U.S. patent application number 13/266152 was filed with the patent office on 2012-04-26 for therapeutic agent for motor disorders.
This patent application is currently assigned to KYOWA HAKKO KIRIN CO., LTD.. Invention is credited to Tomoyuki Kanda, Takashi Sawada, Noriaki Uesaka.
Application Number | 20120101101 13/266152 |
Document ID | / |
Family ID | 43032226 |
Filed Date | 2012-04-26 |
United States Patent
Application |
20120101101 |
Kind Code |
A1 |
Uesaka; Noriaki ; et
al. |
April 26, 2012 |
THERAPEUTIC AGENT FOR MOTOR DISORDERS
Abstract
Provided are an agent for the treatment and/or prophylaxis of a
movement disorder, the agent for the treatment and/or prophylaxis
wherein the movement disorder is extrapyramidal syndrome, the agent
for the treatment and/or prophylaxis wherein the movement disorder
is bradykinesia, gait disturbance, dystonia, dyskinesia or tardive
dyskinesia, the agent for the treatment and/or prophylaxis wherein
the movement disorder is a side effect of L-DOPA and/or dopamine
agonist therapy, and the like, each containing a thiazole
derivative represented by the formula (I) wherein R.sup.1
represents aryl and the like, and R.sup.2 represents pyridyl or the
like, or a pharmaceutically acceptable salt thereof as an active
ingredient. ##STR00001##
Inventors: |
Uesaka; Noriaki; (Shizuoka,
JP) ; Sawada; Takashi; (Shizuoka, JP) ; Kanda;
Tomoyuki; (Shizuoka, JP) |
Assignee: |
KYOWA HAKKO KIRIN CO., LTD.
Chiyoda-ku, Tokyo
JP
|
Family ID: |
43032226 |
Appl. No.: |
13/266152 |
Filed: |
April 28, 2010 |
PCT Filed: |
April 28, 2010 |
PCT NO: |
PCT/JP2010/057563 |
371 Date: |
December 21, 2011 |
Current U.S.
Class: |
514/236.8 ;
514/256; 514/299; 514/301; 514/302; 514/314; 514/342; 514/371;
544/133; 546/112; 546/114; 546/115; 546/169; 546/270.7; 548/181;
548/195 |
Current CPC
Class: |
A61K 31/198 20130101;
C07D 495/04 20130101; A61K 31/4355 20130101; A61P 21/00 20180101;
C07D 491/052 20130101; A61P 25/00 20180101; A61K 31/4709 20130101;
C07D 491/048 20130101; A61K 31/435 20130101; A61K 31/427 20130101;
A61K 31/4365 20130101; A61K 31/5377 20130101; C07D 417/14 20130101;
A61P 25/14 20180101; A61K 31/436 20130101; A61K 31/4439 20130101;
A61P 43/00 20180101; A61P 25/16 20180101; A61K 31/506 20130101 |
Class at
Publication: |
514/236.8 ;
514/342; 514/256; 514/371; 514/302; 514/314; 514/299; 514/301;
546/270.7; 548/195; 548/181; 544/133; 546/115; 546/169; 546/112;
546/114 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/506 20060101 A61K031/506; A61K 31/427
20060101 A61K031/427; A61K 31/4355 20060101 A61K031/4355; A61K
31/4709 20060101 A61K031/4709; A61K 31/436 20060101 A61K031/436;
A61K 31/435 20060101 A61K031/435; A61K 31/4365 20060101
A61K031/4365; C07D 417/14 20060101 C07D417/14; C07D 491/048
20060101 C07D491/048; C07D 491/052 20060101 C07D491/052; C07D
495/04 20060101 C07D495/04; A61P 25/14 20060101 A61P025/14; A61P
25/16 20060101 A61P025/16; A61K 31/4439 20060101 A61K031/4439 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 28, 2009 |
JP |
109434/2009 |
Claims
1-11. (canceled)
12. A pharmaceutical composition comprising: (a) a thiazole
derivative represented by formula (I) ##STR00073## wherein R.sup.1
represents aryl, aralkyl, an aromatic heterocyclic group, aromatic
heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof, and (b) L-DOPA and/or a dopamine agonist.
13. The pharmaceutical composition according to claim 12, wherein
R.sup.1 is phenyl, pyridyl, pyrimidinyl,
5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which
is optionally substituted by 1 to 3 substituents selected from a
fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl,
methoxy and ethoxy, or a pharmaceutically acceptable salt
thereof.
14. The pharmaceutical composition according to claim 13, wherein
R.sup.2 is pyridyl, or a pharmaceutically acceptable salt
thereof.
15. The pharmaceutical composition according to claim 13, wherein
R.sup.2 is tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof.
16. The pharmaceutical composition according to claim 12, wherein
the thiazole derivative is represented by formulas (IA)-(IAA):
##STR00074## ##STR00075## ##STR00076## ##STR00077## or a
pharmaceutically acceptable salt thereof.
17-22. (canceled)
23. A kit, comprising: (a) a first component comprising a thiazole
derivative represented by formula (I) ##STR00078## wherein R.sup.1
represents aryl, aralkyl, an aromatic heterocyclic group, aromatic
heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof, and (b) a second component comprising L-DOPA and/or a
dopamine agonist.
24. The kit according to claim 23, wherein R.sup.1 is phenyl,
pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from a fluorine atom, a chlorine atom, a
bromine atom, methyl, ethyl, methoxy and ethoxy, or a
pharmaceutically acceptable salt thereof.
25. The kit according to claim 24, wherein R.sup.2 is pyridyl, or a
pharmaceutically acceptable salt thereof.
26. The kit according to claim 24, wherein R.sup.2 is
tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof.
27. The kit according to claim 23, wherein the thiazole derivative
is represented by one of formulas (IA)-(IAA): ##STR00079##
##STR00080## ##STR00081## ##STR00082## or a pharmaceutically
acceptable salt thereof.
28. A method of treating and/or preventing progression of a
movement disorder, comprising the steps of: administering to a
patient an effective amount of a thiazole derivative represented by
formula (I) ##STR00083## wherein R.sup.1 represents aryl, aralkyl,
an aromatic heterocyclic group, aromatic heterocycle-alkyl,
aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which
is optionally substituted by 1 to 3 substituents selected from the
group consisting of halogen; lower alkyl optionally substituted by
lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and
vinyl, and R.sup.2 represents pyridyl or tetrahydropyranyl, or a
pharmaceutically acceptable salt thereof.
29. The method according to claim 28, wherein R.sup.1 is phenyl,
pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from a fluorine atom, a chlorine atom, a
bromine atom, methyl, ethyl, methoxy and ethoxy, or a
pharmaceutically acceptable salt thereof.
30. The method according to claim 29, wherein R.sup.2 is pyridyl,
or a pharmaceutically acceptable salt thereof.
31. The method according to claim 29, wherein R.sup.2 is
tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof.
32. The method according to claim 28, wherein the thiazole
derivative is represented by any one of formulas (IA)-(IAA):
##STR00084## ##STR00085## ##STR00086## ##STR00087## or a
pharmaceutically acceptable salt thereof.
33. The method according to claim 28, wherein the movement disorder
is extrapyramidal syndrome.
34. The method according to claim 28, wherein the movement disorder
is bradykinesia, gait disturbance, dystonia, dyskinesia or tardive
dyskinesia.
35. The method according to claim 28, wherein the movement disorder
is a side effect of L-DOPA and/or dopamine agonist therapy.
36. The method according to claim 35, wherein the side effect is a
motor complication.
37. The method according to claim 36, wherein the motor
complication is wearing-off phenomenon.
38. The method according to claim 36, wherein the motor
complication is on-off fluctuation.
39. A method of treating and/or preventing progression of
Parkinson's disease, comprising the steps of: administering to a
patient simultaneously or separately at an interval (a) an
effective amount of a thiazole derivative represented by formula
(I) ##STR00088## wherein R.sup.1 represents aryl, aralkyl, an
aromatic heterocyclic group, aromatic heterocycle-alkyl, aliphatic
heterocycle-alkyl or tetrahydropyranyloxy, each of which is
optionally substituted by 1 to 3 substituents selected from the
group consisting of halogen; lower alkyl optionally substituted by
lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and
vinyl, and R.sup.2 represents pyridyl or tetrahydropyranyl, or a
pharmaceutically acceptable salt thereof, and (b) an effective
amount of L-DOPA and/or a dopamine agonist.
40. The method according to claim 39, wherein R.sup.1 is phenyl,
pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from a fluorine atom, a chlorine atom, a
bromine atom, methyl, ethyl, methoxy and ethoxy, or a
pharmaceutically acceptable salt thereof.
41. The method according to claim 40, wherein R.sup.2 is pyridyl,
or a pharmaceutically acceptable salt thereof.
42. The method according to claim 40, wherein R.sup.2 is
tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof.
43. The method according to claim 39, wherein the thiazole
derivative is represented by any one of formulas (IA)-(IAA):
##STR00089## ##STR00090## ##STR00091## ##STR00092## or a
pharmaceutically acceptable salt thereof.
44-54. (canceled)
55. A compound represented by any one of the following formulas
(IE)-(IAA), or a pharmaceutically acceptable salt thereof:
##STR00093## ##STR00094## ##STR00095## ##STR00096##
56. A combination of: (a) a thiazole derivative represented by
formula (I) ##STR00097## wherein R.sup.1 represents aryl, aralkyl,
an aromatic heterocyclic group, aromatic heterocycle-alkyl,
aliphatic heterocycle-alkyl or tetrahydropyranyloxy, each of which
is optionally substituted by 1 to 3 substituents selected from the
group consisting of halogen; lower alkyl optionally substituted by
lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and
vinyl, and R.sup.2 represents pyridyl or tetrahydropyranyl, or a
pharmaceutically acceptable salt thereof, and (b) L-DOPA and/or a
dopamine agonist, for use in the treatment and/or prophylaxis of
Parkinson's disease.
57. The combination according to claim 56, wherein (a) and (b) are
administered simultaneously.
58. The combination according to claim 56, wherein R.sup.1 is
phenyl, pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from a fluorine atom, a chlorine atom, a
bromine atom, methyl, ethyl, methoxy and ethoxy, or a
pharmaceutically acceptable salt thereof.
59. The combination according to claim 58, wherein R.sup.2 is
pyridyl, or a pharmaceutically acceptable salt thereof.
60. The combination according to claim 58, wherein R.sup.2 is
tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof.
61. The combination according to claim 56, wherein the thiazole
derivative is represented by any one of formulas (IA)-(IAA):
##STR00098## ##STR00099## ##STR00100## ##STR00101## or a
pharmaceutically acceptable salt thereof.
62-73. (canceled)
74. The combination according to claim 56, wherein (a) and (b) are
administered separately at an interval.
75-78. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention relates to an agent for the treatment
and/or prophylaxis of a movement disorder, an agent for the
treatment and/or prophylaxis of Parkinson's disease and the
like.
BACKGROUND ART
[0002] Parkinson's disease is a brain disease characterized by
tremor, bradykinesia, difficulty in gait and coordinated movement
and the like. This disease is associated with damage of a part of
brain which governs muscle movements. Generally, the first symptom
of Parkinson's disease is a limb tremor (shaking or trembling)
particularly when the body is at rest. Tremor often begins in the
hemibody, and frequently occurs in one of the hands. Other common
symptoms include slow movement (bradykinesia), an inability to move
(akinesia), a rigidity of trunk and limbs, a shuffling gait, and a
stooped posture and the like. Patients with Parkinson's disease are
poor in facial expression, and tend to speak in a soft voice.
Parkinson's disease can cause secondary symptoms such as
depression, anxiety, personality change, cognitive impairment,
dementia, sleep disturbances, speech impairments or sexual
dysfunction. The drug therapy of Parkinson's disease currently
employed clinically mainly controls the parkinsonian symptoms by
controlling the imbalance among neurotransmitters. Early stage
patients of Parkinson's disease mostly respond well to a
symptomatic therapy by a dopamine replacement therapy; however, the
disability increases with progression of the disease.
[0003] Although currently available medications for Parkinson's
disease generally provide adequate symptomatic control for several
years, however, many patients develop motor fluctuations and
dyskinesias that compromise clinical response (The New England
Journal of Medicine (N. Eng. J. Med.), vol. 342, p. 1484 (2000) and
the like).
[0004] Although more than thirty years have passed since
discovering L-DOPA, it is still the best agent for treatment of
Parkinson's disease. In the early stages of Parkinson's disease,
patients usually enjoy a good response to L-DOPA. As the disease
progresses, however, L-DOPA tends to become less helpful. This is
not due to the loss of efficacy of L-DOPA, but rather, for example,
to development of motor complications such as end-of-dose
deterioration or adverse fluctuation in motor response including
"wearing-off phenomenon", "on-off fluctuations", and
dyskinesias.
[0005] The "on-off fluctuations" is an event wherein therapeutic
benefit of a medication ("on" state, during which the patients are
relatively free from the symptoms of Parkinson's disease) is
suddenly and unacceptably lost, and the parkinsonian state ("off"
state) appears. Such condition occurs when patients with
Parkinson's disease are under L-DOPA therapy and exposed to L-DOPA
in an amount sufficient to express the efficacy. However, even if
such symptoms are expressed, the treatment effect may recover all
of a sudden.
[0006] The "wearing-off phenomenon" is a phenomenon wherein the
duration of L-DOPA action is decreased in patients with Parkinson's
disease, even though they are under L-DOPA therapy and exposed to
L-DOPA in an amount sufficient to express the efficacy. The
phenomenon is characterized by the gradual reappearance of the
"off" state, and shortening of the "on" state. That is, it refers
to a phenomenon where the duration of the treatment effect of
L-DOPA gradually becomes shorter (duration of the treatment effect
after administration of L-DOPA becomes shorter), which is
remarkably seen in an advanced stage of the disease in patients
with Parkinson's disease under L-DOPA therapy.
[0007] Dyskinesia can be broadly classified into chorea-like
symptoms (hyperactive, purposeless dance-like movement) and
dystonia (sustained, abnormal muscle contraction). In 1974,
Duvoisin first focused on these abnormal involuntary movements, and
found that half or more of patients with Parkinson's disease
develop dyskinesia within 6 months of the treatment. With
increasing period of treatment, both the frequency and severity of
dyskinesia increase. In a study of the potential benefits of
possible neuroprotectants in Parkinson's disease--DATATOP trial--,
L-DOPA induced dyskinesia was observed in 20-30% of patients who
received L-DOPA treatment for a mean of 20.5 months. Ultimately,
most L-DOPA treated patients experienced dyskinesia; up to 80% of
the patients developed dyskinesia within 5 years. (Annals of
Neurology (Ann. Neurol.), vol. 39, p. 37 (1966); The New England
Journal of Medicine (N. Eng. J. Med.), vol. 342, p. 1484 (2000)).
Most dyskinesias occur when L-DOPA or other dopamine receptor
agonists have a concentration in the brain that is sufficient to
hypersensitive dopamine receptors in the putamen (peak dose
dyskinesia). However, dyskinesia also occurs when the dopamine
concentration is low (off-dystonia), or in a stage wherein the
concentration of dopamine rises or falls (biphasic dyskinesia).
[0008] On the other hand, it is known that adenosine is widely
distributed in the whole body, and exhibits a variety of
physiological actions on the central nervous system, the cardiac
muscle, the kidneys, the smooth muscle, and the like through its
receptors (see non-patent document 1), and that an antagonist
thereof is useful for the treatment and/or prophylaxis of various
diseases.
[0009] For example, adenosine A.sub.1 antagonists are known to
facilitate defecation (The Japanese Journal of Pharmacology (Jpn.
J. Pharmacol.), Vol. 68, p. 119 (1995)). Further, the adenosine
A.sub.2A receptors are known to be involved particularly in the
central nervous system, and the antagonists of the adenosine
A.sub.2A receptors are known to be useful as, for example,
therapeutic drugs for Parkinson's disease etc. (see non-patent
document 2), therapeutic drugs for sleep disturbance (see Nature
Neuroscience, p. 858 (2005); patent document 1) and the like. There
are many reports concerning the relationship between adenosine
receptors and Parkinson's disease (see, for example, non-patent
documents 3 and 4).
[0010] In addition, (i) a method of reducing or suppressing side
effects of L-DOPA therapy, (ii) a treatment method by reducing the
dose of L-DOPA in L-DOPA therapy, (iii) a method of prolonging the
duration of effectiveness of the treatment of Parkinson's disease
in L-DOPA therapy, (iv) a method of treating a movement disorder
and the like, each using an adenosine A.sub.2A receptor antagonist,
are known (see patent document 2). To be specific, it is known that
movement disorders such as tremor, bradykinesia, gait disturbance,
akinesia and the like can be suppressed by administering an
adenosine A.sub.2A receptor antagonist represented by the formula
(A) and L-DOPA to patients with Parkinson's disease, and adenosine
A.sub.2A receptor antagonist represented by the formula (A)
suppresses dyskinesia developed by administration of L-DOPA, and
the like. Furthermore, it is known that an adenosine A.sub.2A
receptor antagonist represented by the formula (A) shows an
antiparkinson effect in MPTP-treated common marmoset (see
non-patent document 5), does not provoke dyskinesia (see non-patent
document 6), and does not provoke dyskinesia but potentiates an
antiparkinson effect when used in combination with L-DOPA and/or a
dopamine agonist (see non-patent document 7).
