U.S. patent application number 11/526739 was filed with the patent office on 2007-02-01 for quinoline derivatives and quinazoline derivatives.
This patent application is currently assigned to KIRIN BEER KABUSHIKI KAISHA. Invention is credited to Yasunari Fujiwara, Toshiyuki Isoe, Kazuo Kubo.
Application Number | 20070027318 11/526739 |
Document ID | / |
Family ID | 27456291 |
Filed Date | 2007-02-01 |
United States Patent
Application |
20070027318 |
Kind Code |
A1 |
Kubo; Kazuo ; et
al. |
February 1, 2007 |
Quinoline derivatives and quinazoline derivatives
Abstract
An object of the present invention is to provide compounds which
have antitumor activity and do not change cytomorphosis. Disclosed
are compounds represented by formula (I) and a pharmaceutically
acceptable salts and solvates thereof and pharmaceutical
compositions comprising said compounds: ##STR1## wherein X and Z
each independently represent CH or N; R.sup.1 to R.sup.3 represent
H, substituted alkoxy, unsubstituted alkoxy or the like; R.sup.4
represents H; R.sup.5 to R.sup.8 represent H, halogen, alkyl,
alkoxy, alkylthio, nitro, or amino, provided that R.sup.5 to
R.sup.8 do not simultaneously represent H; R.sup.9 and R.sup.10
represent H, alkyl, or alkylcarbonyl; and R.sup.11 represents
alkyl, alkenyl, alkynyl, or aralkyl.
Inventors: |
Kubo; Kazuo; (Takasaki-Shi,
JP) ; Fujiwara; Yasunari; (Takasaki-Shi, JP) ;
Isoe; Toshiyuki; (Takasaki-Shi, JP) |
Correspondence
Address: |
C. IRVIN MCCLELLAND;OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
KIRIN BEER KABUSHIKI KAISHA
Tokyo-to
JP
|
Family ID: |
27456291 |
Appl. No.: |
11/526739 |
Filed: |
September 26, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10842009 |
May 10, 2004 |
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11526739 |
Sep 26, 2006 |
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09889858 |
Jul 23, 2001 |
6797823 |
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PCT/JP00/00255 |
Jan 20, 2000 |
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10842009 |
May 10, 2004 |
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Current U.S.
Class: |
544/114 ;
544/284; 544/287; 546/153 |
Current CPC
Class: |
C07D 239/88 20130101;
A61P 3/10 20180101; A61P 29/00 20180101; A61P 27/00 20180101; C07D
231/12 20130101; C07D 401/12 20130101; A61P 9/10 20180101; C07D
403/12 20130101; A61P 17/06 20180101; C07D 215/233 20130101; A61P
27/02 20180101; C07D 233/56 20130101; A61P 35/00 20180101; C07D
249/08 20130101; A61P 19/02 20180101 |
Class at
Publication: |
544/114 ;
546/153; 544/287; 544/284 |
International
Class: |
C07D 413/02 20070101
C07D413/02; C07D 403/02 20070101 C07D403/02; C07D 401/02 20070101
C07D401/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 22, 1999 |
JP |
11-014858 |
Feb 3, 1999 |
JP |
11-026691 |
May 21, 1999 |
JP |
11-142493 |
Sep 7, 1999 |
JP |
11-253624 |
Claims
1-52. (canceled)
53. A compound represented by formula (I) or a pharmaceutically
acceptable salt or solvate thereof: ##STR256## wherein X and Z each
represent CH or N; R.sup.1 represents a hydrogen atom, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
nitro, or amino, which C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are optionally substituted by a
halogen atom; hydroxyl; C.sub.1-4 alkoxy; C.sub.1-4 alkoxycarbonyl;
amino on which one or two hydrogen atoms are optionally substituted
by C.sub.1-4 alkyl optionally substituted by hydroxyl or C.sub.1-4
alkoxy; group R.sup.12R.sup.13N--C(.dbd.O)--O-- wherein R.sup.12
and R.sup.13, which may be the same or different, represent a
hydrogen atom or C.sub.1-4 alkyl which alkyl is optionally
substituted by hydroxyl or C.sub.1-4 alkoxy; or group
R.sup.14--(S)m- wherein R.sup.14 represents a saturated or
unsaturated three- to seven-membered carbocyclic or heterocyclic
group optionally substituted by C.sub.1-4 alkyl and m is 0 or 1;
one of R.sup.2, and R.sup.3, represents an unsubstituted C.sub.1-6
alkoxy, and the other represents C.sub.1-6 alkoxy substituted by a
halogen atom; hydroxyl; C.sub.1-4 alkoxy; C.sub.1-4 alkoxycarbonyl;
amino on which one or two hydrogen atoms are optionally substituted
by C.sub.1-4 alkyl optionally substituted by hydroxyl or C.sub.1-4
alkoxy; group R.sup.12R.sup.13N--C(.dbd.O)--O-- wherein R.sup.12
and R.sup.13, which may be the same or different, represent a
hydrogen atom or C.sub.1-4 alkyl which alkyl is optionally
substituted by hydroxyl or C.sub.1-4 alkoxy; or group
R.sup.14--(S)m- wherein R.sup.14 represents a saturated or
unsaturated three- to seven-membered carbocyclic or heterocyclic
group optionally substituted by C.sub.1-4 alkyl; R.sup.4 represents
a hydrogen atom; R.sup.5, R.sup.6, R.sup.7, and R.sup.8, which may
be the same or different, represent a hydrogen atom, a halogen
atom, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
nitro, or amino, provided that R.sup.5, R.sup.6, R.sup.7, and
R.sup.8 do not simultaneously represent a hydrogen atom; R.sup.9
and R.sup.10, which may be the same or different, represent a
hydrogen atom, C.sub.1-6 alkyl, or C.sub.1-4 alkylcarbonyl, the
alkyl portion of which C.sub.1-6 alkyl or C.sub.1-4 alkylcarbonyl
is optionally substituted by a halogen atom; C.sub.1-4 alkoxy;
amino which is optionally substituted by C.sub.1-4 alkyl optionally
substituted by C.sub.1-4 alkoxy; or a saturated or unsaturated
three- to seven-membered carbocyclic or heterocyclic group; and
R.sup.11 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-6 alkoxy), or R.sup.15--(CH.sub.2)n- wherein n is an
integer of 0 to 4 and R.sup.15 represents a saturated or
unsaturated three- to seven-membered carbocyclic or heterocyclic
group which is optionally substituted by a halogen atom, C.sub.1-6
alkyl, or C.sub.1-6 alkoxy and is optionally condensed with other
saturated or unsaturated three- to seven-membered carbocyclic ring
or heterocyclic ring to form a bicyclic ring.
54. The compound according to claim 53, wherein R.sup.1, R.sup.9,
and R.sup.10 represent a hydrogen atom.
55. The compound according to claim 53, wherein R.sup.1 represents
a hydrogen atom and one of or both R.sup.9 and R.sup.10 represent a
group other than a hydrogen atom.
56. The compound according to claim 53, wherein X represents N or
CH and Z represents CH.
57. A compound represented by formula (Ia) or a pharmaceutically
acceptable salt or solvate thereof: ##STR257## wherein X represents
CH or N; wherein one of R.sup.21 and R.sup.22, represents
unsubstituted C.sub.1-6 alkoxy and the other represents a group
R.sup.31--(CH.sub.2)p-O-- wherein R.sup.31 represents a halogen
atom, hydroxyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, amino
on which one or two hydrogen atoms are optionally substituted by
C.sub.1-4 alkyl optionally substituted by hydroxyl or C.sub.1-4
alkoxy, group R.sup.12R.sup.13N--C(.dbd.O)--O-- wherein R.sup.12
and R.sup.13, which may be the same or different, represent a
hydrogen atom or C.sub.1-4 alkyl which alkyl is optionally
substituted by hydroxyl or C.sub.1-4 alkoxy, or group
R.sup.14--(S)m- wherein R.sup.14 represents a saturated or
unsaturated three- to seven-membered carbocyclic or heterocyclic
group optionally substituted by C.sub.1-4 alkyl and m is 0 or 1;
and p is an integer of 1 to 6; R.sup.23, R.sup.24, R.sup.21, and
R.sup.26, which may be the same or different, represent a hydrogen
atom, a halogen atom, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, nitro, or amino, provided that R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 do not simultaneously represent a hydrogen
atom; R.sup.27 and R.sup.28, which may be the same or different,
represent a hydrogen atom, C.sub.1-6 alkyl, or C.sub.1-4
alkylcarbonyl, the alkyl portion of which C.sub.1-6 alkyl or
C.sub.1-4 alkylcarbonyl is optionally substituted by a halogen
atom; C.sub.1-4 alkoxy; amino which is optionally substituted by
C.sub.1-4 alkyl optionally substituted by C.sub.1-4 alkoxy; or a
saturated or unsaturated three- to seven-membered carbocyclic or
heterocyclic group; and R.sup.29 represents C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl (which C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl each are optionally
substituted by a halogen atom or C.sub.1-4 alkoxy), or
R.sup.32--(CH.sub.2)q- wherein q is an integer of 0 to 4 and
R.sup.32 represents a saturated or unsaturated six-membered
carbocyclic or heterocyclic group which is optionally substituted
by a halogen atom, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy and is
optionally condensed with other saturated or unsaturated five- or
six-membered carbocyclic ring or heterocyclic ring to form a
bicyclic ring.
58. The compound according to claim 57, wherein one of R.sup.21 and
R.sup.21 represents unsubstituted C.sub.1-4 alkoxy and the other
represents group R.sup.31--(CH.sub.2)p-O--.
59. The compound according to claim 57, wherein at least one of
R.sup.23, R.sup.24, R.sup.25, and R.sup.26 represents a halogen
atom.
60. The compound according to claim 57, wherein at least one of
R.sup.23, R.sup.24, R.sup.25, and R.sup.26 represents a chlorine
atom or a fluorine atom.
61. The compound according to claim 57, wherein at least one of
R.sup.23, R.sup.24, R.sup.25, and R.sup.26 represents C.sub.1-4
alkyl.
62. The compound according to claim 57, wherein two of R.sup.23,
R.sup.24, R.sup.25, and R.sup.26 represent methyl and the remaining
two represent a hydrogen atom.
63. The compound according to claim 57, wherein at least one of
R.sup.23, R.sup.24, R.sup.25, and R.sup.26 represents nitro, amino,
C.sub.1-4 alkoxy, or C.sub.1-4 alkylthio.
64. The compound according to claim 57, wherein R.sup.23, R.sup.25,
and R.sup.26 represent a hydrogen atom and R.sup.24 represents a
halogen atom, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, nitro, or
amino.
65. The compound according to claim 57, wherein both R.sup.27 and
R.sup.28 represent a hydrogen atom.
66. The compound according to claim 57, wherein any one of or both
R.sup.27 and R.sup.28 represent a group other than a hydrogen
atom.
67. The compound according to claim 57, wherein X represents CH or
N; one of R.sup.21 and R.sup.22 represents unsubstituted C.sub.1-4
alkoxy and the other represents group R.sup.31--(CH.sub.2)p-O--;
R.sup.23, R.sup.25, and R.sup.26 represent a hydrogen atom;
R.sup.24 represents a halogen atom, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, or nitro; R.sup.27 and R.sup.28 represent a hydrogen atom;
and R.sup.29 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-4 alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an
integer of 0 or 1 and R.sup.32 represents phenyl, pyridyl, or
naphthyl which phenyl, pyridyl, and naphthyl are optionally
substituted by a halogen atom, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy.
68. The compound according to claim 67, wherein R.sup.21 represents
unsubstituted C.sub.1-4 alkoxy and R.sup.22 represents group
R.sup.31--(CH.sub.2)p-O--.
69. The compound according to claim 67, wherein R.sup.31 represents
hydroxyl, amino on which one or two hydrogen atoms are optionally
substituted by C.sub.1-4 alkyl optionally substituted by hydroxyl,
or group R.sup.14--(S)m- wherein R.sup.14 represents a saturated or
unsaturated five-membered heterocyclic group containing 1 to 4
nitrogen atoms and optionally substituted by C.sub.1-4 alkyl, or a
saturated or unsaturated six-membered heterocyclic group containing
one or two hetero-atoms selected from nitrogen and oxygen atoms and
optionally substituted by C.sub.1-4 alkyl and m is 0 (zero); and p
is an integer of 1 to 4.
70. The compound according to claim 67, wherein p is 1.
71. The compound according to claim 67, wherein R.sup.31 represents
group R.sup.14--(S)m- wherein R.sup.14 represents an unsaturated
six-membered heterocyclic group containing one or two nitrogen
atoms and optionally substituted by C.sub.1-4 alkyl and m is 0
(zero).
72. The compound according to claim 71, wherein R.sup.14 represents
optionally substituted pyridyl.
73. The compound according to claim 57, wherein X represents CH or
N; one of R.sup.21 and R.sup.22 represents unsubstituted C.sub.1-4
alkoxy and the other represents group R.sup.31--(CH.sub.2)p-O--;
R.sup.23, R.sup.25, and R.sup.26 represent a hydrogen atom;
R.sup.24 represents a halogen atom, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, or nitro; any one of or both R.sup.27 and R.sup.28
represent a group other than a hydrogen atom; and R.sup.29
represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl
(which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
each are optionally substituted by a halogen atom or C.sub.1-4
alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an integer of 0 or
1 and R.sup.32 represents phenyl, pyridyl, or naphthyl which
phenyl, pyridyl, and naphthyl are optionally substituted by a
halogen atom, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy.
74. The compound according to claim 73, wherein R.sup.21 represents
unsubstituted C.sub.1-4 alkoxy and R.sup.22 represents group
R.sup.31--(CH.sub.2)p-O--.
75. The compound according to claim 73, wherein R.sup.31 represents
hydroxyl, amino on which one or two hydrogen atoms are optionally
substituted by C.sub.1-4 alkyl optionally substituted by hydroxyl,
or group R.sup.14--(S)m- wherein R.sup.14 represents a saturated or
unsaturated five-membered heterocyclic group containing 1 to 4
nitrogen atoms and optionally substituted by C.sub.1-4 alkyl, or a
saturated or unsaturated six-membered heterocyclic group containing
one or two hetero-atoms selected from nitrogen and oxygen atoms and
optionally substituted by C.sub.1-4 alkyl and m is 0 (zero); and p
is an integer of 1 to 4.
76. The compound according to claim 73, wherein p is 1.
77. The compound according to claim 73, wherein R.sup.31 represents
group R.sup.14--(S)m- wherein R.sup.14 represents an unsaturated
six-membered heterocyclic group containing one or two nitrogen
atoms and optionally substituted by C.sub.1-4 alkyl and m is 0
(zero).
78. The compound according to claim 77, wherein R.sup.14 represents
optionally substituted pyridyl.
79. The compound according to claim 57, wherein X represents CH or
N; one of R.sup.21 and R.sup.22 represents unsubstituted C.sub.1-4
alkoxy and the other represents group R.sup.31--(CH.sub.2)p-O--;
R.sup.23, R.sup.25, and R.sup.26 represent a hydrogen atom;
R.sup.24 represents a halogen atom, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, or nitro; R.sup.27 represents a hydrogen atom; R.sup.28
represents a group other than a hydrogen atom; and R.sup.29
represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl
(which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
each are optionally substituted by a halogen atom or C.sub.1-4
alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an integer of 0 or
1 and R.sup.32 represents phenyl, pyridyl, or naphthyl which
phenyl, pyridyl, and naphthyl are optionally substituted by a
halogen atom, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy.
80. The compound according to claim 79, wherein R.sup.21 represents
unsubstituted C.sub.1-4 alkoxy and R.sup.22 represents group
R.sup.31--(CH.sub.2)p-O--.
81. The compound according to claim 79, wherein R.sup.31 represents
hydroxyl, amino on which one or two hydrogen atoms are optionally
substituted by C.sub.1-4 alkyl optionally substituted by hydroxyl,
or group R.sup.14--(S)m- wherein R.sup.14 represents a saturated or
unsaturated five-membered heterocyclic group containing 1 to 4
nitrogen atoms and optionally substituted by C.sub.1-4 alkyl, or a
saturated or unsaturated six-membered heterocyclic group containing
one or two hetero-atoms selected from nitrogen and oxygen atoms and
optionally substituted by C.sub.1-4 alkyl and m is 0 (zero); and p
is an integer of 1 to 4.
82. The compound according to claim 79, wherein p is 1.
83. The compound according to claim 79, wherein R.sup.31 represents
group R.sup.14--(S)m- wherein R.sup.14 represents an unsaturated
six-membered heterocyclic group containing one or two nitrogen
atoms and optionally substituted by C.sub.1-4 alkyl and m is 0
(zero).
84. The compound according to claim 83, wherein R.sup.14 represents
optionally substituted pyridyl.
85. The compound according to claim 57, wherein X represents CH or
N; one of R.sup.21 and R.sup.22 represents unsubstituted C.sub.1-4
alkoxy and the other represents group R.sup.31--(CH.sub.2)p-O--;
R.sup.23 and R.sup.26 represent a hydrogen atom; R.sup.24 and
R.sup.25 represent a halogen atom, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, or nitro; R.sup.27 and R.sup.28 represent a hydrogen atom;
R.sup.29 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-4 alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an
integer of 0 or 1 and R.sup.32 represents phenyl, pyridyl, or
naphthyl which phenyl, pyridyl, and naphthyl are optionally
substituted by a halogen atom, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy.
86. The compound according to claim 85, wherein R.sup.21 represents
unsubstituted C.sub.1-4 alkoxy and R.sup.22 represents group
R.sup.31--(CH.sub.2)p-O--.
87. The compound according to claim 85, wherein R.sup.31 represents
hydroxyl, amino on which one or two hydrogen atoms are optionally
substituted by C.sub.1-4 alkyl optionally substituted by hydroxyl,
or group R.sup.14--(S)m- wherein R.sup.14 represents a saturated or
unsaturated five-membered heterocyclic group containing 1 to 4
nitrogen atoms and optionally substituted by C.sub.1-4 alkyl, or a
saturated or unsaturated six-membered heterocyclic group containing
one or two hetero-atoms selected from nitrogen and oxygen atoms and
optionally substituted by C.sub.1-4 alkyl and m is 0 (zero); and p
is an integer of 1 to 4.
88. The compound according to claim 85, wherein p is 1.
89. The compound according to claim 85, wherein R.sup.31 represents
group R.sup.14--(S)m- wherein R.sup.14 represents an unsaturated
six-membered heterocyclic group containing one or two nitrogen
atoms and optionally substituted by C.sub.1-4 alkyl and m is 0
(zero).
90. The compound according to claim 89, wherein R.sup.14 represents
optionally substituted pyridyl.
91. The compound according to claim 57, which is a compound
selected from the group consisting of the following compounds, or a
pharmaceutically acceptable salt or solvate thereof: (51)
N-(2-chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinolyl]oxy}phenyl)--
N'-(2,4-difluorophenyl)urea; (119)
N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-propylurea; (135)
N-(2-chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-propylurea; (142)
N-(2-chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'-
-propylurea; (143)
N-(2-chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'-
-propylurea; (144)
N-(2-chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinolyl]oxy}phenyl)--
N'-propylurea; (145)
N-[2-chloro-4-{(6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinolyl}-
oxy)phenyl]-N'-propylurea; (146)
N-[2-chloro-4-(7-{[2-(1H-1-imidazolyl)-ethoxy]-6-methoxy-4-quinolyl}oxy)p-
henyl]-N'-propylurea; (148)
N-[2-chloro-4-(6-methoxy-7-{[2-(4-methyl-piperazino)ethoxy]-4-quinolyl}ox-
y)phenyl]-N'-propylurea; (149)
N-(2-chloro-4-{[7-(2-hydroxyethoxy)-6-methoxy-4-quinolyl]oxy}phenyl)-N'-p-
ropylurea; (151)
N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinolyl]oxy}phenyl)-
-N'-propylurea; (152)
N-[2-chloro-4-(6-methoxy-7-{[3-(4-methyl-piperazino)propoxy]-4-quinolyl}o-
xy)phenyl]-N'-propylurea; (153)
N-[2-chloro-4-(6-methoxy-7-{[3-(1H-1,2,3-triazol-1-yl)propoxy]-4-quinolyl-
}oxy)phenyl]-N'-propylurea; (157)
N-{2-chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]propoxy}-6-methoxy-4-
-quinolyl)oxy]-phenyl}-N'-propylurea; (159)
N-{2-chloro-4-[(6-methoxy-7-{[5-(1H-1,2,3-triazol-1-yl)pentyl]oxy}-4-quin-
olyl)oxy]phenyl}-N'-propylurea; (160)
N-[2-chloro-4-(7-{[4-(1H-1-imidazolyl)-butoxy]-6-methoxy-4-quinolyl}oxy)p-
henyl]-N'-propylurea; (162)
N-(2-chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-(2,4-difluoro-phenyl)urea; (163)
N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-(2,4-difluoro-phenyl)urea; (164)
N-[2-chloro-4-(6-methoxy-7-{[3-(4-methyl-piperazino)propoxy]-4-quinazolin-
yl}oxy)phenyl]-N'-(2,4-difluorophenyl)urea; (165)
N-{2-chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]propoxy}-6-methoxy-4-
-quinazolinyl)oxy]-phenyl}-N'-(2,4-difluorophenyl)urea; (168)
N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinolyl]oxy}phenyl)-
-N'-(2,4-difluorophenyl)-urea; (169)
N-(2-chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'-
-(2,4-difluorophenyl)-urea; (170)
N-[2-chloro-4-(6-methoxy-7-{[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinolyl}-
oxy)phenyl]-N'-(2,4-difluorophenyl)urea; (184)
N-(2-chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-methylurea; (185)
N-(2-chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-ethylurea; and (186)
N-(2-chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'-
-(2,4-difluorophenyl)-urea.
92. A pharmaceutical composition comprising as active ingredient a
compound according to claim 53 or a pharmaceutically acceptable
salt or solvate thereof.
93. A method for treating a disease selected from the group
consisting of diabetic retinopathy, chronic rheumatism, psoriasis,
and atherosclerosis, comprising: administering, to a subject in
need thereof, an effective amount of a compound according to claim
53 or a pharmaceutically acceptable salt or solvate thereof.
94. A method for treating human glioma, comprising: administering,
to a subject in need thereof, an effective amount of a compound
according to claim 53 or a pharmaceutically acceptable salt or
solvate thereof.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to quinoline derivatives and
quinazoline derivatives having antitumor activity. More
particularly, the present invention relates to quinoline
derivatives and quinazoline derivatives that are useful for the
treatment of diseases such as tumor, diabetic retinopathy, chronic
rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma.
[0003] 2. Background Art
[0004] WO 97/17329 describes quinoline derivatives and quinazoline
derivatives having antitumor activity. WO 97/17329, however,
discloses neither the effects of these quinoline derivatives and
quinazoline derivatives on cytomorphosis nor the compounds
according to the present invention.
SUMMARY OF THE INVENTION
[0005] The present inventors have found that a group of quinoline
derivatives and quinazoline derivatives has antitumor activity and,
at the same time, has no significant effect on cytomorphosis. The
activity of increasing the cell size may be regarded as activity of
inducing tissue disorders.
[0006] An object of the present invention is to provide compounds
which have antitumor activity and, at the same time, have no
significant effect on cytomorphosis.
[0007] According to the present invention, there is provided a
compound represented by formula (I) or a pharmaceutically
acceptable salt or solvate thereof: ##STR2## wherein
[0008] X and Z each represent CH or N;
[0009] R.sup.1, R.sup.2, and R.sup.3, which may be the same or
different, represent a hydrogen atom, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, nitro, or amino,
which C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl are optionally substituted by a halogen atom;
hydroxyl; C.sub.1-4 alkoxy; C.sub.1-4 alkoxycarbonyl; amino on
which one or two hydrogen atoms are optionally substituted by
C.sub.1-4 alkyl optionally substituted by hydroxyl or C.sub.1-4
alkoxy; group R.sup.12R.sup.13N--C(.dbd.O)--O-- wherein R.sup.12
and R.sup.13, which may be the same or different, represent a
hydrogen atom or C.sub.1-4 alkyl which alkyl is optionally
substituted by hydroxyl or C.sub.1-4 alkoxy; or group
R.sup.14--(S)m- wherein R.sup.14 represents a saturated or
unsaturated three- to seven-membered carbocyclic or heterocyclic
group optionally substituted by C.sub.1-4 alkyl and m is 0 or
1;
[0010] R.sup.4 represents a hydrogen atom;
[0011] R.sup.5, R.sup.6, R.sup.7, and R.sup.8, which may be the
same or different, represent a hydrogen atom, a halogen atom;
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, nitro, or
amino, provided that R.sup.5, R.sup.6, R.sup.7, and R.sup.8 do not
simultaneously represent a hydrogen atom;
[0012] R.sup.9 and R.sup.10, which may be the same or different,
represent a hydrogen atom, C.sub.1-6 alkyl, or C.sub.1-4
alkylcarbonyl, the alkyl portion of which C.sub.1-6 alkyl or
C.sub.1-4 alkylcarbonyl is optionally substituted by a halogen
atom; C.sub.1-4 alkoxy; amino which is optionally substituted by
C.sub.1-4 alkyl optionally substituted by C.sub.1-4 alkoxy; or a
saturated or unsaturated three- to seven-membered carbocyclic or
heterocyclic group; and
[0013] R.sup.11 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-6 alkoxy), or R.sup.15--(CH.sub.2)n- wherein n is an
integer of 0 to 4 and R.sup.15 represents a saturated or
unsaturated three- to seven-membered carbocyclic or heterocyclic
group which is optionally substituted by a halogen atom, C.sub.1-6
alkyl, or C.sub.1-6 alkoxy and is optionally condensed with other
saturated or unsaturated three- to seven-membered carbocyclic ring
or heterocyclic ring to form a bicyclic ring.
[0014] The compound according to the present invention is useful,
for example, for the treatment of tumor, diabetic retinopathy,
chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma,
and solid tumor.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Compound
[0016] As used herein, the term "C.sub.1-6 alkyl" and "C.sub.1-6
alkoxy" as a group or a part of a group respectively mean straight
chain or branched chain alkyl and alkoxy having 1 to 6, preferably
1 to 4 carbon atoms.
[0017] As used herein, the term "C.sub.2-6 alkenyl" and "C.sub.2-6
alkynyl" as a group or a part of a group respectively mean straight
chain or branched chain alkenyl and alkynyl having 2 to 6,
preferably 2 to 4 carbon atoms.
[0018] Examples of C.sub.1-6 alkyl include methyl, ethyl, n-propyl,
isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and
n-hexyl.
[0019] Examples of C.sub.1-6 alkoxy include methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and
t-butoxy.
[0020] Examples of C.sub.2-6 alkenyl include allyl, butenyl,
pentenyl, and hexenyl.
[0021] Examples of C.sub.2-6 alkynyl include 2-propynyl, butynyl,
pentynyl, and hexynyl.
[0022] The term "halogen atom" means a fluorine, chlorine, bromine,
or iodine atom.
[0023] The saturated or unsaturated three- to seven-membered
carbocyclic or heterocyclic ring is preferably five- to
seven-membered, more preferably five- or six-membered, saturated or
unsaturated carbocyclic or heterocyclic ring.
[0024] Examples of saturated or unsaturated three- to
seven-membered carbocyclic groups include phenyl, cycloheptyl,
cyclohexyl, and cyclopentyl.
[0025] The saturated or unsaturated three- to seven-membered
heterocyclic ring contains at least one hetero-atom selected from
oxygen, nitrogen, and sulfur atoms. The term "hetero-atom" used
herein means an oxygen, nitrogen, or sulfur atom. Examples of
saturated or unsaturated three- to seven-membered heterocyclic
groups include pyridyl, piperidino, piperazino, morpholino,
imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl,
pyrrolidinyl, and pyrazolyl.
[0026] The saturated or unsaturated heterocyclic group, which may
be represented by R.sup.15 and R.sup.32, may be condensed with
other saturated or unsaturated heterocyclic ring to form a bicyclic
ring. Such condensed cyclic groups include naphthyl, indanyl,
quinolyl, and quinazolinyl.
[0027] R.sup.1 preferably represents a hydrogen atom.
[0028] R.sup.2 and R.sup.3 preferably represents optionally
substituted C.sub.1-6 alkoxy.
[0029] C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl, which may be represented by R.sup.1, R.sup.2,
and R.sup.3, may be substituted by group R.sup.14--(S)m-.
[0030] The carbocyclic or heterocyclic group, which may be
represented by R.sup.14, preferably represents a saturated or
unsaturated five- or six-membered carbocyclic or heterocyclic
group. The carbocyclic group more preferably represents phenyl. The
heterocyclic group more preferably represents a saturated or
unsaturated five-membered heterocyclic group containing one to four
nitrogen atoms or a saturated or unsaturated six-membered
heterocyclic group (preferably pyridyl) containing one or two
hetero-atoms selected from nitrogen and oxygen atoms. More
specifically, the hetero-atom constituting the six-membered
heterocyclic group may be one nitrogen atom and one oxygen atom, or
one or two nitrogen atoms.
[0031] When m is 0 (zero), --(S)m- represents a bond.
[0032] The substituted C.sub.1-6 alkoxy group, which may be
represented by R.sup.1, R.sup.2, and R.sup.3, preferably represents
group R.sup.31--(CH.sub.2)p-O-- wherein R.sup.31 represents a
halogen atom, hydroxyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
amino on which one or two hydrogen atoms each are optionally
substituted by C.sub.1-4 alkyl optionally substituted by hydroxyl
or C.sub.1-4 alkoxy, group R.sup.12R.sup.13N--C(.dbd.O)--O--
wherein R.sup.12 and R.sup.13 are as defined in formula (I), or
group R.sup.14--(S)m- wherein R.sup.14 may be as defined in formula
(I); p is an integer of 1 to 6, preferably 1 to 4, more preferably
1 or 2, particularly preferably 1.
[0033] A group of preferred compounds represented by formula (I)
include:
[0034] compounds wherein R.sup.1 represents a hydrogen atom and
R.sup.2 and R.sup.3 represent unsubstituted C.sub.1-4 alkoxy,
preferably methoxy;
[0035] compounds wherein R.sup.1 represents a hydrogen atom,
R.sup.2 represents substituted C.sub.1-4 alkoxy, preferably group
R.sup.31--(CH.sub.2)p-O--, and R.sup.3 represents unsubstituted
C.sub.1-4 alkoxy, preferably methoxy; and
[0036] compounds wherein R.sup.1 represents a hydrogen atom,
R.sup.2 represents unsubstituted C.sub.1-4 alkoxy, preferably
methoxy, and R.sup.3 represents substituted C.sub.1-4 alkoxy,
preferably group R.sup.31--(CH.sub.2)p-O--.
[0037] Another group of preferred compounds represented by formula
(I) include:
[0038] compounds wherein at least one of R.sup.5, R.sup.6, R.sup.7,
and R.sup.8 represents a halogen atom, preferably a chlorine atom
or a fluorine atom;
[0039] compounds wherein at least one of R.sup.5, R.sup.6, R.sup.7,
and R.sup.8 represents C.sub.1-4 alkyl;
[0040] compounds wherein two of R.sup.5, R.sup.6, R.sup.7, and
R.sup.8 represent methyl and the remaining two represent a hydrogen
atom;
[0041] compounds wherein at least one of R.sup.5, R.sup.6, R.sup.7,
and R.sup.8 represents nitro, amino, C.sub.1-4 alkoxy, or C.sub.1-4
alkylthio;
[0042] compounds wherein R.sup.5, R.sup.7, and R.sup.8 represent a
hydrogen atom and R.sup.6 represents a halogen atom, more
preferably a chlorine atom or a fluorine atom;
[0043] compounds wherein R.sup.5 and R.sup.6 represent C.sub.1-4
alkyl, more preferably methyl, and R.sup.7 and R.sup.8 represent a
hydrogen atom;
[0044] compounds wherein R.sup.5 and R.sup.8 represent a hydrogen
atom and R.sup.6 and R.sup.7 represent C.sub.1-4 alkyl, more
preferably methyl; and
[0045] compounds wherein R.sup.5, R.sup.7, and R.sup.8 represent a
hydrogen atom and R.sup.6 represents C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 alkylthio, nitro, or amino.
[0046] In R.sup.9 and R.sup.10, the saturated or unsaturated three-
to seven-membered carbocyclic or heterocyclic group as the
substituent preferably represents a saturated or unsaturated five-
or six-membered carbocyclic or heterocyclic group.
[0047] R.sup.9 and R.sup.10 preferably represent a hydrogen atom,
methyl, ethyl, propyl, methoxymethyl, formyl, acetyl, benzyl, or
phenetyl.
[0048] Still another group of preferred compounds represented by
formula (I) include:
[0049] compounds wherein R.sup.1, R.sup.9, and R.sup.10 represent a
hydrogen atom; and
[0050] compounds wherein R.sup.1 represents a hydrogen atom and any
one of or both R.sup.9 and R.sup.10 represent a group other than a
hydrogen atom.
[0051] In group R.sup.15--(CH.sub.2)n- which may be represented by
R.sup.11, n is preferably an integer of 0 to 2, more preferably 0
or 1. Preferred examples of R.sup.15 include an optionally
substituted saturated or unsaturated six-membered carbocyclic
group, more preferably phenyl, and an optionally substituted
saturated or unsaturated six-membered heterocyclic group, more
preferably pyridyl.
[0052] The hetero-atom(s) constituting the six-membered
heterocyclic group may more specifically consist of one nitrogen
atom or one nitrogen atom and one oxygen atom.
[0053] A further group of preferred compounds represented by
formula (I) include compounds wherein X represents N or CH and Z
represents CH.
[0054] A still further group of preferred compounds represented by
formula (I) include compounds represented by formula (Ia): ##STR3##
wherein
[0055] X represents CH or N;
[0056] R.sup.21 and R.sup.22, which may be the same or different,
represent unsubstituted C.sub.1-6 alkoxy or group
R.sup.31--(CH.sub.2)p-O-- wherein R.sup.31 represents a halogen
atom, hydroxyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, amino
on which one or two hydrogen atoms are optionally substituted by
C.sub.1-4 alkyl optionally substituted by hydroxyl or C.sub.1-4
alkoxy, group R.sup.12R.sup.13N--C(.dbd.O)--O-- wherein R.sup.12
and R.sup.13, which may be the same or different, represent a
hydrogen atom or C.sub.1-4 alkyl which alkyl is optionally
substituted by hydroxyl or C.sub.1-4 alkoxy, or group
R.sup.14--(S)m- wherein R.sup.14 represents a saturated or
unsaturated three- to seven-membered carbocyclic or heterocyclic
group optionally substituted by C.sub.1-4 alkyl and m is 0 or 1;
and p is an integer of 1 to 6;
[0057] R.sup.23, R.sup.24, R.sup.25, and R.sup.26, which may be the
same or different, represent a hydrogen atom, a halogen atom,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, nitro, or
amino, provided that R.sup.23, R.sup.24, R.sup.25, and R.sup.26 do
not simultaneously represent a hydrogen atom;
[0058] R.sup.27 and R.sup.2, which may be the same or different,
represent a hydrogen atom, C.sub.1-6 alkyl, or C.sub.1-4
alkylcarbonyl, the alkyl portion of which C.sub.1-6 alkyl or
C.sub.1-4 alkylcarbonyl is optionally substituted by a halogen
atom; C.sub.1-4 alkoxy; amino which is optionally substituted by
C.sub.1-4 alkyl optionally substituted by C.sub.1-4 alkoxy; or a
saturated or unsaturated three- to seven-membered carbocyclic or
heterocyclic group; and
[0059] R.sup.29 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-4 alkoxy), or R.sup.32--(CH.sub.2)q- wherein q is an
integer of 0 to 4 and R.sup.32 represents a saturated or
unsaturated six-membered carbocyclic or heterocyclic group which is
optionally substituted by a halogen atom, C.sub.1-4 alkyl, or
C.sub.1-4 alkoxy and is optionally condensed with other saturated
or unsaturated five- or six-membered carbocyclic ring or
heterocyclic ring to form a bicyclic ring.
[0060] R.sup.21 and R.sup.22 may represent unsubstituted C.sub.1-6
alkoxy, preferably methoxy.
[0061] Any one of R.sup.21 and R.sup.22 may represent unsubstituted
C.sub.1-6 alkoxy, preferably methoxy and the other represents group
R.sup.32--(CH.sub.2)p-O--.
[0062] In group R.sup.31--(CH.sub.2)p-O--, p is preferably 1 to 4,
more preferably 1 or 2, particularly preferably 1.
[0063] A group of preferred compounds represented by formula (Ia)
include:
[0064] compounds wherein at least one of R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 represents a halogen atom, preferably a
chlorine atom or a fluorine atom;
[0065] compounds wherein at least one of R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 represents C.sub.1-4 alkyl;
[0066] compounds wherein two of R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 represent methyl and the remaining two represent a
hydrogen atom;
[0067] compounds wherein at least one of R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 represents nitro, amino, C.sub.1-4 alkoxy,
or C.sub.1-4 alkylthio;
[0068] compounds wherein R.sup.23, R.sup.25, and R.sup.26 represent
a hydrogen atom and R.sup.24 represents a halogen atom, more
preferably a chlorine atom or a fluorine atom;
[0069] compounds wherein R.sup.23 and R.sup.24 represent C.sub.1-4
alkyl, more preferably methyl and R.sup.25 and R.sup.26 represent a
hydrogen atom;
[0070] compounds wherein R.sup.23 and R.sup.26 represent a hydrogen
atom and R.sup.24 and R.sup.25 represent C.sub.1-4 alkyl, more
preferably methyl; and
[0071] compounds wherein R.sup.23, R.sup.25, and R.sup.25 represent
a hydrogen atom and R.sup.24 represents C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 alkylthio, nitro, or amino.
[0072] Another group of preferred compounds represented by formula
(Ia) include compounds wherein R.sup.27 and R.sup.28 represent a
hydrogen atom.
[0073] Still another group of preferred compounds represented by
formula (Ia) include compounds wherein any one of or both R.sup.27
and R.sup.28 represent a group other than a hydrogen atom.
[0074] In R.sup.32--(CH.sub.2)q- which may be represented by
R.sup.29, q is preferably an integer of 0 to 2, more preferably 0
or 1. Examples of preferred R.sup.32 include optionally substituted
phenyl and an optionally substituted saturated or unsaturated
six-membered heterocyclic group, more preferably pyridyl. The
hetero-atom(s) constituting the six-membered heterocyclic group may
more specifically consist of one nitrogen atom or one nitrogen atom
and one oxygen atom. The saturated or unsaturated six-membered
carbocyclic group or heterocyclic group, which may be represented
by R.sup.32, is preferably condensed with other saturated or
unsaturated six-membered carbocyclic ring or heterocyclic ring to
form a bicyclic ring.
[0075] A still further group of preferred compounds represented by
formula (Ia) include:
[0076] compounds wherein
[0077] X represents CH or N,
[0078] R.sup.21 and R.sup.22 represent unsubstituted C.sub.1-4
alkoxy,
[0079] R.sup.23, R.sup.25, and R.sup.26 represent a hydrogen
atom,
[0080] R.sup.24 represents a halogen atom, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, or nitro,
[0081] R.sup.27 and R.sup.28 represent a hydrogen atom, and
[0082] R.sup.29 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-4 alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an
integer of 0 or 1 and R.sup.32 represents phenyl, pyridyl, or
naphthyl which phenyl, pyridyl, and naphthyl are optionally
substituted by a halogen atom, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy;
[0083] compounds wherein
[0084] X represents CH or N,
[0085] R.sup.21 and R.sup.22 represent unsubstituted C.sub.1-4
alkoxy,
[0086] R.sup.23, R.sup.25, and R.sup.26 represent a hydrogen
atom,
[0087] R.sup.24 represents a halogen atom, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, or nitro,
[0088] any one of or both R.sup.27 and R.sup.28 represent a group
other than a hydrogen atom, and
[0089] R.sup.29 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-4 alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an
integer of 0 or 1 and R.sup.12 represents phenyl, pyridyl, or
naphthyl which phenyl, pyridyl, and naphthyl are optionally
substituted by a halogen atom, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy;
[0090] compounds wherein
[0091] X represents CH or N,
[0092] R.sup.21 and R.sup.22 represent unsubstituted C.sub.1-4
alkoxy,
[0093] R.sup.23, R.sup.25, and R.sup.26 represent a hydrogen
atom,
[0094] R.sup.24 represents a halogen atom, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, or nitro,
[0095] R.sup.27 represents a hydrogen atom,
[0096] R.sup.28 represents a group other than a hydrogen atom,
and
[0097] R.sup.29 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-4 alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an
integer of 0 or 1 and R.sup.12 represents phenyl, pyridyl, or
naphthyl which phenyl, pyridyl, and naphthyl are optionally
substituted by a halogen atom, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy;
[0098] compounds wherein
[0099] X represents CH or N,
[0100] any one of R.sup.21 and R.sup.22 represents unsubstituted
C.sub.1-4 alkoxy and the other represents group
R.sup.32--(CH.sub.2)p-O--, preferably R.sup.21 represents
unsubstituted C.sub.1-4 alkoxy and R.sup.22 represents group
R.sup.31--(CH.sub.2)p-O--
[0101] R.sup.23, R.sup.25, and R.sup.26 represent a hydrogen
atom,
[0102] R.sup.24 represents a halogen atom, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, or nitro,
[0103] R.sup.27 and R.sup.28 represent a hydrogen atom, and
[0104] R.sup.29 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-4 alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an
integer of 0 or 1 and R.sup.32 represents phenyl, pyridyl, or
naphthyl which phenyl, pyridyl, and naphthyl are optionally
substituted by a halogen atom, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy;
[0105] compounds wherein
[0106] X represents CH or N,
[0107] any one of R.sup.21 and R.sup.22 represents unsubstituted
C.sub.1-4 alkoxy and the other represents group
R.sup.31--(CH.sub.2)p-O--, preferably R.sup.21 represents
unsubstituted C.sub.1-4 alkoxy and R.sup.22 represents group
R.sup.31--(CH.sub.2)p-O--,
[0108] R.sup.23, R.sup.25, and R.sup.26 represent a hydrogen
atom,
[0109] R.sup.24 represents a halogen atom, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, or nitro,
[0110] any one of or both R.sup.27 and R.sup.28 represent a group
other than a hydrogen atom, and
[0111] R.sup.29 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-4 alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an
integer of 0 or 1 and R.sup.32 represents phenyl, pyridyl, or
naphthyl which phenyl, pyridyl, and naphthyl are optionally
substituted by a halogen atom, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy;
[0112] compounds wherein
[0113] X represents CH or N,
[0114] any one of R.sup.21 and R.sup.22 represents unsubstituted
C.sub.1-4 alkoxy and the other represents group
R.sup.31--(CH.sub.2)p-O--, preferably R.sup.21 represents
unsubstituted C.sub.1-4 alkoxy and R.sup.22 represents group
R.sup.31--(CH.sub.2)p-O--,
[0115] R.sup.23, R.sup.25, and R.sup.26 represent a hydrogen
atom,
[0116] R.sup.24 represents a halogen atom, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, or nitro,
[0117] R.sup.27 represents a hydrogen atom,
[0118] R.sup.28 represents a group other than a hydrogen atom,
and
[0119] R.sup.29 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-4 alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an
integer of 0 or 1 and R.sup.32 represents phenyl, pyridyl, or
naphthyl which phenyl, pyridyl, and naphthyl are optionally
substituted by a halogen atom, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy; and
[0120] compounds wherein
[0121] X represents CH or N,
[0122] any one of R.sup.21 and R.sup.22 represents unsubstituted
C.sub.1-4 alkoxy and the other represents group
R.sup.31--(CH.sub.2)p-O--, preferably R.sup.21 represents
unsubstituted C.sub.1-4 alkoxy and R.sup.22 represents group
R.sup.31--(CH.sub.2)p-O--,
[0123] R.sup.23 and R.sup.26 represent a hydrogen atom,
[0124] R.sup.24 and R.sup.25 represent a halogen atom, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, or nitro,
[0125] R.sup.27 and R.sup.28 represent a hydrogen atom, and
[0126] R.sup.29 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl (which C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl each are optionally substituted by a halogen atom
or C.sub.1-4 alkoxy), or --(CH.sub.2)q-R.sup.32 wherein q is an
integer of 0 or 1 and R.sup.32 represents phenyl, pyridyl, or
naphthyl which phenyl, pyridyl, and naphthyl are optionally
substituted by a halogen atom, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy.
[0127] Examples of preferred compounds according to the present
invention include compounds described in Examples 1 to 186.
