U.S. patent application number 15/114874 was filed with the patent office on 2017-01-05 for therapeutic or prophylactic agent for multiple sclerosis.
The applicant listed for this patent is TORAY INDUSTRIES, INC.. Invention is credited to Hiroe Hirokawa, Mie Kaino, Kozue Takagaki.
Application Number | 20170000767 15/114874 |
Document ID | / |
Family ID | 53757081 |
Filed Date | 2017-01-05 |
United States Patent
Application |
20170000767 |
Kind Code |
A1 |
Takagaki; Kozue ; et
al. |
January 5, 2017 |
THERAPEUTIC OR PROPHYLACTIC AGENT FOR MULTIPLE SCLEROSIS
Abstract
A therapeutic or prophylactic agent for multiple sclerosis
includes as an effective component a cyclohexane derivative
represented by Formula (I): ##STR00001## wherein A is a substituent
represented by Formula (IIa) or (IIb): ##STR00002## R.sup.1 and
R.sup.2 are each independently a hydrogen atom, chlorine atom,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, or cyano; R.sup.3 is a hydrogen atom or chlorine atom;
R.sup.4 is a fluorine atom, hydroxymethyl, or hydroxyl; R.sup.5 and
R.sup.6 are each independently a hydrogen atom, fluorine atom,
C.sub.1-C.sub.3 haloalkyl, carboxyl, methoxycarbonyl,
ethoxycarbonyl, C.sub.1-C.sub.4 alkoxy, hydroxyl, or
C.sub.2-C.sub.5 alkylcarbonyloxy, or optionally together form oxo;
R.sup.7 and R.sup.8 are each independently a hydrogen atom or
fluorine atom; Y is an oxygen atom or sulfur atom; and Z is a
nitrogen atom or methane or a pharmaceutically acceptable salt
thereof.
Inventors: |
Takagaki; Kozue;
(Kamakura-shi, JP) ; Kaino; Mie; (Kamakura-shi,
JP) ; Hirokawa; Hiroe; (Kamakura-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TORAY INDUSTRIES, INC. |
Tokyo |
|
JP |
|
|
Family ID: |
53757081 |
Appl. No.: |
15/114874 |
Filed: |
January 29, 2015 |
PCT Filed: |
January 29, 2015 |
PCT NO: |
PCT/JP2015/052420 |
371 Date: |
July 28, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0053 20130101;
A61P 25/28 20180101; A61K 31/421 20130101; A61K 31/415 20130101;
A61K 31/4439 20130101; A61P 25/00 20180101; A61K 31/426
20130101 |
International
Class: |
A61K 31/415 20060101
A61K031/415; A61K 31/426 20060101 A61K031/426; A61K 31/421 20060101
A61K031/421; A61K 31/4439 20060101 A61K031/4439 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 29, 2014 |
JP |
2014-014063 |
Jul 30, 2014 |
JP |
2014-154893 |
Claims
1-6. (canceled)
7. A therapeutic or prophylactic agent for multiple sclerosis,
comprising, as an effective component, a cyclohexane derivative
represented by Formula (I): ##STR00072## wherein A is a substituent
represented by Formula (IIa) or (IIb): ##STR00073## R.sup.1 and
R.sup.2 are each independently a hydrogen atom, chlorine atom,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, or cyano; R.sup.3 is a hydrogen atom or chlorine atom;
R.sup.4 is a fluorine atom, hydroxymethyl, or hydroxyl; R.sup.5 and
R.sup.6 are each independently a hydrogen atom, fluorine atom,
C.sub.1-C.sub.3 haloalkyl, carboxyl, methoxycarbonyl,
ethoxycarbonyl, C.sub.1-C.sub.4 alkoxy, hydroxyl, or
C.sub.2-C.sub.5 alkylcarbonyloxy, or optionally together form oxo;
R.sup.7 and R.sup.8 are each independently a hydrogen atom or
fluorine atom; Y is an oxygen atom or sulfur atom; and Z is a
nitrogen atom or methane or a pharmaceutically acceptable salt
thereof.
8. A therapeutic or prophylactic agent for multiple sclerosis,
comprising, as an effective component, a cyclohexane derivative
represented by Formula (I): ##STR00074## wherein A is a substituent
represented by Formula (IIc) or (IId): ##STR00075## R.sup.1 and
R.sup.2 are each independently a hydrogen atom, chlorine atom,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.4 alkyl, or
C.sub.1-C.sub.4 alkoxy; R.sup.3 is a hydrogen atom or chlorine
atom; R.sup.4 is a fluorine atom, hydroxymethyl, or hydroxyl;
R.sup.5 and R.sup.6 are each independently a hydrogen atom,
fluorine atom, C.sub.1-C.sub.3 haloalkyl, carboxyl, C.sub.1-C.sub.4
alkoxy, hydroxyl, or C.sub.2-C.sub.5 alkylcarbonyloxy, or
optionally together form oxo; Y is an oxygen atom or sulfur atom;
and Z is a nitrogen atom or methane or a pharmaceutically
acceptable salt thereof.
9. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 7, wherein R.sup.1 and R.sup.2 are each
independently trifluoromethyl, methyl, or methoxy.
10. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 7, wherein R.sup.3 is a hydrogen atom.
11. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 7, wherein R.sup.4 is hydroxymethyl or
hydroxyl.
12. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 7, wherein R.sup.3 and R.sup.6 are each
independently a hydrogen atom, fluorine atom, trifluoromethyl,
carboxyl, methoxy, hydroxyl, or acetyloxy, or optionally together
form oxo.
13. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 8, wherein R.sup.1 and R.sup.2 are each
independently trifluoromethyl, methyl, or methoxy.
14. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 8, wherein R.sup.3 is a hydrogen atom.
15. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 9, wherein R.sup.3 is a hydrogen atom.
16. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 8, wherein R.sup.4 is hydroxymethyl or
hydroxyl.
17. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 9, wherein R.sup.4 is hydroxymethyl or
hydroxyl.
18. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 10, wherein R.sup.4 is hydroxymethyl or
hydroxyl.
19. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 8, wherein R.sup.5 and R.sup.6 are each
independently a hydrogen atom, fluorine atom, trifluoromethyl,
carboxyl, methoxy, hydroxyl, or acetyloxy, or optionally together
form oxo.
20. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 9, wherein R.sup.5 and R.sup.6 are each
independently a hydrogen atom, fluorine atom, trifluoromethyl,
carboxyl, methoxy, hydroxyl, or acetyloxy, or optionally together
form oxo.
21. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 10, wherein R.sup.5 and R.sup.6 are each
independently a hydrogen atom, fluorine atom, trifluoromethyl,
carboxyl, methoxy, hydroxyl, or acetyloxy, or optionally together
form oxo.
22. The therapeutic or prophylactic agent for multiple sclerosis
according to claim 11, wherein R.sup.5 and R.sup.6 are each
independently a hydrogen atom, fluorine atom, trifluoromethyl,
carboxyl, methoxy, hydroxyl, or acetyloxy, or optionally together
form oxo.
Description
TECHNICAL FIELD
[0001] This disclosure relates to a therapeutic or prophylactic
agent for multiple sclerosis.
BACKGROUND
[0002] Multiple sclerosis is a disease that characteristically
shows demyelination, in which myelin sheaths covering nerve fibers
of the brain, spinal cord, optic nerves, and the like are
destroyed. In this disease, progression of disorders occurs while
recurrence and remission are repeated. It is known that the
symptoms of this disease vary depending on the lesion area, and
examples of the symptoms include various nervous symptoms such as
visual impairment, quadriplegia, sensory disturbances, and gait
disturbances (Aranami et al., Cell Technology, Vol. 30, No. 10,
2011, pp. 1060-1063).
[0003] As therapeutic agents for multiple sclerosis, adrenocortical
hormones (steroids) are used for acute-phase treatment, and
interferon .beta.-1b and interferon .beta.-1a are used for
prevention of recurrence (Kira et al., "Multiple Sclerosis
Treatment Guidelines 2010," 2010, pp. 11-15).
[0004] Multiple sclerosis shows enhancement of the coagulation
system, and it is known that the symptoms can be ameliorated with a
thrombin inhibitor hirudin in a disease model for multiple
sclerosis (Han et al., Nature, Vol. 451, 2008, pp. 1076-1081).
[0005] WO 2011/126903 reports a low molecular weight compound
having thrombin inhibition activity. However, WO '903 does not show
usefulness of the compound against multiple sclerosis, and shows no
specific data on its pharmacological effect.
[0006] On the other hand, cyclohexane derivatives represented by
the following Formula are known to be effective as an analgesic and
therapeutic agent for neurogenic pain (WO 2010/050577), therapeutic
agent for fibromyalgia (WO 2011/125836), therapeutic agent for
urine storage dysfunction (WO 2011/125838), therapeutic agent for
Alzheimer's disease (WO 2011/136318), and therapeutic agent for
neuropathic pain (WO 2012/015027):
##STR00003##
wherein
[0007] A represents substituted or unsubstituted
1,5-diaryl-1H-pyrazol-3-yl, 4,5-diaryloxazol-2-yl, or the like;
[0008] R.sup.4 represents a fluorine atom, hydroxyl, or the like;
and
[0009] R.sup.5 and R.sup.6 each independently represent a hydrogen
atom, hydroxyl, carboxyl, or the like.
[0010] When a steroid is used in treatment and prophylaxis of
multiple sclerosis, amelioration of acute-phase symptoms can be
seen. However, its effect is transient, and long-term treatment is
difficult. Interferon .beta.-1b and interferon .beta.-1a are used
to prevent recurrence of multiple sclerosis. Since these are
biological preparations, they are expensive. However, their
therapeutic effect cannot necessarily be expected for all patients,
and those preparations are known to be ineffective for some
patients (Aranami et al., Cell Technology, Vol. 30, No. 10, 2011,
pp. 1060-1063 and Kira et al., "Multiple Sclerosis Treatment
Guidelines 2010," 2010, pp. 11-15).
[0011] It could therefore be helpful to provide a therapeutic or
prophylactic agent for multiple sclerosis comprising a nonsteroidal
low molecular weight compound as an effective component.
SUMMARY
[0012] We discovered that a cyclohexane derivative or a
pharmaceutically acceptable salt thereof has an excellent
therapeutic effect and prophylactic effect on multiple
sclerosis.
[0013] We thus provide a therapeutic or prophylactic agent for
multiple sclerosis, comprising, as an effective component, a
cyclohexane derivative represented by Formula (I), or a
pharmaceutically acceptable salt thereof:
##STR00004##
wherein A is a substituent represented by Formula (IIa) or
(IIb):
##STR00005##
[0014] R.sup.1 and R.sup.2 are each independently a hydrogen atom,
chlorine atom, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, or cyano; R.sup.3 is a hydrogen atom or
chlorine atom; R.sup.4 is a fluorine atom, hydroxymethyl, or
hydroxyl; R.sup.5 and R.sup.6 are each independently a hydrogen
atom, fluorine atom, C.sub.1-C.sub.3 haloalkyl, carboxyl,
methoxycarbonyl, ethoxycarbonyl, C.sub.1-C.sub.4 alkoxy, hydroxyl,
or C.sub.2-C.sub.5 alkylcarbonyloxy, or optionally together form
oxo; R.sup.7 and R.sup.8 are each independently a hydrogen atom or
fluorine atom; Y is an oxygen atom or sulfur atom; and Z is a
nitrogen atom or methine.
