U.S. patent application number 13/605329 was filed with the patent office on 2013-04-18 for triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor or erythropoietin production-inducing agent.
This patent application is currently assigned to JAPAN TOBACCO INC.. The applicant listed for this patent is Hiroyuki Abe, Takahiro Hotta, Takashi Ito, Takuya Matsui, Ikuo Mitani, Dai Motoda, Yosuke Ogoshi, Masakazu Terashita, Kazuhito Ueyama, Masahiro Yokota. Invention is credited to Hiroyuki Abe, Takahiro Hotta, Takashi Ito, Takuya Matsui, Ikuo Mitani, Dai Motoda, Yosuke Ogoshi, Masakazu Terashita, Kazuhito Ueyama, Masahiro Yokota.
Application Number | 20130096155 13/605329 |
Document ID | / |
Family ID | 43449466 |
Filed Date | 2013-04-18 |
United States Patent
Application |
20130096155 |
Kind Code |
A1 |
Mitani; Ikuo ; et
al. |
April 18, 2013 |
TRIAZOLOPYRIDINE COMPOUND, AND ACTION THEREOF AS PROLYL HYDROXYLASE
INHIBITOR OR ERYTHROPOIETIN PRODUCTION-INDUCING AGENT
Abstract
The present invention provides a triazolopyridine compound
having a prolyl hydroxylase inhibitory action and an erythropoietin
production-inducing ability. The present invention relates to a
compound represented by the following formula [I]: ##STR00001##
wherein each symbol is as defined in the specification, or a
pharmaceutically acceptable salt thereof, or a solvate thereof, as
well as a prolyl hydroxylase inhibitor or erythropoietin
production-inducing agent containing the compound. The compound of
the present invention shows a prolyl hydroxylase inhibitory action
and an erythropoietin production-inducing ability and is useful as
a prophylactic or therapeutic agent for various diseases and
pathologies (disorders) caused by decreased production of
erythropoietin.
Inventors: |
Mitani; Ikuo; (Takatsuki,
JP) ; Ogoshi; Yosuke; (Takatsuki, JP) ;
Matsui; Takuya; (Takatsuki, JP) ; Yokota;
Masahiro; (Takatsuki, JP) ; Terashita; Masakazu;
(Takatsuki, JP) ; Motoda; Dai; (Takatsuki, JP)
; Ueyama; Kazuhito; (Takatsuki, JP) ; Abe;
Hiroyuki; (Takatsuki, JP) ; Hotta; Takahiro;
(Takatsuki, JP) ; Ito; Takashi; (Takatsuki,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Mitani; Ikuo
Ogoshi; Yosuke
Matsui; Takuya
Yokota; Masahiro
Terashita; Masakazu
Motoda; Dai
Ueyama; Kazuhito
Abe; Hiroyuki
Hotta; Takahiro
Ito; Takashi |
Takatsuki
Takatsuki
Takatsuki
Takatsuki
Takatsuki
Takatsuki
Takatsuki
Takatsuki
Takatsuki
Takatsuki |
|
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP |
|
|
Assignee: |
JAPAN TOBACCO INC.
Tokyo
JP
|
Family ID: |
43449466 |
Appl. No.: |
13/605329 |
Filed: |
September 6, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12837679 |
Jul 16, 2010 |
8283465 |
|
|
13605329 |
|
|
|
|
61273127 |
Jul 30, 2009 |
|
|
|
Current U.S.
Class: |
514/303 ;
546/120 |
Current CPC
Class: |
A61P 5/00 20180101; A61P
43/00 20180101; C07D 471/04 20130101; A61P 7/06 20180101; A61P 7/00
20180101 |
Class at
Publication: |
514/303 ;
546/120 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 17, 2009 |
JP |
2009169565 |
Claims
1. A compound represented by the following formula [I], or a
pharmaceutically acceptable salt thereof, or a solvate thereof:
##STR00258## wherein the partial structural formula: ##STR00259##
is a group represented by: ##STR00260## R.sup.1 is (1) a hydrogen
atom, (2) a C.sub.1-6 alkyl group, (3) a C.sub.6-14 aryl group, (4)
a C.sub.3-8 cycloalkyl group, (5) a C.sub.6-14 aryl-C.sub.1-6 alkyl
group, or (6) a C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl group; R.sup.2
is (1) a hydrogen atom, (2) a C.sub.1-10 alkyl group, (3) a
C.sub.6-14 aryl group optionally substituted by the same or
different 1 to 5 substituents selected from the following group B,
(4) a C.sub.3-8 cycloalkyl group optionally substituted by the same
or different 1 to 5 substituents selected from the following group
B, (5) a C.sub.3-8 cycloalkenyl group optionally substituted by the
same or different 1 to 5 substituents selected from the following
group B, (6) a heteroaryl group optionally substituted by the same
or different 1 to 5 substituents selected from the following group
B (wherein the heteroaryl has, besides carbon atom, 1 to 6 hetero
atoms selected from nitrogen atom, oxygen atom and sulfur atom),
(7) a C.sub.6-14 aryl-C.sub.1-6 alkyl group (wherein C.sub.6-14
aryl is optionally substituted by the same or different 1 to 5
substituents selected from the following group B), or (8) a
C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl group (wherein C.sub.3-8
cycloalkyl is optionally substituted by the same or different 1 to
5 substituents selected from the following group B); R.sup.3 is (1)
a hydrogen atom, (2) a halogen atom, (3) a C.sub.1-6 alkyl group,
(4) a C.sub.6-14 aryl group, (5) a C.sub.3-8 cycloalkyl group, or
(6) a C.sub.6-14 aryl-C.sub.1-6 alkyl group; and R.sup.4 and
R.sup.5 are each independently (1) a hydrogen atom, or (2) a
C.sub.1-6 alkyl group, group B: (a) a halogen atom, (b) a C.sub.1-6
alkyl group, (c) a C.sub.3-8 cycloalkyl group, (d) a cyano group,
and (e) a halo-C.sub.1-6 alkyl group.
2. (canceled)
3. The compound according to claim 1, wherein the partial
structural formula: ##STR00261## is a group represented by the
following formula ##STR00262## or a pharmaceutically acceptable
salt thereof, or a solvate thereof.
4. The compound according to claim 1, wherein the partial
structural formula: ##STR00263## is a group represented by the
following formula ##STR00264## or a pharmaceutically acceptable
salt thereof, or a solvate thereof.
5. The compound according to claim 1, wherein the partial
structural formula: ##STR00265## is a group represented by the
following formula ##STR00266## or a pharmaceutically acceptable
salt thereof, or a solvate thereof.
6. The compound according to claim 1, wherein both R.sup.4 and
R.sup.5 are hydrogen atoms, or a pharmaceutically acceptable salt
thereof, or a solvate thereof
7. The compound according to claim 1, wherein R.sup.3 is a hydrogen
atom, or a pharmaceutically acceptable salt thereof, or a solvate
thereof.
8. The compound according to claim 1, wherein R.sup.1 is a hydrogen
atom, or a pharmaceutically acceptable salt thereof, or a solvate
thereof.
9. The compound according to claim 1, wherein R.sup.2 is (1) a
C.sub.1-10 alkyl group, (2) a C.sub.6-14 aryl group optionally
substituted by the same or different 1 to 5 substituents selected
from the above-mentioned group B, (3) a C.sub.6-14 aryl-C.sub.1-6
alkyl group (wherein C.sub.6-14 aryl is optionally substituted by
the same or different 1 to 5 substituents selected from the
above-mentioned group B), or (4) a C.sub.3-8 cycloalkyl-C.sub.1-6
alkyl group (wherein C.sub.3-8 cycloalkyl is optionally substituted
by the same or different 1 to 5 substituents selected from the
above-mentioned group B), or a pharmaceutically acceptable salt
thereof, or a solvate thereof.
10.-13. (canceled)
14. A compound represented by the following formula [I-1] or a
pharmaceutically acceptable salt thereof, or a solvate thereof:
##STR00267## wherein the partial structural formula: ##STR00268##
is a group represented by: ##STR00269## R.sup.11 is (1) a hydrogen
atom, (2) a C.sub.1-6 alkyl group, (3) a phenyl group, (4) a
C.sub.3-8 cycloalkyl group, (5) a phenyl-C.sub.1-6 alkyl group, or
(6) a C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl group; .sub.R21 .sub.is
(1) a hydrogen atom, (2) a C.sub.1-10 alkyl group, (3) a phenyl
group optionally substituted by the same or different 1 to 5
substituents selected from the following group B, (4) a C.sub.3-8
cycloalkyl group, (5) a C.sub.3-8 cycloalkenyl group, (6) a thienyl
group optionally substituted by the same or different 1 to 5
substituents selected from the following group B, (7) a
phenyl-C.sub.1-6 alkyl group (wherein phenyl is optionally
substituted by the same or different 1 to 5 substituents selected
from the following group B), or (8) a C.sub.3-8
cycloalkyl-C.sub.1-6 alkyl group; R.sup.31 is (1) a hydrogen atom,
(2) a halogen atom, (3) a C.sub.1-6 alkyl group, (4) a phenyl
group, (5) a C.sub.3-8 cycloalkyl group, or (6) a phenyl-C.sub.1-6
alkyl group; and R.sup.41 and R.sup.51 are each independently (1) a
hydrogen atom, or (2) a C.sub.1-6 alkyl group group B: (a) a
halogen atom, (b) a C.sub.1-6 alkyl group, (c) a C.sub.3-8
cycloalkyl group, (d) a cyano group, and (e) a halo-C.sub.1-6 alkyl
group.
15.-25. (canceled)
26. A pharmaceutical composition comprising the compound according
to claim 1, or a pharmaceutically acceptable salt thereof, or a
solvate thereof, and a pharmaceutically acceptable carrier.
27.-34. (canceled)
35. A method of inhibiting prolyl hydroxylase, comprising
administering an effective amount of the compound according to
claim 1, or a pharmaceutically acceptable salt thereof, or a
solvate thereof to a mammal.
36. A method of inducing erythropoietin production, comprising
administering an effective amount of the compound according to
claim 1, or a pharmaceutically acceptable salt thereof, or a
solvate thereof to a mammal.
37. A method of treating anemia, comprising administering an
effective amount of the compound according to claim 1, or a
pharmaceutically acceptable salt thereof, or a solvate thereof to a
mammal.
38. A method of treating renal anemia, comprising administering an
effective amount of the compound according to claim 1, or a
pharmaceutically acceptable salt thereof, or a solvate thereof to a
mammal.
39. A commercial package comprising the pharmaceutical composition
according to claim 26 and a written matter associated therewith,
the written matter stating that the pharmaceutical composition can
or should be used for the treatment or prophylaxis of a disease
selected from anemia and renal anemia.
40. A kit comprising the pharmaceutical composition according to
claim 26 and a written matter associated therewith, the written
matter stating that the pharmaceutical composition can or should be
used for the treatment or prophylaxis of a disease selected from
anemia and renal anemia.
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel triazolopyridine
compound having a prolyl hydroxylase (hereinafter to be also
referred to as "PHD") inhibitory action and an erythropoietin
(hereinafter also referred to as "EPO") production-inducing
ability. The present invention also relates to a prolyl hydroxylase
inhibitor (hereinafter to be also referred to as "PHD inhibitor")
and an erythropoietin production-inducing agent (hereinafter to be
also referred to as "EPO production-inducing agent"), each
containing the triazolopyridine compound.
BACKGROUND OF THE INVENTION
[0002] EPO is a hormone that promotes growth of red blood cell
consisting of 165 amino acids. EPO is mainly produced in the kidney
and partly in the liver, and the production thereof increases under
low oxygen conditions.
[0003] Anemia refers to a condition showing low levels of red blood
cell and hemoglobin in the blood. The symptoms thereof are derived
from oxygen deficiency due to decreased number of red blood cells,
or changes of the circulation dynamics due to increased breathing
rate and cardiac rate to compensate for the oxygen deficiency, and
include "general sick feeling", "easily-fatigued", "short breath",
"palpitation", "heaviness of the head", "dizziness", "bad
complexion", "shoulder stiffness", "difficulty in awakening in the
morning" and the like.
[0004] The cause of anemia is largely divided into low production,
promoted destruction and promoted loss of red blood cells, and
anemia includes anemia due to hematopoiesis abnormality in the bone
marrow, anemia due to shortage of iron, vitamin B.sub.12 or folic
acid, bleeding during accident or operation, anemia associated with
chronic inflammation (autoimmune diseases, malignant tumor,
chronically-transmitted diseases, plasma cell dyscrasia etc.),
anemia associated with endocrine diseases (hypothyroidism,
autoimmune polyglandular syndrome, type IA diabetes, dysfunctional
uterine bleeding etc.), anemia associated with chronic cardiac
failure, anemia associated with ulcer, anemia associated with
hepatic diseases, senile anemia, drug-induced anemia, renal anemia
(anemia associated with renal failure), m anemia associated with
chemical therapy, and the like.
[0005] In 1989, a gene recombinant human EPO preparation was
approved by the U.S. Food and Drug Administration (FDA) for
application to renal anemia, anemia associated with AZT treatment
of HIV patients, anemia associated with chemical therapy of cancer
patients, or for reduction of blood transfusion volume for patients
who underwent an operation. Moreover, its application has been
spreading to anemia of prematurity and the like.
[0006] Renal anemia is treated with an erythropoiesis stimulating
agent (ESA). Renal anemia is mainly caused by decreased EPO
production in the interstitial cells in the periphery of renal
tubule of the kidney. It is an application wherein gene recombinant
human erythropoietin is highly often used for supplement of EPO.
Gene recombinant human erythropoietin has strikingly reduced the
number of patients in need of periodic blood transfusion, improved
various symptoms associated with anemia and greatly contributed to
the improvement of ADL (Activities of daily living) and QOL
(Quality of Life). On the other hand, being a biological
preparation, it is expensive and requires high medical expenses. In
addition, it has a short half-life in blood and requires 2-3 times
of intravenous administration per week from the dialysis circuit in
hemodialysis patients. Thus, the injection frequency is desired to
be decreased to prevent medical accidents, and also from the
aspects of the amount of medical practice and waste. Furthermore,
for peritoneal dialysis patients and patients with renal failure in
predialysis period, for whom subcutaneous administration affording
a longer period of duration has been employed, once per one or two
weeks of administration is still necessary. In this case, the
patients often need to go to the hospital only for the
administration of gene recombinant human erythropoietin, causing
burden on the patients.
[0007] Moreover, a long-acting EPO medicament having a prolonged
half-life in blood by intravenous injection or subcutaneous
injection has been developed by modifying EPO by adding a new sugar
chain or PEG chain. However, since only injection preparations have
been developed, an orally administrable ESA is desired to prevent
medical accidents and reduce burden on patients.
[0008] Moreover, an orally administrable ESA is expected to be
applicable to a wider range of treatments for not only renal anemia
but also anemia caused by various causes.
[0009] As a representative molecule promoting transcription of EPO,
Hypoxia Inducible Factor (hereinafter to be also referred to as
"HIF") can be mentioned. HIF is a protein consisting of a
heterodimer having an oxygen regulatory .alpha.-subunit and a
constitutionally-expressed .beta.-subunit, where proline in the
.alpha.-subunit is hydoxylated by prolyl hydroxylase (PHD) in the
presence of oxygen and the resulting a-subunit is bound to von
Hippel-Lindau (VHL) protein and ubiquitinated. However, since
.alpha.-subunit is not subject to hydroxylation by PHD under low
oxygen conditions, it is not ubiquitinated but bound to an
intranuclear hypoxia response element (HRE) to promote
transcription of EPO present at the downstream of HIF. Therefore,
inhibition of the activity of PHD results in the prevention of
ubiquitination of HIF and stabilization thereof. Consequently, the
EPO production is increased.
[0010] Examples of the diseases expected to be improved by
inhibiting PHD to stabilize HIF include ischemic cardiac diseases
(angina pectoris, myocardial infarction etc.), ischemic
cerebrovascular disorders (cerebral infarction, cerebral embolism,
transient cerebral ischemic attack etc.), chronic renal failures
(ischemic nephropathy, renal tubule interstitial disorder etc.),
diabetic complications (diabetic wound etc.), cognitive impairments
(dementia, Alzheimer's disease, Parkinson's disease, Huntington's
disease etc.) and the like.
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0011] From the findings obtained from the studies heretofore, it
has been clarified that a medicament inhibiting prolyl hydroxylase
(PHD) promotes production of erythropoietin (EPO) and is effective
for the prophylaxis or treatment of various diseases and
pathologies (disorders) caused by decreased production of EPO,
particularly for the treatment of anemia.
[0012] Accordingly, the present invention aims to provide a
medicament having a prolyl hydroxylase (PHD) inhibitory action. In
addition, the present invention aims to provide a medicament having
EPO production-inducing ability.
Means of Solving the Problems
[0013] The present inventors have found a compound having a prolyl
hydroxylase (PHD) inhibitory action and EPO production-inducing
ability, and completed the present invention.
[0014] More particularly, the present invention provides the
following. [0015] [1] A compound represented by the following
formula [I] (hereinafter to be also referred to as "the compound of
the present invention") or a pharmaceutically acceptable salt
thereof, or a solvate thereof:
##STR00002##
[0015] wherein the partial structural formula:
##STR00003##
is a group represented by any of the following formulas:
##STR00004## [0016] R.sup.1 is [0017] (1) a hydrogen atom, [0018]
(2) a C.sub.1-6 alkyl group, [0019] (3) a C.sub.6-14 aryl group,
[0020] (4) a C.sub.3-8 cycloalkyl group, [0021] (5) a C.sub.6-14
aryl-C.sub.1-6 alkyl group, or [0022] (6) a C.sub.3-8
cycloalkyl-C.sub.1-6 alkyl group; [0023] R.sup.2 is [0024] (1) a
hydrogen atom, [0025] (2) a C.sub.1-10 alkyl group, [0026] (3) a
C.sub.6-14 aryl group optionally substituted by the same or
different 1 to 5 substituents selected from the following group B,
[0027] (4) a C.sub.3-8 cycloalkyl group optionally substituted by
the same or different 1 to 5 substituents selected from the
following group B, [0028] (5) a C.sub.3-8 cycloalkenyl group
optionally substituted by the same or different 1 to 5 substituents
selected from the following group B, [0029] (6) a heteroaryl group
optionally substituted by the same or different 1 to 5 substituents
selected from the following group B (wherein the heteroaryl has,
besides carbon atom, 1 to 6 hetero atoms selected from nitrogen
atom, oxygen atom and sulfur atom), [0030] (7) a C.sub.6-14
aryl-C.sub.1-6 alkyl group (wherein C.sub.6-14 aryl is optionally
15 substituted by the same or different 1 to 5 substituents
selected from the following group B), or [0031] (8) a C.sub.3-8
cycloalkyl-C.sub.1-6 alkyl group (wherein C.sub.3-8 cycloalkyl is
optionally substituted by the same or different 1 to 5 substituents
selected from the following group B); [0032] R.sup.3 is [0033] (1)
a hydrogen atom, [0034] (2) a halogen atom, [0035] (3) a C.sub.1-6
alkyl group, [0036] (4) a C.sub.6-14 aryl group, [0037] (5) a
C.sub.3-8 cycloalkyl group, or [0038] (6) a C.sub.6-14
aryl-C.sub.1-6 alkyl group; and [0039] R.sup.4 and R.sup.5 are each
independently [0040] (1) a hydrogen atom, or [0041] (2) a C.sub.1-6
alkyl group, [0042] group B: [0043] (a) a halogen atom, [0044] (b)
a C.sub.1-6 alkyl group, [0045] (c) a C.sub.3-8 cycloalkyl group,
[0046] (d) a cyano group, and [0047] (e) a halo-C.sub.1-6 alkyl
group. [0048] [2] The compound described in the above-mentioned [1]
wherein the partial structural formula:
##STR00005##
[0048] is a group represented by the following formula
##STR00006##
or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0049] [3] The compound described in the above-mentioned
[1], wherein the partial structural formula:
##STR00007##
[0049] is a group represented by the following formula
##STR00008##
or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0050] [4] The compound described in the above-mentioned
[1], wherein 5 the partial structural formula:
##STR00009##
[0050] is a group represented by the following formula
##STR00010##
or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0051] [5] The compound described in the above-mentioned
[1], wherein the partial structural formula:
##STR00011##
[0051] is a group represented by the following formula
##STR00012##
or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0052] [6] The compound described in any of the
above-mentioned [1] to [5], wherein both R.sup.4 and R.sup.5 are
hydrogen atoms, or a pharmaceutically acceptable salt thereof, or a
solvate thereof. [0053] [7] The compound described in any of the
above-mentioned [1] to [5], wherein R.sup.3 is a hydrogen atom, or
a pharmaceutically to acceptable salt thereof, or a solvate
thereof. [0054] [8] The compound described in any of the
above-mentioned [1] to [5], wherein R.sup.1 is a hydrogen atom, or
a pharmaceutically acceptable salt thereof, or a solvate thereof.
[0055] [9] The compound described in any of the above-mentioned [1]
to [5], wherein R.sup.2 is [0056] (1) a C.sub.1-10 alkyl group,
[0057] (2) a C.sub.6-14 aryl group optionally substituted by the
same or different 1 to 5 substituents selected from the
above-mentioned group B, [0058] (3) a C.sub.6-14 aryl-C.sub.1-6
alkyl group (wherein C.sub.6-14 aryl is optionally substituted by
the same or different 1 to 5 substituents selected from the
above-mentioned group B), or [0059] (4) a C.sub.3-8
cycloalkyl-C.sub.1-6 alkyl group (wherein C.sub.3-8 cycloalkyl is
optionally substituted by the same or different 1 to 5 substituents
selected from the above-mentioned group B), or a pharmaceutically
acceptable salt thereof, or a solvate thereof. [0060] [10] The
compound described in the above-mentioned [2], wherein both R.sup.4
and R.sup.5 are hydrogen atoms, or a pharmaceutically acceptable
salt thereof, or a solvate thereof. [0061] [11] The compound
described in the above-mentioned [10], wherein R.sup.3 is a
hydrogen atom, or a pharmaceutically acceptable salt thereof, or a
solvate thereof. [0062] [12] The compound described in the
above-mentioned [11], wherein R.sup.1 is a hydrogen atom, or a
pharmaceutically acceptable salt thereof, or a solvate thereof.
[0063] [13] The compound described in the above-mentioned [12],
wherein R.sup.2 is [0064] (1) a C.sub.1-10 alkyl group, or [0065]
(2) a C.sub.6-14 aryl-C.sub.1-6 alkyl group (wherein C.sub.6-14
aryl is optionally substituted by the same or different 1 to 5
substituents selected from the above-mentioned group B), or a
pharmaceutically acceptable salt thereof, or a solvate thereof.
[0066] [14] A compound represented by the following formula [I-1]
or a pharmaceutically acceptable salt thereof, or a solvate
thereof:
##STR00013##
[0066] wherein the partial structural formula:
##STR00014##
is a group represented by any of the following formulas:
##STR00015## [0067] R.sup.11 is [0068] (1) a hydrogen atom, [0069]
(2) a C.sub.1-6 alkyl group, [0070] (3) a phenyl group, [0071] (4)
a C.sub.3-8 cycloalkyl group, [0072] (5) a phenyl-C.sub.1-6 alkyl
group, or [0073] (6) a C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl group;
[0074] R21 is [0075] (1) a hydrogen atom, [0076] (2) a C.sub.1-10
alkyl group, [0077] (3) a phenyl group optionally substituted by
the same or different 1 to 5 substituents selected from the
following group B, [0078] (4) a C.sub.3-8 cycloalkyl group, [0079]
(5) a C.sub.3-8 cycloalkenyl group, [0080] (6) a thienyl group
optionally substituted by the same or different 1 to 5 substituents
selected from the following group B, [0081] (7) a phenyl-C.sub.1-6
alkyl group (wherein phenyl is optionally substituted by the same
or different 1 to 5 substituents selected from the following group
B), or [0082] (8) a C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl group;
[0083] R.sup.31 is [0084] (1) a hydrogen atom, [0085] (2) a halogen
atom, [0086] (3) a C.sub.1-6 alkyl group, [0087] (4) a phenyl
group, [0088] (5) a C.sub.3-8 cycloalkyl group, or [0089] (6) a
phenyl-C.sub.1-6 alkyl group; and [0090] R.sup.41 and R.sup.51 are
each independently [0091] (1) a hydrogen atom, or [0092] (2) a
C.sub.1-6 alkyl group [0093] group B: [0094] (a) a halogen atom,
[0095] (b) a C.sub.1-6 alkyl group, [0096] (c) a C.sub.3-8
cycloalkyl group, [0097] (d) a cyano group, and [0098] (e) a
halo-C.sub.1-6 alkyl group. [0099] [15] A compound represented by
the following formula:
##STR00016##
[0099] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0100] [16] a compound represented by the following
formula:
##STR00017##
[0100] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0101] [17] A compound represented by the following
formula:
##STR00018##
[0101] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0102] [18] A compound represented by the following
formula:
##STR00019##
[0102] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0103] [19] A compound represented by the following
formula:
##STR00020##
[0103] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0104] [20] A compound represented by the following
formula:
##STR00021##
[0104] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0105] [21] A compound represented by the following
formula:
##STR00022##
[0105] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0106] [22] A compound represented by the following
formula:
##STR00023##
[0106] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0107] [23] A compound represented by the following
formula:
##STR00024##
[0107] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0108] [24] A compound represented by the following
formula:
##STR00025##
[0108] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0109] [25] A compound represented by the following
formula:
##STR00026##
[0109] or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0110] [26] A pharmaceutical composition comprising the
compound described in any of the above-mentioned [1] to [25], or a
pharmaceutically acceptable salt thereof, or a solvate thereof, and
a pharmaceutically acceptable carrier (hereinafter to be also
referred to as "the pharmaceutical composition of the present
invention"). [0111] [27] A prolyl hydroxylase inhibitor comprising
the compound described in any of the above-mentioned [1] to [25],
or a pharmaceutically acceptable salt thereof, or a solvate
thereof. [0112] [28] An erythropoietin production-inducing agent
comprising the compound described in any of the above-mentioned [1]
to [25], or a pharmaceutically acceptable salt thereof, or a
solvate thereof. [0113] [29] A therapeutic agent for anemia
comprising the compound described in any of the above-mentioned [1]
to [25], or a pharmaceutically acceptable salt thereof, or a
solvate thereof. [0114] [30] A therapeutic agent for renal anemia
comprising the compound described in any of the above-mentioned [1]
to [25], or a pharmaceutically acceptable salt thereof, or a
solvate thereof. [0115] [31] Use of the compound described in any
of the above-mentioned [1] to [25], or a pharmaceutically
acceptable salt thereof, or a solvate thereof, for the production
of a prolyl hydroxylase inhibitor. [0116] [32] Use of the compound
described in any of the above-mentioned [1] to [25], or a
pharmaceutically acceptable salt thereof, or a solvate thereof, for
the production of an erythropoietin production-inducing agent.
[0117] [33] Use of the compound described in any of the
above-mentioned [1] to [25], or a pharmaceutically acceptable salt
thereof, or a solvate thereof, for the production of a therapeutic
agent for anemia. [0118] [34] Use of the compound described in any
of the above-mentioned [1] to [25], or a pharmaceutically
acceptable salt thereof, or a solvate thereof, for the production
of a therapeutic agent for renal anemia. [0119] [35] A method of
inhibiting prolyl hydroxylase, comprising administering an
effective amount of the compound described in any of the
above-mentioned [1] to [25], or a pharmaceutically acceptable salt
thereof, or a solvate thereof to a mammal. [0120] [36] A method of
inducing erythropoietin production, comprising administering an
effective amount of the compound described in any of the
above-mentioned [1] to [25], or a pharmaceutically acceptable salt
thereof, or a solvate thereof to a mammal. [0121] [37] A method of
treating anemia, comprising administering an effective amount of
the compound described in any of the above-mentioned [1] to [25],
or a pharmaceutically acceptable salt thereof, or a solvate thereof
to a mammal. [0122] [38] A method of treating renal anemia,
comprising administering an effective amount of the compound
described in any of the above-mentioned [1] to [25], or a
pharmaceutically acceptable salt thereof, or a solvate thereof to a
mammal. [0123] [39] A commercial package comprising the
pharmaceutical composition described in the above-mentioned [26]
and a written matter associated therewith, the written matter
stating that the pharmaceutical composition can or should be used
for the treatment or prophylaxis of a disease selected from anemia
and renal anemia. [0124] [40] A kit comprising the pharmaceutical
composition described in the above-mentioned [26] and a written
matter associated therewith, the written matter stating that the
pharmaceutical composition can or should be used for the treatment
or prophylaxis of a disease selected from anemia and renal
anemia.
DETAILED DESCRIPTION OF THE INVENTION
[0125] The definition of each substituent or each moiety to be used
in the present specification is as follows.
[0126] The "halogen atom" is a fluorine atom, a chlorine atom, a
bromine atom or an iodine atom.
[0127] The "C.sub.1-10 alkyl group" is a straight chain or branched
chain alkyl group having a carbon number of 1 to 10, preferably a
straight chain or branched chain alkyl group having a carbon number
of 1 to 7. For example, a methyl group, an ethyl group, a propyl
group, an isopropyl group, a butyl group, an isobutyl group, a
sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl
group, a tert-pentyl group, an 1-ethylpropyl group, a neopentyl
group, a hexyl group, a 2-ethylbutyl group, a 3,3-dimethylbutyl
group, a 3,3-dimethylpentyl group, a heptyl group, an octyl group,
a nonyl group, a decyl group and the like can be mentioned.
[0128] The "C.sub.1-6 alkyl group" is a straight chain or branched
chain alkyl group having a carbon number of 1 to 6, preferably a
straight chain or branched chain alkyl group having a carbon number
of 1 to 3. For example, those exemplified as the above-mentioned
"C.sub.1-10 alkyl group" and having a carbon number of 1 to 6 can
be mentioned.
[0129] The "C.sub.1-3 alkyl group" is a straight chain or branched
chain alkyl group having a carbon number of 1 to 3. For example,
those exemplified as the above-mentioned alkyl group and having a
carbon number of 1 to 3 can be mentioned.
[0130] The "C.sub.6-14 aryl group" is an aromatic hydrocarbon group
having a carbon number of 6 to 14. For example, a phenyl group, a
naphthyl group, an anthryl group, an indenyl group, an azulenyl
group, a fluorenyl group, a phenanthryl group, a pentalenyl group
and the like can be mentioned, with preference given to a phenyl
group.
[0131] The "C.sub.3-8 cycloalkyl group" is a saturated cycloalkyl
group having a carbon number of 3 to 8, preferably 3 to 5, and, for
example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl
group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group
and the like can be mentioned.
[0132] The "C.sub.3-5 cycloalkyl group" is a saturated cycloalkyl
group having a carbon number of 3 to 5. For example, those
exemplified as the above-mentioned "C.sub.3-8 cycloalkyl group" and
having a carbon number of 3 to 5 can be mentioned.
[0133] The "C.sub.6-14 aryl-C.sub.1-6 alkyl group" is a C.sub.6-14
aryl-C.sub.1-6 alkyl group wherein the C.sub.6-14 aryl moiety
thereof is the "C.sub.6-14 aryl group" defined above and the
C.sub.1-6 alkyl moiety thereof is the .sup."C.sub.1-6 alkyl group"
defined above, with preference given to a C.sub.6-14 aryl-C.sub.1-6
alkyl group wherein the C.sub.1-6 alkyl moiety is a straight chain
C.sub.1-6 alkyl group. Examples of the C.sub.6-14 aryl-C.sub.1-6
alkyl group include a phenylmethyl group, a phenylethyl group, a
phenylpropyl group, a phenylbutyl group, a phenylpentyl group, a
phenylhexyl group, a naphthylmethyl group, a naphthylethyl group, a
naphthylpropyl group, a naphthylbutyl group, a naphthylpentyl
group, a naphthylhexyl group, an anthrylmethyl group, an
indenylmethyl group, an azulenylmethyl group, a fluorenylmethyl
group, a phenanthrylmethyl group, a pentalenylmethyl group and the
like.
