U.S. patent application number 09/853953 was filed with the patent office on 2001-12-13 for pyridone derivatives and process for preparing the same.
This patent application is currently assigned to SUMITOMO PHARMACEUTICALS COMPANY, LIMITED. Invention is credited to Aida, Nagisa, Morishita, Koji, Muraoka, Masami, Ohashi, Naohito, Tanaka, Masashi, Yuri, Masatoshi.
Application Number | 20010051732 09/853953 |
Document ID | / |
Family ID | 27297814 |
Filed Date | 2001-12-13 |
United States Patent
Application |
20010051732 |
Kind Code |
A1 |
Muraoka, Masami ; et
al. |
December 13, 2001 |
Pyridone derivatives and process for preparing the same
Abstract
A process for preparing a pyridone derivative (4), which
comprises reacting the compound (1) with a hypochlorite or a
hypobromite or with lead tetraacetate to give the compound (2), and
reacting the compound (2) with the compound (3). Said process is
preferably especially from the standpoint of safety. 1 wherein
R.sup.1 is hydrogen, alkyl, substituted alkyl, etc.; Y.sup.1 is
hydrogen, alky, substituted alky, etc.; Y.sup.2 and Y.sup.3 are
indenpently hydrogen, halogen, etc.; and L is alkyl, substituted
alkyl, etc.
Inventors: |
Muraoka, Masami;
(Toyonaka-shi, JP) ; Morishita, Koji;
(Nishinomiya-shi, JP) ; Aida, Nagisa; (Abuta-gun,
JP) ; Tanaka, Masashi; (Takaishi-shi, JP) ;
Yuri, Masatoshi; (Nishinomiya-shi, JP) ; Ohashi,
Naohito; (Takatsuki-shi, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
SUMITOMO PHARMACEUTICALS COMPANY,
LIMITED
|
Family ID: |
27297814 |
Appl. No.: |
09/853953 |
Filed: |
May 14, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09853953 |
May 14, 2001 |
|
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09623030 |
Aug 25, 2000 |
|
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09623030 |
Aug 25, 2000 |
|
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PCT/JP99/00718 |
Feb 17, 1999 |
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Current U.S.
Class: |
546/296 ;
546/288; 546/297 |
Current CPC
Class: |
C07D 249/08 20130101;
C07D 213/73 20130101; C07D 231/12 20130101; C07D 471/04 20130101;
C07D 233/56 20130101; C07D 213/75 20130101 |
Class at
Publication: |
546/296 ;
546/297; 546/288 |
International
Class: |
C07D 213/50; C07D
213/84 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 25, 1998 |
JP |
62346/1998 |
Mar 19, 1998 |
JP |
92567/1998 |
Claims
1. A process for preparing a pyridone derivative of the formula
(4): 132wherein R is a hydrogen atom, an alkyl group, a substituted
alkyl group, an alkenyl group, a substituted alkenyl group, an
alkynyl group, a substituted alkynyl group, a cycloalkyl group, or
a substituted cycloalkyl group; Y.sup.1 is a hydrogen atom, an
alkyl group, a substituted alkyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group; Y.sup.2 and Y.sup.3 are independently a hydrogen
atom, a halogen atom, a hydroxy group, a cyano group, a
trifluoromethyl group, a nitro group, an amino group, a mono-lower
alkylamino group, a di-lower alkylamino group, a lower alkoxy
group, a lower alkylthio group, a lower alkylsulfinyl group, a
lower alkylsulfonyl group, an alkyl group, a substituted alkyl
group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, a substituted aromatic group, or Y.sup.2 and
Y.sup.3 may combine each other together with the carbon atoms to
which they bond, and form a substituted or unsubstituted pyridine
ring; and L is an alkyl group, a substituted alkyl group, an
alkenyl group, a substituted alkenyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group, which comprises reacting a compound of the formula
(1): 133wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as
defined above, with a hypochlorite or a hypobromite or with lead
tetraacetate to give a compound of the formula (2): 134wherein
R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined above,
followed by reacting the compound (2) with a compound of the
formula (3): L--NH.sub.2 (3)wherein L is as defined above.
2. The process according to claim 1, wherein a sodium hypochlorite
or a sodium hypobromite is used in the reaction from the compound
(1) to the compound (2).
3. The process according to claim 1, wherein lead tetraacetate is
used in the reaction from the compound (1) to the compound (2).
4. The process for preparing the pyridone derivative according to
any one of claims 1 to 3, wherein Y.sup.2 and Y.sup.3 combine each
other together with the carbon atoms to which they bond, and form a
substituted or unsubstituted pyridine ring, and said pyridine ring
is a group of the following formula (a), (b) or (c): 135
5. The process for preparing the pyridone derivative according to
any one of claims 1 to 3, wherein Y.sup.2 and Y.sup.3 combine each
other together with the carbon atoms to which they bond, and form a
substituted or unsubstituted pyridine ring, and said pyridine ring
is a group of the following formula (a): 136
6. The process for preparing the pyridone derivative according to
claim 4 or 5, wherein Y.sup.1 and L are a substituted aromatic
group, and R.sup.1 is a substituted or unsubstituted alkyl
group.
7. The process for preparing the pyridone derivative according to
claim 6, wherein Y.sup.1 is a 3-methoxyphenyl group, L is a
2,6-diisopropylphenyl group, and R.sup.1 is a butyl group.
8. A process for preparing a pyridone derivative of the formula
(4): 137wherein R.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; Y.sup.2 and Y.sup.3 are independently a
hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a
trifluoromethyl group, a nitro group, an amino group, a mono-lower
alkylamino group, a di-lower alkylamino group, a lower alkoxy
group, a lower alkylthio group, a lower alkylsulfinyl group, a
lower alkylsulfonyl group, an alkyl group, a substituted alkyl
group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, a substituted aromatic group, or Y.sup.2 and
Y.sup.3 may combine each other together with the carbon atoms to
which they bond, and form a substituted or unsubstituted pyridine
ring; and L is an alkyl group, a substituted alkyl group, an
alkenyl group, a substituted alkenyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group, which comprises reacting a compound of the formula
(5): 138wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as
defined above, with a compound of the formula (6): XCO.sub.2R.sup.2
(6)wherein R.sup.2 is a substituted or unsubstituted lower alkyl
group, or a substituted or unsubstituted phenyl group; and X is a
chorine atom or a bromine atom, to give a compound of the formula
(7): 139wherein R.sup.1, R.sup.2, Y.sup.1, Y.sup.2 and Y.sup.3 are
as defined above, followed by reacting the compound (7) with a
compound of the formula (3): L--NH.sub.2 (3)wherein L is as defined
above.
9. The process for preparing the pyridone derivative according to
claim 8, wherein Y.sup.2 and Y.sup.3 combine each other together
with the carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring, and said pyridine ring is a group of
the following formula (a), (b) or (c): 140
10. The process for preparing the pyridone derivative according to
claim 8, wherein Y.sup.2 and Y.sup.3 combine each other together
with the carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring, and said pyridine ring is a group of
the following formula (a): 141
11. The process for preparing the pyridone derivative according to
claim 9 or 10, wherein Y.sup.1 and L are a substituted aromatic
group, and R.sup.1 is a substituted or unsubstituted alkyl
group.
12. The process for preparing the pyridone derivative according to
claim 11, wherein Y.sup.1 is a 3-methoxyphenyl group, L is a
2,6-diisopropylphenyl group, and R.sup.1 is a butyl group.
13. A process for preparing an aminopyridone derivative of the
formula (5): 142wherein R.sup.1 is a hydrogen atom, an alkyl group,
a substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; and Y.sup.2 and Y.sup.3 are
independently a hydrogen atom, a halogen atom, a hydroxy group, a
cyano group, a trifluoromethyl group, a nitro group, an amino
group, a mono-lower alkylamino group, a di-lower alkylamino group,
a lower alkoxy group, a lower alkylthio group, a lower
alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a
substituted alkyl group, a cycloalkyl group, a substituted
cycloalkyl group, an aromatic group, a substituted aromatic group,
or Y.sup.2 and Y.sup.3 may combine each other together with the
carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring, which comprises reacting a compound of
the formula (1): 143wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3
are as defined above, with a hypochlorite or a hypobromite or with
lead tetraacetate to give a compound of the formula (2): 144wherein
R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined above,
followed by subjecting the compound (2) to hydrolysis.
14. The process for preparing the aminopyridone derivative
according to claim 13, wherein Y.sup.2 and Y.sup.3 combine each
other with the carbon atoms to which they bond, and form a
substituted or unsubstituted pyridine ring together, and said
pyridine ring is a group of the following formula (a), (b) or (c):
145
15. The process for preparing the aminopyridone derivative
according to claim 13, wherein Y.sup.2 and Y.sup.3 combine each
other together with the carbon atoms to which they bond, and form a
substituted or unsubstituted pyridine ring, and said pyridine ring
is a group of the following formula (a): 146
16. The process for preparing the aminopyridone derivative
according to claim 14 or 15, wherein Y.sup.1 is a substituted
aromatic group, and R.sup.1 is a substituted or unsubstituted alkyl
group.
17. The process for preparing the aminopyridone derivative
according to claim 16, wherein Y.sup.1 is a 3-methoxyphenyl group,
and R.sup.1 is a butyl group.
18. A process for preparing an aminopyridone derivative of the
formula (5): 147wherein R.sup.1 is a hydrogen atom, an alkyl group,
a substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; and Y.sup.2 and Y.sup.3 are
independently a hydrogen atom, a halogen atom, a hydroxy group, a
cyano group, a trifluoromethyl group, a nitro group, an amino
group, a mono-lower alkylamino group, a di-lower alkylamino group,
a lower alkoxy group, a lower alkylthio group, a lower
alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a
substituted alkyl group, a cycloalkyl group, a substituted
cycloalkyl group, an aromatic group, a substituted aromatic group,
or Y.sup.2 and Y.sup.3 may combine each other together with the
carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring, which comprises heating a compound of
the formula (8): 148wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3
are as defined above, and Ring B is a substituted or unsubstituted
benzene ring, in the presence of a base, to give a compound of the
formula (9): 149wherein R.sup.1, Y.sup.1, Y.sup.2, Y.sup.3 and Ring
B are as defined above, followed by removing the protecting
phthaloyl group thereof.
19. The process for preparing the aminopyridone derivative
according to claim 18, wherein Y.sup.2 and Y.sup.3 combine each
other together with the carbon atoms to which they bond, and form a
substituted or unsubstituted pyridine ring, and said pyridine ring
is a group of the following formula (a), (b) or (c): 150
20. The process for preparing the aminopyridone derivative
according to claim 18, wherein Y.sup.2 and Y.sup.3 combine each
other together with the carbon atoms to which they bond, and form a
substituted or unsubstituted pyridine ring, and said pyridine ring
is a group of the following formula (a): 151
21. The process for preparing the aminopyridone derivative
according to claim 19 or 20, wherein Y.sup.1 is a substituted
aromatic group, and R.sup.1 is a substituted or unsubstituted alkyl
group.
22. The process for preparing the aminopyridone derivative
according to claim 21, wherein Y.sup.1 is a 3-methoxyphenyl group,
and R.sup.1 is a butyl group.
23. A process for preparing an aminopyridone derivative of the
formula (5): 152wherein R.sup.1 is a hydrogen atom, an alkyl group,
a substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; and Y.sup.2 and Y.sup.3 are
independently a hydrogen atom, a halogen atom, a hydroxy group, a
cyano group, a trifluoromethyl group, a nitro group, an amino
group, a mono-lower alkylamino group, a di-lower alkylamino group,
a lower alkoxy group, a lower alkylthio group, a lower
alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a
substituted alkyl group, a cycloalkyl group, a substituted
cycloalkyl group, an aromatic group, a substituted aromatic group,
or Y.sup.2 and Y.sup.3 may combine each other together with the
carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring, which comprises reacting a compound of
the formula (1): 153wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3
are as defined above, with a hypochlorite or a hypobromite.
24. The process for preparing the aminopyridone derivative
according to claim 23, wherein Y.sup.2 and Y.sup.3 combine each
other together with the carbon atoms to which they bond, and form a
substituted or unsubstituted pyridine ring, and said pyridine ring
is a group of the following formula (a), (b) or (c): 154
25. The process for preparing the aminopyridone derivative
according to claim 23, wherein Y.sup.2 and Y.sup.3 combine each
other together with the carbon atoms to which they bond, and form a
substituted or unsubstituted pyridine ring, and said pyridine ring
is a group of the following formula (a): 155
26. The process for preparing the aminopyridone derivative
according to claim 24 or 25, wherein Y.sup.1 is a substituted
aromatic group, and R.sup.1 is a substituted or unsubstituted alkyl
group.
27. The process for preparing the aminopyridone derivative
according to claim 26, wherein Y.sup.1 is a 3-methoxyphenyl group,
and R.sup.1 is a butyl group.
28. A process for preparing a pyridone derivative of the formula
(4): 156wherein R.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; Y.sup.2 and Y.sup.3 are independently a
hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a
trifluoromethyl group, a nitro group, an amino group, a mono-lower
alkylamino group, a di-lower alkylamino group, a lower alkoxy
group, a lower alkylthio group, a lower alkylsulfinyl group, a
lower alkylsulfonyl group, an alkyl group, a substituted alkyl
group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, a substituted aromatic group, or Y.sup.2 and
Y.sup.3 may combine each other ring together with the carbon atoms
to which they bond, and form a substituted or unsubstituted
pyridine; and L is an alkyl group, a substituted alkyl group, an
alkenyl group, a substituted alkenyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group, which comprises reacting a compound of the formula
(3): L--NH.sub.2 (3)wherein L is as defined above, with a compound
of the formula (6): XCO.sub.2R.sup.2 (6)wherein R.sup.2 is a
substituted or unsubstituted lower alkyl group, or a substituted or
unsubstituted phenyl group; and X is a chlorine atom or a bromine
atom, to give a compound of the formula (32): L--NHCO.sub.2R.sup.2
(32)wherein R.sup.2 and L are as defined above, following by
reacting the compound (32) with a compound of the formula (5):
157wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined
above.
29. The process for preparing the pyridone derivative according to
claim 28, wherein Y.sup.2 and Y.sup.3 combine each other together
with the carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring, and said pyridine ring is a group of
the following formula (a), (b) or (c): 158
30. The process for preparing the pyridone derivative according to
claim 28, wherein Y.sup.2 and Y.sup.3 combine each other together
with the carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring, and said pyridine ring is a group of
the following formula (a): 159
31. The process for preparing the pyridone derivative according to
claim 29 or 30, wherein Y.sup.1 and L are a substituted aromatic
group, and R.sup.1 is a substituted or unsubstituted alkyl
group.
32. The process for preparing the pyridone derivative according to
claim 31, wherein Y.sup.1 is a 3-methoxyphenyl group, L is a
2,6-diisopropylphenyl group, and R.sup.1 is a butyl group.
33. A process for preparing a pyridone derivative of the formula
(4): 160wherein R.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; Y.sup.2 and Y.sup.3 are independently a
hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a
trifluoromethyl group, a nitro group, an amino group, a mono-lower
alkylamino group, a di-lower alkylamino group, a lower alkoxy
group, a lower alkylthio group, a lower alkylsulfinyl group, a
lower alkylsulfonyl group, an alkyl group, a substituted alkyl
group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, a substituted aromatic group, or Y.sup.2 and
Y.sup.3 may combine each other together with the carbon atoms to
which they bond, and form a substituted or unsubstituted pyridine
ring; and L is an alkyl group, a substituted alkyl group, an
alkenyl group, a substituted alkenyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group, which comprises reacting a compound of the formula
(5): 161wherein R.sup.1, Y.sub.1, Y.sup.2 and Y.sup.3 are as
defined above, with a compound of the formula (6): L--NCO
(31)wherein L is as defined above.
34. The process for preparing the pyridone derivative according to
claim 33, wherein Y.sup.2 and Y.sup.3 combine each other together
with the carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring, and said pyridine ring is a group of
the following formula (a), (b) or (c): 162
35. The process for preparing the pyridone derivative according to
claim 33, wherein Y.sup.2 and Y.sup.3 combine each other together
with the carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring, and said pyridine ring is a group of
the following formula (a): 163
36. The process for preparing the pyridone derivative according to
claim 34 or 35, wherein Y.sup.1 and L are a substituted aromatic
group, and R.sup.1 is a substituted or unsubstituted alkyl
group.
37. The process for preparing the pyridone derivative according to
claim 36, wherein Y.sup.1 is a 3-methoxyphenyl group, L is a
2,6-diisopropylphenyl group, and R.sup.1 is a butyl group.
38. A pyridone derivative of the formula (10): 164wherein L is an
alkyl group, a substituted alkyl group, an alkenyl group, a
substituted alkenyl group, a cycloalkyl group, a substituted
cycloalkyl group, an aromatic group, or a substituted aromatic
group; Z is a direct bond or --NH--; R.sup.1 is a hydrogen atom, an
alkyl group, a substituted alkyl group, an alkenyl group, a
substituted alkenyl group, an alkynyl group, a substituted alkynyl
group, a cycloalkyl group, or a substituted cycloalkyl group,
provided that when Z is a direct bond, then R.sup.1 is not a
hydrogen atom; Y.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, a cycloalkyl group, a substituted
cycloalkyl group, an aromatic group, or a substituted aromatic
group; Y.sup.22 and Y.sup.32 are independently a hydrogen atom, a
halogen atom, a hydroxy group, a cyano group, a trifluoromethyl
group, a nitro group, an amino group, a mono-lower alkylamino
group, a di-lower alkylamino group, a lower alkoxy group, a lower
alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl
group, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group, or a salt thereof.
39. The pyridone derivative according to claim 38, or a salt
thereof, wherein Z is --NH--.
40. The pyridone derivative according to claim 39, or a salt
thereof, wherein Y.sup.1 is an alkyl group, a substituted alkyl
group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, or a substituted aromatic group.
41. The pyridone derivative according to claim 39 or 40, or a salt
thereof, wherein one of Y.sup.1, Y.sup.2 and Y.sup.3 is an aromatic
group or a substituted aromatic group.
42. The pyridone derivative according to claim 39, 40, or 41, or a
salt thereof, wherein L is an aromatic group or a substituted
aromatic group.
43. The pyridone derivative according to claim 42, or a salt
thereof, wherein one of Y.sup.1, Y.sup.2 and Y.sup.3 is a
substituted phenyl group, and one of the substituents thereof is a
group of the formula: --M.sup.1--E--Q (M.sup.1 is a direct bond, an
oxygen atom, a sulfur atom or a group of the formula: --NR.sup.3--
(R.sup.3 is a hydrogen atom or a lower alkyl group), E is a
divalent aliphatic hydrocarbon group having 1 to 15 carbon atoms
and optionally containing an unsaturated bond, or a phenylene
group, Q is a hydrogen atom, a hydroxy group, a carboxyl group, a
lower alkoxycarbonyl group, a benzyloxycarbonyl group, a halogen
atom, a cyano group, a benzyloxy group, a lower alkoxy group, a
lower alkanoyloxy group, a lower alkylthio group, a lower
alkylsulfinyl group, a lower alkylsulfonyl group, a
benzenesulfonyloxy group being optionally substituted by an alkyl
group, a lower alkanoylamino group, a lower alkoxycarbonylamino
group, a lower alkylsulfonamido group, a phthalimido group, a
cycloalkyl group, an aryl group, a substituted aryl group, a
heteroaryl group, a substituted heteroaryl group, a group of the
formula: --NR.sup.4R.sup.5(R.sup.4 and R.sup.5 are independently a
hydrogen atom, a lower alkyl group, a di-lower
alkylamino-substituted lower alkyl group, a lower
alkoxy-substituted lower alkyl group, a cycloalkyl group, a lower
alkoxycarbonyl group, a heteroarylmethyl group, or an aralkyl
group, or R.sup.4 and R.sup.5 may combine each other together with
the nitrogen atom to which they bond, and form a saturated cyclic
amino group having 4 to 8 carbon atoms as ones forming the said
ring, and optionally having one --NR.sup.20-- (R.sup.20 is a
hydrogen atom, a lower alkyl group, a phenyl group, a lower
alkoxycarbonyl group, or a benzyl group) or one oxygen atom in the
cycle thereof), or a group of the formula:
--C(.dbd.O)NR.sup.4R.sup.5 (R.sup.4 and R.sup.5 are as defined
above)).
44. The pyridone derivative according to claim 43, or a salt
thereof, wherein Y.sup.1 is a substituted phenyl group.
45. The pyridone derivative according to claim 44, or a salt
thereof, wherein M.sup.1 is an oxygen atom.
46. The pyridone derivative according to claim 43, 44, or 45, or a
salt thereof, wherein Q is a hydrogen atom, a hydroxy group, a
carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl
group, a benzyloxy group, a lower alkoxy group, a lower alkanoyloxy
group, a lower alkanoylamino group, a heteroaryl group, a
substituted heteroaryl group, or a group of the formula:
--NR.sup.4R.sup.5.
47. The pyridone derivative according to claim 46, or a salt
thereof, wherein E is an alkylene group having 1 to 4 carbon atoms,
and Q is a substituted or unsubstituted pyridyl group, a
1,2,4-triazol-1-yl group, or a group of the formula:
--NR.sup.4R.sup.5.
48. The pyridone derivative according to claim 43 or 44, or a salt
thereof, wherein M.sup.1 is a direct bond.
49. The pyridone derivative according to claim 48, or a salt
thereof, wherein Q is a hydrogen atom, a hydroxy group, a carboxyl
group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a
benzyloxy group, a lower alkoxy group, a lower alkanoyloxy group, a
lower alkanoylamino group, a heteroaryl group, a substituted
heteroaryl group, or a group of the formula: --NR.sup.4R.sup.5.
50. The pyridone derivative according to claim 48 or 49, or a salt
thereof, wherein --E-- is a group of the formula: 165(wherein
R.sup.6 and R.sup.7 are independently a hydrogen atom, a methyl
group, an ethyl group, or a propyl group, or R.sup.6 and R.sup.7
may combine each other to form a 3- to 7-membered cycloalkane ring,
m is an integer of 0 to 6, and p is an integer of 0 to 6).
51. The pyridone derivative according to claim 50, or a salt
thereof, wherein p is 0.
52. The pyridone derivative according to claim 51, or a salt
thereof, wherein R.sup.6 and R.sup.7 are both hydrogen atoms, and m
is 0 or 1.
53. The pyridone derivative according to claim 47 or 52, or a salt
thereof, wherein R.sup.1 is an alkyl group, a substituted alkyl
group, or a hydrogen atom.
54. The pyridone derivative according to claim 53, or a salt
thereof, wherein Y.sup.22 and Y.sup.32 are hydrogen atoms.
55. A pharmaceutical composition containing a pyridone derivative
as set forth in any one of claims 38 to 54, or a salt thereof.
56. An acyl-CoA: cholesterol acyl transferase (ACAT) inhibitor,
which contains as an active ingredient a pyridone derivative as set
forth in any one of claims 38 to 54, or a salt thereof.
57. An agent for treatment of hyperlipidemia or atherosclerosis,
which contains as an active ingredient a pyridone derivative as set
forth in any one of claims 38 to 54, or a salt thereof.
58. A method for inhibiting acyl-CoA: cholesterol acyl transferase
(ACAT), which comprises administering an effective amount salt
thereof, to a patient in need thereof.
59. A method for treatment of hyperlipidemia or atherosclerosis,
which comprises administering an effective amount of a pyridone
derivative as set forth in any one of claims 38 to 54, or a salt
thereof, to a patient in need thereof.
60. Use of a pyridone derivative as set forth in any one of claims
38 to 54, or a salt thereof, in preparation of a pharmaceutical
composition for inhibiting acyl-CoA: cholesterol acyl transferase
(ACAT).
61. Use of a pyridone derivative as set forth in any one of claims
38 to 54, or a salt thereof, in preparation of an agent for
treatment of hyperlipidemia or atherosclerosis.
Description
TECHNICAL FIELD
[0001] The present invention relates to a pyridone derivative or a
salt thereof, which exhibits acyl-CoA: cholesterol acyl transferase
(ACAT) inhibitory activity, and is useful as an agent for treatment
of hyperlipidemia and atherosclerosis, and a process for preparing
the same.
PRIOR ART
[0002] Cerebral vessel disorders such as stroke, and myocardial
infarction, which rank in high in causes of death in developed
countries, break out with being accompanied by atherosclerosis as
basal disease. From the results of epidemiology research, it is
pointed out that hypercholesterolemia is one of risk factors for
atherosclerosis, and there are mainly used anti-hyperlipidemic
agents, which can reduce cholesterol level in blood, in the
prophylaxis or treatment thereof. However, there is no sufficiently
effective agent in terms of the efficacy thereof. Recently, it is
observed that cells derived from macrophage accumulate cholesterol
ester droplet within the cells and become foam cells in
atherosclerotic lesions, and it is clarified that these foam cells
deeply participate in the developments of atherosclerotic lesions
(Arteriosclerosis, 10, 164-177, 1990). In addition, it is reported
that ACAT activity is increased and cholesterol esters are
accumulated in the vascular wall of atherosclerotic lesions
(Biochem. Biophys. Acta, 617, 458-471, 1980). Therefore, an
inhibitor of ACAT, which catalyses cholesterol esterification, is
expected to suppress the formation or the development of
atherosclerotic lesions as a result of the inhibition of foam cell
formation and of cholesterol ester accumulation in lesions.
[0003] On the other hand, cholesterol in food is absorbed in the
free form at intestinal epidermal cells, and then released in the
form of chylomicron esterified by ACAT into the blood. Therefore,
an inhibitor of ACAT is expected to reduce the cholesterol level in
the blood by the inhibition of absorption of cholesterol in food at
the intestine and of reabsorption of cholesterol released into the
intestine (J. Lipid. Research, 34, 279-294, 1993).
[0004] JP-A-3-181465, JP-A-3-223254 and JP-A-6-501025 disclose some
kinds of quinoline derivatives having an ACAT inhibitory activity,
and JP-A-5-32666 discloses some kinds of thienopyridine derivatives
having an ACAT inhibitory activity, and further JP-A-9-48780
discloses some kinds of naphthyridine derivatives having an ACAT
inhibitory activity.