[0015] We also provide a therapeutic or prophylactic agent for
multiple sclerosis, comprising, as an effective component, a
cyclohexane derivative represented by Formula (I), or a
pharmaceutically acceptable salt thereof:
##STR00006##
wherein A is a substituent represented by General Formula (IIc) or
(IId):
##STR00007##
[0016] R.sup.1 and R.sup.2 are each independently a hydrogen atom,
chlorine atom, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.4 alkyl, or
C.sub.1-C.sub.4 alkoxy; R.sup.3 is a hydrogen atom or chlorine
atom; R.sup.4 is a fluorine atom, hydroxymethyl, or hydroxyl;
R.sup.5 and R.sup.6 are each independently a hydrogen atom,
fluorine atom, C.sub.1-C.sub.3 haloalkyl, carboxyl, C.sub.1-C.sub.4
alkoxy, hydroxyl, or C.sub.2-C.sub.5 alkylcarbonyloxy, or
optionally together form oxo; Y is an oxygen atom or sulfur atom;
and Z is a nitrogen atom or methine.
[0017] Preferably, in the cyclohexane derivative, R.sup.1 and
R.sup.2 are each independently a hydrogen atom, chlorine atom,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.4 alkyl, or C
.sub.1-C.sub.4 alkoxy; R.sup.5 and R.sup.6 are each independently a
hydrogen atom, fluorine atom, C.sub.1-C.sub.3 haloalkyl, carboxyl,
C.sub.1-C.sub.4 alkoxy, hydroxyl, or C.sub.2-C.sub.5
alkylcarbonyloxy, or optionally together form oxo; and each of
R.sup.7 and R.sup.8 is a hydrogen atom.
[0018] More preferably, in the cyclohexane derivative, R.sup.1 and
R.sup.2 are each independently trifluoromethyl, methyl, or methoxy;
R.sup.3 is a hydrogen atom; R.sup.4 is hydroxymethyl or hydroxyl;
and R.sup.5 and R.sup.6 are each independently a hydrogen atom,
fluorine atom, trifluoromethyl, carboxyl, methoxy, hydroxyl, or
acetyloxy (or optionally together form oxo).
[0019] The therapeutic or prophylactic agent for multiple sclerosis
enables remarkable suppression of exacerbation of symptoms of
multiple sclerosis, and effective treatment or prevention of
multiple sclerosis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 is a diagram showing the inhibitory effect of 30
mg/kg Compound 3 against an increase in the neurological symptom
score in a myelin oligodendrocyte glycoprotein-induced mouse
experimental autoimmune encephalomyelitis model.
[0021] FIG. 2 is a diagram showing the inhibitory effect of 3 mg/kg
and 10 mg/kg Compound 3 against an increase in the neurological
symptom score in a myelin oligodendrocyte glycoprotein-induced
mouse experimental autoimmune encephalomyelitis model.
[0022] FIG. 3 is a diagram showing the inhibitory effect of
Compound 3 against an increase in the neurological symptom score in
a proteolipid protein-induced mouse experimental autoimmune
encephalomyelitis model.
[0023] FIG. 4 is a diagram showing the action of Compound 3 against
the thrombin activity.
DETAILED DESCRIPTION
[0024] The therapeutic or prophylactic agent for multiple sclerosis
comprises, as an effective component, a cyclohexane derivative
represented by Formula (I), or a pharmaceutically acceptable salt
thereof:
##STR00008##
wherein A is a substituent represented by the following General
Formula (IIa) or (IIb):
##STR00009##
[0025] R.sup.1 and R.sup.2 are each independently a hydrogen atom,
chlorine atom, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, or cyano; R.sup.3 is a hydrogen atom or
chlorine atom; R.sup.4 is a fluorine atom, hydroxymethyl, or
hydroxyl; R.sup.5 and R.sup.6 are each independently a hydrogen
atom, fluorine atom, C.sub.1-C.sub.3 haloalkyl, carboxyl,
methoxycarbonyl, ethoxycarbonyl, C.sub.1-C.sub.4 alkoxy, hydroxyl,
or C.sub.2-C.sub.5 alkylcarbonyloxy, or optionally together form
oxo; R.sup.7 and R.sup.8 are each independently a hydrogen atom or
fluorine atom; Y is an oxygen atom or sulfur atom; and Z is a
nitrogen atom or methine.
[0026] The therapeutic or prophylactic agent for multiple sclerosis
also comprises, as an effective component, a cyclohexane derivative
represented by Formula (I), or a pharmaceutically acceptable salt
thereof:
##STR00010##
wherein A is a substituent represented by General Formula (IIc) or
(IId):
##STR00011##
[0027] R.sup.1 and R.sup.2 are each independently a hydrogen atom,
chlorine atom, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.4 alkyl, or
C.sub.1-C.sub.4 alkoxy; R.sup.3 is a hydrogen atom or chlorine
atom; R.sup.4 is a fluorine atom, hydroxymethyl, or hydroxyl;
R.sup.5 and R.sup.6 are each independently a hydrogen atom,
fluorine atom, C.sub.1-C.sub.3 haloalkyl, carboxyl, C.sub.1-C.sub.4
alkoxy, hydroxyl, or C.sub.2-C.sub.5 alkylcarbonyloxy, or
optionally together form oxo; Y is an oxygen atom or sulfur atom;
and Z is a nitrogen atom or methine.