[0134] The "C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl group" is a
C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl group wherein the C.sub.3-8
cycloalkyl moiety thereof is the "C.sub.3-8 cycloalkyl group"
defined above and the C.sub.1-6 alkyl moiety thereof is the
"C.sub.1-6 alkyl group" defined above. Examples thereof include a
cyclopropylmethyl group, a cyclopropylethyl group, a
cyclopropylpropyl group, a cyclopropylbutyl group, a
cyclopropylpentyl group, a cyclopropylhexyl group, a
cyclobutylmethyl group, a cyclobutylethyl group, a cyclobutylpropyl
group, a cyclobutylbutyl group, a cyclobutylpentyl group, a
cyclobutylhexyl group, a cyclopentylmethyl group, a
cyclopentylethyl group, a cyclopentylpropyl group, a
cyclopentylbutyl group, a cyclopentylpentyl group, a
cyclopentylhexyl group, a cyclohexylmethyl group, a cyclohexylethyl
group, a cyclohexylpropyl group, a cyclohexylbutyl group, a
cyclohexylpentyl group, a cyclohexylhexyl group, a
cycloheptylmethyl group, a cycloheptylethyl group, a
cycloheptylpropyl group, a cycloheptylbutyl group, a
cycloheptylpentyl group, a cycloheptylhexyl group, a
cyclooctylmethyl group, a cyclooctylethyl group, a cyclooctylpropyl
group, a cyclooctylbutyl group, a cyclooctylpentyl group, a
cyclooctylhexyl group and the like.
[0135] The "C.sub.3-8 cycloalkenyl group" is a cycloalkenyl group
having a carbon number of 3 to 8 and contains at least one,
preferably 1 or 2, double bonds. For example, a cyclopropenyl
group, a cyclobutenyl group, a cyclopentenyl group, a
cyclopentadienyl group, a cyclohexenyl group, a cyclohexadienyl
group (a 2,4-cyclohexadien-1-yl group, a 2,5-cyclohexadien-1-yl
group etc.), a cycloheptenyl group, a cyclooctenyl group and the
like can be mentioned.
[0136] The "heteroaryl group" is an aromatic heterocycle having, as
ring-constituting atom besides carbon atom, 1 to 6 hetero atoms
selected from nitrogen atom, oxygen atom and sulfur atom, wherein
the number of ring-constituting atom is 3 to 14, including
monocycle and fused ring.
[0137] The "monocyclic heteroaryl group" is a monocyclic heteroaryl
group preferably having 1 to 4 hetero atoms and, for example, a
thienyl group (e.g., thiophen-2-yl, thiophen-3-yl), a furyl group
(e.g., furan-2-yl, furan-3-yl etc.), a pyrrolyl group (e.g.,
2-Pyrroline-1-yl group, 3-Pyrroline-3-yl etc.), an oxazolyl group
(e.g., oxazol-2-yl, oxazol-4-yl, oxazol-5-yl etc.), an isoxazolyl
group (e.g., isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl etc.), a
thiazolyl group (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl
etc.), an isothiazolyl group (e.g., isothiazol-3-yl,
isothiazol-4-yl, isothiazol-5-yl etc.), an imidazolyl group (e.g.,
imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl etc.), a
pyrazolyl group (e.g., pyrazol-1-yl, 1H-pyrazol-3-yl,
2H-pyrazol-3-yl, 1H-pyrazol-4-yl etc.), an oxadiazolyl group (e.g.,
1,3,4-oxadiazol-2-yl, 1,2,3-oxadiazol-4-yl, 1,2,4-oxadiazol-3-yl,
1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl etc.), a thiadiazolyl
group (e.g., 1,3,4-thiadiazol-2-yl, 1,2,3-thiadiazol-4-yl,
1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl,
1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl etc.), a triazolyl
group (e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-1-yl,
1,2,3-triazol-1-yl, 1,2,3- triazol-2-yl, 1,3,4-triazol-1-yl etc.),
a tetrazolyl group (e.g., tetrazol-1-yl, tetrazol-2-yl,
1H-tetrazol-5-yl, 2H-tetrazol-5-yl etc.), a pyridyl group (e.g.,
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl etc.), a pyrimidinyl group
(e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl etc.), a
pyridazinyl group (e.g., pyridazin-3-yl, pyridazin-4-yl etc.), a
pyrazinyl group (e.g., pyrazin-2-yl etc.), a triazinyl group (e.g.,
1,3,5-triazin-2-yl etc.) and the like can be mentioned.
[0138] Examples of the "fused heteroaryl group" include a quinolyl
group, an isoquinolyl group, a quinazolinyl group, a quinoxalyl
group, a phthalazinyl group, a cinnolinyl group, a naphthyridinyl
group, an indolyl group, a benzimidazolyl group, an indolinyl
group, a benzofuranyl group, a benzothienyl group, a benzoxazolyl
group, a benzothiazolyl group, a benzodioxinyl group, a
benzothiazolyl group, a tetrahydroquinolyl group, a
dihydrobenzofuranyl group, a dihydrobenzothienyl group, a
dihydrobenzodioxinyl group, an indenothiazolyl group, a
tetrahydrobenzothiazolyl group, a
5,7-dihydropyrrolo[3,4-d]pyrimidinyl group, a
6,7-dihydro-5H-cyclopentapyrimidinyl group, an
imidazo[2,1-b]thiazolyl group, a pteridinyl group, a purinyl group
and the like.
[0139] The "halo-C.sub.1-6 alkyl group" is a "C.sub.1-6 alkyl
group" defined above, which is substituted by the same or different
1 to 5 halogen atoms, and, for example, chloromethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, bromomethyl, chloroethyl,
fluoroethyl, bromoethyl, chioropropyl, fluoropropyl, bromopropyl
and the like can be mentioned.
[0140] The "group B" includes the following substituent groups (a)
to (e). [0141] (a) the "halogen atom" defined above, [0142] (b) the
"C.sub.1-6 alkyl group" defined above, [0143] (c) the "C.sub.3-8
cycloalkyl group" defined above, [0144] (d) a cyano group, and
[0145] (e) the "halo-C.sub.1-6 alkyl group" defined above.
[0146] The "C.sub.6-14 aryl group optionally substituted by the
same or different 1 to 5 substituents selected from group B" is the
"C.sub.6-14 aryl group" defined above, which is optionally
substituted by the same or different 1 to 5 substituents, and
includes unsubstituted C.sub.6-14 aryl group. The substituents are
the same or different and selected from the "group B" defined
above.
[0147] The "C.sub.3-8 cycloalkyl group optionally substituted by
the same or different 1 to 5 substituents selected from group B" is
the "C.sub.3-8 cycloalkyl group" defined above which is optionally
substituted by the same or different 1 to 5 substituents, and
includes unsubstituted C.sub.3-8 cycloalkyl group. The substituents
are the same or different and selected from the "group B" defined
above.
[0148] The "C.sub.3-8 cycloalkenyl group optionally substituted by
the same or different 1 to 5 substituents selected from group B" is
the "C.sub.3-8 cycloalkenyl group" defined above which is
optionally substituted by the same or different 1 to 5
substituents, and includes unsubstituted C.sub.3-8 cycloalkenyl
group. The substituents are the same or different and selected from
the "group B" defined above.
[0149] The "heteroaryl group optionally substituted by the same or
different 1 to 5 substituents selected from group B" is the
"heteroaryl group" defined above which is optionally substituted by
the same or different 1 to 5 substituents, and includes
unsubstituted heteroaryl group. The substituents are the same or
different and selected from the "group B" defined above.
[0150] In the above-mentioned formula [I], preferable groups are as
described below.
[0151] The partial structural formula:
##STR00027##
is a group represented by any of the following formulas:
##STR00028##
[0152] As the partial structural formula, preferred are groups
represented by
##STR00029##
and the like.
[0153] As the partial structural formula, more preferred is a group
represented by
##STR00030##
[0154] R.sup.1 is [0155] (1) a hydrogen atom, [0156] (2) a
C.sub.1-6 alkyl group, [0157] (3) a C.sub.6-14 aryl group, [0158]
(4) a C.sub.3-8 cycloalkyl group, [0159] (5) a C.sub.6-14
aryl-C.sub.1-6 alkyl group, or [0160] (6) a C.sub.3-8
cycloalkyl-C.sub.1-6 alkyl group.
[0161] R.sup.1 is preferably [0162] (1) a hydrogen atom, [0163] (2)
a C.sub.1-3 alkyl group (e.g., methyl), [0164] (3) a C.sub.6-14
aryl group (e.g., phenyl), [0165] (4) a C.sub.3-5 cycloalkyl group
(e.g., cyclopropyl), [0166] (5) a C.sub.6-14 aryl (e.g.,
phenyl)-C.sub.1-3 alkyl (preferably straight chain C.sub.1-3 alkyl,
e.g., ethyl) group, [0167] (6) a C.sub.3-8 cycloalkyl (e.g.,
cyclohexyl)-C.sub.1-3 alkyl (e.g., ethyl) group, or the like.
[0168] R.sup.1 is more preferably a hydrogen atom.
[0169] R.sup.2 is [0170] (1) a hydrogen atom, [0171] (2) a
C.sub.1-10 alkyl group, [0172] (3) a C.sub.6-14 aryl group
optionally substituted by the same or different 1 to 5 substituents
selected from the above-mentioned group B, [0173] (4) a C.sub.3-8
cycloalkyl group optionally substituted by the same or different 1
to 5 substituents selected from the above-mentioned group B, [0174]
(5) a C.sub.3-8 cycloalkenyl group optionally substituted by the
same or different 1 to 5 substituents selected from the
above-mentioned group B, [0175] (6) a heteroaryl group optionally
substituted by the same or different 1 to 5 substituents selected
from the above-mentioned group B (wherein the heteroaryl has,
besides carbon atom, 1 to 6 hetero atoms selected from nitrogen
atom, oxygen atom and sulfur atom), [0176] (7) a C.sub.6-14
aryl-C.sub.1-6 alkyl group (wherein C.sub.6-14 aryl is optionally
substituted by the same or different 1 to 5 substituents selected
from the above-mentioned group B), or [0177] (8) a C.sub.3-8
cycloalkyl-C.sub.1-6 alkyl group (wherein C.sub.3-8 cycloalkyl is
optionally substituted by the same or different 1 to 5 substituents
selected from the above-mentioned group B).
[0178] R.sup.2 is preferably [0179] (1) a hydrogen atom, [0180] (2)
a C.sub.1-10 alkyl group, [0181] (3) a C.sub.6-14 aryl group
optionally substituted by the same or different 1 to 5 substituents
selected from the above-mentioned group B, [0182] (4) a C.sub.3-8
cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl),
[0183] (5) a C.sub.3-8 cycloalkenyl group (e.g., cyclohexenyl),
[0184] (6) a heteroaryl group (preferably monocyclic heteroaryl
group, e.g., thienyl) optionally substituted by the same or
different 1 to 5 (e.g., 1) substituents selected from the
above-mentioned group B [0185] (e.g., (a) a halogen atom (e.g.,
chlorine atom), and (b) a C.sub.1-6 alkyl group (e.g., methyl))
(wherein the heteroaryl has, besides carbon atom, 1 to 6 (e.g., 1
to 4) hetero atoms selected from nitrogen atom, oxygen atom and
sulfur atom (e.g., a sulfur atom)), [0186] (7) a C.sub.6-14
aryl-C.sub.1-6 alkyl group (wherein C.sub.6-14 aryl is optionally
substituted by the same or different 1 to 5 substituents selected
from the above-mentioned group B), or [0187] (8) a C.sub.3-8
cycloalkyl-C.sub.1-3 alkyl group (wherein C.sub.3-8 cycloalkyl is
optionally substituted by the same or different 1 to 5 substituents
selected from the above-mentioned group B).
[0188] R.sup.2 is more preferably [0189] (1) a C.sub.1-10 alkyl
group (e.g., ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,
isopentyl, tert-pentyl, hexyl, 1-ethylpropyl, 2-ethylbutyl,
3,3-dimethylbutyl, 3,3-dimethylpentyl), (2) a C.sub.6-14 aryl group
(e.g., phenyl) optionally substituted by the same or different 1 to
5 (e.g., 1 to 3) substituents selected from the above-mentioned
group B (e.g., (a) a halogen atom (e.g., chlorine atom, fluorine
atom),
[0190] (b) a C.sub.1-3 alkyl group (e.g., methyl),
[0191] (c) a C.sub.3-5 cycloalkyl group (e.g., cyclopropyl),
[0192] (d) a cyano group, and
[0193] (e) a halo-C.sub.1-3 alkyl group (e.g., trifluoromethyl)),
[0194] (3) a C.sub.6-14 aryl (e.g., phenyl)-C.sub.1-6 alkyl
(preferably straight chain C.sub.1-6 alkyl, e.g., methyl, ethyl,
propyl) group (the C.sub.6-.sub.14 aryl is optionally substituted
by the same or different 1 to 5 (e.g., 1 to 3) substituents
selected from the above-mentioned group B [0195] (e.g., (a) a
halogen atom (e.g., chlorine atom, fluorine atom),
[0196] (b) a C.sub.3-8 cycloalkyl group (e.g., cyclopropyl),
and
[0197] (c) a halo-C.sub.1-3 alkyl group (e.g., trifluoromethyl))),
or [0198] (4) a C.sub.3-8 cycloalkyl (e.g., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl)-C.sub.1-3 alkyl (e.g., methyl,
ethyl) group (the C.sub.3-8 cycloalkyl is optionally substituted by
the same or different 1 to 5 substituents selected from the
above-mentioned group B).
[0199] R.sup.2 is still more preferably [0200] (1) a C.sub.1-6
alkyl group (e.g., butyl, pentyl, 1-ethylpropyl), [0201] (2) phenyl
optionally substituted the same or different 1 to 3 substituents
selected from
[0202] (a) a halogen atom (e.g., chlorine atom, fluorine atom),
[0203] (b) a C.sub.1-3 alkyl group (e.g., methyl),
[0204] (c) a C.sub.3-5 cycloalkyl group (e.g., cyclopropyl),
and
[0205] (d) a halo-C.sub.1-3 alkyl group (e.g., trifluoromethyl),
[0206] (3) phenylethyl, or [0207] (4) cyclopentylethyl.
[0208] R.sup.2 is particularly preferably butyl, phenylethyl or
4-fluoro-3-trifluoromethylphenyl.
[0209] In another embodiment of the present invention, R.sup.2 is
preferably [0210] (1) a C.sub.1-10 alkyl group, or [0211] (2) a
C.sub.6-14 aryl-C.sub.1-6 alkyl group (wherein C.sub.6-14 aryl is
optionally substituted by the same or different 1 to 5 substituents
selected from the above-mentioned group B).
[0212] R.sup.3 is [0213] (1) a hydrogen atom, [0214] (2) a halogen
atom, [0215] (3) a C.sub.1-6 alkyl group, [0216] (4) a C.sub.6-14
aryl group, [0217] (5) a C.sub.3-8 cycloalkyl group, or [0218] (6)
a C.sub.6-14 aryl-C.sub.1-6 alkyl group.
[0219] R.sup.3 is preferably [0220] (1) a hydrogen atom, [0221] (2)
a halogen atom (e.g., chlorine atom), [0222] (3) a C.sub.1-6 alkyl
group (e.g., ethyl, pentyl), [0223] (4) a C.sub.6-14 aryl group
(e.g., phenyl), or [0224] (5) a C.sub.6-14 aryl (e.g.,
phenyl)-C.sub.1-6 alkyl (preferably straight chain C.sub.1-6 alkyl,
e.g., ethyl) group.
[0225] R.sup.3 is more preferably a hydrogen atom.
[0226] R.sup.4 and R.sup.5 are each independently [0227] (1) a
hydrogen atom, or [0228] (2) a C.sub.1-6 alkyl group.
[0229] R.sup.4 and R.sup.5 are preferably each independently [0230]
(1) a hydrogen atom, or [0231] (2) a C.sub.1-3 alkyl group (e.g.,
methyl).
[0232] R.sup.4 and R.sup.5 are more preferably both hydrogen
atoms.
[0233] In the formula [I], a compound represented by the following
formula [Ia]
##STR00031##
wherein
[0234] the partial structural formula:
##STR00032##
is a group represented by
##STR00033##
[0235] R.sup.1a is [0236] (1) a hydrogen atom, [0237] (2) a
C.sub.1-3 alkyl group (e.g., methyl), [0238] (3) a C.sub.6-14 aryl
group (e.g., phenyl), [0239] (4) a C.sub.3-5 cycloalkyl group
(e.g., cyclopropyl), [0240] (5) a C.sub.6-14 aryl (e.g.,
phenyl)-C.sub.1-3 alkyl (preferably straight chain C.sub.1-3 alkyl,
e.g., ethyl) group, or [0241] (6) a C.sub.3-8 cycloalkyl (e.g.,
cyclohexyl)-C.sub.1-3 alkyl (e.g., ethyl) group;
[0242] R.sup.2a is [0243] (1) a hydrogen atom, [0244] (2) a
C.sub.1-10 alkyl group, [0245] (3) a C.sub.6-14 aryl group
optionally substituted by the same or different 1 to 5 substituents
selected from the above-mentioned group B, [0246] (4) a C.sub.3-8
cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl),
[0247] (5) a C.sub.3-8 cycloalkenyl group (e.g., cyclohexenyl),
[0248] (6) a heteroaryl group (preferably monocyclic heteroaryl
group, e.g., thienyl) optionally substituted by the same or
different 1 to 5 (e.g., 1) substituents selected from the
above-mentioned group B (e.g., (a) a halogen atom (e.g., chlorine
atom), and
[0249] (b) a C.sub.1-6 alkyl group (e.g., methyl))
(wherein the heteroaryl has, besides carbon atom, 1 to 6 (e.g., 1
to 4) hetero atoms selected from nitrogen atom, oxygen atom and
sulfur atom (e.g., a sulfur atom)), [0250] (7) a C.sub.6-14
aryl-C.sub.1-6 alkyl group (wherein C.sub.6-14 aryl is optionally
substituted by the same or different 1 to 5 substituents selected
from the above-mentioned group B), or [0251] (8) a C.sub.3-8
cycloalkyl-C.sub.1-3 alkyl group (wherein C.sub.3-8 cycloalkyl is
optionally substituted by the same or different 1 to 5 substituents
selected from the above-mentioned group B);
[0252] R.sup.3a is [0253] (1) a hydrogen atom, [0254] (2) a halogen
atom (e.g., chlorine atom), [0255] (3) a C.sub.1-6 alkyl group
(e.g., ethyl, pentyl), [0256] (4) a C.sub.6-14 aryl group (e.g.,
phenyl), or [0257] (5) a C.sub.6-14 aryl (e.g., phenyl)-C.sub.1-6
alkyl (preferably straight chain C.sub.1-6 alkyl, e.g., ethyl)
group; and
[0258] R.sup.4a and R.sup.5a are each independently [0259] (1) a
hydrogen atom, or [0260] (2) a C.sub.1-3 alkyl group (e.g.,
methyl)] is more preferable.
[0261] As the compound of the present invention, a compound
represented by the above-mentioned formula [Ia], wherein
[0262] R.sup.1a is a hydrogen atom;
[0263] R.sup.2a is [0264] (1) a C.sub.1-10 alkyl group (e.g.,
ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl,
tert-pentyl, hexyl, 1-ethylpropyl, 2-ethylbutyl, 3,3-dimethylbutyl,
3,3-dimethylpentyl), [0265] (2) a C.sub.6-14 aryl group (e.g.,
phenyl) optionally substituted by the same or different 1 to 5
(e.g., 1 to 3) substituents selected from the above-mentioned group
B (e.g., (a) a halogen atom (e.g., chlorine atom, fluorine
atom),
[0266] (b) a C.sub.1-3 alkyl group (e.g., methyl),
[0267] (c) a C.sub.3-5 cycloalkyl group (e.g., cyclopropyl),
[0268] (d) a cyano group, and
[0269] (e) a halo-C.sub.1-3 alkyl group (e.g., trifluoromethyl)),
[0270] (3) a C.sub.6-14 aryl (e.g., phenyl) -C.sub.1-6 alkyl
(preferably straight chain C.sub.1-6 alkyl, e.g., methyl, ethyl,
propyl) group (the C.sub.6-.sub.14 aryl is optionally substituted
by the same or different 1 to 5 (e.g., 1 to 3) substituents
selected from the above-mentioned group B (e.g., (a) a halogen atom
(e.g., chlorine atom, fluorine atom),
[0271] (b) a C.sub.3-8 cycloalkyl group (e.g., cyclopropyl),
and
[0272] (c) a halo-C.sub.1-6 alkyl group (e.g., trifluoromethyl))),
or [0273] (4) a C.sub.3-8 cycloalkyl (e.g., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl)-C.sub.1-3 alkyl (e.g., methyl,
ethyl) group (the C.sub.3-8 cycloalkyl is optionally substituted by
the same or different 1 to 5 substituents selected from the
above-mentioned group B);
[0274] R.sup.1 is a hydrogen atom; and
[0275] R.sup.4a and R.sup.5a are both hydrogen atoms;
[0276] is more preferable.
[0277] In another embodiment of the present invention, from
compounds represented by the formula [I], a compound represented by
the following formula [I-1]:
##STR00034##
wherein the partial structural formula:
##STR00035##
is a group represented by any of the following formulas:
##STR00036##
[0278] R.sup.11 is [0279] (1) a hydrogen atom, [0280] (2) a
C.sub.1-6 alkyl group (e.g., methyl), [0281] (3) a phenyl group,
[0282] (4) a C.sub.3-8 cycloalkyl group (e.g., cyclopropyl), [0283]
(5) a phenyl-C.sub.1-6 alkyl group, or [0284] (6) a C.sub.3-8
cycloalkyl-C.sub.1-6 alkyl group;
[0285] R.sup.21 is [0286] (1) a hydrogen atom, [0287] (2) a
C.sub.1-10 alkyl group (e.g., ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, n-pentyl, n-hexyl, 1-ethylpropyl, 3-methylbutyl,
2,2-dimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl,
3,3-dimethylpentyl), [0288] (3) a phenyl group optionally
substituted by the same or different 1 to 5 substituents (e.g.,
fluorine atom, chlorine atom, methyl, cyano, cyclopropyl,
trifluoromethyl) selected from m the above-mentioned group B,
[0289] (4) a C.sub.3-8 cycloalkyl group (e.g., cyclopentyl,
cyclohexyl, cycloheptyl), [0290] (5) a C.sub.3-8 cycloalkenyl group
(e.g., cyclohexenyl), [0291] (6) a thienyl group optionally
substituted by the same or different 1 to 5 substituents (e.g.,
chlorine atom, methyl) selected from the above-mentioned group B,
[0292] (7) a phenyl-C.sub.1-6 alkyl group (e.g., phenylmethyl,
phenylethyl, phenylpropyl) (wherein phenyl is optionally
substituted by the same or different 1 to 5 substituents (e.g.,
fluorine atom, chlorine atom, cyclopropyl, trifluoromethyl)
selected from the above-mentioned group B), or [0293] (8) a
C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl group (e.g., cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl,
cyclobutylethyl, cyclopentylethyl, cyclohexylethyl);
R.sup.31 is
[0293] [0294] (1) a hydrogen atom, [0295] (2) a halogen atom (e.g.,
chlorine atom), [0296] (3) a C.sub.1-6 alkyl group (e.g., ethyl,
n-pentyl), [0297] (4) a phenyl group, [0298] (5) a C.sub.3-8
cycloalkyl group, or [0299] (6) a phenyl-C.sub.1-6 alkyl group
(e.g., phenylethyl); and R.sup.41 and R.sup.51 are each
independently [0300] (1) a hydrogen atom, or [0301] (2) a C.sub.1-6
alkyl group (e.g., methyl) is preferable.
[0302] Of compounds represented by the formula [I-1], a compound
wherein
[0303] R.sup.11 is [0304] (1) a hydrogen atom, [0305] (2) a
C.sub.1-6 alkyl group (e.g., methyl), [0306] (3) a phenyl group, or
[0307] (4) a C.sub.3-8 cycloalkyl group (e.g., cyclopropyl);
[0308] R.sup.21 is [0309] (1) a hydrogen atom, [0310] (2) a
C.sub.1-10 alkyl group (e.g., ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, n-pentyl, n-hexyl, 1-ethylpropyl, 3-methylbutyl,
2,2-dimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl,
3,3-dimethylpentyl). [0311] (3) a phenyl group optionally
substituted by the same or different 1 to 5 substituents (e.g.,
fluorine atom, chlorine atom, methyl, cyano, cyclopropyl,
trifluoromethyl) selected from the above-mentioned group B, [0312]
(4) a C.sub.3-8 cycloalkyl group (e.g., cyclopentyl, cyclohexyl,
cycloheptyl), [0313] (5) a C.sub.3-8 cycloalkenyl group (e.g.,
cyclohexenyl), [0314] (6) a thienyl group optionally substituted by
the same or different 1 to 5 substituents (e.g., chlorine atom,
methyl) selected from the above-mentioned group B, [0315] (7) a
phenyl-C.sub.1-6 alkyl group (e.g., phenylmethyl, phenylethyl,
phenylpropyl) (wherein phenyl is optionally substituted by the same
or different 1 to 5 substituents (e.g., fluorine atom, chlorine
atom, cyclopropyl, trifluoromethyl) selected from the
above-mentioned group B), or [0316] (8) a C.sub.3-8
cycloalkyl-C.sub.1-6 alkyl group (e.g., cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl,
cyclobutylethyl, cyclopentylethyl, cyclohexylethyl);
[0317] R.sup.31 is [0318] (1) a hydrogen atom, [0319] (2) a halogen
atom (e.g., chlorine atom), [0320] (3) a C.sub.1-6 alkyl group
(e.g., ethyl, n-pentyl), [0321] (4) a phenyl group, or [0322] (6) a
phenyl-C.sub.1-6 alkyl group (e.g., phenylethyl);
[0323] R.sup.41 and R.sup.51 are each independently [0324] (1) a
hydrogen atom, or [0325] (2) a C.sub.1-6 alkyl group (e.g.,
methyl), is preferable,
[0326] R.sup.11 is a hydrogen atom, methyl, phenyl, or
cyclopropyl;
[0327] R.sup.21 is a hydrogen atom; ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, n-pentyl, n-hexyl, 1-ethylpropyl, 3-methylbutyl,
2,2-dimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl,
3,3-dimethylpentyl; phenyl optionally substituted by the same or
different 1 to 5 substituents selected from fluorine atom, chlorine
atom, methyl, cyano, cyclopropyl and trifluoromethyl; cyclopentyl,
cyclohexyl, cycloheptyl; cyclohexenyl; thienyl optionally
substituted by the same or different 1 to 5 substituents selected
from chlorine atom and methyl; phenylmethyl, phenylethyl,
phenylpropyl (the phenyl is optionally substituted by the same or
different 1 to 5 substituents selected from fluorine atom, chlorine
atom, cyclopropyl and trifluoromethyl); cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl,
cyclobutylethyl, cyclopentylethyl, or cyclohexylethyl;
[0328] R.sup.31 is a hydrogen atom, a chlorine atom, ethyl,
n-pentyl, phenyl, or phenylethyl; and
[0329] R.sup.41 and R.sup.51 is are each independently a hydrogen
atom or methyl,
is more preferable.
[0330] As the compound of the present invention or a
pharmaceutically acceptable salt thereof, or a solvate thereof, the
compounds described in Examples 1-122 are preferable, the compounds
described in Examples 1, 2, 21, 31, 40, 44, 47, 52, 60, 74, 79,
116, 118, 119, 120, 121 and 122 are particularly preferable.
[0331] A pharmaceutically acceptable salt of the compound
represented by the formula [I] may be any salt as long as it forms
a nontoxic salt with the compound of the present invention.
Examples thereof include salts with inorganic acids, salts with
organic acids, salts with inorganic bases, salts with organic
bases, salts with amino acids and the like.
[0332] Examples of the salt with inorganic acid include a salt with
hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,
hydrobromic acid and the like.
[0333] Examples of the salt with organic acid include salts with
oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid,
malic acid, succinic acid, tartaric acid, acetic acid,
trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic
acid, benzenesulfonic acid, p-toluenesulfonic acid and the
like.
[0334] Examples of the salt with inorganic base include sodium
salt, potassium salt, calcium salt, magnesium salt, ammonium salt
and the like.
[0335] Examples of the salt with organic base include methylamine,
diethylamine, trimethylamine, triethylamine, ethanolamine,
diethanolamine, triethanolamine, ethylenediamine,
tris(hydroxymethyl)methylamine, dicyclohexylamine,
N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline,
choline, cinchonine, meglumine and the like.
[0336] Examples of the salt with amino acid include salts with
lysine, arginine, aspartic acid, glutamic acid and the like.
[0337] Each salt can be obtained by reacting a compound represented
by the formula [I] with an inorganic base, organic base, inorganic
acid, organic acid or amino acid according to a known method.
[0338] The "solvate" is a compound represented by the formula [I]
or a pharmaceutically acceptable salt thereof wherein a molecule of
the solvent is coordinated, and also includes hydrates. As the
solvate, a pharmaceutically acceptable solvate is preferable and
includes, for example, hydrate, ethanolate, dimethylsulfoxidate and
the like of the compound represented by the formula [I] or a
pharmaceutically acceptable salt thereof. Specific examples thereof
include hemihydrate, monohydrate, dihydrate and monoethanolate of
the compound represented by the formula [I], monohydrate of sodium
salt, 2/3 ethanolate of dihydrochloride, and the like of the
compound represented by the formula [I].
[0339] The solvate of the compound of the present invention or a
pharmaceutically acceptable salt thereof can be obtained according
to a method known per se.
[0340] In addition, the compound represented by the formula [1] or
a pharmaceutically acceptable salt thereof, or a solvate thereof
has various isomers. For example, E form and Z form are present as
geometric isomers, when an asymmetric carbon atom is present,
enantiomer and diastereomer are present as stereoisomers based
thereon, and when axial chirality is present, stereoisomers based
thereon are present. Moreover, tautomers can also be present.
Accordingly, the present invention encompasses all these isomers
and mixtures thereof.
[0341] In addition, the compound of the present invention or a
pharmaceutically acceptable salt thereof, or a solvate thereof may
be labeled with an isotope (e.g., .sup.3H, .sup.14C, .sup.35S
etc.).
[0342] As the compound represented by the formula [I] or a
pharmaceutically acceptable salt thereof or a solvate thereof, a
compound represented by the formula [I] or a pharmaceutically
acceptable salt thereof or a solvate thereof, each of which is
substantially purified, is preferable. More preferred is a compound
represented by the formula [I] or a pharmaceutically acceptable
salt thereof or a solvate thereof, each of which is purified to
have a purity usable as a pharmaceutical product.
[0343] In the present invention, a prodrug of the compound
represented by the formula [I] can also be a useful medicament. The
"prodrug" is a derivative of the compound of the present invention
having a chemically or metabolically degradable group which, after
administration to the body, restores to the original compound by,
for example, hydrolysis, solvolysis or decomposition under
physiological conditions, and shows inherent efficacy. It includes
a noncovalent complex, and a salt. Prodrug is utilized for, for
example, improvement of absorption on oral administration, or
targeting to a target moiety.
[0344] Examples of the modified moiety include, in the compound of
the present invention, a highly reactive functional group such as a
hydroxyl group, a carboxyl group, an amino group and the like.
[0345] Specific examples of the hydroxyl-modifying group include an
acetyl group, a propionyl group, an isobutyryl group, a pivaloyl
group, a palmitoyl group, a benzoyl group, a 4-methylbenzoyl group,
a dimethylcarbamoyl group, a dimethylaminomethylcarbonyl group, a
sulfo group, an alanyl group, a fumaryl group and the like. In
addition, sodium salt of 3-carboxybenzoyl group,
2-carboxyethylcarbonyl group and the like can be mentioned.
[0346] Specific examples of the carboxyl-modifying group include a
methyl group, an ethyl group, a propyl group, an isopropyl group, a
butyl group, an isobutyl group, a tert-butyl group, a
pivaloyloxymethyl group, a carboxymethyl group, a
dimethylaminomethyl group, a 1-(acetyloxy)ethyl group, a
1-(ethoxycarbonyloxy)ethyl group, a
1-(isopropyloxycarbonyloxy)ethyl group, a
1-(cyclohexyloxycarbonyloxy)ethyl group, a
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a benzyl group, a
phenyl group, an o-tolyl group, a morpholinoethyl group, an
N,N-diethylcarbamoylmethyl group, a phthalidyl group and the
like.
[0347] Specific examples of the amino-modifying group include a
tert-butyl group, a docosanoyl group, a pivaloyloxymethyl group, an
alanyl group, a hexylcarbamoyl group, a pentylcarbamoyl group, a
3-methylthio-1-(acetylamino)propylcarbonyl group, a
1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, a
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a
(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, a
tetrahydrofuranyl group, a pyrrolidylmethyl group and the like.