##STR00002##
[0011] On the other hand, for example, compounds represented by the
formulas (IA), (IB), (IC), (ID) and the like are known to have
affinity to adenosine A.sub.2A receptors and have a therapeutic
effect for Parkinson's disease (see patent document 3). Moreover,
thiazole derivatives having an adenosine A.sub.2A receptor
antagonistic activity are known (see patent document 4). It is also
known that these compounds are useful as an agent for the treatment
and/or prophylaxis of sleep disturbance (see patent document 1), an
agent for the treatment and/or prophylaxis of migraine (see patent
document 5), an analgesic tolerance inhibitor (see patent document
6) and the like.
##STR00003##
PRIOR DOCUMENT LIST
Patent Documents
[0012] [patent document 1] WO2007/015528 [0013] [patent document 2]
WO2003/063876 [0014] [patent document 3] WO2005/063743 [0015]
[patent document 4] WO2006/137527 [0016] [patent document 5]
WO2010/010908 [0017] [patent document 6] WO2009/145289
Non-Patent Documents
[0017] [0018] [non-patent document 1] Nature Reviews Drug
Discovery, 2006, vol. 5, p. 247 [0019] [non-patent document 2]
Progress in Neurobiology, 2007, vol. 83, p. 332 [0020] [non-patent
document 3] Nature Reviews Drug Discovery, 2006, vol. 5, p. 845
[0021] [non-patent document 4] Current Pharmaceutical Design, 2008,
vol. 14, p. 1475 [0022] [non-patent document 5] Neurology, 1999,
vol. 52, p. 1673 [0023] [non-patent document 6] Annals of
Neurology, 1998, vol. 43, p. 507 [0024] [non-patent document 7]
EXPERIMENTAL NEUROLOGY, 1999, vol. 162, p. 321
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0025] An object of the present invention is to provide an agent
for the treatment and/or prophylaxis of a movement disorder such as
a motor control disorder (e.g., extrapyramidal syndrome or the
like), hypermobility (e.g., dystonia, dyskinesia, tardive
dyskinesia, tremor, chorea, ballism, akathisia, athetosis,
bradykinesia, gait disturbance, freezing, rigidity, postural
instability, myoclonus, tics or Tourette syndrome, postural reflex
disorder or the like), side effects of L-DOPA and/or dopamine
agonist therapy (e.g., wearing-off phenomenon, dyskinesia or the
like), or the like, an agent for the treatment and/or prophylaxis
of Parkinson's disease and the like. Another object is to provide a
thiazole derivative or a pharmaceutically acceptable salt thereof
having a selective adenosine A.sub.2A antagonist, and useful as the
above-mentioned agent for the treatment and/or prevention, or a
pharmaceutically acceptable salt thereof.
Means of Solving the Problems
[0026] The present invention relates to the following
(1)-(100).
(1) An agent for the treatment and/or prophylaxis of a movement
disorder, comprising a thiazole derivative represented by the
formula (I)
##STR00004##
wherein R.sup.1 represents aryl, aralkyl, an aromatic heterocyclic
group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof as an active ingredient. (2) The agent of (1), wherein
R.sup.1 is phenyl, pyridyl, pyrimidinyl,
5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which
is optionally substituted by 1 to 3 substituents selected from a
fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl,
methoxy and ethoxy, and R.sup.2 is pyridyl or tetrahydropyranyl.
(3) The agent of (1), wherein R.sup.1 is pyridyl or pyrimidinyl,
each of which is optionally substituted by 1 to 3 substituents
selected from the group consisting of halogen; lower alkyl
optionally substituted by lower alkoxy or morpholino; lower alkoxy;
lower alkanoyl; and vinyl. (4) The agent of any one of (1)-(3),
wherein R.sup.2 is pyridyl. (5) The agent of any one of (1)-(3),
wherein R.sup.2 is tetrahydropyranyl. (6) The agent of (1), wherein
the thiazole derivative represented by the formula (I) is a
compound represented by any one of the following formulas
(IA)-(IAA).
##STR00005## ##STR00006## ##STR00007## ##STR00008##
##STR00009##
(7) The agent of any one of (1)-(6), wherein the movement disorder
is an extrapyramidal syndrome. (8) The agent of any one of (1)-(6),
wherein the movement disorder is bradykinesia, gait disturbance,
dystonia, dyskinesia or tardive dyskinesia. (9) The agent of any
one of (1)-(6), wherein the movement disorder is a side effect of
L-DOPA and/or dopamine agonist therapy. (10) The agent of (9),
wherein the side effect is a motor complication. (11) The agent of
(10), wherein the motor complication is wearing-off phenomenon.
(12) The agent of (10), wherein the motor complication is on-off
fluctuation. (13) The agent of (10), wherein the motor complication
is dyskinesia. (14) The agent of any one of (1)-(13), wherein the
movement disorder is that developed in an advanced stage of
Parkinson's disease. (15) A pharmaceutical composition comprising
(a) a thiazole derivative represented by the formula (I)
##STR00010##
wherein R.sup.1 represents aryl, aralkyl, an aromatic heterocyclic
group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof, and (b) L-DOPA and/or a dopamine agonist. (16) The
pharmaceutical composition of (15), wherein R.sup.1 is phenyl,
pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from a fluorine atom, a chlorine atom, a
bromine atom, methyl, ethyl, methoxy and ethoxy, and R.sup.2 is
pyridyl or tetrahydropyranyl. (17) The pharmaceutical composition
of (15), wherein R.sup.1 is pyridyl or pyrimidinyl, each of which
is optionally substituted by 1 to 3 substituents selected from the
group consisting of halogen; lower alkyl optionally substituted by
lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and
vinyl. (18) The pharmaceutical composition of any one of (15)-(17),
wherein R.sup.2 is pyridyl. (19) The pharmaceutical composition of
any one of (15)-(17), wherein R.sup.2 is tetrahydropyranyl. (20)
The pharmaceutical composition of (15), wherein the thiazole
derivative represented by the formula (I) is a compound represented
by any one of the following formulas (IA)-(IAA).
##STR00011## ##STR00012## ##STR00013## ##STR00014##
##STR00015##
(21) An agent for the treatment and/or prophylaxis of Parkinson's
disease, comprising (a) a thiazole derivative represented by the
formula (I)
##STR00016##
wherein R.sup.1 represents aryl, aralkyl, an aromatic heterocyclic
group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof, and (b) L-DOPA and/or a dopamine agonist in combination.
(22) The agent of (21), wherein R.sup.1 is phenyl, pyridyl,
pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy,
each of which is optionally substituted by 1 to 3 substituents
selected from a fluorine atom, a chlorine atom, a bromine atom,
methyl, ethyl, methoxy and ethoxy, and R.sup.2 is pyridyl or
tetrahydropyranyl. (23) The agent of (21), wherein R.sup.1 is
pyridyl or pyrimidinyl, each of which is optionally substituted by
1 to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl. (24) The agent of any one
of (21)-(23), wherein R.sup.2 is pyridyl. (25) The agent of any one
of (21)-(23), wherein R.sup.2 is tetrahydropyranyl. (26) The agent
of (21), wherein the thiazole derivative represented by the formula
(I) is a compound represented by any one of the following formulas
(IA)-(IAA).
##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021##
(27) The agent of any one of (21)-(26), for administering (a) and
(b) simultaneously or separately at an interval. (28) The agent of
any one of (21)-(27), wherein the Parkinson's disease is that in an
advanced stage. (29) A kit comprising (a) a first component
comprising a thiazole derivative represented by the formula (I)
##STR00022##
wherein R.sup.1 represents aryl, aralkyl, an aromatic heterocyclic
group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof, and (b) a second component comprising L-DOPA and/or a
dopamine agonist. (30) The kit of (29), wherein R.sup.1 is phenyl,
pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from a fluorine atom, a chlorine atom, a
bromine atom, methyl, ethyl, methoxy and ethoxy, and R.sup.2 is
pyridyl or tetrahydropyranyl. (31) The kit of (29), wherein R.sup.1
is pyridyl or pyrimidinyl, each of which is optionally substituted
by 1 to 3 substituents selected from the group consisting of
halogen; lower alkyl optionally substituted by lower alkoxy or
morpholino; lower alkoxy; lower alkanoyl; and vinyl. (32) The kit
of any one of (29)-(31), wherein R.sup.2 is pyridyl. (33) The kit
of any one of (29)-(31), wherein R.sup.2 is tetrahydropyranyl. (34)
The kit of (29), wherein the thiazole derivative represented by the
formula (I) is a compound represented by any one of the following
formulas (IA)-(IAA).
##STR00023## ##STR00024## ##STR00025## ##STR00026##
##STR00027##
(35) A method of treating and/or preventing a movement disorder,
comprising administering an effective amount of a thiazole
derivative represented by the formula (I)
##STR00028##
wherein R.sup.1 represents aryl, aralkyl, an aromatic heterocyclic
group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof. (36) The method of (35), wherein R.sup.1 is phenyl,
pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from a fluorine atom, a chlorine atom, a
bromine atom, methyl, ethyl, methoxy and ethoxy, and R.sup.2 is
pyridyl or tetrahydropyranyl. (37) The method of (35), wherein
R.sup.1 is pyridyl or pyrimidinyl, each of which is optionally
substituted by 1 to 3 substituents selected from the group
consisting of halogen; lower alkyl optionally substituted by lower
alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl. (38)
The method of any one of (35)-(37), wherein R.sup.2 is pyridyl.
(39) The method of any one of (35)-(37), wherein R.sup.2 is
tetrahydropyranyl. (40) The method of (35), wherein the thiazole
derivative represented by the formula (I) is a compound represented
by any one of the following formulas (IA)-(IAA).
##STR00029## ##STR00030## ##STR00031## ##STR00032##
##STR00033##
(41) The method of any one of (35)-(40), wherein the movement
disorder is extrapyramidal syndrome. (42) The method of any one of
(35)-(40), wherein the movement disorder is bradykinesia, gait
disturbance, dystonia, dyskinesia or tardive dyskinesia. (43) The
method of any one of (35)-(40), wherein the movement disorder is a
side effect of L-DOPA and/or dopamine agonist therapy. (44) The
method of (43), wherein the side effect is a motor complication.
(45) The method of (44), wherein the motor complication is
wearing-off phenomenon. (46) The method of (44), wherein the motor
complication is on-off fluctuation. (47) The method of (44),
wherein the motor complication is dyskinesia. (48) The method of
any one of (35)-(47), wherein the movement disorder is that
developed in an advanced stage of Parkinson's disease. (49) A
method of treating and/or preventing. Parkinson's disease,
comprising administering (a) an effective amount of a thiazole
derivative represented by the formula (I)
##STR00034##
wherein R.sup.1 represents aryl, aralkyl, an aromatic heterocyclic
group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof, and (b) an effective amount of L-DOPA and/or a dopamine
agonist, simultaneously or separately at an interval. (50) The
method of (49), wherein R.sup.1 is phenyl, pyridyl, pyrimidinyl,
5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which
is optionally substituted by 1 to 3 substituents selected from a
fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl,
methoxy and ethoxy, and R.sup.2 is pyridyl or tetrahydropyranyl.
(51) The method of (49), wherein R.sup.1 is pyridyl or pyrimidinyl,
each of which is optionally substituted by 1 to 3 substituents
selected from the group consisting of halogen; lower alkyl
optionally substituted by lower alkoxy or morpholino; lower alkoxy;
lower alkanoyl; and vinyl. (52) The method of any one of (49)-(51),
wherein R.sup.2 is pyridyl. (53) The method of any one of
(49)-(51), wherein R.sup.2 is tetrahydropyranyl. (54) The method of
(49), wherein the thiazole derivative represented by the formula
(I) is a compound represented by any one of the following formulas
(IA)-(IAA).
##STR00035## ##STR00036## ##STR00037## ##STR00038##
##STR00039##
(55) The method of any one of (49)-(54), wherein the Parkinson's
disease is that in an advanced stage. (56) A thiazole derivative
represented by the formula (I)
##STR00040##
wherein R.sup.1 represents aryl, aralkyl, an aromatic heterocyclic
group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof, for use in the treatment and/or prophylaxis of a movement
disorder. (57) The thiazole derivative or a pharmaceutically
acceptable salt thereof of (56), wherein R.sup.1 is phenyl,
pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from a fluorine atom, a chlorine atom, a
bromine atom, methyl, ethyl, methoxy and ethoxy, and R.sup.2 is
pyridyl or tetrahydropyranyl. (58) The thiazole derivative or a
pharmaceutically acceptable salt thereof of (56), wherein R.sup.1
is pyridyl or pyrimidinyl, each of which is optionally substituted
by 1 to 3 substituents selected from the group consisting of
halogen; lower alkyl optionally substituted by lower alkoxy or
morpholino; lower alkoxy; lower alkanoyl; and vinyl. (59) The
thiazole derivative or a pharmaceutically acceptable salt thereof
of any one of (56)-(58), wherein R.sup.2 is pyridyl. (60) The
thiazole derivative or a pharmaceutically acceptable salt thereof
of any one of (56)-(58), wherein R.sup.2 is tetrahydropyranyl. (61)
The thiazole derivative or a pharmaceutically acceptable salt
thereof of (56), wherein the thiazole derivative represented by the
formula (I) is a compound represented by any one of the following
formulas (IA)-(IAA).
##STR00041## ##STR00042## ##STR00043## ##STR00044##
##STR00045##
(62) The thiazole derivative or a pharmaceutically acceptable salt
thereof of any one of (56)-(61), wherein the movement disorder is
extrapyramidal syndrome. (63) The thiazole derivative or a
pharmaceutically acceptable salt thereof of any one of (56)-(61),
wherein the movement disorder is bradykinesia, gait disturbance,
dystonia, dyskinesia or tardive dyskinesia. (64) The thiazole
derivative or a pharmaceutically acceptable salt thereof of any one
of (56)-(61), wherein the movement disorder is a side effect of
L-DOPA and/or dopamine agonist therapy. (65) The thiazole
derivative or a pharmaceutically acceptable salt thereof of (64),
wherein the side effect is a motor complication. (66) The thiazole
derivative or a pharmaceutically acceptable salt thereof of (65),
wherein the motor complication is wearing-off phenomenon. (67) The
thiazole derivative or a pharmaceutically acceptable salt thereof
of (65), wherein the motor complication is on-off fluctuation. (68)
The thiazole derivative or a pharmaceutically acceptable salt
thereof of (65), wherein the motor complication is dyskinesia. (69)
The thiazole derivative or a pharmaceutically acceptable salt
thereof of any one of (56)-(68), wherein the movement disorder is
that developed in an advanced stage of Parkinson's disease. (70) A
compound represented by any one of the following formulas
(IE)-(IAA), or a pharmaceutically acceptable salt thereof.
##STR00046## ##STR00047## ##STR00048## ##STR00049##
##STR00050##
(71) A combination of (a) a thiazole derivative represented by the
formula (I)
##STR00051##
wherein R.sup.1 represents aryl, aralkyl, an aromatic heterocyclic
group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof, and (b) L-DOPA and/or a dopamine agonist, for use in the
treatment and/or prophylaxis of Parkinson's disease. (72) The
combination of (71), wherein the use is for administering (a) and
(b) simultaneously or separately at an interval. (73) The
combination of (71) or (72), wherein R.sup.1 is phenyl, pyridyl,
pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy,
each of which is optionally substituted by 1 to 3 substituents
selected from a fluorine atom, a chlorine atom, a bromine atom,
methyl, ethyl, methoxy and ethoxy, and R.sup.2 is pyridyl or
tetrahydropyranyl. (74) The combination of (71) or (72), wherein
R.sup.1 is pyridyl or pyrimidinyl, each of which is optionally
substituted by 1 to 3 substituents selected from the group
consisting of halogen; lower alkyl optionally substituted by lower
alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl. (75)
The combination of any one of (71)-(74), wherein R.sup.2 is
pyridyl. (76) The combination of any one of (71)-(74), wherein
R.sup.2 is tetrahydropyranyl. (77) The combination of (71) or (72),
wherein the thiazole derivative represented by the formula (I) is a
compound represented by any one of the following formulas
(IA)-(IAA).
##STR00052## ##STR00053## ##STR00054## ##STR00055##
##STR00056##
(78) The combination of any one of (71)-(77), wherein the
Parkinson's disease is that in an advanced stage. (79) Use of a
thiazole derivative represented by the formula (I)
##STR00057##
wherein R.sup.1 represents aryl, aralkyl, an aromatic heterocyclic
group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof, for the manufacture of an agent for the treatment and/or
prophylaxis of a movement disorder. (80) The use of (79), wherein
R.sup.1 is phenyl, pyridyl, pyrimidinyl,
5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which
is optionally substituted by 1 to 3 substituents selected from a
fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl,
methoxy and ethoxy, and R.sup.2 is pyridyl or tetrahydropyranyl.
(81) The use of (79), wherein R.sup.1 is pyridyl or pyrimidinyl,
each of which is optionally substituted by 1 to 3 substituents
selected from the group consisting of halogen; lower alkyl
optionally substituted by lower alkoxy or morpholino; lower alkoxy;
lower alkanoyl; and vinyl. (82) The use of any one of (79)-(81),
wherein R.sup.2 is pyridyl. (83) The use of any one of (79)-(81),
wherein R.sup.2 is tetrahydropyranyl. (84) The use of (79), wherein
the thiazole derivative represented by the formula (I) is a
compound represented by any one of the following formulas
(IA)-(IAA).
