U.S. patent application number 11/829286 was filed with the patent office on 2007-11-15 for xanthine oxidase inhibitor.
This patent application is currently assigned to NIPPON CHEMIPHAR CO., LTD.. Invention is credited to Kunio Kobayashi, Nobutaka Mochiduki, Yoriko Shinohara, Atsushi Tendo, Tomio Yamakawa, Shinichi Yoshida.
Application Number | 20070265283 11/829286 |
Document ID | / |
Family ID | 19164532 |
Filed Date | 2007-11-15 |
United States Patent
Application |
20070265283 |
Kind Code |
A1 |
Yoshida; Shinichi ; et
al. |
November 15, 2007 |
Xanthine Oxidase Inhibitor
Abstract
The invention relates to compounds of the following formula (I)
or their salts: ##STR1## in which R.sup.1 represents OR.sup.4 or
others, in which R.sup.4 is an alkyl group having 1-8 carbon atoms
which may have a substituent or the like; R.sup.2 is halogen,
nitro, cyano, carboxyl, or the like; R.sup.3 is hydrogen, halogen,
hydroxyl, amino, carboxyl, or the like; X is NR.sup.11, oxygen, or
sulfur, in which R.sup.11 is hydrogen, or an alkyl group having 1-8
carbon atom which may have a substituent; and each of Y and Z is
CR.sup.12 or nitrogen, in which R.sup.12 has the same meaning as
R.sup.3 above, and a xanthine oxidase inhibitor containing the
compound as an active ingredient.
Inventors: |
Yoshida; Shinichi; (Chiba,
JP) ; Tendo; Atsushi; (Saitama, JP) ;
Kobayashi; Kunio; (Saitama, JP) ; Mochiduki;
Nobutaka; (Chiba, JP) ; Yamakawa; Tomio;
(Chiba, JP) ; Shinohara; Yoriko; (Chiba,
JP) |
Correspondence
Address: |
REED SMITH, LLP;ATTN: PATENT RECORDS DEPARTMENT
599 LEXINGTON AVENUE, 29TH FLOOR
NEW YORK
NY
10022-7650
US
|
Assignee: |
NIPPON CHEMIPHAR CO., LTD.
|
Family ID: |
19164532 |
Appl. No.: |
11/829286 |
Filed: |
July 27, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10495844 |
Oct 22, 2004 |
7253154 |
|
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PCT/JP02/11893 |
Nov 14, 2002 |
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11829286 |
Jul 27, 2007 |
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Current U.S.
Class: |
514/263.1 ;
514/303; 514/367; 514/375; 514/394; 544/264; 546/112; 548/152;
548/217; 548/304.4 |
Current CPC
Class: |
C07D 513/04 20130101;
C07D 235/18 20130101; A61P 43/00 20180101; C07D 471/04 20130101;
C07D 487/04 20130101; A61P 13/12 20180101; A61P 7/00 20180101; C07D
473/30 20130101; C07D 473/34 20130101; A61P 19/06 20180101; C07D
473/40 20130101; C07D 473/00 20130101; C07D 401/14 20130101; C07D
277/66 20130101; A61P 9/00 20180101; C07D 263/57 20130101; A61P
3/00 20180101 |
Class at
Publication: |
514/263.1 ;
514/303; 514/367; 514/375; 514/394; 544/264; 546/112; 548/152;
548/217; 548/304.4 |
International
Class: |
A61K 31/416 20060101
A61K031/416; A61K 31/421 20060101 A61K031/421; A61K 31/426 20060101
A61K031/426; A61K 31/437 20060101 A61K031/437; A61K 31/52 20060101
A61K031/52; A61P 7/00 20060101 A61P007/00; C07D 221/02 20060101
C07D221/02; C07D 235/00 20060101 C07D235/00; C07D 263/54 20060101
C07D263/54; C07D 277/62 20060101 C07D277/62; C07D 473/00 20060101
C07D473/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 16, 2001 |
JP |
2001-352340 |
Claims
1. Compounds of the following formula (I) or salts thereof ##STR9##
in which R.sup.1 represents an alkyl group having 1-8 carbon atoms,
an alkyl group substituted with 1-3 halogen atoms, OR.sup.4,
CO.sub.2R.sup.5, or S(O), .sub.nR.sup.6; wherein R.sup.4 is
hydrogen, or an alkyl group having 1-8 carbon atoms, an aralkyl
group having an aryl moiety of 6-10 carbon atoms and an alkyl
moiety of 1-4 carbon atoms, an alkylcarbonyl group having 2-9
carbon atoms, an arylcarbonyl group having an aryl moiety of 6-10
carbon atoms, an aralkylcarbonyl group having an aryl moiety of
6-10 carbon atoms and an alkylcarbonyl moiety of 2-5 carbon atoms
or an aryl group having 6-10 carbon atoms which may have a
substituent selected from the group consisting of halogen,
hydroxyl, nitro and cyano; each of R.sup.5 and R.sup.6 is hydrogen
or an alkyl group having 1-8 carbon atoms, an aralkyl group having
an aryl moiety of 6-10 carbon atoms and an alkyl moiety of 1-4
carbon atoms, or an aryl group having 6-10 carbon atoms which may
have a substituent selected from the group consisting of halogen,
hydroxyl, nitro, cyano and amino; and n is an integer of 0 to 2;
R.sup.2 is hydrogen, halogen, nitro, cyano, formyl, an alkyl group
having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms
which is substituted with one to three halogens, or CO.sub.2R.sup.7
wherein R.sup.7 has the same meaning as R.sup.5 above; R.sup.3 is
hydrogen, halogen, hydroxyl, amino, CO.sub.2R.sup.8, PO.sub.3H,
PO(OH)(OR'), S(O).sub.mR.sup.10, or an alkyl group having 1-8
carbon atoms or an alkylaminocarbonyl group having alkyl of 1-8
carbon atoms which may have a substituent selected from the group
consisting of halogen, hydroxyl, nitro, cyano and amino; wherein
each of R.sup.8, R.sup.9, and R.sup.10 has the same meaning as
R.sup.5 above; m has the same meaning as n above; X is NR.sup.11,
oxygen, or sulfur, wherein R.sup.11 is hydrogen, or an alkyl group
having 1-8 carbon atom which may have a substituent selected from
the group consisting of halogen, hydroxyl, nitro, cyano and amino;
and each of Y and Z is CR.sup.12 or nitrogen, wherein R.sup.12 has
the same meaning as R.sup.3 above.
2. The compounds or salts thereof according to claim 1, wherein
R.sup.1 is OR.sub.4.
3. The compounds or salts thereof according to claim 1, wherein
R.sup.1 is an alkoxy group having 1-5 carbon atoms.
4. The compounds or salts thereof according to claim 1, wherein
R.sup.1 is isobutoxy.
5. The compounds or salts thereof according to one of claims 1-4,
wherein R.sup.2 is nitro, cyano, halogen, or carboxyl.
6. The compounds or salts thereof according to one of claims 1-4,
wherein R.sup.2 is nitro or cyano.
7. The compounds or salts thereof according to one 10 of claims
1-6, wherein R.sup.3 is hydrogen, amino, hydroxyl, halogen, or
carboxyl.
8. The compounds or salts thereof according to one of claims 1-7,
wherein X is NH or oxygen, and each of Y and Z are nitrogen.
9. The compounds or salts thereof according to one of claims 1-7,
wherein X is sulfur, oxygen, or NH, Y is CH, C--OH, or
C--CO.sub.2H, and Z is CH.
10. The compounds or salts thereof according to one of claims 1-7,
wherein X is NH, and one of Y and Z is nitrogen and other is
CH.
11. A xanthine oxidase inhibitor containing as an active ingredient
the compound or a salt thereof according to one of claims 1-10.
12. An agent for treating hyperuricemia containing as an active
ingredient the compound or a salt thereof according to one of
claims 1-10.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a xanthine oxidase
inhibitor.
BACKGROUND OF THE INVENTION
[0002] The hyperuricemia causes gout and renal insufficiency and is
also considered to be a factor causing coronary disease.
Furthermore, the hyperuricemia is suggested to closely relate to
the development of diseases of adults such as hypertension.
Therefore, treatment of the hyperuricemia can be effective not only
for treating gout but also for preventing various diseases relating
to daily nutrition and the advancement of age.
[0003] Presently, the hyperuricemia is treated using an inhibitor
for inhibiting production of uremic acid such as allopurinol and an
accelerator for uricotelism such as benzbromalone. However, it is
well known that allopurinol causes side effects such as lesion,
hepatopathy, and myelogenetic troubles. The allopurinol and its
metabolic product (oxypurinol) are excreted from the kidneys.
However, if the excretion of uric acid decreases, the excretion of
these compounds also decreases and the concentrations of these
compounds in blood increase. Therefore, the chance of causing side
effects increases.
[0004] It is reported that benzbromalone also causes hepatopathy.
Accordingly, it is desired to develop new pharmaceuticals so that
the practitioners can select more appropriate pharmaceuticals with
less side effects.
[0005] Recently, the below-mentioned xanthine oxidase inhibitors
having no purine nucleus such as TMX-67 (Teijin Corporation), Y-700
(Mitsubishi Wellpharma Corporation) and KTT651 (Kotobuki
Corporation) have been reported: ##STR2##
[0006] The present inventors have discovered that compounds of the
below-mentioned formula (I) containing a bicyclic condensed hetero
ring have a xanthine oxidase inhibiting effect. The present
invention has been completed based on this discovery.
[0007] There are known, as compounds structurally analogous to the
compounds of the invention, 2-phenylbenzazole compounds (in
Japanese Patent Provisional Publication (Toku-15 hyo) 11-501024)
and 2-phenylbenzimidazole compounds (in Japanese Patent Provisional
Publication 56-5465). The former compounds have an amino group in
the 4th position of the benzene ring and show an antitumor effect,
while the latter compounds have 2-hydroxy-3-N-substituted
aminopropoxy group in the 4th position of the benzene ring and show
a hypotension inducing effect. Accordingly, these compounds differ
from the compounds of the invention in their structures and
pharmacological effects.
SUMMARY OF THE INVENTION
[0008] The present invention has an object: to provide compounds of
the below-mentioned formula (I) which have a xanthine oxidase (XOD)
inhibiting effect.
