U.S. patent application number 12/305809 was filed with the patent office on 2010-09-16 for agent for overcoming resistance to anti-cancer agent.
This patent application is currently assigned to NIPPON CHEMIPHAR CO., LTD.. Invention is credited to Masuharu Hirano, Toshihisa Ishikawa, Hikaru Saito, Tomio Yamakawa.
Application Number | 20100234399 12/305809 |
Document ID | / |
Family ID | 38833563 |
Filed Date | 2010-09-16 |
United States Patent
Application |
20100234399 |
Kind Code |
A1 |
Hirano; Masuharu ; et
al. |
September 16, 2010 |
AGENT FOR OVERCOMING RESISTANCE TO ANTI-CANCER AGENT
Abstract
An agent comprising, as an active ingredient, a xanthine oxidase
inhibitor such as
2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine
potassium salt,
2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine,
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine,
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine
potassium salt,
2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine, TMX-67, and
FYX-051, which can be used as an agent for overcoming anti-cancer
agent resistance.
Inventors: |
Hirano; Masuharu; (Saitama,
JP) ; Yamakawa; Tomio; (Chiba, JP) ; Ishikawa;
Toshihisa; (Kanagawa, JP) ; Saito; Hikaru;
(Kanagawa, JP) |
Correspondence
Address: |
NIXON PEABODY, LLP
401 9TH STREET, NW, SUITE 900
WASHINGTON
DC
20004-2128
US
|
Assignee: |
NIPPON CHEMIPHAR CO., LTD.
Chiyoda-ku, Tokyo
JP
|
Family ID: |
38833563 |
Appl. No.: |
12/305809 |
Filed: |
June 22, 2007 |
PCT Filed: |
June 22, 2007 |
PCT NO: |
PCT/JP2007/063062 |
371 Date: |
February 3, 2009 |
Current U.S.
Class: |
514/260.1 ;
544/255 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 513/04 20130101; A61K 31/519 20130101; A61P 43/00 20180101;
C07D 277/56 20130101; A61K 31/426 20130101; A61P 25/30 20180101;
A61K 31/4745 20130101; C07D 401/14 20130101; A61P 19/06 20180101;
A61K 31/444 20130101; A61K 45/06 20130101; C07D 487/04 20130101;
C07D 277/20 20130101 |
Class at
Publication: |
514/260.1 ;
544/255 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 471/04 20060101 C07D471/04; A61P 35/00 20060101
A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 22, 2006 |
JP |
2006-172290 |
Claims
1. An agent containing a compound having the following formula (I)
or a salt thereof as an active ingredient for overcoming drug
resistance: ##STR00003## wherein R.sup.1 is C.sub.2-8 alkenyl,
C.sub.6-10 aryl, or heteroaryl in which the aryl and heteroaryl can
have a substituent selected from the group consisting of C.sub.1-8
alkyl, C.sub.1-8 alkyl substituted with halogen, C.sub.1-8 alkoxy,
C.sub.1-8 alkoxy substituted with halogen, C.sub.2-8
alkoxycarbonyl, formyl, carboxyl, halogen, hydroxyl, nitro, cyano,
amino, C.sub.6-10 aryl, and C.sub.6-10 aryloxy; R.sup.2 is cyano,
nitro, formyl, carboxyl, carbamoyl, or C.sub.2-8 alkoxycarbonyl; X
is oxygen, --N(R.sup.3)--, or --S(O).sub.n--, and R.sup.3 is a
hydrogen, C.sub.1-8 alkyl, or the group mentioned above for
R.sup.1, or R.sup.1 and R.sup.3 are combined to form morpholinyl,
thiomorpholinyl, or piperazinyl, and n is an integer of 0 to 2; and
Y is oxygen, sulfur, or NH.
2. An agent containing a compound having the following formula (II)
or a salt thereof as an active ingredient for overcoming drug
resistance: ##STR00004## wherein R.sup.1 is C.sub.6-10 aryl or
heteroaryl in which the aryl and heteroaryl can have a substituent
selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8
alkyl substituted with halogen, C.sub.1-8 alkoxy, C.sub.1-8 alkoxy
substituted with C.sub.1-8 alkoxy, C.sub.2-8 alkoxycarbonyl,
formyl, carboxyl, halogen, hydroxyl, nitro, cyano, amino,
C.sub.6-10 aryl, and C.sub.6-10 aryloxy; R.sup.2 is cyano, nitro,
formyl, carboxyl, carbamoyl, or C.sub.2-8 alkoxycarbonyl; R.sup.3
is hydroxyl, amino, carboxyl, mercapto, OR.sup.4, or NHR.sup.5, and
each of R.sup.4 and R.sup.5 is C.sub.1-8 alkyl or C.sub.1-8 alkyl
substituted with a group or atom selected from the group consisting
of halogen, hydroxyl, nitro, cyano, amino, C.sub.6-10 aryl, and
C.sub.6-10 aryloxy; X is oxygen, --N(R.sup.6)--, or --S(O).sub.n--,
and R.sup.6 is a hydrogen, alkyl, or the group mentioned above for
R.sup.1, and n is an integer of 0 to 2; and Y is oxygen or
sulfur.