##STR00058## ##STR00059## ##STR00060## ##STR00061##
##STR00062##
(85) The use of any one of (79)-(84), wherein the movement disorder
is extrapyramidal syndrome. (86) The use of any one of (79)-(84),
wherein the movement disorder is bradykinesia, gait disturbance,
dystonia, dyskinesia or tardive dyskinesia. (87) The use of any one
of (79)-(84), wherein the movement disorder is a side effect of
L-DOPA and/or dopamine agonist therapy. (88) The use of (87),
wherein the side effect is a motor complication. (89) The use of
(88), wherein the motor complication is wearing-off phenomenon.
(90) The use of (88), wherein the motor complication is on-off
fluctuation. (91) The use of (88), wherein the motor complication
is dyskinesia. (92) The use of any one of (79)-(91), wherein the
movement disorder is that developed in an advanced stage of
Parkinson's disease. (93) Use of (a) a thiazole derivative
represented by the formula (I)
##STR00063##
wherein R.sup.1 represents aryl, aralkyl, an aromatic heterocyclic
group, aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from the group consisting of halogen;
lower alkyl optionally substituted by lower alkoxy or morpholino;
lower alkoxy; lower alkanoyl; and vinyl, and R.sup.2 represents
pyridyl or tetrahydropyranyl, or a pharmaceutically acceptable salt
thereof, and (b) L-DOPA and/or a dopamine agonist for the
manufacture of an agent for the treatment and/or prophylaxis of
Parkinson's disease. (94) The use of (93), wherein the agent for
the treatment and/or prophylaxis of Parkinson's disease is that for
administering (a) and (b) simultaneously or separately at an
interval. (95) The use of (93) or (94), wherein R.sup.1 is phenyl,
pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or
tetrahydropyranyloxy, each of which is optionally substituted by 1
to 3 substituents selected from a fluorine atom, a chlorine atom, a
bromine atom, methyl, ethyl, methoxy and ethoxy, and R.sup.2 is
pyridyl or tetrahydropyranyl. (96) The agent of (93) or (94),
wherein R.sup.1 is pyridyl or pyrimidinyl, each of which is
optionally substituted by 1 to 3 substituents selected from the
group consisting of halogen; lower alkyl optionally substituted by
lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and
vinyl. (97) The use of any one of (93)-(96), wherein R.sup.2 is
pyridyl. (98) The use of any one of (93)-(96), wherein R.sup.2 is
tetrahydropyranyl. (99) The use of (93) or (94), wherein the
thiazole derivative represented by the formula (I) is a compound
represented by any one of the following formulas (IA)-(IAA).
##STR00064## ##STR00065## ##STR00066## ##STR00067##
(100) The use of any one of (93)-(99), wherein the Parkinson's
disease is that in an advanced stage.
Effect of the Invention
[0027] The present invention provides an agent for the treatment
and/or prophylaxis of a movement disorder, comprising a thiazole
derivative or a pharmaceutically acceptable salt thereof as an
active ingredient; a pharmaceutical composition comprising (a) a
thiazole derivative or a pharmaceutically acceptable salt thereof
and (b) L-DOPA and/or a dopamine agonist; an agent for the
treatment and/or prophylaxis of Parkinson's disease comprising (a)
a thiazole derivative or a pharmaceutically acceptable salt thereof
and (b) L-DOPA and/or a dopamine agonist in combination; a kit
comprising (a) a first component comprising a thiazole derivative
or a pharmaceutically acceptable salt thereof and (b) a second
component comprising L-DOPA and/or a dopamine agonist; a thiazole
derivative or a pharmaceutically acceptable salt thereof, which has
a selective adenosine A.sub.2A antagonistic activity and is useful
for the treatment of a movement disorder, and the like.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 shows the effect of compound (IC) on the motor
disability score in the Test Example 3. The vertical axis shows the
motor disability score, and the horizontal axis shows time (min)
after administration. .largecircle. shows a combination of solvent
and L-DOPA, and shows a combination of compound (IC) and
L-DOPA.
[0029] FIG. 2 shows the effect of compound (IC) on the maximum
action (minimum motor disability score) in the Test Example 3. The
vertical axis shows the minimum motor disability score, and the
horizontal axis shows the L-DOPA dasage. .largecircle. shows a
combination of solvent and L-DOPA, and shows a combination of
compound (IC) and L-DOPA.
MODE FOR CARRYING OUT THE INVENTION
[0030] The movement disorder is a neurological condition
characterized by motor control disorder such as paucity or lack of
movement, extrapyramidal syndrome or the like, hypermobilities
(e.g., dystonia, dyskinesia, tardive dyskinesia, tremor, chorea,
ballism, akathisia, athetosis, bradykinesia, gait disturbance,
freezing, rigidity, postural instability, myoclonus, tics or
Tourette syndrome, postural reflex disorder or the like) or the
like.
[0031] The movement disorder in the agent for the treatment and/or
prophylaxis of a movement disorder of the present invention means
the above-mentioned movement disorder, and preferably means, for
example, motor control disorder such as extrapyramidal syndrome or
the like, tremor, chorea, athetosis, bradykinesia, gait
disturbance, dystonia, dyskinesia, tardive dyskinesia, postural
reflex disorder or the like. Therefore, the agent for the treatment
and/or prophylaxis of a movement disorder of the present invention
can treat and/or prevent or reduce or suppress these diseases
and/or symptoms (e.g., motor control disorder such as
extrapyramidal syndrome or the like, tremor, chorea, athetosis,
bradykinesia, gait disturbance, dystonia, dyskinesia, tardive
dyskinesia, postural reflex disorder or the like, preferably, for
example, extrapyramidal syndrome, bradykinesia, gait disturbance,
dystonia, dyskinesia, tardive dyskinesia, postural reflex disorder
or the like, and more preferably, extrapyramidal syndrome,
bradykinesia, gait disturbance, dystonia, dyskinesia, tardive
dyskinesia or the like).
[0032] The movement disorder in the agent for the treatment and/or
prophylaxis of a movement disorder of the present invention also
encompasses side effects of L-DOPA and/or dopamine agonist therapy
(e.g., motor complications such as wearing-off phenomenon, on-off
fluctuation, dyskinesia or the like).
[0033] It is known that although L-DOPA provides robust and rapid
therapeutic benefits in Parkinson's disease, eventually, severe and
uncomfortable adverse reactions including motor complications such
as wearing-off phenomenon, on-off fluctuation, dyskinesia and the
like appear (Marsden et al., "Fluctuat ionsind is ability in
Parkinson's disease: clinical aspects" In: Marsden, C D, Fahn S.,
eds. Movement disorders. New York: Butterworth Scientific, p.
96-122 (1982)). It is also known that an administration of L-DOPA
alone causes side effects such as nausea, vomiting, anorexia and
the like.
[0034] A dopamine agonist can also induce dyskinesia. Use of a
dopamine agonist is often limited due to neuropsychiatric side
effects, particularly, hallucination and psychosis. Although a
dopamine agonist provides advantages when used as the adjunct in
the treatment with L-DOPA, control thereby of motor complication
caused by L-DOPA is extremely difficult or even impossible, as
mentioned above (Olanow, Watts and Kollereds., An Algorithm
(Decision Tree) for the Management of Parkinson's Disease:
Treatment Guidelines, Neurology 56, Suppl. 5 (2001)). Furthermore,
it is reported that excessive daytime sleepiness associated with
Parkinson's disease may be aggravated by L-DOPA and/or a dopamine
agonist (Neurology, vol. 67, p. 853 (2006)).
[0035] The side effects in the L-DOPA and/or dopamine agonist
therapy in the present invention refer to the above-mentioned side
effects that occur in the treatment and/or prophylaxis of
Parkinson's disease and the like using L-DOPA and/or a dopamine
agonist. For example, they include motor complications such as
wearing-off phenomenon, on-off fluctuation, dyskinesia and the
like, nausea, vomiting, anorexia, hallucination and psychological
symptom, excessive daytime sleepiness, preferably, motor
complications such as wearing-off phenomenon, on-off fluctuation,
dyskinesia and the like, and the like. That is, the agent for the
treatment and/or prophylaxis of a movement disorder of the present
invention can reduce or suppress a side effect that appears on
administration of L-DOPA and/or a dopamine agonist, specifically, a
motor complication such as wearing-off phenomenon, on-off
fluctuation, dyskinesia or the like, nausea, vomiting, anorexia,
hallucination and psychological symptom, or excessive daytime
sleepiness, preferably, a motor complication such as wearing-off
phenomenon, on-off fluctuation, dyskinesia or the like, more
preferably, a symptom such as wearing-off phenomenon, dyskinesia or
the like.
[0036] As Parkinson's disease progresses, more dopamine cells die
and the remaining cells cannot store sufficient dopamine to
maintain its benefits in the L-DOPA and/or dopamine agonist
therapy. As a result, the duration of action at each dose decreases
and patients need higher or more frequent doses. After 2-5 years,
as many as 50-75% of the patients experience fluctuations in their
response to L-DOPA, for example, in length of on-time and the like.
Along with the fluctuations, the patients develop wearing-off
phenomenon, on-off fluctuation, dyskinesia (involuntary movement)
or the like which accompany the fluctuations in the duration of
action. Thus, continuation of the L-DOPA and/or dopamine agonist
therapy may be difficult due to the onset of such side effects and
the like. Therefore, the agent for the treatment and/or prophylaxis
of a movement disorder of the present invention can extend the
effective time of the treatment with L-DOPA and/or a dopamine
agonist by reducing or suppressing the above-mentioned side
effects. Particularly, the agent for the treatment and/or
prophylaxis of a movement disorder of the present invention can
effectively suppress the wearing-off phenomenon or the like, which
are problematic in L-DOPA therapy of patients with Parkinson's
disease in an advanced stage.
[0037] L-DOPA used for the above-mentioned L-DOPA and/or dopamine
agonist therapy may contain L-DOPA or a salt, hydrate, prodrug or
the like thereof as an active ingredient, and examples thereof
include preparations containing these as an active ingredient and
the like. Examples of the commercially available product include
Menesit (registered trade mark), EC Doparl (registered trade mark),
Doparl (registered trade mark), Madopar (registered trade mark) and
the like. The dopamine agonist may contain a dopamine agonist or a
salt, hydrate, prodrug or the like thereof as an active ingredient,
and examples thereof include preparations containing pramipexole,
talipexole, ropinirole, cabergoline, pergolide or the like, or a
hydrochloride, mesylate or prodrug thereof or the like as an active
ingredient, and the like. Examples of the commercially available
product include Domin (registered trade mark), Permax (registered
trade mark), Cabaser (registered trade mark) and the like.
[0038] The agent for the treatment and/or prophylaxis of
Parkinson's disease of the present invention characteristically
comprises a thiazole derivative or a pharmaceutically acceptable
salt thereof and L-DOPA and/or a dopamine agonist in combination,
and not only can reduce or suppress each symptom of Parkinson's
disease, but also can delay the onset of the side effect caused by
the administration of the aforementioned L-DOPA and/or a dopamine
agonist (e.g., wearing-off phenomenon, on-off fluctuation,
dyskinesia or the like) or suppress the symptoms.
[0039] In the following, the compound represented by the formula
(I) is referred to as Compound (I). The compounds having other
formula numbers are also referred to in the same manner.
[0040] The definition of each group in the formula (I) is as
follows.
[0041] Examples of the lower alkyl moiety of the lower alkyl, the
lower alkoxy and the lower alkanoyl include straight or branched
alkyl having 1 to 10 carbon atoms, and more specific examples
thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,
octyl, nonyl, decyl and the like.
[0042] Examples of the aralkyl include aralkyl having 7 to 16
carbon atoms, and more specific examples thereof include benzyl,
phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl,
phenylheptyl, phenyloctyl, phenylnonyl, phenyldecyl,
naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl,
naphthylpentyl, naphthylhexyl, anthrylmethyl, anthrylethyl and the
like.
[0043] Examples of the aryl include aryl having 6 to 14 carbon
atoms, and more specific examples thereof include phenyl, naphthyl,
azulenyl, anthryl and the like.
[0044] Examples of the aromatic heterocyclic group include a
5-membered or 6-membered monocyclic aromatic heterocyclic group
containing at least one atom selected from a nitrogen atom, an
oxygen atom and a sulfur atom, a bicyclic or tricyclic fused
aromatic heterocyclic group in which 3 to 8-membered rings are
fused, having at least one atom selected from a nitrogen atom, an
oxygen atom, and a sulfur atom, and the like. More specific
examples thereof include furyl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,
benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl,
indazolyl, benzimidazolyl, benzotriazolyl, oxazolopyrimidinyl,
thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,
imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
furo[2,3-b]pyridyl, 6,7-dihydro-5H-cyclopenta[b]pyridyl,
7,8-dihydro-5H-pyrano[4,3-b]pyridyl,
7,8-dihydro-5H-thiopyrano[4,3-b]pyridyl and the like.
[0045] Examples of the aromatic heterocycle-alkyl include a group
wherein an aromatic heterocyclic group is bonded to alkylene. The
aromatic heterocyclic group include those exemplified in the
above-mentioned aromatic heterocyclic group, and the alkylene
include an alkylene having 1 to 10 carbon atoms, and specific
examples thereof include methylene, ethylene, trimethylene,
propylene, tetramethylene, pentamethylene, hexamethylene,
heptamethylene, octamethylene, nonamethylene, decamethylene and the
like. Specific examples of the aromatic heterocycle-alkyl include
pyrrolylmethyl, pyrrolylethyl, thiazolylmethyl, pyridylmethyl,
pyridylethyl, pyrimidinylmethyl, pyrimidinylethyl, indolylmethyl,
benzimidazolylmethyl and the like.
[0046] Examples of the aliphatic heterocycle-alkyl include a group
wherein the aliphatic heterocyclic group is bonded to alkylene.
Examples of the aliphatic heterocyclic group include a 5-membered
or 6-membered monocyclic aliphatic heterocyclic group containing at
least one atom selected from a nitrogen atom, an oxygen atom and a
sulfur atom, a bicyclic or tricyclic fused aliphatic heterocyclic
group in which 3 to 8-membered rings are fused, having at least one
atom selected from a nitrogen atom, an oxygen atom, and a sulfur
atom, and the like. More specific examples thereof include
aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl,
azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl,
piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl,
tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl,
5,6-dihydro-2H-pyridyl, oxazolidinyl, morpholino, morpholinyl,
thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl, 2H-thioxazolyl,
dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl,
benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl,
benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl,
dihydro-2H-chromanyl, dihydro-1H-chromanyl,
dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl,
tetrahydroquinoxalinyl, tetrahydroquinazolinyl,
dihydrobenzodioxanyl and the like. Examples of the alkylene include
alkylene having 1 to 10 carbon atoms, and specific examples thereof
include methylene, ethylene, trimethylene, propylene,
tetramethylene, pentamethylene, hexamethylene, heptamethylene,
octamethylene, nonamethylene, decamethylene and the like. Specific
examples of the aliphatic heterocycle-alkyl include
5,6-dihydro-2H-pyridylmethyl, 5,6-dihydro-2H-pyridylethyl,
tetrahydro-2H-pyranylmethyl, 5,6-dihydro-2H-pyranylmethyl,
5,6-dihydro-2H-pyranylethyl, morpholinomethyl, morpholinoethyl,
piperazinylmethyl, oxazolidinylmethyl and the like.
[0047] The halogen means each atom of fluorine, chlorine, bromine
and iodine.
[0048] Compound (I) or a pharmaceutically acceptable salt thereof
of the present invention or used in the present invention is
preferably a compound having a potent antagonistic activity against
adenosine A.sub.2A receptors from among various subtypes of
adenosine receptors (e.g., adenosine A.sub.1, A.sub.2A, A.sub.2B
and A.sub.3 receptors).
[0049] Accordingly, Compound (I) or a pharmaceutically acceptable
salt thereof of the present invention or used in the present
invention is preferably a compound having a strong affinity for the
adenosine A.sub.2A receptors. For example, the compound is
preferably one having an inhibitory activity of 50% or more at a
test compound concentration of 3.times.10.sup.-8 mol/L, more
preferably one having an inhibitory activity of 50% or more at a
test compound concentration of 1.times.10.sup.-8 mol/L, still more
preferably one having an inhibitory activity of 50% or more at a
test compound concentration of 3.times.10.sup.-9 mol/L, further
preferably one having an inhibitory activity of 50% or more at a
test compound concentration of 1.times.10.sup.-9 mol/L, in the
adenosine A.sub.2A receptor binding test shown in the
below-mentioned Test Example 1. In addition, the compound is
preferably one having an inhibitory activity of 30 nmol/L or less
in an inhibitory constant (Ki value), more preferably one having an
inhibitory activity of 10 nmol/L or less, still more preferably one
having an inhibitory activity of 3 nmol/L or less, further
preferably one having an inhibitory activity of 1 nmol/L or
less.
[0050] Further, Compound (I) or a pharmaceutically acceptable salt
thereof of the present invention or used in the present invention
is preferably a compound having selective affinity for the
adenosine A.sub.2A receptors from among various subtypes of the
adenosine receptors. For example, a compound having a higher
affinity for the adenosine A.sub.2A receptors than that for the
adenosine A.sub.1 receptors is preferable. Specifically, for
example, the compound is preferably a compound having 5 times or
more affinity, more preferably 10 times or more affinity, further
preferably 50 times or more affinity, even more preferably 100
times or more affinity, most preferably 500 times or more affinity
for the adenosine A.sub.2A receptors than that for the adenosine
A.sub.1 receptors.
