-3'-indolyl) ethyl] cantharidinimide N- [2- (2'-Pyridyl) ethyl] cantharidinimide; and N-[2-(3’,4’-Methylenedioxyfenyl)ethyl]cantharidinimide.N- [2- (3 ', 4'-Methylenedioxyphenyl) ethyl] cantharidinimide. 18. Cantharidinimiden volgens één der voorgaande conclusies, met het kenmerk dat de demyeliniserende ziekte is gekozen uit de groep bestaande uit demyelinisatie van myelinoclastische ziekten en demyelinisatie van leukodystrofische ziekten.Cantharidinimides according to any one of the preceding claims, characterized in that the demyelinating disease is selected from the group consisting of demyelination of myelinoclastic diseases and demyelination of leukodystrophic diseases. 19. Cantharidinimiden volgens één der voorgaande conclusies, met het kenmerk dat de demyeliniserende ziekte is gekozen uit de groep bestaande uit inflammatoire demyeliniserende ziekten.Cantharidinimides according to any one of the preceding claims, characterized in that the demyelinating disease is selected from the group consisting of inflammatory demyelinating diseases. 20. Cantharidinimiden volgens één der voorgaande conclusies, met het kenmerk dat de demyeliniserende ziekte is gekozen uit de groep bestaande uit multiple sclerose, klinisch geïsoleerd syndroom, Devic's ziekte, Neuromyelitis optica, anti-MOG auto-immuun encefalomyelitis, Chronische terugkerende inflammatoire optische neuritis, Acute gedissemineerde encefalomyelitis, Acute hemorragische leukoencefalitis, Balo concentrische sclerosis, diffuse myelinoclastische sclerose (Schilder diffuse sclerose), Marburg multiple sclerose, Tumefactieve multiple sclerose en Solitaire sclerose.Cantharidinimides according to any one of the preceding claims, characterized in that the demyelinating disease is selected from the group consisting of multiple sclerosis, clinically isolated syndrome, Devic's disease, Neuromyelitis optics, anti-MOG autoimmune encephalomyelitis, Chronic recurrent inflammatory optic neuritis, Acute disseminated encephalomyelitis, Acute hemorrhagic leukoencephalitis, Balo concentric sclerosis, diffuse myelinoclastic sclerosis (Painter diffuse sclerosis), Marburg multiple sclerosis, Tumefactive multiple sclerosis and Solitary sclerosis. 21. Cantharidinimiden volgens één der voorgaande conclusies, met het kenmerk dat de demyeliniserende ziekte is gekozen uit de groep bestaande uit standaard multiple sclerose, relapsing-remitting multiple sclerose, primair progressieve multiple sclerose, secondair progressieve multiple sclerose en goedaardige multiple sclerose.Cantharidinimides according to any one of the preceding claims, characterized in that the demyelinating disease is selected from the group consisting of standard multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis and benign multiple sclerosis. 22. Formulering voor het behandelen van een demyeliniserende ziekte, met het kenmerk dat de formulering ten minste één cantharidinimide gekozen uit de groep bestaande uit de cantharidinimiden volgens één der conclusies 1-17 omvat.A formulation for treating a demyelinating disease, characterized in that the formulation comprises at least one cantharidinimide selected from the group consisting of the cantharidinimides according to any of claims 1-17.
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