[0128] Another examples of preferred compounds according to the
present invention include the following compounds: [0129]
N-{2-chloro-4-[(6,7-dimethyl-4-quinazolinyl)oxy]-phenyl}-N'-isobutylurea;
[0130]
N-(4-{[7-(benzyloxy)-6-methoxy-4-quinazolinyl]oxy}-2-chloropheny-
l)-N'-propylurea; [0131]
N-(4-{[6-(benzyloxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N'-pro-
pylurea; [0132]
N-(2-chloro-4-{[7-methoxy-6-(3-morpholinopropoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-propylurea; [0133]
N-[2-chloro-4-({6-methoxy-7-[2-(1H-1-imidazolyl)-ethoxy]-4-quinazolinyl}o-
xy)phenyl]-N'-ethylurea; [0134]
N-[2-chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinazoli-
nyl}oxy)phenyl]-N'-ethylurea; [0135]
N-[2-chloro-4-({6-methoxy-7-[3-(1H-1,2,3-triazol-1-yl)propoxy]-4-quinazol-
inyl}oxy)phenyl]-N'-ethylurea; [0136]
N-[2-chloro-4-({6-methoxy-7-[2-(4-methyl-piperazino)ethoxy]-4-quinazoliny-
l}oxy)phenyl]-N'-ethylurea; [0137]
N-(2-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-quinazolinyl]oxy}pheny-
l)-N'-ethylurea; [0138]
N-(2-chloro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-ethylurea; [0139]
N-[2-chloro-4-({6-methoxy-7-[2-(dimethylamino)-ethoxy]-4-quinazolinyl}oxy-
)phenyl]-N'-ethylurea; [0140]
N-[2-chloro-4-({6-methoxy-7-[2-(1H-1-imidazolyl)-ethoxy]-4-quinazolinyl}o-
xy)phenyl]-N'-propylurea; [0141]
N-[2-chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinazoli-
nyl}oxy)phenyl]-N'-propylurea; [0142]
N-[2-chloro-4-({6-methoxy-7-[3-(1H-1,2,3-triazol-1-yl)propoxy]-4-quinazol-
inyl}oxy)phenyl]-N'-propylurea; [0143]
N-(2-chloro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-propylurea; [0144]
N-[2-chloro-4-({6-methoxy-7-[2-(dimethylamino)-ethoxy]-4-quinazolinyl}oxy-
)phenyl]-N'-propylurea; [0145]
N-[2-chloro-4-({6-methoxy-7-[2-(1H-1-imidazolyl)-ethoxy]-4-quinazolinyl}o-
xy)phenyl]-N'-butylurea; [0146]
N-[2-chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinazoli-
nyl}oxy)phenyl]-N'-butylurea; [0147]
N-[2-chloro-4-({6-methoxy-7-[3-(1H-1,2,3-triazol-1-yl)propoxy]-4-quinazol-
inyl}oxy)phenyl]-N'-butylurea; [0148]
N-[2-chloro-4-({6-methoxy-7-[2-(4-methyl-piperazino)ethoxy]-4-quinazoliny-
l}oxy)phenyl]-N'-butylurea; [0149]
N-(2-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-quinazolinyl]oxy}pheny-
l)-N'-butylurea; [0150]
N-(2-chloro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-butylurea; [0151]
N-[2-chloro-4-({6-methoxy-7-[2-(dimethylamino)-ethoxy]-4-quinazolinyl}oxy-
)phenyl]-N'-butylurea; and [0152]
N-[2-chloro-4-({6-methoxy-7-[2-(dimethylamino)-ethoxy]-4-quinolyl}oxy)phe-
nyl]-N'-propylurea.
[0153] Examples of particularly preferred compounds according to
the present invention include: [0154] (13)
N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]-phenyl}-N'-propylurea;
[0155] (51)
N-(2-chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinolyl]oxy}phenyl)--
N'-(2,4-difluorophenyl) urea; [0156] (62)
N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)-oxy]phenyl}-N'-propylurea;
[0157] (76)
N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)-oxy]phenyl}-N'-ethylurea;
[0158] (117)
N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-methylurea;
[0159] (119)
N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-propylurea; [0160] (135)
N-(2-chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-propylurea; [0161] (142)
N-(2-chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'-
-propylurea; [0162] (143)
N-(2-chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'-
-propylurea; [0163] (144)
N-(2-chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinolyl]oxy}phenyl)--
N'-propylurea; [0164] (145)
N-[2-chloro-4-(6-methoxy-7-{[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinolyl}-
oxy)phenyl]-N'-propylurea; [0165] (146)
N-[2-chloro-4-(7-{[2-(1H-1-imidazolyl)-ethoxy]-6-methoxy-4-quinolyl}oxy)p-
henyl]-N'-propylurea; [0166] (148)
N-[2-chloro-4-(6-methoxy-7-{[2-(4-methyl-piperazino)ethoxy]-4-quinolyl}ox-
y)phenyl]-N'-propylurea; [0167] (149)
N-(2-chloro-4-{[7-(2-hydroxyethoxy)-6-methoxy-4-quinolyl]oxy}phenyl)-N'-p-
ropylurea; [0168] (151)
N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinolyl]oxy}phenyl)-
-N'-propylurea; [0169] (152)
N-[2-chloro-4-(6-methoxy-7-{[3-(4-methyl-piperazino)propoxy]-4-quinolyl}o-
xy)phenyl]-N'-propylurea; [0170] (153)
N-[2-chloro-4-(6-methoxy-7-{[3-(1H-1,2,3-triazol-1-yl)propoxy]-4-quinolyl-
}oxy)phenyl]-N'-propylurea; [0171] (157)
N-{2-chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]propoxy}-6-methoxy-4-
-quinolyl)oxy]-phenyl}-N'-propylurea; [0172] (159)
N-{2-chloro-4-[(6-methoxy-7-{[5-(1H-1,2,3-triazol-1-yl)pentyl]oxy}-4-quin-
olyl)oxy]phenyl}-N'-propylurea; [0173] (160)
N-[2-chloro-4-(7-{[4-(1H-1-imidazolyl)-butoxy]-6-methoxy-4-quinolyl}oxy)p-
henyl]-N'-propylurea; [0174] (162)
N-(2-chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-(2,4-difluoro-phenyl)urea; [0175] (163)
N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-(2,4-difluoro-phenyl)urea; [0176] (164)
N-[2-chloro-4-(6-methoxy-7-{[3-(4-methyl-piperazino)propoxy]-4-quinazolin-
yl}oxy)phenyl]-N'-(2,4-difluorophenyl)urea; [0177] (165)
N-{2-chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]propoxy}-6-methoxy-4-
-quinazolinyl)oxy]-phenyl}-N'-(2,4-difluorophenyl)urea; [0178]
(168)
N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinolyl]oxy}phenyl)-
-N'-(2,4-difluorophenyl)-2-0 urea; [0179] (169)
N-(2-chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'-
-(2,4-difluorophenyl)-urea; [0180] (170)
N-[2-chloro-4-(6-methoxy-7-{[2-(1H-1,2,3
triazol-1-yl)ethoxy]-4-quinolyl}oxy)phenyl]-N'-(2,4-difluorophenyl)urea;
[0181] (184)
N-(2-chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-methylurea; [0182] (185)
N-(2-chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-ethylurea; and [0183] (186)
N-(2-chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'-
-(2,4-difluorophenyl)-urea.
[0184] Examples of more preferred compounds according to the
present invention include the following compounds: [0185] (62)
N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)-oxy]phenyl}-N'-propylurea;
[0186] (142)
N-(2-chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'-
-propylurea; and [0187] (169)
N-(2-chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'-
-(2,4-difluorophenyl)-urea.
[0188] The compounds according to the present invention may form
pharmaceutically acceptable salts thereof. Preferred examples of
such salts include: alkali metal or alkaline earth metal salts such
as sodium salts, potassium salts or calcium salts; hydrohalogenic
acid salts such as hydrofluoride salts, hydrochloride salts,
hydrobromide salts, or hydroiodide salts; inorganic acid salts such
as nitric acid salts, perchloric acid salts, sulfuric acid salts,
or phosphoric acid salts; lower alkylsulfonic acid salts such as
methanesulfonic acid salts, trifluoromethanesulfonic acid salts, or
ethanesulfonic acid salts; arylsulfonic acid salts such as
benzenesulfonic acid salts or p-toluenesulfonic acid salts; organic
acid salts such as fumaric acid salts, succinic acid salts, citric
acid salts, tartaric acid salts, oxalic acid salts, maleic acid
salts, acetic acid salts, malic acid salts, lactic acid salts, or
ascorbic acid salts; and amino acid salts such as glycine salts,
phenylalanine salts, glutamic acid salts, or aspartic acid
salts.
[0189] Further, the compounds according to the present invention
may form solvates (for example, hydrates).
[0190] Production of Compounds
[0191] The compounds according to the present invention may be
produced, for example, according to scheme 1 and scheme 2.
##STR4##
[0192] Starting compounds necessary for the synthesis of the
compounds according to the present invention may be commercially
available, or alternatively may be produced according to a
conventional process. For example, a 4-chloroquinoline derivative
may be synthesized by a conventional process as described in Org.
Synth. Col. Vol. 3, 272 (1955), Acta Chim. Hung., 112, 241 (1983)
or WO 98/47873. A 4-chloroquinazoline derivative may be synthesized
by a conventional process as described in J. Am. Chem. Soc., 68,
1299 (1946) or J. Am. Chem. Soc., 68, 1305 (1946).
[0193] Alternatively, the 4-chloroquinazoline derivative may be
produced by a process which comprises the steps of: (1) first
reacting a benzoic ester with formamide to prepare a quinazolone
derivative (see Production Example 34) and (2) then heating the
4-quinazolone derivative using toluene or sulfolane as a solvent in
the presence of phosphorus oxychloride (see Production Examples 35
and 36). The quinazolone derivative is generally synthesized in the
presence of a benzoic ester, sodium methoxide, formamide, and a
solvent such as DMF or methanol. In the step (1), the reaction
proceeds in a system where only the benzoic ester and formaldehyde
are present. This is advantageous in that the synthesis can be
carried out using a small number of starting compounds. The
4-quinazolone derivative is generally halogenated by heating the
quinazolone derivative and phosphorus oxychloride. In this case, in
many cases, due to high reactivity of the quinazoline derivative,
the influence of the solvent has caused the quinazoline derivative
to be returned to the starting compound and consequently made it
impossible to complete the reaction. In the step (2), the reaction
is completed in the presence of toluene or sulfolane, and, thus,
this is advantageous from the viewpoint of an increase in
yield.
[0194] Next, 4-chloroquinoline derivative or a corresponding
quinazoline derivative is allowed to act n nitrophenol in the
presence of a suitable solvent or in the absence of a solvent to
synthesize a 4-(nitrophenoxy)quinoline derivative or a
corresponding quinazoline derivative which is then stirred in a
suitable solvent, for example, N,N-dimethylformamide, in the
presence of a catalyst, for example, palladium hydroxide-carbon or
palladium-carbon, in a hydrogen atmosphere to give a
4-(aminophenoxy)quinoline derivative or a corresponding quinazoline
derivative. Alternatively, a 4-chloroquinoline derivative or a
corresponding quinazoline derivative may be allowed to act on
aminophenol in the presence of a base, for example, sodium hydride,
to give a 4-(aminophenoxy)quinoline derivative or a corresponding
quinazoline derivative.
[0195] Alternatively, the 4-(aminophenoxy)quinoline derivative or
the corresponding quinazoline derivative may also be produced by
dissolving aminophenol in an aqueous sodium hydroxide solution and
then subjecting the solution to a two-phase reaction with a
solution of a 4-chloroquinazoline derivative or a corresponding
quinazoline derivative in an organic solvent in the presence of a
phase transfer catalyst or in the absence of a catalyst (see
Production Examples 37 and 38). In this reaction, for example,
phenol remaining unreacted and a decomposition product of
4-chloroquinazoline are left in the aqueous layer, while the target
product is present in the organic layer. That is, the organic layer
contains only the target product. Therefore, the post-treatment is
advantageously simple. Further, the production of
N-alkylaminophenoxy-quinazoline as a by-product can be
advantageously suppressed. ##STR5##
[0196] The 4-(aminophenoxy)quinoline derivative or the
corresponding quinazoline derivative thus obtained may be reacted
with an acid chloride or an acid anhydride in the presence of a
base, followed by reduction, for example, with lithium aluminum
hydride to introduce a substituent into R.sup.9 (step 1A).
[0197] Alternatively, the 4-(aminophenoxy)quinoline derivative or
the corresponding quinazoline derivative may be reacted with an
aldehyde or a ketone to produce an imine, followed by reduction,
for example, with sodiumboroncyanohydride to introduce a
substituent into R.sup.9 (step 1B).
[0198] The derivative with a substituent introduced into R.sup.9 is
allowed to act on an isocyanate derivative
(O.dbd.C.dbd.N--R.sup.11) by a conventional method (step 2), and a
suitable alkylating agent (R.sup.10Hal) is allowed to act in the
presence of a base, for example, sodium hydride (step 3) to produce
the compound of formula (I).
[0199] Alternatively, R.sup.9 and R.sup.10 may also be introduced
by allowing a suitable alkylating agent (R.sup.9Hal, R.sup.10Hal)
to act on a urea derivative, wherein R.sup.9 and/or R.sup.10
represent a hydrogen atom, in the presence of a base, for example,
sodium hydride (steps 5 and 7).
[0200] The urea derivative, wherein R.sup.9 and/or R.sup.10
represent a hydrogen atom, may be produced by allowing an
isocyanate derivative to act on the 4-(aminophenoxy)quinoline
derivative or the corresponding quinazoline derivative, produced in
scheme 1, according to a conventional method, or by adding a
triphosgene to the 4-(aminophenoxy)quinoline derivative or the
corresponding quinazoline derivative in the presence of a base, for
example, triethylamine, and then reacting the mixture with a
suitable alkylamine (R.sup.11NH.sub.2, R.sup.10R.sup.11NH) (steps 4
and 6).
[0201] The derivative having a specific substituent at the
7-position of the quinoline ring may be produced, for example,
according to scheme 3. ##STR6##
[0202] A suitable substituent (for example, benzyl) may be allowed
to act on a commercially available 4'-hydroxyacetophenone
derivative to protect the hydroxyl group, followed by action of a
nitrating agent (for example, nitric acid-acetic acid) to introduce
a nitro group.
[0203] The nitro group may be then reduced to an amino group which
is then reacted with a formic ester in the presence of a base to
form a quinolone ring, followed by action of a chlorinating agent,
for example, phosphorus oxychloride, to produce a 4-chloroquinoline
derivative.
[0204] The 4-chloroquinoline derivative thus obtained may be
allowed to act on aminophenol in the presence of a base, for
example, sodium hydride, to produce a 4-(aminophenoxy)quinoline
derivative.
[0205] The urea portion may be synthesized by allowing an
isocyanate derivative (O.dbd.C.dbd.N--R.sup.29) to act on the
derivative thus obtained according to a conventional method, or by
treating the derivative with triphosgene and then allowing an
aromatic amine or alkylamine (R.sup.29NH.sub.2) to act on the
treated derivative.
[0206] Next, the protective group (PG) for the hydroxyl group at
the 7-position of the quinoline ring may be removed, followed by
action of an alkyl halide (R.sup.22'Hal wherein R.sup.22 represents
an alkyl portion when R.sup.22 represents alkoxy) in the presence
of a base, or by action of an alcohol derivative (R.sup.22'OH)
according to a conventional method, for example, Mitsunobu
reaction, to produce a compound, according to the present
invention, having an alkoxy group at the 7-position of the
quinoline ring.
[0207] The alkyl halide used in the substitution reaction may be
commercially available or produced according to a process
described, for example, in J. Am. Chem. Soc., 1945, 67, 736.
[0208] The alcohol derivative used in the substitution reaction may
be commercially available or produced according to a process
described, for example, in J. Antibiot. (1993), 46(1), 177 and Ann.
Pharm. Fr. 1977, 35, 503.
[0209] The derivative having a specific substituent at the
6-position of the quinoline ring may be produced using
3'-hydroxyacetophenone derivative as the starting compound
according to scheme 3.
[0210] The derivative having a specific substituent at the
7-position of the quinazoline ring may be produced according to
scheme 4. ##STR7##
[0211] The 2-amino-benzoic ester derivative may be produced by
esterifying a 2-nitro-benzoic acid derivative synthesized according
to a method described, for example, in J. Med. Chem. 1977, 20, 146,
for example, with dimethylsulfuric acid in the presence of a base,
for example, potassium carbonate and then reducing the nitro group,
for example, with iron/acetic acid.
[0212] Next, the compound thus obtained may be allowed to act on
formamide in the presence of a base to form a 4-quinazolone ring,
followed by action of a chlorinating agent, for example, phosphorus
oxychloride, to produce a 4-chloroquinazoline derivative.
[0213] The 4-chloroquinazoline derivative thus obtained may be
allowed to act on an aminophenol derivative in the presence of a
base, for example, sodium hydride, to produce a
4-(aminophenoxy)quinazoline derivative.
[0214] The urea portion may be synthesized by allowing an
isocyanate derivative (O.dbd.C.dbd.N--R.sup.29) to act on the
derivative thus obtained according to a conventional method, or by
treating the derivative with triphosgene and then allowing an
aromatic amine or alkylamine (R.sup.29NH.sub.2) to act on the
treated derivative.
[0215] Next, the protective group (PG) for the hydroxyl group at
the 7-position of the quinazoline ring may be removed, followed by
action of an alkyl halide (R.sup.22'Hal wherein R.sup.22 represents
an alkyl portion when R.sup.22 represents alkoxy) in the presence
of a base, or by action of an alcohol derivative (R.sup.22'OH)
according to a conventional method, for example, Mitsunobu
reaction, to produce a compound, according to the present
invention, having an alkoxy group at the 7-position of the
quinazoline ring.
[0216] The alkyl halide and the alcohol derivative used in the
substitution reaction may be commercially available or produced
according to a process described in the literature referred to in
the description of scheme 3.
[0217] The derivative having a specific substituent at the
6-position of the quinazoline ring may be produced using
3-hydroxybenzaldehyde derivative as the starting compound according
to scheme 4.
[0218] Use of Compounds/Pharmaceutical Composition
[0219] The compounds according to the present invention have
inhibitory activity against tumor proliferation in vivo (see
Pharmacological Test Example 4).
[0220] Further, the compounds according to the present invention
inhibit in vitro the activation of MAPK (mitogen-activated protein
kinase) caused by stimulation of vascular endothelial cells with
VEGF (vascular endothelial growth factor) (see Pharmacological Test
Examples 1 and 2). Upon the stimulation of vascular endothelial
cells with VEGF, MAPK is activated by a signal transmission system
downstream of the receptor, and, consequently, an increase in
phosphorylated MAPK is recognized (Abedi, H. and Zachary, I., J.
Biol. Chem., 272, 15442-15451 (1997)). The activation of MAPK is
known to play an important role in the growth of vascular
endothelial cells in angiogenesis (Merenmies, J. et al., Cell
Growth & Differ., 83-10 (1997); and Ferrara, N. and
Davis-Smyth, T., Endocr. Rev., 18, 4-25 (1997)). Therefore, the
compounds according to the present invention have angiogenesis
inhibitory activity.
[0221] Angiogenesis at pathologic sites is deeply involved mainly
in diseases, such as tumor, diabetic retinopathy, chronic
rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma, and
metastasis of solid tumors (Forkman, J. Nature Med. 1: 27-31
(1995); Bicknell, R., Harris, A. L. Curr. Opin. Oncol. 8: 60-65
(1996)). Therefore, the compounds according to the present
invention can be used in the treatment of diseases, such as tumor,
diabetic retinopathy, chronic rheumatism, psoriasis,
atherosclerosis, and Kaposi's sarcoma, and metastasis of solid
tumors.
[0222] The compounds according to the present invention have no
significant influence on cytomorphosis (see Pharmacological Test
Example 3). Therefore, the compounds according to the present
invention can be administered to living bodies with very excellent
safety.
[0223] According to the present invention, there is provided a
pharmaceutical composition comprising the compound according to the
present invention. The pharmaceutical composition according to the
present invention may be used in the treatment of diseases, such as
tumor, diabetic retinopathy, chronic rheumatism, psoriasis,
atherosclerosis, and Kaposi's sarcoma, and metastasis of solid
tumors.
[0224] Further, according to the present invention, there is
provided a method for treating a disease selected from the group
consisting of tumor, diabetic retinopathy, chronic rheumatism,
psoriasis, atherosclerosis, and Kaposi's sarcoma, comprising the
step of administering the compound according to the present
invention, together with a pharmaceutically acceptable carrier, to
mammals.
[0225] The compounds according to the present invention can be
administered to human and non-human animals orally or parenterally
by administration routes, for example, intravenous administration,
intramuscular administration, subcutaneous administration, rectal
administration, or percutaneous administration. Therefore, the
pharmaceutical composition comprising as an active ingredient the
compound according to the present invention is formulated into
suitable dosage forms according to the administration routes.
[0226] Specifically, oral preparations include tablets, capsules,
powders, granules, and syrups, and parental preparations include
injections, suppositories, tapes, and ointments.
[0227] These various preparations may be prepared by conventional
methods, for example, with commonly used component, such as
excipients, disintegrants, binders, lubricants, colorants, and
diluents.
[0228] Excipients include, for example, lactose, glucose, corn
starch, sorbit, and crystalline cellulose. Disintegrants include,
for example, starch, sodium alginate, gelatin powder, calcium
carbonate, calcium citrate, and dextrin. Binders include, for
example, dimethylcellulose, polyvinyl alcohol, polyvinyl ether,
methylcellulose, ethylcellulose, gum arabic, gelatin,
hydroxypropylcellulose, and polyvinyl pyrrolidone. Lubricants
include, for example, talc, magnesium stearate, polyethylene
glycol, and hydrogenated vegetable oils.
[0229] In preparing injections, if necessary, for example, buffers,
pH adjustors, stabilizers, tonicity agents, and preservatives may
be added.
[0230] The content of the compound according to the present
invention in the pharmaceutical composition according to the
present invention may vary according to the dosage form. In
general, however, the content is 0.5 to 50% by weight, preferably 1
to 20% by weight, based on the whole composition.
[0231] The dose may be appropriately determined in consideration
of, for example, the age, weight, sex, difference in diseases, and
severity of condition of patients, and the preparation may be
administered, for example, in an amount of 0.1 to 100 mg/kg,
preferably 1 to 50 mg/kg. This dose is administered at a time daily
or divided doses of several times daily.
[0232] The compound according to the present invention may be
administered in combination with other medicament(s). In this case,
the compound according to the present invention may be administered
simultaneously with or after or before the administration of other
medicament(s). For example, when the object disease is malignant
tumor, the compound according to the present invention can be
allowed to act on target vascular endothelial cells to allow the
tumor to regress, followed by the administration of a carcinostatic
agent to effectively eliminate the tumor. The type, administration
intervals and the like of the carcinostatic agent may be determined
depending upon, for example, the type of cancer and the condition
of patients. This treatment method is true of diseases other than
the malignant tumor.
[0233] Furthermore, according to the present invention, there is
provided a method for inhibiting the angiogenesis of target blood
vessels, comprising the step of making the compound according to
the present invention in contact with vascular endothelial cells of
target blood vessels. Target blood vessels include blood vessels
involved in feedings to tissues causative of diseases (for example,
tumor tissues, retinopathy tissues, or rheumatism tissues). The
compound according to the present invention may be brought into
contact with the vascular endothelial cells, for example, by
general administration (for example, intravenous administration or
oral administration), local administration (for example,
percutaneous administration or intraarticular administration), or
drug targeting using a carrier (for example, liposome, lipid
microsphere, or polymeric forms of drugs).
EXAMPLES
[0234] The present invention will be described with reference to
the following examples, though it is not limited to these examples
only.
Production Example 1
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline
[0235] Sodium hydride (60 wt %, 0.72 g) was added to dimethyl
sulfoxide (10 ml). The mixture was stirred at 50.degree. C. for 30
min and was then cooled to room temperature. 4-Amino-3-chlorophenol
hydrochloride (1.61 g) was added to the cooled mixture, and the
mixture was stirred at room temperature for 10 min. Next,
4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the
mixture was stirred at 100.degree. C. overnight. Water was added to
the reaction solution, followed by extraction with chloroform. The
chloroform layer was then washed with a saturated aqueous sodium
hydrogencarbonate solution and was dried over anhydrous sodium
sulfate. The solvent was removed by distillation under the reduced
pressure, and methanol was added to the residue. The precipitated
crystal was collected by suction filtration to give 0.89 g (yield
60%) of the title compound.
[0236] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.05 (s, 3H),
4.05 (s, 3H), 4.08 (s, 2H), 6.44 (d, J=5.4 Hz, 1H), 6.85 (d, J=8.5
Hz, 1H), 6.93-6.96 (m, 1H), 7.15 (d, J=2.7 Hz, 1H), 7.41 (s, 1H),
7.54 (s, 1H), 8.48 (d, J=5.1 Hz, 1H)
Production Example 2
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline
[0237] Sodium hydride (60 wt %, 0.72 g) was added to dimethyl
sulfoxide (10 ml). The mixture was stirred at 50.degree. C. for 30
min and was then cooled to room temperature.
4-Amino-2,3-dimethylphenol hydrochloride (1.55 g) was added to the
cooled mixture, and the mixture was stirred at room temperature for
10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added
thereto, and the mixture was stirred at 100.degree. C. overnight.
Water was added to the reaction solution, followed by extraction
with chloroform. The chloroform layer was then washed with a
saturated aqueous sodium hydrogencarbonate solution and was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure, and methanol was added to
the residue. The precipitated crystal was collected by suction
filtration to give 0.94 g (yield 65%) of the title compound.
[0238] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.07 (s, 3H),
2.15 (s, 3H), 3.62 (s, 2H), 4.05 (s, 3H), 4.07 (s, 3H), 6.25 (d,
J=5.4 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 7.42
(s, 1H), 7.64 (s, 1H), 8.42 (d, J=5.4 Hz, 1H)
Production Example 3
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline
[0239] Sodium hydride (60 wt %, 0.36 g) was added to dimethyl
sulfoxide (10 ml), and the mixture was stirred at 50.degree. C. for
30 min and was then cooled to room temperature.
4-Amino-2,5-dimethylphenol (1.23 g) was added to the cooled
mixture, and the mixture was stirred at room temperature for 10
min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added
thereto, and the mixture was stirred at 100.degree. C. overnight.
Water was added to the reaction solution, followed by extraction
with chloroform. The chloroform layer was then washed with a
saturated aqueous sodium hydrogencarbonate solution and was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure, and the residue was
purified by chromatography on silica gel by development with
chloroform/acetone (1/1) to give the title compound.
Production Example 4
3,5-Dichloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline
[0240] Sodium hydride (60 wt %, 0.36 g) was added to dimethyl
sulfoxide (10 ml), and the mixture was stirred at 50.degree. C. for
30 min and was then cooled to room temperature.
4-Amino-2,6-dichlorophenol (1.59 g) was added to the cooled
mixture, and the mixture was stirred at room temperature for 10
min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added
thereto, and the mixture was stirred at 100.degree. C. overnight.
Water was added to the reaction solution, followed by extraction
with chloroform. The chloroform layer was then washed with a
saturated aqueous sodium hydrogencarbonate solution and was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure, and the residue was
purified by chromatography on silica gel by development with
chloroform/acetone (1/1) to give 0.35 g (yield 22%) of the title
compound.
[0241] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.84 (s, 2H),
4.05 (s, 3H), 4.08 (s, 3H), 6.28 (d, J=5.4 Hz, 1H), 6.74 (s, 2H),
7.43 (s, 1H), 7.64 (s, 1H), 8.48 (d, J=5.4 Hz, 1H)
Production Example 5
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline
[0242] Sodium hydride (60 wt %, 0.54 g) was added to dimethyl
sulfoxide (15 ml), and the mixture was stirred at 70.degree. C. for
30 min and was then cooled to room temperature.
4-Amino-3-nitrophenol (2.07 g) was added to the cooled mixture, and
the mixture was stirred at room temperature for 10 min. Next,
4-chloro-6,7-dimethoxyquinoline (1.50 g) was added thereto, and the
mixture was stirred at 100.degree. C. for 4 hr. Water was added to
the reaction solution, followed by extraction with chloroform. The
chloroform layer was then washed with a saturated aqueous sodium
hydrogencarbonate solution and was dried over anhydrous sodium
sulfate. The solvent was removed by distillation under the reduced
pressure, and the residue was purified by chromatography on silica
gel by development with chloroform/acetone (1/1) to give 0.53 g
(yield 23%) of the title compound.
Production Example 6
1-[2-Amino-4-(benzyloxy)-5-methoxyphenyl]-1-ethanone
[0243] 1-(4-Hydroxy-3-methoxyphenyl)-1-ethanone (20 g), potassium
carbonate (18.3 g), tetra-n-butylammonium iodide (4.45 g), and
benzyl bromide (17.3 ml) were dissolved in N,N-dimethylformamide
(300 ml), and a reaction was allowed to proceed at 100.degree. C.
for one hr. The solvent was removed by distillation under the
reduced pressure, and water was added to the residue, followed by
extraction with ethyl acetate. The ethyl acetate layer was dried
over sodium sulfate. Next, the solvent was removed by distillation
under the reduced pressure. The residue and fuming nitric acid
(12.47 ml) were dissolved in acetic acid (120 ml), and a reaction
was allowed to proceed at room temperature for 2 hr. The reaction
solution was neutralized at 0.degree. C. by the addition of an
aqueous sodium hydroxide solution, followed by extraction with
chloroform. The chloroform layer was then dried over sodium
sulfate. Next, the solvent was removed by distillation under the
reduced pressure. The residue was dissolved in ethanol (1160 ml)
and water (120 ml) with heating. Ammonium chloride (19.2 g) and
zinc (101.7 g) were added thereto. The mixture was heated under
reflux for 3 hr. The reaction solution was filtered through Celite,
followed by washing with chloroform/methanol (3/1). The solvent was
removed by distillation under the reduced pressure, and the residue
was made alkaline with an aqueous sodium hydroxide solution, and
the alkaline solution was extracted with chloroform. The chloroform
layer was dried over sodium sulfate. The solvent was removed by
distillation under the reduced pressure, and the residue was
purified by chromatography on silica gel by development with
chloroform/ethyl acetate (10/1) to give 24.95 g (yield 77%) of the
title compound (3 steps).
[0244] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.51 (s, 3H),
3.84 (s, 3H), 5.14 (s, 2H), 6.12 (s, 2H), 7.15-7.62 (m, 7H)
Production Example 7
7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinone
[0245] 1-[2-Amino-4-(benzyloxy)-5-methoxyphenyl]-1-ethanone (24.95
g) was dissolved in tetrahydrofuran (450 ml), and sodium methoxide
(24.87 g) was added to the solution. The mixture was stirred at
room temperature for one hr. Ethyl formate (37.07 ml) was then
added thereto, and the mixture was stirred at room temperature for
2 hr. Water (150 ml) was then added thereto, and the mixture was
stirred overnight. The reaction solution was adjusted to pH 4 by
the addition of concentrated sulfuric acid at 0.degree. C. Water
was added thereto, and the mixture was extracted with chloroform.
The chloroform layer was dried over sodium sulfate. The solvent was
removed by distillation under the reduced pressure. The residue was
purified by chromatography on silica gel by development with
chloroform/methanol (10/1) to give 17.16 g (yield 66%) of the title
compound.
[0246] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.84 (s, 3H),
5.19 (s, 2H), 5.97 (d, J=7.1 Hz, 1H), 7.09 (s, 1H), 7.28-7.51 (m,
6H), 7.78 (d, J=7.3 Hz, 1H), 11.50-11.75 (br, 1H)
Production Example 8
7-(Benzyloxy)-4-chloro-6-methoxyquinoline
[0247] Phosphorus oxychloride (14.19 ml) was added to
7-(benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinone (17.16 g), and
the mixture was heated under reflux for one hr. The solvent was
removed by distillation under the reduced pressure. The residue was
dissolved in chloroform, and the solution was made alkaline by the
addition of an aqueous sodium hydroxide solution, followed by
extraction with chloroform. The chloroform layer was dried over
sodium sulfate. The solvent was removed by distillation under the
reduced pressure, and the residue was purified by chromatography
on-silica gel by development with chloroform/acetone (10/1) to give
3.82 g (yield 21%) of the title compound.
[0248] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.06 (s, 3H),
5.32 (s, 2H), 7.30-7.55 (m, 8H), 8.56 (d, J=4.9 Hz, 1H)
Production Example 9
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylaniline
[0249] Sodium hydride (60 wt %, 1.17 g) was added to dimethyl
sulfoxide (25 ml), and the mixture was stirred at 60.degree. C. for
30 min and was then cooled to room temperature. Next,
4-amino-2,5-dimethylphenol (4.00 g) was added thereto, and the
mixture was stirred at room temperature for 10 min.
7-(Benzyloxy)-4-chloro-6-methoxyquinoline (4.36 g) was then added
thereto. The mixture was stirred for 22 hr before water was added
to the reaction solution, followed by extraction with chloroform.
The chloroform layer was then washed with a saturated aqueous
sodium hydrogencarbonate solution and was dried over anhydrous
sodium sulfate. The solvent was removed by distillation under the
reduced pressure, and methanol was added to the residue to prepare
a suspension. The precipitated crystal was collected by suction
filtration to give 3.04 g (yield 52%) of the title compound.
[0250] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.05 (s, 3H),
2.16 (s, 3H), 3.58 (s, 2H), 4.06 (s, 3H), 5.32 (s, 2H), 6.28 (d,
J=5.1 Hz, 1H), 6.61 (s, 1H), 6.81 (s, 1H), 7.28-7.42 (m, 3H), 7.44
(s, 1H), 7.49-7.54 (m, 2H), 7.63 (s, 1H), 8.39 (d, J=5.1 Hz,
1H)
[0251] Mass analysis, found (ESI-MS, m/z): 401 (M.sup.++1)
Production Example 10
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-N'-(2,4-
-difluorophenyl)urea
[0252]
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylaniline
(300 mg) was dissolved in chloroform (5 ml). 2,4-Difluorophenyl
isocyanate (200 .mu.l) was then added to the solution, and the
mixture was stirred at 70.degree. C. overnight. The reaction
solution was purified by chromatography on silica gel by
development with chloroform/acetone (75/25) to give 368 mg (yield
88%) of the title compound.
[0253] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.17 (s, 3H),
2.26 (s, 3H), 4.06 (s, 3H), 5.33 (s, 2H), 6.29 (d, J=5.1 Hz, 1H),
6.42 (s, 1H), 6.76-6.93 (m, 3H), 6.70 (s, 3H), 7.30-7.54 (m, 7H),
7.60 (s, 1H), 8.04-8.12 (m, 1H), 8.44 (d, J=5.4 Hz, 1H)
Production Example 11
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-N'-(2-m-
ethoxyphenyl)-urea
[0254]
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylaniline
(300 mg) was dissolved in chloroform (5 ml). 2-Methoxyphenyl
isocyanate (0.24 ml) was then added to the solution, and the
mixture was stirred at 70.degree. C. overnight. The reaction
solution was purified by chromatography on silica gel by
development with chloroform/acetone (75/25) to give 365 mg (yield
89%) of the title compound.
[0255] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.17 (s, 3H),
2.28 (s, 3H), 3.83 (s, 3H), 4.07 (s, 3H), 5.33 (s, 2H), 6.26 (s,
3H), 6.29 (d, J=5.4 Hz, 1H), 6.86-7.06 (m, 4H), 7.12 (s, 1H),
7.30-7.41 (m, 3H), 7.46 (s, 1H), 7.50-7.56 (m, 3H), 7.61 (s, 1H),
8.11-8.16 (m, 1H), 8.43 (d, J=5.4 Hz, 1H)
Production Example 12
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chloroaniline
[0256] Sodium hydride (60 wt %, 320 mg) was added to dimethyl
sulfoxide (3.6 ml), and the mixture was stirred at 60.degree. C.
for 30 min and was then cooled to room temperature. Next,
4-amino-3-chlorophenol hydrochloride (720 mg) was added thereto,
and the mixture was stirred at room temperature for 10 min.
7-(Benzyloxy)-4-chloro-6-methoxyguinoline (600 mg) was then added
thereto, and the mixture was stirred at 105.degree. C. for 22 hr.
Water was added to the reaction solution, followed by extraction
with chloroform. The chloroform layer was then washed with a
saturated aqueous sodium hydrogencarbonate solution and was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure, and methanol was added to
the residue to prepare a suspension. The precipitated crystal was
collected by suction filtration to give 533 mg (yield 66%) of the
title compound.
[0257] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.05 (s, 3H),
4.08 (s, 2H), 5.32 (s, 2H), 6.42 (d, J=5.1 Hz, 1H), 6.84 (d, J=8.5
Hz, 1H), 6.93 (dd, J=2.4 Hz, 8.1 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H),
7.29-7.42 (m, 3H), 7.44 (s, 1H), 7.49-7.53 (m, 12H), 7.55 (s, 1H),
8.45 (d, J=5.3 Hz, 1H)
[0258] Mass analysis, found (ESI-MS, m/z): 497 (M.sup.++1)
Production Example 13
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-(2,4-dif-
luorophenyl)-urea
[0259] 4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chloroaniline
(260 mg) was dissolved in chloroform (10 ml). 2,4-Difluorophenyl
isocyanate (198 mg) was then added to the solution, and the mixture
was stirred at room temperature for 2 hr. The reaction solution was
purified by chromatography on silica gel by development with
chloroform/acetone (10/1) to give 337 mg (yield 94%) of the title
compound.
[0260] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.04 (s, 3H),
5.32 (s, 2H), 6.49 (d, J=5.1 Hz, 1H), 6.86-6.96 (m, 3H), 7.10-7.17
(m, 2H), 7.22-7.28 (m, 1H), 7.28-7.41 (m, 3H), 7.45-7.53 (m, 4H),
7.96-8.04 (m, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.49 (d, J=5.4 Hz,
1H)
[0261] Mass analysis, found (ESI-MS, m/z): 562, 564 (M.sup.++1)
Production Example 14
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-(2,4-difluor-
ophenyl)-urea
[0262]
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'--
(2,4-difluorophenyl)urea (215 mg) was dissolved in
dimethylformamide (11 ml). Palladium-carbon (215 mg) was added to
the solution, and the mixture was stirred in a hydrogen atmosphere
at room temperature overnight. Ethyl acetate (30 ml) was added to
the reaction solution, and the mixture was then filtered through
Celite. The solvent was removed by distillation under the reduced
pressure to give 174 mg (yield 96%) of the title compound.
[0263] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.94 (s, 3H),
6.47 (d, J=5.1 Hz, 1H), 7.01-7.11 (m, 1H), 7.18-7.36 (m, 3H),
7.44-7.52 (m, 2H), 7.95 (s, 1H), 7.98-8.13 (m, 1H), 8.23 (d, J=9.5
Hz, 1H), 6.50 (d, J=5.1 Hz, 1H), 8.81 (s, 1H), 9.31 (s, 1H)
[0264] Mass analysis, found (ESI-MS, m/z): 472 (M.sup.++1)
Production Example 15
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylaniline
[0265] Sodium hydride (60 wt %, 0.32 g) was added to dimethyl
sulfoxide (6 ml), and the mixture was stirred at room temperature
for 30 min. 4-Amino-2,3-dimethylphenol (1.10 g) was then added
thereto, and the mixture was stirred at room temperature for 10
min. Next, 7-(benzyloxy)-4-chloro-6-methoxyquinoline (1.20 g) was
added thereto, and the mixture was stirred at 110.degree. C. for 6
hr. A saturated aqueous sodium hydrogencarbonate solution was added
to the reaction solution, followed by extraction with chloroform.
The chloroform layer was dried over anhydrous magnesium sulfate.
The solvent was removed by distillation under the reduced pressure,
and the residue was purified by chromatography on silica gel by
development with chloroform/acetone (6/1) to give 0.78 g (yield
49%) of the title compound.
[0266] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.87 (s, 3H),
1.96 (s, 3H), 3.97 (s, 3H), 4.78 (s, 2H), 5.23 (s, 2H), 6.12 (d,
J=5.3 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H),
7.27-7.51 (m, 7H), 8.31 (d, J=5.3 Hz, 1H)
Production Example 16
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylphenyl)-N'-(2,4-
-difluoro-phenyl)urea
[0267]
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylaniline
(260 mg) was dissolved in N,N-dimethylformamide (5 ml).
2,4-Difluorophenyl isocyanate (121 mg) was then added to the
solution, and a reaction was allowed to proceed at room temperature
overnight. Methanol was added to the reaction solution, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with methanol and was collected by filtration to
give 219 mg (yield 61%) of the title compound.
[0268] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.99 (s, 3H),
2.17 (s, 3H), 3.90 (s, 3H), 5.24 (s, 2H), 6.18 (d, J=5.1 Hz, 1H),
6.95-6.98 (m, 2H), 7.25-7.63 (m, 9H), 8.05-8.08 (m, 1H), 8.34-8.36
(m, 2H), 8.79 (s, 1H)
Production Example 17
7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline
[0269] 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (300 mg) and
3-fluoro-4-nitrophenol (785 mg) were dissolved in chlorobenzene (3
ml), and the solution was stirred at 130.degree. C. for 5 hr.
Chloroform and an aqueous sodium hydroxide solution were added to
the reaction solution, and the mixture was stirred for one hr. The
reaction solution was extracted with chloroform, and the chloroform
layer was dried over anhydrous magnesium sulfate. The solvent was
removed by distillation under the reduced pressure. The residue was
purified by thin-layer chromatography on silica gel by development
with hexane/ethyl acetate (1/1) to give 197 mg (yield 47%) of the
title compound.
[0270] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.83 (s, 3H),
5.25 (s, 2H), 6.91 (d, J=5.1 Hz, 1H), 7.29-7.50 (m, 9H), 8.18-8.23
(m, 1H), 8.56 (d, J=5.1 Hz, 1H)
Production Example 18
4-(4-Amino-3-fluorophenoxy)-6-methoxy-7-quinolinol
[0271] 7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline
(190 mg) was dissolved in N,N-dimethylformamide (5 ml) and
triethylamine (1 ml). Palladium hydroxide (40 mg) was added to the
solution, and the mixture was stirred in a hydrogen atmosphere at
room temperature overnight. The solvent was removed by distillation
under the reduced pressure. The residue was purified by thin-layer
chromatography on silica gel by development with
chloroform/methanol (20/1) to give 75 mg (yield 56%) of the title
compound.
[0272] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.87 (s, 3H),
5.11 (s, 2H), 6.29 (d, J=5.1 Hz, 1H), 6.77-6.80 (m, 2H), 6.93-6.99
(m, 1H), 7.19 (s, 1H), 7.40 (s, 1H), 8.31 (d, J=5.1 Hz, 1H), 10.03
(s, 1H)
Production Example 19
N-(2,4-Difluorophenyl)-N'-{2-fluoro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy-
]phenyl}-urea
[0273] 4-(4-Amino-3-fluorophenoxy)-6-methoxy-7-quinolinol (70 mg)
was dissolved in chloroform (1.5 ml) and N,N-dimethylformamide (1
ml). 2,4-Difluorophenyl isocyanate (43 mg) was then added to the
solution, and a reaction was allowed to proceed at room temperature
for 3 hr. Methanol was added to the reaction solution. The solvent
was removed by distillation under the reduced pressure. The residue
was purified by thin-layer chromatography on silica gel by
development with chloroform/methanol (20/1) to quantitatively give
the title compound.
[0274] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.94 (s, 3H),
6.47 (d, J=5.1 Hz, 1H), 7.04-7.10 (m, 2H), 7.28-7.34 (m, 2H), 7.47
(s, 1H), 8.05-8.15 (m, 2H), 8.30 (s, 1H), 8.43 (d, J=5.1 Hz, 1H),
8.97-9.03 (m, 2H), 10.10 (s, 1H)
Production Example 20
4-Chloro-6-methoxy-7-quinolinol
[0275] 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (100 mg),
thioanisole (300 .mu.l), and methanesulfonic acid (25 .mu.l) were
dissolved in trifluoromethanesulfonic acid (1 ml). The solution was
stirred at room temperature for 30 min. The solvent was removed by
distillation under the reduced pressure. The residue was made
neutral by the addition of an aqueous sodium hydroxide solution,
and hexane was added thereto to prepare a suspension. The crystal
was collected by suction filtration to give 53 mg (yield 75%) of
the title compound.
[0276] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.98 (s, 3H),
7.33 (s, 1H), 7.36 (s, 1H), 7.47 (d, J=4.9 Hz, 1H), 8.54 (d, J=4.9
Hz, 1H), 10.37 (br, 1H)
Production Example 21
4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinoline
[0277] 4-Chloro-6-methoxy-7-quinolinol (50 mg), potassium carbonate
(40 mg), tetra-n-butylammonium iodide (9 mg), and 2-bromoethyl
methyl ether (40 mg) were dissolved in N,N-dimethylformamide (10
ml). The solution was stirred at 70.degree. C. overnight. The
solvent was removed by distillation under the reduced pressure. A
saturated aqueous sodium hydrogencarbonate solution was added to
the residue, followed by extraction with chloroform. The chloroform
layer was dried over sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
hexane/acetone/dichloromethane (6/2/1) to give 47 mg (yield 74%) of
the title compound.