[0051] The affinity for adenosine receptors can be determined
according to a conventional method, for example, according to the
method of Test Example 1 to be mentioned below, or the methods
described in, for example, a document [for example, Naunyn
Schmiedebergs Arch Pharmacol., 355(1), p. 59 (1987); Naunyn
Schmiedebergs Arch Pharmacol. 355(2), p. 204 (1987); Br. J.
Pharmacol. 117(8), p. 1645 (1996) and the like].
[0052] More specifically, Compound (I) is preferably a compound
wherein R.sup.1 is phenyl optionally substituted by 1 to 3
substituents selected from halogen, C.sub.1-6 alkyl optionally
substituted by C.sub.1-6 alkoxy or morpholino, C.sub.1-6 alkanoyl,
vinyl and C.sub.1-6 alkoxy; pyridyl optionally substituted by 1 to
3 substituents selected from halogen, C.sub.1-6 alkyl optionally
substituted by C.sub.1-6 alkoxy or morpholino, C.sub.1-6 alkanoyl,
vinyl and C.sub.1-6 alkoxy; pyrimidinyl optionally substituted by 1
to 3 substituents selected from halogen, C.sub.1-6 alkyl optionally
substituted by C.sub.1-6 alkoxy or morpholino, C.sub.1-6 alkanoyl,
vinyl and C.sub.1-6 alkoxy; 5,6-dihydro-2H-pyridylmethyl optionally
substituted by 1 to 3 substituents selected from halogen, C.sub.1-6
alkyl and C.sub.1-6 alkoxy; 2,3,4,5-tetrahydropyranyloxy; pyrrolyl;
indolyl; oxazolopyridyl; quinolyl; 1H-3,4-dihydropyranopyridinyl;
1H-3,4-dihydrothiopyranopyridinyl; cyclopentapyridyl; or
pyridylmethyl,
more preferably a compound wherein R.sup.1 is phenyl optionally
substituted by 1 to 3 substituents selected from a fluorine atom, a
chlorine atom, methyl and methoxy; pyridyl optionally substituted
by 1 to 3 substituents selected from a fluorine atom, a chlorine
atom, methyl and methoxy; pyrimidinyl optionally substituted by 1
to 3 substituents selected from a fluorine atom, a chlorine atom,
methyl and methoxy; 5,6-dihydro-2H-pyridylmethyl optionally
substituted by 1 to 3 substituents selected from a fluorine atom, a
chlorine atom, methyl and methoxy; or 2,3,4,5-tetrahydropyranyloxy,
still more preferably a compound wherein R.sup.1 is pyridyl
substituted by 1 to 3 substituents selected from a chlorine atom,
methyl and methoxy; pyrimidinyl substituted by 1 to 3 substituents
selected from chlorine atom, methyl and methoxy;
5,6-dihydro-2H-pyridylmethyl; or 2,3,4,5-tetrahydropyranyloxy. More
specifically, Compound (I) is preferably, for example, compounds of
the following formulas (IA)-(IAA), and the like.
##STR00068## ##STR00069## ##STR00070## ##STR00071##
[0053] The pharmaceutically acceptable salts of Compound (I)
include, for example, pharmaceutically acceptable acid addition
salts, metal salts, ammonium salts, organic amine addition salts,
amino acid addition salts, and the like. The pharmaceutically
acceptable acid addition salts of Compound (I) include, for
example, inorganic acid salts such as hydrochloride, hydrobromate,
nitrate, sulfate, and phosphate; organic acid salts such as
acetate, oxalate, maleate, fumarate, citrate, benzoate, and methane
sulfonate, and the like. Examples of the pharmaceutically
acceptable metal salts include alkali metal salts such as a sodium
salt, and a potassium salt; alkaline earth metal salts such as a
magnesium salt, and a calcium salt; an aluminum salt; a zinc salt,
and the like. Examples of the pharmaceutically acceptable ammonium
salts include salts of ammonium, tetramethylammonium, and the like.
Examples of the pharmaceutically acceptable organic amine addition
salts include addition salts of morpholine, piperidine, or the
like. Examples of the pharmaceutically acceptable amino acid
addition salts include addition salts of lysine, glycine,
phenylalanine, aspartic acid, glutamic acid, or the like.
[0054] Compound (I) can be produced according to a known method,
for example, the method described in WO 2005/063743 and the
like.
##STR00072##
wherein R.sup.1 and R.sup.2 are as defined above, and X is a
chlorine atom, a bromine atom or the like.
[0055] Specifically, as shown in the above-mentioned formula,
Compound (I) can be produced, for example, by reacting compound
(Ia) described in WO 2005/063743 with preferably 0.5 to 5
equivalents of compound (Ib) in a solvent such as methanol,
dichloromethane, chloroform, toluene, ethyl acetate, acetonitrile,
tetrahydrofuran (THF), N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA), pyridine, water, or a mixed solvent
thereof and the like, preferably in the presence of 1 to 5
equivalents of a condensing agent such as
1,3-dicyclohexanecarbodiimide (DCC),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride
and the like, if necessary, in the presence of preferably 1 to 5
equivalents of 1-hydroxybenzotriazole (HOBt) monohydrate,
4-dimethylaminopyridine (DMAP) and the like, at a temperature
between -20.degree. C. and the boiling point of the solvent used,
for 5 min to 72 hr.
[0056] Alternatively, Compound (I) can also be produced, for
example, by reacting compound (Ia) described in WO 2005/063743 with
preferably 1 to 10 equivalents of compound (Ic) without solvent or
in a solvent such as dichloromethane, chloroform,
1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, THF, DMF,
DMA, pyridine and the like, if necessary, in the presence of
preferably 1 to 10 equivalents of a base such as potassium
carbonate, triethylamine, 4-dimethylaminopyridine (DMAP) and the
like, at a temperature between -20.degree. C. and 150.degree. C.,
for 5 min to 72 hr.
[0057] Compound (I) may exist as stereoisomers such as geometrical
isomers or optical isomers, or tautomers. The thiazole derivative
or a pharmaceutically acceptable salt thereof of the present
invention encompasses all possible isomers including those and
mixtures thereof. All possible isomers including those and mixtures
thereof can be used for an agent for the treatment and/or
prophylaxis of a movement disorder, a pharmaceutical composition,
an agent for the treatment and/or prophylaxis of Parkinson's
disease, a kit, a method for the treatment and/or prophylaxis of a
movement disorder, a method for the treatment and/or prophylaxis of
Parkinson's disease, a combination, use for the manufacture of an
agent for the treatment and/or prophylaxis of a movement disorder
and use for the manufacture of an agent for the treatment and/or
prophylaxis of Parkinson's disease, of the present invention.
[0058] To obtain a salt of Compound (I), when the Compound (I) is
obtained in the form of a salt, it may be purified as it is.
Further, when the compound is obtained in a free form, the compound
may be dissolved or suspended in a suitable solvent, followed by
addition of an acid or a base to form a salt. Then, the resulting
salt may be isolated and purified.
[0059] The Compound (I) or a pharmaceutically acceptable salt
thereof may exist in the form of an adduct with water or various
solvents. Such adduct is also encompassed in the thiazole
derivative or a pharmaceutically acceptable salt thereof of the
present invention, and can be used for an agent for the treatment
and/or prophylaxis of a movement disorder, a pharmaceutical
composition, an agent for the treatment and/or prophylaxis of
Parkinson's disease, a kit, a method for the treatment and/or
prophylaxis of a movement disorder, a method for the treatment
and/or prophylaxis of Parkinson's disease, a combination, use for
the manufacture of an agent for the treatment and/or prophylaxis of
a movement disorder and use for the manufacture of an agent for the
treatment and/or prophylaxis of Parkinson's disease, of the present
invention.
[0060] L-DOPA used for a pharmaceutical composition, an agent for
the treatment and/or prophylaxis of Parkinson's disease, a kit, a
method for the treatment and/or prophylaxis of Parkinson's disease,
a combination and use for the manufacture of an agent for the
treatment and/or prophylaxis of Parkinson's disease, of the present
invention may contain, as an active ingredient, L-DOPA or a salt,
hydrate, prodrug or the like thereof and, for example, a
preparation and the like containing these as active ingredients can
be used. Such L-DOPA can be obtained, for example, as a
commercially available product, or can be produced by a known
method. Specific examples of the commercially available product
include Menesit (registered trade mark), EC Doparl (registered
trade mark), Doparl (registered trade mark), Madopar (registered
trade mark) and the like.
[0061] The dopamine agonist used for a pharmaceutical composition,
an agent for the treatment and/or prophylaxis of Parkinson's
disease, a kit, a method for the treatment and/or prophylaxis of
Parkinson's disease, a combination and use for the manufacture of
an agent for the treatment and/or prophylaxis of Parkinson's
disease, of the present invention may contain, as an active
ingredient, a dopamine agonist or a salt, hydrate, prodrug or the
like thereof and, for example, a preparation and the like
containing these as active ingredients can be used. Specific
examples thereof include pramipexole, talipexole, ropinirole,
cabergoline, pergolide and the like, or a hydrochloride, mesylate,
prodrug thereof and the like, and a preparation and the like
containing these as active ingredients can also be used. Such
dopamine agonist can be obtained, for example, as a commercially
available product, or can be produced by a known method. Specific
examples of the commercially available product include Domin
(registered trade mark), Permax (registered trade mark), Cabaser
(registered trade mark) and the like.
[0062] The pharmaceutical preparation according to an agent for the
treatment and/or prophylaxis of a movement disorder, a method for
the treatment and/or prophylaxis of a movement disorder and use for
the manufacture of an agent for the treatment and/or prophylaxis of
a movement disorder, of the present invention may contain, as the
active ingredient, Compound (I) or a pharmaceutically acceptable
salt thereof either alone or as a mixture with any other
therapeutic active ingredient. Furthermore, these pharmaceutical
preparations are prepared by mixing the active ingredient with one
or more pharmaceutically acceptable carriers (for example,
diluents, solvents, excipients, or the like), and then subjecting
the mixture to any method well-known in the technical field of
pharmaceutics.
[0063] As for the administration route, it is preferable to select
the most effective route of administration for treatment. Examples
of the administration route include oral administration, and
parenteral administration, for example, such as intravenous or
transdermal administration and the like.
[0064] Examples of the dosage form include tablets, injections,
external preparations, and the like.
[0065] Suitable dosage forms for the oral administration, for
example, tablets, can be prepared by using excipients such as
lactose, disintegrators such as starch, lubricants such as
magnesium stearate, or binders such as hydroxypropylcellulose, or
the like.
[0066] Suitable dosage forms for the parenteral administration, for
example, injections, can be prepared by using diluents or solvents
such as a saline solution, a glucose solution, or a mixture of
brine and glucose solution, or the like. A dosage form suitable for
external preparation is not particularly limited and, for example,
ointment, cream, liniment, lotion, cataplasm, plaster, tape and the
like can be included. For example, ointment, cream and the like can
be produced by, for example, dissolving or mixing-dispersing the
active ingredient in a base such as white petrolatum and the
like.
[0067] The dose and administration frequency of Compound (I) or a
pharmaceutically acceptable salt thereof varies depending on the
efficacy, dose and/or administration form, age and body weight of
patients, properties or severity of the symptoms to be treated and
the like. For general oral administration, 0.001-1000 mg,
preferably 0.05-100 mg, is administered to one adult in one to
several portions a day. For parenteral administration such as
intravenous administration and the like, 0.001-1000 mg, preferably
0.01-100 mg, is generally administered to one adult in one to
several portions a day. For transdermal administration, an external
preparation containing 0.001-10% of Compound (I) or a
pharmaceutically acceptable salt thereof is generally applied once
to several times a day. However, these doses and administration
frequencies vary depending on the aforementioned various
conditions.
[0068] The agent for the treatment and/or prophylaxis of a movement
disorder, the method of treating and/or preventing a movement
disorder and the thiazole derivative or a pharmaceutically
acceptable salt thereof for use in the treatment and/or prophylaxis
of a movement disorder of the present invention shows a superior
therapeutic and/or prophylactic, or reducing and/or suppressive
effect on a movement disorder such as extrapyramidal syndrome,
bradykinesia, gait disturbance, dystonia, dyskinesia, tardive
dyskinesia or the like; and a side effect of L-DOPA and/or dopamine
agonist therapy such as wearing-off phenomenon, on-off fluctuation,
dyskinesia or the like. Particularly, it shows a superior
therapeutic and/or prophylactic, or reducing and/or suppressive
effect on the above-mentioned disease developed in Parkinson's
disease in an advanced stage (e.g., a movement disorder such as
extrapyramidal syndrome, bradykinesia, gait disturbance, dystonia,
dyskinesia, tardive dyskinesia or the like; and a side effect of
L-DOPA and/or dopamine agonist therapy such as wearing-off
phenomenon, on-off fluctuation, dyskinesia or the like).
[0069] As mentioned above, Compound (I) or a pharmaceutically
acceptable salt thereof may be used in combination with one or more
other pharmaceutical components.
[0070] Examples of the other pharmaceutical components used in
combination include known drugs useful as therapeutic and/or
prophylactic drug for Parkinson's disease and the like, and the
like, and the like (Iyaku (Medicine and Drug) Journal, vol. 44, p.
91 (2008)). Specifically, for example, COMT inhibitors (e.g.,
entacapone, tolcapone and the like), MAO inhibitors (e.g.,
selegiline, rasagiline and the like) and the like can be
included.
[0071] When Compound (I) or a pharmaceutically acceptable salt
thereof is used in combination with other pharmaceutical
component(s), Compound (I) or a pharmaceutically acceptable salt
thereof, and other pharmaceutical component(s) may be administered
simultaneously or separately at an interval. The doses vary
depending on the administration subject, the administration route,
the disease, and the combinations of pharmaceutical component, and
the like, and should be decided according to the doses used in the
clinic.
[0072] (a) Compound (I) or a pharmaceutically acceptable salt
thereof and (b) L-DOPA and/or a dopamine agonist used for the
pharmaceutical composition, the agent for the treatment and/or
prophylaxis of Parkinson's disease, the kit, the method for the
treatment and/or prophylaxis of Parkinson's disease, the
combination and the use for the manufacture of an agent for the
treatment and/or prophylaxis of Parkinson's disease, of the present
invention may be used or administered as a single preparation
(combination agent) or as a combination of more than one
preparation, provided that these preparations are formulated
together with, for example, a pharmaceutically acceptable carrier
to contain these active ingredients. In particular, a combination
of two or more preparations is preferred. When used or administered
as a combination of more than one preparation, the preparations may
be used or administered simultaneously or separately at an
interval. Preferably, these preparations are used in the form of,
for example, tablets, injections, external preparations or the
like.
[0073] The dose ratio (weight/weight) of (a) Compound (I) or a
pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a
dopamine agonist can be appropriately adjusted according to a
combination of (a) Compound (I) or a pharmaceutically acceptable
salt thereof and (b) L-DOPA and/or a dopamine agonist used,
efficacy of each of (a) Compound (I) or a pharmaceutically
acceptable salt thereof and (b) L-DOPA and/or a dopamine agonist
and the like. Specifically for example, it is 1/100000 ((a)
Compound (I) or a pharmaceutically acceptable salt thereof/(b)
L-DOPA and/or a dopamine agonist)-1000/1, preferably 1/50000-500/1,
more preferably 1/6000-100/1, further more preferably 1/4000-15/1,
still further more preferably 1/1000-10/1, most preferably
1/100-10/1.
[0074] These preparations are prepared by mixing the active
ingredient with one or more pharmaceutically acceptable carriers
(for example, diluents, solvents, excipients, or the like), and
then subjecting the mixture to any method well known in the
technical field of pharmaceutics.
[0075] Suitable dosage forms for the oral administration, for
example, tablets, can be prepared by using excipients such as
lactose, disintegrators such as starch, lubricants such as
magnesium stearate, binders such as hydroxypropylcellulose, or the
like.
[0076] Suitable dosage forms for the parenteral administration, for
example, injections, can be prepared by using diluents or solvents
such as a saline solution, a glucose solution, or a mixture of
brine and glucose solution, or the like. A dosage form suitable for
external preparation is not particularly limited to and, for
example, ointment, cream, liniment, lotion, cataplasm, plaster,
tape and the like can be included. For example, ointment, cream and
the like can be produced by, for example, dissolving or
mixing-dispersing the active ingredient in a base such as white
petrolatum and the like.
[0077] When administered as a combination of more than one
preparation, for example, (a) a first component comprising Compound
(I) or a pharmaceutically acceptable salt thereof, and (b) a second
component comprising L-DOPA and/or a dopamine agonist may be
separately prepared into a kit, and may be administered to the same
subject in the same route or in different routes simultaneously or
separately at an interval, using the kit.
[0078] As the kit, for example, a kit comprising contents and two
or more containers (for example, vials, bags, etc.) whose material,
shape, and so on are not particularly limited as long as the
containers do not cause degeneration of the components which are
the contents due to external temperature or light nor cause elution
of chemical components from the containers during storage, and
having a form which enables the administration of the above first
and second components which are the contents through separate
routes (for example, tubes, etc.) or the same route is used.
Specific examples thereof include tablet kits, injection kits, and
the like.