[0028] The "C.sub.1-C.sub.4 alkyl" means a linear, branched, or
cyclic alkyl group having 1 to 4 carbon atoms, for example, methyl,
ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl,
n-butyl, sec-butyl, or tert-butyl.
[0029] The "C.sub.1-C.sub.4 alkoxy" means a linear, branched, or
cyclic alkyl-oxy group having 1 to 4 carbon atoms, for example,
methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyloxy,
n-butoxy, sec-butoxy, or tert-butoxy.
[0030] The "C.sub.1-C.sub.3 haloalkyl" means a linear alkyl group
having 1 to 3 carbon atoms whose hydrogen atoms are partially or
entirely substituted by a halogen atom(s) (the halogen atom means a
fluorine atom, chlorine atom, bromine atom, or iodine atom).
Examples of the "C.sub.1-C.sub.3 haloalkyl" include
monochloromethyl, monofluoromethyl, difluoromethyl,
trifluoromethyl, trichloromethyl, and pentafluoroethyl.
[0031] Examples of the "C.sub.2-C.sub.5 alkylcarbonyloxy" include
acetyloxy, ethanoyloxy, propanoyloxy, isopropanoyloxy, butanoyloxy,
isobutanoyloxy, and pivaloyloxy.
[0032] In Formula (I), A is preferably Formula (IIa); Y is
preferably an oxygen atom; and Z is preferably methine.
[0033] In Formula (I), R.sup.1 is preferably a hydrogen atom,
chlorine atom, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl,
methoxy, ethoxy, n-propyloxy, or isopropyloxy; more preferably
trifluoromethyl, methyl, or methoxy; still more preferably
methyl.
[0034] In Formula (I), R.sup.2 is preferably a hydrogen atom,
chlorine atom, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl,
methoxy, ethoxy, n-propyloxy, or isopropyloxy; more preferably
methoxy.
[0035] In Formula (I), R.sup.3 is preferably a hydrogen atom.
R.sup.4 is preferably hydroxymethyl or hydroxyl, more preferably
hydroxyl.
[0036] In Formula (I), R.sup.5 is preferably a hydrogen atom,
fluorine atom, trifluoromethyl, carboxyl, methoxy, ethoxy,
n-propyloxy, isopropyloxy, hydroxyl, acetyloxy, propanoyloxy,
butanoyloxy, or isobutanoyloxy; more preferably a hydrogen atom,
hydroxyl, or carboxyl; still more preferably hydroxyl.
[0037] In Formula (I), R.sup.6 is preferably a hydrogen atom,
fluorine atom, trifluoromethyl, carboxyl, methoxy, ethoxy,
n-propyloxy, isopropyloxy, hydroxyl, acetyloxy, propanoyloxy,
butanoyloxy, or isobutanoyloxy; more preferably a hydrogen atom or
hydroxyl; still more preferably a hydrogen atom. R.sup.5 and
R.sup.6 may together form oxo.
[0038] In Formula (I), each of R.sup.7 and R.sup.8 is preferably a
hydrogen atom.
[0039] Preferred specific examples of cyclohexane derivatives
represented by Formula (I) (hereinafter referred to as cyclohexane
derivative (I)) are shown in Tables 1-1 to 1-4. It should be noted
that these do not restrict this disclosure or its contents.
TABLE-US-00001 TABLE 1-1 Com- pound Structural formula 1
##STR00012## 2 ##STR00013## 3 ##STR00014## 4 ##STR00015## 5
##STR00016## 6 ##STR00017## 7 ##STR00018## 8 ##STR00019## 9
##STR00020## 10 ##STR00021## 11 ##STR00022## 12 ##STR00023## 13
##STR00024## 14 ##STR00025## 15 ##STR00026## 16 ##STR00027##
TABLE-US-00002 TABLE 1-2 Com- pound Structural formula 17
##STR00028## 18 ##STR00029## 19 ##STR00030## 20 ##STR00031## 21
##STR00032## 22 ##STR00033## 23 ##STR00034## 24 ##STR00035## 25
##STR00036## 26 ##STR00037## 27 ##STR00038## 28 ##STR00039## 29
##STR00040## 30 ##STR00041## 31 ##STR00042## 32 ##STR00043##
TABLE-US-00003 TABLE 1-3 Com- pound Structural formula 33
##STR00044## 34 ##STR00045## 35 ##STR00046## 36 ##STR00047## 37
##STR00048## 38 ##STR00049## 39 ##STR00050## 40 ##STR00051## 41
##STR00052## 42 ##STR00053## 43 ##STR00054## 44 ##STR00055## 45
##STR00056## 46 ##STR00057## 47 ##STR00058## 48 ##STR00059##
TABLE-US-00004 TABLE 1-4 Com- pound Structural formula 49
##STR00060## 50 ##STR00061## 51 ##STR00062## 52 ##STR00063## 53
##STR00064## 54 ##STR00065## 55 ##STR00066## 56 ##STR00067## 57
##STR00068## 58 ##STR00069##
[0040] When the cyclohexane derivative (I) or the pharmaceutically
acceptable salt thereof has an asymmetric carbon, all enantiomers
and mixtures thereof are included in the cyclohexane derivative (I)
or the pharmaceutically acceptable salt thereof.
[0041] When there are stereoisomers of the cyclohexane derivative
(I) or the pharmaceutically acceptable salt thereof, all the
stereoisomers and mixtures thereof are included in the cyclohexane
derivative (I) or the pharmaceutically acceptable salt thereof.
