U.S. patent application number 10/951861 was filed with the patent office on 2005-02-24 for aryl substituted pyridines, pyrimidines, pyrazines and triazines and the use thereof.
This patent application is currently assigned to Euro-Celtique S.A.. Invention is credited to Hogenkamp, Derk J., Nguyen, Phong, Shao, Bin.
Application Number | 20050043305 10/951861 |
Document ID | / |
Family ID | 22692096 |
Filed Date | 2005-02-24 |
United States Patent
Application |
20050043305 |
Kind Code |
A1 |
Hogenkamp, Derk J. ; et
al. |
February 24, 2005 |
Aryl substituted pyridines, pyrimidines, pyrazines and triazines
and the use thereof
Abstract
This invention relates aryl substituted pyridines, pyrimidines,
pyrazines and triazines of Formula I: 1 or a pharmaceutically
acceptable salt, prodrug or solvate thereof, wherein A.sub.1,
A.sub.2, A.sub.3, R.sub.1--R.sub.4, X and Y are set in the
specification. The invention is also directed to the use of
compounds of Formula I for the treatment of neuronal damage
following global and focal ischemia, for the treatment or
prevention of neurodegenerative conditions such as amyotrophic
lateral sclerosis (ALS), and for the treatment, prevention or
amelioration of both acute or chronic pain, as antitinnitus agents,
as anticonvulsants, and as antimanic depressants, as local
anesthetics, as antiarrhythmics and for the treatment or prevention
of diabetic neuropathy.
Inventors: |
Hogenkamp, Derk J.;
(Carlsbad, CA) ; Nguyen, Phong; (Placentia,
CA) ; Shao, Bin; (Richboro, PA) |
Correspondence
Address: |
STERNE, KESSLER, GOLDSTEIN & FOX PLLC
1100 NEW YORK AVENUE, N.W.
WASHINGTON
DC
20005
US
|
Assignee: |
Euro-Celtique S.A.
Luxembourg
LU
|
Family ID: |
22692096 |
Appl. No.: |
10/951861 |
Filed: |
September 29, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10951861 |
Sep 29, 2004 |
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09803659 |
Mar 12, 2001 |
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60188188 |
Mar 10, 2000 |
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Current U.S.
Class: |
514/241 ;
514/242; 514/247; 514/252.1; 514/256; 544/182; 544/209; 544/224;
544/333; 544/405 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 25/00 20180101; A61P 27/16 20180101; A61P 25/06 20180101; A61P
21/00 20180101; A61P 27/10 20180101; C07D 239/38 20130101; A61P
25/02 20180101; A61P 9/06 20180101; A61P 25/08 20180101; C07D
403/04 20130101; A61P 25/18 20180101; C07D 251/24 20130101; A61P
25/04 20180101; C07D 213/81 20130101; A61P 29/02 20180101; A61P
23/02 20180101; A61P 25/24 20180101; A61P 25/28 20180101; C07D
239/28 20130101; A61P 9/10 20180101; C07D 241/24 20130101 |
Class at
Publication: |
514/241 ;
514/242; 514/247; 514/252.1; 514/256; 544/182; 544/209; 544/224;
544/333; 544/405 |
International
Class: |
A61K 031/53; A61K
031/501; A61K 031/4965 |
Claims
1-58. (Cancelled).
59. A compound having the Formula I: 27or a pharmaceutically
acceptable salt, prodrug or solvate thereof, wherein: Y is 28or
R.sub.7, provided that when Y is R.sub.7, R.sub.1 is aminocarbonyl;
A.sub.1, A.sub.2 and A.sub.3 are each CR.sub.2; or A.sub.2 is N and
A.sub.1 and A.sub.3 are CR.sub.2; or A.sub.1 and A.sub.3 are N and
A.sub.2 is CR.sub.2; or A.sub.1 and A.sub.2 are N and A.sub.3 is
CR.sub.2; or A.sub.2 and A.sub.3 are N and A.sub.1 is CR.sub.2;
R.sub.1 is selected from the group consisting an optionally
substituted alkyl, amino, alkylthiol, C(O)R.sub.8, SO.sub.2R.sub.8,
OC(O)NH.sub.2, 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl,
5-isoxazolyl, and 3-(1,2,4)-triazolyl; each R.sub.2 is selected
from the group consisting of hydrogen, optionally substituted
alkyl, alkenyl, or alkynyl, halogen, hydroxy, cycloalkyl, cyano,
amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl,
alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,
alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino; or
R.sub.1 and R.sub.2 are taken together with the carbon atoms to
which they are attached to form a heterocyclic ring; R.sub.3,
R.sub.4, R.sub.5, and R.sub.6 are independently selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,
haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,
carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy,
azido, alkoxy, carboxy, carbonylamido and alkylthiol; R.sub.7 is an
optionally substituted alkyl; R.sub.8 is selected from the group
consisting of alkyl, alkenyl, alkynyl, OR.sub.9, amino, alkylamino,
dialkylamino, alkenylamino, dialkylaminoalkenyl,
dialkylaminoalkylamino, dialkylaminoalkenylamino,
alkylaminoalkenyl-amino- , hydroxyaminoalkenylamino, cycloalkyl,
heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all
of which can be optionally substituted, provided that R.sub.8 is
not OR.sub.9 when R.sub.1 is SO.sub.2R.sub.8; wherein R.sub.9 is
selected from the group consisting of hydrogen, optionally
substituted alkyl, and an alkali metal; and X is one of O, S, NH,
or CH.sub.2 when Y is other than R.sub.7; or X is one of O, S, NH,
CH.sub.2 or absent when Y is R.sub.7; with the provisos that: 1)
R.sub.2 is not methoxy if R.sub.5 is trifluoromethyl, R.sub.6 is H,
X is O and R.sub.1 is SO.sub.2CH.sub.2Ph; 2) R.sub.2 is not
NH.sub.2 if R.sub.1 is methylthio, X is O and two of A.sub.1,
A.sub.2 and A.sub.3 are N; 3) R.sub.2 is not methyl if R.sub.1 is
SO.sub.2R.sub.8, wherein R.sub.8 is methylphenyl, R.sub.3 and
R.sub.4 are methoxy, X is S and two of A.sub.1, A.sub.2 and A.sub.3
are N; 4) R.sub.2 is not CCl.sub.3 if R.sub.1 is CCl.sub.3, X is S
and two of A.sub.1, A.sub.2 and A.sub.3 are N; or 5) R.sub.1 and
R.sub.2 are not both NH.sub.2 if X is O or S and two of A.sub.1,
A.sub.2 and A.sub.3 are N.
60. A compound having the Formula II: 29or a pharmaceutically
acceptable salt, prodrug or solvate thereof, wherein: A.sub.1,
A.sub.2 and A.sub.3 are each CR.sub.2; or A.sub.2 is N and A.sub.1
and A.sub.3 are CR.sub.2; or A.sub.1 and A.sub.3 are N and A.sub.2
is CR.sub.2; or A.sub.1 and A.sub.2 are N and A.sub.3 is CR.sub.2;
or A.sub.2 and A.sub.3 are N and A.sub.1 is CR.sub.2; R.sub.1 is
selected from the group consisting an optionally substituted alkyl,
amino, alkylthiol, C(O)R.sub.8, SO.sub.2R.sub.8, OC(O)NH.sub.2,
2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and
3-(1,2,4)-triazolyl; each R.sub.2 is selected from the group
consisting of hydrogen, optionally substituted alkyl, alkenyl, or
alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino,
dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,
arylcarbonylamino, and aralkylcarbonylamino; or R.sub.1 and R.sub.2
are taken together with the carbon atoms to which they are attached
to form a heterocyclic ring; R.sub.3, R.sub.4, R.sub.5, and R.sub.6
are independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy,
nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,
acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido
and alkylthiol; and R.sub.8 is selected from the group consisting
of alkyl, alkenyl, alkynyl, OR.sub.9, amino, alkylamino,
dialkylamino, alkenylamino, dialkylaminoalkenyl,
dialkylaminoalkylamino, dialkylaminoalkenylamino,
alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl,
heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all
of which can be optionally substituted, provided that R.sub.8 is
not OR.sub.9 when R.sub.1 is SO.sub.2R.sub.8; wherein R.sub.9 is
selected from the group consisting of hydrogen, optionally
substituted alkyl, and an alkali metal; and X is one of O, S, NH,
or CH.sub.2; with the provisos that: 1) R.sub.2 is not methoxy if
R.sub.5 is trifluoromethyl, R.sub.6 is H, X is O and R.sub.1 is
SO.sub.2CH.sub.2Ph; 2) R.sub.2 is not NH.sub.2 if R.sub.1 is
methylthio, X is O and two of A.sub.1, A.sub.2 and A.sub.3 are N;
3) R.sub.2 is not methyl if R.sub.1 is SO.sub.2R.sub.8, wherein
R.sub.8 is methylphenyl, R.sub.3 and R.sub.4 are methoxy, X is S
and two of A.sub.1, A.sub.2 and A.sub.3 are N; 4) R.sub.2 is not
CCl.sub.3 if R.sub.1 is CCl.sub.3, X is S and two of A.sub.1,
A.sub.2 and A.sub.3 are N; or 5) R.sub.1 and R.sub.2 are not both
NH.sub.2 if X is O or S and two of A.sub.1, A.sub.2 and A.sub.3 are
N.
61. The compound of claim 60, wherein A.sub.1, A.sub.2 and A.sub.3
are each CR.sub.2; or A.sub.2 is N and A.sub.1 and A.sub.3 are
CR.sub.2; or A.sub.1 and A.sub.3 are N and A.sub.2 is CR.sub.2.
62. The compound of claim 60, wherein R.sub.1 is selected from the
group consisting of an alkyl optionally substituted by halogen or
hydroxy, C(O)R.sub.8, SO.sub.2R.sub.8, 2-imidazolinyl,
2-imidazolyl, 3-pyrazolyl, and 5-isoxazolyl, wherein R.sub.8 is as
defined in claim 60, provided that R.sub.8 is not OR.sub.9 when
R.sub.1 is SO.sub.2R.sub.8.
63. The compound of claim 62, wherein R.sub.8 is selected from the
group consisting of alkyl, alkenyl, OR.sub.9, amino, alkylamino,
dialkylamino, alkenylamino, dialkylaminoalkenyl,
dialkylaminoalkylamino, and heterocycloalkylamino, all of which can
be optionally substituted.
64. The compound of claim 60, wherein R.sub.2 is selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl,
amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,
arylcarbonylamino, and aralkylcarbonylamino.
65. The compound of claim 64, wherein R.sub.2 is selected from the
group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and
aminocarbonyl.
66. The compound of claim 60, wherein R.sub.3, R.sub.4, R.sub.5,
and R.sub.6 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,
hydroxyalkyl, hydroxy, nitro, amino, and cyano.
67. The compound of claim 66, wherein R.sub.3 and R.sub.4 are both
hydrogen and R.sub.5 and R.sub.6 are independently selected from
the group consisting of hydrogen, alkyl, halogen, haloalkyl, and
nitro.
68. The compound of claim 60, wherein X is O or S.
69. The compound of claim 68, wherein X is O.
70. The compound of claim 60, wherein R.sub.2 is hydrogen, X is O
or S and R.sub.1 is aminocarbonyl.
71. The compound of claim 60, wherein A.sub.2 is CR.sub.2, wherein
R.sub.2 is other than H and A.sub.1 and A.sub.3 are each CH.
72. The compound of claim 60, wherein A.sub.2 is N, A.sub.1 is
CR.sub.2, wherein R.sub.2 is other than H, and A.sub.3 is CH.
73. The compound of claim 60, having the Formula III: 30or a
pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein; A.sub.1-A.sub.3, R.sub.2--R.sub.6, R.sub.8 and X are as
defined in claim 60.
74. The compound of claim 73, wherein A.sub.1, A.sub.2 and A.sub.3
are each CR.sub.2; or A.sub.2 is N and A.sub.1 and A.sub.3 are
CR.sub.2; or A.sub.1 and A.sub.3 are N and A.sub.2 is CR.sub.2.
75. The compound of claim 73, wherein R.sub.2 is selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl,
amino, hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,
arylcarbonylamino, and aralkylcarbonylamino.
76. The compound of claim 75, wherein R.sub.2 is selected from the
group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and
aminocarbonyl.
77. The compound of claim 73, wherein R.sub.3, R.sub.4, R.sub.5,
and R.sub.6 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,
hydroxyalkyl, hydroxy, nitro, amino, and cyano.
78. The compound of claim 77, wherein R.sub.3 and R.sub.4 are both
hydrogen and R.sub.5 and R.sub.6 are independently selected from
the group consisting of hydrogen, alkyl, halogen, haloalkyl, and
nitro.
79. The compound of claim 73, wherein R.sub.8 is selected from the
group consisting of alkyl, alkenyl, OR.sub.9, amino, alkylamino,
dialkylamino, alkenylamino, dialkylaminoalkenyl,
dialkylaminoalkylamino, and heterocycloalkylamino, all of which can
be optionally substituted, provided that R.sub.8 is not OR.sub.9
when R.sub.1 is SO.sub.2R.sub.8, and wherein R.sub.9 is as defined
in claim 73.
80. The compound of claim 73, wherein X is O or S.
81. The compound of claim 80, wherein X is O.
82. The compound of claim 73, wherein X is O; A.sub.1, A.sub.2 and
A.sub.3 are each CR.sub.2; or A.sub.2 is N and A.sub.1 and A.sub.3
are CR.sub.2; or A.sub.1 and A.sub.3 are N and A.sub.2 is CR.sub.2;
wherein R.sub.2 is selected from the group consisting of hydrogen,
alkyl, alkoxy, aminoalkyl, and aminocarbonyl; R.sub.3 and R.sub.4
are both hydrogen; R.sub.5 and R.sub.6 are independently selected
from the group consisting of hydrogen, alkyl, halogen, haloalkyl,
and nitro; and R.sub.8 is amino.
83. The compound of claim 73, wherein A.sub.2 is CR.sub.2, wherein
R.sub.2 is other than H and A.sub.1 and A.sub.3 are each CH.
84. The compound of claim 73, wherein A.sub.2 is N, A.sub.1 is
CR.sub.2, wherein R.sub.2 is other than H, and A.sub.3 is CH.
85. The compound of claim 60, having Formula IV: 31or a
pharmaceutically acceptable salt, prodrug or solvate thereof;
wherein: A.sub.1-A.sub.3, R.sub.2--R.sub.6, and X are as defined in
claim 60 and R.sub.8 is selected from the group consisting of
alkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino,
alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino,
cycloalkyl, heterocycloalkyl, cycloalkylalkylamino,
heterocycloalkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl,
and arylalkylamino, all of which can be optionally substituted.
86. The compound of claim 85, wherein A.sub.1, A.sub.2 and A.sub.3
are each CR.sub.2; or A.sub.2 is N and A.sub.1 and A.sub.3 are
CR.sub.2; or A.sub.1 and A.sub.3 are N and A.sub.2 is CR.sub.2, and
R.sub.2 is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl, alkoxy,
aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,
aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and
aralkylcarbonylamino.
87. The compound of claim 86, wherein R.sub.2 is selected from the
group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and
aminocarbonyl.
88. The compound of claim 85, wherein R.sub.3, R.sub.4, R.sub.5,
and R.sub.6 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,
hydroxyalkyl, hydroxy, nitro, amino, and cyano.
89. The compound of claim 88, wherein R.sub.3 and R.sub.4 are both
hydrogen and R.sub.5 and R.sub.6 are independently selected from
the group consisting of hydrogen, alkyl, halogen, haloalkyl, and
nitro.
90. The compound of claim 85, wherein R.sub.8 is selected from the
group consisting of alkyl, alkenyl, amino, alkylamino,
dialkylamino, alkenylamino, dialkylaminoalkenyl, and
heterocycloalkylamino, all of which can be optionally
substituted.
91. The compound of claim 85, wherein X is O or S.
92. The compound of claim 91, wherein X is O.
93. A compound of claim 60, wherein said compound is:
2-methyl-6-(4-phenoxyphenyl)pyridine;
6-(4-phenoxyphenyl)pyridine-2-carbo- xamide;
2-methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine;
6-(4-phenoxyphenyl)pyridine-2-carboxylic acid;
6-(4-phenoxyphenyl)pyridin- e-2-carboxylic acid methylamide;
6-[4-(4-fluorophenoxy)phenyl]pyridine-2-c- arboxamide;
6-[4-(2,4-difluorophenoxy)phenyl]pyridine-2-carboxamide;
6-[4-(4-chloro-2-fluorophenoxy)phenyl]pyridine-2-carboxamide;
6-[4-(4-fluorophenoxy)-3-fluorophenyl]pyridine-2-carboxamide;
6-[4-(4-trifluoromethylphenoxy)phenyl]pyridine-2-carboxamide;
6-(4-phenoxyphenyl)pyrazine-2-carboxamide;
3,5-diamino-6-(4-phenoxyphenyl- )pyrazine-2-carboxamide; or
2-[4-(4-nitrophenoxy)phenyl]-4-methyl-[1,3,5]-- triazine, or a
pharmaceutically acceptable salt, prodrug or solvate thereof.
94. A compound of claim 59, wherein said compound is:
6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid
N-piperidinylethylamide;
6-(4-tert-butylphenyl)pyridine-2-carboxamide;
6-(4-n-butylphenyl)pyridine-2-carboxamide;
6-(4-i-propylphenyl)pyridine-2- -carboxamide;
6-(4-thiomethylphenyl)pyridine-2-carboxamide;
6-(4-ethoxyphenyl)pyridine-2-carboxamide; or
6-(4-methoxyphenyl)pyridine-- 2-carboxamide, or a pharmaceutically
acceptable salt, prodrug or solvate thereof.
95. The compound of claim 59, having the Formula V: 32or a
pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein; A.sub.1-A.sub.3, R.sub.2--R.sub.4, and R.sub.7 are as
defined in claim 59; and X is one of O, S, NH, CH.sub.2 or
absent.
96. The compound of claim 95, wherein A.sub.1, A.sub.2 and A.sub.3
are each CR.sub.2; or A.sub.2 is N and A.sub.1 and A.sub.3 are
CR.sub.2; or A.sub.1 and A.sub.3 are N and A.sub.2 is CR.sub.2.
97. The compound of claim 95, wherein R.sub.7 is a C.sub.1-6 alkyl
optionally substituted with one or more of halogen, hydroxy, nitro,
amino, cyano and alkoxy.
98. The compound of claim 95, wherein R.sub.2 is selected from the
group consisting of hydrogen, alkyl, alkoxy, aminoalkyl and
aminocarbonyl.
99. The compound of claim 95, wherein R.sub.3 and R.sub.4 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy,
nitro, amino, and cyano.