[0079] When (a) Compound (I) or a pharmaceutically acceptable salt
thereof and (b) L-DOPA and/or a dopamine agonist are used or
administered as a combination of plural preparations for the
above-mentioned objects, the dose and administration frequency vary
depending on the efficacy of each active ingredient, dosage form,
age and body weight of a patient, symptom, and the like. It is
preferable to administer each of (a) Compound (I) or a
pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a
dopamine agonist usually at the following dose per day.
[0080] For oral administration as, for example, tablet, (a)
Compound (I) or a pharmaceutically acceptable salt thereof and (b)
L-DOPA and/or a dopamine agonist are administered at 0.1-1000 mg
and 0.1-10000 mg, preferably 0.1-500 mg and 0.1-5000 mg, more
preferably 0.5-500 mg and 1-3000 mg, still more preferably 0.5-300
mg and 1-2000 mg, respectively, per one adult simultaneously or
separately at an interval in one to several portions a day
usually.
[0081] For parenteral administration as, for example, injection and
the like, (a) Compound (I) or a pharmaceutically acceptable salt
thereof and (b) L-DOPA and/or a dopamine agonist are administered
at 0.1-1000 mg and 0.1-10000 mg, preferably 0.1-500 mg and 0.1-5000
mg, more preferably 0.5-500 mg and 1-3000 mg, still more preferably
0.5-300 mg and 1-2000 mg, respectively, per one adult
simultaneously or separately at an interval in one to several
portions a day usually.
[0082] When (a) Compound (I) or a pharmaceutically acceptable salt
thereof and (b) L-DOPA and/or a dopamine agonist are used or
administered as a single preparation for the above-mentioned
objects, the dose and administration frequency vary depending on
the efficacy of each active ingredient, dosage form, age and body
weight of a patient, symptom, and the like. It is preferable to
prepare one preparation containing each dose in the use or
administration of a combination of the above-mentioned plural
preparations, and use or administer same.
[0083] However, such dose and administration frequency vary
depending on the aforementioned various conditions.
[0084] A pharmaceutical composition, an agent for the treatment
and/or prophylaxis of Parkinson's disease, a kit, a method for the
treatment and/or prophylaxis of Parkinson's disease, and a
combination of the present invention can be used for, for example,
the treatment and/or prophylaxis of Parkinson's disease, more
specifically, for patients, for example, patients with Parkinson's
disease in an advanced stage, patients with Parkinson's disease who
developed symptoms of on-off fluctuation, wearing-off phenomenon,
dyskinesia or the like due to L-DOPA therapy or the like, and the
like, and can effectively treat these diseases.
[0085] Next, the therapeutic effect of Compound (I) or a
pharmaceutically acceptable salt thereof on movement disorders, the
effect of combined administration of (a) Compound (I) or a
pharmaceutically acceptable salt thereof and (b) L-DOPA and/or a
dopamine agonist and the like are specifically explained in the
following Test Examples.
Test Example 1
Adenosine Receptor Binding Action
(1) Adenosine A.sub.2A Receptor Binding Test
[0086] The test can be performed according to, for example, the
method of Varani et al. (British Journal of Pharmacology, 1996,
117, p. 1693).
[0087] Specifically, for example, human recombinant receptors are
expressed in HEK-293 cells. The cell membranes of the
receptor-expressing cells are collected, and a cell membrane
suspension is prepared. After dilution with
tris(hydroxymethyl)-aminomethane hydrochloride (Tris HCl) buffer,
tritium-labeled CGS-21680
(.sup.3H-2-[p-(2-carboxyethyl)phenethylamino]-5'-(N-ethylcarboxamido)aden-
osine: 50 mmol/L) and a test compound solution (dimethyl sulfoxide
solution of the test compound) are added to the cell membrane
suspension for binding to the receptors. After the reaction, the
mixture is subjected to rapid suction filtration using glass-fiber
filter paper, and the radioactivity of the glass-fiber filter paper
is measured. In this way, the inhibitory rate of the test compound
for the human adenosine A.sub.2A receptor binding (.sup.3H-CGS21680
binding) can be determined.
[0088] The test can also be performed according to the method of
Bruns et al. (Molecular Pharmacology, Vol. 29, p. 331, 1986).
[0089] Specifically, for example, rat striatum is suspended in 50
ml of ice-cooled Tris HCl buffer (50 mmol/L, pH 7.7) using a
Polytron homogenizer and the suspension is centrifuged. The
resulting precipitate is resuspended by adding Tris HCl buffer (50
mmol/L) thereto, followed by centrifugation in the same manner. The
resulting final precipitate is suspended in Tris HCl buffer (50
mmol/L) [containing magnesium chloride (10 mmol/L), and adenosine
deaminase (0.02 units/mg tissue)] to prepare the suspension at the
tissue concentration of 5 mg (wet weight)/mL. Tritium-labeled
CGS-21680 (final concentration of 6.0 mmol/L), and the test
compound solution (dimethylsulfoxide solution of test compound
diluted with Tris HCl buffer) are added. The mixture is allowed to
stand at 25.degree. C. for 120 minutes, followed by rapid suction
filtration using glass-fiber filter paper, and then immediately
washed with ice-cooled Tris HCl buffer (50 mmol/L). The glass-fiber
filter paper is then placed in a vial, and MicroScinti (PKI) is
added. Then, the radioactivity is measured with a TopCount
(PerkinElmer), whereby the inhibitory rate for rat adenosine
A.sub.2A receptor binding (.sup.3H-CGS21680 binding) of the test
compound can be determined.
[0090] The inhibitory rate can be calculated by the following
equation.
Inhibitory rate ( % ) = ( 1 - Amount of binding in the presence of
drug - amount of non - specific binding Total amount of binding -
amount of non - specific binding ) .times. 100 ##EQU00001##
[0091] In the equation, the total amount of binding refers to the
bound radioactivity of .sup.3H-CGS21680 in the absence of the test
compound. The amount of non-specific binding refers to the bound
radioactivity of .sup.3H-CGS21680 in the presence of 50 .mu.mol/L
of 5'-N-ethylcarboxamideadenosine (NECA) or 100 .mu.mol/L of
cyclopentyladenosine (CPA). The amount of binding in the presence
of drug refers to the bound radioactivity of .sup.3H-CGS21680 in
the presence of the test compound.
[0092] In the above test, the inhibitory rate for the adenosine
A.sub.2A receptor at different concentrations of the test compound
or a pharmaceutically acceptable salt thereof, and the test
compound concentration at which the test compound inhibits binding
by 50% (IC.sub.50) can be calculated by appropriately adjusting the
concentration of the test compound.
[0093] The inhibition constant (Ki value) of the test compound for
the adenosine A.sub.2A receptor binding can be calculated according
to the following equation.
Ki=IC.sub.50/(1+L/Kd)
[0094] In the equation, L denotes the concentration of the
.sup.3H-CGS21680 used in the test, and Kd is the dissociation
constant of the .sup.3H-CGS21680 used in the test.
[0095] Instead of .sup.3H-CGS21680, .sup.3H-SCH58261
(.sup.3H-5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triaz-
olo[1,5-c]pyrimidine) and the like may be used.
(2) Adenosine A.sub.1 Receptor Binding Test
[0096] The inhibition constant (Ki value) of the test compound for
the adenosine A.sub.1 receptor can be calculated in the same manner
as in (1), using the materials below.
[0097] Specifically, for example, human A.sub.1 receptor-expressing
CHO cell membranes are used, and, as the labeled compound, for
example, tritium-labeled DPCPX (1,3-dipropyl-8-cyclopentylxanthine)
is used. The amount of non-specific binding can be determined by
measuring the .sup.3H-DPCPX bound radioactivity in the presence of,
for example, 100 .mu.mol/L of
R(-)-PIA((-)-N.sup.6-2-phenylisopropyl adenosine). The affinity of
the test compound for the human adenosine A.sub.1 receptors can be
confirmed in this manner.
[0098] Alternatively, for example, rat A.sub.1 receptor-expressing
cell membrane (PerkinElmer) is used, and as the labeled compound,
for example, tritium-labeled CHA (N.sup.6-cyclohexyladenosine) is
used. For the measurement of the amount of non-specific binding,
.sup.3H-CHA bound radioactivity is measured in the presence of, for
example, 10 .mu.mol/L of DPCPX, and the affinity of the test
compound for the rat adenosine A.sub.1 receptor can be
confirmed.
[0099] By the foregoing tests (1) and (2), the selective affinities
of the thiazole derivative or a pharmaceutically acceptable salt
thereof used in the present invention for the adenosine A.sub.2A
receptor can be confirmed.
(3) Affinity of Compound (I) or a Pharmaceutically Acceptable Salt
Thereof for Adenosine Receptors
[0100] Some of the examples of the affinities of Compound (I) or a
pharmaceutically acceptable salt thereof for the adenosine A.sub.1
receptor and the adenosine A.sub.2A receptor are presented below.
Note that the test results below are those measured by MDS Pharma
Services Inc. according to the foregoing methods.
TABLE-US-00001 TABLE 1 The affinities for adenosine receptors
Inhibitory rate for Inhibitory rate for human adenosine A.sub.2A
human adenosine A.sub.1 compound receptor binding (.sup.3H-
receptor binding (.sup.3H- No. CGS21680 binding)* DPCPX binding)*
(IA) 92% 14% (IB) 98% 4% (IC) 88% 29% (ID) 100% 28% *Inhibitory
rate at compound of 100 nmol/L
Test Example 2
Adenosine Receptor Binding Activity (2)
[0101] In the same manner as in the above-mentioned Test Example 1,
the affinity of compound (IE)-(IAA) for adenosine receptor was
confirmed (test results were those measured by Ricerca Biosciences,
LLC according to the foregoing methods).
TABLE-US-00002 TABLE 2 The affinities for adenosine receptors
Inhibitory rate for Inhibitory rate for Inhibitory rate for
Inhibitory rate for human adenosine human adenosine human adenosine
human adenosine A.sub.2A receptor binding A.sub.1 receptor A.sub.2A
receptor binding A.sub.1 receptor compound (.sup.3H-CGS21680
binding (.sup.3H-DPCPX compound (.sup.3H-CGS21680 binding
(.sup.3H-DPCPX No. binding)* binding)* No. binding)* binding)* (IE)
93% 33% (IF) 107% 50% (IG) 102% 91% (IH) 98% 67% (II) 85% 19% (IJ)
93% 21% (IK) 92% 24% (IL) 85% 20% (IM) 98% 47% (IN) 93% 21% (IO)
97% 56% (IP) 98% 18% (IQ) 100% 18% (IR) 107% 30% (IS) 90% 10% (IT)
91% 37% (IU) 110% 36% (IV) 98% 23% (IW) 98% 23% (IX) 101% 18% (IY)
97% 8% (IZ) 102% 21% (IAA) 98% 9% *Inhibitory rate at compound of
100 nmol/L
[0102] From the above tests, it is comfirmed that Compound (I)
shows selective affinity for the adenosine A.sub.2A receptor.
Test Example 3
[0103] Therapeutic Effect of Combination of L-DOPA and the Thiazole
Derivative of the Present Invention or a Pharmaceutically
Acceptable Salt Thereof on Common Marmoset that Developed
Parkinson's Disease Symptom by Treatment with
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
[0104] Parkinson's disease is a disease based on the progressive
degeneration and loss of dopaminergic neuron in substantia
nigra-striatum. In primates, a treatment with MPTP, which is a
dopamine neurotoxin, causes selective degeneration and loss of
dopaminergic neuron in substantia nigra-striatum and induces
symptoms of akinesia, muscle rigidity and the like. The primates
treated with MPTP are known as the model of Parkinson's disease
[Proceedings of the National Academy of Science USA, vol. 80, p.
4546 (1983)]. In addition, common marmoset belongs to Haplorhini
and is known to show the symptoms of Parkinson's disease by MPTP,
like other Haplorhini [Neuroscience Letter, vol. 57, p. 37 (1985)].
2 mg/kg of MPTP (Sigma-Aldrich Co. Ltd.) was subcutaneously
administered to the back of common marmoset (CLEA Japan, Inc.) once
a day for 5 days, and 1-2 mg/kg of MPTP was additionally
administered subcutaneously once or twice to the back about 3 weeks
after first administration to prepare common marmoset exhibited
chronic parkinsonian symptoms (lower locomotor activity,
bradykinesia, gait disturbance, abnormal postures, aless
coordinated movements, decreased vocalization and the like)
(MPTP-treated marmoset), and the marmoset was used for the test.
The parkinsonian symptoms were judged using the index described in
a previous report [Annales of Neurology, vol. 43, p. 507 (1998)].
The observation items and scores are shown in Table 2. All
compounds were used as a suspension in 0.5% MC400, 10% aqueous
sucrose solution. The subject animal was placed in an observation
cage (with locomotor activity measuring apparatus) one day before
the test compound administration for preconditioning to the
environment. The symptoms of Parkinson's disease were continuously
monitored through one-way mirror and disability score was scored
each 10 min for 6 hr.
TABLE-US-00003 TABLE 3 Disability Rating Scale Used in Common
Marmoset score Items 0 1 2 3 4 Alertness Normal Reduced Sleepy --
-- Checking Present Reduced Absent -- -- Movement Attention Normal
Abnormal -- -- -- Blinking Posture Normal abnormality of trunk,
upper Grossly limb, lower limb, tail: each 1 Abnormal point
Balance/ Normal Impaired Unstable Falls -- Coordination Reaction to
Normal Reduced Slow Absent -- stimuli Vocalization Normal Reduced
Absent -- --
[0105] The locomotor activity was automatically measured using a
computer by a measuring apparatus with a photocell. When 2.5, 5.0,
7.5 and 10.0 mg/kg of L-DOPA (each containing 1/4 amount of dopa
decarboxylase inhibitor (benserazide hydrochloride)) were each
administered, the parkinsonian symptoms in MPTP-treated marmoset
decreased within increasement of the dosage. 1 mg/kg of compound
(IC) and L-DOPA were simultaneously administered orally.
Co-administration of compound (IC) (1 mg/kg) with the various doses
of L-DOPA(2.5, 5.0, 7.5 and 10.0 mg/kg: each containing 1/4 amount
of benserazide hydrochloride) prolonged the anti-parkinsonian
activity of L-DOPA, and slso enhanced maximum effects of L-DOPA
alone. The time course of influence on motor disability score when
1 mg/kg of compound (IC) and 10 mg/kg of L-DOPA were simultaneously
administered orally in combination is shown in FIG. 1. When 1 mg/kg
of compound (IC) and 10 mg/kg of L-DOPA were simultaneously
administered orally in combination, the action expression time
(on-time) increased as compared to the treatment with 10 mg/kg of
L-DOPA alone. In addition, the maximum improvement values of motor
disability score when 1 mg/kg of compound (IC) and each dose of
L-DOPA (2.5, 5.0, 7.5 and 10.0 mg/kg: each containing 1/4 amount of
benserazide hydrochloride) were simultaneously administered orally
in combination, and when treated with L-DOPA alone are shown in
FIG. 2. When 1 mg/kg of compound (IC) and each dose of L-DOPA were
simultaneously administered orally in combination, the intensity of
the maximum improving maximum effects by each dose of L-DOPA was
enhanced.
[0106] From the above-mentioned test, Compound (I) is considered to
have effects of enhancing the therapeutic effect of L-DOPA on
Parkinson's disease and prolonging the duration of therapeutic
effect of L-DOPA on Parkinson's disease.
Test Example 4
[0107] Therapeutic Effect of Combination of L-DOPA and the Thiazole
Derivative or a Pharmaceutically Acceptable Salt Thereof of the
Present Invention in MPTP-Treated Common Marmoset that Developed
Motor Complication
[0108] 10 mg/kg of L-DOPA (containing 2.5 mg/kg of benserazide
hydrochloride) was administered by gavage to common marmoset that
developed chronic parkinsonian symptoms by treatment with MPTP by
the method described in Test Example 3 (MPTP-treated marmoset)
twice a day at about 6 hr intervals. L-DOPA was repeatedly
administered for more than 3 weeks to induction of motor
complication (dyskinesia symptom, wearing-off phenomenon, on-off
fluctuation and the like) in MPTP-treated marmoset in addition to
parkinsonian symptoms, and the marmoset was used for the test. The
parkinsonian symptoms were judged using rating scale described in a
previous report [Annales of Neurology, vol. 43, p. 507 (1998)] as
in Test Example 2. The locomotor activity was automatically
measured using a computer by a measuring apparatus with a
photocell. All compounds were used as a suspension in 0.5% MC400,
10% aqueous sucrose solution. The subject animal was placed in an
observation cage (with locomotor activity measuring apparatus) one
day before the test compound administration for preconditioning to
the environment. The symptoms of Parkinson's disease were
continuously monitored through one-way mirror and disability score
was scored each 10 min for 6 hr. When 2.5 mg/kg or 10 mg/kg of
L-DOPA (containing 2.5 or 0.625 mg/kg of benserazide hydrochloride)
was administered, the parkinsonian symptoms in MPTP-treated
marmoset decreased with the increasement of dosage. 1 mg/kg of
compound (IC) and 2.5 mg/kg of L-DOPA were simultaneously
administered in combination by gavage. As a result, extension of
duration (on-time) of an anti-parkinsonian activities of L-DOPA
(about 50 min by treatment with L-DOPA 2.5 mg/kg alone, about 150
min by combined administration of 1 mg/kg of compound (IC)), and
enhanced the potency (minimum disability score 5.33.+-.0.80 by
treatment with L-DOPA 2.5 mg/kg alone, 3.83.+-.0.17 by combined
administration of 1 mg/kg of compound (IC)) were observed.