[0278] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.49 (s, 3H),
3.88-3.90 (m, 2H), 4.04 (s, 3H), 4.32-4.35 (m, 2H), 7.35 (d, J=4.9
Hz, 1H), 7.40 (s, 1H), 7.43 (s, 1H), 8.57 (d, J=4.9 Hz, 1H)
Production Example 22
2-Chloro-4-{[(6-methoxy-7-(2-methoxyethoxy)-4-quinolyl]oxy}aniline
[0279] Sodium hydride (60 wt %, 153 mg) was added to dimethyl
sulfoxide (2 ml). The mixture was stirred at 60.degree. C. for 30
min and was then cooled to room temperature. 4-Amino-3-chlorophenol
hydrochloride (343 mg) was added thereto, and the mixture was
stirred at room temperature for 10 min. Next, a solution of
4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline (254 mg) in
dimethyl sulfoxide (2 ml) was added to the reaction solution, and
the mixture was stirred at 110.degree. C. overnight. Water was
added to the reaction solution, followed by extraction with
chloroform. The chloroform layer was then washed with a saturated
aqueous sodium hydrogencarbonate solution and was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by
chromatography on silica gel by development with chloroform/acetone
(7/3) to give the title compound.
[0280] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.49 (s, 3H),
3.89-3.91 (m, 2H), 4.02 (s, 3H), 4.09 (s, 2H), 4.33-4.35 (m, 2H),
6.43 (d, J=5.4 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.93-6.96 (m, 1H),
7.15 (d, J=2.7 Hz, 1H), 7.41 (s, 1H), 7.52 (s, 1H), 8.47 (d, J=5.1
Hz, 1H)
Production Example 23
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline
[0281] Sodium hydride (60 wt %, 5.80 g) was added to dimethyl
sulfoxide (40 ml). The mixture was stirred at 60.degree. C. for 30
min and was then cooled to room temperature. Next,
4-amino-3-chlorophenol hydrochloride (13.05 g) was added thereto.
The mixture was stirred at room temperature for 10 min.
4-Chloro-6,7-dimethoxyquinazoline (8.14 g), which is a
chloroquinazoline derivative synthesized by a conventional method
as described, for example, in J. Am. Chem. Soc., 68, 1299 (1946) or
J. Am. Chem. Soc., 68, 1305 (1946), was then added thereto. The
mixture was stirred at 110.degree. C. for 30 min. Water was then
added to the reaction solution, followed by extraction with
chloroform. The chloroform layer was then washed with a saturated
aqueous sodium hydrogencarbonate solution and was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure, and methanol was added to the residue
to prepare a suspension. The precipitated crystal was collected by
suction filtration to give 9.13 g (yield 76%) of the title
compound.
[0282] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.05-4.08 (m,
8H), 6.85 (d, J=8.5 Hz, 1H), 7.00 (dd, J=2.7 Hz, 8.8 Hz, 1H), 7.21
(d, J=2.7 Hz, 1H), 7.32 (s, 1H), 7.52 (s, 1H), 8.64 (s, 1H)
[0283] Mass analysis, found (ESI-MS, m/z): 332 (M.sup.++1)
Production Example 24
N-Benzyl-N-(2,4-difluorophenyl)amine
[0284] Magnesium sulfate (5.59 g) and a minor amount of acetic acid
were added to a solution of 2,4-difluoroaniline (2.37 ml) and
benzaldehyde (2.36 ml) in methanol (46 ml). The mixture was stirred
at room temperature for 45 min. Sodium boron hydride (2.64 g) was
added thereto under ice cooling, and the mixture was stirred at
room temperature for one hr. The solvent was removed by
distillation under the reduced pressure. Water and ethyl acetate
were added to the residue. The mixture was stirred and was filtered
through Celite. The organic layer was extracted with ethyl acetate
and was dried over anhydrous sodium sulfate. The solvent was
removed by distillation under the reduced pressure. The residue was
purified by chromatography on silica gel by development with
hexane/acetone (30/1) to give 3.04 g (yield 60%) of the title
compound.
[0285] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.34 (s, 2H),
6.56-6.82 (m, 3H), 7.25-7.38 (m, 5H)
Production Example 25
Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate
[0286] Commercially available methyl vanillate (50 g) and potassium
carbonate (76 g) were dissolved in N,N-dimethylformamide (200 ml).
Benzyl bromide (33 ml) was added dropwise to the solution over a
period of 10 min. The mixture was stirred at room temperature
overnight. Water (200 ml) was added thereto, followed by extraction
with ethyl acetate. Saturated brine was then added to the organic
layer, and the mixture was extracted with ethyl acetate. Sodium
sulfate was added to the organic layer to dry the organic layer.
Next, the organic layer was filtered, and the solvent was then
removed by distillation under the reduced pressure. The residue was
dried through a vacuum pump to give 68 g of a white solid.
Subsequently, 100 ml of acetic acid and 200 ml of nitric acid were
added under ice cooling. The mixture was stirred for 8 hr, and
water was then added thereto. The resultant solid was then
collected by filtration, was thoroughly washed with water, and was
dried through a vacuum pump to give 74 g (yield 93%) of the title
compound.
[0287] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.90 (s, 3H),
3.98 (s, 3H), 5.21 (s, 2H), 7.08 (s, 1H), 7.31-7.45 (m, 5H), 7.51
(s, 1H)
Production Example 26
7-(Benzyloxy)-6-methoxy-3,4-dihydro-4-quinazolinone
[0288] Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (15.0 g) was
dissolved in acetic acid (200 ml) at room temperature. Iron
(powder) (13.2 g) was then added to the solution. The temperature
of the mixture was raised to 90.degree. C., and the mixture was
then stirred for one hr. The resultant gray solid was filtered
through Celite, followed by washing with acetic acid. Concentrated
hydrochloric acid was added to the mother liquor. The solvent was
then removed by distillation under the reduced pressure. This
resulted in the precipitation of a solid. The solid was collected
by filtration, was washed with ethyl acetate and ether, and was
dried through a vacuum pump. Subsequently, chloroform and methanol
were added to the solid to prepare a suspension, and a 10% aqueous
sodium hydroxide solution was then added to dissolve the solid,
followed by extraction with chloroform. After washing with water,
the organic layer was dried over sodium sulfate. Next, the organic
layer was filtered, and the solvent was then removed by
distillation under the reduced pressure. The residue was dried
through a vacuum pump to give 9.5 g (yield 70%) of a crude product
of methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate.
[0289] Methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (650 mg) was
dissolved in N,N-dimethylformamide (15 ml) and methanol (3 ml).
Formamide (0.46 ml) and sodium methoxide (373 mg) were added to the
solution. The mixture was heated to 100.degree. C. and was stirred
overnight. The reaction solution was cooled to room temperature,
and 10 ml of water was then added to the cooled reaction solution.
The reaction solution was neutralized with a 1 M aqueous
hydrochloric acid solution to precipitate a solid. The solid was
collected by filtration, was washed with water and ether, and was
then dried through a vacuum pump to give 566 mg (yield 87%) of the
title compound.
[0290] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.88 (s, 3H),
5.25 (s, 2H), 7.23 (s, 1H), 7.33-7.49 (m, 6H), 7.97 (s, 1H), 12.06
(br, 1H)
Production Example 27
7-(Benzyloxy)-4-chloro-6-methoxyquinazoline
[0291] Phosphorus oxychloride (515 ml) was added to
7-(benzyloxy)-6-methoxy-3,4-dihydro-4-quinazolinone (400 mg) and
diisopropylethylamine (0.3 ml), and the mixture was refluxed for 20
min. The reaction solution was cooled to room temperature. A 10%
aqueous sodium hydroxide solution was then added to the reaction
solution, followed by extraction with chloroform. The organic layer
was dried over sodium sulfate. The organic layer was filtered, and
the solvent was then removed by distillation under the reduced
pressure. The residue was dried through a vacuum pump to give 420
mg (yield 99%) of the title compound.
[0292] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.08 (s, 3H),
5.34 (s, 2H), 7.35-7.51 (m, 7H), 8.86 (s, 1H)
Production Example 28
Methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate
[0293] Commercially available methyl 3-hydroxy-4-methoxybenzoate
(10 g) and potassium carbonate (23 g) were dissolved in
N,N-dimethylformamide (50 ml). Benzyl bromide (6.5 ml) was added
dropwise to the solution over a period of 10 min. The mixture was
stirred at room temperature overnight. Water (200 ml) was added
thereto, and the mixture was extracted with ethyl acetate.
Saturated brine was then added to the organic layer, followed by
extraction with ethyl acetate. Sodium sulfate was added to the
organic layer to dry the organic layer. Next, the organic layer was
filtered, and the solvent was then removed by distillation under
the reduced pressure. The residue was dried through a vacuum pump
to give 8.4 g of a white solid. Subsequently, 7.0 g of the solid
was placed in a flask, and 100 ml of acetic acid and 200 ml of
nitric acid were added thereto under ice cooling. The mixture was
stirred for 8 hr, and water was then added thereto. The resultant
solid was collected by filtration, was thoroughly washed with
water, and was dried through a vacuum pump to give 7.9 g (yield
96%) of the title compound.
[0294] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.89 (s, 3H),
3.96 (s, 3H), 5.21 (s, 2H), 7.15 (s, 1H), 7.34-7.45 (m, 6H)
Production Example 29
6-(Benzyloxy)-7-methoxy-3,4-dihydro-4-quinazolinone
[0295] Methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate (15.8 g) was
dissolved in acetic acid (200 ml) at room temperature. Iron
(powder) (13.9 g) was then added to the solution. The mixture was
heated to 90.degree. C. and was stirred for one hr. The resultant
gray solid was filtered through Celite and was washed with acetic
acid. Concentrated hydrochloric acid was added to the mother
liquor, and the solvent was then removed by distillation under the
reduced pressure to precipitate a solid. The solid was collected by
filtration, was washed with ethyl acetate and ether, and was dried
through a vacuum pump. Subsequently, chloroform and methanol were
added to the solid to prepare a suspension, and a 10% aqueous
sodium hydroxide solution was then added to the suspension to
dissolve the solid, followed by extraction with chloroform. The
extract was washed with water, and the organic layer was then dried
over sodium sulfate. Next, the organic layer was filtered, and the
solvent was then removed by distillation under the reduced
pressure. The residue was dried through a vacuum pump to give 10.4
g (yield 73%) of a crude product of methyl
2-amino-5-(benzyloxy)-4-methoxybenzoate.
[0296] Methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate (5.0 g) was
dissolved in N,N-dimethylformamide (150 ml) and methanol (30 ml).
Formamide (3.5 ml) and sodium methoxide (2.8 g) were added to the
solution. The mixture was heated to 100.degree. C. and was then
stirred overnight. The reaction solution was then cooled to room
temperature, and 10 ml of water was then added. The reaction
solution was neutralized with a 1 M aqueous hydrochloric acid
solution to precipitate a solid. The solid was collected by
filtration, was washed with water and ether, and was then dried
through a vacuum pump to give 3.7 g (yield 76%) of the title
compound.
[0297] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.92 (s, 3H),
5.21 (s, 2H), 7.16 (s, 1H), 7.33-7.49 (m, 5H), 7.55 (s, 1H), 7.99
(s, 1H), 12.06 (br, 1H)
Production Example 30
6-(Benzyloxy)-4-chloro-7-methoxyquinazoline
[0298] Phosphorus oxychloride (3.1 ml) was added to
6-(benzyloxy)-7-methoxy-3,4-dihydro-4-quinazolinone (3.5 g) and
diisopropylethylamine (11.5 ml). The mixture was refluxed for 20
min. The reaction solution was cooled to room temperature, and a
10% aqueous sodium hydroxide solution was then added to the cooled
reaction solution, followed by extraction with chloroform. The
organic layer was dried over sodium sulfate. The organic layer was
filtered, and the solvent was then removed by distillation under
the reduced pressure. The residue was dried through a vacuum pump
to give 2.9 g (yield 72%) of the title compound.
[0299] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.07 (s, 3H),
5.32 (s, 2H), 7.35-7.53 (m, 7H), 8.86 (s, 1H)
Production Example 31
4-{[7-(Benzyloxy)-6-methoxy-4-quinazolinyl]oxy}-2-chloroaniline
[0300] 7-(Benzyloxy)-4-chloro-6-methoxyquinazoline (30.0 g) and
tetrabutylammonium chloride (13.9 g) were dissolved in acetone (400
ml), and the solution was stirred at room temperature. A solution
of 4-amino-3-chlorophenol: hydrochloride (36.0 g) in a 20% aqueous
sodium hydroxide solution (64 ml) was added thereto. The mixture
was then heated under reflux for 3 hr. The reaction solution was
cooled to room temperature, and chloroform and water were added to
the cooled reaction solution, followed by extraction with
chloroform. The extract was washed with a saturated aqueous sodium
hydrogencarbonate solution and saturated brine and was then dried
over anhydrous sodium sulfate. Next, sodium sulfate was removed,
and the solvent was then removed by distillation. The residue was
washed with methanol, and the washed solid was subjected to
evaporation to dryness in vacuo through a vacuum pump to give 36.6
g (yield 90%) of the title compound.
[0301] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.96 (s, 3H),
5.34 (s, 2H), 6.86 (d, J=8.8 Hz, 1H), 7.00 (dd, J=2.7 Hz, 8.8 Hz,
1H), 7.22 (d, J=2.7 Hz, 1H), 7.35-7.54 (m, 7H), 8.53 (s, 1H)
Production Example 32
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N'-prop-
ylurea
[0302]
4-{[7-(Benzyloxy)-6-methoxy-4-quinazolinyl]oxy}-2-chloroaniline
(12.2 g) was dissolved in anhydrous chloroform. Triethylamine (8.4
ml) was then added to the solution, and the mixture was stirred at
room temperature. Separately, triphosgene (4.5 g) was dissolved in
anhydrous chloroform (12 ml), and the solution was added dropwise
to the mixed solution. The mixture was stirred at room temperature
for 20 min, and n-propylamine (4.9 ml) was then added thereto,
followed by stirring at room temperature for additional one hr to
precipitate a white solid. This solid was collected by filtration
and was then washed with chloroform to give 9.4 g (yield 63%) of
the title compound.
[0303] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.91 (t, J=7.3
Hz, 3H), 1.44-1.50 (m, 2H), 3.06-3.09 (m, 2H), 3.98 (s, 3H), 5.35
(s, 2H), 6.97-7.01 (m, 1H), 7.23 (dd, J=2.7 Hz, 9.0 Hz, 1H),
7.37-7.57 (m, 9H), 8.20 (d, J=9.3 Hz, 1H), 8.55 (s, 1H)
Production Example 33
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'-propylur-
ea
[0304]
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-
-N'-propylurea (42.2 g) was dissolved in trifluoroacetic acid (200
ml). Methanesulfonic acid (11.1 ml) was then added to the solution,
and the mixture was stirred at 100.degree. C. for 4 hr. The
reaction solution was cooled to room temperature, and
trifluoroacetic acid was removed by distillation under the reduced
pressure. Chloroform and methanol were added to the mixture as the
residue, followed by extraction with a 10% aqueous sodium hydroxide
solution three times. The aqueous layer was neutralized with
concentrated hydrochloric acid to precipitate a solid. The solid
was washed with water, methanol, and ether in that order, and was
then dried in vacuo through a vacuum pump to give 20.7 g (yield
60%) of the title compound.
[0305] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.91 (t, J=7.3
Hz, 3H), 1.42-1.49 (m, 2H), 3.06-3.17 (m, 2H), 3.84 (s, 3H), 6.65
(s, 1H), 7.03 (m, 1H), 7.14 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.20 (s,
1H), 7.35 (d, J=2.7 Hz, 1H), 8.05 (s, 1H), 8.14 (dd, J=2.7 Hz, 8.8
Hz, 1H), 8.19 (s, 1H)
Production Example 34
6,7-Dimethoxy-4-quinazolone
[0306] Formamide (150 ml) was added to methyl
2-amino-3,4-dimethoxybenzoate (20.0 g, 94.8 mmol). The mixture was
heated at 160.degree. C. for 8.5 hr. The reaction solution was
cooled and was then filtered. The collected precipitate was washed
with water (100 ml.times.2 times), and the washed precipitate was
dried in vacuo to give 17.85 g (yield 91.5%) of the target
compound.
[0307] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 4.01 (s, 3H),
4.02 (s, 3H), 7.14 (s, 1H), 7.34 (s, 1H), 7.61 (s, 1H), 7.97 (s,
1H)
Production Example 35
4-Chloro-6,7-dimethoxyquinazoline
[0308] Sulfolane (250 ml) and phosphorus oxychloride (250 ml=412.5
g, 2.69 mol) were added to 6,7-dimethoxy-4-quinazolone (50.1 g,
0.24 mol), and the mixture was stirred at 120.degree. C. for one
hr. The reaction mixture was cooled to room temperature, and the
excess phosphorus oxychloride was then removed by distillation
under the reduced pressure. The residue was poured into ice water
(1000 ml), and chloroform (1000 ml) was added thereto. The aqueous
layer was adjusted to pH 6.5 by the addition of a 20% sodium
hydroxide solution, followed by the separation of the organic layer
from the aqueous layer. The separated organic layer was washed with
water (1000 ml.times.six times), was dried over sodium sulfate, and
was then concentrated under the reduced pressure. Tetrahydrofuran
(470 ml) was added to the residue, and the mixture was refluxed.
The reaction solution was cooled to -5.degree. C. to -10.degree. C.
and was filtered and dried to give 38.5 g (yield 71.4%) of the
target product.
[0309] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 4.09 (s, 3H),
4.09 (s, 3H), 7.14 (s, 1H), 7.34 (s, 1H), 7.61 (s, 1H), 7.97 (s,
1H)
Production Example 36
4-Chloro-6,7-dimethoxyquinazoline
[0310] Toluene (100 ml) and phosphorus oxychloride (7.4 g, 48.6
mmol) were added to 6,7-dimethoxy-4-quinazolone (10.0 g, 48.5
mmol), and the mixture was stirred at 120.degree. C. for 6.5 hr.
The reaction solution was cooled to room-temperature, was then
filtered, was washed with toluene (100 ml, 50 ml), and was dried to
give 11.5 g (yield 91%) of the target product.
Production Example 37
4-(4'-Amino-3'-chloro)-phenoxy-6,7-dimethoxyquinazoline
[0311] Sodium hydroxide (8.5 g, 0.21 mol) and water (90 ml) were
added to and dissolved in 4-amino-3-chlorophenol hydrochloride
(14.6 g, 81 mmol). 4-Chloro-6,7-dimethoxyquinazoline (12 g, 53
mmol) and methyl ethyl ketone (225 ml) were added to the solution,
and the mixture was refluxed for 2 hr. The reaction solution was
cooled to about 50.degree. C., and chloroform (500 ml) and water
(500 ml) were then added to the cooled reaction solution. The
mixture was stirred for 10 min, and the organic layer was then
separated from the aqueous layer. Chloroform (250 ml) was added to
the aqueous layer, and the mixture was stirred for 10 min, followed
by layer separation. The organic layer was concentrated under the
reduced pressure. Methanol (50 ml) was added to the residue, and
the mixture was stirred for 30 min. The reaction solution was then
filtered and was dried to give 15.6 g (yield 85%) of the target
product.
[0312] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.95 (s, 3H),
3.97 (s, 3H), 5.33 (s, 2H), 6.85 (d, J=8.8 Hz, 1H), 6.98 (dd, J=2.8
Hz, J=8.8 Hz, 1H), 7.20 (d, J=2.8 Hz, 1H), 7.36 (s, 1H), 7.51 (s,
1H), 8.53 (s, 1H)
Production Example 38
4-(4'-Amino-3'-chloro)-phenoxy-6,7-dimethoxyquinazoline
[0313] A 20% aqueous sodium hydroxide solution (3.5 ml) and water
(2 ml) were added to and dissolved in 4-amino-3-chlorophenol
hydrochloride (1.3 g, 7.2 mmol). 4-Chloro-6,7-dimethoxyquinazoline
(0.8 g, 3.6 mmol), chloroform (6 ml), and tetrabutylammonium
bromide (0.58 g, 1.8 mmol) were added to the solution, and the
mixture was refluxed for 2 hr. The reaction solution was cooled.
Chloroform (10 ml) and water (10 ml) were then added to the cooled
reaction solution, and the mixture was stirred for 10 min, followed
by the separation of the organic layer from the aqueous layer.
Chloroform (10 ml) was added to the separated aqueous layer, and
the mixture was stirred for 10 min, followed by layer separation.
The organic layer was concentrated under the reduced pressure.
Methanol (2 ml) was added to the residue, and the mixture was
stirred for 30 min. The reaction solution was then filtered and was
dried to give 1.0 g (yield 83%) of the target product.
Example 1
N-(2,4-Difluorobenzyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-fluoropheny-
l}urea
[0314] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in toluene (5.0 ml) and triethylamine (1.0 ml) with
heating. A solution of triphosgene (103 mg) in dichloromethane (1.0
ml) was then added to the solution, and the mixture was heated
under reflux for 3 min. Next, 2,4-difluorobenzylamine (54 mg) was
added thereto, and the mixture was heated under reflux for
additional 5 hr. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, followed by extraction
with chloroform. The chloroform layer was dried over anhydrous
sodium sulfate. The solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography on
silica gel by development with chloroform/acetone (2/1) to give 123
mg (yield 80%) of the title compound.
[0315] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.02 (s, 3H),
4.03 (s, 3H), 4.47 (d, J=5.9 Hz, 2H), 5.78-5.90 (m, 1H), 6.46 (d,
J=5.4 Hz, 1H), 6.74-6.99 (m, 4H), 7.03-7.14 (m, 1H), 7.35-7.44 (m,
2H), 7.50 (s, 1H), 8.16 (t, J=9.0 Hz, 1H), 8.47 (d, J=5.1 Hz,
1H)
[0316] Mass analysis, found (FD-MS, m/z): 483 (M.sup.+)
Example 2
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N'-(2-fluoroethyl)ure-
a
[0317] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in toluene (10 ml) and triethylamine (0.5 ml) with
heating. A solution of triphosgene (47 mg) in dichloromethane (1.0
ml) was then added to the solution, and the mixture was heated
under reflux for 5 min. Next, 2-fluoroethylamine hydrochloride (42
mg) was added thereto, and the mixture was heated under reflux for
additional 8 hr. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, followed by extraction
with ethyl acetate. The ethyl acetate layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by
chromatography on silica gel by development with chloroform/acetone
(2/1) to give 93 mg (yield 72%) of the title compound.
[0318] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.40 (m, 1H),
3.47 (m, 1H), 3.93 (s, 3H), 3.95 (s, 3H), 4.42 (t, J=4.9 Hz, 1H),
4.54 (t, J=4.9 Hz, 1H), 6.51 (d, J=5.4 Hz, 1H), 6.88 (m, 1H), 7.05
(m, 1H), 7.28 (dd, J=2.7 Hz, J=11.7 Hz, 1H), 7.40 (s, 1H), 7.49 (s,
1H), 8.21 (m, 1H), 8.47 (br, 1H), 8.48 (d, J=5.4 Hz, 1H)
[0319] Mass analysis, found (ESI-MS, m/z): 404 (M.sup.++1)
Example 3
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N'-(2-pyridylmethyl)u-
rea
[0320] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in toluene (5 ml) and triethylamine (1 ml). A
solution of triphosgene (104 mg) in dichloromethane was then added
to the solution, and the mixture was refluxed for 5 min. Next,
2-(aminomethyl)pyridine (40 .mu.l) was added thereto, and the
mixture was heated under reflux for 2 hr. A saturated aqueous
sodium hydrogencarbonate solution (1 ml) and chloroform (2 ml) were
added to the reaction solution. The mixture was supported on
diatomaceous earth, followed by extraction with chloroform. The
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/methanol (8/1) to give 126 mg (yield 88%) of the
title compound.
[0321] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.07 (s, 3H),
4.09 (s, 3H), 4.61 (d, J=5.4 Hz, 2H), 6.40-6.50 (br, 1H), 6.61 (d,
J=5.9 Hz, 1H), 6.92-7.01 (m, 2H), 7.21-7.25 (m, 1H), 7.36 (d, J=7.8
Hz, 1H), 7.56 (s, 1H), 7.68-7.78 (m, 2H), 7.75 (s, 1H), 8.27-8.34
(m, 1H), 8.49 (d, J=6.1 Hz, 1H), 8.55 (d, J=4.1 Hz, 1H)
[0322] Mass analysis, found (FD-MS, m/z): 448 (M.sup.+)
Example 4
N-Allyl-N'-{4-[(6,7-dimethoxy-4-quinolyl)-oxy]-2-fluorophenyl}urea
[0323] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in toluene (5 ml) and triethylamine (1 ml), and a
solution of triphosgene (104 mg) in dichloromethane was then added
to the solution. The mixture was heated under reflux for 5 min.
Next, allylamine (22 mg) was added to the reaction solution, and
the mixture was heated under reflux for additional 4 hr. A
saturated aqueous sodium hydrogencarbonate solution (1 ml) and
chloroform (2 ml) were added to the reaction solution, and the
mixture was supported on diatomaceous earth, followed by extraction
with chloroform. The solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography on
silica gel by development with chloroform/acetone (2/1) to give 125
mg (yield 98%) of the title compound.
[0324] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.91-3.96 (m,
2H), 4.06 (s, 3H), 4.09 (s, 3H), 5.14-5.20 (m, 1H), 5.26-5.33 (m,
1H), 5.58-5.66 (br, 1H), 5.86-5.98 (m, 1H), 6.56 (d, J=5.9 Hz, 1H),
6.88-7.01 (m, 2H), 7.23 (s, 1H), 7.55 (s, 1H), 7.66 (s, 1H),
8.26-8.33 (m, 1H), 8.47 (d, J=5.9 Hz, 1H)
[0325] Mass analysis, found (FD-MS, m/z): 397 (M.sup.+)
Example 5
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N'-propylurea
[0326] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in toluene (10 ml) and triethylamine (2 ml), and a
solution of triphosgene (104 mg) in dichloromethane was then added
to the solution. The mixture was heated under reflux for 5 min.
Next, propylamine (29 mg) was added, and the mixture was heated
under reflux for 40 min. A saturated aqueous sodium
hydrogencarbonate solution was added to the reaction solution, and
the mixture was extracted with ethyl acetate. The ethyl acetate
layer was then dried over anhydrous sodium sulfate. The solvent was
removed by distillation under the reduced pressure. The residue was
purified by thin-layer chromatography on silica gel by development
with chloroform/methanol (10/1) to give 89 mg (yield 71%) of the
title compound.
[0327] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.97 (t, J=7.6
Hz, 3H), 1.55-1.64 (m, 2H), 3.24-3.29 (m, 2H), 4.05 (s, 3H), 4.06
(s, 3H), 5.11 (t, J=5.4 Hz, 1H), 6.51 (d, J=5.4 Hz, 1H), 6.74-6.76
(m, 1H), 6.91-6.99 (m, 2H), 7.48 (s, 1H), 7.52 (s, 1H), 8.18-8.23
(m, 1H), 8.49 (d, J=5.6 Hz, 1H)
[0328] Mass analysis, found (FD-MS, m/z): 399 (M.sup.+)
Example 6
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N'-(4-fluorobutyl)ure-
a
[0329] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in toluene (6 ml) and triethylamine (1.0 ml) with
heating, and a solution of triphosgene (104 mg) in dichloromethane
(1.0 ml) was then added to the solution. The mixture was heated
under reflux for 5 min. Next, 4-fluorobutylamine hydrochloride (55
mg) was added to the reaction solution, and the mixture was heated
under reflux for additional 2 hr. A saturated aqueous sodium
hydrogencarbonate solution was added to the reaction solution,
followed by extraction with chloroform. The chloroform layer was
dried over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/acetone (2/1) to give 80 mg (yield 55%) of the title
compound.
[0330] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.66-1.87 (m,
4H), 3.33-3.40 (m, 2H), 4.04 (s, 3H), 4.05 (s, 3H), 4.44 (t, J=5.6
Hz, 1H), 4.56 (t, J=5.7 Hz, 1H), 4.90 (t, J=5.7 Hz, 1H), 6.48-6.52
(m, 2H), 6.93-7.02 (m, 2H), 7.42 (s, 1H), 7.51 (s, 1H), 8.15 (t,
J=8.9 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H)
[0331] Mass analysis, found (FD-MS, m/z): 431 (M.sup.+)
Example 7
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N'-(2-propynyl)urea
[0332] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (150 mg)
was dissolved in chloroform (10 ml) and triethylamine (2 ml), and a
solution of triphosgene (156 mg) in dichloromethane was added to
the solution. The mixture was heated under reflux for 10 min. Next,
propargylamine (53 mg) was added, and the mixture was heated under
reflux for additional 30 min. A saturated aqueous sodium
hydrogencarbonate solution was added to the reaction solution, and
the mixture was extracted with chloroform. The chloroform layer was
dried over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/acetone (2/1) to give 164 mg (yield 87%) of the title
compound.
[0333] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.49-2.51 (m,
1H), 3.90-3.95 (m, 8H), 6.52 (d, J=5.1 Hz, 1H), 6.89-6.92 (m, 1H),
7.04-7.06 (m, 1H), 7.26-7.29 (m, 1H), 7.39 (s, 1H), 7.49 (s, 1H),
8.16-8.20 (m, 1H), 8.46-8.49 (m, 2H)
Example 8
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N'-ethylurea
[0334] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in toluene (8 ml) and triethylamine (1.0 ml) with
heating, and a solution of triphosgene (47 mg) in toluene (1.0 ml)
was then added to the solution. The mixture was heated under reflux
for 5 min. Next, ethylamine hydrochloride (60 mg) was added to the
reaction solution, and the mixture was heated under reflux for
additional 5 hr. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, and the mixture was
extracted with ethyl acetate. The ethyl acetate layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/acetone (2/1) to give 70 mg (yield 53%) of the title
compound.
[0335] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.21 (t, J=7.3
Hz, 3H), 3.34 (m, 2H), 4.06 (s, 3H), 4.08 (s, 3H), 5.64 (br, 1H),
6.55 (d, J=5.6 Hz, 1H), 6.89 (dd, J=2.7 Hz, J=11.2 Hz, 1H), 6.97
(m, 1H), 7.26 (br, 1H), 7.54 (s, 1H), 7.62 (s, 1H), 8.28 (t, J=9.0
Hz, 1H), 8.47 (d, J=5.6 Hz, 1H)
[0336] Mass analysis, found (ESI-MS, m/z): 386 (M.sup.++1)
Example 9
N-Butyl-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}urea
[0337] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in toluene (8 ml) and triethylamine (1.0 ml) with
heating, and a solution of triphosgene (47 mg) in toluene (1.0 ml)
was then-added to the solution. The mixture was heated under reflux
for min. Next, butylamine (80 mg) was added to the reaction
solution, and the mixture was heated under reflux for additional 5
hr. A saturated aqueous sodium hydrogencarbonate solution was added
to the reaction solution, and the mixture was extracted with ethyl
acetate. The ethyl acetate layer was dried over anhydrous sodium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography on silica gel
by development with chloroform/acetone (2/1) to give 117 mg (yield
81%) of the title compound.
[0338] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.94 (t, J=7.3
Hz, 3H), 1.40 (m, 2H), 1.55 (m, 2H), 3.29 (dd, J=7.1 Hz, J=12.9 Hz,
2H), 4.06 (s, 3H), 4.09 (s, 3H), 5.72 (br, 1H), 6.56 (d, J=5.9 Hz,
1H), 6.88 (dd, J=2.7 Hz, J=11.2 Hz, 1H), 6.97 (d, J=9.0 Hz, 1H),
7.33 (s, 1H), 7.55 (s, 1H), 7.65 (s, 1H), 8.30 (t, J=9.0 Hz, 1H),
8.46 (d, J=5.9 Hz, 1H)
[0339] Mass analysis, found (ESI-MS, m/z): 414 (M.sup.++1)
Example 10
N-(sec-Butyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}urea
[0340] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a
solution of triphosgene (104 mg) in dichloromethane was then added
to the solution. The mixture was heated under reflux for 5 min.
Next, sec-butylamine (48 .mu.l) was added to the reaction solution.
The mixture was heated under reflux for 10 min. The solvent was
removed by distillation under the reduced pressure. The residue was
purified by chromatography on silica gel by development with
chloroform/acetone (8/2) to give 117 mg (yield 89%) of the title
compound.
[0341] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.95 (t, J=7.6
Hz, 3H), 1.18 (d, J=6.6 Hz, 3H), 1.47-1.55 (m, 2H), 3.79-3.89 (m,
1H), 4.04 (s, 6H), 5.28 (d, J=8.1 Hz, 1H), 6.48 (d, J=5.4 Hz, 1H),
6.89-6.98 (m, 2H), 7.08 (d, J=2.7 Hz, 1H), 7.42 (s, 1H), 7.51 (s,
1H), 8.20-8.24 (m, J=9.0 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H)
[0342] Mass analysis, found (ESI-MS, m/z): 414 (M.sup.++1).
Example 11
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N'-isobutylurea
[0343] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a
solution of triphosgene (104 mg) in dichloromethane was then added
to the solution. The mixture was heated under reflux for 5 min.
Next, isobutylamine (50>1) was added to the reaction solution,
and the mixture was heated under reflux for 10 min. The reaction
solution was purified by chromatography on silica gel by
development with chloroform/acetone (4/1). Thus, the title compound
was quantitatively obtained.
[0344] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.94 (d, J=6.6
Hz, 6H), 1.77-1.84 (m, 1H), 3.10-3.13 (m, 2H), 4.03 (s, 3H), 4.03
(s, 3H), 5.58 (t, J=5.4 Hz, 1H), 6.47 (d, J=5.4 Hz, H), 6.88-6.97
(m, 2H), 7.18 (s, 1H), 7.41 (s, 1H), 7.50 (s, 1H), 8.18-8.23 (m,
1H), 8.48 (d, J=5.1 Hz, 1H)
[0345] Mass analysis, found (ESI-MS, m/z): 414 (M.sup.++1)
Example 12
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N'-(1,2-dimethylpropy-
l)urea
[0346] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg)
was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a
solution of triphosgene (47 mg) in dichloromethane was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 1,2-dimethylpropylamine (55 .mu.l) was added to the
reaction solution, and the mixture was stirred at room temperature
for 10 min. The solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography on
silica gel by development with chloroform/acetone (2/1) to give 89
mg (yield 65%) of the title compound.
[0347] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.93 (d, J=2.2
Hz, 3H), 0.95 (d, J=2.4 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H), 1.72-1.80
(m, 1H), 3.76-3.84 (m, 1H), 4.04 (s, 3H), 4.05 (s, 3H), 4.91 (d,
J=8.5 Hz, 1H), 6.48 (d, J=5.4 Hz, 1H), 6.74 (d, J=2.9 Hz, 1H),
6.91-6.98 (m, 2H), 7.42 (s, 1H), 7.51 (s, 1H), 8.18-8.23 (m, 1H),
8.49 (d, J=5.4 Hz, 1H)
[0348] Mass analysis, found (ESI-MS, m/z): 428 (M.sup.++1)
Example 13
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-propylurea
[0349] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg)
was dissolved in chloroform (7.5 ml) and triethylamine (1 ml), and
a solution of triphosgene (99 mg) in chloroform was then added to
the solution. The mixture was heated under reflux for 5 min. Next,
n-propylamine (21 mg) was added to the reaction solution, and the
mixture was heated under reflux for additional 2 hr. A saturated
aqueous sodium hydrogencarbonate solution was added to the reaction
solution, and the mixture was supported on diatomaceous earth,
followed by extraction with chloroform. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol (8/1). Thus, the title compound was
quantitatively obtained.
[0350] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.99 (t, J=7.3
Hz, 3H), 1.58-1.65 (m, 2H), 3.24-3.31 (m, 2H), 4.04 (s, 3H), 4.05
(s, 3H), 4.94 (t, J=5.9 Hz, 1H), 6.48 (d, J=5.1 Hz, 1H), 6.77 (s,
1H), 7.11 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.43
(s, 1H), 7.52 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.50 (d, J=5.1 Hz,
1H)
[0351] Mass analysis, found (FD-MS, m/z): 415, 417 (M.sup.+)
Example 14
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(4-fluoro-2-methyl-
phenyl)urea
[0352] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg)
was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a
solution of triphosgene (110 mg) in dichloromethane was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 4-fluoro-2-methylaniline (126 .mu.l) was added to the
reaction solution, and the mixture was stirred at room temperature
for 2 hr. Methanol was added to the reaction solution, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/acetone (2/1) to give 142 mg (yield 79%) of the
title compound.
[0353] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.37 (s, 3H),
4.04 (s 3H), 4.04 (s, 3H), 6.31 (s, 1H), 6.47 (d, J=5.1 Hz, 1H),
6.97-7.06 (m, 3H), 7.11-7.14 (m, 1H), 7.19 (d, J=2.7 Hz, 1H),
7.41-7.44 (m, 2H), 7.50 (s, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.50 (d,
J=5.4 Hz, 1H)
[0354] Mass analysis, found (ESI-MS, m/z): 482, 484 (M.sup.++1)
Example 15
N-(5-Bromo-6-methyl-2-pyridyl)-N'-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)o-
xy]phenyl}urea
[0355] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg)
was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a
solution of triphosgene (110 mg) in dichloromethane was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 6-amino-3-bromo-2-methylpyridine (208 mg) was added to
the reaction solution, and the mixture was stirred at room
temperature for 2 hr. Methanol was added to the reaction solution,
and the solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography on silica gel
by development with chloroform/acetone (2/1) to give 155 mg (yield
77%) of the title compound.
[0356] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.69 (s, 3H),
4.06 (s, 6H), 6.53 (d, J=5.4 Hz, 1H), 6.56 (d, J=8.5 Hz, 1H),
7.14-7.17 (m, 1H), 7.30 (d, J=2.7 Hz, 1H), 7.44 (s, 1H), 7.53 (s,
1H), 7.75 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 8.49 (d, J=9.0 Hz, 1H),
8.52 (d, J=5.4 Hz, 1H), 11.92 (s, 1H)
[0357] Mass analysis, found (ESI-MS, m/z): 543, 545, 547
(M.sup.++1)
Example 16
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(5-chloro-2-pyridy-
l)urea
[0358] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg)
was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a
solution of triphosgene (110 mg) in dichloromethane was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 2-amino-5-chloropyridine (143 mg) was added to the
reaction solution, and the mixture was stirred at room temperature
for 2 hr. Methanol was added to the reaction solution, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/acetone (2/1) to give 148 mg (yield 82%) of the
title compound.
[0359] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.06 (s, 3H),
4.06 (s, 3H), 6.53 (d, J=5.1 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H),
7.14-7.17 (m, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.44 (s, 1H), 7.53 (s,
1H), 7.64-7.67 (m, 1H), 8.28 (d, J=2.7 Hz, 1H), 8.50-8.53 (m, 2H),
8.92 (s, 1H), 12.11 (brs, 1H)
[0360] Mass analysis, found (ESI-MS, m/z): 485, 487, 489
(M.sup.++1)
Example 17
N-(5-Bromo-2-pyridyl)-N'-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl-
}urea
[0361] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg)
was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a
solution of triphosgene (110 mg) in dichloromethane was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 2-amino-5-bromopyridine (192 mg) was added to the
reaction solution, and the mixture was stirred at room temperature
for 2 hr. Methanol was added to the reaction solution, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/acetone (2/1) to give 108 mg (yield 55%) of the
title compound.
[0362] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.06 (s, 3H),
4.06 (s, 3H), 6.53 (d, J=5.1 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H),
7.14-7.18 (m, 1H), 7.30 (d, J=2.7 Hz, 1H), 7.45 (s, 1H), 7.53 (s,
1H), 7.77-7.80 (m, 1H), 8.15 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.50
(d, J=9.0 Hz, 1H), 8.52 (d, J=5.4 Hz, 1H), 12.09 (brs, 1H)
[0363] Mass analysis, found (ESI-MS, m/z): 529, 531, 533
(M.sup.++1)
Example 18
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(2-methoxyphenyl)u-
rea
[0364] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg)
was dissolved in chloroform (10 ml), and 2-methoxyphenyl isocyanate
(54 mg) was added to the solution. The mixture was stirred at
60.degree. C. overnight. Methanol was added to the reaction
solution, and the solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography on
silica gel by development with chloroform/acetone (6/4) to give 111
mg (yield 77%) of the title compound.
[0365] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.85 (s, 3H),
4.04 (s, 3H), 4.05 (s, 3H), 6.50 (d, J=5.1 Hz, 1H), 6.89-6.93 (m,
1H), 6.98-7.03 (m, 1H), 7.05-7.10 (m, 1H), 7.14 (dd, J=2.7 Hz, 9.0
Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.35 (s, 1H), 7.36 (s, 1H), 7.44
(s, 1H), 7.52 (s, 1H), 8.05-8.07 (m, 1H), 8.34 (d, J=9.0 Hz, 1H),
8.52 (d, J=5.4 Hz, 1H)
[0366] Mass analysis, found (ESI-MS, m/z): 480, 482 (M.sup.++1)
Example 19
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(2-methylphenyl)ur-
ea
[0367] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg)
was dissolved in chloroform (10 ml), and o-toluyl isocyanate (59
mg) was added to the solution. The mixture was stirred at room
temperature overnight. Methanol was added to the reaction solution,
and the solvent was removed by distillation under the reduced
pressure. The residue was dissolved in a minor amount of
chloroform, and a large amount of ether was added to the solution
to precipitate a crystal. The crystal was collected by filtration
to give 59 mg (yield 34%) of the title compound.
[0368] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.38 (s, 3H),
4.04 (s, 3H), 4.05 (s, 3H), 6.22 (s, 1H), 6.47 (d, J=5.1 Hz, 1H),
7.01 (s, 1H), 7.11-7.14 (m, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.25-7.35
(m, 3H), 7.42 (s, 1H), 7.46 (d, J=6.8 Hz, 1H), 7.50 (s, 1H), 8.37
(d, J=8.8 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H)
[0369] Mass analysis, found (ESI-MS, m/z): 464, 466 (M.sup.++1)
Example 20
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(5-methyl-2-pyridy-
l)urea
[0370] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg)
was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a
solution of triphosgene (110 mg) in dichloromethane was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 2-amino-5-picoline (120 mg) was added to the reaction
solution, and the mixture was stirred at room temperature for 2 hr.
Methanol was added to the reaction solution, and the solvent was
removed by distillation under the reduced pressure. The residue was
purified by chromatography on silica gel by development with
chloroform/acetone (2/1) to give 119 mg (yield 69%) of the title
compound.
[0371] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.31 (s, 3H),
4.06 (s, 6H), 6.53 (d, J=5.4 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H),
7.13-7.16 (m, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.43 (s, 1H), 7.49-7.52
(m, 1H), 7.54 (s, 1H), 8.00 (s, 1H), 8.14 (s, 1H), 8.52 (d, J=5.1
Hz, 1H), 8.55 (d, J=9.0 Hz, 1H), 12.57 (brs, 1H)
[0372] Mass analysis, found (ESI-MS, m/z): 465, 467 (M.sup.++1)
Example 21
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(6-methyl-2-pyridy-
l)urea
[0373] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg)
was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a
solution of triphosgene (110 mg) in dichloromethane was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 6-amino-2-picoline (120 mg) was added to the reaction
solution, and the mixture was stirred at room temperature for 2 hr.
Methanol was added to the reaction solution, and the solvent was
removed by distillation under the reduced pressure. The residue was
purified by chromatography on silica gel by development with
chloroform/acetone (2/1) to give 73 mg (yield 42%) of the title
compound.
[0374] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.57 (s, 3H),
4.06 (s, 6H), 6.54 (d, J=5.4 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 6.83
(d, J=7.6 Hz, 1H), 7.15-7.18 (m, 1H), 7.30 (d, J=2.7 Hz, 1H), 7.44
(s, 1H), 7.54-7.59 (m, 2H), 8.36 (s, 1H), 8.52 (d, J=5.1 Hz, 1H),
8.57 (d, J=9.0 Hz, 1H), 12.45 (s, 1H)
[0375] Mass analysis, found (ESI-MS, m/z): 465, 467 (M.sup.++1)
Example 22
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(4-methoxyphenyl)u-
rea hydrochloride
[0376] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg)
was dissolved in chloroform (4 ml), and 4-methoxyphenyl isocyanate
(60 .mu.l) was then added to the solution. A reaction was then
allowed to proceed at room temperature overnight. The solvent was
removed by distillation under the reduced pressure. The residue was
dissolved in a minor amount of chloroform, and a large amount of
ether was added thereto. The resultant precipitate was collected by
suction filtration to give 90 mg (yield 67%) of
N-2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl-N'-(4-methoxy-pheny-
l)urea. This product was suspended in 4 ml of methanol, and a
hydrochloric acid-methanol solution was added to the suspension.
The mixture was stirred at room temperature for 4 hr, and the
solvent was then removed by distillation to give the title
compound.