100. The compound of claim 99, wherein R.sub.3 and R.sub.4 are both
hydrogen.
101. The compound of claim 95, wherein X is O or S.
102. The compound of claim 101, wherein X is O.
103. A compound of claim 95, wherein said compound is
6-[(4-trifluoromethoxy)phenyl]pyridine-2-carboxamide or a
pharmaceutically acceptable salt, prodrug or solvate thereof.
104. A pharmaceutical composition, comprising the compound of
formula: 33or a pharmaceutically acceptable salt, prodrug or
solvate thereof, wherein: Y is 34 or R.sub.7, provided that when Y
is R.sub.7, R.sub.1 is aminocarbonyl; A.sub.1, A.sub.2 and A.sub.3
are each CR.sub.2; or A.sub.2 is N and A.sub.1 and A.sub.3 are
CR.sub.2; or A.sub.1 and A.sub.3 are N and A.sub.2 is CR.sub.2; or
A.sub.1 and A.sub.2 are N and A.sub.3 is CR.sub.2; or A.sub.2 and
A.sub.3 are N and A.sub.1 is CR.sub.2; R.sub.1 is selected from the
group consisting an optionally substituted alkyl, amino,
alkylthiol, C(O)R8, SO.sub.2R.sub.8, OC(O)NH.sub.2, 2-imidazolinyl,
2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;
each R.sub.2 is selected from the group consisting of hydrogen,
optionally substituted alkyl, alkenyl, or alkynyl, halogen,
hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino,
alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,
aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and
aralkylcarbonylamino; or R.sub.1 and R.sub.2 are taken together
with the carbon atoms to which they are attached to form a
heterocyclic ring; R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy,
nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,
acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido
and alkylthiol; R.sub.7 is an optionally substituted alkyl; R.sub.8
is selected from the group consisting of alkyl, alkenyl, alkynyl,
OR.sub.9, amino, alkylamino, dialkylamino, alkenylamino,
dialkylaminoalkenyl, dialkylaminoalkylamino,
dialkylaminoalkenylamino, alkylaminoalkenyl-amino,
hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl,
cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be
optionally substituted, provided that R8 is not OR.sub.9 when
R.sub.1 is SO.sub.2R.sub.8; wherein R.sub.9 is selected from the
group consisting of hydrogen, optionally substituted alkyl, and an
alkali metal; and X is one of O, S, NH, or CH.sub.2 when Y is other
than R.sub.7; or X is one of O, S, NH, CH.sub.2 or absent when Y is
R.sub.7; and a pharmaceutically acceptable carrier or diluent; with
the proviso that R.sub.1 and R.sub.2 are not both NH.sub.2 if X is
O or S and two of A.sub.1, A.sub.2 and A.sub.3 are N.
105. A pharmaceutical composition, comprising a compound as claimed
in claim 59 or 60, and a pharmaceutically acceptable carrier or
diluent.
106. A method of treating a disorder responsive to the blockade of
sodium channels in a mammal suffering therefrom, comprising
administering to a mammal in need of such treatment an effective
amount of a compound of formula: 35or a pharmaceutically acceptable
salt, prodrug or solvate thereof, wherein: Y is 36or R.sub.7,
provided that when Y is R.sub.7, R.sub.1 is aminocarbonyl; A.sub.1,
A.sub.2 and A.sub.3 are each CR.sub.2; or A.sub.2 is N and A.sub.1
and A.sub.3 are CR.sub.2; or A.sub.1 and A.sub.3 are N and A.sub.2
is CR.sub.2; or A.sub.1 and A.sub.2 are N and A.sub.3 is CR.sub.2;
or A.sub.2 and A.sub.3 are N and A.sub.1 is CR.sub.2; R.sub.1 is
selected from the group consisting an optionally substituted alkyl,
amino, alkylthiol, C(O)R.sub.8, SO.sub.2R.sub.8, OC(O)NH.sub.2,
2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and
3-(1,2,4)-triazolyl; each R.sub.2 is selected from the group
consisting of hydrogen, optionally substituted alkyl, alkenyl, or
alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino,
dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,
arylcarbonylamino, and aralkylcarbonylamino; or R.sub.1 and R.sub.2
are taken together with the carbon atoms to which they are attached
to form a heterocyclic ring; R.sub.3, R.sub.4, R.sub.5, and R.sub.6
are independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy,
nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,
acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido
and alkylthiol; R.sub.7 is an optionally substituted alkyl; R.sub.8
is selected from the group consisting of alkyl, alkenyl, alkynyl,
OR.sub.9, amino, alkylamino, dialkylamino, alkenylamino,
dialkylaminoalkenyl, dialkylaminoalkylamino,
dialkylaminoalkenylamino, alkylaminoalkenyl-amino,
hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl,
cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be
optionally substituted, provided that R.sub.8 is not OR.sub.9 when
R.sub.1 is SO.sub.2R.sub.8; wherein R.sub.9 is selected from the
group consisting of hydrogen, optionally substituted alkyl, and an
alkali metal; and X is one of O, S, NH, or CH.sub.2 when Y is other
than R.sub.7; or X is one of O, S, NH, CH.sub.2 or absent when Y is
R.sub.7.
107. A method of treating a disorder responsive to the blockade of
sodium channels in a mammal suffering therefrom, comprising
administering to a mammal in need of such treatment an effective
amount of a compound as claimed in claim 59 or 60.
108. A method for treating, preventing or ameliorating neuronal
loss following global and focal ischemia; treating, preventing or
ameliorating neurodegenerative conditions; treating, preventing or
ameliorating pain or tinnitus; treating, preventing or ameliorating
manic depression; providing local anesthesia; or treating
arrhythmias, or treating convulsions, comprising administering to a
mammal in need of such treatment an effective amount of a compound
formula: 37or a pharmaceutically acceptable salt, prodrug or
solvate thereof, wherein: Y is 38or R.sub.7, provided that when Y
is R.sub.7, R.sub.1 is aminocarbonyl; A.sub.1, A.sub.2 and A.sub.3
are each CR.sub.2; or A.sub.2 is N and A.sub.1 and A.sub.3 are
CR.sub.2; or A.sub.1 and A.sub.3 are N and A.sub.2 is CR.sub.2; or
A.sub.1 and A.sub.2 are N and A.sub.3 is CR.sub.2; or A.sub.2 and
A.sub.3 are N and A.sub.1 is CR.sub.2; R.sub.1 is selected from the
group consisting an optionally substituted alkyl, amino,
alkylthiol, C(O)R.sub.8, SO.sub.2R.sub.8, OC(O)NH.sub.2,
2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and
3-(1,2,4)-triazolyl; each R.sub.2 is selected from the group
consisting of hydrogen, optionally substituted alkyl, alkenyl, or
alkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino,
dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,
arylcarbonylamino, and aralkylcarbonylamino; or R.sub.1 and R.sub.2
are taken together with the carbon atoms to which they are attached
to form a heterocyclic ring; R.sub.3, R.sub.4, R.sub.5, and R.sub.6
are independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy,
nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,
acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido
and alkylthiol; R.sub.7 is an optionally substituted alkyl; R.sub.8
is selected from the group consisting of alkyl, alkenyl, alkynyl,
OR.sub.9, amino, alkylamino, dialkylamino, alkenylamino,
dialkylaminoalkenyl, dialkylaminoalkylamino,
dialkylaminoalkenylamino, alkylaminoalkenyl-amino,
hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl,
cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be
optionally substituted, provided that R.sub.8 is not OR.sub.9 when
R.sub.1 is SO.sub.2R.sub.8; wherein R.sub.9 is selected from the
group consisting of hydrogen, optionally substituted alkyl, and an
alkali metal; and X is one of O, S, NH, or CH.sub.2 when Y is other
than R.sub.7; or X is one of O, S, NH, CH.sub.2 or absent when Y is
R.sub.7.
109. A method for treating, preventing or ameliorating neuronal
loss following global and focal ischemia; treating, preventing or
ameliorating neurodegenerative conditions; treating, preventing or
ameliorating pain or tinnitus; treating, preventing or ameliorating
manic depression; providing local anesthesia; or treating
arrhythmias, or treating convulsions, comprising administering to a
mammal in need of such treatment an effective amount of a compound
as claimed in claim 59 or 60.
110. The method of claim 108, wherein the method is for treating,
preventing or ameliorating pain and said pain is one of neuropathic
pain, surgical pain or chronic pain.
111. A method of alleviating or preventing seizure activity in an
animal subject, comprising administering to said animal in need of
such treatment an effective amount of a compound of formula: 39or a
pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein: Y is 40or R.sub.7, provided that when Y is R.sub.7,
R.sub.1 is aminocarbonyl; A.sub.1, A.sub.2 and A.sub.3 are each
CR.sub.2; or A.sub.2 is N and A.sub.1 and A.sub.3 are CR.sub.2; or
A.sub.1 and A.sub.3 are N and A.sub.2 is CR.sub.2; or A.sub.1 and
A.sub.2 are N and A.sub.3 is CR.sub.2; or A.sub.2 and A.sub.3 are N
and A.sub.1 is CR.sub.2; R.sub.1 is selected from the group
consisting an optionally substituted alkyl, amino, alkylthiol,
C(O)R.sub.8, SO.sub.2R.sub.8, OC(O)NH.sub.2, 2-imidazolinyl,
2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;
each R.sub.2 is selected from the group consisting of hydrogen,
optionally substituted alkyl, alkenyl, or alkynyl, halogen,
hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino,
alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,
aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and
aralkylcarbonylamino; or R.sub.1 and R.sub.2 are taken together
with the carbon atoms to which they are attached to form a
heterocyclic ring; R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy,
nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,
acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido
and alkylthiol; R.sub.7 is an optionally substituted alkyl; R.sub.8
is selected from the group consisting of alkyl, alkenyl, alkynyl,
OR.sub.9, amino, alkylamino, dialkylamino, alkenylamino,
dialkylaminoalkenyl, dialkylaminoalkylamino,
dialkylaminoalkenylamino, alkylaminoalkenyl-amino,
hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl,
cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be
optionally substituted, provided that R.sub.8 is not OR.sub.9 when
R.sub.1 is SO.sub.2R.sub.8; wherein R.sub.9 is selected from the
group consisting of hydrogen, optionally substituted alkyl, and an
alkali metal; and X is one of O, S, NH, or CH.sub.2 when Y is other
than R.sub.7; or X is one of O, S, NH, CH.sub.2 or absent when Y is
R.sub.7.
112. A method of alleviating or preventing seizure activity in an
animal subject, comprising administering to said animal in need of
such treatment an effective amount of a compound as claimed in
claim 59 or 60.
Description
BACKGROUND OF THE INVENTION
[0001] This application is a divisional of application Ser. No.
09/803,659, filed Mar. 12, 2001, which claims the priority benefit
under 35 U.S.C. .sctn. 119 of U.S. Provisional Appl. No.
60/188,188, filed Mar. 10, 2000. The entirety of each of these
applications is incorporated by reference herein.
[0002] 1. Field of the Invention
[0003] This invention is in the field of medicinal chemistry. In
particular, the invention relates to novel aryl substituted
pyridines, pyrimidines, pyrazines and triazines, and the discovery
that these compounds are anticonvulsants and act as blockers of
sodium (Na.sup.+) channels.
[0004] 2. Related Art
[0005] Several classes of therapeutically useful drugs, including
local anesthetics such as lidocaine and bupivacaine,
antiarrhythmics such as propafenone and amioclarone, and
anticonvulsants such as lamotrigine, phenytoin and carbamazepine,
have been shown to share a common mechanism of action by blocking
or modulating Na.sup.+ channel activity (Catterall, W. A., Trends
Pharmacol. Sci. 8:57-65 (1987)). Each of these agents is believed
to act by interfering with the rapid influx of Na.sup.+ ions.
[0006] Recently, other Na.sup.+ channel blockers such as BW619C89
and lifarizine have been shown to be neuroprotective in animal
models of global and focal ischemia and are presently in clinical
trials (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994);
Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).
[0007] The neuroprotective activity of Na.sup.+ channel blockers is
due to their effectiveness in decreasing extracellular glutamate
concentration during ischemia by inhibiting the release of this
excitotoxic amino acid neurotransmitter. Studies have shown that
unlike glutamate receptor antagonists, Na.sup.+ channel blockers
prevent hypoxic damage to mammalian white matter (Stys et al., J.
Neurosci. 12:430-439 (1992)). Thus, they may offer advantages for
treating certain types of strokes or neuronal trauma where damage
to white matter tracts is prominent.
[0008] Another example of clinical use of a Na.sup.+ channel
blocker is riluzole. This drug has been shown to prolong survival
in a subset of patients with ALS (Bensimm et al., New Engl. J. Med.
330:585-591 (1994)) and has subsequently been approved by the FDA
for the treatment of ALS. In addition to the above-mentioned
clinical uses, carbamazepine, lidocaine and phenytoin are
occasionally used to treat neuropathic pain, such as from
trigeminal neurologia, diabetic neuropathy and other forms of nerve
damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316
(1995)), and carbamazepine and lamotrigine have been used for the
treatment of manic depression (Denicott et al., J. Clin. Psychiatry
55: 70-76 (1994)). Furthermore, based on a number of similiarities
between chronic pain and tinnitus, (Moller, A. R. Am. J. Otol. 18:
577-585 (1997); Tonndorf, J. Hear. Res. 28: 271-275 (1987)) it has
been proposed that tinnitus should be viewed as a form of chronic
pain sensation (Simpson, J. J. and Davies, E. W. Tip. 20: 12-18
(1999)). Indeed, lignocaine and carbamazepine have been shown to be
efficacious in treating tinnitus (Majumdar, B. et al. Clin.
Otolaryngol. 8: 175-180 (1983); Donaldson, I. Laryngol. Otol. 95:
947-951 (1981)).
[0009] It has been established that there are at least five to six
sites on the voltage-sensitive Na.sup.+ channels which bind
neurotoxins specifically (Catterall, W. A., Science 242:50-61
(1988)). Studies have further revealed that therapeutic
antiarrhythmics, anticonvulsants and local anesthetics whose
actions are mediated by Na.sup.+ channels, exert their action by
interacting with the intracellular side of the Na.sup.+ channel and
allosterically inhibiting interaction with neurotoxin receptor site
2 (Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10:15-43
(1980)). 2
[0010] The compounds are disclosed to be useful as herbicides.
[0011] FR 1477021 discloses a compound of the following formula:
3
[0012] This compound is included in photographic materials.
[0013] FR 1536093 discloses a compound of the following formula:
4
[0014] This compound is used as a dye intermediate.
[0015] U.S. Pat. No. 4,912,218 discloses a compound of the formula:
5
[0016] This compound is used for photopolymerizable
compositions.
[0017] WO 9931088 discloses compounds of the formula: 6
[0018] wherein X is O or S. These compounds are stated to be useful
as angiogenesis inhibitors.
SUMMARY OF THE INVENTION
[0019] The present invention is related to the discovery that aryl
substituted pyridines, pyrimidines, pyrazines and triazines
represented by Formula I are anticonvulsants and act as blockers of
sodium (Na.sup.+) channels.
[0020] The invention is also related with treating a disorder
responsive to the blockade of sodium channels in a mammal suffering
from excess activity of said channels by administering an effective
amount of a compound of Formula I as described herein.
[0021] The present invention is also directed to the use of a
compound of Formula I for the treatment of neuronal damage
following global and focal ischemia, and for the treatment or
prevention of neurodegenerative conditions such as amyotrophic
lateral sclerosis (ALS), for the treatment of tinnitus, as
antimanic depressants, as local anesthetics, as antiarrhythmics, as
anticonvulsants and for the treatment or prevention of diabetic
neuropathy and for the treatment of pain including both acute and
chronic pain and migraine headache.
[0022] A number of compounds useful in the present invention have
not been heretofor reported. Thus, one aspect of the present
invention is directed to the novel aryl substituted pyridines,
pyrimidines, pyrazines and triazines of Formula I.
[0023] Another aspect of the present invention is directed to the
novel compounds of Formula I as blockers of sodium channels.
[0024] A further aspect of the present invention is to provide a
method for treating, preventing or ameliorating neuronal loss
following global and focal ischemia; treating, preventing or
ameliorating pain including acute and chronic pain, and neuropathic
pain; treating, preventing or ameliorating convulsion and
neurodegenerative conditions; treating, preventing or ameliorating
manic depression; using as local anesthesics and anti-arrhythmics,
and treating tinnitus by administering a compound of Formula I to a
mammal in need of such treatment or use.
[0025] Also, an aspect of the present invention is to provide a
pharmaceutical composition useful for treating disorders responsive
to the blockade of sodium ion channels, containing an effective
amount of a compound of Formula I in a mixture with one or more
pharmaceutically acceptable carriers or diluents.
[0026] Additional embodiments and advantages of the invention will
be set forth in part in the description that follows, and in part
will be obvious from the description, or may be learned by practice
of the invention. The embodiments and advantages of the invention
will be realized and attained by means of the elements and
combinations particularly pointed out in the appended claims.
[0027] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention, as
claimed.
DETAILED DESCRIPTION OF THE INVENTION
[0028] The present invention arises out of the discovery that aryl
substituted pyridines, pyrimidines, pyrazines and triazines of
Formula I are anticonvulsants and act as blockers of Na.sup.+
channels. In view of this discovery compounds of Formula I are
useful for treating disorders responsive to the blockade of sodium
ion channels.
[0029] The compounds useful in this aspect of the present invention
are aryl substituted pyridines, pyrimidines, pyrazines and
triazines represented by Formula I: 7
[0030] or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein:
[0031] Y is 8
[0032] or R.sub.7;
[0033] provided that when Y is R.sub.7, R.sub.1 is
aminocarbonyl;
[0034] A.sub.1, A.sub.2 and A.sub.3 are independently CR.sub.2 or
N, provided that A.sub.1, A.sub.2 and A.sub.3 are not all N at the
same time;
[0035] R.sub.1 is selected from the group consisting of an
optionally substituted alkyl, amino, alkylthiol, C(O)R.sub.8,
SO.sub.2R.sub.8, OC(O)NH.sub.2, 2-imidazolinyl, 2-imidazolyl,
3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;
[0036] each R.sub.2 is independently selected from the group
consisting of hydrogen, an optionally substituted alkyl, such as
aminoalkyl, haloalkyl and hydroxyalkyl, alkenyl or alkynyl,
halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino,
dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,
arylcarbonylamino, and aralkylcarbonylamino; or R.sub.1 and R.sub.2
are taken together with the carbon atoms to which they are attached
to form a heterocyclic ring;
[0037] R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino,
cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol,
acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
and
[0038] R.sub.7 is an optionally substituted alkyl;
[0039] R.sub.8 is selected from the group consisting of alkyl,
alkenyl, alkynyl, OR.sub.9, amino, alkylamino, dialkylamino,
alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino,
dialkylaminoalkenylamino, alkylaminoalkenylamino,
hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl,
cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be
optionally substituted, provided that R.sub.8 is not OR.sub.9 when
R.sub.1 is SO.sub.2R.sub.8; wherein
[0040] R.sub.9 is selected from the group consisting of hydrogen,
optionally substituted alkyl, and an alkali metal; and
[0041] X is one of O, S, NH, or CH.sub.2 when Y is other than
R.sub.7; or
[0042] X is one of O, S, NH, CH.sub.2 or absent when Y is
R.sub.7.