[0109] From the results of the above-mentioned Test Example 4,
Compound (I) is considered to have an effect of suppressing
wearing-off phenomenon, which is the side effect of L-DOPA.
Test Example 5
[0110] Influence of Combination of L-DOPA and the Thiazole
Derivative or a Pharmaceutically Acceptable Salt Thereof of the
Present Invention on Dyskinesia in MPTP-Treated Common Marmoset
that Developed Motor Complication
[0111] 10 mg/kg of L-DOPA (containing 2.5 mg/kg of benserazide
hydrochloride) was administered to common marmoset that developed
chronic parkinsonian symptoms by treatment with MPTP by the method
described in Test Example 3 (MPTP-treated marmoset) twice a day at
about 6 hr intervals. L-DOPA was repeatedly administered for more
than 3 weeks to induction of motor complication (dyskinesia
symptom, wearing-off phenomenon, on-off fluctuation and the like)
in MPTP-treated marmoset in addition to parkinsonian symptoms, and
the marmoset was used for the test. The dyskinesia severity was
rating using the rating scale described in a previous report
[Annales of Neurology, vol. 43, p. 507 (1998)] as in Test Example
2. The evaluation items and scores are shown in Table 3. All
compounds were used as a suspension of 0.5% MC400, 10% aqueous
sucrose solution. The subject animal was placed in an observation
cage (with locomotor activity measuring apparatus) one day before
the test compound administration for preconditioning to the
environment. The dyskinesia symptoms were observed through one-way
mirror and scored each 20 min for 6 hr.
TABLE-US-00004 TABLE 4 Dyskinesia Rating Scale Used in Common
Marmoset evaluation item score Dyskinesia absent 0 Fleeting and
rare dyskinetic postures mild 1 More prominent abnormal movements,
but not moderate 2 interfering significantly with normal behavior
Continuous appearance of abnormal behavior to marked 3 influence
normal movement Mostly occupied by abnormal behavior, and no severe
4 normal animal movement
[0112] The locomotor activity was automatically measured using a
computer by a measuring apparatus with a photocell. When 1.25, 2.5,
5.0, 7.5 and 10 mg/kg of L-DOPA (each containing 0.3125, 0.625,
1.25, 1.875 and 2.5 mg/kg of benserazide hydrochloride,
respectively) were each administered, dyskinesia was induced in
MPTP-treated marmoset with increasing dose of L-DOPA. A combination
of 1 mg/kg of compound (IC) and L-DOPA was simultaneously
administered orally. Combined administration of 1 mg/kg of compound
(IC) with the each doses of L-DOPA (1.25, 2.5, 5.0, 7.5 and 10.0
mg/kg: each containing 1/4 amount of benserazide hydrochloride) did
not exacerbate dyskinesia severity problematic for administration
of each dose of L-DOPA alone. When compound (IC) alone was
administered from 0.1 to 10 mg/kg, dyskinesia was not induced.
[0113] From the above-mentioned test, it was considered that
Compound (I) does not exacerbate dyskinesia which is a side effect
of L-DOPA. From the results of Test Examples 3-5, it was considered
that a combined use of L-DOPA and a thiazole derivative such as
Compound (I) and the like does not exacerbate dyskinesia which is a
side effect of L-DOPA, but enhance a therapeutic effect of L-DOPA
on Parkinson's disease (enhancement and prolongation of effect of
L-DOPA).
[0114] From the aforementioned Test Examples 3-5, administration of
Compound (I) or a pharmaceutically acceptable salt thereof is
considered to suppress or reduce side effects (e.g., wearing-off
phenomenon, on-off fluctuation, dyskinesia or the like) of L-DOPA
and/or dopamine agonist therapy for Parkinson's disease or the
like. Particularly, Compound (I) or a pharmaceutically acceptable
salt thereof is considered to be effective for the reducing
wearing-off phenomenon in L-DOPA and/or dopamine agonist
therapy.
[0115] Moreover, a combined use of Compound (I) or a
pharmaceutically acceptable salt thereof and L-DOPA is considered
to effectively treat parkinsonian symptoms (movement disorders
relating to bradykinesia, gait, akinesia, or the like). Moreover,
when Compound (I) or a pharmaceutically acceptable salt thereof is
used in combination with L-DOPA, an improving effect on
parkinsonian symptoms and locomotor activity becomes stronger than
that by the use of L-DOPA alone. Thus, a combined use of Compound
(I) or a pharmaceutically acceptable salt thereof and L-DOPA can
reduce the dose of L-DOPA necessary for achieving the same
improvement level as a treatment with L-DOPA alone, and can
suppress or delay expression of side effects in the circulatory and
gastrointestinal systems, as well as the onset of dyskinesia and
motor complication due to L-DOPA.
[0116] The following more specifically describes the present
invention by way of Examples. It should be noted, however, that the
scope of the present invention is not limited by the following
Examples.
Example 1
[0117] Tablets having the following formulations are prepared
according to the conventional manner. Compound (IA) (40 g), lactose
(286.8 g), and potato starch (60 g) are mixed, and then a 10%
aqueous solution of hydroxypropylcellulose (120 g) is added
thereto. The resulting mixture is kneaded according to the
conventional manner, granulated, and dried to form granules for
tableting. After adding thereto 1.2 g of magnesium stearate
followed by mixing, the mixture is punched with a tableting machine
having a punch measuring 8 mm in diameter (Model RT-15; Kikusui) to
obtain tablets (containing 20 mg of an active ingredient per
tablet).
TABLE-US-00005 TABLE 5 Formulation Compound (IA) 20 mg lactose
143.4 mg potato starch 30 mg hydroxypropylcellulose 6 mg magnesium
stearate 0.6 mg 200 mg
Example 2
[0118] Tablets having the following formulation are prepared in the
same manner as in Example 1.
TABLE-US-00006 TABLE 6 Formulation Compound (IB) 20 mg lactose
143.4 mg potato starch 30 mg hydroxypropylcellulose 6 mg magnesium
stearate 0.6 mg 200 mg
Example 3
[0119] Tablets having the following formulation are prepared in the
same manner as in Example 1.
TABLE-US-00007 TABLE 7 Formulation Compound (IC) 20 mg lactose
143.4 mg potato starch 30 mg hydroxypropylcellulose 6 mg magnesium
stearate 0.6 mg 200 mg
Example 4
[0120] Tablets having the following formulation are prepared
according to the conventional manner. Compound (IA) (40 g), L-DOPA
(40 g), lactose (246.8 g), and potato starch (60 g) are mixed, and
then a 10% aqueous solution of hydroxypropylcellulose (120 g) is
added thereto. The resulting mixture is kneaded according to the
conventional manner, granulated, and dried to form granules for
tableting. After adding thereto 1.2 g of magnesium stearate
followed by mixing, the mixture is punched with a tableting machine
having a punch measuring 8 mm in diameter (Model RT-15; Kikusui) to
obtain tablets (containing compound (IA) (20 mg) and L-DOPA (20 mg)
per tablet).
TABLE-US-00008 TABLE 8 Formulation Compound (IA) 20 mg L-DOPA 20 mg
lactose 123.4 mg potato starch 30 mg hydroxypropylcellulose 6 mg
magnesium stearate 0.6 mg 200 mg
Example 5
[0121] Tablets having the following formulation are prepared in the
same manner as in Example 4.
TABLE-US-00009 TABLE 9 Formulation Compound (IB) 20 mg L-DOPA 20 mg
lactose 123.4 mg potato starch 30 mg hydroxypropylcellulose 6 mg
magnesium stearate 0.6 mg 200 mg
Example 6
[0122] Tablets having the following formulation are prepared in the
same manner as in Example 4.
TABLE-US-00010 TABLE 10 Formulation Compound (IC) 20 mg L-DOPA 20
mg lactose 123.4 mg potato starch 30 mg hydroxypropylcellulose 6 mg
magnesium stearate 0.6 mg 200 mg
Example 7
[0123] Injections having the following formulation are prepared
according to the conventional manner. Compound (IA) (1 g) is added
to distilled water for injection followed by mixing. After
adjusting the pH of the mixture to 7 by adding hydrochloric acid
and a sodium hydroxide aqueous solution thereto, the total volume
is adjusted to 1,000 mL with distilled water for injection. The
resulting mixture is aseptically charged into glass vials in 2-mL
portions to obtain injections (containing 2 mg of an active
ingredient per vial).
TABLE-US-00011 TABLE 11 Formulation Compound (IA) .sup. 2 mg
hydrochloric acid Appropriate amount aqueous sodium hydroxide
solution Appropriate amount distilled water for injection
Appropriate amount 2.00 mL
Example 8
[0124] Injections having the following formulation are prepared in
the same manner as in Example 7.
TABLE-US-00012 TABLE 12 Formulation Compound (IB) .sup. 2 mg
hydrochloric acid Appropriate amount aqueous sodium hydroxide
solution Appropriate amount distilled water for injection
Appropriate amount 2.00 mL
Example 9
[0125] Injections having the following formulation are prepared in
the same manner as in Example 7.
TABLE-US-00013 TABLE 13 Formulation L-DOPA .sup. 2 mg hydrochloric
acid Appropriate amount aqueous sodium hydroxide solution
Appropriate amount distilled water for injection Appropriate amount
2.00 mL
Example 10
[0126] Injections having the following formulation are prepared
according to the conventional manner. Compound IA (1 g) and L-DOPA
(1 g) are added to distilled water for injection followed by
mixing. After adjusting the pH of the mixture to 7 by adding
hydrochloric acid and a sodium hydroxide aqueous solution thereto,
the total volume is adjusted to 1,000 mL with distilled water for
injection. The resulting mixture is aseptically charged into glass
vials in 2-mL portions to obtain injections (containing compound
(IA) (2 mg) and L-DOPA (2 mg) per vial).
TABLE-US-00014 TABLE 14 Formulation Compound (IA) 2 mg L-DOPA 2 mg
hydrochloric acid Appropriate amount aqueous sodium hydroxide
solution Appropriate amount distilled water for injection
Appropriate amount 2.00 mL .sup.
Example 11
[0127] Injections having the following formulation are prepared in
the same manner as in Example 10.
TABLE-US-00015 TABLE 15 Formulation Compound (IC) 2 mg L-DOPA 2 mg
hydrochloric acid Appropriate amount aqueous sodium hydroxide
solution Appropriate amount distilled water for injection
Appropriate amount 2.00 mL .sup.
Example 12
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl)-6-vinylpyridine-
-3-carboxamide (Compound IE)
[0128] step 1 Methyl 6-chloronicotinate (1.51 g, 8.79 mmol) was
dissolved in DMF (35 mL), vinyltributyltin (3.32 mL, 11.4 mmol),
dichlorobis(tri-o-tolylphosphine)palladium (206 mg, 0.262 mmol) and
lithium chloride (554 mg, 13.1 mmol) were added and the mixture was
stirred at 100.degree. C. for 2 hr. The mixture was allowed to cool
to room temperature, and an aqueous potassium fluoride solution was
added thereto. The mixture was filtered through celite and the
residue was washed with ethyl acetate. To the obtained filtrate was
added a saturated aqueous sodium hydrogen carbonate solution, and
the mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=70:30) to give methyl 6-vinylnicotinate (1.22
g, 85%) as a colorless transparent oil.
[0129] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 3.95 (s, 3H), 5.63
(dd, J=1.1, 10.8 Hz, 1H), 6.35 (dd, J=1.1, 17.4 Hz, 1H), 6.87 (dd,
J=10.8, 17.4 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 8.25 (dd, J=2.1, 8.2
Hz, 1H), 9.15-9.18 (m, 1H).
[0130] step 2 Methyl 6-vinylnicotinate (491 mg, 2.97 mmol) obtained
above was dissolved in a 50% methanol aqueous solution (8 mL).
Lithium hydroxide monohydrate (276 mg, 6.57 mmol) was added thereto
and the mixture was stirred at room temperature for 1 hr. The
mixture was cooled to 0.degree. C., then 3 mol/L hydrochloric acid
(3 mL) was added, and the precipitated solid was collected by
filtration to give 6-vinylnicotinic acid (309 mg, 70%) as a white
solid.
[0131] .sup.1H NMR (DMSO-d.sub.6, .delta.ppm): 5.61 (dd, J=1.5,
10.8 Hz, 1H), 6.37 (dd, J=1.5, 17.4 Hz, 1H), 6.89 (dd, J=10.8, 17.4
Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 8.22 (dd, J=2.2, 8.2 Hz, 1H), 9.01
(d, J=2.2 Hz, 1H), 13.35 (brs, 1H).
[0132] step 3
2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (301
mg, 1.08 mmol) described in WO2005/063743 was dissolved in DMF (1.5
mL), EDC hydrochloride (412 mg, 2.15 mmol), DMAP (66 mg, 0.54 mmol)
and 6-vinylnicotinic acid (306 mg, 1.65 mmol) were added thereto,
and the mixture was stirred at 50.degree. C. for 5 hr. The mixture
was allowed to cool to room temperature, water and a saturated
aqueous sodium hydrogen carbonate solution were added thereto and
the mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=50:50), and recrystallized from ethanol-water
to give Compound IE (1.22 g, 85%) as white crystals.
[0133] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
3.11-3.25 (m, 1H), 3.51 (ddd, J=3.1, 11.4, 11.4 Hz, 2H), 4.02-4.11
(m, 2H), 5.71 (dd, J=0.8, 10.7 Hz, 1H), 6.43 (dd, J=0.8, 17.5 Hz,
1H), 6.57 (dd, J=1.7, 3.8 Hz, 1H), 6.90 (dd, J=10.7, 17.5 Hz, 1H),
7.51 (d, J=8.2 Hz, 1H), 7.58 (dd, J=0.5, 1.7 Hz, 1H), 7.84 (d,
J=3.8 Hz, 1H), 8.21 (dd, J=2.4, 8.2 Hz, 1H), 9.13 (d, J=2.4 Hz,
1H), 9.84 (brs, 1H). ESIMS m/z: [M+H].sup.+ 410.
Example 13
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(pyridin-3-yl-
)acetamide (Compound IF)
[0134] 2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone
(105 mg, 0.377 mmol) described in WO2005/063743 was dissolved in
DMF (2.0 mL), EDC hydrochloride (421 mg, 2.20 mmol), HOBt
monohydrate (340 mg, 2.21 mmol) and 3-pyridylacetic acid
hydrochloride (370 mg, 2.14 mmol) were added thereto, and the
mixture was stirred at 80.degree. C. overnight. The mixture was
allowed to cool to room temperature, and water and a saturated
aqueous sodium hydrogen carbonate solution were added thereto. The
precipitated solid was collected by filtration, and dried under
reduced pressure. The obtained solid was purified by silica gel
column chromatography (hexane:ethyl acetate=50:50), and
recrystallized from ethanol-water to give Compound IF (112 mg, 75%)
as white crystals.
[0135] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
3.05-3.16 (m, 1H), 3.45 (ddd, J=2.8, 11.4, 11.4 Hz, 2H), 3.81 (s,
2H), 3.97-4.06 (m, 2H), 6.54 (dd, J=1.8, 3.6 Hz, 1H), 7.32 (dd,
J=7.8, 4.8 Hz, 1H), 7.52-7.54 (m, 1H), 7.62-7.68 (m, 2H), 8.55-8.64
(m, 2H), 9.21 (s, 1H). APCIMS m/z: [M+H].sup.+ 398.
Example 14
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-1H-pyrrole-2-ca-
rboxamide (Compound IG)
[0136] In the same manner as in Example 13, Compound IG (86.0 mg,
65%) was obtained as pale-brown crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (100
mg, 0.360 mmol) described in WO2005/063743 and pyrrole-2-carboxylic
acid (240 mg, 2.18 mmol).
[0137] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
3.08-3.24 (m, 1H), 3.47 (ddd, J=2.7, 11.5, 11.5 Hz, 2H), 4.00-4.09
(m, 2H), 6.34-6.36 (m, 1H), 6.56 (dd, J=1.8, 3.6 Hz, 1H), 6.86-6.88
(m, 1H), 7.06-7.10 (m, 1H), 7.55-7.57 (m, 1H), 7.71 (dd, J=0.7, 3.7
Hz, 1H), 9.49 (brs, 1H), 9.65 (brs, 1H). APCIMS m/z: [M+H].sup.+
372.
Example 15
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-1H-indole-4-car-
boxamide (Compound IH)
[0138] In the same manner as in Example 13, Compound IH (97.6 mg,
63%) was obtained as milky white crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (102
mg, 0.367 mmol) described in WO2005/063743 and indole-4-carboxylic
acid (331 mg, 2.05 mmol).
[0139] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
3.17-3.28 (m, 1H), 3.50 (ddd, J=3.0, 11.2, 11.2 Hz, 2H), 4.02-4.11
(m, 2H), 6.58 (dd, J=1.7, 3.5 Hz, 1H), 7.23-7.36 (m, 2H), 7.43-7.48
(m, 1H), 7.58-7.60 (m, 1H), 7.67 (dd, J=4.2, 7.7 Hz, 2H), 7.76 (dd,
J=0.7, 3.5 Hz, 1H), 8.46 (brs, 1H), 9.70 (brs, 1H). APCIMS m/z:
[M+H].sup.+ 422.
