U.S. patent application number 17/010182 was filed with the patent office on 2020-12-24 for pyrimidine compound.
This patent application is currently assigned to OTSUKA PHARMACEUTICAL CO, LTD.. The applicant listed for this patent is OTSUKA PHARMACEUTICAL CO, LTD.. Invention is credited to Kenta ARAI, Nobuaki ITO, Shin IWATA, Tomoichi SHINOHARA, Masaki SUZUKI.
Application Number | 20200399245 17/010182 |
Document ID | / |
Family ID | 1000005064826 |
Filed Date | 2020-12-24 |
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United States Patent
Application |
20200399245 |
Kind Code |
A1 |
SHINOHARA; Tomoichi ; et
al. |
December 24, 2020 |
PYRIMIDINE COMPOUND
Abstract
The present invention provides a novel pyrimidine compound
represented by Formula [I] and a salt thereof: ##STR00001## [in the
formula, the symbols are as defined in the specification], which is
useful for treating, preventing and/or diagnosing seizure and the
like in disease involving epileptic seizure or convulsive seizure
(including multiple drug resistant seizure, refractory seizure,
acute symptomatic seizure, febrile seizure and status epilepticus),
as well as a medical use therefor.
Inventors: |
SHINOHARA; Tomoichi;
(Narotu-shi, JP) ; IWATA; Shin; (Tokushima-shi,
JP) ; ARAI; Kenta; (Tokushima-shi, JP) ; ITO;
Nobuaki; (Tokushima-shi, JP) ; SUZUKI; Masaki;
(Itano-gun, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OTSUKA PHARMACEUTICAL CO, LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
OTSUKA PHARMACEUTICAL CO,
LTD.
Tokyo
JP
|
Family ID: |
1000005064826 |
Appl. No.: |
17/010182 |
Filed: |
September 2, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16471998 |
Jun 20, 2019 |
10800758 |
|
|
PCT/JP2018/020997 |
May 31, 2018 |
|
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|
17010182 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/14 20130101;
A61P 25/08 20180101; C07D 403/04 20130101; C07F 7/0812
20130101 |
International
Class: |
C07D 403/04 20060101
C07D403/04; A61P 25/08 20060101 A61P025/08; C07D 401/14 20060101
C07D401/14; C07F 7/08 20060101 C07F007/08 |
Foreign Application Data
Date |
Code |
Application Number |
May 31, 2017 |
JP |
PCT/JP2017/020322 |
Claims
1.-12. (canceled)
13. A method for preventing and/or diagnosing seizure in diseases
involving epileptic seizure or convulsive seizure (including
multiple drug resistant seizure, refractory seizure, acute
symptomatic seizure, febrile seizure and status epilepticus), which
comprises administering to a human in need thereof an effective
amount of a compound represented by Formula [I]: ##STR00105##
wherein ring A is phenyl, naphthyl or pyridyl; R.sub.1 is lower
alkyl; R.sub.2 is --O-lower alkyl; R.sub.3 is halogen, lower
alkynyl, lower alkyl optionally substituted with halogen, --O-lower
alkyl optionally substituted with deuterium or halogen, --S-lower
alkyl optionally substituted with halogen, phenyl, pentafluorothio,
--CN, --O-benzyl or --Si-mono-, di- or tri-lower alkyl wherein di
or tri may be same or different alkyl; L is bond, lower alkylene,
--O-- or --S--; each of m and n is 0 or 1; q is 0, 1 or 2, and when
q is 2, each R.sub.3 independently represents the same or different
substituent; and represents single or double bond, or a salt
thereof.
14. The method according to claim 13, wherein ring A is phenyl, L
is --O--, and n is 0.
15. The method according to claim 13, wherein m is 0.
16. The method according to claim 13, wherein R.sub.3 is halogen,
lower alkynyl, lower alkyl or --S-lower alkyl optionally
substituted with halogen.
17. The method according to claim 13, wherein ##STR00106## is
phenyl, monohalophenyl, dihalophenyl, mono-lower alkynylphenyl or
mono-lower alkylphenyl or phenyl substituted with one halogen and
one lower alkyl group.
18. A method for preventing and/or diagnosing seizure in diseases
involving epileptic seizure or convulsive seizure (including
multiple drug resistant seizure, refractory seizure, acute
symptomatic seizure, febrile seizure and status epilepticus), which
comprises administering to a human in need thereof an effective
amount of a compound selected from the group consisting of the
following compounds: ##STR00107## ##STR00108## ##STR00109## or a
salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to a pyrimidine compound and a
salt thereof. The present invention also relates to a medicament
having a pyrimidine compound or a salt thereof as an active
ingredient and useful for treating, preventing and/or diagnosing
seizure and the like in disease involving epileptic seizure or
convulsive seizure.
BACKGROUND ART
[0002] The prevalence of epilepsy is about 1% of the population. It
is considered a common neurological disorder with about 1 million
patients in Japan and a lifetime morbidity rate of 3% to 4%, and it
is estimated that tens of thousands of people develop epilepsy
every year. About 70% of these patients can control their seizure
with existing antiepileptic drugs and pursue their everyday lives
without problems, but the remaining 30% of epileptic patients are
unable to adequately control their seizure, and are anxious that
seizure may occur without warning. Most existing antiepileptic
drugs are aimed to normalize the excitation/inhibition imbalances
in neural activity by suppressing hyperexcitation and excessive
synchronization of neuronal activity, but doses above the optimal
dose may disturb the equilibrium of neuronal activity, and induce
motor dysfunction and epileptic seizure.
[0003] PTL 1 discloses compounds having a pyrimidine in its
structure as compounds for use in the treatment and the like of
diseases or conditions requiring modulators of the Kv3.1 and/or
Kv3.2 channel, including epilepsy.
[0004] PTL 2 and 3 disclose compounds having a pyrimidine skeleton
as kynurenine-3-monooxygenase inhibitors for treating
neurodegerenative conditions including epilepsy.
[0005] PTL 4 discloses uracil compounds as compounds exhibiting
antiepileptic action.
[0006] However, no compound having a structure comprising the
5-position carbon of a pyrimidine bound to the 1-position nitrogen
of a uracil skeleton is either disclosed or suggested in any patent
literature.
CITATION LIST
Patent Literature
[PTL 1] WO 2011/069951
[PTL 2] WO 2013/016488
[0007] [PTL 3] WO 2011/091153 [0008] [PTL 4] WO 2004/009559
DISCLOSURE OF INVENTION
[0009] It is an object of the present invention to provide a novel
pyrimidine compound or a salt thereof useful for treating,
preventing and/or diagnosing seizure and the like in disease
involving epileptic seizure or convulsive seizure, together with a
medical use therefor.
[0010] It is another object of the present invention to provide a
medicament having a wide treatment spectrum in comparison with
existing antiepileptic drugs, whereby the balance of neuronal
excitation/inhibition can be maintained even at doses that
completely suppress epileptic seizure.
[0011] As a result of exhaustive research aimed at solving the
aforementioned problems, the inventors succeeded in synthesizing a
novel pyrimidine compound having a wide treatment spectrum in
comparison with existing antiepileptic drugs. The present invention
was perfected based on these findings.
[0012] That is, the present invention includes the following
embodiments. [0013] [1] A compound represented by Formula [I]:
##STR00002##
[0013] wherein [0014] ring A is phenyl, naphthyl or pyridyl; [0015]
R.sub.1 is lower alkyl; [0016] R.sub.2 is --O-lower alkyl; [0017]
R.sub.3 is halogen, lower alkynyl, lower alkyl optionally
substituted with halogen, --O-lower alkyl optionally substituted
with deuterium or halogen, --S-lower alkyl optionally substituted
with halogen, phenyl, pentafluorothio, --CN, --O-benzyl or
--Si-mono-, di- or tri-lower alkyl wherein di or tri may be same or
different alkyl; [0018] L is bond, lower alkylene, --O-- or --S--;
[0019] each of m and n is 0 or 1; [0020] q is 0, 1 or 2, and when q
is 2, each R.sub.3 independently represents the same or different
substituent; and [0021] represents single or double bond, or a salt
thereof. [0022] [2] The compound or a salt thereof according to
[1], wherein [0023] ring A is phenyl, [0024] L is --O--, and [0025]
n is 0. [0026] [3] The compound or a salt thereof according to [1]
or [2], wherein m is 0. [0027] [4] The compound or a salt thereof
according to any of [1] to [3], wherein R.sub.3 is halogen, lower
alkynyl, lower alkyl or --S-lower alkyl optionally substituted with
halogen. [0028] [5] The compound or a salt thereof according to any
of [1] to [4], wherein
##STR00003##
[0028] is phenyl, monohalophenyl, dihalophenyl, mono-lower
alkynylphenyl or mono-lower alkylphenyl or phenyl substituted with
one halogen and one lower alkyl group. [0029] [6] A compound
selected from the group consisting of the following compounds:
##STR00004## ##STR00005## ##STR00006##
[0029] or a salt thereof. [0030] [7] A pharmaceutical composition
comprising a compound or a salt thereof according to any of [1] to
[6] as an active ingredient and pharmaceutically acceptable carrier
or excipient. [0031] [8] A therapeutic, preventative and/or
diagnostic agent for seizure in disease involving epileptic seizure
or convulsive seizure (including multiple drug resistant seizure,
refractory seizure, acute symptomatic seizure, febrile seizure and
status epilepticus), comprising a compound or a salt thereof
according to any of [1] to [6]. [0032] [9] The therapeutic,
preventative or diagnostic agent according to [8], wherein the
epileptic seizure is selected from focal onset seizure (also called
partial seizure) with motor onset (including automatism, atonic
seizure, clonic seizure, epileptic spasms, hyperkinetic seizure,
myoclonic seizure and tonic seizure) and non-motor onset (including
autonomic seizure, behavior arrest seizure, cognitive seizure,
emotional seizure and sensory seizure), and focal to bilateral
tonic-clonic seizure (secondary generalization of partial seizure);
generalized onset seizure including motor seizure (including
tonic-clonic seizure, clonic seizure, tonic seizure, myoclonic
seizure, myoclonic-tonic-clonic seizure, myoclonic-atonic seizure,
atonic seizure and epileptic spasms) and non-motor seizure
(including typical absence seizure, atypical absence seizure,
myoclonic absence seizure and eyelid myoclonic seizure); and
seizure of unknown onset including motor seizure (including
tonic-clonic seizure and epileptic spasms) and non-motor seizure
(including behavior arrest seizure). [0033] [10] The therapeutic,
preventative or diagnostic agent according to [8], wherein the
disease involving epileptic seizure or convulsive seizure is
selected from Dravet syndrome, Lennox-Gastaut syndrome, West
syndrome (epilepsia nutans), Ohtahara syndrome, Doose syndrome,
Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome,
Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome,
Geschwind syndrome, hemiconvulsion-hemiplegia-epilepsy syndrome,
mesial temporal lobe epilepsy, epilepsy with structural/metabolic
cause (epilepsy after stroke, traumatic epilepsy, infectious
epilepsy, epilepsy associated with cerebrovascular disorder,
epilepsy associated with brain tumor, epilepsy associated with
neurodegenerative disease, epilepsy associated with autoimmune
disorder, etc.), and congenital malformation, congenital metabolic
abnormality (for example, phenylketonuria, mitochondrial disease,
lysosomal disease, Sturge-Weber syndrome, etc.) and congenital
genetic abnormality (Rett's syndrome, Angelman's syndrome, 5p
syndrome, 4p syndrome, Down's syndrome, etc.), etc. [0034] [11] A
therapeutic, preventative and/or diagnostic pharmaceutical
composition for seizure in disease involving epileptic seizure or
convulsive seizure (including multiple drug resistant seizure,
refractory seizure, acute symptomatic seizure, febrile seizure and
status epilepticus), comprising a compound or a salt thereof
according to any of [1] to [6] as an active ingredient. [0035] [12]
The composition according to [11], wherein the epileptic seizure is
selected from focal onset seizure (also called partial seizure)
with motor onset (including automatism, atonic seizure, clonic
seizure, epileptic spasms, hyperkinetic seizure, myoclonic seizure
and tonic seizure) and non-motor onset (including autonomic
seizure, behavior arrest seizure, cognitive seizure, emotional
seizure and sensory seizure), and focal to bilateral tonic-clonic
seizure (secondary generalization of partial seizure); generalized
onset seizure including motor seizure (including tonic-clonic
seizure, clonic seizure, tonic seizure, myoclonic seizure,
myoclonic-tonic-clonic seizure, myoclonic-atonic seizure, atonic
seizure and epileptic spasms) and non-motor seizure (including
typical absence seizure, atypical absence seizure, myoclonic
