U.S. patent application number 11/896072 was filed with the patent office on 2009-02-19 for 5-pyridyl-1, 3-azole compounds, process for producing the same and use there of.
Invention is credited to Naoyuki Kanzaki, Seiji Miwatashi, Shigenori Ohkawa.
Application Number | 20090048307 11/896072 |
Document ID | / |
Family ID | 26454974 |
Filed Date | 2009-02-19 |
United States Patent
Application |
20090048307 |
Kind Code |
A1 |
Ohkawa; Shigenori ; et
al. |
February 19, 2009 |
5-pyridyl-1, 3-azole compounds, process for producing the same and
use there of
Abstract
An optionally N-oxidized compound represented by the formula:
##STR00001## wherein R.sup.1 represents hydrogen, hydrocarbon,
heterocycle, amino, acyl, R.sup.2 represents an aromatic group,
R.sup.3 represents hydrogen, pyridyl, aromatic hydrocarbon, X
represents oxygen, optionally oxidized sulfur, Y represents a bond,
an oxygen, optionally oxidized sulfur, a group represented by the
formula NR.sup.4 (R.sup.4 represents hydrogen, hydrocarbon or acyl)
and Z represents a bond or a divalent acyclic hydrocarbon, or a
salt thereof has an excellent adenosine A.sub.3 receptor
antagonistic activity and is used as an agent for preventing or
treating diseases related to an adenosine A.sub.3 receptor.
Furthermore, the compound (I) or a salt thereof has p38 MAP kinase
inhibitory activity and TNF-.alpha. inhibitory activity and is used
as an agent for preventing or treating diseases related to p38 MAP
kinase and diseases related to TNF-.alpha..
Inventors: |
Ohkawa; Shigenori;
(Takatsuki-shi, JP) ; Kanzaki; Naoyuki;
(Ibaraki-shi, JP) ; Miwatashi; Seiji; (Kawabe-gun,
JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W., SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
26454974 |
Appl. No.: |
11/896072 |
Filed: |
August 29, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11354897 |
Feb 16, 2006 |
7276527 |
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11896072 |
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09959356 |
Feb 7, 2002 |
7101899 |
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PCT/JP00/02575 |
Apr 20, 2000 |
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11354897 |
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Current U.S.
Class: |
514/342 ;
514/340; 546/270.4; 546/271.4 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 25/16 20180101; A61P 11/06 20180101; A61P 1/00 20180101; A61P
17/06 20180101; C07D 417/14 20130101; A61P 31/00 20180101; A61P
31/12 20180101; A61P 3/00 20180101; C07D 417/04 20130101; A61P 7/00
20180101; A61P 9/10 20180101; A61P 43/00 20180101; A61P 19/02
20180101; A61P 37/08 20180101; A61P 3/10 20180101; A61P 9/00
20180101; A61P 25/00 20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/342 ;
546/270.4; 546/271.4; 514/340 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; C07D 413/04 20060101 C07D413/04; C07D 417/04 20060101
C07D417/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 23, 1999 |
JP |
116686/1999 |
Aug 6, 1999 |
JP |
224650/1999 |
Claims
1. An optionally N-oxidized compound represented by the formula:
##STR00244## wherein R.sup.1 represents (i) a hydrogen atom, (ii) a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.3-6 cycloalkyl group, a C.sub.6-14 aryl
group or a C.sub.7-16 aralkyl group [wherein these groups may have
substituents selected from the group (substituent group A)
consisting of oxo, halogen atom, C.sub.1-3 alkylenedioxy, nitro,
cyano, optionally halogenated C.sub.1-6 alkyl, optionally
halogenated C.sub.2-6 alkenyl, carboxy C.sub.2-6 alkenyl,
optionally halogenated C.sub.1-6 alkynyl, optionally halogenated
C.sub.3-6 cycloalkyl, C.sub.6-14 aryl, optionally halogenated
C.sub.1-8 alkoxy, C.sub.1-6 alkoxy-carbonyl-C.sub.1-6 alkoxy,
hydroxy, C.sub.6-14 aryloxy, C.sub.7-16 aralkyloxy, mercapto,
optionally halogenated C.sub.1-6 alkylthio, C.sub.6-14 arylthio,
C.sub.7-16 aralkylthio, amino, mono-C.sub.1-6 alkylamino,
mono-C.sub.6-14 arylamino, di-C.sub.1-6 alkylamino di-C.sub.6-14
arylamino, formyl, carboxy, C.sub.1-6 alkyl-carbonyl, C.sub.3-6
cycloalkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, C.sub.6-14
aryl-carbonyl, C.sub.7-16 aralkyl-carbonyl, C.sub.6-14
aryloxy-carbonyl, C.sub.7-16 aralkyloxy-carbonyl, carbamoyl,
thiocarbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6
alkyl-carbamoyl, C.sub.6-14 aryl-carbamoyl, C.sub.1-6
alkylsulfonyl, C.sub.6-14 arylsulfonyl, C.sub.1-6 alkylsulfinyl,
C.sub.6-14 arylsulfinyl, formylamino, C.sub.1-6
alkyl-carbonylamino, C.sub.6-14 aryl-carbonylamino, C.sub.1-6
alkoxy-carbonylamino, C.sub.1-6 alkylsulfonylamino, C.sub.6-14
arylsulfonylamino, C.sub.1-6 alkyl-carbonyloxy, C.sub.6-14
aryl-carbonyloxy, C.sub.1-6 alkoxy-carbonyloxy, mono-C.sub.1-6
alkyl-carbamoyloxy, di-C.sub.1-6 alkyl-carbamoyloxy, C.sub.6-14
aryl-carbamoyloxy, sulfo, sulfamoyl, sulfinamoyl and sulfinamoyl],
(iii) an acyl group represented by the formula:
--(C.dbd.O)--R.sup.5,--(C.dbd.O)--OR.sup.5,
--(C.dbd.O)--NR.sup.5R.sup.6, --(C.dbd.S)--NHR.sup.5 or
--SO.sub.2--R.sup.7 wherein R.sup.5 represents {circle around (1)}
a hydrogen atom or {circle around (2)} a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-6
cycloalkyl group, a C.sub.6-14 aryl group or a C.sub.7-16 aralkyl
group optionally having substituents selected from the substituent
group A, R.sup.6 represents a hydrogen atom or a C.sub.1-6 alkyl
group, R.sup.7 represents a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-6cycloalkyl
group, a C.sub.6-14 aryl group or a C.sub.7-16 aralkyl group
optionally having substituents selected from the substituent group
A, or (iv) an amino group optionally having substituents selected
from the group consisting of {circle around (1)} a C.sub.1-6 alkyl
group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a
C.sub.3-6 cycloalkyl group, a C.sub.6-14 aryl group or a C.sub.7-16
aralkyl group optionally having substituents selected from the
substituent group A, {circle around (2)} an acyl group as defined
in the (iii), and {circle around (3)} a C.sub.1-6 alkylidene group
optionally having substituents selected from the substituent group
A, R.sup.2 represents a 5 to 10 membered aromatic heterocyclic
group containing 1 to 4 heteroatoms of one or two kinds selected
from the group consisting of a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms, optionally having
substituents selected from the substituent group A; R.sup.3
represents {circle around (1)} a hydrogen atom or {circle around
(2)} a C.sub.6-14 aryl group optionally having substituents
selected from the substituent group A; X represents an optionally
oxidized sulfur atom, Y represents a bond, an oxygen atom, an
optionally oxidized sulfur atom or a group represented by the
formula: NR.sup.4, wherein R.sup.4 represents {circle around (1)} a
hydrogen atom, {circle around (2)} a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.1-6
cycloalkyl group, a C.sub.6-14 aryl group or a C.sub.7-16 aralkyl
group optionally having substituents selected from the substituent
group A or {circle around (3)} an acyl group as defined in the
(iii), and Z represents a bond, a C.sub.1-15 alkylene group, a
C.sub.2-16 alkenylene group or a C.sub.2-16 alkynylene group
optionally having substituents selected from the substituent group
A, or a salt thereof.
2. The compound according to claim 1, wherein Z is a C.sub.1-15
alkylene group, a C.sub.2-16 alkenylene group or a C.sub.2-16
alkynylene group optionally having substituents selected from the
substituent group A.
3. The compound according to claim 1, which is a compound
represented by the formula: ##STR00245## wherein n represents 0 or
1, and other symbols are as defined in claim 1, or a salt
thereof.
4. The compound according to claim 1, wherein R.sup.1 represents
(i) a hydrogen atom, (ii) a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-6 cycloalkyl
group, a C.sub.6-14 aryl group or a C.sub.7-16 aralkyl group
[wherein these groups may have substituents selected from the
substituent group A], (iii) an acyl group represented by the
formula: --(C.dbd.O)--R.sup.5,--(C.dbd.O)--OR.sup.5,
--(C.dbd.O)--NR.sup.5R.sup.6, --(C.dbd.S)--NHR.sup.5 or
--SO.sub.2--R.sup.7 wherein R.sup.5 represents {circle around (1)}
a hydrogen atom or {circle around (2)} a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-6
cycloalkyl group, a C.sub.6-14 aryl group or a C.sub.7-16 aralkyl
group optionally having substituents selected from the substituent
group A, R.sup.6 represents a hydrogen atom or a C.sub.1-6 alkyl
group, R.sup.7 represents a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-6 cycloalkyl
group, a C.sub.6-14 aryl group or a C.sub.7-16 aralkyl group
optionally having substituents selected from the substituent group
A, or (iv) an amino group, wherein the amino group may have
substituents selected from the group consisting of {circle around
(1)} a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.2-6 alkynyl group, a C.sub.3-6 cycloalkyl group, a C.sub.6-14
aryl group or a C.sub.7-16 aralkyl group optionally having
substituents selected from the substituent group A, {circle around
(2)} an acyl group as defined in the (iii), and {circle around (3)}
a C.sub.1-6 alkylidene group optionally having substituents
selected from the substituent group A, R.sup.2 represents a 5 to 10
membered aromatic heterocyclic group containing 1 to 4 heteroatoms
of one or two kinds selected from the group consisting of a
nitrogen atom, a sulfur atom and an oxygen atom in addition to
carbon atoms, optionally having substituents selected from the
substituent group A; R.sup.3 represents {circle around (1)} a
hydrogen atom or {circle around (2)} a C.sub.6-14 monocyclic or
fused polycyclic aromatic hydrocarbon group optionally having
substituents selected from the substituent group A; X represents S,
SO or SO.sub.2; and Y represents a bond, O, S, SO, SO.sub.2 or a
group represented by the formula: NR.sup.4, wherein R.sup.4
represents {circle around (1)} a hydrogen atom, {circle around (2)}
a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.3-6 cycloalkyl group, a C.sub.6-14 aryl or a
C.sub.7-16 aralkyl group optionally having substituents selected
from the substituent group A or {circle around (3)} an acyl group
as defined in the (iii).
5. The compound according to claim 1, wherein R.sup.1 is an amino
group, as defined in (iv) of claim 1.
6. The compound according to claim 1, wherein R.sup.1 is (i) a
C.sub.1-6 alkyl group, (ii) a C.sub.6-14 aryl group optionally
substituted with substituents selected from the group consisting of
C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfonyl and halogen atom, or
(iii) an amino group optionally having 1 or 2 acyl represented by
the formula: --(C.dbd.O)--R.sup.5', wherein R.sup.5' represents
{circle around (1)} a C.sub.1-6 alkyl group or {circle around (2)}
a C.sub.6-14 aryl group.
7. The compound according to claim 1, wherein R.sup.1 is an amino
group optionally having 1 or 2 acyl group represented by
--(C.dbd.O)--R.sup.5'', wherein R.sup.5'' represents a C.sub.6-14
aryl group.
8. (canceled)
9. The compound according to claim 1, wherein R.sup.2 is a 5 to 10
membered aromatic heterocyclic group containing 1 to 4 heteroatoms
of one or two kinds selected from the group consisting of a
nitrogen atom, a sulfur atom and an oxygen atom in addition to
carbon atoms.
10. (canceled)
11. The compound according to claim 1, wherein R.sup.3 is a
C.sub.6-14 aryl group optionally having substituents selected from
the substituent group A.
12. The compound according to claim 1, wherein R.sup.3 is a
C.sub.6-14 aryl group optionally substituted with one or two
C.sub.1-6 alkyl or C.sub.1-6 alkoxy.
13. (canceled)
14. The compound according to claim 1, wherein X is a sulfur
atom.
15. The compound according to claim 1, wherein Y is an oxygen atom
or a group represented by the formula: NR.sup.4, wherein R.sup.4 is
as defined in claim 1.
16. The compound according to claim 1, wherein Y is an oxygen atom,
an optionally oxidized sulfur atom or a group represented by the
formula: NR.sup.4', wherein R.sup.4' represents a C.sub.1-6 alkyl
group.
17. The compound according to claim 1, wherein Y is O, NH or S.
18. The compound according to claim 1, wherein Z is a lower
alkylene group optionally having substituents selected from the
substituent group A.
19. The compound according to claim 1, wherein Z is a bond or a
C.sub.1-6 alkylene group optionally having oxo.
20. The compound according to claim 1, wherein R.sup.1 is (i) a
C.sub.1-6 alkyl group, (ii) a C.sub.6-14 aryl group optionally
substituted with C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfonyl or
halogen atom, or (iii) an amino group optionally having 1 or 2 acyl
group represented by the formula: --(C.dbd.O)--R.sup.5' wherein
R.sup.5' represents {circle around (1)} a C.sub.1-6 alkyl group or
{circle around (2)} a C.sub.6-14 aryl group; R.sup.2 is a 5 to 10
membered aromatic heterocyclic group containing 1 to 4 heteroatoms
of one or two kinds selected from the group consisting of a
nitrogen atom, a sulfur atom and an oxygen atom in addition to
carbon atoms; R.sup.3 is a C.sub.6-14 aryl group optionally
substituted with 1 or 2 C.sub.1-6 alkyl or C.sub.1-6 alkoxy; X is a
sulfur atom; Y is an oxygen atom, an optionally oxidized sulfur
atom or a group represented by the formula: NR.sup.4', wherein
R.sup.4' represents a C.sub.1-6 alkyl group; and Z is a C.sub.1-6
alkylene group optionally having oxo or C.sub.1-6 alkyl or a
bond.
21. The compound according to claim 1, wherein R.sup.1 is an amino
group optionally having 1 or 2 acyl represented by
--(C.dbd.O)--R.sup.5'', wherein R.sup.5'' represents a C.sub.6-14
aryl group; R.sup.2 is a 5 to 10 membered aromatic heterocyclic
group containing 1 to 4 heteroatoms of one or two kinds selected
from the group consisting of a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms; R.sup.3 is a C.sub.6-14
aryl group optionally substituted with 1 or 2 C.sub.1-6 alkyl or
C.sub.1-6 alkoxy; X is a sulfur atom; Y is O, NH or S; and Z is a
bond or a C.sub.1-6 alkylene group optionally having oxo.
22-24. (canceled)
25. A pharmaceutical composition which comprises the compound
according to claim 1 together with a pharmacologically acceptable
carrier.
26-41. (canceled)
42.
N-[4-[4-(3-Methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]-2-thiophenecarboxamide,
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]-2-thiophenecarboxamide, or
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]-N-(2-thienylmethyl)amine, or a salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel 5-pyridyl-1,3-azole
compounds having an excellent medical action, particularly an
adenosine A.sub.3 receptor antagonistic activity, a p38 MAP kinase
inhibitory action, a TNF-.alpha. production-inhibitory action and
the like, a process for producing the same, a pharmaceutical
composition and so on.
BACKGROUND ART
[0002] As a subtype of an adenosine receptor, A.sub.1, A.sub.2a,
A.sub.2b and A.sub.3 are known. Adenosine exhibits tracheostenotic
action to an asthma patient and, on the other hand, theophylline
which is an agent for treating asthma exhibits adenosine
antagonism. In addition, it has been recently shown that the
activation of A.sub.3 receptor in a rat causes degranulation from
mast cells (Journal of Biological Chemistry, vol. 268, 16887-16890,
1993), and that A.sub.3 receptor is present on eosinophils in
peripheral blood and its stimulation activates phospholipase C
(PLC) to increase the intracellular calcium concentration (Blood,
vol. 88, 3569-3574, 1996).
[0003] In addition, cytokines such as TNF-.alpha. (tumor necrosis
factor-.alpha.), IL-1 (interleukin-1) and the like are biological
substances which are produced by a variety of cells such as
monocyte or macrophage in response to the infection and other
cellular stress (Koj, A., Biochim. Biophys. Acta, 1317, 84-94
(1996)). Although these cytokines play an important role in the
immune response when they are present at an appropriate amount, it
is thought that the overproduction is associated with a variety of
inflammatory diseases (Dinarello, C. A., Curr. Opin. Immunol., 3,
941-948 (1991)). p38 MAP kinase which was cloned as a homologue of
MAP kinase is associated with the control of production of these
cytokines and signal transduction system coupled with a receptor
and there is a possibility that the inhibition of p38 MAP kinase
becomes a drug for treating inflammatory diseases (Stein, B.,
Anderson, D., Annual Report in Medicinal Chemistry, edited by
Bristol, J. A., Academic Press, vol. 31, pages 289-298, 1996).
[0004] Hitherto, as a compound exhibiting the selective antagonism
for adenosine A.sub.3 receptor, xanthine derivatives are reported
in GB-A-2288733 and WO 95/11681 and the following compounds are
reported in Journal of Medicinal Chemistry, vol. 40, 2596-2608,
1997:
##STR00002## ##STR00003##
[0005] In addition, in WO 97/33879, there are described an
adenosine A.sub.3 receptor antagonistic agent containing a compound
represented by the formula:
##STR00004##
wherein R represents hydrogen, chlorine, bromine, fluorine, iodine,
hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.1-4
alkylcarboxy, or a salt thereof and, more specifically, a
compound
##STR00005##
is described.
[0006] In addition, as a compound having a p38 MAP kinase
inhibitory action, imidazole derivatives are described in JP-T
7-50317 (WO 93/14081) and oxazole derivatives are described in JP-T
9-505055 (WO 95/13067), respectively.
[0007] On the other hand, as thiazole compounds, the following
compounds are known:
1) 1,3-thiazole derivatives represented by the formula:
##STR00006##
wherein R.sup.1 represents a cycloalkyl group, a cyclic amino
group, an amino group optionally having, as a substituent, 1 or 2
lower alkyl, phenyl, acetyl or lower alkoxycarbonylacetyl, an alkyl
group optionally having, as a substituent, hydroxyl, carboxyl or
lower alkoxycarbonyl, or a phenyl group optionally having, as a
substituent, carboxyl, 2-carboxylethenyl or 2-carboxy-1-propenyl,
R.sup.2 represents a pyridyl group optionally having, as a
substituent, lower alkyl, R.sup.3 represents a phenyl group
optionally having, as a substituent, lower alkoxy, lower alkyl,
hydroxyl, halogen or methylenedioxy, or salts thereof, which have
analgesic, antipyretic, anti-inflammatory, anti-ulcerative,
thromboxane A.sub.2 (TXA.sub.2) synthesizing enzyme-inhibitory, and
platelet coagulation-inhibitory activities (JP-A 60-58981), 2)
1,3-thiazole derivatives represented by the formula:
##STR00007##
wherein R.sup.1 represents an alkyl group, an alkenyl group, an
aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic
group employing carbon as an attachment point or an amino group
optionally having substituents, R.sup.2 represents a pyridyl group
optionally substituted with an alkyl group, R.sup.3 represents a
phenyl group optionally having substituents, or salts thereof,
which have analgesic, antipyretic, anti-inflammatory,
anti-ulcerative, TXA.sup.2 synthesizing enzyme-inhibitory, and
platelet coagulation-inhibitory activities (JP-A 61-10580), 3)
1,3-thiazole derivatives represented by the formula:
##STR00008##
wherein R.sup.1 represents an alkyl group, an alkenyl group, an
aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic
group employing carbon as an attachment point or an amino group
optionally having substituents, R.sup.2 represents a pyridyl group
optionally substituted with an alkyl group, R.sup.3 represents an
aryl group optionally having substituents, or salts thereof, which
have analgesic, antipyretic, anti-inflammatory, anti-ulcerative,
TXA.sub.2 synthesizing enzyme-inhibitory, and platelet
coagulation-inhibitory activities (U.S. Pat. No. 4,612,321), 4)
imidazole derivatives represented by the formula:
##STR00009##
which have an anti-cancer activity and a cytokine inhibitory
activity, more specifically, the following compounds are described
(WO 97/12876):
##STR00010##
[0008] Since an adenosine A.sub.3 antagonist, a p38 MAP kinase
inhibiting agent and a TNF-.alpha. production-inhibiting agent
having the satisfactory activity and effect, safety, (oral)
absorption, (metabolism) stability and the like have not been
found, it is desired the development of the excellent adenosine
A.sub.3 receptor antagonist, the p38 MAP kinase-inhibiting agent
and the TNF-.alpha. production-inhibiting agent as a pharmaceutical
which are effective for preventing or treating adenosine A.sub.3
receptor-related diseases, cytokine-mediated diseases and the
like.
DISCLOSURE OF THE INVENTION
[0009] The present inventors studied variously and, as a result,
first synthesized novel compounds which may be N-oxidized and which
are represented by the formula (I):
##STR00011##
wherein R.sup.1 represents a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an amino group optionally having substituents
or an acyl group, R.sup.2 represents an aromatic group optionally
having substituents, R.sup.3 represents a hydrogen atom, a pyridyl
group optionally having substituents or an aromatic hydrocarbon
group optionally having substituents, X represents an oxygen atom
or an optionally oxidized sulfur atom, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or a group
represented by the formula: NR.sup.4 (wherein R.sup.4 represents a
hydrogen atom, a hydrocarbon group optionally having substituents
or an acyl group) and Z represents a bond or a divalent acyclic
hydrocarbon group optionally having substituents, or a salt thereof
[hereinafter, abbreviated as Compound (I) sometimes], which has a
structural characteristics that a 5-position of a ring represented
by the formula:
##STR00012##
wherein X represents an oxygen atom or an optionally oxidized
sulfur atom, is substituted with a 4-pyridyl group, and further it
has a side chain having an aromatic group at 2-position of the
pyridyl group, found that the resulting Compound (I) have
unexpectedly excellent pharmaceutical activities such as a
selective affinity for an adenosine A.sub.3 receptor and an
adenosine A.sub.3 receptor antagonistic activity, a p38 MAP kinase
inhibitory activity and the like based on the specific chemical
structure, and that the compound has also excellent natures in the
physical properties as a pharmaceutical such as stability and the
like and is sufficiently satisfactory as a pharmaceutical, and
completed the present invention based on these findings.