[0009] The invention resides in the compounds of the following
formula (I) and their salts: ##STR3## in which
[0010] R.sup.1 represents an alkyl group having 1-8 carbon atoms,
an alkyl group substituted with 1-3 halogen atoms, OR.sup.4,
CO.sub.2R.sup.5, or S(O).sub.nR.sup.6; wherein R.sup.4 is hydrogen,
or an alkyl group having 1-8 carbon atoms, an aralkyl group having
an aryl moiety of 6-10 carbon atoms and an alkyl moiety of 1-4
carbon atoms, an alkylcarbonyl group having 2-9 carbon atoms, an
arylcarbonyl group having an aryl moiety of 6-10 carbon atoms, an
aralkylcarbonyl group having an aryl moiety of 6-10 carbon atoms
and an alkylcarbonyl moiety of 2-5 carbon atoms or an aryl group
having 6-10 carbon atoms which may have a substituent selected from
the group consisting of halogen, hydroxyl, nitro and cyano; each of
R.sup.5 and R.sup.6 is hydrogen or an alkyl group having 1-8 carbon
atoms, an aralkyl group having an aryl moiety of 6-10 carbon atoms
and an alkyl moiety of 1-4 carbon atoms, or an aryl group having
6-10-carbon atoms which may have substituent selected from the
group consisting of halogen, hydroxyl, nitro, cyano and amino; and
n is an integer of 0 to 2;
[0011] R.sup.2 is hydrogen, halogen, nitro, cyano, formyl, an alkyl
group having 1-8 carbon atoms, an alkyl group having 1-8 carbon
atoms which is substituted with one to three halogens, or
CO.sub.2R.sup.7 wherein R.sup.7 has the same meaning as R.sup.5
above;
[0012] R.sup.3 is hydrogen, halogen, hydroxyl, amino,
CO.sub.2R.sup.8, PO.sub.3H, PO(OH)(OR.sup.9), S(O).sub.mR.sup.10,
or an alkyl group having 1-8 carbon atoms or an alkylaminocarbonyl
group having alkyl of 1-8 carbon atoms which may have a substituent
selected from the group consisting of halogen, hydroxyl, nitro,
cyano and amino; wherein each of R.sup.8, R.sup.9, and R.sup.10 has
the same meaning as R.sup.5 above; m has the same meaning as n
above;
[0013] X is NR.sup.11, oxygen, or sulfur, wherein R.sup.11 is
hydrogen, or an alkyl group having 1-8 carbon atom which may have a
substituent selected from the group consisting of halogen,
hydroxyl, nitro, cyano and amino; and
[0014] each of Y and Z is CR.sup.12 or nitrogen, wherein R.sup.12
has the same meaning as R.sup.3 above.
[0015] In addition, the invention relates to a xanthine oxidase
inhibitor containing a compound of the formula (I) or a salt
thereof as an active component.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Furthermore, the invention relates to an agent for treating
hyperuricemia containing a compound of the formula (I) or a salt
thereof as an active component.
[0017] The invention is further described below in detail. Examples
of the alkyl groups having 1-8 carbon atoms for R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.11 in the formula (I)
include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
and pentyl.
[0018] Examples of the alkyl groups having 1-8 carbon atoms for
R.sup.1 and R.sup.2 include methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, t-butyl, and pentyl which are substituted with one
to three fluorines, chlorines, or bromines. Examples of the aralkyl
groups having an aryl moiety of 6-10 carbon atoms and an alkyl
moiety of 1-4 carbon atoms for R.sup.4, R.sup.5 and R.sup.6 include
benzyl and phenethyl.
[0019] Examples of the alkylcarbonyl groups having 2-9 carbon atoms
for R.sup.4 include acetyl and propionyl.
[0020] Examples of the arylcarbonyl groups having an aryl moiety of
6-10 carbon atoms include benzoyl.
[0021] Examples of the aralkylcarbonyl groups having an aryl moiety
of 6-10 carbon atoms and an alkylcarbonyl moiety of 2-5 carbon
atoms include benzylcarbonyl.
[0022] Examples of the aryl groups having 6-10 carbon atoms for
R.sup.4, R.sup.5 and R.sup.6 include phenyl and naphthyl.
[0023] Examples of the halogen substituents for R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, or R.sup.11 include fluorine, chlorine,
and bromine. Examples of the alkylaminocarbonyls having an alkyl
moiety of 1-8 carbon atoms include methylaminocarbonyl. [0024] (1)
Preferred is a compound of the formula (I) in which R.sup.1 is
OR.sup.4, and a salt thereof. [0025] (2) Also preferred is a
compound of the formula (I) in which R.sup.1 is an alkoxy group
having 1-5 carbon atoms, and a salt thereof. [0026] (3) Also
preferred is a compound of the formula (I) in which R.sup.1 is
isobutoxy and a salt thereof. [0027] (4) Also preferred is a
compound of the formula (I) in which R.sup.2 is nitro, cyano,
halogen, or carboxyl, and a salt thereof. [0028] (5) Also preferred
is a compound of the formula (I) or according to (1) to (3) above
in which R.sup.3 is nitro or cyano, and a salt thereof [0029] (6)
Also preferred is a compound of the formula (I) or according to (1)
to (5) above in which R.sup.3 is hydrogen, amino, hydroxyl,
halogen, or carboxyl, and a salt thereof. [0030] (7) Also preferred
is a compound of the formula (I) or according to (1) to (6) above
in which X is NH or oxygen, and each of Y and Z is nitrogen, and a
salt thereof. [0031] (8) Also preferred is a compound of the
formula (I) or according to (1) to (6) above in which X is sulfur,
oxygen or NH, and Y is CH, C--OH or C--CO.sub.2H, and Z is CH, and
a salt thereof. [0032] (9) Also preferred is a compound of the
formula (I) or according to (1) to (6) above in which X is NH, and
at least one of Y and Z is nitrogen and another is CH, and a salt
thereof.
[0033] The compound of the formula (I) can be in the form of a
pharmacologically acceptable salt. For instance, R.sup.5, R.sup.7,
or R.sup.8 is an alkali metal such as sodium, potassium, or
lithium.
[0034] Processes for preparing a compound of the formula (I) are
illustrated below. [Synthesis Process 1--in the Case of X.dbd.NH or
O] ##STR4## [in the formula, X is NH or O, and each of R.sup.1,
R.sup.2, R.sup.3, Y and Z has the same meaning as above.]
[0035] The benzamide derivative of the formula (c) can be obtained
by reacting a benzoic acid derivative of the formula (a) with an
aniline derivative of the formula (b).
[0036] The reaction can be carried out in the conventional manner
for the formation of an amide compound. For instance, a benzoic
acid derivative of the formula (a) is first converted into an acid
chloride using thionyl chloride or oxalyl chloride, and then the
acid chloride is reacted with an aniline derivative of the formula
(b) in the presence of a solvent such as water or THF and in the
presence or absence of, a base such as sodium hydrogen carbonate or
triethylamine. Otherwise, a benzoic acid derivative of the formula
(a) is reacted with an aniline derivative of the formula (b) in the
presence of a condensing agent such as DDC or WSC--HCl.
[0037] The resulting benzoic amide of the formula (c) is reacted
with phosphorus oxychloride or heated to give the compound of the
invention represented by the formula (d). [Synthesis Process 2--in
the Case of :X.dbd.S] ##STR5## [in which R is hydrogen or halogen
such as chlorine, and R.sup.1, R.sup.2, R.sup.3, Y and Z are the
same as those identified above.
[0038] The benzamide derivative of the formula (f) can be obtained
by reacting a benzoic acid derivative of the formula (a) with an
aniline derivative of the formula (e).
[0039] The amide forming reaction can be carried out in the same
manner as described in the Synthesis process 1.
[0040] A benzoic thioamide derivative of the formula (g) can be
prepared from a benzoic amide of the formula (f) by treatment with
Lawesson's reagent.
[0041] The thiobenzamide derivative of the formula (g) is then
treated with potassium ferricyanide and sodium hydride, to give a
compound of the invention represented by the formula (h).
[0042] Other compounds represented by the formula (I) can be
prepared in analogous manners.
[0043] Examples of the compounds of the invention are illustrated
in the following tables 1 to 19.
[0044] (1) Examples of the following compounds having NR.sup.11 for
X are set forth in the following tables 1 to 7. TABLE-US-00001
TABLE 1 ##STR6## R.sup.3 position R.sup.1 R.sup.2 4- 4-6 R.sup.11 Y
Z O-isoBu NO.sub.2 H H H N N O-isoBu NO.sub.2 Cl H H N N O-isoBu
CO.sub.2H Cl H H N N O-isoBu Cl Cl H H N N O-isoBu NO.sub.2 Cl H Me
N N O-isoBu NO.sub.2 H Cl H N N O-isoBu CN Cl H H N N O-isoPr CN Cl
H H N N O-isoBu NO.sub.2 OH H H N N O-isoBu CO.sub.2H OH H H N N
O-isoBu CHO OH H H N N O-isoBu NO.sub.2 OH H Me N N O-isoPr
NO.sub.2 H OH H N N O-isoBu CN OH H H N N
[0045] TABLE-US-00002 TABLE 2 R.sup.3 Position R.sup.1 R.sup.2 4-
6- R.sup.11 Y Z O-isoPr CN OH H H N N O-isoBu NO.sub.2 NH.sub.2 H H
N N O-isoBu CO.sub.2H NH.sub.2 H H N N O-isoBu CF.sub.3 NH.sub.2 H
H N N O-isoBu CHO NH.sub.2 H H N N O-isoBu NO.sub.2 NH.sub.2 H Me N
N O-isoPr NO.sub.2 H NH.sub.2 H N N O-Et NO.sub.2 NH.sub.2 H H N N