3. An agent containing a compound selected from the group
consisting of 2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine,
2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine,
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine,
potassium salt of
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, and
potassium salt of
2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine
as an active ingredient for overcoming drug resistance.
4. An agent containing Febuxostat or
4-[5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile as
an active ingredient for overcoming drug resistance.
5. An agent containing a compound having the following formula (I)
or a salt thereof as an active ingredient for overcoming
anti-cancer agent resistance: ##STR00005## wherein R.sup.1 is
C.sub.2-8 alkenyl, C.sub.6-10 aryl, or heteroaryl in which the aryl
and heteroaryl can have a substituent selected from the group
consisting of C.sub.1-8 alkyl, C.sub.1-8 alkyl substituted with
halogen, C.sub.1-8 alkoxy, C.sub.1-8 alkoxy substituted with
halogen, C.sub.2-8 alkoxycarbonyl, formyl, carboxyl, halogen,
hydroxyl, nitro, cyano, amino, C.sub.6-10 aryl, and C.sub.6-10
aryloxy; R.sup.2 is cyano, nitro, formyl, carboxyl, carbamoyl, or
C.sub.2-8 alkoxycarbonyl; X is oxygen, --N(R.sup.3)--, or
--S(O).sub.n--, and R.sup.3 is a hydrogen, C.sub.1-8 alkyl, or the
group mentioned above for R.sup.1, or R.sup.1 and R.sup.3 are
combined to form morpholinyl, thiomorpholinyl, or piperazinyl, and
n is an integer of 0 to 2; and Y is oxygen, sulfur, or NH.
6. An agent containing a compound having the following formula (II)
or a salt thereof as an active ingredient for overcoming
anti-cancer agent resistance: ##STR00006## wherein R.sup.1 is
C.sub.6-10 aryl or heteroaryl in which the aryl and heteroaryl can
have a substituent selected from the group consisting of C.sub.1-8
alkyl, C.sub.1-8 alkyl substituted with halogen, C.sub.1-8 alkoxy,
C.sub.1-8 alkoxy substituted with C.sub.1-8 alkoxy, C.sub.2-8
alkoxycarbonyl, formyl, carboxyl, halogen, hydroxyl, nitro, cyano,
amino, C.sub.6-10 aryl, and C.sub.6-10 aryloxy; R.sup.2 is cyano,
nitro, formyl, carboxyl, carbamoyl, or C.sub.2-8 alkoxycarbonyl;
R.sup.3 is hydroxyl, amino, carboxyl, mercapto, OR.sup.4, or
NHR.sup.5, and each of R.sup.4 and R.sup.5 is C.sub.1-8 alkyl or
C.sub.1-8 alkyl substituted with a group or atom selected from the
group consisting of halogen, hydroxyl, nitro, cyano, amino,
C.sub.6-10 aryl, and C.sub.6-10 aryloxy; X is oxygen,
--N(R.sup.6)--, or --S(O).sub.n--, and R.sup.6 is a hydrogen,
C.sub.1-8 alkyl, or the group mentioned above for R.sup.1, and n is
an integer of 0 to 2; and Y is oxygen or sulfur.
7. An agent containing a compound selected from the group
consisting of 2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine,
2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine,
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine,
potassium salt of
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, and
potassium salt of
2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine
as an active ingredient for overcoming anti-cancer agent
resistance.
8. An agent containing Febuxostat or
4-[5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile as
an active ingredient for overcoming resistance to an anti-cancer
agent.
9. An agent for overcoming resistance to an anti-cancer agent
defined in any one of claims 5 to 8, wherein overexpression of BCRP
in a cancer cell is involved in acquiring anti-cancer agent
resistance.
10. A therapeutic composition against a cancer cell of multidrug
resistance, wherein the composition comprises an anti-cancer agent
and a compound selected from the group consisting of
2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine,
2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine,
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine,
potassium salt of
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine,
potassium salt of
2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine,
Febuxostat, and
4-[5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile.
Description
TECHNICAL FIELD
[0001] The present invention relates to an agent containing a
xanthine oxidase inhibitor as an active ingredient for overcoming
anti-cancer agent resistance.
PRIOR ART
[0002] Chemotherapy is indispensable for cancer treatment. On the
other hand, cancer often develops resistance to chemotherapy. Once
a cancer cell acquires resistance to a anti-cancer agent, the cell
frequently shows resistance to another anti-cancer agent unused in
treatment or multiple drugs having different action mechanisms or
different structures, which is said to be multidrug resistance.
Resistance is an enormous problem in treatment, and multidrug
resistance is a particularly serious problem. It has been desired
to develop an agent for overcoming multidrug resistance. One
mechanism of multidrug resistance is overexpression of ABC
transporters such as P-glycoprotein (ABCB1) and MRP1 (ABCC1), which
are localized in cell membrane. The ABC transporters excrete
intracellular substrates of various structures (such as agents,
physiologically active substances) out of cells in an ATP-dependent
manner. Therefore, overexpression of them decreases intracellular
concentrations of the drugs to cause resistance to various drugs
such as anti-cancer agent.