[0377] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.73 (s, 3H),
4.03 (s, 3H), 4.05 (s, 3H), 6.90 (d, J=9.3 Hz, 2H), 6.97 (d, J=6.6
Hz, 1H), 7.37-7.41 (m, 3H), 7.62 (s, 1H), 7.67 (d, J=2.7 Hz, 1H),
8.39 (d, J=9.0 Hz, 1H), 8.49 (s, 1H), 8.82 (d, J=6.6 Hz, 1H), 9.49
(s, 1H)
Example 23
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(1-naphthyl)urea
[0378] 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg)
was dissolved in chloroform (10 ml), and 1-naphthyl isocyanate (75
mg) was added to the solution. The mixture was stirred at room
temperature overnight. Methanol was added to the reaction solution,
and the solvent was removed by distillation under the reduced
pressure. The residue was dissolved in a minor amount of
chloroform, and a large amount of ether was added to the solution
to precipitate a crystal. The crystal was collected by filtration
to give 105 mg (yield 57%) of the title compound.
[0379] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.03 (s, 3H),
4.04 (s, 3H), 6.44 (d, J=5.4 Hz, 1H), 6.72 (s, 1H), 7.10-7.13 (m,
3H), 7.41 (s, 1H), 7.48 (s, 1H), 7.55-7.69 (m, 4H), 7.88-7.96 (m,
2H), 8.15 (d, J=7.6 Hz, 1H), 8.38-8.40 (m, 1H), 8.48 (d, J=5.1 Hz,
1H)
[0380] Mass analysis, found (ESI-MS, m/z): 500, 502 (M.sup.++1)
Example 24
N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,3-dimethylp-
henyl}urea
[0381] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (710
mg) was dissolved in chloroform (7 ml), and 2,4-difluorophenyl
isocyanate (310 .mu.l) was then added to the solution. The mixture
was heated under reflux for one hr, and a large amount of ether was
added to the reaction solution. The resultant precipitate was
collected by suction filtration to give 735 mg (yield 70%) of the
title compound.
[0382] .sup.1H-NMR (CDCl.sub.3, 400 MHz): b 2.14 (s, 3H), 2.27 (s,
3H), 4.04 (s, 3H), 4.06 (s, 3H), 6.27 (d, J=5.4 Hz, 1H), 6.78-6.89
.mu.m, 2H), 6.95 (s, 1H), 7.03 (d, J=8.5 Hz, 1H), 7.10 (s, 1H),
7.40-7.45 (m, 2H), 7.61 (s, 1H), 8.03-8.12 (m, 1H), 8.46 (d, J=5.4
Hz, 1H)
[0383] Mass analysis, found (FAB-MS, m/z): 480 (M.sup.++1)
Example 25
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-N'-(4-fluoro-2-me-
thylphenyl)urea
[0384] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (110 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 4-fluoro-2-methylaniline (126 .mu.l) was added to
the reaction solution, and the mixture was stirred at room
temperature for 2 hr. Methanol was added to the reaction solution,
and the solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography on silica gel
by development with chloroform/methanol (91/9) to give 160 mg
(yield 91%) of the title compound.
[0385] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.12 (s, 3H),
2.22 (s, 3H), 2.25 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H), 6.24 (d,
J=5.1 Hz, 1H), 6.33 (s, 1H), 6.42 (s, 1H), 6.94-7.03 (m, 3H), 7.43
(s, 1H), 7.46-7.55 (m, 2H), 7.60 (s, 1H), 8.43 (d, J=5.1 Hz,
1H)
[0386] Mass analysis, found (ESI-MS, m/z): 476 (M.sup.++1)
Example 26
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-N'-(3-fluoro-2-me-
thoxyphenyl)urea
[0387] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (110 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 3-fluoro-o-anisidine (132 .mu.l) was added to the
reaction solution, and the mixture was stirred at room temperature
for 2 hr. Methanol was added to the reaction solution, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/methanol (91/9) to give 23 mg (yield 13%) of the
title compound.
[0388] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.15 (s, 3H),
2.32 (s, 3H), 3.84 (d, J=1.7 Hz, 3H), 4.05 (s, 3H), 4.08 (s, 3H),
6.28 (d, J=5.4 Hz, 1H), 6.72-6.77 (m, 1H), 6.96-7.09 (m, 3H), 7.43
(d, J=8.5 Hz, 1H), 7.46 (s, 1H), 7.60 (s, 1H), 7.62 (s, 1H),
8.02-8.05 (m, 1H), 8.46 (d, J=5.4 Hz, 1H)
[0389] Mass analysis, found (ESI-MS, m/z): 492 (M.sup.++1)
Example 27
N-(5-Bromo-6-methyl-2-pyridyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,3-d-
imethylphenyl}urea
[0390] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (110 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 6-amino-3-bromo-2-methylpyridine (208 mg) was
added to the reaction solution, and the mixture was stirred at room
temperature for 2 hr. Methanol was added to the reaction solution,
and the solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography on silica gel
by development with chloroform/methanol (91/9) to give 103 mg
(yield 52%) of the title compound.
[0391] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.16 (s, 3H),
2.42 (s, 3H), 2.65 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H), 6.32 (d,
J=5.1 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 7.44
(s, 1H), 7.64 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz,
1H), 8.29 (s, 1H), 8.45 (d, J=5.4 Hz, 1H), 11.30 (brs, 1H)
[0392] Mass analysis, found (ESI-MS, m/z): 537, 539 (M.sup.++1)
Example 28
N-(5-Chloro-2-pyridyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,3-dimethylp-
henyl}urea
[0393] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (3.00
g) was dissolved in chloroform (150 ml) and triethylamine (6 ml),
and a solution of triphosgene (2.74 g) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 2-amino-5-chloropyridine (2.38 g) was added to
the reaction solution, and the mixture was then stirred at room
temperature for additional 2 hr. A saturated aqueous sodium
hydrogencarbonate solution was added to the reaction solution, and
the mixture was extracted with chloroform. The chloroform layer was
dried over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure, and the residue was
purified by chromatography on silica gel by development with
chloroform/methanol (20/1) to give 3.4 g (yield 77%) of the title
compound.
[0394] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.16 (s, 3H),
2.38 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H), 6.31 (d, J=5.4 Hz, 1H),
6.89 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 7.44 (s, 1H),
7.62-7.68 (m, 2H), 7.90 (d, J=8.8 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H),
8.45 (d, J=5.4 Hz, 1H), 8.50 (s, 1H), 11.23 (brs, 1H)
[0395] Mass analysis, found (ESI-MS, m/z): 479, 481 (M.sup.++1)
Example 29
N-(5-Bromo-2-pyridyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,3-dimethylph-
enyl}urea
[0396] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (110 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 2-amino-5-bromopyridine (192 mg) was added to the
reaction solution, and the mixture was stirred at room temperature
for 2 hr. Methanol was added to the reaction solution, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/methanol (91/9). The solvent was removed by
distillation, and a crystal was precipitated from a minor amount of
methanol and a large amount of ether. The crystal was collected by
filtration to give 80 mg (yield 41%) of the title compound.
[0397] .sup.1H-NMR (CDCl.sub.31 400 MHz): .delta. 2.16 (s, 3H),
2.38 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H), 6.31 (d, J=5.1 Hz, 1H),
6.96 (d, J=8.5 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.45 (s, 1H), 7.64
(s, 1H), 7.75-7.77 (m, 1H), 7.89 (d, J=8.8 Hz, 1H), 8.31 (d, J=2.4
Hz, 1H), 8.45 (d, J=5.4 Hz, 1H), 8.81 (s, 1H), 11.17 (brs, 1H)
[0398] Mass analysis, found (ESI-MS, m/z): 523, 525 (M.sup.++1)
Example 30
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-N'-(2-methoxyphen-
yl)urea
[0399] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120
mg) was dissolved in chloroform (10 ml), and 2-methoxyphenyl
isocyanate (60 .mu.l) was added to the solution. The mixture was
stirred at room temperature overnight. Methanol was added to the
reaction solution, and the solvent was removed by distillation
under the reduced pressure. The residue was dissolved in a minor
amount of chloroform, and a large amount of ether was added thereto
to precipitate a crystal which was then collected by filtration to
give 131 mg (yield 75%) of the title compound.
[0400] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.16 (s, 3H),
2.32 (s, 3H), 3.81 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H), 6.25 (s,
1H), 6.26 (d, J=5.4 Hz, 1H), 6.85-6.87 (m, 1H), 6.97-7.07 (m, 4H),
7.41 (d, J=8.5 Hz, 1H), 7.44 (s, 1H), 7.62 (s, 1H), 8.15-8.17 (m,
1H), 8.45 (d, J=5.4 Hz, 1H)
[0401] Mass analysis, found (ESI-MS, m/z): 474 (M.sup.++1)
Example 31
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-N'-(2-methylpheny-
l)urea
[0402] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120
mg) was dissolved in chloroform (10 ml), and o-toluyl isocyanate
(55 .mu.l) was added to the solution. The mixture was stirred at
room temperature overnight. Methanol was added to the reaction
solution, and the solvent was removed by distillation under the
reduced pressure. The residue was dissolved in a minor amount of
chloroform, and a large amount of ether was added to the solution
to precipitate a crystal which was then collected by filtration to
give 130 mg (yield 70%) of the title compound.
[0403] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.12 (s, 3H),
2.22 (s, 3H), 2.26 (s, 3H), 4.05 (s, 3H), 4.07 (s, 3H), 6.23-6.28
(m, 3H), 7.02 (d, J=8.5 Hz, 1H), 7.14-7.17 (m, 1H), 7.24-7.29 (m,
2H), 7.43 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.60 (s, 1H), 7.63 (d,
J=7.3 Hz, 1H), 8.43 (d, J=5.4 Hz, 1H)
[0404] Mass analysis, found (ESI-MS, m/z): 458 (M.sup.++1)
Example 32
N-(4-Chloro-2-methylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,3-dime-
thylphenyl}urea
[0405] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (110 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 4-chloro-2-methylaniline (130 .mu.l) was added to
the reaction solution, and the mixture was stirred at room
temperature for 2 hr. Methanol was added to the reaction solution,
and the solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography on silica gel
by development with chloroform/methanol (91/9) to give 136 mg
(yield 75%) of the title compound.
[0406] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.14 (s, 3H),
2.18 (s, 3H), 2.27 (s, 3H), 4.05 (s, 3H), 4.07 (s, 3H), 6.24 (d,
J=5.4 Hz, 1H), 6.33 (s, 1H), 6.40 (s, 1H), 7.03 (d, J=8.5 Hz, 1H),
7.19-7.21 (m, 2H), 7.42-7.44 (m, 2H), 7.60 (s, 1H), 7.65 (d, J=9.0
Hz, 1H), 8.44 (d, J=5.1 Hz, 1H)
[0407] Mass analysis, found (ESI-MS, m/z): 492, 494 (M.sup.++1)
Example 33
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-N'-(2-pyridyl)ure-
a
[0408] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (110 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 2-aminopyridine (104 mg) was added to the
reaction solution, and the mixture was heated under reflux
overnight. Methanol was added to the reaction solution, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/methanol (91/9) to give 72 mg (yield 44%) of the
title compound.
[0409] .sup.1H-NMR (CDCl.sub.31 400 MHz): .delta. 2.16 (s, 3H),
2.41 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H), 6.32 (d, J=5.4 Hz, 1H),
6.92-6.98 (m, 2H), 7.04 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.65 (s,
1H), 7.67-7.69 (m, 1H), 7.97 (d, J=8.8 Hz, 1H), 8.25-8.27 (m, 1H),
8.45 (d, J=5.1 Hz, 1H), 8.72 (s, 1H), 11.77 (br, 1H)
[0410] Mass analysis, found (ESI-MS, m/z): 445 (M.sup.++1)
Example 34
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-N'-(5-methyl-2-py-
ridyl)urea
[0411] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (110 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 2-amino-5-picoline (120 mg) was added to the
reaction solution, and the mixture was stirred at room temperature
for 2 hr. Methanol was added to the reaction solution, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/methanol (91/9) to give 122 mg (yield 72%) of the
title compound.
[0412] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.15 (s, 3H),
2.28 (s, 3H), 2.39 (s, 3H), 4.04 (s, 3H), 4.07 (s, 3H), 6.32 (d,
J=5.4 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 7.43
(s, 1H), 7.45-7.48 (m, 1H), 7.64 (s, 1H), 7.99 (d, J=8.8 Hz, 1H),
8.06 (d, J=1.5 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H), 9.23 (s, 1H), 11.77
(br, 1H)
[0413] Mass analysis, found (FD-MS, m/z): 458 (M.sup.+)
Example 35
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-N'-(6-methyl-2-py-
ridyl)urea
[0414] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (110 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 6-amino-2-picoline (120 mg) was added to the
reaction solution, and the mixture was heated under reflux
overnight. Methanol was added to the reaction solution, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/acetone (40/60) to give 64 mg (yield 38%) of the
title compound.
[0415] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.16 (s, 3H),
2.44 (s, 3H), 2.54 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H), 6.32 (d,
J=5.4 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 7.04
(d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.53-7.57 (m, 1H), 7.65 (s, 1H),
7.79 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 8.44 (d, J=5.1 Hz, 1H), 11.76
(br, 1H)
[0416] Mass analysis, found (FD-MS, m/z): 458 (M.sup.+)
Example 36
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-N'-(4-methoxyphen-
yl)urea
[0417] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100
mg) was dissolved in chloroform (4 ml), and 4-methoxyphenyl
isocyanate (60 .mu.l) was then added to the solution. The mixture
was allowed to react at room temperature overnight, and the solvent
was removed by distillation under the reduced pressure. The residue
was dissolved in a minor amount of chloroform, and a large amount
of ether was added to the solution. The resultant precipitate was
then collected by suction filtration to give 115 mg (yield 78%) of
the title compound.
[0418] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.02 (s, 3H),
2.30 (s, 3H), 3.76 (s, 3H), 4.06 (s, 3H), 4.12 (s, 3H), 6.46 (d,
J=6.3 Hz, 1H), 6.78 (d, J=9.0 Hz, 2H), 6.91 (d, J=8.8 Hz, 1H), 7.39
(d, J=9.0 Hz, 2H), 7.67 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.92 (s,
1H), 8.20-8.23 (m, 1H)
[0419] Mass analysis, found (ESI-MS, m/z): 474 (M.sup.++1)
Example 37
N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,5-dimethylp-
henyl}urea
[0420] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (200
mg) was dissolved in chloroform (15 ml), and 2,4-difluorophenyl
isocyanate (88 .mu.l) was then added to the solution. The mixture
was heated under reflux for one hr. The reaction solution was
purified by chromatography on silica gel by development with
chloroform/acetone (4/1) to give 287 mg (yield 97%) of the title
compound.
[0421] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.17 (s, 3H),
2.26 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H), 6.31 (d, J=5.4 Hz, 1H),
6.57 (s, 1H), 6.81-6.95 (m, 3H), 7.00 (s, 1H), 7.43 (s, 1H), 7.55
(s, 1H), 7.59 (s, 1H), 8.05-8.13 (m, 1H), 8.47 (d, J=5.4 Hz,
1H)
[0422] Mass analysis, found (FD-MS, m/z): 479 (M.sup.+)
Example 38
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N'-propylurea
[0423] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (150
mg) was dissolved in chloroform (13 ml) and triethylamine (1.5 ml),
and a solution of triphosgene (151 mg) in chloroform was then added
to the solution. The mixture was heated under reflux for 5 min.
Next, n-propylamine (33 mg) was added to the reaction solution, and
the mixture was heated under reflux for additional 2 hr. A
saturated aqueous sodium hydrogencarbonate solution was added to
the reaction solution, and the mixture was supported on
diatomaceous earth, followed by extraction with chloroform. The
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/acetone (4/1) to give 178 mg (yield 95%) of the
title compound.
[0424] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.94 (t, J=7.3
Hz, 3H), 1.51-1.65 (m, 2H), 2.15 (s, 3H), 2.26 (s, 3H), 3.21-3.28
(m, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 4.63-4.69 (m, 1H), 5.97 (s,
1H), 6.31 (d, J=5.1 Hz, 1H), 6.98 (s, 1H), 7.43 (s, 2H), 7.58 (s,
1H), 8.46 (d, J=5.4 Hz, 1H)
[0425] Mass analysis, found (FD-MS, m/z): 409 (M.sup.+)
Example 39
N-(4-Chloro-2-methylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,5-dime-
thylphenyl}urea
[0426] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (1001
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (92 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 4-chloro-2-methylaniline (44 .mu.l) was added to
the reaction solution, and the mixture was stirred at room
temperature overnight. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, followed by extraction
with chloroform. The chloroform layer was dried over sodium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was dissolved in a minor amount of
chloroform, and a large amount of ether was added to the solution
to precipitate a crystal which was then collected by filtration to
give 118 mg (yield 78%) of the title compound.
[0427] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.16 (s, 3H),
2.21 (s, 3H), 2.23 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H), 6.28 (d,
J=5.4 Hz, 1H), 6.30 (s, 1H), 6.32 (s, 1H), 6.98 (s, 1H), 7.22-7.23
(m, 2H), 7.43 (s, 1H), 7.58 (s, 1H), 7.59-7.63 (m, 2H), 8.45 (d,
J=5.1 Hz, 1H)
[0428] Mass analysis, found (ESI-MS, m/z): 492, 494 (M.sup.++1)
Example 40
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N'-(4-fluoro-2-me-
thylphenyl)urea
[0429] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (92 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 4-fluoro-2-methylaniline (42 .mu.l) was added to
the reaction solution, and the mixture was stirred at room
temperature overnight. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, and the mixture was
extracted with chloroform. The chloroform layer was dried over
sodium sulfate. The solvent was removed by distillation under the
reduced pressure. The residue was dissolved in a minor amount of
chloroform, and a large amount of ether was added to the solution
to precipitate a crystal which was then collected by filtration to
give 108 mg (yield 74%) of the title compound.
[0430] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.15 (s, 6H),
2.30 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H), 6.24 (s, 2H), 6.28 (d,
J=5.1 Hz, 1H), 6.94 (s, 1H), 6.96-7.00 (m, 2H), 7.42 (s, 1H),
7.49-7.52 (m, 1H), 7.58 (s, 1H), 7.64 (s, 1H), 8.44 (d, J=5.1 Hz,
1H)
[0431] Mass analysis, found (ESI-MS, m/z): 476 (M.sup.++1)
Example 41
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N'-(3-fluoro-2-me-
thoxyphenyl)urea
[0432] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (92 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 3-fluoro-o-anisidine (44 .mu.l) was added to the
reaction solution, and the mixture was stirred at room temperature
overnight. A saturated aqueous sodium hydrogencarbonate solution
was added to the reaction solution, and the mixture was extracted
with chloroform. The chloroform layer was dried over sodium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography on silica gel
by development with chloroform/acetone (2/1) to give 126 mg (yield
83%) of the title compound.
[0433] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.16 (s, 3H),
2.27 (s, 3H), 3.83 (d, J=1.7 Hz, 3H), 4.04 (s, 3H), 4.07 (s, 3H),
6.31 (d, J=5.1 Hz, 1H), 6.74-6.79 (m, 1H), 6.97-7.03 (m, 3H), 7.44
(s, 1H), 7.57 (s, 1H), 7.60 (s, 1H), 7.66 (s, 1H), 8.02-8.04 (m,
1H), 8.48 (d, J=5.1 Hz, 1H)
[0434] Mass analysis, found (ESI-MS, m/z): 492 (M.sup.++1)
Example 42
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N'-(2-methylpheny-
l)urea
[0435] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100
mg) was dissolved in chloroform (10 ml), and o-toluyl isocyanate
(46 .mu.l) was added to the solution. The mixture was stirred at
room temperature overnight. Methanol was added to the reaction
solution, and the solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography on
silica gel by development with chloroform/acetone (2/1) to give 111
mg (yield 79%) of the title compound.
[0436] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.12 (s, 6H),
2.26 (s, 3H), 4.03 (s, 3H), 4.05 (s, 3H), 6.27 (d, J=5.1 Hz, 1H),
6.77 (s, 1H), 6.81 (s, 1H), 6.91 (s, 1H), 7.11-7.15 (m, 1H), 7.22
(s, 1H), 7.24 (s, 1H), 7.42 (s, 1H), 7.59 (s, 1H), 7.63 (d, J=7.8
Hz, 1H), 7.68 (s, 1H), 8.43 (d, J=5.4 Hz, 1H)
[0437] Mass analysis, found (ESI-MS, m/z): 458 (M.sup.++1)
Example 43
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N'-(2-methoxyphen-
yl)urea
[0438] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100
mg) was dissolved in chloroform (10 ml), and 2-methoxyphenyl
isocyanate (49 .mu.l) was added to the solution. The mixture was
heated under reflux overnight. Methanol was added to the reaction
solution. The solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography on silica gel
by development with chloroform/acetone (2/1) to quantitatively give
the title compound.
[0439] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.14 (s, 3H),
2.24 (s, 3H), 3.75 (s, 3H), 4.03 (s, 3H), 4.07 (s, 3H), 6.31 (d,
J=5.1 Hz, 1H), 6.84-6.87 (m, 1H), 6.95-7.03 (m, 3H), 7.06 (s, 1H),
7.44 (s, 1H), 7.56 (s, 1H), 7.61 (s, 1H), 7.63 (s, 1H), 8.17-8.20
(m, 1H), 8.46 (d, J=5.1 Hz, 1H)
[0440] Mass analysis, found (ESI-MS, m/z): 474 (M.sup.++1)
Example 44
N-(5-Bromo-6-methyl-2-pyridyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,5-d-
imethylphenyl}urea
[0441] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (92 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 6-amino-3-bromo-2-methylpyridine (69 mg) was
added to the reaction solution, and the mixture was stirred at room
temperature overnight. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, and the mixture was
extracted with chloroform. The chloroform layer was dried over
sodium sulfate. The solvent was removed by distillation under the
reduced pressure. The residue was dissolved in a minor amount of
chloroform, and a larger amount of ether was added to the solution
to precipitate a crystal which was then collected by filtration to
give 80 mg (yield 48%) of the title compound.
[0442] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.18 (s, 3H),
2.42 (s, 3H), 2.65 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H), 6.34 (d,
J=5.4 Hz, 1H), 6.57 (d, J=8.5 Hz, 1H), 6.98 (s, 1H), 7.43 (s, 1H),
7.62 (s, 1H), 7.70 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 8.05 (s, 1H),
8.46 (d, J=5.4 Hz, 1H), 11.17 (br, 1H)
[0443] Mass analysis, found (ESI-MS, m/z): 537, 539 (M.sup.++1)
Example 45
N-(2,6-Dimethoxy-3-pyridyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,5-dime-
thylphenyl}urea
[0444] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100
mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml),
and a solution of triphosgene (92 mg) in dichloromethane was then
added to the solution. The mixture was stirred at room temperature
for 30 min. Next, 3-amino-2,6-dimethoxypyridine (70 mg) was added
to the reaction solution, and the mixture was stirred at room
temperature overnight. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, and the mixture was
extracted with chloroform. The chloroform layer was dried over
sodium sulfate. The solvent was removed by distillation under the
reduced pressure. The residue was dissolved in a minor amount of
chloroform, and a large amount of ether was added to the solution
to precipitate a crystal which was then collected by filtration to
give 124 mg (yield 79%) of the title compound.
[0445] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.17 (s, 3H),
2.27 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H), 4.06 (s, 3H), 4.07 (s,
3H), 6.31 (d, J=5.1 Hz, 1H), 6.34 (d, J=8.5 Hz, 1H), 6.36 (s, 1H),
6.74 (s, 1H), 6.99 (s, 1H), 7.44 (s, 1H), 7.57 (s, 1H), 7.60 (s,
1H), 8.20 (d, J=8.3 Hz, 1H), 8.46 (d, J=5.1 Hz, 1H)
[0446] Mass analysis, found (ESI-MS, m/z): 505 (M.sup.++1)
Example 46
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N'-(4-methoxyphen-
yl)urea
[0447] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100
mg) was dissolved in chloroform (4 ml), and 4-methoxyphenyl
isocyanate (60 .mu.l) was then added to the solution. The mixture
was allowed to react at room temperature overnight. The solvent was
removed by distillation under the reduced pressure. The residue was
dissolved in a minor amount of chloroform, and a large amount of
ether was added to the solution. The resultant precipitate was
collected by suction filtration to give 110 mg (yield 74%) of the
title compound.
[0448] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.07 (s, 3H),
2.26 (s, 3H), 3.76 (s, 3H), 4.03 (s, 3H), 4.08 (s, 3H), 6.39 (d,
J=6.1 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.87 (s, 1H), 7.36 (d, J=9.0
Hz, 2H), 7.55 (br, 1H), 7.62 (s, 1H), 7.67 (s, 1H), 7.80 (s, 1H),
8.19 (br, 1H), 8.27 (d, J=6.1 Hz, 1H)
[0449] Mass analysis, found (ESI-MS, m/z): 474 (M.sup.++1)
Example 47
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitrophenyl}-N'-propylurea
[0450] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (150 mg)
was dissolved in chloroform (10 ml) and triethylamine (1.5 ml), and
a solution of triphosgene (144 mg) in chloroform was then added to
the solution. The mixture was heated under reflux for 5 min. Next,
n-propylamine (31 mg) was added. The mixture was heated under
reflux for additional 2 hr. A saturated aqueous sodium
hydrogencarbonate solution was added to the reaction solution, and
the mixture was supported on diatomaceous earth, followed by
extraction with chloroform. The solvent was removed by distillation
under the reduced pressure. The residue was purified by
chromatography on silica gel by development with chloroform/acetone
(4/1) to give 160 mg (yield 86%) of the title compound.
[0451] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.01 (t, J=7.5
Hz, 3H), 1.59-1.69 (m, 2H), 3.27-3.34 (m, 2H), 4.05 (s, 3H), 4.06
(s, 3H), 4.95-5.01 (br, 1H), 6.47 (d, J=5.4 Hz, 1H), 7.43-7.51 (m,
3H), 8.04 (d, J=2.7 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.81 (d, J=9.3
Hz, 1H), 9.74-9.79 (br, 1H)
[0452] Mass analysis, found (FD-MS, m/z): 426 (M.sup.+)
Example 48
N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-nitrophenyl-
}urea
[0453] 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (100 mg)
was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a
solution of triphosgene (96 mg) in chloroform was then added to the
solution. The mixture was heated under reflux for 5 min. Next,
2,4-difluoroaniline (45 mg) was added to the reaction solution, and
the mixture was further heated under reflux overnight. A saturated
aqueous sodium hydrogencarbonate solution was added to the reaction
solution, and the mixture was supported on diatomaceous earth,
followed by extraction with chloroform. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by thin-layer chromatography on silica gel by development with
chloroform/acetone (3/1) to give 81 mg (yield 56%) of the title
compound.
[0454] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.05 (s, 3H),
4.06 (s, 3H), 6.50 (d, J=5.1 Hz, 1H), 6.91-6.98 (m, 3H), 7.45 (s,
1H), 7.49 (s, 1H), 7.50-7.54 (m, 1H), 7.88-7.97 (m, 1H), 8.05 (d,
J=2.9 Hz, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.77 (d, J=9.3 Hz, 1H), 9.98
(s, 1H)
[0455] Mass analysis, found (FD-MS, m/z): 496 (M.sup.+)
Example 49
N-{3,5-Dichloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(2,4-difluorop-
henyl)urea
[0456] 3,5-Dichloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]-aniline (53
mg) was dissolved in chloroform (5 ml), and 2,4-difluorophenyl
isocyanate (34 .mu.l) was added to the solution. The mixture was
heated under reflux overnight. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/acetone (2/1) to give 56 mg (yield 74%) of the title
compound.
[0457] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.05 (s, 3H),
4.09 (s, 3H), 6.26 (d, J=5.4 Hz, 1H), 6.86-6.93 (m, 2H), 7.05 (s,
1H), 7.44 (s, 1H), 7.46 (s, 1H), 7.60 (s, 2H), 7.64 (s, 1H),
8.01-8.05 (m, 1H), 8.48 (d, J=5.4 Hz, 1H)
[0458] Mass analysis, found (FAB-MS, M/z): 520, 522, 524
(M.sup.++1)
Example 50
N-(2,4-Difluorophenyl)-N'-(2-fluoro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-
-quinolyl]oxy}phenyl)-urea
[0459]
N-(2,4-Difluorophenyl)-N'-{2-fluoro-4-[(7-hydroxy-6-methoxy-4-quin-
olyl)oxy]phenyl}urea (20 mg), potassium carbonate (7 mg),
tetra-n-butylammonium iodide (2 mg), and
N-(2-chloroethyl)morpholine hydrochloride (10 mg) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at
70.degree. C. overnight. A saturated aqueous sodium
hydrogencarbonate solution was added to the reaction solution, and
the mixture was extracted with chloroform. The chloroform layer was
dried over anhydrous magnesium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by thin-layer chromatography on silica gel by development with
chloroform/methanol (30/1) to give 14 mg (yield 57%) of the title
compound.
[0460] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.57 (t, J=4.4
Hz, 4H), 2.88 (m, 2H), 3.69 (t, J=4.4 Hz, 4H), 3.94 (s, 3H), 4.26
(t, J=5.9 Hz, 2H), 6.43 (d, J=5.1 Hz, 1H), 6.77-6.95 (m, 4H), 7.35
(s, 1H), 7.43 (s, 1H), 7.96-8.02 (m, 1H), 8.13-8.17 (m, 1H), 8.44
(d, J=5.1 Hz, 1H)
Example 51
N-(2-Chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-quinolyl]oxy}phenyl)-N'-
-(2,4-difluorophenyl)urea
[0461]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N'-(2,-
4-difluorophenyl)urea (174 mg) was dissolved in
N,N-dimethylformamide (9 ml), and potassium carbonate (64 mg),
tetra-n-butylammonium iodide (14 mg), and
N-(2-chloroethyl)morpholine hydrochloride (86 mg) were then added
to the solution. The mixture was stirred at 70.degree. C. for 17
hr, and a saturated aqueous sodium hydrogencarbonate solution was
then added to the reaction solution, followed by extraction with
chloroform. The chloroform layer was dried over anhydrous sodium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography on silica gel
by development with chloroform/methanol (20/1) to give 75 mg (yield
35%) of the title compound.
[0462] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.60-2.67 (m,
4H), 2.95 (t, J=6.0 Hz, 2H), 3.71-3.79 (m, 4H), 4.01 (s, 3H), 4.33
(t, J=6.0 Hz, 2H), 6.50 (d, J=5.1 Hz, 1H), 6.85-6.97 (m, 2H),
7.09-7.17 (m, 2H), 7.22-7.27 (m, 2H), 7.42 (s, 1H), 7.50 (s, 1H),
7.97-8.01 (m, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.51 (d, J=5.1 Hz,
1H)
[0463] Mass analysis, found (ESI-MS, m/z): 585, 587 (M.sup.++1)
Example 52
N-(2,4-Difluorophenyl)-N'-(4-{[6-methoxy-7-(2-morpholinoethoxy)-4-quinolyl-
]oxy}-2,5-dimethylphenyl)urea
[0464]
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-
-N'-(2,4-difluorophenyl)urea (366 mg) was dissolved in
N,N-dimethylformamide (6 ml), and palladium hydroxide (366 mg) was
added to the solution. The mixture was stirred in a hydrogen
atmosphere at room temperature overnight. The solvent was removed
by distillation under the reduced pressure. The residue was
dissolved in chloroform and methanol. The reaction solution was
filtered through Celite. Next, the solvent was removed by
distillation under the reduced pressure. The residue (213 mg),
potassium carbonate (109 mg), tetra-n-butylammonium iodide (12 mg),
and N-(2-chloroethyl)morpholine hydrochloride (74 mg) were
dissolved in N,N-dimethylformamide (5 ml), and the solution was
stirred at 70.degree. C. overnight. The solvent was removed by
distillation under the reduced pressure. Water was added to the
residue, and the mixture was extracted with chloroform. The
chloroform layer was dried over sodium sulfate. The solvent was
removed by distillation under the reduced pressure. The residue was
purified by thin-layer chromatography on silica gel by development
with chloroform/methanol (10/1) to give 106 mg (yield 55%) of the
title compound.
[0465] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.17 (s, 3H),
2.27 (s, 3H), 2.64 (t, J=4.6 Hz, 4H), 2.96 (t, J=6.0 Hz, 2H), 3.76
(t, J=4.6 Hz, 4H), 4.03 (s, 3H), 4.34 (t, J=6.0 Hz, 2H), 6.31 (d,
J=5.4 Hz, 1H), 6.47 (s, 1H), 6.81-6.92 (m, 3H), 7.00 (s, 1H), 7.43
(s, 1H), 7.54 (s, 1H), 7.58 (s, 1H), 8.05-8.12 (m, 1H), 8.47 (d,
J=5.4 Hz, 1H)
Example 53
N-(4-{[6-Methoxy-7-(2-morpholinoethoxy)-4-quinolyl]oxy}-2,5-dimethylphenyl-
)-N'-(2-methoxyphenyl)-urea
[0466]
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-
-N'-(2-methoxyphenyl)urea (363 mg) was dissolved in
N,N-dimethylformamide (6 ml), and palladium hydroxide (363 mg) was
added to the solution. The mixture was stirred in a hydrogen
atmosphere at room temperature overnight. The solvent was removed
by distillation under the reduced pressure. The residue was
dissolved in chloroform and methanol, and the solution was filtered
through Celite. Next, the solvent was removed by distillation under
the reduced pressure. The residue (191 mg), potassium carbonate
(219 mg), tetra-n-butylammonium iodide (12 mg), and
N-(2-chloroethyl)morpholine hydrochloride (148 mg) were dissolved
in N,N-dimethylformamide (5 ml). The solution was stirred at
70.degree. C. overnight. The solvent was removed by distillation
under the reduced pressure. Water was added to the residue, and the
mixture was extracted with chloroform. The chloroform layer was
dried over sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by thin-layer
chromatography on silica gel by development with
chloroform/methanol (10/1) to give 101 mg (yield 55%) of the title
compound.
[0467] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.17 (s, 3H),
2.28 (s, 3H), 2.64 (t, J=4.5 Hz, 4H), 2.96 (t, J=5.9 Hz, 2H), 3.76
(t, J=4.6 Hz, 4H), 3.83 (s, 3H), 4.04 (s, 3H), 4.34 (t, J=6.0 Hz,
2H), 6.30 (d, J=5.4 Hz, 2H), 6.86-6.90 (m, 1H), 6.96-7.06 (m, 3H),
7.16 (s, 1H), 7.43 (s, 1H), 7.57 (s, 1H), 7.59 (s, 1H), 8.11-8.16
(m, 1H), 8.46 (d, J=5.4 Hz, 1H)
Example 54
N-(2-Chloro-4-{[6-methoxy-7-(2-methoxyethoxy)-4-quinolyl]oxy}phenyl)-N'-(2-
,4-difluorophenyl)urea
[0468] Sodium hydride (60 wt %, 153 mg) was added to dimethyl
sulfoxide (2 ml), and the mixture was stirred at 60.degree. C. for
30 min and was then cooled to room temperature.
4-Amino-3-chlorophenol hydrochloride (343 mg) was added to the
reaction solution, and the mixture was stirred at room temperature
for 10 min. Next, a solution of
4-chloro-6-methoxy-7-(2-methoxyethoxy)-quinoline (254 mg) in
dimethyl sulfoxide (2 ml) was added to the reaction solution. The
mixture was stirred at 110.degree. C. overnight. Water was added to
the reaction solution, followed by extraction with chloroform. The
chloroform layer was then washed with a saturated aqueous sodium
hydrogencarbonate solution and was dried over anhydrous sodium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography on silica gel
by development with chloroform/acetone (7/3) to give 332 mg of a
mixture containing
2-chloro-4-{[(6-methoxy-7-(2-methoxyethoxy)-4-quinolyl]oxy}aniline
as a major product. A 83 mg portion of the mixture was dissolved in
chloroform (5 ml), and 2,4-difluorophenyl isocyanate (32 .mu.l) was
added to the solution. The mixture was heated under reflux
overnight. The solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography on
silica gel by development with chloroform/acetone (2/1) to give 50
mg of the title compound.
[0469] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.75-3.77 (m,
2H), 3.94 (s, 3H), 4.27-4.29 (m, 2H), 6.55 (d, J=5.1 Hz, 1H),
7.04-7.09 (m, 1H), 7.25-7.36 (m, 2H), 7.42 (s, 1H), 7.50 (s, 1H),
7.51 (s, 1H), 8.09-8.15 (m, 1H), 8.24 (d, J=9.0 Hz, 1H), 8.49 (d,
J=5.4 Hz, 1H), 8.82 (s, 1H), 9.31 (s, 1H)
Example 55
N-(2-Chloro-4-{[6-methoxy-7-(2-methoxyethoxy)-4-quinolyl]oxy}phenyl)-N'-(2-
-methoxyphenyl)urea
[0470] Sodium hydride (60 wt %, 153 mg) was added to dimethyl
sulfoxide (2 ml), and the mixture was stirred at 60.degree. C. for
30 min and was then cooled to room temperature.
4-Amino-3-chlorophenol hydrochloride (343 mg) was added to the
reaction solution, and the mixture was stirred at room temperature
for 10 min. Next, a solution of
4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline (254 mg) in
dimethyl sulfoxide (2 ml) was added to the reaction solution, and
the mixture was stirred at 110.degree. C. overnight. Water was
added to the reaction solution, followed by extraction with
chloroform. The chloroform layer was then washed with a saturated
aqueous sodium hydrogencarbonate solution and was then dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by
chromatography on silica gel by development with chloroform/acetone
(7/3) to give 332 mg of a mixture containing
2-chloro-4-{[(6-methoxy-7-(2-methoxyethoxy)-4-quinolyl]oxy}aniline
as a main product. A 83 mg portion of the mixture was dissolved in
chloroform (5 ml), and 2-methoxyphenyl isocyanate (35 .mu.l) was
added to the solution. The mixture was heated under reflux
overnight. The solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography on
silica gel by development with chloroform/acetone (2/1) to give 31
mg of the title compound.
[0471] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.75-3.77 (m,
2H), 3.90 (s, 3H), 3.94 (s, 3H), 4.27-4.29 (m, 2H), 6.55 (d, J=5.1
Hz, 1H), 6.89-7.05 (m, 3H), 7.24-7.27 (m, 1H), 7.42 (s, 1H), 7.48
(d, J=2.7 Hz, 1H), 7.50 (s, 1H), 8.08-8.11 (m, 1H), 8.18-8.22 (m,
1H), 8.49 (d, J=5.4 Hz, 1H), 8.99-9.03 (m, 2H)
Example 56
N-(2,4-Difluorophenyl)-N'-(4-{[6-methoxy-7-(2-methoxyethoxy)-4-quinolyl]ox-
y}-2,3-dimethylphenyl)-urea
[0472]
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl)oxy}-2,3-dimethylphenyl)-
-N'-(2,4-difluorophenyl)urea (213 mg) was dissolved in
N,N-dimethylformamide (5 ml) and triethylamine (1 ml), and
palladium hydroxide (40 mg) was added to the solution. The mixture
was stirred in a hydrogen atmosphere at room temperature overnight.
The reaction solution was filtered through Celite and was then
washed with chloroform/methanol. The solvent was removed by
distillation under the reduced pressure. A 90 mg portion of the
residue (184 mg) was dissolved in N,N-dimethylformamide (1.5 ml),
and potassium carbonate (32 mg), tetra-n-butylammonium iodide (7
mg), and 2-bromoethyl methyl ether (32 mg) were added to the
solution. The mixture was stirred at 70.degree. C. overnight. A
saturated aqueous sodium hydrogencarbonate solution was added to
the reaction solution, and the mixture was extracted with
chloroform. The chloroform layer was dried over anhydrous magnesium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was purified by thin-layer chromatography on
silica gel by development with chloroform/acetone (2/1) to give 110
mg of the title compound.
[0473] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.97 (s, 3H),
2.17 (s, 3H), 3.31 (s, 3H), 3.70 (t, J=4.4 Hz, 2H), 3.90 (s, 3H),
4.21 (t, J=4.4 Hz, 2H), 6.18 (d, J=5.1 Hz, 1H), 6.95-6.98 (m, 2H),
7.22-7.31 (m, 1H), 7.34 (s, 1H), 7.51 (s, 1H), 7.62 (d, J=8.8 Hz,
1H), 8.03-8.10 (m, 1H), 8.36 (d, J=5.1 Hz, 1H), 8.38 (s, 1H), 8.79
(s, 1H)
Example 57
N-(4-{[6-Methoxy-7-(2-methoxyethoxy)-4-quinolyl]oxy}-2,3-dimethylphenyl)-N-
'-(2-methoxyphenyl)-urea
[0474]
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylphenyl)-
-N'-(2-methoxyphenyl)urea (161 mg) was dissolved in
N,N-dimethylformamide (4 ml) and triethylamine (1 ml), and
palladium hydroxide (32 mg) was added to the solution. The mixture
was stirred in a hydrogen atmosphere at room temperature overnight.
The reaction solution was filtered through Celite and was washed
with chloroform/methanol. The solvent was removed by distillation
under the reduced pressure. A 110 mg portion of the residue (223
mg) was dissolved in N,N-dimethylformamide (1.5 ml), and potassium
carbonate (23 mg), tetra-n-butylammonium iodide (5 mg), and
2-bromoethyl methyl ether (23 mg) were added to the solution. The
mixture was stirred at 70.degree. C. overnight. A saturated aqueous
sodium hydrogencarbonate solution was added to the reaction
solution, and the mixture was extracted with chloroform. The
chloroform layer was dried over anhydrous magnesium sulfate. The
solvent was removed by distillation under the reduced pressure. The
residue was purified by thin-layer chromatography on silica gel by
development with chloroform/acetone (2/1) to give 89 mg of the
title compound.
[0475] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.00 (s, 3H),
2.17 (s, 3H), 3.70 (t, J=4.2 Hz, 2H), 3.83 (s, 3H), 3.90 (s, 3H),
4.22 (t, J=4.2 Hz, 2H), 6.19 (d, J=5.1 Hz, 1H), 6.81-6.88 (m, 2H),
6.94-6.97 (m, 2H), 7.34 (s, 1H), 7.51 (s, 1H), 7.58 (d, J=8.8 Hz,
1H), 8.07 (d, J=8.8 Hz, 1H), 8.36 (d, J=5.1 Hz, 1H), 8.48 (s, 1H),
8.58 (s, 1H)
Example 58
N-(2,4-Difluorophenyl)-N'-(4-{[6-methoxy-7-(2-methoxyethoxy-4-quinolyl]oxy-
}-2,5-dimethylphenyl)urea
[0476]
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-
-N'-(2,4-difluorophenyl)urea (366 mg) was dissolved in
N,N-dimethylformamide (6 ml), and palladium hydroxide (366 mg) was
added to the solution. The mixture was stirred in a hydrogen
atmosphere at room temperature overnight. The solvent was removed
by distillation under the reduced pressure. The residue was
dissolved in chloroform and methanol, and the solution was filtered
through Celite. Next, the solvent was removed by distillation under
the reduced pressure. The residue (213 mg), potassium carbonate
(109 mg), tetra-n-butylammonium iodide (12 mg), and 2-bromoethyl
methyl ether (40 .mu.l) were dissolved in N,N-dimethylformamide (5
ml), and the solution was stirred at 70.degree. C. overnight. The
solvent was removed by distillation under the reduced pressure.
Water was added to the residue, and the mixture was extracted with
chloroform. The chloroform layer was dried over sodium sulfate. The
solvent was removed by distillation under the reduced pressure. The
residue was purified by thin-layer chromatography on silica gel by
development with chloroform/methanol (10/1) to give 124 mg (yield
73%) of the title compound.
[0477] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.17 (s, 3H),
2.26 (s, 3H), 3.49 (s, 3H), 3.90 (t, J=4.8 Hz, 2H), 4.03 (s, 3H),
4.34 (t, J=4.8 Hz, 2H), 6.30 (d, J=5.1 Hz, 1H), 6.57 (s, 1H),
6.81-6.95 (m, 3H), 7.00 (s, 1H), 7.43 (s, 1H), 7.55 (s, 1H), 7.57
(s, 1H), 8.05-8.14 (m, 1H), 8.46 (d, J=5.4 Hz, 1H)
[0478] Mass analysis, found (ESI-MS, m/z): 524 (M.sup.++1)
Example 59
N-(4-{[6-Methoxy-7-(2-methoxyethoxy)-4-quinolyl]oxy}-2,5-dimethylphenyl)-N-
'-(2-methoxyphenyl)-urea
[0479]
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-
-N'-(2-methoxyphenyl)urea (363 mg) was dissolved in
N,N-dimethylformamide (6 ml), and palladium hydroxide (363 mg) was
added to the solution. The mixture was stirred in a hydrogen
atmosphere at room temperature overnight. The solvent was removed
by distillation under the reduced pressure, and the residue was
dissolved in chloroform and methanol. The solution was filtered
through Celite. Next, the solvent was removed by distillation under
the reduced pressure. The residue (191 mg), potassium carbonate
(110 mg), tetra-n-butylammonium iodide (12 mg), and 2-bromoethyl
methyl ether (80 mg) were dissolved in N,N-dimethylformamide (5
ml), and the solution was stirred at 70.degree. C. overnight. The
solvent was removed by distillation under the reduced pressure.