O-Me NO.sub.2 NH.sub.2 H H N N CF.sub.3 NO.sub.2 NH.sub.2 H H N N
IsoPr NO.sub.2 NH.sub.2 H H N N OCH.sub.2CO.sub.2Et NO.sub.2
NH.sub.2 H H N N O-isoBu CN NH.sub.2 H H N N O-isoPr CN H NH.sub.2
H N N
[0046] TABLE-US-00003 TABLE 3 R.sup.3 Position R.sup.1 R.sup.2 4-
6- R.sup.11 Y Z O-Et CN NH.sub.2 H H N N O-Me CN NH.sub.2 H H N N
CF.sub.3 CN NH.sub.2 H H N N IPr CN NH.sub.2 H H N N
OCH.sub.2CO.sub.2 CN NH.sub.2 H H N N O-isoBu NO.sub.2 H H H N CH
O-isoBu CO.sub.2H H H H N CH O-isoBu F H H H N CH O-isoBu NO.sub.2
H H Me N CH O-isoPr NO.sub.2 H H H N CH 0-isoBu CN H H H N CH
0-isoPr CN H H H N CH O-isoBu NO.sub.2 H H H N COH O-isoBu NO.sub.2
H H H N CNH.sub.2
[0047] TABLE-US-00004 TABLE 4 R.sup.3 Position R.sup.1 R.sup.2 4-
6- R.sup.11 Y Z O-isoBu NO.sub.2 H H H N CCO.sub.2H O-isoBu
NO.sub.2 H H H CH N O-isoBu CO.sub.2H H H H CH N O-isoBu CF.sub.3 H
H H CH N O-isoBu NO.sub.2 H H Me CH N O-isoPr NO.sub.2 H H H CH N
O-isoBu CN H H H CH N O-isoPr CN H H H CH N O-isoBu NO.sub.2 H H H
CH CH O-isoBu CO.sub.2H H H H CH CH 0-isoBu Cl H H H CH CH 0-isoBu
NO.sub.2 H H Me CH CH O-isoPr NO.sub.2 H H H CH CH O-isoBu CN H H H
CH CH
[0048] TABLE-US-00005 TABLE 5 R.sup.3 Position R.sup.1 R.sup.2 4-
6- R.sup.11 Y Z O-isoPr CN H H H CH CH O-isoBu NO.sub.2 OH H H CH
CH O-isoBu CO.sub.2H OH H H CH CH O-isoBu CHO OH H H CH CH O-isoBu
NO.sub.2 OH H Me CH CH O-isoPr NO.sub.2 H OH H CH CH O-isoBu CH OH
H H CH CH O-isoBu NO.sub.2 H H H CH COH O-isoBu NO.sub.2 H H H H
CNH.sub.2 O-isoBu NO.sub.2 H H H CH CCO.sub.2H O-isoBu NO.sub.2 H H
H COH N O-isoBu NO.sub.2 H H H COH CH O-isoBu CN H H H COH CH
O-isoBu CO.sub.2H H H H COH CH
[0049] TABLE-US-00006 TABLE 6 R.sup.3 Position R.sup.1 R.sup.2 4-
6- R.sup.11 Y Z O-isoBu NO.sub.2 H H H CNH.sub.2 N O-isoBu NO.sub.2
H H H CNH.sub.2 CH O-isoBu NO.sub.2 H H H CCO.sub.2Me N O-isoBu
NO.sub.2 H H H CCO.sub.2ME CH O-isoBu NO.sub.2 H H H CCO.sub.2H N
O-isoBu NO.sub.2 H H H CCO.sub.2H CH O-isoBu CO.sub.2H H H H
CCO.sub.2H CH O-isoBu F H H H CCO.sub.2H CH O-isoBu CHO H H H
CCO.sub.2H CH O-isoBu NO.sub.2 H H Me CCO.sub.2H CH O-isoPr
NO.sub.2 H H H CCO.sub.2H XH O-Et NO.sub.2 H H H CCO.sub.2H CH O-Me
NO.sub.2 H H H CCO.sub.2H CH CF3 NO.sub.2 H H H CCO.sub.2H CH
[0050] TABLE-US-00007 TABLE 7 R.sup.3 Position R.sup.1 R.sup.2 4-
6- R.sup.11 Y Z isoPr NO.sub.2 H H H CCO.sub.2H CH
OCH.sub.2CO.sub.2Et NO.sub.2 H H H CCO.sub.2H CH O-isoBu CN H H H
CCO.sub.2H CH O-isoBu CO.sub.2H H H H CCO.sub.2H CH O-isoBu Cl H H
H CCO.sub.2H CH O-isoBu CF.sub.3 H H Me CCO.sub.2H CH O-isoPr CN H
H H CCO.sub.2H CH O-Et CN H H H CCO.sub.2H CH CF.sub.3 CN H H H
CCO.sub.2H CH IsoPr CN H H H CCO.sub.2H CH OCH.sub.2CO.sub.2Et CN H
H H CCO.sub.2H CH O-isoBu NO.sub.2 H H H CPO.sub.3H N O-isoBu
NO.sub.2 H H H CPO.sub.3H CH O-isoBu NO.sub.2 H H H CCONHMe N
O-isoBu NO.sub.2 H H H CCONHMe CH
[0051] (2) Examples of the following compounds having 0 for X are
set forth in the following tables 8 to 13. TABLE-US-00008 TABLE 8
##STR7## R.sup.3 Position R.sup.1 R.sup.2 4- 6- Y Z O-isoBu
NO.sub.2 H H N N O-isoBu NO.sub.2 Cl H N N O-isoBu Cl Cl H N N
O-isoPr NO.sub.2 Cl H N N O-isoBu CN Cl H N N O-isoPr CN Cl H N N
O-isoBu NO.sub.2 OH H N N O-isoBu CHO OH H N N O-isoPr NO.sub.2 OH
H N N O-isoBu CN OH H N N O-isoPr CN OH H N N O-isoBu NO.sub.2
NH.sub.2 H N N O-isoBu CO.sub.2H NH.sub.2 H N N O-isoBu CF.sub.3
NH.sub.2 H N N
[0052] TABLE-US-00009 TABLE 9 R.sup.3 Position R.sup.1 R.sup.2 4-
6- Y Z O-isoBu CHO NH.sub.2 H N N O-isoPr NO.sub.2 H NH.sub.2 N N
O-Et NO.sub.2 NH.sub.2 H N N O-Me NO.sub.2 NH.sub.2 H N N CF.sub.3
NO.sub.2 NH.sub.2 H N N IsoPr NO.sub.2 NH.sub.2 H N N
OCH.sub.2CO.sub.2Et NO.sub.2 NH.sub.2 H N N O-isoBu CN NH.sub.2 H N
N O-isoPr CN H NH.sub.2 N N O-Et CN NH.sub.2 H N N O-Me CN NH.sub.2
H N N CF.sub.3 CN NH.sub.2 H N N IsoPr CN NH.sub.2 H N N
OCH.sub.2CO.sub.2Et CN NH.sub.2 H N N
[0053] TABLE-US-00010 TABLE 10 R.sup.3 Position R.sup.1 R.sup.2 4-
6- Y Z O-isoBu NO.sub.2 H H N CH O-isoBu F H H N CH O-isoPr
NO.sub.2 H H N CH O-isoBu CN H H N CH O-isoPr CN H H N CH O-isoBu
NO.sub.2 H H N COH O-isoBu NO.sub.2 H H N CNH.sub.2 O-isoBu
NO.sub.2 H H N CCO.sub.2H O-isoBu NO.sub.2 H H CH N O-isoBu
CF.sub.3 H H CH N O-isoPr NO.sub.2 H H CH N O-isoBu CN H H CH N
O-isoPr CN H H CH N O-isoBu NO.sub.2 H H CH CH
[0054] TABLE-US-00011 TABLE 11 R.sup.3 Position R.sup.1 R.sup.2 4-
6- Y Z O-isoBu Cl H H CH CH O-isoPr NO.sub.2 H H CH CH O-isoBu CN H
H CH CH O-isoPr CN H H CH CH O-isoBu NO.sub.2 OH H CH CH O-isoBu
CO.sub.2H OH H CH CH O-isoBu COH OH H CH CH O-isoPr NO.sub.2 H OH
CH CH O-isoBu CN OH H CH CH O-isoBu NO.sub.2 H H CH COH O-isoBu
NO.sub.2 H H CH CNH.sub.2 O-isoBu NO.sub.2 H H CH CCO.sub.2H
O-isoBu NO.sub.2 H H COH N O-isoBu NO.sub.2 H H COH CH
[0055] TABLE-US-00012 TABLE 12 R.sup.3 Position R.sup.1 R.sup.2 4-
6- Y Z O-isoBu CN H H COH CH O-isoBu NO.sub.2 H H CNH.sub.2 N
O-isoBu NO.sub.2 H H CNH.sub.2 CH O-isoBu NO.sub.2 H H CCO.sub.2Me
N O-isoBu NO.sub.2 H H CCO.sub.2Me CH O-isoBu NO.sub.2 H H
CCO.sub.2H N O-isoBu NO.sub.2 H H CCO.sub.2H CH O-isoBu CO.sub.2H H
H CCO.sub.2H CH O-isoBu F H H CCO.sub.2H CH O-isoBu CHO H H
CCO.sub.2H CH O-isoPr NO.sub.2 H H CCO.sub.2H CH O-Et NO.sub.2 H H
CCO.sub.2H CH O-Me NO.sub.2 H H CCO.sub.2H CH CF.sub.3 NO.sub.2 H H
CCO.sub.2H CH
[0056] TABLE-US-00013 TABLE 13 R.sup.3 Position R.sup.1 R.sup.2 4-
6- Y Z IsoPr NO.sub.2 H H CCO.sub.2H CH OCH.sub.2CO.sub.2Et
NO.sub.2 H H CCO.sub.2H CH O-isoBu CN H H CCO.sub.2H CH O-isoBu CN
H H CCO.sub.2H CH O-isoBu Cl H H CCO.sub.2H CH O-isoPr CN H H
CCO.sub.2H CH O-Et CN H H CCO.sub.2H CH CF.sub.3 CN H H CCO.sub.2H
CH IsoPr CN H H CCO.sub.2H CH OCH.sub.2CO.sub.2Et CN H H CCO.sub.2H
CH O-isoBu NO.sub.2 H H CPO.sub.3H N O-isoBu NO.sub.2 H H
CPO.sub.3H CH O-isoBu NO.sub.2 H H CCONHMe N O-isoBu NO.sub.2 H H
CCONHMe CH
[0057] (3) Examples of the following compounds having S for X are
set forth in the following tables 14 to 19. TABLE-US-00014 TABLE 14
##STR8## R.sup.3 Position R.sup.1 R.sup.2 4- 6- Y Z O-isoBu
NO.sub.2 H H N N O-isoBu NO.sub.2 Cl H N N O-isoBu Cl Cl H N N
O-isoPr NO.sub.2 Cl H N N O-isoBu CN Cl H N N O-isoPr CN Cl H N N
O-isoBu NO.sub.2 OH H N N O-isoBu CHO OH H N N O-isoPr NO.sub.2 OH
H N N O-isoBu CN OH H N N O-isoPr CN OH H N N O-isoBu NO.sub.2
NH.sub.2 H N N O-isoBu CO.sub.2H NH.sub.2 H N N O-isoBu CF.sub.3
NH.sub.2 H N N
[0058] TABLE-US-00015 TABLE 15 R.sup.3 Position R.sup.1 R.sup.2 4-
6- Y Z O-isoBu CHO NH.sub.2 H N N O-isoPr NO.sub.2 H NH.sub.2 N N
O-Et NO.sub.2 NH.sub.2 H N N O-Me NO.sub.2 NH.sub.2 H N N CF.sub.3
NO.sub.2 NH.sub.2 H N N isoPr NO.sub.2 NH.sub.2 H N N
OCH2CO.sub.2Et NO.sub.2 NH.sub.2 H N N O-isoBu CN NH.sub.2 H N N
O-isoPr CN H NH.sub.2 N N O-Et CN NH.sub.2 H N N O-Me CN NH.sub.2 H
N N CF.sub.3 CN NH.sub.2 H N N isoPr CN NH.sub.2 H N N
OCH.sub.2CO.sub.2Et CN NH.sub.2 H N N
[0059] TABLE-US-00016 TABLE 16 R.sup.3 Position R.sup.1 R.sup.2 4-
6- Y Z O-isoBu NO.sub.2 H H N CH O-isoBu F H H N CH O-isoPr
NO.sub.2 H H N CH O-isoBu CN H H N CH O-isoPr CN H H N CH O-isoBu
NO.sub.2 H H N COH O-isoBu NO.sub.2 H H N CNH.sub.2 O-isoBu
NO.sub.2 H H N CCO.sub.2H O-isoBu NO.sub.2 H H CH N O-isoBu
CF.sub.3 H H CH N O-isoPr NO.sub.2 H H CH N O-isoBu CN H H CH N
O-isoPr CN H H CH N O-isoBu NO.sub.2 H H CH CH
[0060] TABLE-US-00017 TABLE 17 R.sup.3 Position R.sup.1 R.sup.2 4-
6- Y Z O-isoBu Cl H H CH CH O-isoPr NO.sub.2 H H CH CH O-isoBu CN H
H CH CH O-isoPr CN H H CH CH O-isoBu NO.sub.2 CH H CH CH O-isoBu
CO.sub.2H H H CH CH O-isoBu CHO OH H H CH O-isoPr NO.sub.2 H OH CH
CH O-isoBu CN OH H CH CH O-isoBu NO.sub.2 H H CH COH O-isoBu
NO.sub.2 H H CH CNH.sub.2 O-isoBu NO.sub.2 H H CH CCO.sub.2H
O-isoBu NO.sub.2 H H COH N O-isoBu NO.sub.2 H H COH CH
[0061] TABLE-US-00018 TABLE 18 R.sup.3 Position R.sup.1 R.sup.2 4-
6- Y Z O-isoBu CN H H COH CH O-isoBu NO.sub.2 H H CNH.sub.2 N
O-isoBu NO.sub.2 H H CNH.sub.2 CH O-isoBu NO.sub.2 H H CCO.sub.2Me
N O-isoBu NO.sub.2 H H CCO.sub.2Me CH O-isoBu NO.sub.2 H H
CCO.sub.2H N O-isoBu NO.sub.2 H H CCO.sub.2H CH O-isoBu CO.sub.2H H
H CCO.sub.2H CH O-isoBu F H H CCO.sub.2H CH O-isoBu CHO H H
CCO.sub.2H CH O-isoPr NO.sub.2 H H CCO.sub.2H CH O-Et NO.sub.2 H H
CCO.sub.2H CH O-Me NO.sub.2 H H CCO.sub.2H CH CF.sub.3 NO.sub.2 H H
CCO.sub.2H CH
[0062] TABLE-US-00019 TABLE 19 R.sup.3 Position R.sup.1 R.sup.2 4-
6- Y Z IsoPr NO.sub.2 H H CCO.sub.2H CH OCH.sub.2CO.sub.2Et
NO.sub.2 H H CCO.sub.2H CH O-isoBu CN H H CCO.sub.2H CH O-isoBu CN
H H CCO.sub.2H CH O-isoBu Cl H H CCO.sub.2H CH O-isoPr CN H H
CCO.sub.2H CH O-Et CN H H CCO.sub.2H CH CF.sub.3 CN H H CCO.sub.2H
CH IsoPr CN H H CCO.sub.2H CH OCH.sub.2CO.sub.2Et CN H H CCO.sub.2H
CH O-isoBu NO.sub.2 H H CPO.sub.3H N O-isoBu NO.sub.2 H H
CPO.sub.3H CH O-isoBu NO.sub.2 H H CCONHMe N O-isoBu NO.sub.2 H H
CCONHMe CH
[0063] The pharmacological actions of the present invention are
described below.