[0003] Breast Cancer Resistance Protein (BCRP/ABCG2) has recently
been identified as an ABC transporter (Doyle L A et al.: Proc Natl
Acad Sci USA., 95:15665-15670 (1998); Allikmets R et al.: Cancer
Res., 58:5337-5339 (1998); and Miyake K et al.: Cancer Res.,
59:8-13 (1999)).
[0004] BCRP excretes SN-38, which is an active metabolite of
irinotecan, or anti-cancer agents such as mitoxantrone and
topotecan out of cells. Therefore, BCRP has been noted as a
molecular target to overcome anti-cancer agent resistance (cf., JP
2003-63989 A).
[0005] It has been known that the compound having a condensed
dicyclic heterocyclic ring represented by the below-mentioned
formula (I) or (II) has xanthine oxidase (XOD) inhibitory action
(cf., WO 2005/121153 A1, WO 2003/042185 A1, WO 2007/004688 A1).
[0006] Febuxostat (TMX-67) and
4-[5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile
(FYX-051) have xanthine oxidase inhibitory action. They are
available agents for treating hyperuricemia.
[0007] However, it has not been known that the compound represented
by the below-mentioned formula (I) or (II), TMX-67 or the like has
BCRP inhibitory action.
DISCLOSURE OF INVENTION
[0008] An object of the invention is to provide an agent for
overcoming drug resistance or an agent for overcoming anti-cancer
agent resistance.
[0009] The present inventors have discovered that the compound
represented by the below-mentioned formula (I) or (II), TMX-67 or
the like, which has xanthine oxidase inhibitory action, also has
BCRP inhibitory action. The present invention has been completed
based on the discovery.
[0010] The present invention resides in an agent containing a
compound having the following formula (I) or a salt thereof as an
active ingredient for overcoming drug resistance:
##STR00001##
[0011] wherein R.sup.1 is C.sub.2-8 alkenyl, C.sub.6-10 aryl, or
heteroaryl in which the aryl and heteroaryl can have a substituent
selected from the group consisting of C.sub.1---8 alkyl, C.sub.1-8
alkyl substituted with halogen, C.sub.1-8 alkoxy, C.sub.1-8 alkoxy
substituted with halogen, C.sub.2-8 alkoxycarbonyl, formyl,
carboxyl, halogen, hydroxyl, nitro, cyano, amino, C.sub.6-10 aryl,
and C.sub.6-10 aryloxy;
[0012] R.sup.2 is cyano, nitro, formyl, carboxyl, carbamoyl, or
C.sub.2-8 alkoxycarbonyl;
[0013] X is oxygen, --N(R.sup.3)--, or --S(O).sub.n--, and R.sup.3
is a hydrogen, C.sub.1-5 alkyl, or the group mentioned above for
R.sup.1, or R.sup.1 and R.sup.3 are combined to form morpholinyl,
thiomorpholinyl, or piperazinyl, and n is an integer of 0 to 2;
and
[0014] Y is oxygen, sulfur, or NH.
[0015] The invention also resides in an agent containing a compound
having the following formula (II) or a salt thereof as an active
ingredient for overcoming drug resistance:
##STR00002##
[0016] wherein R.sup.1 is C.sub.6-10 aryl or heteroaryl in which
the aryl and heteroaryl can have a substituent selected from the
group consisting of C.sub.1-8 alkyl, C.sub.1-8 alkyl substituted
with halogen, C.sub.1-8 alkoxy, C.sub.1-8 alkoxy substituted with
C.sub.1-8 alkoxy, C.sub.2-8 alkoxycarbonyl, formyl, carboxyl,
halogen, hydroxyl, nitro, cyano, amino, C.sub.6-10 aryl, and
C.sub.6-10 aryloxy;
[0017] R.sup.2 is cyano, nitro, formyl, carboxyl, carbamoyl, or
C.sub.2-8 alkoxycarbonyl;
[0018] R.sup.3 is hydroxyl, amino, carboxyl, mercapto, OR.sup.4, or
NHR.sup.5, and each of R.sup.4 and R.sup.5 is C.sub.1-8 alkyl or
C.sub.1-8 alkyl substituted with a group or atom selected from the
group consisting of halogen, hydroxyl, nitro, cyano, amino,
C.sub.6-10 aryl, and C.sub.6-10 aryloxy;
[0019] X is oxygen, --N(R.sup.6)--, or --S(O).sub.n--, and R.sup.6
is a hydrogen, C.sub.1-8 alkyl, or the group mentioned above for
R.sup.1, and
[0020] n is an integer of 0 to 2; and
[0021] Y is oxygen or sulfur.
[0022] The invention also resides in an agent containing Febuxostat
or 4-[5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile
as an active ingredient for overcoming drug resistance.
[0023] The present invention further resides in an agent containing
a compound having the above-mentioned formula (I) or a salt thereof
as an active ingredient for overcoming anti-cancer agent
resistance.
[0024] The invention also resides in an agent containing a compound
having the following formula (II) or a salt thereof as an active
ingredient for overcoming anti-cancer agent resistance.