absence seizure and eyelid myoclonic seizure); and seizures of
unknown onset including motor seizure (including tonic-clonic
seizure and epileptic spasms) and non-motor seizure (including
behavior arrest seizure). [0036] [13] The composition according to
[11], wherein the disease involving epileptic seizure or convulsive
seizure is selected from Dravet syndrome, Lennox-Gastaut syndrome,
West syndrome (epilepsia nutans), Ohtahara syndrome, Doose
syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi
syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari
syndrome, Geschwind syndrome, hemiconvulsion-hemiplegia-epilepsy
syndrome, mesial temporal lobe epilepsy, epilepsy with
structural/metabolic cause (epilepsy after stroke, traumatic
epilepsy, infectious epilepsy, epilepsy associated with
cerebrovascular disorder, epilepsy associated with brain tumor,
epilepsy associated with neurodegenerative disease, epilepsy
associated with autoimmune disorder, etc.), and congenital
malformation, congenital metabolic abnormality (for example,
phenylketonuria, mitochondrial disease, lysosomal disease,
Sturge-Weber syndrome, etc.) and congenital genetic abnormality
(Rett's syndrome, Angelman's syndrome, 5p syndrome, 4p syndrome,
Down's syndrome, etc.), etc. [0037] [14] A method for treating,
preventing and/or diagnosing seizure in disease involving epileptic
seizure or convulsive seizure (including multiple drug resistant
seizure, refractory seizure, acute symptomatic seizure, febrile
seizure and status epilepticus), wherein comprising administering
to a human in need thereof an effective amount of a compound or a
salt thereof according to any of [1] to [6]. [0038] [15] The method
according to [14], wherein the epileptic seizure is selected from
focal onset seizure (also called partial seizure) with motor onset
(including automatism, atonic seizure, clonic seizure, epileptic
spasms, hyperkinetic seizure, myoclonic seizure and tonic seizure)
and non-motor onset (including autonomic seizure, behavior arrest
seizure, cognitive seizure, emotional seizure and sensory seizure),
and focal to bilateral tonic-clonic seizure (secondary
generalization of partial seizure); generalized onset seizure
including motor seizure (including tonic-clonic seizure, clonic
seizure, tonic seizure, myoclonic seizure, myoclonic-tonic-clonic
seizure, myoclonic-atonic seizure, atonic seizure and epileptic
spasms) and non-motor seizure (including typical absence seizure,
atypical absence seizure, myoclonic absence seizure and eyelid
myoclonic seizure); and seizure of unknown onset including motor
seizure (including tonic-clonic seizure and epileptic spasms) and
non-motor seizure (including behavior arrest seizure). [0039] [16]
The method according to [14], wherein the disease involving
epileptic seizure or convulsive seizure is selected from Dravet
syndrome, Lennox-Gastaut syndrome, West syndrome (epilepsia
nutans), Ohtahara syndrome, Doose syndrome, Landau-Kleffner
syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos
syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind
syndrome, hemiconvulsion-hemiplegia-epilepsy syndrome, mesial
temporal lobe epilepsy, epilepsy with structural/metabolic cause
(epilepsy after stroke, traumatic epilepsy, infectious epilepsy,
epilepsy associated with cerebrovascular disorder, epilepsy
associated with brain tumor, epilepsy associated with
neurodegenerative disease, epilepsy associated with autoimmune
disorder, etc.), and congenital malformation, congenital metabolic
abnormality (for example, phenylketonuria, mitochondrial disease,
lysosomal disease, Sturge-Weber syndrome, etc.) and congenital
genetic abnormality (Rett's syndrome, Angelman's syndrome, 5p
syndrome, 4p syndrome, Down's syndrome, etc.), etc. [0040] [17] A
compound or a salt thereof according to any of [1] to [6] for use
in the treatment, prevention and/or diagnosis of seizure in disease
involving epileptic seizure or convulsive seizure (including
multiple drug resistant seizure, refractory seizure, acute
symptomatic seizure, febrile seizure and status epilepticus).
[0041] [18] The compound or a salt thereof according to [17],
wherein the epileptic seizure is selected from focal onset seizure
(also called partial seizure) with motor onset (including
automatism, atonic seizure, clonic seizure, epileptic spasms,
hyperkinetic seizure, myoclonic seizure and tonic seizure) and
non-motor onset (including autonomic seizure, behavior arrest
seizure, cognitive seizure, emotional seizure and sensory seizure),
and focal to bilateral tonic-clonic seizure (secondary
generalization of partial seizure); generalized onset seizure
including motor seizure (including tonic-clonic seizure, clonic
seizure, tonic seizure, myoclonic seizure, myoclonic-tonic-clonic
seizure, myoclonic-atonic seizure, atonic seizure and epileptic
spasms) and non-motor seizure (including typical absence seizure,
atypical absence seizure, myoclonic absence seizure and eyelid
myoclonic seizure); and seizure of unknown onset including motor
seizure (including tonic-clonic seizure and epileptic spasms) and
non-motor seizure (including behavior arrest seizure). [0042] [19]
The compound or a salt thereof according to [17], wherein the
disease involving epileptic seizure or convulsive seizure is
selected from Dravet syndrome, Lennox-Gastaut syndrome, West
syndrome (epilepsia nutans), Ohtahara syndrome, Doose syndrome,
Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome,
Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome,
Geschwind syndrome, hemiconvulsion-hemiplegia-epilepsy syndrome,
mesial temporal lobe epilepsy, epilepsy with structural/metabolic
cause (epilepsy after stroke, traumatic epilepsy, infectious
epilepsy, epilepsy associated with cerebrovascular disorder,
epilepsy associated with brain tumor, epilepsy associated with
neurodegenerative disease, epilepsy associated with autoimmune
disorder, etc.), and congenital malformation, congenital metabolic
abnormality (for example, phenylketonuria, mitochondrial disease,
lysosomal disease, Sturge-Weber syndrome, etc.) and congenital
genetic abnormality (Rett's syndrome, Angelman's syndrome, 5p
syndrome, 4p syndrome, Down's syndrome, etc.), etc. [0043] [20] Use
of a compound or a salt thereof according to any of [1] to [6] in
the manufacture of a medicament for treating, preventing and/or
diagnosing seizure in disease involving epileptic seizure or
convulsive seizure (including multiple drug resistant seizure,
refractory seizure, acute symptomatic seizure, febrile seizure and
status epilepticus). [0044] [21] The use according to [20], wherein
the epileptic seizure is selected from focal onset seizure (also
called partial seizure) with motor onset (including automatism,
atonic seizure, clonic seizure, epileptic spasms, hyperkinetic
seizure, myoclonic seizure and tonic seizure) and non-motor onset
(including autonomic seizure, behavior arrest seizure, cognitive
seizure, emotional seizure and sensory seizure), and focal to
bilateral tonic-clonic seizure (secondary generalization of partial
seizure); generalized onset seizure including motor seizure
(including tonic-clonic seizure, clonic seizure, tonic seizure,
myoclonic seizure, myoclonic-tonic-clonic seizure, myoclonic-atonic
seizure, atonic seizure and epileptic spasms) and non-motor seizure
(including typical absence seizure, atypical absence seizure,
myoclonic absence seizure and eyelid myoclonic seizure); and
seizure of unknown onset including motor seizure (including
tonic-clonic seizure and epileptic spasms) and non-motor seizure
(including behavior arrest seizure). [0045] [22] The use according
to [20], wherein the disease involving epileptic seizure or
convulsive seizure is selected from Dravet syndrome, Lennox-Gastaut
syndrome, West syndrome (epilepsia nutans), Ohtahara syndrome,
Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome,
Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome,
Tassinari syndrome, Geschwind syndrome,
hemiconvulsion-hemiplegia-epilepsy syndrome, mesial temporal lobe
epilepsy, epilepsy with structural/metabolic cause (epilepsy after
stroke, traumatic epilepsy, infectious epilepsy, epilepsy
associated with cerebrovascular disorder, epilepsy associated with
brain tumor, epilepsy associated with neurodegenerative disease,
epilepsy associated with autoimmune disorder, etc.), and congenital
malformation, congenital metabolic abnormality (for example,
phenylketonuria, mitochondrial disease, lysosomal disease,
Sturge-Weber syndrome, etc.) and congenital genetic abnormality
(Rett's syndrome, Angelman's syndrome, 5p syndrome, 4p syndrome,
Down's syndrome, etc.), etc.
[0046] The compound and a salt thereof of the present invention are
highly effective for treating, preventing and/or diagnosing disease
and the like involving epileptic seizure, convulsive seizure or the
like. Moreover, the compound and a salt thereof of the present
invention have excellent feature for use as active ingredient in
pharmaceuticals, and for example have excellent feature such as few
side effects, tolerability, stability (storage stability, metabolic
stability, etc.) and the like. Furthermore, the compound and a salt
thereof of the present invention have a wide treatment spectrum in
comparison with existing antiepileptic drugs.
DESCRIPTION OF EMBODIMENTS
[0047] The phrases and terms used in this specification are
explained in detail below.
[0048] The "lower alkyl" may be C.sub.1-6 linear or branched alkyl,
and specific examples include methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, hexyl, isohexyl, 3-methylpentyl and the like. Lower
alkyl having deuterium atoms substituted for 1 to 3 hydrogen atoms
is also included.
[0049] The "halogen" is fluorine, chlorine, bromine or iodine, and
fluorine, chlorine or iodine is preferred. Fluorine or chlorine is
more preferred.
[0050] The "lower alkynyl" may be a C.sub.2-6 linear or branched
alkynyl, and specific examples include ethynyl, (1- or 2-)propynyl,
1-methyl-(1- or 2-)propynyl, 1-ethyl-(1- or 2-)propynyl, (1-, 2- or
3-)butynyl, (1-, 2-, 3- or 4-)pentynyl, (1-, 2-, 3-, 4- or
5-)hexynyl and the like.
[0051] Examples of the "lower alkyl optionally substituted with
halogen" include C.sub.1-6 linear or branched alkyl optionally
substituted with 1 to 4 halogens, and specific examples include
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl,
3-methylpentyl, fluoromethyl, chloromethyl, bromomethyl,
iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl,
trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl,
2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,
1,1,2,2-tetrafluoroethyl, 3-chloropropyl, 2,3-dichloropropyl,
4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl,
3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexyl and the
like.
[0052] Examples of the "lower alkylene" include C.sub.1-6 linear or
branched alkylene, and specific examples include methylene,
ethylene, 1-methylethylene, 2-methylethylene, trimethylene,
2-methyltrimethylene, 2,2-dimethyltrimethylene,
1-methyltrimethylene, methylmethylene, ethylmethylene,
dimethylmethylene, tetramethylene, pentamethylene, hexamethylene
and the like.
[0053] Each of the groups defined in this specification may be
bound appropriately to another group via a linker such as --O--,
--CO--, --COO--, --S--, --SO--, --SO.sub.2--, --Si--, --O--CO-- or
the like.
[0054] The various substituents in the compound represented by
General Formula [I] of the present invention (hereunder called
"compound [I] of the present invention") are explained below.
[0055] The ring A in the compound [I] of the present invention is
phenyl, naphthyl or pyridyl, and is preferably phenyl.
[0056] R.sub.1 in the compound [I] of the present invention is
lower alkyl, and is preferably a C.sub.1-6 alkyl, or more
preferably methyl or ethyl.
[0057] R.sub.2 in the compound [I] of the present invention is
--O-lower alkyl, and is preferably --O--C.sub.1-6 alkyl, or more
preferably methoxy.
[0058] R.sub.3 in the compound [I] of the present invention is
halogen, lower alkynyl, lower alkyl optionally substituted with
halogen, --O-lower alkyl optionally substituted with deuterium or
halogen, --S-lower alkyl optionally substituted with halogen,
phenyl, pentafluorothio, --CN, --O-benzyl or --Si-mono-, di- or
tri-lower alkyl wherein di or tri may be same or different alkyl,
and is preferably halogen, lower alkynyl, lower alkyl or
trifluoromethylthio, or more preferably fluorine, chlorine,
ethynyl, methyl or trifluoromethylthio, or still more preferably
fluorine, ethynyl or methyl.
[0059] L in the compound [I] of the present invention is bond,
lower alkylene, --O-- or --S--, and is preferably bond or --O--, or
more preferably --O--.