[0348] Examples of the "pharmaceutical composition" include oral
preparations such as tablet, capsule, granule, powder, troche,
syrup, emulsion, suspension and the like, and parenteral agents
such as external preparation, suppository, injection, eye drop,
nasal preparation, pulmonary preparation and the like.
[0349] The pharmaceutical composition of the present invention is
produced according to a method known in the art of pharmaceutical
preparations, by mixing a compound represented by the formula [I]
or a pharmaceutically acceptable salt thereof or a solvate thereof
with a suitable amount of at least one kind of pharmaceutically
acceptable carrier and the like as appropriate. While the content
of the compound represented by the formula [I] or a
pharmaceutically acceptable salt thereof, or a solvate thereof in
the pharmaceutical composition varies depending on the dosage form,
dose and the like, it is, for example, 0.1 to 100 wt % of the whole
composition.
[0350] Examples of the "pharmaceutically acceptable carrier"
include various organic or inorganic carrier substances
conventionally used as preparation materials, for example,
excipient, disintegrant, binder, glidant, lubricant and the like
for solid preparations, and solvent, solubilizing agent, suspending
agent, isotonicity agent, buffering agent, soothing agent and the
like for liquid preparations. Where necessary, moreover, additives
such as preservative, antioxidant, colorant, sweetening agent and
the like are used.
[0351] Examples of the "excipient" include lactose, sucrose,
D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline
cellulose, crystalline cellulose, carmellose, carmellose calcium,
sodium carboxymethyl starch, low-substituted
hydroxypropylcellulose, gum arabic and the like.
[0352] Examples of the "disintegrant" include carmellose,
carmellose calcium, carmellose sodium, sodium carboxymethyl starch,
croscarmellose sodium, crospovidone, low-substituted
hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline
cellulose and the like.
[0353] Examples of the "binder" include hydroxypropylcellulose,
hydroxypropylmethylcellulose, povidone, crystalline cellulose,
sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic
and the like.
[0354] Examples of the "glidant" include light anhydrous silicic
acid, magnesium stearate and the like.
[0355] Examples of the "lubricant" include magnesium stearate,
calcium stearate, talc and the like.
[0356] Examples of the "solvent" include purified water, ethanol,
propylene glycol, macrogol, sesame oil, corn oil, olive oil and the
like.
[0357] Examples of the "solubilizing agents" include propylene
glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine,
sodium carbonate, sodium citrate and the like.
[0358] Examples of the "suspending agent" include benzalkonium
chloride, carmellose, hydroxypropylcellulose, propylene glycol,
povidone, methylcellulose, glycerol monostearate and the like.
[0359] Examples of the "isotonicity agent" include glucose,
D-sorbitol, sodium chloride, D-mannitol and the like.
[0360] Examples of the "buffering agent" include sodium
hydrogenphosphate, sodium acetate, sodium carbonate, sodium citrate
and the like.
[0361] Examples of the "soothing agent" include benzyl alcohol and
the like.
[0362] Examples of the "preservative" include ethyl
parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium
dehydroacetate, sorbic acid and the like.
[0363] Examples of the "antioxidant" include sodium sulfite,
ascorbic acid and the like.
[0364] Examples of the "colorant" include food colors (e.g., Food
Color Red No. 2 or 3, Food Color Yellow No. 4 or 5 etc.),
.beta.-carotene and the like.
[0365] Examples of the "sweetening agent" include saccharin sodium,
dipotassium glycyrrhizinate, aspartame and the like.
[0366] The compound of the present invention or a pharmaceutically
acceptable salt thereof, or a solvate thereof has an EPO
production-inducing activity due to a prolyl hydroxylase (PHD)
inhibitory action, and can be used for the prophylaxis or treatment
of various diseases and pathologies (disorders) caused by decreased
production of EPO.
[0367] As the various diseases and pathologies (disorders) caused
by decreased production of EPO, anemia and the like can be
mentioned.
[0368] In general, anemia includes anemia due to hematopoiesis
abnormality in the bone marrow, anemia due to shortage of iron,
vitamin B.sub.12 or folic acid, bleeding during accident or
operation, anemia associated with chronic inflammation (autoimmune
diseases, malignant tumor, chronically-transmitted diseases, plasma
cell dyscrasia etc.), anemia associated with endocrine diseases
(hypothyroidism, autoimmune polyglandular syndrome, type IA
diabetes, dysfunctional uterine bleeding etc.), anemia associated
with chronic cardiac failure, anemia associated with ulcer, anemia
associated with hepatic diseases, senile anemia, drug-induced
anemia, renal anemia (anemia associated with renal failure), anemia
associated with chemical therapy, and the like.
[0369] Examples of the diseases expected to be improved by
inhibiting PHD to stabilize HIF include ischemic cardiac diseases
(angina pectoris, myocardial infarction etc.), ischemic
cerebrovascular disorders (cerebral infarction, cerebral embolism,
transient cerebral ischemic attack etc.), chronic renal failures
(ischemic nephropathy, renal tubule interstitial disorder etc.),
diabetic complications (diabetic wound etc.), cognitive impairments
(dementia, Alzheimer's disease, Parkinson's disease, Huntington's
disease etc.) and the like.
[0370] The prolyl hydroxylase (PHD) inhibitor and EPO
production-inducing agent of the present invention is preferably
used as a therapeutic agent for anemia, more preferably a
therapeutic agent for renal anemia.
[0371] The pharmaceutical composition of the present invention can
be administered orally or parenterally (e.g., topical, rectal,
intravenous administration etc.) to human as well as mammals other
than human (e.g., mouse, rat, hamster, guinea pig, rabbit, cat,
dog, swine, bovine, horse, sheep, monkey etc.). The dose varies
depending on the subject of administration, disease, symptom,
dosage form, administration route and the like. For example, the
daily dose for oral administration to an adult patient (body
weight: about 60 kg) is generally within the range of about 1 mg to
1 g, based on the compound of the present invention as the active
ingredient. This amount can be administered in one to several
portions.
[0372] Since the compound of the present invention or a
pharmaceutically acceptable salt thereof, or a solvate thereof
inhibits PHD and induces production of EPO, it can be used as an
active ingredient of a therapeutic agent or prophylactic agent for
anemia.
[0373] To "inhibit PHD" means to specifically inhibit the function
of prolyl hydroxylase and eliminate or attenuate the activity. For
example, it means to specifically inhibit the function as prolyl
hydroxylase based on the conditions in the below-mentioned
Experimental Example 1. To "inhibit PHD" preferably means to
inhibit human PHD. As a "PHD inhibitor", preferred is a "human PHD
inhibitor".
[0374] To "induce production of EPO" means that the production of
erythropoietin in the kidney etc. is promoted. For example, it
means that the production of erythropoietin is induced based on the
conditions of the below-mentioned Experimental Example 2. To
"induce production of EPO" preferably means to "induce production
of human EPO". An "EPO production-inducing agent" is preferably a
"human EPO production-inducing agent".
[0375] The above-mentioned compound represented by the formula [I]
or a pharmaceutically acceptable salt thereof, or a solvate thereof
can be used in combination with one or a plurality of other
medicaments (hereinafter to be also referred to as a concomitant
drug) according to a method generally employed in the medical field
(hereinafter to be referred to as combined use).
[0376] The administration period of the above-mentioned compound
represented by the formula [I] or a pharmaceutically acceptable
salt thereof, or a solvate thereof, and a concomitant drug is not
limited, and they may be administered to an administration subject
as combination preparation, or the both preparations may be
administered simultaneously or at given intervals. In addition, the
pharmaceutical composition of the present invention and a
concomitant drug may be used as a medicament in the form of a kit.
The dose of the concomitant drug is similar to the
clinically-employed dose and can be appropriately selected
according to the subject of administration, disease, symptom,
dosage form, administration route, administration time, combination
and the like. The administration form of the concomitant drug is
not particularly limited, and it only needs to be combined with the
compound of the present invention or a pharmaceutically acceptable
salt thereof, or a solvate thereof.
[0377] Examples of the concomitant drug include an agent for the
treatment and/or prophylaxis of anemia and the like, and the
compound of the present invention can be used in combination.
[0378] Examples of the "therapeutic agent and/or prophylaxis agent
of anemia" include ferrous citrate, iron sulfate and the like.
[0379] As PHD, PHD2 and PHD3 can be mentioned.
[0380] Next, the production methods of the compound of the present
invention or a pharmaceutically acceptable salt thereof, or a
solvate thereof are specifically explained. However, it is needless
to say that the present invention is not limited to such production
methods. For production of the compound of the present invention or
a pharmaceutically acceptable salt thereof, or a solvate thereof,
the order of reactions can be appropriately changed. The reaction
can be started from the step or substitution moiety that seems to
be reasonable.
[0381] In addition, an appropriate substituent conversion
(conversion or further modification of substituent) step may be
inserted between respective steps. When a reactive functional group
is present, protection and deprotection can be appropriately
performed. To promote progress of the reaction, moreover, a reagent
other than the exemplified reagent can be used as appropriate.
Furthermore, a starting compound whose production method is not
described is either commercially available or can be prepared
easily by a combination of known synthetic reactions.
[0382] The compound obtained in each step can be purified by a
conventional method such as distillation, recrystallization, column
chromatography and the like. In some cases, the compound can be
applied to the next step without isolation and purification.
[0383] In the following production method, the "room temperature"
means 1-40.degree. C.
Production Method I-1
##STR00037## ##STR00038##
[0384] wherein R.sup.11a and R.sup.11c are each a
carboxyl-protecting group such as a methyl group, an ethyl group, a
benzyl group, a tert-butyl group and the like, R.sup.11b is a
hydroxyl-protecting group such as an acetyl group, a benzyl group,
a methyl group, an ethyl group, an isopropyl group, a
trimethylsilyl group, a triethylsilyl group, a
tert-butyldimethylsilyl group, a triisopropylsilyl group, a
tert-butyldiphenylsilyl group and the like, X.sup.11a and X.sup.11b
are each a halogen atom such as a chlorine atom, a bromine atom, an
iodine atom, a fluorine atom and the like, a leaving group such as
a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a
trifluoromethanesulfonyloxy group and the like.
Step 1
[0385] Compound [I-1-2] can be obtained by subjecting compound
[I-1-1] to metalation according to a conventional method, and
introducing a carboxyl group using carbon dioxide. Metalation is
performed by reaction with an organic metal reagent such as
n-butyllithium, sec-butyllithium, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide,
potassium bis(trimethylsilyl)amide, lithium amide, sodium amide and
the like under low temperature conditions in hexane, benzene,
toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane and the like
alone or a mixed solvent thereof, which is followed by reaction
with carbon dioxide to give compound [I-1-2].
Step 2
[0386] Compound [I-1-3] can be obtained by introducing a protecting
group into the carboxyl group of compound [I-1-2] according to a
conventional method. For example, when the protecting group is a
tert-butyl group, compound [I-1-3] can be obtained by reaction with
tert-butyl 2,2,2-trichloroacetimidate under low temperature to
heating conditions in the presence of an acid such as
p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride,
boron trichloride, boron tribromide, aluminum trichloride, hydrogen
chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic
acid, trifluoroacetic acid and the like in hexane, chloroform,
methylene chloride, ethyl acetate, toluene, 1,4-dioxane,
tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide,
N,N-dimethylformamide, acetonitrile and the like alone or a mixed
solvent thereof.
Step 3
[0387] Compound [I-1-4] can be obtained by introducing a hydroxyl
group protected by a protecting group represented by R.sup.11b into
compound [I-1-3] according to a conventional method. For example,
when a hydroxyl group protected by a benzyl group is introduced,
compound [I-1-3] is reacted with benzyl alcohol under low
temperature to heating conditions in the presence of a base such as
triethylamine, potassium tert-butoxide, potassium carbonate, sodium
hydride, n-butyllithium, lithium diisopropylamide and the like in
hexane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile,
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene and the
like alone or a mixed solvent thereof, whereby compound [I-1-4] can
be obtained.
Step 4
[0388] Compound [I-1-5] can be obtained by reacting compound
[I-1-4] with hydrazine monohydrate under low temperature to heating
conditions in chloroform, toluene, 1,4-dioxane, tetrahydrofuran,
1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl
sulfoxide, N,N-dimethylformamide, acetonitrile, water and the like
alone or a mixed solvent thereof.
Step 5
[0389] Compound [I-1-6] can be obtained by reacting compound
[I-1-5] with an orthoester compound such as trimethyl orthoformate,
triethyl orthoformate and the like or formic acid under low
temperature to heating conditions in the presence of an acid such
as p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride,
boron trichloride, boron tribromide, hydrogen chloride, hydrogen
bromide, phosphoric acid, sulfuric acid and the like in hexane,
chloroform, methylene chloride, ethyl acetate, toluene,
1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol,
ethanol, 2-propanol, dimethyl sulfoxide, N,N-dimethylformamide,
acetonitrile and the like alone or a mixed solvent or without
solvent.
Step 6
[0390] Compound [I-1-7] can be obtained by performing an endocyclic
rearrangement reaction of compound [I-1-6] at room temperature to
under heating conditions in the presence of a base such as sodium
hydroxide, morpholine, piperidine, pyrrolidine and the like in
hexane, chloroform, methylene chloride, ethyl acetate, toluene,
1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran,
1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl
sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide,
acetonitrile and the like alone or a mixed solvent thereof.
Step 7
[0391] Compound [I-1-8] can be obtained by removing the
carboxyl-protecting group of compound [I-1-7] according to a
conventional method. For example, when R.sup.11a is a tert-butyl
group, compound [I-1-8] can be obtained by reaction with an acid
such as p-toluenesulfonic acid, methanesulfonic acid, boron
trifluoride, boron trichloride, boron tribromide, aluminum
trichloride, hydrogen chloride, hydrogen bromide, phosphoric acid,
sulfuric acid, acetic acid, trifluoroacetic acid and the like under
low temperature to heating conditions in hexane, chloroform,
methylene chloride, ethyl acetate, toluene, 1,2-dimethoxyethane,
1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol,
dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide,
acetonitrile, water and the like alone or a mixed solvent thereof.
When R.sup.11a is a methyl group, ethyl group or tert-butyl group,
compound [I-1-8] can be obtained by hydrolyzing compound [I-1-7]
under low temperature to heating conditions in the presence of a
base such as sodium hydroxide, potassium hydroxide, potassium
carbonate, sodium carbonate, lithium hydroxide and the like in a
mixed solvent of water and a solvent such as methanol, ethanol,
2-propanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,
N,N-dimethylformamide, acetonitrile and the like.
Step 8
[0392] Compound [I-1-9] can be obtained by introducing a protecting
group into the carboxyl group of compound [I-1-8] according to a
conventional method. For example, when the protecting group is an
ethyl group, compound [I-1-9] can be obtained by reacting compound
[I-1-8] with N,N-dimethylformamide diethyl acetal under low
temperature to heating conditions in chloroform, methylene
chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran,
1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl
sulfoxide, N,N-dimethylformamide, acetonitrile and the like alone
or a mixed solvent thereof.
[0393] Step 7 and step 8 may be omitted. In this case,
R.sup.11a=R.sup.11c.
Step 9
[0394] Compound [I-1-10] can be obtained by introducing a leaving
group onto the pyridine ring of compound [I-1-9] according to a
conventional method. Disubstituted compound [I-1-11] may be
obtained. When the leaving group is an iodine atom, compound
[I-1-10] and compound [I-1-11] can be obtained by reaction with an
organic metal reagent such as n-butyllithium, sec-butyllithium,
lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium
bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide,
lithium amide, sodium amide and the like under low temperature
conditions in hexane, toluene, 1,2-dimethoxyethane, diethyl ether,
1,4-dioxane, tetrahydrofuran and the like alone or a mixed solvent
thereof to perform metalation, followed by reaction with
iodine.
Production Method 1-2
##STR00039##
[0395] wherein R.sup.12a is a carboxyl-protecting group such as a
methyl group, an ethyl group, a benzyl group, a tert-butyl group
and the like, and other symbols are as defined above. Even when
R.sup.2 of [1-2-1] to [1-2-4] is other than the defined
substituents, it can be used as long as the defined substituent can
be finally obtained by appropriate substituent conversion.
Step 1
[0396] Compound [I-2-1] can be obtained by introducing substituent
R.sup.2 or a precursor thereof into compound [I-1-10] according to
a conventional method. For example, when R.sup.2 is a butyl group,
compound [I-2-1] can be obtained by reacting compound [I-1-10] with
butylboronic acid at room temperature to under heating conditions
in the presence of a palladium catalyst such as
[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride,
tetrakis(triphenylphosphine)palladium,
bis(triphenylphosphine)palladium(II) dichloride, palladium
acetate-triphenylphosphine and the like and a base such as
potassium acetate, potassium carbonate, potassium hydrogen
carbonate, sodium hydrogen carbonate, potassium phosphate,
triethylamine, diisopropylethylamine, sodium hydrogenphosphate,
cesium carbonate and the like, by adding a silver salt as necessary
such as silver carbonate, silver nitrate, silver(I) oxide and the
like in hexane, N,N-dimethylformamide, N,N-dimethylacetamide,
acetonitrile, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane,
toluene, water and the like alone or a mixed solvent thereof.
Step 2
[0397] Compound [I-2-2] can be obtained by removing the
carboxyl-protecting group of compound [I-2-1] in the same manner as
in production method I-1, step 7.
Step 3
[0398] Compound [I-2-3] can be obtained by condensing compound
[I-2-2] with a glycine derivative represented by
H2NC(R.sup.4)(R.sup.5)COOR.sup.12a according to a conventional
method. For example, compound [I-2-3] can be obtained by condensing
compound [I-2-2] with a glycine derivative represented by
H.sub.2NC(R.sup.4) (R.sup.5)COOR.sup.12a under low temperature to
heating conditions in the presence of a condensing agent such as
dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or a salt thereof,
diphenylphosphoryl azide and the like and, as necessary,
N-hydroxysuccinimide, 1-hydroxybenzotriazole, dimethylaminopyridine
and the like and, as necessary, adding a base such as potassium
carbonate, sodium hydrogen carbonate, cesium carbonate,
triethylamine, diisopropylethylamine, morpholine, pyridine and the
like in a solvent such as N,N-dimethylformamide, acetonitrile,
tetrahydrofuran, chloroform, ethyl acetate, methylene chloride,
toluene and the like.
Step 4
[0399] Compound [I-2-4] can be obtained by removing
hydroxyl-protecting group R.sup.11b of compound [I-2-3] according
to a conventional method. For example, when R.sup.11b is a benzyl
group, compound [I-2-4] can be obtained by hydrogenation under room
temperature to heating conditions under a hydrogen atmosphere at
normal pressure to under pressurization conditions in the presence
of a catalyst such as palladium carbon, palladium hydroxide,
platinum oxide, platinum carbon, Raney-nickel and the like in
hexane, methanol, ethanol, 2-propanol, tetrahydrofuran,
N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, acetic
acid, water and the like alone or a mixed solvent thereof.
Step 5
[0400] Compound [I-2-5] can be obtained in the same manner as in
production method I-1, step 7, by removing the carboxyl-protecting
group of compound [1-2-4].
Production Method 1-3
##STR00040##
[0401] wherein even when R.sup.2 and R.sup.3 of [I-3-1] and [I-3-2]
are other than the defined substituents, they can be used as long
as the defined substituents can be finally obtained by appropriate
substituent conversion, and other symbols are as defined above.
Step 1
[0402] Compound [I-3-1] can be obtained by introducing substituents
R.sup.2 and R.sup.3 or a precursor thereof into compound [I-1-11]
in the same manner as in production method I-2, step 1. For
example, when an alkenyl group is introduced as a precursor of
R.sup.2 and R.sup.3, compound [I-3-1] can be obtained by reacting
compound [I-1-11] with alkenylboronic acid in the same manner as in
production method I-2, step 1.
Step 2
[0403] Compound [I-3-2] can be obtained by deprotection of
R.sup.11b of compound [I-3-1] in the same manner as in production
method I-2, step 4.
Step 3
[0404] Compound [I-3-3] can be obtained by reacting compound
[I-3-2] with a glycine derivative represented by H.sub.2NC(R.sup.4)
(R.sup.5)COOH. For example, compound [I-3-3] can be obtained by
reacting compound [I-3-2] with a sodium salt of glycine derivative
at room temperature to under heating conditions in hexane,
chloroform, methylene chloride, toluene, 1,4-dioxane,
tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol,
2-propanol, 2-methoxyethanol, dimethyl sulfoxide,
N,N-dimethylformamide, acetonitrile, water and the like alone or a
mixed solvent thereof.
Production Method I-4
##STR00041##
[0405] wherein even when R.sup.3 of [I-4-2] and [I-4-3] is other
than the defined substituents, it can be used as long as the
defined substituents can be finally obtained by appropriate
substituent conversion, and other symbols are as defined above.
Step 1
[0406] Compound [I-4-1] can be obtained by stirring compound
[I-1-11] under low temperature to heating conditions in the
presence of a palladium catalyst such as
[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride,
tetrakis(triphenylphosphine)palladium,
bis(triphenylphosphine)palladium(II) dichloride, palladium
acetate-triphenylphosphine and the like and a reducing agent such
as tri-n-butyltin hydride and the like in hexane, chloroform,
methylene chloride, ethyl acetate, benzene, toluene,
1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethyl ether,
acetonitrile, water and the like alone or a mixed solvent
thereof.
Step 2
[0407] Compound [I-4-2] can be obtained by substitution of
X.sup.11b of compound [I-4-1] by R.sup.3 or a precursor thereof in
the same manner as in production method 1-2, step 1.
Step 3
[0408] Compound [I-4-3] can be obtained by deprotection of
R.sup.11b of compound [I-4-2] in the same manner as in production
method I-2, step 4.
Step 4
[0409] Compound [I-4-4] can be obtained by reacting compound
[I-4-3] with a glycine derivative represented by H.sub.2NC(R.sup.4)
(R.sup.5)COOH or a salt with a metal species thereof in the same
manner as in production method I-3, step 3.
Production Method I-5
##STR00042##
[0410] wherein each symbol is as defined above.
Step 1
[0411] Compound [I-5-1] can be obtained by introducing substituent
R.sup.3 into compound [I-1-10] according to a conventional method.
For example, when R.sup.3 is a chloro group, compound [I-5-1] can
be obtained by reacting compound [I-1-10] with a chlorinating agent
such as hexachloroethane and the like under low temperature
conditions in the presence of an organic metal reagent such as
n-butyllithium, lithium hexamethyl disilazide, sodium
bis(trimethylsilyl)amide, potassium hexamethyl disilazide, lithium
diisopropylamide, tert-butoxide and the like in hexane, benzene,
toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane and the like
alone or a mixed solvent thereof.
Step 2
[0412] Compound [I-5-2] can be obtained by substituting substituent
X.sup.11b of compound [I-5-1] by substituent R.sup.2 or a precursor
thereof in the same manner as in production method I-2, step 1.
Step 3
[0413] Compound [I-5-3] can be obtained by deprotection of
R.sup.11b of compound [I-5-2] in the same manner as in production
method I-2, step 4.
Step 4
[0414] Compound [I-5-4] can be obtained by reacting compound
[I-5-3] with a glycine derivative represented by H.sub.2NC(R.sup.4)
(R.sup.5)COOH or a salt with a metal species thereof in the same
manner as in production method I-3, step 3.
Production Method I-6
##STR00043## ##STR00044##
[0415] wherein R.sup.16a is a hydroxyl-protecting group such as an
acetyl group, a benzyl group, a methyl group, an ethyl group, an
isopropyl group, a trimethylsilyl group, a triethylsilyl group, a
tert-butyldimethylsilyl group, a triisopropylsilyl group, a
tert-butyldiphenylsilyl group and the like, R.sup.16b and R.sup.16c
are each a carboxyl-protecting group such as a methyl group, an
ethyl group, a benzyl group, a tert-butyl group and the like,
X.sup.16a is a halogen atom such as a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like, or a leaving
group such as a p-toluenesulfonyloxy group, a methanesulfonyloxy
group, a trifluoromethanesulfonyloxy group and the like, and other
symbols are as defined above. Even when R.sup.2 of [1-6-4] to
[1-6-10] are other than the defined substituents, they can be used
as long as the defined substituents can be finally obtained by
appropriate substituent conversion.
Step 1
[0416] Compound [I-6-2] can be obtained by introducing a hydroxyl
group protected by a protecting group R.sup.16a into compound
[I-6-1] in the same manner as in production method I-1, step 3.
Step 2
[0417] Compound [I-6-3] can be obtained by introducing a carboxyl
group protected by a protecting group R.sup.16b into compound
[I-6-2] in the same manner as in production method I-1, step 1.
Step 3
[0418] Compound [I-6-4] can be obtained by introducing substituent
R.sup.2 or a precursor thereof into compound [I-6-3] in the same
manner as in production method I-2, step 1.
Step 4
[0419] Compound [I-6-5] can be obtained from compound [I-6-4] in
the same manner as in production method I-1, step 4.
Step 5
[0420] Compound [I-6-6] can be obtained from compound [I-6-5] in
the same manner as in production method I-1, step 5.
Step 6
[0421] Compound [I-6-7] can be obtained from compound [I-6-6J in
the same manner as in production method I-1, step 6.
Step 7
[0422] Compound [I-6-8] can be obtained by removing the
carboxyl-protecting group of compound [I-6-7] in the same manner as
in production method I-1, step 7.
Step 8
[0423] Compound [I-6-9] can be obtained by condensing compound
[I-6-8] with a glycine derivative represented by H.sub.2NC
(R.sup.4) (R.sup.5)COOR.sup.16c in the same manner as in production
method I-2, step 3.
Step 9
[0424] Compound [I-6-10] can be obtained by removing the
hydroxyl-protecting group R.sup.16a of compound [I-6-9] in the same
manner as in production method I-2, step 4.
Step 10
[0425] Compound [I-6-11] can be obtained by removing the
carboxyl-protecting group of compound [I-6-10] in the same manner
as in production method I-1, step 7.
Production Method I-7
##STR00045##
[0426] wherein R.sup.17a is a carboxyl-protecting group such as a
methyl group, an ethyl group, a benzyl group, a tert-butyl group
and the like, X.sup.17a is a halogen atom such as a fluorine atom,
a chlorine atom, a bromine atom, an iodine atom and the like, or a
leaving group such as a p-toluenesulfonyloxy group, a
methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and
the like.
Step 1
[0427] Compound [I-7-2] can be obtained by reacting compound
[I-7-1] with cyanamide in the presence of an organic metal reagent
such as nickel(II) acetylacetonate and the like under low
temperature to heating conditions in hexane, ethyl acetate,
chloroform, methylene chloride, toluene, 1,4-dioxane,
tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol,
2-propanol, dimethyl sulfoxide, N,N-dimethylformamide,
N-methyl-2-pyrrolidone, acetonitrile, water and the like alone or a
mixed solvent thereof.
Step 2
[0428] Compound [I-7-3] can be obtained by converting the hydroxyl
group of compound [I-7-2] to a leaving group according to a
conventional method. For example, when the leaving group X.sup.17a
is a chlorine atom, compound [I-7-3] can be obtained by
chlorinating compound [I-7-2] with thionyl chloride, oxalyl
chloride, triphosgene, phosphorus pentachloride, phosphorus
oxychloride and the like under low temperature to heating
conditions in hexane, ethyl acetate, acetone, chloroform, methylene
chloride, toluene, 1,4-dioxane, tetrahydrofuran,
1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl
sulfoxide, N,N-dimethylformamide, 2-pyrrolidone, acetonitrile and
the like alone or a mixed solvent thereof or without solvent in the
presence of, where necessary, a base such as triethylamine,
pyridine, 4-(dimethylamino)pyridine, N-methylmorpholine,
diisopropylethylamine, tetramethylethylenediamine and the like and,
where necessary, N,N-dimethylformamide.
Step 3
[0429] Compound [I-7-4] can be obtained by reacting compound
[I-7-3] with N,N-dimethylformamide dialkyl acetal under low
temperature to heating conditions in ethyl acetate, chloroform,
toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane,
methanol, ethanol, 2-propanol, dimethyl sulfoxide,
N,N-dimethylformamide, acetonitrile and the like alone or a mixed
solvent thereof, and then with hydroxylamine or a hydrochloride
thereof.
Step 4
[0430] Compound [I-7-5] can be obtained by subjecting compound
[I-7-4] to a dehydrating reaction using polyphosphoric acid,
thionyl chloride, phosphorus oxychloride, p-toluenesulfonyl
chloride, acetic anhydride, acetyl chloride, trifluoroacetic
anhydride and the like under low temperature to high temperature
conditions in hexane, ethyl acetate, acetone, chloroform, toluene,
1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl
sulfoxide, N,N-dimethylformamide, acetonitrile and the like alone
or a mixed solvent thereof.
Production Method I-8
##STR00046##
[0431] wherein R.sup.18a is a hydroxyl-protecting group such as an
acetyl group, a benzyl group, a methyl group, an ethyl group, an
isopropyl group, a trimethylsilyl group, a triethylsilyl group, a
tert-butyldimethylsilyl group, a triisopropylsilyl group, a
tert-butyldiphenylsilyl group and the like, R.sup.18b is a
carboxyl-protecting group such as methyl group, an ethyl group, a
benzyl group, a tert-butyl group and the like, and other symbols
are as defined above.
Step 1
[0432] Compound [I-8-1] can be obtained by introducing substituent
R.sup.2 or a precursor thereof into compound [I-7-5] according to a
conventional method in the same manner as in production method I-2,
step 1.
Step 2
[0433] Compound [I-8-2] can be obtained by introducing a hydroxyl
group protected by a protecting group represented by R.sup.18a into
compound [I-8-1]. For example, when a hydroxyl group protected by a
methyl group is introduced, compound [I-8-2] can be obtained by
reacting compound [I-8-1] with sodium methoxide under low
temperature to heating conditions in hexane, dimethyl sulfoxide,
N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane, toluene, methanol, water and the like alone or
a mixed solvent thereof, or with a base such as triethylamine,
potassium tert-butoxide, sodium methoxide, potassium carbonate,
sodium hydride, n-butyllithium, lithium diisopropylamide and the
like under low temperature to heating conditions in methanol alone
or a mixed solvent with hexane, dimethyl sulfoxide,
N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane, toluene and the like.
Step 3
[0434] Compound [I-8-3] can be obtained by removing the
carboxyl-protecting group of compound [I-8-2] in the same manner as
in production method I-1, step 7.
Step 4
[0435] Compound [I-8-4] can be obtained by condensing compound
[I-8-3] with a glycine derivative represented by H.sub.2NC
(R.sup.4) (R.sup.5) COOR.sup.18b in the same manner as in
production method I-2, step 3.
Step 5
[0436] Compound [I-8-5] can be obtained by removing the
hydroxyl-protecting group R.sup.18a and the carboxyl-protecting
group R.sup.18b of compound [I-8-4] according to a conventional
method. For example, when R.sup.18a is a methyl group and R.sup.18b
is a tert-butyl group, compound [I-8-5] can be obtained by stirring
compound [I-8-4] at room temperature to under heating conditions in
the presence of an acid such as p-toluenesulfonic acid,
methanesulfonic acid, boron trifluoride, boron trifluoride-diethyl
ether complex, boron trichloride, boron tribromide, hydrogen
chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic
acid, trifluoroacetic acid and the like in hexane, ethyl acetate,
acetone, chloroform, methylene chloride, ethyl acetate, toluene,
1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran,
1,2-dimethoxyethane, methanol, ethanol, isopropanol, dimethyl
sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide,
acetonitrile, acetic acid, water and the like alone or a mixed
solvent thereof.
Production Method I-9
##STR00047##
[0437] wherein R.sup.19a is a carboxyl-protecting group such as a
methyl group, an ethyl group, a benzyl group, a tert-butyl group
and the like, R.sup.19b is a metal species forming a salt with
carboxylic acid or phenol, such as lithium, sodium, calcium etc.,
and other symbols are as defined above.
Step 1
[0438] Compound [I-9-1] can be obtained by removing the
carboxyl-protecting group of compound [I-8-1] in the same manner as
in production method I-1, step 7.