[0005] These patent publications disclose processes for preparation
of these compounds, for example, in the above JP-A-9-48780, an
ureidonaphthyridine derivative which is a pyridone derivative and
its intermediate, an amino derivative are prepared by the following
process. 2
[0006] wherein Ring A is a substituted or unsubstituted pyridine
ring; R.sup.1 is a hydrogen atom, an alkyl group, a substituted
alkyl group, a cycloalkyl group, or a substituted cycloalkyl group;
Y.sup.1 is an alkyl group, a substituted. alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; L is an alkyl group, a substituted
alkyl group, an alkenyl group, a substituted alkenyl group, a
cycloalkyl group, a substituted cycloalkyl group, an aromatic
group, or a substituted aromatic group.
[0007] That is, a carboxy derivative of the formula (11) is
azidated with an azidating agent, and subsequently heated to
convert into an isocyanate derivative of the formula (12), which is
further reacted with an amine derivative of the formula (3) to give
an ureido derivative of the formula (13), or alternatively the
isocyanate derivative (12) is hydrolyzed to give an amine
derivative of the formula (14).
DISCLOSURE OF INVENTION
[0008] However, the present inventors have found that the azidating
agents used in the above process and the compounds prepared by
azidating the carboxyl derivative of the formula (II) have a risk
of explosion and therefore, they are not suitable for large-scale
production with respect to safety.
[0009] An object of the present invention is to provide a process
for preparing pyridone derivatives and aminopyridone derivatives,
especially a preferable process thereof with respect to safety, and
to provide a novel pyridone derivative.
[0010] The present inventors have intensively studied in order to
solve the above problems, and have found that pyridone derivatives
and aminopyridone derivatives can safely be prepared by the
following Processes [1] to [37], and further have found that novel
pyridone derivatives of the following [38] to [54] exhibit a potent
ACAT inhibitory activity, and then have accomplished the present
invention.
[0011] That is, the gist of the present invention is as
follows.
[0012] [1] A process for preparing a pyridone derivative of the
formula (4): 3
[0013] wherein R.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; Y.sup.2 and Y.sup.3 are independently a
hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a
trifluoromethyl group, a nitro group, an amino group, a mono-lower
alkylamino group, a di-lower alkylamino group, a lower alkoxy
group, a lower alkyithio group, a lower alkylsulfinyl group, a
lower alkylsulfonyl group, an alkyl group, a substituted alkyl
group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, a substituted aromatic group, or Y.sup.2 and
Y.sup.3 may combine each other together with the carbon atoms to
which they bond, and form a substituted or unsubstituted pyridine
ring; and L is an alkyl group, a substituted alkyl group, an
alkenyl group, a substituted alkenyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group,
[0014] which comprises reacting a compound of the formula (1):
4
[0015] wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined
above, with a hypochlorite or a hypobromite or with lead
tetraacetate to give a compound of the formula (2): 5
[0016] wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined
above, followed by reacting the compound (2) with a compound of the
formula (3):
L--NH.sub.2 (3)
[0017] wherein L is as defined above.
[0018] [2] The process according to the above [1], wherein a sodium
hypochlorite or a sodium hypobromite is used in the reaction from
the compound (1) to the compound (2).
[0019] [3] The process according to the above [1], wherein lead
tetraacetate is used in the reaction from the compound (1) to the
compound (2).
[0020] [4] The process for preparing the pyridone derivative
according to any one of the above [1] to [3], wherein Y.sup.2 and
Y.sup.3 combine each other together with the carbon atoms to which
they bond, and form a substituted or unsubstituted pyridine ring,
and said pyridine ring is a group of the following formula (a), (b)
or (c): 6
[0021] [5] The process for preparing the pyridone derivative
according to any one of the above [1] to [3], wherein Y.sup.2 and
Y.sup.3 combine each other together with the carbon atoms to which
they bond, and form a substituted or unsubstituted pyridine ring,
and said pyridine ring is a group of the following formula (a):
7
[0022] [6] The process for preparing the pyridone derivative
according to the above [4] or [5], wherein Y.sup.1 and L are a
substituted aromatic group, and R.sup.1 is a substituted or
unsubstituted alkyl group.
[0023] [7] The process for preparing the pyridone derivative
according to the above [6], wherein Y.sup.1 is a 3-methoxyphenyl
group, L is a 2,6-diisopropylphenyl group, and R.sup.1 is a butyl
group.
[0024] [8] A process for preparing a pyridone derivative of the
formula (4): 8
[0025] wherein R.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; Y.sup.2 and Y.sup.3 are independently a
hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a
trifluoromethyl group, a nitro group, an amino group, a mono-lower
alkylamino group, a di-lower alkylamino group, a lower alkoxy
group, a lower alkylthio group, a lower alkylsulfinyl group, a
lower alkylsulfonyl group, an alkyl group, a substituted alkyl
group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, a substituted aromatic group, or Y.sup.2 and
Y.sup.3 may combine each other together with the carbon atoms to
which they bond, and form a substituted or unsubstituted pyridine
ring; and L is an alkyl group, a substituted alkyl group, an
alkenyl group, a substituted alkenyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group,
[0026] which comprises reacting a compound of the formula (5):
9
[0027] wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined
above, with a compound of the formula (6):
XCO.sub.2R.sup.2 (6)
[0028] wherein R.sup.2 is a substituted or unsubstituted lower
alkyl group, or a substituted or unsubstituted phenyl group; and X
is a chorine atom or a bromine atom, to give a compound of the
formula (7): 10
[0029] wherein R.sup.1, R.sup.2, Y.sup.1, Y.sup.2 and Y.sup.3 are
as defined above, followed by reacting the compound (7) with a
compound of the formula (3):
L--NH.sub.2 (3)
[0030] wherein L is as defined above.
[0031] [9] The process for preparing the pyridone derivative
according to the above [8], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a), (b) or (c):
11
[0032] [10] The process for preparing the pyridone derivative
according to the above [8], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a): 12
[0033] [11] The process for preparing the pyridone derivative
according to the above [9] or [10], wherein Y.sup.1 and L are a
substituted aromatic group, and R.sup.1 is a substituted or
unsubstituted alkyl group.
[0034] [12] The process for preparing the pyridone derivative
according to the above [11], wherein Y.sup.1 is a 3-methoxyphenyl
group, L is a 2,6-diisopropylphenyl group, and R.sup.1 is a butyl
group.
[0035] [13] A process for preparing an aminopyridone derivative of
the formula (5): 13
[0036] wherein R.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; and Y.sup.2 and Y.sup.3 are
independently a hydrogen atom, a halogen atom, a hydroxy group, a
cyano group, a trifluoromethyl group, a nitro group, an amino
group, a mono-lower alkylamino group, a di-lower alkylamino group,
a lower alkoxy group, a lower alkylthio group, a lower
alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a
substituted alkyl group, a cycloalkyl group, a substituted
cycloalkyl group, an aromatic group, a substituted aromatic group,
or Y.sup.2 and Y.sup.3 may combine each other together with the
carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring, which comprises reacting a compound of
the formula (1): 14
[0037] wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined
above, with a hypochlorite or a hypobromite or with lead
tetraacetate to give a compound of the formula (2): 15
[0038] wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined
above, followed by subjecting the compound (2) to hydrolysis.
[0039] [14] The process for preparing the aminopyridone derivative
according to the above [13], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a), (b) or (c):
16
[0040] [15] The process for preparing the aminopyridone derivative
according to the above [13], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a): 17
[0041] [16] The process for preparing the aminopyridone derivative
(according to the above [14] or [15], wherein Y.sup.1 is a
substituted aromatic group, and R.sup.1 is a substituted or
unsubstituted alkyl group.
[0042] [17] The process for preparing the aminopyridone derivative
according to the above [16], wherein Y.sup.1 is a 3-methoxyphenyl
group, and R.sup.1 is a butyl group.
[0043] [18] A process for preparing an aminopyridone derivative of
the formula (5): 18
[0044] wherein R.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; and Y.sup.2 and Y.sup.3 are
independently a hydrogen atom, a halogen atom, a hydroxy group, a
cyano group, a trifluoromethyl group, a nitro group, an amino
group, a mono-lower alkylamino group, a di-lower alkylamino group,
a lower alkoxy group, a lower alkylthio group, a lower
alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a
substituted alkyl group, a cycloalkyl group, a substituted
cycloalkyl group, an aromatic group, a substituted aromatic group,
or Y.sup.2 and Y.sup.3 may combine each other together with the
carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring,
[0045] which comprises heating a compound of the formula (8):
19
[0046] wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined
above, and Ring B is a substituted or unsubstituted benzene ring,
in the presence of a base, to give a compound of the formula (9):
20
[0047] wherein R.sup.1, Y.sup.1, Y.sup.2, Y.sup.3 and Ring B are as
defined above, followed by removing the protecting phthaloyl group
thereof.
[0048] [19] The process for preparing the aminopyridone derivative
according to the above [18], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a), (b) or (c):
21
[0049] [20] The process for preparing the aminopyridone derivative
according to the above [18], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a): 22
[0050] [21] The process for preparing the aminopyridone derivative
according to the above [19] or [20], wherein Y.sup.1 is a
substituted aromatic group, and R.sup.1 is a substituted or
unsubstituted alkyl group.
[0051] [22] The process for preparing the aminopyridone derivative
according to the above [21], wherein Y.sup.1 is a 3-methoxyphenyl
group, and R.sup.1 is a butyl group.
[0052] [23] A process for preparing an arninopyridone derivative of
the formula (5): 23
[0053] wherein R.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; and Y.sup.2 and Y.sup.3 are
independently a hydrogen atom, a halogen atom, a hydroxy group, a
cyano group, a trifluoromethyl group, a nitro group, an amino
group, a mono-lower alkylamino group, a di-lower alkylamino group,
a lower alkoxy group, a lower alkylthio group, a lower
alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a
substituted alkyl group, a cycloalkyl group, a substituted
cycloalkyl group, an aromatic group, a substituted aromatic group,
or Y.sup.2 and Y.sup.3 may combine each other together with the
carbon atoms to which they bond, and form a substituted or
unsubstituted pyridine ring,
[0054] which comprises reacting a compound of the formula (1):
24
[0055] wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined
above, with a hypochlorite or a hypobromite.
[0056] [24] The process for preparing the aminopyridone derivative
according to the above [23], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a), (b) or (c):
25
[0057] [25] The process for preparing the aminopyridone derivative
according to the above [23], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a): 26
[0058] [26] The process for preparing the aminopyridone derivative
according to the above [24] or [25], wherein Y.sup.1 is a
substituted aromatic group, and R.sup.1 is a substituted or
unsubstituted alkyl group.
[0059] [27] The process for preparing the aminopyridone derivative
according to the above [26], wherein Y.sup.1 is a 3-methoxyphenyl
group, and R.sup.1 is a butyl group.
[0060] [28] A process for preparing a pyridone derivative of the
formula (4): 27
[0061] wherein R.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; Y.sup.2 and Y.sup.3 are independently a
hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a
trifluoromethyl group, a nitro group, an amino group, a mono-lower
alkylamino group, a di-lower alkylamino group, a lower alkoxy
group, a lower alkylthio group, a lower alkylsulfinyl group, a
lower alkylsulfonyl group, an alkyl group, a substituted alkyl
group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, a substituted aromatic group, or Y.sup.2 and
Y.sup.3 may combine each other together with the carbon atoms to
which they bond, and form a substituted or unsubstituted pyridine
ring; and L is an alkyl group, a substituted alkyl group, an
alkenyl group, a substituted alkenyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group,
[0062] which comprises reacting a compound of the formula (3):
L--NH.sub.2 (3)
[0063] wherein L is as defined above, with a compound of the
formula (6):
XCO.sub.2R.sup.2 (6)
[0064] wherein R.sup.2 is a substituted or unsubstituted lower
alkyl group, or a substituted or unsubstituted phenyl group; and X
is a chlorine atom or a bromine atom, to give a compound of the
formula (32)
L--NHCO.sub.2R.sup.2 (32)
[0065] wherein R.sup.2 and L are as defined above, following by
reacting the compound (32) with a compound of the formula (5):
28
[0066] wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined
above.
[0067] [29] The process for preparing the pyridone derivative
according to the above [28], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a), (b) or (c):
29
[0068] [30] The process for preparing the pyridone derivative
according to the above [28], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a): 30
[0069] [31] The process for preparing the pyridone derivative
according to the above [29] or [30], wherein Y.sup.1 and L are a
substituted aromatic group, and R.sup.1 is a substituted or
unsubstituted alkyl group.
[0070] [32] The process for preparing the pyridone derivative
according to the above [31], wherein Y.sup.1 is a 3-methoxyphenyl
group, L is a 2,6-diisopropylphenyl group, and R.sup.1 is a butyl
group.
[0071] [33] A process for preparing a pyridone derivative of the
formula (4): 31
[0072] wherein R.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl
group, an alkynyl group, a substituted alkynyl group, a cycloalkyl
group, or a substituted cycloalkyl group; Y.sup.1 is a hydrogen
atom, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group; Y.sup.2 and Y.sup.3 are independently a
hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a
trifluoromethyl group, a nitro group, an amino group, a mono-lower
alkylamino group, a di-lower alkylamino group, a lower alkoxy
group, a lower alkylthio group, a lower alkylsulfinyl group, a
lower alkylsulfonyl group, an alkyl group, a substituted alkyl
group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, a substituted aromatic group, or Y.sup.2 and
Y.sup.3 may combine each other together with the carbon atoms to
which they bond, and form a substituted or unsubstituted pyridine
ring; and L is an alkyl group, a substituted alkyl group, an
alkenyl group, a substituted alkenyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group,
[0073] which comprises reacting a compound of the formula (5):
32
[0074] wherein R.sup.1, Y.sup.1, Y.sup.2 and Y.sup.3 are as defined
above, with a compound of the formula (6):
L--NCO (31)
[0075] wherein L is as defined above.
[0076] [34] The process for preparing the pyridone derivative
according to the above [33], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a), (b) or (c):
33
[0077] [35] A process for preparing the pyridone derivative
according to the above 33], wherein Y.sup.2 and Y.sup.3 combine
each other together with the carbon atoms to which they bond, and
form a substituted or unsubstituted pyridine ring, and said
pyridine ring is a group of the following formula (a): 34
[0078] [36] The process for preparing the pyridone derivative
according to the above 34] or [35], wherein Y.sup.1 and L are a
substituted aromatic group, and R.sup.1 is a substituted or
unsubstituted alkyl group.
[0079] [37] The process for preparing the pyridone derivative
according to the above [36], wherein Y.sup.1 is a 3-methoxyphenyl
group, L is a 2,6-diisopropylphenyl group, and R.sup.1 is a butyl
group.
[0080] [38] A pyridone derivative of the formula (10): 35
[0081] wherein L is an alkyl group, a substituted alkyl group, an
alkenyl group, a substituted alkenyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group;
[0082] Z is a direct bond or --NH--;
[0083] R.sup.1 is a hydrogen atom, an alkyl group, a substituted
alkyl group, an alkenyl group, a substituted alkenyl group, an
alkynyl group, a substituted alkynyl group, a cycloalkyl group, or
a substituted cycloalkyl group, provided that when Z is a direct
bond, then R.sup.1 is not a hydrogen atom;
[0084] Y.sup.1 is a hydrogen atom, an alkyl group, a substituted
alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, or a substituted aromatic group;
[0085] Y.sup.22 and Y.sup.32 are independently a hydrogen atom, a
halogen atom, a hydroxy group, a cyano group, a trifluoromethyl
group, a nitro group, an amino group, a mono-lower alkylamino
group, a di-lower alkylamino group, a lower alkoxy group, a lower
alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl
group, an alkyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, or a
substituted aromatic group, or a salt thereof.
[0086] [39] The pyridone derivative according to the above [38], or
a salt thereof, wherein Z is --NH--.
[0087] [40] The pyridone derivative according to the above [39], or
a salt thereof, wherein Y.sup.1 is an alkyl group, a substituted
alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an
aromatic group, or a substituted aromatic group.
[0088] [41] The pyridone derivative according to the above [39] or
[40], or a salt thereof, wherein one of Y.sup.1, Y.sup.2 and
Y.sup.3 is an aromatic group or a substituted aromatic group.
[0089] [42] The pyridone derivative according to the above [39],
[40] or [41], or a salt thereof, wherein L is an aromatic group or
a substituted aromatic group.
[0090] [43] The pyridone derivative according to the above [42], or
a salt thereof, wherein one of Y.sup.1, Y.sup.2 and Y.sup.3 is a
substituted phenyl group, and one of the substituents thereof is a
group of the formula: --M.sup.1--E--Q (M.sup.1 is a direct bond, an
oxygen atom, a sulfur atom or a group of the formula: --NR.sup.3--
(R.sup.3 is a hydrogen atom or a lower alkyl group), E is a
divalent aliphatic hydrocarbon group having 1 to 15 carbon atoms
and optionally containing an unsaturated bond, or a phenylene
group, Q is a hydrogen atom, a hydroxy group, a carboxyl group, a
lower alkoxy-carbonyl group, a benzyloxycarbonyl group, a halogen
atom, a cyano group, a benzyloxy group, a lower alkoxy group, a
lower alkanoyloxy group, a lower alkylthio group, a lower
alkylsulfinyl group, a lower alkylsulfonyl group, a
benzenesulfonyloxy group being optionally substituted by an alkyl
group, a lower alkanoylamino group, a lower alkoxycarbonylamino
group, a lower alkylsulfonamido group, a phthalimido group, a
cycloalkyl group, an aryl group, a substituted aryl group, a
heteroaryl group, a substituted heteroaryl group, a group of the
formula: --NR.sup.4R.sup.5 (R.sup.4 and R.sup.5 are independently a
hydrogen atom, a lower alkyl group, a di-lower
alkylamino-substituted lower alkyl group, a lower
alkoxy-substituted lower alkyl group, a cycloalkyl group, a lower
alkoxycarbonyl group, a heteroarylmethyl group, or an aralkyl
group, or R.sup.4 and R.sup.5 may combine each other together with
the nitrogen atom to which they bond, and form a saturated cyclic
amino group having 4 to 8 carbon atoms as ones forming the said
ring, and optionally having one --NR.sup.20--(R.sup.20 is a
hydrogen atom, a lower alkyl group, a phenyl group, a lower
alkoxycarbonyl group, or a benzyl group) or one oxygen atom in the
cycle thereof), or a group of the formula:
--C(.dbd.O)NR.sup.4R.sup.5(R.sup.4 and R.sup.5 are as defined
above)).
[0091] [44] The pyridone derivative according to the above [43], or
a salt thereof, wherein Y.sup.1 is a substituted phenyl group.
[0092] [45] The pyridone derivative according to the above [44], or
a salt thereof, wherein M.sup.1 is an oxygen atom.
[0093] [46] The pyridone derivative according to the above [43],
[44] or [45], or a salt thereof, wherein Q is a hydrogen atom, a
hydroxy group, a carboxyl group, a lower alkoxycarbonyl group, a
benzyloxycarbonyl group, a benzyloxy group, a lower alkoxy group, a
lower alkanoyloxy group, a lower alkanoylamino group, a heteroaryl
group, a substituted heteroaryl group, or a group of the formula:
--NR.sup.4R.sup.5.
[0094] [47] The pyridone derivative according to the above [46], or
a salt thereof, wherein E is an alkylene group having 1 to 4 carbon
atoms, and Q is a substituted or unsubstituted pyridyl group, a
1,2,4-triazol-1-yl group, or a group of the formula:
--NR.sup.4R.sup.5.
[0095] [48] The pyridone derivative according to the above [43] or
[44], or a salt thereof, wherein M.sup.1 is a direct bond.
[0096] [49] The pyridone derivative according to the above [48], or
a salt thereof, wherein Q is a hydrogen atom, a hydroxy group, a
carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl
group, a benzyloxy group, a lower alkoxy group, a lower alkanoyloxy
group, a lower alkanoylamino group, a heteroaryl group, a
substituted heteroaryl group, or a group of the formula:
--NR.sup.4R.sup.5.
[0097] [50] The pyridone derivative according to the above [48] or
[49], or a salt thereof, wherein --E-- is a group of the formula:
36
[0098] (wherein R.sup.6 and R.sup.7 are independently a hydrogen
atom, a methyl group, an ethyl group, or a propyl group, or R.sup.6
and R.sup.7 may combine each other to form a 3- to 7-membered
cycloalkane ring, m is an integer of 0 to 6, and p is an integer of
0 to 6).
[0099] [51] The pyridone derivative according to the above [50], or
a salt thereof, wherein p is 0.
[0100] [52] The pyridone derivative according to the above [51], or
a salt thereof, wherein R.sup.6 and R.sup.7 are both hydrogen
atoms, and m is 0 or 1.
[0101] [53] The pyridone derivative according to the above [47] or
[52], or a salt thereof, wherein R.sup.1 is an alkyl group, a
substituted alkyl group, or a hydrogen atom.
[0102] [54] The pyridone derivative according to the above [53], or
a salt thereof, wherein Y.sup.22 and Y.sup.32 are both hydrogen
atoms.
[0103] [55] A pharmaceutical composition containing a pyridone
derivative as set forth in any one of the above [38] to [54], or a
salt thereof.
[0104] [56] An acyl-CoA: cholesterol acyl transferase (ACAT)
inhibitor, which contains as an active ingredient a pyridone
derivative as set forth in any one of the above [38] to [54], or a
salt thereof.
[0105] [57] An agent for treatment of hyperlipidemia or
atherosclerosis, which contains as an active ingredient a pyridone
derivative as set forth in any one of the above [38] to [54], or a
salt thereof.
[0106] [58] A method for inhibiting acyl-CoA: cholesterol acyl
transferase (ACAT), which comprises a administering an effective
amount of a pyridone derivative as set forth in any one of the
above [38]to [54], or a salt thereof, to a patient in need
thereof.
[0107] [59] A method for treatment of hyperlipidemia or
atherosclerosis, which comprises administering an effective amount
of a pyridone derivative as set forth in any one of the above [38]
to [54], or a salt thereof, to a patient in need thereof.
[0108] [60] Use of a pyridone derivative as set forth in any one of
the above [38] to [54], or a salt thereof, in preparation of a
pharmaceutical composition for inhibiting acyl-CoA: cholesterol
acyl transferase (ACAT).
[0109] [61] Use of a pyridone derivative as set forth in any one of
the above [38] to [54], or a salt thereof, in preparation of an
agent for treatment of hyperlipidemia or atherosclerosis.
[0110] Each group in the present invention is explained below.
[0111] Incidentally, throughout the description, when the present
compounds have substituents such as hydroxy group, amino group,
alkylamino group, carboxyl group, etc., then these groups may
optionally be protected when the present methods are carried out.
The protecting groups for hydroxy group, amino group, alkylamino
group, carboxyl group, etc., may be conventional protecting groups
which are used in the field of the organic chemistry, for example,
as described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2nd ed.,
John Wiley & Sons, Inc.; New York. For example, the protected
hydroxy group may be benzyloxy group and 2-methoxyethoxymethoxy
group, and the protected amino group may be benzylamino group and
acetylamino group, and the protected alkylamino group may be
N-benzyl-N-alkyl-amino group and N-acetyl-N-alkylamino group, and
the protected carboxyl group may be tert-butoxycarbonyl group and
methoxy-methoxycarbonyl group.
[0112] Ring B is a substituted or unsubstituted benzene ring, and
the substituted benzene ring has one or more substituents which are
the same or different.
[0113] The substituent of the benzene ring may be, for example, a
lower alkyl group, a halogen atom, a cyano group, a trifluoromethyl
group, a nitro group, a protected amino group, a protected lower
alkylamino group, a di-lower alkylamino group, a lower alkoxy
group, a lower alkylthio group, a lower alkylsulfinyl group, a
lower alkylsulfonyl group, etc.
[0114] The pyridine ring formed by combining Y.sup.2 and Y.sup.3
together with the carbon atoms to which they bond is a substituted
or unsubstituted pyridine ring, and the nitrogen atom thereof may
be located at any position except for the fused positions of the
fused ring, and the substituted pyridine ring has one or more
substituents which are the same or different.
[0115] Besides, the substituent of the pyridine ring formed by
combining Y.sup.2 and Y.sup.3 together with the carbon atoms to
which they bond may be, for example, a lower alkyl group, a halogen
atom, a cyano group, a trifluoromethyl group, a nitro group, a
protected amino group, a protected lower alkylamino group, a
di-lower aIkylamino group, a lower alkoxy group, a lower alkylthio
group, a lower alkylsulfinyl group, a lower alkylsulfonyl group,
etc.
[0116] The alkyl group or the alkyl moiety of the substituted alkyl
group for Y.sup.1, Y.sup.2, Y.sup.3 and R.sup.1 includes, for
example, a straight chain or branched chain alkyl group having 1 to
15 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl,
2-butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 3-pentyl,
3-methylbutyl, hexyl, 3-hexyl, 4-methyl-pentyl, 4-heptyl, octyl,
4-octyl, decyl, etc.
[0117] The alkenyl group or the alkenyl moiety of the substituted
alkenyl group for R.sup.1 includes, for example, a straight chain
or branched chain alkenyl group having 2 to 15 carbon atoms, such
as vinyl, allyl, 2-propenyl, 2-methyl-2-propenyl, 2-butenyl,
3-butenyl, 3-methyl-2-butenyl, 4-pentenyl, 3-hexenyl,
3-ethyl-2-pentenyl, 4-ethyl-3-hexenyl, etc.
[0118] The alkynyl group or the alkynyl moiety of the substituted
alkynyl group for R.sup.1 includes, for example, a straight chain
or branched chain alkynyl group having 3 to 15 carbon atoms, such
as 2-propynyl, 3-butynyl, 4-pentynyl, 3-hexynyl,
5-methyl-2-hexynyl, 6-methyl-4- heptynyl, etc.
[0119] The alkyl group or the alkyl moiety of the substituted alkyl
group for L includes, for example, a straight chain or branched
chain alkyl group having 1 to 20 carbon atoms, such as methyl,
ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,
1-dimethylethyl, pentyl, 3-pentyl, hexyl, heptyl, octyl, undecyl,
dodecyl, hexadecyl, 2,2-dimethyl-dodecyl, 2-tetradecyl,
n-octadecyl, etc.