[0064] The xanthine oxidase inhibiting action (in vitro test) of
the compound of the invention was confirmed by measuring inhibition
of oxidation of xanthine by xanthine oxidase, as described in
Example 13. As is clear from Table 20, the compounds of the
invention show excellent xanthine oxidase inhibiting action.
[0065] The xanthine oxidase inhibiting action was further confirmed
in vivo tests by measuring the uric acid concentration in a plasma
obtained from mouse into which the compound of the invention had
been orally administered. See Example 1-B, Table 21.
[0066] Accordingly, it is expected that the compounds of the
invention having the formula (I) are employable for preventing or
treating hyperuricemia and gout.
[0067] The compound of the invention can be administered into human
beings by appropriate administration methods such as oral
administration and parenteral administration.
[0068] The compounds of the invention can be prepared in the form
of known pharmaceutical preparations such as pellets, granules,
powders, capsules, suspensions, injections, and suppositories. For
the preparations, a conventionally employed excipients,
disintegrators, binder, lubricants, dyes, diluents, or the like are
employed. The excipient may be lactose, D-mannitol, crystalline
cellulose, or glucose. The disintegrator may be starch or
carboxymethylcellulose calcium (CMC--Ca). The lubricant may be
magnesium stearate or talc. The binder may be
hydroxypropylcellulose (HPC), gelatin, or polyvinylpyrrolidone
(PVP).
[0069] Generally, the adult dosage of the compound of the invention
is approximately 0.1 to 100 mg/day when it is administered in the
form of an injection, and approximately 1 to 2,000 mg/day when it
is orally administered. The dosage can be adjusted depending on age
and clinical conditions.
[0070] The present invention is further described below by the
following non-limiting examples.
EXAMPLE 1
8-(4-Isobutoxy-3-nitrophenyl)-6-chloropurine(A) and
6-amino-8-(4-isobutoxy-3-nitrophenyl)15
oxazolo[4,5-d]pyrimidine(B)
(1) Methyl 4-hydroxy-3-nitrobenzoate
[0071] 4-Hydroxy-3-nitrobenzoic acid (10.0 g, 54.6 mmol) was
suspended in methanol (60 mL). After addition of conc. sulfuric
acid (0.1 mL), the suspension was heated overnight under reflux.
The methanol was distilled off under reduced pressure. The residue
was dissolved in ethyl acetate (40 mL), washed successively with
aqueous sodium hydrogen carbonate (20 mL.times.2) and saturated
aqueous brine (20 mL), and dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, to give 6.27 g
(yield 58%) of the desired compound in the form of a pale brown
crystalline product.
[0072] M. p. 72-73.degree. C. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta.: 3.95 (3H, s), 7.22 (1H, d, J=9 Hz), 8.24 (1H, dd, J=2 Hz,
9 Hz), 8.83 (1H, d, J=2 Hz), 10.89 (1H, s).
(2) Methyl 4-isobutyloxy-3-nitrobenzoate
[0073] Isobutyl bromide (10.5 mL, 95.8 mmol) was added to a
suspension of methyl 4-hydroxy-3-nitrobenzoate (6.26 g, 31.8 mmol)
and potassium carbonate (13.2 g, 95.5 mmol) in dry DMF (40 mL). The
resulting mixture was stirred at 90.degree. C. for 44 hours and
then cooled to room temperature. Subsequently, ice-water (80 mL)
was added to the cooled mixture. The precipitated crystalline
product was collected by filtration, washed with water (50 mL), and
dried for 30 min in air. The dried crystalline product was then
washed with hexane (40 mL), and dried in air to give 7.03 g (yield
87%) of the desired compound in the form of a pale orange
crystalline product.
[0074] M.p.: 77-77.degree. C.
[0075] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.: 1.07 (6H, d, J=7
Hz), 2.1-2.3 (1H, m), 3.93 (2H, d, J=7 Hz), 3.93 (3H, s), 7.09 (1H,
20 d, J=9 Hz), 8.18 (1H, dd, J=2 Hz, 9 Hz), 8.50 (1H, d, J=2
Hz).
(3) 4-Isobutyloxy-3-nitrobenzoic acid
[0076] Methyl 4-isobutyloxy-3-nitrobenzoate (2.50 g, 9.87 mmol) was
dissolved in a mixture of methanol (10 mL) and 25 THF (10 mL).
After addition of 2M aqueous sodium hydroxide (7.5 mL, 15.0 mmol),
the solution was stirred for 18 hours at room temperature. The
solvent was distilled off under reduced pressure, and were added to
the residue water (20 mL) and 3M aqueous hydrochloric acid to
adjust 30 the solution to pH 1. The precipitated crystalline
product was collected by filtration. The crystalline product washed
with water (20 mL.times.2) and dried at 50.degree. C. for 4 hours
under reduced pressure, to give 2.31 g (yield 98%) of the desired
compound in the form of a white crystalline product.
[0077] M.p.: 184-186.degree. C.
[0078] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.: 1.08 (6H, d, J=6
Hz), 2.1-2.3 (1H, m), 3.95 (2H, d, J=6 Hz), 7.13 (1H, d, J=9 Hz),
8.24 (1H, dd, J=2 Hz, 9 Hz), 8.56 (1H, d, J=2 Hz).
(4)
4-Amino-6-hydroxy-5-(4-isobutoxy-3-nitrobenzoyl)aminopyridine
[0079] 4,5-Diamino-6-hydroxypyrimidine (527 mg, 4.18 mmol) was
added to an aqueous suspension of sodium hydrogen carbonate (3.15
g, 41.8 mmol) in water (10 mL) under cooling with ice.
Subsequently, a solution of 4-isobutoxy-3-nitrobenzoyl chloride
(1.08 g, 4.18 mmol) in ethyl acetate (10 mL) was added. The
resulting mixture was stirred for 3 hours under cooling with ice,
made acetic by addition of 6 M hydrochloric acid, placed under
reduced pressure at room temperature to distill ethyl acetate off,
and stirred for 30 min. at room temperature. The precipitated solid
product was collected by filtration, washed successively with water
and diethyl ether, and dried successively in air and reduced
pressure, to give 963 mg (yield 69%) of the desired compound in the
form of a powdery product.
[0080] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.00 (6H, d,
J=6 Hz), 2.0-2.1 (1H, m), 4.03 (2H, d, J=6 Hz), 6.37 (2H, broad,
s), 7.45 (1H, d, J=9 Hz), 7.78 (1H, s), 8.22 (1H, dd, J=2 Hz, 9
Hz), 8.44 (1H, d, J=2 Hz), 9.18 (1H, s), 11.70 (1H, s).
(5) 8-(4-Isobutoxy-3-nitrophenyl)-6-chloropurine(A) and
6-amino-8-(4-isobutoxy-3-nitrophenyl)oxazolo[4,5-d]pyrimidine
(B)
[0081] A mixture of
4-amino-6-hydroxy-5-(4-isobutoxy-3-nitrobenzoyl)aminopyridine (354
mg, 1.07 mmol) and phosphorus oxychloride (6 mL) was stirred at.
120.degree. C. for 4.5 hours. Excessive phosphorus oxychloride was
distilled off under reduced pressure. The residue was stirred for
30 min., after addition of ice-water. The insolubles (1) were
removed by filtration and the filtrate was stirred for 30 min.,
after addition of aqueous 0.5 M sodium hydroxide (24 mL). The
insolubles were then removed by filtration, and the aqueous portion
was made acidic by addition of acetic acid. The precipitated solid
product was collected by filtration. The collected solid product
and the insolubles (2) were combined and subjected to silica gel
column chromatography and eluted using ethyl acetate/n-hexane (2/1)
to give 45 mg (yield 13%) of the desired compound (A) and 60 mg
(yield 17%) of the desired compound (B), both in the form of a pale
yellow powdery product.
[0082] (A) .sup.1H NMR (CDCl.sub.3-CD.sub.3OD, 400 MHz) .delta.:
1.10 (6H, d, 25 J=7 Hz), 2.2-2.3 (1H, m), 3.98 (2H, d, J=7 Hz),
7.23 (1H, d, J=9 Hz), 8.48 (1H, dd, J=2 Hz, 9 Hz), 8.64 (1H, d, J=2
Hz), 8.74 (1H, s).
[0083] (B) 1H NMR (DMSO-d6, 400 MHz) .delta.: 1.01 (6H, d, J=7 Hz),
2.1-2.2 (1H, m), 4.07 (2H, d, J=7 Hz), 7.60 (1H, d, J=9 Hz), 7.77
(2H, broad, s), 8.25 (1H, s), 8.32 (1H, dd, J=2 Hz, 9 Hz), 8.55
(1H, d, J=2 Hz).
[0084] FAB-MS (m/e): 330 (M+1).
EXAMPLE 2
8-(4-Isobutoxy-3-nitrophenyl)-6-hydroxypurine
[0085] A suspension of 8-(4-isobutoxy-3-nitrophenyl)-6-chloropurine
(30 mg, 0.086 mmol) in aqueous 2M hydrochloric acid (4.5 mL) was
heated to 120.degree. C. for 3 hours under stirring. The suspension
was then cooled to room temperature. The precipitated solid product
was collected by filtration, washed with water, and dried in air.
The dried product was heated to 100.degree. C. after addition of
aqueous 2M hydrochloric acid (27 mL). The insolubles were removed
while the aqueous portion was still hot. The filtrate was stirred
overnight. The precipitated solid product was collected by
filtration, washed with water, and dried in air, to give 12 mg
(yield 43%) of the desired compound in the form of a yellow powdery
product.
[0086] hu 1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.00 (6H, d, J=7
Hz), 2.0-2.2 (1H, m), 4.03 (2H, d, J=6 Hz), 7.55 (1H, d, J=9 Hz),
8.02 (1H, s), 8.39 (1H, dd, J=2 Hz, 9 Hz), 8.65 (1H, d, J=2 Hz),
12.28 (1H, s).