Water was added to the residue, and the mixture was extracted with
chloroform. The chloroform layer was dried over sodium sulfate. The
solvent was removed by distillation under the reduced pressure. The
residue was purified by thin-layer chromatography on silica gel by
development with chloroform/methanol (10/1) to give 128 mg (yield
76%) of the title compound.
[0480] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.17 (s, 3H),
2.28 (s, 3H), 3.49 (s, 3H), 3.83 (s, 3H), 3.90 (t, J=4.8 Hz, 2H),
4.04 (s, 3H), 4.35 (t, J=4.9 Hz, 2H), 6.30 (d, J=5.4 Hz, 1H), 6.33
(s, 1H), 6.86-6.90 (m, 1H), 6.96-7.06 (m, 3H), 7.17 (s, 1H), 7.43
(s, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 8.12-8.17 (m, 1H), 8.45 (d,
J=5.1 Hz, 1H)
[0481] Mass analysis, found (ESI-MS, m/z): 518 (M.sup.++1)
Example 60
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylphenyl)-N'-(2-m-
ethoxyphenyl)-urea
[0482]
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylaniline
(260 mg) was dissolved in N,N-dimethylformamide (5 ml), and
2-methoxyphenyl isocyanate (116 mg) was then added to the solution.
The mixture was allowed to react at room temperature overnight. A
saturated aqueous sodium hydrogencarbonate solution was added to
the reaction solution, and the mixture was extracted with
chloroform. The chloroform layer was dried over anhydrous magnesium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was purified by thin-layer chromatography on
silica gel by development with chloroform/acetone (2/1) to give 169
mg (yield 47%) of the title compound.
[0483] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): b 1.99 (s, 3H), 2.02
(s, 3H), 3.83 (s, 3H), 3.90 (s, 3H), 5.25 (s, 2H), 6.18 (d, J=5.3
Hz, 1H), 6.81-6.87 (m, 2H), 6.95 (d, J=6.1 Hz, 1H), 7.29-7.59 (m,
7H), 8.07 (d, J=6.1 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H), 8.48 (s, 1H),
8.58 (s, 1H)
Example 61
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-(2,4-difluorop-
henyl)urea
[0484] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (214
mg) was dissolved in chloroform (5 ml), and 2,4-difluorophenyl
isocyanate (180 .mu.l) was then added to the solution. The mixture
was allowed to react at 70.degree. C. for 4 hr, and a large amount
of ether was added to the reaction solution. The resultant
precipitate was collected by suction filtration to give 146 mg
(yield 46%) of the title compound.
[0485] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): b 3.98 (s, 3H), 3.99
(s, 3H), 7.03-7.10 (m, 1H), 7.28-7.37 (m, 2H), 7.40 (s, 1H), 7.56
(s, 2H), 8.08-8.21 (m, 2H), 8.57 (s, 1H), 8.80 (s, 1H), 9.30 (s,
1H)
[0486] Mass analysis, found (ESI-MS, m/z): 487, 489 (M.sup.++1)
Example 62
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-propylurea
[0487] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (5.13
g) was dissolved in chloroform (100 ml) and triethylamine (50 ml),
and a solution of triphosgene (4.59 g) in chloroform (3 ml) was
then added to the solution. The mixture was stirred for 30 min.
Next, n-propylamine (2.74 g) was added to the reaction solution,
and the mixture was stirred for additional 2 hr. A saturated
aqueous sodium hydrogencarbonate solution was added to the reaction
solution, and the mixture was extracted with chloroform. The
chloroform layer was dried over anhydrous sodium sulfate. The
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/methanol (50/1) to give 4.14 g (yield 64%) of the
title compound.
[0488] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.91 (t, J=7.3
Hz, 3H), 1.41-1.53 (m, 2H), 3.05-3.12 (m, 2H), 3.97 (s, 3H), 3.99
(s, 3H), 6.99 (t, J=5.4 Hz, 1H), 7.22 (dd, J=2.7 Hz, 9.0 Hz, 1H),
7.38 (s, 1H), 7.46 (d, J=2.9 Hz, 1H), 7.54 (s, 1H), 8.04 (s, 1H),
8.20 (d, J=9.3.degree. Hz, 1H), 8.55 (s, 1H)
[0489] Mass analysis, found (ESI-MS, m/z): 417 (M.sup.++1)
Example 63
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-phenyl}-N'-ethylurea
[0490] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a
solution of triphosgene (50 mg) in chloroform was then added to the
solution. The mixture was stirred at room temperature for 30 min.
Next, ethylamine hydrochloride (69 mg) was added to the reaction
solution, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
solution was purified by HPLC by development with
chloroform/methanol to give 10 mg (yield 16%) of the title
compound.
[0491] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.07 (t, J=7.3
Hz, 3H), 3.11-3.14 (m, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 6.10 (t,
J=5.4 Hz, 1H), 7.14 (d, J=9.0 Hz, 2H), 7.37 (s, 1H), 7.46 (d, J=9.0
Hz, 2H), 7.55 (s, 1H), 8.49 (br, 1H), 8.53 (s, 1H)
[0492] Mass analysis, found (ESI-MS, m/z): 369 (M.sup.++1)
Example 64
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-phenyl}-N'-propylurea
[0493] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a
solution of triphosgene (50 mg) in chloroform was then added to the
solution. The mixture was stirred at room temperature for 30 min.
Next, propylamine (21 .mu.l) was added to the reaction solution,
and the mixture was further stirred at room temperature overnight.
Methanol was added to the reaction solution, and the solution was
purified by HPLC by development with chloroform/methanol to give 30
mg (yield 47%) of the title compound.
[0494] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): b 0.89 (t, J=7.6 Hz,
3H), 1.41-1.50 (m, 2H), 3.04-3.08 (m, 2H), 3.97 (s, 3H), 3.99 (s,
3H), 6.15 (t, J=5.9 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.37 (s, 1H),
7.46 (d, J=9.0 Hz, 2H), 7.55 (s, 1H), 8.48 (br, 1H), 8.53 (s,
1H)
[0495] Mass analysis, found (ESI-MS, m/z): 383 (M.sup.++1)
Example 65
N-Butyl-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}urea
[0496] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a
solution of triphosgene (50 mg) in chloroform was then added to the
solution. The mixture was stirred at room temperature for 30 min.
Next, butylamine (22 .mu.l) was added to the reaction solution, and
the mixture was further stirred at room temperature overnight.
Methanol was added to the reaction solution, and the mixture was
purified by HPLC by development with chloroform/methanol to give 29
mg (yield 43%) of the title compound.
[0497] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.91 (t, J=7.3
Hz, 3H), 1.28-1.47 (m, 4H), 3.07-3.12 (m, 2H), 3.97 (s, 3H), 3.99
(s, 3H), 6.12 (t, J=5.6 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.37 (s,
1H), 7.46 (d, J=9.0 Hz, 2H), 7.55 (s, 1H), 8.47 (br, 1H), 8.53 (s,
1H)
[0498] Mass analysis, found (ESI-MS, m/z): 397 (M.sup.++1)
Example 66
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-phenyl}-N'-pentylurea
[0499] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a
solution of triphosgene (50 mg) in chloroform was then added to the
solution. The mixture was stirred at room temperature for 30 min.
Next, amylamine (26 .mu.l) was added to the reaction solution, and
the mixture was stirred at room temperature overnight. Methanol was
added to the reaction solution, and the mixture was purified by
HPLC by development with chloroform/methanol to give 21 mg (yield
30%) of the title compound.
[0500] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.89 (t, J=7.1
Hz, 3H), 1.27-1.47 (m, 4H), 1.41-1.48 (m, 2H), 3.06-3.11 (m, 2H),
3.97 (s, 3H), 3.99 (s, 3H), 6.13 (t, J=5.6 Hz, 1H), 7.15 (d, J=9.0
Hz, 2H), 7.37, (s, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.55 (s, 1H), 8.47
(br, 1H), 8.53 (s, 1H)
[0501] Mass analysis, found (ESI-MS, m/z): 411 (M.sup.++1)
Example 67
N-(sec-Butyl)-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}urea
[0502] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy)aniline (50 mg) was
dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a
solution of triphosgene (50 mg) in chloroform was then added to the
solution. The mixture was stirred at room temperature for 30 min.
Next, sec-butylamine (23 .mu.l) was added, and the mixture was
stirred at room temperature overnight. Methanol was added to the
reaction solution, and the mixture was purified by HPLC by
development with chloroform/methanol to give 33 mg (yield 49%) of
the title compound.
[0503] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.88 (t, J=7.3
Hz, 3H), 1.08 (d, J=6.6 Hz, 3H), 1.40-1.47 (m, 2H), 3.58-3.64 (m,
1H), 3.97 (s, 3H), 3.99 (s, 3H), 5.98 (t, J=8.1 Hz, 1H), 7.15 (d,
J=9.0 Hz, 2H), 7.37 (s, 1H), 7.46 (d, J=9.0 Hz, 2H), 7.55 (s, 1H),
8.38 (s, 1H), 8.53 (s, 1H)
[0504] Mass analysis, found (ESI-MS, m/z): 397 (M.sup.++1)
Example 68
N-Allyl-N'-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenyl}urea
[0505] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a
solution of triphosgene (50 mg) in chloroform was then added to the
solution. The mixture was stirred at room temperature for 30 min.
Next, allylamine hydrochloride (31 mg) was added to the reaction
solution, and the mixture was stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 21 mg (yield 33%) of the title
compound.
[0506] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.73-3.76 (m,
2H), 3.97 (s, 3H), 3.99 (s, 3H), 5.07-5.21 (m, 2H), 5.84-5.92 (m,
1H), 6.28 (t, J=5.6 Hz, 1H), 7.16 (d, J=9.0 Hz, 2H), 7.38 (s, 1H),
7.47 (d, J=9.0 Hz, 2H), 7.55 (s, 1H), 8.53 (s, 1H), 8.59 (s,
1H)
[0507] Mass analysis, found (ESI-MS, m/z): 381 (M.sup.++1)
Example 69
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)-oxy]phenyl}-N'-(2-propynyl)urea
[0508] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a
solution of triphosgene (50 mg) in chloroform was then added to the
solution. The mixture was stirred at room temperature for 30 min.
Next, propargylamine hydrochloride (31 mg) was added to the
reaction solution, and the mixture was stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 26 mg (yield 41%) of the title
compound.
[0509] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.11-3.12 (m,
1H), 3.89-3.90 (m, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 6.49 (t, J=5.9
Hz, 1H), 7.17 (d, J=9.0 Hz, 2H), 7.38 (s, 1H), 7.48 (d, J=8.8 Hz,
2H), 7.55 (s, 1H), 8.53 (s, 1H), 8.68 (s, 1H)
[0510] Mass analysis, found (ESI-MS, m/z): 379 (M.sup.++1)
Example 70
N-(2,4-Difluorobenzyl)-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}ure-
a
[0511] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a
solution of triphosgene (50 mg) in chloroform was then added to the
solution. The mixture was stirred at room temperature for 30 min.
Next, 2,4-difluorobenzylamine (22 .mu.l) was added to the reaction
solution, and the mixture was stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 32 mg (yield 41%) of the title
compound.
[0512] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.97 (s, 3H),
3.98 (s, 3H), 4.32-4.33 (m, 2H), 6.66 (t, J=5.9 Hz, 1H), 7.06-7.10
(m, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.19-7.24 (m, 1H), 7.37 (s, 1H),
7.40-7.44 (m, 1H), 7.48 (d, J=9.0 Hz, 2H), 7.55 (s, 1H), 8.52 (s,
1H), 8.69 (s, 1H)
[0513] Mass analysis, found (ESI-MS, m/z): 467 (M.sup.++1)
Example 71
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-phenyl}-N'-(2-pyridylmethyl)urea
[0514] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a
solution of triphosgene (50 mg) in chloroform was then added to the
solution. The mixture was stirred at room temperature for 30 min.
Next, 2,4-difluorobenzylamine (31 .mu.l) was added to the reaction
solution, and the mixture was stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 31 mg (yield 43%) of the title
compound.
[0515] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.42 (s, 2H),
3.98 (s, 3H), 3.99 (s, 3H), 7.16-7.19 (m, 2H), 7.22-7.27 (m, 3H),
7.38 (s, 1H), 7.57 (s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.88-7.92 (m,
1H), 8.46-8.48 (m, 1H), 8.54 (s, 11H), 8.87 (s, 1H), 12.19 (s,
1H)
[0516] Mass analysis, found (FD-MS, m/z): 431 (M.sup.+)
Example 72
N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}ure-
a
[0517] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate
(24 .mu.l) was then added to the solution. The mixture was heated
under reflux overnight. The precipitated crystal was collected by
filtration and was washed to give 55 mg (yield 72%) of the title
compound.
[0518] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): b 3.98 (s, 3H), 3.99
(s, 3H), 7.04-7.08 (m, 2H), 7.24 (d, J=8.8 Hz, 2H), 7.29-7.35 (m,
1H), 7.38 (s, 1H), 7.54 (d, J=9.0 Hz, 2H), 7.56 (s, 1H), 8.06-8.14
(m, 1H), 8.51-8.54 (m, 1H), 8.54 (s, 1H), 9.11-9.12 (m, 1H)
[0519] Mass analysis, found (ESI-MS, m/z): 453 (M.sup.++1)
Example 73
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-phenyl}-N'-(4-fluorophenyl)urea
[0520] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml), and p-fluorophenyl isocyanate (23
.mu.l) was then added to the solution. The mixture was heated under
reflux overnight. Methanol was added to the reaction solution, and
the mixture was purified by HPLC by development with
chloroform/methanol to give 26 mg (yield 36%) of the title
compound.
[0521] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.98 (s, 3H),
3.99 (s, 3H), 7.11-7.15 (m, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.38 (s,
1H), 7.46-7.50 (m, 2H), 7.54 (d, J=9.0 Hz, 2H), 7.56 (s, 1H), 8.54
(s, 1H), 8.72 (s, 1H), 8.75 (s, 1H)
[0522] Mass analysis, found (ESI-MS, m/z): 435 (M.sup.++1)
Example 74
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-phenyl}-N'-(2-methylphenyl)urea
[0523] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml), and o-toluyl isocyanate (25 .mu.l)
was then added to the solution. The mixture was heated under reflux
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 30 mg (yield 41%) of the title
compound.
[0524] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.26 (s, 3H),
3.98 (s, 3H), 3.99 (s, 3H), 6.93-6.98 (m, 1H), 7.13-7.19 (m, 2H),
7.22 (d, J=8.8 Hz, 2H), 7.38 (s, 1H), 7.54-7.56 (m, 3H), 7.83-7.86
(m, 1H), 7.93 (s, 1H), 8.54 (s, 1H), 9.10-9.11 (m, 1H)
[0525] Mass analysis, found (ESI-MS, m/z): 431 (M.sup.++1)
Example 75
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-phenyl}-N'-(2-methoxyphenyl)urea
[0526] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was
dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (27
.mu.l) was then added to the solution. The mixture was heated under
reflux overnight. Methanol was added to the reaction solution, and
the mixture was purified by HPLC by development with
chloroform/methanol to give 34 mg (yield 45%) of the title
compound.
[0527] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.89 (s, 3H),
3.98 (s, 3H), 3.99 (s, 3H), 6.89-7.05 (m, 3H), 7.22 (d, J=8.8 Hz,
2H), 7.38 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.56 (s, 1H), 8.13-8.15
(m, 1H), 8.23-8.24 (m, 1H), 8.54 (s, 1H), 9.40-9.41 (m, 1H)
[0528] Mass analysis, found (ESI-MS, m/z): 447 (M.sup.++1)
Example 76
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-ethylurea
[0529] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (200
mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml),
and a solution of triphosgene (179 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, ethylamine hydrochloride (246 mg) was added to the
reaction solution, and the mixture was stirred at room temperature
overnight. A saturated aqueous sodium hydrogencarbonate solution
was added to the reaction solution, and the mixture was extracted
with chloroform. The chloroform layer was dried over anhydrous
sodium sulfate. The solvent was removed by distillation under the
reduced pressure. The residue was purified by HPLC by development
with chloroform/methanol to give 159 mg (yield 65%) of the title
compound.
[0530] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.08 (t, J=7.1
Hz, 3H), 3.11-3.16 (m, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 6.96 (t,
J=5.6 Hz, 1H), 7.23 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.39 (s, 1H), 7.47
(d, J=2.7 Hz, 1H), 7.55 (s, 1H), 8.02 (s, 1H), 8.20 (d, J=9.3 Hz,
1H), 8.56 (s, 1H)
[0531] Mass analysis, found (ESI-MS, m/z): 403 (M.sup.++1)
Example 77
N-Butyl-N'-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}urea
[0532] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml),
and a solution of triphosgene (45 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, butylamine (22 .mu.l) was added to the reaction
solution, and the mixture was stirred at room temperature for
additional 30 min. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, and the mixture was
extracted with chloroform. The chloroform layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by HPLC by
development with chloroform/methanol to give 30 mg (yield 46%) of
the title compound.
[0533] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): b 0.91 (t, J=7.3 Hz,
3H), 1.31-1.46 (m, 4H), 3.09-3.14 (m, 2H), 3.97 (s, 3H), 3.99 (s,
3H), 6.96 (t, J=5.6 Hz, 1H), 7.23 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.39
(s, 1H), 7.47 (d, J=2.7 Hz, 1H), 7.55 (s, 1H), 8.03 (s, 1H), 8.20
(d, J=9.0 Hz, 1H), 8.56 (s, 1H)
[0534] Mass analysis, found (ESI-MS, m/z): 431 (M.sup.++1)
Example 78
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-pentylurea
[0535] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml),
and a solution of triphosgene (45 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, amylamine (26 .mu.l) was added to the reaction solution,
and the mixture was stirred at room temperature for additional 30
min. A saturated aqueous sodium hydrogencarbonate solution was
added to the reaction solution, and the mixture was extracted with
chloroform. The chloroform layer was dried over anhydrous sodium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was purified by HPLC by development with
chloroform/methanol to give 33 mg (yield 49%) of the title
compound.
[0536] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.90 (t, J=7.1
Hz, 3H), 1.24-1.34 (m, 4H), 1.43-1.48 (m, 2H), 3.08-3.14 (m, 2H),
3.97 (s, 3H), 3.99 (s, 3H), 6.97 (t, J=5.1 Hz, 1H), 7.23 (dd, J=2.7
Hz, 9.0 Hz, 1H), 7.39 (s, 1H), 7.47 (d, J=2.8 Hz, 1H), 7.55 (s,
1H), 8.03 (s, 1H), 8.20 (d, J=9.0 Hz, 1H), 8.56 (s, 1H)
[0537] Mass analysis, found (ESI-MS, m/z): 445 (M.sup.++1)
Example 79
N-(sec-Butyl)-N'-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}ure-
a
[0538] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml),
and a solution of triphosgene (45 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, sec-butylamine (23 .mu.l) was added to the reaction
solution, and the mixture was stirred at room temperature for
additional 30 min. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, and the mixture was
extracted with chloroform. The chloroform layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by HPLC by
development with chloroform/methanol to give 34 mg (yield 52%) of
the title compound.
[0539] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.89 (t, J=7.6
Hz, 3H), 1.09 (d, J=6.6 Hz, 3H), 1.43-1.46 (m, 2H), 3.58-3.66 (m,
1H), 3.97 (s, 3H), 3.99 (s, 3H), 6.88 (d, J=7.6 Hz, 1H), 7.22 (dd,
J=2.4 Hz, 9.3 Hz, 1H), 7.39 (s, 1H), 7.47 (d, J=2.7 Hz, 1H), 7.55
(s, 1H), 7.98 (s, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.55-8.56 (m,
1H)
[0540] Mass analysis, found (ESI-MS, m/z): 431 (M.sup.++1)
Example 80
N-Allyl-N'-{2-chloro-4-[(6,7-dimethoxy-4-quinazol)oxy]phenyl}urea
[0541] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml),
and a solution of triphosgene (45 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, allylamine hydrochloride (21 mg) was added to the
reaction solution, and the mixture was stirred at room temperature
for additional 30 min. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, and the mixture was
extracted with chloroform. The chloroform layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by HPLC by
development with chloroform/methanol to give 45 mg (yield 72%) of
the title compound.
[0542] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.76-3.79 (m,
2H), 3.97 (s, 3H), 3.99 (s, 3H), 5.10-5.24 (m, 2H), 5.85-5.94 (m,
1H), 7.11 (t, J=5.4 Hz, 1H), 7.24 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.39
(s, 1H), 7.49 (d, J=2.7 Hz, 1H), 7.55 (s, 1H), 8.14 (s, 1H), 8.19
(d, J=9.0 Hz, 1H), 8.56 (s, 1H)
[0543] Mass analysis, found (ESI-MS, m/z): 415 (M.sup.++1)
Example 81
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-(2-propynyl)ur-
ea
[0544] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml),
and a solution of triphosgene (45 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, propargylamine hydrochloride (21 mg) was added to the
reaction solution, and the mixture was stirred at room temperature
for additional 30 min. The precipitated crystal was collected by
filtration and was washed to give 38 mg (yield 61%) of the title
compound.
[0545] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.16-3.17 (m,
1H), 3.93-3.95 (ma 2H), 3.97 (s, 3H), 3.99 (s, 3H), 7.25 (dd, J=2.7
Hz, 9.0 Hz, 1H), 7.30 (t, J=5.6 Hz, 1H), 7.39 (s, 1H), 7.50 (d,
J=2.7 Hz, 1H), 7.55 (s, 1H), 8.16 (d, J=9.3 Hz, 1H), 8.18 (s, 1H),
8.56 (s, 1H)
[0546] Mass analysis, found (ESI-MS, m/z): 413 (M.sup.++1)
Example 82
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-(2,4-difluorob-
enzyl)urea
[0547] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml),
and a solution of triphosgene (45 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 2,4-difluorobenzylamine (22 .mu.l) was added to the
reaction solution, and the mixture was stirred at room temperature
for additional 30 min. The precipitated crystal was collected by
filtration and was washed to give 48 mg (yield 64%) of the title
compound.
[0548] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.97 (s, 3H),
3.99 (s, 3H), 4.33-4.36 (m, 2H), 7.08-7.12 (m, 1H), 7.22-7.28 (m,
2H), 7.39 (s, 1H), 7.42-7.46 (m, 1H), 7.49 (d, J=2.7 Hz, 1H), 7.54
(s, 1H), 8.18-8.20 (m, 2H), 8.56 (s, 1H)
[0549] Mass analysis, found (ESI-MS, m/z): 501 (M.sup.++1)
Example 83
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-(2-pyridylmeth-
yl)urea
[0550] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml),
and a solution of triphosgene (45 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 2-(methylamino)pyridine (19 .mu.l) was added to the
reaction solution, and the mixture was stirred at 60.degree. C. for
additional one hr. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, and the mixture was
extracted with chloroform. The chloroform layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by HPLC by
development with chloroform/methanol to give 26 mg (yield 37%) of
the title compound.
[0551] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.51 (s, 2H),
4.07 (s, 3H), 4.07 (s, 3H), 7.03-7.10 (m, 2H), 7.19 (dd, J=2.7 Hz,
9.0 Hz, 1H), 7.35 (s, 1H), 7.36 (d, J=2.7 Hz, 1H), 7.54 (s, 1H),
7.76-7.81 (m, 1H), 8.38-8.43 (m, 1H), 8.56 (d, J=9.0 Hz, 1H), 8.64
(s, 1H), 13.53 (s, 1H)
[0552] Mass analysis, found (ESI-MS, m/z): 466 (M.sup.++1)
Example 85
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-(4-fluoropheny-
l)urea
[0553] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (5 ml), and p-fluorophenyl
isocyanate (21 .mu.l) was then, added to the solution. The mixture
was stirred at 60.degree. C. for one hr. The precipitated crystal
was collected by filtration and was washed to give 57 mg (yield
81%) of the title compound.
[0554] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.98 (s, 3H),
3.99 (s, 3H), 7.13-7.17 (m, 2H), 7.30 (dd, J=2.4 Hz, 8.8 Hz, 1H),
7.40 (s, 1H), 7.48-7.51 (m, 2H), 7.55-7.56 (m, 2H), 8.21 (d, J=9.0
Hz, 1H), 8.31 (s, 1H), 8.57 (s, 1H)
[0555] Mass analysis, found (ESI-MS, m/z): 469 (M.sup.++1)
Example 86
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-(2-methoxyphen-
yl)urea
[0556] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (5 ml), and 2-methoxyphenyl
isocyanate (24 .mu.l) was then added to the solution. The mixture
was stirred at 60.degree. C. for one hr. Methanol was added to the
reaction solution, and the mixture was purified by HPLC by
development with chloroform/methanol to give 39 mg (yield 54%) of
the title compound.
[0557] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.90 (s, 3H),
3.98 (s, 3H), 3.99 (s, 3H), 6.89-7.05 (m, 3H), 7.29 (dd, J=2.7 Hz,
9.0 Hz, 1H), 7.40 (s, 1H), 7.54 (d, J=2.7 Hz, 1H), 7.56 (s, 1H),
8.09-8.16 (m, 2H), 8.58 (s, 1H), 8.96-9.02 (m, 2H)
[0558] Mass analysis, found (ESI-MS, m/z): 418 (M.sup.++1)
Example 87
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-(5-chloro-2-py-
ridyl)urea
[0559] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml),
and a solution of triphosgene (45 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 2-amino-5-chloropyridine (23 mg) was added to the
reaction solution, and the mixture was stirred at 60.degree. C. for
additional one hr. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, and the mixture was
extracted with chloroform. The chloroform layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by HPLC by
development with chloroform/methanol to give 39 mg (yield 53%) of
the title compound.
[0560] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.98 (s, 3H),
4.00 (s, 3H), 7.33 (dd, J=2.7 Hz, 9.3 Hz, 1H), 7.40 (s, 1H),
7.43-7.48 (m, 1H), 7.56 (s, 1H), 7.60 (d, J=2.7 Hz, 1H), 7.91 (dd,
J=2.7 Hz, 9.0 Hz, 1H), 8.35 (d, J=8.8 Hz, 1H), 8.40 (d, J=2.4 Hz,
1H), 8.58 (s, 1H), 10.17 (s, 1H)
[0561] Mass analysis, found (ESI-MS, m/z): 486 (M.sup.++1).
Example 88
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluorophenyl}-N'-propylurea
[0562] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50
mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (47 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, propylamine (20 .mu.l) was added to the reaction
solution, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 9 mg (yield 14%) of the title
compound.
[0563] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.90 (t, J=7.6
Hz, 3H), 1.43-1.49 (m, 2H), 3.05-3.10 (m, 2H), 3.97 (s, 3H), 3.99
(s, 3H), 6.61 (t, J=5.6 Hz, 1H), 7.05-7.07 (m, 1H), 7.27-7.31 (m,
1H), 7.38 (s, 1H), 7.54 (s, 1H), 8.14-8.19 (m, 1H), 8.28-8.29 (m,
1H), 8.55 (s, 1H)
[0564] Mass analysis, found (ESI-MS, m/z): 401 (M.sup.++1)
Example 89
N-Butyl-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-fluorophenyl}urea
[0565] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50
mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (47 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, butylamine (24>1) was added, and the mixture was
further stirred at room temperature overnight. Methanol was added
to the reaction solution, and the mixture was purified by HPLC by
development with chloroform/methanol to give 25 mg (yield 38%) of
the title compound.
[0566] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.91 (t, J=7.3
Hz, 3H), 1.30-1.47 (m, 4H), 3.09-3.13 (m, 2H), 3.97 (s, 3H), 3.99
(s, 3H), 6.58 (t, J=5.6 Hz, 1H), 7.04-7.07 (m, 1H), 7.28-7.31 (m,
1H), 7.38 (s, 1H), 7.54 (s, 1H), 8.14-8.19 (m, 1H), 8.26-8.28 (m,
1H), 8.55 (s, 1H)
[0567] Mass analysis, found (ESI-MS, m/z): 415 (M.sup.++1)
Example 90
N-(sec-Butyl)-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-fluorophenyl}ure-
a
[0568] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50
mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (47 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, sec-butylamine (25 .mu.l) was added to the reaction
solution, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 12 mg (yield 18%) of the title
compound.
[0569] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.89 (t, J=7.6
Hz, 3H), 1.08 (d, J=6.6 Hz, 3H), 1.39-1.48 (m, 2H), 3.58-3.64 (m,
1H), 3.97 (s, 3H), 3.99 (s, 3H), 6.51 (d, J=7.6 Hz, 1H), 7.04-7.08
(m, 1H), 7.30 (dd, J=2.4 Hz, 11.7 Hz, 1H), 7.39 (s, 1H), 7.54 (s,
1H), 8.16-8.22 (m, 2H), 8.56 (s, 1H)
[0570] Mass analysis, found (ESI-MS, m/z): 415 (M.sup.++1)
Example 91
N-Allyl-N'-{4-[(6,7-dimethoxy-4-6-quinazolinyl)oxy]-2-fluorophenyl}urea
[0571] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50
mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (47 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, allylamine hydrochloride (30 mg) was added to the
reaction solution, and the mixture was further stirred at room
temperature overnight. Methanol was added to the reaction solution,
and the mixture was purified by HPLC by development with
chloroform/methanol to give 18 mg (yield 28%) of the title
compound.
[0572] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.75-3.79 (m,
2H), 3.97 (s, 3H), 3.99 (s, 3H), 5.08-5.22 (m, 2H), 5.84-5.94 (m,
1H), 6.72 (t, J=5.9 Hz, 1H), 7.06-7.08 (m, 1H), 7.30-7.33 (m, 1H),
7.39 (s, 1H), 7.54 (s, 1H), 8.13-8.18 (m, 1H), 8.40 (s, 1H), 8.56
(s, 1H)
[0573] Mass analysis, found (ESI-MS, m/z): 399 (M.sup.++1)
Example 92
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluorophenyl}-N'-(2-propynyl)ur-
ea
[0574] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50
mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (47 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, propargylamine hydrochloride (29 mg) was added to the
reaction solution, and the mixture was further stirred at room
temperature overnight. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction solution, and the mixture was
extracted with chloroform. The chloroform layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was washed with chloroform
to give 21 mg (yield 33%) of the title compound.
[0575] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.15 (t, J=2.4
Hz, 1H), 3.91-3.94 (m, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 7.07-7.11
(m, 1H), 7.33 (dd, J=2.4 Hz, 11.7 Hz, 1H), 7.39 (s, 1H), 7.54 (s,
1H), 8.09-8.15 (m, 1H), 8.47-8.48 (m, 1H), 8.56 (s, 1H)
[0576] Mass analysis, found (ESI-MS, m/z): 397 (M.sup.++1)
Example 93
N-(2,4-Difluorobenzyl)-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-fluorop-
henyl}urea
[0577] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50
mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (47 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, 2,4-difluorobenzylamine (28 .mu.l) was added to the
reaction solution, and the mixture was further stirred at room
temperature overnight. The precipitated crystal was collected by
filtration and was washed to give 20 mg (yield 26%) of the title
compound.
[0578] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.97 (s, 3H),
3.99 (s, 3H), 4.34 (d, J=5.8 Hz, 2H), 7.07-7.11 (m, 3H), 7.21-7.27
(m, 1H), 7.30-7.33 (m, 1H), 7.39 (s, 1H), 7.41-7.47 (m, 1H), 7.54
(s, 1H), 8.12-8.16 (m, 1H), 8.46-8.47 (m, 1H), 8.55 (s, 1H)
[0579] Mass analysis, found (FD-MS, m/z): 484 (M.sup.+)
Example 94
N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-fluorop-
henyl}urea
[0580] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50
mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl
isocyanate (29 .mu.l) was then added to the solution. The mixture
was stirred at 60.degree. C. overnight. The precipitated crystal
was collected by filtration and was washed to give 50 mg (yield
67%) of the title compound.
[0581] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.98 (s, 3H),
3.99 (s, 3H), 7.04-7.08 (m, 1H), 7.13-7.15 (m, 1H), 7.29-7.40 (m,
3H), 7.55 (s, 1H), 8.10-8.23 (m, 2H), 8.57 (s, 1H), 8.97-9.04 (m,
2H)
[0582] Mass analysis, found (ESI-MS, m/z): 471 (M.sup.++1)
Example 95
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluorophenyl}-N'-(2-methylpheny-
l)urea
[0583] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50
mg) was dissolved in chloroform (3 ml), and o-toluyl isocyanate (30
.mu.l) was then added to the solution. The mixture was stirred at
60.degree. C. overnight. Methanol was added to the reaction
solution, and the mixture was purified by HPLC by development with
chloroform/methanol to give 17 mg (yield 24%) of the title
compound.
[0584] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.27 (s, 3H),
3.98 (s, 3H), 3.99 (s, 3H), 6.95-6.98 (m, 1H), 7.12-7.20 (m, 3H),
7.36-7.39 (m, 2H), 7.55 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.21-8.26
(m, 1H), 8.35 (s, 1H), 8.57 (s, 1H), 9.00-9.02 (m, 1H)
[0585] Mass analysis, found (ESI-MS, m/z): 449 (M.sup.++1)
Example 96
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluorophenyl}-N'-(2-methoxyphen-
yl)urea
[0586] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50
mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl
isocyanate (32 .mu.l) was then added to the solution. The mixture
was stirred at 60.degree. C. overnight. Methanol was added to the
reaction solution, and the mixture was purified by HPLC by
development with chloroform/methanol to give 22 mg (yield 30%) of
the title compound.
[0587] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.89 (s, 3H),
3.98 (s, 3H), 3.99 (s, 3H), 6.88-7.04 (m, 3H), 7.11-7.14 (m, 1H),
-7.35-7.39 (m, 1H), 7.40 (s, 1H), 7.56 (s, 1H), 8.12-8.15 (m, 1H),
8.19-8.25 (m, 1H), 8.5-7 (s, 1H), 8.75-8.78 (m, 1H), 9.26-9.29 (m,
1H)
[0588] Mass analysis, found (ESI-MS, m/z): 465 (M.sup.++1)
Example 97
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylphenyl}-N'-propylurea
[0589] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylaniline (50
mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml),
and a solution of triphosgene (48 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, propylamine (20 .mu.l) was added to the reaction
solution, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 30 mg (yield 47%) of the title
compound.
[0590] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.89 (t, J=7.5
Hz, 3H), 1.41-1.50 (m, 2H), 2.03 (s, 3H), 3.03-3.08 (m, 2H), 3.98
(s, 3H), 3.99 (s, 3H), 6.13 (t, J=5.4 Hz, 1H), 7.04 (d, J=8.5 Hz,
1H), 7.28 (dd, J=2.4 Hz, 8.5 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.38
(s, 1H), 7.58 (s, 1H), 8.39 (s, 1H), 8.50 (s, 1H)
[0591] Mass analysis, found (ESI-MS, m/z): 397 (M.sup.++1)
Example 98
N-Butyl-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-3-methylphenyl}urea
[0592] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylaniline (50
mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml),
and a solution of triphosgene (48 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, butylamine (24 .mu.l) was added to the reaction
solution, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 31 mg (yield 47%) of the title
compound.
[0593] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.91 (t, J=7.3
Hz, 3H), 1.29-1.46 (m, 4H), 2.03 (s, 3H), 3.07-3.12 (m, 2H), 3.98
(s, 3H), 3.99 (s, 3H), 6.11 (t, J=5.6 Hz, 1H), 7.05 (d, J=8.8 Hz,
1H), 7.27 (dd, J=2.3 Hz, 8.5 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.38
(s, 1H), 7.58 (s, 1H), 8.39 (s, 1H), 8.51 (s, 1H)
[0594] Mass analysis, found (ESI-MS, m/z): 411 (M.sup.++1)
Example 99
N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-3-methylp-
henyl}urea
[0595] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylaniline (50
mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl
isocyanate (23 .mu.l) was then added to the solution. The mixture
was heated under reflux overnight. The precipitated crystal was
collected by filtration and was washed to give 59 mg (yield 79%) of
the title compound.
[0596] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.07 (s, 3H),
3.99 (s, 3H), 3.99 (s, 3H), 7.03-7.08 (m, 1H), 7.14 (d, J=8.5 Hz,
1H), 7.29-7.37 (m, 2H), 7.39 (s, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.60
(s, 1H), 8.07-8.14 (m, 1H), 8.52 (s, 1H), 9.03-9.05 (m, 1H)
[0597] Mass analysis, found (ESI-MS, m/z): 467 (M.sup.++1)
Example 100
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylphenyl}-N'-(4-fluoropheny-
l)urea
[0598] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylaniline (50
mg) was dissolved in chloroform (3 ml), and p-fluorophenyl
isocyanate (22 .mu.l) was then added to the solution. The mixture
was heated under reflux overnight. The precipitated crystal was
collected by filtration and was washed to give 42 mg (yield 58%) of
the title compound.
[0599] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.07 (s, 3H),
3.98 (s, 3H), 3.99 (s, 3H), 7.10-7.14 (m, 3H), 7.35 (dd, J=2.4 Hz,
8.5 Hz, 1H), 7.39 (s, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.46-7.49 (m,
2H), 7.59 (s, 1H), 8.51 (s, 1H), 8.66 (s, 1H), 8.70 (s, 1H)
[0600] Mass analysis, found (ESI-MS, m/z): 449 (M.sup.++1)
Example 101
N-{4-[(6,7-Dimethoxy-4-quinazol)oxy]-3-methylphenyl}-N'-(2-methoxyphenyl)u-
rea
[0601] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylaniline (50
mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl
isocyanate (26 .mu.l) was then added to the solution. The mixture
was heated under reflux overnight. Methanol was added to the
reaction solution, and the mixture was purified by HPLC by
development with chloroform/methanol to give 41 mg (yield 55%) of
the title compound.
[0602] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.07 (s, 3H),
3.89 (s, 3H), 3.99 (s, 3H), 3.99 (s, 3H), 6.88-6.97 (m, 2H),
7.01-7.03 (m, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.35 (dd, J=2.4 Hz, 8.5
Hz, 1H), 7.39 (s, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.60 (s, 1H),
8.13-8.15 (m, 1H), 8.23 (s, 1H), 8.52 (s, 1H), 9.33 (s, 1H)
[0603] Mass analysis, found (ESI-MS, m/z): 461 (M.sup.++1)
Example 102
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylphenyl]-N'-propylurea
[0604] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylaniline (50
mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml),
and a solution of triphosgene (48 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, propylamine (20 .mu.l) was added to the reaction
solution, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 30 mg (yield 47%) of the title
compound.
[0605] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.90 (t, J=7.3
Hz, 3H), 1.42-1.51 (m, 2H), 2.21 (s, 3H), 3.04-3.09 (m, 2H), 3.97
(s, 3H), 3.99 (s, 3H), 6.53 (t, J=5.6 Hz, 1H), 7.02 (dd, J=2.7 Hz,
8.8 Hz, 1H), 7.08 (d, J=2.7 Hz, 1H), 7.37 (s, 1H), 7.54 (s, 1H),
7.65 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 8.53 (s, 1H)
[0606] Mass analysis, found (ESI-MS, m/z): 397 (M.sup.++1)
Example 103
N-Butyl-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-methylphenyl}urea
[0607] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylaniline (50
mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml),
and a solution of triphosgene (48 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, butylamine (24 .mu.l) was added to the reaction
solution, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 37 mg (yield 56%) of the title
compound.
[0608] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.92 (t, J=7.1
Hz, 3H), 1.31-1.48 (m, 4H), 2.21 (s, 3H), 3.08-3.13 (m, 2H), 3.97
(s, 3H), 3.99 (s, 3H), 6.50 (t, J=5.4 Hz, 1H), 7.02 (dd, J=2.7 Hz,
8.8 Hz, 1H), 7.08 (d, J=2.7 Hz, 1H), 7.37 (s, 1H), 7.54 (s, 1H),
7.64 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 8.53 (s, 1H)
[0609] Mass analysis, found (ESI-MS, m/z): 411 (M.sup.++1)
Example 104
N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-methylp-
henyl}urea
[0610] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylaniline (50
mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl
isocyanate (23>1) was then added to the solution. The mixture
was heated under reflux overnight. The precipitated crystal was
collected by filtration and was washed to quantitatively give the
title compound.
[0611] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.29 (s, 3H),
3.98 (s, 3H), 3.99 (s, 3H), 7.03-7.11 (m, 2H), 7.16 (d, J=2.7 Hz,
1H), 7.29-7.35 (m, 1H), 7.38 (s, 1H), 7.55 (s, 1H), 7.87-7.90 (m,
1H), 8.13-8.19 (m, 1H), 8.36-8.39 (m, 1H), 8.55 (s, 1H), 8.92-8.95
(m, 1H)
[0612] Mass analysis, found (ESI-MS, m/z): 467 (M.sup.++1)
Example 105
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylphenyl}-N'-(4-fluoropheny-
l)urea
[0613] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylaniline (50
mg) was dissolved in chloroform (3 ml), and p-fluorophenyl
isocyanate (22 .mu.l) was then added to the solution. The mixture
was heated under reflux overnight. The precipitated crystal was
collected by filtration and was washed to quantitatively give the
title compound.
[0614] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.28 (s, 3H),
3.98 (s, 3H), 3.99 (s, 3H), 7.08-7.15 (m, 4H), 7.38 (s, 1H),
7.47-7.50 (m, 2H), 7.55 (s, 1H), 7.84-7.88 (m, 1H), 7.98 (s, 1H),
8.55 (s, 1H), 9.03-9.05 (m, 1H)
[0615] Mass analysis, found (ESI-MS, m/z): 449 (M.sup.++1)
Example 106
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylphenyl}-N'-(2-methoxyphen-
yl)urea
[0616] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylaniline (50
mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl
isocyanate (26 .mu.l) was then added to the solution. The mixture
was heated under reflux overnight. The precipitated crystal was
collected by filtration and was washed to give 70 mg (yield 95%) of
the title compound.
[0617] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.29 (s, 3H),
3.90 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 6.87-6.97 (m, 2H),
7.02-7.04 (m, 1H), 7.08 (dd, J=2.9 Hz, 8.8 Hz, 1H), 7.14 (d, J=2.7
Hz, 1H), 7.38 (s, 1H), 7.55 (s, 1H), 7.84 (d, J=8.8 Hz, 1H),
8.13-8.15 (m, 1H), 8.55 (s, 1H), 8.58 (s, 1H), 8.61-8.62 (m,
1H)
[0618] Mass analysis, found (ESI-MS, m/z): 461 (M.sup.++1)
Example 107
N-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitrophenyl}-N'-propylurea
[0619] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (50 mg)
was dissolved in chloroform (10 ml) and triethylamine (0.2 ml), and
a solution of triphosgene (43 mg) in chloroform was then added to
the solution. The mixture was stirred at room temperature for 30
min. Next, propylamine (18 .mu.l) was added to the reaction
solution, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 24 mg (yield 38%) of the title
compound.
[0620] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.91 (t, J=7.6
Hz, 3H), 1.45-1.51 (m, 2H), 3.06-3.09 (m, 2H), 3.98 (s, 3H), 4.00
(s, 3H), 7.40 (s, 1H), 7.52 (br, 1H), 7.58 (s, 1H), 7.67-7.70 (m,
1H), 8.04-8.06 (m, 1H), 8.38-8.41 (m, 1H), 8.57 (s, 1H), 9.35 (s,
1H)
[0621] Mass analysis, found (ESI-MS, m/z): 428 (M.sup.++1)
Example 108
N-Butyl-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-nitrophenyl}urea
[0622] 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (50 mg)
was dissolved in chloroform (10 ml) and triethylamine (0.2 ml), and
a solution of triphosgene (43 mg) in chloroform was then added to
the solution. The mixture was stirred at room temperature for 30
min. Next, butylamine (22 .mu.l) was added to the reaction
solution, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 15 mg (yield 23%) of the title
compound.
[0623] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.91 (t, J=7.3
Hz, 3H), 1.30-1.49 (m, 4H), 3.10-3.15 (m, 2H), 3.98 (s, 3H), 4.00
(s, 3H), 7.40 (s, 1H), 7.51 (br, 1H), 7.57 (s, 1H), 7.68 (dd, J=2.9
Hz, 9.3 Hz, 1H), 8.05 (d, J=2.9 Hz, 1H), 8.40 (d, J=9.2 Hz, 1H),
8.57 (s, 1H), 9.35 (s, 1H)
[0624] Mass analysis, found (ESI-MS, m/z): 442 (M.sup.++1)
Example 109
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N-methoxymethyl-N-
'-propylurea
[0625]
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-phenyl}-N'-propy-
lurea (100 mg) was dissolved in anhydrous tetrahydrofuran (30 ml),
and sodium hydride (60 wt %, 88 mg) was added to the solution. The
mixture was stirred at room temperature for 15 min. Next,
chloromethyl methyl ether (67 .mu.l) was added to the reaction
solution, and the mixture was stirred at room temperature for
additional 30 min. The solvent was removed by distillation under
the reduced pressure, and water was added to the residue. The
mixture was extracted with chloroform. The chloroform layer was
dried over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 18 mg
(yield 18%) of the title compound.