[0043] Accordingly, compounds useful in the present invention are
aryl substituted pyridines, pyrimidines, pyrazines and triazines
represented by Formula II: 9
[0044] or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein:
[0045] A.sub.1, A.sub.2 and A.sub.3 are independently CR.sub.2 or
N, provided that A.sub.1, A.sub.2 and A.sub.3 are not all N at the
same time;
[0046] R.sub.1 is selected from the group consisting of an
optionally substituted alkyl, amino, alkylthiol, C(O)R.sub.8,
SO.sub.2R.sub.8, OC(O)NH.sub.2, 2-imidazolinyl, 2-imidazolyl,
3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;
[0047] each R.sub.2 is independently selected from the group
consisting of hydrogen, an optionally substituted alkyl, such as
aminoalkyl, haloalkyl and hydroxyalkyl, alkenyl or alkynyl,
halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino,
dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,
arylcarbonylamino, and aralkylcarbonylamino; or R.sub.1 and R.sub.2
are taken together with the carbon atoms to which they are attached
to form a heterocyclic ring;
[0048] R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino,
cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol,
acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;
[0049] R.sub.8 is selected from the group consisting of alkyl,
alkenyl, alkynyl, OR.sub.9, amino, alkylamino, dialkylamino,
alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino,
dialkylaminoalkenylamino, alkylaminoalkenylamino,
hydroxyaminoalkenylamino, cycloalkyl, heterocycloalkyl,
cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be
optionally substituted, provided that R.sub.8 is not OR.sub.9 when
R.sub.1 is SO.sub.2R.sub.8; wherein
[0050] R.sub.1 is selected from the group consisting of hydrogen,
optionally substituted alkyl, and an alkali metal; and
[0051] X is one of O, S, NH, or CH.sub.2.
[0052] Another group of compounds useful in this aspect of the
present invention are aryl substituted pyridines, pyrimidines,
pyrazines and triazines represented by the general Formula II,
wherein A.sub.1, A.sub.2, A.sub.3, R.sub.1--R.sub.6 and
R.sub.8--R.sub.11 are as described above, with the provisos
that
[0053] 1) R.sub.2 is not methoxy if R.sub.5 is trifluoromethyl,
R.sub.6 is H, X is O and R.sub.1 is SO.sub.2CH.sub.2Ph;
[0054] 2) R.sub.2 is not NH.sub.2 if R.sub.1 is methylthio, X is O
and two of A.sub.1, A2 and A.sub.3 are N;
[0055] 3) R.sub.2 is not methyl if R.sub.1 is SO.sub.2R.sub.8,
wherein R.sub.8 is methylphenyl, R.sub.3 and R.sub.4 are methoxy, X
is S and two of A.sub.1, A.sub.2 and A.sub.3 are N;
[0056] 4) R.sub.2 is not CCl.sub.3 if R.sub.1 is CCl.sub.3, X is S
and two of A.sub.1, A.sub.2 and A.sub.3 are N; or
[0057] 5) R.sub.1 and R.sub.2 are not both NH.sub.2 if X is O or S
and two of A.sub.1, A.sub.2 and A.sub.3 are N.
[0058] Examples of bridges formed by R.sub.1 and R.sub.2 taken
together are --CH.sub.2NCH.sub.2--, --C(O)NC(O)-- and
--C(NH.sub.2).dbd.NH--CH.dbd- .CH--.
[0059] Preferably, A.sub.1, A.sub.2 and A.sub.3 are each CR.sub.2
(pyridyl); or A.sub.1 is N and A.sub.2 and A.sub.3 are CR.sub.2
(pyrimidinyl); or A.sub.3 is N and A.sub.1 and A.sub.2 are CR.sub.2
(pyrimidyl); or A.sub.2 is N and A.sub.1 and A.sub.3 are CR.sub.2
(pyrazinyl); or A.sub.1 and A.sub.3 are N and A.sub.2 is CR.sub.2
(1,3,5-triazinyl). More preferably, A.sub.1, A.sub.2 and A.sub.3
are each CR.sub.2 (pyridyl); or A.sub.1 is N and A.sub.2 and
A.sub.3 are CR.sub.2 (pyrimidinyl); or A.sub.3 is N and A.sub.1 and
A.sub.2 are CR.sub.2 (pyrimidyl); or A.sub.2 is N and A.sub.1 and
A.sub.3 are CR.sub.2 (pyrazinyl). Most preferably, A.sub.1, A.sub.2
and A.sub.3 are each CR.sub.2 (pyridyl); or A.sub.1 is N and
A.sub.2 and A.sub.3 are CR.sub.2 (pyrimidinyl); or A.sub.3 is N and
A.sub.1 and A.sub.2 are CR.sub.2 (pyrimidyl).
[0060] Preferably, R.sub.1 is selected from the group consisting of
an alkyl optionally substituted by halogen or hydroxy, thiomethyl,
C(O)R.sub.8, SO.sub.2R.sub.8, 2-imidazolinyl, 2-imidazolyl,
3-pyrazolyl, and 5-isoxazolyl, wherein R.sub.8 is selected from the
group consisting of alkyl, alkenyl, OR.sub.9, amino, alkylamino,
dialkylamino, alkenylamino, dialkylaminoalkenyl,
dialkylaminoalkylamino, and heterocycloalkylamino, all of which can
be optionally substituted, provided that R.sub.8 is not OR.sub.9
when R.sub.1 is SO.sub.2R.sub.8.
[0061] Preferably, R.sub.2 is selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino, hydroxyalkyl,
alkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,
aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and
aralkylcarbonylamino, more preferably hydrogen, alkyl, alkoxy,
aminoalkyl and aminocarbonyl.
[0062] Preferably, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy,
nitro, amino, and cyano. More preferably, R.sub.3, R.sub.4, R.sub.5
and R.sub.6 are independently selected from the group consisting of
hydrogen, alkyl, halogen, haloalkyl, and nitro. Preferred values of
R.sub.3--R.sub.6 include hydrogen, halo, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 hydroxyalkyl, nitro, amino, ureido, cyano,
C.sub.1-C.sub.6 acylamido, hydroxy, thiol, C.sub.1-C.sub.6 acyloxy,
azido, C.sub.1-C.sub.6 alkoxy, or carboxy. The groups
R.sub.3--R.sub.6 each take the place of a hydrogen atom that would
otherwise be present in any position on the aryl ring to which the
R group is attached. Especially preferred are compounds where
R.sub.3 and R.sub.4 are both hydrogen, R.sub.6 is hydrogen and
R.sub.5 is a fluoro in the para-position.
[0063] Preferably, R.sub.7 is a straight or a branched alkyl group
of C.sub.1-C.sub.10 carbon atoms, more preferably C.sub.1-.sub.6
carbon atoms, optionally substituted with one or more of halogen,
hydroxy, nitro, amino, cyano, and alkoxy.
[0064] Preferably, R.sub.8 is selected from the group consisting of
alkyl, alkenyl, OR.sub.9, amino, alkylamino, dialkylamino,
alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, and
heterocycloalkylamino, all of which can be optionally substituted,
wherein R.sub.9 is as defined above, provided that R.sub.8 is not
OR.sub.9 when R.sub.1 is SO.sub.2R.sub.8.
[0065] Preferably X is O or S, more preferably X is O.
[0066] When X is CH.sub.2, R.sub.1 is preferably aminocarbonyl.
[0067] When A.sub.1, A.sub.2 and A.sub.3 are each CR.sub.2 and one
R.sub.2 is other than H, said R.sub.2 is preferably in the position
of A.sub.2. When A.sub.1 is N, A.sub.2 and A.sub.3 both are
CR.sub.2 and one R.sub.2 is other than H, said R.sub.2 is
preferably in the position of A.sub.2. When A.sub.3 is N, A.sub.1
and A.sub.2 both are CR.sub.2 and one R.sub.2 is other than H, said
R.sub.2 is preferably in the position of A.sub.2. When A.sub.2 is
N, A.sub.1 and A.sub.3 both are CR.sub.2 and one R.sub.2 is other
than H, said R.sub.2 is preferably in the position of A.sub.1.
[0068] In one aspect of the invention, preferred compounds falling
within the scope of Formula II include compounds wherein X is O or
S. In this aspect of the invention R.sub.1 is preferably
aminocarbonyl, and R.sub.2 is preferably hydrogen. Preferred
R.sub.3--R.sub.6 groups are as described above.
[0069] Since the compounds of Formula I are blockers of sodium
(Na.sup.+) channels, a number of diseases and conditions mediated
by sodium ion influx can be treated employing these compounds.
Therefore, the invention is related to a method of treating,
preventing or ameliorating neuronal loss associated with stroke,
global and focal ischemia, CNS trauma, hypoglycemia and surgery,
spinal cord trauma; as well as treating or ameliorating
neurodegenerative diseases including Alzheimer's disease,
amyotrophic lateral sclerosis, Parkinson's disease, treating or
ameliorating anxiety, convulsions, glaucoma, migraine headache, and
muscle spasm. The compounds of Formula I are also useful as
antitinnitus agents, antimanic depressants, as local anesthetics,
and as antiarrhythmics; as well as for treating, preventing or
ameliorating pain including surgical, chronic and neuropathic pain.
In each instance, the methods of the present invention require
administering to an animal in need of such treatment an effective
amount of a sodium channel blocker of the present invention, or a
pharmaceutically acceptable salt or prodrug thereof.
[0070] The invention also relates to aryl-substituted pyridines,
pyrimidines, pyrazines and triazines represented by Formula III:
10
[0071] or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein:
[0072] A.sub.1-A.sub.3, R.sub.2--R.sub.6, R.sub.8 and X are defined
previously with respect to Formulae I-II.
[0073] Preferred compounds falling within the scope of Formula III
include compounds wherein R.sub.2 is hydrogen, R.sub.8 is amino,
and X is O and S. R.sub.3 through R.sub.6 have preferred values as
described above for Formula II. Further, preferably R.sub.8 is
selected from the group consisting of alkyl, alkenyl, amino,
alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl,
dialkylaminoalkylamino, and heterocycloalkylamino, all of which can
be optionally substituted.
[0074] Further, the invention relates to aryl-substituted
pyridines, pyrimidines, pyrazines and triazines represented by
Formula IV: 11
[0075] or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein:
[0076] A.sub.1-A.sub.3, R.sub.2--R.sub.6, and X are defined
previously with respect to Formulae I-III and R.sub.8 is selected
from the group consisting of alkyl, alkenyl, alkynyl, amino,
alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl,
dialkylaminoalkylamino, cycloalkyl, heterocycloalkyl,
cycloalkylalkylamino, heterocycloalkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, and arylalkylamino, all of which can be
optionally substituted. Preferably, R.sub.8 is selected from the
group consisting of alkyl, alkenyl, amino, alkylamino,
dialkylamino, alkenylamino, dialkylaminoalkenyl,
dialkylaminoalkylamino, and heterocycloalkylamino, all of which can
be optionally substituted. More preferably, R.sub.8 is selected
from the group consisting of optionally substituted alkyl,
cycloalkyl, aryl and amino. R.sub.3 through R.sub.6 have preferred
values as described above for Formula II.
[0077] Preferred compounds falling within the scope of Formula IV
include compounds wherein R.sub.2 is hydrogen, R.sub.8 is amino,
and X is O and S.
[0078] Also, the present invention relates to compounds of Formula
V: 12
[0079] or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein:
[0080] A.sub.1-A.sub.3, R.sub.2--R.sub.4, and R.sub.7 are defined
previously with respect to Formula I-IV, and X is one of O, S, NH,
CH.sub.2 or absent.
[0081] Preferred compounds falling within the scope of Formulae V
include compounds wherein R.sub.2 is hydrogen, and X is O and S.
Preferably, R.sub.7 is a straight or branched chain C.sub.1-6, more
preferably C.sub.1-4 alkyl, optionally substituted with one or more
of halogen, especially fluoro or chloro. R.sub.3 and R.sub.4 have
preferred values as described above for Formula II.
[0082] Exemplary preferred compounds that may be employed in this
method of invention include, without limitation:
[0083] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxamide;
[0084] 4-[4-(4-nitrophenoxy)phenyl]pyrimidine-2-carboxamide;
[0085] 4-[4-(4-methoxyphenoxy)phenyl]pyrimidine-2-carboxamide;
[0086]
4-[4-(4-trifluoromethylphenoxy)phenyl]pyrimidine-2-carboxamide;
[0087]
4-[4-(3-chloro-2-cyanophenoxy)phenyl]pyrimidine-2-carboxamide;
[0088]
4-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-2-carboxamide;
[0089]
4-[4-(2,4-difluorophenoxy)phenyl]pyrimidine-2-carboxamide;
[0090]
4-[4-(2-chloro-4-fluorophenoxy)phenyl]pyrimidine-2-carboxamide;
[0091]
1-[4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-yl]-ethanone;
[0092] 2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxamide;
[0093] 2-[4-(4-fluorophenoxy)phenyl]-4-methylpyrimidine;
[0094] 2-methyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine;
[0095] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic
acid;
[0096] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid
sodium salt;
[0097] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid
methylamide;
[0098] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid
dimethylamide;
[0099] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid
tert-butylamide;
[0100]
2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide;
[0101]
2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxylic
acid;
[0102] 2-(4-phenoxyphenyl)-6-(dimethylamino)pyrimidine-4-carboxylic
acid dimethylamide;
[0103] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid
2-hydroxyethylamide;
[0104] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid
hydroxymethyleneamide;
[0105]
2-(2-hydroxyprop-2-yl)-4-[4-(4-fluorophenoxy)phenyl]pyrimidine;
[0106] 4-[4-(2,4-difluorophenoxy)phenyl]pyrimidine-2-carboxylic
acid 2-morpholin-4-yl-ethyl amide;
[0107]
2-(4,5-dihydro-1H-imidazol-2-yl)-4-[4-(4-fluorophenoxy)phenyl]-pyri-
midine hydrochloride salt;
[0108] 2-(3-pyrazolyl)-4-[4-(4-fluorophenoxy)phenyl]pyrimidine;
[0109]
2-(5-isoxazolyl)-4-[4-(4-fluorophenoxy)phenyl]pyrimidine;
[0110]
2-(1-methyl-3-pyrazolyl)-4-[4-(4-fluorophenoxy)phenyl]pyrimidine;
[0111]
2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid
methylamide;
[0112]
3-dimethylamino-1-{4-[4-(4-fluorophenoxy)phenyl}pyrimidin-2-yl]prop-
enone;
[0113] 2-thiomethyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine;
[0114]
2-methanesulfonyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine;
[0115]
2-[4-(4-chloro-2-fluorophenoxy)phenyl]-4-methyl-pyrimidine;
[0116]
4-[4-(4-fluorophenoxy)-3-fluorophenyl]pyrimidine-2-carboxamide;
and
[0117]
2-[4-(4-fluorophenoxy)-3-fluorophenyl]pyrimidine-4-carboxamide.
[0118] Additional useful compounds of the present invention
include:
[0119] 2-methyl-6-(4-phenoxyphenyl)pyridine;
[0120] 6-(4-phenoxyphenyl)pyridine-2-carboxamide;
[0121] 2-methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine;
[0122] 6-(4-phenoxyphenyl)pyridine-2-carboxylic acid;
[0123] 6-(4-phenoxyphenyl)pyridine-2-carboxylic acid
methylamide;
[0124] 6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide;
[0125] 6-[(4-trifluoromethoxy)phenyl]pyridine-2-carboxamide;
[0126] 6-[4-(2,4-difluorophenoxy)phenyl]pyridine-2-carboxamide;
[0127]
6-[4-(4-chloro-2-fluorophenoxy)phenyl]pyridine-2-carboxamide;
[0128]
6-[4-(4-fluorophenoxy)-3-fluorophenyl]pyridine-2-carboxamide;
[0129]
6-[4-(4-trifluoromethylphenoxy)phenyl]pyridine-2-carboxamide;
[0130] 6-(4-phenoxyphenyl)pyrazine-2-carboxamide;
[0131] 3,5-diamino-6-(4-phenoxyphenyl)pyrazine-2-carboxamide;
and
[0132] 2-[4-(4-nitrophenoxy)phenyl]-4-methyl-[1,3,5]-triazine.
[0133] Further useful compounds of the invention include:
[0134] 6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid
N-piperidinylethylamide;
[0135] 6-(4-tert-butylphenyl)pyridine-2-carboxamide;
[0136] 6-(4-n-butylphenyl)pyridine-2-carboxamide;
[0137] 6-(4-i-propylphenyl)pyridine-2-carboxamide;
[0138] 6-(4-thiomethylphenyl)pyridine-2-carboxamide;
[0139] 6-(4-ethoxyphenyl)pyridine-2-carboxamide; and
[0140] 6-(4-methoxyphenyl)pyridine-2-carboxamide.
[0141] Furthermore, useful compounds of the invention include:
[0142] 2-dimethylamino-4-[4-(4-fluorophenoxy)phenyl]pyrimidine;
[0143] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid
ethyl ester;
[0144] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carbamate;
[0145] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid
2-chloroethylamide;
[0146]
1-[4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-yl]-2,2-dibromoethanon-
e;
[0147] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid
methylaminomethyleneamide hydrochloride;
[0148]
2-[3-(1,2,4-triazolyl)]-4-[4-(4-fluorophenoxy)phenyl]pyrimidine;
[0149]
2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid
dimethylaminomethyleneamide;
[0150] 4-[4-(2,4-difluorophenoxy)phenyl]pyrimidine-2-carboxylic
acid methyl ester;
[0151] 2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid
methyl ester;
[0152] 2-[4-(4-fluorophenoxy)phenyl]-4-[3-(
1,2,4-triazolyl)]pyrimidine;
[0153] 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid
hydroxymethyleneamide;
[0154]
2-(4-phenoxyphenyl)-6-(dimethylamino)pyrimidine-4-carboxamide;
[0155] 2-(4-phenoxyphenyl)-6-(dimethylamino)pyrimidine-4-carboxylic
acid dimethylamide;
[0156] 2-methyl-3-cyano-6-[4-(4-fluorophenoxy)phenyl]pyridine;
[0157] 6-[4-(4-fluorophenoxy)phenyl]pyridine-2,3-dicarboxamide;
[0158]
2-methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine-3-carboxamide;
[0159] 6-(4-phenoxyphenyl)pyridine-2-carboxylic acid
dimethylamide;
[0160] 5-cyano-6-(4-phenoxyphenyl)pyridine-2-carboxamide;
[0161] 5-hydroxy-6-(4-phenoxyphenyl)pyridine-2-carboxamide; and
[0162] 5-methoxy-6-(4-phenoxyphenyl)pyridine-2-carboxamide.