[0087] FAB-MS (m/e): 330 (M+1).
EXAMPLE 3
8-(4-Isobutoxy-3-nitrophenyl)-1H-benzimidazole
[0088] 1,2-Phenylenediamine (1.09 g, 10.1 mmol) was dissolved in
THF (20 mL). The solution was cooled with ice water, and to the
cooled solution was dropwise added to a solution of
4-isobutoxy-3-nitrobenzoyl chloride (1.00 mmol) in THF (3 mL) for
more than 30 min. The mixture was then stirred for 3 hours under
cooling with ice-water. The solvent was distilled off under reduced
pressure. The residue was suspended in water (20 mL) and stirred
for 30 min., at room temperature. The obtained crystalline product
was collected by filtration, washed with water (5 mL.times.3), and
dried at room temperature under reduced pressure, to give 291 mg
(yield 88%) of the desired amide product in the form of a pale
yellow crystalline product.
[0089] The amide product (165 mg, 0.50 mmol) and phosphoryl
chloride (3.0 mL) were together heated under reflux for 3 hours,
and then allowed to stand and cooled to room temperature. The
reaction mixture was poured into ice-water (50 mL), and the aqueous
mixture was stirred for 30 min. The obtained crystalline product
was collected by filtration, washed with water (5 mL.times.5), and
dried at room temperature under reduced pressure, to give 142 mg
(yield 91%) of the desired compound in the form of a pale yellow
crystalline product.
[0090] M.p.: 235-240.degree. C. (decomp.)
[0091] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.02 (6H, d,
J=6 Hz), 2.0-2.2 (1H, m), 4.07 (2H, d, J=6 Hz), 7.3-7.4 (2H, m),
7.63 (1H, d, J=9 Hz), 7.7-7.8 (2H, m), 8.50 (1H, dd, 25 J=2 Hz, 9
Hz), 8.75 (1H, d, J=2 Hz).
EXAMPLE 4
2-(4-Isobutoxy-3-nitrophenyl)imidazolo[4,5b]pyridine(1)2-Amino-3-(isobutox-
y-3-nitrobenzoyl)aminopyridine
[0092] Sodium hydrogen carbonate (350 mg, 4.17 mmol) was added to a
solution of 2,3-diaminopyridine (228 mg, 2.09 mmol) in water (2 mL)
under cooling with ice. To the solution was further added a
solution of 4-isobutoxy-35 nitrobenzoyl chloride (108 mg, 2.09
mmol) in ethyl acetate (2 mL). The mixture was stirred for 2 hours
under cooling with ice. The ethyl acetate was distilled off under
reduced pressure, and to the residue was added water. The resulting
solid product was collected by filtration, dried in air, subjected
to silica gel column chromatography, and eluted using
chloroform/methanol (30/1). There was produced 54 mg (yield 41%) of
the desired compound in the form of a yellow powdery product.
[0093] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.00 (6H, d,
J=7 Hz), 2.0-2.1 (1H, m), 4.04 (2H, d, J=6 Hz), 5.83 (2H, s), 6.60
(1H, dd, J=5 Hz, 7 Hz), 7.48 (1H, J=9 Hz), 7.50 (1H, d, J=5 Hz),
7.81 (1H, broad d, J=5 Hz), 8.25 (1H, broad d, J=9 Hz), 8.52 (1H,
broad s), 9.72 (1H, s).
(2) 2-(4-isobutoxy-3-nitrophenyl)imidazolo[4,5-b]-pyridine
[0094] A mixture of
2-amino-3-(4-isobutoxy-3-nitrobenzoyl)-aminopyridine (40 mg) and
phosphorus oxychloride (2 mL) was heated to 120.degree. C. for 8
hours under stirring. Excessive phosphorus oxychloride was
distilled off under reduced pressure, and ice water was added to
the residue. The precipitated solid product was collected by
filtration, washed with water, and dried successively in air and at
60.degree. C. under reduced pressure, to give 42 mg (yield 100%) of
the desired compound in the form of a white powdery product.
[0095] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.01 (6H, d,
J=7 Hz), 2.1-2.2 (1H, m), 4.06 (2H, d, J=6 Hz), 7.3-7.35 (1H, m),
7.60 (1H, d, J=9 Hz), 8.10 (1H, broad s), 8.40 (1H, broad s), 8.48
(1H, dd, J=2 Hz, 9 Hz), 8.73 (1H, d, J=2 Hz).
EXAMPLE 5
4-Hydroxy-2-(4-isobutyloxy-3-nitrophenyl) 1,3-benzoxazole
(1) 2-Aminoresorcinol
[0096] 2-Nitroresorcinol (1.00 g, 6.45 mmol) was dissolved in
ethanol (10 mL). The solution was then stirred for 6 hours at room
temperature in the presence of 10% Pd/C (340 mg, 0.32 mmol) under
hydrogen gas atmosphere. Insolubles were removed by filtration, and
the solvent was distilled off under reduced pressure, to give 779
mg (yield 97%) of the desired compound in the form of a brown
crystalline product.
[0097] M.P.: 153-155.degree. C. (decomp.)
[0098] .sup.1H NMR (CD.sub.3OD/CDCl.sub.3=1/20, 400 MHz) .delta.:
6.37 (2H, d, J=8 Hz), 6.54 (1H, t, J=8 Hz).
(2) 4-Hydroxy-2-(4-isobutyloxy-3-nitrophenyl)-1,3-benzoxazole
[0099] 4-Isobutyloxy-3-nitrobenzoic acid (480 mg, 2.01 mmol) and
2-aminoresorcinol (250 mg, 2.00 mmol) were suspended in dry
dichloromethane (12 mL).
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(WSC.HCl) (420 mg, 2.19 mmol), dry THF (6 mL) and dry DMF (6 mL)
were added to the suspension. The mixture was then stirred for 19
hours at room temperature. Water (40 mL) and chloroform (20 mL)
were added, and the organic portion was separated. The organic
portion was then washed successively with water (20 mL.times.2) and
aqueous saturated brine (20 mL), dried over anhydrous sodium
sulfate, and placed under reduced pressure to distill the solvent
off.
[0100] The residue was purified by silica gel column chromatography
(methanol/chloroform=1/100) and subsequently crystallized from
chloroform/hexane (1/3, 1.6 mL), to give 97 mg (yield 14%) of
N-(2,6-dihydroxyphenyl.)-4-isobutyloxy-3-nitrobenzamide in the form
of a brown crystalline product.
[0101] Forty mg (0.12 mmol) of the above-obtained product was
heated to 225-227.degree. C. for one hour and purified by silica
gel column chromatography (ethyl acetate/hexane=1/2), to give 13.6
mg (yield 36%) of the desired compound in the form of a pale yellow
crystalline product.
[0102] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.05 (6H, d,
J=6 Hz), 2.0-2.2 (1H, m), 4.07 (2H, d, J=7 Hz), 6.79 (1H, dd, J=1
Hz, 7 Hz), 7.1-7.3 (2H, m), 7.59 (1H, d, J=9 Hz), 8.37 (1H, dd, J=2
Hz, 9 Hz), 8.58 (1H, d, J=2 Hz).
[0103] IR (KBr) cm.sup.-1: 2962, 2933, 1624, 1527, 1506, 1489,
1470, 1350, 1273, 1244, 1169, 1007.
[0104] FAB-MS (m/e): 329 (M+1).
EXAMPLE 6
6-Amino-8-(4-isobutoxy-3-nitrophenyl)purine (1)
4,6-Diamino-5-(4-isobutoxy-3-nitrobenzoyl)aminopyridine
[0105] A solution of 4-isobutoxy-3-nitrobenzoyl chloride (538 mg,
2.09 mmol) in 1,4-dioxane (2 mL) was dropwise added to a suspension
of 4,5,6-triaminopyrimidine sulfate (466 mg, 2.09 mmol) in aqueous
1M sodium hydroxide (4.18 30 mL) under cooling with ice. The
resulting mixture was stirred for 4 hours at the same temperature.
Water (12 mL) was added to the reaction mixture. The precipitated
solid product was collected by filtration, dried in air, and
subjected to silica gel column chromatography. The elute using
chloroform/methanol (10/1) gave 144 mg (yield 20%) of the desired
compound in the form of a yellow powdery product.
[0106] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.00 (6H, d,
J=7 Hz), 2.0-2.1 (1H, m), 4.03 (2H, d, J=7 Hz), 5.99 (4H, s), 7.45
10 (1H, d, J=9 Hz), 7.76 (1H, s), 8.23 (1H, dd, =2 Hz, 9 Hz), 8.49
(1H, d, J=2 Hz), 9.26 (1H, s).
(2) 6-Amino-8-(4-isobutoxy-3-nitrophenyl)purine
[0107] A mixture of
4,6-diamino-5-(4-isobutoxy-3-nitrobenzoyl)aminopyridine (40 mg,
0.115 mmol) and phosphorus oxychloride (2 mL) was heated to
120.degree. C. for 8 hours under stirring. Excessive phosphorus
oxychloride was distilled off under reduced pressure. Ice-water was
added to the residue. The precipitated solid product was collected
by filtration, washed with water, and dried in air. Methanol (1.5
mL) was added to the dried product was added methanol (1.5 mL), and
the mixture was stirred for 2 hours at room temperature.
[0108] The precipitated solid product was collected by filtration
and dried in air, to give 20 mg (yield 74%) of the desired compound
in the form of a yellow powder product.
[0109] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.00 (6H, d,
J=6 Hz), 2.0-2.1 (1H, m), 4.08 (2H, d, J=6 Hz), 7.63 (1H, d, J=9
Hz), 8.38 (1H, dd, J=2 Hz, 9 Hz), 8.58 (1H, s), 8.64 (1H, d, J=2
Hz).
EXAMPLE 7
4-Hydroxy-2-(4-isobutoxy-3-nitrophenyl)-1H-benzimidazole
[0110] 2,3-diaminophenol (1.86 g, 15.0 mmol) was suspended in dry
THF (150 mL). A solution of 4-isobutoxy-3-nitrobenzoyl chloride
(2.50 mmol) in THF (10 mL) for a period of more than 30 minutes was
dropwise added to the suspension. The resulting mixture was stirred
for 3.5 hours under cooling with ice. The solvent was distilled off
under reduced pressure. The residue was suspended in water (150 mL)
and stirred for one hour at room temperature. The crystalline
product was collected by filtration, washed with water (20
mL.times.5), and dried at room temperature under reduced pressure.
The obtained crude product was purified by silica gel column
chromatography (methanol/chloroform=1/25), to give 250 mg (yield
29%) of an amide compound in the form of a brown crystalline
product.
[0111] The obtained amide product (225 mg) was heated to
185.degree. C. for 15 min. The heated product was allowed to stand
to room temperature. The obtained crude product was purified by
silica gel column chromatography (ethyl acetate/hexane=1/1), to
give 83 mg (yield 39%) of the desired compound in the form of a
brown crystalline product.
[0112] M.p.: 244-249.degree. C. (decomp.)
[0113] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.01 (6H, d,
J=6 Hz), 2.0-2.2 (1H, m), 4.03 (2H, d, J=6 Hz), 6.58 (1H, bs),
6.9-7.1 (2H, m), 7.54 (1H, d, J=9 Hz), 8.42 (1H, bs), 8.69 (1H,
bs), 9.76 (1H, bs), 12.86 (1H, bs).