[0120] The alkenyl group or the alkenyl moiety of the substituted
alkenyl group for L includes, for example, a straight chain or
branched chain alkenyl group having 3 to 20 carbon atoms and having
1 to 2 double bonds, such as 2-propenyl, 2-butenyl,
3-methyl-2-butenyl, 3-pentenyl, 2-octenyl, 5-nonenyl, 4-undecenyl,
5-heptadecenyl, 3-octadecenyl, 9-octadecenyl,
2,2-dimethyl-9-octadecenyl, 9,12-octadecadienyl, etc.
[0121] The cycloalkyl group or the cycloalkyl moiety of the
substituted cycloalkyl group includes, for example, a cycloalkyl
group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
[0122] The aromatic group includes, for example, an aryl group and
a heteroaryl group.
[0123] The aryl group includes, for example, an aryl group having
carbon atoms of not more than 10, such as phenyl group, naphthyl
group, etc.
[0124] The heteroaryl group includes, for example, a 5- to
6-membered heteromonocyclic group having 1 to 2 nitrogen atoms, a
5- to 6-membered heteromonocyclic group having 1 to 2 nitrogen
atoms and one oxygen atom or one sulfur atom, a 5-membered
heteromonocyclic group having one oxygen atom or one sulfur atom, a
heterobicyclic group formed by fusing a 6-membered ring and a 5- or
6-membered ring and having 1 to 4 nitrogen atoms, such as
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl,
3-oxadiazolyl, 1-imidazolyl, 2-imidazolyl, 2-thiazolyl,
3-isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 2-furyl, 3-furyl,
3-pyrrolyl, 2-quinolyl, 8-quinolyl, 2-quinazolinyl, 8-purinyl,
etc.
[0125] The substituted aromatic group has one or more substituents
which are the same or different, and the substituents are, for
example, a halogen atom, a cyano group, a trifluoromethyl group, a
nitro group, a hydroxy group, a methylenedioxy group, a lower alkyl
group, a lower alkoxy group, a benzyloxy group, a lower alkanoyloxy
group, an amino group, a mono-lower alkylamino group, a di-lower
alkylamino group, a carbamoyl group, a lower alkylaminocarbonyl
group, a di-lower alkylaminocarbonyl group, a carboxyl group, a
lower alkoxycarbonyl group, a lower alkylthio group, a lower
alkylsulfinyl group, a lower alkyl-sulfonyl group, a lower
alkanoylamino group, a lower alkylsulfonamido group, or a group of
the formula: --M.sup.1--E--Q (M.sup.1 is a direct bond, an oxygen
atom, a sulfur atom, or a group of the formula: --NR.sup.3--
(R.sup.3 is a hydrogen atom or a lower alkyl group), E is a
divalent aliphatic hydrocarbon group having 1 to 15 carbon atoms
and optionally containing an unsaturated bond, or a phenylene
group, Q is a hydrogen atom, a hydroxy group, a carboxyl group, a
lower alkoxycarbonyl group, a benzyloxycarbonyl group, a halogen
atom, a cyano group, a benzyloxy group, a lower alkoxy group, a
lower alkanoyloxy group, a lower alkylthio group, a lower
alkylsulfinyl group, a lower alkylsulfonyl group, a
benzenesulfonyloxy group being optionally substituted by an alkyl
group, a lower alkanoylamino group, a lower alkoxycarbonylamino
group, a lower alkylsulfonamido group, a phthalimido group, a
cycloalkyl group, an aryl group, a substituted aryl group, a
heteroaryl group, a substituted heteroaryl group, a group of the
formula: --NR.sup.4R.sup.5 (R.sup.4 and R.sup.5 are independently a
hydrogen atom, a lower alkyl group, a di-lower
alkylamino-substituted lower alkyl group, a lower
alkoxy-substituted lower alkyl group, a cycloalkyl group, a lower
alkoxycarbonyl group, a heteroarylmethyl group, or an aralkyl
group, or R.sup.4 and R.sup.5 may combine each other together with
the nitrogen atom to which they bond, and form a saturated cyclic
amino group having 4 to 8 carbon atoms as ones forming the said
ring, and optionally having one --NR.sup.20--(R.sup.20 is a
hydrogen atom, a lower alkyl group, a phenyl group, a lower
alkoxycarbonyl group, or a benzyl group) or one oxygen atom in the
cycle thereof), or a group of the formula:
--C(.dbd.O)NR.sup.4R.sup.5 (R.sup.4 and R.sup.5 are as defined
above)).
[0126] The divalent aliphatic hydrocarbon group having 1 to 15
carbon atoms and optionally having an unsaturated bond includes,
for example, an alkylene chain having 1 to 6 carbon atoms,
preferably having 1 to 4 carbon atoms, such as methylene, ethylene,
trimethylene, tetramethylene, pentamethylene, hexamethylene, etc.,
an alkenylene chain such as propenylene, butenylene, etc., an
alkynylene chain such as ethynylene, propynylene, butynylene, or as
the group--E-- an alkynylene chain such as an alkynylene of the
following formula: 37
[0127] (R.sup.6 and R.sup.7 are independently a hydrogen atom, a
methyl group, an ethyl group or a propyl group, or R.sup.6 and
R.sup.7 may combine each other to form a 3- to 7-membered
cycloalkane ring, m is an integer of 0 to 6, preferably 0 or 1, and
p is an integer of 0 to 6, preferably 0 or 1).
[0128] The 3- to 7-membered cycloalkane ring formed by combining
R.sup.6 and R.sup.7 includes, for example, cyclopropane,
cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.
[0129] The substituted aryl group for Q has one or more
substituents which are the same or different, and the substituents
are, for example, a halogen atom, a cyano group, a trifluoromethyl
group, a nitro group, a hydroxy group, a methylenedioxy group, a
lower alkyl group, a lower alkoxy group, a benzyloxy group, a lower
alkanoyloxy group, an amino group, a mono-lower alkylamino group, a
di-lower alkylamino group, a carbamoyl group, a lower
alkylaminocarbonyl group, a di-lower alkylaminocarbonyl group, a
carboxyl group, a lower alkoxycarbonyl group, a lower alkylthio
group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a
lower alkanoylamino group, or a lower alkylsulfonamido group.
[0130] The heteroaryl group or the heteroaryl moiety of the
heteroarylmethyl group include, for example, a 5- to 6-membered
cyclic group having 1 to 3 nitrogen atoms, a 5-membered cyclic
group having one oxygen atom or one sulfur atom, or a bicyclic
group formed by fusing a 6-membered ring and a 5- or 6-membered
ring, and having 1 to 4 nitrogen atoms, such as 2-pyridyl,
3-pyridyl, 4-pyridyl, 1-pyrrolyl, 1-imidazolyl, 1,2,4-triazol-1-yl,
2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-quinolyl, etc.
[0131] The substituted heteroaryl group for Q has one or more
substituents which are the same or different, and the substituents
are, for example, a lower alkyl group, a lower alkoxy group, a
halogen atom, etc.
[0132] The saturated cyclic amino group formed by NR.sup.4R.sup.5
includes, for example, a group represented by the formula: 38
[0133] (wherein R.sup.20 is a hydrogen atom, a lower alkyl group, a
phenyl group, a lower alkoxycarbonyl group, or a benzyl group) such
as a 4-lower alkyl-1-piperazinyl, 4-phenyl-1-piperazinyl,
4-benzyl-1-piperazinyl, etc., or a monocyclic group such as
1-pyrrolidinyl, 1-piperidinyl, 1-homopiperidinyl, 4-morpholinyl,
etc., or a bicyclic group such as 3-azabicyclo[3.2.2]nonane,
etc.
[0134] The substituted alkyl group, the substituted cycloalkyl
group, the substituted alkenyl group, and the substituted alkynyl
group have one or more substituents which are the same or
different, and the substituents are, for example, a halogen atom, a
cyano group, a phenoxy group, a benzyloxy group, a trifluoromethyl
group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy
group, an amino group, a mono-lower alkylamino group, a di-lower
alkylamino group, a carbamoyl group, a lower alkylaminocarbonyl
group, a di-lower alkylaminocarbonyl group, a lower
alkoxycarbonylamino group, a carboxyl group, a lower alkoxycarbonyl
group, a lower alkylthio group, a lower alkylsulfinyl group, a
lower alkylsulfonyl group, a lower alkanoylamino group, a lower
alkylsulfonamido group, a tri-lower alkylsilyl group, a phthalimido
group, a heteroaryl group, a saturated heterocyclic group, or a
group of the formula: --M.sup.2--E--Q (M.sup.2 is an oxygen atom, a
sulfur atom, or a group of the formula: --NR.sup.21 (R.sup.21 is a
hydrogen atom or a lower alkyl group), E and Q are as defined
above).
[0135] The saturated heterocyclic group includes, for example, a 5-
to 8-membered cyclic group having one nitrogen atom, a 6- to
8-membered cyclic group having two nitrogen atoms, and a 6- to
8-membered cyclic group having one nitrogen atom and one oxygen
atom, such as 1-piperidinyl, 1-pyrrolidinyl, etc.
[0136] The substituted alkyl group includes an alkyl group having 1
to 6 carbon atoms which is substituted by a cycloalkyl group or a
substituted cycloalkyl group, or an aralkyl group or a substituted
aralkyl group.
[0137] The aralkyl group or the substituted aralkyl group includes
an alkyl group having 1 to 6 carbon atoms which is substituted by
the above-mentioned aryl group or substituted aryl group, for
example, benzyl, 1-phenylethyl, 2-phenylethyl, 2-naphthylmethyl,
etc.
[0138] The phenylene group may be o-phenylene group, m-phenylene
group, and p-phenylene group.
[0139] The term lower in the present invention means that alkyl
moiety described with lower is a lower alkyl group, and including
the cases when the lower alkyl group is a moiety of other
substituents, the lower alkyl group may be an alkyl group having 1
to 6 carbon atoms such as methyl, ethyl, propyl, 2-propyl, butyl,
pentyl, hexyl, etc.
[0140] The halogen atom is fluorine atom, chlorine atom, bromine
atom, and iodine atom.
[0141] The substituent of the substituted or unsubstituted alkyl
group for R.sup.2 may be, for example, lower alkoxy group.
[0142] The substituent of the substituted or unsubstituted phenyl
group for R.sup.2 may be, for example, a lower alkyl group, a lower
alkoxy group, and a halogen atom.
[0143] The compounds of the formula (10) in the above [38] are
novel compounds which were found by the present inventors for the
first time. In the compounds (10) in the above [38], preferable
groups for exhibiting biological activities are exemplified
below.
[0144] The preferable groups for Y.sup.1 are, for example, a phenyl
group or pyridyl group which may optionally be substituted. The
substituted phenyl group and the substituted pyridyl group have one
or more substituents which are the same or different, and the
preferable substituents are, for example, a halogen atom (e.g.,
fluorine atom, chlorine atom, etc.), a cyano group, a
trifluoromethyl group, a nitro group, a hydroxy group,
methylenedioxy group, a lower alkyl group, a lower alkoxy group, a
lower alkanoyloxy group, an amino group, a mono-lower alkylamino
group, a di-lower aIkylamino group, a carbamoyl group, a lower
alkylaminocarbonyl group, a di-lower alkylaminocarbonyl group, a
carboxyl group, a lower alkoxycarbonyl group, a lower alkylthio
group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a
lower alkanoylamino group, a lower alkylsulfonamido group, or a
group of the formula: --M.sup.1--E--Q (M.sup.1, E and Q are as
defined above).
[0145] The preferable groups for E are, for example, a straight
alkylene, alkenylene or alkynylene chain having 1 to 6 carbon
atoms, and the more preferable ones are a straight alkylene or
alkynylene chain having 1 to 3 carbon atoms. The preferable groups
for Q are, for example, a hydroxy group, a halogen atom, a cyano
group, a lower alkoxy group, a lower alkanoyloxy group, a lower
alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl
group, a lower alkanoylamino group, a lower alkylsulfonamido group,
a heteroaryl group, or a group of the formula: --NR.sup.4R.sup.5
(R.sup.4 and R.sup.5 are as defined above), and the more preferable
ones are a substituted or unsubstituted heteroaryl group (e.g.,
2-pyridyl, 3-pyridyl, 2-methylpyridin-3-yl, 4-pyridyl,
1-imidazolyl, 1,2,4-triazol-1-yl, etc.), or a group of the formula:
--NR.sup.4R.sup.5 (R.sup.4 and R.sup.5 are as defined above). The
preferable group of the formula: --NR.sup.4R.sup.5 (R.sup.4 and
R.sup.5 are as defined above) includes, for example, dimethylamino,
diethylamino, diisopropylamino, pyrrolidinyl, piperidinyl,
morpholinyl, 4-methylpiperazinyl, etc.
[0146] The preferable group of the formula: --M.sup.1--E--Q
includes, for example, 2-pyridylmethoxy, 3-pyridylmethoxy,
4-pyridylmethoxy, (2-methylpyridin-3-yl)methoxy,
(2,4-dimethylpyridin-3 -yl)methoxy, 2-hydroxyethoxy,
2-acetoxyethoxy, 2-(2-pyridyl)ethoxy, 2-(3-pyridyl)ethoxy,
2-(4-pyridyl)ethoxy, 2-(diethylamino)ethoxy,
2-(dimethylamino)ethoxy, 2-(piperidino)ethoxy,
2-(1-pyrrolidinyl)ethoxy, 2-(morpholino)ethoxy,
2-(1,2,4-triazol-1-yl)ethoxy, 3-hydroxypropoxy, 3-acetoxypropoxy,
3-(2-pyridyl)propoxy, 3-(3-pyridyl)propoxy, 3-(4-pyridyl)propoxy,
3-(diethylamino)propoxy, 3-(dimethylamino)propoxy,
3-(piperidino)propoxy, 3-(1-pyrrolidinyl)propoxy,
3-(morpholino)propoxy, 2-(1,2,4-triazol-1-yl)-propoxy,
3-dimethylamino-1-propynyl, 3-diethylamino-1-pyropynyl,
3-(1-pyrrolidinyl)-1-propynyl,
3-(N-methyl-N-(3-pyridylmethyl)amino)-1-propynyl,
2-(diethylamino)ethylth- io, N-methyl-N-(3-pyridylmethyl)amino,
3-(diethylamino)propyl, etc.
[0147] The preferable groups for L are a phenyl or heteroaryl group
which may optionally be substituted, and the more preferable groups
for L are a phenyl or pyridyl group which is substituted by 1 to 3
groups selected from a group consisting of a halogen atom (e.g., a
fluorine atom, chlorine atom, etc.), a lower alkyl group, a lower
alkoxy group and a lower alkylthio group, or a phenyl group
substituted by a lower alkyl group and a group of the formula:
--M.sup.1--E--Q (M.sup.1, E and Q are as defined above). The
preferable groups for E are, for example, a straight alkylene,
alkenylene or alkynylene chain having 1 to 6 carbon atoms, and the
more preferable ones are a straight alkylene or alkynylene chain
having 1 to 3 carbon atoms.
[0148] The preferable groups for Q are, for example, a hydroxy
group, a heteroaryl group, or a group of the formula:
--NR.sup.4R.sup.5 (R.sup.4 and R.sup.5 are as defined above), and
the more preferable ones are a substituted or unsubstituted
heteroaryl group (e.g., 2-pyridyl, 3-pyridyl, 2-methylpyridin-3-yl,
4-pyridyl, 1-imidazolyl, 2-isopropyl-1-imidazolyl, 1-pyrazolyl,
1,2,4-triazol-1-yl, etc.), or a group of the formula:
--NR.sup.4R.sup.5 (R.sup.4 and R.sup.5 are as defined above).
[0149] The preferable group of the formula: --NR.sup.4R.sup.5
(R.sup.4 and R.sup.5 are as defined above) includes, for example,
dimethylamino, diethylamino, diisopropylamino, pyrrolidinyl,
piperidinyl, morpholinyl, 4-methylpiperazinyl, etc.
[0150] The preferable groups for L are, for example,
2,6-diisopropylphenyl, 2,4,6-trimethylphenyl,
2,4,6-trimethoxyphenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl,
2-tert-butyl-5-(morpholinometh- yl)phenyl,
2-tert-butyl-5-(2-isopropyl- l-imidazolyl)phenyl,
2-tert-butyl-5-(1-pyrazolyl)phenyl,
2-tert-butyl-5-{N-methyl-N-(2-pyridyl- methyl)aminomethyl}phenyl,
2-tert-butyl-5-{N-methyl-N-(3-pyridylmethyl)ami- nomethyl}phenyl,
2-tert-butyl-5-{N-methyl-N-(4-pyridylmethyl)aminomethyl}p- henyl,
2,4-bis(methylthio)pyridin-3-yl,
2-tert-butyl-5-{N-ethyl-N-(3-pyrid- ylmethyl)aminomethyl}phenyl,
2,4-bis(methylthio)-6-methylpyridin-3-yl, etc.
[0151] The acid for forming an acid addition salt includes, for
example, inorganic acids such as hydrochloric acid, hydrobromic
acid, hydroiodic acid, nitric acid, sulfuric acid, etc., or organic
acids such as acetic acid, oxalic acid, citric acid, malic acid,
tartaric acid, fumaric acid, maleic acid, methanesulfonic acid,
etc.
[0152] When the compounds of the present invention have an acidic
group such as carboxyl group, then the present compounds may be in
the form of a salt with an organic base (e.g., diethanolamine salt,
ethylenediamine salt, N-methylglucamine salt), a salt with an
alkaline earth metal (e.g., calcium salt, magnesium salt), or a
salt with an alkali metal (e.g., lithium salt, potassium salt,
sodium salt).
[0153] The compounds of the present invention may have a
stereoisomer due to an asymmetric carbon atom thereof. In such
cases, the present compounds also include each isomer or a mixture
thereof.
[0154] The present compounds and a salt thereof may be in the form
of an anhydrous product thereof, or in the form of a solvate
thereof such as hydrate.
[0155] The compounds of the above-mentioned formula (10) or a salt
thereof can be administered either parenterally or orally when used
as the above-mentioned drug. The present compounds can be
formulated into liquid preparations such as solutions, emulsions,
suspensions, etc., and can be administered in the form of an
injection, and if necessary, buffering agents, solubilizers and
isotonic agents may be added thereto. The present compounds can
also be administered rectally in the form of a suppository. The
present compounds can also be administered orally in the form of a
conventional administration form such as tablets, capsules, syrups,
and suspension. These pharmaceutical preparations can be formulated
by mixing an active ingredient with conventional carriers or
diluents, binding agents or stabilizers by a conventional
manner.
[0156] The dosage and the frequency of administration of the
present compounds may vary according to the conditions, ages,
weights of the patients and the administration form, etc., but when
the present compound is administered orally, the daily dosage
thereof is in the range of 1 to 500 mg for an adult, once a day, or
divided into 2-4 dosage units.
[0157] Processes [1] to [37] and the processes for preparing the
compounds [38] to [54] will be described in detail. In the
description of the present processes, the compounds used therein
have an reactive group such as amino group, alkylamino group, lower
alkylamino group, hydroxy group, carboxyl group as a substituent,
then these groups may optionally be protected or deprotected to
give the desired compounds.
[0158] The protecting groups for amino group, alkylamino group,
lower alkylamino group, hydroxy group, carboxyl group, etc., may be
conventional protecting groups which are used in the field of the
organic chemistry (e.g., the protecting group for hydroxy group may
be benzyl group or acetyl group: the protecting group for amino
group may be benzyl group, etc.), and these protecting groups may
be introduced or removed by a conventional method, as described in
PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2nd ed., John Wiley &
Sons, Inc.; New York. 39
[0159] wherein L is an alkyl group, a substituted alkyl group, an
alkenyl group, a substituted alkenyl group, a cycloalkyl group, a
substituted cycloalkyl group, an aromatic group, or a substituted
aromatic group; Ring B is a substituted or unsubstituted benzene
ring; R.sup.1 is a hydrogen atom, an alkyl group, a substituted
alkyl group, an alkenyl group, a substituted alkenyl group, an
alkynyl group, a substituted alkynyl group, a cycloalkyl group, or
a substituted cycloalkyl group; R.sup.2 is a substituted or
unsubstituted lower alkyl group, or a substituted or unsubstituted
phenyl group; R.sup.10 is a lower alkyl group; X is a chlorine atom
or a bromine atom; Y.sup.1 is a hydrogen atom, an alkyl group, a
substituted alkyl group, a cycloalkyl group, a substituted
cycloalkyl group, an aromatic group, or a substituted aromatic
group; and Y.sup.2 and Y.sup.3 are independently a hydrogen atom, a
halogen atom, a hydroxy group, a cyano group, a trifluoromethyl
group, a nitro group, an amino group, a mono-lower alkylamino
group, a di-lower alkylamino group, a lower alkoxy group, a lower
alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl
group, an allyl group, a substituted alkyl group, a cycloalkyl
group, a substituted cycloalkyl group, an aromatic group, a
substituted aromatic group, or Y.sup.2 and Y.sup.3 may combine each
other together with the carbon atoms to which they bond, and form a
substituted or unsubstituted pyridine ring.
[0160] a) Step from the compound (15) to the compound (1):
[0161] The carbamoylpyridone derivative of the formula (1) can
preferably be obtained by reacting the ester derivative of the
formula (15) with formaldehyde in an amount of 1 to 10 mole
equivalents, preferably in an amount of 2 to 7 mole equivalents, in
the presence of a base (e.g., an alkali metal salt of alcohol such
as sodium methoxide, sodium ethoxide, or an alkali metal ammonia
such as sodium amide) in an amount of 1 to 10 mole equivalents,
preferably in an amount of 2 to 7 equivalents, in a solvent at a
temperature of from room temperature to 100.degree. C., preferably
at a temperature of from 50.degree. C. to 80.degree. C. The solvent
may be any solvent which does not disturb the reaction, for
example, ethers (e.g., dimethoxyethane, tetrahydrofuran, dioxane,
etc), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.),
halogenated hydrocarbons (e.g., chloroform, dichloroethane,
chlorobenzene, dichlorobenzene, etc.), and amides (e.g.,
N,N-dimethyl-formamide, N,N-dimethylacetamide, etc.). The
preferable solvent is N,N-dimethylformamide. The amide derivative
(1) can be also obtained by treating the ester derivative (15) with
an excess amount of liquid ammonia in a solvent or without solvent
at a temperature of from 0.degree. C. to 120.degree. C., preferably
at a temperature of from room temperature to 60.degree. C., and if
necessary, under pressure using an autoclave. The solvent is
usually methanol.
[0162] b) Step from the compound (16) to the compound (1):
[0163] The carbamoylpyridone derivative of the formula (1) can be
also prepared by converting the carboxylic acid derivative (16) to
an acid halide (e.g., an acid chloride or acid bromide) thereof,
and reacting with ammonia. The solvent may be any solvent which
does not disturb the reaction, for example, ethers (e.g., diethyl
ether, dimethoxyethane, tetrahydrofuran, dioxane, etc), aromatic
hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated
hydrocarbons (e.g., dichloromethane, chloroform, dichloroethane,
chlorobenzene, dichlorobenzene, etc.), and amides (e.g.,
N,N-dimethylformamide, N,N-dimethylacetamide, etc.). The conversion
to an acid halide may be carried out by a conventional method, for
example, an acid chloride can preferably be obtained by reacting
with thionyl chloride in an amount of 1 to 3 mole equivalents at a
temperature of from 50.degree. C. to 80.degree. C. in an aromatic
hydrocarbons (e.g., benzene, toluene, etc.). The reaction with
ammonia is carried out by a conventional method, for example, by
reacting with conc. aqueous ammonia in a solvent at a temperature
of from -10.degree. C. to 60.degree. C., preferably at a
temperature of from 0.degree. C. to 30.degree. C. The solvent may
be any solvent which does not disturb the reaction, for example,
ethers (e.g., diethyl ether, dimethoxyethane, tetrahydrofuran,
dioxane, etc), aromatic hydrocarbons (e.g., benzene, toluene,
xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane,
chloroform, dichloroethane, chlorobenzene, dichlorobenzene, etc.),
and amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide,
etc.).
[0164] c) Steps from the compound (1) to the compound (4), and from
the compound (5) to the compound (4):
[0165] The 2-carbamoylpyridone derivative (1) is reacted with lead
tetraacetate in an amount of 1 to 3 mole equivalents, preferably in
an amount of 1 to 1.5 mole equivalent in a solvent at a temperature
of from 0.degree. C. to 80.degree. C., preferably at a temperature
of from room temperature to 60.degree. C., to give the isocyanate
derivative (2). The solvent may be any solvent which does not
disturb the reaction, for example, aromatic hydrocarbons (e.g.,
benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g.,
dichloromethane, dichloroethane, etc.), and amides (e.g.,
N,N-dimethylformamide, N,N-dimethylacetamide, etc.). The preferable
solvent is N,N-dimethylformamide. The isocyanate derivative (2)
thus obtained may be isolated and subjected to the subseqent
reaction into a new solvent, or alternatively the reaction mixture
may be used in the subsequent reaction without isolation of the
isocyanate derivative (2), the reaction is carried out with the
amine derivative (3) in an amount of 1 to 3 mole equivalents,
preferably in an amount of 1 to 1.5 mole equivalents at a
temperature of from 0.degree. C. to 120.degree. C., preferably at a
temperature of from room temperature to 60.degree. C., up to a
boiling point of the solvent, to give the 2-pyridone derivative
(4). The solvent may be any solvent which does not disturb the
reaction, for example, ethers (e.g., diethyl ether,
dimethoxyethane, tetrahydrofuran, dioxane, etc), aromatic
hydrocarbons (e.g., benzene, toluene, xylene, etc.), esters (e.g.,
ethyl acetate, propyl acetate, etc.), halogenated hydrocarbons
(e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene,
dichlorobenzene, etc.), ketones (e.g., acetone, methyl ethyl
ketone, etc.), nitrites (e.g., acetonitrile, isobutyronitrile,
etc.), and amides (e.g., N,N-dimethylformamide,
N,N-dimethylacetamide, etc.). The preferable solvent is aromatic
hydrocarbons (e.g., benzene, toluene, etc.), halogenated
hydrocarbons (e.g., dichloromethane, dichloroethane, etc.), and
amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, etc.).
Especially preferable solvent is N,N-dimethylformamide.
[0166] When the amine derivative (3) is used in the form of an acid
addition salt thereof, the reaction may smoothly proceed by
converting the compound (3) into a free form, if necessary. In this
case, an agent for converting the compound (3) into a free form is
preferably a tertiary amine such as triethylamine, etc., or
pyridine, etc.