[0042] Examples of the "pharmaceutically acceptable salt" include
inorganic acid salts such as hydrochloric acid salt, sulfuric acid
salt, phosphoric acid salt, and hydrobromic acid salt; organic acid
salts such as oxalic acid salt, malonic acid salt, citric acid
salt, fumaric acid salt, lactic acid salt, salt, malic acid salt,
succinic acid salt, tartaric acid salt, acetic acid salt,
trifluoroacetic acid salt, maleic acid salt, gluconic acid salt,
benzoic acid salt, ascorbic acid salt, methanesulfonic acid salt,
p-toluenesulfonic acid salt, and cinnamic acid salt; inorganic base
salts such as sodium salt, potassium salt, calcium salt, magnesium
salt, and ammonium salt; and organic base salts such as methylamine
salt, diethylamine salt, trimethylamine salt, triethylamine salt,
pyridinium salt, triethanolamine salt, ethylenediamine salt, and
guanidine salt. The cyclohexane derivative (I) or the
pharmaceutically acceptable salt thereof may form a hydrate or
solvate, or may show crystal polymorphisms.
[0043] The cyclohexane derivative (I) or the pharmaceutically
acceptable salt thereof can be synthesized according to, for
example, the method described in WO 2010/050577.
[0044] Effectiveness of the cyclohexane derivative (I) or the
pharmaceutically acceptable salt thereof for treatment or
prevention of multiple sclerosis can be evaluated using a disease
model. Examples of the disease model include experimental
autoimmune encephalomyelitis models (Journal of Neuroscience
Research, 2006, Vol. 84, pp. 1225-1234; International Immunology,
1997, Vol. 9, pp. 1243-1251). Experimental autoimmune
encephalomyelitis models are animal models prepared by immunizing
laboratory animals with myelin oligodendrocyte glycoprotein
(hereinafter referred to as MOG) or proteolipid protein
(hereinafter referred to as PLP), or a partial peptide thereof, to
induce neuropathy such as hind limb paralysis due to demyelination
of the central nervous system. Because of similarity of symptoms
and pathological findings in these animal models to those in
humans, these models are widely used to study the pharmacological
effects of therapeutic agents and prophylactic agents for multiple
sclerosis. The effectiveness for treatment or prevention of
multiple sclerosis can be evaluated with the above-described
experimental autoimmune encephalomyelitis models using, for
example, as an index, a decrease in the neurological symptom score,
which is a characteristic index of multiple sclerosis.
[0045] The action of the cyclohexane derivative (I) or the
pharmaceutically acceptable salt thereof on the thrombin activity
can be evaluated using an in vitro test. Examples of the in vitro
test include a method in which the protease activity of thrombin is
measured. Examples of the method of evaluating the protease
activity of thrombin include a method in which cleavage of a
substrate by thrombin is measured utilizing fluorescence resonance
energy transfer (FRET) (Advanced Functional Materials, Vol. 20, No.
18, 2010, pp. 3175-3182).
[0046] The therapeutic or prophylactic agent for multiple sclerosis
described above may be used as an excellent pharmaceutical product
which is useful for treatment and prevention of multiple sclerosis
in mammals (for example, mouse, rat, hamster, rabbit, cat, dog,
cow, sheep, monkey, or human).
[0047] In terms of the dosage form of the therapeutic or
prophylactic agent for multiple sclerosis described above, the
cyclohexane derivative (I) or the pharmaceutically acceptable salt
thereof may be orally or parenterally administered as it is, or as
a mixture with a pharmaceutically acceptable carrier.
[0048] In oral administration of a formulation containing the
cyclohexane derivative (I) or the pharmaceutically acceptable salt
thereof, examples of its dosage form include tablets (including
sugar-coated tablets and film-coated tablets), balls, granules,
powders, capsules (including soft capsules and microcapsules),
syrups, emulsions, and suspensions. In parenteral administration,
examples of the dosage form include injection solutions, infusions,
drops, and suppositories. The cyclohexane derivative (I) or the
pharmaceutically acceptable salt thereof may also be effectively
used in combination with an appropriate base (for example, butyric
acid polymer, glycolic acid polymer, butyric acid/glycolic acid
copolymer, mixture of butyric acid polymer and glycolic acid
polymer, or polyglycerol fatty acid ester) to provide a
sustained-release formulation.
[0049] The formulation in the above-described dosage form
containing the cyclohexane derivative (I) or the pharmaceutically
acceptable salt thereof may be prepared according to a known
production method commonly used in the field of pharmaceutical
preparations. In such cases, the formulation may be prepared by
including, if necessary, one or more of diluents, binders,
lubricants, disintegrators, sweeteners, surfactants, suspending
agents, emulsifiers, and the like that are commonly used in the
field of pharmaceutical preparations.
[0050] In the preparation of tablets containing the cyclohexane
derivative (I) or the pharmaceutically acceptable salt thereof, one
or more of diluents, binders, disintegrators, lubricants and the
like may be included. In the preparation of balls and granules, one
or more of diluents, binders, disintegrators and the like may be
included. In the preparation of powders and capsules, one or more
of diluents and the like may be included. In the preparation of
syrups, one or more of sweeteners and the like may be included. In
the preparation of emulsions or suspensions, one or more of
surfactants, suspending agents, emulsifiers and the like may be
included.
[0051] Examples of the diluents include lactose, glucose, starch,
sucrose, microcrystalline cellulose, powdered glycyrrhiza,
mannitol, sodium hydrogen carbonate, calcium phosphate, and calcium
sulfate.
[0052] Examples of the binders include starch paste liquids, gum
arabic liquids, gelatin liquids, tragacanth liquids,
carboxymethylcellulose liquids, sodium alginate liquids, and
glycerin.