EXAMPLE 8
2-(4-Isobutoxy-3-nitrophenyl)benzoxazole-7carboxylic acid
(1) Methyl 3-aminosalicylate
[0114] 3-Aminosalicylic acid (690 mg, 4.51 mmol), methanol 5 (45
mL), and conc. sulfuric acid (0.9 mL) were mixed, and heated for 55
hours under reflux. The methanol was distilled off under reduced
pressure. To the residue was added cooled water. The aqueous
residue was made alkaline by addition of aqueous saturated sodium
hydrogen carbonate under cooling with ice. Thus precipitated
crystalline product were collected by filtration, washed with two
portions of water, and dried in vacuo at 40.degree. C. for 40 min.,
to give 710 mg of a pale pink crystalline product. The product was
suspended in chloroform (35 mL), and insolubles were removed by
filtration. The filtrate was dried over sodium sulfate and then
concentrated under reduced pressure to give 181 mg (yield 25.9%) of
the desired compound in the form of a brown crystalline product.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.: 3.88 (2H:, broad s),
3.94 (3H, s), 6.71 (1H, dd, J=8 Hz, 8 Hz), 6.87 (1H, d, J=8 Hz),
7.24 (1H, m), 10.88 (1H, s).
[0115] (2) Methyl 3-(4-isobutoxy-3-nitrobenzoylamino)salicylate
4-Isobutoxy-3-nitrobenzoic acid (259 mg, 1.08 mmol) and methyl
3-aminosalicylate (181 mg, 1.08 mmol) were dissolved in dry
dichloromethane (25 mL). WSC.HCl (207 mg, 1.08 mmol) was added to
the resulting solution. The mixture was then stirred for 14 hours
at room temperature. The solvent was distilled off at room
temperature under reduced pressure. Water was added to the residue
and the aqueous residue was subjected to extraction with, ethyl
acetate. The ethyl acetate portion was successively washed with 2M
hydrochloric acid, water, aqueous saturated sodium hydrogen
carbonate, and aqueous saturated brine, and dried over sodium
sulfate. The solvent was distilled off under reduced pressure, to
give 320 mg of a brown oil. The obtained oil was subjected to
silica gel column chromatography. The oil washed from the column
with ethyl acetate/hexane (1/4) and then eluted using ethyl
acetate/hexane (1/2), to give 115 mg (yield 27.4%) of the desired
compound in the form of a white crystalline product.
[0116] M.P.: 142-1440C.
[0117] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.: 1.08 (6H, d, J=7
Hz), 2.115 2.3 (1H, m), 3.95 (2H, d, J=6 Hz), 3.99 (3H, s), 6.96
(1H, dd, J=8 Hz, 8 Hz), 7.16 (1H, d, J=9 Hz), 7.61 (1H, dd, J=2 Hz,
8 Hz), 8.09 (1H, dd, J=2 Hz, 9 Hz), 8.40 (1H, d, J=2 Hz), 8.51 (1H,
broad s), 8.67 (1H, dd, J=2 Hz, 8 Hz), 11.40 (1H, s).
[0118] IR (KBr, cm 1):3320, 1700, 1645, 1.620, 1545, 1530, 1435,
1340, 1270.
(3) Methyl
2-(4-isobutoxy-3-nitrophenyl)benzoxazole-7-carboxylate
[0119] Methyl 3-(4-isobutoxy-3-nitrobenzoylamino)salicylate (115
mg, 0.3 mmol) and phosphorus oxychloride (1.1 mL) were mixed and
stirred at 110.degree. C. for 4 hours. The stirred mixture was then
cooled to room temperature, poured onto ice blocks, and extracted
with ethyl acetate. The ethyl acetate portion was successively
washed with water, aqueous saturated water, and aqueous saturated
brine, and dried over sodium sulfate. The solvent was distilled off
under reduced pressure, to give 97 mg of a pale yellow crystalline
product. The obtained product was recrystallized from ethyl acetate
(2 mL), to give 40 mg of the desired compound in the form of a
white crystalline product. The mother liquor was concentrated, and
the residue was recrystallized from ethyl acetate-hexane, to give
42 mg of the desired compound in the form of a white crystalline
product. Total 82 mg (yield 73%)
[0120] M.P.: 128-1290C
[0121] .sup.1H NMR (CDCl.sub.3) .delta.: 1.09 (6H, d, J=7 Hz),
2.1-2.3 (1H, m), 3.98 (2H, d, J=6 Hz), 4.07 (3H, s), 7.22 (1H, d,
J=9 Hz), 7.44 (1H, dd, J=8 Hz, 8 Hz), 7.95 (1H, dd, J=1 Hz, 8 Hz),
8.01 (1H, dd, J=1 Hz, 8 Hz), 8.45 (1H, dd, J=2 Hz, 159 Hz), 8.75
(1H, d, J=2 Hz).
[0122] IR (KBr, cm 1): 1720, 1625, 1520, 1345, 1315, 1300,
1285.
(4) 2-(4-Isobutoxy-3-nitrophenyl)benzox:azole-7-carboxylic acid
[0123] Methyl
2-(4-isobutoxy-3-nitrophenyl)benzoxazole-7-carboxylate (22 mg, 0.06
mmol) was suspended in methanol (1.8 mL). Tetrahydrofuran (2.4 mL)
and 1M NaOH (0.6 mL) were successively added to the suspension, and
the mixture was stirred at 50.degree. C. for 2 hours. A small
amount of insoluble was removed by filtration, and the filtrate was
concentrated under reduced pressure. The residue was suspended in
water, made acidic by addition of 2M hydrochloric acid (0.6 mL),
and extracted with ethyl acetate. The ethyl acetate portion washed
successively with water and aqueous saturated brine, and dried over
sodium sulfate. The solvent was distilled off under reduced
pressure, to give 21 mg of a pale yellow crystalline product. The
obtained product was recrystallized from ethyl acetate-hexane (4
mL-8 mL), to give 15 mg (yield 70%) of the desired compound in the
form of a pale yellow crystalline product.
[0124] M. P.:258-2600C.
[0125] .sup.1H NMR (CDCl3) .delta.: 1.10 (6H, d, J=7 Hz), 2.1-2.3
(1H, m), 3.99 (2H, d, J=6 Hz), 7.25 (1H, d, J=:9 Hz), 7.48 (1H, 10
dd, J=8 Hz, 8 Hz), 8.01 (1H, dd, J=1 Hz, 8 Hz), 8.07 (1H, dd, J=1
Hz, 8 Hz), 8.47 (1H, dd, J=2 Hz, 9 Hz), 8.78 (1H, d, J=2 Hz).
EXAMPLE 9
2-(4-Isobutoxy-3-nitrophenyl)-3H-imidazo[4,5-c]pyridine
[0126] 4-Isobutoxy-3-nitrobenzoic acid (240 mg, 1.00 mmol) and
3,4-diaminopyridine (153 mg, 1.40 mmol) were dissolved in dry DMF
(10 mL). To the solution was added DCC (227 mg, 1.10 mmol) under
cooling with ice. The solution was then stirred for 3 days at room
temperature. Icewater (30 mL) was added, and the precipitated
crystalline product was filtered, and washed with water (3
mL.times.3). The obtained residue was purified by silica gel column
chromatography (methanol/chloroform=1/15), to give 13 mg (yield 4%)
of an amide compound in the form of a pale brown crystalline
product.
[0127] Subsequently, 8 mg (0.024 mmol) of the amide product; was
heated to 190.degree. C. for 15 min, and allowed to stand to room
temperature. The obtained crude product was subjected to thin layer
chromatography (methanol/chloroform=1/10), to give 5 mg (yield 66%)
of the desired compound in the form of a yellow crystalline
product.
[0128] .sup.1H NMR (CDCl.sub.3/CD.sub.3OD=20/1, 400 MHz) .delta.:
1.09 (6H, d, J=7 Hz), 2.1-2.3 (1H, m), 3.97 (2H, d, J==7 Hz), 7.25
(1H, 5 d, J=9 Hz), 7.64 (1H, d, J=6 Hz), 8.30 (1H, d, J=6 Hz), 8.44
(1H, dd, J=2 Hz, 9 Hz), 8.66 (1H, d, J=2 Hz), 8.93 (1H, s).
EXAMPLE 10
2-(3-Cyano-4-isobutyloxyphenyl)-1,3-benzothiazole-7-carboxylic
acid
(1) Ethyl 3-Cyano-4-isobutylbenzoate
[0129] Ethyl 4-nitrobenzoate (50.0 g, 256 mmol) and potassium
cyamide (51.2 g, 786 mmol) were added to DMSO (380 mL), stirred at
100.degree. C. for 4 hours, and cooled to room temperature. DMSO
was distilled off, and to the residue was added ice-water (200 mL).
The aqueous residue washed with ethyl acetate (100 mL). To the
mixture was added conc. hydrochloric acid, to change the pH of the
mixture to 1. The mixture was then extracted with ethyl acetate
(200 mL), washed with aqueous saturated brine (50 mL), dried over
anhydrous sodium sulfate, and placed under reduced pressure to
distill the solvent off. There was obtained 51.4 g of ethyl
3-cyano-4-hydroxybenzoate as a crude product.
[0130] Isobutyl bromide (56.1 mL, 512 mmol) was added to a
suspension of the ethyl 3-cyano-4-hydroxybenzoate crude product
(51.4 g) and potassium carbonate (70.8 g, 512 mmol) in dry DMF (200
mL), stirred at 100.degree. C. for 10 hours, and cooled to room
temperature. Ice-water (500 mL) was then added to the cooled
suspension. The aqueous mixture was extracted with ethyl acetate
(200 mL.times.2). The ethyl acetate portion washed successively
with water (500 mL.times.2) and aqueous saturated brine (200 mL),
dried over anhydrous sodium sulfate, and placed under reduced
pressure to distill the solvent off. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane=1/4). The
resulting crystalline product was dissolved in ethyl acetate (50
mL) under heating. The mixture was kept hot, while hexane (100 mL)
was added to the mixture. The hexane solution was stirred and
cooled to room temperature, and further stirred for 10 min. under
cooling with ice. The precipitated crystalline product was
collected by filtration, washed successively with ethyl
acetate/hexane (1/5, 60 mL) mixture and hexane (500 mL), and dried
in air, to give 20.8 g (yield 33%) of the desired compound in the
form of a pale yellow crystalline product.
[0131] M.P.: 105.6-106.40C
[0132] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.: 1.09 (6H, d, J=7
Hz), 1.39 (3H, t, J=7 Hz), 2.1-2.3 (1H, m), 3.90 (2H, d, J=7 Hz),
4.37 (2H, q, J=7 Hz), 6.98 (1H, d, J=9 Hz), 8.19 (1H, dd, J=2 Hz, 9
Hz), 8.25 (1H, d, J=2 Hz).
(2) 3-Cyano-4-isobutylbenzoic acid
[0133] Ethyl 3-cyano-4-isobutyloxybenzoate (20.0 g, 80.9 mmol) was
dissolved in a mixture of ethanol (100 mL) and THF (100 mL).
Aqueous 2M sodium hydroxide (45 mL, 90.0 mmol) was added to the
resulting solution, and the mixture was stirred at 30.degree. C.
for 4 hours. The solvent was distilled off under reduced pressure.
Water (100 mL) was added to the residue and further aqueous 2M
hydrochloric acid to obtain an aqueous mixture of pH 1. The
precipitated crystalline product was collected by filtration,
washed with water (200 mL.times.2), and dried in air, to give 17.5
g (yield 99%) of the desired compound in the form of a white
crystalline product.