Example 16
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(morpholin-4--
ylmethyl)pyridine-4-carboxamide (Compound II)
[0140] step 1
2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (2.00
g, 7.19 mmol)described in WO2005/063743 was dissolved in DMF (35
mL), EDC hydrochloride (5.50 g, 28.6 mmol), HOBt monohydrate (4.40
g, 28.8 mmol) and 2-(chloromethyl)isonicotinic acid (4.93 g, 28.7
mmol) obtained by the method described in WO03/043636 were added
thereto, and the mixture was stirred at 80.degree. C. overnight.
The mixture was allowed to cool to room temperature, and water and
a saturated aqueous sodium hydrogen carbonate solution were added
thereto. The precipitated solid was collected by filtration, and
dried under reduced pressure. The obtained solid was purified by
silica gel column chromatography (hexane:ethyl acetate=50:50) to
give
2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-y-
l]pyridine-4-carboxamide (700 mg, 23%) as a pale-brown solid.
[0141] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.84-1.97 (m, 4H),
3.12-3.23 (m, 1H), 3.46-3.57 (m, 2H), 4.02-4.11 (m, 2H), 4.75 (s,
2H), 6.52 (dd, J=3.6, 1.7 Hz, 1H), 7.50 (dd, J=1.7, 0.7 Hz, 1H),
7.70 (dd, J=5.1, 1.7 Hz, 1H), 7.79 (dd, J=3.6, 0.7 Hz, 1H),
7.92-7.95 (m, 1H), 8.79 (dd, J=5.1, 0.7 Hz, 1H).
[0142] step 2
2-(Chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-y-
l]pyridine-4-carboxamide (70.0 mg, 0.162 mmol) obtained in step 1
was dissolved in acetonitrile (2.0 mL), then morpholine (70.0
.mu.L, 2.15 mmol) was added thereto, and the mixture was stirred
with heating under reflux for 1 hr. The mixture was allowed to cool
to room temperature, water and a saturated aqueous sodium hydrogen
carbonate solution were added thereto. The mixture was extracted
with ethyl acetate, and the organic layer was washed with saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (chloroform:methanol=95:5), and
reslurried with hexane-ethyl acetate to give Compound II (54.6 mg,
71%) as a pale-brown solid.
[0143] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
2.51-2.59 (m, 4H), 3.10-3.24 (m, 1H), 3.51 (ddd, J=3.0, 11.3, 11.3
Hz, 2H), 3.75-3.82 (m, 6H), 4.01-4.13 (m, 2H), 6.59 (dd, J=1.8, 3.6
Hz, 1H), 7.60 (dd, J=0.7, 1.8 Hz, 1H), 7.69 (dd, J=1.8, 5.1 Hz,
1H), 7.84 (dd, J=0.7, 3.6 Hz, 1H), 7.93-7.95 (m, 1H), 8.82 (dd,
J=0.7, 5.1 Hz, 1H). ESIMS m/z: [M+H].sup.+ 483.
Example 17
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-methoxymethyl-
pyridine-4-carboxamide (Compound IJ)
[0144] Under ice-cooling, 60% sodium hydride (10.0 mg, 0.250 mmol)
was dissolved in DMF (1.0 mL), methanol (110 .mu.L, 2.72 mmol) was
slowly added dropwise thereto, and the mixture was stirred at
0.degree. C. for 10 min. Then,
2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-y-
l]pyridine-4-carboxamide (81.0 mg, 0.189 mmol) obtained in step 1
of Example 16, which was dissolved in DMF (1.0 mL), was slowly
added dropwise thereto, and the mixture was stirred at room
temperature for 5 hr. To the mixture were added water and a
saturated aqueous sodium hydrogen carbonate solution, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=50:50), and recrystallized from ethanol-water
to give Compound IJ (45.0 mg, 56%) as white crystals.
[0145] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
3.14-3.23 (m, 1H), 3.52 (ddd, J=3.0, 11.2, 11.2 Hz, 2H), 3.53 (s,
3H), 4.02-4.18 (m, 2H), 4.65 (s, 2H), 6.52 (dd, J=1.8, 3.6 Hz, 1H),
7.50 (d, J=1.1 Hz, 1H), 7.71 (dd, J=1.3, 5.1 Hz, 1H), 7.79 (d,
J=3.6 Hz, 1H), 7.85 (s, 1H), 8.77 (d, J=5.1 Hz, 1H), 10.41 (brs,
1H). APCIMS m/z: [M+H].sup.+ 428.
Example 18
2-Ethoxymethyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]p-
yridine-4-carboxamide (Compound IK)
[0146] In the same manner as in Example 17, Compound IK (47.0 mg,
57%) was obtained as white crystals from
2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-y-
l]pyridine-4-carboxamide (80.0 mg, 0.185 mmol) and ethanol (200
.mu.L, 3.54 mmol).
[0147] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.36 (t, J=7.1 Hz,
3H), 1.80-2.01 (m, 4H), 3.11-3.28 (m, 1H), 3.51 (ddd, J=3.2, 11.4,
11.4 Hz, 2H), 3.72 (q, J=7.1 Hz, 2H), 4.00-4.12 (m, 2H), 4.73 (s,
2H), 6.58 (dd, J=1.7, 3.6 Hz, 1H), 7.58 (dd, J=0.7, 1.7 Hz, 1H),
7.72 (dd, J=1.7, 5.0 Hz, 1H), 7.84 (dd, J=0.7, 3.6 Hz, 1H), 7.92
(dd, J=0.7, 1.7 Hz, 1H), 8.80 (d, J=5.0 Hz, 1H), 9.95 (brs, 1H).
APCIMS m/z: [M+H].sup.+ 442.
Example 19
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-isopropoxymet-
hylpyridine-4-carboxamide (Compound IL)
[0148] In the same manner as in Example 17, Compound IL (30.2 mg,
36%) was obtained as white crystals from
2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-y-
l]pyridine-4-carboxamide (80.1 mg, 0.185 mmol) and 2-propanol (350
.mu.L, 4.60 mmol).
[0149] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.31 (d, J=6.0 Hz,
6H), 1.80-2.01 (m, 4H), 3.15-3.22 (m, 1H), 3.51 (ddd, J=2.8, 11.4,
11.4 Hz, 2H), 3.78-3.86 (qq, J=6.0, 6.0 Hz, 1H), 4.01-4.11 (m, 2H),
4.73 (s, 2H), 6.58 (dd, J=1.8, 3.6 Hz, 1H), 7.59 (dd, J=0.6, 1.8
Hz, 1H), 7.71 (dd, J=1.5, 5.1 Hz, 1H), 7.85 (dd, J=0.4, 3.5 Hz,
1H), 7.93 (d, J=0.6 Hz, 1H), 8.79 (dd, J=0.4, 5.1 Hz, 1H), 9.91
(brs, 1H). APCIMS m/z: [M+H].sup.+ 456.
Example 20
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]furo[2,3-b]pyrid-
ine-5-carboxamide (Compound IM)
[0150] 2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone
(125 mg, 0.450 mmol) described in WO2005/063743 was dissolved in
DMF (2.2 mL), EDC hydrochloride (173 mg, 0.900 mmol), HOBt
monohydrate (138 mg, 0.900 mmol) and
furo[2,3-b]pyridine-5-carboxylic acid (147 mg, 0.900 mmol) obtained
in the method described in Tetrahedron Letters, vol. 35, p. 9355
(1994) were added thereto, and the mixture was stirred at
50.degree. C. for 2 hr, then at 70.degree. C. for 1 hr. To the
mixture were added EDC hydrochloride (173 mg, 0.900 mmol), HOBt
monohydrate (138 mg, 0.900 mmol) and
furo[2,3-b]pyridine-5-carboxylic acid (147 mg, 0.900 mmol), and the
mixture was stirred at 70.degree. C. for 1.5 hr. The mixture was
added to water--a saturated aqueous sodium hydrogen carbonate
solution (1:1) and the precipitated solid was collected by
filtration and dried. The obtained solid was purified by silica gel
column chromatography (hexane:ethyl acetate=50:50), and
recrystallized from ethanol-water to give Compound IM (81.2 mg,
43%).
[0151] .sup.1H NMR (DMSO-d.sub.6, .delta.ppm): 1.56-1.77 (m, 4H),
3.16-3.26 (m, 1H), 3.37-3.47 (m, 2H), 3.87-3.92 (m, 2H), 6.71 (dd,
J=1.9, 3.5 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.45 (dd, J=0.9, 3.5
Hz, 1H), 7.91 (dd, J=0.9, 1.9 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.86
(d, J=2.4 Hz, 1H), 9.04 (d, J=2.4 Hz, 1H). ESIMS m/z: [M+H].sup.+
424.
Example 21
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(pyridin-2-yl-
)acetamide (Compound IN)
[0152] In the same manner as in step 3 of Example 12, Compound IN
(125 mg, 58%) was obtained as white crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (154
mg, 0.553 mmol) described in WO2005/063743 and 2-pyridylacetic acid
hydrochloride (196 mg, 1.13 mmol).
[0153] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.78-1.95 (m, 4H),
3.01-3.21 (m, 1H), 3.47 (ddd, J=2.6, 11.4, 11.4 Hz, 2H), 3.98-4.09
(m, 2H), 4.03 (s, 2H), 6.57 (dd, J=1.8, 3.6 Hz, 1H), 7.25-7.34 (m,
2H), 7.59 (dd, J=0.7, 1.8 Hz, 1H), 7.70 (dd, J=0.7, 3.5 Hz, 1H),
7.74 (ddd, J=1.8, 7.7, 7.7 Hz, 1H), 8.69-8.73 (m, 1H), 12.09 (brs,
1H). APCIMS m/z: [M+H].sup.+ 398.
Example 22
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-methoxypyridi-
ne-3-carboxamide (Compound IO)
[0154] In the same manner as in step 3 of Example 12, Compound IO
(121 mg, 54%) was obtained as white crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (150
mg, 0.539 mmol) described in WO2005/063743 and 6-methoxynicotinic
acid (101 mg, 0.659 mmol).
[0155] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
3.10-3.25 (m, 1H), 3.51 (ddd, J=2.9, 11.4, 11.4 Hz, 2H), 4.02-4.11
(m, 2H), 4.04 (s, 3H), 6.55 (dd, J=1.7, 3.5 Hz, 1H), 6.87 (d, J=8.8
Hz, 1H), 7.53-7.57 (m, 1H), 7.83 (dd, J=0.6, 3.5 Hz, 1H), 8.10 (dd,
J=2.6, 8.8 Hz, 1H), 8.77 (dd, J=0.6, 2.6 Hz, 1H), 9.93 (brs, 1H).
APCIMS m/z: [M+H].sup.+ 414.
Example 23
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]quinoline-3-carb-
oxamide (Compound IP)
[0156] In the same manner as in step 3 of Example 12, Compound IP
(178 mg, 76%) was obtained as pale-yellow crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (151
mg, 0.543 mmol) described in WO2005/063743 and
quinoline-3-carboxylic acid (142 mg, 0.820 mmol).
[0157] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
3.15-3.25 (m, 1H), 3.52 (ddd, J=2.9, 11.4, 11.4 Hz, 2H), 4.06-4.10
(m, 2H), 6.47 (dd, J=1.7, 3.5 Hz, 1H), 7.47 (dd, J=0.7, 1.6 Hz,
1H), 7.66-7.74 (m, 2H), 7.87-7.95 (m, 2H), 8.20 (dd, J=0.9, 8.4 Hz,
1H), 8.71 (d, J=1.8 Hz, 1H), 9.43 (d, J=2.4 Hz, 1H), 10.55 (s, 1H).
APCIMS m/z: [M+H].sup.+ 434.
Example 24
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-5,6-dimethylpyr-
idine-3-carboxamide (Compound IQ)
[0158] step 1 5,6-Dimethylpyridine-3-carbonitrile (502 mg, 3.79
mmol) obtained by the method described in J. Heterocyclic Chem.,
vol. 24, p. 351 (1987) was suspended in 70% aqueous ethanol (4.5
mL), sodium hydroxide (444 mg, 11.1 mmol) was added thereto, and
the mixture was stirred with heating under reflux for 3 hr. The
mixture was ice-cooled to 0.degree. C., and 6 mol/L hydrochloric
acid (1.9 ml) was added thereto. The mixture was concentrated under
reduced pressure and the obtained residue was suspended in
chloroform-methanol. The inorganic salt was removed by filtration,
and the obtained filtrate was concentrated under reduced pressure
to give 5,6-dimethylpyridine-3-carboxylic acid (569 mg, 99%) as a
pale-pink crude solid.
[0159] .sup.1H NMR (DMSO-d.sub.6, .delta.ppm): 2.23 (s, 3H), 2.39
(s, 3H), 7.83 (d, J=1.7 Hz, 1H), 8.64 (d, J=1.7 Hz, 1H).
[0160] step 2 In the same manner as in step 3 of Example 12,
Compound IQ (112 mg, 49%) was obtained as white crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (151
mg, 0.550 mmol) described in WO2005/063743 and
5,6-dimethylpyridine-3-carboxylic acid (166 mg, 1.10 mmol) obtained
above.
[0161] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
2.34 (s, 3H), 2.59 (s, 3H), 3.12-3.23 (m, 1H), 3.51 (ddd, J=2.9,
11.3, 11.3 Hz, 2H), 4.04-4.09 (m, 2H), 6.49 (dd, J=2.0, 3.6 Hz,
1H), 7.47 (d, J=1.7 Hz, 1H), 7.79 (dd, J=0.5, 3.5 Hz, 1H), 7.89 (d,
J=1.7 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H). ESIMS m/z: [M+H].sup.+
412.
Example 25
5-Ethyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-
-3-carboxamide (Compound IR)
[0162] In the same manner as in step 3 of Example 12, Compound IR
(145 mg, 65%) was obtained as white crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (151
mg, 0.543 mmol) described in WO2005/063743 and 5-ethylnicotinic
acid (128 mg, 0.814 mmol).
[0163] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.32 (t, J=7.6 Hz,
3H), 1.83-2.01 (m, 4H), 2.77 (q, J=7.6 Hz, 2H), 3.11-3.26 (m, 1H),
3.51 (ddd, J=2.9, 11.4, 11.4 Hz, 2H), 4.01-4.11 (m, 2H), 6.54 (dd,
J=1.8, 3.6 Hz, 1H), 7.51-7.53 (m, 1H), 7.80 (dd, J=0.7, 3.6 Hz,
1H), 8.03-8.06 (m, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.99 (d, J=2.0 Hz,
1H), 10.24 (brs, 1H). ESIMS m/z: [M+H].sup.+ 412.
Example 26
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-7,8-dihydro-5H--
pyrano[4,3-b]pyridine-3-carboxamide (Compound IS)
[0164] step 1 Sodium hydride (2.06 g, 51.5 mmol) was suspended in
diethyl ether (40 mL), and methanol (2.1 ml, 51.8 mmol) was added
slowly at -5.degree. C. thereto. To the mixture was added ethanol
(6 mL), and the mixture was stirred at room temperature for 5 min,
and cooled to 0.degree. C. A mixture of tetrahydro-4H-pyran-4-one
(4.61 mL, 49.9 mmol) and ethyl formate (4.11 ml, 51.1 mmol) was
slowly added thereto. The mixture was stirred at room temperature
for 2 hr, and the resultant product was extracted with water (30
ml) (aqueous solution A).
[0165] Then, an aqueous piperidine-acettic acid solution prepared
by dissolving acetic acid (1.5 mL) in water (3.5 mL) and adding
piperidine (2.6 mL) thereto, and 2-cyanoacetamide (4.62 g, 54.9
mmol) were added to the above-mentioned aqueous solution A, and the
mixture was stirred with heating under reflux for 4 hr. To the
mixture was added acetic acid (3.6 mL) and, after cooling 0.degree.
C., the precipitated solid was collected by filtration to give
2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-carbonitrile
(1.72 g, 20%) as a white solid.
[0166] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 2.89 (t, J=5.6 Hz,
2H), 3.99 (t, J=5.6 Hz, 2H), 4.54 (s, 2H), 7.59 (s, 1H). APCIMS
m/z: [M-H].sup.- 175.
[0167] step 2
2-Oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-carbonitrile
(2.50 g, 14.4 mmol) obtained in step 1 was dissolved in phosphoryl
chloride (20 mL), and the mixture was stirred with heating under
reflux for 4 hr. The mixture was allowed to cool to room
temperature, and slowly added to a saturated aqueous sodium
hydrogen carbonate solution at 0.degree. C., then the mixture was
extracted with chloroform. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=50:50) to give
2-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.85
g, 66%) as a white solid.
[0168] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 3.07 (t, J=5.8 Hz,
2H), 4.07 (t, J=5.8 Hz, 2H), 4.75-4.76 (m, 2H), 7.63 (s, 1H).
[0169] step 3
2-Chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.77
g, 9.09 mmol) obtained in step 2 was dissolved in ethanol (30 mL),
acetic acid (9 mL) and zinc (2.60 g) were added thereto, and the
mixture was stirred with heating under reflux for 4 hr. The mixture
was allowed to cool to room temperature, then filtered through
celite, and the filtrate was concentrated under reduced pressure.
To the obtained residue was added a saturated aqueous sodium
hydrogen carbonate solution and the mixture was extracted with
chloroform. The organic layer was washed with saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=50:50) to give
7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.06 g, 73%)
as a white solid.