[0626] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.89 (t, J=7.6
Hz, 3H), 1.46-1.55 (m, 2H), 3.20 (br, 2H), 3.48 (s, 3H), 4.07 (s,
3H), 4.08 (s, 3H), 4.54 (br, 2H), 7.29 (dd, J=2.7 Hz, 8.5 Hz, 1H),
7.37 (s, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 7.50 (d, J=2.7
Hz, 1H), 8.66 (s, 1H)
[0627] Mass analysis, found (ESI-MS, m/z): 461 (M.sup.++1)
Example 110
N-Acetyl-N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-propy-
lurea
[0628]
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-phenyl}-N'-propy-
lurea (100 mg) was dissolved in anhydrous tetrahydrofuran (30 ml),
and sodium hydride (60 wt %, 88 mg) was added to the solution. The
mixture was stirred at room temperature for 15 min. Next, acetyl
chloride (63 .mu.l) was added to the reaction solution, and the
mixture was stirred at room temperature for additional 2 hr. The
solvent was removed by distillation under the reduced pressure, and
water was added to the residue. The mixture was extracted with
chloroform. The chloroform layer was dried over anhydrous sodium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was purified by HPLC by development with
chloroform/acetone to give 27 mg (yield 26%) of the title
compound.
[0629] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.98 (t, J=7.3
Hz, 3H), 1.59-1.68 (m, 2H), 2.04 (s, 3H), 3.27-3.36 (m, 2H), 4.07
(s, 3H), 4.08 (s, 3H), 7.31-7.33 (m, 1H), 7.35 (s, 1H), 7.41 (d,
J=9.0 Hz, 1H), 7.50-7.51 (m, 2H), 8.63 (s, 1H), 9.08 (br, 1H)
[0630] Mass analysis, found (ESI-MS, m/z): 459 (M.sup.++1)
Example 111
N'-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N-methyl-N-propy-
lurea
[0631] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (56
mg) was dissolved in chloroform (4 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (50 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, N-methylpropylamine (26 .mu.l) was added to the reaction
solution, and the mixture was stirred at room temperature for
additional one hr. Methanol was added to the reaction solution, and
the mixture was purified by HPLC by development with
chloroform/methanol. The solvent was removed by distillation, and
the resultant crystal was washed with hexane to give 42 mg (yield
58%) of the title compound.
[0632] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.99 (t, J=7.3
Hz, 3H), 1.64-1.74 (m, 2H), 3.08 (s, 3H), 3.34 (t, J=7.6 Hz, 2H),
4.07 (s, 3H), 4.08 (s, 3H), 7.00 (s, 1H), 7.17 (dd, J=2.7 Hz, 9.3
Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.38 (s, 1H), 7.53 (s, 1H), 8.41
(d, J=9.0 Hz, 1H), 8.64 (s, 1H)
[0633] Mass analysis, found (ESI-MS, m/z): 431 (M.sup.++1)
Example 112
N'-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N-ethyl-N-propyl-
urea
[0634] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (80
mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (72 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 15
min. Next, N-ethylpropylamine (44 .mu.l) was added to the reaction
solution, and the mixture was stirred at room temperature for
additional 30 min. Methanol was added to the reaction solution, and
the mixture was purified by HPLC by development with
chloroform/methanol. The solvent was removed by distillation. The
resultant crystal was washed with hexane to give 40 mg (yield 37%)
of the title compound.
[0635] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.00 (t, J=7.3
Hz, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.69-1.74 (m, 2H), 3.32 (t, J=7.6
Hz, 2H), 3.43 (q, J=7.1 Hz, 2H), 4.07 (s, 3H), 4.07 (s, 3H), 7.02
(s, 1H), 7.17 (dd, J=2.9 Hz, 9.2 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H),
7.36 (s, 1H), 7.53 (s, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.63 (s,
1H)
[0636] Mass analysis, found (ESI-MS, m/z): 445 (M.sup.++1)
Example 113
N'-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N,N-dipropylurea
[0637] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (100
mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (90 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 15
min. Next, dipropylamine (62 .mu.l) was added to the reaction
solution, and the mixture was stirred at room temperature for
additional 30 min. Methanol was added to the reaction solution, and
the mixture was purified by HPLC by development with
chloroform/methanol. The solvent was removed by distillation, and
the resultant crystal was washed with hexane to give 48 mg (yield
35%) of the title compound.
[0638] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.99 (t, J=7.3
Hz, 6H), 1.66-1.76 (m, 4H), 3.32 (t, J=7.8 Hz, 4H), 4.07 (s, 3H),
4.07 (s, 3H), 7.03 (s, 1H), 7.16 (dd, J=2.7 Hz, 9.3 Hz, 1H), 7.31
(d, J=2.7 Hz, 1H), 7.34 (s, 1H), 7.52 (s, 1H), 8.43 (d, J=9.0 Hz,
1H), 8.63 (s, 1H)
[0639] Mass analysis, found (ESI-MS, m/z): 459 (M.sup.++1)
Example 114
N-Butyl-N'-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N-methyl-
urea
[0640] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (80
mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (72 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 15
min. Next, N-methylbutylamine (43 .mu.l) was added to the reaction
solution, and the mixture was stirred at room temperature for
additional 30 min. Methanol was added to the reaction solution, and
the mixture was purified by HPLC by development with
chloroform/methanol. The solvent was removed by distillation, and
the resultant crystal was washed with hexane to give 26 mg (yield
24%) of the title compound.
[0641] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 0.99 (t, J=7.3
Hz, 3H), 1.38-1.43 (m, 2H), 1.62-1.66 (m, 2H), 3.07 (s, 3H), 3.40
(t, J=7.3 Hz, 2H), 4.07 (s, 3H), 4.07 (s, 3H), 7.00 (s, 1H), 7.17
(dd, J=2.7 Hz, 9.3 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.36 (s, 1H),
7.53 (s, 1H), 8.41 (d, J=9.3 Hz, 1H), 8.63 (s, 1H)
[0642] Mass analysis, found (ESI-MS, m/z): 445 (M.sup.++1)
Example 115
N'-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N-(4-chloropheny-
l)-N-methylurea
[0643] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (80
mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml),
and a solution of triphosgene (72 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 15
min. Next, 4-chloro-N-methylaniline (35 .mu.l) was added to the
reaction solution, and the mixture was heated under reflux for
additional 30 min. Methanol was added to the reaction solution, and
the mixture was purified by HPLC by development with
chloroform/methanol, and the solvent was removed by distillation.
The resultant crystal was washed with ether to give 83 mg (yield
69%) of the title compound.
[0644] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 3.36 (s, 3H),
4.06 (s, 3H), 4.07 (s, 3H), 6.89 (s, 1H), 7.17 (dd, J=2.7 Hz, 9.0
Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.33-7.35 (m, 3H), 7.48-7.50 (m,
3H), 8.41 (d, J=9.0 Hz, 1H), 8.61 (S, 1H)
[0645] Mass analysis, found (ESI-MS, m/z): 499 (M.sup.++1)
Example 116
N'-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N,N-diethylurea
[0646] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (2 ml) and triethylamine (0.5 ml),
and a solution of triphosgene (48 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, diethylamine (0.5 ml) was added to the reaction
solution, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 37 mg (yield 93%) of the title
compound.
[0647] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.30 (t, J=7.1
Hz, 6H), 3.44 (q, J=7.1 Hz, 4H), 4.12 (s, 3H), 4.20 (s, 3H), 7.16
(dd, J=2.7 Hz, 9.0 Hz, 1H), 7.27 (s, 1H), 7.31 (d, J=2.7 Hz, 1H),
7.59 (s, 1H), 8.15 (s, 1H), 8.48 (d, J=9.0 Hz, 1H), 8.81 (s,
1H)
[0648] Mass analysis, found (ESI-MS, m/z): 431 (M.sup.++1)
Example 117
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N'-methylurea
[0649] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (2 ml) and triethylamine (0.5 ml),
and a solution of triphosgene (48 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, the reaction solution was cooled to -78.degree. C., and
methylamine hydrochloride (130 mg) was added to the cooled reaction
solution. The temperature of the mixture was spontaneously raised,
and the mixture was further stirred at room temperature overnight.
Methanol was added to the reaction solution, and the mixture was
purified by HPLC by development with chloroform/methanol to give 41
mg (yield 70%) of the title compound.
[0650] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.68 (d, J=4.4
Hz, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 6.86-6.88 (m, 1H), 7.21 (dd,
J=2.7 Hz, 9.0 Hz, 1H), 7.37 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.53
(s, 1H), 8.07 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.54 (s, 1H)
[0651] Mass analysis, found (ESI-MS, m/z): 389 (M.sup.++1)
Example 118
N'-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}-N,N-dimethylurea
[0652] 2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50
mg) was dissolved in chloroform (2 ml) and triethylamine (0.5 ml),
and a solution of triphosgene (48 mg) in chloroform was then added
to the solution. The mixture was stirred at room temperature for 30
min. Next, the reaction solution was cooled to -78.degree. C., and
dimethylamine hydrochloride (250 mg) was added to the cooled
reaction solution. The temperature of the mixture was spontaneously
raised, and the mixture was further stirred at room temperature
overnight. Methanol was added to the reaction solution, and the
mixture was purified by HPLC by development with
chloroform/methanol to give 33 mg (yield 53%) of the title
compound.
[0653] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.11 (s, 6H),
4.12 (s, 3H), 4.20 (s, 3H), 7.05 (s, 1H), 7.17 (dd, J=2.4 Hz, 9.3
Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.59 (s, 1H), 8.15 (s, 1H), 8.46
(d, J=9.3 Hz, 1H), 8.82 (s, 1H)
[0654] Mass analysis, found (ESI-MS, m/z): 403 (M.sup.++1)
Example 119
N-(2-Chloro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinazolinyl]oxy}pheny-
l)-N'-propylurea
[0655]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (75 mg), potassium carbonate (51 mg), and
1,3-dibromopropane (76 .mu.l) was dissolved in
N,N-dimethylformamide (4 ml), and the solution was stirred at room
temperature for 3 hr. The solvent was removed by distillation under
the reduced pressure. Water was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 74 mg (yield 78%) of
N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)--
N'-propylurea as an intermediate. The intermediate (74 mg),
potassium carbonate (51 mg), and morpholine (130 .mu.l) were
dissolved in N,N-dimethylformamide (4 ml), and the solution was
stirred at room temperature overnight. The solvent was removed by
distillation under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 49 mg (yield 63%) of the title
compound.
[0656] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.89 (t, J=7.44
Hz, 3H), 1.41-1.50 (m, 2H), 1.97 (t, J=6.83 Hz, 1H), 2.33-2.49 (m,
4H), 3.04-3.09 (m, 2H), 3.32-3.38 (m, 4H), 3.52-3.68 (m, 3H), 4.03
(s, 3H), 4.23-4.29 (m, 1H), 4.32 (t, J=5.89 Hz, 1H), 6.98 (t,
J=5.49 Hz, 1H), 7.21 (dd, J=2.68, 9.03 Hz, 1H), 7.36 (s, 1H), 7.46
(d, J=2.68 Hz, 1H), 7.53 (d, J=7.81 Hz, 1H), 8.03 (s, 1H), 8.18 (d,
J=9.27 Hz, 1H), 8.54 (d, J=4.39 Hz, 1H)
[0657] Mass analysis, found (ESI-MS, m/z): 529 (M.sup.+)
Example 120
N-(2-Chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-quinazolinyl]oxy}phenyl-
)-N'-propylurea
[0658]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (72 mg), potassium carbonate (30 mg), and
1,2-dibromoethane (62 .mu.l) were dissolved in
N,N-dimethylformamide (4 ml), and the solution was stirred at room
temperature for 3 hr. The solvent was removed by distillation under
the reduced pressure. Water was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 40 mg (yield 45%) of
N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N-
'-propylurea as an intermediate. The intermediate (45 mg),
potassium carbonate (30 mg), and morpholine (80 .mu.l) were
dissolved in N,N-dimethylformamide (2 ml), and the solution was
stirred at room temperature overnight. The solvent was removed by
distillation under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 42 mg (yield 56%) of the title
compound.
[0659] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.89 (t, J=7.32
Hz, 3H), 1.43-1.49 (m, 2H), 2.32-2.38 (m, 2H), 2.66 (bs, 1H), 2.79
(t, J=5.86 Hz, 1H), 3.04-3.09 (m, 2H), 3.29-3.36 (m, 4H), 3.53 (m,
1H), 3.57-3.59 (m, 2H), 3.96 (s, 3H), 4.31 (t, J=5.85 Hz, 1H), 6.98
(m, 1H), 7.21-7.23 (m, 1H), 7.41 (s, 1H), 7.46-7.47 (m, 1H), 7.55
(d, J=12.69 Hz, 1H), 8.03 (s, 1H), 8.19 (d, J=9.27 Hz, 1H), 8.55
(d, J=5.37 Hz, 1H)
[0660] Mass analysis, found (ESI-MS, m/z): 517 (M.sup.++1)
Example 121
N-(2-Chloro-4-{[7-(3-hydroxypropoxy)-6-methoxy-4-quinazolinyl]oxy}phenyl)--
N'-propylurea
[0661]
N-(2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (55 mg), potassium carbonate (20 mg), and
3-bromo-1-propanol (62 .mu.l) were dissolved in
N,N-dimethylformamide (4 ml), and the solution was stirred at room
temperature for 3 hr. The solvent was removed by distillation under
the reduced pressure. Water was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 25 mg (yield 40%) of the title
compound.
[0662] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.91 (t, J=7.44
Hz, 3H), 1.24 (bs, 1H), 1.43-1.52 (m, 2H), 1.97 (t, J=6.22 Hz, 2H),
3.06-3.11 (m, 2H), 3.56-3.71 (m, 2H), 3.97 (s, 3H), 4.27 (m, 2H),
6.99 (t, J=5.62 Hz, 1H), 7.23 (dd, J=2.68, 9.03 Hz, 1H), 7.38 (d,
J=9.03 Hz, 1H), 7.47 (d, J=2.68 Hz, 1H), 7.54 (s, 1H), 8.05 (s,
1H), 8.20 (d, J=9.03 Hz, 1H), 8.55 (s, 1H)
[0663] Mass analysis, found (ESI-MS, m/z): 461 (M.sup.++1)
Example 122
N-(2-Chloro-4-{[7-(2-hydroxyethoxy)-6-methoxy-4-quinazolinyl]oxy}phenyl)-N-
'-propylurea
[0664]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (50 mg), potassium carbonate (30 mg), and
ethylenebromohydrin (44 .mu.l) were dissolved in
N,N-dimethylformamide (4 ml), and the solution was stirred at room
temperature for 3 hr. The solvent was removed by distillation under
the reduced pressure. Water was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 12 mg (yield 22%) of the title
compound.
[0665] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.91 (t, J=7.44
Hz, 3H), 1.42-1.49 (m, 2H), 3.06-3.11 (m, 2H), 3.80-3.83 (m, 2H),
3.98 (s, 3H), 4.22 (t, J=4.64 Hz, 2H), 4.98 (t, J=5.37 Hz, 1H),
6.99 (t, J=5.37 Hz, 1H), 7.33 (dd, J=2.69 Hz, 9.03 Hz, 1H), 7.39
(s, 1H), 7.48 (d, J=2.68 Hz, 1H), 7.55 (s, 1H), 8.05 (s, 1H), 8.19
(d, J=9.27 Hz, 1H), 8.55 (s, 1H)
[0666] Mass analysis, found (ESI-MS, m/z): 447 (M.sup.++1)
Example 123
N-(2-Chloro-4-{[6-methoxy-7-(4-pyridylmethoxy)-4-quinazolinyl]oxy}phenyl)--
N'-propylurea
[0667] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'-propyl-
urea, 80 mg), potassium carbonate (138 mg), and
4-chloromethylpyridine hydrochloride (41 mg), were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at
80.degree. C. for 3 hr. Water was added to the reaction mixture,
followed by extraction with chloroform-propanol (3/1). The organic
layer was dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under the reduced pressure. The residue was
purified by HPLC to give 65 mg (yield 66%) of the title
compound.
[0668] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.96 (t, J=7.6
Hz, 3H), 1.53-1.64 (m, 2H), 3.25 (dd, J=7.3 Hz, 12.9 Hz, 2H), 4.07
(s, 3H), 5.32 (s, 2H), 6.66 (s, 1H), 7.14 (dd, J=2.7 Hz, 9.0 Hz,
1H), 7.27 (s, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.41 (d, J=5.9 Hz, 2H),
7.54 (s, 1H), 8.24 (d, J=9.0 Hz, 1H), 8.59 (s, 1H), 8.63 (d, J=6.1
Hz, 2H)
[0669] Mass analysis, found (ESI-MS, m/z): 494 (M.sup.++1)
Example 124
N-[2-Chloro-4-({6-methoxy-7-[(5-morpholinopentyl)oxy]-4-quinazolinyl}oxy)p-
henyl]-N'-propylurea
[0670]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (70 mg), potassium carbonate (30 mg), and pentamethylene
bromide (80 .mu.L) were dissolved in N,N-dimethylformamide (5 ml),
and the solution was stirred at room temperature for 3 hr. The
solvent was removed by distillation under the reduced pressure.
Water was added to the residue, and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was removed by distillation under the
reduced pressure. The residue was washed with ether to give 43 mg
(yield 46%) of
N-[4-({7-(5-bromopentyl)oxy}-6-methoxy-4-quinazolinyl)oxy]-2-chlorophenyl-
]-N'-propylurea as an intermediate. The intermediate (43 mg),
potassium carbonate (30 mg), and morpholine (70 .mu.l) were
dissolved in N,N-dimethylformamide (4 ml), and the solution was
stirred at room temperature overnight. The solvent was removed by
distillation under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 30 mg (yield 68%) of the title
compound.
[0671] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.71 (t, J=7.32
Hz, 3H), 2.28 (t, J=7.20 Hz, 2H), 2.63 (m, 2H), 3.08-3.14 (m, 5H),
3.29-3.30 (m, 5H), 3.47 (bs, 1H), 3.73 (m, 1H), 3.86-3.90 (m, 2H),
4.36 (t, J=4.65 Hz, 3H), 4.46 (t, J=4.76 Hz, 1H), 4.77 (s, 1H),
4.99 (t, J=6.34 Hz, 2H), 7.80 (m, 1H), 8.02 (dd, J=2.68 Hz, 9.27
Hz, 1H), 8.18 (s, 1H), 8.27 (d, J=2.68 Hz, 1H), 8.34 (s, 1H), 8.85
(s, 1H), 9.00 (d, J=9.03 Hz, 1H), 9.35 (s, 1H)
[0672] Mass analysis, found (ESI-MS, m/z): 559 (M.sup.++1)
Example 125
N-{2-Chloro-4-[(6-methoxy-7-{[5-(1H-1,2,3-triazol-1-yl)pentyl]oxy}-4-quina-
zolinyl)oxy]phenyl}-N'-propylurea
[0673] Triazole (0.41 ml), 1-bromo-5-chloropentane (1.0 ml),
tetrabutylammonium iodide (10 mg), and a 3 M aqueous sodium
hydroxide solution (1 ml) were dissolved in acetone (10 ml), and
the solution was stirred at 50.degree. C. for 18 hr. Water was
added to the reaction mixture, and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous sodium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography by development
with chloroform to give an intermediate (390 mg).
[0674] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'-propyl-
urea, 80 mg), potassium carbonate (138 mg), and the above
intermediate (52 mg) were dissolved in N,N-dimethylformamide (1
ml), and the solution was stirred at 120.degree. C. for 5 hr. Water
was added to the reaction mixture, and the mixture was extracted
with chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by HPLC to
give 41 mg (yield 38%) of the title compound.
[0675] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.96 (t, J=7.6
Hz, 3H), 1.50-1.65 (m, 4H), 1.90-2.08 (m, 4H), 3.24 (dd, J=7.1 Hz,
12.9 Hz, 2H), 4.01 (s, 3H), 4.17 (t, J=6.6 Hz, 2H), 4.44 (t, J=7.3
Hz, 2H), 4.88-4.94 (m, 1H), 6.32 (s, 1H), 7.14 (dd, J=2.7 Hz, 9.0
Hz, 1H), 7.25 (s, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.48 (s, 1H), 7.55
(s, 1H), 7.70 (s, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.58 (s, 1H)
[0676] Mass analysis, found (ESI-MS, m/z): 540 (M.sup.++1)
Example 126
N'-(2-Chloro-4-{[6-methoxy-7-(4-pyridylmethoxy)-4-quinazolinyl]oxy}phenyl)-
-N,N-diethylurea
[0677] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-diet-
hylurea, 83 mg), potassium carbonate (138 mg), and
4-chloromethylpyridine hydrochloride (49 mg) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate. The solvent
was removed by distillation under the reduced pressure. The residue
was purified by HPLC to give 57 mg (yield 56%) of the title
compound.
[0678] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.26 (t, J=7.3
Hz, 6H), 3.41 (q, J=7.1 Hz, 4H), 4.08 (s, 3H), 5.32 (s, 2H), 6.98
(s, 1H), 7.14 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.27 (s, 1H), 7.29 (d,
J=2.7 Hz, 1H), 7.41 (d, J=5.9 Hz, 2H), 7.55 (s, 1H), 8.37 (d, J=9.0
Hz, 1H), 8.58 (s, 1H), 8.63 (d, J=5.9 Hz, 2H)
[0679] Mass analysis, found (ESI-MS, m/z): 508 (M.sup.++1)
Example 127
N-(2-Chloro-4-{[6-methoxy-7-(4-morpholinobutoxy)-4-quinazolinyl]oxy}phenyl-
)-N'-propylurea
[0680]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (70 mg), potassium carbonate (30 mg), and pentamethylene
bromide (80 .mu.l) were dissolved in N,N-dimethylformamide (5 ml),
and the solution was stirred at room temperature for 3 hr. The
solvent was removed by distillation under the reduced pressure.
Water was added to the residue, and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous sodium
sulfate. The solvent was removed by distillation under the reduced
pressure. The residue was washed with ether to give 43 mg (yield
46%) of
N-(4-{[7-(4-bromobutoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N-
'-propylurea as an intermediate. The intermediate (43 mg),
potassium carbonate (30 mg), and morpholine (40 .mu.l) were
dissolved in N,N-dimethylformamide (4 ml), and the solution was
stirred at room temperature overnight. The solvent was removed by
distillation under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 23 mg (yield 53%) of the title
compound.
[0681] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.99 (t, J=7.32
Hz, 3H), 1.56-1.62 (m, 13H), 2.00-2.08 (m, 2H), 3.26-3.28 (ma 2H),
4.04 (s, 3H), 4.24 (m, 2H), 4.72-4.77 (m, 1H), 6.65 (s, 1H), 6.99
(s, 1H), 7.19-7.26 (m, 1H), 7.30 (s, 1H), 7.32-7.34 (m, 1H), 7.51
(s, 1H), 8.25 (d, J=9.03 Hz, 1H), 8.61 (s, 1H)
[0682] Mass analysis, found (ESI-MS, m/z): 545 (M.sup.++1)
Example 128
N-[2-Chloro-4-({6-methoxy-7-[2-(4-methylpiperazino)ethoxy]-4-quinazolinyl}-
oxy)phenyl]-N'-propylurea
[0683]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (60 mg), potassium carbonate (30 mg), and
1,2-dibromoethane (70 .mu.l) were dissolved in
N,N-dimethylformamide (4 ml), and the solution was stirred at room
temperature for 3 hr. The solvent was removed by distillation under
the reduced pressure. Water was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 46 mg (yield 62%) of
N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N-
'-propylurea as an intermediate. The intermediate (46 mg),
potassium carbonate (20 mg), and N-methylpiperazine (50 .mu.l) were
dissolved in N,N-dimethylformamide (3 ml), and the solution was
stirred at room temperature overnight. The solvent was removed by
distillation under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 24 mg (yield 50%) of the title
compound.
[0684] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.99 (t, J=7.32
Hz, 3H), 1.61-1.64 (m, 2H), 2.75 (m, 2H), 3.00-3.16 (m, 4H),
3.25-3.16 (m, 4H), 3.25-3.29 (m, 2H), 4.02 (s, 3H), 4.27-4.35 (m,
2H), 4.78-4.83 (m, 2H), 5.33 (s, 3H), 6.69 (s, 1H), 7.17 (dd,
J=2.68 Hz, 9.03 Hz, 1H), 7.31 (s, 1H), 7.49 (s, 1H), 8.26 (d,
J=9.27 Hz, 1H), 8.59 (s, 1H)
[0685] Mass analysis, found (ESI-MS, m/z): 530 (M.sup.++1)
Example 129
N-{2-Chloro-4-[(7-{2-[(2-hydroxyethyl)-(methyl)amino]ethoxy}-6-methoxy-4-q-
uinazolinyl)oxy]-phenyl}-N'-propylurea
[0686]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (65 mg), potassium carbonate (30 mg), and
1,2-dibromoethane (30 .mu.l) were dissolved in
N,N-dimethylformamide (4 ml), and the solution was stirred at room
temperature for 3 hr. The solvent was removed by distillation under
the reduced pressure. Water was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 36 mg (yield 45%) of
N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N-
'-propylurea as an intermediate. The intermediate (36 mg),
potassium carbonate (30 mg), and N-methylethanolamine (30 .mu.l)
were dissolved in N,N-dimethylformamide (3 ml), and the solution
was stirred at room temperature overnight. The solvent was removed
by distillation under the reduced pressure. A saturated aqueous
sodium hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 21 mg (yield 55%) of the title
compound.
[0687] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.98 (t, J=7.32
Hz, 3H), 1.59 (m, 2H), 1.94 (bs, 1H), 3.23 (m, 2H), 4.03 (s, 3H),
4.07-4.15 (m, 4H), 4.76 (m, 4H), 5.35 (s, 3H), 7.10-7.17 (m, 1H),
7.28 (s, 3H), 7.40 (s, 1H), 7.54 (s, 1H), 8.37 (d, J=9.03 Hz, 1H),
8.64 (s, 1H)
[0688] Mass analysis, found (ESI-MS, m/z): 504 (M.sup.++1)
Example 130
N-[2-Chloro-4-({6-methoxy-7-[3-(4-methylpiperazino)propoxy]-4-quinazolinyl-
}oxy)phenyl]-N'-propylurea
[0689]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (75 mg), potassium carbonate (30 mg), and
1,3-dibromopropane (75 .mu.l) were dissolved in
N,N-dimethylformamide (4 ml), and the solution was stirred at room
temperature for 3 hr. The solvent was removed by distillation under
the reduced pressure. Water was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 50 mg (yield 52%) of
N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)--
N'-propylurea as an intermediate. The intermediate (30 mg),
potassium carbonate (20 mg), and N-methylpiperazine (40 .mu.l) were
dissolved in N,N-dimethylformamide (3 ml), and the solution was
stirred at room temperature overnight. The solvent was removed by
distillation under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 20 mg (yield 63%) of the title
compound.
[0690] .sup.1-NMR (CDCl.sub.3, 400 MHz): .delta. 0.99 (t, J=7.32
Hz, 3H), 1.58-1.62 (m, 2H), 2.25-2.50 (m, 3H), 2.70-2.85 (m, 3H),
2.92-2.98 (m, 3H), 3.25 (m, 2H), 4.04 (s, 3H), 4.25 (m, 2H), 4.83
(m, 3H), 5.34 (s, 3H), 6.70 (s, 1H), 7.21 (dd, J=2.68, 9.03 Hz,
1H), 7.26 (s, 2H), 7.31 (s, 1H), 7.49 (s, 1H), 8.18 (d, J=9.27 Hz,
1H), 8.59 (s, 1H)
[0691] Mass analysis, found (ESI-MS, m/z): 544 (M.sup.++1)
Example 131
N'-[2-Chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinazoli-
nyl}oxy)phenyl]-N,N-diethylurea
[0692] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-diet-
hylurea, 83 mg), potassium carbonate (138 mg), and
2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzenesulfonate (59 mg)
were dissolved in N,N-dimethylformamide (1 ml), and the solution
was stirred at 80.degree. C. for 18 hr. Water was added to the
reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was washed with ether to
give an intermediate. Triphosgene (90 mg) was added to a solution
of the intermediate and triethylamine (0.027 ml) in chloroform (1
ml) at 0.degree. C., and the mixture was stirred for 30 min. The
reaction mixture was cooled to 0.degree. C., and diethylamine
(0.044 ml) was then added dropwise to the cooled reaction mixture.
The temperature of the mixture was raised to room temperature over
a period of 2 hr. A saturated aqueous sodium hydrogencarbonate
solution was added to the reaction mixture, followed by extraction
with chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by HPLC to
give 30 mg (yield 29%) of the title compound.
[0693] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.26 (t, J=7.1
Hz, 6H), 3.41 (q, J=7.1 Hz, 4H), 4.03 (s, 3H), 4.53 (t, J=4.9 Hz,
2H), 4.94 (t, J=5.1 Hz, 2H), 6.98 (s, 1H), 7.13 (dd, J=2.7 Hz, 9.0
Hz, 1H), 7.26 (s, 1H), 7.73 (s, 1H), 7.94 (s, 1H), 8.38 (d, J=9.0
Hz, 1H), 8.60 (s, 1H)
Example 132
3-{[4-(3-Chloro-4-{[(diethylamino)-carbonyl]amino}phenoxy)-6-methoxy-7-qui-
nazolinyl]oxy}-propyl-N,N-diethylcarbamate
[0694] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-diet-
hylurea, 83 mg), potassium carbonate (138 mg), and
3-bromo-1-propanol (0.027 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at
80.degree. C. for 18 hr. Water was added to the reaction mixture,
and the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate. The solvent
was removed by distillation under the reduced pressure. The residue
was washed with ether to give an intermediate. Triphosgene (90 mg)
was added to a solution of the intermediate and triethylamine
(0.027 ml) in chloroform (1 ml) at 0.degree. C., and the mixture
was stirred for 30 min. The reaction mixture was cooled to
0.degree. C., and diethylamine (0.044 ml) was then added dropwise
to the cooled reaction mixture. The temperature of the mixture was
raised to room temperature over a period of 2 hr. A saturated
aqueous sodium hydrogencarbonate solution was added to the reaction
mixture, and the mixture was extracted with chloroform-propanol
(3/1). The organic layer was dried over anhydrous sodium sulfate.
The solvent was removed by distillation under the reduced pressure.
The residue was purified by HPLC to give 19 mg (yield 17%) of the
title compound.
[0695] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.04 (t, J=7.1
Hz, 6H), 1.22 (t, J=7.3 Hz, 6H), 3.09 (q, J=7.1 Hz, 4H), 3.36 (q,
J=7.1 Hz, 4H), 3.75 (t, J=6.3 Hz, 2H), 3.97 (s, 3H), 4.29 (t, J=6.1
Hz, 2H), 6.93 (s, 1H), 7.10 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.24 (d,
J=2.7 Hz, 1H), 7.27 (s, 1H), 7.45 (s, 1H), 8.33 (d, J=9.3 Hz, 1H),
8.55 (s, 1H)
Example 133
N-[2-Chloro-4-({6-methoxy-7-[3-(4-pyridylthio)propoxy]-4-quinazolinyl}oxy)-
phenyl]-N'-propylurea
[0696] A starting compound
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)--
N'-propylurea, 80 mg), potassium carbonate (138 mg), and
4-mercaptopyridine (22 mg) were dissolved in N,N-dimethylformamide
(1 ml), and the solution was stirred at room temperature for 3 hr.
Water was added to the reaction mixture, and the mixture was
extracted with chloroform-propanol (3/1). The organic layer was
dried over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 60 mg (yield 72%) of the title compound.
[0697] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.91 (t, J=7.6
Hz, 3H), 1.50-1.60 (m, 2H), 2.24-2.32 (m, 2H), 3.11-3.2.4 (m, 4H),
3.99 (s, 3H), 4.25 (t, J=5.9 Hz, 2H), 4.70-4.80 (m, 1H), 6.62 (s,
1H), 7.11 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.11-7.16 (m, 2H), 7.23 (s,
1H), 7.25 (d, J=2.7 Hz, 1H), 7.45 (s, 1H), 8.19 (d, J=9.0 Hz, 1H),
8.30-8.34 (m, 2H), 8.55 (s, 1H)
[0698] Mass analysis, found (ESI-MS, m/z): 554 (M.sup.++1)
Example 134
N-{2-Chloro-4-[(6-methoxy-7-{3-[(1-methyl-1H-1,2,3,4-tetrazol-5-yl)thio]pr-
opoxy}-4-quinazolinyl)-oxy]phenyl}-N'-propylurea
[0699] A starting compound
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)--
N'-propylurea, 80 mg), potassium carbonate (138 mg), and
5-mercapto-1-tetrazole (23 mg) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 3 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 71 mg (yield 85%) of the
title compound.
[0700] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.91 (t, J=7.3
Hz, 3H), 1.51-1.56 (m, 2H), 2.39-2.48 (m, 2H), 3.17-3.23 (m, 2H),
3.56 (t, J=7.1 Hz, 2H), 3.86 (s, 3H), 3.97 (s, 3H), 4.27 (t, J=5.9
Hz, 2H), 4.75-4.82 (m, 1H), 6.63 (s, 1H), 7.10 (dd, J=2.7 Hz, 9.0
Hz, 1H), 7.24 (d, J=3.7 Hz, 1H), 7.44 (s, 1H), 8.19 (d, J=9.0 Hz,
1H), 8.55 (s, 1H)
[0701] Mass analysis, found (ESI-MS, m/z): 559 (M.sup.++1)
Example 135
N-(2-Chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-propylurea
[0702]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (500 mg), potassium carbonate (857 mg), and
1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide
(5 ml), and the solution was stirred at room temperature for 3 hr.
The solvent was removed by distillation under the reduced pressure.
Water was added to the residue, and the mixture was extracted with
chloroform/2-propanol (4/1). The organic layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was washed with ether to
give 451 mg (yield 71%) of
N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N-
'-propylurea.
N-(4-{[7-(3-Bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N-
'-propylurea (70 mg), potassium carbonate (54 mg), and piperidine
(39 .mu.l) were dissolved in N,N-dimethylformamide (2 ml), and the
solution was stirred at room temperature overnight. The solvent was
removed by distillation under the reduced pressure. A saturated
aqueous sodium hydrogencarbonate solution was added to the residue,
and the mixture was extracted with chloroform. The organic layer
was dried over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol (20/1) to give 35 mg (yield 50%) of the title
compound.
[0703] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.98 (t, J=7.6
Hz, 3H), 1.46 (br, 2H), 1.54-1.66 (m, 8H), 2.15 (br, 2H), 2.44 (br,
2H), 2.55 (br, 2H), 3.20-3.30 (m, 2H), 4.04 (s, 3H), 4.27 (t, J=6.6
Hz, 2H), 4.77 (t, J=5.9 Hz, 1H), 6.65 (s, 1H), 7, 17 (dd, J=2.7 Hz,
9.0 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.33 (s, 1H), 7.49 (s, 1H),
8.24 (d, J=9.0 Hz, 1H), 8.61 (s, 1H)
Example 136
N-[2-Chloro-4-({7-methoxy-6-[2-(4-methylpiperazino)ethoxy]-4-quinazolinyl}-
oxy)phenyl]-N'-propylurea
[0704]
N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (500 mg), potassium carbonate (857 mg), and
1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide
(5 ml), and the solution was stirred at room temperature for 3 hr.
The solvent was removed by distillation under the reduced pressure.
Water was added to the residue, and the mixture was extracted with
chloroform/2-propanol (4/1). The organic layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was washed with ether to
give 451 mg (yield 71%) of
N-(4-{[6-(2-bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N'-
-propylurea.
N-(4-{[6-(2-Bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N'-
-propylurea (50 mg), potassium carbonate (40 mg), and
N-methylpiperazine (50 .mu.l) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature overnight. The solvent was removed by distillation
under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 20 mg (yield 44%) of the title
compound.
[0705] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.98 (t, J=7.3
Hz, 3H), 1.56-1.65 (m, 2H), 1.77 (br, 4H), 2.31 (s, 3H), 2.53 (br,
2H), 2.71 (br, 2H), 2.97 (t, J=6.1 Hz, 3H), 3.24-3.29 (m, 2H), 4.04
(s, 3H), 4.32 (t, J=6.1 Hz, 2H), 4.83 (br, 1H), 6.69 (s, 1H), 7.16
(dd, J=2.7 Hz, 9.0 Hz, 1H), 7.30 (s, 1H), 7.31 (s, 1H), 7.55 (s,
1H), 8.25 (d, J=9.0 Hz, 1H), 8.62 (s, 1H)
[0706] Mass analysis, found (ESI-MS, m/z): 529 (M.sup.++1)
Example 137
N-[2-Chloro-4-({7-methoxy-6-[3-(4-methyl-piperazino)propoxy]-4-quinazoliny-
l}oxy)phenyl]-N'-propylurea
[0707]
N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
propylurea (500 mg), potassium carbonate (857 mg), and
1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide
(5 ml), and the solution was stirred at room temperature for 3 hr.
The solvent was removed by distillation under the reduced pressure.
Water was added to the residue, and the mixture was extracted with
chloroform/2-propanol (4/1). The organic layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was washed with ether to
give 451 mg (yield 71%) of
N-(4-{[6-(3-bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N-
'-propylurea.
N-(4-{[6-(3-Bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N-
'-propylurea (50 mg), potassium carbonate (40 mg), and
N-methylpiperazine (50 .mu.l) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature overnight. The solvent was removed by distillation
under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 20 mg (yield 44%) of the title
compound.
[0708] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.98 (t, J=7.6
Hz, 3H), 1.58-1.64 (m, 2H), 1.71 (br, 4H), 2.31 (s, 3H), 2.53 (br,
2H), 2.71 (br, 2H), 2.11-2.17 (m, 2H), 2.30 (s, 3H), 2.59-2.62 (m,
2H), 3.24-3.29 (m, 2H), 4.04 (s, 3H), 4.26 (t, J=6.6 Hz, 2H), 4.80
(br, 1H), 6.67 (s, 1H), 7.17 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.31 (s,
1H), 7.31 (s, 1H), 7.52 (s, 1H), 8.25 (d, J=9.0 Hz, 1H), 8.61 (s,
1H)
[0709] Mass analysis, found (ESI-MS, m/z): 543 (M.sup.++1)
Example 138
N-(2-Chloro-4-{[7-methoxy-6-(2-pyridyl-methoxy)-4-quinazolinyl]oxy}phenyl)-
-N'-propylurea
[0710] A starting compound
(N-{2-chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy)phenyl}-N'-propyl-
urea, 80 mg), potassium carbonate (138 mg), and
2-(chloromethyl)pyridine hydrochloride (41 mg) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at
120.degree. C. for 3 hr. Water was added to the reaction mixture,
and the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ethyl acetate to give 54 mg (yield 55%) of
the title compound.
[0711] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.91 (t, J=7.6
Hz, 3H), 1.51-1.58 (m, 2H), 3.17-3.22 (m, 2H), 4.02 (s, 3H), 4.69
(br, 1H), 5.36 (s, 2H), 6.57 (s, 1H), 7.08 (dd, J=2.7 Hz, 9.0 Hz,
1H), 7.21-7.29 (m, 2H), 7.53-7.55 (m, 2H), 7.66-7.71 (m, 1H), 8.15
(d, J=9.0 Hz, 1H), 8.55-8.57 (m, 2H)
[0712] Mass analysis, found (ESI-MS, m/z): 494 (M.sup.++1)
Example 139
N-(2-Chloro-4-{[7-methoxy-6-(3-morpholino-propoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-propylurea
[0713] A starting compound
(N-(4-{[6-(3-propoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N'-pr-
opylurea, 54 mg), potassium carbonate (138 mg), and morpholine
(0.017 ml) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at 120.degree. C. for 3 hr. Water was added to
the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was washed with ethyl
acetate to give 42 mg (yield 77%) of the title compound.
[0714] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.91 (t, J=7.6
Hz, 3H), 1.47-1.59 (m, 4H), 1.88-2.00 (m, 2H), 2.35-2.48 (m, 4H),
3.20 (dd, J=7.3 Hz, 12.9 Hz, 2H), 3.62-3.74 (m, 4H), 3.97 (s, 3H),
4.15 (t, J=6.3 Hz, 2H), 4.74-4.80 (m, 1H), 6.63 (s, 1H), 7.09 (dd,
J=2.7 Hz, 9.0 Hz, 1H), 7.24 (d, J=2.7 Hz, 1H), 7.42 (s, 1H), 8.18
(d, J=9.0 Hz, 1H), 8.54 (s, 1H)
[0715] Mass analysis, found (ESI-MS, m/z): 530 (M.sup.++1)
Example 140
N-{2-Chloro-4-[(6-{3-(2-hydroxyethyl)-(methyl)amino]propoxy}-7-methoxy-4-q-
uinazolinyl)oxy]-phenyl}-N'-propylurea
[0716] A starting compound
(N-(4-{[6-(3-bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)--
N'-propylurea, 51 mg), potassium carbonate (68 mg), and
2-(methylamino)ethanol (15 mg) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at
80.degree. C. for 3 hr. Water was added to the reaction mixture,
and the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by HPLC by development with
chloroform/methanol to give 25 mg (yield 48%) of the title
compound.
[0717] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.95 (t, J=7.6
Hz, 3H), 1.53-1.62 (m, 2H), 2.08-2.15 (m, 2H), 2.30 (s, 3H), 2.58
(t, J=5.4 Hz, 2H), 2.68 (t, J=7.1 Hz, 2H), 3.21-3.26 (m, 2H), 3.60
(t, J=5.4 Hz, 2H), 4.02 (s, 3H), 4.23 (t, J=6.3 Hz, 2H), 5.06 (t,
J=5.6 Hz, 1 Hz), 6.79 (s, 1H), 7.13 (dd, J=2.7 Hz, 9.0 Hz, 1H),
7.27-7.28 (m, 2H), 7.48 (s, 1H), 8.21 (d, J=9.0 Hz, 1H), 8.58 (s,
1H)
Example 141
N-(2-Chloro-4-{[6-methoxy-7-(2-pyridyl
methoxy)-4-quinolyl]oxy}phenyl)-N'-propylurea
[0718] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy)phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and 2-chloromethylpyridine
hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1
ml), and the solution was stirred at 80.degree. C. for 3 hr. Water
was added to the reaction mixture, and the mixture was extracted
with chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under the reduced pressure. The residue was purified by HPLC to
give 81 mg (yield 82%) of the title compound.
[0719] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.97 (t, J=7.6
Hz, 3H), 1.54-1.65 (m, 2H), 3.25 (dd, J=7.1 Hz, 12.9 Hz, 2H), 4.05
(s, 3H), 4.75-4.82 (m, 1H), 5.42 (s, 2H), 6.46 (d, J=5.4 Hz, 1H),
6.67 (s, 1H), 7.08 (dd, J=2.9 Hz, 9.0 Hz, 1H), 7.19 (d, J=2.7 Hz,
1H), 7.44 (s, 1H), 7.53 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.69 (dt,
J=2.0 Hz, 7.8 Hz, 1H), 8.25 (d, J=9.0 Hz, 1H), 8.46 (d, J=5.1 Hz,
1H), 8.61 (d, J=4.6 Hz, 1H)
[0720] Mass analysis, found (ESI-MS, m/z): 493 (M.sup.++1)
Example 142
N-(2-Chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'--
propylurea
[0721] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and 3-chloromethylpyridine
hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1
ml), and the solution was stirred at 80.degree. C. for 3 hr. Water
was added to the reaction mixture, and the mixture was extracted
with chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC to give 70 mg (yield 71%) of the title compound.
[0722] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.97 (t, J=7.3
Hz, 3H), 1.54-1.65 (m, 2H), 3.25 (dd, J=7.3 Hz, 12.9 Hz, 2H), 4.02
(s, 3H), 4.82-4.90 (m, 1H), 5.30 (s, 2H), 6.47 (d, J=5.4 Hz, 1H),
6.72 (s, 1H), 7.09 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.19 (d, J=2.7 Hz,
1H), 7.32 (dd, J=4.9 Hz, 7.8 Hz, 1H), 7.47 (s, 1H), 7.52 (s, 1H),
7.84 (d, J=7.8 Hz, 1H), 8.26 (d, J=9.3 Hz, 1H), 8.47 (d, J=5.4 Hz,
1H), 8.58 (d, J=3.2 Hz, 1H), 8.75 (s, 1H)
[0723] Mass analysis, found (ESI-MS, m/z): 493 (M.sup.++1)
Example 143
N-(2-Chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'--
propylurea
[0724] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine
hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1
ml), and the solution was stirred at 80.degree. C. for 3 hr. Water
was added to the reaction mixture, and the mixture was extracted
with chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC to give 71 mg (yield 71%) of the title compound.