[0010] The present invention relates to
(1) an optionally N-oxidized compound represented by the
formula:
##STR00013##
wherein R.sup.1 represents a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an amino group optionally having substituents
or an acyl group, R.sup.2 represents an aromatic group optionally
having substituents, R.sup.3 represents a hydrogen atom, a pyridyl
group optionally having substituents or an aromatic hydrocarbon
group optionally having substituents, X represents an oxygen atom
or an optionally oxidized sulfur atom, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or a group
represented by the formula: NR.sup.4 (wherein. R.sup.4 represents a
hydrogen atom, a hydrocarbon group optionally having substituents
or an acyl group) and Z represents a bond or a divalent acyclic
hydrocarbon group optionally having substituents, or a salt
thereof, (2) the compound according to (1), wherein Z is a divalent
acyclic hydrocarbon group optionally having substituents, (3) the
compound according to (1), which is a compound represented by the
formula:
##STR00014##
wherein n represents 0 or 1, and other symbols are as defined in
(1), or a salt thereof, (4) the compound according to (1) or (3),
wherein R.sup.1 represents (i) a hydrogen atom, (ii) a C.sub.1-6
alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group,
a C.sub.3-6 cycloalkyl group, a C.sub.6-14 aryl group or a
C.sub.7-16 aralkyl group [these groups may have substituents
selected from the group (substituent group A) consisting of oxo,
halogen atom, C.sub.1-3 alkylenedioxy, nitro, cyano, optionally
halogenated C.sub.1-6 alkyl, optionally halogenated C.sub.2-6
alkenyl, carboxy C.sub.2-6 alkenyl, optionally halogenated
C.sub.2-6 alkynyl, optionally halogenated C.sub.3-6 cycloalkyl,
C.sub.6-14 aryl, optionally halogenated C.sub.1-8 alkoxy, C.sub.1-6
alkoxy-carbonyl-C.sub.1-6 alkoxy, hydroxy, C.sub.6-14 aryloxy,
C.sub.7-16 aralkyloxy, mercapto, optionally halogenated C.sub.1-6
alkylthio, C.sub.6-14 arylthio, C.sub.7-16 aralkylthio, amino,
mono-C.sub.1-6 alkylamino, mono-C.sub.6-14 arylamino, di-C.sub.1-6
alkylamino, di-C.sub.6-14 arylamino, formyl, carboxy, C.sub.1-6
alkyl-carbonyl, C.sub.3-6 cycloalkyl-carbonyl, C.sub.1-6
alkoxy-carbonyl, C.sub.6-14 aryl-carbonyl, C.sub.7-16
aralkyl-carbonyl, C.sub.6-14 aryloxy-carbonyl, C.sub.7-16
aralkyloxy-carbonyl, 5 or 6 membered heterocyclic carbonyl,
carbamoyl, thiocarbamoyl, mono-C.sub.1-6 alkyl-carbamoyl,
di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-14 aryl-carbamoyl, 5 or 6
membered heterocyclic carbamoyl, C.sub.1-6 alkylsulfonyl,
C.sub.6-14 arylsulfonyl, C.sub.1-6 alkylsulfinyl, C.sub.6-14
arylsulfinyl, formylamino, C.sub.1-6 alkyl-carbonylamino,
C.sub.6-14 aryl-carbonylamino, C.sub.1-6 alkoxy-carbonylamino,
C.sub.1-6 alkylsulfonylamino, C.sub.6-14 arylsulfonylamino,
C.sub.1-6 alkyl-carbonyloxy, C.sub.6-14 aryl-carbonyloxy, C.sub.1-6
alkoxy-carbonyloxy, mono-C.sub.1-6 alkyl-carbamoyloxy, di-C.sub.1-6
alkyl-carbamoyloxy, C.sub.6-14 aryl-carbamoyloxy, nicotinoyloxy, 5
to 7 membered saturated cyclic amino optionally having 1 to 4
heteroatoms of one or two kinds selected from a nitrogen atom, a
sulfur atom and an oxygen atom in addition to one nitrogen atom and
carbon atoms (this cyclic amino may have substituents selected from
the group consisting of C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.1-6
alkyl-carbonyl, 5 to 10 membered aromatic heterocyclic group and
oxo), 5 to 10 membered aromatic heterocyclic group containing 1 to
4 heteroatoms of one or two kinds selected from a nitrogen atom, a
sulfur atom and an oxygen atom in addition to carbon atoms, sulfo,
sulfamoyl, sulfinamoyl and sulfinamoyl] (iii) a 5 to 14 membered
heterocyclic group containing 1 to 4 heteroatoms of one or two
kinds selected from a nitrogen atom, a sulfur atom and an oxygen
atom in addition to carbon atoms optionally having substituents
selected from the substituent group A, (iv) an acyl group
represented by the formula:
-(C.dbd.O)--R.sup.5,--(C.dbd.O)--OR.sup.5,--(C.dbd.O)--NR.sup.5R.sup.6,--
-(C.dbd.S)--NHR.sup.5 or --SO.sub.2--R.sup.7
(wherein R.sup.5 represents {circle around (1)} a hydrogen atom,
{circle around (2)} a C.sub.1-6 alkyl group, an C.sub.2-6 alkenyl
group, an C.sub.2-6 alkynyl group, a C.sub.3-6 cycloalkyl group, a
C.sub.6-14 aryl group or a C.sub.7-16 aralkyl group optionally
having substituents selected from the substituent group A or
{circle around (3)} a 5 to 14 membered heterocyclic group
containing 1 to 4 heteroatoms of one or two kinds selected from a
nitrogen atom, a sulfur atom and an oxygen atom in addition to
carbon atoms optionally having substituents selected from the
substituent group A, R.sup.6 represents a hydrogen atom or a
C.sub.1-6 alkyl group, R.sup.7 represents {circle around (1)} a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.3-6 cycloalkyl group, a C.sub.6-14 aryl
group or a C.sub.7-16 aralkyl group optionally having substituents
selected from the substituent group A or {circle around (2)} a 5 to
14 membered heterocyclic group containing 1 to 4 heteroatoms of one
or two kinds selected from a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms optionally having
substituents selected from the substituent group A), (v) an amino
group (this amino group may have substituents selected from the
group consisting of {circle around (1)} a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-6
cycloalkyl group, a C.sub.6-14 aryl group or a C.sub.7-16 aralkyl
group optionally having substituents selected from the substituent
group A, {circle around (2)} a 5 to 14 membered heterocyclic group
containing 1 to 4 heteroatoms of one or two kinds selected from a
nitrogen atom, a sulfur atom and an oxygen atom in addition to
carbon atoms optionally having substituents selected from the
substituent group A, {circle around (3)} an acyl group as defined
in the (iv), and {circle around (4)} a C.sub.1-6 alkylidene group
optionally having substituents selected from the substituent group
A), or (vi) a 5 to 7 membered non-aromatic cyclic amino group
optionally containing 1 to 4 heteroatoms of one or two kinds
selected from a nitrogen atom, a sulfur atom and an oxygen atom in
addition to one nitrogen atom and carbon atoms (this cyclic amino
may have substituents selected from the group consisting of
C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.1-6 alkyl-carbonyl, 5 to 10
membered aromatic heterocyclic group and oxo);
[0011] R.sup.2 represents {circle around (1)} a C.sub.6-14
monocyclic or fused polycyclic aromatic hydrocarbon group
optionally having substituents selected from the substituent group
A or {circle around (2)} a 5 to 14 membered aromatic heterocyclic
group containing 1 to 4 heteroatoms of one or two kinds selected
from a nitrogen atom, a sulfur atom and an oxygen atom in addition
to carbon atoms, optionally having substituents selected from the
substituent group A;
[0012] R.sup.3 represents {circle around (1)} a hydrogen atom,
{circle around (2)} a pyridyl group optionally having substituents
selected from the substituent group A, or {circle around (3)}
C.sub.6-14 monocyclic or fused polycyclic aromatic hydrocarbon
group optionally having substituents selected from the substituent
group A;
[0013] X represents O, S, SO or SO.sub.2;
[0014] Y represents a bond, O, S, SO, SO.sub.2 or a group
represented by the formula: NR.sup.4 (wherein R.sup.4 represents
{circle around (1)} a hydrogen atom, {circle around (2)} a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.3-6 cycloalkyl group, a C.sub.6-14 aryl
group or a C.sub.7-16 aralkyl group optionally having substituents
selected from the substituent group A or {circle around (3)} an
acyl group as defined in the (iv)),
[0015] Z represents a bond, a C.sub.1-15 alkylene group, a
C.sub.2-16 alkenylene group or a C.sub.2-16 alkynylene group
optionally having substituents selected from the substituent group
A,
(5) the compound according to (1), wherein R.sup.1 is an amino
group optionally having substituents, (6) the compound according to
(1), wherein R.sup.1 is (i) a C.sub.1-6 alkyl group, (ii) a
C.sub.6-14 aryl group optionally substituted with substituents
selected from C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfonyl and
halogen atom, or (iii) an amino group optionally having 1 or 2 acyl
represented by the formula: --(C.dbd.O)--R.sup.5' (wherein R.sup.5'
represents {circle around (1)} a C.sub.1-6 alkyl group, {circle
around (2)} a C.sub.6-14 aryl group or {circle around (3)} a 5 to
14 membered heterocyclic group containing 1 to 4 heteroatoms of one
or two kinds selected from a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms), (7) the compound
according to (1), wherein R.sup.1 is an amino group optionally
having 1 or 2 acyl group represented by --(C.dbd.O)--R.sup.5''
(wherein R.sup.5'' represents {circle around (1)} a C.sub.6-14 aryl
group or {circle around (2)} a 5 to 14 membered heterocyclic group
containing 1 to 4 heteroatoms of one or two kinds selected from a
nitrogen atom, a sulfur atom and an oxygen atom in addition to
carbon atoms), (8) the compound according to (1), wherein R.sup.2
is a C.sub.6-14 aryl group optionally having substituents, (9) the
compound according to (1), wherein R.sup.2 is a C.sub.6-14 aryl
group optionally substituted with halogen atom or C.sub.1-6 alkoxy,
or a 5 to 14 membered aromatic heterocyclic group containing 1 to 4
heteroatoms of one or two kinds selected from a nitrogen atom, a
sulfur atom and an oxygen atom in addition to carbon atoms, (10)
the compound according to (1), wherein R.sup.2 is a C.sub.6-14 aryl
group, or a 5 to 14 membered heterocyclic group containing 1 to 4
heteroatoms of one or two kinds selected from nitrogen atom, a
sulfur atom and an oxygen atom in addition to carbon atoms, (11)
the compound according to (1), wherein R.sup.3 is a C.sub.6-14 aryl
group optionally having substituents, (12) the compound according
to (1), wherein R.sup.3 is a C.sub.6-14 aryl group optionally
substituted with one or two C.sub.1-6 alkyl or C.sub.1-6 alkoxy,
(13) the compound according to (1), wherein X is an optionally
oxidized sulfur atom, (14) the compound according to (1), wherein X
is a sulfur atom, (15) the compound according to (1), wherein Y is
an oxygen atom or a group represented by the formula: NR.sup.4
(wherein R.sup.4 is as defined in (1)), (16) the compound according
to (1), wherein Y is an oxygen atom, an optionally oxidized sulfur
atom or a group represented by the formula: NR.sup.4' (wherein
R.sup.4' represents a C.sub.1-6 alkyl group), (17) the compound
according to (1), wherein Y is O, NH or S, (18) the compound
according to (1), wherein Z is a lower alkylene group optionally
having substituents, (19) the compound according to (1), wherein Z
is a bond or a C.sub.1-6 alkylene group optionally having oxo, (20)
the compound according to (1), wherein R.sup.1 is (i) a C.sub.1-6
alkyl group, (ii) a C.sub.6-14 aryl group optionally substituted
with C.sub.1-6 alkylthio, C.sub.1-6 sulfonyl and halogen atom, or
(iii) an amino group optionally having 1 or 2 acyl group
represented by the formula: --(C.dbd.O)--R.sup.5' (wherein R.sup.5'
represents {circle around (1)} a C.sub.1-6 alkyl group, {circle
around (2)} a C.sub.6-14 aryl group or {circle around (3)} a 5 to
14 membered heterocyclic group containing 1 to 4 heteroatoms of one
or two kinds selected from a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms;
[0016] R.sup.2 is a C.sub.6-14 aryl group optionally substituted
with halogen atom or C.sub.1-6 alkoxy, or a 5 to 14 membered
aromatic heterocyclic group containing 1 to 4 heteroatoms of one or
two kinds selected from a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms;
[0017] R.sup.3 is a C.sub.6-14 aryl group optionally substituted
with 1 or 2 C.sub.1-6 alkyl or C.sub.1-6 alkoxy;
[0018] X is a sulfur atom;
[0019] Y is an oxygen atom, an optionally oxidized sulfur atom or a
group represented by the formula: NR.sup.4' (wherein R.sup.4'
represents a C.sub.1-6 alkyl group);
[0020] Z is a C.sub.1-6 alkylene group optionally having oxo or
C.sub.1-6 alkyl or a bond,
(21) the compound according to (1), wherein R.sup.1 is an amino
group optionally having 1 or 2 acyl represented by
--(C.dbd.O)--R.sup.5'' (wherein R.sup.5'' represents {circle around
(1)} a C.sub.6-14 aryl group or {circle around (2)} a 5 to 14
membered heterocyclic group containing 1 to 4 heteroatoms of one or
two kinds selected from a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms);
[0021] R.sup.2 is a C.sub.6-14 aryl group or a 5 to 14 membered
aromatic heterocyclic group containing 1 to 4 heteroatoms of one or
two kinds selected from a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms;
[0022] R.sup.3 is a C.sub.6-14 aryl group optionally substituted
with 1 or 2 C.sub.1-6 alkyl or C.sub.1-6 alkoxy;
[0023] X is a sulfur atom; Y is O, NH or S; Z is a bond or a
C.sub.1-6 alkylene group optionally having oxo, [0024] (22)
N-[5-(2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]a-
cetamide (Example Compound No. 9), [0025]
N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]ac-
etamide (Example Compound No. 10), [0026]
N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide
(Example Compound No. 13), [0027]
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]p-
henylacetamide (Example Compound No. 14), [0028]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetam-
ide (Example Compound No. 15-2), [0029]
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylaceta-
mide (Example Compound No. 15-3), [0030]
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetam-
ide (Example Compound No. 15-4), [0031]
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]phenylacetamide (Example Compound No. 15-6), [0032]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
(Example Compound No. 16-1), [0033]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpro-
pionamide (Example Compound No. 16-2), [0034]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methox-
yphenyl)propionamide (Example Compound No. 16-3), [0035]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbut-
yramide (Example Compound No. 16-S), [0036]
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide
(Example Compound No. 16-7), [0037]
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpr-
opionamide (Example Compound No. 16-8), [0038]
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
(Example Compound No. 16-9), [0039]
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpro-
pionamide (Example Compound No. 16-10), [0040]
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]b-
enzamide (Example Compound No. 16-11), [0041]
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]--
3-phenylpropionamide (Example Compound No. 16-12), [0042]
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]benzamide (Example Compound No. 16-15), [0043]
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-3-phenylpropionamide (Example Compound No. 16-16), [0044]
N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]ami-
ne (Example Compound No. 19-2), [0045]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenyl-
ethyl)amine (Example Compound No. 19-3), [0046]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenyl-
propyl)amine (Example Compound No. 19-4), [0047]
N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]am-
ine (Example Compound No. 19-5), [0048]
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-pheny-
lethyl)amine (Example Compound No. 19-6), [0049]
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-pheny-
lpropyl)amine (Example Compound No. 19-7), [0050]
N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]ami-
ne (Example Compound No. 19-8), [0051]
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenyl-
ethyl)amine (Example Compound No. 19-9), [0052]
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenyl-
propyl)amine (Example Compound No. 19-10), [0053]
N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl-
]-2-pyridyl]amine (Example Compound No. 19-17), [0054]
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-N-(2-phenylethyl)amine (Example Compound No. 19-18), [0055]
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-N-(3-phenylpropyl)amine (Example Compound No. 19-19), [0056]
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]benzamide (Example Compound No. 20), [0057]
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]phenylacetamide (Example Compound No. 21-1), [0058]
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]-3-phenylpropionamide (Example Compound No. 21-2), [0059]
N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol--
5-yl]-2-pyridyl]amine (Example Compound No. 21-5), [0060]
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]-N-(3-phenylpropyl)amine (Example Compound No. 21-6), [0061]
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]-N-(2-phenylethyl)amine (Example Compound No. 25-1), [0062]
N-(4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,-
3-thiazol-5-yl]-2-pyridyl]amine (Example Compound No. 25-2), or
salts thereof, (23) a prodrug of the compound according to (1),
(24) a process for producing the compound according to (1), which
comprises: reacting a compound represented by the formula:
##STR00015##
[0062] wherein Hal represents a halogen atom, and other symbols are
as defined as (1), or a salt thereof with a compound represented by
the formula:
R.sup.1--CSNH.sub.2 (VIII)
wherein R.sup.1 is as defined in (1), or a salt thereof, to obtain
a compound represented by the formula:
##STR00016##
wherein each symbol is as defined in (1), or a salt thereof, or
(ii) reacting a compound represented by the formula:
##STR00017##
wherein Hal represents halogen atom, and other symbols are as
defined as (1), or a salt thereof with a compound represented by
the formula:
R.sup.2-Z-YH (XI)
wherein each symbol is as defined in (1), or a salt thereof, to
obtain a compound represented by the formula:
##STR00018##
wherein each symbol is as defined in (1), or a salt thereof, or
(iii) reacting a compound represented by the formula:
##STR00019##
wherein each symbol is as defined in (1), or a salt thereof with a
compound represented by the formula:
R.sup.2-ZL (XVIII)
wherein L represents a leaving group, and other symbols are as
defined in (1), or a salt thereof, to obtain a compound represented
by the formula:
##STR00020##
wherein each symbol is as defined in (1), or a salt thereof, or
(iv) reacting a compound represented by the formula:
##STR00021##
wherein each symbol is as defined in (1), or a salt thereof with
peroxy acid, hydrogen peroxide or alkyl hydroperoxide, to obtain a
compound represented by the formula:
##STR00022##
wherein each symbol is as defined in (1), or a salt thereof, (25) a
pharmaceutical composition which comprises the compound according
to (1) or a prodrug thereof, (26) the composition according to
(25), which is an adenosine A.sub.3 receptor antagonist, (27) the
composition according to (25), which is an agent for preventing or
treating adenosine A.sub.3 receptor-related diseases, (28) the
composition according to (25), which is an agent for preventing or
treating asthma or allergic diseases, (29) the composition
according to (25), which is an agent for preventing or treating
brain edema, cerebrovascular disease or head trauma, (30) the
composition according to (25), which is an agent for inhibiting p38
MAP kinase, (31) the composition according to (25), which is a
TNF-.alpha. production-inhibiting agent, (32) the composition
according to (25), which is an agent for preventing or treating
cytokine-mediated diseases, (33) the composition according to (25),
which is an agent for preventing or treating inflammation,
Addison's disease, autoimmune hemolytic anemia, Crohn's disease,
psoriasis, rheumatism, spinal trauma, brain edema, multiple
sclerosis, Alzheimer's disease, Parkinson's syndrome, amyotrophic
lateral sclerosis, diabetes, arthritis, toxemia, Crohn's disease,
ulcerative colitis, chronic pneumonia, silicosis, pulmonary
sarcoidosis, pulmonary tuberculosis, cachexia, arteriosclerosis,
Creutzfeldt-Jakob disease, virus infection, atopic dermatitis,
systemic lupus erythematosus, AIDS encephalopathy, meningitis,
angina, cardiac infarction, congestive heart failure, hepatitis,
transplantation, dialysis hypotension or disseminated intravascular
coagulation, (34) a method for antagonizing an adenosine A.sub.3
receptor comprising administering an effective amount of an
optionally N-oxidized compound represented by the formula:
##STR00023##
wherein R.sup.1 represents a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an amino group optionally having substituents
or an acyl group, R.sup.2 represents an aromatic group optionally
having substituents, R.sup.3 represents a hydrogen atom, a pyridyl
group optionally having substituents or an aromatic hydrocarbon
group optionally having substituents, X represents an oxygen atom
or an optionally oxidized sulfur atom, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or a group
represented by the formula: NR.sup.4 (wherein R.sup.4 represents a
hydrogen atom, a hydrocarbon group optionally having substituents
or an acyl group) and Z represents a bond or a divalent acyclic
hydrocarbon group optionally having substituents, or a salt thereof
or a prodrug thereof to mammals, (35) a method for inhibiting p38
MAP kinase comprising administering an effective amount of an
optionally N-oxidized compound represented by the formula:
##STR00024##
wherein R.sup.1 represents a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an amino group optionally having substituents
or an acyl group, R.sup.2 represents an aromatic group optionally
having substituents, R.sup.3 represents a hydrogen atom, a pyridyl
group optionally having substituents or an aromatic hydrocarbon
group optionally having substituents, X represents an oxygen atom
or an optionally oxidized sulfur atom, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or a group
represented by the formula: NR.sup.4 (wherein R.sup.4 represents a
hydrogen atom, a hydrocarbon group optionally having substituents
or an acyl group) and Z represents a bond or a divalent acyclic
hydrocarbon group optionally having substituents, or a salt thereof
or a prodrug thereof to mammals, (36) a method for inhibiting
TNF-.alpha. production comprising administering an effective amount
of an optionally N-oxidized compound represented by the
formula:
##STR00025##
wherein R.sup.1 represents a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an amino group optionally having substituents
or an acyl group, R.sup.2 represents an aromatic group optionally
having substituents, R.sup.3 represents a hydrogen atom, a pyridyl
group optionally having substituents or an aromatic hydrocarbon
group optionally having substituents, X represents an oxygen atom
or an optionally oxidized sulfur atom, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or a group
represented by the formula: NR.sup.4 (wherein R.sup.4 represents a
hydrogen atom, a hydrocarbon group optionally having substituents
or an acyl group) and Z represents a bond or a divalent acyclic
hydrocarbon group optionally having substituents, or a salt thereof
or a prodrug thereof to mammals, (37) a method for preventing or
treating asthma, allergic diseases, inflammation, Addison's
disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis,
rheumatism, cerebral hemorrhage, cerebral infarction, head trauma,
spinal trauma, brain edema, multiple sclerosis, Alzheimer's
disease, Parkinson's syndrome, amyotrophic lateral sclerosis,
diabetes, arthritis, toxemia, Crohn's disease, ulcerative colitis,
chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary
tuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob
disease, virus infection, atopic dermatitis, systemic lupus
erythematosus, AIDS encephalopathy, meningitis, angina, cardiac
infarction, congestive heart failure, hepatitis, transplantation,
dialysis hypotension or disseminated intravascular coagulation
comprising administering an effective amount of an optionally
N-oxidized compound represented by the formula:
##STR00026##
wherein R.sup.1 represents a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an amino group optionally having substituents
or an acyl group, R.sup.2 represents an aromatic group optionally
having substituents, R.sup.3 represents a hydrogen atom, a pyridyl
group optionally having substituents or an aromatic hydrocarbon
group optionally having substituents, X represents an oxygen atom
or an optionally oxidized sulfur atom, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or a group
represented by the formula: NR.sup.4 (wherein R.sup.4 represents a
hydrogen atom, a hydrocarbon group optionally having substituents
or an acyl group) and Z represents a bond or a divalent acyclic
hydrocarbon group optionally having substituents, or a salt thereof
or a prodrug thereof to mammals, (38) use of an optionally
N-oxidized compound represented by the formula:
##STR00027##
wherein R.sup.1 represents a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an amino group optionally having substituents
or an acyl group, R.sup.2 represents an aromatic group optionally
having substituents, R.sup.3 represents a hydrogen atom, a pyridyl
group optionally having substituents or an aromatic hydrocarbon
group optionally having substituents, X represents an oxygen atom
or an optionally oxidized sulfur atom, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or a group
represented by the formula: NR.sup.4 (wherein R.sup.4 represents a
hydrogen atom, a hydrocarbon group optionally having substituents
or an acyl group) and Z represents a bond or a divalent acyclic
hydrocarbon group optionally having substituents, or a salt thereof
or a prodrug thereof for preparing an agent for antagonizing an
adenosine A.sub.3 receptor, (39) use of an optionally N-oxidized
compound represented by the formula:
##STR00028##
wherein R.sup.1 represents a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an amino group optionally having substituents
or an acyl group, R.sup.2 represents an aromatic group optionally
having substituents, R.sup.3 represents a hydrogen atom, a pyridyl
group optionally having substituents or an aromatic hydrocarbon
group optionally having substituents, X represents an oxygen atom
or an optionally oxidized sulfur atom, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or a group
represented by the formula: NR.sup.4 (wherein R.sup.4 represents a
hydrogen atom, a hydrocarbon group optionally having substituents
or an acyl group) and Z represents a bond or a divalent acyclic
hydrocarbon group optionally having substituents, or a salt thereof
or a prodrug thereof for preparing an agent for inhibiting p38 MAP
kinase, (40) use of an optionally N-oxidized compound represented
by the formula:
##STR00029##
wherein R.sup.1 represents a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an amino group optionally having substituents
or an acyl group, R.sup.2 represents an aromatic group optionally
having substituents, R.sup.3 represents a hydrogen atom, a pyridyl
group optionally having substituents or an aromatic hydrocarbon
group optionally having substituents, X represents an oxygen atom
or an optionally oxidized sulfur atom, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or a group
represented by the formula: NR.sup.4 (wherein R.sup.4 represents a
hydrogen atom, a hydrocarbon group optionally having substituents
or an acyl group) and Z represents a bond or a divalent acyclic
hydrocarbon group optionally having substituents, or a salt thereof
or a prodrug thereof for preparing an agent for inhibiting a
TNF-.alpha. production, and (41) use of an optionally N-oxidized
compound represented by the formula:
##STR00030##
wherein R.sup.1 represents a hydrogen atom, a hydrocarbon group
optionally having substituents, a heterocyclic group optionally
having substituents, an amino group optionally having substituents
or an acyl group, R.sup.2 represents an aromatic group optionally
having substituents, R.sup.3 represents a hydrogen atom, a pyridyl
group optionally having substituents or an aromatic hydrocarbon
group optionally having substituents, X represents an oxygen atom
or an optionally oxidized sulfur atom, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or a group
represented by the formula: NR.sup.4 (wherein R.sup.4 represents a
hydrogen atom, a hydrocarbon group optionally having substituents
or an acyl group) and Z represents a bond or a divalent acyclic
hydrocarbon group optionally having substituents, or a salt thereof
or a prodrug thereof for preparing an agent for preventing or
treating asthma, allergic diseases, inflammation, Addison's
disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis,
rheumatism, cerebral hemorrhage, cerebral infarction, head trauma,
spinal trauma, brain edema, multiple sclerosis, Alzheimer's
disease, Parkinson's syndrome, amyotrophic lateral sclerosis,
diabetes, arthritis, toxemia, Crohn's disease, ulcerative colitis,
chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary
tuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob
disease, virus infection, atopic dermatitis, systemic lupus
erythematosus, AIDS encephalopathy, meningitis, angina, cardiac
infarction, congestive heart failure, hepatitis, transplantation,
dialysis hypotension or disseminated intravascular coagulation.
[0063] Furthermore, the present invention relates to
(42) the compound according to (1), wherein R.sup.1 is an amino
group optionally having one or two acyl groups represented by the
formula: --(C.dbd.O)--R.sup.5, --(C.dbd.O)--OR.sup.5,
--(C.dbd.O)--NR.sup.5R.sup.6, --(C.dbd.S)--NHR.sup.5 or
--SO.sub.2--R.sup.7 wherein each symbols are defined in (4), (43)
the compound according to (1), wherein R.sup.1 is a C.sub.1-6 alkyl
group optionally having substituents, (44) the compound according
to (1), wherein R.sup.1 is a C.sub.6-14 aryl group optionally
having a C.sub.1-6 alkylsulfonyl group, (45) the compound according
to (7), wherein R.sup.5'' is a phenyl group or a pyridyl group,
(46) the compound according to (1), wherein R.sup.2 is a C.sub.6-14
aryl group optionally having substituents or a 5 to 14 membered
aromatic heterocyclic group containing 1 to 4 heteroatoms of one or
two kinds selected from a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms optionally having
substituents, (47) the compound according to (1), wherein R.sup.2
is a phenyl group or a pyridyl group, and (48) the compound
according to (1), wherein R.sup.3 is a phenyl group optionally
substituted by one or two C.sub.1-6 alkyl or C.sub.1-6 alkoxy.
BEST MODE TO PRACTICE THE INVENTION
[0064] In the aforementioned formula, R.sup.1 represents a hydrogen
atom, a hydrocarbon group optionally having substituents, a
heterocyclic group optionally having substituents, an amino group
optionally having substituents or acyl group.
[0065] As "acyl group" represented by R.sup.1, for example, there
are an acyl group represented by the formula: --(C.dbd.O)--R.sup.5,
--(C.dbd.O)--OR.sup.5, --(C.dbd.O)--NR.sup.5R.sup.6,
--(C.dbd.S)--NHR.sup.5 or --SO.sub.2--R.sup.7 (wherein R.sup.5
represents a hydrogen atom, a hydrocarbon group optionally having
substituents or a heterocyclic group optionally having
substituents, R.sup.6 represents a hydrogen atom or a C.sub.1-6
alkyl, R.sup.7 represents a hydrocarbon group optionally having
substituents or a heterocyclic group optionally having
substituents) and the like.
[0066] In the aforementioned formula, as "hydrocarbon group" of
"hydrocarbon group optionally having substituents", for example,
there are an acyclic or cyclic hydrocarbon group (for example,
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl and the like)
and the like. Among them, acyclic or cyclic hydrocarbon groups
having carbon number of 1 to 16 are preferable.
[0067] As "alkyl", for example, C.sub.1-6 alkyl (for example,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, hexyl and the like) is preferable and, in
particular, C.sub.1-3 alkyl (for example, methyl, ethyl, propyl and
isopropyl) and the like are preferable.
[0068] As "alkenyl", for example, C.sub.2-6 alkenyl (for example,
vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl and
the like) and the like are preferable.
[0069] As "alkynyl", for example, C.sub.2-6 alkynyl (for example,
ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl and
the like) and the like are preferable.
[0070] As "cycloalkyl", for example, C.sub.3-6 cycloalkyl (for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the
like) and the like are preferable.
[0071] As "aryl", for example, C.sub.6-14 aryl (for example,
phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,
4-biphenylyl, 2-anthryl and the like) and the like are
preferable.
[0072] As "aralkyl", for example, C.sub.7-16 aralkyl (for example,
benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl,
2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl,
5-phenylpentyl and the like) and the like are preferable.
[0073] As "substituents" of "hydrocarbon group optionally having
substituents" represented by R.sup.5, for example, there are oxo,
halogen atom (for example, fluorine, chlorine, bromine, iodine and
the like), C.sub.1-3 alkylenedioxy (for example, methylenedioxy,
ethylenedioxy and the like), nitro, cyano, optionally halogenated
C.sub.1-6 alkyl, optionally halogenated C.sub.2-6 alkenyl, carboxy
C.sub.2-6 alkenyl (for example, 2-carboxylethenyl,
2-carboxy-2-methylethenyl and the like), optionally halogenated
C.sub.2-6 alkynyl, optionally halogenated C.sub.3-6 cycloalkyl,
C.sub.6-14 aryl (for example, phenyl, 1-naphthyl, 2-naphthyl,
2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like),
optionally halogenated C.sub.1-8 alkoxy, C.sub.1-6
alkoxy-carbonyl-C.sub.1-6 alkoxy (for example,
methoxycarbonylmethyloxy and the like), hydroxy, C.sub.6-14 aryloxy
(for example, phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the
like), C.sub.7-16 aralkyloxy (for example, benzyloxy, phenethyloxy
and the like), mercapto, optionally halogenated C.sub.1-6
alkylthio, C.sub.6-14 arylthio (for example, phenylthio,
1-naphthylthio, 2-naphthylthio and the like), C.sub.7-16
aralkylthio (for example, benzylthio, phenethylthio and the like),
amino, mono-C.sub.1-6 alkylamino (for example, methylamino,
ethylamino and the like), mono-C.sub.6-14 arylamino (for example,
phenylamino, 1-naphthylamino, 2-naphthylamino and the like),
di-C.sub.1-6 alkylamino (for example, dimethylamino, diethylamino,
ethylmethylamino and the like), di-C.sub.6-14 arylamino (for
example, diphenylamino and the like), formyl, carboxy, C.sub.1-6
alkyl-carbonyl (for example, acetyl, propionyl and the like),
C.sub.3-6 cycloalkyl-carbonyl (for example, cyclopropylcarbonyl,
cyclopentylcarbonyl, cyclohexylcarbonyl and the like), C.sub.1-6
alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, tert-butoxycarbonyl and the like), C.sub.6-14
aryl-carbonyl (for example, benzoyl, 1-naphthoyl, 2-naphthoyl and
the like), C.sub.7-16 aralkyl-carbonyl (for example, phenylacetyl,
3-phenylpropionyl and the like), C.sub.6-14 aryloxy-carbonyl (for
example, phenoxycarbonyl and the like), C.sub.7-16
aralkyloxy-carbonyl (for example, benzyloxycarbonyl,
phenethyloxycarbonyl and the like), 5 or 6 membered heterocyclic
carbonyl (for example, nicotinoyl, isonicotinoyl, thenoyl, furoyl,
morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl,
pyrrolidin-1-ylcarbonyl and the like), carbamoyl, thiocarbamoyl,
mono-C.sub.1-6 alkyl-carbamoyl (for example, methylcarbamoyl,
ethylcarbamoyl and the like), di-C.sub.1-6 alkyl-carbamoyl (for
example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl
and the like), C.sub.6-14 aryl-carbamoyl (for example,
phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the
like), 5 or 6 membered heterocyclic carbamoyl (for example,
2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl,
2-thienylcarbamoyl, 3-thienylcarbamoyl and the like), C.sub.1-6
alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl and the
like), C.sub.6-14 arylsulfonyl (for example, phenylsulfonyl,
1-naphthylsulfonyl, 2-naphthylsulfonyl and the like), C.sub.1-6
alkylsulfinyl (for example, methylsulfinyl, ethylsulfinyl and the
like), C.sub.6-14 arylsulfinyl (for example, phenylsulfinyl,
1-naphthylsulfinyl, 2-naphthylsulfinyl and the like), formylamino,
C.sub.1-6 alkyl-carbonylamino (for example, acetylamino and the
like), C.sub.6-14 aryl-carbonylamino (for example, benzoylamino,
naphthylamino and the like), C.sub.1-6 alkoxy-carbonylamino (for
example, methoxycarbonylamino, ethoxycarbonylamino,
propoxycarbonylamino, butoxycarbonylamino and the like), C.sub.1-6
alkylsulfonylamino (for example, methylsulfonylamino,
ethylsulfonylamino and the like), C.sub.6-14 arylsulfonylamino (for
example, phenylsulfonylamino, 2-naphthylsulfonylamino,
1-naphthylsulfonylamino and the like), C.sub.1-6 alkyl-carbonyloxy
(for example, acetoxy, propionyloxy and the like), C.sub.6-14
aryl-carbonyloxy (for example, benzoyloxy, naphthylcarbonyloxy and
the like), C.sub.1-6 alkoxy-carbonyloxy (for example,
methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,
butoxycarbonyloxy and the like), mono-C.sub.1-6 alkyl-carbamoyloxy
(for example, methylcarbamoyloxy, ethylcarbamoyloxy and the like),
di-C.sub.1-6 alkyl-carbamoyloxy (for example, dimethylcarbamoyloxy,
diethylcarbamoyloxy and the like), C.sub.6-14 aryl-carbamoyloxy
(for example, phenylcarbamoyloxy, naphthylcarbamoyloxy and the
like), nicotinoyloxy, 5 to 7 membered saturated cyclic amino
optionally having substituents, 5 to 10 membered aromatic
heterocyclic group (for example, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,
5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl,
2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,
2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), sulfo,
sulfamoyl, sulfinamoyl, sulfinamoyl and the like.