[0025] The invention furthermore resides in an agent containing
Febuxostat or
4-[5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile as
an active ingredient for overcoming anti-cancer agent
resistance.
[0026] The invention also resides in a therapeutic composition
against a cancer cell of multidrug resistance, wherein the
composition comprises an anti-cancer agent and a compound selected
from the group consisting of
2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine,
2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine,
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine,
potassium salt of
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, and
potassium salt of
2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine,
Febuxostat and
4-[5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile.
BEST EMBODIMENTS OF INVENTION
[0027] The present invention is described below in more detail.
[0028] The compound described in the formula (I) can be prepared
according to methods described in the above-mentioned WO
2005/121153 A1, WO 2003/042185 A1, WO 2007/004688 A1 and the
below-mentioned reference examples.
[0029] The compound described in the formula (I) preferably is a
compound described below or a salt thereof.
(1-1) A compound having the above-mentioned formula (I) or a salt
thereof, wherein R.sup.1 is phenyl, naphthyl, furyl, pyrrolyl,
thienyl, piperidyl, pyrimidinyl, pyranyl, pyridyl, thiazolyl,
imidazolyl, indolyl, or quinolyl in which the phenyl, naphthyl,
furyl, pyrrolyl, thienyl, piperidyl, pyrimidinyl, pyranyl, pyridyl,
thiazolyl, imidazolyl, indolyl, and quinolyl can have a substituent
selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8
alkyl substituted with halogen, C.sub.1-8 alkoxy, C.sub.1-8 alkoxy
substituted with halogen, C.sub.2-8 alkoxycarbonyl, formyl,
carboxyl, halogen, hydroxyl, nitro, cyano, amino, C.sub.6-10 aryl,
and C.sub.6-10 aryloxy (1-2) A compound having the above-mentioned
formula (I) or a salt thereof, wherein R.sup.1 is phenyl or pyridyl
in which the phenyl and pyridyl can have a substituent selected
from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 alkyl
substituted with halogen, C.sub.1-8 alkoxy, C.sub.1-8 alkoxy
substituted with halogen, C.sub.2-8 alkoxycarbonyl, formyl,
carboxyl, halogen, hydroxyl, nitro, cyano, amino, C.sub.6-10 aryl,
and C.sub.6-10 aryloxy (1-3) A compound having the above-mentioned
formula (I) or a salt thereof, wherein R.sup.1 is phenyl or pyridyl
in which the phenyl and pyridyl can have a substituent selected
from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 alkyl
substituted with halogen, C.sub.1-8 alkoxy, carboxyl, halogen,
hydroxyl, nitro, cyano, and amino (1-4) A compound having the
above-mentioned formula (I), a compound defined in one of (1-1) to
(1-3), or a salt thereof, wherein R.sup.2 is cyano or nitro (1-5) A
compound having the above-mentioned formula (I), a compound defined
in one of (1-1) to (1-3), or a salt thereof, wherein R.sup.2 is
cyano (1-6) A compound having the above-mentioned formula (I), a
compound defined in one of (1-1) to (1-5), or a salt thereof,
wherein X is oxygen, NH, or sulfur (1-7) A compound having the
above-mentioned formula (I), a compound defined in one of (1-1) to
(1-5), or a salt thereof, wherein X is oxygen or sulfur (1-8) A
compound having the above-mentioned formula (I), a compound defined
in one of (1-1) to (1-7), or a salt thereof, wherein Y is sulfur or
NH (1-9) A compound having the above-mentioned formula (I), a
compound defined in one of (1-1) to (1-7), or a salt thereof,
wherein Y is sulfur (1-10) A compound having the above-mentioned
formula (I) or a salt thereof, wherein R.sup.1 is phenyl or pyridyl
in which the phenyl and pyridyl can have a substituent selected
from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 alkyl
substituted with halogen, C.sub.1-8 alkoxy, carboxyl, halogen,
hydroxyl, nitro, cyano, and amino; R.sup.2 is cyano or nitro; X is
oxygen or sulfur; and Y is sulfur or NH (1-11) A compound having
the above-mentioned formula (I) or a salt thereof, wherein R.sup.1
is phenyl or pyridyl in which the phenyl and pyridyl can have a
substituent selected from the group consisting of C.sub.1-8 alkyl,
C.sub.1-8 alkyl substituted with halogen, C.sub.1-8 alkoxy,
carboxyl, halogen, hydroxyl, nitro, cyano, and amino; R.sup.2 is
cyano or nitro; X is oxygen or sulfur; and Y is sulfur (1-12) A
compound having the above-mentioned formula (I) or a salt thereof,
wherein R.sup.1 is phenyl or pyridyl in which the phenyl and
pyridyl can have a substituent selected from the group consisting
of C.sub.1-8 alkyl, C.sub.1-8 alkyl substituted with halogen,
C.sub.1-8 alkoxy, carboxyl, halogen, hydroxyl, nitro, cyano, and
amino; R.sup.2 is cyano or nitro; X is oxygen; and Y is sulfur
(1-13) 2-(3-Cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine and
2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine
(which are particularly preferred)
[0030] WO 2005/121153 A1 discloses a process for preparation of the
compound described in the formula (II).