[0167] On the other hand, the carbamoylpyridone derivative (1) is
converted into the isocyanate derivative (2) by reacting it with a
hypochlorite or a hypobromite in an amount of 1 to 10 mole
equivalents, preferably in an amount of 1 to 5 mole equivalent in a
mixed solvent of water and an organic solvent at a temperature of
from 0.degree. C. to 80.degree. C., preferably at a temperature of
from room temperature to 50.degree. C., and then further reacted
with the amine derivative (3) in an amount of 1 to 3 mole
equivalents, preferably in an amount of 1 to 1.5 mole equivalent,
to give the pyridone derivative (4). When the isocyanate derivative
(2) is prepared, the reaction may proceed quickly by addition of a
phase transfer catalyst in an amount of 0.05 to 0.2 mole
equivalent. The phase transfer catalyst is preferably
tetrabutylammonium hydrogen sulfate. The preferable hypochlorite or
hypobromite is sodium hypobromite. The sodium hypobromite is
usually prepared from aqueous sodium hydroxide solution and bromine
at 0.degree. C. to 10.degree. C. in the reaction system. The
organic solvent may be any solvent which does not disturb the
reaction, for example, ethers (e.g., dimethoxyethane,
tetrahydrofuran, dioxane, etc), aromatic hydrocarbons (e.g.,
benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g.,
dichloromethane, chloroform, dichloroethane, chlorobenzene,
dichlorobenzene, etc.), and amides (e.g., N,N-dimethylformamide,
N,N-dimethylacetamide, etc.). When the isocyanate derivative (2) is
reacted with the amine derivative (3), the yield of the reaction
may be improved by addition of acetic acid in a volume of 10 to 30%
of the volume of the reaction solvent.
[0168] The compound (5) and the compound (31) are reacted in the
same manner as in the above reaction of the compound (2) and the
compound (3) to give the compound (4). The compound (31) is
disclosed in literatures or may be prepared by a conventional
method for preparation of an isocyanate as disclosed in
literatures. Besides, in the same manner as in the preparation of
the compound (2) from the compound (1), the compound (31) can be
prepared from a compound of the formula (33):
L--CONH.sub.2 (33)
[0169] which is disclosed in literatures or may be prepared by a
conventional method for preparation of an amide compound.
[0170] d) Step from the compound (1) to the compound (5):
[0171] The carbamoylpyridone derivative (1) is reacted with a
hypochlorite or hypobromite in an amount of 1 to 10 mole
equivalents, preferably in an amount of 1 to 5 mole equivalents in
a mixed solvent of water and an organic solvent at a temperature of
from 0.degree. C. to 80.degree. C., preferably at a temperature of
from room temperature to 50.degree. C., and the resulting
isocyanate derivative (2) is subjected to hydrolysis to give the
aminopyridone derivative (5). By addition of a phase transfer
catalyst in an amount of 0.05 to 0.2 mole equivalent in the step of
production of the isocyanate derivative, the reaction may quickly
proceed. The phase transfer catalyst is preferably
tetrabutylammonium hydrogen sulfate. The hydrolysis is usually
carried out by subsequently stirring the reaction mixture
containing the compound (2) at 30.degree. C. to 50.degree. C. The
preferable hypochlorite or hypobromite is, for example, sodium
hypobromite. The sodium hypobromite is usually prepared from an
aqueous sodium hydroxide solution and bromine at 0.degree. C. to
10.degree. C. The solvent may be any solvent which does not disturb
the reaction, for example, ethers (e.g., diethyl ether,
dimethoxyethane, tetrahydrofuran, dioxane, etc.), aromatic
hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated
hydrocarbons (e.g., dichloromethane, chloroform, dichloroethane,
chlorobenzene, dichlorobenzene, etc.), and amides (e.g.,
N,N-dimethylformamide, N,N-dimethylacetamide, etc.). The preferable
solvent is, for example, tetrahydrofuran and toluene.
[0172] The carbamoylpyridone derivative (1) can be converted into
the aminopyridone derivative (5) by Hofmann reaction. The Hofmann
reaction is carried out by reacting with a hypochlorite or a
hypobromite in an amount of 1 to 3 mole equivalents, preferably in
an amount of 1 to 1.5 mole equivalent in a solvent at a temperature
of from 0.degree. C. to 80.degree. C., preferably at a temperature
of from room temperature to 50.degree. C. The hypochlorite or
hypobromite is usually sodium hypobromite. The solvent may be any
solvent which does not disturb the reaction, for example, ethers
(e.g., diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane,
etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene,
etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform,
dichloroethane, chlorobenzene, dichlorobenzene, etc.), and amides
(e.g., N,N-dimethylformamide, N,N-dimethylacetamide, etc.).
[0173] e) Step from the compound (5) to the compound (4):
[0174] The aminopyridone derivative (5) is reacted with a
halocarbonate (6) in an amount of 1 to 10 mole equivalents,
preferably in an amount of 1 to 3 mole equivalents, at a
temperature of from room temperature to a boiling point of the
solvent, preferably at a temperature of from room temperature to
80.degree. C., and the resulting carbamic acid ester derivative (7)
is reacted with the amine derivative (3) in an amount of 1 to 5
mole equivalents, preferably 1 to 2 mole equivalents at a
temperature of from room temperature to a boiling point of the
solvent, preferably at a temperature of from room temperature to
100.degree. C., in the presence of 4-dimethylaminopyridine in an
amount of 1 to 3 mole equivalents, preferably in an amount of 1 to
1.5 mole equivalent, to give the pyridone derivative (4). The
preferable halocarbonate is phenyl chlorocarbonate. The reaction is
usually carried out in a solvent, and the solvent may be any
solvent which does not disturb the reaction, for example, ethers
(e.g., isopropyl ether, tetrahydrofuran, dioxane, etc.), aromatic
hydrocarbons (e.g., benzene, toluene, etc.), esters (e.g., methyl
acetate, ethyl acetate, etc.), halogenated solvents (e.g.,
dichloromethane, chloroform, etc.), and N,N-dimethylformamide,
dimethylsulfoxide, etc. The reaction may be promoted by addition of
a base. The base includes, for example, sodium carbonate, potassium
carbonate, triethylamine, pyridine, N,N-dimethylaniline, etc.
40
[0175] wherein R.sup.1, R.sup.2,Y.sup.1, Y.sup.2, Y.sup.3 and L are
as defined above.
[0176] Alternatively, in the same manner as in the preparation of
the carbamic acid ester derivative (7) from the amine derivative
(5) as mentioned above, the carbamic acid ester derivative (32) is
obtained from the amine derivative (3) and the halocarbonate (6) in
an amount of 1 to 10 mole equivalents, preferably in an amount of 1
to 3 mole equivalents, and said compound (32) is reacted with the
amine derivative (5) in the same manner as in the preparation of
the pyridone derivative (4) from the amine derivative (7) as
mentioned above, to give the pyridone derivative (4).
[0177] f) Step from the compound (17) to the compound (8):
[0178] The aminoketone derivative (17). is reacted with an acid
halide of N-phthaloylglycine of the formula (18) in an amount of 1
to 5 mole equivalents, preferably in an amount of 1 to 2.5 mole
equivalents, in a solvent, at a temperature of from room
temperature to 100.degree. C., preferably at a temperature of from
room temperature to 80.degree. C., to give the amide derivative
(8). The reaction is preferably carried out by addition of a base
in an amount of 1 mole equivalent or more. The base includes, for
example, a tertiary amine such as triethylamine, or pyridine. The
solvent may be any solvent which does not disturb the reaction, for
example, ethers (e.g., dimethoxyethane, tetrahydrofuran, dioxane,
etc), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.),
esters (e.g., ethyl acetate, propyl acetate, etc.), halogenated
hydrocarbons (e.g., dichloromethane, chloroform, dichloroethane,
chlorobenzene, dichlorobenzene, etc.), nitrites (e.g.,
acetonitrile, isobutyronitrile, etc.), and amides (e.g.,
N,N-dimethylformamide, N,N-dimethylacetamide, etc.). The preferable
solvent may be aromatic hydrocarbons such as benzene, toluene, etc.
The amide derivative (8) can usually be used in the subsequent
reaction without further purification. Moreover, the reaction
mixture containing the amide derivative (8) can also be used in the
subsequent reaction.
[0179] g) Step from the compound (8) to the compound (9):
[0180] Subsequently, the amide derivative (8) is subjected to
cyclization reaction by heating it in a solvent in the presence of
a base in an amount of 1 to 20 mole equivalents, preferably in an
amount of 1 to 7 mole equivalents, at 50-120.degree. C., preferably
at 70-110.degree. C., to give the 1,2-dihydro-2-pyridone derivative
(9). The compound (9) is usually used in the subsequent reaction
without further purification. The base is preferably an alkali
metal carbonate such as sodium carbonate, potassium carbonate, etc.
The solvent may be aromatic hydrocarbons (e.g., benzene, toluene,
xylene, etc.), and amides (e.g., N,N-dimethylformamide,
N,N-dimethylacetamide, etc.). The preferable solvent is
N,N-dimethylacetamide.
[0181] h) Step from the compound (9) to the compound (5):
[0182] The 3-aminopyridone derivative (5) is prepared by removing
the protecting phthaloyl group of the 1,2-dihydro-2-pyridone
derivative (9). The removal of the protecting phthaloyl group may
be carried out by a conventional method which is usually used in
the field of the organic chemistry, for example, as described in
PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2nd ed., John Wiley &
Sons, Inc.; New York. The preferable method of deprotection is a
method of adding an excess amount of an alcohol solution or aqueous
solution of a lower alkylamine (e.g., methylamine) at 0-50.degree.
C., preferably at room temperature, to the reaction system wherein
the compound (9) is produced.
[0183] i) Step of preparing the compound (17):
[0184] The aminoketone derivative (17) wherein R.sup.1 is a
hydrogen atom, i.e., the derivative (19) may be prepared by the
method disclosed in the literature (e.g., J. Heterocyclic Chem., 2,
105-112, 1989; J. Heterocyclic Chem., 13, 1283-1288, 1976) or a
modified method thereof. In addition, the aminoketone derivative
(17) wherein R.sup.1 is a group other than a hydrogen atom may be
prepared by the following Reaction Scheme. 41
[0185] wherein Y.sup.1, Y.sup.2 and Y.sup.3 are as defined above,
R.sup.11 is an alkyl group, a substituted alkyl group, an alkenyl
group, a substituted alkenyl group, an alkynyl group, a substituted
alkynyl group, a cycloalkyl group, or a substituted cycloalkyl
group, and G is a leaving group.
[0186] The aminoketone derivative (19) is reacted with an
alkylating agent (20) in the presence of a base at a temperature of
from 0.degree. C. to 150.degree. C., preferably at a temperature of
from room temperature to 80.degree. C. in a solvent to give the
compound (21). The solvent may be alcohols (e.g., methanol,
ethanol, etc.), ethers (e.g., tetrahydrofuran, dioxane, etc.),
ketones (e.g., acetone, 2-butanone, etc.), dimethylformamide, etc.
The base may be an alkali metal hydroxide (e.g., sodium hydroxide,
potassium hydroxide, etc.), an alkali metal alcoholate (e.g.,
sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an
alkali metal hydride (e.g., sodium hydride, etc.), an alkali metal
carbonate (e.g., potassium carbonate, sodium carbonate, etc.), and
an organic base (e.g., triethylamine). The leaving group for G is
usually a halogen atom such as chlorine, bromine, iodine, etc., or
aromatic sulfonyloxy group such as p-toluenesulfonyloxy group.
[0187] The ester derivative (15) and the carboxylic acid derivative
(16) may be prepared by the method disclosed in the literature
(e.g., JP-A-9-48780; Australian J. Chem., 1983, 36, 1431; J. Chem.
Soc., 1908, 1022; J. Chem. Soc., 1904, 1726; J. Chem. Soc., 1915,
792; J. Am. Chem. Soc., 1956, 78, 4683), or a modified method
thereof.
[0188] The present compound (10) wherein Z is a direct bond may be
prepared by the following method. 42
[0189] wherein L, R.sup.1, Y.sup.1, Y.sup.22 and Y.sup.32 are as
defined above.
[0190] The amine derivative (24) or an acid addition salt thereof
is condensed with the carboxylic acid derivative (25) using a
condensing agent in a solvent at a temperature of from 0.degree. C.
to 100.degree. C., preferably at a temperature of from 0.degree. C.
to 60.degree. C., and if necessary, the resultant is further
subjected to deprotection reaction to give the amide derivative
(11). The condensing agent may be dicyclohexylcarbodiimide (DCC),
N,N'-carbodiimidazole, diethyl cyanophosphate (DEPC),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSC),
etc. The reaction may preferably proceed by addition of a base in
an amount of 1 to 5 mole equivalents, preferably in an amount of 1
to 3 mole equivalents, to the amount of the amine derivative (24)
or an acid addition salt thereof. The base may be a tertiary amine
such as triethylamine, diisopropylethylamine, or pyridine, etc. The
solvent may be any solvent which does not disturb the reaction, for
example, ethers (e.g., diethyl ether, dimethoxyethane,
tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (e.g.,
benzene, toluene, xylene, etc.), esters (e.g., ethyl acetate,
propyl acetate, etc.), halogenated hydrocarbons (e.g.,
dichloromethane, chloroform, dichloroethane, chlorobenzene,
dichlorobenzene, etc.), ketones (e.g., acetone, methyl ethyl
ketone, etc.), nitriles (e.g., acetonitrile, isobutyronitrile,
etc.), and amides (e.g., N,N-dimethylformamide,
N,N-dimethylacetamide, etc.).
[0191] Alternatively, the carboxylic acid derivative (25) is
converted into a reactive derivative thereof, which is further
reacted with the amine derivative (24) in a solvent at a
temperature of from -10.degree. C. to 120.degree. C., preferably at
a temperature of from 0.degree. C. to 60.degree. C. to give the
amide derivative (26). The reactive derivative of the carboxylic
acid derivative (25) may be, for example, an acid chloride, an acid
bromide, an acid anhydride, or a mixed acid anhydride with methyl
carbonate, ethyl carbonate, or the like, and the reaction may
preferably proceed by addition of a base in an amount of 1 to 5
mole equivalents, preferably in an amount of 1 to 3 mole
equivalents. The base may be a tertiary amine (e.g.,
triethylamine), pyridine, an alkali metal carbonate (e.g., sodium
carbonate, potassium carbonate), and an alkali metal hydrogen
carbonate (e.g., sodium hydrogen carbonate). The solvent may be any
solvent which does not disturb the reaction, for example, ethers
(e.g., diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane,
etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene,
etc.), esters (e.g., ethyl acetate, propyl acetate, etc.),
halogenated hydrocarbons (e.g., dichloromethane, chloroform,
dichloroethane, chlorobenzene, dichlorobenzene, etc.), ketones
(e.g., acetone, methyl ethyl ketone, etc.), nitrites (e.g.,
acetonitrile, isobutyronitrile, etc.), and amides (e.g.,
N,N-dimethylformamide, N,N-dimethylacetamide, etc.).
[0192] Some of the present compounds (10) wherein Z is --NH-- can
also be prepared by the following method. 43
[0193] wherein L, R.sup.11, Y.sup.1, Y.sup.22, Y.sup.32 and G are
as defined above.
[0194] The urea derivative (22) is converted into the urea
derivative (23) by reacting with an alkylating agent (20). The
alkylation reaction is carried out in a solvent at a temperature of
from 0.degree. C. to 100.degree. C., preferably at a temperature of
from room temperature to 70.degree. C. in the presence of a base.
The solvent may be, for example, ethers (e.g., tetrahydrofuran,
dioxane, etc.), ketones (e.g., acetone, 2-butanone, etc.), aromatic
hydrocarbons (e.g., benzene, toluene, etc.), and
dimethyl-formamide. The base may be sodium hydride, potassium
carbonate, sodium carbonate, triethylamine, etc. The leaving group
for G is usually a halogen atom (e.g., chlorine, bromine, iodine,
etc.) or an aromatic sulfonyloxy group (e.g., p-toluenesulfonyloxy
group).
[0195] The substituents for L, R.sup.1, Y.sup.1, Y.sup.22 and
Y.sup.32 of the pyridone derivative (10) can be converted each
other, if necessary. For example, a lower alkylthio group can be
converted into a lower alkylsulfonyl group by oxidation, a nitro
group can be converted into an amino group by reduction reaction,
an amino group can be converted into a mono- or di-alkyl group by
alkylation, or an amino group can be acylated. Further, a
3-chloropropoxy group is converted into a 3-(1-imidazolyl)-propoxy
group. In addition, a halogen atom such as bromine, iodine can be
converted into a 1-propargyl group having a hydroxy group or an
amino group at the 3-position by using a palladium catalyst. Said
propargyl group can be further converted into a propyl group by
hydrogenation reaction. Such conversion reactions of the
substituents can be carried out by a conventional technique which
is usually used in the field of the organic chemistry.
[0196] The alkylation reaction as shown in the following scheme may
be carried out as one of these conversion reactions of substiuents.
44
[0197] wherein G, E, Z, L, R.sup.11, Y.sup.22, Y.sup.32 and Q are
as defined above, M.sup.2 is an oxygen atom, a sulfur atom or a
group of the formula: --NR.sup.21--(R.sup.21 is as defined
above).
[0198] The compound (27) is reacted with the alkylating agent (28)
in a solvent, and if necessary, followed by deprotection to give
the compound (29). The reaction is usually carried out in a solvent
at a temperature of from 0.degree. C. to 100.degree. C., preferably
at a temperature of from room temperature to 70.degree. C., in the
presence of a base. The solvent may be, for example, ethers (e.g.,
tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (e.g.,
benzene, toluene, etc.), ketones (e.g., acetone, methyl ethyl
ketone, etc.), and dimethylformamide. The base may be, for example,
sodium hydride, potassium carbonate, sodium carbonate,
triethylamine, etc. When potassium carbonate or sodium carbonate is
used, the yield may be improved by addition of sodium iodide or
potassium iodide. The leaving group for G is usually a halogen atom
(e.g., chlorine, bromine, iodine, etc.) or an aromatic sulfonyloxy
group (e.g., p-toluenesulfonyloxy group).
[0199] The intermediate (2) or (5) of the present invention may be
prepared, for example, by the method as disclosed below or a
modified method thereof. 45
[0200] wherein R.sup.1, R.sup.11, Y.sup.1, Y.sup.2, Y.sup.3 and G
are as defined above, and R.sup.10 is a lower alkyl group.
[0201] The starting compound (30) may be prepared by the method
disclosed in the literature (e.g., JP-A-9-48780; Australian J.
Chem., 1983, 36, 1431; J. Chem. Soc., 1908, 1022; J. Chem. Soc.,
1904, 1726; J. Chem. Soc., 1915, 792; J. Am. Chem. Soc., 1956, 78,
4683) or a modified method thereof. The lower alkyl group for
R.sup.10 is preferably an alkyl group having 1 to 4 carbon atoms
such as methyl, ethyl, propyl, isopropyl, butyl, etc.
[0202] The ester derivative (30) is converted into the compound
(15) by alkylation reaction, if necessary. The alkylation reaction
is carried out by reacting with the alkylating agent (20) in a
solvent at a temperature of from 0.degree. C. to 150.degree. C.,
preferably at a temperature of from room temperature to 80.degree.
C., in the presence of a base. The solvent may be alcohols (e.g..
methanol, ethanol, etc.), ethers (e.g., tetrahydrofuran, dioxane,
etc.), ketones (e.g., acetone, 2-butanone, etc.), and
dimethyl-formamide. The base may be sodium hydroxide, potassium
hydroxide, sodium methoxide, sodium ethoxide, potassium t-butoxide,
sodium hydride, potassium carbonate, sodium carbonate,
triethylamine, etc. The leaving group for G is usually a halogen
atom (e.g. chlorine, bromine, iodine, etc.) or an aromatic
sulfonyloxy group (e.g., p-toluene-sulfonyloxy group, etc.).
[0203] Subsequently, the compound (15) is subjected to hydrolysis
to give the carboxylic acid derivative (16). The hydrolysis is
carried out by a conventional method, for example, by using a
hydroxide of an alkali metal or alkaline earth metal (e.g., sodium
hydroxide, potassium hydroxide, barium hydroxide, etc.), in a
solvent (e.g., methanol, ethanol, isopropanol, tetrahydrofuran,
dioxane, dimethoxyethane, etc.) at a temperature of from 0.degree.
C. to 150.degree. C., preferably at a temperature of from 0.degree.
C. to 100.degree. C. The carboxylic acid derivative (16) is
converted into an acid azide thereof by using an azidating agent
(e.g., diphenyl-phosphorylazide (DPPA), etc.) in an amount of 1 to
3 mole equivalents, in a solvent in the presence of a base (e.g.,
triethylamine, N-methyl-morpholine, etc.) at a temperature of from
0.degree. C. to 120.degree. C., preferably at a temperature of from
room temperature to 80.degree. C., and the resulting acid azide
compound is usually heated at a temperature of from 20.degree. C.
to 150.degree. C., preferably at a temperature of from 30.degree.
C. to 100.degree. C. without isolation from the reaction system, to
give the compound (2). Moreover, in the same manner as in the
hydrolysis of the compound (15), the compound (2) is subjected to
hydrolysis to give the compound (5).
[0204] The compounds of the present invention prepared by the
present methods and the intermediates thereof may be purified by a
conventional method, for example, column chromatography,
recrystallization, etc. The solvent for recrystallization may
properly be selected from alcohols (e.g., methanol, ethanol,
2-propanol, etc.), ethers (e.g., diethyl ether, etc.), esters
(e.g., ethyl acetate, etc.), aromatic solvents (e.g., toluene,
etc.), ketones (e.g., acetone, etc.), hydrocarbons (e.g., hexane,
etc.) or a mixture of these solvent.
[0205] The compounds of the present invention prepared by the above
Processes are listed below. The abbreviation used in Tables 1 to 12
is shown. That is, Imd denotes 1-imidazolyl group, 2-Me--Imd
denotes 2-methyl-1-imidazolyl group, Pyrz denotes 1-pyrazolyl
group, Triaz denotes 1,2,4-triazol-1-yl group, Morp denotes
morpholino group, Quin denotes quinolyl group, Py denotes pyridyl
group, Pipe denotes piperidino group, Pyrro denotes 1-pyrrolidinyl
group, Pipera denotes 1-piperazinyl group, Phe denotes phenyl
group, Me denotes methyl group, Et denotes ethyl group, Pr denotes
propyl group, iPr denotes isopropyl group, Bu denotes butyl group,
tBu denotes tert-butyl group, Hex denotes hexyl group, cHex denotes
cyclohexyl group, and Bn denotes benzyl group, respectively.