Step 2
[0439] Compound [I-9-2] can be obtained by condensing compound
[I-9-1] with a glycine derivative represented by H.sub.2NC(R.sup.4)
(R.sup.5)COOR.sup.19a in the same manner as in production method
I-2, step 3.
Step 3
[0440] Compound [I-9-3] can be obtained by reacting compound
[I-9-2] with a base. For example, when R.sup.19b is sodium,
compound [I-9-3] can be obtained by reacting compound [I-9-2] with
sodium hydroxide at room temperature to under heating conditions in
dimethyl sulfoxide, N,N-dimethylformamide, dimethylacetamide,
acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,
toluene, methanol, ethanol, 2-methoxyethanol, 2-ethoxyethanol,
water and the like alone or a mixed solvent thereof.
Step 4
[0441] Compound [1-9-4] can be obtained by reacting compound
[I-9-3] with an acid such as acetic acid, p-toluenesulfonic acid,
methanesulfonic acid, trifluoroacetic acid, hydrogen chloride,
hydrogen bromide, phosphoric acid, sulfuric acid and the like under
low temperature to heating conditions in dimethyl sulfoxide,
N,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran,
1,4-dioxane, 1,2-dimethoxyethane, toluene, methanol, ethanol,
2-methoxyethanol, 2-ethoxyethanol, water and the like alone or a
mixed solvent thereof.
Production Method II-1
##STR00048## ##STR00049##
[0442] wherein R.sup.21a is a hydroxyl-protecting group such as a
benzyl group, an acetyl group, a methyl group, an ethyl group, an
isopropyl group, a trimethylsilyl group, a triethylsilyl group, a
tert-butyldimethylsilyl group, a triisopropylsilyl group, a
tert-butyldiphenylsilyl group and the like, R.sup.21b is a
carboxyl-protecting group such as methyl group, an ethyl group, a
benzyl group, a tert-butyl group and the like, and other symbols
are as defined above. Even when R.sup.2 of [II-1-8] to [II-1-9] are
other than the defined substituents, they can be used as long as
the defined substituents can be finally obtained by appropriate
substituent conversion.
Step 1
[0443] Compound [II-1-2] can be, obtained by reacting compound
[II-1-1] with 2,5-hexanedione under low temperature to heating
conditions in the presence of an acid such as p-toluenesulfonic
acid, methanesulfonic acid, boron trifluoride, boron trichloride,
boron tribromide, aluminum trichloride, hydrogen chloride, hydrogen
bromide, phosphoric acid, sulfuric acid, sulfamic acid, acetic
acid, trifluoroacetic acid and the like in hexane, chloroform,
methylene chloride, ethyl acetate, methanol, ethanol, 2-propanol,
toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane,
dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, water and
the like alone or a mixed solvent thereof.
Step 2
[0444] Compound [II-1-3] can be obtained by introducing a hydroxyl
group protected by a protecting group represented by R.sup.21a into
compound [II-1-2] in the same manner as in production method I-1,
step 3.
Step 3
[0445] Compound [II-1-4] can be obtained by stirring compound
[II-1-3] under low temperature to heating conditions in the
presence of a base such as triethylamine, potassium tert-butoxide,
potassium carbonate, sodium hydride, lithium diisopropylamide and
the like and hydroxylammonium chloride in methanol, ethanol,
2-propanol, dimethyl sulfoxide, N,N-dimethylformamide,
acetonitrile, water and the like alone or a mixed solvent
thereof.
Step 4
[0446] Compound [II-1-4] is reacted with N,N-dimethylformamide
dimethyl acetal at room temperature to under heating conditions in
ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran,
1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl
sulfoxide, N,N-dimethylformamide, acetonitrile and the like alone
or a mixed solvent thereof to give a compound, which is reacted
with hydroxylamine or a salt thereof in the presence of a base such
as triethylamine, diisopropylethylamine, morpholine, pyridine and
the like under low temperature to high temperature conditions in
hexane, ethyl acetate, acetone, chloroform, toluene, 1,4-dioxane,
tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol,
2-propanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile
and the like alone or a mixed solvent thereof, and reacted with
polyphosphoric acid or hydroxylamine-O-sulfonic acid, whereby
compound [II-1-5] can be obtained.
Step 5
[0447] Compound [II-1-6] can be obtained by introducing a carboxyl
group into compound [II-1-5] in the same manner as in production
method I-1, step 1.
Step 6
[0448] Compound [II-1-7] can be obtained by introducing a
protecting group R.sup.21b into the carboxyl group of compound
[II-1-6] according to a conventional method. For example, when
R.sup.21b is an ethyl group, compound [II-1-7] can be obtained by
reacting compound [II-1-6] with N,N-dimethylformamide diethyl
acetal at room temperature to under heating conditions in hexane,
chloroform, methylene chloride, ethyl acetate, toluene,
1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl
sulfoxide, N,N-dimethylformamide, acetonitrile and the like alone
or a mixed solvent thereof.
Step 7
[0449] Compound [II-1-8] can be obtained by introducing a
substituent R.sup.2 or a precursor thereof into compound [II-1-7]
according to a conventional method. For example, when a
tert-butylacetylene group is introduced, compound [II-1-8] can be
obtained by reacting compound [II-1-7] with tert-butylacetylene at
room temperature to under heating conditions in the presence of a
palladium catalyst such as
[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride,
tetrakis(triphenylphosphine)palladium,
bis(triphenylphosphine)palladium(II) dichloride, palladium
acetate-triphenylphosphine and the like, a base such as potassium
acetate, potassium carbonate, potassium hydrogen carbonate, sodium
hydrogen carbonate, potassium phosphate, triethylamine,
diisopropylethylamine, sodium hydrogenphosphate, cesium carbonate
and the like and copper iodide in hexane, N,N-dimethylformamide,
N,N-dimethylacetamide, acetonitrile, 1,2-dimethoxyethane,
tetrahydrofuran, 1,4-dioxane, toluene, water and the like alone or
a mixed solvent thereof.
Step 8
[0450] Compound [II-1-9] can be obtained by deprotection of the
hydroxyl-protecting group R.sup.21a of compound [II-1-8] in the
same manner as in production method 1-2, step 4.
Step 9
[0451] Compound [II-1-10] can be obtained from compound [II-1-9] in
the same manner as in production method I-3, step 3.
[0452] In this production method, a production method when R.sup.1
is a hydrogen atom has been described. When R.sup.1 is the
aforementioned substituent and other than a hydrogen atom,
N,N-dimethylformamide dimethyl acetal substituted by a desired
substituent may be used instead of N,N-dimethylformamide dimethyl
acetal in step 4, and step 5 and the following can be performed by
a method similar to the method described in this production
method.
[0453] Production method III-1
##STR00050## ##STR00051##
wherein R.sup.31a and R.sup.31d are each a carboxyl-protecting
group such as a methyl group, an ethyl group, a benzyl group, a
tert-butyl group and the like, R.sup.31b and R.sup.31c are each an
amino-protecting group such as a benzyloxycarbonyl group, a
tert-butoxycarbonyl group, a benzyl group and the like, X.sup.31a
and X.sup.31b are each a halogen atom such as a fluorine atom, a
chlorine atom, a bromine atom, an iodine atom and the like, a
leaving group such as a p-toluenesulfonyloxy group, a
methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and
the like, and other symbols are as described above.
Step 1
[0454] Compound [III-1-2] can be obtained by introducing a leaving
group X.sup.31b according to a conventional method into compound
[III-1-1] obtained by deprotecting R.sup.11b of compound [I-1-4] in
the same manner as in production method I-2, step 4. For example,
when X.sup.31b is a bromine atom, compound [III-1-2] can be
obtained by reacting compound [III-1-1] with bromine or
N-bromosuccinimide under low temperature to heating conditions in
hexane, chloroform, methylene chloride, ethyl acetate, toluene,
tetrahydrofuran, 1,4-dioxane, acetonitrile, water and the like
alone or a mixed solvent thereof.
Step 2
[0455] Compound [III-1-3] can be obtained by introducing R.sup.31b
into compound [III-1-2] according to a conventional method. For
example, when R.sup.31b is a benzyl group, compound [III-1-3] can
be obtained by reacting compound [III-1-2] with benzyl chloride or
benzyl bromide in the presence of a base such as potassium
carbonate, potassium tert-butoxide, sodium hydride, cesium
carbonate and the like in ethyl acetate, chloroform, toluene,
1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl
sulfoxide, N,N-dimethylformamide, acetonitrile, water and the like
alone or a mixed solvent thereof.
Step 3 and Step 4
[0456] [III-1-6] can be obtained by deprotecting R.sup.31a of
compound [III-1-3] in the same manner as in production method I-1,
step 7, converting the compound to acid chloride according to a
conventional method, reacting the acid chloride with a glycine
derivative represented by H.sub.2NC(R.sup.4) (R.sup.5)COOR.sup.31d
in the presence of a base such as triethylamine,
diisopropylethylamine, pyridine and the like under low temperature
to heating conditions in hexane, chloroform, methylene chloride,
ethyl acetate, toluene, tetrahydrofuran and the like alone or a
mixed solvent thereof to give compound [III-1-4], and reacting the
compound with compound [III-1-5] under low temperature to heating
conditions in the presence of a base such as triethylamine,
diisopropylethylamine, pyridine and the like in hexane, chloroform,
methylene chloride, ethyl acetate, toluene, tetrahydrofuran,
1,4-dioxane and the like alone or a mixed solvent thereof.
Step 5
[0457] Compound [III-1-7] can be obtained from compound [III-1-6]
in the same manner as in production method I-2, step 1.
Step 6
[0458] Compound [III-1-8] can be obtained by deprotection of
R.sup.31b of compound [III-1-7] in the same manner as in production
method I-2, step 4.
Step 7
[0459] Compound [III-1-9] can be obtained by removing the
amino-protecting group R.sup.31c of compound [III-1-8] according to
a conventional method. For example, when R.sup.31c is a
tert-butoxycarbonyl group, compound [III-1-9] can be obtained by
stirring under low temperature to room temperature conditions in
the presence of an acid such as hydrogen chloride, sulfuric acid,
hydrogen bromide, phosphoric acid, acetic acid, trifluoroacetic
acid and the like in hexane, chloroform, methylene chloride, ethyl
acetate, toluene, methanol, ethanol, 2-propanol, tetrahydrofuran,
1,4-dioxane, acetonitrile, water and the like alone or a mixed
solvent thereof.
Step 8
[0460] Compound [III-1-10] can be obtained from compound [III-1-9]
in the same manner as in production method I-1, step 5.
Step 9
[0461] Compound [III-1-11] can be obtained by removing the
carboxyl-protecting group of compound [III-1-10] in the same manner
as in production method I-1, step 7.
Production Method III-2
##STR00052##
[0462] wherein R.sup.32a is a carboxyl-protecting group such as a
methyl group, an ethyl group, a benzyl group, a tert-butyl group
and the like, and other symbols are as defined above.
Step 1
[0463] Compound [III-2-1] can be obtained from compound [I-6-5] in
the same manner as in production method I-1, step 5.
Step 2
[0464] Compound [III-2-2] can be obtained by removing the
carboxyl-protecting group of compound [III-2-1] in the same manner
as in production method I-1, step 7.
Step 3
[0465] Compound [III-2-3] can be obtained by condensing compound
[III-2-2] with a glycine derivative represented by
H.sub.2NC(R.sup.4) (R.sup.5)COOR.sup.32a in the same manner as in
production method I-2, step 3.
Step 4
[0466] Compound [III-2-4] can be obtained by deprotection of
R.sup.16a of compound [III-2-3] in the same manner as in production
method I-2, step 4.
Step 5
[0467] Compound [III-2-5] can be obtained by removing the
carboxyl-protecting group of compound [III-2-4] in the same manner
as in production method I-1, step 7.
Production Method IV-1
##STR00053##
[0468] wherein R.sup.41a is a hydroxyl-protecting group such as an
acetyl group, a benzyl group, a methyl group, an ethyl group, an
isopropyl group, a trimethylsilyl group, a triethylsilyl group, a
tert-butyldimethylsilyl group, a triisopropylsilyl group, a
tert-butyldiphenylsilyl group and the like, R.sup.41b is a
carboxyl-protecting group such as a methyl group, an ethyl group, a
benzyl group, a tert-butyl group and the like, X.sup.41a and
X.sup.41b are each a halogen atom such as a chlorine atom, a
bromine atom, an iodine atom and the like, a leaving group such as
a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a
trifluoromethanesulfonyloxy group, a p-toluenesulfonyl group, a
methanesulfonyl group and the like, and other symbols are as
defined above.
Step 1
[0469] Compound [IV-1-2] can be obtained by converting the leaving
group X.sup.41a of compound [IV-1-1] to a formyl group according to
a conventional method. Compound [IV-1-2] can be obtained by
reacting compound [IV-1-1] with an organic metal reagent such as
n-butyllithium, sec-butyllithium, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide,
potassium bis(trimethylsilyl)amide, lithium amide, sodium amide and
the like under low temperature conditions in hexane, benzene,
toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane and the like
alone or a mixed solvent thereof, and then with
N,N-dimethylformamide.
Step 2 and Step 3
[0470] Compound [IV-1-4] can be obtained by reacting compound
[IV-1-2] with hydrazine having a leaving group X.sup.41b under room
temperature to under heating conditions in ethyl acetate,
chloroform, toluene, 1,4-dioxane, tetrahydrofuran,
1,2-dimethoxyethane, methanol, ethanol, isopropanol, dimethyl
sulfoxide, N,N-dimethylformamide, acetonitrile and the like alone
or a mixed solvent thereof, then adding a base such as morpholine,
piperidine, pyrrolidine and the like, and stirring the mixture.
Step 4
[0471] Compound [IV-1-5] can be obtained from compound [IV-1-4] in
the same manner as in production method I-1, step 1.
Step 5
[0472] Compound [IV-1-6] can be obtained by condensing compound
[IV-1-5] with a glycine derivative in the same manner as in
production method I-2, step 3.
Step 6
[0473] Compound [IV-1-7] can be obtained by deprotection of
R.sup.41a of compound [IV-1-6] in the same manner as in production
method I-2, step 4.
Step 7
[0474] Compound [IV-1-8] can be obtained by removing the
carboxyl-protecting group of compound [IV-1-7] in the same manner
as in production method I-1, step 7.
[0475] In this production method, a production method when R.sup.1
is a hydrogen atom has been described. When R.sup.1 is the
aforementioned substituent and other than a hydrogen atom,
N,N-dimethylformamide substituted by a desired substituent may be
used instead of N,N-dimethylformamide in step 1, and step 2 and the
following can be performed by a method similar to the method
described in this production method.
EXAMPLES
[0476] Now the production method of the compound of the present
invention or a pharmaceutically acceptable salt thereof, or a
solvate thereof is specifically explained by way of Examples.
However, the present invention is not limited by the Examples.
Example 1
Production of
{[5-(4-fluoro-3-trifluoromethylphenyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyr-
idine-8-carbonyl]amino}acetic acid hydrochloride
Step 1-1
##STR00054##
[0478] Under a nitrogen stream, diisopropylamine (198 ml) and
tetrahydrofuran (1000 ml) were mixed, and n-butyllithium (2.76M,
500 ml) was added dropwise under cooling in dry ice/hexane bath.
After stirring in the dry ice/hexane bath for 1 hr,
2,4-dichloropyridine was added dropwise. After stirring under
cooling in the dry ice/hexane bath for 1 hr, carbon dioxide was
blown until the temperature rise ceased while preventing a
temperature of not less than -60.degree. C. Carbon dioxide was
further blown for 30 min under cooling in the dry ice/hexane bath,
and 4N hydrochloric acid (1000 ml) was added dropwise. The aqueous
layer was extracted twice with ethyl acetate (each 1000 ml, 500
ml). The organic layers were combined, dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The obtained
solid was slurried in hexane to give the compound described in the
above-mentioned scheme (243 g, 96%).
[0479] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 7.74 (1H, d, J=5.6 Hz),
8.47 (1H, d, J=5.6 Hz), 14.53 (1H, br s).
Step 1-2
##STR00055##
[0481] The compound (234 g) obtained in step 1-1 and
tetrahydrofuran (1200 ml) were mixed, and boron trifluoride-diethyl
ether complex (8 ml) was added. Then, tert-butyl
2,2,2-trichloroacetimidate (361 ml) was added dropwise under
ice-cooling. To this reaction mixture were added saturated aqueous
sodium hydrogen carbonate solution (1200 ml) and water (1200 ml),
and the aqueous layer was extracted with ethyl acetate (1200 ml).
The organic layer was washed with saturated brine, dried over
sodium sulfate, filtered, and concentrated under reduced pressure.
Hexane (1800 ml) was added to the obtained residue. Insoluble
material was filtered off, and the filtrate was concentrated under
reduced pressure to give the compound described in the
above-mentioned scheme (326 g) as a crude product.
[0482] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.63 (9H, s), 7.31 (1H, d,
J=5.2 Hz), 8.31 (1H, d, J=5.2 Hz).
Step 1-3
##STR00056##
[0484] Under a nitrogen stream, sodium hydride (60% oil suspension)
(58 g) and N,N-dimethylformamide (1000 ml) were mixed under
ice-cooling. The compound (326 g) obtained in step 1-2 was
dissolved in N,N-dimethylformamide (300 ml) and added thereto. To
this mixture was added a mixture of benzyl alcohol (136 ml) and
N,N-dimethylformamide(200 ml). After stirring under ice-cooling for
15 min, sodium hydride (60% oil suspension) (5.2 g) was added.
After stirring under ice-cooling for 20 min more, water (3000 ml)
was added and the precipitated solid was filtered, and the filtrate
was dried under reduced pressure at 50.degree. C. overnight. The
solid was purified by column chromatography (eluent: hexane/ethyl
acetate=10/1-ethyl acetate alone). The obtained solid was further
slurried in hexane to give the object product. The filtrate at this
time was concentrated, purified by column chromatography, and
slurried in hexane to give the object product. They were combined
to give the compound described in the above-mentioned scheme (334
g, 83% yield).
[0485] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.55 (9H, s), 5.17 (2H,
s), 6.83 (1H, d, J=6.0 Hz), 7.32-7.42 (5H, m), 8.24 (1H, d, J=6.0
Hz).
Step 1-4
##STR00057##
[0487] The compound (167 g) obtained in step 1-3, hydrazine
monohydrate (127 ml) and 1,4-dioxane (1200 ml) were mixed, and the
reaction mixture was stirred at 94.degree. C. for 17 hr. After
cooling to room temperature, ethyl acetate (1700 ml) was added, and
the mixture was washed successively with saturated aqueous sodium
hydrogen carbonate solution (500 ml)/water (500 ml), saturated
aqueous sodium hydrogen carbonate solution (250 ml)/water (250 ml),
and saturated aqueous sodium hydrogen carbonate solution (200
ml)/water (200 ml). The organic layer was dried over sodium
sulfate, filtered, and concentrated under reduced pressure. By
performing the operation twice, the compound described in the
above-mentioned scheme (266 g) was obtained as a crude product.
[0488] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42 (9H, s), 3.98 (2H, br
s), 5.09 (2H, s), 6.32 (1H, d, J=5.6 Hz), 7.28-7.45 (5H, m), 7.96
(1H, br s), 8.08 (1H, d, J=5.6 Hz).
Step 1-5
##STR00058##
[0490] The compound (266 g) obtained in the same manner as in step
1-4 and trimethyl orthoformate (1000 ml) were mixed,
p-toluenesulfonic acid monohydrate (80 g) was added, and the
mixture was stirred at 56.degree. C. for 1 hr. The reaction mixture
was concentrated under reduced pressure, and the obtained residue
was slurried in hexane/ethyl acetate=2/1. Furthermore, the residue
was slurried in saturated aqueous sodium hydrogen carbonate
solution/water=1/1 to give the compound described in the
above-mentioned scheme (209 g, 76%).
[0491] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 1.49 (9H, s), 5.36 (2H,
s), 7.22 (1H, d, J=7.6 Hz), 7.32-7.50 (5H, m), 8.62 (1H, d, J=7.6
Hz), 9.13 (1H, s).
Step 1-6
##STR00059##
[0493] The compound (200 g) obtained in step 1-5 and ethyl acetate
(600 ml) were mixed, morpholine (160 ml) was added and the mixture
was stirred at 74.degree. C. for 3 hr. The mixture was allowed to
cool to room temperature, and water (600 ml) was added. The aqueous
layer was extracted with ethyl acetate (400 ml), the organic layers
were combined and washed successively with 5% aqueous potassium
hydrogensulfate solution (600 ml) and saturated brine. The organic
layer was dried over sodium sulfate, filtered, and concentrated
under reduced pressure to give the compound described in the
above-mentioned scheme (194 g, 97%).
[0494] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.59 (9H, s), 5.28 (2H,
s), 6.85 (1H, d, J=7.6 Hz), 7.33-7.46 (5H, m), 8.29 (1H, s), 8.50
(1H, d, J=7.6 Hz).
Step 1-7
##STR00060##
[0496] Under a nitrogen stream, the compound (194 g) obtained in
step 1-6 and tetrahydrofuran (600 ml) were mixed under cooling in a
dry ice/hexane bath, and a solution of iodine (151 g) in
tetrahydrofuran (500 ml) was added dropwise. To this mixture was
added dropwise 1.6M lithium bis(trimethylsilyl)amide (788 ml) while
preventing a temperature of not less than -60.degree. C. After
stirring under cooling in a dry ice/hexane bath for 2 hr, 4N
hydrochloric acid-ethyl acetate (315 ml) was added dropwise while
preventing a temperature of not less than -60.degree. C. To this
reaction mixture were added sodium sulfite (76 g), saturated
aqueous ammonium chloride solution (1000 ml), water (800 ml) and
hexane/ethyl acetate=1/1 (1000 ml). The organic layer was washed
successively with saturated aqueous sodium hydrogen carbonate
solution (500 ml) and saturated brine (800 ml), dried over sodium
sulfate, filtered, and concentrated under reduced pressure to give
a crude product. The crude product was slurried in hexane to give
the compound described in the above-mentioned scheme (188 g,
70%).
[0497] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 1.46 (9H, s), 5.39 (2H,
s), 7.33-7.51 (5H, m), 7.87 (1H, s), 8.43 (1H, s).
Step 1-8
##STR00061##
[0499] The compound (60 g) obtained in step 1-7,
4-fluoro-3-(trifluoromethyl)phenylboronic acid (29 g),
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane complex (1:1) (5.4 g), potassium phosphate (113 g)
and 1,2-dimethoxyethane (600 ml) were mixed, and the mixture was
stirred at 80.degree. C. for 1 hr. Water was added to the reaction
mixture, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The obtained solid was purified by column chromatography
(eluent: chloroform/ethyl acetate=10/1) to give a crude product of
the compound described in the above-mentioned scheme. This was
slurried in diisopropyl ether/hexane=1/1 (500 ml) to give the
compound described in the above-mentioned scheme (45 g, 70%).
[0500] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.61 (9H, s), 5.33 (2H,
s), 6.88 (1H, s), 7.35-7.48 (6H, m), 8.04 (1H, dd, J=6.7, 2.1 Hz),
8.11-8.15 (1H, m), 8.31 (1H, s).
Step 1-9
##STR00062##
[0502] The compound (45 g) obtained in step 1-8 and 1,4-dioxane
(450 ml) were mixed, and 4N aqueous sodium hydroxide solution (116
ml) was added at room temperature. After stirring at 100.degree. C.
for 17 hr, the reaction mixture was concentrated under reduced
pressure. Water (450 ml) was added thereto, and the mixture was
neutralized with 6N hydrochloric acid (77 ml) under ice-cooling,
and the precipitated solid was collected by filtration to give the
compound described in the above-mentioned scheme (43 g).
[0503] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 5.51 (2H, s), 7.34-7.38
(1H, m), 7.41-7.45 (2H, m), 7.50-7.52 (2H, m), 7.63 (1H, s), 7.80
(1H, dd, J=10.5, 10 8.9 Hz), 8.40-8.48 (2H, m), 8.48 (1H, s).
Step 1-10
##STR00063##
[0505] The compound (43 g) obtained in step 1-9, glycine ethylester
hydrochloride (15 g), 1-hydroxybenzotriazole hydrate (17 g) and
N,N-dimethylformamide (430 ml) were mixed, and triethylamine(15 ml)
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21
g) were added at room temperature. After stirring at room
temperature for 1 hr, water (860 ml) and saturated aqueous sodium
hydrogen carbonate solution (215 ml) were added, and the
precipitated solid was collected by filtration to give the compound
described in the above-mentioned scheme (43 g, 84%).
[0506] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (3H, t, J=7.1 Hz),
4.28 (2H, q, J=7.1 Hz), 4.35 (2H, d, J=4.8 Hz), 5.47 (2H, s), 6.95
(1H, s), 7.32-7.43 (4H, m), 7.54 (2H, d, J=7.3 Hz), 8.01 (1H, dd,
J=6.4, 2.0 Hz), 8.10-8.14 (1H, m), 8.31 (1H, s), 9.72 (1H, t, J=4.8
Hz).
Step 1-11
##STR00064##
[0508] The compound (43 g) obtained in step 1-10 and
trifluoroacetic acid (430 ml) were mixed and, after stirring at
80.degree. C. for 6 hr, the reaction mixture was concentrated under
reduced pressure. Methanol (86 ml) and water (430 ml) were added to
the residue, and the mixture was stirred at room temperature for 30
min, and the precipitated solid was collected by filtration. This
was purified by column chromatography (eluent: chloroform/ethyl
acetate=10/1) to give the compound described in the above-mentioned
scheme (28 g, 79%).
[0509] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.34 (3H, t, J=7.3 Hz),
4.30 (2H, q, J=7.3 Hz), 4.33 (2H, d, J=5.2 Hz), 6.87 (1H, s), 7.41
(1H, dd, J=9.7, 8.9 Hz), 8.16-8.20 (1H, m), 8.24 (1H, dd, J=6.9,
2.4 Hz), 8.26 (1H, s), 10.15 (1H, t, J=5.2 Hz), 14.13 (1H, s).
Step 1-12
##STR00065##
[0511] The compound (27 g) obtained in step 1-11 and 2-propanol
(540 ml) were mixed, and 4N aqueous lithium hydroxide solution (64
ml) was added at room temperature. After stirring at 70.degree. C.
for 1 hr, 6N hydrochloric acid (43 ml) was added. This was allowed
to gradually cool with stirring and crystals were precipitated at
37.degree. C. Water (270 ml) was added and the crystals were
collected by filtration to give the compound described in the
above-mentioned scheme (22 g, 87%).
[0512] .sup.1H-NMR (DMSO-D.sub.6) .delta.:4.24 (2H, d, J=5.6 Hz),
7.30 (1H, s), 7.77 (1H, dd, J=10.5, 9.3 Hz), 8.36-8.40 (1H, m),
8.47 (1H, d, J=6.9 Hz), 8.60 (1H, s), 9.97 (1H, br s), 14.38 (1H,
br s).
[0513] The obtained compound was converted to hydrochloride
according to a conventional method to give the compound of Example
1.
[0514] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 4.25 (d, 2H, J=5.6 Hz),
7.31 (s, 1H), 7.73-7.82 (m, 1H), 8.34-8.43 (m, 1H), 8.43-8.51 (m,
1H), 8.61 (s, 1H), 9.99 (t, 1H, J=5.6 Hz).
Example 2
Production of
[(7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]ac-
etic acid hydrochloride
Step 2-1
##STR00066##
[0516] The compound (5.00 g) obtained in step 1-7, toluene (35 ml)
and phenylacetylene (1.34 ml) were mixed, and
bis(triphenylphosphine)palladium dichloride (0.233 g), copper
iodide (0.063 g) and triethylamine (1.85 ml) were successively
added under ice-cooling. After stirring at room temperature for 2
hr, 5% aqueous ammonia (35 ml) was added to the reaction mixture.
The organic layer was further washed successively with 5% aqueous
ammonia, saturated aqueous ammonium chloride solution and saturated
brine, and dried over anhydrous magnesium sulfate. After
filtration, the filtrate was concentrated under reduced pressure,
and the obtained residue was purified by column chromatography
(eluent: hexane/ethyl acetate=3/1-1/1). The obtained compound was
slurried in hexane to give the compound described in the
above-mentioned scheme (3.84 g, 82%).
[0517] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 1.48 (9H, s), 5.42 (2H,
s), 7.36 (1H, tt, J=7.1, 1.8 Hz),7.40-7.45 (2H, m), 7.48 (2H, dt,
J=7.0, 1.9 Hz), 7.51-7.58 (3H, m), 7.72 (2H,dd, J=7.7, 1.6 Hz),
7.78 (1H, s), 8.49 (1H, s).
Step 2-2
##STR00067##
[0519] The compound (3.84 g) obtained in step 2-1, toluene (29 ml)
and ethyl acetate (9.5 ml) were mixed, a mixture of methanesulfonic
acid (2.34 ml) and ethyl acetate (2.34 ml) was added dropwise over
10 min at room temperature with stirring. After stirring at room
temperature for 3 hr, ethyl acetate (9.5 ml) was added to the
reaction mixture, and the solid was collected by filtration to give
the compound described in the above-mentioned scheme (4.94 g,
98%).
[0520] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 2.38 (6H, s), 5.48 (2H,
s), 7.37 (1H, tt, J=7.2, 1.7 Hz),7.41-7.45 (2H, m), 7.48-7.52 (2H,
m), 7.53-7.62 (3H, m), 7.71-7.75 (2H, m), 7.86 (1H, s), 8.67 (1H,
s).
Step 2-3
##STR00068##
[0522] The compound (4.94 g) obtained in step 2-2 and
N,N-dimethylformamide (30 ml) were mixed at room temperature, and
water (50 ml) was added dropwise at 0.degree. C. over 10 min. The
precipitated solid was collected by filtration to give the compound
described in the above-mentioned scheme (3.20 g, 98%).
[0523] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 5.45 (2H, s), 7.36 (1H,
tt, J=7.4, 2.1 Hz), 7.43 (2H, t, J=7.3 Hz), 7.49 (2H, d, J=7.5 Hz),
7.52-7.60 (3H, m), 7.72 (2H, dd, J=6.7,1.9 Hz), 7.78 (1H, s), 8.51
(1H, s), 13.59 (1H, s).
Step 2-4
##STR00069##
[0525] The compound (3.20 g) obtained in step 2-3 was reacted with
glycine ethyl ester hydrochloride (1.33 g) by a method similar to
Example 1, step 1-10, to give the compound described in the
above-mentioned scheme (3.38 g, 81%).
[0526] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 1.21 (3H, t, J=7.1 Hz),
4.10 (2H, d, J=5.7 Hz), 4.13 (2H, q, J=7.5 Hz), 5.44 (2H, s), 7.34
(1H, tt, J=7.2, 1.7 Hz), 7.38-7.43 (2H, m), 7.52-7.58 (5H, m),
7.71-7.74 (2H, m), 7.75 (1H, s), 8.52 (1H, s), 9.18 (1H, t, J=5.8
Hz).
[0527] Step 2-5
##STR00070##
[0528] To a solution of the compound (3.38 g) obtained in step 2-4
in tetrahydrofuran (34 ml) and methanol (17 ml) was added 5%
palladium carbon (0.34 g), and the mixture was stirred under a
hydrogen atmosphere and normal pressure for 4 hr. The reaction
mixture was filtered through celite, and concentrated under reduced
pressure. The obtained residue was purified by column
chromatography (eluent: chloroform/methanol=20/0-20/1) and slurried
in hexane/diisopropyl ether=1/1 to give the compound described in
the above-mentioned scheme (2.29 g, 83%).
[0529] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 1.23 (3H, t, J=7.2 Hz),
3.12 (2H, t, J=7.8 Hz), 3.41 (2H, t, J=7.9 Hz), 4.17 (2H, q, J=7.1
Hz), 4.29 (2H, d, J=5.7 Hz), 6.82 (1H, s), 7.18-7.32 (5H, m), 8.58
(1H, s), 9.87 (1H, t, J=5.6 Hz), 14.12 (1H, s).
Step 2-6
##STR00071##
[0531] The compound (2.28 g) obtained in step 2-5 was hydrolyzed by
a method similar to step 1-12, and the obtained compound was
converted to hydrochloride according to a conventional method to
give the title compound (2.16 g).