[0074] The "hydrocarbon group" may have 1 to 5, preferably 1 to 3
aforementioned substituents at a substitutable position and, when
the number of substituents is 2 or more, respective substituents
may be the same or different.
[0075] As aforementioned "optionally halogenated C.sub.1-6 alkyl",
for example, there are C.sub.1-6 alkyl (for example, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
hexyl and the like) and the like optionally having 1 to 5,
preferably 1 to 3 halogen atoms (for example, fluorine, chlorine,
bromine, iodine and the like). Examples thereof are methyl,
chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,
ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,
propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,
4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,
6,6,6-trifluorohexyl and the like.
[0076] As the aforementioned "optionally halogenated C.sub.2-6
alkenyl", for example, there are C.sub.2-6 alkenyl (for example,
vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl,
5-hexen-1-yl) and the like optionally having 1 to 5, preferably 1
to 3 halogen atoms (for example, fluorine, chlorine, bromine,
iodine and the like).
[0077] As the aforementioned "optionally halogenated C.sub.2-6
alkynyl", there are C.sub.2-6 alkynyl (for example, 2-butyn-1-yl,
4-pentyn-1-yl, 5-hexyn-1-yl and the like) and the like optionally
having 1 to 5, preferably 1 to 3 halogen atoms (for example,
fluorine, chlorine, bromine, iodine and the like).
[0078] As the aforementioned "optionally halogenated C.sub.3-6
cycloalkyl", for example, there are C.sub.3-6 cycloalkyl (for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the
like) and the like optionally having 1 to 5, preferably 1 to 3
halogen atoms (for example, fluorine, chlorine, bromine, iodine and
the like). Examples thereof are cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl,
2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the
like.
[0079] As the aforementioned "optionally halogenated C.sub.1-8
alkoxy", for example, there are C.sub.1-8 alkoxy (for example,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, pentyloxy, hexyloxy and the like) and the like
optionally having 1 to 5, preferably 1 to 3 halogen atoms (for
example, fluorine, chlorine, bromine, iodine and the like).
Examples thereof are methoxy, difluoromethoxy, trifluoromethoxy,
ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,
4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy
and the like.
[0080] As the aforementioned "optionally halogenated C.sub.1-6
alkylthio", for example, there are C.sub.1-6 alkylthio (for
example, methylthio, ethylthio, propylthio, isopropylthio,
butylthio, sec-butylthio, tert-butylthio and the like) and the like
optionally having 1 to 5, preferably 1 to 3 halogen atoms (for
example, fluorine, chlorine, bromine, iodine and the like).
Examples thereof are methylthio, difluoromethylthio,
trifluoromethylthio, ethylthio, propylthio, isopropylthio,
butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the
like.
[0081] As "5 to 7 membered saturated cyclic amino" of the
aforementioned "5 to 7 membered saturated cyclic amino optionally
having substituents", there are 5 to 7 membered saturated cyclic
amino optionally containing 1 to 4 heteroatoms of one or two kinds
selected from a nitrogen atom, a sulfur atom and an oxygen atom in
addition to one nitrogen atom and carbon atoms and examples thereof
are pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,
thiomorpholino, hexahydroazepin-1-yl and the like.
[0082] As "substituents" of the "5 to 7 membered saturated cyclic
amino optionally having substituents", for example, there are 1 to
3 C.sub.1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the
like), C.sub.6-14 aryl (for example, phenyl, 1-naphthyl,
2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and
the like), C.sub.1-6 alkyl-carbonyl (for example, acetyl, propionyl
and the like), 5 to 10 membered aromatic heterocyclic group (for
example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,
1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,
1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,
2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,
3-benzo[b]furanyl and the like), oxo and the like.
[0083] As "heterocyclic group" of "heterocyclic group optionally
having substituents" represented by R.sup.5, for example, there is
a monovalent group obtained by removing one arbitrary hydrogen atom
from a 5 to 14 membered (monocyclic, bicyclic or tricyclic)
heterocycle containing 1 to 4 heteroatoms of one or two kinds
selected from a nitrogen atom, a sulfur atom and an oxygen atom in
addition to carbon atoms, preferably (i) a 5 to 14 membered
(preferably 5 to 10 membered, particularly preferably 5 to 6
membered) aromatic heterocycle, (ii) a 5 to 10 membered (preferably
5 to 6 membered) non-aromatic heterocycle or (iii) a 7 to 10
membered bridged heterocycle.
[0084] As the aforementioned "5 to 14 membered (preferably 5 to 10
membered) aromatic heterocycle", there are an aromatic heterocycle
such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole,
benzoxazole, benzothiazole, benzisothiazole,
naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole,
pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole,
1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline,
phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,
carbazole, .beta.-carboline, phenanthridine, acridine, phenazine,
thiazole, isothiazole, phenothiazine, isoxazole, furazan,
phenoxazine and the like, and a ring formed by fusing these rings
(preferably monocyclic) with 1 or a plurality (preferably 1 to 2)
of aromatic rings (for example, benzene ring and the like).
[0085] As the aforementioned "5 to 10 membered non-aromatic
heterocycle", for example, there are pyrrolidine, imidazoline,
pyrazolidine, pyrazoline, piperidine, piperazine, morpholine,
thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline,
thiadiazole, dithiazole and the like.
[0086] As the aforementioned "7 to 10 membered bridged
heterocycle", for example, there are quinuclidine,
7-azabicyclo[2.2.1]heptane and the like.
[0087] The "heterocyclic group" is preferably a 5 to 14 membered
(preferably 5 to 10 membered) (monocyclic or bicyclic) heterocyclic
group containing preferably 1 to 4 heteroatoms of one or two kinds
selected from a nitrogen atom, a sulfur atom and an oxygen atom in
addition to carbon atoms. More particularly, examples thereof are
an aromatic heterocyclic group such as 2-thienyl, 3-thienyl,
2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,
3-quinolyl, 4-quinolyl, S-quinolyl, 8-quinolyl, 1-isoquinolyl,
3-isoquinolyl, 4-isoquinolyl, 8-isoquinolyl, pyrazinyl,
2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl,
3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl,
3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,
2-benzo[b]furanyl, 3-benzo[b]furanyl and the like, and a
non-aromatic heterocyclic group such as 1-pyrrolidinyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl,
2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino,
2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl,
2-piperazinyl, morpholino, thiomorpholino and the like.
[0088] Among them, for example, a 5 or 6 membered heterocyclic
group containing 1 to 3 heteroatoms selected from a nitrogen atom,
a sulfur atom and an oxygen atom in addition to carbon atoms is
further preferable. More particularly, examples thereof are
2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl,
3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl,
3-isothiazolyl, 3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl,
3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl,
3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl,
3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino,
thiomorpholino and the like.
[0089] As "substituents" of "heterocyclic group optionally having
substituents", for example, there are the same "substituents" as
substituents of "hydrocarbon group optionally having substituents"
represented by R.sup.5.
[0090] The "heterocyclic group" may have 1 to 5, preferably 1 to 3
aforementioned substituents at a substitutable position and, when
the number of substituents is 2 or more, respective substituents
may be the same or different.
[0091] As "C.sub.1-6 alkyl" represented by R.sup.6, for example,
there are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl and the like.
[0092] As "hydrocarbon group optionally having substituents" and
"heterocyclic group optionally having substituents" represented by
R.sup.7, for example, there are the aforementioned "hydrocarbon
group optionally having substituents" and "heterocyclic group
optionally having substituents" represented by R.sup.5,
respectively.
[0093] As "hydrocarbon group optionally having substituents" and
"heterocyclic group optionally having substituents" represented by
R.sup.1, for example, there are the aforementioned "hydrocarbon
group optionally having substituents" and "heterocyclic group
optionally having substituents" represented by R.sup.5,
respectively.
[0094] As "amino group optionally having substituents" represented
by R.sup.1, for example, there are (1) an amino group optionally
having 1 or 2 substituents and (2) a cyclic amino group optionally
having substituents and the like.
[0095] As "substituents" of "amino group optionally having 1 or 2
substituents" of the aforementioned (1), for example, there are a
hydrocarbon group optionally having substituents, a heterocyclic
group optionally having substituents, an acyl group, an alkylidene
group optionally having substituents and the like. As these
"hydrocarbon group optionally having substituents" and
"heterocyclic group optionally having substituents", there are the
same "hydrocarbon group optionally having substituents" and
"heterocyclic group optionally having substituents" as those
represented by R.sup.5 described above, respectively. As the "acyl
group", there is the same "acyl group" as that by represented by
R.sup.1 as described above.
[0096] As "alkylidene group" of "alkylidene group optionally having
substituents", for example, there are a C.sub.1-6 alkylidene group
(for example, methylidene, ethylidene, propylidene and the like)
and the like. As "substituents" of "alkylidene group optionally
having substituents", there are 1 to 5, preferably 1 to 3 same
substituents as "substituents" of "hydrocarbon group optionally
having substituents" represented by R.sup.5.
[0097] When the number of the aforementioned "substituents" of
"amino group optionally having 1 or 2 substituents" is 2,
respective substituents may be the same or different.
[0098] As "cyclic amino group" of "cyclic amino group optionally
having substituents" of the aforementioned (2), there are a 5 to 7
membered non-aromatic cyclic amino group optionally containing 1 to
4 heteroatoms of one or two kinds selected from a nitrogen atom, a
sulfur atom and an oxygen atom in addition to one nitrogen atom and
carbon atoms. More particularly, examples thereof are
pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,
thiomorpholino, hexahydroazepin-1-yl, imidazolidin-1-yl,
2,3-dihydro-1H-imidazol-1-yl, tetrahydro-1(2H)-pyrimidinyl,
3,6-dihydro-1(2H)-pyrimidinyl, 3,4-dihydro-1(2H)-pyrimidinyl and
the like. As "substituents" of "cyclic amino optionally having
substituents", there are 1 to 3 same ones as "substituents" of "5
to 7 membered saturated cyclic amino group" which were described in
detail as "substituents" of "hydrocarbon group optionally having
substituents" represented by R.sup.5.
[0099] Examples of the 5 to 7 membered non-aromatic cyclic amino
group having 1 oxo, there are 2-oxoimidazolidin-1-yl,
2-oxo-2,3-dihydro-1H-imidazol-1-yl,
2-oxotetrahydro-1(2H)-pyrimidinyl,
2-oxo-3,6-dihydro-1(2H)-pyrimidinyl,
2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, 2-oxopyrrolidin-1-yl,
2-oxopiperidino, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl,
2-oxo-2,3,4,5,6,7-hexahydroazepin-1-yl and the like.
[0100] As R.sup.1, an amino group optionally having substituents,
an aryl group optionally having substituents and an alkyl group
optionally having substituents and the like are preferable.
[0101] As further preferable example of the "amino group optionally
having substituents" is an amino group optionally having 1 or 2
acyl represented by the formula: --(C.dbd.O)--R.sup.5,
--(C.dbd.O)--OR.sup.5, --(C.dbd.O)--NR.sup.5R.sup.6,
--(C.dbd.S)--NHR.sup.5 or --SO.sub.2--R.sup.7 [wherein respective
symbols represent the same meanings as described above].
Particularly preferable example is an amino group optionally having
1 or 2 acyl represented by the formula: --C(C.dbd.O)--R.sup.5 or
--(C.dbd.O)--NR.sup.5R.sup.6 [wherein respective symbols represent
the same meanings as described above].
[0102] As the "aryl group optionally having substituents", for
example, there is preferably a C.sub.6-14 aryl group (preferably a
phenyl group and the like) optionally having 1 to 5 substituents
selected from C.sub.1-6 alkylthio, C.sub.6-14 arylthio, C.sub.1-6
alkylsulfinyl, C.sub.6-14 arylsulfinyl, C.sub.1-6 alkylsulfonyl,
C.sub.6-14 arylsulfonyl and carboxy.
[0103] As the "alkyl group optionally having substituents", for
example, a C.sub.1-6 alkyl group (for example, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the
like) optionally substituted with 1 to 3 substituents selected from
halogen atom, C.sub.1-6 alkoxy, hydroxy, carboxy and C.sub.1-6
alkoxy-carbonyl and the like are preferable, and particularly
C.sub.1-3 alkyl group such as methyl, ethyl and the like is
preferable.
[0104] Among them, as R.sup.1, (i) C.sub.1-6 alkyl group (for
example, C.sub.1-4 alkyl group such as methyl, ethyl, propyl,
butyl), (ii) a C.sub.6-14 aryl group (for example, a phenyl group)
optionally substituted with substituents selected from C.sub.1-6
alkylthio (for example, methylthio), C.sub.1-6 alkylsulfonyl (for
example, methylsulfonyl) and halogen atom (for example, chlorine
atom, fluorine atom) or (iii) an amino group optionally having 1 or
2 acyl represented by the formula: --(C.dbd.O)--R.sup.5' (wherein
R.sup.5' represents {circle around (1)} a C.sub.1-6 alkyl group
(for example, C.sub.1-3 alkyl group such as methyl), {circle around
(2)} a C.sub.6-14 aryl group (for example, a phenyl group) or
{circle around (3)} a 5 to 14 membered heterocyclic group
containing 1 to 4 heteroatoms of one or two kinds selected from a
nitrogen atom, a sulfur atom and an oxygen atom in addition to
carbon atoms (for example, a 5 to 6 membered heterocyclic group
containing 1 to 2 heteroatoms selected from a nitrogen atom, a
sulfur atom and an oxygen atom in addition to carbon atoms such as
pyridyl group) are preferable. As R.sup.5' and R.sup.5'', a phenyl
group or a pyridyl group is suitable.
[0105] In the aforementioned formula, R.sup.2 represents an
aromatic group optionally having substituents.
[0106] As "aromatic group" of "aromatic group optionally having
substituents" represented by R.sup.2, for example, there are an
aromatic hydrocarbon group, an aromatic heterocyclic group and the
like.
[0107] As the "aromatic hydrocarbon group", examples thereof
include a C.sub.6-14 monocyclic or fused polycyclic (bicyclic or
tricyclic) aromatic hydrocarbon group, etc. As examples, there are
a C.sub.6-14 aryl group and the like such as phenyl, 1-naphthyl,
2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and
the like and, further preferably, a C.sub.6-10 aryl group and the
like (for example, phenyl, 1-naphthyl, 2-naphthyl and the like,
preferably phenyl and the like).
[0108] As the "aromatic heterocyclic group", there is a monovalent
group obtained by removing one arbitrary hydrogen atom from 5 to 14
membered (preferably 5 to 10 membered) aromatic heterocycle
containing 1 to 4 heteroatoms of one or two kinds selected from
nitrogen atom, sulfur atom and oxygen atom in addition to carbon
atoms.
[0109] As the aforementioned "5 to 14 membered (preferably 5 to 10
membered) aromatic heterocycle", for example, there are an aromatic
heterocycle such as thiophene, benzo[b]thiophene, benzo[b]furan,
benzimidazole, benzoxazole, benzothiazole, benzisothiazole,
naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole,
pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole,
1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline,
phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,
carbazole, .beta.-carboline, phenanthridine, acridine, phenazine,
thiazole, isothiazole, phenothiazine, isoxazole, furazan,
phenoxazine and the like, and a ring formed by fusing these rings
(preferably monocycle) with 1 or a plurality of (preferably 1 or 2)
aromatic rings (for example, benzene ring and the like).
[0110] As the "aromatic heterocyclic group", there are preferably a
5 to 14 membered (preferably 5 to 10 membered) (monocyclic or
bicyclic) aromatic heterocyclic group containing preferably 1 to 4
heteroatoms of one or two kinds selected from a nitrogen atom, a
sulfur atom and an oxygen atom in addition to carbon atoms and the
like and, more particularly, there are an aromatic heterocyclic
group such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,
5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl,
4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl,
3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl,
2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,
2-benzo[b]furanyl, 3-benzo[b]furanyl and the like.
[0111] As "substituents" of "aromatic group optionally having
substituents", there are 1 to 5, preferably 1 to 3 same
substituents as "substituents" of "hydrocarbon group optionally
having substituents" represented by R.sup.5. When the number of
substituents is 2 or more, respective substituents may be the same
or different.
[0112] As R.sup.2, (1) a C.sub.6-14 aryl group optionally having
substituents and (2) a 5 to 14 membered aromatic heterocyclic group
containing 1 to 4 heteroatoms of one or two kinds selected from a
nitrogen atom, a sulfur atom and an oxygen atom in addition to
carbon atoms are preferable and, among them, (1) a C.sub.6-14 aryl
group (for example, phenyl group, naphthyl group) optionally
substituted with halogen atom (for example, chlorine atom, fluorine
atom) or C.sub.1-6 alkoxy (for example, methoxy), (2) a 5 to 14
membered aromatic heterocyclic group containing 1 to 4 heteroatoms
of one or two kinds selected from a nitrogen atom, a sulfur atom
and an oxygen atom in addition to carbon atoms (for example, a 5 to
6 membered aromatic heterocyclic group containing 1 to 2
heteroatoms selected from a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms such as pyridyl group,
thienyl group) and the like are preferable and, in particular, a
phenyl group, a pyridyl group and the like are suitable.
[0113] In the aforementioned formula, R.sup.3 represents a hydrogen
atom, a pyridyl group optionally having substituents or an aromatic
hydrocarbon group optionally having substituents.
[0114] As "substituents" of "pyridyl group optionally having
substituents" represented by R.sup.3, there are the same
substituents as "substituents" of "hydrocarbon group optionally
having substituents" represented by R.sup.5.
[0115] The "pyridyl group" may, for example, have 1 to 5,
preferably 1 to 3 aforementioned substituents at substitutable
positions and, when the number of substituents is 2 or more,
respective substituents may be the same or different. In addition,
an intracyclic nitrogen atom may be N-oxidized.
[0116] As "aromatic hydrocarbon group" of "aromatic hydrocarbon
group optionally having substituents" represented by R.sup.3, there
is the same aromatic hydrocarbon group as "aromatic hydrocarbon
group" of "aromatic hydrocarbon group optionally having
substituents" represented by R.sup.2 and, preferably, there are a
C.sub.6-14 aryl group and the like such as phenyl, 1-naphthyl,
2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and
the like and, further preferably, a C.sub.6-10 aryl group and the
like (for example, phenyl, 1-naphthyl, 2-naphthyl and the like,
preferably phenyl and the like) and the like. As "substituents" of
"aromatic hydrocarbon group optionally having substituents"
represented by R.sup.3, there are the same substituents as
substituents of "aromatic group optionally having substituents"
represented by R.sup.2
[0117] As R.sup.3, a C.sub.6-14 aryl group optionally having
substituents is preferable and, among them, a C.sub.6-14 aryl group
optionally substituted with 1 or 2 C.sub.1-6 alkyl (for example,
methyl, ethyl and the like) or C.sub.1-6 alkoxy (for example,
methoxy, ethoxy and the like) is preferable and, in particular, a
phenyl group optionally substituted with 1 or 2 C.sub.1-6 alkyl or
C.sub.1-6 alkoxy (for example, 3-methoxyphenyl, 2-methylphenyl,
2,4-dimethylphenyl and the like) is suitable.
[0118] In the aforementioned formula, X represents an oxygen atom
or an optionally oxidized sulfur atom.
[0119] As "optionally oxidized sulfur atom" represented by X, there
are S, SO and SO.sub.2.
[0120] As X, there is preferably an optionally oxidized sulfur
atom. Further preferably, it is S.
[0121] In the aforementioned formula, Y represents a bond, an
oxygen atom, an optionally oxidized sulfur atom or the formula
NR.sup.4 (wherein R.sup.4 represents a hydrogen atom, a hydrocarbon
group optionally having substituents or an acyl group).
[0122] As "optionally oxidized sulfur atom" represented by Y, there
are S, SO and SO.sub.2.
[0123] As "hydrocarbon group optionally having substituents"
represented by R.sup.4, for example, there is the same group as
"hydrocarbon group optionally having substituents" represented by
R.sup.5. Among them, a C.sub.1-6 alkyl group such as methyl, ethyl
and the like and, in particular, a C.sub.1-3 alkyl group such as
methyl and the like is preferable.
[0124] As "acyl group" represented by R.sup.4, there is the same
group as "acyl group" represented by R.sup.1.
[0125] As Y, an oxygen atom, an optionally oxidized sulfur atom, a
group represented by the formula NR.sup.4 (wherein R.sup.4
represents the same meaning as that described above) and the like
are preferable and, among them, an oxygen atom, an optionally
oxidized sulfur atom, a group represented by the formula NR.sup.4'
(R.sup.4' represents a hydrogen group or a C.sub.1-6 alkyl group)
and the like are preferable and, further, an oxygen atom, S,
SO.sub.2, NH, N(CH.sub.3) and the like are preferable and, in
particular, O or NH is suitable.
[0126] In the aforementioned formula, Z represents a bond or a
divalent acyclic hydrocarbon group optionally having
substituents.
[0127] As "divalent acyclic hydrocarbon group" of "divalent acyclic
hydrocarbon group optionally having substituents", for example,
there are a C.sub.1-15 alkylene group (for example, methylene,
ethylene, propylene, butylene, pentamethylene, hexamethylene,
heptamethylene, octamethylene and the like, preferably a C.sub.1-6
alkylene group and the like), a C.sub.2-16 alkenylene group (for
example, vinylene, propylene, 1-butenylene, 2-butenylene,
1-pentenylene, 2-pentenylene, 3-pentenylene and the like), a
C.sub.2-16 alkynylene group (ethynylene, propynylene, 1-butenylene,
2-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene and the
like) and the like, preferably, a C.sub.1-15 alkylene group,
particularly preferably, a C.sub.1-6 alkylene group and the like.
As "substituents" of "divalent acyclic hydrocarbon group optionally
having substituents" represented by Z, for example, there are the
same substituents as "substituents" of "hydrocarbon group
optionally having substituents" represented by R.sup.5.
[0128] As Z, a lower alkylene group optionally having C.sub.1-3
alkyl (for example, methyl), oxo and the like (for example, a
C.sub.1-6 alkylene group such as methylene, ethylene, propylene and
the like, in particular, a C.sub.1-3 alkylene group) is preferable
and, among them, a C.sub.1-6 alkylene group optionally having oxo
(for example, a C.sub.1-3 alkylene group such as methylene,
ethylene, propylene, in particular, methylene) is suitable.
[0129] More particularly, as Z, --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --CO--, --CH.sub.2CO--,
--(CH.sub.2).sub.2CO--, --CH(CH.sub.3)-- and the like are used and,
in particular, --CH.sub.2--, --CO-- and the like are suitable.
[0130] A nitrogen atom in Compound (I) may be N-oxidized. For
example, a nitrogen atom which is a constituent atom of 4-pyridyl
group as a substituent at 5-position of a ring represented by the
formula:
##STR00031##
wherein a symbol in the formula represents the same meaning as that
described above, may be N-oxidized. As Compound (I), for example, a
compound represented by the formula:
##STR00032##
wherein n represents 0 or 1, and other symbols represents the same
meanings as those described above, or salts thereof are
preferable.
[0131] As Compound (I), compounds shown by the following (A) to (F)
are preferably used.
(A) Compound (I) wherein R.sup.1 is an amino group optionally
having substituents, R.sup.2 is a C.sub.6-14 aryl group optionally
having substituents, R.sup.3 is a C.sub.6-14 aryl group optionally
having substituents, X is a sulfur atom, Y is an oxygen atom or a
group represented by the formula NR.sup.4 (wherein R.sup.4
represents the same meaning as that described above) or (and) Z is
a lower alkylene group optionally having substituents. (B) Compound
(I) wherein R.sup.1 is (i) a C.sub.1-6 alkyl group (for example, a
C.sub.1-4 alkyl group such as methyl, ethyl, propyl, butyl and the
like), (ii) a C.sub.6-14 aryl group (for example, a phenyl group)
optionally substituted with substituents selected from C.sub.1-6
alkylthio (for example, methylthio), C.sub.1-6 alkylsulfonyl (for
example, methylsulfonyl) and halogen atom (for example, chlorine
atom, fluorine atom), or (iii) an amino group optionally having 1
or 2 acyl represented by the formula: --(C.dbd.O)--R.sup.5'
[wherein R.sup.5' represents {circle around (1)} a C.sub.1-6 alkyl
group (for example, C.sub.1-3 alkyl group such as methyl and the
like), {circle around (2)} a C.sub.6-14 aryl group (for example, a
phenyl group) or {circle around (3)} a 5 to 14 membered
heterocyclic group containing 1 to 4 heteroatoms of one or two
kinds selected from a nitrogen atom, a sulfur atom and an oxygen
atom in addition to carbon atoms (for example, a 5 to 6 membered
heterocyclic group containing 1 to 2 heteroatoms selected from a
nitrogen atom, a sulfur atom and an oxygen atom in addition to
carbon atoms such as a pyridyl group);
[0132] R.sup.2 is a C.sub.6-14 aryl group (for example, a phenyl
group, a naphthyl group) optionally substituents with halogen atom
(for example, chlorine atom, fluorine atom) or C.sub.1-6 alkoxy
(for example, methoxy), or a 5 to 14 membered aromatic heterocyclic
group containing 1 to 4 heteroatoms of one or two kinds selected
from a nitrogen atom, a sulfur atom and an oxygen atom in addition
to carbon atoms (for example, a 5 to 6 membered aromatic
heterocyclic group containing 1 to 2 heteroatoms selected from a
nitrogen atom, a sulfur atom and an oxygen atom in addition to
carbon atoms such as a pyridyl group, a thienyl group and the
like);
R.sup.3 is a C.sub.6-14 aryl group (particularly, a phenyl group)
optionally substituted with 1 or 2 C.sub.1-6 alkyl (for example,
methyl) or C.sub.1-6 alkoxy (for example, methoxy); X is a sulfur
atom; Y is an oxygen atom, an optionally oxidized sulfur atom or a
group represented by the formula NR.sup.4' (R.sup.4' is a hydrogen
atom or a C.sub.1-6 alkyl group) (in particular, an oxygen atom, S,
SO.sub.2, NH, N(CH.sub.3) and the like);
[0133] Z is a C.sub.1-6 alkylene group (in particular, a C.sub.1-3
alkylene group) optionally having oxo or C.sub.1-6 alkyl (for
example, C.sub.1-3 alkyl such as methyl) or a bond.