[0163] Useful aryl groups are C.sub.6-14 aryl, especially
C.sub.6-10 aryl. Typical C.sub.6-14 aryl groups include phenyl,
naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl,
biphenylenyl and fluorenyl groups.
[0164] Useful cycloalkyl groups are C.sub.3-8 cycloalkyl. Typical
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl.
[0165] Useful halo or halogen groups include fluorine, chlorine,
bromine and iodine.
[0166] Useful alkyl groups include straight-chained and branched
C.sub.1-10 alkyl groups, more preferably C.sub.1-6 alkyl groups.
Typical C.sub.1-10 alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl
groups. Also contemplated is a trimethylene group substituted on
two adjoining positions on the benzene ring of the compounds of the
invention.
[0167] Useful alkenyl groups are C.sub.2-6 alkenyl groups,
preferably C.sub.2-4 alkenyl. Typical C.sub.2-4 alkenyl groups
include ethenyl, propenyl, isopropenyl, butenyl, and
sec-butenyl.
[0168] Useful alkynyl groups are C.sub.2-6 alkynyl groups,
preferably C.sub.2-4 alkynyl. Typical C.sub.2-4 alkynyl groups
include ethynyl, propynyl, butynyl, and 2-butynyl groups.
[0169] Useful arylalkyl groups include any of the above-mentioned
C.sub.1-10 alkyl groups substituted by any of the above-mentioned
C.sub.6-14 aryl groups. Useful values include benzyl, phenethyl and
naphthylmethyl.
[0170] Useful arylalkenyl groups include any of the above-mentioned
C.sub.2-4 alkenyl groups substituted by any of the above-mentioned
C.sub.6-14 aryl groups.
[0171] Useful arylalkynyl groups include any of the above-mentioned
C.sub.2-4 alkynyl groups substituted by any of the above-mentioned
C.sub.6-14 aryl groups. Useful values include phenylethynyl and
phenylpropynyl.
[0172] Useful cycloalkylalkyl groups include any of the
above-mentioned C.sub.1-10 alkyl groups substituted by any of the
above-mentioned cycloalkyl groups.
[0173] Useful haloalkyl groups include C.sub.1-10 alkyl groups
substituted by one or more fluorine, chlorine, bromine or iodine
atoms, e.g. fluoromethyl, difluoromethyl, trifluoromethyl,
pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups.
[0174] Useful hydroxyalkyl groups include C.sub.1-10 alkyl groups
substituted by hydroxy, e.g. hydroxymethyl, hydroxyethyl,
hydroxypropyl and hydroxybutyl groups.
[0175] Useful alkoxy groups include oxygen substituted by one of
the C.sub.1-10 alkyl groups mentioned above.
[0176] Useful alkylthio groups include sulfur substituted by one of
the C.sub.1-10 alkyl groups mentioned above.
[0177] Useful acylamino groups are any acyl group, particularly
C.sub.2-6 alkanoyl or C.sub.6-10 aryl(C.sub.2-6)alkanoyl attached
to an amino nitrogen, e.g. acetamido, propionamido, butanoylamido,
pentanoylamido, hexanoylamido, and benzoyl.
[0178] Useful acyloxy groups are any C.sub.1-6 acyl (alkanoyl)
attached to an oxy (--O--) group, e.g. acetoxy, propionoyloxy,
butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
[0179] The term heterocyclic is used herein to mean saturated or
wholly or partially unsaturated 3-7 membered monocyclic, or 7-10
membered bicyclic ring system, which consists of carbon atoms and
from one to four heteroatoms independently selected from the group
consisting of O, N, and S, wherein the nitrogen and sulfur
heteroatoms can be optionally oxidized, the nitrogen can be
optionally quaternized, and including any bicyclic group in which
any of the above-defined heterocyclic rings is fused to a benzene
ring, and wherein the heterocyclic ring can be substituted on
carbon or on a nitrogen atom if the resulting compound is stable.
Examples include, but are not limited to, pyrrolidine, piperidine,
piperazine, morpholine, imidazoline, pyrazolidine, benzodiazepines,
and the like.
[0180] Useful heterocycloalkyl groups include any of the
above-mentioned C.sub.1-10 alkyl groups substituted by any of the
above-mentioned heterocyclic groups.
[0181] Useful heterocycloalkylamino groups include any of the
above-mentioned heterocycloalkyl groups attached to an amino
nitrogen, such as N-piperidinylethylamino.
[0182] Useful alkylamino and dialkylamino groups are --NHR.sub.10
and --NR.sub.10R.sub.11, wherein R.sub.10 and R.sub.11 are
C.sub.1-10 alkyl groups.
[0183] Useful dialkylaminoalkyl groups include any of the
above-mentioned C.sub.1-10 alkyl groups substituted by any of the
above-mentioned dialkylamino groups.
[0184] Useful dialkylaminoalkylamino groups include any of the
above-mentioned dialkylaminoalkyl groups attached to an amino
nitrogen, such as dimethylaminoethylamino.
[0185] Aminocarbonyl group is --C(O)NH.sub.2.
[0186] Useful alkylaminocarbonyl groups are carbonyl groups
substituted by --NHR.sub.10 and --NR.sub.10R.sub.11, wherein
R.sub.10 and R.sub.11 are C.sub.1-10 alkyl groups.
[0187] Useful alkylthiol groups include any of the above-mentioned
C.sub.1-10 alkyl groups substituted by a --SH group.
[0188] A carboxy group is --COOH.
[0189] An azido group is --N.sub.3.
[0190] An ureido group is --NH--C(O)--NH.sub.2.
[0191] An amino group is --NH.sub.2.
[0192] An amide group is an organic radical having --NHC(O)-- as a
functional group.
[0193] Optional substituents on R.sub.1, R.sub.2, and
R.sub.7--R.sub.11 include any one of halo, halo(C.sub.1-6) alkyl,
aryl, heterocycle, cycloalkyl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl(C.sub.1-6)alkyl, aryl(C.sub.2-6)alkenyl,
aryl(C.sub.2-6)alkynyl, cycloalkyl(C.sub.1-6)alkyl,
heterocyclo(C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl,
amino(C.sub.1-6)alkyl, carboxy(C.sub.1-6)alkyl,
alkoxy(C.sub.1-6)alkyl, nitro, amino, ureido, cyano, acylamino,
hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, aminocarbonyl, and
C.sub.1-6 alkylthiol groups mentioned above. Preferred optional
substituents include: halo, halo(C.sub.1-6)alkyl,
hydroxy(C.sub.1-6)alkyl, amino(C.sub.1-6)alkyl, hydroxy, nitro,
C.sub.1-6 alkyl, alkoxy and amino.
[0194] Certain of the compounds of Formulae I-V may exist as
optical isomers and the invention includes both the racemic
mixtures of such optical isomers as well as the individual
enantiomers that may be separated according to methods that are
well know to those of ordinary skill in the art.
[0195] Examples of pharmaceutically acceptable addition salts
include inorganic and organic acid addition salts such as
hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate,
tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate
and oxalate.
[0196] Examples of prodrugs include esters or amides of Formulae
I-V with R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 as
hydroxyalkyl or aminoalkyl, and these may be prepared by reacting
such compounds with anhydrides such as succinic anhydride.
[0197] The invention is also directed to a method for treating
disorders responsive to the blockade of sodium channels in animals
suffering thereof. Particular preferred embodiments of the aryl
substituted heteraryl compounds for use in method of this invention
are represented by previously defined Formulae I-V.
[0198] The compounds of this invention may be prepared using
methods known to those skilled in the art. 4-Aryl pyrimidine
derivatives of compounds of Formula III can be prepared as
illustrated by exemplary reactions in Scheme 1. Formation of the
pyrimidine ring was accomplished as described by Fischer, G. W. (J.
Heterocyclic Chem. 30: 1517-1519 (1993)), and Domagala, J. M. et
al. (J. Heterocyclic. Chem. 26: 1147-1158 (1989)). Oxidation of the
methyl pyrimidine employed the method of Sakamoto, T. et al. (Chem.
Pharm. Bull. 28: 571-577 (1980)). 13
[0199] Pyrazine derivatives of compounds of Formula III can be
prepared as illustrated by exemplary reactions in Scheme 2 using
the method of Ohta, A. et al. (J. Heterocycl. Chem. 20: 311-320
(1983)), Sato, N. et al. (J. Chem. Soc. Perkin Trans. 1 21:
3167-3172 (1997)) and Gainer, (J. Org. Chem. 24: 691 (1959)).
14
[0200] 2-Aryl pyrimidine derivatives of compounds of Formula III
can be prepared as shown in Scheme 3. The pyrimidine ring was
prepared as described by Burdeska, K. et al. (Helv. Chim. Acta. 64:
113-152 (1981)). 15
[0201] The 2-arylpyrimidine-4-carboxamides can also be prepared by
coupling 2-chloropyrimidine-4-carboxamide and a boronic acid or
boronate as shown in Scheme 4. 16
[0202] 2-Chloropyrimidine-4-carboxamide is prepared from
4-methyl-2-pyrimidinol hydrochloride using the procedure of Daves
et al. (J. Heterocycl. Chem. 1: 130-133 (1964)). The chloride is
then coupled with a boronic acid or boronate using the procedure
described above.
[0203] Pyridine amides of Formula III can be synthesized as shown
in Scheme 5: 17
[0204] 6-Bromopicolinic acid (commercially available, marketed by,
e.g., Aldrich) is converted to the corresponding amide and coupled
with aryl boronic acids in the presence of catalytic
Pd(PPh.sub.3).sub.4. See for example Daines, R. A. et al. (Bioorg.
Med. Chem. Lett. 7:2673-2676 (1997)). The boronic acids are
commercially available, or they can also be prepared from the
corresponding bromides or iodides via the Grignard reagent or
organolithium species using the procedures of Bettman, et al. (J.
Am. Chem. Soc. 56:1865-1866 (1934)), Baldwin, J. E. et al.
(Tetrahedron Lett. 39:707-710 (1998)), Li, J. J. et al. (J. Med
Chem. 38:4570-4578 (1995)) and Piettre, S. R. et al. (J. Med. Chem.
40:4208-4221 (1997)). Rather than using boronic acids, aryl
boronates can be used and are prepared from aryl bromides, iodides
and triflates using the method of Murata, M. et al. (J. Org. Chem.
65:164-168 (2000)) and coupled using the method of Giroux, A. et
al. (Tetrahedron 38:3841 (1997)).
[0205] Alternatively, 2-bromo-6-methylpyridine can be coupled with
4-bromoboronic acid and the bromide formed subjected to Ullmann
coupling with a phenol in the presence of Cs.sub.2CO.sub.3 and
copper powder (Buchwald, S. L. et al., J. Am. Chem. Soc.
119:10539-10540 (1997)). The methyl group on the pyridine is then
converted in two steps to the desired amide using the method
described above. 18
[0206] Pyrazines can be prepared by coupling a suitably substituted
6-halopyrazine with an aryl boronic acid using the method described
in the synthesis of the corresponding pyridine as shown in the
Scheme 7 below. 19
[0207] 1,3,5-Triazines of the present invention can be prepared,
for example, using the method of Chen et al. (J. Org. Chem.
60:8428-8430 (1995)) as follows: 20
[0208] 5-Aryl-1,2,4-triazines of the invention can be prepared
using the procedure of Benson, S. et al. (J. Org. Chem. 55:
3257-3269 (1990)) as shown in Scheme 9. Ethyl thiooxamate (Aldrich)
can be converted to the corresponding hydrazone using the method of
Raetz and Schroeder (J. Org. Chem. 23: 1931-1933 (1958)). 21
[0209] 3-Aryl-1,2,4-triazines of the invention can be prepared as
shown in Scheme 10. The sodium salt of hydrazine can be added to a
benzonitrile using the method of Kauffmann, T. et al. (Angew. Chem.
75: 344 (1963)). Formation of the triazine ring can be accomplished
as described by Shkurko, O. P. et al. (Chem. Heterocycl. Compd
(Engl. Transl.) 23: 216-221 (1987)). Conversion to the desired
amide can be carried out as disclosed in Rykowski and Makosza
(Tetrahedron Lett. 25: 4795-4796 (1984)) and Rykowski, A. et al.
(J. Heterocycl. Chem. 33: 1567-1572 (1996)). 22
[0210] The compounds of Formula V can be prepared by the methods
described above using suitable starting compounds.
[0211] The compounds of the present invention were assessed by
electrophysiological assays in dissociated hippocampal neurons for
sodium channel blocker activity. These compounds also could be
assayed for binding to the neuronal voltage-dependent sodium
channel using rat forebrain membranes and [.sup.3H]BTX-B.
[0212] Sodium channels are large transmembrane proteins that are
expressed in various tissues. They are voltage sensitive channels
and are responsible for the rapid increase of Na.sup.+ permeability
in response to depolarization associated with the action potential
in many excitable cells including muscle, nerve and cardiac
cells.
[0213] One aspect of the present invention is the discovery of the
mechanism of action of the compounds herein described as specific
Na.sup.+ channel blockers. Based upon the discovery of this
mechanism, these compounds are contemplated to be useful in
treating or preventing neuronal loss due to focal or global
ischemia, and in treating or preventing neurodegenerative disorders
including ALS, anxiety, and epilepsy. They are also expected to be
effective in treating, preventing or ameliorating neuropathic pain,
surgical pain, chronic pain and tinnitus. The compounds are also
expected to be useful as antiarrhythmics, anesthetics and antimanic
depressants.
[0214] The present invention is directed to compounds of Formulae
I-V that are blockers of voltage-sensitive sodium channels.
According to the present invention, those compounds having
preferred sodium channel blocking properties exhibit an IC.sub.50
of about 100 .mu.M or less in the electrophysiological assay
described herein. Preferably, the compounds of the present
invention exhibit an IC.sub.50 of 10 .mu.M or less. Most
preferably, the compounds of the present invention exhibit an
IC.sub.50 of about 1.0 .mu.M or less. Substituted heteroaryl
compounds of the present invention may be tested for their Na.sup.+
channel blocking activity by the following electrophysiological and
binding assays.
[0215] Electrophysiological Assay 1:
[0216] Cell preparation: HEK-293 (NaIIA-B2) cell line stably
expressing the rBIIA isoform of Na.sup.+ channels was established
in-house. The cells were cultured using standard techniques, as
described previously (Verdoorn, T. A, et al., Neuron 4:919-928
(1990)). For electrophysiology, cells were plated onto
poly-D-lysine pre-coated Cellware 35 mm Petri dishes (BIOCOAT,
Becton Dickinson) at a density of .about.10.sup.4 cells/dish on the
day of re-seeding from confluent cultures. Our experience has been
that cells are suitable for recordings for 2-3 days after
plating.
[0217] Patch-clamp recordings of voltage-sensitive Na.sup.+
currents: Whole-cell voltage-clamp recordings were made using
conventional patch-clamp techniques (Hamill et al., Pfluegers Arch.
391:85-100 (1981)) with an Axopatch 200A amplifier (Axon
Instruments, Foster City, Calif.). The recording chamber was
continuously superfused with the external solution (150 mM NaCl,
5.4 mM KCl, 1.8 mM CaCl.sub.2, 1 mM MgCl.sub.2, 10 mM HEPES, 10 mM
glucose, pH 7.4 adjusted with NaOH, osmolality .about.320 mmol/kg)
at a speed of about 1 mL/min. Recording pipettes were pulled from
the thick-walled capillaries (WPI, Sarasota, Fla.) and
fire-polished. The pipette resistances ranged from 1 to 3 M.OMEGA.
when the pipettes were filled with internal solution containing (in
mM): 130 CsF, 20 NaCl, 2 MgCl.sub.2, 10 EGTA, 10 HEPES, pH adjusted
to 7.4 with CsOH, osmolality .about.310 mmol/kg. Drugs and
intervening wash-outs were applied through a linear array of flow
pipes (Drummond Microcaps, 2 .mu.L, 64-mm length). Compounds are
dissolved in dimethylsulfoxide (DMSO) to make a 30 mM stock
solution, which was subsequently diluted into the external solution
to give final concentrations of 0.1-100 .mu.M. At the highest (1%)
concentration, DMSO inhibited the size of Na.sup.+ current only
slightly. Currents were recorded at room temperature (22-25.degree.
C.), filtered at 3 kHz with an active 8-pole Bessel filter
(Frequency Devices, Haverhill, Mass.), digitized at 10-50 .mu.s
intervals, and stored using Digidata 1200 analog/digital interface
with Pclamp6/Clampex software (Axon Instruments). Series resistance
was cancelled typically by .about.75% when necessary.
[0218] The following voltage pulse protocols were used to assess
the potency and kinetics of inhibition of the Na.sup.+ channels by
the compounds (FIG. 1).
[0219] Current-voltage relationship (IV-curve), protocol A, was
used to report the voltage at which the maximal inward Na.sup.+
current is achieved. This voltage was used throughout the
experiment as testing voltage, V.sub.t. The steady-state
inactivation (or, availability) curve, protocol C, was used to get
the voltage at which almost complete (.gtoreq.95%) inactivation of
Na.sup.+ channels occurs; it served as voltage for conditioning
prepulse, V.sub.c, throughout the experiment. Protocol B reports
how fast the channels recover from inactivation at hyperpolarized
voltages. This permitted us to set up the duration of the
hyperpolarization gap which is used in measurement of the kinetics
of binding of compounds to inactivated Na.sup.+ channels (protocol
D). Channel repriming under control conditions was fast
(.gtoreq.90% recovery during first 5-10 ms). If a drug
substantially retards the repriming process then it becomes
possible (protocol D) to accurately measure the kinetics of binding
of the inhibitor to inactivated channels as well as the
steady-state affinity (k.sub.+ and K.sub.i). To estimate k.sub.+
values the reduction in peak currents in successive trials with
varying pre-pulse duration was plotted as a function of pre-pulse
duration and the time constant (.tau.) measured by mono-exponential
fit. A plot of 1/.tau. as a function of antagonist concentration
then allowed calculating of the macroscopic binding rates of the
antagonists. To determine K.sub.i values the partial inhibition
curves measured by fractional responses in steady-state were fitted
with the logistic equation:
I/I.sub.control=1/(1+([antagonist]/K.sub.j).sup.p), Eq.1
[0220] where I.sub.control is the maximal Na.sup.+ current in the
absence of antagonist, [antagonist] is the drug concentration,
K.sub.i is the concentration of antagonist that produces half
maximal inhibition, and p is the slope factor.