[0060] n in the compound [I] of the present invention is 0 or 1,
and is preferably 0.
[0061] m in the compound [I] of the present invention is 0 or 1,
and is preferably 0.
[0062] q in the compound [I] of the present invention is 0, 1 or 2,
and when q is 2, each R.sub.3 independently represents the same or
different substituent. Preferably q is 1 or 2, and more preferably
q is 1.
[0063] in the compound [I] of the present invention is single or
double bond, and is preferably single bond.
[0064] In the compound [I] of the present invention, the options
and preferred embodiments for the above substituents as presented
include all combinations of these forms as long as they are
consistent combinations.
[0065] Preferred embodiments of the compound [I] of the present
invention are given below. [0066] (1) Those in which the ring A in
Formula [I] is phenyl, and L is --O--. [0067] (2) Those in which
R.sub.2 in Formula [I] is --O-lower alkyl. [0068] (3) Those in
which R.sub.3 in Formula [I] is halogen, lower alkynyl, lower alkyl
or --S-lower alkyl optionally substituted with halogen.
[0069] More preferred embodiments of the compound [I] are given
below. [0070] (1) Those in which the ring A in Formula [I] is
phenyl, L is --O-- and n is 0. [0071] (2) Those in which R.sub.2 in
Formula [I] is methoxy. [0072] (3) Those in which R.sub.3 in
Formula [I] is halogen or lower alkyl.
[0073] Still more preferred embodiments of the compound [I] are
given below. [0074] (1) Those in which L in Formula [I] is --O--, m
and n are each 0, and
##STR00007##
[0075] is phenyl, fluorophenyl, difluorophenyl, chlorophenyl,
bromophenyl, ethynylphenyl, methylphenyl, trifluoromethylthio or
methyl- and fluorine-substituted phenyl.
[0076] In the present invention, moreover, a compound selected from
the group consisting of the following compounds or their salts is
preferred.
##STR00008## ##STR00009##
[0077] In this specification, the options and preferred embodiments
for the different features of the compound, method and composition
of the present invention as presented include all possible
combinations of the options and preferred embodiments for these
different features as long as they are consistent combinations.
[0078] Methods for manufacturing the compound [I] of the present
invention are explained below. The compound [I] of the present
invention can be manufactured based on the manufacturing methods
described below for example. The manufacturing methods described
below are examples, and the method for manufacturing the compound
[I] is not limited thereby.
[0079] In the reaction formulae below, when performing an
alkylation reaction, hydrolysis reaction, amination reaction,
esterification reaction, amidation reaction etherification
reaction, nucleophilic substitution reaction, addition reaction,
oxidation reaction, reduction reaction or the like, these reactions
are themselves performed by known methods. Examples of such methods
include the methods described in Experimental Chemistry (Fifth
Edition, edited by The Chemical Society of Japan, Maruzen Co.,
Ltd.); Organic Functional Group Preparations Second Edition,
Academic Press, Inc., 1989; Comprehensive Organic Transformations,
VCH Publishers, Inc., 1989; and P. G. M. Wuts and T. W. Greene,
Greene's Protective Groups in Organic Synthesis (Fourth Edition,
2006) and the like.
##STR00010##
[0080] (In the formula, all symbols are as defined above.)
[0081] A compound [Ia] included in the compound [I] of the present
invention can be manufactured by the reaction shown by the Reaction
Formula 1 above. Specifically, a compound [III] (acrylic acid) is
added by 1,4-addition to the amino group of the compound [II], and
the amino group of the product is then converted with urea to a
urea derivative, which can then be cyclized (intramolecular
amidation) to manufacture the compound [Ia].
[0082] The "solvent" used in this reaction may be any solvent that
is inactive in the reaction, and examples thereof include water,
ethers (such as dioxane, tetrahydrofuran, diethyl ether,
1,2-dimethoxyethane, diethylene glycol dimethyl ether or ethylene
glycol dimethyl ether), halohydrocarbons (such as methylene
chloride, chloroform, 1,2-dichloroethane or carbon tetrachloride),
aromatic hydrocarbons (such as benzene, toluene or xylene), lower
alcohols (such as methanol, ethanol or isopropanol) and polar
solvents (such as N,N-dimethylformamide (DMF), N-methylpyrrolidine
(NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoric acid
triamide or acetonitrile). One of these solvents alone or a mixture
of two or more kinds may be used.
[0083] The "acid" used in this reaction may be an inorganic acid,
organic acid or the like for example. Examples of the "inorganic
acid" include hydrochloric acid, sulfuric acid, nitric acid,
hydrobromic acid and phosphoric acid. Examples of the "organic
acid" include acetic acid, trifluoracetic acid, oxalic acid,
phthalic acid, fumaric acid, tartaric acid, maleic acid, citric
acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid
and 10-camphorsulfonic acid.
[0084] The other reaction conditions (reaction temperature,
reaction time, etc.) may be selected appropriately based on known
1,4-addition reactions and amidation reactions.
##STR00011##
[0085] (In the formula, X is a leaving group, L.sub.1 is --O--,
--S-- or lower alkylene, and the other symbols are as defined
above.)
[0086] A compound [Ib] included in the compound [I] of the present
invention can be manufactured by the reaction represented by the
Reaction Formula 2. Specifically, the leaving group X of compound
[V] is dissociated, and replaced with the compound [IV] to
manufacture the compound [Ib].
[0087] Examples of the "leaving group" used in the reaction above
include halogen, C.sub.1-18 alkanesulfonyl, lower
alkanesulfonyloxy, arenesulfonyloxy, aralkylsulfonyloxy,
perhalomethanesulfonyloxy, sulfonio, toluenesulfoxy and the like.
Examples of preferred leaving group in the reaction include
halogen.
[0088] Examples of "halogen" above include fluorine, chlorine,
bromine and iodine.
[0089] Examples of the "C.sub.1-18 alkanesulfonyl" include
C.sub.1-18 linear or branched alkanesulfonyl, and specific examples
include methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl,
butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl,
octadecanesulfonyl and the like.
[0090] Examples of the "lower alkanesulfonyloxy" include C.sub.1-6
linear or branched alkanesulfonyloxy, and specific examples include
methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy,
2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy,
1-pentanesulfonyloxy, 1-hexanesulfonyloxy and the like.
[0091] Examples of the "arenesulfonyloxy" include
naphthalenesulfonyloxy and benzenesulfonyloxy, which may have 1 to
3 substituents selected from the group consisting of halogen,
nitro, C.sub.1-6 linear or branched alkoxy and C.sub.1-6 linear or
branched alkyl groups on the phenyl ring. Specific examples of
these "benzenesulfonyloxy which may have substituents" include
benzenesulfonyloxy, 4-methylbenzenesulfonyloxy,
2-methylbenzenesulfonyloxy, 4-nitrobenzenesulfonyloxy,
4-methoxybenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy,
3-chlorobenzenesulfonyloxy and the like. Specific examples of
"naphthalenesulfonyloxy" include .alpha.-naphthalenesulfonyloxy,
.beta.-naphthalenesulfonyloxy and the like.
[0092] Examples of the "aralkanesulfonyloxy" include
naphthyl-substituted C.sub.1-6 linear or branched alkanesulfonyloxy
and phenyl-substituted C.sub.1-6 linear or branched
alkanesulfonyloxy which may have 1 to 3 substituents selected from
the group consisting of halogen, nitro, C.sub.1-6 linear or
branched alkoxy and C.sub.1-6 linear or branched alkyl on the
phenyl ring. Specific examples of these "phenyl-substituted
alkanesulfonyloxy" include phenylmethanesulfonyloxy,
2-phenylethanesulfonyloxy, 4-phenylbutanesulfonyloxy,
4-tolylmethanesulfonyloxy, 2-tolylmethanesulfonyloxy,
(4-nitrophenyl)methanesulfonyloxy,
(4-methoxyphenyl)methanesulfonyloxy,
(3-chlorophenyl)methanesulfonyloxy and the like. Examples of
"naphthyl-substituted alkanesulfonyloxy" include
.alpha.-naphthylmethanesulfonyloxy,
.beta.-naphthylmethanesulfonyloxy and the like.
[0093] A specific example of "perhaloalkanesulfonyloxy" group is
trifluoromethanesulfonyloxy.
[0094] Specific examples of the "sulfonio" include
dimethylsulfonio, diethylsulfonio, dipropylsulfonio,
di(2-cyanoethyl)sulfonio, di(2-nitroethyl)sulfonio,
di-(aminoethyl)sulfonio, di(2-methylaminoethyl)sulfonio,
di-(2-dimethylaminoethyl)sulfonio, di-(2-hydroxyethyl)sulfonio,
di-(3-hydroxypropyl)sulfonio, di-(2-methoxyethyl)sulfonio,
di-(2-carbamoylethyl)sulfonio, di-(2-carboxyethyl)sulfonio,
di-(2-methoxycarbonylethyl)sulfonio, diphenylsulfonio and the
like.
[0095] The "solvent" used in this reaction may be any solvent that
is inactive in the reaction, and examples thereof include water,
ethers (such as dioxane, tetrahydrofuran, diethyl ether,
1,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene
glycol dimethyl ether), halohydrocarbons (such as methylene
chloride, chloroform, 1,2-dichloroethane and carbon tetrachloride),
aromatic hydrocarbons (such as benzene, toluene and xylene), lower
alcohols (such as methanol, ethanol and isopropanol) and polar
solvents (such as N,N-dimethylformamide (DMF), N-methylpyrrolidine
(NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoric acid
triamide and acetonitrile). One of these solvents alone or a
mixture of two or more kinds may be used.
[0096] The "base" used in this reaction may be an inorganic base,
organic base or the like for example. Examples of the "inorganic
base" include alkali metal hydroxides (such as sodium hydroxide and
potassium hydroxide), alkali earth metal hydroxides (such as
magnesium hydroxide and calcium hydroxide), alkali metal carbonates
(such as sodium carbonate and potassium carbonate), alkali earth
metal carbonates (such as magnesium carbonate and calcium
carbonate), alkali metal bicarbonate salts (such as sodium
bicarbonate and potassium bicarbonate) and the like. Examples of
the "organic base" include trialkylamines (such as trimethylamine
and triethylamine), picoline, and 1,5-diazabicyclo[4.3.0]non-5-ene,
1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene
and the like.
[0097] The other reaction conditions (reaction temperature,
reaction time, etc.) may be determined appropriately based on known
nucleophilic reactions.
[0098] In each of the reactions in the above reaction formulae, the
reaction product can be used in the next reaction either as is in
the form of the reaction solution or as a crude product, but it can
also be isolated from the reaction mixture by normal methods and
easily purified by normal separation techniques. Examples of normal
separation techniques include recrystallization, distillation and
chromatography.
[0099] The starting raw material compounds, intermediate compounds
and object compounds in each of the above steps and the compound
[I] of the present invention itself all include geometric isomers,
stereoisomers, optical isomers and tautomers. The respective
isomers can be separated by ordinary optical resolution methods.
They can also be manufactured from raw material compounds having
suitable optical activity.
[0100] The compound [I] of the present invention can be
manufactured by the synthesis methods shown in the reaction
formulae above, or by analogous methods.
[0101] Unless specific production methods are specified, the raw
material compounds used in the manufacture of the compound [I] of
the present invention may be commercial compounds, or may be
produced by known methods or analogous methods.
[0102] The starting raw material compounds and object compounds in
each step above may be used in the form of appropriate salts.
Examples of such salts include salts similar to those given as
examples of salts of compound [I] of the present invention
below.
[0103] When the compounds obtained in each step or commercial
products are free compounds, they can be converted to the object
salts by known methods. When the compounds obtained in each step or
commercial products are salts, they can be converted to free form
or into other object salts by known methods.
[0104] The compound [I] of the present invention also includes
embodiments that are pharmaceutically acceptable salts, and in some
cases the compounds may also form an acid addition salt or a salt
with a base depending on the kinds of substituents. Examples of the
"acid" here include inorganic acids such as hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid;
and organic acids such as methanesulfonic acid, p-toluenesulfonic
acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric
acid, malic acid, lactic acid and the like. Examples of the "base"
include inorganic bases such as sodium hydroxide, potassium
hydroxide, calcium hydroxide, sodium carbonate, potassium
carbonate, sodium bicarbonate and potassium bicarbonate; organic
bases such as methylamine, diethylamine, trimethylamine,
triethylamine, ethanolamine, diethanolamine, triethanolamine,
ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine,
N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline and
choline; and ammonium salts and the like. The compound may also
form a salt with an amino acid such as lysine, arginine, aspartic
acid, glutamic acid or the like.