[0725] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.97 (t, J=7.6
Hz, 3H), 1.54-1.65 (m, 2H), 3.25 (dd, J=7.1 Hz, 12.9 Hz, 2H), 4.05
(s, 3H), 4.86-4.92 (m, 1H), 5.32 (s, 2H), 6.48 (d, J=4.7 Hz, 1H),
6.73 (s, 1H), 7.08 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.19 (d, J=2.9 Hz,
1H), 7.38 (s, 1H), 7.41 (d, J=6.1 Hz, 2H), 7.54 (s, 1H), 8.26 (d,
J=9.0 Hz, 1H), 8.46 (d, J=5.4 Hz, 1H), 8.61 (d, J=6.1 Hz, 2H)
[0726] Mass analysis, found (ESI-MS, m/z): 493 (M.sup.++1)
Example 144
N-(2-Chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-quinolyl]oxy}phenyl)-N'-
-propylurea
[0727] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 100 mg), potassium carbonate (172 mg), and 1,2-dibromoethane
(0.086 ml) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at room temperature for 3 hr. Water was added
to the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give an intermediate
(N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy)-2-chlorophenyl)-N-pro-
pylurea). The intermediate, potassium carbonate (138 mg), and
morpholine (0.17 ml) were dissolved in N,N-dimethylformamide (1
ml), and the solution was stirred at 80.degree. C. for 2 hr. Water
was added to the reaction mixture, and the mixture was extracted
with chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 70 mg (yield 54%) of the title
compound.
[0728] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.91 (t, J=7.6
Hz, 3H), 1.50-1.59 (m, 2H), 2.57 (t, J=4.6 Hz, 4H), 2.88 (t, J=5.9
Hz, 2H), 3.18-3.23 (m, 2H), 3.68 (t, J=4.6 Hz, 4H), 3.94 (s, 3H),
4.26 (t, J=5.9 Hz, 2H), 4.98 (t, J=5.3 Hz, 2H), 6.41 (d, J=5.3 Hz,
1H), 6.74 (br, 1H), 7.03 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.14 (d, J=2.7
Hz, 1H), 7.34 (s, 1H), 7.43 (s, 1H), 8.42 (d, J=5.1 Hz, 1H)
[0729] Mass analysis, found (ESI-MS, m/z): 515 (M.sup.++1)
Example 145
N-[2-Chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinolyl}o-
xy)phenyl]-N'-propylurea
[0730] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and
2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzenesulfonate (59 mg)
were dissolved in N,N-dimethylformamide (1 ml), and the solution
was stirred at 120.degree. C. for 5 hr. Water was added to the
reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform-methanol to give 92 mg
(yield 92%) of the title compound.
[0731] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.97 (t, J=7.6
Hz, 3H), 1.57-1.63 (m, 2H), 3.23-3.28 (m, 2H), 4.01 (s, 3H), 4.52
(t, J=5.1 Hz, 2H), 4.81 (br, 1H), 4.93 (t, J=5.1 Hz, 2H), 6.47 (d,
J=5.4 Hz, 1H), 6.69 (s, 1H), 7.08 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.18
(d, J=2.7 Hz, 1H), 7.37 (s, 1H), 7.51 (s, 1H), 7.72 (d, J=1.0 Hz,
1H), 7.97 (d, J=1.0 Hz, 1H), 8.26 (d, J=9.0 Hz, 1H), 8.48 (d, J=5.4
Hz, 1H)
[0732] Mass analysis, found (ESI-MS, m/z): 497 (M.sup.++1)
Example 146
N-[2-Chloro-4-({7-[2-(1H-1-imidazolyl)-ethoxy]-6-methoxy-4-quinolyl}oxy)ph-
enyl]-N'-propylurea
[0733] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and
2-(1H-1-imidazolyl)ethyl 4-methyl-1-benzenesulfonate (59 mg) were
dissolved in N,N-dimethylformamide (1 ml), and the solution was
stirred at 120.degree. C. for 5 hr. Water was added to the reaction
mixture, and the mixture was extracted with chloroform-propanol
(3/1). The organic layer was dried over anhydrous sodium sulfate.
The solvent was removed by distillation under the reduced pressure,
and the residue was purified by HPLC by development with
chloroform/methanol to give 81 mg (yield 82%) of the title
compound.
[0734] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.96 (t, J=7.6
Hz, 3H), 1.50-1.65 (m, 2H), 1.90-2.08 (m, 2H), 3.24 (dd, J=7.1 Hz,
12.9 Hz, 2H), 4.01 (s, 3H), 4.17 (t, J=6.6 Hz, 2H), 4.44 (t, J=7.3
Hz, 2H), 4.88-4.94 (m, 1H), 6.32 (s, 1H), 7.14 (dd, J=2.7 Hz, 9.0
Hz, 1H), 7.25 (s, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.48 (s, 1H), 7.55
(s, 1H), 7.70 (s, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.58 (s, 1H)
[0735] Mass analysis, found (ESI-MS, m/z): 496 (M.sup.++1)
Example 147
N-(2-Chloro-4-{[7-(3-hydroxypropoxy)-6-methoxy-4-quinolyl]oxy}phenyl)-N'-p-
ropylurea
[0736] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and 3-bromo-1-propanol
(0.027 ml) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at room temperature for 18 hr. Water was added
to the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 94 mg
(yield 100%) of the title compound.
[0737] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.92 (t, J=7.6
Hz, 3H), 1.45-1.62 (m, 2H), 2.09-2.18 (m, 2H), 3.21 (dd, J=7.1 Hz,
12.9 Hz, 2H), 3.87 (t, J=5.6 Hz, 2H), 3.94 (s, 3H), 4.31 (t, J=6.1
Hz, 2H), 4.81-4.87 (m, 1H), 6.42 (d, J=5.1 Hz, 1H), 6.69 (s, 1H),
7.03 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.14 (d, J=2.7 Hz, 1H), 7.36 (s,
1H), 7.43 (s, 1H), 8.20 (d, J=9.0 Hz, 1H), 8.42 (d, J=5.4 Hz,
1H)
Example 148
N-[2-Chloro-4-({6-methoxy-7-[2-(4-methyl-piperazino)ethoxy]-4-quinolyl}oxy-
)phenyl]-N'-propylurea
[0738] A starting compound
(N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-pr-
opylurea, 50 mg), potassium carbonate (138 mg), and
1-methylpiperazine (0.055 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 54 mg (yield 100%) of the
title compound.
[0739] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.92 (t, J=7.3
Hz, 3H), 1.49-1.62 (m, 2H), 2.24 (s, 3H), 2.35-2.70 (m, 2H), 2.90
(t, J=4.6 Hz, 2H), 3.21 (dd, J=7.3 Hz, 12.9 Hz, 2H), 3.94 (s, 3H),
4.26 (t, J=6.1 Hz, 2H), 4.75-4.85 (m, 1H), 6.41 (d, J=5.1 Hz, 1H),
6.67 (s, 1H), 7.04 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.14 (d, J=2.7 Hz,
1H), 7.34 (s, 1H), 7.42 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.42 (d,
J=5.1 Hz, 1H)
[0740] Mass analysis, found (ESI-MS, m/z): 528 (W+1)
Example 149
N-(2-Chloro-4-{[7-(2-hydroxyethoxy)-6-methoxy-4-quinolyl]oxy}phenyl)-N'-pr-
opylurea
[0741] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and 2-bromoethanol (0.021
ml) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at room temperature for 18 hr. Water was added
to the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 80 mg
(yield 90%) of the title compound.
[0742] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.96 (t, J=7.6
Hz, 3H), 1.54-1.65 (m, 2H), 3.25 (dd, J=7.1 Hz, 12.9 Hz, 2H), 3.99
(s, 3H), 4.07 (t, J=4.4 Hz, 2H), 4.28 (t, J=4.6 Hz, 2H), 6.46 (d,
J=5.4 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 7.08 (s, 1H), 7.08 (dd,
J=2.7 Hz, 9.0 Hz, 1H), 7.42 (s, 1H), 7.49 (s, 1H), 8.25 (d, J=9.0
Hz, 1H), 8.48 (d, J=2.9 Hz, 1H)
Example 150
N-{2-Chloro-4-[(7-{2-[(2-hydroxyethyl)-(methyl)amino]ethoxy}-6-methoxy-4-q-
uinolyl)oxy]phenyl}-N'-propylurea
[0743] A starting compound
(N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-pr-
opylurea, 50 mg), potassium carbonate (138 mg), and
2-(methylamino)ethanol (0.040 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 53 mg (yield 106%) of the
title compound.
[0744] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.97 (t, J=7.6
Hz, 3H), 1.54-1.65 (m, 2H), 2.42 (s, 3H), 2.69 (t, J=5.1 Hz, 2H),
3.00 (t, J=5.6 Hz, 2H), 3.26 (dd, J=7.1 Hz, 12.7 Hz, 2H), 3.64 (t,
J=5.1 Hz, 2H), 3.99 (s, 3H), 4.26 (t, J=5.6 Hz, 2H), 4.66-4.69 (m,
1H), 6.46 (d, J=5.1 Hz, 1H), 6.70 (s, 1H), 7.09 (dd, J=2.7 Hz, 9.0
Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 7.39 (s, 1H), 7.47 (s, 1H), 8.24
(d, J=9.0 Hz, 1H), 8.47 (d, J=5.1 Hz, 1H)
[0745] Mass analysis, found (ESI-MS, m/z): 503 (M.sup.++1)
Example 151
N-(2-Chloro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy}phenyl)-N-
'-propylurea
[0746] A starting compound
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-p-
ropylurea, 52 mg), potassium carbonate (138 mg), and morpholine
(0.044 ml) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at room temperature for 18 hr. Water was added
to the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 23 mg (yield 44%) of the title compound.
[0747] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.92 (t, J=7.6
Hz, 3H), 1.49-1.60 (m, 2H), 2.02-2.11 (m, 2H), 2.40-2.47 (m, 4H),
2.52 (t, J=7.1 Hz, 2H), 3.21 (dd, J=7.1 Hz, 12.9 Hz, 2H), 3.62-3.69
(m, 4H), 3.95 (s, 3H), 4.20 (t, J=6.6 Hz, 2H), 4.70-4.78 (m, 1H),
6.41 (d, J=5.1 Hz, 1H), 6.64 (s, 1H), 7.04 (dd, J=2.7 Hz, 9.0 Hz,
1H), 7.15 (d, J=2.7 Hz, 1H), 7.37 (s, 1H), 7.43 (s, 1H), 8.20 (d,
J=9.0 Hz, 1H), 8.42 (d, J=5.4 Hz, 1H)
Example 152
N-[2-Chloro-4-(6-methoxy-7-{[3-(4-methyl-piperazino)propoxy]-4-quinolyl}ox-
y)phenyl]-N-propylurea
[0748] A starting compound
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-p-
ropylurea, 52 mg), potassium carbonate (138 mg), and
1-methylpiperazine (0.055 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 41 mg (yield 76%) of the
title compound.
[0749] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.92 (t, J=7.6
Hz, 3H), 1.49-1.64 (m, 2H), 2.02-2.10 (m, 2H), 2.23 (s, 3H),
2.30-2.56 (m, 8H), 2.52 (t, J=7.3 Hz, 2H), 3.20 (dd, J=7.1 Hz, 12.9
Hz, 2H), 3.94 (s, 3H), 4.19 (t, J=6.8 Hz, 2H), 4.83-4.92 (m, 1H),
6.40 (d, J=5.1 Hz, 1H), 6.69 (s, 1H), 7.03 (dd, J=2.9 Hz, 9.3 Hz,
1H), 7.14 (d, J=2.7 Hz, 1H), 7.35 (s, 1H), 7.42 (s, 1H), 8.19 (d,
J=9.0 Hz, 1H), 8.42 (d, J=5.4 Hz, 1H)
[0750] Mass analysis, found (ESI-MS, m/z): 542 (M.sup.++1)
Example 153
N-[2-Chloro-4-(6-methoxy-7-{[3-(1H-1,2,3-triazol-1-yl)propoxy]-4-quinolyl}-
oxy)phenyl]-N'-propylurea
[0751] Triazole (0.41 ml), 1-bromo-3-chloropropane (0.79 ml),
tetrabutylammonium iodide (10 mg), and a 3 M aqueous sodium
hydroxide solution (1 ml) were dissolved in acetone (10 ml), and
the solution was stirred at 50.degree. C. for 18 hr. Water was
added to the reaction mixture, and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography by
development with chloroform to give an intermeidate (327 mg).
[0752] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and the intermediate (43
mg) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at 80.degree. C. for 3 hr. Water was added to
the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 54 mg
(yield 52%) of the title compound.
[0753] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.97 (t, J=7.6
Hz, 3H), 1.54-1.65 (m, 2H), 2.49-2.58 (m, 2H), 3.26 (dd, J=7.1 Hz,
13.2 Hz, 2H), 4.01 (s, 3H), 4.15 (t, J=5.9 Hz, 2H), 4.69 (t, J=6.6
Hz, 2H), 4.90-5.00 (m, 1H), 6.46 (d, J=5.1 Hz, 1H), 6.77 (s, 1H),
7.08 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 7.36 (s,
1H), 7.51 (s, 1H), 7.61 (s, 1H), 7.67 (s, 1H), 8.26 (d, J=9.0 Hz,
1H), 8.47 (d, J=5.4 Hz, 1H)
[0754] Mass analysis, found (ESI-MS, m/z): 511 (M.sup.++1)
Example 154
N-[2-Chloro-4-({7-[3-(1H-1-imidazolyl)-propoxy]-6-methoxy-4-quinolyl}oxy)p-
henyl]-N'-propylurea
[0755] Imidazole (680 mg), 1-bromo-3-chloropropane (0.79 ml),
tetrabutylammonium iodide (10 mg), and a 3 M aqueous sodium
hydroxide solution (1 ml) were dissolved in acetone (10 ml), and
the solution was stirred at 50.degree. C. for 18 hr. Water was
added to the reaction mixture, and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography by
development with chloroform to give an intermediate
(1-(3-chloropropyl)-1H-imidazole, 525 mg).
[0756] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and the intermediate (42
mg) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at 80.degree. C. for 3 hr. Water was added to
the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 23 mg
(yield 23%) of the title compound.
[0757] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.91 (t, J=7.3
Hz, 3H), 1.48-1.60 (m, 2H), 2.27-2.36 (m, 2H), 3.20 (dd, J=6.8 Hz,
12.9 Hz, 2H), 3.97 (s, 3H), 4.06 (t, J=5.9 Hz, 2H), 4.21 (t, J=6.8
Hz, 2H), 6.39 (d, J=5.4 Hz, 1H), 6.90 (s, 1H), 6.98-7.04 (m, 2H),
7.12 (d, J=2.7 Hz, 1H), 7.30 (s, 1H), 7.44-7.48 (m, 2H), 8.22 (d,
J=9.0 Hz, 1H), 8.41 (d, J=5.4 Hz, 1H)
Example 155
N-{2-Chloro-4-[(7-{2-[di(2-hydroxyethyl)-amino]ethoxy}-6-methoxy-4-quinoly-
l)oxy]phenyl}-N'-propylurea
[0758] A starting compound
(N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-pr-
opylurea, 50 mg), potassium carbonate (138 mg), and
1-methylpiperazine (0.055 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the mixture was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 46 mg (yield 92%) of the
title compound.
[0759] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.92 (t, J=7.3
Hz, 3H), 1.50-1.60 (m, 2H), 2.74 (t, J=4.9 Hz, 4H), 3.04 (t, J=4.9
Hz, 2H), 3.15-3.24 (m, 2H), 3.60 (t, J=5.1 Hz, 4H), 3.94 (s, 3H),
4.17 (t, J=5.0 Hz, 2H), 6.41 (d, J=5.4 Hz, 1H), 6.75 (s, 1H), 7.04
(dd, J=2.4 Hz, 8.8 Hz, 1H), 7.14 (d, J=2.7 Hz, 1H), 7.38 (s, 1H),
7.43 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.42 (d, J=5.4 Hz, 1H)
Example 156
N-{2-Chloro-4-[(7-{3-[di(2-hydroxyethyl)-amino]propoxy}-6-methoxy-4-quinol-
yl)oxy]phenyl}-N'-propylurea
[0760] A starting compound
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-p-
ropylurea, 52 mg), potassium carbonate (138 mg), and diethanolamine
(53 mg) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at room temperature for 18 hr. Water was added
to the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 41 mg (yield 82%) of the title compound.
[0761] .sup.1H-NMR (CDCl.sub.3 400 MHz): .delta. 0.89 (t, J=7.3 Hz,
3H), 1.46-1.56 (m, 2H), 1.97-2.05 (m, 2H), 2.63 (t, J=5.1 Hz, 4H),
2.69 (t, J=6.1 Hz, 2H), 3.19 (dd, J=7.1 Hz, 13.2 Hz, 2H), 3.60 (t,
J=4.9 Hz, 4H), 3.94 (s, 3H), 4.32 (t, J=5.9 Hz, 2H), 5.27-5.35 (m,
1H), 6.37 (d, J=5.4 Hz, 1H), 6.94 (s, 1H), 7.01 (dd, J=2.9 Hz, 9.0
Hz, 1H), 7.10 (d, J=2.7 Hz, 1H), 7.42 (s, 1H), 7.53 (s, 1H), 8.19
(d, J=9.0 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H)
[0762] Mass analysis, found (ESI-MS, m/z): 547 (M.sup.++1)
Example 157
N-{2-Chloro-4-[(7-{3-[(2-hydroxy-ethyl)(methyl)amino]propoxy}-6-methoxy-4--
quinolyl)oxy]-phenyl}-N'-propylurea
[0763] A starting compound
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-p-
ropylurea, 52 mg), potassium carbonate (138 mg), and
2-(methylamino)ethanol (0.040 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 51 mg (yield 98%) of the
title compound.
[0764] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.91 (t, J=7.6
Hz, 3H), 1.45-1.59 (m, 2H), 2.05 (t, J=6.8 Hz, 2H), 2.24 (s, 3H),
2.51 (t, J=5.1 Hz, 2H), 2.59 (t, J=7.1 Hz, 2H), 3.20 (dd, J=6.8 Hz,
12.9 Hz, 2H), 3.57 (t, J=5.4 Hz, 2H), 3.95 (s, 3H), 4.22 (t, J=6.3
Hz, 2H), 5.00-5.08 (m, 1H), 6.40 (d, J=5.1 Hz, 1H), 6.79 (s, 1H),
7.03 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.13 (d, J=2.7 Hz, 1H), 7.426 (s,
1H), 7.433 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.40 (d, J=5.4 Hz,
1H)
[0765] Mass analysis, found (ESI-MS, m/z): 517 (M.sup.++1)
Example 158
N-[2-Chloro-4-({6-methoxy-7-[4-(1H-1,2,3-triazol-1-yl)butoxy]-4-quinolyl}o-
xy)phenyl]-N'-propylurea
[0766] Triazole (0.41 ml), 1-bromo-4-chlorobutane (0.93 ml),
tetrabutylammonium iodide (10 mg), and a 3 M aqueous sodium
hydroxide solution (1 ml) were dissolved in acetone (10 ml), and
the solution was stirred at 50.degree. C. for 18 hr. Water was
added to the reaction mixture, and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography by
development with chloroform to give an intermediate
(1-(4-chlorobutyl)-1H-1,2,3-triazole, 314 mg).
[0767] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and the intermediate (48
mg) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at 80.degree. C. for 3 hr. Water was added to
the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 42 mg
(yield 40%) of the title compound.
[0768] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.96 (t, J=7.3
Hz, 3H), 1.54-1.65 (m, 2H), 1.88-1.98 (m, 2H), 2.14-2.24 (m, 2H),
3.26 (dd, J=6.6 Hz, 13.2 Hz, 2H), 3.99 (s, 3H), 4.20 (t, J=5.9 Hz,
2H), 4.55 (t, J=7.1 Hz, 2H), 5.00-5.06 (m, 1H), 6.46 (d, J=5.4 Hz,
1H), 6.80 (s, 1H), 7.08 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.19 (d, J=2.7
Hz, 1H), 7.37 (s, 1H), 7.49 (s, 1H), 7.68-7.72 (m, 2H), 8.26 (d,
J=9.0 Hz, 1H), 8.47 (d, J=5.1 Hz, 1H)
[0769] Mass analysis, found (ESI-MS, m/z): 525 (M.sup.++1)
Example 159
N-{2-chloro-4-[(6-methoxy-7-{[5-(1H-1,2,3-triazol-1-yl)pentyl]oxy}-4-quino-
lyl)oxy]phenyl}-N'-propylurea
[0770] Triazole (0.41 ml), 1-bromo-5-chloropentane (1.0 ml),
tetrabutylammonium iodide (10 mg), and a 3 M aqueous sodium
hydroxide solution (1 ml) were dissolved in acetone (10 ml), and
the solution was stirred at 50.degree. C. for 18 hr. Water was
added to the reaction mixture, and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography by
development with chloroform to give an intermediate
(1-(5-chloropentyl-1H-1,2,3-triazole, 390 mg).
[0771] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and the intermediate (51
mg) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at 80.degree. C. for 3 hr. Water was added to
the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 33 mg
(yield 31%) of the title compound.
[0772] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.92 (t, J=7.6
Hz, 3H), 1.47-1.59 (m, 2H), 1.85-2.03 (m, 4H), 3.21 (dd, J=6.6 Hz,
13.2 Hz, 2H), 3.94 (s, 3H), 4.11 (t, J=6.3 Hz, 2H), 4.38 (t, J=7.1
Hz, 2H), 4.86-4.94 (m, 1H), 6.41 (d, J=5.4 Hz, 1H), 6.71 (s, 1H),
7.03 (dd, J=2.4 Hz, 9.0 Hz, 1H), 7.14 (d, J=2.7 Hz, 1H), 7.31 (s,
1H), 7.43 (s, 1H), 7.51 (s, 1H), 7.64 (s, 1H), 8.20 (d, J=9.0 Hz,
1H), 8.41 (d, J=5.4 Hz, 1H)
[0773] Mass analysis, found (ESI-MS, m/z): 539 (M.sup.++1)
Example 160
N-[2-Chloro-4-({7-[4-(1H-1-imidazolyl)-butoxy]-6-methoxy-4-quinolyl}oxy)ph-
enyl]-N'-propylurea
[0774] Imidazole (680 mg), 1-bromo-4-chlorobutane (0.93 ml),
tetrabutylammonium iodide (10 mg), and a 3 M aqueous sodium
hydroxide solution (1 ml) were dissolved in acetone (10 ml), and
the solution was stirred at 50.degree. C. for 18 hr. Water was
added to the reaction mixture, and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was removed by distillation under the
reduced pressure. The residue was purified by chromatography by
development with chloroform to give an intermediate
(1-(4-chlorobutyl)-1H-imidazole, 756 mg).
[0775] A starting compound
(N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N'-propylurea-
, 80 mg), potassium carbonate (138 mg), and the intermediate (48
mg) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at 80.degree. C. for 3 hr. Water was added to
the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 29 mg
(yield 28%) of the title compound.
[0776] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.96 (t, J=7.3
Hz, 3H), 1.54-1.65 (m, 2H), 1.83-1.95 (m, 2H), 1.98-2.08 (m, 2H),
3.25 (dd, J=6.8 Hz, 12.7 Hz, 2H), 4.00 (s, 3H), 4.10 (t, J=7.1 Hz,
2H), 4.20 (t, J=6.1 Hz, 2H), 5.08-5.16 (m, 1H), 6.46 (d, J=5.1 Hz,
1H), 6.83 (s, 1H), 6.97 (s, 1H), 7.06 (S, 1H), 7.08 (dd, J=2.9 Hz,
9.3 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.37 (s, 1H), 7.49 (s, 1H),
7.58 (s, 1H), 8.26 (d, J=9.0 Hz, 1H), 8.46 (d, J=5.4 Hz, 1H)
Example 161
N-(2-Chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy)-4-quinazolinyl]oxy}phenyl)-
-N'-(2,4-difluoro-phenyl)urea
[0777] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'-(2,4--
difluoro-phenyl)urea, 80 mg), potassium carbonate (138 mg), and
4-chloromethylpyridine hydrochloride (41 mg) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 50 mg (yield 52%) of the
title compound.
[0778] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.03 (s, 3H),
5.46 (s, 2H), 7.03-7.11 (m, 1H), 7.28-7.38 (m, 1H), 7.47 (s, 1H),
7.50 (d, J=5.9 Hz, 2H), 7.56 (d, J=2.7 Hz, 1H), 7.61 (s, 1H), 7.95
(s, 1H), 8.09-8.18 (m, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.57 (s, 1H),
8.63 (d, J=5.9 Hz, 2H), 8.81 (s, 1H), 9.30 (s, 1H)
Example 162
N-(2-Chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinazolinyl]oxy}pheny-
l)-N'-(2,4-difluoro-phenyl)urea
[0779] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'-(2,4--
difluoro-phenyl)urea, 100 mg), potassium carbonate (857 mg), and
1,2-dibromoethane (0.085 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give an intermediate
(N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N-
'-(2,4-difluorophenyl)urea). The intermediate, potassium carbonate
(138 mg), and morpholine (0.05 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by HPLC by development with
chloroform/methanol to give 57 mg (yield 46%) of the title
compound.
[0780] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.54-2.63 (m,
4H), 2.85-2.94 (m, 2H), 3.66-3.73 (m, 4H), 3.97 (s, 3H), 4.25-4.32
(m, 2H), 6.77-6.88 (m, 2H), 7.09 (s, 1H), 7.14 (dd, J=2.7 Hz, 9.0
Hz, 1H), 7.257 (s, 1H), 7.264 (s, 1H), 7.44 (s, 1H), 7.90-7.99 (m,
1H), 8.22 (d, J=9.0 Hz, 1H), 8.56 (s, 1H)
[0781] Mass analysis, found (ESI-MS, m/z): 586 (M.sup.++1)
Example 163
N-(2-Chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-(2,4-difluoro-phenyl)urea
[0782] A starting compound
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)--
N'-(2,4-difluorophenyl)urea, 59 mg), potassium carbonate (857 mg),
and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide
(1 ml), and the solution was stirred at room temperature for 18 hr.
Water was added to the reaction mixture, and the mixture was
extracted with chloroform-propanol (3/1). The organic layer was
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 53 mg (yield 89%) of the title compound.
[0783] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.06-2.16 (m,
2H), 2.43-2.57 (m, 4H), 2.56 (t, J=6.8 Hz, 2H), 3.68-3.75 (m, 4H),
4.03 (s, 3H), 4.27 (t, J=6.6 Hz, 2H), 6.79-6.91 (m, 2H), 7.14 (s,
1H), 7.19 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.28 (s, 1H), 7.29 (d, J=9.0
Hz, 1H), 7.33 (s, 1H), 7.49 (s, 1H), 8.26 (d, J=9.0 Hz, 1H), 8.61
(s, 1H)
[0784] Mass analysis, found (ESI-MS, m/z): 600 (M.sup.++1)
Example 164
N-[2-Chloro-4-({6-methoxy-7-[3-(4-methyl-piperazino)propoxy)]-4-quinazolin-
yl}oxy)phenyl]-N'-(2,4-difluorophenyl)urea
[0785] A starting compound
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)--
N'-(2,4-difluorophenyl)urea, 59 mg), potassium carbonate (138 mg),
and 1-methylpiperazine (0.055 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 58 mg (yield 95%) of the
title compound.
[0786] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.01-2.12 (m,
2H), 2.23 (s, 3H), 2.23-2.80 (m, 8H), 2.51 (t, J=7.1 Hz, 2H), 3.97
(s, 3H), 4.20 (t, J=7.2 Hz, 2H), 6.73-6.87 (m, 2H), 7.13 (dd, J=2.7
Hz, 9.0 Hz, 1H), 7.24 (d, J=2.7 Hz, 1H), 7.27 (s, 1H), 7.30 (s,
1H), 7.44 (s, 1H), 7.91-8.00 (m, 2H), 8.21 (d, J=9.0 Hz, 1H), 8.56
(s, 1H)
Example 165
N-{2-Chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]propoxy}-6-methoxy-4--
quinazolinyl)oxy]-phenyl]-N'-(2,4-difluorophenyl)urea
[0787] A starting compound
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)--
N'-(2,4-difluorophenyl)urea, 59 mg), potassium carbonate (138 mg),
and 2-(methylamino)ethanol (0.040 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 58 mg (yield 100%) of the
title compound.
[0788] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.06-2.16 (m,
2H), 2.30 (s, 3H), 2.57 (t, J=5.1 Hz, 2H), 2.65 (t, J=6.8 Hz, 1H),
3.63 (t, J=5.4 Hz, 2H), 4.02 (s, 3H), 4.28 (t, J=6.1 Hz, 2H),
6.79-6.91 (m, 2H), 7.18 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.28 (d, J=2.7
Hz, 1H), 7.37 (s, 1H), 7.48 (s, 1H), 7.96-8.06 (m, 2H), 8.26 (d,
J=9.0 Hz, 1H), 8.59 (s, 1H)
[0789] Mass analysis, found (ESI-MS, m/z): 588 (M.sup.++1)
Example 166
N-[2-Chloro-4-({6-methoxy-7-[2-(4-methyl-piperazino)ethoxy]-4-quinolyl}oxy-
)phenyl]-N'-(2,4-difluorophenyl)urea
[0790] A starting compound
(N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-(2-
,4-difluorophenyl)urea, 50 mg), potassium carbonate (138 mg), and
1-methylpiperazine (0.055 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 48 mg (yield 93%) of the
title compound.
[0791] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.31 (s, 3H),
2.40-2.75 (m, 8H), 2.95 (t, J=6.1 Hz, 2H), 3.99 (s, 3H), 4.31 (t,
J=5.9 Hz, 2H), 6.48 (d, J=5.1 Hz, 1H), 6.85-6.96 (m, 3H), 7.1.2
(dd, J=2.7 Hz, 9.0 Hz, 1H), 7.15 (s, 1H), 7.22 (d, J=2.7 Hz, 1H),
7.40 (s, 1H), 7.47 (s, 1H), 7.94-8.03 (m, 1H), 8.25 (d, J=9.0 Hz,
1H), 8.49 (d, J=5.1 Hz, 1H)
Example 167
N-{2-Chloro-4-[(7-{2-[(2-hydroxyethyl)-(methyl)amino]ethoxy}-6-methoxy-4-q-
uinolyl)oxy]phenyl}-N'-(2,4-difluorophenyl)urea
[0792] A starting compound
(N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-(2-
,4-difluorophenyl)urea, 50 mg), potassium carbonate (138 mg), and
2-(methylamino)ethanol (0.040 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 48 mg (yield 97%) of the
title compound.
[0793] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.44 (s, 3H),
2.71 (t, J=4.9 Hz, 2H), 3.02 (t, J=5.6 Hz, 4H), 3.66 (t, J=5.1 Hz,
2H), 3.97 (s, 3H), 4.27 (t, J=5.6 Hz, 2H), 6.46 (d, 3=5.4 Hz, 1H),
6.80-6.93 (m, 2H), 7.11 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.19 (d, J=2.7
Hz, 1H), 7.45 (s, 1H), 7.96-8.04 (m, 1H), 8.25 (d, J=9.0 Hz, 1H),
8.48 (d, J=5.1 Hz, 1H)
Example 168
N-(2-Chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinolyl]oxy}phenyl)--
N'-(2,4-difluorophenyl)-urea
[0794] A starting compound
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-(-
2,4-difluorophenyl)urea, 50 mg), potassium carbonate (138 mg), and
morpholine (0.044 ml) were dissolved in N,N-dimethylformamide (1
ml), and the solution was stirred at room temperature for 18 hr.
Water was added to the reaction mixture, and the mixture was
extracted with chloroform-propanol (3/1). The organic layer was
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 32 mg (yield 64%) of the title compound.
[0795] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.06-2.16 (m,
2H), 2.43-2.51 (m, 4H), 2.56 (t, J=7.3 Hz, 2H), 3.68-3.74 (m, 4H),
4.00 (s, 3H), 4.25 (t, J=6.6 Hz, 2H), 6.47 (d, J=5.1 Hz, 1H),
6.84-6.93 (m, 2H), 7.06 (s, 1H), 7.12 (dd, J=2.7 Hz, 9.0 Hz, 1H),
7.22 (d, J=2.9 Hz, 1H), 7.42 (s, 1H), 7.47 (s, 1H), 7.95-8.04 (m,
1H), 8.25 (d, J=9.0 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H)
Example 169
N-(2-Chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'--
(2,4-difluorophenyl)-urea
[0796]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N'-(2,-
4-difluorophenyl)urea (55 mg), potassium carbonate (31 mg), and
3-picolyl chloride hydrochloride (22 mg) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at
80.degree. C. for one hr. The solvent was removed by distillation
under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The chloroform layer was
dried over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 30 mg (yield 48%) of the title compound.
[0797] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.03 (s, 3H),
5.31 (s, 2H), 6.49 (d, J=5.4 Hz, 1H), 6.77-6.88 (m, 2H), 7.10-7.16
(m, 2H), 7.31-7.35 (m, 1H), 7.48 (s, 1H), 7.54 (s, 1H), 7.86 (d,
J=7.8 Hz, 1H), 7.96 (s, 1H), 8.03-8.10 (m, 1H), 8.32 (d, J=9.0 Hz,
1H), 8.42 (s, 1H), 8.49 (d, J=5.4 Hz, 1H), 8.59 (d, J=3.9 Hz, 1H),
8.77 (s, 1H)
Example 170
N-[2-Chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinolyl}o-
xy)phenyl]-N'-(2,4-difluorophenyl)urea
[0798]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N'-(2,-
4-difluorophenyl)urea (55 mg), potassium carbonate (31 mg), and
2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzenesulfonate (36 mg)
were dissolved in N,N-dimethylformamide (1 ml), and the solution
was stirred at 80.degree. C. for one hr. The solvent was removed by
distillation under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The chloroform layer was
dried over anhydrous sodium sulfate. The solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 46 mg (yield 72%) of the title compound.
[0799] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 4.02 (s, 3H),
4.53 (d, J=4.9 Hz, 2H), 4.95 (d, J=5.1 Hz, 2H), 6.47 (d, J=5.1 Hz,
1H), 6.83-6.92 (m, 2H), 7.11 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.16 (d,
J=2.7 Hz, 1H), 7.39 (s, 1H), 7.52 (s, 1H), 7.58 (s, 1H), 7.70 (s,
1H), 7.76 (s, 1H), 8.00 (s, 1H), 8.01-8.07 (m, 1H), 8.29 (d, J=9.0
Hz, 1H), 8.49 (d, J=5.4 Hz, 1H)
Example 171
N-(2-Methoxy-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinazolinyl]oxy}phe-
nyl)-N'-propylurea
[0800]
N-4-[(7-Hydroxy-6-methoxy-4-quinazolinyl)oxy]-2-methoxyphenyl}-N'--
propylurea (100 mg), potassium carbonate (138 mg), and
1,3-dibromopropane (56 mg) were dissolved in N,N-dimethylformamide
(5 ml), and the solution was stirred at room temperature for 3 hr.
The solvent was removed by distillation under the reduced pressure.
Water was added to the residue, and the mixture was extracted with
chloroform/2-propanol (4/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 53 mg (yield 41%) of
N-(4-[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy-2-methoxy-phenyl}-N-
'-propylurea.
N-(4-{[6-(3-Bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N-
'-propylurea (50 mg), potassium carbonate (60 mg), and
N-methylpiperazine (100 .mu.l) were dissolved in
N,N-dimethylformamide (2 ml), and the solution was stirred at room
temperature for 16 hr. The solvent was removed by distillation
under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by chromatography on silica gel by development with
chloroform/methanol to give 22 mg (yield 42%) of the title
compound.
[0801] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.97 (t, J=7.6
Hz, 3H), 1.56-1.60 (m, 2H), 2.14 (br, 2H), 2.50 (br, 4H), 2.58 (br,
2H), 3.23-3.26 (m, 2H), 3.74 (br, 4H), 3.87 (s, 3H), 4.04 (s, 3H),
4.27-4.31 (m, 2H), 4.62-4.64 (m, 1H), 6.65 (s, 1H), 6.79-6.85 (m,
2H), 7.33 (s, 1H), 7.53 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.62 (s,
1H)
[0802] Mass analysis, found (ESI-MS, m/z): 526 (M.sup.++1)
Example 172
N-(2,4-Difluorophenyl)-N'-(2-methoxy-4-{[6-methoxy-7-(3-morpholinopropoxy)-
-4-quinazolinyl]oxy}-phenyl)urea
[0803]
N-(2,4-Difluorophenyl)-N'-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)o-
xy]-2-methoxyphenylurea (375 mg), potassium carbonate (442 mg), and
1,3-dibromopropane (242 mg) were dissolved in N,N-dimethylformamide
(5 ml), and the solution was stirred at room temperature for 3 hr.
The solvent was removed by distillation under the reduced pressure.
Water was added to the residue, followed by extraction with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate,
and the solvent was removed by distillation under the reduced
pressure. The residue was washed with ether to give 210 mg (yield
45%) of
N-{4-[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy-2-methoxyphenyl}-N'-
-(2,4-difluoro-phenyl)urea.
N-(4-{[6-(3-Bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N-
'-propylurea (130 mg), triethylamine (0.5 ml), and morpholine (0.5
ml) were dissolved in N,N-dimethylformamide (4 ml), and the
solution was stirred at room temperature for 18 hr. The solvent was
removed by distillation under the reduced pressure. A saturated
aqueous sodium hydrogencarbonate solution was added to the residue,
and the mixture was extracted with chloroform. The organic layer
was dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under the reduced pressure. The residue was
purified by chromatography on silica gel by development with
chloroform/methanol to give 81 mg (yield 62%) of the title
compound.
[0804] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.97-2.00 (m,
2H), 2.39 (br, 4H), 2.49-2.51 (m, 2H), 3.58-3.60 (m, 4H), 3.88 (s,
3H), 3.98 (s, 3H), 4.25 (t, J=6.3 Hz, 2H), 4.27-4.31 (m, 2H),
4.62-4.64 (m, 1H), 6.84 (dd, J=2.7 Hz, 8.8 Hz, 1H), 7.03-7.07 (m,
2H), 7.28-7.34 (m, 1H), 7.38 (s, 1H), 7.55 (s, 1H), 8.11-8.17 (m,
2H), 8.55 (s, 1H), 8.74 (s, 1H), 9.18 (s, 1H)
[0805] Mass analysis, found (ESI-MS, m/z): 596 (M.sup.++1)
Example 173
N-(2-Methoxy-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinolyl]oxy}phenyl)-
-N'-propylurea
[0806] A starting compound
(N-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-propylure-
a, 80 mg), potassium carbonate (138 mg), and 1,3-dibromopropane
(0.10 ml) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at room temperature for 18 hr. Water was added
to the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give an intermediate. The intermediate, potassium
carbonate (138 mg), and morpholine (0.040 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by chromatography on silica gel by development
with chloroform/methanol to give 74 mg (yield 71%) of the title
compound.
[0807] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.95 (t, J=7.6
Hz, 3H), 1.52-1.69 (m, 2H), 2.06-2.15 (m, 2H), 2.43-2.49 (m, 4H),
2.55 (t, J=7.3 Hz, 2H), 3.23 (dd, J=6.1 Hz, 12.9 Hz, 2H), 3.67-3.72
(m, 4H), 3.81 (s, 3H), 4.00 (s, 3H), 4.24 (t, J=6.8 Hz, 2H), 6.44
(d, J=5.1 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.76 (dd, J=2.4 Hz, 8.8.
Hz, 1H), 7.40 (s, 1H), 7.53 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.44
(d, J=5.1 Hz, 1H)
Example 174
N-(2-Methoxy-4-{[6-methoxy-7-(4-pyridylmethoxy)-4-quinolyl]oxy}phenyl)-N'--
propylurea
[0808] A starting compound
(N-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-propylure-
a, 80 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine
hydrochloride (48 mg) were dissolved in N,N-dimethylformamide (1
ml), and the solution was stirred at room temperature for 18 hr.
Water was added to the reaction mixture, and the mixture was
extracted with chloroform-propanol (3/1). The organic layer was
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 65 mg
(yield 67%) of the title compound.
[0809] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.95 (t, J=7.3
Hz, 3H), 1.52-1.69 (m, 2H), 3.24 (dd, J=7.3 Hz, 12.9 Hz, 2H), 3.82
(s, 3H), 4.06 (s, 3H), 4.63-4.69 (m, 1H), 5.32 (s, 2H), 6.46 (d,
J=5.4 Hz, 1H), 6.68 (d, J=2.7 Hz, 1H), 6.77 (dd, J=2.4 Hz, 8.5 Hz,
1H), 7.37 (s, 1H), 7.42 (d, J=6.1 Hz, 2H), 7.59 (s, 1H), 8.14 (d,
J=8.5 Hz, 1H), 8.43 (d, J=5.4 Hz, 1H), 8.61 (d, J=6.1 Hz, 2H)
Example 175
N-Ethyl-N'-(4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinolyl]oxy}-2,5-dime-
thylphenyl)urea
[0810] A starting compound
(N-ethyl-N'-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}u-
rea, 76 mg), potassium carbonate (138 mg), and 1,2-dibromoethane
(0.085 ml) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at room temperature for 18 hr. Water was added
to the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give an intermediate
(N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-N-
'-ethylurea). The intermediate, potassium carbonate (138 mg), and
morpholine (0.044 ml) were dissolved in N,N-dimethylformamide (1
ml), and the solution was stirred at room temperature for 18 hr.
Water was added to the reaction mixture, and the mixture was
extracted with chloroform-propanol (3/1). The organic layer was
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 72 mg
(yield 73%) of the title compound.
[0811] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.10 (t, J=7.3
Hz, 3H), 2.07 (s, 3H), 2.16 (s, 3H), 2.53-2.59 (m, 4H), 2.88 (t,
J=5.9 Hz, 2H), 3.20-3.30 (m, 2H), 3.66-3.71 (m, 4H), 3.96 (s, 3H),
4.26 (t, J=5.9 Hz, 2H), 4.73-4.82 (m, 1H), 6.16 (s, 1H), 6.23 (d,
J=5.4 Hz, 1H), 6.88 (s, 1H), 7.35 (s, 1H), 7.40 (s, 1H), 7.50 (s,
1H), 8.38 (d, J=5.1 Hz, 1H)
Example 176
N-[4-({6-Methoxy-7-[3-(4-methylpiperazino)-propoxy]-4-quinolyl}oxy)-2,5-di-
methylphenyl]-N'-propylurea
[0812] A starting compound
(N-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N'-propyl-
urea, 80 mg), potassium carbonate (138 mg), and 1,3-dibromopropane
(0.10 ml) were dissolved in N,N-dimethylformamide (1 ml), and the
solution was stirred at room temperature for 18 hr. Water was added
to the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give an intermediate
(N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)--
N'-propylurea). The intermediate, potassium carbonate (138 mg), and
1-methylpiperazine (0.055 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the mixture was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 33 mg (yield 31%) of the
title compound.
[0813] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 0.91 (t, J=7.6
Hz, 3H), 1.50-1.58 (m, 2H), 2.07-2.20 (m, 2H), 2.12 (s, 3H), 2.23
(s, 3H), 2.28 (s, 3H), 2.33-2.70 (m, 10H), 3.21 (dd, J=7.3 Hz, 13.4
Hz, 2H), 4.00 (s, 3H), 4.24 (t, J=6.6 Hz, 2H), 4.64-4.76 (m, 1H),
5.95-6.05 (m, 1H), 6.27 (d, J=5.1 Hz, 1H), 6.95 (s, 1H), 7.39-7.43
(m, 2H), 7.54 (s, 1H), 8.42 (d, J=5.1 Hz, 1H)
[0814] Mass analysis, found (ESI-MS, m/z): 536 (M.sup.++1)
Example 177
N-(2,4-Difluorophenyl)-N'-[4-({6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethox-
y]-4-quinolyl}oxy)-2,5-dimethylphenyl]urea
[0815] A starting compound
(N-(2,4-difluorophenyl)-N'-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2,5-d-
imethylphenyl}urea, 93 mg), potassium carbonate (138 mg), and
2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzenesulfonate (52 mg)
were dissolved in N,N-dimethylformamide (1 ml), and the solution
was stirred at 80.degree. C. for 5 hr. Water was added to the
reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 33 mg
(yield 30%) of the title compound.