[0532] 1H-NMR (DMSO-D6) .delta.: 3.12 (t, 2H, J=7.8 Hz), 3.41 (t,
2H, J=7.8 Hz), 4.21 (d, 2H, J=5.6 Hz), 6.81 (s, 1H), 7.14-7.33 (m,
5H), 8.60 (s, 1H), 9.85 (t, 1H, J=5.6 Hz).
Example 3
Production of
[(5-butyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic
acid hydrochloride
Step 3-1
##STR00072##
[0534] The compound (0.2 g) obtained in step 1-7,
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane complex (1:1) (0.011 g), butylboronic acid (0.050
g), silver(I) oxide (0.12 g), potassium carbonate (0.15 g) and
tetrahydrofuran (1.6 ml) were mixed, and the mixture was stirred at
80.degree. C. for 40 hr. Insoluble material was filtered off, and
the filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography (eluent: hexane/ethyl
acetate=8/2-6/4) to give the compound described in the
above-mentioned scheme (0.13 g, 77%).
[0535] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 0.91 (t, 3H, J=7.7 Hz),
1.28-1.39 (m, 2H), 1.48 (s, 9H), 1.71-1.81 (m, 2H), 3.11 (t, 2H,
J=7.7 Hz), 5.38 (s, 2H), 7.23 (s, 1H), 7.32-7.51 (m, 5H), 8.39 (s,
1H).
Step 3-2
##STR00073##
[0537] The carboxyl-protecting group of the compound (53.7 g)
obtained in step 3-1 was removed in the same manner as in step 2-2
to give a carboxylic acid form as a mixture (69.8 g, 80%) with
methanesulfonic acid (290 mol %). The mixture was treated in the
same manner as in step 2-3 to give the compound described in the
above-mentioned scheme as a mixture (42.8 g, 99%) with
methanesulfonic acid (50 mol %).
[0538] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 0.91 (t, 3H, J=7.7 Hz),
1.29-1.40 (m, 2H), 1.71-1.80 (m, 2H), 2.34 (s, 1.5H), 3.14 (t, 2H,
J=7.7 Hz), 5.47 (s, 2H), 7.32-7.45 (m, 4H),7.48-7.53 (m, 2H), 8.73
(s, 1H).
Step 3-3
##STR00074##
[0540] By a method similar to step 1-10, the compound (42.8 g)
obtained in step 3-2 was reacted with glycine ethyl ester
hydrochloride (19.3 g) to give the compound described in the
above-mentioned scheme (43.5 g, 92%).
[0541] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (t, 3H, J=7.5 Hz),
1.31 (t, 3H, J=7.1 Hz), 1.34-1.43 (m, 2H), 1.70-1.79 (m, 2H), 3.11
(t, 2H, J=7.5 Hz), 4.26 (q, 2H, J=7.1 Hz), 4.33 (d, 2H, J=5.2 Hz),
5.41 (s, 2H), 6.69 (s, 1H), 7.29-7.55 (m, 5H), 8.28 (s, 1H), 9.77
(t, 1H, J=5.2 Hz).
Step 3-4
##STR00075##
[0543] In the same manner as in step 2-5, the compound described in
the above-mentioned scheme (5.0 g, 90%) was obtained from the
compound (7.2 g) obtained in step 3-3.
[0544] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 0.93 (t, 3H, J=7.5 Hz),
1.22 (t, 3H, J=7.3 Hz), 1.33-1.44 (m, 2H), 1.71-1.81 (m, 2H), 3.09
(t, 2H, J=7.5 Hz), 4.16 (q, 2H, J=7.3 Hz), 4.29 (d, 2H, J=5.6 Hz),
6.85 (s, 1H), 8.54 (s, 1H), 9.88 (br s, 1H), 14.14 (s, 1H).
Step 3-5
##STR00076##
[0546] In the same manner as in step 1-12, the compound described
in the above-mentioned scheme (4.56 g) was obtained from the
compound (4.94 g) obtained in step 3-4.
[0547] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 0.93 (t, 3H, J=7.5 Hz),
1.33-1.44 (m, 2H), 1.71-1.80 (m, 2H), 3.10 (t, 2H, J=7.5 Hz), 4.20
(d, 2H, J=5.2 Hz), 6.85 (s, 1H), 8.55 (s, 1H), 9.84 (br s, 1H),
14.26 (br s, 1H).
Step 3-6
##STR00077##
[0549] The compound (4.56 g) obtained in step 3-5 and 4N
hydrochloric acid/ethyl acetate solution (91 ml) were mixed, and
the mixture was stirred at room temperature for 1.5 hr. The
reaction suspension was concentrated under reduced pressure, hexane
(100 ml) was added to the residue and the mixture was concentrated
twice under reduced pressure. To the residue was added a mixed
solution (100 ml) of diethyl ether/hexane=1/2 and the mixture was
stirred for 30 min. The solid was collected by filtration to give
the title compound (4.88 g, 96%).
[0550] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 0.93 (t, 3H, J=7.5 Hz),
1.34-1.44 (m, 2H), 1.71-1.80 (m, 2H), 3.10 (t, 2H, J=7.5 Hz), 4.21
(d, 2H, J=5.6 Hz), 6.86 (s, 1H), 8.57 (s, 1H), 9.83 (t, 1H, J=5.6
Hz).
Example 4
Production of
[(5,6-diethyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]ac-
etic acid hydrochloride
Step 4-1
##STR00078##
[0552] Under a nitrogen stream, the compound (3.98 g) obtained in
the same manner as in step 1-6 and tetrahydrofuran (40 ml) were
mixed, and a solution of iodine (3.4 g) in tetrahydrofuran (16 ml)
was added dropwise under cooling with dry ice/denatured ethanol. To
this mixture was added dropwise 1M lithium bis(trimethylsilyl)amide
(26.8 ml) over 10 min. After stirring as is for 2.5 hr, the
reaction mixture was poured into a mixture of saturated aqueous
ammonium chloride solution (40 ml) and water (40 ml) under
ice-cooling. To this mixture was added sodium sulfite (1.7 g), and
the organic layer was separated from the mixture. The organic layer
was concentrated under reduced pressure, the obtained residue was
combined with the aqueous layer, and the mixture was extracted
twice with ethyl acetate. The organic layer was washed with
saturated brine (70 ml), dried over sodium sulfate, sodium sulfate
was filtered off, and the filtrate was concentrated under reduced
pressure. The obtained residue was purified by column
chromatography. The obtained purification product was
recrystallized from heptane/chloroform to give the compound
described in the above-mentioned scheme (0.295 g, 4%).
[0553] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (t, 3H, J=7.1 Hz),
4.50 (q, 2H, J=7.1 Hz), 5.22 (s, 2H), 7.36-7.56 (m, 5H), 8.33 (s,
1H).
Step 4-2
##STR00079##
[0555] In the same manner as in Example 1, step 1-8, the compound
described in the above-mentioned scheme (0.019 g, 30%) was obtained
from the compound (0.1 g) obtained in step 4-1.
[0556] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (t, 3H, J=7.1 Hz),
4.50 (q, 2H, J=7.1 Hz), 5.09 (s, 2H), 5.73 (dd, 1H, J=17.7, 1.4
Hz), 5.76 (dd, 1H, J=11.5, 1.4 Hz), 6.05 (dd, 1H, J=11.5, 1.4 Hz),
6.77 (dd, 1H, J=17.7, 11.7 Hz), 6.87 (dd, 1H, J=17.7, 1.2Hz), 7.14
(dd, 1H, J=17.7, 11.5 Hz), 7.35-7.44 (m, 5H), 8.37 (s, 1H).
Step 4-3
##STR00080##
[0558] In the same manner as in Example 2, step 2-5, the compound
described in the above-mentioned scheme (0.020 g, 75%) was obtained
from the compound (0.036 g) obtained in step 4-2.
[0559] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (t, 3H, J=7.5 Hz),
1.36 (t, 3H, J=7.5 Hz), 1.52 (t, 3H, J=7.3 Hz), 2.78 (q, 2H, J=7.5
Hz), 3.25 (q, 2H, J=7.5 Hz), 4.64 (q, 2H,J=7.3 Hz), 8.26 (s, 1H),
13.10 (s, 1H).
Step 4-4
##STR00081##
[0561] The compound (0.020 g) obtained in step 4-3 and
2-methoxyethanol (2 ml) were mixed, and glycine sodium salt (0.030
g) was added. After stirring at 130.degree. C. for 1.5 hr, the
mixture was cooled to room temperature. 1N Hydrochloric acid (0.34
ml) and water (10 ml) were added to the reaction mixture and the
mixture was stirred. The precipitate was collected by filtration
and dried under reduced pressure. To the obtained solid were added
ethyl acetate (1 ml) and 4N hydrochloric acid-ethyl acetate (0.1
ml) and the mixture was stirred at room temperature for 20 min. The
solid was collected by filtration to give the title compound (0.052
mg, 67%).
[0562] .sup.1H-NMR (DMSO-D6) .delta.: 1.15 (t, 3H, J=7.5 Hz), 1.29
(t, 3H, J=7.5 Hz), 2.72 (q, 2H, J=7.5 Hz), 3.20 (q, 2H, J=7.6 Hz),
4.21 (d, 2H, J=5.6 Hz), 8.52 (s, 1H), 9.95 (t, 1H, J=5.6 Hz).
Example 5
Production of
[(7-hydroxy-6-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]ac-
etic acid hydrochloride
Step 5-1
##STR00082##
[0564] The compound (1.31 g) obtained by a method similar to
Example 4, step 4-1, tetrakis(triphenylphosphine)palladium(0)
(0.137 g) and tetrahydrofuran (15 ml) were mixed, and
tri-n-butyltin hydride (0.7 ml) was added under ice-cooling. After
stirring under ice-cooling for 20 min, the mixture was stirred at
room temperature for 20 min, and concentrated under reduced
pressure. The obtained residue was purified by column
chromatography (eluent: hexane/ethyl acetate=10/0-1/1) to give the
compound described in the above-mentioned scheme (0.44 g, 44%).
[0565] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (t, 3H, J=7.2 Hz),
4.51 (q, 2H, J=7.2 Hz), 5.23 (s, 2H), 7.36-7.56 (m, 5H), 8.31 (s,
1H), 8.99 (s, 1H).
Step 5-2
##STR00083##
[0567] In the same manner as in Example 1, step 1-8, the compound
described in the above-mentioned scheme (0.078 g, 109%) was
obtained from the compound (0.070 g) obtained in step 5-1.
[0568] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (t, 3H, J=7.1 Hz),
4.54 (q, 2H, J=7.1 Hz), 5.17 (s, 2H), 7.13 (d, 1H, J=9.3 Hz),
7.29-7.45 (m, 11H), 8.34 (s, 1H), 8.80 (s, 1H).
Step 5-3
##STR00084##
[0570] In the same manner as in Example 2, step 2-5, the compound
described in the above-mentioned scheme (0.037 g, 72%) was obtained
from the compound (0.070 g) obtained in step 5-2.
[0571] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.54 (t, 3H, J=7.2 Hz),
3.00 (s, 4H), 4.66 (q, 2H, J=7.2 Hz), 7.16-7.31 (m, 5H), 8.20 (s,
1H), 8.23 (s, .sup.1H), 13.17 (s, 1H).
[0572] The compound obtained in this step was converted to
hydrochloride in the same manner as in Example 4, step 4-4 and
according to a conventional method to give the title compound.
[0573] 1H-NMR (DMSO-D6) .delta.: 2.93 (s, 4H), 4.22 (d, 2H, J=5.7
Hz), 7.19 (tt, 1H, J=7.1, 1.8 Hz), 7.23-7.31 (m, 4H), 8.50 (s, 1H),
8.78 (s, 1H), 9.97 (s, 1H).
Example 6
Production of
[(5-butyl-6-chloro-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)ami-
no]acetic acid hydrochloride
Step 6-1
##STR00085##
[0575] The compound (200 mg) obtained by a method similar to
Example 4, step 4-1, hexachloroethane (224 mg) and tetrahydrofuran
(4.0 ml) were mixed, and lithium bis(trimethylsilyl)amide (0.473
ml) was added at -78.degree. C. After stirring at -78.degree. C.
for 2 hr, the mixture was slowly warmed to -40.degree. C.
Thereafter, the mixture was added dropwise to saturated aqueous
sodium hydrogen carbonate solution, and ethyl acetate was added.
The organic layer was separated from the mixture, and the aqueous
layer was extracted twice with ethyl acetate. The organic layers
were combined, washed twice with saturated brine, dried over sodium
sulfate, and concentrated under reduced pressure. The concentrated
residue was purified by column chromatography (eluent: hexane/ethyl
acetate=3/1-2/1) to give a crude product (180 mg) containing the
compound described in the above-mentioned scheme as a main
component.
Step 6-2
##STR00086##
[0577] In the same manner as in Example 3, step 3-1, the compound
described in the above-mentioned scheme (71 mg) was obtained from
the compound (180 mg) obtained in step 6-1.
[0578] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 0.94 (3H, t, J=7.5 Hz),
1.28 (3H, t, J=7.1 Hz), 1.37-1.47 (2H, m), 1.68-1.75 (2H, m),
3.32-3.37 (2H, m), 4.37 (2H, q, J=7.1 Hz), 5.19 (2H, s), 7.37-7.52
(5H, m), 8.57 (1H, s).
Step 6-3
##STR00087##
[0580] The compound (70 mg) obtained in step 6-2 and
trifluoroacetic acid (1 ml) were mixed, and the mixture was stirred
at room temperature for 3 hr. To this reaction mixture was added
chloroform and the mixture was concentrated under reduced pressure.
To the concentrated residue was added 4N hydrochloric acid-ethyl
acetate (1 ml) and the mixture was stirred. Hexane (3 ml) was added
and the mixture was stirred. The solid was collected by filtration
to give the compound described in the above-mentioned scheme (50
mg, 83%).
[0581] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 0.92 (3H, t, J=7.3 Hz),
1.31 (3H, t, J=7.1 Hz), 1.37-1.45 (2H, m), 1.62-1.69 (2H, m), 3.17
(2H, t, J=7.7 Hz), 4.35 (2H, q, J=7.1 Hz), 8.69 (1H, s).
Step 6-4
##STR00088##
[0583] In the same manner as in Example 4, step 4-4, the compound
described in the above-mentioned scheme (48 mg, 88%) was obtained
from the compound (50 mg) obtained in step 6-3.
[0584] 1H-NMR (DMSO-D.sub.6) .delta.: 0.93 (t, 3H, J=7.3 Hz),
1.36-1.47 (m, 2H), 1.64-1.72 (m, 2H), 3.15-3.28 (m, 2H), 4.15 (d,
2H, J=2.8 Hz), 8.74 (br s, 1H), 10.20 (br s, 1H).
Example 7
Production of
[(7-hydroxy-2-methyl-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl-
)amino]acetic acid hydrochloride
Step 7-1
##STR00089##
[0586] 2,4,6-Trichloropyridine (50 g) and N,N-dimethylformamide
(400 ml) were mixed, and sodium hydride (60% oil suspension) (11.5
g) was added by portions under ice-cooling. To this mixture was
added dropwise under ice-cooling benzyl alcohol (28 ml) over 40
min, and the mixture was stirred at the same temperature for 3 hr.
Water (550 ml) was added dropwise under ice-cooling and the
resulting solid was collected by filtration to give the compound
described in the above-mentioned scheme (50 g, 72%).
[0587] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.11 (s, 2H), 6.86 (s,
2H), 7.36-7.46 (m, 5H).
Step 7-2
##STR00090##
[0589] Under cooling in a dry ice/acetone bath, tetrahydrofuran
(250 ml) and n-butyllithium (1.65M, 119 ml) were mixed, a solution
of the compound (50 g) obtained in step 7-1 in tetrahydrofuran (110
ml) was added dropwise over 30 min. To this mixture was added
dropwise a solution of di-tert-butyl-dicarbonate (45 ml) in
tetrahydrofuran (100 ml) over 1 hr, and the mixture was stirred at
the same temperature for 30 min. Water (450 ml) was added to quench
the reaction, ethyl acetate (200 ml) was added to separate the
organic layer and the organic layer was washed with water (200 ml)
and saturated brine (200 ml). The organic layer was concentrated
under reduced pressure and the residue was purified by column
chromatography (eluent: hexane/ethyl acetate=50/0-11/1) and the
obtained solid was further slurried in hexane (100 ml) to give the
compound described in the above-mentioned scheme (15.7 g, 31%).
[0590] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.53 (s, 9H), 5.11 (s,
2H), 6.86 (s, 1H), 7.32-7.46 (m, 5H).
Step 7-3
##STR00091##
[0592] The compound (15 g) obtained in step 7-2 and 1,4-dioxane
(150 ml) were mixed, potassium carbonate (18 g), phenylvinylboric
acid (7.1 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloride dichloromethane complex (1:1) (1.8 g) and water (45 ml)
were added and the mixture was stirred at 80.degree. C. for 1.5 hr
with heating. Phenylvinylboric acid (0.64 g) was added and the
mixture was stirred for 1.5 hr. The mixture was cooled to room
temperature, and water, ethyl acetate and saturated brine were
added to separate the organic layer. The organic layer was
concentrated under reduced pressure and the obtained residue was
purified by column chromatography (eluent: chloroform). To the
obtained solid was added isopropyl alcohol (100 ml) and the mixture
was slurried at 70.degree. C. for 0.5 hr and under ice-cooling to
give the compound described in the above-mentioned scheme (11.5 g,
62%).
[0593] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.55 (s, 9H), 5.21 (s,
2H), 6.87 (s, 1H), 7.01 (d, 1H, J=15.9 Hz), 7.30-7.44 (m, 8H), 7.56
(d, 2H, J=7.1 Hz), 7.65 (d, 1H, J=16.1 Hz).
Step 7-4
##STR00092##
[0595] The compound (11.5 g) obtained in step 7-3, ethyl acetate
(120 ml) and 2% platinum-carbon (2.5 g) were mixed, and the mixture
was stirred under a hydrogen atmosphere (3.8 kgf/cm.sup.2) at room
temperature for 23 hr. The reaction mixture was filtered through
celite, and the filtrate was concentrated under reduced pressure to
give the compound described in the above-mentioned scheme (11.5 g,
100%).
[0596] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.55 (s, 9H), 3.02 (br s,
4H), 5.05 (s, 2H), 6.55 (s, 1H), 7.16-7.41 (m, 10H).
Step 7-5
##STR00093##
[0598] In the same manner as in Example 1, step 1-4, the compound
described in the above-mentioned scheme (11.9 g, 104%) was obtained
from the compound (11.5 g) obtained in step 7-4.
[0599] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (s, 9H), 2.92 (t, 2H,
J=8.2 Hz), 3.03 (t, 2H, J=8.2 Hz), 4.05 (br s, 2H), 5.00 (s, 2H),
6.10 (s, 1H), 7.16-7.43 (m, 10H), 8.10 (s, 1H).
Step 7-6
##STR00094##
[0601] The compound (126 mg) obtained in step 7-5,
p-toluenesulfonic acid monohydrate (50 mg) and trimethyl
orthoformate (1 ml) were mixed, toluene (1 ml) was added and the
mixture was heated at 60.degree. C. for 1 hr. The reaction mixture
was added dropwise at room temperature to saturated aqueous sodium
hydrogen carbonate solution, and ethyl acetate was added to
separate the organic layer. The organic layer was concentrated
under reduced pressure and the concentrated residue was purified by
thin layer chromatography (eluent: chloroform/methanol=9:1) to give
the compound described in the above-mentioned scheme (32 mg,
24%).
[0602] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.51 (9H, s), 2.93 (3H,
s), 3.06 (2H, t, J=7.6 Hz), 3.52 (2H, t, J=7.6 Hz), 5.16 (2H, s),
6.72 (1H, s), 7.14-7.48 (10H, m).
Step 7-7
##STR00095##
[0604] In the same manner as in Example 1, step 1-6, the compound
described in the above-mentioned scheme (29 mg, 53%) was obtained
from the compound (55 mg) obtained in step 7-6.
[0605] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.49 (9H, s), 2.52 (3H,
s), 3.13 (2H, t, J=7.6 Hz), 3.42 (2H, t, J=7.7 Hz), 5.16 (2H, s),
6.83 (1H, s), 7.15-7.19 (3H, m), 7.24-7.28 (2H,m), 7.32-7.44 (5H,
m).
Step 7-8
##STR00096##
[0607] The compound (54 mg) obtained in step 7-7 and chloroform
(0.5 ml) were mixed, trifluoroacetic acid (0.22 ml) was added, and
the mixture was stirred at room temperature for 2 hr. The reaction
mixture was concentrated under reduced pressure, and the residue
was azeotropically distilled with toluene to give a crude product
(69 mg) containing the compound described in the above-mentioned
scheme as a main component.
[0608] The compound obtained in this step was treated in the same
manner as in Example 1, step 1-10 to step 1-12, and the obtained
compound was converted to hydrochloride by a conventional method to
give the title compound.
[0609] .sup.1H-NMR (DMSO-D6) .delta.: 2.52 (s, 3H), 3.10 (t, 2H,
J=7.8 Hz), 3.35 (t, 2H, J=7.8 Hz), 4.19 (d, 2H, J=5.7 Hz), 6.69 (s,
1H), 7.18-7.31 (m, 5H), 9.81 (t, 1H, J=5.5 Hz).
Example 8
Production of
{[8-(3,3-dimethyl-butyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridine-5-carbon-
yl]amino}acetic acid hydrochloride
Step 8-1
##STR00097##
[0610] 2-Amino-3,5-dibromopyridine (50.4 g), 2,5-hexanedione (23.5
g) and p-toluenesulfonic acid monohydrate (2.7 g) were dissolved in
toluene (300 ml), and the mixture was heated under reflux for 5 hr
while removing water. The mixture was allowed to cool to room
temperature, ethyl acetate was added, and the mixture was washed
successively with saturated aqueous sodium hydrogen carbonate
solution, water and saturated brine (once each). The organic layer
was dried over sodium sulfate, filtered, and concentrated under
reduced pressure to give a crude product (66.6 g) of the compound
described in the above-mentioned scheme.
[0611] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.00 (6H, s), 5.92 (2H,
s), 8.22 (1H, d, J=2.4 Hz), 8.63 (1H, d, J=2.4 Hz).
Step 8-2
##STR00098##
[0613] In the same manner as in Example 1, step 1-3, the compound
described in the above-mentioned scheme (58.4 g, 82%) was obtained
from the compound (66.6 g) obtained in step 8-1.
[0614] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.99 (6H, s), 5.15 (2H,
s), 5.89 (2H, s), 7.37-7.48 (5H, m), 7.64 (1H, d, J=2.8 Hz), 8.31
(1H, d, J=2.8 Hz).
Step 8-3
##STR00099##
[0616] The compound (58.4 g) obtained in step 8-2, hydroxylammonium
chloride (233 g), ethanol (600 ml) and water (350 ml) were mixed.
To this mixture was added dropwise at room temperature
triethylamine (46 ml), ethanol (100 ml) was added and the mixture
was heated under reflux at a bath temperature of 95.degree. C. for
89 hr. The reaction mixture was ice-cooled, and 50% aqueous sodium
hydroxide solution (96 ml), 8N aqueous sodium hydroxide solution
(134 ml) and saturated aqueous sodium hydrogen carbonate solution
(50 ml) were successively added. Water (1800 ml) was added at room
temperature, the mixture was stirred for 1 hr and a precipitated
solid was collected by filtration. The precipitated solid was dried
under reduced pressure overnight and the crude product (49 g) was
slurried in 2-propanol (120 ml) to give the compound described in
the above-mentioned scheme (34.3 g, 75%).
[0617] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.60 (2H, br s), 5.00 (2H,
s), 7.31-7.40 (5H, m), 7.41 (1H, d, J=2.8 Hz), 7.83 (1H, d, J=2.8
Hz).
Step 8-4
##STR00100##
[0619] The compound (7.25 g) obtained in step 8-3,
N,N-dimethylformamide (11 ml) and N,N-dimethylformamide dimethyl
acetal (11 ml) were mixed, and the mixture was stirred with heating
at 130.degree. C. for 15 min. After stirring at room temperature
for 20 min, the mixture was concentrated under reduced pressure. To
the obtained residue were added methanol (58 ml) and pyridine (4.2
ml), and hydroxylamine-O-sulfonic acid (4.1 g) was added to the
mixture under ice-cooling. After stirring at room temperature
overnight, water (29 ml) and saturated aqueous sodium hydrogen
carbonate solution (58 ml) were added under ice-cooling, and the
mixture was stirred at room temperature for 1 hr. The resulting
solid was collected by filtration to give the compound described in
the above-mentioned scheme (6.13 g, 78%).
[0620] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.09 (s, 2H), 7.36-7.45
(m, 5H), 7.66 (d, 1H, J=2.0 Hz), 8.19 (d, 1H, J=2.0 Hz), 8.29 (s,
1H).
Step 8-5
##STR00101##
[0622] In the same manner as in Example 1, step 1-1, the compound
described in the above-mentioned scheme (5.67 g, 49%) was obtained
from the compound (10 g) obtained in step 8-4.
[0623] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 5.33 (s, 2H), 7.31-7.49
(m, 5H), 8.37 (s, 1H), 8.56 (s, 1H).
Step 8-6
##STR00102##
[0625] To the compound (5.68 g) obtained in step 8-5 was added
toluene (57 ml), and N,N-dimethylformamide diethyl acetal (4.5 ml)
was added in 3 portions at 80.degree. C. After completion of the
reaction, the mixture was concentrated under reduced pressure, and
the obtained residue was purified by column chromatography (eluent:
chloroform/ethyl acetate=10/1-4/1). Hexane was added to the
obtained compound, and the precipitated solid was slurried to give
the compound described in the above-mentioned scheme (4.68 g,
69%).
[0626] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (t, 3H, J=7.1 Hz),
4.53 (q, 2H, J=7.1 Hz), 5.21 (s, 2H), 7.35-7.43 (m, 5H), 7.72 (s,
1H), 8.38 (s, 1H).
Step 8-7
##STR00103##
[0628] The compound (100 mg) obtained in step 8-6,
tert-butylacetylene (0.1 ml), bis(triphenylphosphine)palladium(II)
dichloride (18 mg), and copper iodide(I) (5 mg) were added to a
screw bottle. To this mixture were added tetrahydrofuran (0.4 ml)
and triethylamine (0.8 ml) and the bottle was tightly sealed. The
mixture was stirred at room temperature for 1 hr, passed though a
small amount of silica gel and concentrated under reduced pressure.
The residue was purified twice by thin layer chromatography
(eluent: hexane/ethyl acetate=2/1) to give the compound described
in the above-mentioned scheme (85 mg, 85%).
Step 8-8
##STR00104##
[0630] In the same manner as in Example 2, step 2-5, the compound
described in the above-mentioned scheme (62 mg, 94%) was obtained
from the compound (85 mg) obtained in step 8-7.
[0631] In the same manner as in Example 4, step 4-4, the title
compound was obtained from the compound obtained in this step.
[0632] .sup.1H-NMR .delta.: 0.98 (s, 9H), 1.57-1.66 (m, 2H),
2.89-2.99 (m, 2H), 4.25 (d, 2H, J=5.4 Hz), 7.42 (s, 1H), 8.64 (s,
1H), 10.42 (t, 1H, J=5.4 Hz), 13.28 (s, 1H).
Example 9
Production of
[(7-hydroxy-6-phenyl[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl)amino]aceti-
c acid
Step 9-1
##STR00105##
[0634] The hydroxyl-protecting group of the compound obtained in
Example 1, step 1-3 was removed in the same manner as in Example 2,
step 2-5. To a solution of the obtained compound (3.30 g) in
chloroform (30 ml) was added under ice-cooling N-bromosuccinimide
(2.82 g). After stirring at room temperature for 5 hr, the reaction
mixture was separated by adding saturated aqueous sodium hydrogen
carbonate solution (20 ml). The organic layer was further washed
with aqueous sodium sulfite solution and saturated brine, and dried
over anhydrous magnesium sulfate. After filtration, the mixture was
concentrated under reduced pressure to give the compound described
in the above-mentioned scheme (5.37 g) as a crude product.
[0635] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66 (9H, s), 8.39 (1H,
s), 12.77 (1H, s).
Step 9-2
##STR00106##
[0637] To a solution of the compound (5.37 g) obtained in step 9-1
in N,N-dimethylformamide were added under ice-cooling potassium
carbonate (2.19 g) and benzyl bromide (1.88 ml) and the mixture was
stirred at room temperature for 20 hr. The reaction mixture was
separated by adding water (50 ml) and ethyl acetate (50 ml). The
organic layer was further washed with saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by column chromatography
(eluent: hexane/ethyl acetate=3/1-1/2) to give the compound
described in the above-mentioned scheme (3.73 g, 2 steps 65%).
[0638] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58 (9H, s), 5.21 (2H,
s), 7.19-7.21 (2H, m), 7.37-7.46 (3H,m), 7.76 (1H, s).
Step 9-3
##STR00107##
[0640] To the compound (610 mg) obtained in step 9-2 was added
trifluoroacetic acid (180 ml) under ice-cooling, and the mixture
was stirred at room temperature for 2 hr. The reaction mixture was
diluted with chloroform (6 ml) and concentrated under reduced
pressure. Chloroform (6 ml) was added again to the residue, thionyl
chloride (0.18 ml) and N,N-dimethylformamide (one drop) were added,
and the mixture was heated at 70.degree. C. for 30 min. The
obtained solution was concentrated under reduced pressure to give
the compound described in the above-mentioned scheme (540 mg,
98%).
Step 9-4
##STR00108##
[0642] To a solution of the compound (540 mg) obtained in step 9-3
in tetrahydrofuran (6 ml) were added under ice-cooling
diisopropylethylamine (0.29 ml) and glycine tert-butyl ester (0.21
ml), and the mixture was stirred for 2 hr. To the reaction mixture
were added diisopropylethylamine (0.29 ml) and tert-butyl
carbazate, and the mixture was heated at 70.degree. C. for 3 hr.
The reaction mixture was concentrated under reduced pressure, and
the residue was purified by column chromatography (eluent:
hexane/ethyl acetate=3/1-3/2) to give the compound described in the
above-mentioned scheme (790 mg, 92%).
[0643] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (9H, s), 1.48 (9H,
s), 4.05 (2H, d, J=5.5 Hz), 5.24 (2H, s), 6.27 (1H, s), 7.14 (2H,
t, J=4.1 Hz), 7.34-7.41 (3H, m), 7.47 (1H, s), 11.50 (1H, t, J=5.4
Hz), 11.83 (1H, s).
Step 9-5
##STR00109##
[0645] In the same manner as in Example 1, step 1-8, the compound
described in the above-mentioned scheme (280 g, 84%) was obtained
from the compound (330 mg) obtained in step 9-4.
[0646] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (9H, s), 1.48 (9H,
s), 4.06 (2H, d, J=5.5 Hz), 5.30 (2H, s), 6.16 (1H, s), 7.17 (2H,
d, J=7.4 Hz), 7.18 (1H, s), 7.28-7.40 (6H, m), 7.43-7.46 (2H, m),
11.79 (1H, s), 11.85 (1H, t, J=5.4 Hz).
Step 9-6
##STR00110##
[0648] In the same manner as in Example 2, step 2-5, the compound
described in the above-mentioned scheme (86 mg, 87%) was obtained
from the compound (120 mg) obtained in step 9-5.
[0649] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (9H, s), 1.49 (9H,
s), 4.15 (2H, s), 7.06-7.29 (8H, m), 10.40 (1H, s), 10.95 (1H,
s).
Step 9-7
##STR00111##
[0651] To a solution of the compound (110 mg) obtained in step 9-6
in chloroform (0.3 ml) was added 4N hydrochloric acid dioxane
solution (1 ml), and the mixture was stirred under ice-cooling for
2 hr. The reaction mixture was concentrated under reduced pressure
to give the compound described in the above-mentioned scheme (84
mg, 87%).
[0652] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.49 (9H, s), 4.04 (2H,
s), 7.36-7.47 (5H, m), 7.57 (1H, s).
Step 9-8
##STR00112##
[0654] To the compound (41 mg) obtained in step 9-7 was added
trimethyl orthoformate (0.41 ml), and the mixture was heated at
100.degree. C. for 30 min. The reaction mixture was concentrated
under reduced pressure, and the residue was dissolved in chloroform
(1 ml). Trifluoroacetic acid (2 ml) was added and the mixture was
stirred at room temperature for 3 hr. The reaction mixture was
concentrated under reduced pressure, 4N hydrochloric acid dioxane
solution (1 ml) was added, and the mixture was stirred at room
temperature for 30 min. The reaction mixture was concentrated under
reduced pressure and the residue was slurried in water to give the
title compound (29 mg, 89%).