[0105] The present invention also encompasses various hydrates,
solvates and crystal polymorphisms of the compound [I] and salts
thereof.
[0106] The compound [I] of the present invention also includes
compounds in which one or more isotope atoms have been substituted
for one or more atoms. Examples of isotope atoms include deuterium
(.sup.2H), tritium (.sup.3H), .sup.13C, .sup.15N, .sup.18O and the
like.
[0107] The compound [I] of the present invention includes
pharmaceutically acceptable prodrugs. Examples of substituents that
can be modified to make prodrugs include reactive functional groups
such as --OH, --COOH, amino and the like. The modifying groups of
these functional groups are selected appropriately from the
"substituents" in this specification.
[0108] The compound [I] or a salt thereof of the present invention
may be in the form of a pharmaceutically acceptable co-crystal or
co-crystal salts. A co-crystal or co-crystal salt here means a
crystalline substance composed at room temperature of two or more
independent solids each having different physical properties (such
as structure, melting point, heat of fusion and the like).
Co-crystals and co-crystal salts can be manufactured appropriately
by well-known co-crystallization methods.
[0109] The compound [I] and a salt thereof of the present invention
have excellent effects in the treatment, prevention and/or
diagnosis of seizure in disease involving epileptic seizure or
convulsive seizure. The term epileptic seizure is applicable to any
of the seizure types classified below: focal onset seizure (also
called partial seizure) with motor onset (including automatism,
atonic seizure, clonic seizure, epileptic spasms, hyperkinetic
seizure, myoclonic seizure and tonic seizure) and non-motor onset
(including autonomic seizure, behavior arrest seizure, cognitive
seizure, emotional seizure and sensory seizure), and focal to
bilateral tonic-clonic seizure (secondary generalization of partial
seizure); generalized onset seizure including motor seizure
(including tonic-clonic seizure, clonic seizure, tonic seizure,
myoclonic seizure, myoclonic-tonic-clonic seizure, myoclonic-atonic
seizure, atonic seizure and epileptic spasms) and non-motor seizure
(including typical absence seizure, atypical absence seizure,
myoclonic absence seizure and eyelid myoclonic seizure); and
seizures of unknown onset including motor seizure (including
tonic-clonic seizure and epileptic spasms) and non-motor seizure
(including behavior arrest seizure).
[0110] Examples of the disease involving epileptic seizure or
convulsive seizure include Dravet syndrome, Lennox-Gastaut
syndrome, West syndrome (epilepsia nutans), Ohtahara syndrome,
Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome,
Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome,
Tassinari syndrome, Geschwind syndrome,
hemiconvulsion-hemiplegia-epilepsy syndrome, mesial temporal lobe
epilepsy, epilepsy with structural/metabolic cause (epilepsy after
stroke, traumatic epilepsy, infectious epilepsy, epilepsy
associated with cerebrovascular disorder, epilepsy associated with
brain tumor, epilepsy associated with neurodegenerative disease,
epilepsy associated with autoimmune disorder, etc.), and congenital
malformation, congenital metabolic abnormality (for example,
phenylketonuria, mitochondrial disease, lysosomal disease,
Sturge-Weber syndrome, etc.) and congenital genetic abnormality
(Rett's syndrome, Angelman's syndrome, 5p syndrome, 4p syndrome,
Down's syndrome, etc.).
[0111] The compound [I] or a salt thereof of the present invention
is also effective in the treatment, prevention and/or diagnosis of
multiple drug resistant seizure, refractory seizure, acute
symptomatic seizure, febrile seizure and status epilepticus. In the
present invention, multiple drug resistant seizure and refractory
seizure are defined as seizure that cannot be controlled because
one or two or more antiepileptic drugs are ineffective or
insufficiently effective or the like, regardless of the type of
epileptic seizure as described above.
[0112] Moreover, the compound [I] and a salt thereof of the present
invention have excellent features for use as active ingredients in
pharmaceuticals, and for example have excellent features such as
few side effects, tolerability, stability (storage stability,
metabolic stability, etc.) and the like. These groups of compounds
of the present invention also have effects as preventative and/or
therapeutic agents against refractory epileptic seizure in which
conventional drug therapy is not successful.
[0113] Next, a medical preparation (hereunder also called a
"pharmaceutical composition") containing a compound [I] or a salt
thereof of the present invention as an active ingredient is
explained.
[0114] The medical preparation is obtained by formulating a
compound [I] or a salt thereof of the present invention in the form
of an ordinary medical preparation, and is prepared using a
compound [I] or a salt thereof of the present invention and a
pharmaceutically acceptable carrier. Examples of the carrier
include commonly used diluents or excipients such as fillers,
bulking agents, binders, humectants, disintegrants, surfactants,
lubricants and the like.
[0115] Such a medical preparation can be selected from various
forms according to the therapeutic objective, and examples thereof
include tablets, pills, powders, liquids, suspensions, emulsions,
granules, capsules, suppositories, injections (liquids,
suspensions, etc.) and the like.
[0116] A wide range of known carriers may be used when molding the
preparation in the form of a tablet, and examples thereof include
excipients such as lactose; binders such as polyvinylpyrrolidone;
disintegrants such as starch; absorption aids such as sodium lauryl
sulfate; humectants such as glycerin and starch; adsorbants such as
colloidal silicic acid; and lubricants such as magnesium stearate,
polyethylene glycol and the like.
[0117] Moreover, the tablet may as necessary be made into a tablet
with an ordinary coating, such as for example a sugar-coated
tablet, gelatin-coated tablet, enteric coated tablet, film-coated
tablet, double tablet or multilayer tablet.
[0118] A wide range of known carriers may be used when molding the
preparation in the form of a pill, and examples thereof include
excipients such as glucose; binders such as gum arabic powder; and
disintegrants such as laminaran and the like.
[0119] A wide range of known diluents may be used when forming the
preparation as a liquid, emulsion or suspension, and examples
thereof include water and the like. Ordinary solubilizing agents
and buffers may also be included, as well as colorants,
preservatives, aromatics, flavorings, sweeteners and other drugs
and the like as necessary.
[0120] A wide range of known carriers may be used when forming the
preparation as a suppository, and examples thereof include cocoa
butter and the like.
[0121] When the preparation is an injection, the liquid, emulsion
or suspension is preferably sterilized, and is also preferably
isotonic with blood. An amount of sodium chloride sufficient to
prepare an isotonic injection may be included in the injection, and
another drug, soothing agent or the like may also be included.
[0122] The amount of the compound [I] or a salt thereof that is
contained in the medical preparation is not particularly limited
and may be selected appropriately from a wide range, but normally
the compound [I] or a salt thereof of the present invention is
preferably contained in the amount of 1% to 70% of the medical
preparation.
[0123] The method for administering the medical preparation of the
present invention is not particularly limited, and it can be
administered by a method suited to the dosage form, the age and sex
of the patient, the disease status and other conditions. For
example, it can be administered orally if it is in the form of a
tablet, pill, liquid, suspension, emulsion, granules or capsules.
If it is an injection, it can be administered intravenously either
alone or in a mixture with an ordinary replacement fluid such as
glucose or amino acids, or else it can be administered by itself
intramuscularly, intradermally, subcutaneously or intraperitoneally
as necessary. In the case of a suppository, it can be administered
in the rectum.
[0124] The dose of the medical preparation may be selected
according to the administration method, the age and sex of the
patient, the severity of the disease and other conditions, but
normally 0.01 to 100 mg or preferably 0.1 to 50 mg per 1 kg of body
weight can be administered per day in one or more
administrations.
[0125] This dose is affected by various conditions, and in some
cases a dose below the aforementioned range may be sufficient,
while in others a dose above the aforementioned range may be
necessary.
[0126] The compound [I] or a salt thereof of the present invention
can be used in combination with various treatment or preventative
agents for disease for which the compound [I] is thought to be
effective. Such combined use may be by simultaneous administration,
or else by separate administration, either continuously or with a
suitable interval in between. Preparations that are administered
simultaneously may be formulated separately or combination.
[0127] A pharmaceutical composition containing the compound [I] or
a salt thereof of the present invention together with a
pharmaceutically acceptable carrier and/or excipient is provided by
one embodiment of the present invention.
[0128] Another embodiment provides a therapeutic, preventative
and/or diagnostic agent for seizure in disease involving epileptic
seizure or convulsive seizure (including multiple drug resistant
seizure, refractory seizure, acute symptomatic seizure, febrile
seizure and status epilepticus), containing the compound [I] or a
salt thereof of the present invention together with a
pharmaceutically acceptable carrier and/or excipient.
[0129] Yet another embodiment provides a therapeutic, preventative
and/or diagnostic pharmaceutical composition for seizure in disease
involving epileptic seizure or convulsive seizure (including
multiple drug resistant seizure, refractory seizure, acute
symptomatic seizure, febrile seizure and status epilepticus),
containing the compound [I] or a salt thereof of the present
invention together with a pharmaceutically acceptable carrier
and/or excipient.
[0130] Yet another embodiment provides a method for treating,
preventing and/or diagnosing seizure in disease involving epileptic
seizure or convulsive seizure (including multiple drug resistant
seizure, refractory seizure, acute symptomatic seizure, febrile
seizure and status epilepticus), which comprises administering to a
human in need thereof an effective amount of the compound [I] or a
salt thereof of the present invention.
[0131] Yet another embodiment provides the compound [I] or a salt
thereof of the present invention for use in the treatment,
prevention and/or diagnosis of seizure in disease involving
epileptic seizure or convulsive seizure (including multiple drug
resistant seizure, refractory seizure, acute symptomatic seizure,
febrile seizure and status epilepticus).
[0132] Yet another embodiment provides the use of the compound [I]
or a salt thereof of the present invention in the manufacture of a
drug for treating, preventing and/or diagnosing seizure in disease
involving epileptic seizure or convulsive seizure (including
multiple drug resistant seizure, refractory seizure, acute
symptomatic seizure, febrile seizure and status epilepticus).
Examples
[0133] The present invention is explained in further detail below
through the following Test Examples, Reference Examples and
Examples, but these do not limit the present invention, and these
may be changed to the extent that they do not deviate from the
scope of the present invention.
[0134] The following abbreviations are used in this
Description.