[0221] Electrophysiological Assay 2:
[0222] Electrophysiological Assay 2 was used to measure potencies
of compounds of the present invention rBIIa/beta 1 sodium channels
expressed in Xenopus oocytes.
[0223] Preparation of cRNA encoding cloned rat brain type. IIa
(rBIIa) and beta 1 (.beta.1): cDNA clones encoding the rat brain
beta 1 subunit were cloned in house using standard methods, and
mRNA were prepared by standard methods. mRNA encoding rBIIa was
provided by Dr. A. Golden (UC Irvine). The mRNAs were diluted and
stored at -80.degree. C. in 1 .mu.L aliquots until injection.
[0224] Preparation of oocytes: Mature female Xenopus laevis were
anaesthetized (20-40 min) using 0.15% 3-aminobenzoic acid ethyl
ester (MS-222) following established procedures (Woodward, R. M.,
et al., Mol. Pharmacol. 41:89-103 (1992)).
[0225] Two to six ovarian lobes were surgically removed. Oocytes at
developmental stages V-VI were dissected from the ovary, oocytes
were still surrounded by enveloping ovarian tissues. Oocytes were
defolliculated on the day of surgery by treatment with collagenase
(0.5 mg/mL Sigma Type I, or Boehringer Mannheim Type A, for 0.5-1
hr). Treated oocytes were vortexed to dislodge epithelia, washed
repeatedly and stored in Barth's medium containing 88 mM NaCl, 1 mM
KCl, 0.41 mM CaCl.sub.2, 0.33 mM Ca(NO.sub.3).sub.2, 0.82 mM
MgSO.sub.4, 2.4 mM NaHCO.sub.3, 5 mM HEPES, pH 7.4 adjusted with
0.1 mg/mL gentamycin sulphate.
[0226] Micro-injection of oocytes: Defolliculated oocytes were
micro-injected using a Nanoject injection system (Drummond
Scientific Co., Broomall, Pa.). Injection pipettes were beveled to
minimize clogging. Tip diameter of injection pipettes was 15-35
.mu.m. Oocytes were microinjected with approximately 50 nL 1:10
ratio mixtures of cRNAs for rBIIa and beta I respectively.
[0227] Electrophysiology: Membrane current responses were recorded
in frog Ringer solution containing 115 mM NaCl, 2 mM KCl, 1.8 mM
CaCl.sub.2, 5 mM HEPES, pH 7.4. Electrical recordings were made
using a conventional two-electrode voltage clamp (Dagan TEV-200)
over periods ranging between 1-7 days following injection. The
recording chamber was a simple gravity fed flow-through chamber
(volume 100-500 mL depending on adjustment of aspirator). Oocytes
were placed in the recording chamber, impaled with electrodes and
continuously perfused (5-15 mL min.sup.-1) with frog Ringer's
solution. The tested compounds were applied by bath perfusion.
[0228] Voltage protocols for evoking sodium channel currents: The
standard holding potential for whole oocyte clamp was -120 mV.
Standard current-voltage relationships were elicited by 40ms
depolarizing steps starting from -60 mV to +50 mV in 10 mV
increments. Peak currents were measured as the maximum negative
current after depolarizing voltage steps. The voltage from maximum
current response was noted and used for the next voltage
protocol.
[0229] The purpose was to find compounds that are state dependent
modifiers of neuronal sodium channels. Preferably, the compounds
have a low affinity for the rested/closed state of the channel, but
a high affinity for the inactivated state. The following voltage
protocol was used to measure a compounds affinity for the
inactivated state. Oocytes were held at a holding potential of -120
mV. At this membrane voltage, nearly all of the channels would be
in the closed state. Then a 4 second depolarization was made to the
voltage where the maximum current was elicited. At the end of this
depolarization, nearly all the channels would be in the inactivated
state. A 10 ms hyperpolarizing step was then made in order to
remove some channels from the incativated state. A final
depolarizing test pulse was used to assay the sodium current after
this prolonged depolarization (see analysis below). Sodium currents
were measured at this test pulse before and after the application
of the tested compound. Data was acquired using pClamp 8.0 software
and analyzed with clampfit software (Axon instruments).
[0230] Data analysis: Apparent inhibition constants (K.sub.i
values) for antagonists were determined from single point
inhibition data using the following equation (a generalized form of
the Cheng-Prusoff equation) (Leff, P. and I. G. Dougall, TiPS
14:110-112 (1993)).
K.sub.i=(FR/1-FR)*[drug] Eq.2
[0231] Where FR is the fractional response and is defined as sodium
current elicited from the final depolarizing test pulse prior to
application of the drug divided by the sodium current measured in
the presence of the drug. [drug] is the concentration of the drug
used.
[0232] Drugs: Drugs were initially made up at concentrations of
2-10 mM in DMSO. Dilutions were then made to generate a series of
DMSO stocks over the range 0.3 .mu.M to 10 mM--depending upon the
potency of the compound. Working solutions were made by 1000-3000
fold dilution of stocks into Ringer. At these dilutions DMSO alone
had little or no measurable effects on membrane current responses.
DMSO stocks of drugs were stored in the dark at 4.degree. C. Ringer
solutions of drugs were made up fresh each day of use.
[0233] In Vitro Binding Assay:
[0234] The ability of compounds of the present invention to
modulate either site 1 or site 2 of the Na.sup.+ channel was
determined following the procedures fully described in Yasushi, J.
Biol. Chem. 261:6149-6152 (1986) and Creveling, Mol. Pharmacol.
23:350-358 (1983), respectively. Rat forebrain membranes were used
as sources of Na.sup.+ channel proteins. The binding assays were
conducted in 130 .mu.M choline chloride at 37.degree. C. for
60-minute incubation with [.sup.3H] saxitoxin and [.sup.3H]
batrachotoxin as radioligands for site 1 and site 2,
respectively.
[0235] In Vivo Pharmacology:
[0236] The compounds of the present invention may be tested for in
vivo anticonvulsant activity after i.v., p.o. or i.p. injection
using a number of anticonvulsant tests in mice, including the
maximum electroshock seizure test (MES). Maximum electroshock
seizures were induced in male NSA mice weighing between 15-20 g and
male Sprague-Dawley rats weighing between 200-225 g by application
of current (50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec
duration, D.C., mice; 99 mA, 125 pulses/sec, 0.8 msec pulse width,
2 sec duration, D.C., rats) using a Ugo Basile ECT device (Model
7801). Mice were restrained by gripping the loose skin on their
dorsal surface and saline-coated corneal electrodes were held
lightly against the two corneae. Rats were allowed free movement on
the bench top and ear-clip electrodes were used. Current was
applied and animals were observed for a period of up to 30 seconds
for the occurrence of a tonic hindlimb extensor response. A tonic
seizure was defined as a hindlimb extension in excess of 90 degrees
from the plane of the body. Results were treated in a quantal
manner.
[0237] The compounds may be tested for their antinociceptive
activity in the formalin model as described in Hunskaar, S., O. B.
Fasmer, and K. Hole, J. Neurosci. Methods 14. 69-76 (1985). Male
Swiss Webster NIH mice (20-30 g; Harlan, San Diego, Calif.) were
used in all experiments. Food was withdrawn on the day of
experiment. Mice were placed in Plexiglass jars for at least 1 hour
to accommodate to the environment. Following the accommodation
period mice were weighed and given either the compound of interest
administered i.p. or p.o., or the appropriate volume of vehicle
(10% Tween-80). Fifteen minutes after the i.p. dosing, and 30
minutes after the p.o. dosing mice were injected with formalin (20
.mu.L of 5% formaldehyde solution in saline) into the dorsal
surface of the right hind paw. Mice were transferred to the
Plexiglass jars and monitored for the amount of time spent licking
or biting the injected paw. Periods of licking and biting were
recorded in 5 minute intervals for 1 hour after the formalin
injection. All experiments were done in a blinded manner during the
light cycle. The early phase of the formalin response was measured
as licking/biting between 0-5 minutes, and the late phase was
measured from 15-50 minutes. Differences between vehicle and drug
treated groups were analyzed by one-way analysis of variance
(ANOVA). A P value.ltoreq.0.05 was considered significant. Having
activity in blocking the acute and second phase of formalin-induced
paw-licking activity, the compounds are considered to be
efficacious for acute and chronic pain.
[0238] The compounds may be tested for their potential for the
treatment of chronic pain (antiallodynic and antihyperalgesic
activities) in the Chung model of peripheral neuropathy. Male
Sprague-Dawley rats weighing between 200-225 g were anesthetized
with halothane (1-3% in a mixture of 70% air and 30% oxygen) and
their body temperature controlled during anesthesia through use of
a homeothermic blanket. A 2-cm dorsal midline incision was then
made at the L5 and L6 level and the para-vertibral muscle groups
retracted bilaterally. L5 and L6 spinal nerves were then be
exposed, isolated, and tightly ligated with 6-0 silk suture. A sham
operation was performed exposing the contralateral L5 and L6 spinal
nerves as a negative control.
[0239] Tactile Allodynia: Rats were transferred to an elevated
testing cage with a wire mesh floor and allowed to acclimate for
five to ten minutes. A series of Semmes-Weinstein monofilaments
were applied to the plantar surface of the hindpaw to determine the
animal's withdrawal threshold. The first filament used possessed a
buckling weight of 9.1 gms (0.96 log value) and was applied up to
five times to see if it elicited a withdrawal response. If the
animal had a withdrawal response then the next lightest filament in
the series would be applied up to five times to determine if it
could elicit a response. This procedure was repeated with
subsequent lesser filaments until there was no response and the
lightest filament that elicited a response was recorded. If the
animal did not have a withdrawal response from the initial 9.1 gms
filament then subsequent filaments of increased weight were applied
until a filament elicited a response and this filament was then
recorded. For each animal, three measurements were made at every
time point to produce an average withdrawal threshold
determination. Tests were performed prior to and at 1, 2, 4 and 24
hours post drug administration. Tactile allodynia and mechanical
hyperalgesia tests were conducted concurrently.
[0240] Mechanical Hyperalgesia: Rats were transferred to an
elevated testing cage with a wire mesh floor and allowed to
acclimate for five to ten minutes. A slightly blunted needle was
touched to the plantar surface of the hindpaw causing a dimpling of
the skin without penetrating the skin. Administration of the needle
to control paws typically produced a quick flinching reaction, too
short to be timed with a stopwatch and arbitrarily given a
withdrawal time of 0.5 second. The operated side paw of neuropathic
animals exhibited an exaggerated withdrawal response to the blunted
needle. A maximum withdrawal time of ten seconds was used as a
cutoff time. Withdrawal times for both paws of the animals were
measured three times at each time point with a five-minute recovery
period between applications. The three measures were used to
generate an average withdrawal time for each time point. Tactile
allodynia and mechanical hyperalgesia tests were conducted
concurrently.
[0241] The compounds may be tested for their neuroprotective
activity after focal and global ischemia produced in rats or
gerbils according to the procedures described in Buchan et al.
(Stroke, Suppl. 148-152 (1993)) and Sheardown et al. (Eur. J.
Pharmacol. 236:347-353 (1993)) and Graham et al. (J. Pharmacol.
Exp. Therap. 276:1-4 (1996)).
[0242] The compounds may be tested for their neuroprotective
activity after traumatic spinal cord injury according to the
procedures described in Wrathall et al. (Exp. Neurology 137:119-126
(1996)) and Iwasaki et al. (J. Neuro Sci. 134:21-25 (1995)).
[0243] Compositions within the scope of this invention include all
compositions wherein the compounds of the present invention are
contained in an amount that is effective to achieve its intended
purpose. While individual needs vary, determination of optimal
ranges of effective amounts of each component is within the skill
of the art. Typically, the compounds may be administered to
mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an
equivalent amount of the pharmaceutically acceptable salt thereof,
per day of the body weight of the mammal being treated for
epilepsy, neurodegenerative diseases, anesthetic, arrhythmia, manic
depression, and pain. For intramuscular injection, the dose is
generally about one-half of the oral dose.
[0244] In the method of treatment or prevention of neuronal loss in
global and focal ischemia, brain and spinal cord trauma, hypoxia,
hypoglycemia, status epilepsy and surgery, the compound can be
administrated by intravenous injection at a dose of about 0.025 to
about 10 mg/kg.
[0245] The unit oral dose may comprise from about 0.01 to about 50
mg, preferably about 0.1 to about 10 mg of the compound. The unit
dose may be administered one or more times daily as one or more
tablets each containing from about 0.1 to about 10, conveniently
about 0.25 to 50 mg of the compound or its solvates.
[0246] In addition to administering the compound as a raw chemical,
the compounds of the invention may be administered as part of a
pharmaceutical preparation containing suitable pharmaceutically
acceptable carriers comprising excipients and auxiliaries which
facilitate processing of the compounds into preparations which can
be used pharmaceutically. Preferably, the preparations,
particularly those preparations which can be administered orally
and which can be used for the preferred type of administration,
such as tablets, dragees, and capsules, and also preparations which
can be administered rectally, such as suppositories, as well as
suitable solutions for administration by injection or orally,
contain from about 0.01 to 99 percent, preferably from about 0.25
to 75 percent of active compound(s), together with the
excipient.
[0247] Also included within the scope of the present invention are
the non-toxic pharmaceutically acceptable salts of the compounds of
the present invention. Acid addition salts are formed by mixing a
solution of the particular heteroaryl compound of the present
invention with a solution of a pharmaceutically acceptable
non-toxic acid such as hydrochloric acid, fumaric acid, maleic
acid, succinic acid, acetic acid, citric acid, tartaric acid,
carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid,
and the like. Basic salts are formed by mixing a solution of the
heteroaryl compound of the present invention with a solution of a
pharmaceutically acceptable non-toxic base such as sodium
hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate
and the like.
[0248] The pharmaceutical compositions of the invention may be
administered to any animal that may experience the beneficial
effects of the compounds of the invention. Foremost among such
animals are mammals, e.g., humans, although the invention is not
intended to be so limited.
[0249] The pharmaceutical compositions of the present invention may
be administered by any means that achieve their intended purpose.
For example, administration may be by parenteral, subcutaneous,
intravenous, intramuscular, intraperitoneal, transdermal, or buccal
routes. Alternatively, or concurrently, administration may be by
the oral route. The dosage administered will be dependent upon the
age, health, and weight of the recipient, kind of concurrent
treatment, if any, frequency of treatment, and the nature of the
effect desired.
[0250] The pharmaceutical preparations of the present invention are
manufactured in a manner which is itself known, for example, by
means of conventional mixing, granulating, dragee-making,
dissolving, or lyophilizing processes. Thus, pharmaceutical
preparations for oral use can be obtained by combining the active
compounds with solid excipients, optionally grinding the resulting
mixture and processing the mixture of granules, after adding
suitable auxiliaries, if desired or necessary, to obtain tablets or
dragee cores.
[0251] Suitable excipients are, in particular, fillers such as
saccharides, for example lactose or sucrose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example
tricalcium phosphate or calcium hydrogen phosphate, as well as
binders such as starch paste, using, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, tragacanth,
methyl cellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,
disintegrating agents may be added such as the above-mentioned
starches and also carboxymethyl-starch, cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof, such as
sodium alginate. Auxiliaries are, above all, flow-regulating agents
and lubricants, for example, silica, talc, stearic acid or salts
thereof, such as magnesium stearate or calcium stearate, and/or
polyethylene glycol. Dragee cores are provided with suitable
coatings that, if desired, are resistant to gastric juices. For
this purpose, concentrated saccharide solutions may be used, which
may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
polyethylene glycol and/or titanium dioxide, lacquer solutions and
suitable organic solvents or solvent mixtures. In order to produce
coatings resistant to gastric juices, solutions of suitable
cellulose preparations such as acetylcellulose phthalate or
hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or
pigments may be added to the tablets or dragee coatings, for
example, for identification or in order to characterize
combinations of active compound doses.
[0252] Other pharmaceutical preparations which can be used orally
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer such as glycerol or
sorbitol. The push-fit capsules can contain the active compounds in
the form of granules which may be mixed with fillers such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids. such as fatty oils, or liquid
paraffin. In addition, stabilizers may be added.
[0253] Possible pharmaceutical preparations, which can be used
rectally, include, for example, suppositories, which consist of a
combination of one or more of the active compounds with a
suppository base. Suitable suppository bases are, for example,
natural or synthetic triglycerides, or paraffin hydrocarbons. In
addition, it is also possible to use gelatin rectal capsules which
consist of a combination of the active compounds with a base.
Possible base materials include, for example, liquid triglycerides,
polyethylene glycols, or paraffin hydrocarbons.
[0254] Suitable formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form,
for example, water-soluble salts and alkaline solutions. In
addition, suspensions of the active compounds as appropriate oily
injection suspensions may be administered. Suitable lipophilic
solvents or vehicles include fatty oils, for example, sesame oil,
or synthetic fatty acid esters, for example, ethyl oleate or
triglycerides or polyethylene glycol-400 (the compounds are soluble
in PEG-400). Aqueous injection suspensions may contain substances
which increase the viscosity of the suspension, and include, for
example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
Optionally, the suspension may also contain stabilizers.
[0255] The following examples are illustrative, but not limiting,
of the method and compositions of the present invention. Other
suitable modifications and adaptations of the variety of conditions
and parameters normally encountered in clinical therapy and which
are obvious to those skilled in the art are within the spirit and
scope of the invention.
EXAMPLE 1
4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide
[0256] a) 1-[4-(4-Fluorophenoxy)phenyl]ethanone: A mixture of
4-fluorophenol (4.45 g, 39.3 mmol), 4-fluoroacetophenone (4.4 mL,
36 mmol), and potassium carbonate (13 g, 94 mmol) in DMF (40 mL)
was refluxed overnight. The mixture was allowed to cool to room
temperature, then partitioned between ethyl acetate (200 mL) and
water (200 mL). The separated aqueous layer was extracted with
ethyl acetate (3.times.100 mL). The combined ethyl acetate layers
were washed with an aqueous sodium hydroxide solution (2N, 200 mL),
washed twice with water (200 mL each), dried over sodium sulfate,
filtered, and evaporated under reduced pressure to give a dark oil.
The oil solidified on standing at room temperature overnight. The
weight of crude 1-[4-(4-fluorophenoxy)phenyl]e- thanone was 6.7 g
(80%). .sup.1H NMR (CDCl.sub.3): 7.96 (d, J=9.0 Hz, 2H), 7.11-7.06
(m, 4H), 6.98 (d, J=8.7 Hz, 2H), 2.59 (s, 3H).