(C) Compound (I) wherein R.sup.1 is an amino group optionally
having 1 or 2 acyl represented by the formula
--(C.dbd.O)--R.sup.5'' (wherein R.sup.5'' represents {circle around
(1)} a C.sub.6-14 aryl group (for example, phenyl group) or {circle
around (2)} a 5 to 14 membered heterocyclic group containing 1 to 4
heteroatoms of one or two kinds selected from a nitrogen atom, a
sulfur atom and an oxygen atom in addition to carbon atoms (for
example, a 5 to 6 membered heterocyclic group containing 1 to 2
heteroatoms selected from a nitrogen atom, a sulfur atom and an
oxygen atom in addition to carbon atoms such as a pyridyl
group);
[0134] R.sup.2 is a C.sub.6-14 aryl group (for example, a phenyl
group) or a 5 to 14 membered aromatic heterocyclic group containing
1 to 4 heteroatoms of one or two kinds selected from a nitrogen
atom, a sulfur atom and an oxygen atom in addition to carbon atoms
(for example, a 5 to 6 membered aromatic heterocyclic group
containing 1 to 2 heteroatoms selected from a nitrogen atom, a
sulfur atom and an oxygen atom in addition to carbon atoms such as
a pyridyl group);
[0135] R.sup.3 is a C.sub.6-14 aryl group (in particular, a phenyl
group) optionally substituted with 1 or 2 C.sub.1-6 alkyl (for
example, methyl) or C.sub.1-6 alkoxy (for example, methoxy);
[0136] X is a sulfur atom;
[0137] Y is O, NH or S;
[0138] Z is a bond or a C.sub.1-6 alkylene group (in particular, a
C.sub.1-3 alkylene group optionally having oxo, such as methylene,
ethylene and the like) optionally having oxo.
(D) Compound (I) prepared in Examples 1-79. [0139] (E)
[4-(3,5-dimethylphenyl)-5-(2-phenylmethyloxy-4-pyridyl)-1,3-thiazol-2-yl]-
amine (Example Compound No. 1), [0140]
N-[4-[2-benzoylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benz-
amide (Example Compound No. 2), [0141]
N-[4-(4-methoxyphenyl)-5-[2-[(3-pyridylcarbonylamino)]-4-pyridyl]-1,3-thi-
azol-2-yl]nicotinamide (Example Compound No. 3), [0142]
N-[4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
(Example Compound No. 4), [0143]
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamid-
e (Example Compound No. 5), [0144]
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylam-
ine (Example Compound No. 6), [0145]
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamid-
e hydrochloride (Example Compound No. 7), [0146]
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylam-
ine dihydrochloride (Example Compound No. 8). [0147] (F)
N-[5-[2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]a-
cetamide (Example Compound No. 9), [0148]
N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]ac-
etamide (Example Compound No. 10), [0149]
N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide
(Example Compound No. 13), [0150]
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]p-
henylacetamide (Example Compound No. 14), [0151]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetam-
ide (Example Compound No. 15-2), [0152]
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylaceta-
mide (Example Compound No. 15-3), [0153]
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetam-
ide (Example Compound No. 15-4), [0154]
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]phenylacetamide (Example Compound No. 15-6), [0155]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
(Example Compound No. 16-1), [0156]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpro-
pionamide (Example Compound No. 16-2), [0157]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methox-
yphenyl)propionamide (Example Compound No. 16-3), [0158]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbut-
yramide (Example Compound No. 16-5), [0159]
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide
(Example Compound No. 16-7), [0160]
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpr-
opionamide (Example Compound No. 16-8), [0161]
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
(Example Compound No. 16-9), [0162]
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpro-
pionamide (Example Compound No. 16-10), [0163]
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]b-
enzamide (Example Compound No. 16-11), [0164]
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]--
3-phenylpropionamide (Example Compound No. 16-12), [0165]
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]benzamide (Example Compound No. 16-15), [0166]
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-3-phenylpropionamide (Example Compound No. 16-16), [0167]
N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]ami-
ne (Example Compound No. 19-2), [0168]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenyl-
ethyl)amine (Example Compound No. 19-3), [0169]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenyl-
propyl)amine (Example Compound No. 19-4), [0170]
N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]am-
ine (Example Compound No. 19-5), [0171]
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-pheny-
lethyl)amine (Example Compound No. 19-6), [0172]
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-pheny-
lpropyl)amine (Example Compound No. 19-7), [0173]
N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]ami-
ne (Example Compound No. 19-8), [0174]
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenyl-
ethyl)amine. (Example Compound No. 19-9), [0175]
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenyl-
propyl)amine (Example Compound No. 19-10), [0176]
N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl-
]-2-pyridyl]amine (Example Compound No. 19-17), [0177]
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-N-(2-phenylethyl)amine (Example Compound No. 19-18), [0178]
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-N-(3-phenylpropyl)amine (Example Compound No. 19-19), [0179]
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]benzamide (Example Compound No. 20), [0180]
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]phenylacetamide (Example Compound No. 21-1), [0181]
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]-3-phenylpropionamide (Example Compound No. 21-2), [0182]
N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol--
5-yl]-2-pyridyl]amine (Example Compound No. 21-5), [0183]
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]-N-(3-phenylpropyl)amine (Example Compound No. 21-6), [0184]
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]-N-(2-phenylethyl)amine (Example Compound No. 25-1), [0185]
N-(4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,-
3-thiazol-5-yl]-2-pyridyl]amine (Example Compound No. 25-2).
[0186] As a salt of Compound (I), for example, there are a metal
salt, ammonium salt, a salt with an organic base, salt with an
inorganic acid, a salt with an organic acid, a salt with basic or
acidic amino acid and the like. As a suitable metal salt, there are
alkali metal salt such as sodium salt, potassium salt and the like;
alkaline earth metal salt such as calcium salt, magnesium salt,
barium salt and the like; aluminum salt and the like. As a suitable
example of a salt with an organic base, for example, there are
salts with trimethylamine, triethylamine, pyridine, picoline,
2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,
cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine
and the like. As a suitable example of a salt with an inorganic
acid, for example, there are salts with hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and
the like. As a suitable example of a salt with an organic acid, for
example, there are salts with formic acid, acetic acid,
trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid,
tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
and the like. As a suitable example of a salt with a basic amino
acid, for example, there are salts with alginine, lysine, ornithine
and the like. As a suitable example of a salt with an acidic amino
acid, for example, there are salts with aspartic acid, glutamic
acid and the like.
[0187] Among them, pharmaceutically acceptable salts are
preferable. For example, when a compound has an acidic functional
group therein, there are inorganic salts such as alkali metal salt
(for example, sodium salt, potassium salt and the like), alkaline
earth metal salt (for example, calcium salt, magnesium salt, barium
salt and the like), ammonium salts and the like and, when a
compound has a basic functional group therein, there are salts with
inorganic acids such as hydrochloric acid, hydrobromic acid, nitric
acid, sulfuric acid, phosphoric acid and the like, and salts with
organic acids such as acetic acid, phthalic acid, fumaric acid,
oxalic acid, tartaric acid, maleic acid, citric acid, succinic
acid, methanesulfonic acid, p-toluenesulfonic acid and the
like.
[0188] A process for producing Compound (I) will be described
below. Compound (Ia), (Ib), (Ic) or (Id) is a compound included in
Compound (I).
[0189] Compound (I) is obtained by a method shown by the following
reaction formulas 1, 2, 4 and 5 or a similar method to that.
[0190] Respective symbols in compounds in the following reaction
formulas 1, 2, 4 and 5 have the same meanings as those described
above. Compounds in the reaction formulas include salts thereof
and, as the salts, for example, there are the same as those of
Compound (I).
##STR00033##
[0191] Compounds (II), (III), (V), (VIII), (XI), (XII), (XVII),
(XVIII), (XIX), (XX), (XXI), (XXII), (XXVI) and (XXVII) can be used
as they are when they are commercially available or can be prepared
by a method known per se or according to the similar method to
this.
[0192] Compound (IV) can be obtained by condensing Compound (II)
and Compound (III) in the presence of a base.
[0193] An amount of Compound (III) to be used is about 0.5 to about
3 moles, preferably about 0.8 to about 2 moles relative to 1 mole
of Compound (II).
[0194] An amount of a base to be used is about 1 to about 30 moles,
preferably about 1 to about 10 moles relative to 1 mole of Compound
(II).
[0195] As the "base", for example, there are a basic salt such as
sodium carbonate, potassium carbonate, cesium carbonate, sodium
acetate and the like, an inorganic base such as sodium hydroxide,
potassium hydroxide and the like, an aromatic amine such as
pyridine, lutidine and the like, a tertiary amine such as
triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like, an alkali metal hydride such as
sodium hydride, potassium hydride and the like, a metal amide such
as sodium amide, lithium diisopropylamide, lithium
hexamethyldisilazide and the like, a metal alkoxide such as sodium
methoxide, sodium ethoxide, potassium tert-butoxide and the
like.
[0196] It is advantageous that this reaction is conducted without a
solvent or in the presence of an inert solvent. Although the
solvent is not particularly limited as long as the reaction
proceeds, for example, halogenated hydrocarbons, aliphatic
hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols,
water or a mixture of two or more of them are used.
[0197] A reaction temperature is usually about -5 to about
200.degree. C., preferably about 5 to about 150.degree. C. A
reaction time is usually about 5 minutes to about 72 hours,
preferably about 0.5 to about 20 hours.
[0198] Although the reaction product can be used as the reaction
solution itself or as a crude product in the next step, it can be
isolated from the reaction mixture according to the conventional
method and can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0199] Compound (VI) can be obtained by treating Compound (IV) with
a base and condensing the obtained compound with Compound (V).
[0200] In Compound (V), L represents a leaving group. As "leaving
group" denoted by L, for example, there are {circle around (1)}
C.sub.1-6 alkoxy (for example, methoxy, ethoxy and the like),
{circle around (2)} di-C.sub.1-6 alkylamino (for example,
dimethylamino, diethylamino and the like), {circle around (3)}
N--C.sub.6-10 aryl-N--C.sub.1-6 alkylamino (for example,
N-phenyl-N-methylamino and the like), {circle around (4)} 3 to 7
membered cyclic amino (for example, pyrrolidino, morpholino,
methylaziridin-1-yl and the like) optionally substituted with
C.sub.6-10 aryl and (or) C.sub.1-6 alkyl, {circle around (5)}
N--C.sub.1-6 alkyl-N--C.sub.1-6 alkoxyamino
(N-methoxy-N-methylamino and the like) and the like. Further, as
"leaving group" denoted by L, for example, there are hydroxy,
halogen atom (for example, fluorine, chlorine, bromine, iodine and
the like), optionally halogenated C.sub.1-5 alkylsulfonyloxy (for
example, methanesulfonyloxy, ethanesulfonyloxy,
trichloromethanesulfonyloxy and the like), C.sub.6-10
arylsulfonyloxy optionally having substituents and the like. As
"C.sub.6-10 arylsulfonyloxy optionally having substituents", for
example, there are C.sub.6-10 arylsulfonyloxy (for example,
phenylsulfonyloxy, naphthylsulfonyloxy and the like) optionally
having 1 to 3 substituents selected from C.sub.1-6 alkyl, C.sub.1-6
alkoxy and nitro. Examples thereof are benzenesulfonyloxy,
m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy and the like.
[0201] An amount of a base to be used is about 0.8 to about 3
moles, preferably about 1 to about 1.2 moles relative to 1 mole of
Compound (IV).
[0202] As the "base", for example, metal amides such as sodium
amide, lithium diisopropylamide, lithium hexamethyldisilazide and
the like are used.
[0203] It is advantageous that this reaction is conducted without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, aliphatic hydrocarbons, aromatic hydrocarbons,
ethers or a mixture of two or more of them and the like are
used.
[0204] A reaction temperature is usually about -78 to about
60.degree. C., preferably about -78 to about 20.degree. C. A
reaction time is usually about 5 minutes to about 24 hours,
preferably about 0.5 to about 3 hours.
[0205] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0206] Compound (VII) can be obtained by treating Compound (VI)
with halogens or a metal halide. This reaction is performed in the
presence of a base or a basic salt if desired.
[0207] An amount of halogens or a metal halide to be used is about
1 to about 5 moles, preferably about 1 to about 2 moles relative to
1 mole of Compound (VI).
[0208] As the "halogens", there are bromine, chlorine, iodine and
the like.
[0209] As the "metal halide", there are copper halide such as
copper (II) bromide, copper (II) chloride and the like.
[0210] An amount of a base to be used is about 1 to about 30 moles,
preferably about 1 to about 10 moles relative to 1 mole of Compound
(VI).
[0211] As the "base", for example, there are inorganic bases such
as sodium hydroxide, potassium hydroxide, lithium hydroxide and the
like, basic salts such as sodium carbonate, potassium carbonate,
cesium carbonate, sodium hydrogencarbonate and the like, aromatic
amines such as pyridine, lutidine and the like, tertiary amines
such as triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like.
[0212] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, ethers, esters, aromatic hydrocarbons, aliphatic
hydrocarbons, amides, halogenated hydrocarbons, nitrites,
sulfoxides, organic acids, aromatic amines or a mixture of two or
more of them and the like are used.
[0213] A reaction temperature is about -20 to about 150.degree. C.,
preferably about 0 to about 100.degree. C. A reaction time is
usually about 5 minutes to about 24 hours, preferably about 10
minutes to about 5 hours.
[0214] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0215] Compound (Ia) can be obtained by condensing Compound (VII)
with Compound (VIII). This reaction is performed in the presence of
a base if desired.
[0216] In Compound (VII), Hal represents halogens.
[0217] When Compound (VIII) is commercially available, it can be
used as it is, or can be obtained by the method known per se or a
method according to the known method or further a method shown in
the reaction formula 3.
[0218] An amount of Compound (VIII) to be used is about 0.5 to
about 3 moles, preferably about 0.8 to about 2 moles relative to 1
mole of Compound (VII).
[0219] An amount of a base to be used is about 1 to about 30 moles,
preferably about 1 to about 10 moles relative to 1 mole of Compound
(VII).
[0220] As the "base", for example, there are alkali metal such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the
like, basic salts such as sodium carbonate, potassium carbonate,
cesium carbonate, sodium hydrogencarbonate and the like, aromatic
amines such as pyridine, lutidine and the like, tertiary amines
such as triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like.
[0221] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, halogenated hydrocarbons, aliphatic hydrocarbons,
aromatic hydrocarbons, ethers, amides, alcohols, nitrites or a
mixture of two or more of them and the like are used.
[0222] A reaction temperature is about -5 to about 200.degree. C.,
preferably about 5 to about 150.degree. C. A reaction time is
usually about 5 minutes to about 72 hours, preferably about 0.5 to
about 30 hours.
[0223] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0224] Compound (IX) can be obtained by treating Compound (Ia) with
an acid.
[0225] An amount of an acid to be used is about 1 to about 100
moles, preferably about 1 to about 30 moles relative to 1 mole of
Compound (Ia).
[0226] As the "acid", for example, there are mineral acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid and the like,
organic acids such as acetic acid, propionic acid, trifluoroacetic
acid and the like.
[0227] This reaction is performed in the presence of an inert
solvent for a reaction. The solvent is not particularly limited as
long as a reaction proceeds but, for example, water, a mixture of
water and amides, a mixture of water and alcohols and the like are
used.
[0228] A reaction temperature is usually about 20 to about
200.degree. C., preferably about 60 to about 150.degree. C. A
reaction time is usually about 30 minutes to about 72 hours,
preferably about 1 to about 30 hours.
[0229] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0230] Compound (X) is obtained by treating Compound (IX) with a
halogenating agent.
[0231] An amount of a halogenating agent to be used is about 1 to
about 10 moles, preferably about 1 to about 5 moles relative to 1
mole of Compound (IX).
[0232] As the "halogenating agent", there are thionyl chloride,
phosphorus pentachloride, phosphorus oxychloride and the like.
[0233] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, ethers, aromatic hydrocarbons, aliphatic
hydrocarbons, amides, halogenated hydrocarbons, nitriles,
sulfoxides, organic acids, aromatic amines or a mixture of two or
more of them and the like are used.
[0234] A reaction temperature is usually about -20 to about
150.degree. C., preferably about 0 to about 100.degree. C. A
reaction time is usually about 5 minutes to about 24 hours,
preferably about 10 minutes to about 5 hours.
[0235] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0236] Compound (Ib) can be obtained by condensing Compound (X)
with Compound (XI). This reaction is performed in the presence of a
base if desired.
[0237] An amount of a base to be used is about 0.8 to about 30
moles, preferably about 1 to about 10 moles relative to 1 mole of
Compound (X).
[0238] As the "base", for example, there are basic salts such as
sodium carbonate, potassium carbonate, cesium carbonate and the
like, inorganic bases such as sodium hydroxide, potassium hydroxide
and the like, aromatic amines such as pyridine, lutidine and the
like, tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like, alkali metal hydrides such as
sodium hydride, potassium hydride and the like, metal amides such
as sodium amide, lithium diisopropylamide, lithium
hexamethyldisilazide and the like, metal alkoxides such as sodium
methoxide, sodium ethoxide, potassium tert-butoxide and the
like.
[0239] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, aliphatic hydrocarbons, aromatic hydrocarbons,
ethers or a mixture of two or more of them and the like are
used.
[0240] A reaction temperature is usually about -78 to about
200.degree. C., preferably about room temperature to about
170.degree. C. A reaction time is usually about 5 minutes to about
72 hours, preferably about 0.5 to about 24 hours.
[0241] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
##STR00034##
[0242] Compound (XIII) is obtained from Compound (XII) by a method
described in Synthesis, p.p. 877-882, 1996 or Journal of Organic
Chemistry, vol. 61, p.p. 4810-4811, 1996.
[0243] Compound (XIV) is obtained by treating Compound (XIII) with
a base and condensing the obtained compound with Compound (V).
[0244] An amount of a base is about 0.8 to about 5 moles,
preferably about 2 to about 2.5 moles.
[0245] As the "base", for example, alkyllithiums such as
n-butyllithium and the like and metal amides such as sodium amide,
lithium diisopropylamide, lithium hexamethyldisilazide and the like
are used.
[0246] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, aliphatic hydrocarbons, aromatic hydrocarbons,
ethers or a mixture of two or more of them and the like are
used.
[0247] A reaction temperature is usually about -78 to about
60.degree. C., preferably about -78 to about 20.degree. C. A
reaction time is usually about 5 minutes to about 24 hours,
preferably about 0.5 to about 3 hours.
[0248] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0249] Compound (XV) can be obtained by treating Compound (XIV)
with halogens or a metal halide. This reaction is performed
optionally in the presence of a base or a basic salt.
[0250] An amount of halogens or a metal halide to be used is about
1 to about 5 moles, preferably about 1 to about 2 moles relative to
1 mole of Compound (XIV).
[0251] As the "halogens", there are bromine, chlorine, iodine and
the like.
[0252] As the "metal halide", there are copper halide such as
copper (II) bromide, copper (II) chloride and the like.
[0253] An amount of a base to be used is about 1 to about 10 moles,
preferably about 1 to about 3 moles relative to 1 mole of Compound
(XIV).
[0254] As the "base", for example, there are alkali metal such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the
like, basic salts such as sodium carbonate, potassium carbonate,
cesium carbonate, sodium hydrogencarbonate, sodium acetate and the
like, aromatic amines such as pyridine, lutidine and the like,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like.
[0255] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, ethers, esters, aromatic hydrocarbons, aliphatic
hydrocarbons, amides, halogenated hydrocarbons, nitriles,
sulfoxides, organic acids, aromatic amines or a mixture of two or
more of them and the like are used.
[0256] A reaction temperature is usually about -20 to about
150.degree. C., preferably about 0 to about 100.degree. C. A
reaction time is usually about 5 minutes to about 24 hours,
preferably about 10 minutes to about 5 hours.
[0257] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0258] Compound (XVI) can be obtained by condensing Compound (XV)
and Compound (VIII). This reaction is performed optionally in the
presence of a base.
[0259] In Compound (XV), Hal represents halogens.
[0260] When Compound (VIII) is commercially available, it can be
used as it is, or is obtained by the method known per se or a
method according to the known method, or further by a method shown
by the following reaction formula 3.
[0261] An amount of Compound (VIII) to be used is about 0.5 to
about 3 moles, preferably about 0.8 to about 2 moles relative to 1
mole of Compound (XV).
[0262] An amount of a base to be used is about 1 to about 30 moles,
preferably about 1 to about 10 moles relative to 1 mole of Compound
(XV).
[0263] As the "base", for example, there are basic salts such as
sodium carbonate, potassium carbonate, cesium carbonate, sodium
hydrogencarbonate, sodium acetate and the like, aromatic amines
such as pyridine, lutidine and the like, tertiary amines such as
triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like.
[0264] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, halogenated hydrocarbons, aliphatic hydrocarbons,
aromatic hydrocarbons, ethers, amides, alcohols, nitrites or a
mixture of two or more of them and the like are used.
[0265] A reaction temperature is about -5 to about 200.degree. C.,
preferably about 5 to about 150.degree. C. A reaction time is
usually about 5 minutes to about 72 hours, preferably about 0.5 to
about 30 hours.
[0266] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0267] Compound (XVII) is obtained by deprotecting Compound (XVI)
using an acid or a base.
[0268] An amount of an acid or a base to be used is about 0.1 to
about 50 moles, preferably about 1 to about 20 moles relative to 1
mole of Compound (XVI).
[0269] As the "acid", for example, mineral acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid and the like,
Lewis acids such as boron trichloride, boron tribromide and the
like, the use of Lewis acid together with thiols or sulfides,
organic acids such as trifluoroacetic acid, p-toluenesulfonic acid
and the like are used.
[0270] As the "base", for example, metal hydroxides such as sodium
hydroxide, potassium hydroxide, barium hydroxide and the like,
basic salts such as sodium carbonate, potassium carbonate and the
like, metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide and the like, organic bases such as
triethylamine, imidazole, formamidine and the like are used.
[0271] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, alcohols, ethers, aromatic hydrocarbons,
aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxides, water
or a mixture of two or more of them and the like are used.
[0272] A reaction time is usually about 10 minutes to about 50
hours, preferably about 30 minutes to about 12 hours. A reaction
temperature is about 0 to about 200.degree. C., preferably about 20
to about 120.degree. C.
[0273] Compound (Ic) can be obtained by condensing Compound (XVII)
with Compound (XVIII) optionally in the presence of a base.
[0274] An amount of Compound (XVIII) to be used is about 0.8 to
about 5 moles, preferably about 1 to about 3 moles relative to 1
mole of Compound (XVII).
[0275] An amount of a base to be used is about 0.1 to about 3
moles, preferably about 0.3 to about 1.2 moles relative to 1 mole
of Compound (XVII).
[0276] As the "base", for example, there are basic salts such as
sodium carbonate, potassium carbonate, cesium carbonate, sodium
acetate and the like, inorganic base such as sodium hydroxide,
potassium hydroxide and the like, aromatic amines such as pyridine,
lutidine and the like, tertiary amines such as triethylamine,
tripropylamine, tributylamine, cyclohexyldimethylamine,
4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,
N-methylpyrrolidine, N-methylmorpholine and the like, alkali metal
hydrides such as sodium hydride, potassium hydride and the like,
metal amides such as sodium amide, lithium diisopropylamide,
lithium hexamethyldisilazide and the like, metal alkoxides such as
sodium methoxide, sodium ethoxide, potassium tert-butoxide and the
like.
[0277] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, aliphatic hydrocarbons, aromatic hydrocarbons,
ethers or a mixture of two or more of them and the like are
used.
[0278] A reaction temperature is usually about -78 to about
100.degree. C., preferably about -78 to about 70.degree. C. A
reaction time is usually about 5 minutes to about 24 hours,
preferably about 0.5 to about 20 hours.
[0279] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
Thereafter, compounds wherein R.sup.4 is other than hydrogen atom
can be synthesized by performing alkylation or acylation if
desired.
##STR00035##
[0280] Compound (XX) is obtained by condensing Compound (XIX) and
amines represented by the formula R.sup.6H.
[0281] R.sup.6 represents "amino optionally having substituents"
represented by the above-mentioned R.sup.1.
[0282] In Compound (XIX), R.sup.5 represents an alkoxy group. As
the "alkoxy group", for example, there are a C.sub.1-6 alkoxy group
such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the
like.
[0283] An amount of the "amines" to be used is about 1 to about 30
moles, preferably about 1 to about 10 moles relative to 1 mole of
Compound (XIX).
[0284] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, halogenated hydrocarbons, aliphatic hydrocarbons,
aromatic hydrocarbons, ethers, amides, alcohols, nitriles, ketones
or a mixture of two or more of them and the like are used.
[0285] A reaction temperature is about -5 to about 200.degree. C.,
preferably about 5 to about 120.degree. C. A reaction time is
usually about 5 minutes to about 72 hours, preferably about 0.5 to
about 30 hours.
[0286] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0287] Compound (VIII) is obtained by hydrolysing Compound (XX)
using an acid or a base.
[0288] An amount of an acid or a base to be used is about 0.1 to
about 50 moles, preferably about 1 to about 20 moles relative to 1
mole of Compound (XX), respectively.
[0289] As the "acid", for example, mineral acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid and the like,
Lewis acids such as boron trichloride, boron tribromide and the
like, the use of Lewis acid together with thiols or sulfides,
organic acids such as trifluoroacetic acid, p-toluenesulfonic acid
and the like are used.
[0290] As the "base", for example, metal hydroxides such as sodium
hydroxide, potassium hydroxide, barium hydroxide and the like,
basic salts such as sodium carbonate, potassium carbonate, sodium
acetate and the like, metal alkoxides such as sodium methoxide,
sodium ethoxide, potassium tert-butoxide and the like, organic
bases such as triethylamine, imidazole, formamidine and the like
are used.
[0291] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, alcohols, ethers, aromatic hydrocarbons,
aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxides, water
or a mixture of two or more of them and the like are used.
[0292] A reaction time is usually about 10 minutes to about 50
hours, preferably about 30 minutes to about 12 hours. A reaction
temperature is about 0 to about 200.degree. C., preferably about 20
to about 120.degree. C.
[0293] Compound (VIII) can be obtained by treating Compound (XXI)
with hydrogen sulfide in the presence of a base.
[0294] An amount of hydrogen sulfide is about 1 mole to about 30
moles relative to 1 mole of Compound (XXI).
[0295] An amount of a base to be used is about 1 to about 30 moles,
preferably about 1 to about 10 moles relative to 1 mole of Compound
(XXI).
[0296] As the "base", for example, there are aromatic amines such
as pyridine, lutidine and the like, tertiary amines such as
triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like, ammonia and the like.
[0297] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, halogenated hydrocarbons, aliphatic hydrocarbons,
aromatic hydrocarbons, ethers, aromatic amines or a mixture of two
or more of them and the like are used.
[0298] This reaction is performed under atmospheric pressure or
under pressurized condition. A reaction temperature is usually
about -20 to about 80.degree. C., preferably about -10 to about
30.degree. C. A reaction time is usually about 5 minutes to about
72 hours, preferably about 0.5 to about 30 hours.
[0299] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0300] Compound (VIII) can also be obtained by treating Compound
(XXII) with phosphorus pentasulfide or Lawesson's reagent.
[0301] An amount of phosphorus pentasulfide or Lawesson's reagent
to be used is about 0.5 to about 10 moles, preferably about 0.5 to
about 3 moles relative to 1 mole of Compound (XXII).
[0302] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, ethers, aromatic hydrocarbons, aliphatic
hydrocarbons, halogenated hydrocarbons or a mixture of two or more
of them and the like are used.
[0303] A reaction time is usually 10 minutes to about 50 hours,
preferably about 30 minutes to about 12 hours. A reaction
temperature is usually about 0 to about 150.degree. C., preferably
about 20 to about 120.degree. C.
[0304] Although a product (VIII) can be used as the reaction
solution itself or as a crude product in the next reaction, it can
be isolated from the reaction mixture by the conventional method,
and can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0305] When Compound (I) (including Compound (Ia), (Ib) and (Ic))
is acylamino compound, an objective compound can be also obtained
by subjecting the corresponding amine compound to an acylating
reaction known per se.