[0135] REX: Reference Example number
[0136] EX: Example number
[0137] STR: Structural formula (in the formula, the label "Chiral"
indicates the absolute configuration of a structure)
[0138] RProp: Manufacturing method (numbers indicate that the
compound was manufactured using the corresponding raw materials in
the same way as the reference example compound having that number
as a reference example number)
[0139] Prop: Manufacturing method (numbers indicate that the
compound was manufactured using the corresponding raw materials in
the same way as the example compound having that number as an
example number)
[0140] Data: Physical property data (NMR1: .delta. (ppm) in
.sup.1H-NMR in dimethylsulfoxide-d.sub.6; NMR2: .delta. (ppm) in
.sup.1H-NMR in CDCl.sub.3)
[0141] Ph: Phenyl
[0142] 9-BBN: 9-Borabicyclo[3.3.1]nonane
[0143] CDI: 1,1'-Carbonyldiimidazole
[0144] DBU: 1,8-Diazabicyclo[5.4.0]-7-undecene
[0145] DIBOC: Di-t-butyl dicarbonate
[0146] WSC: 3-Ethyl-1-(3-dimethylaminopropyl)carbodiimide
[0147] DEAD: Diethylazodicarboxylate
[0148] DPPA: Diphenylphosphoryl azide
[0149] HOBt: 1-Hydroxybenzotriazole
[0150] NCS: N-Chlorosuccinimide
[0151] DCC: Dicyclohexylcarbodiimide
[0152] DHP: 3,4-Dihydro-2H-pyran
[0153] DMAP: 4-(Dimethylamino)pyridine
[0154] ZCl: Benzyl chloroformate
[0155] PPTS: Pyridinium p-toluenesulfonate
[0156] MCPBA: m-Chloroperbenzoic acid
[0157] BBr.sub.3: Boron tribromide
[0158] n-BuLi: n-Butyl lithium
[0159] NaH: Sodium hydride
[0160] DIPEA: Diisopropylethylamine
[0161] KOtBu: Potassium t-butoxide
[0162] LDA: Lithium diisopropylamide
[0163] LHMDS: Lithium hexamethyldisilazide
[0164] NaOtBu: Sodium t-butoxide
[0165] DIBAL: Diisobutyl aluminum hydride
[0166] LAH: Lithium aluminum hydride
[0167] NaBH.sub.4: Sodium borohydride
[0168] Pd/C: Palladium on carbon
[0169] AcOEt: Ethyl acetate
[0170] DCE: 1,2-Dichloroethane
[0171] DCM: Dichloromethane
[0172] DMA: N,N-Dimethylacetamide
[0173] DME: Dimethoxyethane
[0174] DMF: N,N-Dimethylformamide
[0175] DMSO: Dimethylsulfoxide
[0176] Et.sub.2O: Diethyl ether
[0177] MeOH: Methanol
[0178] EtOH: Ethanol
[0179] Hexane: n-Hexane
[0180] IPA: 2-Propanol
[0181] IPE: Diisopropyl ether
[0182] MeCN: Acetonitrile
[0183] MEK: 2-Butanone
[0184] NMP: N-Methylpyrrolidone
[0185] PEG: Polyethylene glycol
[0186] TEA: Triethylamine
[0187] TFA: Trifluoracetic acid
[0188] THF: Tetrahydrofuran
[0189] AcOH: Acetic acid
[0190] HCl: Hydrochloric acid
[0191] KOH: Potassium hydroxide
[0192] LiOH: Lithium hydroxide
[0193] NaOH: Sodium hydroxide
[0194] K.sub.3PO.sub.4: Tripotassium phosphate
[0195] Cs.sub.2CO.sub.3: Cesium carbonate
[0196] K.sub.2CO.sub.3: Potassium carbonate
[0197] KHCO.sub.3: Potassium bicarbonate
[0198] NaHCO.sub.3: Sodium bicarbonate
[0199] AcONa: Sodium acetate [0200] In the examples below, "room
temperature" normally indicates from about 10.degree. C. to about
35.degree. C. The ratios indicated for mixed solvents are volume
ratios unless otherwise specified. Percentages indicate weight %
unless otherwise specified. [0201] The .sup.1H-NMR (proton nuclear
magnetic resonance) spectra were measured by Fourier transform type
NMR (using any of Bruker AVANCE 300 (300 MHz), Bruker AVANCE 500
(500 MHz), Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE III 500
(500 MHz). [0202] When a basic gel is described for silica gel
column chromatography, an aminopropylsilane bonded silica gel is
used. [0203] The absolute configuration of the compound was
determined by known X-ray crystal structure analysis methods (for
example, Shigeru Oba and Shigenobu Yano, "Basic Course for Chemists
12, X-ray Crystal Structure Analysis" (First Edition, 1999)), or
estimated from empirical rules of Shi asymmetric epoxidation
(Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-Gui
Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401. Yuanming Zhu, Yong
Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29,
2437-2440).
REFERENCE EXAMPLES
Reference Example 1
5-Nitro-2-phenoxypyrimidine
##STR00012##
[0205] Phenol (6.61 mL) and K.sub.2CO.sub.3 (12.99 g) were
suspended in DMF (80 mL), 2-chloro-5-nitropyrimidine (10 g) was
added, and the mixture was stirred overnight at room temperature.
Water was added to the reaction solution, and the resulting solid
was washed with water to obtain the object compound (6.55 g).
[0206] NMR2: 7.17-7.24 (2H, m), 7.31-7.39 (1H, m), 7.45-7.53 (2H,
m), 9.33 (2H, s).
Reference Example 2
2-Phenoxypyrimidine-5-amine
##STR00013##
[0208] 5-Nitro-2-phenoxypyrimidine (7.45 g) and 50% aqueous 10%
Pd/C (3 g) were suspended in EtOH (100 mL), and stirred for 16
hours at room temperature under a hydrogen atmosphere. The reaction
solution was filtered through Celite, the filtrate was
concentrated, and the resulting solid was washed with IPE to obtain
the object compound (4.73 g).
[0209] NMR2: 3.50 (2H, brs), 7.13-7.24 (3H, m), 7.35-7.45 (2H, m),
8.07 (2H, s).
Reference Example 3
2-(2-Fluorophenoxy)-5-nitropyrimidine
##STR00014##
[0211] o-Fluorophenol (6.71 mL) and K.sub.2CO.sub.3 (12.99 g) were
suspended in DMF (100 mL), after which 2-chloro-5-nitropyrimidine
(10 g) was added and stirred for 8 hours at room temperature. Water
was added to the reaction solution, and the resulting solid was
washed with water to obtain the object compound (13.67 g).
[0212] NMR2: 7.20-7.38 (4H, m), 9.33 (2H, s).
Reference Example 4
2-(2-Fluorophenoxy)pyrimidine-5-amine
##STR00015##
[0214] 2-(2-Fluorophenoxy)-5-nitropyrimidine (13.67 g) and 50%
aqueous 10% Pd/C (3 g) were suspended in EtOH (130 mL), and stirred
for 1 hour at room temperature under a hydrogen atmosphere. The
reaction solution was filtered through Celite, the filtrate was
concentrated, and the resulting solid was washed with IPE to obtain
the object compound (8.25 g).
[0215] NMR2: 3.51 (2H, brs), 7.13-7.30 (4H, m), 8.05 (2H, s).
Reference Example 5
2-(3-Fluorophenoxy)-5-nitropyrimidine
##STR00016##
[0217] m-Fluorophenol (5.45 mL) and K.sub.2CO.sub.3 (10.40 g) were
suspended in DMF (80 mL), 2-chloro-5-nitropyrimidine (8 g) was
added, and the mixture was stirred overnight at room temperature.
Water was added to the residue, which was then extracted with
AcOEt, and the organic layer was separated, washed with water and
saturated saline, dried with sodium sulfate, and concentrated to
obtain the object compound (8.63 g).
[0218] NMR2: 6.93-7.12 (3H, m), 7.38-7.48 (1H, m), 9.34 (2H,
s).
Reference Example 6
2-(3-Fluorophenoxy)pyrimidine-5-amine
##STR00017##
[0220] 2-(3-Fluorophenoxy)-5-nitropyrimidine (8.65 g) and 50%
aqueous 10% Pd/C (3 g) were suspended in EtOH (100 mL), and stirred
for 16 hours at room temperature under a hydrogen atmosphere. The
reaction solution was filtered through Celite, and the filtrate was
concentrated to obtain a crude product. The crude product was
purified by medium pressure preparative liquid chromatography
(DMC/AcOEt=10:1.fwdarw.1:1), and the resulting solid was then
washed with hexane to obtain the object compound (3.77 g).
[0221] NMR2: 3.55 (2H, brs), 6.86-7.00 (3H, m), 7.30-7.39 (1H, m),
8.08 (2H, s).
Reference Example 7
1-[2-(Methylthio)pyrimidin-5-yl]pyrimidine-2,4(1H,3H)-dione
##STR00018##
[0223] A mixture of 5-bromo-2-(methylthio)pyrimidine (2.77 g),
uracil (2.27 g), copper iodide (0.257 g), picolinic acid (0.33 g)
and K.sub.3PO.sub.4 (5.73 g) was suspended in DMSO (30 mL), and
stirred overnight at 150.degree. C. under a nitrogen atmosphere.
Aqueous citric acid solution was added to the reaction solution,
which was then extracted with AcOEt. The organic layer was
separated, washed with water and saturated saline, dried with
sodium sulfate and concentrated to obtain a crude product. The
crude product was purified by medium pressure preparative liquid
chromatography (Hexane:AcOEt=10:1.fwdarw.0:1) to obtain the object
compound (577 mg).
[0224] NMR1: 2.56 (3H, s), 5.77 (1H, d, J=7.9 Hz), 7.80 (1H, d,
J=7.9 Hz), 8.76 (2H, s), 11.62 (1H, brs).
Reference Example 8
2-(Dodecylthio)-5-nitropyrimidine
##STR00019##
[0226] Dodecylmercaptan (24.77 mL) was dissolved in DMF (150 mL)
and cooled to 0.degree. C., 60% NaH (4.14 g) was added and stirred
for 10 minutes, and 2-chloro-5-nitropyrimidine (15 g) was added to
the mixture, which was then stirred for 1 hour at 0.degree. C.
Water was added to the reaction solution, and the resulting solid
was washed with water to obtain the object compound (26.01 g).
[0227] NMR2: 0.88 (3H, t, J=7.0 Hz), 1.18-1.38 (16H, m), 1.38-1.50
(2H, m), 1.64-1.76 (2H, m), 3.23 (2H, t, =7.5 Hz), 9.23 (2H,
s).
Reference Example 9
2-(Dodecylthio)pyrimidine-5-amine
##STR00020##
[0229] 2-(Dodecylthio)-5-nitropyrimidine (26.01 g) was dissolved in
EtOH (250 mL), ammonium chloride (25.6 g) aqueous solution (100 mL)
and zinc powder (52.2 g) were added, and the mixture was stirred
under reflux for 5 hours. AcOEt was added to the reaction solution
and stirred overnight, after which the reaction solution was
filtered through Celite, and the filtrate was concentrated. Water
was added to the residue, which was then extracted with AcOEt. The
organic layer was separated, washed with water and saturated
saline, dried with sodium sulfate, and concentrated to obtain a
crude product. The crude product was purified by medium pressure
preparative liquid chromatography (Hexane:AcOEt=4:1.fwdarw.1:1),
and washed with hexane to obtain the object compound (20.17 g).
[0230] NMR2: 0.88 (3H, t, J=7.0 Hz), 1.15-1.40 (16H, m), 1.40-1.51
(2H, m), 1.62-1.81 (2H, m), 3.10 (2H, t, J=7.4 Hz), 3.49 (2H, brs),
8.08 (2H, s).
Reference Example 10
1-[2-(Dodecylthio)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione
##STR00021##
[0232] 2-(Dodecylthio)pyrimidine-5-amine (11 g) was dissolved in
toluene (100 mL), acrylic acid (3.83 mL) was added, and the mixture
was stirred overnight at 110.degree. C. The reaction solution was
concentrated, the residue was dissolved in AcOH (100 mL), urea
(3.35 g) was added, and the mixture was stirred for 2 days at
110.degree. C. The reaction solution was concentrated and washed
with saturated sodium bicarbonate aqueous solution, and the
resulting crystal was filtered out. The resulting solid was
dissolved in a 10% MeOH/DCM mixed solution, dried with sodium
sulfate and filtered, and the filtrate was concentrated. The
resulting solid was washed with EtOH to obtain the object compound
(5.67 g).
[0233] NMR2: 0.88 (3H, t, J=7.0 Hz), 1.17-1.38 (16H, m), 1.38-1.50
(2H, m), 1.68-1.79 (2H, m), 2.89 (2H, t, J=6.7 Hz), 3.14 (2H, t,
J=7.4 Hz), 3.88 (2H, t, J=6.7 Hz), 7.48 (1H, brs), 8.52 (2H,
s).
Reference Example 11
1-[2-(Dodecylsulfonyl)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dio-
ne
##STR00022##
[0235]
1-[2-(Dodecylthio)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)--
dione (7.17 g) was suspended in DCM (80 mL) and cooled, after which
aqueous 77% MCPBA (10.23 g) was added, and the mixture was stirred
overnight at room temperature. Dimethylsulfide was added to the
reaction solution and stirred, after which saturated sodium
bicarbonate aqueous solution was added and the DCM was distilled
off under reduced pressure. The resulting solid was washed with
water to obtain the object compound (7.15 g).
[0236] NMR1: 0.85 (3H, t, J=7.0 Hz), 1.15-1.45 (18H, m), 1.60-1.73
(2H, m), 2.78 (2H, t, J=6.6 Hz), 3.53-3.61 (2H, m), 4.01 (2H, t,
J=6.6 Hz), 9.08 (2H, s), 10.83 (1H, brs).
Reference Example 12
1-[2-(Methylthio)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione
##STR00023##
[0238] 2-(Methylthio)pyrimidine-5-amine (4.61 g) was suspended in
water (25 mL), acrylic acid (4.48 mL) was added, and the mixture
was stirred for 2 days at 70.degree. C. in a nitrogen atmosphere.
The reaction solution was concentrated, the residue was dissolved
in AcOH (25 mL), urea (2.94 g) was added, and the mixture was
stirred for 3 days at 90.degree. C. The reaction solution was
concentrated, and the residue was neutralized by addition of
saturated sodium bicarbonate aqueous solution and extracted with
AcOEt. The organic layer was separated, washed with water and
saturated saline, dried with sodium sulfate, and concentrated to
obtain a crude product. The crude product was purified by medium
pressure preparative liquid chromatography
(Hexane:AcOEt=4:1.fwdarw.0:1), and washed with EtOH to obtain the
object compound (478 mg).