[0031] The compound described in the formula (II) preferably is a
compound described below or a salt thereof.
(2-1) A compound having the above-mentioned formula (II) or a salt
thereof, wherein R.sup.1 is phenyl, naphthyl, furyl, pyrrolyl,
thienyl, imidazolyl, pyrimidinyl, thiazolyl, pyridyl, indolyl, or
quinolyl in which the phenyl, naphthyl, furyl, pyrrolyl, thienyl,
imidazolyl, pyrimidinyl, thiazolyl, pyridyl, indolyl, and quinolyl
can have a substituent selected from the group consisting of
C.sub.1-8 alkyl, C.sub.1-8 alkyl substituted with halogen,
C.sub.1-8 alkoxy, C.sub.2-5 alkoxycarbonyl, formyl, carboxyl,
halogen, hydroxyl, nitro, cyano, amino, C.sub.6-10 aryl, and
C.sub.6-10 aryloxy (2-2) A compound having the above-mentioned
formula (II) or a salt thereof, wherein R.sup.1 is phenyl which can
have a substituent selected from the group consisting of C.sub.1-8
alkyl, C.sub.1-5 alkyl substituted with halogen, C.sub.1-8 alkoxy,
C.sub.2-8 alkoxycarbonyl, formyl, carboxyl, halogen, hydroxyl,
nitro, cyano, amino, C.sub.6-10 aryl, and C.sub.6-10 aryloxy (2-3)
A compound having the above-mentioned formula (II) or a salt
thereof, wherein R.sup.1 is phenyl which can have a substituent
selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8
alkyl substituted with halogen, C.sub.1-8 alkoxy, C.sub.2-8
alkoxycarbonyl, formyl, carboxyl, halogen, phenyl, and phenoxy
(2-4) A compound having the above-mentioned formula (II), a
compound defined in one of (2-1) to (2-3), or a salt thereof,
wherein R.sup.2 is cyano or nitro (2-5) A compound having the
above-mentioned formula (II), a compound defined in one of (2-1) to
(2-3), or a salt thereof, wherein R.sup.2 is cyano (2-6) A compound
having the above-mentioned formula (II), a compound defined in one
of (2-1) to (2-5), or a salt thereof, wherein R.sup.3 is hydroxyl
(2-7) A compound having the above-mentioned formula (II), a
compound defined in one of (2-1) to (2-6), or a salt thereof,
wherein the substitution position of R.sup.3 is 4-position of
condensed (dicyclic) heterocyclic ring (2-8) A compound having the
above-mentioned formula (II), a compound defined in one of (2-1) to
(2-7), or a salt thereof, wherein X is oxygen, NH, or sulfur (2-9)
A compound having the above-mentioned formula (II), a compound
defined in one of (2-1) to (2-7), or a salt thereof, wherein X is
oxygen (2-10) A compound having the above-mentioned formula (II), a
compound defined in one of (2-1) to (2-9), or a salt thereof,
wherein Y is sulfur (2-12)
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine,
potassium salt of
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, and
potassium salt of
2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine
(which are particularly preferred active ingredients)
[0032] The agent of the present invention for overcoming resistance
is intended for anti-cancer agents such as irinotecan, SN-38, which
is an active metabolite of irinotecan, mitoxantrone, topotecan,
methotrexate, doxorubicin, daunorubicin, etoposide, gefitinib, and
imatinib.
[0033] There is no specific limitation on kinds of cancers targeted
with the agent of the present invention for overcoming anti-cancer
agent resistance, so long as the cancers overexpressing BCRP.
Examples of cancers with resistance include blood cancer
(hematological malignancy), liver cancer, colon cancer, lung
cancer, breast cancer, ovarian cancer, cervical cancer,
osteosarcoma, brain tumor, pancreatic cancer, and prostate
cancer.
[0034] The pharmacological effects of the invention are described
below.
[0035] Below-described Example 1 is an experiment confirming an
effect of compounds on BCRP-mediated methotrexate transport.
[0036] As is evident from Table 1, it has been confirmed that each
of the compound 1 (potassium salt of
2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine)-
, the compound 2
(2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine),
the compound 3 (potassium salt of
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine),
the compound 4
(2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine), TMX-67, and
FYX-051 strongly inhibits BCRP-mediated methotrexate transport.
[0037] Below described Example 2 is an experiment confirming an
effect of compounds on anti-cancer agent resistance in
BCRP-overexpressing cells (Flp-In-293/BCRP).
[0038] Each of the compounds 1 and 2 reverses resistance of
Flp-In-293/ABCG2 cells to SN-38 in a concentration-dependent
manner. The compound 1 and the compound 2 reversed the resistance
by about 96% and about 90% respectively at the concentration of 5
.mu.mol/L. Further, the compounds do not affect viability of
Flp-In-293/ABCG2 cells up to the examined concentration of 10
.mu.mol/L. Therefore, it has been confirmed that the compounds 1
and 2 exhibit effect of overcoming anti-cancer agent resistance in
BCRP-overexpressing cells without exhibiting toxicity to the cells.