[0306] For example, among Compound (I), a compound wherein R.sup.1
is acylamino group optionally having substituents is obtained by
reacting the corresponding 2-thiazolamine and an acylating agent
optionally in the presence of a base or an acid.
[0307] An amount of an acylating agent to be used is about 1 to
about 5 moles, preferably about 1 to about 2 moles relative to 1
mole of the corresponding 2-thiazolamine.
[0308] As the "acylating agent", for example, there are carboxylic
acids corresponding to an objective acyl group or a reactive
derivative thereof (for example, acid halide, acid anhydride, ester
and the like) and the like.
[0309] An amount of a base or an acid to be used is about 0.8 to
about 5 moles, preferable about 1 to about 2 moles relative to 1
mole of the corresponding 2-thiazolamine.
[0310] As the "base", for example, there are triethylamine,
pyridine, 4-dimethylaminopyridine and the like.
[0311] As the "acid", for example, there are methanesulfonic acid,
p-toluenesulfonic acid, camphorsulfonic acid and the like.
[0312] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, ethers, aromatic hydrocarbons, aliphatic
hydrocarbons, amides, halogenated hydrocarbons, nitrites,
sulfoxides, aromatic amines or a mixture of two or more of them and
the like are used.
[0313] A reaction temperature is about -20 to about 150.degree. C.,
preferably about 0 to about 100.degree. C. A reaction time is
usually 5 minutes to about 24 hours, preferably about 10 minutes to
about 5 hours.
[0314] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0315] Compound (Id) is also obtained by a method shown by the
reaction formula 4 or a method according that method.
##STR00036##
[0316] Compound (Id) is obtained by treating Compound (I) with an
organic peroxy acid.
[0317] An amount of an organic peroxy acid to be used is about 0.8
to about 10 moles, preferable about 1 to about 3 moles-relative to
1 mole of Compound (I).
[0318] As the "organic peroxy acid", for example, there are
peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid
and the like.
[0319] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, halogenated hydrocarbons, aliphatic hydrocarbons,
aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides,
alcohols, nitriles, ketones or a mixture of two or more of them and
the like are used.
[0320] A reaction temperature is about -20 to about 130.degree. C.,
preferably about 0 to about 100.degree. C. A reaction time is
usually 5 minutes to about 72 hours, preferably about 0.5 to about
12 hours.
[0321] Alternatively, Compound (Id) is also obtained by treating
Compound (I) with hydrogen peroxide or alkyl hydroperoxide
optionally in the presence of a base, an acid or a metal oxide.
[0322] An amount of hydrogen peroxide or alkyl hydroperoxide to be
used is about 0.8 to about 10 moles, preferably about 1 to 3 moles
to 1 mole of Compound (I).
[0323] As the "alkyl hydroperoxide", for example, there are
tert-butyl hydroperoxide, cumene hydroperoxide and the like.
[0324] An amount of a base, an acid or a metal oxide to be used is
about 0.1 to about 30 moles, preferably 0.8 to about 5 moles
relative to 1 mole of Compound (I).
[0325] As the "base", for example, there are inorganic bases such
as sodium hydroxide, potassium hydroxide and the like, basic salts
such as sodium carbonate, potassium carbonate, sodium acetate and
the like.
[0326] As the "acid", for example, there are mineral acids such as
hydrochloric acid, sulfuric acid, perchloric acid and the like,
Lewis acids such as boron trifluoride, aluminum chloride, titanium
tetrachloride and the like, organic acids such as formic acid,
acetic acid and the like.
[0327] As the "metal oxide", for example, there are vanadium oxide
(V.sub.2O.sub.5), osmium tetroxide (OsO.sub.4), tungsten oxide
(WO.sub.3), molybdenum oxide (MoO.sub.3), selenium dioxide
(SeO.sub.2), chromium oxide (CrO.sub.3) and the like.
[0328] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, halogenated hydrocarbons, aliphatic hydrocarbons,
aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides,
alcohols, nitriles, ketones or a mixture of two or more of them and
the like are used.
[0329] A reaction temperature is about -20 to about 130.degree. C.,
preferably about 0 to about 100.degree. C. A reaction time is
usually 5 minutes to about 72 hours, preferably about 0.5 to about
12 hours.
[0330] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0331] Alternatively, Compound (Ic) is also obtained by a method
shown by the following reaction formula 5:
##STR00037##
[0332] Compound (XXIII) is obtained by deprotecting Compound (XIV)
using an acid or a base.
[0333] An amount of an acid or a base to be used is about 0.1 to
about 50 moles, preferably about 1 to about 20 moles relative to
one mole of Compound (XIV), respectively.
[0334] As the "acid", for example, mineral acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid and the like,
Lewis acids such as boron trichloride, boron tribromide and the
like, the use of Lewis acid together with thiols or sulfides,
organic acids such as trifluoroacetic acid, p-toluenesulfonic acid
and the like are used.
[0335] As the "base", for example, metal hydroxides such as sodium
hydroxide, potassium hydroxide, barium hydroxide and the like,
basic salts such as sodium carbonate, potassium carbonate and the
like, metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide and the like, organic bases such as
triethylamine, imidazole, formamidine and the like are used.
[0336] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, alcohols, ethers, aromatic hydrocarbons,
aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxides, water
or a mixture of two or more of them and the like are used.
[0337] A reaction time is usually about 10 minutes to about 50
hours, preferably about 30 minutes to about 12 hours. A reaction
temperature is about 0 to about 200.degree. C., preferably about 20
to about 120.degree. C.
[0338] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0339] Compound (XXIV) is obtained by condensing Compound (XXIII)
and Compound (XVIII) optionally in the presence of a base.
[0340] An amount of Compound (XVIII) to be used is about 0.8 to
about 5 moles, preferably about 1 to about 3 moles relative to one
mole of Compound (XXIII).
[0341] An amount of a base to be used is about 0.1 to about 3
moles, preferably about 0.3 to about 1.2 moles relative to 1 mole
of Compound (XXIII).
[0342] As the "base", for example, basic salts such as sodium
carbonate, potassium carbonate, cesium carbonate, sodium acetate
and the like, inorganic bases such as sodium hydroxide, potassium
hydroxide and the like, aromatic amines such as pyridine, lutidine
and the like, tertiary amines such as triethylamine,
tripropylamine, tributylamine, cyclohexyldimethylamine,
4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,
N-methylpyrrolidine, N-methylmorpholine and the like, alkali metal
hydrides such as sodium hydride, potassium hydride and the like,
metal amides such as sodium amide, lithium diisopropylamide,
lithium hexamethyldisilazide and the like, metal alkoxides such as
sodium methoxide, sodium ethoxide, potassium tert-butoxide and the
like.
[0343] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, aliphatic hydrocarbons, aromatic hydrocarbons,
ethers, water or a mixture of two or more of them and the like are
used.
[0344] A reaction temperature is usually about -78 to about
100.degree. C., preferably about -78 to about 70.degree. C. A
reaction time is usually about 5 minutes to about 24 hours,
preferably about 0.5 to about 20 hours.
[0345] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0346] Compound (XXV) is obtained by treating Compound (XXIV) with
halogens or a metal halide. This reaction is performed optionally
in the presence of a base or a basic salt.
[0347] An amount of halogens or a metal halide to be used is about
1 to about 5 moles, preferably about 1 to about 2 moles relative to
one mole of Compound (XXIV).
[0348] As the "halogens", there are bromine, chlorine, iodine and
the like.
[0349] As the "metal halide", there are copper halide such as
copper (II) bromide, copper (II) chloride and the like.
[0350] An amount of a base to be used is about 1 to about 10 moles,
preferably about 1 to about 3 moles relative to 1 mole of Compound
(XXIV).
[0351] As the "base", for example, there are alkali metals such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the
like, basic salts such as sodium carbonate, potassium carbonate,
cesium carbonate, sodium hydrogencarbonate, sodium acetate and the
like, aromatic amines such as pyridine, lutidine and the like,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like.
[0352] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, ethers, esters, aromatic hydrocarbons, aliphatic
hydrocarbons, amides, halogenated hydrocarbons, nitrites,
sulfoxides, organic acids, aromatic amines or a mixture of two or
more of them and the like are used.
[0353] A reaction temperature is usually about -20 to about
150.degree. C., preferably about 0 to about 100.degree. C. A
reaction time is usually about 5 minutes to about 24 hours,
preferably about 10 minutes to about 5 hours.
[0354] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0355] Compound (Ic) is obtained by condensing Compound (XXV) and
Compound (VIII). This reaction is performed optionally in the
presence of a base.
[0356] In Compound (XXV), Hal represents halogens.
[0357] An amount of Compound (VIII) to be used is about 0.5 to
about 3.0 moles, preferably about 0.8 to about 2 moles relative to
1 mole of Compound (XXV).
[0358] An amount of a base to be used is about 1 to about 30 moles,
preferably about 1 to about 10 moles relative to 1 mole of Compound
(XXV).
[0359] As the "base", for example, there are basic salts such as
sodium carbonate, potassium carbonate, cesium carbonate, sodium
hydrogencarbonate, sodium acetate and the like, aromatic amines
such as pyridine, lutidine and the like, tertiary amines such as
triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like.
[0360] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, halogenated hydrocarbons, aliphatic hydrocarbons,
aromatic hydrocarbons, ethers, amides, alcohols, nitriles or a
mixture of two or more of them and the like are used.
[0361] A reaction temperature is usually about -5 to about
200.degree. C., preferably about 5 to about 150.degree. C. A
reaction time is usually about 5 minutes to about 72 hours,
preferably about 0.5 to about 30 hours.
[0362] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
Thereafter, if desired, compounds other than a compound wherein
R.sup.4 is hydrogen atom may be synthesized by performing
alkylation or acylation.
##STR00038##
[0363] Compound (XXVII) is obtained by treating Compound (XXVI)
with a base and condensing the obtained compound with Compound
(V).
[0364] In Compound (XXVI), Hal' represents halogen atoms such as
fluorine, chlorine, bromine and iodine.
[0365] An amount of a base to be used is about 0.8 to about 5
moles, preferably about 1 to about 1.2 moles relative to 1 mole of
Compound (XXVI).
[0366] As the "base", for example, alkyllithiums such as
n-butyllithium and the like, metal amides such as sodium amide,
lithium diisopropylamide, lithium hexamethyldisilazide and the like
are used.
[0367] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, aliphatic hydrocarbons, aromatic hydrocarbons,
ethers or a mixture of two or more of them and the like are
used.
[0368] A reaction temperature is usually about -78 to about
60.degree. C., preferably about -78 to about 20.degree. C. A
reaction time is usually about 5 minutes to about 24 hours,
preferably about 0.5 to about 3 hours.
[0369] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0370] Compound (XXVIII) is obtained by treating Compound (XXVII)
with halogens or a metal halide. This reaction is performed
optionally in the presence of a base or a basic salt.
[0371] In Compound (XXVII), Hal' represents halogens such as
fluorine, chlorine, bromine and iodine.
[0372] An amount of halogens or a metal halide to be used is about
1 to about 5 moles, preferably about 1 to about 2 moles relative to
one mole of Compound (XXVII).
[0373] As the "halogens", there are bromine, chlorine, iodine and
the like.
[0374] As the "metal halide", there are copper halide such as
copper (II) bromide, copper (II) chloride and the like.
[0375] An amount of a base to be used is about 1 to about: 10
moles, preferably about 1 to about 3 moles relative to 1 mole of
Compound (XXVII).
[0376] As the "base", for example, there are alkali metals such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the
like, basic salts such as sodium carbonate, potassium carbonate,
cesium carbonate, sodium hydrogencarbonate, sodium acetate and the
like, aromatic amines such as pyridine, lutidine and the like,
tertiary amines such as triethylamine, tripropylamine,
tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like.
[0377] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, ethers, esters, aromatic hydrocarbons, aliphatic
hydrocarbons, amides, halogenated hydrocarbons, nitrites,
sulfoxides, organic acids, aromatic amines or a mixture of two or
more of them and the like are used.
[0378] A reaction temperature is usually about -20 to about
150.degree. C., preferably about 0 to about 100.degree. C. A
reaction time is usually about 5 minutes to about 24 hours,
preferably about 10 minutes to about 5 hours.
[0379] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0380] Compound (X) is obtained by condensing Compound (XXVIII) and
Compound (VIII). This reaction is performed optionally in the
presence of a base.
[0381] In Compound (XXVIII), Hal and Hal' denote halogen atoms such
as fluorine, chlorine, bromine and iodine.
[0382] An amount of Compound (VIII) to be used is about 0.5 to
about 3 moles, preferably about 0.8 to about 2 moles relative to 1
mole of Compound (XXVIII).
[0383] An amount of a base to be used is about 1 to about 30 moles,
preferably about 1 to about 10 moles relative to 1 mole of Compound
(XXVIII).
[0384] As the "base", for example, there are basic salts such as
sodium carbonate, potassium carbonate, cesium carbonate, sodium
hydrogencarbonate, sodium acetate and the like, aromatic amines
such as pyridine, lutidine and the like, tertiary amines such as
triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like.
[0385] It is advantageous that this reaction is performed without a
solvent or in the presence of an inert solvent for a reaction. The
solvent is not particularly limited as long as a reaction proceeds
but, for example, halogenated hydrocarbons, aliphatic hydrocarbons,
aromatic hydrocarbons, ethers, amides, alcohols, nitriles or a
mixture of two or more of them and the like are used.
[0386] A reaction temperature is usually about -5 to about
200.degree. C., preferably about 5 to about 150.degree. C. A
reaction time is usually about 5 minutes to about 72 hours,
preferably about 0.5 to about 30 hours.
[0387] Although a product can be used as the reaction solution
itself or as a crude product in the next reaction, it can be
isolated from the reaction mixture by the conventional method, and
can be easily purified by a separating means such as
recrystallization, distillation, chromatography and the like.
[0388] In the above respective reactions, when starting compounds
have amino, carboxy, hydroxy as substituents, a protecting groups
which are generally used in the peptide chemistry or the like may
be introduced into these groups and, after reaction, a desired
compound can be obtained by removing protecting groups if
needed.
[0389] As a protecting group for amino, for example, formyl or
C.sub.1-6 alkyl-carbonyl (for example, acetyl, propionyl and the
like), phenylcarbonyl, C.sub.1-6 alkoxy-carbonyl (for example,
methoxycarbonyl, ethoxycarbonyl and the like), phenyloxycarbonyl,
C.sub.7-10 aralkyloxy-carbonyl (for example, benzyloxycarbonyl and
the like), trityl, phthaloyl and the like which may have
substituents, respectively, are used. As these substituents,
halogen atoms (for example, fluorine, chlorine, bromine, iodine and
the like), C.sub.1-6 alkyl-carbonyl (for example, acetyl,
propionyl, valeryl and the like), nitro and the like are used and
the number of substituents is 1 to 3.
[0390] As a protecting group for carboxy, for example, C.sub.1-6
alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl,
tert-butyl and the like), phenyl, trityl, silyl and the like which
may have substituents, respectively, are used. As these
substituents, halogen atoms (for example, fluorine, chlorine,
bromine, iodine and the like), formyl, C.sub.1-6 alkyl-carbonyl
(for example, acetyl, propionyl, butylcarbonyl and the like),
nitro, C.sub.1-6 alkyl (for example, methyl, ethyl, tert-butyl and
the like), C.sub.6-10 aryl (for example, phenyl, naphthyl and the
like) and the like are used and the number of substituents is 1 to
3.
[0391] As a protecting group for hydroxy, for example, C.sub.1-6
alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl,
tert-butyl and the like), phenyl, C.sub.7-11 aralkyl (for example,
benzyl and the like), formyl, C.sub.1-6 alkyl-carbonyl (for
example, acetyl, propionyl and the like), phenyloxycarbonyl,
C.sub.7-11 aralkyloxy-carbonyl (for example, benzyloxycarbonyl and
the like), tetrahydropyranyl, tetrahydrofuranyl, silyl and the like
which may have substituents, respectively, are used. As these
substituents, halogen atoms (for example, fluorine, chlorine,
bromine, iodine and the like), C.sub.1-6 alkyl (for example,
methyl, ethyl, tert-butyl and the like), C.sub.7-11 aralkyl (for
example, benzyl and the like), C.sub.6-10 aryl (for example,
phenyl, naphthyl and the like), nitro and the like are used and the
number of substituents is 1 to 4.
[0392] In addition, as a method of removing a protecting group, the
method known per se or a method according to this method is used
and, for example, method by treating with an acid, a base, the
ultraviolet ray, hydrazine, phenylhydrazine, sodium
N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium
acetate and the like or a method of reduction is used.
[0393] In any cases, Compound (I) can be synthesized by further,
optionally, performing the known deprotection, acylation,
alkylation, hydrogenation, oxidation, reduction, carbon chain
extension and substituent exchange reaction alone or in a
combination of two or more of them. As these reactions, the
reactions described in Shinjikkenkagakukoza 14, vol. 15, 1977
(Maruzen Press) are adopted.
[0394] As the above "alcohols", for example, there are methanol,
ethanol, propanol, isopropanol, tert-butanol and the like.
[0395] As the above "ethers", for example, there are diethyl ether,
diisopropyl ether, diphenyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane and the like.
[0396] As the above "halogenated hydrocarbons", for example, there
are dichloromethane, chloroform, 1,2-dichloroethane, carbon
tetrachloride and the like.
[0397] As the above "aliphatic hydrocarbons", for example, there
are hexane, pentane, cyclohexane and the like.
[0398] As the above "aromatic hydrocarbons", for example, there are
benzene, toluene, xylene, chlorobenzene and the like.
[0399] As the above "aromatic amines", for example, there are
pyridine, lutidine, quinoline and the like.
[0400] As the above "amides", for example, there are
N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric
triamide and the like.
[0401] As the above "ketones", for example, there are acetone,
methyl ethyl ketone and the like.
[0402] As the above "sulfoxides", for example, there are dimethyl
sulfoxide and the like.
[0403] As the above "nitriles", for example, acetonitrile,
propionitrile and the like.
[0404] As the above "organic acids", for example, there are acetic
acid, propionic acid, trifluoroacetic acid and the like.
[0405] When a desired product is obtained in a free form by the
above reaction, it may be converted into a salt according to the
conventional method or, when a desired product is obtained as a
salt, it can be converted into a free form or another salt
according to the conventional method. Compound (I) thus obtained
can be isolated and purified from the reaction solution by the
known means, for example, trans-solvation, concentration, solvent
extraction, fractional distillation, crystallization,
recrystallization, chromatography and the like.
[0406] When Compound (I), (Ia), (Ib), (Ic) or (Id) is present as a
configurational isomer, diastereomer, conformer or the like, each
can be optionally isolated by the above separation and purification
means. In addition, Compound (I), (Ia), (Ib), (Ic) or (Id) is in
the form of its racemate, they can be separated into S- and R-forms
by any conventional optical resolution.
[0407] When Compound (I), (Ia), (Ib), (Ic) or (Id) exists
stereoisomer, both the isomers alone and mixtures of each isomers
are included in the scope of the present invention.
[0408] In addition, Compound (I), (Ia), (Ib), (Ic) or (Id) may be
hydrated or anhydrated.
[0409] Compound (I) may be labeled with an isotope (for example,
.sup.3H, .sup.14C, .sup.35S) or the like.
[0410] A prodrug of Compound (I) refers to a compound which is
converted into Compound (I) by an enzyme, gastric acid or the like
under the physiological conditions, that is, a compound which
undergoes enzymatic oxidation, reduction, hydrolysis or the like to
be converted into Compound (I), and a compound which undergoes
hydrolysis or the like by gastric acid or the like to be converted
into Compound (I). As a prodrug of Compound (I), there are a
compound in which an amino group of Compound (I) is acylated,
alkylated or phosphorylated (for example, a compound in which an
amino group of Compound (I) is eicosanoylation, alanylation,
pentylaminocarbonylation,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,
tetrahydrofuranylation, pyrrolidinylmethylation,
pivaloyloxymethylation, tert-butylation); a compound in which a
hydroxy group of Compound (I) is acylated, alkylated,
phosphorylated or boronylated (for example, a compound in which a
hydroxy group of Compound (I) is acetylated, palmitoylated,
propanoylated, pivaloylated, succinylated, fumarylated, alanylated,
dimethylaminomethylcarbonylated); a compound in which a carboxy
group of Compound (I) is esterified or amidated (a compound in
which a carboxy group of Compound (I) is ethylesterified,
phenylesterified, carboxymethylesterified,
dimethylaminomethylesterified, pivaloyloxymethylesterified,
ethoxycarbonyloxyethylesterified, phthalidylesterified,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified,
cyclohexyloxycarbonylethylesterified, methylamidated); and the
like. These compounds can be prepared from Compound (I) by the
method known per se.
[0411] Alternatively, a prodrug of Compound (I) may be a compound
which is changed into Compound (I), (Ia), (Ib), (Ic) or (Id) under
the physiological conditions described in "Iyakuhin no kaihatsu",
published by Hirokawashoten in 1990, vol. 7, Melecular Design,
pages 163-198.
[0412] Compound (I) of the present invention shows the high
affinity for adenosine receptor, in particular, A.sub.3 receptor
and has the low toxicity and little side effect and, therefore, is
useful as a safe drug.
[0413] A pharmaceutical composition of the present invention
containing Compound (I) shows an excellent adenosine A.sub.3
receptor antagonistic activity to a mammal (for example, mouse,
rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human being and
the like) and is also excellent in (oral) absorption, (metabolism)
stability and the like and, therefore, can be used as an agent for
preventing or treating adenosine A.sub.3 receptor-related diseases,
for example, asthma, allergic disease, inflammation, Addison's
disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis,
rheumatism, central nervous disease (for example, cerebrovascular
disease such as cerebral hemorrhage, cerebral infarction, head
trauma, spinal trauma, brain edema, multiple sclerosis and the
like), neurodegenerative disease (for example, Alzheimer's disease,
Parkinson's syndrome, amyotrophic lateral sclerosis (ALS)),
diabetes and the like. Preferably, Compound (I) is an agent for
preventing or treating central nervous disease, asthma, allergic
disease and the like.
[0414] Compound (I) of the present invention also shows an
excellent p38 MAP kinase inhibitory activity and TNF-.alpha.
inhibitory activity (TNF-.alpha. production inhibitory activity,
TNF-.alpha. action inhibitory activity) and is also useful as a
safe drug based these activities.
[0415] For example, a pharmaceutical composition of the present
invention containing Compound (I) can be used as an agent: for
preventing or treating p38 MAP kinase related diseases and
TNF-.alpha. related disease, for example, arthritis (for example,
rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty
arthritis, synovitis), toxemia (for example, sepsis, septic shock,
endotoxin shock, Gram-negative sepsis, toxic shock syndrome),
inflammatory bowel disease (for example, Crohn's disease,
ulcerative colitis), inflammatory pulmonary disease (for example,
chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary
tuberculosis), or cachexia (for example, cachexia derived from
infection, carcinocachexia, cachexia derived from acquired
immunodeficiency syndrome (AIDS)), arteriosclerosis,
Creutzfeldt-Jakob disease, virus infection (for example, virus
infection such as cytomegalovirus, influenza virus, herpesvirus and
the like), atopic dermatitis, systemic lupus erythematosus, AIDS
encephalopathy, meningitis, angina, cardiac infarction, congestive
heart failure, hepatitis, transplantation, dialysis hypotension,
disseminated intravascular coagulation and the like to a mammal
(for example, mouse, rat, hamster, rabbit, cat, dog, cow, sheep,
monkey, human being and the like). Preferably, Compound (I) is used
as an agent for preventing or treating rheumatism and the like.
[0416] A preparation of the present invention containing Compound
(I) has low toxicity and can be safely administered orally or
parenterally (for example, locally, rectally or intravenously or
the like) as it is or by mixing Compound (I) with a
pharmacologically acceptable carrier into, for example,
pharmaceutical preparations such as tablet (including dragee, film
coated-tablet and the like), powders, granules, capsules (including
soft capsules), solutions, injections, suppositories, sustained
releasing preparations and the like according to the method known
per se normally used in preparation of pharmaceutical preparations.
A content of Compound (I) in a preparation of the present invention
is about 0.01 to 100% by weight relative to the whole preparation.
A dose is different depending upon an administration subject, route
of administration, diseases and the like and the preparation may be
administered, as an adenosine A.sub.3 receptor antagonistic agent,
for example, as an oral agent to an asthma patient (weight about 60
kg), about 0.1 to about 30 mg active ingredient (Compound (I))/kg
weight per day, preferably about 1 to 20 mg/kg weight per day, once
or a few times per day.
[0417] As a pharmacologically acceptable carrier which may be used
for preparing a preparation of the present invention, there are the
conventional various organic or inorganic carriers as a
pharmaceutical material, for example, excipient, lubricant, binder
and disintegrating agent in solid preparations, or solvent,
solubilizing agent, suspending agent, isotonicity, buffer and
soothing agent in liquid preparations. Further, if needed,
additives such as the conventional preservative, antioxidant,
colorant, sweeting agent, adsorbing agent, wetting agent and the
like can be appropriately used at an appropriate amount.
[0418] As an excipient, for example, there are lactose, sucrose,
D-mannitol, starch, corn starch, crystalline cellulose, light
silicic acid anhydride and the like.
[0419] As a lubricant, for example, there are magnesium stearate,
calcium stearate, talc, colloidal silica and the like.
[0420] As a binder, for example, there are crystalline cellulose,
sucrose, D-mannitol, dextrin, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch,
sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose
and the like.
[0421] As a disintegrating agent, for example, there are starch,
carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium
carboxymethyl starch, L-hydroxypropyl cellulose and the like.
[0422] As a solvent, for example, there are water for injection,
alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive
oil and the like.
[0423] As a solubilizing agent, for example, there are polyethylene
glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,
trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
sodium citrate and the like.
[0424] As a suspending agent, for example, there are surfactants
such as stearyl triethanolamine, sodium lauryl sulfate, lauryl
aminopropionate, lecithin, benzalkonium chloride, benzethonium
chloride, glyceryl monostearate and the like; hydrophilic polymers
such as polyvinyl alcohol, polyvinylpyrrolidone, sodium
carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose and the like.
[0425] As an isotonicity, for example, there are glucose,
D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
[0426] As a buffer, for example, there are buffering solutions such
as phosphate, acetate, carbonate, citrate and the like.
[0427] As a soothing agent, for example, there are benzyl alcohol
and the like.
[0428] As a preservative, for example, there are
p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl
alcohol, dehydroacetic acid, sorbic acid and the like.
[0429] As an antioxidant, for example, there are sulfites, ascorbic
acid, .alpha.-tocopherol and the like.
[0430] The present invention will be explained in detail by way of
the following Reference Examples, Examples, Preparation Examples
and Test Examples but these are more examples and not limit the
present invention and can be varied without departing the scope of
the present invention.
[0431] "Room temperature" in the following Reference Examples and
Examples indicates normally about 10.degree. C. to about 35.degree.
C. "%" indicates percentage by weight unless otherwise indicated,
provided that yield represents mol/mol %.
[0432] Abbreviations used elsewhere indicate the following
meanings:
[0433] s: singlet
[0434] d: doublet
[0435] t: triplet
[0436] q: quartet
[0437] dd: double doublet
[0438] ddd: double double doublet
[0439] dt: double triplet
[0440] br: broad
[0441] J: coupling constant
[0442] Hz: Hertz
[0443] CDCl.sub.3: deuterated chloroform
[0444] .sup.1H-NMR: proton nuclear magnetic resonance spectrum
[0445] Me: methyl
EXAMPLES
Reference Example 1
2-phenylmethyloxy-4-methylpyridine
[0446] Sodium hydride (60% paraffin dispersion, 5.0 g, 120 mmol)
was washed with hexane (5 mL) twice and suspended in
tetrahydrofuran (200 mL). To this suspension was added dropwise a
solution of benzyl alcohol (14 g, 120 mmol) in tetrahydrofuran (50
mL) at 0.degree. C. and then, the mixture was allowed to warm up to
room temperature with stirring for 15 minutes. To this solution was
added a solution of 2-bromo-4-methylpyridine (19.5 mL, 110 mmol) in
tetrahydrofuran (50 mL) and heated to reflux for 14 hours. To the
reaction mixture was added water (200 mL) and extracted with ethyl
acetate. The extract was dried and the solvent was distilled off.