[0655] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 4.06 (2H, d, J=5.5 Hz),
7.39-7.46 (3H, m), 7.60 (2H, dd, J=8.3, 1.4 Hz), 8.39 (1H, s), 8.86
(1H, s), 10.50 (1H, t, J=5.7 Hz), 12.59 (1H, s), 13.75 (1H, s).
Example 10
Production of
[(7-hydroxy[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl)amino]acetic
acid hydrochloride
Step 10-1
##STR00113##
[0657] In the same manner as in the deprotection reaction of the
carboxyl-protecting group in Example 9, step 9-8, a crude product
containing the compound described in the above-mentioned scheme as
a main component was obtained from the compound (0.050 g) obtained
in Example 1, step 1-5.
[0658] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 5.60 (s, 2H), 7.35-7.55
(m, 5H), 7.69 (d, 1H, J=7.7 Hz), 9.03 (d, 1H, J=7.7 Hz), 9.48 (s,
1H).
Step 10-2
##STR00114##
[0660] In the same manner as in Example 1, step 1-10, the compound
described in the above-mentioned scheme (0.024 g, 41%) was obtained
from the compound obtained in step 10-1.
[0661] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.51 (s, 9H), 4.23 (d, 2H,
J=5.6 Hz), 5.35 (s, 2H), 6.81 (d, 1H, J=7.7 Hz), 7.26-7.51 (m, 5H),
8.10 (d, 1H, J=7.7 Hz), 8.67 (s, 1H), 9.66 (br s, 1H).
[0662] The compound obtained in this step was subjected to removal
of the hydroxyl-protecting group and carboxyl-protecting group in
the same manner as above, and the obtained compound was converted
to hydrochloride by a conventional method to give the title
compound.
[0663] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 4.07 (s, 2H), 6.65 (d,
1H, J=7.7 Hz), 8.32 (d, 1H, J=7.7 Hz), 8.99 (s, 1H), 10.09 (s,
1H).
Example 11
Production of
[(6-hydroxy[1,2,3]triazolo[1,5-a]pyridine-7-carbonyl)amino]acetic
acid
Step 11-1
##STR00115##
[0665] 2-Bromo-5-hydroxypyridine (5.8 g), N,N-dimethylformamide (58
ml) and potassium carbonate (5.1 g) were mixed, benzyl bromide (4.4
ml) was added under ice-cooling and the mixture was stirred at room
temperature for 13 hr. To the reaction mixture were added ethyl
acetate (58 ml) and water (87 ml) and the organic layer was
separated from the mixture and washed successively with water (60
ml, 30 ml) twice and with saturated brine (30 ml). The organic
layer was dried over anhydrous magnesium sulfate, and filtered. The
filtrate was concentrated under reduced pressure. The obtained
residue was purified by column chromatography (eluent: hexane/ethyl
acetate=10/1-7/1) to give the compound described in the
above-mentioned scheme (7.4 g, 83%).
[0666] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.09 (s, 2H), 7.15 (dd,
1H, J=8.1, 3.2 Hz), 7.33-7.38 (m, 1H), 7.36 (d, 1H, J=8.1 Hz),
7.40-7.41 (m, 4H), 8.13 (d, 1H, J=3.2 Hz).
Step 11-2
##STR00116##
[0668] To n-butyllithium (1.54 mol/1 hexane solution 25 ml) was
added dropwise a solution of the compound (1 g) obtained in step
11-1 in toluene (4 ml) at -78.degree. C. over 7 min. The reaction
mixture was stirred at -78.degree. C. for 50 min, and a solution of
N,N-dimethylformamide (0.352 ml) in toluene (4 ml) was added
dropwise. The reaction mixture was further stirred at -78.degree.
C. for 1 hr, water (6 ml) was added at -10.degree. C., and the
mixture was stirred at room temperature for 2 hr. The organic layer
and the aqueous layer were separated, the aqueous layer was
extracted twice with toluene (5 ml). The organic layers were
combined and washed with saturated brine (10 ml). The organic layer
was dried over anhydrous magnesium sulfate, and the mixture was
filtered. The filtrate was concentrated under reduced pressure and
the obtained residue was purified by column chromatography (eluent:
hexane/ethyl acetate=10/1-7/1) to give the compound described in
the above-mentioned scheme (641 mg, 79%).
[0669] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.21 (s, 2H), 7.35-7.45
(m, 6H), 7.95 (d, 1H, J=8.9 Hz), 8.51 (d, 1H, J=2.8 Hz), 9.99 (s,
1H).
Step 11-3
##STR00117##
[0671] The compound (637 mg) obtained in step 11-2, methanol (6.4
ml) and tosylhydrazide (574 mg) were mixed, and the mixture was
heated under reflux for 10 min. The reaction mixture was
concentrated under reduced pressure, morpholine (6.4 ml) was added,
and the mixture was heated under reflux for 30 min. The reaction
mixture was concentrated under reduced pressure, and ethyl acetate
(12 ml), 2M aqueous sodium carbonate solution (6 ml) and water (5
ml) were added. Further, tetrahydrofuran (6 ml) was added and the
organic layer was separated. The aqueous layer was extracted twice
with ethyl acetate (5 ml), and the organic layers were combined and
washed with saturated brine (10 ml). The organic layer was dried
over anhydrous magnesium sulfate, and filtered. The filtrate was
concentrated under reduced pressure and the obtained solid was
slurried in diisopropyl ether to give the compound described in the
above-mentioned scheme (566 mg, 84%).
[0672] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.12 (s, 2H), 7.11 (dd,
1H, J=9.7, 2.0 Hz), 7.36-7.47 (m, 5H), 7.61 (dd, 1H, J=9.7, 0.8
Hz), 7.99 (d, 1H, J=0.8 Hz), 8.34 (d, 1H, J=2.0 Hz).
Step 11-4
##STR00118##
[0674] The compound (200 mg) obtained in step 11-3 and
tetrahydrofuran (2 ml) were mixed, and lithium diisopropylamide (2M
tetrahydrofuran, heptane, ethylbenzene solution, 0.45 ml) was added
at -40.degree. C. After stirring at -40.degree. C. for 1 hr, dry
ice was added, and the mixture was allowed to warm to room
temperature by stirring for 1 hr. Thereafter, methanol (2 ml) was
added, and the reaction mixture was concentrated under reduced
pressure to give the compound described in the above-mentioned
scheme as a crude product. This was directly used for the next
step.
Step 11-5
##STR00119##
[0676] In the same manner as in Example 1, step 1-10, the compound
described in the above-mentioned scheme (85 mg, 28% (2 step)) was
obtained from the crude product obtained in step 11-4.
[0677] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80 (s, 3H), 4.38 (d, 2H,
J=5.2 Hz), 5.32 (s, 2H), 7.24 (d, 1H, J=9.7 Hz), 7.31-7.41 (m, 3H),
7.46-7.49 (m, 2H), 7.75 (d, 1H, J=9.7 Hz), 8.11 (s, 1H), 8.79 (br
s, 1H).
Step 11-6
##STR00120##
[0679] In the same manner as in Example 2, step 2-5, the compound
described in the above-mentioned scheme (40 mg, 76%) was obtained
from the compound (72 mg) obtained in step 11-5.
[0680] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.83 (s, 3H), 4.37 (d, 2H,
J=6.0 Hz), 7.17 (d, 1H, J=9.7 Hz), 7.80 (d, 1H, J=9.7 Hz), 8.12 (s,
1H), 10.57 (br s, 1H), 13.56 (s, 1H).
[0681] The compound obtained in this step was subjected to removal
of the carboxyl group in the same manner as above to give the title
compound.
[0682] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 4.28 (d, 2H, J=5.2 Hz),
7.31 (d, 1H, J=9.7 Hz), 8.20 (d, 1H, J=9.7 Hz), 8.39 (s, 1H), 10.36
(t, 1H, J=5.2 Hz), 13.82 (s, 1H).
Example 116
Production of
[(7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]ac-
etic acid
[0683] step 116-1
##STR00121##
[0684] Cyanamide (1.4 g) and 1,4-dioxane (20 ml) were mixed, and
dimethyl 1,3-acetonedicarboxylate (2.0 g) and nickel(II)
acetylacetonate (0.30 g) were added. The mixture was heated under
reflux for 16 hr. The mixture was cooled to room temperature,
stirred for 1 hr and the resulting solid was collected by
filtration. To the obtained solid was added methanol (6.0 ml) and
the mixture was stirred at room temperature for 1.5 hr. The solid
was collected by filtration to give the compound described in the
above-mentioned scheme (1.4 g, 64%).
[0685] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 3.80 (s, 3H), 4.92 (s,
1H), 7.20 (s, 2H), 10.29 (s, 1H), 11.51 (s, 1H).
Step 116-2
##STR00122##
[0687] The compound (30 g) obtained in step 116-1, phosphorus
oxychloride (150 ml) and N,N-diisopropylethylamine (30 ml) were
mixed, and the mixture was stirred at room temperature for 3 days.
The reaction mixture was concentrated, and azeotropically distilled
3 times with toluene. Under ice-cooling, methanol (30 ml) and water
(150 ml) were added and the mixture was stirred at room temperature
for 1 hr. The resulting solid was collected by filtration, and
combined with the solid resulting from the filtrate. Methanol (50
ml) was added and the mixture was stirred at room temperature for 1
hr. The solid was collected by filtration to give primary crystals.
The filtrate was concentrated, and methanol (10 ml) was added to
the residue, and the resulting solid was collected by filtration to
give a secondary crystal. The primary crystal and the secondary
crystal were combined to give the compound described in the
above-mentioned scheme (21 g, 59%).
[0688] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 3.84 (s, 3H), 6.84 (s,
1H), 7.16 (br s, 2H).
Step 116-3
##STR00123##
[0690] The compound (2.2 g) obtained in step 116-2 and 2-propanol
(31 ml) were mixed, and N,N-dimethylformamide dimethyl acetal (2.9
ml) was added. The mixture was heated under reflux for 30 min. The
reaction mixture was cooled to room temperature,
hydroxylamine.hydrochloride (1.4 g) was added, and the mixture was
stirred at room temperature for 30 min. The reaction mixture was
concentrated to an about half amount, and water (40 ml) and
2-propanol (6.6 ml) were added. The mixture was stirred at room
temperature for 30 min, and the resulting solid was collected by
filtration to give the compound described in the above-mentioned
scheme (2.2 g, 84%).
[0691] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 3.92 (s, 3H), 7.37 (s,
1H), 7.85 (d, 1H, J=9.5 Hz), 10.12 (d, 1H, J=9.5 Hz), 10.83 (s,
1H).
Step 116-4
##STR00124##
[0693] The compound (0.66 g) obtained in step 116-3 and
tetrahydrofuran (6.6 ml) were mixed, and trifluoroacetic anhydride
(0.37 ml) was added. The mixture was heated under reflux for 22 hr.
The reaction mixture was cooled to room temperature, ethyl acetate
and saturated aqueous sodium hydrogen carbonate solution were
added, and the organic layer was separated. The organic layer was
washed with saturated brine, and dried over sodium sulfate. After
filtration, the filtrate was concentrated under reduced pressure
and the obtained residue was purified by column chromatography
(eluent: chloroform/ethyl acetate=4/1) to give the compound
described in the above-mentioned scheme (0.32 g, 51%).
[0694] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 3.99 (s, 3H), 7.92 (s,
1H), 8.71 (s, 1H).
Step 116-5
##STR00125##
[0696] The compound (1.0 g) obtained in step 116-4,
phenethylboronic acid (1.2 g), potassium carbonate (1.7 g),
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane complex (1:1) (0.083 g), cyclopentyl methyl ether
(6.0 ml) and water (0.15 ml) were mixed, and the mixture was
stirred with heating at 50.degree. C. for 6 hr. The reaction
mixture was cooled to room temperature, and the organic layer was
washed twice with 3% aqueous diethylenetriamine solution (10 ml)
and saturated brine (5 ml). Sodium sulfate and metal scavenger
silica gel (1 g) were added and the mixture was stirred at room
temperature for 1 hr, and filtered through a Kiriyama funnel packed
with silica gel (1 g). The filtrate was concentrated under reduced
pressure to give the compound described in the above-mentioned
scheme (1.87 g) as a crudely purified product.
[0697] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.17 (t, 2H, J=7.8 Hz),
3.48 (t, 2H, J=7.8 Hz), 4.08 (s, 3H), 6.84 (s, 1H), 7.18-7.28 (m,
5H), 8.42 (s, 1H).
Step 116-6
##STR00126##
[0699] The compound (1.87 g) obtained in step 116-5 and
tetrahydrofuran were mixed, and 4N aqueous sodium hydroxide
solution (4.0 ml) was added under ice-cooling. After stirring at
room temperature for 2 hr, the reaction mixture was neutralized
with concentrated hydrochloric acid (1.4 ml) under ice-cooling. To
the suspension were added ethanol (5 ml) and water (1.3 ml) and the
mixture was stirred for 1 hr. The solid was collected by filtration
to give the compound described in the above-mentioned scheme (0.847
g, 69%).
[0700] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 3.13 (t, 2H, J=7.8 Hz),
3.45 (t, 2H, J=7.8 Hz), 7.23-7.31 (m, 5H), 8.65 (s, 1H), 14.19 (s,
1H).
Step 116-7
##STR00127##
[0702] The compound (0.200 g) obtained in step 116-6, acetonitrile
(1.0 ml), 1-hydroxybenzotriazole monohydrate (0.122 g) and glycine
methyl ester hydrochloride (0.100 g) were mixed, and triethylamine
(0.111 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (0.153 g) were added under ice-cooling. The mixture
was stirred at room temperature for 2 hr. Saturated aqueous sodium
hydrogen carbonate solution (2 ml) was added to the reaction
mixture and the precipitated solid was collected by filtration to
give the compound described in the above-mentioned scheme (0.194 g,
78%).
[0703] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.18 (t, 2H, J=7.8 Hz),
3.48 (t, 2H, J=7.8 Hz), 3.81 (s, 3H), 4.34 (d, 2H, J=5.2 Hz), 6.92
(s, 1H), 7.15-7.33 (m, 5H), 8.42 (s, 1H), 9.90 (s, 1H).
Step 116-8
##STR00128##
[0705] The compound (0.150 g) obtained in step 116-7,
2-ethoxyethanol (0.75 ml) and 8N aqueous sodium hydroxide solution
(0.23 ml) were mixed and the mixture was stirred at 90.degree. C.
for 18 hr. To this mixture were added ethanol (0.75 ml) and water
(0.23 ml) and the mixture was stirred at room temperature for 1 hr.
The solid was collected by filtration to give a crudely purified
product of the compound described in the above-mentioned scheme
(0.19 g).
[0706] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 2.99-3.11 (m, 4H), 3.58
(d, 2H, J=4.4 Hz), 6.01 (s, 1H), 7.20-7.27 (m, 5H), 7.86 (s, 1H),
11.23 (t, 1H, J=4.4 Hz).
Step 116-9
##STR00129##
[0708] The compound (0.19 g) obtained in step 116-8 and water (0.63
ml) were mixed and the mixture was warmed to 50.degree. C. Acetone
(0.78 ml) and 6N hydrochloric acid (0.2 ml) were added, and the
mixture was stirred at the same temperature for 1 hr. After
stirring under ice-cooling for 1 hr, the solid was collected by
filtration to give the compound described in the above-mentioned
scheme (0.11 g, 80%).
[0709] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 3.12 (t, 2H, J=7.9 Hz),
3.40 (t, 3H, J=7.9 Hz), 4.22 (d, 2H, J=5.2 Hz), 6.79 (s, 1H),
7.21-7.29 (m, 5H), 8.58 (s, 1H), 9.84 (t, 1H, J=5.2 Hz), 12.97 (s,
1H), 14.22 (s, 1H).
Step 116-10
##STR00130##
[0711] The compound (0.050 g) obtained in step 116-9 and methanol
(3 ml) were mixed and the mixture was heated to 60.degree. C. The
solution was cooled to room temperature and stirred for one day.
The solid was collected by filtration to give the title compound
(0.031 g, 61%).
[0712] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 3.12 (t, 2H, J=7.9 Hz),
3.40 (t, 3H, J=7.9 Hz), 4.22 (d, 2H, J=5.2 Hz), 6.79 (s, 1H),
7.21-7.29 (m, 5H), 8.58 (s, 1H), 9.84 (t, 1H, J=5.2 Hz), 12.97 (s,
1H), 14.22 (s, 1H).
Example 117
Production of
[(5-butyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)amino]acetic
acid
Step 117-1
##STR00131##
[0714] The compound (0.050 g) obtained in step 116-4, butylboronic
acid (0.042 g), silver(I) oxide (0.071 g), potassium carbonate
(0.084 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloride dichloromethane complex (1:1) (0.008 g) and
tetrahydrofuran (1.0 ml) were mixed, and the mixture was heated
under reflux for 10 hr. Insoluble material was filtered off through
celite, and saturated aqueous sodium hydrogen carbonate solution
and ethyl acetate were added. The organic layer was separated from
the mixture. The organic layer was washed twice with saturated
aqueous sodium hydrogen carbonate solution and saturated brine,
dried over sodium sulfate and filtered. The filtrate was
concentrated under reduced pressure and the obtained residue was
purified by thin layer chromatography (eluent: hexane/ethyl
acetate=1/1) to give the compound described in the above-mentioned
scheme (0.046 g, 77%).
[0715] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (t, 3H, J=7.4 Hz),
1.45-1.53 (m, 2H), 1.79-1.87 (m, 2H), 3.18 (t, 2H, J=7.9 Hz), 4.08
(s, 3H), 6.92 (s, 1H), 8.38 (s, 1H).
Step 117-2
##STR00132##
[0717] The compound (0.043 g) obtained in step 117-1 and methanol
(0.22 ml) were mixed, and 28% sodium methoxide methanol solution
(0.014 ml) was added. The mixture was stirred at room temperature
for 4 hr. Water (0.22 ml) was added, and the mixture was stirred at
room temperature for 1 hr. 1N Hydrochloric acid (0.16 ml) was added
to the reaction mixture, and the resulting solid was collected by
filtration to give the compound described in the above-mentioned
scheme (0.026 g, 66%).
[0718] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.01 (t, 3H, J=7.3 Hz),
1.46-1.57 (m, 2H), 1.82-1.90 (m, 2H), 3.21 (t, 2H, J=7.9 Hz), 4.15
(s, 3H), 6.77 (s, 1H), 8.28 (s, 1H).
Step 117-3
##STR00133##
[0720] The compound (0.025 g) obtained in step 117-2 and
N,N-dimethylformamide (0.50 ml) were mixed, and
1-hydroxybenzotriazole monohydrate (0.016 g) and glycine
tert-butylester (0.015 ml) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.020
g) were added. The mixture was stirred at room temperature for 1.5
hr. Under ice-cooling, 5% aqueous sodium hydrogen carbonate
solution and water were added to the reaction mixture and the
resulting solid was collected by filtration to give the compound
described in the above-mentioned scheme (0.033 g, 94%).
[0721] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00 (t, 4H, J=7.3 Hz),
1.51 (s, 9H), 1.80-1.90 (m, 2H), 3.18 (t, 2H, J=7.9 Hz), 4.21 (d,
2H, J=5.2 Hz), 6.72 (s, 1H), 8.29 (s, 1H), 9.72 (t, 1H, J=4.2
Hz).
Step 117-4
##STR00134##
[0723] The compound (0.030 g) obtained in step 117-3 and 25%
hydrogen bromide acetic acid solution (0.60 ml) were mixed, and the
mixture was heated under reflux for 3 hr. The reaction mixture was
concentrated under reduced pressure. To the obtained residue were
added water (0.60 ml) and 4N aqueous sodium hydroxide solution
(0.23 ml) under ice-cooling. Then, 2N hydrochloric acid (0.23 ml)
was added under ice-cooling, and the resulting solid was collected
by filtration to give the compound described in the above-mentioned
scheme (0.010 g, 42%).
[0724] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 0.93 (t, 3H, J=7.5 Hz),
1.33-1.44 (m, 2H), 1.71-1.80 (m, 2H), 3.10 (t, 2H, J=7.5 Hz), 4.20
(d, 2H, J=5.2 Hz), 6.85 (s, 1H), 8.55 (s, 1H), 9.84 (br s, 1H),
14.26 (br s, 1H).
Step 117-5
##STR00135##
[0726] The compound (0.100 g) obtained in step 117-4 and methyl
ethyl ketone (1.0 ml) were mixed, and heated to 80.degree. C.
Heptane (1.0 ml) was added to the solution, and the mixture was
stirred at room temperature overnight. The solid was collected by
filtration to give the title compound (0.089 g, 89%).
[0727] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 0.93 (t, 3H, J=7.5 Hz),
1.33-1.44 (m, 2H), 1.71-1.80 (m, 2H), 3.10 (t, 2H, J=7.5 Hz), 4.20
(d, 2H, J=5.2 Hz), 6.85 (s, 1H), 8.55 (s, 1H), 9.84 (br s, 1H),
14.26 (br s, 1H).
[0728] In the same manner as in the above-mentioned Examples 1 to
11, Example 116 or 117, or other conventional methods as necessary,
the compounds of Examples 12 to 115 and Examples 118 to 122 shown
in the following Tables 3 to 24 were produced.
[0729] The structural formulas and property data of the compounds
of Examples 1 to 122 are shown in the following Tables 1 to 24.
TABLE-US-00001 TABLE 1 Ex. compound structural .sup.1H-NMR, MS MS
No. name formula .delta. ppm (M + H) (M - H) 1 {[5-(4-fluoro-3-
trifluoromethyl phenyl)-7- hydroxy[1,2,4]tria- zolo[1,5-a]pyridine-
8-carbonyl]amino} acetic acid hydrochloride ##STR00136##
.sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d, 2H, J = 5.6
Hz), 7.31 (s, 1H), 7.73- 7.82 (m, 1H), 8.34- 8.43 (m, 1H),
8.43-8.51 (m, 1H), 8.61 (s, 1H), 9.99 (t, 1H), J = 5.6 Hz). 399 397
2 [(7-hydroxy-5- phenethyl[1,2,4]tria- zolo[1,5-a]pyridine-8-
carbonyl)amino] acetic acid hydrochloride ##STR00137## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 3.12 (t, 2H, J = 7.8 Hz), 3.41 (t,
2H, J = 7.8 Hz), 4.21 (d, 2H, J = 5.6 Hz), 6.81 (s, 1H), 7.14-7.33
(m, 5H), 8.60 (s, 1H), 9.85 (t, 1H, J = 5.6 Hz). 341 339 3
[(5-butyl-7- hydroxy[1,2,4]tria- zolo[1,5- a]pyridine-8-
carbonyl)amino] acetic acid hydrochloride ##STR00138## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 0.93 (t, 3H, J = 7.4 Hz), 1.39
(td, 2H, J = 14.8, 7.4 Hz), 1.72-1.79 (m, 2H, 3.10 (t, 2H, J = 7.7
Hz), 4.21 (d, 2H, J = 5.5 Hz), 6.85 (s, 1H), 8.56 (s, 1H), 9.84 (t,
1H, J = 5.6 Hz). 293 291 4 [(5,6-diethyl-7- hydroxy[1,2,4]tria-
zolo[1,5- a]pyridine-8- carbonyl)amino] acetic acid hydrochloride
##STR00139## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 1.15 (t,
3H, J = 7.5 Hz), 1.29 (t, 3H, J = 7.5 Hz), 2.72 (q, 2H, J = 7.5
Hz), 3.20 (q, 2H, J = 7.6 Hz), 4.21 (d, 2H, J = 5.6 Hz), 8.52 (s,
1H), 9.95 (t, 1H, J = 5.6 Hz). 293 291 5 [(7-hydroxy-6-
phenethyl[1,2,4]tria- zolo[1,5- a]pyridine-8- carbonyl)amino]
acetic acid hydrochloride ##STR00140## .sup.1H-NMR (DMSO-D.sub.6,
400 MHz) .delta.: 2.93 (s, 4H), 4.22 (d, 2H, J = 5.7 Hz), 7.19 (tt,
1H, J = 7.1, 1.8 Hz), 7.23-7.31 (m, 4H), 8.50 (s, 1H), 8.78 (s,
1H), 9.97 (s, 1H). 341 339
TABLE-US-00002 TABLE 2 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta. ppm (M + H) (M - H) 6 [(5-butyl-6-
chloro-7- hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl)amino] acetic acid hydrochloride ##STR00141## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 0.93 (t, 3H, J = 7.3 Hz),
1.36-1.47 (m, 2H), 1.64-1.72 (m, 2H), 3.15-3.28 (m, 2H), 4.15 (d,
2H, J = 2.8 Hz), 8.74 (br s, 1H), 10.20 (br s, 1H). 327 325 7
[(7-hydroxy-2- methyl-5- phenethyl[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl)amino] acetic acid hydrochloride
##STR00142## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 2.52 (s,
3H), 3.10 (t, 2H, J = 7.8 Hz), 3.35 (t, 2H, J = 7.8 Hz), 4.19 (d,
2H, J = 5.7 Hz), 6.69 (s, 1H), 7.18- 7.31 (m, 5H), 9.81 (t, 1H, J =
5.5 Hz). 355 353 8 {[8-(3,3- dimethylbutyl)- 6-hydroxy[1,2,4]
triazolo[1,5- a]pyridine-5- carbonyl]amino} acetic acid
hydrochloride ##STR00143## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 0.98 (s, 9H), 1.57-1.66 (m, 2H), 2.89-2.99 (m, 2H), 4.25
(d, 2H, J = 5.4 Hz), 7.42 (s, 1H), 8.64 (s, 1H), 10.42 (t, 1H, J =
5.4 Hz), 13.28 (s, 1H). 321 319 9 [(7-hydroxy-6- phenyl[1,2,4]
triazolo[4,3- a]pyridine-8- carbonyl)amino] acetic acid
##STR00144## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.06 (d,
2H, J = 5.5 Hz), 7.39-7.46 (m, 3H), 7.60 (dd, 2H, J = 8.3, 1.4 Hz),
8.39 (s, 1H), 8.86 (s, 1H), 10.50 (t, 1H, J = 5.7 Hz), 12.59 (s,
1H), 13.75 (s, 1H). 313 311 10 [(7- hydroxy[1,2,4] triazolo[4,3-
a]pyridine-8- carbonyl)amino] acetic acid hydrochloride
##STR00145## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.07 (s,
2H), 6.65 (d, 1H, J = 7.7 Hz), 8.32 (d, 1H, J = 7.7 Hz), 8.99 (s,
1H), 10.09 (s, 1H). 237 235 11 [(6- hydroxy[1,2,3] triazolo[1,5-
a]pyridine-7- carbonyl)amino] acetic acid ##STR00146## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.28 (d, 2H, J = 5.2 Hz), 7.31 (d,
1H, J = 9.7 Hz), 8.20 (d, 1H, J = 9.7 Hz), 8.39 (s, 1H), 10.36 (t,
1H, J = 5.2 Hz), 13.82 (s, 1H). 237 235
TABLE-US-00003 TABLE 3 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta. ppm (M + H) (M - H) 12
[(7-hydroxy[1,2, 4]triazolo[1,5- a]pyridine-8- carbonyl)amino]
acetic acid hydrochloride ##STR00147## .sup.1H-NMR (DMSO-D.sub.6,
400 MHz) .delta.: 4.22 (d, 2H, J = 5.6 Hz), 6.93 (d, 1H, J = 7.7
Hz), 8.56 (s, 1H), 8.96 (d, 1H, J = 7.7 Hz), 9.81-9.91 (m, 1H). 237
235 13 [(7-hydroxy-2- phenyl[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl)amino] acetic acid hydrochloride ##STR00148## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.27 (d, 2H, J = 5.6 Hz), 6.94 (d,
1H, J = 7.7 Hz), 7.55-7.58 (m, 3H), 8.31-8.33 (m, 2H), 9.00 (d, 1H,
J = 7.3 Hz), 10.11 (t, 1H, J = 5.2 Hz). 313 311 14 ({5-[2-(4-
chlorophenyl) ethyl]-7- hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl}amino) acetic acid hydrochloride ##STR00149## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 3.12 (2H, t, J = 7.9 Hz), 3.40
(2H, t, J = 7.7 Hz), 4.21 (2H, d, J = 5.6 Hz), 6.80 (1H, s), 7.27
(2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 8.59 (1H, s), 9.85
(1H, t, J = 5.6 Hz). 375 373 15 [(2-cyclopropyl- 7-hydroxy-5-
phenethyl[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl)amino] acetic
acid hydrochloride ##STR00150## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 1.04- 1.12 (m, 4H), 2.17- 2.23 (m, 1H), 3.10 (t, 2H, J =
7.9 Hz) 3.29- 3.37 (m, 2H), 4.18 (d, 2H, J = 5.3 Hz), 6.66 (s, 1H),
7.18-7.32 (m, 5H), 9.84 (t, 1H, J = 4.9 Hz), 14.10 (s, 1H). 381 379
16 ({7-hydroxy-5- [2-(4- trifluoromethyl phenyl)ethyl]
[1,2,4]triazolo[1, 5-a]pyridine-8- carbonyl}amino) acetic acid
hydrochloride ##STR00151## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 3.21 (2H, t, J = 7.8 Hz), 3.44 (2H, t, J = 7.8 Hz), 4.20
(2H, d, J = 5.8 Hz), 6.83 (1H, s), 7.48 (2H, d, J = 8.1 Hz), 7.66
(2H, d, J = 8.1 Hz), 8.59 (1H, s), 9.81-9.88 (1H, m). 409 407 17
({5-[2-(4- fluorophenyl) ethyl]-7- hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl}amino) acetic acid hydrochloride
##STR00152## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 3.11 (2H,
t, J = 7.9 Hz), 3.39 (2H, t, J = 7.7 Hz), 4.21 (2H, d, J = 5.2 Hz),
6.80 (1H, s), 7.07-7.16 (2H, m), 7.23-7.30 (2H, m), 8.60 (1H, s),
9.85 (1H, t, J = 5.4 Hz). 359 357
TABLE-US-00004 TABLE 4 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta. ppm (M + H) (M - H) 18 {[7-hydroxy-5-
(3-methylbutyl) [1,2,4]triazolo[1, 5-a]pyridine-8- carbonyl]amino}
acetic acid hydrochloride ##STR00153## .sup.1H-NMR (DMSO-D.sub.6,
400 MHz) .delta.: 0.95 (6H, d, J = 6.5 Hz), 1.58-1.70 (3H, m),
3.07-3.13 (2H, m), 4.21 (2H, d, J = 5.6 Hz), 6.87 (1H, s), 8.57
(1H, s), 9.85 (1H, t, J = 5.6 Hz). 307 305 19 ({5-[2-(3,5-
difluorophenyl) ethyl]-7- hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl}amino) acetic acid hydrochloride
##STR00154## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 3.15 (2H,
t, J = 7.8 Hz), 3.42 (2H, t, J = 7.8 Hz), 4.20 (2H, d, J = 5.6 Hz),
6.83 (1H, s), 6.97-7.11 (3H, m), 8.58-8.61 (1H, m), 9.79-9.89 (1H,
m). 377 375 20 [(5-cyclopentyl- methyl-7- hydroxy[1,2,4]
triazolo[1,5- a]pyridine-8- carbonyl)amino] acetic acid
hydrochloride ##STR00155## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 1.21- 1.32 (2H, m), 1.45- 1.55 (2H, m), 1.59- 1.74 (4H,
m), 2.40- 2.49 (1H, m), 3.09 (2H, d, J = 7.3 Hz), 4.21 (2H, d, J =
5.6 Hz), 6.88 (1H, s), 8.55 (1H, s), 9.85 (1H, t, J = 5.6 Hz). 319
317 21 {[5-(3,5- difluorophenyl)- 7-hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid hydrochloride
##STR00156## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d,
2H, J = 5.8 Hz), 7.29 (s, 1H), 7.56 (tt, 1H, J = 9.3, 2.3 Hz),
7.78-7.86 (m, 2H), 8.62 (s, 1H), 9.99 (t, 1H, J = 5.8 Hz). 349 347
22 [(7-hydroxy-5- phenyl[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl)amino] acetic acid hydrochloride ##STR00157## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d, 2H, J = 5.6 Hz), 7.12 (s,
1H), 7.59- 7.62 (m, 3H), 7.99- 8.02 (m, 2H), 8.58 (s, 1H), 9.98 (t,
1H, J = 5.6 Hz). 313 311 23 {[5-(3-chloro-4- fluorophenyl)-7-
hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic
acid hydrochloride ##STR00158## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.25 (d, 2H, J = 5.6 Hz), 7.23 (s, 1H), 7.67 (dd, 1H, J =
8.9, 8.9 Hz), 8.05 (ddd, 1H, J = 8.9, 2.4, 4.8 Hz), 8.30 (dd, 1H, J
= 7.3, 2.4 Hz), 8.60 (s, 1H), 9.98 (t, 1H, J = 5.4 Hz). 365 363
TABLE-US-00005 TABLE 5 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta. ppm (M + H) (M - H) 24 {[5-(3,3-
dimethylbutyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00159## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 0.98 (s, 9H), 1.59-1.70 (m, 2H),
3.01-3.13 (m, 2H), 4.21 (d, 2H, J = 5.6 Hz), 6.89 (s, 1H), 8.57 (s,
1H), 9.84 (t, 1H, J = 5.6 Hz). 321 319 25 {[5-(3,4-
difluorophenyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00160## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d, 2H, J = 5.5 Hz), 7.22 (s,
1H) , 7.69 (dt, 1H, J = 15.0, 5.3 Hz), 7.92-7.94 (m, 1H), 8.17
(ddd, 1H, J = 11.9, 7.7, 2.2 Hz), 8.60 (s, 1H), 9.98 (t, 1H, J =
5.5 Hz). 349 347 26 {[7-hydroxy-5- (p-tolyl)[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid hydrochloride
##STR00161## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 2.42 (s,
3H), 4.24 (d, 2H, J = 5.5 Hz), 7.09 (s, 1H), 7.40 (d, 2H, J = 8.2
Hz), 7.93 (d, 2H, J = 8.2 Hz), 8.58 (s, 1H), 9.97 (t, 1H, J = 5.5
Hz). 327 325 27 [(5- cyclohexyl-7- hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl)amino] acetic acid hydrochloride
##STR00162## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 1.21-
1.62 (5H, m), 1.69- 1.79 (1H, m), 1.80- 1.88 (2H, m), 1.98- 2.09
(2H, m), 3.31- 3.43 (1H, m), 4.20 (2H, d, J = 5.8 Hz), 6.76 (1H,
s), 8.56 (1H, s), 9.80-9.87 (1H, m). 319 317 28 [(5- cyclohexyl-
methyl-7- hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl)amino] acetic acid hydrochloride ##STR00163## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 0.98- 1.23 (5H, m), 1.56- 1.70
(5H, m), 1.90- 1.99 (1H, m), 3.00 (2H, d, J = 7.2 Hz), 4.21 (2H, d,
J = 5.6 Hz) 6.84 (1H, s), 8.55 (1H, s), 9.85 (1H, t, J = 5.6 Hz).