[0134] M.P.: 220.4-221.60C
[0135] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.: 1.09 (6H, d, J=6
Hz), 2.1-2.3 (1H, m), 3.91 (2H, d, J=6 Hz), 7.00 (1H, d, J=9 Hz),
8.21 (1H, dd, J=2 Hz, 9 Hz), 8.27 (1H, d, J=2 Hz).
(3) Methyl 3-amino-2-chlorobenzoate
[0136] A mixture of 3-amino-2-chlorobenzoic acid (500 mg, 2.91
mmol), conc. sulfuric acid (6 mL), and methanol (150 mL) was heated
under reflux for 24 hours, and placed under reduced pressure to
distill the solvent off. The residue was neutralized by addition of
aqueous saturated sodium hydrogen carbonate. The neutralized
mixture was extracted with toluene, dried over anhydrous magnesium
sulfate, and placed under reduced pressure to distill the solvent
off. There was obtained 497 mg (yield 92%) of the desired compound
in the form of pale brown oil.
[0137] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.: 3.91 (3H, s),
4.23 (2H, broad s), 6.89 (1H, dd, J=1 Hz, 8 Hz), 7.10 (1H, dd, J=8
Hz, 8 Hz), 7.16 (1H, dd, J=1 Hz, 8 Hz).
(4) Methyl
2-chloro-3-(3-cyano-4-isobutyloxybenzoylamino)benzoate
[0138] Oxalyl chloride (889 mg, 7.0 mmol) was dropwise added to a
solution of 3-cyano-4-isobutyloxybenzoic acid (767 mg, 3.5 mmol) in
dichloromethane (10 mL) under cooling with ice. Subsequently, a
catalytic amount of DMF was added. The mixture was then stirred for
one hour at room temperature, heated under reflux for 3 hours, and
placed under reduced pressure to distill the solvent off. Toluene
was added to the residue and the solvent was distilled off under
reduced pressure. THF (10 mL) was added to the residue. Further, a
solution of methyl 3 amino-2-chlorobenzoate (497 mg, 2.68 mmol) and
triethylamine (1.39 mL, 10 mmol) in THF (10 mL). The resulting
mixture was stirred for 14 hours at room temperature, and toluene
and aqueous 1M hydrochloric acid were added. The organic portion
was taken out, washed with aqueous 1M hydrochloric acid and aqueous
saturated sodium hydrogen carbonate, dried over anhydrous magnesium
sulfate, and placed under reduced pressure to distill the solvent
off.
[0139] The residue was purified by silica gel column chromatography
(ethyl acetate/toluene=1/20), to give 900 mg (purity 82%, yield
71%) of the desired compound as an oil.
[0140] .sup.1H NMR (CDCl.sub.3,500 MHz) .delta.: 1.06 (6H, d, J=6
Hz), 2.1-2.4 (1H, m), 3.87 (2H, d, J=6 Hz), 3.95 (3H, s), 6.93 (1H,
d, J=9 Hz), 7.1-7.3 (2H, m), 7.83 (1H, dd, J=2 Hz, 8 Hz), 7.89 (1H,
dd, J=2 Hz, 9 Hz), 7.98 (1H, d, J=2 Hz).
(5) Methyl
2-chloro-3-(3-cyano-4-isobutyloxybenzoylamino)benzoate
[0141] A solution of methyl
2-chloro-3-(3-cyano-4-isobutyl-oxybenzoylamino) benzoate (1.07 g,
purity 82%, 2.27 mmol) and Lawesson's reagent (1.23 g, 2.77 mmol)
in toluene (20 mL) was heated under reflux for 5 hours, and placed
under reduced pressure to distill the solvent off. The residue was
purified by silica gel column chromatography (ethyl
acetate/toluene=1/40), to give 670 mg (yield 73%) of the desired
compound as an oil.
[0142] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.: 1.09 (6H, d, J=7
Hz), 2.2-2.3 (11H, m), 3.92 (2H, d, J=7 Hz), 3.96 (3H, s), 7.01
(1H, d, J=9 Hz), 7.1-7.3 (1H, m), 7.43 (1H, dd, J=8 Hz, 8 Hz), 7.78
(1H, dd, J=1 Hz, 8 Hz), 8.10 (1H, d, J=9 Hz), 8.15 (1H, 5 d, J=1
Hz).
(6) Methyl
2-(3-cyano-4-isobutyloxyphenyl)-1,3-benzothiazole-7-carboxylate
[0143] A solution of methyl
2-chloro-3-(3-cyano-4-isobutyloxybenzoylamino) benzoate (670 mg,
1.66 mmol) in THF (5 mL) was dropwise added to a suspension of
sodium hydride (200 mg, 4.98 mmol) in THF (5 mL) under cooling with
ice. The mixture was stirred for 2 hours at room temperature,
poured into ice-water, and extracted with toluene. The toluene
portion was dried over anhydrous magnesium sulfate, and placed
under reduced pressure to distill the solvent off. The residual
crystalline product was recrystallized from hexane, to give 288 mg
(yield 47%) of the desired compound in the form of a crystalline
product.
[0144] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.: 1.11 (6H, d, J=6
Hz), 2.1-2.3 (1H, m), 3.93 (2H, d, J=6 Hz), 4.05 (3H, s), 7.08 (1H,
d, J=9 Hz), 7.59 (1H, dd, J=8 Hz, 8 Hz), 8.13 (1H, dd, J=2 Hz, 8
Hz), 8.24 (1H, dd, J=2 Hz, 8 Hz), 8.27 (1H, dd, J=2 Hz, 9 Hz), 8.39
(1H, d, J=2 Hz).
(7) 2-(3-Cyano-4-isobutyloxyphenyl)-1,3-benzothiazole-7-carboxylic
acid
[0145] Methyl
2-(3-cyano-4-isobutyloxyphenyl)-1,3-benzothiazole-carboxylate (288
mg, 0.786 mmol) was dissolved in a mixed solvent (50 mL) of
methanol/ethanol/THF (2/1/2), and, then a solution of potassium
hydroxide (281 mg, 5 mmol) in water (10 mL) was added and stirred
for one hour at room temperature. The mixture was made acidic by
addition of aqueous 1M hydrochloric acid, and placed under reduced
pressure to distill the solvent off. The residue was extracted with
chloroform. The chloroform portion was then dried over anhydrous
magnesium sulfate and placed under reduced pressure too distill the
solvent off. The residual crystalline product was recrystallized
from toluene, to give 230 mg (yield 83%) of the desired compound in
the form of a white crystalline product.
[0146] M.p.: 268-270.degree. C.
[0147] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.04 (6H, d,
J=7 Hz), 2.0-2.2 (1H, m), 4.05 (2H, d, J=7 Hz), 7.44 (1H, d, J=9
Hz), 7.69 (1H, dd, J=8 Hz, 8 Hz), 8.10 (1H, dd, J=1 Hz, 8 Hz), 8.30
(1H, dd, J=1 Hz, 8 Hz), 8.41 (1.H, dd, J=2 Hz, 9 Hz), 8.47 (1H, d,
J=2 Hz).
[0148] IR (KBr, cm-1): 2966, 2875, 1608, 1518, 1477, 1471, 1396,
1306, 1282, 1240, 1238, 1211, 1155, 1009.
EXAMPLE 11
2-(3-Cyano-4-isobutyloxyphenyl)benzimidazole-7-carboxylic acid
(1) 3-Nitrophthalamine
[0149] 3-Nitrobenzoic anhydride (9.65 g, 50 mmol) was divided into
three portions and added by portions to aqueous ammonia (28%) under
cooling with ice. The mixture was stirred at 60.degree. C. for 12
hours, and placed under reduced pressure to distill the solvent
off. The residue was made acidic by addition of aqueous 12M
hydrochloric acid. The precipitated crystalline product was
collected by filtration, washed with water, and dried in air, to
give 9.86 g (yield 94%) of the desired compound in the form of a
white crystalline product.
[0150] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 7.65 (1H, broad
s), 7.78 5 (1H, dd, J=8 Hz, 8 Hz), 8.06 (1H, broad s), 8.18 (1H,
dd, J=1 Hz, 8 Hz), 8.24 (1H, dd, J=1 Hz, 8 Hz).
(2) 3-Nitroanthranilic acid
[0151] Bromine (2.56 mL, 48 mmol) was dropwise added to an aqueous
potassium hydroxide solution (24.1 g, 430 mmol in 110 mL) under
cooling with ice. The resulting solution was added to
3-nitrophthalamine (9.86 g, 47 mmol), and the mixture was stirred
at 60.degree. C. for 3 hours, and then stirred for 12 hours at room
temperature. The precipitated orange crystalline product was
collected by filtration, dissolved in water (50 ml), and made
acidic by addition of aqueous 6M hydrochloric acid. The
precipitated crystalline product was collected by filtration,
washed with several portions of water, and dried in air, to give
6.0 g (yield 70%) of the desired compound in the form of a yellow
crystalline product.
(3) Methyl 3-nitroanthranilate
[0152] Thionyl chloride (14.6 mL, 200 mmol) was dropwise added to
methanol (150 mL) under cooling with ice. The resulting solution
was added 3-nitroanthranilic acid (3.65 g, 20 mmol), heated under
reflux for 23 hours, and then placed under reduced pressure to
distill the solvent off. To the residue were added toluene and
aqueous saturated sodium hydrogen carbonate. The organic portion
was taken out, dried over anhydrous magnesium sulfate, and placed
under reduced pressure to distill the solvent off.
[0153] There was obtained 2.68 g (yield 68) of the desired compound
in the form of a yellow crystalline product.
[0154] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.: 3.92 (3H, s),
6.66 (1H, dd, J=8 Hz, 8 Hz), 8.24 (1H, dd, J=2 Hz, 8 Hz), 8.38 (1H,
dd, 5 J=2 Hz, 8 Hz).
(4) Methyl 3-aminoanthranilate
[0155] To a solution of methyl 3-nitroanthranilate (1.44 g, 7.34
mmol) in methanol (50 mL) was added 10% Pd/C (300 mg), and the
resulting mixture was stirred for 12 hours at room temperature
under hydrogen atmosphere. The 10% Pd/C was removed, and the
solvent was distilled off under reduced pressure, to give 1.22
(quantitative yield) of the desired compound in the form of a brown
crystalline product.
(5) Methyl 3-(3-cyano-4-isobutyloxybenzoylamino)anthranilate
[0156] Thionyl chloride (3.06 mL, 42 mmol) and a catalytic amount
of DMF were successively added to a solution of
3cyano-4-isobutyloxybenzoic acid (1.53 g, 7.0 mmol) in
dichloromethane (15 mL). The mixture was heated under reflux for 4
hours, and placed under reduced pressure to distill the solvent
off. To the residue was added THF (20 mL) under cooling with ice.
The residue solution was then dropwise added to a solution of
methyl 3-amino anthranilate (1.22 g, 7.34 mmol) and triethylamine
(2 mL) in THF (20 mL), and the mixture was stirred at 45.degree. C.
for 5 hours. The precipitated crystalline product was collected by
filtration and washed with several portions of ethyl acetate, to
give 2.11 g (yield 82%) of the desired compound in the form of a
pale green crystalline product.