[0257] b) 3-Dimethylamino-1-[4-(4-fluorophenoxy)phenyl]-propenone:
A mixture of crude 1-[4-(4-fluorophenoxy)phenyl]ethanone (17.9
mmol) and N,N-dimethylformamide dimethylacetal (2.6 mL, 18.4 mmol)
in DMF (20 mL) was refluxed for 24 hours. The solution was then
partitioned between ethyl acetate and water. The aqueous layer was
extracted twice with ethyl acetate and the combined ethyl acetate
layers were washed twice with water, dried over sodium sulfate,
filtered, and evaporated under reduce pressure to give
3-dimethylamino-1-[4-(4-fluorophenoxy)phenyl]-propenone as a yellow
solid, mp 115-118.degree. C.
[0258] c) 2-Methyl-4-[4-(4-fluorophenoxy)phenyl]-pyrimidine:
Acetamidine hydrochloride (2.00 g, 20.1 mmol) and potassium
tert-butoxide (2.37 g, 20.1 mmol) in anhydrous THF (20 mL) were
refluxed for 50 minutes.
3-Dimethylamino-1-[4-(4-fluorophenoxy)phenyl]-propenone (3.96 g,
13.9 mmol) in anhydrous THF (20 mL) was added to the reaction and
refluxed for an additional 4 hours. The reaction was allowed to
cool to room temperature and concentrated in vacuo. The residue was
partitioned between ethyl acetate and water. The aqueous layer was
extracted twice with ethyl acetate. The combined organic layers
were dried over sodium sulfate, filtered, and evaporated under
reduced pressure to give solid. The crude product was purified by
column chromatography (7:3 hexane/ethyl acetate) to give 1.7 g
(44%) of the title compound as a yellow solid. .sup.1H NMR
(CDCl.sub.3) .delta. 8.61 (d, J=5.1 Hz, 1H), 8.05 (d, J=8.4 Hz,
2H), 7.42 (d, J=5.7 Hz, 1H), 7.05-7.02 (m, 6H), 2.77 (s, 3H).
[0259] d) 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxylic
acid: 4-[4-(4-Fluorophenoxy)phenyl]-2-methyl-pyrimidine (1.70 g,
6.03 mmol) and selenium dioxide (1.16 g, 10.4 mmol) in pyridine (40
mL) were refluxed overnight. The mixture was filtered to remove a
solid that had formed. The filtrate was evaporated under reduced
pressure. The residue was added to a 2N aqueous sodium hydroxide
solution. The resulting solid was collected by filtration and
partitioned between aqueous hydrochloric acid (2N) and ethyl
acetate. The aqueous layer was extracted two more times with ethyl
acetate. The combined organic layers were dried over sodium
sulfate, filtered, and evaporated under reduced pressure to give
1.5 g (80%) of the acid as a solid. .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.95 (d, J=5.4 Hz, 1H), 8.25 (d, J=8.7 Hz, 2H), 8.18 (d,
J=5.4 Hz, 1H), 7.30 (t, J=8.7 Hz, 2H), 7.22-7.17 (m, 2H), 7.13 (d,
J=9.3 Hz, 2H).
[0260] e) 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide: A
mixture of 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxylic
acid (1.00 g, 3.23 mmol) and carbonyl diimidazole (1.10 g, 6.78
mmol) in DMF (10 mL) were stirred at room temperature for 2 hours.
Solid ammonium acetate (2.10 g, 27.2 mmol) was then added to the
reaction. After stirring overnight at room temperature, the
reaction was diluted with ethyl acetate, washed several times with
water, dried over sodium sulfate, filtered, and evaporated under
reduced pressure. The crude product was purified by column
chromatography (gradient from 100% ethyl acetate to 95:5 ethyl
acetate/methanol) to give 669 mg (67%) of the desired product as
yellow solid, mp 180-182.degree. C. .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.94 (d, J=5.1 Hz, 1H), 8.38 (d, J=8.7 Hz, 2H), 8.34 (bs,
1H), 8.15 (d, J=5.4 Hz, 1H), 7.83 (bs, 1H), 7.30 (t, J=8.4 Hz, 2H),
7.22-7.17 (m, 2H), 7.12, (d, J=8.7 Hz, 2H).
[0261] The following compounds were prepared similarly:
[0262] 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid
methylamide;
[0263] 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid
dimethylamide;
[0264] 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid
tert-butylamide;
[0265]
4-[4-(4-Trifluoromethylphenoxy)phenyl]-pyrimidine-2-carboxamide;
[0266] 4-[4-(2,4-Difluorophenoxy)phenyl]-pyrimidine-2-carboxamide;
and
[0267] 4-[4-(4-Nitrophenoxy)phenyl]-pyrimidine-2-carboxamide.
[0268] Further, the following compounds can be prepared
similarly:
[0269] 4-[4-(4-methoxyphenoxy)phenyl]pyrimidine-2-carboxamide;
[0270]
4-[4-(3-chloro-2-cyanophenoxy)phenyl]pyrimidine-2-carboxamide;
and
[0271]
4-[4-(4-fluorophenoxy)-3-fluorophenyl]pyrimidine-2-carboxamide.
EXAMPLE 2
2-Methanesulfonyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine
[0272] a) 2-Thiomethyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine: A
mixture of 3-dimethylamino-1-[4-(4-fluorophenoxy)phenyl]-propenone
(551 mg, 1.93 mmol) and thiourea (294 mg, 3.86 mmol) suspended in 5
mL of ethanol was treated with 1.6 mL (1.93 mmol) of a stock
solution prepared from 382 mg of 85% KOH in 5 mL of ethanol added
dropwise via syringe. The resulting solution was heated at reflux
for 4 hours. Once at room temperature, the yellow precipitate (348
mg) that formed was isolated by filtration and washed with ethanol
(2 mL). The solid (338 mg) was then suspended in 5 mL of water and
0.25 mL (2.6 mmol) of dimethyl sulfate was added. After 5 minutes,
1.6 mL of a 2N aqueous NaOH solution was added. After stirring
overnight, the mixture was extracted with ether (3.times.15 mL).
The organic layers were pooled, washed with water and brine, dried
(Na.sub.2SO.sub.4) and concentrated. Flash chromatography (silica
gel; 3:1 hexane/ethyl acetate) afforded 226 mg of the thiol as an
off-white solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.51 (d, 1H,
J=5.1 Hz), 8.08 (d, 2H, J=8.8 Hz), 7.31 (d, 1H, J=5.5 Hz),
7.11-7.00 (m, 6H), 2.64 (s, 3H).
[0273] b)
2-Methanesulfonyl-4-[4-(4-fluorophenoxy)phenyl]pyrimidine: A
solution of 205 mg. (0.656 mmol) of
2-thiomethyl-4-[4-(4-fluorophenoxy)ph- enyl]pyrimidine in 8 mL of
CH.sub.2Cl.sub.2 was treated with a solution of 321 mg of
m-chloroperoxybenzoic acid (57-86%) in CH.sub.2Cl.sub.2 (2 mL).
After stirring for 2 hours at room temperature, the reaction was
extracted with 20 mL each of water, a 5% aqueous sodium hydrogen
sulfite solution, water and brine. After drying (Na.sub.2SO.sub.4),
the solvent was removed in vacuo and the residue was purified by
flash chromatography (silica gel; 3:1 EtOAc/hexane) affording 183
mg (81%) of the title compound as a white solid, mp 146-147.degree.
C. .sup.1H NMR (CDCl.sub.3) .delta. 8.90 (d, 1H, J=5.5 Hz), 8.19
(d, 2H, J=8.8 Hz), 7.87 (d, 1H, J=5.5 Hz), 7.13-7.09 (m, 6H), 3.45
(s, 3H).
EXAMPLE 3
1-[4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-yl]-ethanone
[0274] a) 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxylic
acid ethyl ester: A mixture of
4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid (3.15 g,
10.2 mmol), iodoethane (2.0 mL, 25 mmol), and cesium carbonate
(7.00 g, 21.5 mmol) in DMF (100 mL) was maintained at 70-80.degree.
C. for 16 hours. The mixture was then partitioned between water and
ethyl acetate. The aqueous layer was extracted twice with ethyl
acetate. The combined organic layers were washed 3 times with
water, dried over sodium sulfate, filtered, and evaporated under
reduced pressure to give an oil. Purification by column
chromatography (1:1 hexane/ethyl acetate) afforded the desired
product (2.14 g, 62%) as an oil which solidified upon standing at
room temperature overnight, mp 61-63.degree. C. .sup.1H NMR
(CDCl.sub.3): .delta. 8.88 (d, J=5.4 Hz, 1H), 8.16 (d, J=8.7 Hz,
2H), 7.77 (d, J=5.4 Hz, 1H), 7.12-7.05 (m. 6H), 4.55 (q, J=7.5 Hz,
2H), 1.49 (t, J=7.5 Hz, 3H).
[0275] b)
1-[4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-yl]-ethanone: To a
solution of 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxylic
acid ethyl ester (0.66 g, 1.95 mmol) in anhydrous THF (20 mL) at
-78.degree. C. under nitrogen was added a 1.4 M solution of methyl
magnesium bromide in ether (1.4 mL, 1.96 mmol) in one portion. The
reaction was stirred at -78.degree. C. for 30 minutes, quenched
with water and partitioned between water and ethyl acetate. The
aqueous layer was extracted with ethyl acetate and the combined
organic layers were dried over sodium sulfate, filtered, and
evaporated under reduced pressure to give a solid. The crude
product was then subjected to column chromatography (6:4
hexane/ethyl acetate) affording 0.36 g (60%) of the desired product
as a solid. .sup.1H NMR (CDCl.sub.3): .delta. 8.90 (d, J=4.2 Hz,
1H), 8.16 (d, J=8.4 Hz, 2H), 7.76 (d, J=4.8 Hz, 1H), 7.09-7.06 (m,
6H), 2.85 (s, 3H
EXAMPLE 4
2-[4-(4-Chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide
[0276] a) 4-(4-Chloro-2-fluorophenoxy)benzonitrile: A mixture of
4-fluorobenzonitrile (5.0 g, 41.3 mmol), 4-chloro-2-fluorophenol
(4.7 mL, 44 mmol), and potassium carbonate (13.8 g, 99.8 mmol) in
DMF (100 ml) was refluxed overnight. After cooling to room
temperature, the mixture was diluted with ethyl acetate, washed
twice with a 2N aqueous sodium hydroxide solution, washed with
water, dried over sodium sulfate, filtered, and evaporated under
reduced pressure to give very light yellow solid. The weight of
crude product was 7.56 g (74%). .sup.1H NMR (CDCl.sub.3): .delta.
7.61 (d, J=8.1 Hz. 2H), 7.27-7.07 (m, 3H), 6.98 (d, J=8.7 Hz,
2H).
[0277] b)
2-[4-(4-Chloro-2-fluorophenoxy)phenyl]-4-methyl-pyrimidine:
Hydrogen chloride gas was bubbled through a solution of
4-(4-chloro-2-fluorophenoxy)benzonitrile (1.64 g, 6.64 mmol) in
ethanol (100 mL) under N.sub.2 at 0.degree. C. for 15 minutes. The
solution was stoppered, and stirred at room temperature for 24
hours and concentrated to dryness. The residue was dissolved in
ethanol (100 mL), ammonium carbonate (6.3 g, 65 mmol) was added and
the resulting mixture was stirred at room temperature for 24 hours.
The mixture was filtered and the filtrate was evaporated under
reduced pressure to give a white solid. The crude intermediate was
not purified, and was carried on to the next step. .sup.1H NMR
(DMSO-d.sub.6): .delta. 7.90 (d, J=8.4, 2H), 7.40-7.25 (m, 3H).
7.18 (d, J=8.4, 2H).
[0278] A mixture of the crude amidine and potassium tert-butoxide
(0.72 g, 6.1 mmol) in methanol (100 mL) was refluxed for 30
minutes. Acetylacetaldehyde dimethyl acetal (AADDA; 0.8 mL, 5.4
mmol) was added and the reaction was heated at reflux overnight.
Additional potassium tert-butoxide (0.72 g, 6.1 mmol) and AADDA
(0.8 mL, 5.4 mmol) were added. After 6 hours at reflux, the
reaction was allowed to cool to room temperature and partitioned
between water and ethyl acetate. The aqueous layer was extracted
once with ethyl acetate. The combined organic layers were dried
with sodium sulfate, filtered, and evaporated under reduced
pressure to give a dark brown solid. Column chromatography (85/15
hexane/ethyl acetate to 8/2 hexane/ethyl acetate) afforded 0.90 g
(43% yield from the benzonitrile) of the desired product as solid.
.sup.1H NMR (CDCl.sub.3): .delta. 8.60 (d, J=5.1 Hz, 1H), 8.42 (d,
J=8.4 Hz, 2H), 7.24-7.02 (m, 6H), 2.56 (s, 3H).
[0279] c)
2-[4-(4-Chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid:
A mixture of
2-[4-(4-chloro-2-fluorophenoxy)phenyl]-4-methyl-pyrimi- dine (0.90
g, 2.87 mmol), and selenium dioxide (0.62 g, 5.6 mmol) in pyridine
(50 mL) was refluxed overnight. The mixture was allowed to cool to
room temperature, then filtered through a bed of Celite. The
filtrate was evaporated under reduced pressure. The residue was
dissolved in ethyl acetate, and washed twice with a 2N aqueous
hydrochloric acid solution. The organic layer was separated, dried
over sodium sulfate, filtered, and evaporated under reduced
pressure to give 0.808 g (82%) of a light yellow solid. .sup.1H NMR
(DMSO-d.sub.6): .delta. 9.11 (d, J=5.1 Hz, 1H), 8.46 (d, J=8.7 Hz,
2H), 7.87 (d, J=4.5 Hz, 1H), 7.38-7.35 (m, 3H), 7.15 (d, J=9.0 Hz,
2H)
[0280] d)
2-[4-(4-Chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide: A
solution of
2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxy- lic
acid (0.6 g, 1.74 mmol), and carbonyl diimidazole (0.54 g, 3.3
mmol) in DMF (20 mL) was stirred at room temperature under nitrogen
for 30 minutes. Solid ammonium acetate (2.0 g, 26 mmol) was added
and the reaction was stirred overnight. The reaction was then
diluted with ethyl acetate, washed 3 times with water, dried over
sodium sulfate, filtered, and evaporated under reduced pressure to
give a yellow solid. The crude product was purified by column
chromatography (4:1 dichloromethane/ethyl acetate) to give 331 mg
(55%) of the final product as a white solid, mp 198-200.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 9.01 (d, J=4.8 Hz, 1H), 8.44 (d,
J=8.4 Hz, 2H), 7.96 (d, J=4.2 Hz, 1H), 7.88 (bs, 1H), 7.26-7.23 (m,
1H), 7.16-7.10 (m, 2H), 7.06 (d, J=8.7 Hz, 2H), 5.75 (bs, 1H).
[0281] The following compound was prepared similarly:
2-[4-(4-Chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxylic acid
methylamide.
EXAMPLE 5
2-Chloropyrimidine-4-carboxamide
[0282] a) 2-Hydroxy-4-pyrimidinecarboxaldehyde, oxime: A solution
of 4-methyl-2-pyrimidinol hydrochloride (14.7 g, 0.100 mol) in 100
mL of 50% aqueous HOAc at 12.degree. C. was treated with solid
NaNO.sub.2 (10.47 g, 0.150 mol) added in one portion. Brown gas
evolved and a yellow precipitate formed as the reaction temperature
rose to 42.degree. C. After stirring at room temperature for 3
hours, the solid precipitate was isolated by filtration and washed
with cold water (2.times.50 mL). The resulting solid was
recrystallized from 550 mL of boiling water, affording 11.9 g (85%)
of the oxime as yellow-brown needles, mp 222-226.degree. C.
(decomp.). .sup.1H NMR (DMSO-d.sub.6): .delta. 12.4 (br s, 1H),
11.9 (br s, 1H), 7.95 (d, J=6.3 Hz, 1H), 7.79 (s, 1H), 6.68 (d, 1H,
J=6.6 Hz).
[0283] b) 2-Chloro-4-cyanopyrimidine: To neat POCl.sub.3 (40 mL,
65.8 g, 0.429 mol) cooled in an ice-water bath was added powdered
solid 2-hydroxy-4-pyrimidinecarboxaldehyde, oxime (10.0 g, 71.9
mmol) in portions. The cold bath was removed and the mixture was
slowly heated to reflux. When the reaction began to reflux on its
own, heating was stopped. Once the reflux had subsided, neat
N,N-dimethylaniline (5 mL, 4.78 g, 39.4 mmol) was added via
syringe. The resulting dark solution was heated at reflux for 30
minutes. Once at room temperature, the reaction was slowly added to
300 g of crushed ice. The resulting dark mixture was extracted with
ether (4.times.100 mL). The pooled ether layers were then washed
with water (2.times.50 mL), a sat. aqueous NaHCO.sub.3 solution
(2.times.50 mL) and water (2.times.50 mL). After drying
(Na.sub.2SO.sub.4) the mixture was filtered and concentrated in
vacuo. 1.5 g of the resulting red oil was dissolved in a min. of
CH.sub.2Cl.sub.2 and added to 15 cm of flash silica in a 4 cm.
diameter column. Elution with 100% gave 1.4 g of a yellow solid.
The remainder of the red oil (3.6 g ) was chromatographed on silica
gel, afforded a total of 4.72 g (47%) of the nitrile as a yellow
solid, mp 49.5-52.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 8.89
(d, 1H, J=4.8 Hz), 7.62 (d, 1H, J=4.8 Hz).
[0284] c) 2-Chloropyrimidine-4-carboxamide: To 15 mL of
concentrated H.sub.2SO.sub.4 at 15.degree. C. was added finely
ground 2-chloro-4-cyanopyrimidine (4.0 g, 28.7 mmol). The mixture
that formed was allowed to warm to room temperature and stirred for
5 hours. The resulting light yellow solution was then slowly added
to 80 g of crushed ice. The mixture was filtered, washed with cold
water (2.times.25 mL) and a saturated aqueous NaHCO.sub.3 solution
(25 mL), to give 490 mg of the amide as a yellow solid, mp
151-152.degree. C. The mother liquor was extracted with EtOAc
(3.times.50 mL). The pooled organic layers were washed with water
(25 mL) and a saturated aqueous NaHCO.sub.3 solution (2.times.25
mL). After drying (Na.sub.2SO.sub.4), the EtOAc was removed in
vacuo, affording an additional 2.5 g of the amide as a yellow
solid. Total yield of the title compound was 2.99 g (66%). .sup.1H
NMR (CDCl.sub.3): .delta. 8.88 (d, 1H, J=4.8 Hz), 8.07 (d, 1H,
J=4.8 Hz), 7.65 (br s, 1H), 5.93 (br s, 1H).