[0816] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.10 (s, 3H),
2.19 (s, 3H), 4.01 (s, 3H), 4.51 (t, J=4.9 Hz, 2H), 4.93 (t, J=5.4
Hz, 2H), 4.94 (s, 1H), 6.28 (d, J=5.1 Hz, 1H), 6.75-6.88 (m, 2H),
6.90 (s, 1H), 7.36 (s, 1H), 7.58 (s, 1H), 7.60 (s, 1H), 7.73 (s,
1H), 7.99 (s, 1H), 8.08 (dd, J=9.3 Hz, 15.1 Hz, 1H), 8.41 (d, J=5.1
Hz, 1H)
Example 178
N'-(2-Chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinazolinyl]oxy}phen-
yl)-N,N-dimethylurea
[0817] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dime-
thylurea, 80 mg), potassium carbonate (138 mg), and
1,2-dibromoethane (0.085 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give an intermediate
(N'-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)--
N,N-dimethylurea). The intermediate, potassium carbonate (138 mg),
and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide
(1 ml), and the solution was stirred at room temperature overnight.
Water was added to the reaction mixture, and the mixture was
extracted with chloroform-propanol (3/1). The organic layer was
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 72 mg
(yield 72%) of the title compound.
[0818] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.58-2.66 (m,
4H), 2.90-2.98 (m, 2H), 3.08 (s, 6H), 3.70-3.79 (m, 4H), 4.02 (s,
3H), 4.29-4.37 (m, 2H), 6.97 (s, 1H), 7.15 (dd, J=2.7 Hz, 9.0 Hz,
1H), 7.24-7.26 (m, 1H), 7.29 (s, 1H), 7.49 (s, 1H), 8.36 (d, J=9.3
Hz, 1H), 8.60 (s, 1H)
[0819] Mass analysis, found (ESI-MS, m/z): 502 (M.sup.++1)
Example 179
N'-(2-Chloro-4-{[6-methoxy-(4-morpholino-butoxy)-4-quinazolinyl]oxy}phenyl-
)-N,N-dimethylurea
[0820] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dime-
thylurea, 80 mg), potassium carbonate (138 mg), and
1,4-dibromobutane (0.12 ml) were dissolved in N,N-dimethylformamide
(1 ml), and the solution was stirred at room temperature for 18 hr.
Water was added to the reaction mixture, and the mixture was
extracted with chloroform-propanol (3/1). The organic layer was
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give an intermediate
(N'-(4-{[7-(4-bromobutoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)--
N,N-dimethylurea). The intermediate, potassium carbonate (138 mg),
and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide
(1 ml), and the solution was stirred at room temperature overnight.
Water was added to the reaction mixture, and the mixture was
extracted with chloroform-propanol (3/1). The organic layer was
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 47 mg
(yield 44%) of the title compound.
[0821] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 1.67-1.77 (m,
2H), 1.93-2.03 (m, 2H), 2.39-2.50 (m, 4H), 3.67 (s, 6H), 3.64-3.75
(m, 4H), 4.02 (s, 3H), 4.21 (t, J=6.6 Hz, 2H), 6.97 (s, 1H), 7.16
(dd, J=2.7 Hz, 9.3 Hz, 1H), 7.26 (s, 1H), 7.28 (s, 1H), 7.29 (d,
J=2.7 Hz, 1H), 7.48 (s, 1H), 8.36 (d, J=9.3 Hz, 1H), 8.59 (s,
1H)
Example 180
N'-(2-Chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy-4-quinazolinyl]oxy}phenyl)-
-N,N-dimethylurea
[0822] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dime-
thylurea, 50 mg), potassium carbonate (138 mg), and
4-chloromethylpyridine hydrochloride (49 mg) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was purified by HPLC by development with
chloroform/methanol to give 37 mg (yield 60%) of the title
compound.
[0823] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.07 (s, 6H),
4.07 (s, 3H), 5.32 (s, 2H), 6.97 (s, 1H), 7.15 (dd, J=2.7 Hz, 9.0
Hz, 1H), 7.26 (s, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.41 (d, J=6.1 Hz,
1H), 7.55 (s, 1H), 8.37 (d, J=9.0 Hz, 1H), 8.58 (s, 1H), 8.63 (d,
J=6.1 Hz, 1H)
[0824] Mass analysis, found (ESI-MS, m/z): 480 (M.sup.++1)
Example 181
Methyl
2-{[4-(3-chloro-4-{[(dimethylamino)carbonyl]amino}phenoxy)-6-methox-
y-7-quinazolinyl]oxy}acetate
[0825] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dime-
thylurea, 50 mg), potassium carbonate (138 mg), and bromoethyl
acetate (49 mg) were dissolved in N,N-dimethylformamide (1 ml), and
the solution was stirred at room temperature for 18 hr. Water was
added to the reaction mixture, and the mixture was extracted with
chloroform-propanol (3/1). The organic layer was dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was purified
by HPLC by development with chloroform/methanol to give 37 mg
(yield 60%) of the title compound.
[0826] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 3.07 (s, 6H),
3.82 (s, 3H), 4.06 (s, 3H), 4.87 (s, 2H), 6.97 (s, 1H), 7.14 (dd,
J=2.7 Hz, 9.0 Hz, 1H), 7.18 (s, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.54
(s, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.60 (s, 1H)
Example 182
N'-[2-Chloro-4-({6-methoxy-7-[3-(4-methylpiperazino)propoxy]-4-quinazoliny-
l}oxy)phenyl]-N,N-dimethylurea
[0827] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dime-
thylurea, 400 mg), potassium carbonate (966 mg), and
1,3-dibromopropane (0.51 ml) were dissolved in
N,N-dimethylformamide (5 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 398 mg (yield 78%) of an
intermediate
(N'-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-
-N,N-dimethylurea). The intermediate (51 mg), potassium carbonate
(138 mg), and 1-methylpiperazine (0.055 ml) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 46 mg (yield 85%) of the
title compound.
[0828] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.06-2.16 (m,
2H), 2.29 (s, 3H), 2.30-2.60 (m, 10H), 3.07 (s, 6H), 4.02 (s, 3H),
4.25 (t, J=6.8 Hz, 2H), 6.96 (s, 1H), 7.15 (dd, J=2.7 Hz, 9.0 Hz,
1H), 7.29 (d, J=2.7 Hz, 1H), 7.30 (s, 1H), 7.48 (s, 1H), 8.36 (d,
J=9.0 Hz, 1H), 8.59 (s, 1H)
[0829] Mass analysis, found (ESI-MS, m/z): 529 (M.sup.++1)
Example 183
N'-{2-Chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]propoxy}-6-methoxy-4-
-quinazolinyl)oxy]-phenyl}-N,N-dimethylurea
[0830] A starting compound
(N'-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dime-
thylurea, 400 mg), potassium carbonate (966 mg), and
1,3-dibromopropane (0.51 ml) were dissolved in
N,N-dimethylformamide (5 ml), and the mixture was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 398 mg (yield 78%) of an
intermediate
(N'-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-
-N,N-dimethylurea). The intermediate (51 mg), potassium carbonate
(138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in
N,N-dimethylformamide (1 ml). The mixture was stirred at room
temperature for 18 hr. Water was added to the reaction mixture, and
the mixture was extracted with chloroform-propanol (3/1). The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under the reduced pressure. The
residue was washed with ether to give 49 mg (yield 97%) of the
title compound.
[0831] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta. 2.01-2.11 (m,
2H), 2.25 (s, 3H), 2.52 (t, J=5.1 Hz, 2H), 2.61 (t, J=7.1 Hz, 2H),
3.03 (s, 6H), 3.57 (t, J=5.1 Hz, 2H), 3.98 (s, 3H), 4.23 (t, J=6.6
Hz, 2H), 6.92 (s, 1H), 7.10 (dd, J=2.7 Hz, 9.3 Hz, 1H), 7.24 (d,
J=2.7 Hz, 1H), 7.31 (s, 1H), 7.44 (s, 1H), 8.31 (d, J=9.0 Hz, 1H),
8.54 (s, 1H)
[0832] Mass analysis, found (ESI-MS, m/z): 504 (M.sup.++1)
Example 184
N-(2-Chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-methylurea
[0833]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
methylurea (2.0 g) was dissolved in N,N-dimethylformamide (50 ml),
and triphenylphosphine (2.8 g), piperidinopropanol (0.9 g), and
diethyl azodicarboxylate (1.9 g) were added to the solution. The
mixture was stirred at room temperature for 2 hr.
Triphenylphosphine (2.8 g), piperidinopropanol (0.6 g), and diethyl
azodicarboxylate (1.9 g) were then again added to the reaction
solution, followed by stirring at room temperature for additional
10 hr. The solvent was removed by distillation under the reduced
pressure. The residue was purified by chromatography on silica gel
by development with chloroform/methanol (20/1) to give 650 mg
(yield 25%) of the title compound.
[0834] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.37-1.43 (m,
2H), 1.43-1.53 (m, 4H), 1.96-2.00 (m, 2H), 2.29-2.50 (m, 6H), 2.68
(d, J=4.6 Hz, 3H), 3.97 (s, 3H), 4.23 (t, J=6.3 Hz, 2H), 6.82-6.85
(m, 1H), 7.23 (dd, J=2.7 Hz, 9.0 Hz, 1H), 7.38 (s, 1H), 7.47 (d,
J=2.7 Hz, 1H), 7.54 (s, 1H), 8.07 (s, 1H), 8.17 (d, J=9.0 Hz, 1H),
8.55 (s, 1H)
[0835] Mass analysis, found (ESI-MS, m/z): 500 (M.sup.++1)
Example 185
N-(2-chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phen-
yl)-N'-ethylurea
[0836]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N'--
ethylurea (2.7 g) was dissolved in N,N-dimethylformamide (30 ml),
and triphenylphosphine (3.6 g), piperidinopropanol (1.2 g), and
diethyl azodicarboxylate (2.4 g) were added to the solution. The
mixture was stirred at room temperature for 2 hr.
Triphenylphosphine (3.6 g), piperidinopropanol (0.8 g), and diethyl
azodicarboxylate (1.9 g) were then again added to the reaction
solution. The mixture was stirred at room temperature for
additional 10 hr. The solvent was removed by distillation under the
reduced pressure, and the residue was purified by chromatography on
silica gel by development with chloroform/methanol (20/1) to give
1.5 g (yield 42%) of the title compound.
[0837] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.08 (t, J=7.0
Hz, 3H), 1.38-1.41 (m, 2H), 1.47-1.53 (m, 4H), 1.95-2.00 (m, 2H),
2.31-2.46 (m, 6H), 3.10-3.17 (m, 2H), 3.97 (s, 3H), 4.23 (t, J=6.3
Hz, 2H), 6.96 (t, J=5.6 Hz, 1H), 7.23 (dd, J=2.7 Hz, 9.0 Hz, 1H),
7.37 (s, 1H), 7.47 (d, J=2.7 Hz, 1H), 7.54 (s, 1H), 8.02 (s, 1H),
8.19 (d, J=9.3 Hz, 1H), 8.55 (s, 1H)
[0838] Mass analysis, found (ESI-MS, m/z): 514 (M.sup.++1)
Example 186
N-(2-Chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N'--
(2,4-difluorophenyl)-urea
[0839]
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N'-(2,-
4-difluorophenyl)urea (55 mg), potassium carbonate (62 mg), and
4-(chloromethyl)pyridine hydrochloride (22 mg) were dissolved in
N,N-dimethylformamide (1 ml), and the solution was stirred at
80.degree. C. for one hr. The solvent was removed by distillation
under the reduced pressure. A saturated aqueous sodium
hydrogencarbonate solution was added to the residue, and the
mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under the reduced pressure. The residue was washed
with ether to give 35 mg (yield 55%) of the title compound.
[0840] .sup.1H-NMR (DMSO, 400 MHz): .delta. 3.98 (s, 3H), 5.41 (s,
2H), 6.56 (d, J=5.1 Hz, 1H), 7.04-7.10 (m, 1H), 7.25-7.37 (m, 2H),
7.47 (s, 1H), 7.49-7.52 (m, 4H), 7.55 (s, 1H), 8.08-8.15 (m, 1H),
8.24 (d, J=9.0 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H), 8.60-8.63 (m, 1H),
8.81-8.83 (m, 1H), 9.30-9.31 (m, 1H)
[0841] Mass analysis, found (ESI-MS, m/z): 563 (M.sup.++1)
[0842] The structures of the compounds described in the examples
are as follows. TABLE-US-00001 X Z R.sup.1 R.sup.2 R.sup.3 R.sup.4
R.sup.5 R.sup.6 R.sup.7 R.sup.8 R.sup.9 R.sup.10 R.sup.11 1 CH CH H
CH.sub.3O CH.sub.3O H H F H H H H ##STR8## 2 CH CH H CH.sub.3O
CH.sub.3O H H F H H H H ##STR9## 3 CH CH H CH.sub.3O CH.sub.3O H H
F H H H H ##STR10## 4 CH CH H CH.sub.3O CH.sub.3O H H F H H H H
##STR11## 5 CH CH H CH.sub.3O CH.sub.3O H H F H H H H ##STR12## 6
CH CH H CH.sub.3O CH.sub.3O H H F H H H H ##STR13## 7 CH CH H
CH.sub.3O CH.sub.3O H H F H H H H ##STR14## 8 CH CH H CH.sub.3O
CH.sub.3O H H F H H H H ##STR15## 9 CH CH H CH.sub.3O CH.sub.3O H H
F H H H H ##STR16## 10 CH CH H CH.sub.3O CH.sub.3O H H F H H H H
##STR17## 11 CH CH H CH.sub.3O CH.sub.3O H H F H H H H ##STR18## 12
CH CH H CH.sub.3O CH.sub.3O H H F H H H H ##STR19## 13 CH CH H
CH.sub.3O CH.sub.3O H H Cl H H H H ##STR20## 14 CH CH H CH.sub.3O
CH.sub.3O H H Cl H H H H ##STR21## 15 CH CH H CH.sub.3O CH.sub.3O H
H Cl H H H H ##STR22## 16 CH CH H CH.sub.3O CH.sub.3O H H Cl H H H
H ##STR23## 17 CH CH H CH.sub.3O CH.sub.3O H H Cl H H H H ##STR24##
18 CH CH H CH.sub.3O CH.sub.3O H H Cl H H H H ##STR25## 19 CH CH H
CH.sub.3O CH.sub.3O H H Cl H H H H ##STR26## 20 CH CH H CH.sub.3O
CH.sub.3O H H Cl H H H H ##STR27## 21 CH CH H CH.sub.3O CH.sub.3O H
H Cl H H H H ##STR28## 22 CH CH H CH.sub.3O CH.sub.3O H H Cl H H H
H ##STR29## 23 CH CH H CH.sub.3O CH.sub.3O H H Cl H H H H ##STR30##
24 CH CH H CH.sub.3O CH.sub.3O H CH.sub.3 CH.sub.3 H H H H
##STR31## 25 CH CH H CH.sub.3O CH.sub.3O H CH.sub.3 CH.sub.3 H H H
H ##STR32## 26 CH CH H CH.sub.3O CH.sub.3O H CH.sub.3 CH.sub.3 H H
H H ##STR33## 27 CH CH H CH.sub.3O CH.sub.3O H CH.sub.3 CH.sub.3 H
H H H ##STR34## 28 CH CH H CH.sub.3O CH.sub.3O H CH.sub.3 CH.sub.3
H H H H ##STR35## 29 CH CH H CH.sub.3O CH.sub.3O H CH.sub.3
CH.sub.3 H H H H ##STR36## 30 CH CH H CH.sub.3O CH.sub.3O H
CH.sub.3 CH.sub.3 H H H H ##STR37## 31 CH CH H CH.sub.3O CH.sub.3O
H CH.sub.3 CH.sub.3 H H H H ##STR38## 32 CH CH H CH.sub.3O
CH.sub.3O H CH.sub.3 CH.sub.3 H H H H ##STR39## 33 CH CH H
CH.sub.3O CH.sub.3O H CH.sub.3 CH.sub.3 H H H H ##STR40## 34 CH CH
H CH.sub.3O CH.sub.3O H CH.sub.3 CH.sub.3 H H H H ##STR41## 35 CH
CH H CH.sub.3O CH.sub.3O H CH.sub.3 CH.sub.3 H H H H ##STR42## 36
CH CH H CH.sub.3O CH.sub.3O H CH.sub.3 CH.sub.3 H H H H ##STR43##
37 CH CH H CH.sub.3O CH.sub.3O H H CH.sub.3 CH.sub.3 H H H
##STR44## 38 CH CH H CH.sub.3O CH.sub.3O H H CH.sub.3 CH.sub.3 H H
H ##STR45## 39 CH CH H CH.sub.3O CH.sub.3O H H CH.sub.3 CH.sub.3 H
H H ##STR46## 40 CH CH H CH.sub.3O CH.sub.3O H H CH.sub.3 CH.sub.3
H H H ##STR47## 41 CH CH H CH.sub.3O CH.sub.3O H H CH.sub.3
CH.sub.3 H H H ##STR48## 42 CH CH H CH.sub.3O CH.sub.3O H H
CH.sub.3 CH.sub.3 H H H ##STR49## 43 CH CH H CH.sub.3O CH.sub.3O H
H CH.sub.3 CH.sub.3 H H H ##STR50## 44 CH CH H CH.sub.3O CH.sub.3O
H H CH.sub.3 CH.sub.3 H H H ##STR51## 45 CH CH H CH.sub.3O
CH.sub.3O H H CH.sub.3 CH.sub.3 H H H ##STR52## 46 CH CH H
CH.sub.3O CH.sub.3O H H CH.sub.3 CH.sub.3 H H H ##STR53## 47 CH CH
H CH.sub.3O CH.sub.3O H H NO.sub.2 H H H H ##STR54## 48 CH CH H
CH.sub.3O CH.sub.3O H H NO.sub.2 H H H H ##STR55## 49 CH CH H
CH.sub.3O CH.sub.3O H Cl H Cl H H H ##STR56## 50 CH CH H CH.sub.3O
##STR57## H H F H H H H ##STR58## 51 CH CH H CH.sub.3O ##STR59## H
H Cl H H H H ##STR60## 52 CH CH H CH.sub.3O ##STR61## H H CH.sub.3
CH.sub.3 H H H PGET,0066 53 CH CH H CH.sub.3O ##STR62## H H
CH.sub.3 CH.sub.3 H H H ##STR63## 54 CH CH H CH.sub.3O
CH.sub.3O(CH.sub.2).sub.2O H H Cl H H H H ##STR64## 55 CH CH H
CH.sub.3O CH.sub.3O(CH.sub.2).sub.2O H H Cl H H H H ##STR65## 56 CH
CH H CH.sub.3O CH.sub.3O(CH.sub.2).sub.2O H CH.sub.3 CH.sub.3 H H H
H ##STR66## 57 CH CH H CH.sub.3O CH.sub.3O(CH.sub.2).sub.2O H
CH.sub.3 CH.sub.3 H H H H ##STR67## 58 CH CH H CH.sub.3O
CH.sub.3O(CH.sub.2).sub.2O H H CH.sub.3 CH.sub.3 H H H ##STR68## 59
CH CH H CH.sub.3O CH.sub.3O(CH.sub.2).sub.2O H H CH.sub.3 CH.sub.3
H H H ##STR69## 60 CH CH H CH.sub.3O ##STR70## H CH.sub.3 CH.sub.3
H H H H ##STR71## 61 N CH H CH.sub.3O CH.sub.3O H H Cl H H H H
##STR72## 62 N CH H CH.sub.3O CH.sub.3O H H Cl H H H H ##STR73## 63
N CH H CH.sub.3O CH.sub.3O H H H H H H H ##STR74## 64 N CH H
CH.sub.3O CH.sub.3O H H H H H H H ##STR75## 65 N CH H CH.sub.3O
CH.sub.3O H H H H H H H ##STR76## 66 N CH H CH.sub.3O CH.sub.3O H H
H H H H H ##STR77## 67 N CH H CH.sub.3O CH.sub.3O H H H H H H H
##STR78## 68 N CH H CH.sub.3O CH.sub.3O H H H H H H H ##STR79## 69
N CH H CH.sub.3O CH.sub.3O H H H H H H H ##STR80## 70 N CH H
CH.sub.3O CH.sub.3O H H H H H H H ##STR81## 71 N CH H CH.sub.3O
CH.sub.3O H H H H H H H ##STR82## 72 N CH H CH.sub.3O CH.sub.3O H H
H H H H H ##STR83## 73 N CH H CH.sub.3O CH.sub.3O H H H H H H H
##STR84## 74 N CH H CH.sub.3O CH.sub.3O H H H H H H H ##STR85## 75
N CH H CH.sub.3O CH.sub.3O H H H H H H H ##STR86## 76 N CH H
CH.sub.3O CH.sub.3O H H Cl H H H H ##STR87## 77 N CH H CH.sub.3O
CH.sub.3O H H Cl H H H H ##STR88## 78 N CH H CH.sub.3O CH.sub.3O H
H Cl H H H H ##STR89## 79 N CH H CH.sub.3O CH.sub.3O H H Cl H H H H
##STR90## 80 N CH H CH.sub.3O CH.sub.3O H H Cl H H H H ##STR91## 81
N CH H CH.sub.3O CH.sub.3O H H Cl H H H H ##STR92## 82 N CH H
CH.sub.3O CH.sub.3O H H Cl H H H H ##STR93## 83 N CH H CH.sub.3O
CH.sub.3O H H Cl H H H H ##STR94## 85 N CH H CH.sub.3O CH.sub.3O H
H Cl H H H H ##STR95## 86 N CH H CH.sub.3O CH.sub.3O H H Cl H H H H
##STR96## 87 N CH H CH.sub.3O CH.sub.3O H H Cl H H H H ##STR97## 88
N CH H CH.sub.3O CH.sub.3O H H F H H H H ##STR98## 89 N CH H
CH.sub.3O CH.sub.3O H H F H H H H ##STR99## 90 N CH H CH.sub.3O
CH.sub.3O H H F H H H H ##STR100## 91 N CH H CH.sub.3O CH.sub.3O H
H F H H H H ##STR101## 92 N CH H CH.sub.3O CH.sub.3O H H F H H H H
##STR102## 93 N CH H CH.sub.3O CH.sub.3O H H F H H H H ##STR103##
94 N CH H CH.sub.3O CH.sub.3O H H F H H H H ##STR104## 95 N CH H
CH.sub.3O CH.sub.3O H H F H H H H ##STR105## 96 N CH H CH.sub.3O
CH.sub.3O H H F H H H H ##STR106## 97 N CH H CH.sub.3O CH.sub.3O H
CH.sub.3 H H H H H ##STR107## 98 N CH H CH.sub.3O CH.sub.3O H
CH.sub.3 H H H H H ##STR108## 99 N CH H CH.sub.3O CH.sub.3O H
CH.sub.3 H H H H H ##STR109## 100 N CH H CH.sub.3O CH.sub.3O H
CH.sub.3 H H H H H ##STR110## 101 N CH H CH.sub.3O CH.sub.3O H
CH.sub.3 H H H H H ##STR111## 102 N CH H CH.sub.3O CH.sub.3O H H
CH.sub.3 H H H H ##STR112## 103 N CH H CH.sub.3O CH.sub.3O H H
CH.sub.3 H H H H ##STR113## 104 N CH H CH.sub.3O CH.sub.3O H H
CH.sub.3 H H H H ##STR114## 105 N CH H CH.sub.3O CH.sub.3O H H
CH.sub.3 H H H H ##STR115## 106 N CH H CH.sub.3O CH.sub.3O H H
CH.sub.3 H H H H ##STR116## 107 N CH H CH.sub.3O CH.sub.3O H H
NO.sub.2 H H H H ##STR117## 108 N CH H CH.sub.3O CH.sub.3O H H
NO.sub.2 H H H H ##STR118## 109 N CH H CH.sub.3O CH.sub.3O H H Cl H
H CH.sub.2OCH.sub.3 H ##STR119## 110 N CH H CH.sub.3O CH.sub.3O H H
Cl H H CH.sub.3C(.dbd.O)-- H ##STR120## 111 N CH H CH.sub.3O
CH.sub.3O H H Cl H H H CH.sub.3 ##STR121## 112 N CH H CH.sub.3O
CH.sub.3O H H Cl H H H CH.sub.3CH.sub.2 ##STR122## 113 N CH H
CH.sub.3O CH.sub.3O H H Cl H H H CH.sub.3(CH.sub.2).sub.2
##STR123## 114 N CH H CH.sub.3O CH.sub.3O H H Cl H H H CH.sub.3
##STR124## 115 N CH H CH.sub.3O CH.sub.3O H H Cl H H H CH.sub.3
##STR125## 116 N CH H CH.sub.3O CH.sub.3O H H Cl H H H
CH.sub.3CH.sub.2 ##STR126## 117 N CH H CH.sub.3O CH.sub.3O H H Cl H
H H H CH.sub.3 113 N CH H CH.sub.3O CH.sub.3O H H Cl H H H CH.sub.3
CH.sub.3
119 N CH H CH.sub.3O ##STR127## H H Cl H H H H ##STR128## 120 N CH
H CH.sub.3O ##STR129## H H Cl H H H H ##STR130## 121 N CH H
CH.sub.3O ##STR131## H H Cl H H H H ##STR132## 122 N CH H CH.sub.3O
##STR133## H H Cl H H H H ##STR134## 123 N CH H CH.sub.3O
##STR135## H H Cl H H H H ##STR136## 124 N CH H CH.sub.3O
##STR137## H H Cl H H H H ##STR138## 125 N CH H CH.sub.3O
##STR139## H H Cl H H H H ##STR140## 126 N CH H CH.sub.3O
##STR141## H H Cl H H H CH.sub.3CH.sub.2 ##STR142## 127 N CH H
CH.sub.3O ##STR143## H H Cl H H H H ##STR144## 128 N CH H CH.sub.3O
##STR145## H H Cl H H H H ##STR146## 129 N CH H CH.sub.3O
##STR147## H H Cl H H H H ##STR148## 130 N CH H CH.sub.3O
##STR149## H H Cl H H H H ##STR150## 131 N CH H CH.sub.3O
##STR151## H H Cl H H H CH.sub.3CH.sub.2 ##STR152## 132 N CH H
CH.sub.3O ##STR153## H H Cl H H H CH.sub.3CH.sub.2 ##STR154## 133 N
CH H CH.sub.3O ##STR155## H H Cl H H H H ##STR156## 134 N CH H
CH.sub.3O ##STR157## H H Cl H H H H ##STR158## 135 N CH H CH.sub.3O
##STR159## H H Cl H H H H ##STR160## 136 N CH H ##STR161##
CH.sub.3O H H Cl H H H H ##STR162## 137 N CH H ##STR163## CH.sub.3O
H H Cl H H H H ##STR164## 138 N CH H ##STR165## CH.sub.3O H H Cl H
H H H ##STR166## 139 N CH H ##STR167## H H Cl H H H H ##STR168##
140 N CH H ##STR169## CH.sub.3O H H Cl H H H H ##STR170## 141 CH CH
H CH.sub.3O ##STR171## H H Cl H H H H ##STR172## 142 CH CH H
CH.sub.3O ##STR173## H H Cl H H H H ##STR174## 143 CH CH H
CH.sub.3O ##STR175## H H Cl H H H H ##STR176## 144 CH CH H
CH.sub.3O ##STR177## H H Cl H H H H ##STR178## 145 CH CH H
CH.sub.3O ##STR179## H H Cl H H H H ##STR180## 146 CH CH H
CH.sub.3O ##STR181## H H Cl H H H H ##STR182## 147 CH CH H
CH.sub.3O ##STR183## H H Cl H H H H ##STR184## 148 CH CH H
CH.sub.3O ##STR185## H H Cl H H H H ##STR186## 149 CH CH H
CH.sub.3O ##STR187## H H Cl H H H H ##STR188## 150 CH CH H
CH.sub.3O ##STR189## H H Cl H H H H ##STR190## 151 CH CH H
CH.sub.3O ##STR191## H H Cl H H H H ##STR192## 152 CH CH H
CH.sub.3O ##STR193## H H Cl H H H H ##STR194## 153 CH CH H
CH.sub.3O ##STR195## H H Cl H H H H ##STR196## 154 CH CH H
CH.sub.3O ##STR197## H H Cl H H H H ##STR198## 155 CH CH H
CH.sub.3O ##STR199## H H Cl H H H H ##STR200## 156 CH CH H
CH.sub.3O ##STR201## H H Cl H H H H ##STR202## 157 CH CH H
CH.sub.3O ##STR203## H H Cl H H H H ##STR204## 158 CH CH H
CH.sub.3O ##STR205## H H Cl H H H H ##STR206## 159 CH CH H
CH.sub.3O ##STR207## H H Cl H H H H ##STR208## 160 CH CH H
CH.sub.3O ##STR209## H H Cl H H H H ##STR210## 161 N CH H CH.sub.3O
##STR211## H H Cl H H H H ##STR212## 162 N CH H CH.sub.3O
##STR213## H H Cl H H H H ##STR214## 163 N CH H CH.sub.3O
##STR215## H H Cl H H H H ##STR216## 164 N CH H CH.sub.3O
##STR217## H H Cl H H H H ##STR218## 165 N CH H CH.sub.3O
##STR219## H H Cl H H H H ##STR220## 166 CH CH H CH.sub.3O
##STR221## H H Cl H H H H ##STR222## 167 CH CH H CH.sub.3O
##STR223## H H Cl H H H H ##STR224## 168 CH CH H CH.sub.3O
##STR225## H H Cl H H H H ##STR226## 169 CH CH H CH.sub.3O
##STR227## H H Cl H H H H ##STR228## 170 CH CH H CH.sub.3O
##STR229## H H Cl H H H H ##STR230## 171 N CH H CH.sub.3O
##STR231## H H CH.sub.3O H H H H ##STR232## 172 N CH H CH.sub.3O
##STR233## H H CH.sub.3O H H H H ##STR234## 173 CH CH H CH.sub.3O
##STR235## H H CH.sub.3O H H H H ##STR236## 174 CH CH H CH.sub.3O
##STR237## H H CH.sub.3O H H H H ##STR238## 175 CH CH H CH.sub.3O
##STR239## H H CH.sub.3 CH.sub.3 H H H ##STR240## 176 CH CH H
CH.sub.3O ##STR241## H H CH.sub.3 CH.sub.3 H H H ##STR242## 177 CH
CH H CH.sub.3O ##STR243## H H CH.sub.3 CH.sub.3 H H H ##STR244##
178 N CH H CH.sub.3O ##STR245## H H Cl H H H CH.sub.3 CH.sub.3 179
N CH H CH.sub.3O ##STR246## H H Cl H H H CH.sub.3 CH.sub.3 180 N CH
H CH.sub.3O ##STR247## H H Cl H H H CH.sub.3 CH.sub.3 181 N CH H
CH.sub.3O ##STR248## H H Cl H H H CH.sub.3 CH.sub.3 182 N CH H
CH.sub.3O ##STR249## H H Cl H H H CH.sub.3 CH.sub.3 183 N CH H
CH.sub.3O ##STR250## H H Cl H H H CH.sub.3 CH.sub.3 184 N CH H
CH.sub.3O ##STR251## H H Cl H H H H CH.sub.3 185 N CH H CH.sub.3O
##STR252## H H Cl H H H H ##STR253## 186 CH CH H CH.sub.3O
##STR254## H H Cl H H H H ##STR255##
Pharmacological Test Example 1
Measurement of Inhibitory Activity Against Activation of MAPK
within Vascular Endothelial Cells Induced by VEGF Stimulation
[0843] Human funicular venous vascular endothelial cells (purchased
from Chronetics) were cultured in an EGM-2 medium (purchased from
Chronetics) within an incubator containing 5% carbon dioxide until
50 to 70% confluent, and the culture was inoculated into wells,
containing the same medium, in a 96-well flat-bottom plate in an
amount of 1.5.times.10.sup.5 per well. After cultivation at
37.degree. C. overnight, the medium was replaced by an EBM-2 medium
containing 0.5% fetal calf serum (purchased from Chronetics),
followed by cultivation for 24 hr. A solution of the test compound
in dimethyl sulfoxide was added to each well, and the cultivation
was continued at 37.degree. C. for additional one hr. A human
recombinant vascular endothelial growth factor (hereinafter
abbreviated to "VEGF") was added to a final concentration of 50
ng/ml, and the stimulation of cells was carried out at 37.degree.
C. for 8 min. The medium was removed, the cells were washed with
phosphate buffered saline (pH 7.4), and 10 .mu.l of a
solubilization buffer (Tris buffered saline (pH 7.4) containing 1%
Triton X100, 2 mM sodium orthovanadylate, and 1 mM disodium
ethylenediaminetetraacetate) was then added thereto. The mixture
was shaken at 4.degree. C. for one hr to solubilize the cells. An
equal amount of Tris buffered saline containing 1% sodium
laurylsulfate was added to and thoroughly mixed with the solution.
This solution (2 .mu.l) was adsorbed on a PVDF filter by dot
blotting, and this filter was subjected to immunoblotting with
anti-tyrosine phosphorylated MAPK antibody (purchased from Daiichi
Pure Chemicals).
[0844] The level of phosphorylated MAPK was quantitatively
determined with a densitometer, and the percentage phosphorylated
MAPK in the presence of the test compound was determined by
presuming the level of phosphorylated MAPK with the addition of
VEGF in the absence of the test compound to be 100% and the level
of phosphorylated MAPK in the absence of the test compound and VEGF
to be 0%. The test compound concentration (IC.sub.50) necessary for
inhibiting 50% of the activation of MAPK was calculated based on
the percentage of phosphorylated MAPK.
[0845] The results were as summarized in Table 1. TABLE-US-00002
TABLE 1 Compound IC.sub.50 (nM) 1 1.8 4 2.1 5 2.9 7 5.2 8 11.0 9
5.1 10 7.8 11 15.0 13 2.2 14 0.7 16 2.9 17 11.0 18 0.6 19 0.6 20
8.5 21 3.4 22 0.4 23 5.4 24 0.6 25 3.9 26 5.3 28 4.0 29 4.4 30 1.7
31 2.5 32 7.3 33 3.5 34 4.2 35 3.7 36 3.3 37 2.3 40 12.0 41 4.9 42
5.9 43 3.8 45 2.0 46 4.3 47 4.0 48 0.5 49 4.3 50 0.5 52 4.4 53 5.9
54 0.5 55 2.8 56 5.1 57 6.5 58 5.1 59 5.8 62 16.0 63 70.0 64 42.0
65 36.0 66 21.0 67 345.0 68 45.0 69 67.0 70 6.8 71 750.0 72 3.9 73
<2 74 6.0 75 1.2 76 8.0 77 71.0 78 4.1 79 30.0 80 13.0 82 3.8 83
>1000 85 0.7 86 0.6 87 58.0 89 45.0 90 42.0 92 46.0 93 14.0 94
1.8 95 2.7 96 <1 97 518.0 98 450.0 99 8.8 100 5.2 102 150.0 103
53.0 104 5.3 105 2.3 106 <1 107 10.2
Pharmacological Test Example 2
Measurement of Inhibitory Activity Against KDR Phosphorylation by
ELISA
[0846] NIH 3T3 cells (Sawano A et al., Cell Growth &
Differentation, 7, 213-221 (1996), "Flt-1 but not KDR/Flk-1
tyrosine kinase is a receptor for placenta growth factor, which is
related to vascular endothelial growth factor") prepared by
transfection of human KDR were cultured in a DMEM medium containing
10% fetal calf serum (purchased from GIBCO BRL) within a 5% carbon
dioxide incubator until 50 to 70% confluent. The harvested cells
were inoculated into wells, containing the same medium, in a
collagen-type one-coat 96-well flat-bottom plate in an amount of
1.5.times.10.sup.4 per well, followed by cultivation at 37.degree.
C. overnight. The medium was then replaced by a DMEM medium
containing 0.1% fetal calf serum. A solution of the test compound
in dimethyl sulfoxide was added to each well, and the cultivation
was continued at 37.degree. C. for additional one hr. A human
recombinant vascular endothelial growth factor (hereinafter
abbreviated to "VEGF") was added to a final concentration of 100
ng/ml, and the stimulation of cells was carried out at 37.degree.
C. for 2 min. The medium was removed, the cells were washed with
phosphate buffered saline (pH 7.4), and 50 .mu.l of a
solubilization buffer (20 mM HEPES (pH 7.4), 150 mM NaCl, 0.2%
Triton X-100, 10% glycerol, 5 mM sodium orthovanadylate, 5 mM
disodium ethylenediaminetetraacetate, and 2 mM
Na.sub.4P.sub.2O.sub.7) was then added thereto. The mixture was
shaken at 4.degree. C. for 2 hr to prepare a cell extract.
[0847] Separately, phosphate buffered saline (50 .mu.l, pH 7.4)
containing 5 .mu.g/ml of anti-phospho-tyrosine antibody (PY20;
purchased from Transduction Laboratories) was added to a microplate
for ELISA (Maxisorp; purchased from NUNC), followed by standing at
4.degree. C. overnight to form a solid phase on the wells. After
washing of the plate, 300 .mu.l of a blocking solution was added,
followed by standing at room temperature for 2 hr to perform
blocking. After washing, the whole quantity of the cell extract was
transferred to the wells, and the plate was then allowed to stand
at 4.degree. C. overnight. After washing, an anti-KDR antibody
(purchased from Santa Cruz) was allowed to react at room
temperature for one hr, and, after washing, a peroxidase-labeled
anti-rabbit Ig antibody (purchased from Amershamy was allowed to
react at room temperature for one hr. After washing, a chromophoric
substrate for peroxidase (purchased from Sumitomo Bakelite Co.,
Ltd.) was added thereto to initiate a reaction. After a suitable
level of color development, a reaction termination solution was
added to stop the reaction, and the absorbance at 450 nm was
measured with a microplate reader. The KDR phosphorylation activity
for each well was determined by presuming the absorbance with the
addition of VEGF and without the addition of the medicament to be
100% KDR phosphorylation activity and the absorbance without the
medicament and VEGF to be 0% KDR phosphorylation activity. The
concentration of the test compound was varied on several levels,
the inhibition (%) of KDR phosphorylation was determined for each
case, and the concentration of the test compound necessary for
inhibiting 50% of KDR phosphorylation (IC.sub.50) was
calculated.
[0848] The results were as summarized in Table 2. TABLE-US-00003
TABLE 2 Compound IC.sub.50 (nM) 62 11.0 63 150.0 64 150.0 65 27.0
66 15.0 67 63.0 68 24.0 69 64.0 70 32.0 71 350.0 72 3.5 73 1.0 74
11.0 75 1.4 76 3.5 77 6.0 78 3.4 79 18.0 80 2.7 81 4.1 82 8.4 83
840.0 85 0.5 86 1.5 87 110.0 88 61.0 89 24.0 90 57.0 92 63.0 93
37.0 94 2.3 95 3.8 96 0.4 97 490.0 98 330.0 99 25.0 100 13.0 101
3.0 102 105.0 103 78.0 104 3.9 105 2.0 106 1.5 107 11.0 108 5.0 110
>1000 111 >1000 112 >1000 113 >1000 114 >1000 115
>1000 116 >1000 117 24.0 118 >1000 119 3.6 120 3.9 121
12.5 122 5.8 123 8.9 124 1.9 125 2.6 126 >1000 127 1.1 131
>1000 132 >1000 133 8.3 134 5.0 135 1.0 136 160.0 137 24.0
138 40.0 139 15.0 140 36.0 141 14.0 142 2.6 143 3.5 144 1.6 145 0.8
146 1.0 147 1.0 148 15.0 149 1.6 150 1.8 151 0.5 152 0.8 153 1.5
154 1.5 155 2.1 156 0.8 157 0.4 158 1.6 159 1.9 160 0.9 161 3.9 162
1.0 163 1.4 164 0.9 165 0.6 166 2.2 167 2.1 168 4.0 169 3.7 170 1.1
175 4.7 176 3.7 177 2.3 178 >1000 179 >1000 180 >1000 181
>1000 182 >1000 183 >1000 184 0.2 185 0.5 186 6.3
Pharmacological Test Example 3
Karyomorphosis Test
[0849] A375 human melanoma cells (2.times.10.sup.4) (obtained from
Japanese Foundation for Cancer Research) were incolulated on a
culture slide (manufactured by Falcon) and were cultured at
37.degree. C. After the elapse of 5 hr from the initiation of the
cultivation, the test compound was added to 10 .mu.M and 1 .mu.M,
and the cultivation was continued for additional 48 hr. After the
fixation of cells, 50 .mu.g/ml propidium iodide solution containing
ribonuclease (200 .mu.g/ml) was added to stain nuclei. The stained
nuclei were observed under a fluorescent microscope to analyze the
nuclei for abnormality of karyomorphosis. The change in
karyomorphosis for test compounds was evaluated as (2+) when the
change in karyomorphosis of cells took place at 1 .mu.M; was
evaluated as (+) when the change in karyomorphosis of cells took
place at 10 M; and was evalauted as (-) when the change in
karyomorphosis of cells did not take place at 10 .mu.M.
[0850] The results were as summarized in Table 3. TABLE-US-00004
TABLE 3 Compound No. Change in morphosis 13 (-) 14 (-) 15 (-) 16
(-) 17 (-) 18 (-) 20 (-) 21 (-) 22 (-) 24 (-) 25 (-) 26 (-) 28 (-)
29 (-) 30 (-) 31 (-) 32 (-) 33 (-) 34 (-) 35 (-) 36 (-) 37 (-) 38
(-) 39 (-) 40 (-) 41 (-) 42 (-) 43 (-) 44 (-) 45 (-) 46 (-) 47 (-)
48 (-) 49 (-) 52 (-) 53 (-) 55 (-) 58 (-) 59 (-) 60 (-) 61 (-) 62
(-)
Pharmacological Test Example 4
Antitumor Effect on Human Glioma Cells (GL07)
[0851] Human glioma cells GL07 (obtained from Central Laboratories
for Experimental Animals) were transplanted into nude mice. When
the tumor volume became about 100 mm.sup.3, the mice were grouped.
In this case, grouping was carried out so that each group consisted
of four mice and the average tumor volume was even among the
groups. The test compound was orally or intraperitoneally
administered at a dose of 20 mg/kg to the test groups every day
once a day for 9 days, while the medium was administered to the
control group in the manner as in the test groups. The tumor growth
inhibition rate (TGIR) was calculated as follows: The tumor growth
inhibition rate (TGIR)=(1-Tx/Cx).times.100 wherein Cx represents
the volume of tumor at day x for the control group when the tumor
volume at the day of the start of the administration was presumed
to be 1; and Tx represents the volume of tumor for test compound
administration groups.
[0852] The tumor growth inhibition rate for representative examples
of a group of compounds according to the present invention is shown
in Table 4. TABLE-US-00005 TABLE 4 Administration Ex. No. site
TGIR, % 4 Oral 61 5 Oral 59 9 Intraperitoneal 59 13 Intraperitoneal
52 14 Intraperitoneal 81 16 Intraperitoneal 77 17 Intraperitoneal
85 18 Oral 57 24 Oral 63 25 Intraperitoneal 68 28 Intraperitoneal
84 29 Oral 64 37 Intraperitoneal 70 48 Intraperitoneal 90 50 Oral
59 51 Oral 65 54 Oral 59 62 Oral 78 64 Oral 37 66 Oral 26 67 Oral
30 68 Oral 57 69 Oral 26 71 Oral 67 73 Oral 34 74 Oral 28 77 Oral
26 78 Oral 21 79 Oral 28 80 Oral 52 82 Oral 27 83 Oral 31 85 Oral
26 89 Oral 40 93 Oral 29 94 Oral 29 97 Oral 48 98 Oral 38 99 Oral
33 100 Oral 36 101 Oral 44 102 Oral 24 103 Oral 23 104 Oral 22 105
Oral 20 107 Oral 49 109 Oral 71 110 Oral 26 111 Oral 78 112 Oral 81
113 Oral 61 114 Oral 60 115 Oral 74 116 Oral 83 119 Oral 40 120
Oral 30 121 Oral 22 122 Oral 21 123 Oral 31 124 Oral 27 125 Oral 30
126 Oral 52 127 Oral 25 128 Oral 21 129 Oral 25 130 Oral 32 131
Oral 31 132 Oral 24 133 Oral 20 134 Oral 29 135 Oral 62 136 Oral 23
137 Oral 20 138 Oral 21 139 Oral 27 140 Oral 21 141 Oral 28 142
Oral 48 143 Oral 53 144 Oral 56 145 Oral 57 146 Oral 48 147 Oral 34
148 Oral 54 149 Oral 47 150 Oral 22 151 Oral 44 152 Oral 44 153
Oral 53 154 Oral 34 155 Oral 29 156 Oral 24 157 Oral 44 158 Oral 39
159 Oral 40 160 Oral 43 161 Oral 39 162 Oral 40 163 Oral 52 164
Oral 55 165 Oral 44 166 Oral 27 167 Oral 28 168 Oral 42 169 Oral 55
170 Oral 64 171 Oral 13 172 Oral 42 173 Oral 21 174 Oral 19 175
Oral 17 176 Oral 22 177 Oral 35 178 Oral 28 179 Oral 33 180 Oral 45
181 Oral 21 182 Oral 31 183 Oral 22 184 Oral 48 185 Oral 59 186
Oral 47 TGIR, % = Tumor growth inhibition rate (%)
* * * * *