The crude product was distilled under reduced pressure to obtain 13
g of the title compound (67 mmol, yield 67%).
[0447] Boiling point 116-118.degree. C. (400 Pa)
[0448] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.30 (3H, s), 5.37 (2H,
s), 6.63 (1H, s), 6.72 (1H, d, J=5.1 Hz), 7.29-7.50 (5H, m), 8.03
(1H, d, J=5.1 Hz)
Reference Example 2
N-(3,5-dimethylbenzoyl)propyleneimine
[0449] 3,5-Dimethylbenzoic acid (25 g, 0.17 mol) and
N,N-dimethylformamide (0.1 mL) were added to thionyl chloride (50
mL) at 0.degree. C. The mixture was heated to reflux for 2 hours.
The excess thionyl chloride was distilled off under reduced
pressure and toluene (50 mL) was added to the residue. Toluene was
distilled off under reduced pressure to obtain oily
3,5-dimethylbenzoyl chloride. A solution of propyleneimine (14 mL,
0.18 mol) in tetrahydrofuran (160 mL) was added to 1N aqueous
sodium hydroxide (180 mL). To the solution was added dropwise
3,5-dimethylbenzoyl chloride at 0.degree. C. After complete
addition, the mixture was further stirred for 30 minutes. The
reaction mixture was extracted with ethyl acetate. The extract was
dried and the solvent was distilled off to obtain 31 g of the title
compound (0.16 mol, yield 99%).
[0450] Oily Product
[0451] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (3H, d, J=5.5 Hz),
2.13 (1H, d, J=3.7 Hz), 2.37 (6H, s), 2.47-2.62 (2H, m), 7.19 (1H,
s), 7.64 (2H, s)
Reference Example 3
1-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone
[0452] A solution of diisopropylamine (9.6 mL, 69 mmol) in
anhydrous tetrahydrofuran (60 mL) was cooled to -50.degree. C. and
a solution of 1.6 M n-butyllithium in hexane (43 mL, 69 mmol) was
added dropwise with stirring. After complete addition, the mixture
was stirred for 10-minutes and subsequently a solution of
2-phenylmethyloxy-4-methylpyridine (12 g, 62 mmol) in anhydrous
tetrahydrofuran (12 mL) at -30.degree. C. After additional stirring
for 1 h, a solution of N-(3,5-dimethylbenzoyl)propyleneimine (12 g,
62 mmol) in anhydrous tetrahydrofuran (12 mL) was added at
-30.degree. C. After complete addition, the resulting mixture was
allowed to warm up to room temperature and the mixture was stirred
for 2 hours. Water (60 mL) was added to the reaction mixture and
extracted with ethyl acetate. The extract was washed with water,
dried and the solvent was distilled off. The residue was purified
by silica gel column chromatography (hexane-ethyl acetate, 5:1) to
obtain 9.1 g of the title compound (27 mmol, yield 44%).
[0453] Oily Product
[0454] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.37 (6H, s), 4.20 (2H,
s), 5.37 (2H, s), 6.72 (1H, s), 6.81 (1H, d, J=5.1 Hz), 7.22 (1H,
s), 7.30-7.49 (5H, m), 7.59 (2H, s), 8.12 (1H, d, J=5.1 Hz)
Reference Example 4
2-bromo-1-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone
hydrobromide
[0455]
1-(3,5-Dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone (3.3
g, 10 mmol) was dissolved in acetic acid (10 mL) and bromine (0.51
mL, 10 mmol) was added to the solution and stirred at room
temperature for 30 minutes. The precipitated crude crystals were
collected by filtration and washed with diethyl ether to obtain 4.8
g of the title compound (9.8 mmol, yield 98%).
[0456] mp. 88-90.degree. C.
Reference Example 5
N-(4-methoxybenzoyl)propyleneimine
[0457] A solution of propyleneimine (25 mL, 0.36 mol) in
tetrahydrofuran (200 mL) was added to 2N aqueous sodium hydroxide
(180 mL). To this mixture was added dropwise a solution of
4-methoxybenzoyl chloride (51 g, 0.30 mol) in tetrahydrofuran (100
mL) at 0.degree. C. After complete addition, the mixture was
stirred further for 30 minutes. The reaction mixture was extracted
with ethyl acetate. The extract was dried and the solvent was
distilled off to obtain 49 g of the title compound (0.26 mol, yield
86%).
[0458] Oily Product
[0459] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (3H, d, J=5.6 Hz),
2.11 (1H, d, J=3.0 Hz), 2.51-2.57 (2H, m), 3.87 (3H, s), 6.94 (2H,
d, J=8.8 Hz), 8.00 (2H, d, J=8.8 Hz)
Reference Example 6
1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone
[0460] A solution of 2-tert-butoxycarbonylamino-4-methylpyridine
(20 g, 97 mmol) in anhydrous tetrahydrofuran (300 mL) was cooled to
-78.degree. C. and a solution of 1.6 M n-butyllithium in hexane
(140 mL, 0.22 mol) was added dropwise with stirring. After complete
addition, the mixture was stirred at room temperature for 30
minutes. And then, the mixture was cooled to -78.degree. C. A
solution of N-(4-methoxybenzoyl)propyleneimine in anhydrous
tetrahydrofuran (50 mL) was added dropwise to the mixture. After
complete addition, the mixture was stirred at room temperature for
2 hours. Water (100 mL) and diisopropyl ether (300 mL) were added
to the reaction mixture and the resulting crude crystals were
collected by filtration. The crude crystals were recrystallized
from tetrahydrofuran-hexane to obtain 23 g of the title compound
(67 mmol, yield 69%).
[0461] mp. 187-190.degree. C.
Reference Example 7
4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine
[0462] Bromine (0.68 mL, 13 mmol) was added to a solution of
1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone
(4.5 g, 13 mmol) in acetic acid (100 mL) and the mixture was
stirred at room temperature for 30 minutes. The reaction mixture
was concentrated. The residue was dissolved in acetonitrile (40 mL)
and to the solution was added thiourea (1.1 g, 14 mmol) and
triethylamine (1.9 mL, 14 mmol) were added and the mixture was
stirred at 80.degree. C. for 2 hours. The reaction mixture was
cooled to room temperature and concentrated. A saturated aqueous
sodium hydrogencarbonate (200 mL) was added to the residue and the
resulting solid was collected by filtration and washed with water.
2N hydrochloric acid (35 mL) was added to the solids and the
mixture was stirred at 100.degree. C. for 45 minutes. The reaction
mixture was cooled to room temperature and, thereafter, 8N aqueous
sodium hydroxide (10 mL) and a saturated aqueous solution of sodium
hydrogencarbonate (100 mL) were added. The resulting crude crystals
were collected by filtration, and were washed with water. The crude
crystals were recrystallized from ethanol to obtain 2.7 g of the
title compound (9.1 mmol, yield 69%).
[0463] mp. 251-254.degree. C.
Reference Example 8
2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl)ethanone
[0464] 2N-hydrochloric acid (30 mL) was added to
1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone
(6.1 g, 18 mmol) and the mixture was stirred at 100.degree. C. for
2 hours. The reaction mixture was cooled to room temperature and,
thereafter, 8N-aqueous sodium hydroxide (10 mL) was added. The
resulting crude crystals were filtered and washed with water. The
crude crystals were recrystallized from tetrahydrofuran-hexane to
obtain 4.0 g of the title compound (16 mmol, yield 92%).
[0465] mp. 170-174.degree. C.
Reference Example 9
2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone
[0466] Benzoyl chloride (4.4 g, 31 mmol) and
4-dimethylaminopyridine (0.57 g, 4.7 mmol) were added to a solution
of 2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (3.8 g, 16
mmol) in N,N-dimethylacetamide (80 mL) and the mixture was stirred
at 70.degree. C. for 12 hours. After the reaction mixture was
cooled to room temperature, water (50 mL) was added. The mixture
was extracted with ethyl acetate and the organic layer was washed
with a saturated aqueous solution of sodium chloride. The layer was
dried over magnesium sulfate, filtered and concentrated. The
residue was dissolved in tetrahydrofuran (80 mL) and methanol (20
mL) and 1N-aqueous solution of sodium hydroxide (50 mL) was added.
The mixture was stirred at room temperature for 3 hours. The
reaction mixture was concentrated and water (100 mL) was added. The
mixture was extracted with ethyl acetate and the organic layer was
washed with a saturated aqueous solution of sodium chloride. The
layer was dried over magnesium sulfate, filtered and concentrated.
The residue was recrystallized from ethyl acetate-hexane to obtain
3.1 g of the title compound (8.9 mmol, yield 57%).
[0467] mp. 136-139.degree. C.
Reference Example 10
1-(3,5-dimethylphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone
[0468] A solution of 2-tert-butoxycarbonylamino-4-methylpyridine
(17 g, 82 mmol) in anhydrous tetrahydrofuran (250 mL) was cooled to
-78.degree. C. and a 1.6N solution of n-butyllithium in hexane (120
mL, 0.19 mol) was added dropwise with stirring. After complete
addition, the mixture was stirred at 0.degree. C. for 30 minutes
and cooled to -78.degree. C. A solution of
N-(3,5-dimethylbenzoyl)propyleneimine (21 g, 0.11 mol) in anhydrous
tetrahydrofuran (50 mL) was added dropwise to the mixture. After
complete addition, the mixture was stirred at room temperature for
2 hours. Water (100 mL) was added to the reaction mixture and
extracted with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride, dried over magnesium
sulfate, filtered and concentrated. The residue was recrystallized
from tetrahydrofuran-hexane to obtain 13 g of the title compound
(37 mmol, yield 46%).
[0469] mp. 133-136.degree. C.
Reference Example 11
2-(2-amino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone
[0470] 2N-hydrochloric acid (50 mL) was added to
1-(3,5-dimethylphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone
(12 g, 36 mmol) and the mixture was stirred at 100.degree. C. for 1
hour. After the reaction mixture was cooled to room temperature, an
8N aqueous solution of sodium hydroxide (15 mL) was added and
extracted with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride, dried over magnesium
sulfate, filtered and concentrated. The residue was recrystallized
from ethyl acetate to obtain 6.8 g of the title compound (28 mmol,
yield 77%).
[0471] mp. 123-126.degree. C.
Reference Example 12
2-(2-benzoylamino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone
[0472] Benzoyl chloride (7.5 g, 53 mmol) and
4-dimethylaminopyridine (1.0 g, 8.3 mmol) were added to a solution
of 2-(2-amino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone (6.4 g, 27
mmol) in N,N-dimethylacetamide (100 mL) and the mixture was stirred
at 70.degree. C. for 12 hours. After the reaction mixture was
cooled to room temperature, water (50 mL) was added. The mixture
was extracted with ethyl acetate. The organic layer was washed with
a saturated aqueous solution of sodium chloride. The layer was
dried over magnesium sulfate, filtered and concentrated. The
residue was dissolved in a mixed solvent of tetrahydrofuran (150
mL) and methanol (40 mL) and 1N aqueous solution of sodium
hydroxide (50 mL) was added. The mixture was stirred at room
temperature for 3 hours. The reaction mixture was concentrated,
water (100 mL) was added and neutralized with 2N-hydrochloric acid
and a saturated aqueous solution of sodium hydrogencarbonate. The
mixture was extracted with ethyl acetate and the organic layer was
washed with a saturated aqueous solution of sodium chloride. The
layer was dried over magnesium sulfate, filtered and concentrated.
The residue was purified by silica gel column chromatography
(hexane-ethyl acetate, 2:1) to obtain 6.4 g of the title compound
(19 mmol, yield 70%).
[0473] Oily Product
[0474] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.39 (6H, s), 4.33 (2H,
s), 6.98-7.01 (1H, m), 7.23 (1H, s), 7.45-7.58 (3H, m), 7.63 (2H,
s), 7.89-7.94 (2H, m), 8.21 (1H, d, J=5.2 Hz), 8.36 (1H, s), 8.71
(1H, br)
Reference Example 13
[0475] According to Reference Example 5 and using 3-methylbenzoyl
chloride and 3-methoxybenzoyl chloride, respectively, instead of
4-methoxybenzoyl chloride, the following Reference Example
compounds 13-1 and 13-2 were synthesized.
Reference Example Compound 13-1
N-(3-methylbenzoyl)propyleneimine
[0476] Oily Product
[0477] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (3H, d, J=5.5 Hz),
2.14 (1H, d, J=3.3 Hz), 2.41 (3H, s), 2.51-2.66 (2H, m), 7.32-7.39
(2H, m), 7.79-7.87 (2H, m).
Reference Example Compound 13-2
N-(3-methoxybenzoyl)propyleneimine
[0478] Oily Product
[0479] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.40 (3H, d, J=5.9 Hz),
2.14 (1H, d, J=2.9 Hz), 2.52-2.65 (2H, m), 3.86 (3H, s), 7.10 (1H,
ddd, J=8.4, 2.6, 1.1 Hz), 7.37 (1H, dd, J=8.4, 7.3 Hz), 7.55 (1H,
dd, J=2.6, 1.5 Hz), 7.63 (1H, ddd, J=7.3, 1.5, 1.1 Hz)
Reference Example 14
[0480] According to Reference Example 6 and using
N-(3-methylbenzoyl)propyleneimine instead of
N-(4-methoxybenzoyl)propyleneimine, the following Reference Example
compound 14 was synthesized.
Reference Example Compound 14
2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone
[0481] mp. 144-146.degree. C.
Reference Example 15
4-(methylthio)thiobenzamide
[0482] 4-Methylthiobenzonitrile (12 g) was dissolved in a 4N
solution of hydrogen chloride in ethyl acetate (130 mL). To this
solution was added O,O-diethyl dithiophosphate (15 mL) and the
mixture was stirred at room temperature for 22 hours. Water (100
mL) was added to the reaction mixture and extracted with ethyl
acetate. After the insoluble materials were filtered off, the
filtrate was washed with a saturated aqueous solution of sodium
chloride and dried and, thereafter, the solvent was distilled off.
The residue was recrystallized from ethyl acetate to obtain 10 g of
the title compound (yield 67%)
[0483] mp. 176-178.degree. C.
Reference Example 16
[0484] According to Reference Example 15 and using
4-fluorobenzonitrile, 2-chlorobenzonitrile, butyronitrile and
valeronitrile, respectively, instead of 4-methylthiobenzonitrile,
the following Reference Example compounds 16-1-16-4 were
synthesized.
Reference Example Compound 16-1
4-fluorothiobenzamide
[0485] mp. 156-157.degree. C.
Reference Example Compound 16-2
2-chlorothiobenzamide
[0486] mp. 58-59.degree. C.
Reference Example Compound 16-3
Thiobutyramide
[0487] Oily Product
[0488] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, t, J=7.6 Hz),
1.72-1.93 (2H, m), 2.64 (2H, t, J=7.6 Hz), 7.02 (1H, br s), 7.77
(1H, br s)
Reference Example Compound 16-4
Thiovaleramide
[0489] Oily Product
[0490] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (3H, t, J=7.3 Hz),
1.31-1.49 (2H, m), 1.68-1.83 (2H, m), 2.67 (2H, t, J=7.7 Hz), 6.92
(1H, br s), 7.73 (1H, br s)
Reference Example 17
4-[2-methyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine
[0491] Bromine (1.0 mL, 18 mmol) was added to a solution of
2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone
(6.0 g, 18 mmol) in acetic acid (50 mL) and the mixture was stirred
at room temperature for 30 minutes. The reaction mixture was
concentrated. The residue was dissolved in N,N-dimethylformamide
(50 mL) and to the solution was added thioacetamide (1.4 g, 19
mmol) and the resulting mixture was stirred at room temperature for
20 hours. To the reaction mixture was added a saturated aqueous
solution of sodium hydrogencarbonate (200 mL) and extracted with
ethyl acetate. The extract was dried and the solvent was distilled
off. 2N-hydrochloric acid (30 mL) was added to the resulting solid
and the mixture was stirred at 100.degree. C. for 1 hour. After the
reaction mixture was cooled to room temperature, the mixture was
basified with a 2N aqueous solution of sodium hydroxide (200 mL)
and a saturated aqueous solution of sodium hydrogen carbonate. The
resulting mixture was extracted with ethyl acetate and the extract
was washed with water. The extract was dried and concentrated. The
residue was purified by silica gel column chromatography (ethyl
acetate) to obtain 2.8 g of the title compound (yield 54%).
[0492] mp. 152-153.degree. C.
Reference Example 18
[0493] According to Reference Example 17 and using thiopropionamide
and 4-(methylthio)thiobenzamide, respectively, instead of
thioacetamide, the following Reference Example compounds 18-1 and
18-2 were synthesized.
Reference Example Compound 18-1
4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine
[0494] mp. 144-146.degree. C.
Reference Example Compound 18-2
4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylam-
ine
[0495] mp. 181-183.degree. C.
Reference Example 19
[0496] According to Reference Example 17 and using
1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone
instead of
2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone,
the following Reference Example compound 19 was synthesized.
Reference Example Compound 19
4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridylamine
[0497] mp. 140-141.degree. C.
Reference Example 20
[0498] According to Reference Example 8 and using
2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone
instead of
1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone,
the following Reference Example compound 20 was synthesized.
Reference Example Compound 20
2-(2-amino-4-pyridyl)-1-(3-methylphenyl)ethanone
[0499] mp. 119-120.degree. C.
Reference Example 21
2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone
hydrobromide
[0500] Bromine (3.2 mL, 62 mol) was added to a solution of
2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone
(20 g, 61 mmol) in acetic acid (60 mL) and the mixture was stirred
at 80.degree. C. for 2 hours. After the reaction mixture was cooled
to room temperature, the precipitate was filtered to obtain 19 g
(yield 81%) of the title compound.
[0501] mp. 182-185.degree. C.
Reference Example 22
[0502] According to Reference Example 9 and using
2-(2-amino-4-pyridyl)-1-(3-methylphenyl)ethanone instead of
2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl)ethanone, the following
Reference Example compound 22 was synthesized.
Reference Example Compound 22
N-[4-[2-(3-methylphenyl)-2-oxoethyl]-2-pyridyl]benzamide
[0503] mp. 67-69.degree. C.
Reference Example 23
4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine
[0504] 2-(2-Amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone
hydrobromide (5.0 g, 13 mmol) was dissolved in
N,N-dimethylformamide (40 mL), to the solution was added
4-fluorothiobenzamide (2.1 g, 13 mmol) and the mixture was stirred
at room temperature for 16 hours. A saturated aqueous solution of
sodium hydrogencarbonate (200 mL) was added to the reaction mixture
and the mixture was extracted with ethyl acetate. The extract was
dried and the solvent was distilled off. The residue was
recrystallized from ethanol to obtain 3.9 g (11 mmol, yield 83%) of
the title compound.
[0505] mp. 160-162.degree. C.
Reference Example 24
[0506] According to Reference Example 23 and using
2-chlorothiobenzamide, thiobutyramide and thiovaleramide,
respectively, instead of 4-fluorothiobenzamide, the following
Reference Example compounds 24-1-24-3 were synthesized.
[0507] Reference Example compound
24-1:4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl-
amine
[0508] mp. 175-177.degree. C.
Reference Example compound 24-2
4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine
[0509] mp. 113-115.degree. C.
Reference Example compound 24-3
4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine
[0510] Oily Product
[0511] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (3H, t, J=7.3 Hz),
1.39-1.59 (2H, m), 1.74-1.92 (2H, m), 2.34 (3H, s), 3.04 (2H, t,
J=7.4 Hz), 41.14 (2H, br s), 6.44 (1H, s), 6.56 (1H, dd, J=5.1, 1.5
Hz), 7.09-7.26 (3H, m), 7.41 (1H, s), 7.96 (1H, d, J=5.4 Hz)
Reference Example 25
2-fluoro-4-methylpyridine
[0512] The title compound was obtained in the same manner as
described in Journal of Medicinal Chemistry, vol. 33, 1667-1675,
1990.
[0513] Boiling point 82-86.degree. C. (10 kPa)
Reference Example 26
2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone
[0514] A solution of diisopropylamine (44 mL, 0.31 mol) in
anhydrous tetrahydrofuran (300 mL) was cooled to -78.degree. C.
under argon atmosphere and a 1.6M solution of n-butyllithium in
hexane (190 mL, 0.31 mol) was added dropwise to the solution. After
complete addition, the mixture was stirred for 10 minutes and
subsequently a solution of 2-fluoro-4-methylpyridine (34.5 g, 0.31
mol) in anhydrous tetrahydrofuran (30 mL) was added. The reaction
mixture was stirred at -10.degree. C. for 30 minutes. The reaction
solution was cooled to -78.degree. C. and a solution of
N-(3-methylbenzoyl)propyleneimine (52 g, 0.30 mol) in anhydrous
tetrahydrofuran (30 mL) was added dropwise. After complete
addition, the mixture was stirred at room temperature for 2 hours.
Water (100 mL) was added to the reaction mixture and the mixture
was extracted with ethyl acetate. The extract was washed with
water, dried and the solvent was distilled off. The residue was
recrystallized from isopropyl ether to obtain 35 g (yield 52%) of
the title compound.
[0515] mp. 66-67.degree. C.
Reference Example 27
[0516] According to Reference Example 26 and using
N-(3-methoxybenzoyl)propyleneimine instead of
N-(3-methylbenzoyl)propyleneimine, the following Reference Example
compound 27 was synthesized.
Reference Example compound 27
2-(2-fluoro-4-pyridyl)-1-(3-methoxyphenyl)ethanone
[0517] Oily Product
[0518] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.86 (3H, s), 4.31 (2H,
s), 6.86 (1H, s), 7.03-7.19 (2H, m), 7.31-7.59 (3H, m), 8.18 (1H,
d, J=5.6 Hz)
Reference Example 28
[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine
[0519] Bromine (1.9 mL, 37 mmol) was added to a solution of
2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone (8.5 g, 37 mmol)
in acetic acid (50 mL) and the mixture was stirred at room
temperature for 1 hour. The reaction mixture was concentrated.
Triethylamine (5.2 mL, 37 mmol) was added to a mixture of this
residue and thiourea (3.0 g, 40 mmol) in acetonitrile (50 mL) and
the mixture was stirred at 80.degree. C. for 2 hours. A saturated
aqueous solution of sodium hydrogencarbonate (50 mL) was added to
the reaction mixture and the precipitated solid was collected by
filtration. After the resulting solid was washed with water, it was
dried. The crude crystals were recrystallized from ethanol to
obtain 3.7 g (yield 35%) of the title compound.
[0520] mp. 214-218.degree. C.
Reference Example 29
[0521] According to Reference Example 28 and using
2-(2-fluoro-4-pyridyl)-1-(3-methoxyphenyl)ethanone instead of
2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone, the following
Reference Example compound 29 was synthesized.
Reference Example compound 29
[5-(2-fluoro-4-pyridyl)-4-(3-methoxyphenyl)-1,3-thiazol-2-yl]amine
[0522] mp. 190-191.degree. C.
Reference Example 30
5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiaz-
ole
[0523] Bromine (2.7 mL, 52 mmol) was added to a solution of
2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone (12 g, 53 mmol)
in acetic acid (90 mL) and the mixture was stirred at room
temperature for 2 hours. The reaction mixture was concentrated.
This residue was dissolved in N,N-dimethylformamide (60 mL),
4-(methylthio)thiobenzamide (9.6 g, 52 mmol) was added and the
mixture was stirred at room temperature for 15 hours. A saturated
aqueous solution of sodium hydrogencarbonate (100 mL) was poured
into the reaction mixture and the mixture was extracted with ethyl
acetate. The extract was washed with water, dried and the solvent
was distilled off. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate, 4:1) to obtain 4.7 g (yield
23%) of the title compound.
[0524] mp. 97-100.degree. C.
Reference Example 31
5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-t-
hiazole
[0525] To a solution of
5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thia-
zole (2.7 g, 6.9 mmol) in N,N-dimethylformamide (60 mL) was added
m-chloroperbenzoic acid (3.3 g, 14 mmol) and the mixture was
stirred at room temperature for 1 hour. An 8N aqueous solution of
sodium hydroxide was added to the reaction mixture and the
resulting solid was collected by filtration. This solid was
recrystallized from ethanol to obtain 2.5 g (yield 85%) of the
title compound.
[0526] mp. 196-199.degree. C.
Example 1
[4-(3,5-dimethylphenyl)-5-(2-phenylmethyloxy-4-pyridyl)-1,3-thiazol-2-yl]a-
mine
[0527] Triethylamine (1.4 mL, 10 mmol) was added dropwise to a
solution of
2-bromo-1-(3,5-dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone
hydrobromide (4.8 g, 9.8 mmol) and thiourea (0.77 g, 11 mmol) in
acetonitrile (40 mL) and the mixture was stirred at room
temperature for 3 hours. The solvent was removed under reduced
pressure, a saturated aqueous solution of sodium hydrogencarbonate
was added to the residue and extracted with ethyl acetate. The
organic layer was washed with water, dried and the solvent was
distilled off. The resulting crude crystals were recrystallized
from ethyl acetate to obtain 2.0 g (5.2 mmol, yield 53%) of the
title compound.
[0528] mp. 141-143.degree. C.
Example 2
N-[4-[2-benzoylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benza-
mide
[0529] Benzoyl chloride (0.59 g, 4.2 mmol) and
4-dimethylaminopyridine (0.05 g, 0.4 mmol) were added to a solution
of 4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine
(0.42 g, 1.4 mmol) in N,N-dimethylacetamide (10 mL) and the mixture
was stirred at 70.degree. C. for 19 hours. After the reaction
mixture was cooled to room temperature, a saturated aqueous
solution of sodium hydrogencarbonate (50 mL) was added. The
resulting crude crystals were collected by filtration and washed
with water. The crude crystals were recrystallized from ethanol to
obtain 0.26 g (0.51 mmol, yield 37%) of the title compound.
[0530] mp. 230-233.degree. C.
Example 3
N-[4-(4-methoxyphenyl)-5-[2-[(3-pyridylcarbonylamino)]-4-pyridyl]-1,3-thia-
zol-2-yl]nicotinamide
[0531] Nicotinoyl chloride hydrochloride (0.72 g, 4.1 mmol) and
4-dimethylaminopyridine (0.05 g, 0.4 mmol) were added to a solution
of 4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine
(0.41 g, 1.4 mmol) in N,N-dimethylacetamide (10 mL) and the mixture
was stirred at 70.degree. C. for 19 hours. After the reaction
mixture was cooled to room temperature, a saturated aqueous
solution of sodium hydrogencarbonate (50 mL) was added. The
resulting crude crystals were collected by filtration and washed
with water. The crude crystals were recrystallized from ethanol to
obtain 0.23 g (0.44 mmol, yield 33%) of the title compound.
[0532] mp. 229-232.degree. C.
Example 4
N-[4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
[0533] Bromine (0.11 mL, 2.1 mmol) was added to a solution of
2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (0.72 g,
2.1 mmol) in acetic acid (20 mL) at 0.degree. C. and the mixture
was stirred at room temperature for 1 hour. The reaction mixture
was concentrated. The residue was dissolved in acetonitrile (20
mL), to the solution were added thiourea (0.17 g, 2.2 mmol) and
triethylamine (0.35 mL, 2.5 mmol) and the mixture was stirred at
80.degree. C. for 5 hours. After the reaction mixture was cooled to
room temperature, a saturated aqueous solution of sodium
hydrogencarbonate (200 mL) was added and the resulting solid was
filtered and washed with water. The resulting crude crystals were
collected by filtration and washed with water. The crude crystals
were recrystallized from ethanol to obtain 0.17 g (0.43 mmol, yield
21%) of the title compound.
[0534] mp. 221-224.degree. C.
Example 5
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
[0535] Bromine (1.0 mL, 19 mmol) was added to a solution of
2-(2-benzoylamino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone (6.4 g,
19 mmol) in acetic acid (80 mL) at 0.degree. C. and the mixture was
stirred at room temperature for 1 hour. The reaction mixture was
concentrated. The residue was dissolved in acetonitrile (100 mL),
to the solution were added thiourea (1.5 g, 19 mmol) and
triethylamine (2.8 mL, 20 mmol) and the mixture was stirred at
80.degree. C. for 3 hours. After the reaction mixture was cooled to
room temperature, a saturated aqueous solution of sodium
hydrogencarbonate (200 mL) was added and the resulting solid was
collected by filtration and washed with water. The resulting crude
crystals were collected by filtration and washed with water. The
crude crystals were recrystallized from ethanol to obtain 5.0 g (13
mmol, yield 68%) of the title compound.