333 331
TABLE-US-00006 TABLE 6 Ex. compound MS MS No. name structural
formula .sup.1H-MNR, .delta. ppm (M + H) (M - H) 29 {[7-hydroxy-5-
(3-phenylpropyl) [1,2,4]triazolo[1, 5-a]pyridine-8- carbonyl]amino}
acetic acid ##STR00164## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 2.07- 2.15 (m, 2H), 2.71 (t, 2H, J = 7.7 Hz), 3.12 (t, 2H,
J = 7.6 Hz), 4.21 (d, 2H, J = 5.5 Hz), 6.85 (s, 1H), 7.15-7.31 (m,
5H), 8.55 (s, 1H), 9.84 (t, 1H, J = 5.5 Hz). 355 353 30
[(5-cyclopentyl- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl) amino] acetic acid hydrochloride ##STR00165## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 1.68- 1.84 (m, 6H), 2.14- 2.21 (m,
2H), 3.69- 3.76 (m, 1H), 4.21 (d, 2H, J = 5.7 Hz), 6.83 (s, 1H),
8.56 (s, 1H), 9.85 (t, 1H, J = 5.6 Hz). 305 303 31 {[5-(3-fluoro-5-
trifluoromethyl phenyl)-7- hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid hydrochloride
##STR00166## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d,
2H, J = 5.6 Hz), 7.37 (s, 1H), 7.99 (d, 1H, J = 9.3 Hz), 8.23 (d,
1H, J = 9.3 Hz), 8.30 (s, 1H), 8.63 (s, 1H), 10.00 (t, 1H, J = 5.6
Hz). 399 397 32 {[5-(4- fluorophenyl)- 7-hydroxy[1,2,4]
triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic acid
hydrochloride ##STR00167## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.24 (d, 2H, J = 5.7 Hz), 7.14 (s, 1H), 7.41- 7.48 (m,
2H), 8.07- 8.13 (m, 2H), 8.59 (s, 1H), 9.97 (t, 1H, J = 5.7 Hz).
331 329 33 {[7-hydroxy-5-(3- trifluoromethyl phenyl)[1,2,4]
triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic acid
hydrochloride ##STR00168## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.25 (d, 2H, J = 5.5 Hz), 7.28 (s, 1H), 7.84 (t, 1H, J =
7.9 Hz), 7.98 (d, 1H, J = 7.9 Hz), 8.28 (d, 1H, J = 7.9 Hz), 8.41
(s, 1H), 8.61 (s, 1H), 10.00 (t, 1H, J = 5.7 Hz). 381 379
TABLE-US-00007 TABLE 7 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta. ppm (M + H) (M - H) 34
{[5-(2-fluoro-5- trifluoromethyl phenyl)-7- hydroxy[1,2,4]
triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic acid
hydrochloride ##STR00169## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.25 (d, 2H, J = 5.6 Hz), 7.28 (s, 1H), 7.73 (dd, 1H, J =
9.1, 9.1 Hz), 8.10 (ddd, 1H, J = 9.1, 4.5, 2.0 Hz), 8.24 (dd, 1H, J
= 6.4, 2.0 Hz), 8.57 (s, 1H), 9.95 (t, 1H, J = 5.6 Hz). 399 397 35
[(7-hydroxy-5- isopropyl[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl)amino] acetic acid hydrochloride ##STR00170## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 1.37 (d, 6H, J = 7.3 Hz), 3.67
(sept, 1H, J = 7.3 Hz), 4.21 (d, 2H, J = 5.6 Hz), 6.82 (s, 1H),
8.59 (s, 1H), 9.84 (t, 1H, J = 5.6 Hz). 279 277 36 {[5-(3-chloro-5-
trifluoromethyl phenyl)-7- hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid hydrochloride
##STR00171## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d,
2H, J = 5.6 Hz), 7.37 (s, 1H), 8.14 (s, 1H), 8.37 (s, 1H), 8.41 (s,
1H), 8.62 (s, 1H), 9.99 (t, 1H, J = 5.6 Hz). 415 413 37 {[5-(3-
cyanophenyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00172## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d, 2H, J = 5.7 Hz), 7.28 (s,
1H), 7.81 (t, 1H, J = 7.9 Hz), 8.08 (dt, 1H, J = 7.9, 1.0 Hz), 8.34
(d, 1H, J = 8.4 Hz), 8.48 (t, 1H, J = 1.3 Hz), 8.61 (s, 1H), 9.99
(t, 1H, J = 5.7 Hz). 338 336 38 ({5-[2-(4- cyclopropyl-
phenyl)ethyl]-7- hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl}amino) acetic acid hydrochloride ##STR00173## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 0.59- 0.64 (m, 2H), 0.88- 0.93 (m,
2H), 1.83- 1.90 (m, 1H), 3.06 (t, 2H, J = 7.9 Hz), 3.37 (t, 2H, J =
7.9 Hz), 4.21 (d, 2H, J = 5.6 Hz), 6.81 (s, 1H), 6.99 (d, 2H, J =
8.1 Hz), 7.11 (d, 2H, J = 8.1 Hz), 8.60 (s, 1H), 9.84 (t, 1H, J =
5.6 Hz). 381 379
TABLE-US-00008 TABLE 8 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta. ppm (M + H) (M - H) 39 {[5-(2,2-
dimethylpropyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00174## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 0.97 (s, 9H), 3.12 (s, 2H), 4.21
(d, 2H, J = 5.6 Hz), 6.78 (s, 1H), 8.53 (s, 1H), 9.88 (t, 1H, J =
5.6 Hz). 307 305 40 {[5-(1- ethylpropyl)-7- hydroxy[1,2,4]
triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic acid
hydrochloride ##STR00175## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 0.78 (t, 6H, J = 7.3 Hz), 1.72-1.94 (m, 4H), 3.37-3.48 (m,
1H), 4.21 (d, 2H, J = 5.6 Hz), 6.85 (s, 1H), 8.55 (s, 1H), 9.88 (t,
1H, J = 5.6 Hz). 307 305 41 {[5-(3-chloro-5- fluorophenyl)-7-
hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic
acid hydrochloride ##STR00176## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.24 (d, 2H, J = 5.8 Hz), 7.28 (s, 1H), 7.73 (dt, 1H, J =
8.7, 2.1 Hz), 7.88-7.91 (m, 1H), 7.98-8.00 (m, 1H), 8.60 (s, 1H),
9.97 (t, 1H, J = 5.6 Hz). 365 363 42 {[5-(3- fluorophenyl)-7-
hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic
acid hydrochloride ##STR00177## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.25 (d, 2H, J = 5.5 Hz), 7.21 (s, 1H), 7.47 (tdd, 1H , J
= 8.6, 2.6, 0.7 Hz), 7.64 (td, 1H, J = 8.1, 6.0 Hz), 7.87 (dt, 1H,
J = 7.8, 1.0 Hz), 7.90 (dt, 1H, J = 10.1, 2.1 Hz), 8.60 (s, 1H),
9.99 (t, 1H, J = 5.4 Hz). 331 329 43 [(7-hydroxy-5- isobutyl[1,2,4]
triazolo[1,5- a]pyridine-8- carbonyl)amino] acetic acid
##STR00178## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 0.94 (d,
6H, J = 6.9 Hz), 2.28 (tsept, 1H, J = 6.9, 7.3 Hz), 2.98 (d, 2H, J
= 7.3 Hz), 4.21 (d, 2H, J = 5.6 Hz), 6.85 (s, 1H), 8.55 (s, 1H),
9.85 (t, 1H, J = 5.6 Hz). 293 291 44 {[5-(3- chlorophenyl)-7-
hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic
acid ##STR00179## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.25
(d, 2H, J = 5.6 Hz), 7.22(s, 1H) , 7.59- 7.71 (m, 2H), 7.96 (d, 1H,
J = 7.7 Hz), 8.11 (s, 1H), 8.59 (s, 1H), 9.98 (br s, 1H), 12.99 (br
s, 1H), 14.38 (br s, 1H). 347, 349 345, 347
TABLE-US-00009 TABLE 9 Ex. compound MS MS No. name structural
fomula .sup.1H-NMR, .delta. ppm (H + H) (H - H) 45 {[5-(2-
ethylbutyl)-7- hydroxy [1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00180## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 0.85 (t, 6H, J = 7.4 Hz),
1.25-1.39 (m, 4H), 1.94-2.02 (m, 1H), 3.03 (d, 2H, J = 7.3 Hz),
4.21 (d, 2H, J = 5.5 Hz), 6.87 (s, 1H), 8.56 (s, 1H), 9.85 (t, 1H,
J = 5.5 Hz). 321 319 46 {[5-(3,5- dichlorophenyl)- 7-hydroxy[1,2,4]
triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic acid
hydrochloride ##STR00181## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.25 (d, 3H, J = 5.6 Hz), 7.30 (s, 1H), 7.89 (t, 1H, J =
3.5 Hz) ,8.08 (s, 1H), 8.09 (s, 1H), 8.61 (s, 1H), 9.99 (t, 1H, J =
5.6 Hz). 381, 383 379, 381 47 {[5-(2- cyclopropyl- ethyl)-7-
hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic
acid hydrochloride ##STR00182## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 0.00- 0.05 (2H, m), 0.35- 0.42 (2H, m), 0.72- 0.81 (1H,
m), 1.64- 1.73 (2H, m), 3.15- 3.21 (2H, m), 4.20 (2H, d, J = 5.6
Hz), 6.86 (1H, s), 8.55 (1H, s), 9.79-9.87 (1H, m). 305 303 48
{[5-(3,3- dimethylpentyl)- 7-hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid hydrochloride
##STR00183## .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta.: 0.91 (t,
3H, J = 7.6 Hz), 0.98 (s, 6H), 1.39 (q, 2H, J = 7.5 Hz), 1.70 (ddd,
2H, J= 8.7, 4.7, 3.8 Hz), 3.08-3.14 (m, 2H), 4.24 (s, 2H), 6.82 (s,
1H), 8.54 (s, 1H). 335 333 49 {[7-hydroxy-5- (3,4,5-
trifluorophenyl) [1,2,4]triazolo [1,5-a]pyridine-8- carbonyl]amino}
acetic acid hydrochloride ##STR00184## .sup.1H-NMR (DMSO-D.sub.6,
400 MHz) .delta.: 4.25 (d, 2H, J = 5.5 Hz), 7.28 (s, 1H), 8.09 (dd,
2H, J = 9.0, 6.8 Hz), 8.62 (s,1H), 9.98 (t, 1H, J = 5.1Hz). 367 365
50 {[5-(4- chlorophenyl)- 7-hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid hydrochloride
##STR00185## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d,
2H, J = 5.6 Hz), 7.17(s, 1H, 7.67 (d, 2H, J =8 .6 Hz), 8.05 (d, 2H,
J = 8.6 Hz), 8.59 (s, 1H), 9.98 (t, 1H, J = 5.6 Hz). 347 345
TABLE-US-00010 TABLE 10 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta. ppm (M + H) (M - H) 51 [(7-hydroxy-5-
(m-tolyl)[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl)amino] acetic
acid hydrochloride ##STR00186## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 2.42 (3H, s), 4.24 (2H, d, J = 5.6 Hz), 7.09 (1H, s),
7.41-7.51 (2H, 1H), 7-78-7.84 (2H, m), 8.58 (1H, s), 9.98 (1H, t, J
= 5.6 Hz). 327 325 52 {[5-(3- cyclopropyl-5- fluorophenyl)-
7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic
acid hydrochloride ##STR00187## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 0.82- 0.86 (m, 2H), 1.01- 1.06 (m, 2H), 2.03- 2.10 (m,
1H), 4.24 1H (d, 2H, J = 5.6 Hz), 7.15-7.18 (m, 1H), 7.20 (s, 1H),
7.56 (dd, 1H, J = 1.4, 1.4 Hz), 7.62-7.65 (m, 1H), 8.59, 1H), 9.98
1H, J = 5.6 Hz). 371 369 53 [(5- cyclobutylmethyl- 7-hydroxy[1,2,4]
triazolo[1,5- a]pyridine-8- carbonyl)amino] acetic acid)
hydrochloride ##STR00188## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 1.72- 1.90 (m, 4H), 1.98- 2.10 (m, 2H), 2.80- 2.92 (m,
1H), 3.20 (d, 2H, J = 7.4 Hz), 4.20 (d, 2H, J = 5.6 Hz), 6.79 (s,
1H), 8.55 (s, 1H), 9.83 (t, 1H, J = 5.6 Hz). 305 303 54 {[5-(2-
cyclobutylethyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00189## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 1.54- 1.67 (m, 2H), 1.72- 1.92 (m,
4H), 1.95- 2.06 (m, 2H), 2.26- 2.37 (m, 1H), 3.00 (t, 2H, J = 7.7
Hz), 4.21 (d, 2H, J = 5.6 Hz), 6.85 (s, 1H), 8.56 (s, 1H), 9.85 (t,
1H, J = 5.6 Hz). 319 317 55 {[5-(2-fluoro-3- trifluoromethyl
phenyl)-7- hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00190## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.24 (2H, d, J = 5.6 Hz), 7.25
(1H, s), 7.61- 7.68 (1H, m), 8.03- 8.13 (2H, m), 8.57 (1H, s),
9.87-10.01 (1H, m). 399 397
TABLE-US-00011 TABLE 11 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta. ppm (M + H) (M - H) 56
{[5-(3-chloro-2- fluorophenyl)-7- hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid hydrochloride
##STR00191## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (2H,
d, J = 5.6 Hz), 7.21 (1H, s), 7.47 (1H, dd, J = 7.9, 3.9 Hz), 7.73
(1H, dd, J = 7.1, 3.5 Hz), 7.88 (1H, dd, J = 7.7, 3.8 Hz), 8.56
(1H, s), 9.95 (1H, t, J = 5.0 Hz). 365 363 57 {[7-hydroxy-5-(4-
trifluoromethyl phenyl)[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00192## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.24 (2H, d, J = 5.6 Hz), 7.23
(1H, s), 7.96 (2H, d, J = 8.1 Hz), 8.21 (2H, d, J = 8.1 Hz), 8.59
(1H, s), 9.99 (1H, t, J = 5.3 Hz). 381 379 58 [(5-cycloheptyl-7-
hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl)amino] acetic
acid hydrochloride ##STR00193## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 1.52- 1.86 (m, 10H), 1.96- 2.04 (m, 2H), 3.50- 3.59 (m,
1H), 4.21 (d, 2H, J = 5.5 Hz), 6.78 (s, 1H), 9.86 (t, 1H, 1H), 8.56
(s, J = 5.5 Hz). 333 331 59 {[5-(2,3- difluorophenyl)-
7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic
acid hydrochloride ##STR00194## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.25 (d, 2H, J = 5.7 Hz), 7.20 (s, 1H), 7.45 (tdd, 1H, J =
8.2, 4.9, 1.4 Hz), 7.59 (ddt, 1H, J = 8.3, 5.4, 1.2 Hz), 7.70-7.77
(m, 1H), 8.56 (s, 1H), 9.95 (t, 1H, J = 5.6 Hz). 349 347 60
{[5-(2-cyclo- pentylethyl)-7- hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid hydrochloride
##STR00195## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 1.11-
1.19 (m, 2H), 1.47- 1.61 (m, 4H), 1.74- 1.87 (m, 5H), 3.10 (t, 2H,
J = 7.5 Hz), 4.21 (d, 2H, J = 5.6 Hz) 6.87 (s, 1H), 8.56 (s, 1H),
9.84 (t, 1H, J = 5.6 Hz). 333 331
TABLE-US-00012 TABLE 12 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta. ppm (M + H) (M - H) 61 {[5-(2-
fluorophenyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00196## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d, 2H, J = 5.6 Hz), 7.13 (s,
1H), 7.41- 7.48 (m, 2H), 7.66- 7.72 (m, 1H), 7.74- 7.78 (m, 1H),
8.55 (s, 1H), 9.95 (t, 1H, J = 5.6 Hz). 331 329 62 {[5-(4-chloro-2-
fluorophenyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00197## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d, 2H, J = 5.2 Hz), 7.16 (s,
1H), 7.55 (dd, 1H, J = 8.1, 1.4 Hz), 7.74 (dd, 1H, J = 10.0, 1.4
Hz), 7.81 (dd, 1H, J = 8.1, 8.1 Hz), 8.56 (s, 1H), 9.94 (t, 1H, J =
5.2 Hz). 365 363 63 {[5-(4- fluorobenzyl)- 7-hydroxy[1,2,4]
triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic acid
hydrochloride ##STR00198## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.20 (2H, d, J = 5.5 Hz), 4.46 (2H, s), 6.74 (1H, s), 7.16
(2H, dd, J = 8.9, 4.5 Hz), 7.45 (2H, dd, J = 8.6, 5.5 Hz), 8.57
(1H, s), 9.83 (1H, t, J = 5.4 Hz). 345 343 64 (R)-2-{[5-(3,5-
difluorophenyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} propionic acid hydrochloride ##STR00199##
.sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 1.52 (d, 3H, J = 7.1
Hz), 4.58-4.67 (m, 1H), 7.28 (br s, 1H), 7.51- 7.59 (m, 1H), 7.81
(d, 2H, J = 6.4 Hz), 8.62 (s, 1H), 10.08-10.15 (br m, 1H). 363 361
65 [(7-hydroxy-5- propyl[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl)amino] acetic acid hydrochloride ##STR00200## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 0.97 (t, 3H, J = 7.4 Hz), 1.80
(tq, 2H, J = 7.4, 7.4 Hz), 3.07 (t, 2H, J = 7.4 Hz), 4.21 (d, 1H, J
= 5.7 Hz), 6.85 (s, 1H), 8.56 (s, 1H), 9.84 (t, 1H, J = 5.7 Hz).
279 277
TABLE-US-00013 TABLE 13 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta. ppm (M + H) (M - H) 66 2-{[5-(3,5-
difluorophenyl)- 7-hydroxy-[1,2, 4]triazolo[1,5- a]pyridine-8-
carbonyl]amino) propionic acid hydrochloride ##STR00201##
.sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 1.52 (d, 3H, J = 7.1
Hz), 4.58-4.67 (m, 1H), 7.28 (br s, 1H), 7.51- 7.59 (m, 1H), 7.81
(d, 2H, J = 6.4 Hz), 8.62 (s, 1H), 10.08- 10.15 (br m, 1H). 363 361
67 (S)-2-{[5-(3,5- difluorophenyl)- 7-hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} propionic acid hydrochloride
##STR00202## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 1.52 (d,
3H, J = 7.1 Hz), 4.60-4.67 (m, 1H), 7.31 (s, 1H), 7.56 (t, 1H, J =
9.3 Hz), 7.82 (d, 2H, J = 6.6 Hz), 8.61 (s, 1H), 10.10 (d, 1H, J=
6.6 Hz), 13.16 (br s, 1H), 14.32 (s, 1H). 363 361 68 2-{[5-(3,5-
difluorophenyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino}- 2- methylpropionic acid hydrochloride ##STR00203##
.sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 1.63 (s, 6H), 7.27 (s,
1H), 7.51-7.60 (m, 1H), 7.76-7.83 (m, 2H), 8.61 (s, 1H), 10.15 (s,
1H). 377 375 69 (S)-2-[(7- hydroxy-5- phenethyl[1,2,4]
triazolo[1,5- a]pyridine-8- carbonyl)amino] propionic acid
hydrochloride ##STR00204## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 1.49 (d, 3H, J = 7.3 Hz), 3.12 (t, 2H, J = 7.8 Hz), 3.41
(t, 2H, J = 7.8 Hz), 4.56-4.63 (m, 1H), 6.81 (s, 1H), 7.18-7.33 (m,
5H), 8.61 (s, 1H), 9.97 (d, 1H, J = 7.1 Hz). 355 353 70 (R)-2-[(7-
hydroxy-5- phenethyl[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl)amino] propionic acid hydrochloride ##STR00205##
.sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 1.49 (d, 3H, J = 7.3
Hz), 3.12 (t, 2H, J = 7.8 Hz), 3.41 (t, 2H, J = 7.8 Hz), 4.56-4.63
(m, 1H), 6.80 (s, 1H), 7.18-7.33 (m, 5H), 8.61 (s, 1H), 9.97 (d,
1H, J = 7.1 Hz). 355 353
TABLE-US-00014 TABLE 14 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 71 [(7-hydroxy-6-
pentyl[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl) amino]acetic
acid hydrochloride ##STR00206## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 0.87 (t, 3H, J = 6.9 Hz), 1.28-1.36 (m, 4H), 1.61 (t, 2H,
J = 7.6 Hz), 2.62 (t, 2H, J = 7.6 Hz), 4.21 (d, 2H, J = 5.3 Hz),
8.50 (s, 1H), 8.88 (s, 1H), 9.93 (s, 1H), 14.81 (s, 1H). 307 305 72
{[7-hydroxy-5- (5-methyl- thiophen-2-yl) [1,2,4]triazolo
[1,5-a]pyridine- 8-carbonyl] amino}acetic acid hydrochloride
##STR00207## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 2.58 (s,
3H), 4.23 (d, 2H, J = 5.5 Hz), 7.07 (d, 1H, J = 3.7 Hz), 7.50 (s,
1H), 8.27 (d, 1H, J = 4.0 Hz), 8.67 (s, 1H), 9.85-9.90 (br m, 1H).
333 331 73 [(5-hexyl-7- hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl) amino]acetic acid hydrcchloride ##STR00208## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 0.85 (3H, t, J = 7.0 Hz),
1.23-1.41 (6H, m), 1.71-1.81 (2H, m), 3.08 (2H, t, J = 7.7 Hz),
4.20 (2H, d, J = 5.6 Hz), 6.85 (1H, s), 8.56 (1H, s), 9.79-9.86
(1H, m). 321 319 74 [(7-hydroxy-5- pentyl[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl) amino]acetic acid hydrochloride
##STR00209## .sup.1H-NMR (DMSO-D.sub.6, 400 MHZ) .delta.: 0.84-
0.91 (m, 3H), 1.29- 1.40 (m, 4H), 1.72- 1.83 (m, 2H), 3.09 (t, 2H,
J = 7.5 Hz), 4.21 (d, 2H, J = 5.4 Hz), 6.86 (s, 1H), 8.56 (s, 1H),
9.83 (t, 1H, J = 5.4 Hz). 307 305 75 {[5-(2,5- difluorophenyl)-
7-hydroxy [1,2,4]triazolo [1,5-a]pyridine- 8-carbonyl] amino}acetic
acid hydrochloride ##STR00210## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.25 (d, 2H, J = 5.6 Hz), 7.19 (s, 1H), 7.49- 7.60 (m,
2H), 7.67- 7.73 (m, 1H), 8.56 (s, 1H), 9.95 (t, 1H, J = 5.6 Hz).
349 347
TABLE-US-00015 TABLE 15 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 76 {[7-hydroxy-5-
(2,3,5- trifluorophenyl) [1,2,4]triazolo [1,5-a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00211## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d, 2H, J = 5.5 Hz), 7.25 (s,
1H), 7.58-7.64 (m, 1H), 7.86-7.93 (m, 1H), 8.59 (s, 1H), 9.95 (t,
1H, J = 5.5 Hz). 367 365 77 {[5-(2,4- difluorophenyl)-
7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic
acid hydrochloride ##STR00212## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.25 (d, 2H, J = 5.2 Hz), 7.14 (s, 1H), 7.30-7.39 (m, 1H),
7.50-7.60 (m, 1H), 7.81-7.89 (m, 1H), 8.55 (s, 1H), 9.94 (t, 1H, J
= 5.4 Hz). 349 347 78 {[5-{4-chloro- 3-fluorophenyl)-
7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic
acid hydrochloride ##STR00213## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.24 (d, 2H, J = 5.6 Hz), 7.26 (s, 1H), 7.82-7.86 (m, 1H),
7.93 (dd, 1H, J = 8.5, 1.6 Hz), 8.13 (dd, 1H, J = 10.5, 2.0 Hz),
8.61 (s, 1H), 9.98 (t, 1H, J = 5.4 Hz). 365 363 79 {[5-(3-fluoro-
5-methylphenyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid hydrochloride ##STR00214## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 2.43 (s, 3H), 4.25 (d, 2H, J = 5.3
Hz), 7.18 (s, 1H), 7.32 (d, 1H, J = 9.3 Hz), 7.70 (d, 2H, J = 10.4
Hz), 8.60 (d, 1H, J = 0.7 Hz), 9.99 (t, 1H, J = 5.3 Hz). 345 343 80
[(6-chloro-7- hydroxy-5- phenethyl[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl)amino] acetic acid hydrochloride
##STR00215## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 3.05 (t,
2H, J = 7.8 Hz), 3.56 (t, 2H, J = 7.8 Hz), 4.17 (d, 2H, J = 5.1
Hz), 7.16-7.22 (m, 3H), 7.23-7.29 (m, 2H), 8.60 (s, 1H). 375 373 81
[(6-chloro-7- hydroxy-5- propyl[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl)amino] acetic acid hydrochloride ##STR00216## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 3.09 (t, 2H, J = 7.8 Hz), 3.28 (t,
2H, J = 7.8 Hz), 4.25 (d, 2H, J = 5.6 Hz), 7.16-7.32 (m, 5H), 7.36
(s, 1H), 8.68 (s, 1H), 10.42 (t, 1H, J = 5.6 Hz), 13.26 (s, 1H).