EXAMPLE 6
6-[(4-Trifluoromethoxy)phenyl]pyridine-2-carboxamide
[0285] a) 6-Bromopyridine-2-carboxamide: Reaction of
6-bromopicolinic acid (Aldrich) with carbonyl diimidazole in DMF
followed by the addition of an excess of ammonium acetate was
carried out as described above, affording the amide as a white
solid, mp 130-135.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 8.17
(d, 1H, J=7.5 Hz), 7.73 (t, 1H, J=7.8 Hz), 7.64 (d, 1H, J=7.5 Hz),
5.66 (br s, 1H).
[0286] b) 6-[(4-Trifluoromethoxy)phenyl]pyridine-2-carboxamide: A
mixture of 6-bromopyridine-2-carboxamide (110 mg, 0:547 mmol),
4-(trifluoromethoxy)phenylboronic acid (Aldrich; 138 mg, 0.670
mmol), sodium carbonate (185 mg) and Pd(PPh.sub.3).sub.4 (32 mg, 5
mol %) in 10 mL of toluene and 2.5 mL each of water and EtOH was
heated at reflux overnight. After cooling to room temperature, the
mixture was partitioned between water and EtOAc. The aqueous layer
was washed twice with EtOAc and the pooled organic layers were
washed with water (3.times.), dried (Na2SO4), filtered and
concentrated to dryness. Flash chromatography (6:4 hexane/acetone)
afforded 122 mg (79%) of the title compound as a white solid, mp
133-135.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 8.19 (d, J=7.5
Hz, 1H), 8.04 (d, J=9.0 Hz, 2H), 7.96 (t, J=7.8 Hz, 1H), 7.94 (bs,
1H), 7.87 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.1 Hz, 2H), 5.76 (bs,
1H).
EXAMPLE 7
3-Dimethylamino-1-{4-[4-(4-fluorophenoxy)phenyl]pyrimidin-2-yl}propenone
[0287] A solution of
1-{4-[4-(4-fluorophenoxy)phenyl]pyrimidin-2-yl}ethano- ne (0.36 g,
1.17 mmol) and N,N-dimethylformamide dimethyl acetal (94%, 0.25 mL,
1.77 mmol) in DMF (10 mL) was refluxed for several hours. The
reaction was cooled to room temperature, then partitioned between
ethyl acetate (50 mL) and water (50 mL). The aqueous layer was
extracted with ethyl acetate (2.times.50 mL). The combined organic
layers were washed with water (3.times.50 mL), dried over sodium
sulfate, filtered, and evaporated under reduced pressure to give an
oil. The oil was purified by column chromatography (100% ethyl
acetate to 8:2 ethyl acetate/methanol) to give 182 mg (43% yield)
of the final product as a brownish yellow solid, mp 151-153.degree.
C. .sup.1H NMR (CDCl.sub.3): .delta. 8.87 (d, J=5.1 Hz, 1H), 8.16
(d, J=9.0 Hz, 2H), 7.98 (d, J=12.9 Hz, 1H), 7.67 (d, J=5.4 Hz, 1H),
7.11-7.05 (m, 6H), 6.43 (bd, 1H), 3.19 (s, 3H), 3.00 (s, 3H).
EXAMPLE 8
4-[4-(4-Fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid,
(2-hydroxyethyl)amide
[0288] To a mixture of
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxyli- c acid (1.03
g, 3.1 mmol), ethanolamine (0.31 mL, 5.08 mmol), and
1-hydroxybenzotriazol hydrate (0.53 g, 3.46 mmol) in DMF (20 mL)
under nitrogen at 0.degree. C. was added 4-methylmorpholine (0.76
mL, 6.9 mmol), and 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide
hydrochloride (0.68 g, 3.48 mmol). The mixture was allowed to warm
to room temperature overnight. The reaction was diluted with ethyl
acetate, washed 3 times with water, dried over sodium sulfate,
filtered, and evaporated under reduced pressure to give the desired
product as an oil. .sup.1H NMR (CDCl.sub.3): .delta. 8.82 (d, J=5.7
Hz, 1H), 8.50 (bs, 1H), 8.10 (d, J=8.7 Hz, 2H), 7.71 (d, J=5.1 Hz,
1H), 7.08-7.03 (m. 6H), 3.88 (t, J=4.2 Hz, 2H), 3.70 (q, J=4.8 Hz,
2H), 3.25 (bs, 1H).
EXAMPLE 9
6-(4-Phenoxyphenyl)pyridine-2-carboxylic acid methylamide
[0289] 6-Bromopicolinic acid (Aldrich) was coupled with methyl
amine using carbonyl diimidazole (CDI) as coupling reagent to
afford 6-bromopyridine-2-carboxylic acid methylamide. The
6-bromopyridine-2-carboxylic acid methylamide underwent Suzuki
coupling with 4-phenoxyphenylboronic acid. in the presence of
tetrakis(triphenylphosphine)palladium as catalyst to give
6-(4-phenoxyphenyl)pyridine-2-carboxylic acid methylamide as a
solid. .sup.1H NMR (CDCl.sub.3): .delta. 8.12 (d, J=7.8 Hz, 1H),
7.98 (d, J=8.7 Hz, 2H), 7.90 (t, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz,
1H), 7.38 (t, J=8.4 Hz, 2H), 7.18-7.06 (m, 5H), 3.08 (d, J=5.4 Hz,
3H).
EXAMPLE 10
6-[4-(4-Fluorophenoxy)phenyl]pyridine-2-carboxamide
[0290] a) 2-Methyl-6-(4-bromophenyl)pyridine: To a mixture of
4-bromophenylboronic acid (3.14 g, 15.6 mmol),
2-bromo-6-methylpyridine (1.7 ml, 14.9 mmol), solid sodium
carbonate (5.1 g, 31.9 mmol) in toluene (60 mL), water (15 mL), and
ethanol (15 mL) was added tetrakis(triphenylphosphine)palladium (0)
(890 mg, 0.77 mmol). The mixture was refluxed (100-110.degree. C.)
overnight. The reaction was allowed to cool to room temperature,
then partitioned between ethyl acetate and water. The aqueous layer
was extracted one more time with ethyl acetate. The combined
organic layers were dried over sodium sulfate, filtered, and
evaporated under reduced pressure to give the crude product.
Purification by flash chromatography (silica gel; 4% EtOAc/hexane)
afforded 2.5 g (87%) of the product as a white solid. .sup.1H NMR
(CDCl.sub.3): .delta. 7.88 (d, J=9.0 Hz, 2H), 7.67-7.56 (m, 3H),
7.48 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 2.61 (s, 3H).
[0291] b) 2-Methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine: A mixture
of 2-methyl-6-(4-bromophenyl)pyridine (3.25 g, 13 mmol),
4-fluorophenol (2.5 g, 22 mmol), cesium carbonate (11.2 g, 34
mmol), and copper powder (4.5 g) in DMF (50 mL) was refluxed
overnight. The reaction was allowed to cool to room temperature,
filtered and partitioned between ethyl acetate and water. The
aqueous layer was extracted two times with ethyl acetate. The
combined organic layers were washed three times with water, dried
over sodium sulfate, filtered, and evaporated under reduced
pressure to give a solid that was subjected to flash chromatography
(silica gel; 4% EtOAc/hexane) to give 1.8 g (50%) of the product as
a white solid. .sup.1H NMR (CDCl.sub.3): .delta. 7.94 (d, J=9.0 Hz,
2H), 7.61 (t, J=7.6 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.08-7.01 (m,
7H), 2.61 (s, 3H).
[0292] c) 6-[4-(4-Fluorophenoxy)phenyl]pyridine-2-carboxamide: A
mixture of 2 methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine (1.8 g,
6.45 mmol), and selenium dioxide (3.6 g, 32.4 mmol) in pyridine (30
mL) was heated at reflux overnight. Once at room temperature, the
reaction was filtered through Celite. The filtrate was partitioned
between ethyl acetate and an aqueous hydrochloric acid solution
(2N). The aqueous layer was extracted two more times with ethyl
acetate. The combined organic layers were washed with an aqueous
hydrochloric acid solution (2N), dried over sodium sulfate,
filtered, and evaporated under reduced pressure to give 1.8 g (90%)
of the crude acid as a yellow solid. The crude acid (1.2 g, 3.88
mmol) was dissolved in DMF (50 mL) and carbonyl diimidazole (1.3 g,
8.0 mmol) was added. The resulting solution was stirred at room
temperature for 1 hour. Solid ammonium acetate (3.1 g, 39 mmol) was
added and the mixture was stirred overnight. The reaction was
partitioned between ethyl acetate and water. The aqueous layer was
extracted two times with ethyl acetate. The combined organic layers
were washed three times with water, dried over sodium sulfate,
filtered, and evaporated under reduced pressure to give the crude
product. Purification by flash chromatography (silica gel column;
65/35 hexane/acetone) afforded 509 mg (42%) of the title compound,
mp 150-152.degree. C. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.32 (d,
J=9.0 Hz, 2H), 8.31 (bs, 1H), 8.12 (d, J=8.1 Hz, 1H), 8.03 (dd,
J=8.1, 7.2 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.69 (bs, 1H), 7.27 (t,
J=9.0 Hz, 2H), 7.18-7.13 (m, 2H), 7.07 (d, J=9.0, 2H).
[0293] The following compounds can be prepared similarly:
[0294] 6-[4-(2,4-difluorophenoxy)phenyl]pyridine-2-carboxamide;
[0295]
6-[4-(4-chloro-2-fluorophenoxy)phenyl]pyridine-2-carboxamide;
[0296]
6-[4-(4-fluorophenoxy)-3-fluorophenyl]pyridine-2-carboxamide;
and
[0297]
6-[4-(4-trifluoromethylphenoxy)phenyl]pyridine-2-carboxamide.
EXAMPLE 11
6-(4-Phenoxyphenyl)pyridine-2-carboxamide
[0298] 6-(4-Phenoxyphenyl)pyridine-2-carboxamide was prepared by
the method used for its 4-fluoro analog in Example 10, except
4-phenoxyphenylboronic acid (Aldrich) was used in place of
4-bromophenylboronic acid.
[0299] a) 2-Methyl-6-(4-phenoxyphenyl)pyridine: .sup.1H NMR
(CDCl.sub.3): .delta. 7.95 (d, J=9.0 Hz, 2H), 7.60 (t, J=7.5 Hz,
1H), 7.46 (d, J=7.5 Hz, 1H), 7.34 (t, J=7.8 Hz, 2H), 7.13-7.02 (m,
6H), 2.61 (s, 3H).
[0300] b) 6-(4-Phenoxyphenyl)pyridine-2-carboxylic acid: .sup.1H
NMR (DMSO-d.sub.6): .delta. 13.1 (bs, 1H), 8.21 (d, J=8.4 Hz, 2H),
8.16 (d, J=7.8 Hz, 1H), 8.04 (t, J=7.2 Hz, 1H), 7.96 (d, J=7.2 Hz,
1H), 7.44 (t, J=7.6 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.11 (dd,
J=8.4, 7.5 Hz, 4H).
[0301] c) 6-(4-Phenoxyphenyl)pyridine-2-carboxamide: .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.33 (d, J=8.7 Hz, 2H), 8.31 (bs, 1H), 8.12
(d, J=7.8 Hz, 1H), 8.03 (t, J=7.6 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H),
7.69 (bs, 1H), 7.43 (dd, J=8.7, 7.5 Hz, 2H), 7.19 (t, J=7.8 Hz,
1H), 7.09 (d, J=8.7 Hz, 4H), mp 178-180.degree. C., 45% yield from
starting materials (3 steps).
EXAMPLE 12
2-[4-(4-Fluorophenoxy)phenyl]pyrimidine-4-carboxamide
[0302] a) 4-(4-Fluorophenoxy)benzonitrile: A mixture of
4-fluorophenol (5.1 g, 45.5 mmol), 4-fluorobenzonitrile (4.58 g,
37.8 mmol) and potassium carbonate (12 g, 86.8 mmol) in DMF (150
mL) was refluxed overnight. The reaction was allowed to cool to
room temperature and partitioned between ethyl acetate and water.
The aqueous layer was extracted twice with ethyl acetate. The
combined organic layers were washed three times with water, dried
over sodium sulfate, filtered, and evaporated under reduced
pressure to give 7.5 g (93%) of crude
4-(4-fluorophenoxy)benzonitrile as solid. .sup.1H NMR (CDCl.sub.3):
.delta. 7.60 (d, J=9.0 Hz, 2H), 7.10-6.96 (m, 6H). Ref. Tanaka, A.
et al. (J. Med. Chem. 41:4408-4420 (1998))
[0303] b) 4-(4-Fluorophenoxy)benzamidine acetate:
4-(4-Fluorophenoxy)benzo- nitrile (4.7 g, 22.4 mmol) was dissolved
in ethanol. The solution was cooled to 0.degree. C. and HCl gas was
bubbled through the solution for 20 minutes. The reaction was
stoppered and stirred at room temperature overnight. The solution
was evaporated under reduced pressure and the solid residue that
formed was dissolved in ethanol and treated with solid ammonium
acetate (6.0 g, 75.5 mol). After stirring overnight, pure amidine
was isolated by filtration. Additional product was isolated from
the filtrate. The solid obtained after the filtrate was
concentrated to dryness was triturated with hexane (4 times) and
recrystallized twice from EtOH. The total weight of amidine
obtained was 2.92 g (45% yield). .sup.1H NMR (DMSO-d.sub.6):
.delta. 7.85 (d, J=8.0 Hz, 2H), 7.31 (t, J=8.7 Hz, 2H), 7.21-7.17
(m, 2H), 7.11 (d, J=8.0 Hz 2H), 1.77 (s, 3H).
[0304] c) 2-[4-(4-Fluorophenoxy)phenyl]-4-methylpyrimidine: A 1M
solution of potassium tert-butoxide in THF (11 mL, 11 mmol) was
added via syringe to a solution of 4-(4-fluorophenoxy)benzamidine
acetate (2.92 g, 10.2 mmol) in DMF. The resulting mixture was
heated at 100.degree. C. for 2 hours. Acetylacetaldehyde dimethyl
acetal (2 mL, 13.6 mmol) was added via syringe. The reaction was
maintained between 100-110.degree. C. overnight when TLC indicated
complete reaction. The reaction was allowed to cool to room
temperature and partitioned between water and EtOAc. The aqueous
layer was extracted with EtOAc and the combined organic layers were
washed with water (3 times), dried over MgSO.sub.4, filtered, and
evaporated under reduced pressure to give the desired product as a
yellow oil. .sup.1H NMR (CDCl.sub.3): .delta. 8.60 (d, J=5.1, 1H),
8.40 (d, J=9.0, 2H), 7.05-7.00 (m, 7H), 2.57 (s, 3H). This material
was carried on without further purification.
[0305] d) 2-[4-(4-Fluorophenoxy)phenyl]pyrimidine-4-carboxylic
acid: A mixture of 2-[4-(4-fluorophenoxy)phenyl]-4-methylpyrimidine
(yellow oil from previous step), selenium dioxide (3.0 g, 27 mmol)
and pyridine (30 mL) was refluxed overnight. The reaction was
allowed to cool to room temperature and filtered to remove selenium
metal. The filtrate was evaporated under reduced pressure and the
residue was treated with an aqueous 2N HCl solution. The resulting
solid was triturated with hexane (3.times.) and dried in vacuo,
affording 2.72 g (86%) of the acid. .sup.1H NMR (DMSO-d.sub.6):
.delta.13.8 (bs, 1H), 9.10 (d, J=5.0 Hz, 1H), 8.45 (d, J=9.0 Hz,
2H), 7.86 (d, J=5.0 Hz, 1H), 7.30 (t, J=9.0 Hz, 2H), 7.22-7.17 (m,
2H), 7.11 (d, J=9.0 Hz, 2H).
[0306] e) 2-[4-(4-Fluorophenoxy)phenyl]pyrimidine-4-carboxamide: To
a solution of 2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxylic
acid (2.00 g, 6.45 mmol) in DMF was added carbonyl diimidazole
(2.00 g, 12.3 mmol). After stirring at room temperature for 1 hour,
solid ammonium acetate (5.00 g, 62.9 mmol) was added. After
stirring overnight at room temperature, the reaction was
partitioned between water and EtOAc. The aqueous layer was
extracted with ethyl acetate and the pooled organic layers were
washed with water (3 times), dried (Na.sub.2SO.sub.4), filtered,
and evaporated under reduced pressure to give the crude product as
solid. Column chromatography (silica gel) afforded 1.1 g (55%) of
the desired product as a light tan solid (99.80% pure by HPLC), mp
195-197.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 9.01 (d, J=4.8
Hz, 1H), 8.43 (d, J=8.7 Hz, 2H), 7.95 (d, J 4.8 Hz, 1H), 7.89 (bs,
1H), 7.08-7.04 (m, 6H), 5.72 (bs, 1H).
[0307] The following compound can be prepared similarly:
2-[4-(4-fluorophenoxy)-3-fluorophenyl]pyrimidine-4-carboxamide;
EXAMPLE 13
3,5-Diamino-6-(4-phenoxyphenyl)pyrazine-2-carboxamide
[0308] To a mixture of 4-phenoxyphenylboronic acid (0.22 g, 1.02
mmol), 3,5-diamino-6-chloropyrazine-2-carboxamide (0.176 g, 0.919
mmol), sodium carbonate (0.33 g, 2.06 mmol) in toluene (14 mL),
ethanol (3.5 mL), and water (3.5 mL) was added
tetrakis(triphenylphosphine)palladium (60 mg). The mixture was
refluxed overnight. The reaction was allowed to cool to room
temperature, then partitioned between water and ethyl acetate. The
aqueous layer was extracted one more time with ethyl acetate. The
combined organic layers were washed with water, dried over sodium
sulfate, filtered, and evaporated under reduced pressure to give
the crude product as a solid. Flash chromatography (Silica gel; 6:4
ethyl acetate/dichloromethane to 7:3 ethyl acetate/dichloromethane)
and subsequent recrystalization from chloroform afforded 81 mg
(27%) of the desired product as white solid. .sup.1H NMR
(CDCl.sub.3): .delta. 7.58 (d, J=9.0 Hz, 2H), 7.37 (t, J=7.8 Hz,
2H), 7.38 (bs, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.10-7.05 (m, 4H), 5.26
(bs, 1H), 4.97 (s, 4H).