1TABLE 1 46 Y.sup.1 Y.sup.2 Y.sup.3 R.sup.1 L Me H H Bu
2,6-di-iPr-Phe Et H H Bu 2,6-di-iPr-Phe Pr H H Bu 2,6-di-iPr-Phe
iPr H H Bu 2,6-di-iPr-Phe Bu H H Bu 2,6-di-iPr-Phe
(CH.sub.2).sub.9CH.sub.3 H H Bu 2,6-di-iPr-Phe
(CH.sub.2).sub.10CH.sub.3 H H Bu 2,6-di-iPr-Phe
(CH.sub.2).sub.14CH.sub.3 H H Bu 2,6-di-iPr-Phe Ph H H Bu
2,6-di-iPr-Phe 2-Py H H Bu 2,6-di-iPr-Phe 3-Py H H Bu
2,6-di-iPr-Phe 4-Py H H Bu 2,6-di-iPr-Phe H Ph H Bu 2,6-di-iPr-Phe
H H Ph Bu 2,6-di-iPr-Phe H H Ph H 2,6-di-iPr-Phe H H Ph Me
2,6-di-iPr-Phe H H Ph Et 2,6-di-iPr-Phe H H Ph Pr 2,6-di-iPr-Phe H
H Ph iPr 2,6-di-iPr-Phe
[0206]
2TABLE 2 47 A.sup.1 A.sup.2 A.sup.3 A.sup.4 Y.sup.2 Y.sup.3 R.sup.1
L MeO H H H H H H 2,6-di-iPr-Phe MeO H H H H H Me 2,6-di-iPr-Phe
MeO H H H H H Et 2,6-di-iPr-Phe MeO H H H H H Pr 2,6-di-iPr-Phe MeO
H H H H H iPr 2,6-di-iPr-Phe MeO H H H H H Bu 2,6-di-iPr-Phe MeO H
H MeO H H H 2,6-di-iPr-Phe MeO H H MeO H H Me 2,6-di-iPr-Phe MeO H
H MeO H H Et 2,6-di-iPr-Phe MeO H H MeO H H Pr 2,6-di-iPr-Phe MeO H
H MeO H H iPr 2,6-di-iPr-Phe MeO H H MeO H H Bu 2,6-di-iPr-Phe EtO
H H MeO H H Bu 2,6-di-iPr-Phe PrO H H MeO H H Bu 2,6-di-iPr-Phe
iPrO H H MeO H H Bu 2,6-di-iPr-Phe MeO H H MeO Me H Bu
2,6-di-iPr-Phe MeO H MeO H H H Bu 2,6-di-iPr-Phe MeO MeO H H H H Bu
2,6-di-iPr-Phe MeO H H Me H H Bu 2,6-di-iPr-Phe MeO H H F H H Bu
2,6-di-iPr-Phe MeO H H Cl H H Bu 2,6-di-iPr-Phe MeO H H Br Me H Bu
2,6-di-iPr-Phe MeO H H Br H H Bu 2,6-di-iPr-Phe
[0207]
3TABLE 3 48 A.sup.1 A.sup.5 Y.sup.2 Y.sup.3 R.sup.1 L MeO
CH.sub.2-3-Py H H Bu 2-iPr-Phe MeO CH.sub.2-3-Py H H Bu
2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H Bu 2-Me-Phe MeO CH.sub.2-3-Py
H H Bu 2,6-di-Me-Phe MeO CH.sub.2-3-Py H H Bu 2,4,6-tri-Me-Phe MeO
CH.sub.2-3-Py H H Bu 2-F-Phe MeO CH.sub.2-3-Py H H Bu 2,6-di-F-Phe
MeO CH.sub.2-3-Py H H Bu 2,4,6-tri-F-Phe MeO CH.sub.2-3-Py H H Bu
2-iPr-Phe MeO CH.sub.2-3-Py H H Bu 2-iPr-6-Me-Phe MeO CH.sub.2-3-Py
H H Bu 2-Et-Phe MeO CH.sub.2-3-Py H H Bu 2,6-di-Et-Phe MeO
CH.sub.2-3-Py H H Bu 2-iPr-6-Me-Phe MeO CH.sub.2-3-Py H H Bu
2-Et-6-iPr-Phe MeO CH.sub.2-3-Py H H Bu 2-Me-6-tBu-Phe MeO
CH.sub.2-3-Py H H Bu 2,4,6-tri-MeO-Phe MeO CH.sub.2-3-Py H H Bu
2-EtO-Phe MeO CH.sub.2-3-Py H H Bu 2-MeS-Phe MeO CH.sub.2-3-Py H H
Bu 2-CF.sub.3-Phe MeO CH.sub.2-3-Py H H Bu 2-Br-Phe MeO
CH.sub.2-3-Py H H Bu 2,6-di-Br-Phe MeO CH.sub.2-3-Py H H Bu
2-Cl-Phe MeO CH.sub.2-3-Py H H Bu 2,6-di-Cl-Phe MeO CH.sub.2-3-Py H
H Bu 2-Cl-6-Me-Phe MeO CH.sub.2-3-Py H H Bu 2,4-di-Cl-Phe MeO
CH.sub.2-3-Py H H Bu 2-Cl-3-Py MeO CH.sub.2-3-Py H H Bu 3-Quin MeO
CH.sub.2-3-Py H H Bu 5-Quin MeO CH.sub.2-3-Py H H Bu 6-Quin MeO
CH.sub.2-3-Py H H Bu 8-Quin
[0208]
4TABLE 4 49 A.sup.1 A.sup.5 Y.sup.2 Y.sup.3 R.sup.1 L MeO Bn H H Bu
2,6-di-iPr-Phe MeO CH.sub.2-2-Py H H Bu 2,6-di-iPr-Phe MeO
CH.sub.2-4-Py H H Bu 2,6-di-iPr-Phe MeO (CH.sub.2).sub.2--NMe.sub.2
H H Bu 2,6-di-iPr-Phe MeO (CH.sub.2).sub.2--NiPr.sub.2 H H Bu
2,6-di-iPr-Phe MeO (CH.sub.2).sub.2-Morp H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.2-Pipe H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.2-Pyrro H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.2-Pipera H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.2-Triaz H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.2--OH H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.2--OAc H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.2--Cl H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.2-2-Py H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3-3-Py H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.2-4-Py H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3--NMe.sub.2 H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3--NiPr.sub.2 H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3-Morp H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3-Pipe H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3-Pipera H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3-Pyrro H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3--OH H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3--OAc H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3--Cl H H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3-Triaz H H Bu 2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H
H 2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H Me 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H Et 2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H Pr
2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H iPr 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H 3-Butenyl 2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H
3-Butynyl 2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H 4-Pentenyl
2,6-di-iPr-Phe
[0209]
5TABLE 5 50 A.sup.1 A.sup.5 Y.sup.2 Y.sup.3 R.sup.1 L MeO
CH.sub.2-3-Py H H CH.sub.2-Ph 2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H
CH.sub.2-2-Py 2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H CH.sub.2-3-Py
2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H CH.sub.2-4-Py 2,6-di-iPr-Phe
MeO CH.sub.2-3-Py H H CH.sub.2CO.sub.2H 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H CH.sub.2CN 2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H
CH.sub.2OH 2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H CH.sub.2OMe
2,6-di-iPr-Phe MeO CH.sub.2-3-Py H H Bn 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H (CH.sub.2).sub.2OH 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H (CH.sub.2).sub.2CN 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H (CH.sub.2).sub.2NH.sub.2 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H (CH.sub.2).sub.2NMe.sub.2 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H (CH.sub.2).sub.2NHAc 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H (CH.sub.2).sub.3OH 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H (CH.sub.2).sub.3CN 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H (CH.sub.2).sub.3NH.sub.2 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H (CH.sub.2).sub.3NMe.sub.2 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py H H (CH.sub.2).sub.3NHAc 2,6-di-iPr-Phe Me
CH.sub.2-3-Py H H Bu 2,6-di-iPr-Phe Br CH.sub.2-3-Py H H Bu
2,6-di-iPr-Phe Cl CH.sub.2-3-Py H H Bu 2,6-di-iPr-Phe F
CH.sub.2-3-Py H H Bu 2,6-di-iPr-Phe CF.sub.3 CH.sub.2-3-Py H H Bu
2,6-di-iPr-Phe EtO CH.sub.2-3-Py H H Bu 2,6-di-iPr-Phe BnO
CH.sub.2-3-Py H H Bu 2,6-di-iPr-Phe HO CH.sub.2-3-Py H H Bu
2,6-di-iPr-Phe AcNH CH.sub.2-3-Py H H Bu 2,6-di-iPr-Phe MeO
CH.sub.2-3-Py Me H Bu 2,6-di-iPr-Phe MeO CH.sub.2-3-Py Me H Bu
2,6-di-F-Phe MeO CH.sub.2-3-Py Me H Bu 2,4,6-tri-F-Phe MeO
CH.sub.2-3-Py Me H Bu 2,4,6-tri-MeO-Phe MeO CH.sub.2-2-Py Me H Bu
2,6-di-iPr-Phe
[0210]
6TABLE 6 51 A.sup.1 A.sup.5 Y.sup.2 Y.sup.3 R.sup.1 L MeO
CH.sub.2-3-Py Me H Bu 2,6-di-iPr-Phe MeO (CH.sub.2).sub.2-Morp Me H
Bu 2,6-di-iPr-Phe MeO (CH.sub.2).sub.2-Pipe Me H Bu 2,6-di-iPr-Phe
MeO (CH.sub.2).sub.2-Pyrro Me H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.2-Triaz Me H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3-Morp Me H Bu 2,6-di-iPr-Phe MeO
(CH.sub.2).sub.3-Triaz Me H Bu 2,6-di-iPr-Phe MeO CH.sub.2-2-Py Me
H (CH.sub.2).sub.2OMe 2,6-di-iPr-Phe MeO CH.sub.2-2-Py Me H
(CH.sub.2).sub.3CN 2,6-di-iPr-Phe
[0211]
7TABLE 7 52 A.sup.1 A.sup.5 Y.sup.2 R.sup.1 L MeO Me H Bu
2,6-bis-MeS-4-Me-Phe MeO Me H Bu 2,4-bis-MeS-6-Me-3-Py MeO Me H Bu
2-tBu-5-(CH.sub.2-Morp)-Phe MeO Me H Bu 2-tBu-5-(CH.sub.2-Pipe)-Ph-
e MeO Me H Bu 2-tBu-5-(CH.sub.2-Pyrro)-Phe MeO Me H Bu
2-tBu-5-(CH.sub.2-Pipera)-Phe MeO Me H Bu 2-tBu-5-(CH.sub.2-Imd)-P-
he MeO Me H Bu 2-tBu-5-(CH.sub.2-Pyrz)-Phe MeO Me H Bu
2-tBu-5-CH.sub.2-(4-Me-Pyrz)-Phe MeO Me H Bu
2-tBu-5-(CH.sub.2--NMe.sub.2)-Phe MeO Me H Bu
2-tBu-5-(CH.sub.2-NEt.sub.2)-Phe MeO Me H Bu
2-tBu-5-(CH.sub.2-NPr.sub.2)-Phe MeO Me H Bu
2-tBu-5-(CH.sub.2--NiPr.sub.2)-Phe MeO Me H Bu
2-tBu-5-{CH.sub.2--NMe(--CH.sub.2-2-Py)}-Phe MeO Me H Bu
2-tBu-5-{CH.sub.2--NMe(--CH.sub.2-3-Py)}-Phe MeO Me H Bu
2-tBu-5-{CH.sub.2--NMe(--CH.sub.2-4-Py)}-Phe MeO Me H Bu
2-tBu-5-{CH.sub.2-NEt(--CH.sub.2-2-Py)}-Phe MeO Me H Bu
2-tBu-5-{CH.sub.2--NH(--CH.sub.2-2-Py)}-Phe MeO Me H Bu
2-iPr-5-(CH.sub.2-Imd)-Phe H Me H Bu 2,6-bis-MeS-4-Me-3-Py H Me H
Bu 2-tBu-5-(CH.sub.2-Morp)-Phe H Me H Bu
2-tBu-5-(CH.sub.2-Pipe)-Phe H Me H Bu 2-tBu-5-(CH.sub.2-Pyrro)-Phe
H Me H Bu 2-tBu-5-(CH.sub.2-Imd)-Phe H Me H Bu
2-tBu-5-(CH.sub.2-Pyrz)-Phe H Me H Bu 2-tBu-5-CH.sub.2-(4-Me-Pyrz)-
-Phe H Me H Bu 2-tBu-5-(CH.sub.2--NMe.sub.2)-Phe H Me H Bu
2-tBu-5-(CH.sub.2-NEt.sub.2)-Phe H Me H Bu 2-tBu-5-(CH.sub.2-NPr.s-
ub.2)-Phe H Me H Bu 2-tBu-5-(CH.sub.2-NiPr.sub.2)-Phe
[0212]
8TABLE 8 53 A.sup.1 A.sup.5 Y.sup.2 R.sup.1 L H Me H Bu
2-tBu-5-{CH.sub.2--NMe(--CH.su- b.2-2-Py)}-Phe H Me H Bu
2-tBu-5-{CH.sub.2--NMe(--CH.sub.2-3-Py)}-P- he H Me H Bu
2-tBu-5-{CH.sub.2--NMe(--CH.sub.2-4-Py)}-Phe H Me H Bu
2-tBu-5-{CH.sub.2-NEt(--CH.sub.2-2-Py)}-Phe H Me H Bu
2-tBu-5-{CH.sub.2--NH(--CH.sub.2-2-Py)}-Phe H Me H Bu
2-iPr-5-(CH.sub.2-Imd)-Phe MeO CH.sub.2-3-Py H Bu
2,6-di-MeS-4-Me-Phe MeO CH.sub.2-3-Py H Bu 2,6-di-MeS-6-Me-3-Py MeO
CH.sub.2-3-Py H Bu 2-tBu-5-(CH.sub.2-Morp)-Phe MeO CH.sub.2-3-Py H
Bu 2-tBu-5-(CH.sub.2-Pipe)-Phe MeO CH.sub.2-3-Py H Bu
2-tBu-5-(CH.sub.2-Pyrro)-Phe MeO CH.sub.2-3-Py H Bu
2-tBu-5-(CH.sub.2-Pipera)-Phe MeO CH.sub.2-3-Py H Bu
2-tBu-5-(CH.sub.2-Imd)-Phe MeO CH.sub.2-3-Py H Bu
2-tBu-5-(CH.sub.2-Pyrz)-Phe MeO CH.sub.2-3-Py H Bu
2-tBu-5-CH.sub.2-(4-Me-Pyrz)-Phe MeO CH.sub.2-3-Py H Bu
2-iPr-5-CH.sub.2-Imd-Phe MeO Me Me Bu 2,6-di-MeS-4-Me-Phe MeO Me Me
Bu 2,4-di-MeS-6-Me-3-Py MeO Me Me Bu 2-tBu-5-(CH.sub.2-Morp)-Phe
MeO Me Me Bu 2-tBu-5-(CH.sub.2-Pipe)-P- he MeO Me Me Bu
2-tBu-5-(CH.sub.2-Pyrro)-Phe MeO Me Me Bu
2-tBu-5-(CH.sub.2-Pipera)-Phe MeO Me Me Bu 2-tBu-5-(CH.sub.2-Imd)--
Phe MeO Me Me Bu 2-tBu-5-(CH.sub.2-Pyrz)-Phe MeO Me Me Bu
2-tBu-5-CH.sub.2-(4-Me-Pyrz)-Phe MeO Me Me Bu
2-iPr-5-CH.sub.2-Imd-Phe MeO Me Me H 2-tBu-5-(CH.sub.2-Morp)-Phe
MeO Me Me Me 2-tBu-5-(CH.sub.2-Morp)-Phe MeO Me Me Et
2-tBu-5-(CH.sub.2-Morp)-Phe MeO Me Me Pr 2-tBu-5-(CH.sub.2-Morp)-P-
he MeO Me Me iPr 2-tBu-5-(CH.sub.2-Morp)-Phe
[0213]
9TABLE 9 54 A.sup.1 R.sup.6 R.sup.7 R.sup.16 R.sup.17 R.sup.1
Y.sup.2 L MeO H H H H Bu H 2,6-di-iPr-Phe MeO H H H Me Bu H
2,6-di-iPr-Phe MeO H H H Et Bu H 2,6-di-iPr-Phe MeO H H H iPr Bu H
2,6-di-iPr-Phe MeO H H H Hex Bu H 2,6-di-iPr-Phe MeO H H H cHex Bu
H 2,6-di-iPr-Phe MeO H H H CH.sub.2NEt.sub.2 Bu H 2,6-di-iPr-Phe
MeO H H H (CH.sub.2).sub.2NEt.sub.2 Bu H 2,6-di-iPr-Phe MeO H H Me
Me Bu H 2,6-di-iPr-Phe MeO H H Et Et Bu H 2,6-di-iPr-Phe MeO H H Et
Et Bu Me 2,6-di-iPr-Phe MeO H H iPr iPr Bu H 2,6-di-iPr-Phe MeO H H
Hex Hex Bu H 2,6-di-iPr-Phe MeO H H Me Bn Bu H 2,6-di-iPr-Phe MeO H
H Et Bn Bu H 2,6-di-iPr-Phe MeO H H H CH.sub.2-2-Py Bu H
2,6-di-iPr-Phe MeO H H H CH.sub.2-3-Py Bu H 2,6-di-iPr-Phe MeO H H
H CH.sub.2-4-Py Bu H 2,6-di-iPr-Phe MeO H H Me CH.sub.2-2-Py Bu H
2,6-di-iPr-Phe MeO H H Me CH.sub.2-3-Py Bu H 2,6-di-iPr-Phe MeO H H
Me CH.sub.2-4-Py Bu H 2,6-di-iPr-Phe MeO H H Me CH.sub.2-4-Py Bu Me
2,6-di-iPr-Phe MeO H H (CH.sub.2).sub.4 Bu H 2,6-di-iPr-Phe MeO H H
(CH.sub.2).sub.5 Bu H 2,6-di-iPr-Phe MeO H H (CH.sub.2).sub.6 Bu H
2,6-di-iPr-Phe MeO H H (CH.sub.2).sub.4--O--(CH.sub.2).sub.2 Bu H
2,6-di-iPr-Phe
[0214]
10TABLE 10 55 A.sup.1 R.sup.6 R.sup.7 R.sup.16 R.sup.17 R.sup.1
Y.sup.2 L MeO H H Et Et Bu H 2-iPr-Phe MeO H H Et Et Bu H
2,4,6-tri-Me-Phe MeO H H Et Et Bu H 2,6-di-F-Phe MeO H H Et Et Bu H
2,4,6-tri-F-Phe MeO H H Et Et Bu H 2-Me-6-tBu-Phe MeO H H Et Et Bu
H 2,4,6-tri-MeO-Phe MeO H H Et Et Bu H 2,6-bis-MeS-4-Me-Phe MeO H H
Et Et Bu H 2-tBu-5-(CH.sub.2-Imd)-Phe MeO H H Et Et Bu H
2-tBu-5-(CH.sub.2-Pyrz)-Phe MeO H H Et Et Bu H
2-iPr-5-(CH.sub.2-Imd)-Phe EtO H H Et Et Bu H 2-iPr-Phe EtO H H Et
Et Bu H 2,6-di-iPr-Phe EtO H H Et Et Bu H 2,4,6-tri-Me-Phe EtO H H
Et Et Bu H 2,6-di-F-Phe EtO H H Et Et Bu H 2,4,6-tri-F-Phe EtO H H
Et Et Bu H 2-Me-6-tBu-Phe EtO H H Et Et Bu H 2,4,6-tri-MeO-Phe EtO
H H Et Et Bu H 2,6-bis-MeS-4-Me-Phe EtO H H Et Et Bu H
2-tBu-5-(CH.sub.2-Imd)-Phe HO H H Et Et Bu H 2-iPr-Phe HO H H Et Et
Bu H 2,6-di-iPr-Phe HO H H Et Et Bu H 2,4,6-tri-Me-Phe HO H H Et Et
Bu H 2,6-di-F-Phe HO H H Et Et Bu H 2,4,6-tri-F-Phe HO H H Et Et Bu
H 2-Me-6-tBu-Phe HO H H Et Et Bu H 2,4,6-tri-MeO-Phe HO H H Et Et
Bu H 2,6-bis-MeS-4-Me-Phe HO H H Et Et Bu H
2-tBu-5-(CH.sub.2-Imd)-Phe F H H Et Et Bu H 2-iPr-Phe F H H Et Et
Bu H 2,6-di-iPr-Phe F H H Et Et Bu H 2,4,6-tri-Me-Phe
[0215]
11TABLE 11 56 A.sup.1 R.sup.6 R.sup.7 R.sup.16 R.sup.17 R.sup.1
Y.sup.2 L F H H Et Et Bu H 2,6-di-F-Phe F H H Et Et Bu H
2,4,6-tri-F-Phe F H H Et Et Bu H 2-Me-6-tBu-Phe F H H Et Et Bu H
2,4,6-tri-MeO-Phe F H H Et Et Bu H 2,6-bis-MeS-4-Me-Phe F H H Et Et
Bu H 2-tBu-5-(CH.sub.2-Imd)-Phe MeO Me Me Et Et Bu H 2,6-di-iPr-Phe
MeO Et Et Et Et Bu H 2,6-di-iPr-Phe MeO H H Et Et Me H
2,6-di-iPr-Phe MeO H H Et Et Et H 2,6-di-iPr-Phe MeO H H Et Et Pr H
2,6-di-iPr-Phe MeO H H Et Et iPr H 2,6-di-iPr-Phe
[0216]
12TABLE 12 57 Y.sup.1 Y.sup.2 Y.sup.3 R.sup.1 L Me H H Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 Et H H Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 Pr H H Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 iPr H H Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 Bu H H Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 (CH.sub.2).sub.9CH.sub.-
3 H H Bu C(CH.sub.3).sub.2(CH2).sub.9CH.sub.3
(CH.sub.2).sub.10CH.sub.3 H H Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.- 3
(CH.sub.2).sub.14CH.sub.3 H H Bu C(CH.sub.3).sub.2(CH.sub.2).sub-
.9CH.sub.3 Ph H H Bu C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 2-Py
H H Bu C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 3-Py H H Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 4-Py H H Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 H Ph H Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 H H Ph Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 H H Ph H
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 H H Ph Me
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 H H Ph Et
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 H H Ph Pr
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 H H Ph iPr
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 3-MeO--Ph H H H
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 3-MeO--Ph H H Me
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 3-MeO--Ph H H Et
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 3-MeO--Ph H H Pr
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 3-MeO--Ph H H iPr
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 3-MeO--Ph H H Bu
C(CH.sub.3).sub.2(CH.sub.2).sub.9CH.sub.3 3-MeO--Ph H H Bu
(CH.sub.2).sub.3CH.sub.3 3-MeO--Ph H H Bu (CH.sub.2).sub.9CH.sub.-
3 3-MeO--Ph H H Bu (CH.sub.2).sub.19CH.sub.3 3-MeO--Ph H H Bu
Ph
EXAMPLES
[0217] The present invention is illustrated by Examples, but should
not be construed to be limited thereto.
Example 1
[0218] Preparation of
N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-
-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl) urea: 58
[0219] To a suspension of
1-butyl-3-carbamoyl-4-(3-methoxyphenyl)-1,2-dihy-
dro-2-oxo-1,8-naphthyridine (10.0 g, 27.2 mmol) in
N,N-dimethylformamide (100 ml) was added lead tetracetate (14.5 g,
32.6 mmol), and the mixture was stirred at room temperature for 0.5
hour. Subsequently, to the mixture was added 2,6-diisopropylaniline
(5.3 g, 30 mmol) at the same temperature, and the mixture was
stirred at 40.degree. C. for 50.degree. C. for 1.5 hour. After
allowed to cool, ethyl acetate (500 ml) was added to the mixture,
and the mixture was filtered through a celite pad. The filtrate was
washed successively with water, 4 N aqueous hydrochloric acid
solution, water and a saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and concentrated under reduced
pressure to the volume of about 100 ml. The resultant was stirred
for 2 hours under cooling with ice-water, and the compound (9.81 g,
18.6 mmol, 68%) as colorless crystals.
[0220] M.p. 179-182.degree. C.
Example 2
[0221] Preparation of
N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-
-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea: 59
[0222] To a 1 N aqueuos sodium hydroxide solution (48 ml, 48 mmol)
was added dropwise bromine (1.2 ml, 24 mmol) under ice-cooling, and
the mixture was stirred for 30 minutes. The pale yellow solution
thus obtained was added dropwise to a suspension of
1-butyl-3-carbamoyl-4-(3-m-
ethoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine (2.1 g, 6 mmol)
and tetrabutylammonium hydrogen sulfate (102 mg, 0.3 mmol) in
toluene (210 ml) at room temperature, and the mixture was stirred
at the same temperature for 4 hours. To the mixture was added a
solution of acetic acid (35 ml) and 2,6-diisopropylaniline (1.6 g,
9.0 mmol) in toluene (35 ml) at room temperature, and the mixture
was stirred at the same temperature for 1.5 hour. Water was added
to the reaction solution, and the mixture was extracted with ethyl
acetate, washed with water, washed with a saturated aqueous sodium
chloride solution, and dried over anhydrous magnesium sulfate. The
residue was concentrated under reduced pressure, and purified by
silica gel column chromatography (ethyl acetate/hexane={fraction
(1/10)} to 1/2) to give the title compound (2.34 g, 4.44 mmol, 74%)
as a colorless solid.
[0223] M.p. 178-181.degree. C.
Example 3
[0224] Preparation of
1-butyl-3-amino-4-(3-methoxyphenyl)-1,2-dihydro-2-ox-
o-1,8-naphthyridine; 60
[0225] To a 1 N aqueous sodium hydroxide-solution (88 ml, 88 mmol)
was added dropwise bromine (1.0 ml, 19.4 mmol) under ice-cooling,
and the mixture was stirred for 30 minutes. The pale yellow
solution thus obtained was added dropwise to a suspension of
1-butyl-3-carbamoyl-4-(3-m- ethoxyphenyl)-1,2-dihydro-2-oxo-
1,8-naphthyridine (5.0 g, 14.2 ml) and tetrabutylammonium hydrogen
sulfate (250 mg. 0.71 mmol) in tetrahydrofuran (500 ml) at room
temperature, and the mixture was stirred at the same temperature
for 6.5 hours. Water was added to the reaction solution, and the
mixture was extracted with ethyl acetate, washed with water, washed
with a saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. To the concentrated residue was added 2-propanol (40 ml),
and the mixture was stirred for 3 hours under ice-cooling. The
precipitated solid was collected by filtration to give the title
compound (3.49 g, 10.8 mmol, 76%) as pale yellow powder.
[0226] M.p. 138-141.degree. C.
Example 4
[0227] Preparation of
N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-
-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea: 61
[0228] To a solution of
3-amino-1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2--
oxo-1,8-naphthyridine (1.70 g, 5.26 mmol) in tetrahydrofuran (14
ml) was added phenyl chlorocarbonate (1.32 ml, 10.5 ml), and the
mixture was stirred at 40-50.degree. C. for 3 hours. The mixture
was allowed to cool, and thereto was added water, and the mixture
was extracted with water. The extract was washed with a 5% aqueous
sodium chloride solution, dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. The resulting residue was
dissolved in dimethylformamide (10 ml), and thereto was added a
solution of 2,6-diisopropylaniline (1.24 g, 6.31 mmol) and
dimethylformamide (5 ml) and 4-dimethylaminopyridine (0.62 g, 5.26
mmol), and the mixture was stirred at room temperature for one
hour. To the reaction solution was added water, and the mixture was
extracted with ethyl acetate. The extract was washed successively
with a 5% aqueous sodium hydrogen carbonate solution and a 5%
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
crystallized from ethyl acetate to give the title compound (1.75 g,
3.32 mmol) as colorless crystals.
[0229] M.p. 179-182.degree. C.
Example 5
[0230] Preparation of
1-butyl-3-phthalimide-4-(3-methoxyphenyl)-1,2-dihydr-
o-2-oxo-1,8-naphthyridine: 62
[0231] To a solution of
1-{(N-butyl-N-phthalimidacetyl)amino}-3-(3-methoxy-
benzoyl)pyridine (3.44 g, 7.30 mmol) in N,N-dimethylformamide (18
ml) was added potassium carbonate (6.05 g, 43.8 mmol), and the
mixture was stirred at 90-100.degree. C. for 3 hours. The mixture
was cooled to room temperature, and water was added thereto, and
the mixture was extracted with ethyl acetate. The extract was
washed successively with a 5% aqueous sodium hydrogen carbonate
solution and a 5% aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure to give the title compound (2.15 g, 4.74 mmol, 65%) as
brown crystals, which were used in the subsequent reaction without
further purification.
[0232] .sup.1H NMR .delta. (CDCl.sub.3) 0.91 (3 H, t, J=7.3 Hz),
1.38-1.45 (2 H, m), 1.68-1.79 (2 H, m), 3.66 (3 H, s), 4.52 (2 H,
t, J=7.3 Hz), 6.81-6.88 (3 H, m), 7.07 (1 H, dd, J=8.1 Hz, 4.81
Hz), 7.22 (1 H, ddd, J=7.5 Hz, 7.5 Hz, 3.3 Hz), 7.58-7.63 (3 H, m),
7.70-7.76 (2 H, m), 8.60 (1 H, dd, J=4.8 Hz, 1.7 Hz)
Example 6
[0233] Preparation of
1-butyl-3-amino-4-(3-methoxyphenyl)-1,2-dihydro-2-ox-
o-1,8-naphthyridine: 63
[0234] To a solution of
1-butyl-3-phthalimide-4-(3-methoxyphenyl)-1,2-dihy-
dro-2-oxo-1,8-naphthyridine (2.15 g, 4.74 mmol) in ethanol (16 ml)
was added a 30% solution of methylamine in ethanol (4 ml), and the
mixture was stirred at room temperature for 5 hours. The mixture
was concentrated under reduced pressure, and the residue was
dissolved in ethyl acetate. The mixture was washed successively
with a 5% aqueous sodium hydrogen carbonate solution and a 5%
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl
acetate/hexane={fraction (1/10)} to 1/4) to give the title compound
(0.78 g, 2.43 mmol, 51%) as colorless crystals.