[0053] Examples of the disintegrators include starch and calcium
carbonate.
[0054] Examples of the lubricants include magnesium stearate,
stearic acid, calcium stearate, and purified talc.
[0055] Examples of the sweeteners include glucose, fructose, invert
sugar, sorbitol, xylitol, glycerol, and simple syrup.
[0056] Examples of the surfactants include sodium lauryl sulfate,
polysorbate 80, sorbitan monofatty acid esters, and polyoxyl 40
stearate.
[0057] Examples of the suspending agents include gum arabic, sodium
alginate, sodium carboxymethylcellulose, methyl cellulose, and
bentonite.
[0058] Examples of the emulsifiers include gum arabic, tragacanth,
gelatin, and polysorbate 80.
[0059] In the preparation of the formulation containing the
cyclohexane derivative (I) or the pharmaceutically acceptable salt
thereof into the dosage form described above, one or more of
coloring agents, preservatives, aromatics, correctives,
stabilizers, thickeners, and the like, which are commonly used in
the field of formulations, may be added thereto.
[0060] The daily dose of the formulation varies depending on the
conditions and the body weight of the patient, the type of the
compound, the administration route, and the like. For example, in
oral administration to an adult (with a body weight of about 60
kg), the formulation is preferably administered at a daily dose 1
mg to 1000 mg, at one time or dividedly in two or three times. In
parenteral administration using an injection solution, the
formulation is preferably administered by intravenous injection at
a daily dose of 0.01 to 100 mg/kg body weight.
[0061] The therapeutic or prophylactic agent for multiple sclerosis
described above may also be used in combination with one or more
other therapeutic or prophylactic agents for multiple sclerosis, or
with one or more therapeutic or prophylactic agents for a
symptom(s) such as convulsion or spasm in patients with multiple
sclerosis.
[0062] Examples of the other therapeutic or prophylactic agents for
multiple sclerosis include adrenocortical steroids (such as
prednisolone and methylprednisolone), immunosuppresssants (such as
fingolimod, methotrexate, azathioprine, cyclophosphamide,
cyclosporin A, tacrolimus, mizoribine, and leflunomide), interferon
preparations (such as interferon .alpha., interferon .beta.-1b, and
interferon .beta.-1a), copolymer I, immunoglobulin, mitoxantrone,
glatiramer acetate, T cell receptor vaccines, adhesion molecule
inhibitors, analgesics (such as indomethacin and diclofenac), and
muscle relaxants (such as tizanidine, eperisone, afloqualone,
baclofen, diazepam, and dantrolene sodium).
[0063] Examples of the therapeutic or prophylactic agents for a
symptom(s) such as convulsion or spasm in patients with multiple
sclerosis include anticonvulsants (such as carbamazepine,
phenytoin, clonazepam, and amitriptyline).
EXAMPLES
[0064] Our agents and methods are described below more specifically
by way of Examples. However, this disclosure is not limited to
these Examples.
Evaluation of Cyclohexane Derivative (I) or Pharmaceutically
Acceptable Salt Thereof at 30 mg/kg in MOG-Induced Mouse
Experimental Autoimmune Encephalomyelitis Model
[0065] The action of the cyclohexane derivative (I) or the
pharmaceutically acceptable salt thereof against an increase in the
neurological symptom score in a MOG-induced mouse experimental
autoimmune encephalomyelitis model was evaluated. The mouse
experimental autoimmune encephalomyelitis model was prepared
according to the method described in Journal of Neuroscience
Research, 2006, Vol. 84, pp. 1225-1234 with partial
modification.
[0066] A MOG 35-55 administration solution, which was prepared by
mixing equal volumes of a PBS solution containing a partially
synthesized peptide of MOG (MOG 35-55; CS Bio Company Inc.) whose
concentration was adjusted to 4 mg/mL and Freund's complete
adjuvant, was intracutaneously inoculated to both lateral regions
of each C57BL/6J mouse (male, 7-weeks old) (Charles River
Laboratories Japan) in a total amount of 0.1 mL (0.05 mL per side).
Further, on the day of inoculation of the MOG 35-55 administration
solution, and two days thereafter, 200 .mu.L of pertussis toxin
(Sigma) whose concentration was adjusted to 1 .mu.g/mL was
intraperitoneally administered to each mouse.
[0067] As a test compound,
1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexane-cis-1,4-di-
ol (hereinafter referred to as Compound 3), which is represented by
the following chemical formula, was used. Compound 3 was
synthesized according to the method described in WO
2010/050577.
##STR00070##
[0068] Comparative Control Compound 1, which is represented by
Comparative Chemical Formula 1, was synthesized by subjecting
Reference Example 99 (N-Boc-protected compound) described in WO
2008/105383 to Boc removal using trifluoroacetic acid and the like.
Comparative Control Compound 2, which is represented by the
following chemical formula, was synthesized based on the synthesis
method of Comparative Example 2 described in WO 2010/050577.
##STR00071##
[0069] From three days before inoculation of the MOG 35-55
administration solution, Compound 3 was orally administered to mice
twice daily at a dose of 30 mg/kg for 16 successive days. Compound
3 was used as a suspension in 0.5% methylcellulose solution. The
group in which Compound 3 was administered to mice was provided as
the Compound 3 administration group. To provide a vehicle
administration group, 0.5% methylcellulose solution was
administered in the same manner.
[0070] Thirteen days after inoculation of the MOG 35-55
administration solution, the neurological symptom score was scored
(0: normal, 1: limp tail or hind limb weakness, 2: limp tail and
hind limb weakness, 3: partial hind limb paralysis, 4: complete
hind limb paralysis, 5: moribund state). Scoring was carried out
using the method described in Current Protocols in Immunology (John
Wiley & Sons, Inc., 2000, pp. 15.1.1-15.1.20).