[0536] mp. 120-123.degree. C.
Example 6
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylami-
ne
[0537] Aluminum lithium hydride (0.16 g, 4.1 mmol) was added to a
suspension of aluminum chloride (0.55 g, 4.1 mmol) in anhydrous
tetrahydrofuran (30 mL) and the mixture was stirred at room
temperature for 15 minutes. A solution of
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamid-
e (0.40 g, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added
to the mixture and the resulting mixture was heated to reflux for 2
hours. After the reaction mixture was cooled to room temperature,
water was added and extracted with ethyl acetate. The organic layer
was washed with a saturated aqueous solution of sodium chloride,
dried over magnesium sulfate, filtered and concentrated. The
residue was recrystallized from ethyl acetate-hexane to obtain 0.20
g (0.51 mmol, yield 51%) of the title compound.
[0538] mp. 99-102.degree. C.
Example 7
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
hydrochloride
[0539] A 10% solution of hydrogen chloride in methanol (10 mL) was
added to a suspension of
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamid-
e (0.45 g, 1.1 mmol) in methanol (30 mL) and the mixture was
stirred at room temperature for 30 minutes. The solvent was
distilled off and the residue was recrystallized from methanol to
obtain 0.36 g (0.83 mmol, yield 73%) of the title compound.
[0540] mp. 202-207.degree. C.
Example 8
N-[4-[2-amino-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine
dihydrochloride
[0541] A 10% solution of hydrogen chloride in methanol (10 mL) was
added to a suspension of
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylam-
ine (0.80 g, 2.1 mmol) in methanol (50 mL) and the mixture was
stirred at room temperature for 5 hours. The solvent was distilled
off and the residue was recrystallized from methanol-ethyl acetate
to obtain 0.73 g (1.6 mmol, yield 76%) to obtain the title
compound.
[0542] mp. 161-163.degree. C.
[0543] The structures of the compounds obtained in Examples 1 to 6
are shown below:
Example 1
##STR00039##
[0544] Example 2
##STR00040##
[0545] Example 3
##STR00041##
[0546] Example 4
##STR00042##
[0547] Example 5
##STR00043##
[0548] Example 6
##STR00044##
[0549] Example 9
N-[5-[2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]ac-
etamide
[0550] Acetyl chloride (0.26 mL, 3.7 mmol) and
4-dimethylaminopyridine (0.09 g, 0.76 mmol) were added to a
solution of
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamid-
e (0.96 g, 2.4 mmol) in N,N-dimethylacetamide (20 mL) and the
mixture was stirred at 70.degree. C. for 16 hours. After the
reaction mixture was cooled to room temperature, a saturated
aqueous solution of sodium hydrogencarbonate (50 mL) was added. The
resulting crude crystals were collected by filtration and washed
with water. The crude crystals were recrystallized from ethyl
acetate to obtain 0.32 g (yield 30%) of the title compound.
[0551] mp. 238-241.degree. C.
Example 10
[0552] According to Example 9 and using
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzy-
lamine instead of
N-[4-[(2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzami-
de, the following Example compound 10 was synthesized.
Example Compound 10
N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]ace-
tamide
[0553] mp. 217-219.degree. C.
Example 11
[0554] According to Example 4 and using N-methylthiourea instead of
thiourea, the following Example compound II was synthesized.
Example Compound 11
N-[4-[4-(4-methoxyphenyl)-2-methylamino-1,3-thiazol-5-yl]-2-pyridyl]benzam-
ide
[0555] mp. 237-241.degree. C.
Example 12
[0556] According to Example 4 and using
N-[4-[2-(3-methylphenyl)-2-oxoethyl]-2-pyridyl]benzamide instead of
2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone, the
following Example compound 12 was synthesized.
Example Compound 12
N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
[0557] mp. 216-217.degree. C.
Example 13
N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide
[0558] Bromine (0.18 mL, 3.5 mmol) was added to a solution of
2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (1.2 g,
3.4 mmol) in acetic acid (10 mL) and the mixture was stirred at
room temperature for 30 minutes. The reaction mixture was
concentrated. The residue was dissolved in N,N-dimethylformamide
(20 mL), thioacetamide (0.30 g, 19 mmol) was added to the solution
and the mixture was stirred at room temperature for 20 hours. An
aqueous saturated solution of sodium hydrogencarbonate (20 mL) was
added to the reaction mixture, the resulting mixture was extracted
with ethyl acetate and the extract was washed with water. The
extract was dried and concentrated. The residue was purified by
silica gel column chromatography (hexane:ethyl acetate, 1:1) to
obtain 0.68 g (yield 50%) of the title compound.
[0559] mp. 134-135.degree. C.
Example 14
N-[4-[2-[(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]p-
henylacetamide
[0560] Phenylacetyl chloride (0.33 mL, 2.5 mmol) and
triethylamine
(0.31 mL, 2.2 mmol) were added to a solution of
4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine
(0.81 g, 2.2 mmol) in tetrahydrofuran (20 mL) and the mixture was
stirred at room temperature for 13 hours. An aqueous saturated
solution of sodium hydrogencarbonate (20 mL) was added to the
reaction mixture, the resulting mixture was extracted with ethyl
acetate and the extract was washed with water. This extract was
dried and concentrated. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate, 2:1) to obtain 0.86 g
(yield 80%) of the title compound.
[0561] mp. 187-190.degree. C.
Example 15
[0562] According to Example 14 and using
4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridylamine,
4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,
4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine,
4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine,
4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine
and
4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyri-
dylamine, respectively, instead of
4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine-
, the following Example compounds 15-1-15-6 were synthesized.
Example Compound 15-1
N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]phenylaceta-
mide
[0563] mp. 118-120.degree. C.
Example Compound 15-2
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetami-
de
[0564] mp. 107-108.degree. C.
Example Compound 15-3
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetam-
ide
[0565] mp. 109-111.degree. C.
Example Compound 15-4
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetami-
de
[0566] mp. 92-93.degree. C.
Example Compound 15-5
N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]ph-
enylacetamide
[0567] mp. 141-142.degree. C.
Example Compound 15-6
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridy-
l]phenylacetamide
[0568] mp. 205-206.degree. C.
Example 16
[0569] According to Examples 14 and 15 and using benzoyl
chloride,
[0570] 3-phenylpropionyl chloride, 3-(4-methoxyphenyl)propionyl
chloride, 3-(4-fluorophenyl)propionyl chloride, 4-phenylbutyryl
chloride, 5-phenylvaleryl chloride, 2-thiophenecarbonyl chloride
and 2-naphthoyl chloride, respectively, instead of phenylacetyl
chloride, the following Example compounds 16-1-16-18 were
synthesized.
Example Compound 16-1
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
[0571] mp. 113-114.degree. C.
Example Compound 16-2
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylprop-
ionamide
[0572] mp. 126-127.degree. C.
Example Compound 16-3
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxy-
phenyl)propionamide
[0573] mp. 137-138.degree. C.
Example Compound 16-4
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-fluorop-
henyl)propionamide
[0574] mp. 116-117.degree. C.
Example Compound 16-5
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbuty-
ramide
[0575] mp. 92-93.degree. C.
Example Compound 16-6
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-5-phenylvale-
ramide
[0576] mp. 86-87.degree. C.
Example Compound 16-7
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide
[0577] Amorphous Powder
[0578] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (3H, t, J=7.1 Hz),
1.80-1.99 (2H, m), 2.34 (3H, s), 3.04 (2H, t, J=7.7 Hz), 6.88 (1H,
dd, J=5.2, 1.7 Hz), 7.15-7.63 (7H, m), 7.90-7.95 (2H, m), 8.11 (1H,
d, J=5.2 Hz), 8.51 (1H, s), 8.61 (1H, br s)
Example Compound 16-8
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpro-
pionamide
[0579] mp. 103-104.degree. C.
Example Compound 16-9
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide
[0580] Amorphous Powder
[0581] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.99 (3H, t, J=7.2 Hz),
1.40-1.60 (2H, m), 1.76-1.93 (2H, m), 2.34 (3H, s), 3.06 (2H, t,
J=7.7 Hz), 6.88 (1H, dd, J=5.0, 1.7 Hz), 7.10-7.26 (3H, m), 7.41
(1H, s), 7.46-7.61 (3H, m), 7.94 (2H, dd, J=8.1, 1.5 Hz), 8.10 (1H,
d, J=5.0 Hz), 8.52 (1H, s), 8.71 (1H, br s)
Example Compound 16-10
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylprop-
ionamide
[0582] mp. 77-78.degree. C.
Example Compound 16-11
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]be-
nzamide
[0583] mp. 126-128.degree. C.
Example Compound 16-12
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-
-phenylpropionamide
[0584] mp. 169-171.degree. C.
Example Compound 16-13
N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]be-
nzamide
[0585] mp. 138-140.degree. C.
Example Compound 16-14
N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-
-phenylpropionamide
[0586] mp. 156-158.degree. C.
Example Compound 16-15
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridy-
l]benzamide
[0587] mp. 180-182.degree. C.
Example Compound 16-16
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridy-
l]-3-phenylpropionamide
[0588] mp. 174-175.degree. C.
Example Compound 16-17
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridy-
l]-2-thiophenecarboxamide
[0589] mp. 145-147.degree. C.
Example Compound 16-18
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridy-
l]-2-naphthamide mp. 184-186.degree. C.
Example 17
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-methylphen-
ylacetamide
[0590] Sodium hydride (60% paraffin dispersion, 58 mg, 1.5 mmol)
was added to a solution of
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetam-
ide (0.50 g, 1.2 mmol) in dimethyl sulfoxide (5 mL) and the mixture
was stirred at room temperature for 1 hour. Methyl iodide (0.09 mL,
1.5 mmol) was added to this reaction solution and the mixture was
stirred at room temperature for 1 hour. A 10% aqueous solution of
ammonium chloride was added to the reaction mixture and the mixture
was extracted with ethyl acetate. The extract was washed with a
saturated aqueous solution of sodium chloride, dried and
concentrated. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate, 7:1.fwdarw.4:1) and washed
with hexane to obtain 0.18 g (yield 35%) of the title compound.
[0591] mp. 75-76.degree. C.
Example 18
[0592] According to Example 17 and using
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpro-
pionamide instead of
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetam-
ide, the following Example compound 18 was synthesized.
Example Compound 18
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-methyl-3-p-
henylpropionamide
[0593] Oily Product
[0594] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46 (3H, t, J=7.5 Hz),
2.32 (3H, s), 2.51 (2H, t, J=7.9 Hz), 2.93 (2H, t, J=7.9 Hz), 3.10
(2H, q, J=7.5 Hz), 3.22 (3H, s), 6.98 (1H, s), 7.03-7.29 (9H, m),
7.37 (1H, s), 8.37 (1H, d, J=3.6 Hz)
Example 19
[0595] According to Example 6 and using
N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide,
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetam-
ide,
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-pheny-
lpropionamide,
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide,
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylaceta-
mide,
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phe-
nylpropionamide,
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetam-
ide,
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-pheny-
lpropionamide,
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]b-
enzamide,
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2--
pyridyl]phenylacetamide,
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]--
3-phenylpropionamide,
N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]b-
enzamide,
N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2--
pyridyl]phenylacetamide,
N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]--
3-phenylpropionamide,
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]benzamide,
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]phenylacetamide,
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-3-phenylpropionamide and
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-2-naphthamide, respectively, instead of
N-[4-[2-amino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamid-
e, the following Example compounds 19-1-19-20 were synthesized.
Example Compound 19-1
N-benzyl-N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]am-
ine
[0596] mp. 132-133.degree. C.
Example Compound 19-2
N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amin-
e
[0597] mp. 106-107.degree. C.
Example Compound 19-3
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenyle-
thyl)amine
[0598] mp. 97-98.degree. C.
Example Compound 19-4
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylp-
ropyl)amine
[0599] mp. 52-53.degree. C.
Example Compound 19-5
N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]ami-
ne
[0600] Oily Product
[0601] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06 (3H, t, J=7.4 Hz),
1.77-1.96 (2H, m), 2.33 (3H, s), 3.00 (2H, t, J=7.7 Hz), 4.38 (2H,
d, J=5.4 Hz), 4.83 (1H, br t), 6.32 (1H, s), 6.53 (1H, dd, J=5.4,
1.6 Hz), 7.10-7.40 (9H, m), 8.01 (1H, d, J=5.4 Hz)
Example Compound 19-6
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenyl-
ethyl)amine
[0602] Oily Product
[0603] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (3H, t, J=7.5 Hz),
1.78-1.93 (2H, m), 2.32 (3H, s), 2.81 (2H, t, J=7.0 Hz), 3.01 (2H,
t, J=7.7 Hz), 3.42 (2H, dt, J=6.2, 7.0 Hz), 4.52 (1H, br t), 6.30
(1H, s), 6.51 (1H, dd, J=5.2, 1.5 Hz), 7.11-7.34 (8H, m), 7.43 (1H,
s), 8.00 (1H, d, J=5.2 Hz)
Example Compound 19-7
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenyl-
propyl)amine
[0604] Oily Product
[0605] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (3H, t, J=7.4 Hz),
1.78-1.93 (4H, m), 2.32 (3H, s), 2.66 (2H, t, J=7.2 Hz), 3.01 (2H,
t, J=7.7 Hz), 3.16 (2H, dt, J=6.2, 7.2 Hz), 4.52 (1H, br s), 6.26
(1H, s), 6.49 (1H, dd, J=5.2, 1.5 Hz), 7.07-7.32 (8H, m), 7.42 (1H,
s), 7.98 (1H, d, J=5.2 Hz)
Example Compound 19-8
N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amin-
e
[0606] Oily Product
[0607] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.97 (3H, t, J=7.3 Hz),
1.38-1.59 (2H, m), 1.73-1.90 (2H, m), 2.33 (3H, s), 3.02 (2H, t,
J=7.7 Hz), 4.37 (2H, d, J=5.7 Hz), 4.83 (1H, t, J=7.3 Hz), 6.31
(1H, s), 6.52 (1H, d, J=5.5 Hz), 7.09-7.43 (9H, m), 8.00 (1H, d,
J=5.5 Hz)
Example Compound 19-9
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenyle-
thyl)amine
[0608] Oily Product
[0609] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (3H, t, J=7.3 Hz),
1.39-1.59 (2H, m), 1.74-1.92 (2H, m), 2.32 (3H, s), 2.81 (2H, t,
J=7.0 Hz), 3.04 (2H, t, J=7.7 Hz), 3.41 (2H, dt, J=6.1, 7.0 Hz),
4.55 (1H, t, J=6.1 Hz), 6.30 (1H, s), 6.51 (1H, d, J=5.1 Hz),
7.06-7.19 (3H, m), 7.20-7.38 (5H, m), 7.43 (1H, s), 7.99 (1H, d,
J=5.1 Hz)
Example Compound 19-10
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylp-
ropyl)amine
[0610] Oily Product
[0611] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (3H, t, J=7.1 Hz),
1.39-1.57 (2H, m), 1.75-1.98 (4H, m), 2.32 (3H, s), 2.67 (2H, t,
J=7.8 Hz), 3.04 (2H, t, J=7.7 Hz), 3.16 (2H, dt, J=5.9, 6.2 Hz),
4.52 (1H, t, J-5.9 Hz), 6.26 (1H, s), 6.49 (1H, d, J=5.1 Hz),
7.06-7.38 (8H, m), 7.42 (1H, s), 7.97 (1H, d, J=5.1 Hz)
Example Compound 19-11
N-benzyl-N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]amine
[0612] mp. 143-146.degree. C.
Example Compound 19-12
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-
-(2-phenylethyl)amine
[0613] mp. 97-98.degree. C.
Example Compound 19-13
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-
-(3-phenylpropyl)amine
[0614] mp. 110-112.degree. C.
Example Compound 19-14
N-benzyl-N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-p-
yridyl]amine
[0615] mp. 84-86.degree. C.
Example Compound 19-15
N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-
-(2-phenylethyl)amine
[0616] mp. 113-114.degree. C.
Example Compound 19-16
N-[4-[2-(2-chlorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-
-(3-phenylpropyl)amine
[0617] mp. 101-102.degree. C.
Example Compound 19-17
N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-
-2-pyridyl]amine
[0618] mp. 134-136.degree. C.
Example Compound 19-18
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridy-
l]-N-(2-phenylethyl)amine
[0619] mp. 137-139.degree. C.
Example Compound 19-19
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridy-
l]-N-(3-phenylpropyl)amine
[0620] mp. 106-107.degree. C.
Example Compound 19-20
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridy-
l]-N-(2-naphthylmethyl)amine
[0621] mp. 144-145.degree. C.
Example 20
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-py-
ridyl]benzamide
[0622] To a solution of
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]benzamide (0.50 g, 1.0 mmol) in N,N-dimethylformamide (5 mL) was
added m-chloroperbenzoic acid (0.55 g, 2.2 mmol) and the mixture
was stirred at room temperature for 1 hour. An 8N aqueous solution
of sodium hydroxide was added to the reaction mixture and the
resulting solid was collected by filtration. This solid was
recrystallized from ethanol to obtain 0.29 g (yield 54%) of the
title compound.
[0623] mp. 212-214.degree. C.
Example 21
[0624] According to Example 20 and using
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]phenylacetamide,
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-3-phenylpropionamide,
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-2-thiophenecarboxamide,
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-2-naphthamide,
N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl-
]-2-pyridyl]amine,
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-N-(3-phenylpropyl)amine and
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]-N-(2-naphthylmethyl)amine, respectively, instead of
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyrid-
yl]benzamide, the following Example compounds 21-1-21-7 were
synthesized.
Example Compound 21-1
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-py-
ridyl]phenylacetamide
[0625] mp. 244-245.degree. C.
Example Compound 21-2
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-py-
ridyl]-3-phenylpropionamide
[0626] mp. 236-237.degree. C.
Example Compound 21-3
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-py-
ridyl]-2-thiophenecarboxamide
[0627] mp. 199-201.degree. C.
Example Compound 21-4
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-py-
ridyl]-2-naphthamide
[0628] mp. 231-233.degree. C.
Example Compound 21-5
N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-
-yl]-2-pyridyl]amine
[0629] mp. 148-150.degree. C.
Example Compound 21-6
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-py-
ridyl]-N-(3-phenylpropyl) amine
[0630] mp. 167-168.degree. C.
Example Compound 21-7
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-py-
ridyl]-N-(2-naphthylmethyl)amine mp. 167-168.degree. C.
Example 22
N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzylamin-
e
[0631] A mixture of
[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine
(0.29 g, 1.0 mmol) and benzylamine (1.2 mL, 11 mmol) was stirred at
150.degree. C. for 3 hours. After the reaction mixture was cooled
to room temperature, a saturated aqueous solution of sodium
hydrogencarbonate (20 mL) was added, the resulting mixture was
extracted with ethyl acetate and extract was washed with water.
This extract was dried and concentrated. The residue was purified
by silica gel column chromatography (hexane:ethyl acetate, 1:1) to
obtain 0.16 g (yield 41%) of the title compound.
[0632] mp. 178-179.degree. C.
Example 23
[0633] According to Example 22 and using 4-methoxybenzylamine,
3-methoxybenzylamine, 2-methoxybenzylamine, 4-chlorobenzylamine,
3-chlorobenzylamine, (R)-1-phenylethylamine, (S)-1-phenylethylamine
and N-benzyl-N-methylamine instead of benzylamine, the following
Example compounds 23-1-23-8 were synthesized.
Example Compound 23-1
N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(4-methoxy-
benzyl)amine
[0634] mp. 183-184.degree. C.
Example Compound 23-2
N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-methoxy-
benzyl)amine
[0635] mp. 152-154.degree. C.
Example Compound 23-3
N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-methoxy-
benzyl)amine
[0636] mp. 158-159.degree. C.
Example Compound 23-4
N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(4-chlorob-
enzyl)amine
[0637] mp. 182-183.degree. C.
Example Compound 23-5
N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-chlorob-
enzyl)amine
[0638] mp. 180-181.degree. C.
Example Compound 23-6
(R)--N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(1-ph-
enylethyl)amine
[0639] mp. 94-98.degree. C.
Example Compound 23-7
(S)--N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(1-ph-
enylethyl)amine
[0640] mp. 93-96.degree. C.
Example Compound 23-8
N-[4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzyl-N-m-
ethylamine
[0641] mp. 138-140.degree. C.
Example 24
[0642] According to Example 22 and using
[5-(2-fluoro-4-pyridyl)-4-(3-methoxyphenyl)-1,3-thiazol-2-yl]amine
instead of
[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,
the following Example compound 22 was synthesized.
Example Compound 24
N-[4-[2-amino-4-(3-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzylami-
ne
[0643] mp. 217-218.degree. C.
Example 25
[0644] According to Example 22 and using
5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3--
thiazole instead of
[5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine,
and using 2-phenylethylamine, 4-fluorobenzylamine,
N-benzyl-N-methylamine, N-methyl-2-phenylethylamine and
2-thienylmethylamine, respectively, instead of benzylamine, the
following Example compounds 25-1-25-5 were synthesized.
Example Compound 25-1
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-py-
ridyl]-N-(2-phenylethyl)amine
[0645] mp. 174-176.degree. C.
Example Compound 25-2
N-(4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-
-thiazol-5-yl]-2-pyridyl]amine
[0646] mp. 155-158.degree. C.
Example Compound 25-3
N-benzyl-N-methyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3--
thiazol-5-yl]-2-pyridyl]amine
[0647] mp. 165-166.degree. C.
Example Compound 25-4
N-methyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-
-yl]-2-pyridyl]-N-(2-phenylethyl) amine
[0648] mp. 116-117.degree. C.
Example Compound 25-5
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-py-
ridyl]-N-(2-thienylmethyl)amine
[0649] mp. 107-109.degree. C.
Example 26
4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-5-(2-phenylthio-4-pyridyl)-1-
,3-thiazole
[0650] A mixture of
5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3--
thiazole (0.40 g, 0.94 mmol) and thiophenol (1.0 mL, 9.7 mmol) was
stirred at 150.degree. C. for 10 hours. After the reaction mixture
was cooled to room temperature, a saturated aqueous solution of
sodium hydrogencarbonate was added, the resulting mixture was
extracted with ethyl acetate and washed with water. This extract
was dried and concentrated. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate, 1:1) and
recrystallized from ethanol to obtain 0.34 g (yield 70%) of the
title compound.
[0651] mp. 116-118.degree. C.
Example 27
5-(2-benzylthio-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1-
,3-thiazole
[0652] After sodium hydride (60% paraffin dispersion, 0.13 g, 3.2
mmol) was washed with hexane twice, it was suspended in
N,N-dimethylformamide (15 mL). Phenylmethanethiol (0.35 mL, 3.0
mmol) was added to this suspension and stirred for 10 minutes. A
solution of
5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3--
thiazole (0.49 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) was
added to this mixture and stirred for 1 hour. An 8N aqueous
solution of sodium hydroxide was added to the reaction mixture, the
resulting mixture was extracted with ethyl acetate, and the extract
was washed with water. This extract was dried and concentrated. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate, 2:1) to obtain 0.48 g (yield 79%).
[0653] mp. 182-185.degree. C.
Example 28
4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-5-(2-phenylsulfonyl-4-pyridy-
l)-1,3-thiazole
[0654] To a solution of
4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-5-(2-phenylthio-4-pyridyl)--
1,3-thiazole (0.48 g, 0.93 mmol) in N,N-dimethylformamide (10 mL)
was added m-chloroperbenzoic acid (0.51 g, 2.4 mmol) and the
mixture was stirred at room temperature for 1 hour. An 8N aqueous
solution of sodium hydroxide was added to the reaction mixture and
the resulting solid was collected by filtration. The solid was
recrystallized from ethanol to obtain 0.42 g (yield 82%) of the
title compound.
[0655] mp. 126-128.degree. C.
[0656] Compounds prepared in the above Examples 9-28 are shown in
table 1 to Table 6.