[0235] .sup.1H NMR .delta. (CDCl.sub.3) 1.01 (3 H, t, J=7.3 Hz),
1.44-1.54 (2 H, m), 1.76-1.86 (2 H, m), 3.84 (3 H, s), 4.49 (2 H,
brs), 4.66 (2 H, t, J=7.5 Hz), 6.87-7.04 (4 H, m), 7.42-7.50 (2 H,
m), 8.35 (1 H, dd, J=4.6 Hz, 1.8 Hz)
Example 7
[0236] Preparation of
1-butyl-3-amino-4-(3-methoxyphenyl)-1,2-dihydro-2-ox-
o-1,8-naphthyridine: 64
[0237] To a suspension of N-phthaloylglycine (4.76 g, 23.2 mmol) in
toluene (24 ml) were added thionyl chloride (5.08 ml, 69.6 mmol)
and dimethylformamide (0.4 ml), and the mixture was stirred at
50-60.degree. C. for 30 minutes, cooled, and concentrated under
reduced pressure to remove the solvent. To the resulting solid was
added toluene (12 ml), and further thereto were added a solution of
2-(butylamino)-3-(3-methoxybenzo- yl)pyridine (3.30 g, 11.6 mmol)
in toluene (15 ml) and pyridine (27 ml), and the mixture was
stirred at 80-90.degree. C. for 2 hours. After allowed to cool, to
the mixture were added potassium carbonate (9.62 g, 69.6 mmol) and
N,N-dimethylformamide (54 ml), and the mixture was further stirred
at 90- 100.degree. C. for 8 hours. After allowed to cool, a 40%
aqueous methylamine solution (4.99 ml, 58.0 mmol) was added, and
the mixture was stirred at room temperature for one hour. Water was
added to the reaction solution, and the mixture was extracted with
toluene. The extract was washed successively with 1 N hydrochloric
acid, water, a 5% aqueous sodium hydrogen carbonate solution and a
5% aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The resulting
solid was recrytallized from 2-propanol to give the title compound
(2.30 g, 7.11 mmol, 61%) as colorless prisms.
[0238] M.p. 140- 142.degree. C.
Example 8
[0239] Preparation of
N-{1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydro-pyr-
idin-3-yl}-N'-(2,6-diisopropylphenyl)urea: 65
[0240] To a solution of
1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyrid-
ine-3-carboxylic acid (4.61 g, 15.3 mmol) in DMF (dimethyformamide;
50 ml) were added DPPA (diphenylphosphoryl azide; 5.06 g, 18.4
mmol) and triethylamine (2.7 ml), and the mixture was stirred at
about 50.degree. C. for one hour. To the mixture was added
2,6-diisopropylaniline (3.26 g, 18.4 mmol), and the mixture was
stirred at about 70.degree. C. for 4.5 hours. To the reaction
solution was added water, and the mixture was extracted with ethyl
acetate, washed with a saturated aqueous sodium chloride solution,
and dried over anhydrous magnesium sulfate. The solvent was
distilled off, and the resulting residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:1) to give the title
compound (6.51 g, yield; 90%) as to white crystals.
[0241] M.p. 176-178.degree. C.
[0242] IR (KBr) 3324, 3068, 1703, 1643, 1565 cm.sup.-1
Example 9
[0243] Preparation of
N-{1-butyl-2-oxo-4-(3-hydroxy)phenyl-1,2-dihydro-pyr-
idin-3-yl}-N'-(2,6-diisopropylphenyl)urea: 66
[0244] To a solution of
N-{1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydropy-
ridin-3-y}-N'-(2,6-dihydropropylphenyl)urea (3.84 g, 8.07 mmol) in
methylene chloride (100 ml) was added BBr.sub.3 boron tribromide;
3.1 ml, 32.3 mmol), and the mixture was stirred at room temperature
for 2 hours. Water was added to the reaction solution, and basified
with a saturated aqueous sodium hydrogen carbonate solution. The
mixture was extracted with ethyl acetate, washed with a saturated
aqueous sodium chloride solution, and dried over magnesium sulfate.
The solvent was evaporated under reduced pressure, and the
resulting crystals were collected by filtration to give the title
compound (3.61 g, yield; 97%) as white crystals.
[0245] M.p. 188-191.degree. C.
Example 10
[0246] Preparation of
N-[1-butyl-2-oxo-4-[3-{3-(1,2,4-triazol-1-yl)propoxy-
}-phenyl]-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
67
[0247] To a solution of
N-{1-butyl-2-oxo-4-(3-hydroxy)phenyl-1,2-dihydropy-
ridin-3-yl}-N'-(2,6-diisopropylphenyl)urea (500 mg, 1.08 mmol) in
DMF (5 ml) were added potassium carbonate (4.48 g, 32.4 mmol),
1-(3-bromopropyl)-1,2,4-triazole (247 mg, 1.30 mmol), and sodium
iodide (81 mg, 0.54 mmol), and the mixture was stirred at about
50.degree. C. for 9 hours. Potassium carbonate was removed by
filtration, and water was added to the filtrate, and extracted with
ethyl acetate. The extract was washed with a saturated aqueous
sodium chloride solution, and dried over magnesium sulfate. The
solvent was evaporated under reduced pressure, and the resulting
residue was purified by silica gel column chromatography (ethyl
acetate) to give the title compound (420 mg, yield; 68%) as pale
yellow amorphous.
[0248] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.94 (t, J=7.21 Hz, 3 H),
1.00 (bs, 12 H), 1.28-1.41 (m, 2 H), 1.63-1.71 (m, 2 H), 2.15-2.26
(m, 2 H), 2.88-2.91 (m, 2 H), 3.94-3.99 (m, 4 H), 4.35 (t, J=7.0
Hz, 2 H), 6.23 (d, J=7.2 Hz, 1 H), 6.86 (d J=7.9 H, 1 H), 6.99-7.07
(m, 4 H), 7.13 (dd, J=7.9, 7.9 Hz, 1 H), 7.26 (dd, J=7.9, 7.9 Hz, 1
H), 7.54 (d, J=7.2 Hz, 1 H), 7.77 (s, 1 H), 7.81 (s, 1 H), 7.96 (s,
1 H), 8.52 (s, 1 H)
[0249] IR (KBr) 3321, 1706, 1645, 1584 cm.sup.-1
[0250] Preparation of the hydrochloride thereof:
[0251] To a solution of
N-[1-butyl-2-oxo-4-[3-{3-(1,2,4-triazol-1-yl)-prop- oxy}phenyl]-
1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (330 mg,
0.578 mmol) in THF (tetrahydrofuran; 5 ml) was added 1 N solution
of hydrochoric acid in ether (1.7 ml), and the mixture was stirred.
The solvent was evaporated under reduced pressure, and to the
residue was added ether. The precipitated crystals were collected
by filtration, and dried to give the hydrochloride of the title
compound (305 mg, 87%) as pale yellow crystals.
[0252] M.p. 90-95.degree. C.
[0253] IR (KBr) 3262, 1645, 1600 cm.sup.-1
Example 11
[0254] Preparation of
N-[1-butyl-2-oxo-4-{(3-(3-pyridylmethoxy)phenyl}-1,2-
-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea 68
[0255] The title compound was obtained in the same manner as in
Example 10 from
N-{1-butyl-2-oxo-4-(3-hydroxy)phenyl)-1,2-dihydropyridin-3-yl}-N'-(2-
,6-diisopropylphenyl)urea and 3-chloromethylpyridine
hydrochloride.
[0256] .sup.1H NMR .delta. (CD.sub.3OD) 0.99 (t, J=7.3 Hz, 3 H),
1.05 (bs, 12 H), 1.39-1.44 (m, 2 H), 1.75-1.78 (m, 2 H), 2.99 (m, 2
H), 4.05 (t, J=7.50 Hz, 2 H), 5.18 (s, 2 H), 6.37 (d, J=7.0 Hz, 1
H), 7.04-7.06 (m, 3 H), 7.14-7.21 (m, 3 H), 7.36 (dd, J=7.9, 7.9
Hz, 1 H), 7.44-7.52 (m, 2 H), 7.76 (d, J=7.0 Hz, 1 H), 8.50 (d,
J=4.8 Hz, 1 H), 8.64 (s, 1 H)
[0257] The hydrochloride of the title compound was obtained in the
same manner as in Example 10.
[0258] M.p. 98-100.degree. C.
[0259] IR (KBr) 3152, 1646, 1583 cm.sup.-1
Example 12
[0260] Preparation of
N-[1-butyl-2-oxo-4-[3-(2-diethylaminoethoxy)phenyl}--
1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea 69
[0261] The title compound was obtained in the same manner as in
Example 10 from
N-{1-butyl-2-oxo-4-(3-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N'-(2,-
6-diisopropylphenyl)urea and N,N-diethylaminoethyl chloride
hydrochloride.
[0262] .sup.1H NMR 67 (DMSO-d.sub.6) 0.91-1.06 (m, 21 H), 1.29-1.38
(m, 2 H), 1.63-1.71 (m, 2 H), 2.57 (bs, 2 H), 2.81 (bs, 2 H),
2.88-2.97 (m, 2 H), 2.88-2.91 (m, 2 H), 3.94-4.03 (m, 6 H), 6.23
(d, J=7.2 Hz, 1 H), 6.87 (d, J=8.1 Hz, 1 H), 7.00-7.03 (m, 4 H),
7.13 (dd, J=7.7, 7.7 Hz, 1 H), 7.26 (dd, J=8.1, 8.1 H, I1 H), 7.53
(d, J=7.2 Hz, 1 H), 7.77 (s, 1 H), 7.82 (s, 1 H)
[0263] The hydrochloride of the title compound was obtained in the
same manner as in Example 10.
[0264] M.p. 125-130.degree. C.
[0265] IR (KBr) 3272, 1692, 1646, 1601 cm.sup.-1
Example 13
[0266] Preparation of
N-{1-butyl-2-oxo-4-(3-bromo)phenyl-1,2-dihydropyridi-
n-3-yl)-N'-(2,6-diisopropylphenyl) urea 70
[0267] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(3-bromo)phenyl-1,2-dihydropyridin-3-carboxylic
acid and 2,6-diisopropylaniline.
[0268] M.p. 169-172.degree. C.
[0269] IR (KBr) 3314, 1710, 1645, 1586 cm.sup.-1
Example 14
[0270] Preparation of
N-[1-butyl-2-oxo-4-[3-{3-(diethylamino)-1-propynyl}--
phenyl]-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
71
[0271] To a solution of
N-{1-butyl-2-oxo-4-(3-bromo)phenyl-1,2-dihydropyri-
din-3-yl}-N'-(2,6-diisopropylphenyl)urea (1.23 g, 2.35 mmol) in DMF
(6 ml) were added N,N-diethylpropargylamine (784 mg),
triphenylphosphine (100 mg, 0.376 mmol), copper iodide (36 mg,
0.188 mmol), triethylamine (2.0 ml), and 10% palladium on active
carbon (100 mg, 0.094 mmol), and the mixture was stirred at about
80.degree. C. for 13 hours. The mixture was filtered through a
cerite pad, and the filtrate was diluted with ethyl acetate, washed
with a saturated aqueous sodium chloride solution and dried over
magnesium sulfate. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
chromatography (chloroform:methanol=30:1) to give the title
compound (813 mg, yield; 62%).
[0272] M.p. 76-82.degree. C.
[0273] IR (KBr) 3323, 1709, 1645, 1584 cm.sup.-1
[0274] Preparation of the hydrochloride thereof:
[0275] To a solution of
N-[1-butyl-2-oxo-4-[3-{3-(diethylamino)-1-propynyl-
}phenyl]-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)-urea
(393 mg, 0.707 mmol) in THF (5 ml) was added 1 N solution of
hydrochoric acid in ether (2.1 ml), and the mixture was stirred.
The solvent was evaporated under reduced pressure, and to the
residue was added hexane. The precipitated crystals were collected
by filtration, and dried to give the hydrochloride of the title
compound (414 mg, yield; 99%) as brown crystals.
[0276] .sup.1H NMR .delta. (CD.sub.3OD) 0.99 (t, J=7.5 Hz, 3 H),
1.06 (bd, 12 H), 1.38 (t, J=7.2 Hz, 6 H), 1.38-1.46 (m, 2 H),
1.73-1.83 (m, 2 H), 2.84-2.93 (m, 2 H), 3.37 (q, J=7.2 Hz, 4 H),
4.06 (t, J=7.5 Hz, 2 H), 4.36 (s, 2 H), 6.34 (d, J=7.0 Hz, 1 H),
7.05 (d, J=7.3 Hz, 2 H), 7.16 (dd, J=6.8, 6.8 Hz, 1 H), 7.45 (dd,
J=7.5, 7.5 Hz, 1 H), 7.52-7.65 (m, 4 H)
Example 15
[0277] Preparation of
N-{1-butyl-2-oxo-4-(3-bromo)phenyl-5-methyl-1,2-dihy-
dropyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea: 72
[0278] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(3-bromo)phenyl-5-methyl-1,2-dihydropyridin-3-carbox-
ylic acid and 2,6-diisopropylaniline.
[0279] M.p. 199-200.degree. C.
[0280] IR (KBr) 3315, 3266, 3226, 1719, 1650, 1575 cm.sup.-1
Example 16
[0281] Preparation of
N-[1-butyl-2-oxo-4-[3-{3-(diethylamino)-1-propynyl}--
phenyl]-5-methyl-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
73
[0282] The title compound was obtained in the same manner as in
Example 14 from
N-{1-butyl-2-oxo-4-(3-bromo)phenyl-5-methyl-1,2-dihydropyridin-3-yl}-
-N'-(2,6-diisopropylphenyl)urea and N,N-diethylpropargylamine.
[0283] .sup.1H NMR .delta. (CD.sub.3OD) 0.99 (t, J=7.3 Hz, 6 H),
1.07-1.15 (m, 15 H), 1.35-1.47 (m, 2 H), 1.73-1.80 (m, 2 H), 1.84
(s, 3 H), 2.67 ((q, J=7.3 Hz, 4 H), 2.83 (bs, 2 H), 3.67 (s, 2 H),
4.03 (t, J=7.3 Hz, 2 H), 7.05 (d, J=7.3 Hz, 2 H), 7.16 (dd, J=7.3,
7.3 Hz, 1 H), 7.24-7.31 (m, 2 H), 7.38-7.46 (m, 3 H)
[0284] The hydrochloride of the title compound was obtained in the
same manner as in Example 10.
[0285] M.p. 159-162.degree. C.
[0286] IR (KBr) 3320, 2236, 1654, 1574 cm.sup.-1
Example 17
[0287] Preparation of
N-{1-butyl-2-oxo-4-(5-bromo-2-methoxy)phenyl-1,2-dih-
ydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea: 74
[0288] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(5-bromo-2-methoxy)phenyl-1,2-dihydropyridin-3-carbo-
xylic acid and 2,6-diisopropylaniline.
[0289] M.p. 179-181.degree. C.
[0290] IR (KBr) 3322, 1671, 1645, 1584 cm.sup.-1
[0291] Example 18
[0292] Preparation of
N-[1-butyl-2-oxo-4-[5-{3-(diethylamino)-1-propynyl}--
2-methoxy]phenyl-5-methyl-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphen-
yl) urea: 75
[0293] The title compound was obtained in the same manner as in
Example 14 from
N-{1-butyl-2-oxo-4-(5-bromo-2-methoxy)phenyl-5-methyl-1,2-dihydropyr-
idin-3-yl}-N'-(2,6-diisopropylphenyl)urea and
N,N-diethylpropargylamine.
[0294] .sup.1H NMR .delta. (CD.sub.3OD) 0.96 (t, J=7.3 Hz, 3 H),
0.98-1.13 (m, 18 H), 1.33-1.46 (m, 2 H), 1.69-1.79 (m, 2 H), 2.66
(q, J=7.2 Hz, 4 H), 2.81-2.90 (m, 2 H), 2.81-2.90 (m, 2 H), 3.64
(s, 2 H), 3.82 (s, 3 H), 4.01 (t, J=7.2 Hz, 2 H), 6.27 (d, J=7.2
Hz, 1 H), 7.02-7.05 (m, 3 H), 7.14 (dd, J=7.0, 7.0 Hz, 1 H), 7.33
(d, J=1.8 Hz, 1 H), 7.42-7.45 (m, 2 H)
[0295] The hydrochloride of the title compound was obtained in the
same manner as in Example 10.
[0296] M.p. 208-210.degree. C.
[0297] IR (KBr) 3437, 2232, 1646, 1599 cm.sup.-1
Example 19
[0298] Preparation of
N-{1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydro-
pyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea: 76
[0299] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyridin-3-carboxyli-
c acid and 2,6-diisopropylaniline.
[0300] M.p. 165-167.degree. C.
Example 20
[0301] Preparation of
N-{1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydro-
pyridin-3yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3yl}urea:
77
[0302] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyridin-3-carboxyli-
c acid and 3-amino-2,4-bis(methylthio)-6-methylpyridine.
[0303] M.p. 193-197.degree. C. (decomposed)
[0304] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.94 (t, J=7.5 Hz, 3 H),
1.34 (tq, J=7.5, 7.5 Hz, 2 H), 1.67 (tt, J=7.5, 7.5 Hz, 2 H), 2.30
(s, 3 H), 2.39 (s, 3 H), 3.68 (s, 6 H), 3.93 (t, J=7.5 Hz, 2 H),
6.13 (d, J=7.2 Hz, 1 H), 6.76-6.83 (m, 3 H), 6.92 (d, J=8.8 Hz, 1
H), 7.45 (d, J=7.2 Hz, 1 H), 7.70 (bs, 1 H), 7.90 (bs, 1 H)
Example 21
[0305] Preparation of
N-{1-butyl-2-oxo-4-(2-methoxy-5-bromo)phenyl-1,2-dih-
ydropyridin-3-yl}-
N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea: 78
[0306] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2-methoxy-5-bromo)phenyl-1,2-dihydropyridin-3-carbo-
xylic acid and 3-amino-2,4-bis(methylthio)-6-methylpyridine.
[0307] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.94 (t, J=7.2 Hz, 3 H),
1.33-1.35 (m, 2 H), 1.67 (m, 2 H), 2.32 (s, 6 H), 2.39 (s, 3 H),
3.72 (s, 3 H), 3.94 (bs, 2 H), 6.11 (d, J=6.8 Hz, 1 H), 6.76 (s, 1
H), 6.96 (d, J=6.8 Hz, 1 H), 7.24 (s, 1 H), 7.38 (d, J=8.8 Hz, 1
H), 7.43 (d, J=8.8 Hz, 1 H), 7.87 (s, 1 H), 8.00 (s, 1 H)
Example 22
[0308] Preparation of
N-{1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydro-
pyridin-3-yl}-N'-(2-tert-butyl-5-morpholinomethyl phenyl)urea:
79
[0309] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyridin-3-carboxyli-
c acid and 2-tert-butyl-5-morpholinomethylaniline.
[0310] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.94 (t, J=7.2 Hz, 3 H),
1.21 (s, 9 H), 1.36 (tq, J=7.2, 7.2 Hz, 2 H), 1.69 (tt, J=7.2, 7.2
Hz, 2 H), 2.30 (bs,4 H), 3.30 (s, 2 H), 3.54 (bs, 4 H), 3.66 (s, 6
H), 3.94 (t, J=7.2 Hz, 2 H), 6.15 (d, J=7.2 Hz, 1 H), 6.77 (d,
J=3.1 Hz, 1 H), 6.82 (dd, J=3.1, 8.3 Hz, 1 H), 6.88 (s, 1 H), 6.94
(d, J=9.0 Hz, 1 H), 6.97 (d, J=9.0 Hz, 1 H), 7.48 (d, J=7.2 Hz, 1
H), 7.59 (s, 1 H), 7.84 (s, 1 H)
[0311] The hydrochloride of the title compound was obtained in the
same manner as in Example 10.
[0312] M.p. 157-162.degree. C. (decomposed)
Example 23
[0313] Preparation of
N-{1-butyl-2-oxo-4-(2-methoxy-5-benzyloxy)phenyl-1,2-
-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea: 80
[0314] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2-methoxy-5-benzyloxy)phenyl-1,2-dihydropyridin-3-c-
arboxylic acid and 2,6-diisopropylaniline.
[0315] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.94 (t, J=7.3 Hz; 3 H),
1.35 (tq, J=7.3, 7.3 Hz, 2 H), 1.66-1.68 (m, 2 H), 2.83-2.89 (m, 2
H), 3.69 (s, 3 H), 3.94 (t, J=7.3 Hz, 2 H), 4.99 (s, 2 H), 6.13 (d,
J=7.2 Hz, 1 H), 6.88 (s, 1 H), 6.91-6.95 (m, 2 H), 7.01 (d, J=7.7
Hz, 2 H), 7.13 (dd, J=7.7, 7.7 Hz, 1 H), 7.31-7.46 (m, 6 H), 7.69
(s, 1 H), 7.82 (s, 1 H)
Example 24
[0316] Preparation of
N-{1-butyl-2-oxo-4-(2-hydroxy-5-bromo)phenyl-1,2-dih-
ydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea: 81
[0317] To a solution of
N-{1-butyl-2-oxo-4-(2-methoxy-5-bromo)phenyl-1,2-d-
ihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea (1.00 g, 1.80
mmol) in methylene chloride (10 ml) was added BBr.sub.3 (0.51 ml,
5.40 mmol) under ice-cooling, and the mixture was stirred under
reflux for 3 hours. The reaction solution was poured into
ice-water, and the mixture was extracted with chloroform. The
extract was washed with a saturated aqueous sodium chloride
solution, and dried over magnesium sulfate. The solvent was
evaporated under reduced pressure, and to the residue was added
ethyl acetate. The precipitated crystals were collected by
filtration, and dried to give the title compound (662 mg, 64%) as
colorless crystals.
[0318] M.p. 163-165.degree. C.
[0319] IR (KBr) 3302, 2963, 1691, 1645, 1577, 1548 cm.sup.-1
Example 25
[0320] Preparation of
N-[1-butyl-2-oxo-4-[2-hydroxy-5-{3-(diethylamino)-1--
propynyl}phenyl]-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)-urea:
82
[0321] To a solution of propylene oxide (0.07 ml, 1.04 mmol) in
methylene chloride (10 ml) was added BBr.sub.3 (0.29 ml, 3.11 mmol)
under ice-cooling, and the mixture was stirred for 30 minutes. To
the mixture was added
N-[1-butyl-2-oxo-4-[2-methoxy-5-{3-(diethylamino)-1-propynyl}ph-
enyl]-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)- urea
(303 mg, 0.518 mmol), and the mixture was stirred under reflux for
4 hours. To the reaction solution was added a 10% aqueous sodium
hydroxide solution, and the mixture was acidified with 3 N
hydrochloric acid. The mixture was extracted with chloroform, and
the extract was washed with a saturated aqueous sodium chloride
solution, and dried over magnesium sulfate. The solvent was
evaporated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (ethyl acetate:
hexane=1:30) to give the title compound (77 mg, <26%) as
colorless crystals.
[0322] The hydrochloride of the title compound was obtained in the
same manner as in Example 10.
[0323] M.p. 184-185.degree. C.
[0324] IR (KBr) 3240, 2963, 2231, 1698, 1645, 1571 cm.sup.-1
Example 26
[0325] Preparation of
N-{1-butyl-2-oxo-4-(2-methoxy-5-hydroxy)phenyl-1,2-d-
ihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea: 83
[0326] Pentamethylbenzene (815 mg, 5.50 mmol) was dissolved in TFA
(11 ml), and thereto was added
N-{1-butyl-2-oxo-4-(2-methoxy-5-benzyloxy)phen-
yl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea (320
mg, 0.550 mmol) under ice-cooling, and the mixture was stirred at.
50.degree. C. for 3 hours. To the reaction solution were added
ether and water, and the mixture was stirred under ice-cooling. The
precipitated crystals were collected by filtration, and dried to
give the title compound (270 mg, 100%) as colorless crystals.
[0327] M.p. 208-210.degree. C.
[0328] IR (KBr) 3357, 3152, 2965, 1688, 1644, 1581 cm.sup.-1
Example 27
[0329] Preparation of
N-[1-butyl-2-oxo-4-{2-methoxy-5-(3-pyridylmethoxy)}--
phenyl-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
84
[0330] The title compound was obtained in the same manner as in
Example 10 from
N-[1-butyl-2-oxo-4-(2-methoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3--
yl]-N'-(2,6-diisopropylphenyl)urea and 3-chloromethylpyridine
hydrochloride.
[0331] The hydrochloride of the title compound was obtained in the
same manner as in Example 10.
[0332] .sup.1H NMR .delta. (CD.sub.3OD) 1.00 (t, J=7.3 Hz, 3 H),
1.06 (d, J=4.4 Hz, 12 H), 1.41-1.48 (m, 2 H), 1.75-1.85 (m, 2 H),
2.89 (bs, 2 H), 3.82 (s, 3 H), 4.07 (t, J=6.6 Hz, 2 H), 5.32 (s, 2
H), 6.32 (d, J=6.8 Hz, 1 H), 7.03-7.07 (m, 5 H), 7.18 (dd, J=8.1,
8.1 Hz, 1 H), 7.54 (d, J=6.6 Hz, 1 H), 8.00 (dd, J=6.8, 6.8 Hz, 1
H), 8.68 (d, J=8.1 Hz, 1 H), 8.76 (d, J=6.8 Hz, 1 H), 8.94 (s, 1
H)
Example 28
[0333] Preparation of
N-[1-butyl-2-oxo-4-(2-isopropoxy-5-bromo)phenyl-1,2--
dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea: 85
[0334] The title compound was obtained in the same manner as in
Example 10 from
N-[1-butyl-2-oxo-4-(2-hydroxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl-
]-N'-(2,6-diisopropylphenyl)urea and isopropyl iodide.