[0170] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 3.10 (t, J=5.8 Hz,
2H), 4.10 (t, J=5.8 Hz, 2H), 4.79 (s, 2H), 7.59 (d, J=1.7 Hz, 1H),
8.71 (d, J=1.7 Hz, 1H). APCIMS m/z: [M+H].sup.+ 161.
[0171] step 4 In the same manner as in step 1 of Example 24,
7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carboxylic acid (318 mg,
47%) was obtained as a white solid from
7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (609 mg, 3.80
mmol) obtained above.
[0172] .sup.1H NMR (DMSO-d.sub.6, .delta.ppm): 2.86 (t, J=5.8 Hz,
2H), 3.95 (t, J=5.8 Hz, 2H), 4.70 (s, 2H), 7.80 (d, J=1.7 Hz, 1H),
8.76 (d, J=1.7 Hz, 1H). ESIMS m/z: [M-H].sup.- 178.
[0173] step 5 In the same manner as in step 3 of Example 12,
Compound IS (178 mg, 74%) was obtained as white crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (152
mg, 0.546 mmol) described in WO2005/063743 and
7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carboxylic acid (432 mg,
2.00 mmol) obtained above.
[0174] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
3.10 (t, J=5.6 Hz, 2H), 3.13-3.24 (m, 1H), 3.51 (ddd, J=2.8, 11.4,
11.4 Hz, 2H), 4.03-4.14 (m, 4H), 4.79 (s, 2H), 6.50 (dd, J=1.7, 3.6
Hz, 1H), 7.46 (dd, J=0.6, 1.7 Hz, 1H), 7.78 (dd, J=0.6, 3.6 Hz,
1H), 7.82 (d, J=2.2 Hz, 1H), 8.94 (d, J=2.2 Hz, 1H), 10.58 (s, 1H).
ESIMS m/z: [M+H].sup.+ 440.
Example 27
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6,7-dihydro-5H--
cyclopenta[b]pyridine-3-carboxamide (Compound IT)
[0175] step 1 6,7-Dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile
(901 mg, 6.25 mmol) obtained by the method described in J.
Heterocyclic Chem., vol. 24, p. 351 (1987) was suspended in 6 mol/L
hydrochloric acid (9 mL), and the mixture was stirred with heating
under reflux for 5 hr. The mixture was ice-cooled to 0.degree. C.,
and the precipitated solid was collected by filtration to give
6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid
hydrochloride (543 mg, 44%) as a pale-brown solid.
[0176] .sup.1H NMR (DMSO-d.sub.6, .delta.ppm): 2.16 (tt, J=7.4, 7.8
Hz, 2H), 3.02 (t, J=7.4 Hz, 2H), 3.10 (t, J=7.8 Hz, 2H), 8.34 (s,
1H), 8.92 (s, 1H).
[0177] step 2 In the same manner as in step 3 of Example 12,
Compound IT (134 mg, 58%) was obtained as white crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (152
mg, 0.546 mmol) described in WO2005/063743 and
6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid
hydrochloride (165 mg, 0.827 mmol) obtained above.
[0178] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.78-2.01 (m, 4H),
2.16-2.28 (m, 2H), 3.01 (t, J=7.6 Hz, 2H), 3.10 (t, J=7.7 Hz, 2H),
3.11-3.25 (m, 1H), 3.51 (ddd, J=3.0, 11.4, 11.4 Hz, 2H), 4.00-4.10
(m, 2H), 6.52 (dd, J=1.8, 3.6 Hz, 1H), 7.51 (dd, J=0.7, 1.7 Hz,
1H), 7.80 (dd, J=0.7, 3.6 Hz, 1H), 7.95-8.00 (m, 1H), 8.87-8.91 (m,
1H), 10.20 (brs, 1H). ESIMS m/z: [M+H].sup.+ 424.
Example 28
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-1H-indole-2-car-
boxamide (Compound IU)
[0179] In the same manner as in Example 13, Compound IU (97.5 mg,
63%) was obtained as pale-brown crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (102
mg, 0.366 mmol) described in WO2005/063743 and indole-2-carboxylic
acid (350 mg, 2.17 mmol).
[0180] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
3.10-3.24 (m, 1H), 3.50 (ddd, J=2.7, 11.5, 11.5 Hz, 2H), 4.01-4.11
(m, 2H), 6.59 (dd, J=1.7, 3.5 Hz, 1H), 7.14 (dd, J=0.9, 2.2 Hz,
1H), 7.19-7.25 (m, 1H), 7.36-7.43 (m, 1H), 7.46-7.52 (m, 1H), 7.60
(dd, J=0.7, 1.7 Hz, 1H), 7.72-7.77 (m, 1H), 7.83 (dd, J=0.7, 3.5
Hz, 1H), 9.21 (brs, 1H), 9.66 (brs, 1H). APCIMS m/z: [M+H].sup.+
422.
Example 29
6-Ethyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-
-3-carboxamide (Compound IV)
[0181] Compound IE (90.0 mg, 0.220 mmol) obtained in Example 12%
was dissolved in ethanol (10 mL) under an argon atmosphere, 10%
palladium carbon (10%-Pd/C; containing water) (88.9 mg) was added
thereto, and mixture was stirred at room temperature overnight
under a hydrogen atmosphere. The mixture was filtered through
celite, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by preparative thin layer
chromatography (hexane:ethyl acetate=30:70), and recrystallized
from ethanol-water to give Compound IV (70.0 mg, 77%) as white
crystals.
[0182] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.36 (t, J=7.6 Hz,
3H), 1.80-2.01 (m, 4H), 2.94 (q, J=7.6 Hz, 2H), 3.11-3.27 (m, 1H),
3.51 (ddd, J=3.0, 11.3, 11.3 Hz, 2H), 3.99-4.13 (m, 2H), 6.54 (dd,
J=1.7, 3.5 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.52 (dd, J=0.7, 1.7
Hz, 1H), 7.81 (dd, J=0.7, 3.6 Hz, 1H), 8.15 (dd, J=2.2, 8.2 Hz,
1H), 9.08 (d, J=2.2 Hz, 1H), 10.13 (brs, 1H). ESIMS m/z:
[M+H].sup.+ 412.
Example 30
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-propylpyridin-
e-3-carboxamide (Compound IW)
[0183] step 1 In the same manner as in step 1 of Example 12, methyl
6-(1-propenyl)nicotinate (327 mg, 37%) was obtained as a colorless
transparent oil from methyl 6-chloronicotinate (862 mg, 6.48 mmol)
and allyltributyltin (2.20 ml, 7.09 mmol).
[0184] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.97 (dd, J=1.7, 6.8
Hz, 3H), 3.95 (s, 3H), 6.55 (dq, J=1.7, 15.7 Hz, 1H), 6.92 (dq,
J=6.8, 15.7 Hz, 1H), 7.25-7.30 (m, 1H), 8.19 (dd, J=2.2, 8.2 Hz,
1H), 9.11 (dd, J=0.5, 2.2 Hz, 1H).
[0185] step 2 In the same manner as in step 2 of Example 12,
6-(1-propenyl)nicotinic acid (251 mg, 84%) was obtained as
milk-white crystals from methyl 6-(1-propenyl)nicotinate (326 mg,
1.84 mmol) obtained above.
[0186] .sup.1H NMR (DMSO-d.sub.5, .delta.ppm): 1.91 (dd, J=1.8, 6.8
Hz, 3H), 6.58 (dq, J=1.8, 15.5 Hz, 1H), 6.91 (dq, J=6.8, 15.5 Hz,
1H), 7.48 (dd, J=0.5, 8.3 Hz, 1H), 8.15 (dd, J=2.2, 8.3 Hz, 1H),
8.95 (dd, J=0.5, 2.2 Hz, 1H), 13.24 (brs, 1H). ESIMS m/z:
[M+H].sup.+ 164.
[0187] step 3 In the same manner as in step 3 of Example 12,
N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-(1-propenyl)-
pyridine-3-carboxamide (125 mg, 33%) was obtained as white crystals
from 2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone
(257 mg, 0.908 mmol) described in WO2005/063743 and
6-(1-propenyl)nicotinic acid (251 mg, 1.26 mmol) obtained
above.
[0188] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.82-1.96 (m, 4H),
2.01 (dd, J=1.4, 6.8 Hz, 3H), 3.12-3.23 (m, 1H), 3.52 (ddd, J=3.0,
11.2, 11.2 Hz, 2H), 4.02-4.11 (m, 2H), 6.54-6.62 (m, 2H), 7.00 (dd,
J=6.8, 15.5 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.55 (dd, J=0.8, 1.6
Hz, 1H), 7.82 (d, J=3.6 Hz, 1H), 8.15 (dd, J=2.4, 8.3 Hz, 1H), 9.08
(d, J=2.4 Hz, 1H), 10.00 (brs, 1H). ESIMS m/z: [M+H].sup.+ 424.
[0189] step 4 In the same manner as in Example 29, the title
Compound IW (96.0 mg, 76%) was obtained as white crystals from
N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-(1-propenyl)-
pyridine-3-carboxamide (125 mg, 0.296 mmol) obtained above.
[0190] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.00 (t, J=7.3 Hz,
3H), 1.75-1.97 (m, 6H), 2.88 (t, J=7.6 Hz, 2H), 3.13-3.24 (m, 1H),
3.51 (ddd, J=3.1, 11.4, 11.4 Hz, 2H), 4.02-4.11 (m, 2H), 6.55 (dd,
J=1.8, 3.6 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.53-7.55 (m, 1H), 7.81
(d, J=3.6 Hz, 1H), 8.15 (dd, J=2.5, 8.2 Hz, 1H), 9.09 (d, J=2.1 Hz,
1H), 10.14 (s, 1H). ESIMS m/z: [M+H].sup.+ 426.
Example 31
N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-7,8-dihydro-5H--
thiopyrano[4,3-b]pyridine-3-carboxamide (Compound IX)
[0191] step 1 In the same manner as in step 1 of Example 26,
2-oxo-1,5,7,8-tetrahydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile
(3.06 g, 37%) was obtained as a pale-yellow solid from
tetrahydro-4H-thiopyran-4-one (5.00 g, 43.0 mmol).
[0192] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 2.93 (t, J=6.0 Hz,
2H), 3.11 (t, J=6.0 Hz, 2H), 3.58 (s, 2H), 7.67 (s, 1H), 13.4 (brs,
1H).
[0193] step 2 In the same manner as in step 2 of Example 26,
2-chloro-7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile
(1.75 g, 58%) was obtained from
2-oxo-1,5,7,8-tetrahydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile
(2.78 g, 14.4 mmol) obtained above.
[0194] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 3.01 (t, J=6.1 Hz,
2H), 3.27 (t, J=6.1 Hz, 2H), 3.78 (s, 2H), 7.71 (s, 1H).
[0195] step 3 In the same manner as in step 3 of Example 26,
7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (804 mg,
55%) was obtained from
2-chloro-7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile
(1.75 g, 8.31 mmol) obtained above.
[0196] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 3.04 (t, J=6.2 Hz,
2H), 3.30 (t, J=6.2 Hz, 2H), 3.81 (s, 2H), 7.68 (d, J=2.0 Hz, 1H),
8.69 (d, J=2.0 Hz, 1H).
[0197] step 4 In the same manner as in step 1 of Example 27,
7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carboxylic acid
hydrochloride (901 mg, 78%) was obtained from
7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (874 mg,
4.96 mmol) obtained above.
[0198] .sup.1H NMR (DMSO-d.sub.6, .delta.ppm): 3.01 (t, J=6.2 Hz,
2H), 3.24 (t, J=6.2 Hz, 2H), 3.96 (s, 2H), 8.27-8.36 (m, 1H), 8.92
(d, J=1.8 Hz, 1H). ESIMS m/z: [M-H].sup.- 194.
[0199] step 5 In the same manner as in step 3 of Example 12,
Compound IX (79.0 mg, 68%) was obtained as pale-brown crystals from
2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (70.7
mg, 0.254 mmol) described in WO2005/063743 and
7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carboxylic acid
hydrochloride (90.9 mg, 0.392 mmol) obtained above.
[0200] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.81-2.01 (m, 4H),
3.05 (t, J=6.2 Hz, 2H), 3.15-3.22 (m, 1H), 3.33 (t, J=6.0 Hz, 2H),
3.51 (ddd, J=2.9, 11.4, 11.4 Hz, 2H), 3.83 (s, 2H), 4.03-4.10 (m,
2H), 6.53 (dd, J=1.8, 3.5 Hz, 1H), 7.51 (dd, J=0.7, 1.8 Hz, 1H),
7.81 (dd, J=0.7, 3.5 Hz, 1H), 7.94-7.96 (m, 1H), 8.95 (d, J=2.2 Hz,
1H). ESIMS m/z: [M+H].sup.+ 456.
Example 32
5-Acetyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-meth-
ylpyridine-3-carboxamide (Compound IY)
[0201] step 1 In the same manner as in step 2 of Example 12,
5-acetyl-6-methylpyridine-3-carboxylic acid (462 mg, quantitative)
was obtained as a yellow solid from ethyl
5-acetyl-6-methylpyridine-3-carboxylate (561 mg, 2.71 mmol)
obtained by the method described in Synthesis, vol. 5, p. 400
(1986).
[0202] .sup.1H NMR (DMSO-d.sub.6, .delta.ppm): 2.63 (s, 3H), 2.66
(s, 3H), 8.54 (d, J=2.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H).
[0203] step 2
2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (71.2
mg, 0.256 mmol) described in WO2005/063743 was dissolved in DMF
(0.5 ml), (benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate (PyBOP) (262 mg, 0.510 mmol),
diisopropylethylamine (DIPEA) (150 .mu.L, 0.860 mmol) and
5-acetyl-6-methylpyridine-3-carboxylic acid (93.2 mg, 0.520 mmol)
obtained above were added thereto, and the mixture was stirred at
80.degree. C. overnight. The mixture was allowed to cool to room
temperature, water and a saturated aqueous sodium hydrogen
carbonate solution were added thereto and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure and the obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=50:50), and reslurried with ethanol-water to give Compound
IY (87.4 mg, 77%) as a pale-yellow solid.
[0204] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.81-2.01 (m, 4H),
2.67 (s, 3H), 2.86 (s, 3H), 3.13-3.23 (m, 1H), 3.51 (ddd, J=2.9,
11.4, 11.4 Hz, 2H), 4.03-4.10 (m, 2H), 6.56 (dd, J=1.7, 3.5 Hz,
1H), 7.55 (dd, J=0.6, 1.7 Hz, 1H), 7.82 (d, J=0.6, 3.5 Hz, 1H),
8.54 (d, J=2.4 Hz, 1H), 9.11 (d, J=2.4 Hz, 1H). ESIMS m/z:
[M+H].sup.+ 440.
Example 33
5-Ethyl-N-[4-(3-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-
-3-carboxamide (Compound IZ)
[0205] In the same manner as in step 3 of Example 12, Compound IZ
(177 mg, 79%) was obtained as white crystals from
2-amino-4-(3-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (151
mg, 0.541 mmol) obtained by the method described in WO2005/063743
and 5-ethylnicotinic acid (249 mg, 1.64 mmol).
[0206] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.34 (t, J=7.6 Hz,
3H), 1.80-2.01 (m, 4H), 2.80 (q, J=7.6 Hz, 2H), 3.11-3.18 (m, 1H),
3.51 (ddd, J=2.8, 11.4, 11.4 Hz, 2H), 4.01-4.10 (m, 2H), 7.01 (dd,
J=0.7, 1.8 Hz, 1H), 7.45-7.48 (m, 1H), 8.10-8.13 (m, 1H), 8.63 (dd,
J=0.7, 1.5 Hz, 1H), 8.71-8.76 (m, 1H), 9.02-9.05 (m, 1H). ESIMS
m/z: [M+H].sup.+ 412.
Example 34
N-[4-(3-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6,7-dihydro-5H--
cyclopenta[b]pyridine-3-carboxamide (Compound IAA)
[0207] In the same manner as in step 3 of Example 12, Compound IAA
(71.1 mg, 39%) was obtained as white crystals from
2-amino-4-(3-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (120
mg, 0.432 mmol) and
6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid
hydrochloride (172 mg, 0.870 mmol).
[0208] .sup.1H NMR (CDCl.sub.3, .delta.ppm): 1.80-2.01 (m, 4H),
2.18-2.30 (m, 2H), 3.03-3.20 (m, 5H), 3.52 (ddd, J=2.9, 11.3, 11.3
Hz, 2H), 4.01-4.10 (m, 2H), 7.03 (dd, J=0.6, 2.0 Hz, 1H), 7.48 (dd,
J=1.7, 1.7 Hz, 1H), 8.08-8.10 (m, 1H), 8.68-8.70 (m, 1H), 8.95-8.97
(m, 1H). ESIMS m/z: [M+H].sup.+ 424.
Reference Example 1
[0209] Compounds (IA)-(ID) were obtained according to the method
described in WO2005/063743.
INDUSTRIAL APPLICABILITY
[0210] The present invention can be utilized for the treatment
and/or prophylaxis of, for example, movement disorders
(specifically, for example, extrapyramidal syndrome, side effects
of L-DOPA and/or dopamine agonist therapy and the like), or the
treatment and/or prophylaxis of Parkinson's disease.
EXPLANATION OF SYMBOLS
[0211] .largecircle. combination of solvent and L-DOPA [0212]
combination of compound (IC) and L-DOPA
* * * * *