[0071] The results are shown in FIG. 1. The ordinate represents the
neurological symptom score (mean.+-.standard error, n=10). In the
abscissa, "Vehicle" indicates the group in which 0.5%
methylcellulose solution was orally administered to the mice to
which the MOG 35-55 administration solution was inoculated (vehicle
administration group), and "Compound 3" indicates the group in
which Compound 3 was orally administered twice daily at a dose of
30 mg/kg to the mice to which the MOG 35-55 administration solution
was inoculated (Compound 3 administration group).
[0072] In the vehicle administration group, the inoculation of the
MOG 35-55 administration solution caused an increase in the
neurological symptom score to 2.8. In contrast, in the Compound 3
administration group, the increase in the neurological symptom
score was remarkably suppressed. The rate of suppression of
exacerbation of neurological symptoms by Compound 3 was 85.7%.
[0073] Comparative Control Compound 1 and Comparative Control
Compound 2 were similarly evaluated. That is, from three days
before inoculation of the MOG 35-55 administration solution,
Comparative Control Compound 1 or Comparative Control Compound 2
suspended in 0.5% methylcellulose solution was orally administered
to mice twice daily at a dose of 30 mg/kg for 16 successive days.
Thirteen days after inoculation of the MOG 35-55 administration
solution, the neurological symptom score was scored. The rates of
suppression of exacerbation of neurological symptoms by Comparative
Control Compound 1 and Comparative Control Compound 2 were 3.3% and
6.5%, respectively.
[0074] From these results, it became clear that the cyclohexane
derivative (I) or the pharmaceutically acceptable salt thereof
shows a remarkable inhibitory effect on neurological symptoms of
multiple sclerosis.
Evaluation of Cyclohexane Derivative (I) or Pharmaceutically
Acceptable Salt Thereof at 3 mg/kg and 10 mg/kg in MOG-Induced
Mouse Experimental Autoimmune Encephalomyelitis Model
[0075] Action of the cyclohexane derivative (I) or the
pharmaceutically acceptable salt thereof against an increase in the
neurological symptom score in a MOG-induced mouse experimental
autoimmune encephalomyelitis model was evaluated.
[0076] A MOG 35-55 administration solution, which was prepared by
mixing equal volumes of a PBS solution containing a partially
synthesized peptide of MOG (MOG 35-55; CS Bio Company Inc.) whose
concentration was adjusted to 4 mg/mL and Freund's complete
adjuvant, was intracutaneously inoculated to both lateral regions
of each C57BL/6J mouse (male, 10-weeks old) (Charles River
Laboratories Japan) in a total amount of 0.1 mL (0.05 mL per side).
Further, on the day of inoculation of the MOG 35-55 administration
solution, and two days thereafter, 200 .mu.L of pertussis toxin
(Sigma) whose concentration was adjusted to 1 .mu.g/mL was
intraperitoneally administered to each mouse. As a test compound,
Compound 3 was used.
[0077] From two days after inoculation of the MOG 35-55
administration solution, Compound 3 was orally administered to mice
twice daily at a dose of 3 mg/kg and 10 mg/kg for 12 successive
days. Compound 3 was used as a suspension in 0.5% methylcellulose
solution. The group in which Compound 3 was administered to mice
was provided as the Compound 3 administration group. To provide a
vehicle administration group, 0.5% methylcellulose solution was
administered in the same manner.
[0078] Fourteen days after inoculation of the MOG 35-55
administration solution, the neurological symptom score was scored
(0: normal, 1: limp tail or hind limb weakness, 2: limp tail and
hind limb weakness, 3: partial hind limb paralysis, 4: complete
hind limb paralysis, 5: moribund state). Scoring was carried out
using the method described in Current Protocols in Immunology (John
Wiley & Sons, Inc., 2000, pp. 15.1.1-15.1.20).
[0079] The results are shown in FIG. 2. The ordinate represents the
neurological symptom score (mean.+-.standard error, n=8). In the
abscissa, "Vehicle" indicates the group in which 0.5%
methylcellulose solution was orally administered to the mice to
which the MOG 35-55 administration solution was inoculated (vehicle
administration group), and "Compound 3" indicates the group in
which Compound 3 was orally administered twice daily at a dose of 3
mg/kg and 10 mg/kg to the mice to which the MOG 35-55
administration solution was inoculated (Compound 3 administration
group).
[0080] In the vehicle administration group, inoculation of the MOG
35-55 administration solution caused an increase in the
neurological symptom score to 1.3. In contrast, in administration
of Compound 3 at 3 mg/kg and 10 mg/kg, the increase in the
neurological symptom score was remarkably suppressed. The rates of
suppression of exacerbation of neurological symptoms were 53.8% and
61.5%, respectively.
[0081] From these results, it became clear that the cyclohexane
derivative (I) or the pharmaceutically acceptable salt thereof
shows a remarkable inhibitory effect on neurological symptoms of
multiple sclerosis from a dose of 3 mg/kg.
Evaluation of Cyclohexane Derivative (I) or Pharmaceutically
Acceptable Salt Thereof in PLP-Induced Mouse Experimental
Autoimmune Encephalomyelitis Model
[0082] Action of the cyclohexane derivative (I) or the
pharmaceutically acceptable salt thereof against an increase in the
neurological symptom score in a PLP-induced mouse experimental
autoimmune encephalomyelitis model was evaluated. The mouse
experimental autoimmune encephalomyelitis model was prepared
according to the method described in International Immunology,
1997, Vol. 9, pp. 1243-1251 with partial modification.