[0239] NMR2: 2.58 (3H, s), 2.90 (2H, t, J=6.7 Hz), 3.89 (2H, t,
J=6.7 Hz), 7.61 (1H, brs), 8.54 (2H, s).
Reference Example 13
1-[2-(Methylsulfonyl)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dion-
e
##STR00024##
[0241]
1-[2-(Methylthio)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-d-
ione (520 mg) was suspended in DCM (10 mL), aqueous 77% MCPBA (1174
mg) was added, and the mixture was stirred overnight at room
temperature in a nitrogen atmosphere. Dimethylsulfide was added to
the reaction solution and stirred, and the solid was washed with
DCM to obtain the object compound (449 mg).
[0242] NMR1: 2.78 (2H, t, J=6.6 Hz), 3.42 (3H, s), 4.01 (2H, t,
J=6.6 Hz), 9.08 (2H, s), 10.82 (1H, brs).
Reference Example 14
Diethyl 2-(5-nitropyrimidin-2-yl)-2-phenylmalonate
##STR00025##
[0244] Diethylphenyl malonate (21.64 mL) was suspended in DMF (100
mL) solution and ice cooled, and 60% NaH (4.02 g) was added and was
stirred for 30 minutes, after which 2-chloro-5-nitropyrimidine (8.0
g) was added and stirred for 1 hour at 80.degree. C. Water was
added to the reaction solution, which was then extracted with
AcOEt. The organic layer was separated, washed with water and
saturated saline, dried with sodium sulfate and concentrated to
obtain a crude product. The crude product was purified by medium
pressure preparative liquid chromatography
(Hexane:AcOEt=95:5.fwdarw.75:25) to obtain the object compound
(10.04 g).
[0245] NMR2: 1.29 (6H, t, J=7.1 Hz), 4.37 (4H, q, J=7.1 Hz),
7.31-7.40 (3H, m), 7.43-7.50 (2H, m), 9.46 (2H, s).
Reference Example 15
2-Benzylpyrimidine-5-amine
##STR00026##
[0247] Diethyl 2-(5-aminopyrimidin-2-yl)-2-phenylmalonate (1.13 g)
was dissolved in ethylene glycol (10 mL), and 5 M NaOH aqueous
solution (3.43 mL) was added and stirred for 2 days at 120.degree.
C. Citric acid aqueous solution was added to neutralize the
reaction solution, which was then extracted with AcOEt. The organic
layer was separated, washed with water and saturated saline, dried
with sodium sulfate, and concentrated to obtain a crude product.
The crude product was purified by medium pressure preparative
liquid chromatography (Hexane:AcOEt=1:1.fwdarw.0:1) to obtain the
object compound (502 mg).
[0248] NMR2: 3.59 (2H, brs), 4.18 (2H, s), 7.16-7.24 (1H, m),
7.26-7.35 (4H, m), 8.14-8.19 (2H, m).
[0249] The compounds of Reference Examples 16 to 36 were each
manufactured as in Reference Examples 1 and 2.
[0250] The structural formulae and physiochemical data for the
compounds of Reference Examples 16 to 36 are each shown in Tables
1-1 and 1-2.
TABLE-US-00001 TABLE 1-1 REX STR Data 16 ##STR00027## NMR2;
7.38-7.45 (1H, m), 7.47-7.53 (1H, m), 7.58-7.65 (2H, m), 9.34 (2H,
s). 17 ##STR00028## NMR2; 3.56 (2H, brs), 7.32-7.39 (1H, m),
7.41-7.55 (3H, m), 8.07 (2H, s). 18 ##STR00029## NMR2; 7.10-7.25
(3H, m), 7.51 (1H, t, J = 8.3 Hz), 9.34 (2H, s). 19 ##STR00030##
NMR2; 3.55 (2H, brs), 7.03-7.09 (2H, m), 7.09-7.14 (1H, m), 7.40
(1H, t, J = 8.7 Hz), 8.08 (2H, s). 20 ##STR00031## NMR2; 7.12-7.22
(4H, m), 9.33 (2H, s). 21 ##STR00032## NMR2; 3.51 (2H, brs),
7.03-7.17 (4H, m), 8.06 (2H, s). 22 ##STR00033## NMR2; 6.93-7.06
(2H, m), 7.22-7.31 (1H, m), 9.33 (2H, s). 23 ##STR00034## NMR2;
3.52 (2H, brs), 6.35-6.99 (2H, m), 7.22 (1H, dt J = 5.6 Hz, 8.9
Hz), 8.04 (2H, s). 24 ##STR00035## NMR2; 7.02-7.12 (2H, m),
7.23-7.34 (1H, m), 9.35 (2H, s). 25 ##STR00036## NMR2; 3.53 (2H,
brs), 6.95-7.05 (2H, m), 7.11-7.21 (1H, m), 8.04 (2H, s). 26
##STR00037## NMR2; 6.76-6.88 (3H, m), 9.35 (2H, s).
TABLE-US-00002 TABLE 1-2 REX STR Data 27 ##STR00038## NMR2; 3.59
(2H, brs), 6.61-6.77 (3H, m), 8.08 (2H, s). 28 ##STR00039## NMR2;
6.93-7.02 (1H, m), 7.06-7.14 (1H, m), 7.23-7.32 (1H, m), 9.34 (2H,
s). 29 ##STR00040## NMR2; 3.56 (2H, brs), 6.87-6.95 (1H, m),
7.00-7.07 (1H, m), 7.12- 7.22 (1H, m), 8.06 (2H, s). 30
##STR00041## NMR2; 4.09 (3H, brs), 7.16-7.23 (2H, m), 7.28-7.36
(1H, m), 7.41- 7.51 (2H, m). 9.08 (2H, s). 31 ##STR00042## NMR2;
3.45 (2H, brs), 4.03 (3H, s), 7.14-7.24 (3H, m), 7.34-7.43 (2H, m),
7.69 (2H, s). 32 ##STR00043## NMR2; 1.26 (6H, t, J = 7.1 Hz), 3.73
(2H, brs), 4.32 (4H, q, J = 7.1 Hz), 7.24-7.34 (3H, m), 7.41-7.47
(2H, m), 8.18 (2H, s). 33 ##STR00044## NMR2; 0.85-0.91 (3H, m),
1.18- 1.40 (16H, m), 1.40-1.51 (2H, m), 1.70-1.80 (2H, m), 3.18
(2H, t, J = 7.3 Hz), 4.17 (3H, s), 9.01 (1H, s). 34 ##STR00045##
NMR2; 0.85-0.91 (3H, m), 1.21- 1.36 (16H, m), 1.35-1.49 (2H, m),
1.66-1.76 (2H, m), 3.08 (2H, t, J = 7.4 Hz), 3.48 (2H, brs), 4.01
(3H, s), 7.80 (1H, s). 35 ##STR00046## NMR2; 0.84-0.91 (3H, m),
1.22- 1.36 (16H, m), 1.36-1.49 (2H, m), 1.69-1.79 (2H, m), 2.84
(2H, t, J = 6.7 Hz), 3.12 (2H, t, J = 7.4 Hz), 3.68 (2H, t, J = 6.7
Hz), 4.03 (3H, s), 7.46 (1H, brs), 8.23 (1H, s). 36 ##STR00047##
NMR2; 0.84-0.92 (3H, m), 1.20- 1.40 (16H, m), 1.40-1.53 (2H, m),
1.85-1.96 (2H, m), 2.89 (2H, t, J = 6.6 Hz), 3.46-3.55 (2H, m),
3.77 (2H, t, J = 6.6 Hz), 4.19 (3H, s), 7.52 (1H, brs), 8.61 (1H,
s).
EXAMPLES
Example 1
1-(2-Phenoxypyrimidin-5-yl)-5,6-dihydropyrimidine-2,4(1H,3H)-dione
##STR00048##
[0252] 2-Phenoxypyrimidine-5-amine (1.00 g) and acrylic acid (1.10
mL) were dissolved in toluene (10 mL), and stirred for 3 days at
80.degree. C. The reaction solution was concentrated, the residue
was dissolved in AcOH (10 mL), urea (642 mg) was added and the
mixture was heated to reflux for 2 days. The reaction solution was
concentrated, the crude product was purified by medium pressure
preparative liquid chromatography (AcOEt/MeOH=1:0.fwdarw.9:1), and
the resulting solid was washed with EtOH to obtain the object
compound (233 mg).
[0253] NMR2: 2.90 (2H, t, J=6.7 Hz), 3.88 (2H, t, J=6.7 Hz),
7.17-7.24 (2H, m), 7.26-7.33 (1H, m), 7.40-7.49 (2H, m), 7.54 (1H,
brs), 8.55 (2H, s).
Example 2
1-[2-(2-Fluorophenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dio-
ne
##STR00049##
[0255] 2-(2-Fluorophenoxy)pyrimidine-5-amine (1.00 g) and acrylic
acid (0.67 mL) were dissolved in propionitrile (10 mL), and stirred
for 2 days at 110.degree. C. The reaction solution was
concentrated, the residue was dissolved in AcOH (10 mL), urea (585
mg) was added, and the mixture was heated to reflux overnight. The
reaction solution was concentrated, the crude product was purified
by medium pressure preparative liquid chromatography
(Hexane/AcOEt=1:1.fwdarw.0:1), and the resulting solid was washed
with EtOH to obtain the object compound (289 mg).
[0256] NMR2: 2.90 (2H, t, J=6.7 Hz), 3.89 (2H, t, J=6.7 Hz),
7.12-7.34 (4H, m), 7.59 (1H, brs), 8.55 (2H, s).
Example 3
1-[2-(3-Fluorophenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dio-
ne
##STR00050##
[0258] 2-(3-Fluorophenoxy)pyrimidine-5-amine (500 mg) and acrylic
acid (0.50 mL) were dissolved in toluene (2.5 mL), and stirred
overnight at 80.degree. C. The reaction solution was concentrated,
the residue was dissolved in AcOH (2.5 mL), urea (293 mg) was
added, and the mixture was heated to reflux for 2 days. The
reaction solution was concentrated, the crude product was purified
by medium pressure preparative liquid chromatography
(DCM/AcOEt=4:1.fwdarw.1:1), and the resulting solid was washed with
IPE to obtain the object compound (63 mg).
[0259] NMR2: 2.91 (2H, t, J=6.7 Hz), 3.90 (2H, t, J=6.7 Hz),
6.92-7.08 (3H, m), 7.34-7.48 (1H, m), 7.58 (1H, brs), 8.57 (2H,
s).
Example 4
1-(2-Phenoxypyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione
##STR00051##
[0261] 1-[2-(Methylthio)pyrimidin-5-yl]pyrimidine-2,4(1H,3H)-dione
(440 mg) was suspended in DCM (10 mL), aqueous 77% MCPBA (1002 mg)
was added, and the mixture was stirred overnight at room
temperature under a nitrogen atmosphere. Dimethyl sulfide was added
to the reaction solution, which was then stirred and concentrated
under reduced pressure, after which the residue was dissolved in
DMF (4 mL), phenol (0.33 mL) and K.sub.2CO.sub.3 (772 mg) were
added, and the mixture was stirred overnight at room temperature.
This was then stirred for 3 hours at 70.degree. C. Water was added
to the reaction solution, which was then extracted with AcOEt. The
organic layer was separated, washed with water and saturated
saline, dried with sodium sulfate and concentrated to obtain a
crude product. The crude product was purified by medium pressure
preparative liquid chromatography (Hexane/AcOEt=1:1.fwdarw.0:1),
and the resulting solid was washed with IPE and recrystallized from
aqueous EtOH to obtain the object compound (270 mg).
[0262] NMR2: 5.93 (1H, dd, J=2.2 Hz, 8.0 Hz), 7.19-7.27 (3H, m),
7.27-7.35 (1H, m), 7.42-7.51 (2H, m), 8.46 (1H, brs), 8.59 (2H,
s).
Example 5
1-[2-(3-Fluorophenoxy)pyrimidin-5-yl]-3-methyl-5,6-dihydropyrimidine-2,4(1-
H,3H)-dione
##STR00052##
[0264]
1-[2-(3-Fluorophenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,-
3H)-dione (500 mg) and K.sub.2CO.sub.3 (343 mg) were suspended in
DMF (5 ml), methyl iodide (0.11 mL) was added, and the mixture was
stirred for 1 hour at 70.degree. C. Water was added to the reaction
solution, which was then extracted with AcOEt. The organic layer
was separated, washed with water and saturated saline, dried with
sodium sulfate, and concentrated to obtain the object compound (197
mg).