In addition, in the experiments conducted in the same manner as in
Example 2, the compound 5
(2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine),
TMX-67, and FYX-051 do not exhibit toxicity to the cells at the
concentration of 10 .mu.mol/L, and each of them reversed the
resistance by about 96%, about 82% and about 39% respectively at
the concentration of 5 .mu.mol/L.
[0039] On the other hand, among the known agents having xanthine
oxidase (XOD) inhibitory action, allopurinol and oxypurinol do not
have an inhibitory action on BCRP-mediated methotrexate transport,
and do not exhibit an effect of overcoming resistance to SN-38.
Further, Y-700
(1-[3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic
acid) also does not exhibit an effect of overcoming resistance to
SN-38(Comparison example 1 and 2).
[0040] As is described above, the agent having xanthine oxidase
(XOD) inhibitory action, particularly the compound represented by
the above-mentioned formula (I) or (II), TMX-67, or FYX-051 can be
used as an active ingredient for overcoming drug resistance,
particularly as an active ingredient for overcoming anti-cancer
agent resistance.
[0041] The agent for overcoming drug resistance or the agent for
overcoming anti-cancer agent resistance of the invention can be
administered to human by ordinary administration methods such as
oral administration or parenteral administration.
[0042] The agent can be granulated in ordinary manners for the
preparation of pharmaceuticals. For instance, the agent can be
processed to give pellets, granule, powder, capsule, suspension,
injection, suppository, and the like.
[0043] For the preparation of these pharmaceuticals, ordinary
additives such as vehicles, disintegrators, binders, lubricants,
dyes, and diluents can be used. As the vehicles, lactose,
D-mannitol, crystalline cellulose and glucose can be mentioned.
Further, there can be mentioned starch and carboxymethylcellulose
calcium (CMC-Ca) as the disintegrators, magnesium stearate and talc
as the lubricants, and hydroxypropylcellulose (HPC), gelatin and
polyvinylpyrrolidone (PVP) as the binders.
[0044] The agent of the invention can be administered to an adult
generally in an amount of 0.1 mg to 100 mg a day by parenteral
administration and 1 mg to 2,000 mg a day by oral administration.
The dosage can be adjusted in consideration of age and conditions
of the patient.
[0045] A therapeutic agent (composition) comprising an agent for
overcoming anti-cancer agent resistance and a known anti-cancer
agent can be prepared according to a preparation method of a
conventional composition. The two agents can also separately be
administered to a patient at the same time or at some
intervals.
[0046] In case of hematological malignancy, solid tumor with
metastasis and the like, the administration of anti-cancer agent
induces abrupt tumor necrosis resulting in the release of a large
amount of the intracellular components of the tumor cells into
blood. As a result, hyperuricemia, hyperkalemia, or hypocalcemia
occurs and these symptoms sometimes induce renal failure or cardiac
arrest (tumor lysis syndrome). The active ingredient of the
invention has xanthine oxidase inhibitory action as well as effect
of overcoming anti-cancer agent resistance. Therefore, the
ingredient of the invention is also effective in treating
hyperurcemia caused with tumor lysis.
[0047] The invention is further described by the following
examples, but is not limited to these examples.
EXAMPLES
Reference Example 1
(1) 4-Chloro-N-(4-chloro-5-pyrimidinyl)-3-cyanobenzamide
[0048] 4-Chloro-3-cyanobenzoic acid (7.01 g, 38.6 mmol) was
suspended in benzene (70 mL). Thionyl chloride (3.6 mL, 49.6 mmol)
was added to the suspension, and the mixture was refluxed with
heating for 4 hours. The reaction liquid was condensed under
reduced pressure. 5-Amino-4-chloropyrimidine (5.00 g, 38.6 mmol),
dichloromethane (70 mL), and pyridine (3.6 mL, 44.5 mmol) were
added to the obtained acid chloride. The mixture was stirred at
room temperature for 7 hours. Chloroform (50 mL) and water (50 mL)
was added to the reaction solution to filtrate crystals. The
obtained crystals were washed with chloroform (20 mL) and water (20
mL), and air-dried to obtain 7.35 g (yield: 65%) of the subject
compound as white crystals. Further, 0.62 g (yield: 8%) of the
subject compound was obtained from a mixed solution of mother
liquid and washings as pale brown crystals (secondary crystals).
The total yield was 73%.
[0049] mp: 189-190.degree. C.
[0050] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.=7.34 (1H, d, J=8
Hz), 8.07 (1H, dd, J=2 Hz,8 Hz), 8.13 (1H,s), 8.23 (1H, d, J=2 Hz),
8.83 (1H,s), 9.79 (1H,s).
(2) 2-(4-Chloro-3-cyanophenyl)thiazolo[5,4-d]pyrimidine
[0051] The above-obtained
4-chloro-N-(4-chloro-5-pyrimidinyl)-3-cyanobenzamide (7.98 g, 27.2
mmol) and Lawesson's reagent (8.25 g, 20.4 mmol) were suspended in
toluene (150 mL). The suspension was refluxed with heating for 8
hours, and cooled to room temperature to filtrate precipitated
crystals. The crystals were washed with chloroform (75.times.2),
and air-dried to obtain 7.25 g (yield: 98%) of the subject compound
as pale yellow crystals.