[0335] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.94 (t, J=7.3 Hz, 3 H),
1.05 (bs, 12 H), 1.19 (d, J=5.9 Hz, 6 H), 1.31-1.38 (m, 2 H),
1.65-1.72 (m, 2 H), 2.81-2.91 (m, 2 H), 3.96 (m, 2 H), 4.55 (m, 1
H), 6.16 (d, J=7.2 Hz, 1 H), 6.98 (d. J=8.4 Hz, 1 H), 7.02 (d,
J=7.3 Hz, 2 H), 7.14 (dd, J=7.3, 7.3 Hz, 1 H), 7.33 (d, J=2.6 Hz, 1
H), 7.38 (dd, J=2.6, 8.4 Hz, 1 H), 7.44 (d, J=7.2 Hz, 1 H), 7.86
(s, 2 H)
Example 29
[0336] Preparation of
N-[1-butyl-2-oxo-4-[2-isopropoxy-5-{3-(diethylamino)-
-1-propynyl}]phenyl-1,2
-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)-u- rea: 86
[0337] The title compound was obtained in the same manner as in
Example 14 from
N-[1-butyl-2-oxo-4-(2-isopropoxy-5-bromo)phenyl-1,2-dihydropyridin-3-
-yl]-N'-(2,6-diisopropylphenyl)urea.
[0338] The hydrochloride of the title compound was obtained in the
same manner as in Example 10.
[0339] M.p. 133-142.degree. C.
[0340] IR (KBr) 3324, 2964, 2231, 1691, 1647, 1597 cm.sup.-1
Example 30
[0341] Preparation of N-{1-butyl-2-oxo-4-(2-hydroxy-5-bromo)phenyl-
1,2-dihydropyridin-3-yl}-N'-(2,4-bis(methylthio)-6-methylpyridin-3-yl]ure-
a: 87
[0342] The title compound was obtained in the same manner as in
Example 24 from
N-{1-butyl-2-oxo-4-(2-methoxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl-
}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea.
[0343] M.p. 138-142.degree. C.
Example 31
[0344] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-bromo)phenyl-1,2--
dihydropyridin-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl]urea:
88
[0345] The title compound was obtained in the same manner as in
Example 10 from
N-{1-butyl-2-oxo-4-(2-hydroxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl-
}-N'-(2,4-bis(methylthio)-6-methylpyridin-3-yl}urea and isopropyl
iodide.
[0346] .sup.1H NMR .delta. (CD.sub.3OD) 0.86 (t, J=7.2 Hz, 3 H),
1.14 (bs, 6 H), 1.30 (tq, J=7.3, 7.3 Hz, 2 H), 1.60-1.70 (m, 2 H),
2.24 (s, 3 H), 2.29 (s, 3 H), 2.34 (s, 3 H), 3.92 (t, J=7.2 Hz, 2
H), 4.47 (bs, 1 H), 6.19 (bs, 1 H), 6.63 (bs, 1 H), 6.85 ((d, J=7.9
Hz, 1 H), 7.31-7.33 (m, 2 H), 7.37 (d, J=7.21 Hz, 1 H)
Example 32
[0347] Preparation of
N-[1-butyl-2-oxo-4-{2-(3-pyridylmethoxy)-5-bromo}-ph-
enyl-1,2-dihydropyridin-3-yl]-N'-(2,4-bis(methylthio)-6-methylpyridin-3-yl-
}urea: 89
[0348] The title compound was obtained in the same manner as in
Example 10 from
N-{1-butyl-2-oxo-4-(2-hydroxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl-
}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea and
3-chloromethylpyridine hydrochloride.
[0349] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.94 (t, J=7.3 Hz, 3 H),
1.04 (bs, 12 H), 1.32-1.37 (m, 2 H), 1.69-1.74 (m, 2 H), 2.79 (br,
2 H), 3.97 (br, 1 H), 5.29 (s, 2 H), 6.26 (d, J=7.0 Hz, 1 H), 7.03
(d, J=7.7 Hz, 2 H), 7.09 (d, J=8.8 Hz, 1 H), 7.15 (dd, J=7.7, 7.7
Hz, 1 H), 7.38 (d, J=2.4 Hz, 1 H), 7.44-7.47 (m, 2 H), 7.79 (dd,
J=5.1, 8.3 Hz, 1 H), 7.99 (s, 2 H), 8.45 (d, J=8.3 Hz, 1 H), 8.78
(d, J=5.1 Hz, 1 H), 8.83 (s, 1 H)
Example 33
[0350] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl--
1,2-dihydropyridin-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}-ure-
a: 90
[0351] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-1,2-dihydropyridin--
3-carboxylic acid and 2,6-diisopropylaniline.
[0352] M.p. 82-84.degree. C.
[0353] IR (KBr) 3324, 2962, 1711, 1643, 1580 cm.sup.-1
Example 34
[0354] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,-
2-dihydropyridin-3-yl}-N'-{2,6-diisopropylphenyl)urea: 91
[0355] The title compound was obtained in the same manner as in
Example 26 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-1,2-dihydropyrid-
in-3-yl}-N'-(2,6-diisopropylphenyl)urea.
[0356] M.p. 174-177.degree. C.
[0357] IR (KBr) 3295, 2963, 1688, 1645, 1578 cm.sup.-1
Example 35
[0358] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-methoxy)phenyl-1,-
2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl-3-yl)urea: 92
[0359] The title compound was obtained in the same manner as in
Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-
-3-yl}-N'-(2,6-diisopropylphenyl)urea and methyl iodide.
[0360] M.p. 170-172.degree. C.
[0361] IR (KBr) 3326, 2959, 1706, 1647 cm.sup.-1
Example 36
[0362] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl--
1,2-dihydropyridin-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}-ure-
a: 93
[0363] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-3-carboxylic acid
and 3-amino-2,4-bis(methylthio)-6-methylpyridine.
[0364] M.p. 119-125.degree. C.
[0365] IR (KBr) 3317, 2961, 1700, 1678, 16412, 1576 cm.sup.-1
Example 37
[0366] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,-
2-dihydropyridin-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:
94
[0367] The title compound was obtained in the same manner as in
Example 26 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-1,2-dihydropyrid-
in-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}-urea.
[0368] M.p. 192-198.degree. C.
[0369] IR (KBr) 3318, 2961, 1700, 1644 cm.sup.-1
Example 38
[0370] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-methoxy)phenyl-1,-
2-dihydropyridin-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:
95
[0371] The title compound was obtained in the same manner as in
Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-
-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}-urea and
methyl iodide.
[0372] M.p. 169-170.degree. C.
[0373] IR (KBr) 3318, 2961, 1700, 1642, 1582 cm.sup.-1
Example 39
[0374] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxy)phenyl--
1,2-dihydropyridin-3-yl}-N'-{2,6-diisopropylphenyl)urea: 96
[0375] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxy)phenyl-1,2-dihydropyridin--
3-carboxylic acid and 2,6-diisopropylaniline.
[0376] M.p. 86-87.degree. C. (flocculated and decomposed)
[0377] IR (KBr) 3318, 2963, 2868, 1643, 1581, 1499, 1466, 1382,
1207 cm.sup.-1
Example 40
[0378] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)phenyl-1,-
2-dihydropyridin-3-yl}-N'-{2,6-diisopropylphenyl)urea: 97
[0379] The title compound was obtained in the same manner as in
Example 26 from
N-(1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxy)phenyl-1,2
-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea.
[0380] M.p. 196-197.degree. C. (decomposed)
[0381] IR (KBr) 3217, 2964, 1687, 1645, 1578, 1498, 1464, 1334,
1212 cm.sup.-1
Example 41
[0382] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-5-(2-pyridylmethoxy-
)-phenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
98
[0383] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea and
2-chloromethylpyridine hydrochloride.
[0384] M.p. 184-185.degree. C. (decomposed)
[0385] IR (KBr) 3252, 2964, 2869, 1646, 1602, 1520, 1467, 1382,
1213 cm.sup.-1
Example 42
[0386] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-5-(3-pyridylmethoxy-
)-phenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
99
[0387] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea and
3-chloromethylpyridine hydrochloride.
[0388] M.p. 138-140.degree. C. (flocculated and decomposed)
[0389] IR (KBr) 3250, 3066, 2964, 2869, 1642, 1606, 1545, 1498,
1468, 1383 cm.sup.-1
Example 43
[0390] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-5-(2-piperidinoetho-
xy)-phenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
100
[0391] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea and
1-(2-chloroethyl)piperidine hydrochloride.
[0392] M.p. 130-132.degree. C. (flocculated and decomposed)
[0393] IR (KBr) 3324, 2964, 2869, 1647, 1587, 1489, 1382, 1216
cm.sup.-1
Example 44
[0394] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-5-(2-morpholino-eth-
oxy)phenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
101
[0395] The hydrochloride of the title compound was obtained in the
same manner as in example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea and
4-(2-chloroethyl)morpholine hydrochloride.
[0396] M.p. 96-98.degree. C. (flocculated and decomposed)
[0397] IR (KBr) 3327, 2964, 2870, 1616, 1583, 1499, 1467, 1383
cm.sup.1
Example 45
[0398] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-5-(2-diethylamino-e-
thoxy)phenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
102
[0399] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea and
2-chlorotriethylamine hydrochloride.
[0400] M.p. 73-75.degree. C. (flocculated and decomposed)
[0401] IR (KBr) 3318, 2963, 2870, 1646, 1582, 1498, 1468, 1383,
1214 cm.sup.-1
Example 46
[0402] Preparation of
N-[1-butyl-2-oxo-4-]2-isopropoxy-5-{3-(1,2,4-triazol-
-1-yl)propoxy}phenyl]-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)--
urea: 103
[0403] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea and
1-(3-bromopropyl)-1,2,4-triazole.
[0404] M.p. 84-86.degree. C. (flocculated and decomposed)
[0405] IR (KBr) 3320, 2964, 2870, 1645, 1582, 1500, 1467, 1383,
1214 cm.sup.-1
Example 47
[0406] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-5-(4-pyridylmethoxy-
)-phenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
104
[0407] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl) - urea
and 4-chloromethylpyridine hydrochloride.
[0408] M.p. 95-97.degree. C. (decomposed)
[0409] IR (KBr) 3254, 2963, 2869, 1644, 1605, 1501, 1468, 1383,
1224 cm.sup.-1
Example 48
[0410] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-methoxy)phenyl-1,-
2-dihydropyridin-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:
105
[0411] To a solution of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)-phenyl-
-1,2-dihydropyridin-3-yl}-N'-(2,4-bis(methylthio)-6-methylpyridin-3-yl}ure-
a (880 mg, 1.62 mmol) in dimethyolformamide (10 ml) were added
potassium carbonate (689 mg, 4.99 mmol) and methyl iodide (1.55 ml,
2.49 mmol), and the mixture was stirred at about 50.degree. C. for
6 hours. The mixture was diluted with ethyl acetate, and the
reaction was quenched by addition of water, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and a saturated aqueous sodium chloride solution, and the
solvent was evaporated under reduced pressure to give a crude
product. The crude product thus obtained was purified by silica gel
column chromatography (ethyl acetate), and crystallized from ethyl
acetate/diethyl ether to give the title compound.
[0412] The crystals thus obtained were dissolved in tetrahydrofuran
(4 ml) under heating, and converted into a hydrochloride thereof
with 1 N hydrochloric acid/diethyl ether (1 ml). To the mixture was
added diethyl ether (10 ml) for crystallization, and the crystals
were collected by filtration to give the hydrochloride of the title
compound (391 mg, 0.68 mmol).
[0413] M.p. 212-214.degree. C. (flocculated and decomposed)
[0414] IR (KBr)3245, 2959, 1691, 1611, 1530, 1442, 1382, 1304
cm.sup.-1
Example 49
[0415] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-4-(3-pyridylmethoxy-
)-phenyl)-1,2-dihydropyridin-3-yl]-N'-{2,4-bis(methylthio)-6-methylpyridin-
-3-yl}urea: 106
[0416] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-y-
l}urea and 3-chloromethylpyridine hydrochloride.
[0417] M.p. 176-178.degree. C. (flocculated and decomposed)
[0418] IR (KBr) 3424, 2958, 1689, 1608, 1570, 1430, 1383, 1304
cm.sup.-1
Example 50
[0419] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-4-(2-piperidinoetho-
xy)-phenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)
urea: 107
[0420] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea and
1-(2-chloroethyl)piperidine hydrochloride.
[0421] M.p. 122-124.degree. C. (flocculated and decomposed)
[0422] IR (KBr) 3338, 2963, 1646, 1578, 1508, 1466, 1301, 1190,
1110 cm.sup.-1
Example 51
[0423] Preparation of
N-[1-butyl-2-oxo-4-(2-isopropoxy-4-(3-piperidinoprop-
oxy)phenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)-urea:
108
[0424] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea and
1-(3-chloropropyl)piperidine hydrochloride.
[0425] M.p. 116-118.degree. C. (flocculated and decomposed)
[0426] IR (KBr) 3400, 2962, 1644, 1578, 1466, 1383, 1300, 1190,
1111, 926 cm.sup.-1
Example 52
[0427] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-4-(2-morpholinoetho-
xy)phenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
109
[0428] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea and
4-(2-chloroethyl)morpholine hydrochloride.
[0429] M.p. 117-119.degree. C. (flocculated and decomposed)
[0430] IR (KBr) 3400, 2966, 1644, 1578, 1465, 1384, 1301, 1190,
1134, 1107 cm.sup.-1
Example 53
[0431] Preparation of
N-[1-butyl-2-oxo-4-[2-isopropoxy-4-{3-(1,2,4-triazol-
-1-yl)propoxyphenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)-u-
rea: 110
[0432] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)p-
henyl-1,2-dihydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)-urea and
1-(3-bromopropyl)-1,2,4-triazole.
[0433] M.p. 98-104.degree. C. (flocculated and decomposed)
[0434] IR (KBr) 3328, 2964, 1643, 1576, 1508, 1466, 1384, 1301,
1190, 1112 cm.sup.-1
Example 54
[0435] Preparation of
N-{1-butyl-2-oxo-4-(2-methoxy-5-fluorophenyl)-1,2-di-
hydropyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea: 111
[0436] The title compound was obtained in- the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2-methoxy-5-fluorophenyl)-1,2-dihydropyridine-3-car-
boxylic acid and 2,6-diisopropylaniline.
[0437] M.p. 165-166.degree. C. (flocculated and decomposed)
[0438] IR (KBr) 3321, 2961, 2872, 1701, 1644, 1579, 1517, 1467,
1258, 1210 cm.sup.-1
Example 55
[0439] Preparation of
N-{1-butyl-2-oxo-4-(2-methoxy-5-fluorophenyl)-1,2-di-
hydropyridin-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:
112
[0440] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2-methoxy-5-fluorophenyl)-1,2-dihydropyridine-3-car-
boxylic acid and 3-amino-2,4-bis(methylthio)-6-methylpyridine.
[0441] M.p. 194-196.degree. C.
[0442] IR (KBr) 3319, 2958, 2928, 1701, 1642, 1579, 1500, 1434,
1212 cm.sup.-1
Example 56
[0443] Preparation of N-{1-butyl-2-oxo-4-(2-methoxyphenyl)-1,2
-dihydropyridin-3-yl}-N'-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:
113
[0444] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2-methoxyphenyl)-1,2-dihydropyridine-3-carboxylic
acid and 3-amino-2,4-bis(methylthio)-6-methylpyridine.
[0445] M.p. 196-199.degree. C.
[0446] IR (KBr) 3318, 2958, 2925, 2872, 1701, 1641, 1578, 1516,
1255, 1211 cm.sup.-1
Example 57
[0447] Preparation of
N-[1-butyl-2-oxo-4-{2-(3-dimethylaminopropoxy)phenyl-
}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea: 114
[0448] a) Preparation of
1-butyl-2-oxo-3-amino-4-(2-methoxyphenyl)-1,2-dih-
ydropyridine:
[0449] The title compound was obtained in the same manner as in
Example 3 from
1-butyl-2-oxo-3-carbamoyl-4-(2-methoxyphenyl)-1,2-dihydropyridine.
[0450] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.93 (t, J=7.3 Hz, 3 H),
3.76 (s, 3 H), 4.53 (s, 2 H)
[0451] b) Preparation of
1-butyl-2-oxo-3-amino-4-(2-hydroxyphenyl)-1,2-dih-
ydropyridine:
[0452] The title compound was obtained in the same manner as in
Example 9 from
1-butyl-2-oxo-3-amino-4-(2-methoxyphenyl)-1,2-dihydropyridine.
[0453] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.90 (t, J=7.3 Hz, 3 H),
3.89 (d, J=5.6, 2 H), 7.14-7.22 (m, 2 H)
[0454] c) Preparation of
1-butyl-2-oxo-3-amino-4-{2-(3-dimethylaminopropox-
y)phenyl}-1,2-dihydropyridine:
[0455] The title compound( was obtained in the same manner as in
Example 10 from
1-butyl-2-oxo-3-amino-4-(2-hydroxyphenyl)-1,2-dihydropyridine and
3-dimethylaminopropyl chloride hydrochloride.
[0456] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.89 (t, J=7.3 Hz, 3 H),
2.10 (s, 6 H)
[0457] d) Preparation of
N-[1-butyl-2-oxo-4-{2-(3-dimethylaminopropoxy)-ph-
enyl-1,2-dihydropyridin-3-yl}-N'- (2,6-diisopropylphenyl)urea:
[0458] The title compound was obtained in the same manner as in
Example 4 from
1-butyl-2-oxo-3-amino-4-{2-(3-dimethylaminopropoxy)-phenyl}-1,2-dihy-
dropyridine and 2,6-diisopropylaniline.
[0459] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.88-1.07 (m, 15 H), 2.18
(s, 6 H)
[0460] The title compound was converted into a hydrochloride
thereof in the same manner as in Example 10.
[0461] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.85-1.10 (m, 15 H),
1.28-1.40 (m, 2 H), 2.51 (s, 3 H), 2.53 (s, 3 H), 3.00-3.10 (m, 2
H)
[0462] IR (KBr) 3316, 2952, 2869, 1645, 1580, 1523, 1467, 1383,
1227 cm.sup.-1
Example 58
[0463] Preparation of
N-[1-butyl-2-oxo-4-{2-(2-piperidinoethoxy-5-methoxyp-
henyl)}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
115
[0464] a) Preparation of
1-butyl-2-oxo-3-amino-4-(2-benzyloxy-5-methoxyphe-
nyl)-1,2-dihydropyridine:
[0465] The title compound was obtained in the same manner as in
Example 3 from
1-butyl-2-oxo-3-carbamoyl-4-(2-benzyloxy-5-methoxyphenyl)-1,2-dihydr-
opyridine.
[0466] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.90 (t, J=7.3 Hz, 3 H),
3.71 (s, 3 H), 4.65 (s, 2 H), 5.02 (s, 2 H), 6.03 (d, J=7.0 Hz, 1
H)
[0467] b) Preparation of
1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxypheny-
l)-1,2-dihydropyridine:
[0468] To a solution of
1-butyl-2-oxo-3-amino-4-(2-benzyloxy-5-methoxyphen-
yl)-1,2-dihydropyridine (1.20 g, 3.17 mmol) in methanol (20 ml) was
added 10% Pd/C (50% wet, 300 mg), and the mixture was stirred at
room temperature for one hour under hydrogen atmosphere. After
confirming the completion of the reaction, the reaction solution
was filtered through a cerite pad, and the filtrate was
concentrated to give the title compound (883 mg) as pale yellow
amorphous, which was used in the subsequent reaction without
further purification.
[0469] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.94 (t, J=7.3 Hz, 3 H),
3.68 (s, 3 H), 4.68 (s, 2 H)
[0470] c) Preparation of
1-butyl-2-oxo-3-amino-4-{2-(2-piperidinoethoxy)-5-
-methoxyphenyl}-1,2-dihydropyridine:
[0471] The title compound was obtained in the same manner as in
Example 10 from
1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-di-
hydropyridine and 1-(2-chloroethyl)piperidine hydrochloride.
[0472] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.91 (t, J=3 Hz, 3 H),
1.25-1.43 (m, 8 H), 1.61-1.68 (m, 2 H), 2.29-2.32 (m, 2 H),
2.50-2.56 (m, 2 H), 3.72 (s, 3 H), 4.71 (br s, 2 H)
[0473] d) Preparation of
N-[1-butyl-2-oxo-4-{2-(2-piperidinoethoxy)-5-meth-
oxyphenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
[0474] The title compound was obtained in the same manner as in
Example 4 from
1-butyl-2-oxo-3-amino-4-{2-(2-piperidinoethoxy)-5-methoxyphenyl}-1,2-
-dihydropyridine and 2,6-diisopropylaniline.
[0475] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.82-0.98 (m, 15 H),
1.23-1.42 (m, 8 H), 1.62-1.67 (m, 2 H), 2.82-2.87 (m, 2 H), 3.67
(s, 3 H), 3.91-3.97 (m, 4 H)
[0476] The title compound was converted into a hydrochloride
thereof in the same manner as in Example 10.
[0477] M.p. 146-148.degree. C.
[0478] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.82-1.14 (m, 19 H),
1.26-1.37 (m, 2 H), 1.60-1.69 (m, 2 H), 3.73 (s, 3 H), 7.89 (s, 1
H), 7.98 (s, 1 H)
[0479] IR (KBr) 3307, 2961, 2870, 1646, 1587, 1499, 1467, 1383,
1216 cm.sup.-1
Example 59
[0480] Preparation of
N-]1-butyl-2-oxo-4-{2-(2-morpholinoethoxy)-5-methoxy-
-phenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
116
[0481] a) Preparation of
1-butyl-2-oxo-3-amino-4-{2-(2-morpholinoethoxy)-5-
-methoxyphenyl}-1,2-dihydropyridine:
[0482] The title compound was obtained in the same manner as in
Example 10 from
1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-dihydropyrid-
ine and 4-(2-chloroethyl)morpholine hydrochloride.
[0483] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.90 (t, J=7.3 Hz, 3 H),
3.71 (s, 3 H), 4.68 (s, 3 H)
[0484] b) Preparation of
N-[1-butyl-2-oxo-4-{2-(2-morpholinoethoxy)-5-meth-
oxyphenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
[0485] The title compound was obtained in the same manner as in
Example 4 from
1-butyl-2-oxo-3-amino-4-{2-(2-morpholinoethoxy)-5-methoxyphenyl}-1,2-
-dihydropyridine and 2,6-diisopropylaniline.
[0486] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.85-0.99 (m, 15 H),
2.82-2.90 (m, 2 H), 3.46-3.52 (m, 4 H), 3.68 (s, 3 H), 3.91-4.06
(m, 4 H)
[0487] The title compound was converted into a hydrochloride
thereof in the same manner as in Example 10.
[0488] M.p. 156-158.degree. C. (decomposed)
[0489] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.90-1.08 (m, 15 H),
2.80-3.05 (m, 2 H), 3.20-3.45 (m, 2 H), 3.67-3.76 (m, H), 4.27-4.33
(br, 2 H)
[0490] IR (KBr) 3308, 2963, 2871, 1813, 1646, 1590, 1500, 1466,
1216 cm.sup.-1
Example 60
[0491] Preparation of
N-[1-butyl-2-oxo-4-[2-{3-(1,2,4-triazol-1-yl)propoxy-
}-5-methoxyphenyl]-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)-ure-
a: 117
[0492] a) Preparation of
1-butyl-2-oxo-3-amino-4-[2-{3-(1,2,4-triazol-1-yl-
)propoxy}-5-methoxyphenyl]-1,2-dihydropyridine:
[0493] The title compound was obtained in the same manner as in
Example 10 from
1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-dihydropyrid-
ine and 1-(3-bromopropyl)-1,2,4-triazole.
[0494] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.88 (t, J=7.3 Hz, 3 H),
3.68 (s, 3 H), 4.70 (s, 2 H), 7.93 (s, 1 H), 8.36 (s, 1 H)
[0495] b) Preparation of
N-[1-butyl-2-oxo-4-[2-{3-(1,2,4-triazol-1-yl)-pro-
poxy}-5-methoxyphenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)-
urea:
[0496] The title compound was obtained in the same manner as in
Example 4 from
1-butyl-2-oxo-3-amino-4-[2-{3-(1,2,4-triazol-1-yl)-propoxy}-5-methox-
yphenyl]-1,2-dihydropyridine and 2,6-diisopropylaniline.
[0497] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.85-1.02 (m, 15 H),
2.75-2.90 (m, 2 H), 3.68 (s, 3 H), 7.94 (s, 1 H), 8.27 (s, 1 H)
[0498] The title compound was converted into a hydrochloride
thereof in the same manner as in Example 10.
[0499] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.84-1.05 (m, 15 H),
1.23-1.35 (m, 2 H), 2.05-2.12 (m, 2 H), 3.68 (s, 3 H), 3.84-3.96
(m, 4 H), 7.82 (s, 1 H), 7.85 (s, 1 H), 8.04 (s, 1 H), 8.46 (s, 1
H)
[0500] IR (KBr) 3307, 2963, 2871, 1642, 1580, 1502, 1468, 1217
cm.sup.-1
Example 61
[0501] Preparation of
N-[1-butyl-2-oxo-4-{2-(3-piperidinopropoxy)-5-methox-
yphenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
118
[0502] a) Preparation of
1-butyl-2-oxo-3-amino-4-{2-(3-piperidinopropoxy)--
5-methoxyphenyl}-1,2-dihydropyridine:
[0503] The title compound was obtained in the same manner as in
Example 10 from
1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-dihydropyrid-
ine and 1-(3-chloropropyl)piperidine hydrochloride.
[0504] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.90 (t, J=7.3 Hz, 3 H),
1.22-1.45 (m, 8 H), 1.57-1.74 (m, 4 H), 3.72 (s, 3 H), 3.86-3.92
(m, 4 H), 4.61 (s, 2 H)
[0505] b) Preparation of
N-1-butyl-2-oxo-4-{2-(3-piperidinopropoxy)-5-meth-
oxyphenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
[0506] The title compound was obtained in the same manner as in
Example 4 from
1-butyl-2-oxo-3-amino-4-{2-(3-piperidinopropoxy)-5-methoxyphenyl}-1,-
2-dihydropyridine and 2,6-diisopropylaniline.
[0507] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.85-1.11 (m, 15 H),
1.29-1.44 (m, 8 H), 1.63-1.73 (m, 4 H), 2.81-2.87 (m, 2 H), 3.67
(s, 3 H), 3.86-3.97 (m, 4 H), 7.68 (s, 1 H), 7.77 (s, 1 H)
[0508] The title compound was converted into a hydrochloride
thereof in the same manner as in Example 10.