[0265] NMR2: 2.94 (2H, t, J=6.7 Hz), 3.25 (3H, s), 3.83 (2H, t,
J=6.7 Hz), 6.92-7.08 (3H, m), 7.35-7.45 (1H, m), 8.55 (2H, s).
Example 6
1-[2-(3-Fluoro-2-methylphenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1-
H,3H)-dione
##STR00053##
[0267]
1-[2-(Dodecylsulfonyl)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,-
3H)-dione (500 mg), 3-fluoro-2-methylphenol (193 mg) and
K.sub.2CO.sub.3 (244 mg) were suspended in DMF (7 mL), stirred at
room temperature under a nitrogen atmosphere, and then stirred for
3 hours at 80.degree. C. Water was added to the reaction solution,
and the resulting solid was washed with water to obtain the object
compound (143 mg).
[0268] NMR2: 2.12 (3H, d, J=1.8 Hz), 2.90 (2H, t, J=6.7 Hz), 3.89
(2H, t, J=6.7 Hz), 6.93 (1H, d, J=8.2 Hz), 6.95-7.03 (1H, m),
7.18-7.27 (1H, m), 7.61 (1H, brs), 8.55 (2H, s).
Example 7
1-[2-(3-Ethylphenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dion-
e
##STR00054##
[0270]
1-[2-(3-Ethynylphenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H-
,3H)-dione (312 mg) was dissolved in a mixed EtOH/THF (5/5 mL)
solution, and aqueous 10% Pd/C (108 mg) was added and stirred for 3
hours under a hydrogen atmosphere. The reaction solution was
filtered through Celite and washed with AcOEt, and the filtrate was
concentrated to obtain a crude product. The crude product was
purified by medium pressure preparative liquid chromatography
(Hexane:AcOEt=1:1.fwdarw.0:1), and the resulting solid was washed
with EtOH to obtain the object compound (99 mg).
[0271] NMR2: 1.26 (3H, t, J=7.6 Hz), 2.69 (2H, q, J=7.6 Hz), 2.90
(2H, t, J=6.7 Hz), 3.88 (2H, t, J=6.7 Hz), 6.97-7.08 (2H, m),
7.09-7.16 (1H, m), 7.35 (1H, t, J=7.8 Hz), 7.60 (1H, brs), 8.54
(2H, s).
Example 8
1-[2-(Phenylthio)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione
##STR00055##
[0273]
1-[2-(Methylsulfonyl)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3-
H)-dione (224 mg), K.sub.2CO.sub.3 (172 mg) and thiophenol (0.10
mL) were suspended in DMF (5 mL), stirred at room temperature under
a nitrogen atmosphere, and then stirred for 10 hours at 70.degree.
C. Water was added to the residue, which was then extracted with
AcOEt. The organic layer was separated, washed with water and
saturated saline, dried with sodium sulfate, and concentrated to
obtain a crude product. The crude product was purified by medium
pressure preparative liquid chromatography
(Hexane:AcOEt=1:1.fwdarw.0:1), and then washed with EtOH to obtain
the object compound (47 mg).
[0274] NMR2: 2.88 (2H, t, J=6.6 Hz), 3.85 (2H, t, J=6.6 Hz),
7.40-7.50 (3H, m), 7.58 (1H, brs). 7.60-7.68 (2H, m), 8.50 (2H,
s).
[0275] The compounds of Examples 9 to 56 were each manufactured as
in Examples 1 to 8. The structural formulae and physiochemical data
for the compounds of the Examples 9 to 56 are each shown in Tables
2-1 to 2-6.
TABLE-US-00003 TABLE 2-1 EX STR Data 9 ##STR00056## NMR2; 2.91 (2H,
t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 7.37- 7.45 (1H, m),
7.47-7.64 (4H, m), 8.57 (2H, s). 10 ##STR00057## NMR2; 2.91 (2H, t,
J = 6.6 Hz), 3.90 (2H, t, J = 6.6 Hz), 7.07- 7.22 (3H, m), 7.46
(1H, t, J = 8.3 Hz), 7.54 (1H, brs), 8.57 (2H, s). 11 ##STR00058##
NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.89 (2H, t, J = 6.7 Hz), 7.06-
7.22 (4H, m), 7.48 (1H, brs), 8.55 (2H, s). 12 ##STR00059## NMR2;
2.91 (2H, t, J = 6.7 Hz), 3.89 (2H, t, J = 6.7 Hz), 7.06- 7.22 (4H,
m), 7.48 (1H, brs), 8.55 (2H, s). 13 ##STR00060## NMR2; 2.90 (2H,
t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 6.98- 7.08 (2H, m),
7.17-7.26 (1H, m), 7.54 (1H, brs), 8.56 (2H, s). 14 ##STR00061##
NMR2; 2.92 (2H, t, J = 6.7 Hz), 3.91 (2H, t, J = 6.7 Hz), 6.70-
6.85 (3H, m), 7.56 (1H, brs), 8.58 (2H, s). 15 ##STR00062## NMR2;
2.91 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 6.92- 7.02 (1H,
m), 7.04-7.14 (1H, m), 7.17-7.29 (1H, m), 7.56 (1H, brs), 8.56 (2H,
s). 16 ##STR00063## NMR2; 1.35 (3H, d, J = 6.7 Hz), 2.63-2.73 (1H,
m), 3.10 (1H, dd, J = 5.9 Hz, 16.7 Hz), 3.95-4.08 (1H, m),
7.17-7.25 (2H, m), 7.26-7.34 (1H, m), 7.41-7.52 (2H, m), 7.61 (1H,
brs), 8.51 (1H, s).
TABLE-US-00004 TABLE 2-2 EX STR Data 17 ##STR00064## NMR2; 6.94
(3H, t, J = 7.4 Hz), 1.61-1.84 (2H, m), 2.76-2.86 (1H, m), 3.06
(1H, dd, J = 6.2 Hz, 16.8 Hz), 3.72-3.82 (1H, m), 7.18-7.34 (3H,
m), 7.41-7.50 (2H, m), 7.54 (1H, brs), 8.53 (2H, s). 18
##STR00065## NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.69 (2H, t, J = 6.7
Hz), 4.00 (3H, s), 7.17-7.24 (2H, m), 7.24-7.31 (1H, m), 7.37-7.50
(3H, m), 8.20 (1H, s). 19 ##STR00066## NMR2; 2.88 (2H, t, J = 6.7
Hz), 3.90 (2H, t, J = 6.7 Hz), 4.31 (2H, s), 7.20-7.40 (5H, m),
7.56 (1H, brs), 8.69 (2H, s). 20 ##STR00067## NMR2; 2.90 (2H, t, J
= 6.7 Hz), 3.88 (2H, t, J = 6.7 Hz), 6.06 (2H, s), 6.79-6.86 (2H,
m), 6.88-6.93 (1H, m), 7.30-7.46 (6H, m), 7.54 (1H, brs), 8.55 (2H,
s). 21 ##STR00068## NMR2: 2.90 (2H, t, J = 6.7 Hz), 3.82 (3H, s),
3.88 (2H, t, J = 6.7 Hz), 6.73-6.87 (3H, m), 7.34 (1H, brs), 8.55
(2H, s). 22 ##STR00069## NMR2; 2.39 (3H, s), 2.90 (2H, t, J = 6.7
Hz), 3.88 (2H, t, J = 6.7 Hz), 6.96-7.05 (2H, m), 7.06-7.13 (1H,
m), 7.32 (1H, t, J = 7.8 Hz), 7.66 (1H, brs), 8.54 (2H, s). 23
##STR00070## NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7
Hz), 7.33- 7.39 (1H, m), 7.47-7.60 (4H, m), 8.57 (2H, s). 24
##STR00071## NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.91 (2H, t, J = 6.7
Hz), 7.36- 7.42 (1H, m), 7.50-7.60 (2H, m), 7.62-7.72 (2H, m), 8.58
(2H, s).
TABLE-US-00005 TABLE 2-3 EX STR Data 25 ##STR00072## NMR2; 2.90
(2H, t, J = 6.7 Hz), 3.88 (2H, t, J = 6.7 Hz), 6.72- 6.87 (3H, m),
7.34 (1H, t, J = 8.2 Hz), 7.58 (1H, brs), 8.55 (2H, s). 26
##STR00073## NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7
Hz), 7.08- 7.14 (1H, m), 7.22-7.29 (2H, m), 7.37 (1H, t, J = 8.1
Hz), 7.56 (1H, brs), 8.56 (2H, s). 27 ##STR00074## NMR2; 2.92 (2H,
t, J = 6.7 Hz), 3.91 (2H, t, J = 6.7 Hz), 7.43- 7.62 (5H, m), 8.58
(2H, s). 28 ##STR00075## NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.11 (1H,
s), 3.89 (2H, t, J = 6.7 Hz), 7.17-7.24 (1H, m), 7.32-7.35 (1H, m),
7.36-7.43 (2H, m), 7.63 (1H, brs), 8.56 (2H, s). 29 ##STR00076##
NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 7.37-
7.43 (1H, m), 7.55-7.66 (2H, m), 8.54 (1H, dd, J = 1.4 Hz, 4.8 Hz),
8.55-8.60 (3H, m). 30 ##STR00077## NMR2; 2.93 (2H, t, J = 6.6 Hz),
3.99 (2H, t, J = 6.6 Hz), 7.46- 7.54 (3H, m), 7.59 (1H, brs),
8.41-8.48 (2H, m), 8.83 (2H, s). 31 ##STR00078## NMR2; 2.89 (2H, t,
J = 6.7 Hz), 3.87 (2H, t, J = 6.7 Hz), 7.10- 7.20 (1H, m),
7.33-7.46 (3H, m), 7.50 (1H, brs), 8.52 (2H, s). 32 ##STR00079##
NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.89 (2H, t, J = 6.7 Hz), 7.34 (1H,
dd, J = 2.4 Hz, 8.9 Hz), 7.43-7.57 (3H, m), 7.65 (1H, d, J = 2.4
Hz), 7.80-7.90 (2H, m), 7.91 (1H, d, J = 8.9 Hz), 8.56 (2H, s).
TABLE-US-00006 TABLE 2-4 EX STR Data 33 ##STR00080## NMR2; 2.91
(2H, t, J = 6.7 Hz), 3.92 (2H, t, J = 6.7 Hz), 7.06- 7.10 (1H, m),
7.25-7.29 (1H, m), 7.48 (1H, brs), 7.80 (1H, t, J = 7.9 Hz), 8.60
(2H, s). 34 ##STR00081## NMR2; 2.21 (3H, s), 2.90 (2H, t, J = 6.7
Hz), 3.88 (2H, t, J = 6.7 Hz), 7.07-7.14 (1H, m), 7.17-7.24 (1H,
m), 7.24-7.34 (2H, m), 7.55 (1H, brs), 8.54 (2H, s). 35
##STR00082## NMR2; 2.38 (3H, s), 2.90 (2H, t, J = 6.7 Hz), 3.87
(2H, t, J = 6.7 Hz), 7.05-7.12 (2H, m), 7.21- 7.26 (2H, m), 7.60
(1H, brs), 8.54 (2H, s). 36 ##STR00083## NMR2; 2.16 (3H, s), 2.34
(2H, s), 2.89 (2H), t, J = 6.7 Hz), 3.88 (2H, t, J = 6.7 Hz), 6.98
(1H, d, J = 8.1 Hz), 7.03-7.13 (2H, m), 7.57 (1H, brs), 8.53 (2h,
s). 37 ##STR00084## NMR2; 2.34 (6H, s), 2.90 (2H, t, J = 6.7 Hz),
3.88 (2H, t, J = 6.7 Hz), 6.78-6.84 (2H, m), 6.89- 6.94 (1H, m),
7.50 (1H, brs), 8.54 (2H, s). 38 ##STR00085## NMR2; 2.16 (3H, s),
2.90 (2H, t, J = 6.7 Hz), 3.89 (2H, t, J = 6.7 Hz), 6.82-6.95 (2H,
m), 7.21- 7.27 (1H, m), 7.64 (1H, brs), 8.56 (2H, s). 39
##STR00086## NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7
Hz), 7.21- 7.31 (2H, m), 7.33-7.40 (1H, m), 7.47-7.56 (2H, m), 8.56
(2H, s). 40 ##STR00087## NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.89 (2H,
t, J = 6.7 Hz), 7.11- 7.19 (2H, m), 7.37-7.43 (2H, m), 7.68 (1H,
brs), 8.55 (2H, s). 41 ##STR00088## NMR2; 5.94 (1H, dd, J = 2.2 Hz,
8.0 Hz), 6.95-7.08 (3H, m), 7.23- 7.28 (1H, m), 7.38-7.46 (1H, m),
8.39 (1H, brs), 8.61 (2H, s).