[0052] mp: 278-280.degree. C. (decomposition)
[0053] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.=7.99 (1H, d,
J=9 Hz), 8.47 (1H, dd, J=2 Hz,9 Hz), 8.70 (1H, d, J=2 Hz), 9.20
(1H,s), 9.54 (1H,s).
(3)
2-[3-Cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine
[0054] 4-Fluorophenol (383 mg, 3.42 mmol) was added to a suspension
of 55% sodium hydride (150 mg, 3.44 mmol) and dried DMSO (7 mL).
The mixture was stirred at 50.degree. C. for 30 minutes. The
above-mentioned 2-(4-chloro-3-cyanophenyl)thiazolo[5,4-d]pyrimidine
(776 mg, 2.85 mmol) was added to the reaction liquid. The mixture
was stirred at 50.degree. C. for 4 hours, and cooled to room
temperature. Water (35 mL) was added to the reaction liquid to
filtrate precipitated crystals. The crystals were washed with water
(20 mL), and air-dried. The obtained crystals were purified by a
silica gel column chromatography (chloroform), washed with ether
(15 mL), and dried to obtain 701 mg (yield: 71%) of the subject
compound as pale yellow crystals.
[0055] mp: 175-177.degree. C.
[0056] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.=6.94 (1H, d, J=9
Hz), 7.1-7.2 (4H, m), 8.18 (1H, dd, J=2 Hz,9 Hz), 8.44 (1H, d,J=2
Hz), 9.13 (1H,s), 9.35 (1H,s).
[0057] IR (KBr) cm.sup.-1: 2233, 1606, 1564, 1419, 1300, 1119,
1011, 916, 893, 847, 829, 777, 760, 758, 723, 702, 700, 650, 648,
597, 526, 496, 490.
[0058] FAB-MS (m/e): 349(M+1)
Reference Example 2
2-(3-Cyano-4-phenoxyphenyl)thiazolo[5,4,-d]pyrimidine
[0059] Phenol (45 mg, 0.48 mmol) was added to a suspension of 55%
sodium hydride (23 mg, 0.53 mmol) and dried DMSO (1 mL). The
mixture was stirred at room temperature for 30 minutes. The
above-mentioned 2-(4-chloro-3-cyanophenyl)thiazolo[5,4-d]pyrimidine
(120 mg, 0.44 mmol) was added to the reaction liquid. The mixture
was stirred at 60.degree. C. for 4 hours, and cooled to room
temperature. Water (5 mL) was added to the reaction liquid to
filtrate precipitated crystals. The crystals were washed with water
(5 mL), ethanol (1 mL), and then ether (2 mL) in the order. The
crystals were dried at room temperature under reduced pressure to
obtain 100 mg (yield: 69%) of the subject compound as pale brown
crystals.
[0060] mp: 154-156.degree. C.
[0061] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.=7.08 (1H, d,
J=9 Hz), 7.2-7.4 (3H, m), 7.5-7.6 (2H, m), 8.42 (1H, dd, J=2 Hz,9
Hz), 8.69 (1H, d, J=2 Hz), 9.18 (1H,s), 9.52 (1H,s).
[0062] IR (KBr) cm.sup.-1: 3037, 2227, 1605, 1587, 1560, 1525,
1504, 1470, 1369, 1365, 1257, 1238, 1190, 1171.
[0063] FAB-MS (m/e): 331(M+1)
Example 1
Action on BCRP-Mediated Methotrexate Transport
(Testing Method)
[0064] In the experiment, plasma membrane was prepared from
BCRP-expressing Sf9 cells. Its membrane vesicle was used (Ishikawa
et al.: Methods of Enzymol., 400:485-510 (2005)).
[0065] The activity of methotrexate transport was measured using 96
wells-plate according to the following method.
Preparation and Composition of Reaction Solution
[0066] 50 .mu.L of solution containing sucrose (250 mmol/L) and
Tris/Hepes (10 mmol/L, pH: 7.4)
[0067] 30 .mu.L of solution containing ATP (3.33 mmol/L), creatine
phosphate (33.3 mmol/L), and MgCl.sub.2 (33.3 mmol/L)
[0068] (or solution containing creatine phosphate (33.3 mmol/L) and
MgCl.sub.2 (33.3 mmol/L))
[0069] 5 .mu.L of creatine kinase (2 mg/mL)
[0070] 2 .mu.L of [.sup.3H]methotrexate (10 mmol/L, final
concentration: 200 .mu.mol/L)
[0071] 3 .mu.L of test compound
[0072] 10 .mu.L of membrane sample of BCRP-expressing Sf9 cells
(total protein: 50 .mu.g)
[0073] Total: 100 .mu.L
[0074] The reaction solution was incubated at 37.degree. C. for 20
minutes. 1 mL of ice-cooled solution containing sucrose (250
mmol/L), EDTA (2 mmol/L), and Tris/Hepes (10 mmol/L, pH: 7.4) was
quickly added to the reaction solution to stop the reaction. Each
270 .mu.L of the mixed solution was poured into each well of
MultiScreen.TM. (Millipore), and sucked. The wells were washed four
times with 200 .mu.L of ice-cooled solution containing sucrose (250
mmol/L) and Tris/Hepes (10 mmol/L, pH: 7.4). The radioactivity
trapped on a filter of each well was measured. The amount of
methotrexate transported into the membrane vesicle was calculated
from the radioactivity.