[0509] M.p. 173-176.degree. C. (decomposed)
[0510] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.80-1.10 (m, 15 H),
1.95-1.99 (m, 2 H), 2.76-2.82 (m, 2 H), 2.94-3.02 (m, 2 H),
3.12-3.16 (m, 2 H), 3.70 (s, 3 H), 3.80-4.05 (m, 4 H), 7.91 (s, 1
H), 8.03 (s, 1 H)
[0511] IR (KBr) 3244, 2960, 2869, 1694, 1596, 1499, 1468, 1215
cm.sup.-1
Example 62
[0512] Preparation of
N-[1-butyl-2-oxo-4-{2-(3-pyridylmethoxy)-5-methoxyph-
enyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
119
[0513] a) Preparation of
1-butyl-2-oxo-3-amino-4-{2-(3-pyridylmethoxy)-5-m-
ethoxyphenyl}-1,2-dihydropyridine:
[0514] The title compound was obtained in the same manner as in
Example 10 from
1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-dihydropyrid-
ine and 3-chloromethylpyridine hydrochloride.
[0515] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.89 (t, J=7.3 Hz, 3 H),
3.72 (s, 3 H), 4.69 (s, 2 H), 5.07 (s, 2 H)
[0516] b) Preparation of
N-[1-butyl-2-oxo-4-{2-(3-pyridylmethoxy)-5-methox-
yphenyl}-1,2-dihydropyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea:
[0517] The title compound was obtained in the same manner as in
Example 4 from
1-butyl-2-oxo-3-amino-4-{2-(3-pyridylmethoxy)-5-methoxyphenyl}-1,2-d-
ihydropyridine and 2,6-diisopropylaniline.
[0518] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.82-1.30 (m, 15 H), 3.69
(s, 3 H), 5.03 (s, 2 H), 6.82-6.86 (m, 2 H), 6.98-7.14 (m, 4 H),
7.79 (s, 1 H), 7.85 (s, 1 H), 8.54 (s, 1 H)
[0519] The title compound was converted into a hydrochloride
thereof in the same manner as in Example 10.
[0520] M.p. 138-141.degree. C. (decomposed)
[0521] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.80-1.08 (m, 15 H),
1.27-1.37 (m, 2 H), 1.62-1.70 (m, 2 H), 2.70-2.90 (m, 2 H), 3.70
(s, 3 H), 5.21 (s, 2 H), 8.81 (s, 1 H)
[0522] IR (KBr) 2870, 1756, 1712, 1644, 1580, 1500, 1469, 1197
cm.sup.-1
Example 63
[0523] Preparation of
N-1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxyphenyl)-1-
,2-dihydropyridin-3-yl}-N'-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}-urea-
: 120
[0524] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxyphenyl)-1,2-dihydropyridine-
-3-carboxylic acid and 2-tert-butyl-5-(1-pyrazolylmethyl)aniline,
and further the hydrochloride thereof was obtained in the same
manner as in Example 10.
[0525] M.p. 102-103.degree. C.
[0526] IR (KBr) 2963, 2872, 1645, 1578, 1528, 1498 cm.sup.-1
Example 64
[0527] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxyphenyl)-1,-
2-dihydropyridin-3-yl}-N'-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}urea:
121
[0528] The title compound was obtained in the same manner as in
Example 58 b) from
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxyphenyl)-1,2-dihydropy-
ridin-3-yl}-N'-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}urea, and
further the hydrochloride thereof was obtained in the same manner
as in Example 10.
[0529] M.p. 142-143.degree. C.
[0530] IR (KBr) 2968, 2873, 1645, 1578, 1539, 1497 cm.sup.-1
Example 65
[0531] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-methoxyphenyl)
-1,2-dihydropyridin-3-yl}-N'-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}ur-
ea: 122
[0532] The title compound was obtained in the same manner as in
Example 48 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxyphenyl)-1,2-dihydropyridin-
-3-yl}-N'-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}-urea, and
further the hydrochloride thereof was obtained in the same manner
as in Example 10.
[0533] M.p. 99-100.degree. C.
[0534] IR (KBr) 2963, 2873, 1644, 1580, 1421 cm.sup.-1
[0535] Example 66
[0536] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-5-(3-pyridylmethoxy-
)-phenyl}-1,2-dihydropyridin-3-yl]-N'-{2-tert-butyl-5-(1-pyrazolylmethyl)--
phenyl}urea: 123
[0537] The hydrochloride of the title compound was obtained in the
same manner as in Example 10 from
N-{1-butyl-2-oxo-5-(2-isopropoxy-5-hydroxyph-
enyl)-1,2-dihydropyridin-3-yl}-N'-{2-tert-butyl-5-(1-pyrazolylmethyl)pheny-
l}urea and 3-chloromethylpyridine.
[0538] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.94 (t, J=7.3 Hz, 3 H),
1.13 (d, J=6.0 Hz, 6 H), 1.17 (s, 9 H), 3.96 (t, J=7.0 Hz, 2 H),
7.20 (d, J=8.8 Hz, 1 H)
Example 67
[0539] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxyphenyl)--
1,2-dihydropyridin-3-yl}-N'-{2-tert-butyl-5-(1-imidazolylmethyl)phenyl}-ur-
ea: 124
[0540] The title compound was obtained in the same manner as in
Example 8 from
1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxyphenyl)-1,2-dihydropyridine-
-3-carboxylic acid and 2-tert-butyl-5-(1-imidazolylmethyl)aniline,
and the hydrochloride thereof was further obtained in the same
manner as in Example 10.
[0541] M.p. 138-140.degree. C.
[0542] IR (KBr) 2963, 2871, 1643, 1607, 1574, 1541 cm.sup.-1
Example 68
[0543] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxyphenyl)-1,-
2-dihydropyridin-3-yl}-N'-(2-tert-butyl-5-(
1-imidazolylmethyl)phenyl}urea- : 125
[0544] The title compound was obtained in the same manner as in
Example 58 b) from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxyphenyl)-1,2-dihydropy-
ridin-3-yl}-N'-{2-tert-butyl-5-(1-imidazolylmethyl)phenyl}urea, and
the hydrochloride thereof was further obtained in the same manner
as in Example 10.
[0545] M.p. 162-163.degree. C.
[0546] IR (KBr) 2962, 2872, 1642, 1610, 1579, 1541 cm.sup.-1
Example 69
[0547] Preparation of
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-methoxyphenyl)-1,-
2-dihydropyridin-3-yl}-N'-{2-tert-butyl-5-(1-imidazolylmethyl)phenyl}urea:
126
[0548] The title compound was obtained in the same manner as in
Example 48 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxyphenyl)-1,2-dihydropyridin-
-3-yl}-N'-{2-tert-butyl-5-(1-imidazolylmethyl)phenyl}-urea, and
further they hydrochloride thereof was obtained in the same manner
as in Example 10.
[0549] M.p. 147-148.degree. C.
[0550] IR (KBr) 2962, 2871, 1646, 1604, 1508, 1466 cm.sup.-1
Example 70
[0551] Preparation of
N-[1-butyl-2-oxo-4-{2-isopropoxy-4-(3-pyridylmethoxy-
)-phenyl}-1,2-dihydropyridin-3-yl]-N'-{2-tert-butyl-5-(1-imidazolylmethyl)-
-phenyl}urea: 127
[0552] The title compound was obtained in the same manner as in
Example 10 from
N-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxyphenyl)-1,2-dihydropyridin-
-3-yl}-N'-{2-tert-butyl-5-(1-imidazolylmethyl)phenyl}-urea and
3-chloromethylpyridine, and the hydrochloride thereof was further
obtained in the same manner as in Example 10.
[0553] .sup.1H NMR .delta. (DMSO-d.sub.6) 0.94 (t, J=7.3 Hz, 3 H),
1.13 (d, J=6.0 Hz, 6 H), 1.17 (s, 9 H), 5.15 (s, 2 H), 5.24 (s, 2
H), 7.20 (d, J=8.8 Hz)
[0554] M.p. 1 1. 1-112.degree. C.
[0555] IR (KBr) 2964, 2872, 1643, 1607, 1577, 1543 cm.sup.-1
[0556] Reference Example 1
[0557] Preparation of
1-butyl-3-carbamoyl-4-(3-methoxyphenyl)-1,2-dihydro--
2-oxo-1,8-naphthyridine: 128
[0558] A mixture of
1-butyl-3-ethoxycarbonyl-4-(3-methoxyphenyl)-1,2-dihyd-
ro-2-oxo-1,8-naphthyridine (45.0 g, 120 mmol), formamide (15.5 ml,
390 mmol) and dimethylformamide (120 ml) was dissolved at
60.degree. C., and thereto was added a 25% solution of sodium
methoxide in methanol (108 ml, 390 mmol), and the mixture was
stirred at 60.degree. C. for 9 hours. The mixture was cooled to
0.degree. C., and thereto was added water (1.2 liter), and the
mixture was stirred for 15 minutes. The precipitated solid was
collected by filtration, washed with ethanol, and to dried to give
the title compound (37.8 g, yield; 87 %) as white powder.
[0559] M.p. 239-240.degree. C.
[0560] Reference Example 2
[0561] Preparation of
1-butyl-3-carbamoyl-4-(3-methoxyphenyl)-1,2-dihydro--
2-oxo-1,8-naphthyridine: 129
[0562] To a suspension of
1-butyl-3-carboxy-4-(3-methoxyphenyl)-1,2-dihydr-
o-2-oxo-1,8-naphthyridine (10.0 g, 28.4 mmol) in toluene (300 ml)
was added thionyl chloride (2.95 g, 34.1 mmol), and the mixture was
stirred at room temperature for 0.5 hour, and then stirred at
90-100.degree. C. for 6 hours. After allowed to cool, the mixture
was concentrated under reduced pressure. To the concentrated
residue was added toluene, and the mixture was concentrated again
under reduced pressure. The concentrated residue was dissolved in
dioxane (100 ml), and the mixture was added dropwise into conc.
aqueous ammonia (80 ml) in an ice-bath. The mixture was stirred at
room temperature for 6 hours, and poured into water. The
precipitated crystals were collected by filtration, dispersed in
ethanol (50 ml), and the mixture was stirred for one hour. The
solid thus obtained was collected by filtration to give the title
compound (9.12 g, 24.8 mmol, yield; 87%) as colorless powder.
[0563] M.p. 239-240.degree. C.
[0564] Reference Example 3
[0565] Preparation of 2-(butylamino) -3-(3-methoxybenzoyl)pyridine:
130
[0566] To a suspension of sodium hydride (60%, 578 mg, 14.5 mmol)
in tetrahydrofuran (15 ml) was added dropwise a solution of
3-(2-aminopyridyl)-(3-methoxyphenyl)ketone (3.00 g, 13.1 mmol) in
tetrahydrofuran (24 ml) under ice-cooling, and further thereto was
added dropwise a solution of butyl iodide (3.63 g, 19.7 mmol) in
tetrahydrofuran at room temperature, and the mixture was stirred at
50-60.degree. C. for 6 hours. The mixture was cooled to room
temperature, and thereto was added water. The mixture was extracted
with toluene, and washed successively with a 5% aqueous sodium
hydrogen carbonate solution, water and a 5% aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane=1/4) to give the title
compound (2.96 g, 10.4 mmol, 79%) as yellow oil.
[0567] .sup.1H NMR .delta. (CDCl.sub.3) 0.98 (3 H, t, J=7.3 Hz),
1.43-1.55 (2 H, m), 1.65-1.75 (2 H, m), 3.56-3.62 (2 H, m), 3.85 (3
H, s), 6.47 (1H, dd, J=7.9 Hz, 4.8 Hz), 7.06-7.13 (3 H, m), 7.37 (1
H, dd, J=8.3 Hz, 8.3 Hz), 7.76 (1 H, dd, J=7.9 Hz, 2.0 Hz), 8.32 (1
H, dd, J=4.8 Hz, 2.0 Hz), 8.82 (1 H, brs)
[0568] Reference Example 4
[0569] Preparation of
2{(N-butyl-N-phthalimideacetyl)amino}-3-(3-methoxybe-
nzoyl)pyridine: 131
[0570] To a suspension of N-phthaloylglycine (4.76 g, 23.2 mmol) in
toluene (24 ml) were added thionyl chloride (5.08 ml, 69.6 mmol)
and dimethylformamide (0.4 ml), and the mixture was stirred at
50-60.degree. C. for 30 minutes. After allowed to cool, the solvent
was evaporated under reduced pressure. The residue was subjected
twice to azeotropic distillation with toluene, and the residue was
suspended in dioxane (20 ml). The mixture was added dropwise to a
solution of 2-(butylamino)-3-(3-methoxybenzoyl)pyridine (3.30 g,
11.6 mmol) in pyridine (27 ml) at room temperature. The mixture was
stirred at 50-60.degree. C. for one hour, stirred at 60-70.degree.
C. for one hour, and further stirred at 70-80.degree. C. for one
hour. The mixture was cooled to room temperature, and water was
added therein, and the mixture was extracted with ethyl acetate.
The extract was washed with successively with 1 N hydrochloric
acid, water, a 5% aqueous sodium hydrogen carbonate solution, and a
5% aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, concentrated under reduced pressure, and purified by
silica gel column chromatography (ethyl acetate/hexane=1/2) to give
the title compound (3.77 g, 8.00 mmol, 69%) as yellow
amorphous.
[0571] .sup.1H NMR .delta. (CDCl.sub.3) 0.74 (3 H, t, J=7.3 Hz, 3
Hz), 1.11-1.23 (2 H, m), 1.36-1.43 (2 H, m), 3.36-3.46 (2 H, m),
3.88 (3 H, s), 4.45 (2 H, s), 7.11-7.25 (2 H, m), 7.27-7.51 (2 H,
m), 7.67-7.75 (3 H, m), 7.77-7.94 (3 H, m), 8.74 (1 H, s)
[0572] Reference Example 5
[0573] Preparation of
1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridin-
e-3-carboxylic acid:
[0574] a) Preparation of ethyl
2-cyano-3-(3-methoxy)phenyl-crotonate:
[0575] To a solution of 3-methoxyacetophenone (25 g, 166 mmol) in
toluene (40 ml) were added ethyl cyanoacetate (18.8 g, 166 mmol),
ammonium acetate (2.6 g, 33.2 mmol) and acetic acid (7.6 ml, 133
mmol), and the mixture was stirred under reflux for about 6 hours.
To the reaction solution was added water, and the mixture was
extracted with ethyl acetate. The extract was washed with a
saturated aqueous sodium chloride solution and dried over magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
resulting residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:10) to give the title compound (13.9 g,
yield; 34%) as brown oil.
[0576] .sup.1H NMR .delta. (CDCl.sub.3) 1.14 and 1.26 (t and t,
J=7.2 and 7.2 Hz, 3 H), 2.53 and 2.68 (s and s, 3 H), 3.80 and 3.83
(s and s, 3 H), 4.12 and 4.34 (q and q, J=7.2 and 7.2 Hz, 2 H),
6.68-6.75 and 6.91-7.02 (m and m, 3 H), 7.26-7.39 (m, 1 H)
[0577] b) Preparation of ethyl
2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridi- ne-3-carboxylate:
[0578] To ethyl 2-cyano-3-(3-methoxy)phenyl-crotonate (12.3 g, 50.1
mmol) was added N,N-dimethylformamide dimethyl acetal (17 ml), and
the mixture was stirred at room temperature for about 5 hours. The
solvent was evaporated under reduced pressure, and thereto was
added 80% aqueous acetic acid solution (625 ml), and the mixture
was stirred under reflux for about 2 hours. The solvent was
evaporated under reduced pressure, and water was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The extract was washed with a saturated aqueous sodium
chloride solution, and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure, and the resulting
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=2:1) to give the title compound (8.69 g, yield; 67%)
as brown crystals.
[0579] M.p. 153-156.degree. C.
[0580] IR (KBr) 3433, 1727, 1646, 1531 cm.sup.-1
[0581] c) Preparation of ethyl
1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihyd-
ropyridine-3-carboxylate:
[0582] To a solution of ethyl
2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridin- e-3-carboxylate (7.69
g, 29.9 mmol) in DMF (60 ml) were added potassium carbonate (12.4
g, 89.7 mmol) and butyl iodide (5.1 ml, 44.9 mmol), and the mixture
was stirred at room temperature for about 3 hours. Water was added
to the reaction solution, and the mixture was extracted with ethyl
acetate. The extract was washed with a saturated aqueous sodium
chloride solution, and dried over magnesium sulfate. The solvent
was evaporated under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (ethyl
acetate:hexane=1:1) to give the title compound (7.65 g, yield; 78%)
as brown oil.
[0583] .sup.1H NMR .delta. (CDCl.sub.3) 0.97 (t, J=7.3 Hz, 3 H),
1.11 (t, J=7.2 Hz, 3 H), 1.37-1.47 (m, 2 H), 1.73-1.83 (m, 2 H),
3.82 (s, 3 H), 3.97 (t, J=7.3 Hz, 2 H), 4.19 (q, J=7.2 Hz, 2 H),
6.23 (d, J=7.0 Hz, 1 H), 6.92-7.01 (m, 3 H), 7.26-7.34 (m, 2 H)
[0584] IR (neat) 2960, 1732, 1650, 1600 cm.sup.-1
[0585] d) Preparation of
1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyri-
dine-3-carboxylic acid:
[0586] To a solution of ethyl
1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydr-
opyridine-3-carboxylate (6.05 g, 18.4 mmol) in ethanol (30 ml) was
added sodium hydroxide (2.94 g, 73.5 mmol), and the mixture was
stirred under reflux for about 7 hours. The pH value of the mixture
was adjusted to pH 3 with 3 N aqueous hydrochloric acid solution,
and the precipitated crystals were collected by filtration, and
dried to give the title compound (5.00 g, yield; 90%) as brown
crystals.
[0587] M.p. 108-110.degree. C.
[0588] IR (KBr) 3420, 1737, 1627, 1568 cm.sup.-1
[0589] Reference Example 6
[0590] Preparation of
1-butyl-2-oxo-4-(3-bromo)phenyl-1,2-dihydropyridine-- 3-carboxylic
acid:
[0591] The title compound was obtained in the same manner as in
Reference Example 5.
[0592] .sup.1H NMR .delta. (CDCl.sub.3) 1.01 (t, J=7.3 Hz, 3 H),
1.40-1.47 (m, 2 H), 1.79 (m, 2 H), 4.11 (t, J=7.5 Hz, 2 H), 6.37
(d, J=7.0 Hz, 1 H), 7.20 (d, J=7.7 Hz, 1 H), 7.28 (dd, J=7.7, 7.7
Hz, 1 H), 7.40 (dd, J=2.0, 2.0 Hz, 1 H), 7.53 (d, J=7.7 Hz, 1 H),
7.56 (d, J=7.0 Hz, 1 H)
[0593] M.p. 139-142.degree. C.
[0594] IR (KBr) 3437, 1732, 1626, 1565 cm.sup.-1
[0595] Reference Example 7
[0596] Preparation of
1-butyl-2-oxo-4-(3-bromo)phenyl-5-methyl-1,2-dihydro-
pyridine-3-carboxylic acid:
[0597] The title compound was obtained in the same manner as in
Reference Example 5.
[0598] .sup.1H NMR .delta. (CDCl.sub.3) 1.02 (t, J=7.3 Hz, 3 H),
1.41-1.48 (m, 2 H), 1.79-1.86 (m, 2 H), 1.80 (s, 3 H), 4.09 (t,
J=7.3 Hz, 2 H), 7.00 (ddd, J=1.5, 1.5, 7.7 Hz, 1 H), 7.20 (dd,
J=1.5, 1.5 Hz, 1 H), 7.32 (dd, J=7.7, 7.7 Hz, 1 H), 7.44 (d, J=1.1
Hz, 1 H), 7.51 (ddd, J=1.1, 1.5, 7.7 Hz, 1 H)
[0599] M.p. 197-198.degree. C.
[0600] IR (KBr) 3437, 3068, 1732, 1633, 1564 cm.sup.-1
[0601] Reference Example 8
[0602] Preparation of
1-butyl-2-oxo-4-(5-bromo-2-methoxy)phenyl-1,2-dihydr-
opyridine-3-carboxylic acid:
[0603] The title compound was obtained in the same manner as in
Reference Example 5.
[0604] .sup.1H NMR .delta. (CDCl.sub.3) 1.01 (t, J=7.3 Hz, 3 H),
1.38-1.57 (m, 2 H), 1.79-1.89 (m, 2 H), 3.74 (s, 3 H), 4.03-4.16
(m, 2 H), 6.35 (d, J=6.8 Hz, 1 H), 6.80 (d, J=8.8 Hz, 1 H), 7.19
(d, J=2.6 Hz, 1 H), 7.45 (dd, J=2.6, 8.8 Hz, 1 H), 7.56 (d, J=6.8
Hz, 1 H)
[0605] M.p. 179-180.degree. C.
[0606] IR (KBr) 3436, 3033, 2969, 1720, 1623, 1568 cm.sup.-1
[0607] Reference Example 9
[0608] Preparation of
1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyr-
idine-3-carboxylic acid:
[0609] The title compound was obtained in the same manner as in
Reference Example 5.
[0610] .sup.1H NMR .delta. (CDCl.sub.3) 1.01 (t, J=7.5 Hz, 3 H),
1.45 (tq, J=7.5, 7.5 Hz, 2 H), 1.84 (tt, J=7.5, 7.5 Hz, 2 H), 3.72
(s, 3 H), 3.77 (s, 3 H), 4.01-4.12 (br, 2 H), 6.39 (d, J=6.8 Hz, 1
H), 6.67 (dd, J=0.7, 2.6 Hz, 1 H), 6.84-6.88 (m, 2 H), 7.53 (d,
J=6.8 Hz, 1 H)
[0611] Reference Example 10
[0612] Preparation of
1-butyl-2-oxo-4-(2-methoxy-5-benzyloxy)phenyl-1,2-di-
hydropyridine-3-carboxylic acid:
[0613] The title compound was obtained in the same manner as in
Reference Example 5.
[0614] .sup.1H NMR .delta. (CDCl.sub.3) 1.01 (t, J=7.3 Hz, 3 H),
1.44 (tq, J=7.3, 7.3 Hz, 2 H), 1.84 (tt, J=7.3, 7.3 Hz, 2 H), 3.72
(s, 3 H), 4.11 (br, 2 H), 5.01 (s, 2 H), 6.37 (d, J=7.0 Hz, 1 H),
6.76 (d, J=3.1 Hz, 1 H), 6.85 (d, J=9.0 Hz, 1 H), 6.96 (dd, J=3.1,
9.0 Hz, 1 H), 7.30-7.44 (m, 5 H), 7.52 (d, J=7.0 Hz, 1 H)
[0615] Reference Example 11
[0616] Preparation of
1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-1,2-
-dihydropyridine-3-carboxylic acid:
[0617] The title compound was obtained from
1-acetyl-2-isopropoxy-4-benzyl- oxybenzene in the same manner as in
Reference Example 5.
[0618] .sup.1H NMR .delta. (CDCl.sub.3) 1.00 (t, J=7.3 Hz, 3 H),
1.23 (d, J=5.5 Hz, 6 H), 1.43 (tq, J=7.3, 7.3 Hz, 2 H), 1.83 (tt,
J=7.3, 7.3 Hz, 2H), 4.08 (br, 2 H), 4.45 (qq, J=5.5, 5.5 Hz, 1 H),
5.06 (s, 2 H), 6.40 (d, J=6.8 Hz, 1 H), 6.55 (d, J=2.2 Hz, 1 H),
6.59 (dd, J=2.2, 8.4 Hz, 1 H), 7.05 (d, J=8.4 Hz, 1 H), 7.31-7.49
(m, 6 H)
[0619] The ACAT inhibitory activity of the present compounds can be
evaluated by the following method.
[0620] Experiment
[0621] 5 1. Assay of ACAT inhibitory activity in a specimen
prepared from rabbit liver:
[0622] An enzyme specimen ACAT was prepared according to the method
disclosed in the literature: J. Lipid. Research, 30, 681-690, 1989,
from the liver of New Zealand white rabbit, which had been fed with
1% cholesterol feed for one month. The ACAT activity was determined
according to the method disclosed in the literature: J. Lipid
Research, 24, 1127-1134, 1983, i.e., using radioactive
[1-.sup.14C]oleoyl-CoA and endogenous cholesterol contained in the
liver microsome, and calculated from the radioactivity of the
labeled cholesterol oleate. The results are shown in Table 13.
13 TABLE 13 Test compound ACAT inhibitory activity (Example No.)
IC.sub.50 (nM) 18 (hydrochloride) 295
[0623] 2. Assay of ACAT inhibitory activity in the macrophage
derived from rat peritoneal:
[0624] The rat peritoneal-derived macrophage was prepared according
to the method disclosed in the literature: Biochimica et Biophysica
Acta, 1126, 73-80, 1992. The ACAT activity was determined by a
modified method of the method disclosed in the above literature:
Biochimica et Biophysica Acta, 1126, 73-80, 1992, i.e., using
radioactive [9,10-.sup.3H]oleic acid and exogenous cholesterol
contained in the liposome which was re-constituted according to the
method disclosed in the literature: Biochimica et Biophysica Acta,
1213, 127-134, 1994, and calculated from the radioactivity of the
labeled cholesterolyl oleate. The results are shown in Table
14.
14 TABLE 14 Test compound ACAT inhibitory activity (Example No.)
IC.sub.50 (nM) 18 (hydrochloride) 16
INDUSTRIAL APPLICABILITY
[0625] The pyridone derivative and the aminopyridone derivative can
safely be prepared by the present invention. Besides, the pyridone
derivative of the present invention and a salt thereof strongly
inhibits ACAT activity in a specimen of rabbit liver or in rat
peritoneal-derived macrophage. Therefore, the pyridone derivative
of the present invention or a salt thereof is useful not only as an
agent for treatment of hyperlipidemia, but also in the prophylaxis
or therapeutic treatment of atherosclerosis per se or various
diseases accompanied by atherosclerosis, for example, cerebral
infarction, cerebral thrombosis, transient cerebral ischemia,
angina pectoris, myocardial infarction, peripheral thrombus or
occlusion.
* * * * *