[0157] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta.: 1.03 (6H, d,
J=7 Hz), 2.0-2.2 (1H, m), 3.82 (3H, s), 4.02 (2H, d, J=7 Hz),
6.5-6.7 (3H, m), 7.35 (1H, dd, J=2 Hz, 8 Hz), 7.39 (1H, d, J=9 Hz),
7.72 (1H, dd, J=2 Hz, 8 Hz), 8.25 (1H, dd, J=2 Hz, 59 Hz), 8.41
(1H, d, J=2 Hz), 9.74 (1H, S).
(6) 2-(3-Cyano-4-isobutyloxyphenyl)benzimidazole-7-carboxylic
acid
[0158] A solution of methyl
3-(3-cyano-4-isobutyloxybenzoylamino)anthranilate (341 mg, 0.93
mmol) in glacial acetic acid (10 mL) was heated under reflux for 2
hours, cooled, and placed under reduced pressure to distill the
solvent off. To the residue was added a solution of sodium
hydroxide (240 mg, 10 mmol) in methanol (20 mL), and the mixture
was stirred for 5 hours at room temperature. The reaction mixture
was made acidic by addition of aqueous 1M hydrochloric acid, and
placed under reduced pressure to distill the solvent off. To the
residue were added ethyl acetate and water. The organic portion was
taken out, dried over anhydrous magnesium sulfate, and placed under
reduced pressure to distill the solvent off. The residue washed
with hot toluene, to give 300 mg (yield 960) of the desired
compound in the form of a pale yellow crystalline product.
[0159] M.p.: 299-302.degree. C.
[0160] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.04 (6H, d,
J=7 Hz), 2.0-2.2 (1H, m), 4.03 (2H, d, J=7 Hz), 7.32 (1H, dd, J=8
Hz, 8 Hz), 7.42 (1H, d, J=9 Hz), 7.82 (1H, d, J=8 Hz), 7.91 (1H, d,
J=8 Hz), 8.58 (1H, dd, J=2 Hz, 9 Hz), 8.79 (1H, broad s), 12.46
(1H, broad s), 13.48 (1H, broad s).
[0161] IR (KBr, cm-1): 3319, 1500, 1498, 1433, 1302, 1281, 1238,
1209, 1147, 762.
EXAMPLE 12
2-(3-Cyano-4-isobutyloxyphenyl)-7-hydroxy 1,3-benzothiazole
[0162] (1) 3-Cyano-4-isobutyloxy-N-(3-methoxyphenyl)benzamide
Dichloromethane (20 mL) was added to a mixture of
3cyano-4-isobutyloxybenzoic acid (2.19 g, 10 mmol), m-anisidine
(1.85 g, 15 mmol), 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide
hydrochloride (WSC.HCl, 3.83 g, 20 mmol), and
4-(dimethylamino)pyridine (244 mg, 2.0 mmol). The resulting mixture
was then stirred for 21 hours at room temperature. To the mixture
was added aqueous 1M hydrochloric acid (30 mL), and the resulting
mixture was extracted with ethyl acetate (40 mL). The ethyl acetate
portion washed with aqueous saturated sodium hydrogen carbonate,
dried over anhydrous magnesium sulfate, and placed under reduced
pressure to distill the solvent off. The residue was recrystallized
from toluene, to give 2.87 g (yield 89%) of the desired compound in
the form of a crystalline product.
[0163] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.: 1.09 (6H, d, J=6
Hz), 2.1-2.3 (1H, m), 3.83 (3H, s), 3.90 (2H, d, J=6 Hz), 6.72 (1H,
dd, J=1 Hz, 8 Hz), 7.03 (1H, d, J=8 Hz), 7.12 (1H, dd, J=1 Hz, 8
Hz), 7.2-7.3 (1H, m), 7.40 (1H, dd, J=2 Hz, 2 Hz), 7.92 (1H, broad
s), 8.0-8.2 (1H, m).
(2) 3-Cyano-4-isobutyloxy-N-(3-methoxyphenyl)thiobenzamide
[0164] A solution of
3-cyano-4-isobutyloxy-N-(3-methoxyphenyl)benzamide (972 mg, 3.0
mmol) and Lawesson's reagent (808 mg, 2.0 mmol) in toluene (5 mL)
was heated under reflux for 3.5 hours. After addition of toluene
(approx. 20 mL), the heated solution was allowed overnight to lapse
at room temperature. The precipitated crystalline product was
collected by filtration, to give 900 mg (yield 88%) of the desired
compound in the form of a yellow crystalline product.
[0165] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.: 1.08 (6H, d, J=7
Hz), 2.1-2.3 (1H, m), 3.83 (3H, s), 3.89 (2H, d, J=7 Hz), 6.8-7.0
(2H, m), 7.0-7.8 (2H, m), 7.8-8.2 (2H, m), 8.8-8.6 (1H, m).
(3) 2-(3-Cyano-4-isobutyloxyphenyl)-7-methoxy-1,3-benzothiazole
[0166] Dioxane (70 mL) and water (70 mL) were added to a mixture of
3-cyano-4-isobutyloxy-N-(3-methoxyphenyl)thiobenzamide (900 mg,
2.64 mmol), potassium ferricyanide (2.61 g, 7.93 mmol), and
potassium hydroxide (892 mg, 15.9 mmol). The resulting mixture was
stirred for 20 hours at room temperature. The mixture was then
placed under reduced pressure to distill the solvent off, and
extracted with ethyl acetate (50 mL). The ethyl acetate portion
washed with water, dried over anhydrous magnesium sulfate, and
placed under reduced pressure to distill the solvent off. The
residue was purified by silica gel column chromatography (ethyl
acetate/toluene=1/20-1/10), to give 322 mg (yield 36%) of the
desired compound in the form of a pale yellow crystalline
product.
[0167] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.: 1.10 (6H, d, J=6
Hz), 2.1-2.3 (1H, m), 3.92 (2H, d, J=6 Hz), 4.02 (3H, s), 6.85 (1H,
30 d, J=8 Hz), 7.06 (1H, d, J=9 Hz), 7.45 (1H, dd, J=8 Hz, 8 Hz),
7.68 (1H, d, J=8 Hz), 8.23 (1H, dd, J=2 Hz, 9 Hz), 8.30 (1H, d, J=2
Hz).
(4) 2-(3-Cyano-4-isobutyloxyphenyl)-7-hydroxy-1,3-benzothiazole
[0168] Ethane thiol (0.45 mL, 6.08 mmol) was added to lithium metal
(14 mg, 2.02 mmol), and the mixture was stirred for one hour at
room temperature. To tire mixture were then added dry DMF (5 mL)
and 2-(3-cyano-4-isobutyloxyphenyl)-7-methoxy-1,3-benzothiazole
(150 mg, 0.44 mmol). The resulting mixture was stirred at
80.degree. C. for 8.5 hours, cooled to room temperature, and, after
addition of icewater (10 mL), made to pH 7 by addition of aqueous
1M hydrochloric acid. The mixture was then extracted with ethyl
acetate (20 mL). The ethyl acetate portion washed successively with
water (10 mL) and aqueous saturated brine (10 mL), dried over
anhydrous sodium sulfate, and placed under reduced pressure to
distill the solvent off. The residue was purified by silica, gel
column chromatography (ethyl acetate/hexane=1/3), and suspended in
hexane. The obtained crystalline product was collected by
filtration, washed with hexane, and dried in air, to give 17 mg
(yield 12%) of the desired compound in the form of a pale yellow
crystalline product.
[0169] M.p.: 200-202.degree. C.
[0170] hu 1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 1.04 (6H, d, J=6
Hz), 2.0-2.2 (1H, m), 4.03 (2H, d, J=6 Hz), 6.87 (1H, d, J=8 Hz),
7.36 (1H, dd, J=8 Hz, 8 Hz), 7.42 (1H, d, J=9 Hz), 7.51 (1H, d, J=8
Hz), 8.33 (1H, dd, J=2 Hz, 9 Hz), 8.38 (1H, d, J=2 Hz).
[0171] IR (KBr, cm-:L): 3319, 2960, 2873, 2231, 1579, 1470, 1392,
1281, 1022, 787.
EXAMPLE 13
Pharmacological Experiment 1
In Vitro Test
[0172] 1. Preparation of Test Sample
[0173] The test compound was dissolved in dimethylsulfoxide and
diluted with 50 mM phosphate buffer (pH 7.5), to give a solution of
a predetermined concentration
[0174] 2. Measurement
[0175] 250 gL of each of the solutions of the test compound having
different concentrations was added to 1 mL of a solution of
Xanthine (SIGMA, 300 .mu.M) in the 50 mM phosphor buffer (pH 7.5).
The mixture was then pre-incubated at 37.degree. C. for 10 min.
Subsequently, to the pre-incubated mixture was added 250 mL of Cow
milk Xanthine Oxidase (Roche) diluted with the 50 mM phosphate
buffer (pH 7.5) to give a solution of 30 mU concentration. The
mixture was then kept at 37.degree. C. for 15 min for performing a
reaction. The reaction was terminated by addition of 1N
hydrochloric acid. Subsequently, the absorbance (OD 290 mm) was
measured by means of a spectrophotometer (HITACHI U-2000), to
obtain the inhibition ratio.
[0176] The inhibition ratio was calculated according to the
following fommula: Inhibition
ratio(%)=[1-(B-C)/(A-C)].times.100
[0177] A: absorbance of control
[0178] B: absorbance measured in the case of using test
compound
[0179] C: absorbance of blank
[0180] 3. Test Results
[0181] The test results are set forth in Table 20. TABLE-US-00020
TABLE 20 Example number IC.sub.50 (nM) Example 1-A 63.2 Example 1-B
44.8 Example 2 11.1 Example 6 75.9 Example 7 102.0 Example 8 18.6
Example 9 58.4 Example 10 50.0 Example 11 22.3 Example 12 161.3
Allopurinol 542.1
[0182] As is apparent from Table 20, the compounds of the present
invention show a xanthine oxidase inhibiting action superior to
allopurinol.
EXAMPLE 14
Pharmacological Experiment 2
In Vivo Test
[0183] 1. Test Animals, and Grouping
[0184] ICR mouse (Japan Charles River Co., Ltd., 6 W) was employed
as test animal. One group comprised mice, and a vehicle control
group was set for each experiment.
[0185] 2. Preparation and Administration of the Test Compound
[0186] The test compound was suspended in aqueous 0.50
methylcellulose solution to for administration.
[0187] Dosage is 3 mg/10 mL/kg for each of the control groups and
all test groups. The administration was made by single oral
administration.
[0188] 3. Procedure of Experiment
[0189] The test compound was orally administered once, and the
whole blood was collected from main artery in the presence of
heparin after one hour. From the collected whole blood was
separated plasma in the conventional manner, and the plasma was
subjected to measurement of uric acid value by the enzyme method by
means of an automatic analytical apparatus (HITACHI 7060E).
[0190] The inhibition ratio was calculated according to the
following formula: Inhibition ratio(%)=(100-A/B).times.100
[0191] A: average uric acid value in plasma of the group into which
the test compound was administered.
[0192] B: average uric acid value in plasma of the vehicle control
group
[0193] 4. Test Results
[0194] Test results are set forth in Table 21. TABLE-US-00021 TABLE
21 Example number Inhibition ratio (%) Example 1-B 60.7 Example 6
63.8 Example 8 56.8 Example 10 56.1 Example 11 51.4
[0195] As is apparent from Table 21, the compounds of the present
invention show a significant xanthine oxidase inhibiting action
even in the experiment of in vivo.
* * * * *