[0075] Further, the IC.sub.50 value of the test compound
[concentration inhibiting methotrexate transport by 50%, inhibitory
concentration (.mu.mol/L)] was obtained according to the
above-mentioned method.
(Results)
[0076] As is shown in Table 1, it was confirmed that each of the
compound 1 to 4, TMX-67, and FYX-051 strongly inhibits the
BCRP-mediated methotrexate transport.
[0077] Action on BCRP-Mediated Methotrexate Transport
TABLE-US-00001 TABLE 1 Test compound IC.sub.50 (.mu.mol/L) Compound
1 0.46 Compound 2 1.1 Compound 3 0.23 Compound 4 0.66 TMX-67 0.25
FYX-051 0.77 Compound 1: Potassium salt of
2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine
Compound 2: 2-[3-Cyano-4-(4-
fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine Compound 3 Potassium
salt of
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine
Compound 4:
2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine
Comparison example 1
Action on BCRP-Mediated Methotrexate Transport
(Testing Method)
[0078] Action on BCRP-mediated methotrexate transport was tested
with respect to allopurinol and oxypurinol in the same manner as in
Example 1.
(Results)
[0079] Each of allopurinol and oxypurinol did not exhibit an
inhibitory action even at concentration of 100 mmol/L.
Example 2
Influence on anti-cancer agent resistance in BCRP-overexpressing
cells (Flp-In-293/BCRP)
(Testing Method)
[0080] Flp-In-293/ABCG2 cells and Flp-In-293/Mock cells were used
in the experiment (Wakabayashi et al.: J. Exp. Ther. Oncol.,
5:205-222 (2006)).
[0081] The cells were cultured under the atmosphere of 5% CO.sub.2
using DMEM containing FCS (10%), penicillin (100 I/mL),
streptomycin (100 .mu.g/mL), amphotericin B (250 ng/mL), hygromycin
B (100 .mu.g/mL), and L-glutamine (2 mmol/L).
[0082] The resistance of Flp-In-293 cells to an agent was profiled
by counting living cells using MTT assay. In more detail, the cells
were seeded in 96-wells plate at the concentration of
2.times.10.sup.3 cells/well, and cultured for 24 hours. SN-38 and
the compound 1 (potassium salt of
2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine
or compound 2
(2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine)
were added to the cells, and the cells were further incubated for
72 hours. The cells were treated with MTT (500 .mu.g/mL), and were
further incubated for 4 hours. Then the cells were treated with 100
.mu.L of 10% SDS, and were incubated overnight. The formed
MTT-formazan (metabolite of MTT, which is formed by living cells)
was measured at the wavelength of 570 nm and 630 nm.
(Results)
[0083] Each of the compounds 1 and 2 reversed the resistance of
Flp-In-293/ABCG2 cells to SN-38 in a concentration-dependent
manner. The compound 1 reversed the resistance by about 96%, and
the compound 2 reversed by about 90% at the concentration of 5
.mu.mol/L. Further, the compounds did not affect viability of
Flp-In-293/ABCG2 cells up to the examined concentration of 10
.mu.mol/L.
[0084] Therefore, it has been confirmed that the compounds 1 and 2
do not exhibit toxicity to the cells, and do exhibit effect of
overcoming anti-cancer agent resistance in the BCRP-overexpressing
cells without exhibiting toxicity to the cells.
Example 3 and Comparison example 2
Influence on Anti-Cancer Agent Resistance in BCRP-Overexpressing
Cells (Flp-In-293/BCRP)
(Testing Method)
[0085] Influence on anti-cancer agent resistance in
BCRP-overexpressing cells (Flp-In-293/BCRP) was tested in the same
manner as in Example 2 with respect to
2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine
(compound 5), TMX-67, FYX-051, allopurinol, oxypurinol, and
Y-700.
(Results)
(i) Degree of Overcoming Resistance to SN-38
[0086] The compound 5, TMX-67 and FYX-051 reversed the resistance
by about 96%, about 82%, and about 39% respectively at the
concentration of 5 .mu.mol/L. On the other hand, allopurinol and
oxypurinol did not exhibit an effect of overcoming resistance to
SN-38. Further, Y-700 also did not exhibit an effect of overcoming
the resistance in the concentration not exhibiting toxicity to the
cells.
(ii) Toxicity to the Cells
[0087] The compound 5, TMX-67, FYX-051, allopurinol, and oxypurinol
did not exhibit toxicity to the cells at the concentration of 10
.mu.mol/L. Y-700 exhibits toxicity to the cells at the
concentration of 5 .mu.mol/L or higher.
* * * * *