TABLE-US-00007 TABLE 2-5 EX STR Data 42 ##STR00089## NMR2; 2.85
(2H, t, J = 6.7 Hz), 3.70 (2H, t, J = 6.7 Hz), 4.00 (3H, s),
6.90-7.05 (3H, m), 7.33-7.44 (1H, m), 7.52 (1H, brs), 8.22 (1H, s).
43 ##STR00090## NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J -
6.7 Hz), 7.01- 7.08 (1H, m), 7.21-(1H, dd, J = 1.5 Hz, 8.1 Hz),
7.40-7.48 (1H, m), 7.58 (1H, brs), 7.80 (1H, dd, J = 1.5 Hz, 7.9
Hz), 8.56 (2H, s). 44 ##STR00091## NMR2; 2.91 (2H, t, J = 6.7 Hz),
3.90 (2H, t, J = 6.7 Hz), 7.13- 7.19 (1H, m), 7.31 (1H, t, J = 8.0
Hz), 7.37-7.45 (2H, m), 8.56 (2H, s). 45 ##STR00092## NMR2; 2.90
(2H, t, J = 6.7 Hz), 3.88 (2H, t, J = 6.7 Hz), 7.13- 7.23 (1H, m),
7.33-7.72 (9H, m, 8.56 (2H, s). 46 ##STR00093## NMR2; 2.84 (2H, t,
J = 6.7 Hz), 3.78 (2H, t, J = 6.7 Hz), 7.18- 7.56 (10H, m), 8.39
(2H, s). 47 ##STR00094## NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.69 (2H,
t, J = 6.7 Hz), 3.99 (3H, s), 7.17-7.34 (4H, m), 7.46 (1H, brs),
8.20 (1H, s). 48 ##STR00095## NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.69
(2H, t, J = 6.7 Hz), 3.99 (3H, s), 7.06-7.20 (4H, m), 7.50 (1H,
brs), 8.20 (1H, s). 49 ##STR00096## NMR2; 2.90 (2H, t, J = 6.7 Hz),
3.89 (2H, t, J = 6.7 Hz), 6.94- 7.02 (2H, m), 7.64 (1H, brs),
7.72-7.78 (2H, m), 8.55 (2H, s).
TABLE-US-00008 TABLE 2-6 EX STR Data 50 ##STR00097## NMR2; 2.91
(2H, t, J = 6.7 Hz), 3.08 (1H, s), 3.89 (2H, t, J = 6.7 Hz),
7.13-7.21 (2H, m), 7.48-7.63 (3H, m), 8.56 (2H, s). 51 ##STR00098##
NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.69 (2H, t, J = 6.7 Hz), 4.01 (3H,
s), 7.09-7.15 (1H, m), 7.22-7.29 (2H, m), 7.33-7.39 (1H, m), 7.49
(1H, brs), 8.22 (1H, s). 52 ##STR00099## NMR2; 2.85 (2H, t, J = 6.7
Hz), 3.70 (2H, t, J = 6.7 Hz), 4.01 (3H, s), 6.98-7.08 (2H, m),
7.16-7.25 (1H, m), 7.44 (1H, brs), 8.21 (1H, s). 53 ##STR00100##
NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.69 (2H, t, J = 6.7 Hz), 4.00 (3H,
s), 6.88-7.01 (2H, m), 7.18-7.25 (1H, m), 7.45 (1H, brs), 8.20 (1H,
s). 54 ##STR00101## NMR2; 2.86 (2H, t, J = 6.7 Hz), 3.70 (2H, t, J
= 6.7 Hz), 4.02 (3H, s), 6.70-6.85 (3H, m), 7.48 (1H, brs), 8.23
(1H, s). 55 ##STR00102## NMR2; 1.29 (9H, s), 2.74 (2H, t, J = 6.7
Hz), 3.32 (2H, t, J = 6.7 Hz), 6.99-7.02 (1H, m), 7.19- 7.20 (1H,
m), 7.28-7.30 (1H, m), 7.35-7.38 (1H, m), 8.64 (2H, s), 10.6 (1H,
s). 56 ##STR00103## NMR2; 0.26 (9H, s), 2.74 (2H, t, J = 6.64 Hz),
3.82 (2H, t, J = 6.64 Hz), 7.18-7.21 (1H, m), 7.30 (1H, brd, J =
2.30 Hz), 7.39- 7.47 (m, 2H), 8.64 (2H, s), 10.6 (1H, brs).
TEST EXAMPLES
[0276] Pharmacological test results for typical compounds of the
present invention are given below and the pharmacological actions
of these compounds are explained, but the present invention is not
limited by these test examples.
Test Example 1
[0277] Audiogenic Seizure Model
[0278] The animal model used in this test is a phenotype model for
partial seizure (including secondary generalized seizure) and
generalized tonic-clonic seizure, and has high clinical
predictability. This test was performed in accordance with the
report of De Sarro et al (Br J Pharmacol. 1988 February; 93(2):
247-56. Anticonvulsant effects of some calcium entry blockers in
DBA/2 mice. De Sarro G B, Meldrum B S, Nistico G.).
[0279] In this test example, the example compounds shown in Table 3
below were used as test compounds. The following compound (compound
of Example 5 of WO 2004/009559), which is the most similar compound
when the substituent position is taken into consideration, was used
as a comparative example compound.
##STR00104##
[0280] The test compounds were suspended in 5% gum arabic/distilled
water (w/v), and administered by forced oral administration to male
and female DBA/2 mice (Japan SLC, Inc., 3 weeks old, 8 per group)
at a dose of 30 mg/kg. After one hour of the oral administration of
the test compound, each mouse was placed in a transparent acrylic
cylinder 30 cm high and 23 cm in diameter, and 30 seconds were
allowed for habituation. Then, they were exposed to auditory
stimulation (12.6 kHz, 100-110 dB) for 1 minute or until a tonic
seizure occurred.
[0281] The seizure response was assessed using the following scale,
0: no seizure, 1: wild running, 2: clonic seizure, 3: tonic seizure
and 4: respiratory arrest. The maximum response was recorded as the
seizure severity score.
[0282] The seizure suppression rate for each compound
administration group was calculated according to the following
formula.
seizure suppression rate ( % ) = ( 1 - seizure severity score of
compound administration group seizure severity score of solvent
administration group ) .times. 100 [ Math . 1 ] ##EQU00001##
[0283] The results are shown in Table 3.
TABLE-US-00009 TABLE 3 Seizure suppression EX rate (%) 1 100 2 100
3 100 4 100 5 100 6 89 7 88 8 100 9 94 10 86 11 97 12 96 13 100 14
92 15 83 16 100 18 100 21 93 22 100 23 100 24 90 25 89 26 100 28
100 30 97 31 79 37 77 38 100 40 81 41 96 42 96 44 85 45 92 47 87 48
96 50 82 52 93 53 83 54 93 56 82 Comparative
27.asterisk-pseud..asterisk-pseud. Example* *Compound of Example 5
of WO 2004/009559 **A 10x dose (300 mg/kg) was required to reach a
seizure suppression rate of 100%.
Test Example 2
[0284] Maximal Electroshock Seizure (MES) Model
[0285] This test is performed to evaluate the anticonvulsant
activity of the compound. The mouse model used in this test is a
phenotype model of generalized tonic-clonic seizure and secondary
generalized partial seizure. This test was performed in accordance
with the report of A J Hill et al (Br J Pharmacol. 2012 December;
167(8): 1629-42. Cannabidivarin is anticonvulsant in mouse and rat,
Hill A J, et al.).
[0286] In this test example, the compounds of Examples 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 21, 22, 23, 24, 25,
26, 28, 30, 31, 37, 38, 40, 41, 42, 44, 45, 47, 48, 50, 52, 53, 54
and 56 were used as the test compounds.
[0287] The test compound was suspended in 5% gum arabic/distilled
water (w/v), and administered by forced oral administration to male
ICR mice (Japan SLC, Inc., 5 to 6 weeks old, 8 per group) at a dose
of 30 mg/kg. After one hour of the oral administration of the test
compound, the mice were stimulated by an application of electrical
current (30 mA, 100 Hz, 0.2 second) through auricular electrodes
using an electroconvulsive device (UGO BASILE SRL). Then, the
incidence of tonic hindlimb extension seizure was recorded. In this
test, tonic hindlimb extension seizures were induced in all mice of
the solvent administration group, but the rate of seizure
suppression was 75% or more with the example compounds 1, 2, 3, 5,
8, 10, 12, 13, 14, 16, 18, 22, 26, 28, 30, 31, 38, 42, 47, 48 and
54, and the suppression rate was 50% or more with the example
compounds 4, 6, 9, 11, 23, 41 and 45.
Test Example 3
[0288] Subcutaneous Pentylenetetrazole (scPTZ) Model
[0289] This test is performed to evaluate the anticonvulsant
activity of the compound as in Test Example 2. Unlike the phenotype
of Test Example 2, the animal model used in this test is a
phenotype model of generalized absence seizure and myoclonic
seizure.
[0290] In this test example, the example compounds 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 21, 22, 23, 24, 25, 26,
28, 30, 31, 37, 38, 40, 41, 42, 44, 45, 47, 48, 52, 53, 54, and 56
were used as the test compounds.
[0291] The test compound was suspended in 5% gum arabic/distilled
water (w/v), and administered by forced oral administration to male
ICR mice (Japan SLC, Inc., 5 to 6 weeks old, 10 per group) at a
dose of 30 mg/kg. After 1 hour, 85 mg/kg of pentylenetetrazole
dissolved in saline was administered subcutaneously, and the
occurrence of clonic convulsions was evaluated for 30 minutes.
[0292] In this test, clonic convulsions were induced in all mice of
the solvent administration group, but the rate of suppression
against clonic convulsions was 75% or more with the example
compounds 1, 2, 3, 4, 5, 11, 13, 14, 22, 23 and 28, and the
suppression rate was 50% or more with the example compounds 12, 26,
41, 42, 44 and 56.
Test Example 4
[0293] Rotarod Test
[0294] This test is performed to evaluate the effect of the
compound on the motor coordination.
[0295] The example compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 18, 21, 22, 23, 24, 25, 26, 28, 30, 31, 37, 38, 40,
41, 42, 44, 45, 47, 48, 50, 52, 53, 54 and 56 were used as test
compounds in this test.
[0296] Male ICR mice (Japan SLC, Inc., 5-6 weeks, 8 per group) were
trained to remain on a fixed speed (15 rpm) rotating rod of rotarod
apparatus (Muromachi Kikai Co., Ltd.) for 2 minutes. The test
compound was suspended in 5% gum arabic/distilled water (w/v), and
administered by forced oral administration at a dose of 30 mg/kg.
After 1 hour of oral administration, the mice were again placed on
the rod accelerated from 4 rpm to 40 rpm over 5 minutes and the
latency to fall off the rod was recorded for 200 seconds. The
falling latency of the compound administration group was calculated
as a relative value relative to the average value of the falling
latency in the solvent administration group.
[0297] In this test, the rate of motor dysfunction with the example
compounds 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18,
21, 22, 23, 24, 25, 26, 28, 30, 31, 37, 38, 40, 41, 42, 44, 47, 48,
50, 52, 53, 54 and 56 was 25% or less.
INDUSTRIAL APPLICABILITY
[0298] Thus, since the compound of the present invention exhibits
anticonvulsive action in all cases in multiple animal models used
to evaluate antiepileptic drugs, it is useful as an antiepileptic
drug with a wide treatment spectrum (compound for preventing and/or
treating seizure in disease involving epileptic seizure or
convulsive seizure (including multiple drug resistant seizure,
refractory seizure, acute symptomatic seizure, febrile seizure and
status epilepticus)). Moreover, the compound of the present
invention is useful as a diagnostic compound for disease involving
epileptic seizure or convulsive seizure (including multiple drug
resistant seizure, refractory seizure, acute symptomatic seizure,
febrile seizure and status epilepticus).
* * * * *