TABLE-US-00001 TABLE 1 ##STR00045## Example Compound No. R.sup.2 Z
Y R.sup.1 R.sup.3 mp/.degree. C. 9 ##STR00046## --CO-- --NH--
--NHCOMe ##STR00047## 238-241 10 ##STR00048## --CH.sub.2-- --NH--
--NHCOMe ##STR00049## 217-219 11 ##STR00050## --CO-- --NH-- --NHMe
##STR00051## 237-241 12 ##STR00052## --CO-- --NH-- --NH.sub.2
##STR00053## 216-217 13 ##STR00054## --CO-- --NH-- --Me
##STR00055## 134-135 14 ##STR00056## --CH.sub.2CO-- --NH--
##STR00057## ##STR00058## 187-190 15-1 ##STR00059## --CH.sub.2CO--
--NH-- --Me ##STR00060## 118-120 15-2 ##STR00061## --CH.sub.2CO--
--NH-- --CH.sub.2Me ##STR00062## 107-108 15-3 ##STR00063##
--CH.sub.2CO-- --NH-- --(CH.sub.2).sub.2Me ##STR00064## 109-111
15-4 ##STR00065## --CH.sub.2CO-- --NH-- --(CH.sub.2).sub.3Me
##STR00066## 92-93 15-5 ##STR00067## --CH.sub.2CO-- --NH--
##STR00068## ##STR00069## 141-142 15-6 ##STR00070## --CH.sub.2CO--
--NH-- ##STR00071## ##STR00072## 205-206 16-1 ##STR00073## --CO--
--NH-- --CH.sub.2Me ##STR00074## 113-114 16-2 ##STR00075##
--(CH.sub.2).sub.2CO-- --NH-- --CH.sub.2Me ##STR00076## 126-127
TABLE-US-00002 TABLE 2 ##STR00077## Example Compound No R.sup.2 Z Y
R.sup.1 R.sup.3 mp/.degree. C. 16-3 ##STR00078##
--(CH.sub.2).sub.2CO-- --NH-- --CH.sub.2Me ##STR00079## 137-138
16-4 ##STR00080## --(CH.sub.2).sub.2CO-- --NH-- --CH.sub.2Me
##STR00081## 116-117 16-5 ##STR00082## --(CH.sub.2).sub.3CO--
--NH-- --CH.sub.2Me ##STR00083## 92-93 16-6 ##STR00084##
--(CH.sub.2).sub.4CO-- --NH-- --CH.sub.2Me ##STR00085## 86-87 16-7
##STR00086## --CO-- --NH-- --(CH.sub.2).sub.2Me ##STR00087##
amorphous 16-8 ##STR00088## --(CH.sub.2).sub.2CO-- --NH--
--(CH.sub.2).sub.2Me ##STR00089## 103-104 16-9 ##STR00090## --CO--
--NH-- --(CH.sub.2).sub.3Me ##STR00091## amorphous 16-10
##STR00092## --(CH.sub.2).sub.2CO-- --NH-- --(CH.sub.2).sub.3Me
##STR00093## 77-78 16-11 ##STR00094## --CO-- --NH-- ##STR00095##
##STR00096## 126-128 16-12 ##STR00097## --(CH.sub.2).sub.2CO--
--NH-- ##STR00098## ##STR00099## 169-171 16-13 ##STR00100## --CO--
--NH-- ##STR00101## ##STR00102## 138-140 16-14 ##STR00103##
--(CH.sub.2).sub.2CO-- --NH-- ##STR00104## ##STR00105## 156-158
16-15 ##STR00106## --CO-- --NH-- ##STR00107## ##STR00108## 180-182
16-16 ##STR00109## --(CH.sub.2).sub.2CO-- --NH-- ##STR00110##
##STR00111## 174-175
TABLE-US-00003 TABLE 3 ##STR00112## Example Compound No R.sup.2 Z Y
R.sup.1 R.sup.3 mp/.degree. C. 16-17 ##STR00113## --CO-- --NH--
##STR00114## ##STR00115## 145-147 16-18 ##STR00116## --CO-- --NH--
##STR00117## ##STR00118## 184-186 17 ##STR00119## --CH.sub.2CO--
--NMe-- --CH.sub.2Me ##STR00120## 75-76 18 ##STR00121##
--(CH.sub.2).sub.2CO-- --NMe-- --CH.sub.2Me ##STR00122## oil 19-1
##STR00123## --CH.sub.2-- --NH-- --Me ##STR00124## 132-133 19-2
##STR00125## --CH.sub.2-- --NH-- --CH.sub.2Me ##STR00126## 106-107
19-3 ##STR00127## --(CH.sub.2).sub.2-- --NH-- --CH.sub.2Me
##STR00128## 97-98 19-4 ##STR00129## --(CH.sub.2).sub.3-- --NH--
--CH.sub.2Me ##STR00130## 52-53 19-5 ##STR00131## --CH.sub.2--
--NH-- --(CH.sub.2).sub.2Me ##STR00132## oil 19-6 ##STR00133##
--(CH.sub.2).sub.2-- --NH-- --(CH.sub.2).sub.2Me ##STR00134## oil
19-7 ##STR00135## --(CH.sub.2).sub.3-- --NH-- --(CH.sub.2).sub.2Me
##STR00136## oil 19-8 ##STR00137## --CH.sub.2-- --NH--
--(CH.sub.2).sub.3Me ##STR00138## oil 19-9 ##STR00139##
--(CH.sub.2).sub.2-- --NH-- --(CH.sub.2).sub.3Me ##STR00140##
oil
TABLE-US-00004 TABLE 4 ##STR00141## Example Compound No R.sup.2 Z Y
R.sup.1 R.sup.3 mp/.degree. C. 19-10 ##STR00142##
--(CH.sub.2).sub.3-- --NH-- --(CH.sub.2).sub.3Me ##STR00143## oil
19-11 ##STR00144## --CH.sub.2-- --NH-- ##STR00145## ##STR00146##
143-146 19-12 ##STR00147## --(CH.sub.2).sub.2-- --NH-- ##STR00148##
##STR00149## 97-98 19-13 ##STR00150## --(CH.sub.2).sub.3-- --NH--
##STR00151## ##STR00152## 110-112 19-14 ##STR00153## --CH.sub.2--
--NH-- ##STR00154## ##STR00155## 84-86 19-15 ##STR00156##
--(CH.sub.2).sub.2-- --NH-- ##STR00157## ##STR00158## 113-114 19-16
##STR00159## --(CH.sub.2).sub.3-- --NH-- ##STR00160## ##STR00161##
101-102 19-17 ##STR00162## --CH.sub.2-- --NH-- ##STR00163##
##STR00164## 134-136 19-18 ##STR00165## --(CH.sub.2).sub.2-- --NH--
##STR00166## ##STR00167## 137-139 19-19 ##STR00168##
--(CH.sub.2).sub.3-- --NH-- ##STR00169## ##STR00170## 106-107 19-20
##STR00171## --CH.sub.2-- --NH-- ##STR00172## ##STR00173## 144-145
20 ##STR00174## --CO-- --NH-- ##STR00175## ##STR00176## 212-214
TABLE-US-00005 TABLE 5 ##STR00177## Example Compound No R.sup.2 Z Y
R.sup.1 R.sup.3 mp/.degree. C. 21-1 ##STR00178## --CH.sub.2CO--
--NH-- ##STR00179## ##STR00180## 244-245 21-2 ##STR00181##
--(CH.sub.2).sub.2CO-- --NH-- ##STR00182## ##STR00183## 236-237
21-3 ##STR00184## --CO-- --NH-- ##STR00185## ##STR00186## 199-201
21-4 ##STR00187## --CO-- --NH-- ##STR00188## ##STR00189## 231-233
21-5 ##STR00190## --CH.sub.2-- --NH-- ##STR00191## ##STR00192##
148-150 21-6 ##STR00193## --(CH.sub.2).sub.3-- --NH-- ##STR00194##
##STR00195## 167-168 21-7 ##STR00196## --CH.sub.2-- --NH--
##STR00197## ##STR00198## 167-168 22 ##STR00199## --CH.sub.2--
--NH-- --NH.sub.2 ##STR00200## 178-179 23-1 ##STR00201##
--CH.sub.2-- --NH-- --NH.sub.2 ##STR00202## 183-184 23-2
##STR00203## --CH.sub.2-- --NH-- --NH.sub.2 ##STR00204## 152-154
23-3 ##STR00205## --CH.sub.2-- --NH-- --NH.sub.2 ##STR00206##
158-159 23-4 ##STR00207## --CH.sub.2-- --NH-- --NH.sub.2
##STR00208## 182-183 23-5 ##STR00209## --CH.sub.2-- --NH--
--NH.sub.2 ##STR00210## 180-181 23-6 ##STR00211## --CHMe-- (R)
--NH-- --NH.sub.2 ##STR00212## 94-98
TABLE-US-00006 TABLE 6 ##STR00213## Example Compound No R.sup.2 Z Y
R.sup.1 R.sup.3 mp/.degree. C. 23-7 ##STR00214## --CHMe-- (S)
--NH-- --NH.sub.2 ##STR00215## 93-96 23-8 ##STR00216## --CH.sub.2--
--NMe-- --NH.sub.2 ##STR00217## 138-140 24 ##STR00218##
--CH.sub.2-- --NH-- --NH.sub.2 ##STR00219## 217-218 25-1
##STR00220## --(CH.sub.2).sub.2-- --NH-- ##STR00221## ##STR00222##
174-176 25-2 ##STR00223## --CH.sub.2-- --NH-- ##STR00224##
##STR00225## 155-158 25-3 ##STR00226## --CH.sub.2-- --NMe--
##STR00227## ##STR00228## 165-166 25-4 ##STR00229##
--(CH.sub.2).sub.2-- --NMe-- ##STR00230## ##STR00231## 116-117 25-5
##STR00232## --CH.sub.2-- --NH-- ##STR00233## ##STR00234## 107-109
26 ##STR00235## -- --S-- ##STR00236## ##STR00237## 116-118 27
##STR00238## --CH.sub.2-- --S-- ##STR00239## ##STR00240## 182-185
28 ##STR00241## -- --SO.sub.2-- ##STR00242## ##STR00243##
126-128
Preparation Example 1
TABLE-US-00007 [0657] (1) Compound of Example 1 50 mg (2) Lactose
34 mg (3) Corn starch 10.6 mg (4) Corn starch (pasty) 5 mg (5)
Magnesium stearate 0.4 mg (6) Calcium carboxymethylcellulose 20 mg
Total 120 mg
[0658] According to the conventional method, the above (1) to (6)
were mixed, compressed with a compressing machine to obtain
tablets.
Preparation Example 2
TABLE-US-00008 [0659] (1) Example compound 16-1 10.0 mg (2) Lactose
60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium
stearate 2.0 mg
[0660] 10.0 mg of Example compound 16-1 and a mixture of 60.0 mg of
lactose and 35.0 mg of corn starch were granulated by passing
through a 1 mm mesh sieve using 0.03 ml of a 10% aqueous gelatin
solution (3.0 mg as gelatin) and, thereafter, dried at 40.degree.
C. and re-passed through a sieve. The granules thus obtained were
mixed with 2.0 mg of magnesium stearate and compressed. The
resulting core tablet is coated with a sugar coating of a
suspension of sucrose, titanium dioxide, talc and arabic gum in
water. The tablet coated with a coating is polished with beeswax to
obtain a coated tablet.
Preparation Example 3
TABLE-US-00009 [0661] (1) Example compound 16-1 10.0 mg (2) Lactose
70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5)
Magnesium stearate 3.0 mg
[0662] After 10.0 mg of Example compound 16-1 and 3.0 mg of
magnesium stearate are granulated with 0.07 ml of an aqueous
solution of soluble starch (7.0 mg as soluble starch), the granules
are dried and mixed with 70.0 mg of lactose and 50.0 mg of corn
starch. The mixture is compressed to obtain tablets.
Preparation Example 4
TABLE-US-00010 [0663] (1) Example compound 18 5.0 mg (2) Sodium
chloride 20.0 mg (3) Distilled water to total 2 ml
[0664] 5.0 mg of Example 18 and 20.0 mg of sodium chloride are
dissolved in distilled water and water is added to total 2.0 ml.
The solution is filtered and filled into a 2 ml of ampule under
sterile conditions. After the ampule is sterilized, it is sealed to
obtain a solution for injection.
Experimental Example 1
[0665] Genetic procedures were according to a method described in
Molecular Cloning, published by Cold Spring Harbor, Laboratory,
1989 or a method described in the attached protocol of the
reagent.
[0666] 1) Cloning of Human Adenosine A.sub.3 Receptor
[0667] Cloning of an adenosine A.sub.3 receptor gene was performed
from human brain cDNA by a PCR method. A PCR reaction was performed
with a DNA thermal cycler 480 (Perkin Elmer) by using 1 ng of brain
cDNA (Toyobo, QUICK-Clone cDNA) as a template, adding each 50
.mu.mol of a primer set 5'-CGCCTCTAGACAAGATGCCCAACAACAGCACTGC-3'
(SEQ ID NO:1) and 5'-CGGGGTCGACACTACTCAGAATTCTTCTCAATGC-3' (SEQ ID
NO:2) made by reference to adenosine A.sub.3 receptor gene base
sequence reported by Salvatore et al. (Proc. Natl. Acad., Sci.
U.S.A., 90:10365-10369, 1993) and employing Takara LA PCR Kit Ver.
2 (Takara Shuzo) (reaction conditions: 35 cycles of 1 minute at
95.degree. C., 1 minute at 66.degree. C., 2 minutes at 75.degree.
C.). The resulting PCR product was subjected to agarose gel
electrophoresis and 1.0 kb of DNA fragment was recovered and,
thereafter, an adenosine A.sub.3 receptor gene was cloned using
Original TA Cloning Kit (Funakoshi).
[0668] Next, the resulting plasmid was digested with a restriction
enzyme XbaI (Takara Shuzo), treated with T4 DNA polymerase (Takara
Shuzo) into end-blunted fragments and further digested with SalI
(Takara Shuzo) to obtain adenosine A.sub.3 receptor gene
fragments.
[0669] 2) Preparation of a Plasmid for Expressing of Human
Adenosine A.sub.3 Receptor
[0670] A SR.alpha. promoter derived from pTB1411 described in JP-A
5-076385 was digested with BglII (Takara Shuzo), blunted, and
ligated to EcoRI (Takara Shuzo)-digested pCI vector (Promega) with
a DNA Ligation kit (Takara Shuzo) to make pCI-SR.alpha.. Next, this
pCI-SR.alpha. was digested with ClaI (Takara Shuzo) and treated
with T4 DNA polymerase (Takara Shuzo) to blunt-ended. On the other
hand, after pGFP-C1 (Toyobo) was digested with Bsu36I (Daiichi Pure
Chemicals), treated with T4 DNA polymerase (Takara Shuzo) to
blunted end to obtain 1.63 kb of DNA fragment, and both were
ligated with a DNA Ligation kit (Takara Shuzo) and competent cells
of Escherichia coli JM109 were transformed to obtain the plasmid
pMSR.alpha.neo.
[0671] Next, after pMSR.alpha.neo was digested with EcoRI (Takara
Shuzo), treated with a T4 DNA polymerase (Takara Shuzo) to blunted
end, and further digesting with SalI (Takara Shuzo) to obtain a 5.4
kb DNA fragment. The obtained DNA fragment and the fragments of
adenosine A.sub.3 receptor gene obtained in the above 1) were
mixed, ligated with a DNA Ligation kit (Takara Shuzo) and competent
cells of Escherichia coli JM109 (Takara Shuzo) were transformed to
obtain the plasmid pA.sub.3SR.alpha..
[0672] 3) Introduction of a Plasmid for Expressing Human Adenosine
A.sub.3 Receptor into CHO (dhfr-) Cells and Expression
[0673] CHO (dhfr-) cells obtained by culturing on Ham F12 medium
(Nihonseiyaku) containing 10% bovine fetal serum (Lifetec Oriental)
in a 750 ml tissue culture flask (Vecton Dickinson) were peeled
with 0.5 g/L trypsin-0.2 g/L EDTA (Lifetec Oriental) and,
thereafter, the cells were washed with PBS (Lifetec Oriental) and
centrifuged (1000 rpm, 5 minutes), which was suspended in PBS.
[0674] Next, a DNA was introduced into cells using a gene pulser
(BioRad) according to the following conditions. That is,
8.times.10.sup.6 cells and 10 .mu.g of the plasmid
pA.sub.3SR.alpha. for expressing human adenosine A.sub.3 receptor
were added to 0.4 cm gapped cuvette and electroporation was
performed with 0.8 ml volume, and under voltage 0.25 kV and
capacitance 960 .mu.F. Thereafter, the cells were transferred to
Ham F12 medium containing 10% bovine fetal serum, cultured for 24
hours, the cells were peeled again and centrifuged, then, suspended
in Ham F12 medium containing 10% bovine fetal serum to which
Geneticin (Lifetec Oriental) had been added to 500 .mu.g/ml, which
was diluted to 10.sup.4 cells/ml to seed on a 96-well plate (Becton
Dickinson) to obtain Geneticin-resistant strain.
[0675] Next, the resulting Geneticin-resistant strain was cultured
on a 24 well-plate (Becton Dickinson) and, thereafter, an adenosine
A.sub.3 receptor expressing cell was selected among the resistant
strains. That is, a reaction was conducted in an assay buffer I
(HBSS (Wako Pure Chemicals) containing 0.1% BSA, 0.25 mM PMSF, 1
.mu.g/ml pepstatin and 20 .mu.g/ml leupeptin) for 1 hour, washed
with an assay buffer I, the radioactivity was measured with a
.gamma.-counter to select a cell to which a ligand is specifically
bound, A.sub.3Ar/CHO strain.
[0676] 4) Preparation of a Cell Membrane Fraction of a Cell for
Expressing Adenosine A.sub.3 Receptor
[0677] After the A.sub.3AR/CHO strain obtained in the above 3) was
cultured in Ham F12 medium containing 10% bovine fetal serum for 2
days, the cells were peeled with 0.02% EDTA-containing PBS, the
cells were recovered by centrifugation, suspended in an assay
buffer II (50 mM Tris-hydrochloric acid (pH 7.5), 1 mM EDTA, 10 mM
magnesium chloride, 0.25 mM PMSF, 1 .mu.g/mL pepstatin, 20 .mu.g/ml
leupeptin), and the cells were lysed by treating three times with a
polytron homogenizer (Model PT-3000, KINEMATICA AG) at 20,000 rpm
for 20 seconds. After the cells were ground, they were centrifuged
at 20,000 rpm for 10 minutes to obtain the supernatant containing
the membrane fraction. This supernatant was centrifuged with a
supercentrifuge (Model L8-70M, rotor 70Ti, Beckmann) at 30,000 rpm
for 1 hour to obtain the precipitates containing the membrane
fraction.
[0678] Next, the precipitates were suspended in an assay buffer II
containing 2 unit/ml adenosine deaminase (Boehringer Mannheim),
treated at 30.degree. C. for 30 minutes and, thereafter,
centrifuged again as described above to obtain the precipitates
containing the membrane fraction.
[0679] 5) Adenosine A.sub.3 Receptor Binding Test
[0680] On a 96 well-microplate, [.sup.3H]-NECA (Amersham) as a
ligand was added to an assay buffer II containing the 100 .mu.g/ml
membrane fraction obtained in the above 4) and various
concentrations of test compounds so that the concentration of the
ligand was 10 nM, followed by reaction at room temperature for 1
hour. Then, the membrane fraction was transferred to unifilter GF/C
(Packard) by filtering the reaction solution using Cell Harvester
(Packard) and washed three times with 50 mM cooled Tris buffer (pH
7.5). After the filter was dried, Microscint 0 (Packard) was added
to the filter, the radioactivity was measured with a TopCount
(Packard) and the concentration (IC.sub.50) of a test compound
necessary for decreasing an amount of binding of [.sup.3H]-NECA to
the membrane fraction by 50% was calculated with PRISM 2.01
(Graphpad Software).
[0681] As the result, the IC.sub.50 value of the compound of
Example 1 was 11.6 nM. It can be seen that Compound (I) is the
excellent affinity for adenosine A.sub.3 receptor.
Experimental Example 2
[0682] The genetic manipulations described below were according to
a method described in the book (Maniatis et al., Molecular Cloning,
Cold Spring Harbor Laboratory, 1989) or a method described in the
protocol attached to the reagent.
[0683] (1) Cloning of Human p38 Map Kinase Gene and Preparation of
Recombinant Baculovirus
[0684] Cloning of human p38 MAP kinase gene was performed by a PCR
method using a primer set
P38-U:5'-ACCACTCGAGATGGACTACAAGGACGACGATGACAAGTCTCAGGAGAGGCCCACGTTCTACC-3-
' [SEQ ID NO:3] and PAG-L:5'-ACCCGGTACCACCAGGTGCTCAGGACTCCATCTCT-3'
[SEQ ID NO:4] made by reference to the base sequence of p38 MAP
kinase gene reported by Han et al. (Science 265 (5173), 808-811
(1994)) and employing kidney cDNA (Toyobo, QUICK-Clone cDNA) as a
template.
[0685] A PCR reaction was performed by a Hot Start method using
AmpliWax PCR Gem 100 (Takara Shuzo). As the lower mixed solution, 2
.mu.L 10.times.LA PCR Buffer, 3 .mu.L 2.5 mM DNTP solution, each
2.5 .mu.L of 12.5 .mu.M primer solution, and 10 .mu.L sterile
distilled water were mixed. As the upper mixed solution, 1 .mu.L
human cardiac cDNA (1 ng/mL) as a template, 3 .mu.L 10.times.LA PCR
Buffer, 1 .mu.L 2.5 mM DNTP solution, 0.5 .mu.L TaKaRa LA Taq DNA
polymerase (Takara Shuzo), and 24.5 .mu.L sterile distilled water
were mixed. One AmpliWax PCR Gem 100 (Takara Shuzo) was added to
the prepared lower mixed solution to treat at 70.degree. C. for 5
minutes and for 5 minutes in an ice and, thereafter, the upper
mixed solution was added to prepare a reaction solution for PCR. A
tube containing the reaction solution was set at a thermal cycler
(Perkin Elmer), which was treated at 95.degree. C. for 2 minutes.
Further, after repeating 35 times a cycle of 15 seconds at
95.degree. C. and 2 minutes at 68.degree. C., treatment was
performed at 72.degree. C. for 8 minutes. The resulting PCR product
was subjected to agarose gel (1%) electrophoresis, 1.1 kb DNA
fragment containing p38 MAP kinase gene was recovered from the gel
and, thereafter, which was inserted into pT7Blue-T vector (Takara
Shuzo) to make the plasmid pHP38.
[0686] The 4.8 kb XhoI-KpnI fragment of the plasmid pFASTBAC1
(CIBCOBRL) and the 1.1 kb XhoI-Kpn fragment of the above plasmid
pHP38 were ligated to make the plasmid pFBHP38.
[0687] The plasmid pFBHP38 and BAC-TO-BAC Baculovirus Expression
System (GIBCOBRL) were used to prepare the recombinant Baculovirus
virusstock BAC-HP38.
[0688] (2) Cloning of Human MKK3 Gene and Preparation of
Recombinant Baculovirus
[0689] Cloning of human MKK3 gene was performed by a PCR method
using a primer set
MKK-U:5'-ACAAGAATTCATAACATATGGCTCATCATCATCATCATCATTCCAAGCCACCCGCACCCAA-3'
[SEQ ID NO:5] and MKK-L: 5'-TCCCGTCTAGACTATGAGTCTTCTCCCAGGAT-3'
[SEQ ID NO:6] made by reference to the base sequence of MKK3 gene
reported by Derijard, B. et al., Science 267 (5198), 682-685 (1995)
and using kidney cDNA (Toyobo, QUICK-Clone cDNA).
[0690] A PCR reaction was performed by a Hot Start method using
AmpliWax PCR Gem 100 (Takara Shuzo). As the lower mixed solution, 2
.mu.L 10.times.LA PCR Buffer, 3 .mu.L 2.5 mM dNTP solution, each
2.5 .mu.L of 12.5 .mu.M primer solution, and 10 .mu.L sterile
distilled water were mixed. As the upper mixed solution, 1 .mu.L
human kidney cDNA (1 ng/mL), 3 .mu.L 10.times.LA PCR Buffer, 1
.mu.L 2.5 mM dNTP solution, 0.5 .mu.L TaKaRa LA taq DNA polymerase
(Takara Shuzo) and 24.5 .mu.L sterile distilled water were mixed.
One AmpliWax PCR Gem 100 (Takara Shuzo) was added to the prepared
lower mixed solution to treat at 70.degree. C. for 5 minutes and
for 5 minutes in an ice and, thereafter, the upper mixed solution
was added to prepare a reaction solution for PCR. A tube containing
the reaction solution was set at a thermal cycler (Perkin Elmer),
which was treated at 95.degree. C. for 2 minutes. Further, after
repeating 35 times a cycle of 15 seconds at 95.degree. C. and 2
minutes at 68.degree. C., treatment was performed at 72.degree. C.
for 8 minutes. The resulting PCR product was subjected to agarose
gel (1%) electrophoresis, 1.0 kb DNA fragment containing MKK3 gene
was recovered from the gel and, thereafter, which was inserted into
pT7Blue-T vector (Takara Shuzo) to make the plasmid pHMKK3.
[0691] In order to mutate MKK3 into a constitutive active form
(from Ser to Glu at 189 position, from Thr to Glu at position 193),
a primer set
SER-U:5'-GGCTACTTGGTGGACGAGGTGGCCAAGGAGATGGATGCCGGCTGC-3' [SEQ ID
NO:7] and SER-L:5'-GCAGCCGGCATCCATCTCCTTGGCCACCTCGTCCACCAAGTAGCC-31
[SEQ ID NO:8] was used to introduce a mutation by QuickChange
Site-Directed Mutagenesis Kit (Stratagene), to obtain pcaMKK3.
[0692] 4.8 kb EcoRI-XbaI fragment of the plasmid pFASTBAC1
(CIBCOBRL) and the 1.0 kb EcoRI-XbaI fragment of the above plasmid
pcaMKK 3 were ligated to make the plasmid pFBcaMKK3.
[0693] The plasmid pFBcaMKK3 and BAC-TO-BAC Baculovirus Expression
System (GIBCOBRL) were used to prepare the recombinant Baculovirus
virusstock BAC-caMKK3.
[0694] (3) Preparation of Active Form p38 MAP Kinase
[0695] The Sf-21 cells were seeded on 100 ml Sf-900II SFM medium
(GIBCOBRL) to 1.times.10.sup.6 cells/mL and cultured at 27.degree.
C. for 24 hours. After each 0.2 mL of the virusstock BAC-HP38 of
recombinant Baculovirus and BAC-caMKK3 were added, the culturing
was further performed for 48 hours. After the cells were separated
from the culturing solution by centrifugation (3000 rpm, 10 min),
the cells were washed twice with PBS. After the cells were
suspended in 10 ml Lysis buffer (25 mM HEPES (pH 7.5), 1% Triton X,
130 mM NaCl, 1 mM EDTA, 1 mM DTT, 25 mM .beta.-glycerophosphate, 20
mM leupeptin, 1 mM APMSF, 1 mM Sodium orthovanadate), the cells
were lysed by treating twice with a homogenizer (POLYTRON) at 20000
rpm for 2 minutes. By using Anti-FLAG M2 Affinity Gel (Eastman
Chemical) from the supernatant obtained by centrifugation (40000
rpm, 45 minutes), active form p38 MAP kinase was purified.
[0696] (4) Measurement of the p38 MAP Kinase Inhibitory
Activity
[0697] 2.5 .mu.L of a test compound dissolved in DMSO was added to
37.5 .mu.L reaction solution (25 mM HEPES (pH 7.5), 10 mM Magnesium
Acetate) containing 260 ng active form p38 MAP kinase and 1 .mu.g
Myelin Basic Protein, which was maintained at 30.degree. C. for 5
minutes. The reaction was initiated by adding 10 .mu.L ATP solution
(2.5 .mu.M ATP, 0.1 .mu.Ci [g-.sup.32P]ATP). After the reaction was
performed at 30.degree. C. for 60 minutes, the reaction was stopped
by adding 50 .mu.L 20% TCA solution. After the reaction solution
was allowed to stand at 0.degree. C. for 20 minutes, an acid
insoluble fraction was transferred to GF/C filter (Packard Japan)
using Cell Harvester (Packard Japan) and washed with 250 mM
H.sub.3PO.sub.4. After drying at 45.degree. C. for 60 minutes, 40
.mu.M Microscint 0 (Packard Japan) was added and the radioactivity
was measured with a TopCount (Packard Japan). The concentration
(IC.sub.50 value) necessary for inhibiting uptake of .sup.32P into
an acid insoluble fraction by 50% was calculated with PRISM 2.01
(Graphpad Software).
[0698] The results are shown in Table 7.
TABLE-US-00011 TABLE 7 Example No. IC.sub.50 (.mu.M) 1 0.43 2 0.063
3 0.023 4 0.020 5 0.029 6 0.023
[0699] From this, it can be seen that Compound (I) has the p38 MAP
kinase inhibitory activity.
Experimental Example 3
Measurement of Inhibiting Activity of TNF-.alpha. Production
[0700] After THP-1 cells which had been cultured on PRMI 1640
medium (manufactured by Life Technologies, Inc.) containing 1%
non-activated bovine fetal serum (manufactured by Life
Technologies, Inc., U.S.A.) and 10 mM HEPES (pH 7.5) seeded on a
96-well plate to 1.times.10.sup.5 cells/well, 1 .mu.L test compound
dissolved in DMSO was added to there. After incubation at
37.degree. C. for 1 hour in a CO.sub.2 incubator, LPS (Wako Pure
Chemicals) was added to the final concentration 5 .mu.g/mL. After
cultured at 37.degree. C. for 4 hours in a CO.sub.2 incubator, the
supernatant was obtained by centrifugation. The concentration of
TNF-.alpha. in the supernatant was measured with ELISA (R&D
System, Quantikine Kit). The concentration (IC.sub.50 value)
necessary for inhibiting TNF-.alpha. production by 50% was
calculated by PRIMS 2.01 (Graphpad Software).
[0701] The results are shown in Table 8.
TABLE-US-00012 TABLE 8 Example No. IC.sub.50 (.mu.M) 3 0.026 4
0.014 5 0.020 6 0.140
[0702] From this, it can be seen that Compound (I) has the
excellent inhibitory activity of TNF-.alpha. production.
INDUSTRIAL APPLICABILITY
[0703] Compound (I) or a salt thereof has the excellent adenosine
A.sub.3 receptor antagonism and can be used as an agent for
preventing or treating adenosine A.sub.3 receptor related diseases.
Further, Compound (I) or a salt thereof shows the excellent p38 MAP
kinase inhibiting activity and TNF-.alpha. inhibiting activity, and
can be also used as an agent for preventing or treating p38 MAP
kinase related diseases and TNF-.alpha. related diseases.
Sequence CWU 1
1
8134DNAArtificial SequenceOligonucleotide designed to act as PCT
primer for detection of adenosine A3 receptor gene. 1cgcctctaga
caagatgccc aacaacagca ctgc 34234DNAArtificial
SequenceOligonucleotide designed to act as PCT primer for detection
of adenosine A3 receptor gene. 2cggggtcgac actactcaga attcttctca
atgc 34362DNAArtificial SequenceOligonucleotide designed to act as
PCR primer for detection of p38 MAP kinase gene. 3accactcgag
atggactaca aggacgacga tgacaagtct caggagaggc ccacgttcta 60cc
62435DNAArtificial SequenceOligonucleotide designed to act as PCR
primer for detection of p38 MAP kinase gene. 4acccggtacc accaggtgct
caggactcca tctct 35561DNAArtificial SequenceOligonucleotide
designed to act as PCR primer for detection of MKK3 gene.
5acaagaattc ataacatatg gctcatcatc atcatcatca ttccaagcca cccgcaccca
60a 61632DNAArtificial SequenceOligonucleotide designed to act as
PCR primer for detection of MKK3 gene. 6tcccgtctag actatgagtc
ttctcccagg at 32745DNAArtificial SequenceOligonucleotide designed
to act as primer for mutation of MKK3 gene. 7ggctacttgg tggacgaggt
ggccaaggag atggatgccg gctgc 45845DNAArtificial
SequenceOligonucleotide designed to act as primer for mutation of
MKK3 gene. 8gcagccggca tccatctcct tggccacctc gtccaccaag tagcc
45
* * * * *