313 311
TABLE-US-00016 TABLE 16 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 82 {[5-(4-
cyclopropyl-2- fluorophenyl)- 7-hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid hydrochloride
##STR00217## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 0.82-
0.86 (m, 2 H), 1.05- 1.10 (m, 2H), 2.04- 2.11 (m, 1H), 4.24 (d, 2H,
J = 5.6 Hz), 7.06 (s, 1H), 7.14 (d, 1H, J = 8.1 Hz), 7.15 (d, 1H, J
= 7.7 Hz), 7.62 (dd, 1H, J = 7.7, 7.7 Hz), 8.53 (s, 1H), 9.94 (t,
1H, J = 5.6 Hz). 371 369 83 [(6-hydroxy-8- phenyl[1,2,4]
triazolo[1,5- a]pyridine-5- carbonyl)amino] acetic acid
hydrochloride ##STR00218## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.28 (d, 2H, J = 5.5 Hz), 7.50-7.63 (m, 3H), 7.80 (s, 1H),
8.21 (d, 2H, J = 7.3 Hz), 8.74 (s, 1H), 10.53 (t, 1H, J = 5.5 Hz),
13.36 (s, 1H). 313 311 84 {[8-(3- chlorophenyl)- 6-hydroxy[1,2,4]
triazolo[1,5- a]pyridine-5- carbonyl]amino} acetic acid
##STR00219## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.28 (d,
2H, J = 5.6 Hz), 7.58-7.64 (m, 2H), 7.92 (s, 1H), 8.15- 8.21 (m,
1H), 8.37- 8.39 (m, 1H), 8.76 (s, 1H), 10.54 (t, 1H, J = 5.4 Hz),
13.06 (s, 1H), 13.36 (s, 1H). 347 345 85 {[8-(3,5- difluorophenyl)-
6-hydroxy[1,2,4] triazolo[1,5- a]pyridine-5- carbonyl]amino} acetic
acid hydrochloride ##STR00220## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.28 (d, 2H, J = 5.6 Hz), 7.47 (tt, 1H, J = 9.3, 2.3 Hz),
8.03 (s, 1H), 8.06-8.14 (m, 2H), 8.78 (s, 1H), 10.54 (t, 1H, J =
5.4 Hz), 13.35 (s, 1H). 349 347 86 [(8-benzyl-6- hydroxy[1,2,4]
triazolo[1,5- a]pyridine-5- carbonyl)amino] acetic acid
hydrochloride ##STR00221## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.24 (d, 2H, J = 5.6 Hz), 4.33 (s, 2H), 7.20- 7.25 (m,
1H), 7.28- 7.33 (m, 2H), 7.35 (s, 1H), 7.38-7.41 (m, 2H), 8.66 (s,
1H), 10.40 (t, 1H, J = 5.6 Hz), 13.27 (s, 1H). 327 325
TABLE-US-00017 TABLE 17 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 87 [(6-hydroxy-8-
phenethyl[1,2,4] triazolo[1,5- a]pyridine-5- carbonyl)amino] acetic
acid hydrochloride ##STR00222## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 3.09 (t, 2H, J = 7.8 Hz), 3.28 (t, 2H, J = 7.8 Hz), 4.25
(d, 2H, J = 5.6 Hz), 7.16-7.32 (m, 5H), 7.36 (s, 1H), 8.68 (s, 1H),
10.42 (t, 1H, J = 5.6 Hz), 13.26 (s, 1H). 341 339 88 {[8-(2-
chlorophenyl)- 6-hydroxy[1,2,4] triazolo[1,5- a]pyridine-5-
carbonyl]amino} acetic acid ##STR00223## .sup.1H-NMR (DMSO-D.sub.6,
400 MHz) .delta.: 4.28 (d, 2H, J = 5.6 Hz), 7.49-7.59 (m, 2H),
7.60-7.63 (m, 2H), 7.67 (dd, 1H, J = 7.9, 1.4 Hz), 8.66 (s, 1H),
10.50 (t, 1H, J = 5.6 Hz), 13.06 (s, 1H), 13.37 (s, 1H). 347 345 89
{[8-(3,5- dichlorophenyl)- 6-hydroxy[1,2,4] triazolo[1,5-
a]pyridine-5- carbonyl]amino} acetic acid hydrochloride
##STR00224## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.28 (d,
2H, J = 5.3 Hz), 7.80 (t, 1H, J = 1.9 Hz), 8.03 (s, 1H), 8.36 (d,
2H, J = 1.8 Hz), 8.77 (s, 1H), 10.53 (t, 1H, J = 5.3 Hz), 13.34 (s,
1H). 381 379 90 ({8-[2-(4- fluorophenyl) ethyl]-6- hydroxy[1,2,4]
triazolo[1,5- a]pyridine-5- carbonyl}amino) acetic acid
hydrochloride ##STR00225## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 3.09 (t, 2H, J = 7.9 Hz), 3.27 (t, 2H, J = 7.7 Hz), 4.25
(d, 2H, J = 5.5 Hz), 7.10 (t, 2H, J = 8.9 Hz), 7.26 (dd, 2H, J =
8.7, 5.8 Hz), 7.35 (s, 1H), 8.66 (s, 1H), 10.42 (t, 1H, J = 5.3
Hz), 13.26 (s, 1H). 359 357 91 [(8- cyclohexylmethyl-
6-hydroxy[1,2,4] triazolo[1,5-a] pyridine-5- carbonyl)amino] acetic
acid hydrochloride ##STR00226## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 0.94- 1.23 (m, 5H), 1.53-1.70 (m, 5H), 1.80-1.94 (m, 1H),
2.86 (d, 2H, J = 7.2 Hz), 4.25 (d, 2H, J = 5.6 Hz), 7.36 (s, 1H),
8.62 (s, 1H), 10.42 (t, 1H, J = 5.6 Hz), 13.28 (s, 1H). 333 331
TABLE-US-00018 TABLE 18 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 92 [(8-cyclohexyl-
6-hydroxy[1,2,4] triazolo[1,5- a]pyridine-5- carbonyl)amino] acetic
acid hydrochloride ##STR00227## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 1.23- 1.34 (m, 1H), 1.38- 1.49 (m, 2H), 1.57- 1.67 (m,
2H), 1.73- 1.77 (m, 1H), 1.82- 1.86 (m, 2H), 1.91- 1.96 (m, 2H),
3.15- 3.22 (m, 1H), 4.25 (d, 2H, J = 5.6 Hz), 7.33 (s, 1H), 8.63
(s, 1H), 10.42 (t, 1H, J = 5.6 Hz), 13.29 (s, 1H). 319 317 93
[(8-cyclohex-1- enyl-6-hydroxy [1,2,4]triazolo [1,5-a]pyridine-
5-carbonyl) amino] acetic acid hydrochloride ##STR00228##
.sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 1.62- 1.68 (m, 2H),
1.74- 1.80 (m, 2H), 2.31- 2.35 (m, 2H), 2.49- 2.54 (m, 2H), 4.25
(d, 2H, J = 5.6 Hz), 7.33 (s, 1H), 7.58-7.61 (m, 1H), 8.66 (s, 1H),
10.48 (t, 1H, J = 5.6 Hz), 13.28 (s, 1H). 317 315 94 {[8-(3-chloro-
4-fluorophenyl)- 6-hydroxy[1,2,4] triazolo[1,5- a]pyridine-5-
carbonyl]amino} acetic acid hydrochloride ##STR00229## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.28 (d, 2H, J = 5.5 Hz), 7.64 (t,
1H, J = 8.9 Hz), 7.94 (s, 1H), 8.29 (dq, 1H, J = 8.7, 2.3 Hz), 8.57
(dd, 1H, J = 7.2, 2.3 Hz), 8.77 (s, 1H), 10.52 (t, 1H, J = 5.5 Hz),
13.36 (s, 1H). 365 363 95 {[8-(3,4- dichlorophenyl)-
6-hydroxy[1,2,4] triazolo[1,5- a]pyridine-5- carbonyl]amino} acetic
acid hydrochloride ##STR00230## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.28 (d, 2H, J = 5.5 Hz), 7.84 (d, 1H, J = 8.4 Hz), 7.97
(s, 1H), 8.25 (dd, 1H, J = 8.4, 2.2 Hz), 8.60 (d, 1H, J = 2.2 Hz),
8.77 (s, 1H), 10.52 (t, 1H, J = 5.5 Hz), 13.35 (s, 1H). 381 379
TABLE-US-00019 TABLE 19 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 96 {[8-(5-
chlorothiophen- 2-yl)-6- hydroxy[1,2,4] triazolo[1,5- a]pyridine-5-
carbonyl]amino} acetic acid hydrochloride ##STR00231## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.26 (d, 2H, J = 5.5 Hz), 7.35 (d,
1H, J = 4.2 Hz), 8.06 (s, 1H), 8.22 (d, 1H, J = 4.2 Hz), 8.78 (s,
1H), 10.41 (t, 1H, J = 5.5 Hz), 13.35 (s, 1H). 353 351 97
{[8-(3,5-bis- trifluoromethyl phenyl)-6- hydroxy[1,2,4]
triazolo[1,5- a]pyridine-5- carbonyl]amino} acetic acid
hydrochloride ##STR00232## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.29 (d, 2H, J = 5.5 Hz), 8.24 (s, 1H), 8.29 (s, 1H), 8.82
(s, 1H), 8.98 (s, 2H), 10.55 (t, 1H, J = 5.5 Hz), 13.36 (s, 1H).
449 447 98 {[8-(2- cyclohexylethyl)- 6-hydroxy[1,2,4] triazolo[1,5-
a]pyridine-5- carbonyl]amino} acetic acid hydrochloride
##STR00233## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 0.85-
1.34 (m, 6H), 1.53- 1.82 (m, 7H), 2.94- 3.02 (m, 2H), 4.25 (d, 2H,
J = 5.6 Hz),7.40 (s, 1H), 8.63 (s, 1H), 10.41 (t, 1H, J = 5.6 Hz),
13.28 (s, 1H). 347 345 99 {[8-(2- cyclopentylethyl)-
6-hydroxy[1,2,4] triazolo[1,5- a]pyridine-5- carbonyl]amino} acetic
acid hydrochloride ##STR00234## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 1.07- 1.22 (m, 2H), 1.41- 1.65 (m, 4H), 1.70- 1.86 (m,
5H), 2.93- 3.02 (m, 2H), 4.25 (d, 2H, J = 5.6 Hz), 7.40 (s, 1H),
8.64 (s, 1H), 10.41 (t, 1H, J = 5.6 Hz), 13.28 (s, 1H). 333 331 100
({6-hydroxy-8- [2-(2- trifluoromethyl phenyl)ethyl] [1,2,4]triazolo
[1,5-a]pyridine- 5-carbonyl}amino) acetic acid hydrochloride
##STR00235## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 3.21-
3.35 (m, 4H), 4.25 (d, 2H, J = 5.6 Hz), 7.38 (s, 1H), 7.44 (t, 1H,
J = 7.5 Hz), 7.56 (d, 1H, J = 7.7 Hz), 7.63 (t, 1H, J = 7.7 Hz),
7.70 (d, 1H, J = 7.5 Hz), 8.68 (s, 1H), 10.43 (t, 1H, J = 5.6 Hz),
13.28 (s, 1H). 409 407
TABLE-US-00020 TABLE 20 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 101 ({6-hydroxy-
8-[2-(3- trifluoromethyl phenyl)ethyl] [1,2,4]triazolo
[1,5-a]pyridine- 5-carbonyl} amino) acetic acid hydrochloride
##STR00236## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 3.20 (dd,
2H, J = 9.4, 6.5 Hz), 3.32 (dd, 2H, J = 9.4, 6.5 Hz), 4.25 (d, 2H,
J = 5.6 Hz), 7.40 (s, 1H), 7.49-7.59 (m, 3H), 7.63 (s, 1H), 8.68
(s, 1H), 10.42 (t, 1H, J = 5.6 Hz), 13.27 (s, 1H). 409 407 102
({6-hydroxy- 8-[2-(4- trifluoromethyl phenyl)ethyl] [1,2,4]triazolo
[1,5-a]pyridine- 5-carbonyl} amino) acetic acid hydrochloride
##STR00237## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 3.17-
3.24 (m, 2H), 3.28- 3.36 (m, 2H), 4.25 (d, 2H, J = 5.6 Hz), 7.40
(s, 1H), 7.48 (d, 2H, J = 7.9 Hz), 7.65 (d, 2H, J = 7.9 Hz), 8.68
(s, 1H), 10.42 (t, 1H, J = 5.6 Hz), 13.27 (s, 1H). 409 407 103
{[8-(3-chloro- 5-cyclopropyl- phenyl)-6- hydroxy[1,2,4]
triazolo[1,5- a]pyridine-5- carbonyl] amino} acetic acid
hydrochloride ##STR00238## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 0.84- 0.90 (m, 2H), 1.01- 1.06 (m, 2H), 2.03- 2.10 (m,
1H), 4.28 (d, 2H, J = 5.4 Hz), 7.31 (dd, 1H, J = 1.8, 1.8 Hz), 7.83
(dd, 1H, J = 1.8, 1.8 Hz), 7.93 (s, 1H), 8.13 (dd, 1H, J = 1.8, 1.8
Hz), 8.75 (s, 1H), 10.53 (t, 1H, J = 5.4 Hz), 13.35 (s, 1H). 387
385 104 {[8-(3-fluoro-5- trifluoromethyl phenyl)-6- hydroxy[1,2,4]
triazolo[1,5- a]pyridine-5- carbonyl] amino} acetic acid
hydrochloride ##STR00239## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.29 (d, 2H, J = 5.5 Hz), 7.89 (d, 1H, J = 8.6 Hz), 8.12
(s, 1H), 8.46 (d, 1H, J = 8.6 Hz), 8.63 (s, 1H), 8.80 (s, 1H),
10.54 (t, 1H, J = 5.5 Hz), 13.36 (s, 1H). 399 397 105
{[8-(3-chloro-5- fluorophenyl)- 6-hydroxy [1,2,4] triazolo[1,5-
a]pyridine- carbonyl] amino} acetic acid hydrochloride ##STR00240##
.sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.28 (d, 2H, J = 5.3
Hz), 7.62-7.67 (m, 1H), 8.03 (s, 1H), 8.13- 8.19 (m, 1H), 8.31 (s,
1H), 8.78 (s, 1H), 10.54 (t, 1H, J = 5.3 Hz), 13.35 (s, 1H). 365
363
TABLE-US-00021 TABLE 21 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 106 {[8-(4-fluoro-
3-trifluoromethyl phenyl)-6- hydroxy[1,2,4] triazolo[1,5-
a]pyridine-5- carbonyl]amino} acetic acid hydrochloride
##STR00241## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 4.29 (d,
2H, J = 5.6 Hz), 7.71-7.80 (m, 1H), 8.03 (s, 1H), 8.56- 8.63 (m,
1H), 8.73- 8.82 (m, 2H), 10.53 (t, 1H, J = 5.6 Hz), 13.37 (s, 1H).
399 397 107 [(6- hydroxy[1,2,4] triazolo[1,5- a]pyridine-5-
carbonyl)amino] acetic acid hydrochloride ##STR00242## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.27 (d, 2H, J = 5.3 Hz), 7.56 (d,
1H, J = 9.7 Hz), 8.09 (d, 1H, J = 9.7 Hz), 8.68 (s, 1H), 10.49 (t,
1H, J = 5.3 Hz), 13.29 (br s, 1H). 237 235 108 {[8-(4-
chlorophenyl)- 6-hydroxy[1,2,4] triazolo[1,5- a]pyridine-5-
carbonyl]amino} acetic acid ##STR00243## .sup.1H-NMR (DMSO-D.sub.6,
400 MHz) .delta.: 4.24 (d, 2H, J = 5.2 Hz), 7.62-7.67 (m, 2H), 7.86
(s, 1H), 8.26- 8.31 (m, 2H), 8.74 (s, 1H), 10.53 (t, 1H, J = 5.2
Hz), 13.31 (br s, 1H). 347 345 109 ({8-[2-(3,5- difluoro-
phenyl)ethyl]- 6-hydroxy[1,2,4] triazolo[1,5- a]pyridine-5-
carbonyl}amino) acetic acid hydrochloride ##STR00244## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 3.13 (t, 2H, J = 7.9 Hz), 3.30 (t,
2H, J = 7.9 Hz), 4.25 (d, 2H, J = 5.2 Hz), 6.98-7.08 (m, 3H), 7.40
(s, 1H), 8.67 (s, 1H), 10.42 (t, 1H, J = 5.2 Hz), 13.27 (br s, 1H).
377 375 110 {[6-hydroxy-8- (3- trifluoromethyl phenyl)[1,2,4]
triazolo[1,5- a]pyridine-5- carbanyl]amino} acetic acid
hydrochloride ##STR00245## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 4.29 (d, 2H, J = 5.5 Hz), 7.82 (t, 1H, J = 7.9 Hz), 7.91
(d, 1H, J = 7.9 Hz), 8.00 (s, 1H), 8.48 (d, 1H, J = 7.9 Hz), 8.70
(s, 1H), 8.78 (s, 1H), 10.54 (t, 1H, J = 5.5 Hz), 13.36 (br s, 1H).
381 379
TABLE-US-00022 TABLE 22 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 111 [(7-hydroxy-
3,6- diphenyl[1,2,4] triazolo[4,3- a]pyridine-8- carbonyl)amino]
acetic acid hydrochloride ##STR00246## .sup.1H-NMR (DMSO-D.sub.6,
400 MHz) .delta.: 4.09 (d, 2H, J = 5.5 Hz), 7.36-7.44 (m, 3H),
7.57-7.66 (m, 5H), 7.90 (d, 2H, J = 7.3 Hz), 8.00 (s, 1H), 10.56
(t, 1H, J = 5.3 Hz), 12.61 (s, 1H), 13.95 (s, 1H). 389 387 112
[(7-hydroxy-3- methyl-6- phenyl[1,2,4] triazolo[4,3- a]pyridine-8-
carbonyl)amino] acetic acid hydrochloride ##STR00247## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 2.62 (s, 3H), 4.05 (d, 2H, J = 5.5
Hz), 7.39- 7.46 (m, 3H), 7.63 (d, 2H, J = 6.8 Hz), 8.21 (s, 1H),
10.54 (t, 1H, J = 5.3 Hz), 12.58 (s, 1H), 13.44 (s, 1H). 327 325
113 [(7-hydroxy-3- phenyl[1,2,4] triazolo[4,3- a]pyridine-8-
carbonyl)amino] acetic acid ##STR00248## .sup.1H-NMR (DMSO-D.sub.6,
400 MHz) .delta.: 4.06- 4.24 (m, 2H), 6.47- 6.74 (m, 1H), 7.58-
7.71 (m, 3H), 7.78- 7.89 (m, 2H), 7.99- 8.42 (m, 1H), 9.99- 10.43
(m, 1H). 313 311 114 [(7-hydroxy-3- phenethyl[1,2,4] triazolo[4,3-
a]pyridine-8- carbonyl)amino] acetic acid hydrochloride
##STR00249## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 3.08 (t,
2H, J = 7.7 Hz), 3.28 (t, 2H, J = 7.7 Hz), 4.05 (d, 2H, J = 5.2
Hz), 6.46 (d, 1H, J = 7.3 Hz), 7.16-7.25 (m, 1H), 7.26-7.32 (m,
4H), 8.19 (d, 1H, J= 7.3 Hz), 10.33 (br s, 1H), 13.52 (br s, 1H).
341 339 115 {[3-(2- cyclohexylethyl)- 7-hydroxy[1,2,4]
triazolo[4,3- a]pyridine-8- carbonyl]amino} acetic acid
hydrochloride ##STR00250## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz)
.delta.: 0.90- 0.98 (m, 2H), 1.17- 1.22 (m, 3H), 1.28- 1.40 (m,
1H), 1.62- 1.67 (m, 5H), 1.75- 1.78 (m, 2H), 2.96 (t, 2H, J = 7.9
Hz), 4.04 (d, 2H, J = 5.2 Hz), 6.52 (d, 1H, J = 7.7 Hz), 8.21 (d,
1H, J = 7.7 Hz), 10.28 (br s, 1H). 347 345
TABLE-US-00023 TABLE 23 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 116 [(7-hydroxy-5-
phenethyl[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl)amino] acetic
acid ##STR00251## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 3.12
(t, 2H, J = 7.9 Hz), 3.40 (t, 3H, J = 7.9 Hz), 4.22 (d, 2H, J = 5.2
Hz), 6.79 (s, 1H), 7.21-7.29 (m, 5H), 8.58 (s, 1H), 9.84 (t, 1H, J
= 5.2 Hz), 12.97 (s, 1H), 14.22 (s, 1H). 341 339 117 [(5-butyl-7-
hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl)amino] acetic
acid ##STR00252## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.: 0.93
(t, 3H, J = 7.5 Hz), 1.33-1.44 (m, 2H), 1.71-1.80 (m, 2H), 3.10 (t,
2H, J = 7.5 Hz), 4.20 (d, 2H, J = 5.2 Hz), 6.85 (s, 1H), 8.55 (s,
1H), 9.84 (br s, 1H), 14.26 (br s, 1H). 293 291 118 {[5-(3-fluoro-
5- trifluoromethyl phenyl)-7- hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid ##STR00253## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.25 (d, 2H, J = 5.1 Hz), 7.39 (s,
1H), 7.99 (d, 1H, J = 8.6 Hz), 8.23 (d, 1H, J = 9.5 Hz), 8.31 (s,
1H), 8.62 (s, 1H), 9.98 (s, 1H), 13.01 (s, 1H), 14.41 (s, 1H). 399
397 119 [(7-hydroxy-5- pentyl[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl)amino] acetic acdd ##STR00254## .sup.1H-NMR (DMSO-D.sub.6,
400 MHz) .delta.: 0.88 (t, 3H, J = 7.6 Hz), 1.28- 1.40 (m, 4H),
1.73- 1.83 (m, 2H), 3.09 (t, 2H, J = 7.6 Hz), 4.21 (d, 2H, J = 5.5
Hz), 6.85 (s, 1H), 8.54 (s, 1H), 9.84 (t, 1H, J = 5.5 Hz), 12.94
(s, 1H), 14.25 (s, 1H). 307 305
TABLE-US-00024 TABLE 24 Ex. compound MS MS No. name structural
formula .sup.1H-NMR, .delta.ppm (M + H) (M - H) 120 {[5-(3-
chlorophenyl)- 7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8-
carbonyl]amino} acetic acid ##STR00255## .sup.1H-NMR (DMSO-D.sub.6,
400 MHz) .delta.: 4.24 (d, 2H, J = 5.3 Hz), 7.22 (s, 1H), 7.58-7.70
(m, 2H), 7.96 (d, 1H, J = 7.7 Hz), 8.11 (s, 1H), 8.59 (s, 1H), 9.97
(s, 1H), 14.38 (s, 1H). 347 345 121 {[5-(4-fluoro-
3-trifluoromethyl phenyl)-7- hydroxy[1,2,4] triazolo[1,5-
a]pyridine-8- carbonyl]amino} acetic acid ##STR00256## .sup.1H-NMR
(DMSO-D.sub.6, 400 MHz) .delta.: 4.24 (2H, d, J = 5.6 Hz), 7.30
(1H, s), 7.77 (1H, dd, J = 10.5, 9.3 Hz), 8.36-8.40 (1H, m), 8.47
(1H, d, J = 6.9 Hz), 8.60 (1H, s), 9.97 (1H, br s), 14.38 (1H, br
s). 399 397 122 {[5-(3- cyclopropyl-5- fluorophenyl)-
7-hydroxy[1,2,4] triazolo[1,5- a]pyridine-8- carbonyl]amino} acetic
acid ##STR00257## .sup.1H-NMR (DMSO-D.sub.6, 400 MHz) .delta.:
0.81-0.87 (m, 2H), 1.00-1.07 (m, 2H), 2.03-2.10 (m, 1H), 4.22 (d,
2H, J = 5.6 Hz), 7.13-7.23 (m, 2H), 7.56 (s, 1H), 7.63 (d, 1H, J =
9.3 Hz), 8.58 (s, 1H), 9.99 (s, 1H), 14.36 (s, 1H). 371 369
[0730] Examples of the Formulation Example of the present invention
include the following formulations. However, the present invention
is not limited by such Formulation Examples.
Formulation Example 1
Production of Capsule
TABLE-US-00025 [0731] 1) compound of Example 1 30 mg 2)
microcrystalline cellulose 10 mg 3) lactose 19 mg 4) magnesium
stearate 1 mg
[0732] 1), 2), 3) and 4) are mixed and filled in a gelatin
capsule.
Formulation Example 2
Production of Tablet
TABLE-US-00026 [0733] 1) compound of Example 1 10 g 2) lactose 50 g
3) cornstarch 15 g 4) carmellose calcium 44 g 5) magnesium stearate
1 g
[0734] The total amount of 1), 2), 3) and 30 g of 4) are kneaded
with water, vacuum dried and sieved. The sieved powder is mixed
with 14 g of 4) and 1 g of 5), and the mixture is tableted by a
tableting machine. In this way, 1000 tablets containing 10 mg of
the compound of Example 1 per tablet are obtained.
[0735] Next, the evaluation methods of the human PHD inhibitory
activity and human EPO production-inducing activity of the compound
of the present invention or a pharmaceutically acceptable salt
thereof, or a solvate thereof are explained.
Experimental Example 1
Measurement of Human PHD Inhibitory Activity
i) Expression and Purification of Human PHD2
[0736] Human PHD2 was expressed in insect cell (Sf9 cell). FLAG-tag
was inserted into the N-terminal in the translational region of
human PHD2-registered sequence (NM.sub.--022051), and the sequence
was introduced into a pVL1393 vector, and the sequence was
confirmed. The vector and baculovirus were cotransfected into Sf9,
and human PHD2 expression baculovirus was isolated in Sf9. By using
the virus, human PHD2-expressed cell was prepared. After the cell
was cultured at 27.degree. C. for 72 hr, cell lysing solution
containing various protease inhibitors was added, and the cell was
disrupted by sonication. The cell lysate was flowed into a column
filled with ANTI-FLAG M2 Affinity Gel Freezer Safe (SIGMA), washed,
and the N-terminal FLAG-tag-added human PHD2 was eluted and
collected. The purification product was confirmed to be human PHD2
enzyme by Western-Blotting using an anti-FLAG antibody and an
anti-PHD2 antibody.
ii) Expression and Purification of VBC Complex
[0737] VBC complex (VHL/Elongin B/Elongin C) was expressed in
Escherichia coli (BL21(DE3)). GST-fusion was inserted into the
N-terminal in the translational region of human VHL-registered
sequence (NM.sub.--000551). FLAG-tag was inserted into the
N-terminal in the translational region of human Elongin
B-registered sequence (NM.sub.--207013), and the sequences were
introduced into a pETDuet-1 vector, and the sequences were
confirmed. His-tag was inserted into the N-terminal in the
translational region of human Elongin C-registered sequence
(NM.sub.--005648), and the sequence was introduced into a
pRSFDuet-1 vector, and the sequence was confirmed. After these
expression vectors were transfected into Escherichia coli
(BL21(DE3)), Escherichia coli was cultured at 37.degree. C. in the
medium containing IPTG. The collected Escherichia coli was
disrupted by sonication and flowed into a column filled with
Ni--NTA superflow (QIAGEN), washed, and the product was eluted and
collected. The eluate was flowed into a column filled with
Glutathione Sepharose 4B, washed, and the product was eluted and
collected. The purification product was confirmed to be human
VHL.cndot.human Elongin B and human Elongin C by Western-Blotting
using an anti-GST antibod.cndot.an anti-FLAG antibody and an
anti-His antibody.
iii) Binding Activity of VBC Complex
[0738] The binding activity of the VBC complex obtained in the
aforementioned ii) to 19 residues of Biotin-labeled partial peptide
(HIF-1.alpha.-C19) based on the sequence of HIF-la or
Biotin-labeled partial peptide (HIF-1.alpha.-C19 (Hyp)) wherein
proline residue in said sequence is hydroxylated was measured on
streptavidin Coated Plate. For detection, ELISA using an anti-GST
antibody was performed, and binding of VBC complex only to
hydroxylated HIF-la partial peptide was confirmed.
iv) Measurement of Human PHD Inhibitory Activity
[0739] As for human PHD2 enzyme activity, hydroxylation of proline
residue contained in the 19 residues of the partial peptide based
on the sequence of HIF-la as a substrate was measured by TR-FRET
(Time-Resolved Fluorescence Resonance Energy Transfer) method.
[0740] The enzyme and substrate were each diluted with 50 mM
tris-hydrochloride buffer (pH 7.5) containing 50 .mu.M iron
sulfate, 120 mM NaCl, 0.1% BSA, 0.1 mM ascorbic acid, 10 .mu.M
2-oxoglutaric acid, 0.2 mM CHAPS, and the test compound was diluted
with dimethyl sulfoxide (DMSO).
[0741] A test compound and a substrate solution were added to a
96-well plate. The reaction was started by addition of a human PHD2
enzyme solution (final concentration 1 nM) to the reaction system.
After incubation at 25.degree. C. for 30 min, a stop solution
containing EDTA was added, and a VBC complex solution containing
europium (Eu) and Xlent was added, and the amount of hydroxylated
proline residue was quantified by time-resolved fluorescence
spectroscopy. The time-resolved fluorescence in each well was
measured, and the human PHD inhibitory activity (%) of the test
compound was calculated based on the values of enzyme non-addition
well and test compound non-addition well. The human PHD inhibitory
activity of each compound is shown by IC.sub.50 (.mu.M) or as human
PHD inhibitory activity (%) at 30 .mu.M in the following Tables 25
to 29. In these Tables, the values consisting solely of numbers
show IC.sub.50 (.mu.M) and those containing % show human PHD
inhibitory activity (%) at 30 .mu.m.
TABLE-US-00027 TABLE 25 Ex. IC.sub.50 (.mu.M) or inhibitory
activity No. (%) at 30 .mu.M in vitro 1 0.42 2 0.22 3 0.45 4 7.15 5
1.17 6 0.87 7 1.59 8 0.49 9 1.57 10 1.33 11 0.29 12 0.82 13 1.31 14
0.23 15 1.80 16 0.32 17 0.29 18 0.48 19 0.26 20 0.59 21 0.25 22
0.21 23 0.19 24 0.57 25 0.25 26 0.33 27 0.74 28 1.38 29 0.92
TABLE-US-00028 TABLE 26 Ex. IC.sub.50 (.mu.M) or inhibitory
activity No. (%) at 30 .mu.M in vitro 30 0.98 31 0.80 32 0.38 33
0.46 34 0.43 35 0.88 36 0.72 37 0.20 38 0.59 39 1.25 40 0.87 41
0.26 42 0.24 43 0.93 44 0.20 45 0.92 46 0.29 47 0.56 48 0.59 49
0.24 50 0.18 51 0.26 52 0.89 53 0.50 54 0.44 55 0.23 56 0.19 57
0.20 58 0.55
TABLE-US-00029 TABLE 27 Ex. IC.sub.50 (.mu.M) or inhibitory
activity No. (%) at 30 .mu.M in vitro 59 0.26 60 0.74 61 0.22 62
0.28 63 0.36 64 6.88 65 0.72 66 1.50 67 0.90 68 5.94 69 1.62 70 38%
71 2.47 72 0.40 73 7.09 74 0.85 75 0.21 76 0.22 77 0.24 78 0.15 79
0.23 80 0.71 81 6.09 82 0.15 83 0.19 84 0.11 85 0.16 86 0.83 87
0.37
TABLE-US-00030 TABLE 28 Ex. IC.sub.50 (.mu.M) or inhibitory
activity No. (%) at 30 .mu.M in vitro 88 0.16 89 0.12 90 0.29 91
1.53 92 0.69 93 0.51 94 0.11 95 0.12 96 0.29 97 0.13 98 1.13 99
0.87 100 0.82 101 0.37 102 0.51 103 0.18 104 0.19 105 0.10 106 0.23
107 0.65 108 0.16 109 0.17 110 0.15 111 1.10 112 3.09 113 0.56 114
1.20 115 1.80
TABLE-US-00031 TABLE 29 Ex. IC.sub.50 (.mu.M) or inhibitory
activity No. (%) at 30 .mu.M in vitro 116 0.18 117 0.39 118 0.64
119 0.64 120 0.12 121 0.33 122 0.96
Experimental Example 2
Human EPO Production Activity
[0742] The activity of the test compound on human EPO production
was measured using Hep3B (AMC) established from human liver-derived
cell line.
[0743] Hep3B cells were cultured in Eagle-MEM medium containing 10%
fetal bovine serum, and the test compound was diluted with dimethyl
sulfoxide (DMSO).
[0744] Hep3B cells were cultured in a 96-well plate, and a test
compound was added at each concentration 24 hr later. After
incubation at 37.degree. C. for 24 hr, the culture supernatant was
collected. The concentration of human EPO produced in the culture
supernatant was measured using a human EPO-ELISA kit (manufactured
by StemCell Technologies, 01630) according to the manufacturer's
explanation, and the human EPO production activity (%) of the test
compound was calculated based on the maximum value of production
under the above conditions and the value without addition of the
test compound. The human EPO production activity of each compound
is shown by EC.sub.50 (.mu.M) or as human EPO production activity
(%) at 30 .mu.M in the following Tables 30 to 34. In these Tables,
the values consisting solely of numbers show EC.sub.50 (.mu.M) and
those containing % show human EPO production activity (%) at 30
.mu.m.
TABLE-US-00032 TABLE 30 Ex. EC.sub.50 (.mu.M) or production
activity No. (%) at 30 .mu.M in vitro 1 9.9 2 10.9 3 12.4 4 38% 5
11.5 6 20.8 7 18.4 8 13.4 9 1% 10 0% 11 1% 12 5% 13 1% 14 5.1 15
29.1 16 7.0 17 8.8 18 6.1 19 6.6 20 6.6 21 12.0 22 13.7 23 7.8 24
5.4 25 14.1 26 7.5 27 7.7 28 13.9 29 11.3
TABLE-US-00033 TABLE 31 Ex. EC.sub.50 (.mu.M) or production
activity No. (%) at 30 .mu.M in vitro 30 15.4 31 12.1 32 15.6 33
10.1 34 15.0 35 43% 36 10.5 37 11% 38 8.7 39 22.3 40 17.7 41 9.1 42
14.2 43 23.6 44 10.4 45 9.9 46 4.8 47 12.0 48 4.5 49 11.7 50 5.6 51
9.1 52 10.4 53 8.9 54 4.5 55 8.9 56 8.4 57 4.7 58 4.7
TABLE-US-00034 TABLE 32 Ex. EC.sub.50 (.mu.M) or production
activity No. (%) at 30 .mu.M in vitro 59 49% 60 8.4 61 28.8 62 10.1
63 19.7 64 0% 65 49% 66 21.1 67 14.3 68 0% 69 12.0 70 1% 71 15.8 72
4.0 73 34% 74 8.3 75 23.7 76 18.0 77 18.7 78 6.6 79 7.8 80 23.3 81
33% 82 5.4 83 20.7 84 11.0 85 20.6 86 6% 87 18.5
TABLE-US-00035 TABLE 33 Ex. EC.sub.50 (.mu.M) or production
activity No. (%) at 30 .mu.M in vitro 88 14% 89 4.2 90 16.6 91 43%
92 18.5 93 16.0 94 9.7 95 4.3 96 5.9 97 3.5 98 25.6 99 20.2 100
18.0 101 6% 102 16.0 103 6.9 104 6.3 105 5.9 106 6.0 107 4% 108 8.9
109 13.7 110 6.5 111 0% 112 0% 113 0% 114 0% 115 0%
TABLE-US-00036 TABLE 34 EC.sub.50 (.mu.M) or production Ex. No.
activity (%) at 30 .mu.M in vitro 116 5.6 117 7.7
[0745] As is clear from the above-mentioned results, the compound
of the present invention or a pharmaceutically acceptable salt
thereof, or a solvate thereof has a human PHD inhibitory activity
and a human EPO production activity.
INDUSTRIAL APPLICABILITY
[0746] The compound of the present invention or a pharmaceutically
acceptable salt thereof, or a solvate thereof inhibits binding of
HIF and PHD based on its PHD inhibitory activity and stabilizes
HIF, which enables promotion of EPO production.
[0747] Hence, the compound of the present invention or a
pharmaceutically acceptable salt thereof, or a solvate thereof can
be a medicament effective for the prophylaxis or treatment of
various diseases and pathologies (disorders) caused by decreased
production of EPO, and can be effectively used for the treatment of
anemia.
* * * * *