[0083] A PLP 139-151 administration solution, which was prepared by
mixing equal volumes of a PBS solution containing a partially
synthesized peptide of PLP (PLP 139-151; Kokusan Chemical Co.,
Ltd.) whose concentration was adjusted to 2 mg/mL and Freund's
complete adjuvant, was intracutaneously inoculated to both lateral
regions of each SJL mouse (female, 6-weeks old) (Charles River
Laboratories Japan) in a total amount of 0.1 mL (0.05 mL per side).
Further, on the day of inoculation of the PLP 139-151
administration solution, and two days thereafter, 200 .mu.L of
pertussis toxin (Sigma) whose concentration was adjusted to 1
.mu.g/mL was intraperitoneally administered to each mouse. As a
test compound, Compound 3 was used.
[0084] From two days after inoculation of the PLP 139-151
administration solution, Compound 3 was orally administered to mice
twice daily at a dose of 10 mg/kg for 7 successive days. Compound 3
was used as a suspension in 0.5% methylcellulose solution. The
group in which Compound 3 was administered to mice was provided as
the Compound 3 administration group. To provide a vehicle
administration group, 0.5% methylcellulose solution was
administered in the same manner.
[0085] Nine days after inoculation of the PLP 139-151
administration solution, the neurological symptom score was scored
(0: normal, 1: limp tail or hind limb weakness, 2: limp tail and
hind limb weakness, 3: partial hind limb paralysis, 4: complete
hind limb paralysis, 5: moribund state). Scoring was carried out
using the method described in Current Protocols in Immunology (John
Wiley & Sons, Inc., 2000, pp. 15.1.1-15.1.20).
[0086] The results are shown in FIG. 3. The ordinate represents the
neurological symptom score (mean.+-.standard error, n=8). In the
abscissa, "Vehicle" indicates the group in which 0.5%
methylcellulose solution was orally administered to the mice to
which the PLP 139-151 administration solution was inoculated
(vehicle administration group), and "Compound 3" indicates the
group in which Compound 3 was orally administered twice daily at a
dose of 10 mg/kg to the mice to which the PLP 139-151
administration solution was inoculated (Compound 3 administration
group).
[0087] In the vehicle administration group, inoculation of the PLP
139-151 administration solution caused an increase in the
neurological symptom score to 1.1. In contrast, in the Compound 3
administration group, the increase in the neurological symptom
score was remarkably suppressed. The rate of suppression of
exacerbation of neurological symptoms by Compound 3 was 66.4%.
[0088] From these results, it became clear that the cyclohexane
derivative (I) or the pharmaceutically acceptable salt thereof
shows a remarkable inhibitory effect on neurological symptoms of
multiple sclerosis.
Effect on Thrombin Activity
[0089] The action of the cyclohexane derivative (I) or the
pharmaceutically acceptable salt thereof on the thrombin activity
was evaluated using a SensoLyte (registered trademark) 520 thrombin
activity assay kit manufactured by Anaspec Inc., which utilizes
fluorescence resonance energy transfer (FRET).
[0090] The test compound was dissolved in dimethylsulfoxide
(hereinafter referred to as DMSO), and diluted with the assay
buffer included in the kit to a final DMSO concentration of 0.5 to
1%. In each well of a 384-well black plate (Corning), the test
compound (final concentration, 0.1 nmol/L to 30 .mu.mol/L), and
thrombin diluted with the assay buffer (final concentration, 300
ng/mL) were added, and the plate was then incubated at room
temperature for 10 minutes. A well containing neither thrombin nor
the test compound, and a well which contains thrombin, but does not
contain the test compound, were also provided. To the wells,
5-FAM/QXL 520 thrombin substrate diluted with the assay buffer
(final concentration, 300 nmol/L) was added, and the resulting
mixtures were incubated at room temperature for 2 hours.
Thereafter, the fluorescence value was measured by excitation at
485 nm and detection at 520 nm.
[0091] As a test compound, Compound 3, which is included in the
cyclohexane derivative (I) or the pharmaceutically acceptable salt
thereof, was used. As a positive control, Argatroban, which is a
selective thrombin inhibitor, was used.
[0092] The thrombin activity inhibition rate (%) was calculated
according to Equation 1, and regression analysis was carried out to
obtain a sigmoid curve (variable slope), thereby calculating the
IC50 value of the thrombin activity inhibition by the test
compound:
Thrombin activity inhibition rate (%)=(1-((fluorescence value in
the presence of both thrombin and the test compound)-(fluorescence
value in the absence of both thrombin and the test
compound))/((fluorescence value in the presence of thrombin and
absence of the test compound)-(fluorescence value in the absence of
both thrombin and the test compound))).times.100 Equation 1.
[0093] The results are shown in FIG. 4. The ordinate represents the
thrombin activity inhibition rate (%) (mean.+-.standard error,
n=4). The abscissa represents the test compound concentration
(nmol/L).
[0094] As a result, while the IC50 value of Argatroban was 3.0
nmol/L, the thrombin activity inhibition rate of Compound 3 at the
maximum concentration, 30 .mu.mol/L, was 17.2%.
[0095] From these results, it became clear that the cyclohexane
derivative (I) or the pharmaceutically acceptable salt thereof does
not inhibit the thrombin activity.
INDUSTRIAL APPLICABILITY
[0096] Since the cyclohexane derivative (I) or the pharmaceutically
acceptable salt thereof remarkably suppresses exacerbation of
symptoms of multiple sclerosis, it can be used as a therapeutic or
prophylactic agent for multiple sclerosis.
* * * * *