EXAMPLE 14
6-(4-Phenoxyphenyl)pyrazine-2-carboxamide
[0309] a) 2-Chloro-6-(4-phenoxyphenyl)pyrazine: A mixture of
4-phenoxyphenylboronic acid (0.54 g, 2.52 mmol),
2,6-dichloropyrazine (1.28 g, 7.73 mmol), sodium carbonate (1.15 g,
7.18 mmol), and tetrakis(triphenylphosphine)palladium (0.15 g, 0.13
mmol) in toluene (50 mL), ethanol (12 mL), and water (12 mL) was
heated at reflux overnight. The reaction was allowed to cool to
room temperature, then partitioned between water and ethyl acetate.
The aqueous layer was extracted one more time with ethyl acetate.
The combined organic layers were washed with water, dried over
sodium sulfate, filtered, and evaporated under reduced pressure to
give crude product as a solid. Purification by column
chromatography gave 0.49 g (69%) of
2-chloro-6-(4-phenoxyphenyl)pyrazine as a solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.87 (s, 1H), 8.47 (s, 1H), 7.99 (d, J=9.0
Hz, 2H), 7.38 (t, J=8.1 Hz, 2H), 7.15 (t, J=7.2 Hz, 1H), 7.12-7.06
(m, 4H).
[0310] b) 6-(4-Phenoxyphenyl)pyrazine-2-carboxamide: A mixture of
2-chloro-6-(4-phenoxyphenyl)pyrazine (0.49 g, 1.73 mmol), potassium
cyanide (98%, 0.30 g, 4.51 mmol), and
tetrakis(triphenylphosphine)palladi- um (0.10 g, 0.086 mmol) in DMF
was refluxed overnight. Workup as described as above and column
chromatography gave 35 mg (7%) of
6-(4-phenoxyphenyl)pyrazine-2-carboxamide as a solid. .sup.1H NMR
(CDCl.sub.3): .delta. 9.30 (s, 1H), 9.16 (s, 1H), 8.01 (d, J=8.7
Hz, 2H), 7.75 (bs, 1H), 7.40 (t, J=8.4 Hz, 2H), 7.21-7.08 (m, 5H),
5.84 (bs, 1H).
EXAMPLE 15
2-[4-(4-Nitrophenoxy)phenyl]-4-methyl-[1,3,5]triazine
[0311] a) N-Dimethylaminomethylene-4-(4-nitrophenoxy)benzamide: A
solution of 4-(4-nitrophenoxy)benzonitrile (0.90 g, 3.75 mmol),
potassium hydroxide (2.0 g, 30 mmol) in water (10 mL), a 30%
aqueous hydrogen peroxide solution (4 mL, 39 mmol) and ethanol (50
mL) was refluxed for several hours. The reaction was allowed to
cool to room temperature, then partitioned between water and ethyl
acetate. The separated organic layer was washed several times with
water, dried over MgSO.sub.4, filtered, and evaporated under
reduced pressure to give the amide intermediate as a solid. The
amide and N,N-dimethylformide dimethyl acetal in DMF (20 mL) were
heated to 100-120 0.degree. C. for 2 hours. Once at room
temperature, water was added and 0.93 g (79%) of the amide was
isolated by filtration as a yellow solid. .sup.1H NMR (CDCl.sub.3):
.delta. 8.66 (s, 1H), 8.34 (d, J=8.7 Hz, 2H), 8.22 (d, J=9.0 Hz.
2H), 7.10 (d, J=9.0 Hz, 2H), 7.06 (d, J=9.0 Hz, 2H), 3.23 (s, 3H),
3.22 (s, 3H).
[0312] b) 2-[4-(4-Nitrophenoxy)phenyl]-4-methyl-[1,3,5]triazine: A
mixture of N-dimethylaminomethylene-4-(4-nitrophenoxy)benzamide
(0.93 g, 2.97 mmol), acetamidine hydrochloride (0.32 g, 3.2 mmol)
and potassium tert-butoxide (95%, 0.33 g, 2.79 mmol) in dioxane was
refluxed overnight. The reaction was allowed to cool to room
temperature, then partitioned between water and ethyl acetate. The
aqueous layer was extracted one more time with ethyl acetate. The
combined organic layers were washed twice with water, dried over
sodium sulfate, filtered, and evaporated under reduced pressure to
give the crude product. Purification by column chromatography gave
24 mg (3%) of the title compound as a light yellow solid, mp
148-149.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 9.08 (s, 1H),
8.59 (d, J=8.1 Hz, 2H), 8.25 (d, J=8.1 Hz, 2H), 7.19 (d, J=9.3 Hz,
2H), 7.11 (d, J=8.4 Hz, 2H), 2.74 (s, 3H).
EXAMPLE 16
6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid
N-piperidinylethylamide (3)
[0313] 23
[0314] a) 6-Bromopyridine-2-carboxylic acid N-piperidinylethylamide
(2): To a solution of 6-bromopicolinic acid (5.0 g, 24.8 mmol) (1)
and 1-(2-aminoethyl)-piperidine (3.3 g, 26.0 mmol) in DMF was added
N-hydroxybenzotriazole (HOBt) (3.4 g, 24.8 mmol) and
5-(3,4-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide (DIC) (3.1
g, 24.8 mmol). The reaction was allowed to stir 24 hours at ambient
temperature. The reaction was diluted with dichloromethane, and
water was then added. The phases were separated, and the aqueous
phase was extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulfate. The solution was
filtered and then concentrated to give the product as a pale-yellow
solid. Purification of compound 2 was then carried out by silica
gel chromatography.
[0315] b) 6-[4-(fluorophenoxy)phenyl]pyridine carboxylic acid
N-piperidinylethylamide (3): 4-(4-fluorophenoxy)phenyl boronic acid
(557 mg, 2.4 mmol) was added to a solution of compound 2 (624 mg,
2.0 mmol) in 1,2-dimethoxyethane (DME) (6 mL), followed by water (2
mL) and potassium carbonate (746 mg, 5.4 mmol). Pd(PPh.sub.3).sub.4
(92 mg, 0.08 mmol) was added to this mixture, and the reaction was
heated at 85.degree. C. for 16 hours under an argon atmosphere. The
reaction was allowed to cool to ambient temperature, and the phases
were separated. The aqueous phase was extracted three times with
ethyl acetate, and the combined organic phases were dried over
sodium sulfate. The solution was filtered, concentrated, and then
filtered over a bed of florisil to give crude compound 3.
Purification of compound 3 was then carried out by silica gel
chromatography. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.48
(bs, 2H), 1.61-1.67 (m, 4H), 2.48 (bs, 2H), 2.59 (t, 2H, J=6.3 Hz),
7.05-7.07 (m, 5H), 7.64-7.71 (m, 1H), 7.81-7.91 (m, 5H), 8.80 (bs,
1H).
EXAMPLE 17
6-(4-tert-butylphenyl)pyridine-2-carboxamide (8a)
6-(4-n-butylphenyl)pyridine-2-carboxamide (8b)
6-(4-i-propylphenyl)pyridine-2-carboxamide (8c)
6-(4-thiomethylphenyl)pyridine-2-carboxamide (8d)
6-(4-ethoxyphenyl)pyridine-2-carboxamide (8e)
6-(4-methoxyphenyl)pyridine-2-carboxamide (8f)
[0316] 24
[0317] a) Compound 6: 20% piperidine in DMF was added to
polystyrene-Rink-amide resin having 9-fluorenylmethoxycarbonyl
(FMOC) protective group (PS-rink-NH-FMOC resin) (4) (4.45 g, 4.14
mmol) in a solid-phase reaction vessel, and the reaction was shaken
for 1.5 hours at ambient temperature. The resin was washed (DMF
twice, dichloromethane twice, DMF) and then treated again with 20%
piperidine in DMF. It was shaken for an additional 1 hour, and the
washing sequence was repeated. DMF was added to the resin, followed
by N-hydroxybenzotriazole (HOBt) (3.4 g, 24.8 mmol),
6-bromopicolinic acid (1, 5.0 g, 24.8 mmol), and a solution of
5-(3,4-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide (DIC) (3.1
g, 24.8 mmol) in DMF. The mixture was shaken for 24 hours at
ambient temperature and then drained. The resin was washed (DMF
twice, dichloromethane twice, DMF) and dried. Compound 6 was split
into individual reaction vessels.
[0318] b) Compounds 7a-7f: 1,2-Dimethoxyethane (DME) (2.5 mL) was
added to the individual reaction vessels containing compound 6
(0.25 mmol), followed by the addition of the phenyl boronic acid
(1.5 mmol). To this mixture was added water (1.0 mL), potassium
carbonate (3.8 mmol), and Pd(PPh.sub.3).sub.4 (0.043 mmol). The
reactions were heated at 85.degree. C. for 16 hours. After
returning to ambient temperature, the reactions were drained, and
the resin was washed (1:1 DME-water twice, water, 1:1 DME-water
twice, DME twice, water twice, THF twice, dichloromethane twice) to
yield 7a-7f.
[0319] c) Compounds 8a-8f: Compounds 7a-7f were shaken in the
presence of 1:1 trifluoroacetic acid (TFA)-dichloromethane for 1.5
hours. The reactions were filtered, the resins were washed with
dichloromethane, and the solvent was then evaporated. Purification
of compounds 8a-8f was carried out by first filtering over a bed of
florisil followed by subjection to silica gel chromatography.
[0320] 6-(4-tert-butylphenyl)pyridine-2-carboxamide (8a): .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 1.38 (s, 9H), 5.65 (bs, 1H),
7.55 (d, 2H, J=8.9 Hz), 7.85-7.99 (m, 4H), 8.05 (bs, 1H), 8.15 (d,
1H, J=8.6 Hz).
[0321] 6-(4-n-butylphenyl)pyridine-2-carboxamide (8b): .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 0.95 (t, 3H, J=7.3 Hz), 1.36-1.42
(m, 2H), 1.61-1.69 (m, 2H), 2.69 (t, 2H, J=7.6 Hz), 5.68 (bs, 1H),
7.32 (d, 2H, J=8.4 Hz), 7.86-7.94 (m, 4H), 8.03 (bs, 1H), 8.13 (d,
1H, J=7.3 Hz).
[0322] 6-(4-i-propylphenyl)pyridine-2-carboxamide (8c): .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 1.31 (d, 6H, J=6.9 Hz), 2.95-3.02
(m, 1H), 5.65 (bs, 1H), 7.37 (d, 2H, J=8.2 Hz), 7.86-7.95 (m, 4H),
8.05 (bs, 1H), 8.14 (d, 1H, J=7.3 Hz).
[0323] 6-(4-thiomethylphenyl)pyridine-2-carboxamide (8d): .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 2.56 (s, 3H), 7.38 (d, 2H, J=8.7
Hz), 7.93-8.09 (m, 5H).
[0324] 6-(4-ethoxyphenyl)pyridine-2-carboxamide (8e): .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 1.46 (t, 3H, J=7.0 Hz), 4.11 (q, 2H,
J=6.8 Hz), 7.01 (d, 2H, J=8.9 Hz), 7.82-7.91 (m, 2H), 7.97 (d, 2H,
J=8.9 Hz), 8.01 (bs, 1H), 8.10 (d, 1, J=8.6 Hz H).
[0325] 6-(4-methoxyphenyl)pyridine-2-carboxamide (8f): .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 3.90 (s, 3H), 7.05 (d, 2H, J=8.9
Hz), 7.90-8.05 (m, 5H).
EXAMPLE 18
2-Methyl-4-dimethylamino-6-[4-(4-fluorophenoxy)phenyl]pyridine
(14)
4-Methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide
(18)
4-Methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxylic acid
dimethylaminoethylamide (19)
[0326] 25
[0327] Yields of the above reactions were not optimized. MS spectra
for all compounds were obtained with LCMS. The reactions were
followed by either TLC or/and LCMS or/and .sup.1H NMR.
[0328] a) Compound 10: A solution of 10 g (100 mmol) of
2,4-pentadione (9) and 11.2 g (120 mmol) of aniline in 100 mL
toluene and catalytical amount of p-toluenesulfonic acid
monohydrate was refluxed in a round bottom flask equipped with
azotropic apparatus and condenser for 12 hours. The solution was
concentrated to dryness and the product was used without
purification. .sup.1H NMR (CDCl.sub.3): .delta. 7.35 (t, 2H, J=5.69
Hz), 7.19 (t, 1H, J=6.4 Hz), 7.10 (d, 2H, J=7.5 Hz), 5.19 (s, 1H),
2.10 (s, 3H), 1.99 (s,3H).
[0329] b) 2-Methyl-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinone (12):
31 mL of 1.6 M n-BuLi (50 mmol) was added dropwise to a solution of
7.21 g (51 mmol) of 2,2,6,6-tetrametylpiperidine in 80 mL THF at
-78.degree. C. under inert atomosphere. After the addition, the
reaction mixture was stirred for 30 minutes at the same
temperature. A solution of 3 g (17 mmol) of compound 10 in 10 mL of
THF at -78.degree. C. was added to this solution dropwise. After
the addition, the reaction mixture was stirred for 30 minutes. To
the resulting dark red solution was added dropwise a solution of
2.7 g (17 mmol) of compound 11 in 13 mL of THF at -78.degree. C.
After the addition, the mixture was slowly warmed to -50.degree. C.
and stirred at that temperature for one hour. The reaction mixture
was poured into cold, saturated aqueous solution of NH.sub.4Cl and
extracted twice with ethyl acetate. The organic phase was washed
with saturated brine, dried with magnesium sulfate, and filtrated.
The filtrate was concentrated to dryness.
2-Methyl-6-[4-(4-fluorophenoxy)phenyl]-4-pyridin- one was used
without purification. .sup.1H NMR (CDCl.sub.3): .delta. 7.54 (d,
2H, H=3.8 Hz), 7.31 (m, 2H), 6.90-7.10 (m, 4H), 5.23 (s, 1H), 5.08
(s,1H), 2.03 (s, 3H).
[0330] c) 4-Chloro-2-methyl-6-[4-(4-fluorophenoxy)phenyl]pyridine
(13): To a flask containing 20 mL of POCl.sub.3 at 120.degree. C.
oil bath was carefully added a solution of 5 g (17 mmol) of crude
compound 12 and 2.6 mL of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU)
(17 mmol) in 20 mL of methylene chloride. After the addition, the
reaction mixture was refluxed for one hour. The resulting mixture
was concentrated to dryness and diluted with ethyl acetate (EtOAc).
Saturated aqueous NaHCO.sub.3 was carefully added to the solution
to adjust pH to 5-6. The organic phase was separated and the
aqueous phase was extracted with the same volume of EtOAc. The
combined organic phases were then washed with brine and dried with
magnisium sulfate, filtered and concentrated to dryness. The
residue was purified with flash chromatography (silica gel, 5%
EtOAc/hexane) to get 1.8 g of compound 13 and 850 mg of a mixture
of compound 13 and unreacted compound 11. .sup.1H NMR (CDCl.sub.3):
.delta. 7.93 (d, 2H, J=6.7 Hz), 7.48 (d, 1H, J=1.36 Hz), 7.09 (d,
1H, J=1.5 Hz), 7.00 (m, 6H), 2.59 (s, 3H). MS: 314.1.
[0331] d)
2-Methyl-4-dimethylamino-6-[4-(4-fluorophenoxy)-phenyl]pyridine
(14): 26
[0332] Method 1: A mixture of 800 mg (2.5 mmol) of compound 13 and
101 mg of 60% NaH (2.5 mmol) in 5 ml N,N-dimethyl ethylendiamine
was heated in a sealed tube at 120.degree. C. for six hours. To the
cooled reaction mixture was carefully added methanol to quench NaH.
The resulting mixture was concentrated to dryness, and the residue
was purified by flash chromatography (silica gel, 10%
MeOH/CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to get 100 mg of compound
14.
[0333] Method 2: To a 3-neck round bottom flask at -78.degree. C.,
dimethylamine was condensed and then transferred to a sealed vessel
containing compound 13 at -78.degree. C. The sealed vessel was
slowly warmed to room temperature and stirred for 48 hours to give
a 10% clean conversion. .sup.1H NMR (CDCl.sub.3): .delta. 7.89 (d,
2H, J=6.7 Hz), 7.00 (m, 6H), 6.69 (d, 1H, J=2.3 Hz), 6.35 (d, 1H,
J=2.3 Hz), 3.03 (s, 6H), 2.51 (s, 3H). MS: 323.2.
[0334] e)
2-Methyl-4-methoxy-6-[4-(4-fluorophenoxy)phenyl]pyrimidine (15): A
sealed tube containing 1.8 g (4.8 mmol) of compound 13 in 10 ml of
25 wt-% NaOMe in methanol was heated in 85.degree. C. for four
hours. The cooled reaction mixture was concentrated to dryness and
diluted with ethyl acetate. The mixture was washed with saturated
aqueous NH.sub.4Cl and then brine. The organic phase was dried with
magnisium sulfate, filtered, and concentrated to dryness to give
1.5 g of clean compound 15. .sup.1H NMR (CDCl.sub.3): .delta. 7.92
(d, 2H, J=6.8 Hz), 7.00 (m, 7H), 6.62 (d, 1H, J=2.1 Hz), 3.88 (s,
3H), 2.57 (s, 3H). MS: 310.2.
[0335] f)
4-Methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxylic acid
(16): To a solution of 1.5 g (4.8 mmol) of compound 15 in 36 ml of
pyridine was added 2.1 g of SeO2 (19 mmol) and the resulting
solution was refluxed for 3 days. The cooled reaction mixture was
concentrated to dryness and diluted with methanol, filtered, and
concentrated to give 100% conversion. .sup.1H NMR (CDCl.sub.3):
.delta. 7.92 (d, 2H, J=8.8 Hz), 7.69 (s, 1H), 7.38 (m, 3H), 7.07
(m, 4H), 3.97 (s, 3H). MS: 320.9.
[0336] g)
4-Methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxylic acid
methyl ester (17): To the methanol solution of the crude compound
16 was slowly added 0.701 ml (9.6 mmol) of thionyl chloride
carefully. After the addition, the resulting solution was refluxed
for 12 hours. The cooled reaction mixture was filtered, and
concentrated to dryness. The residue was then filtered through a
plug of silica gel with 10% Et.sub.3N in EtOAc. The filtrate was
concentrated to dryness to yield 1.6 g of clean compound 17.
.sup.1H NMR (CDCl.sub.3): .delta. 7.98 (d, 2H, J=8.7 Hz), 7.61 (d,
1H, J=2.2 Hz), 7.33 (d, 1H, J=2.2 Hz), 7.00 (m, 6H), 4.05 (s, 3H),
4.00 (s, 3H). MS: 354.1.
[0337] h)
4-Methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide (18):
140 mg (0.39 mmol) of compound 17 was added to a solution of 10 ml
of 2M NH.sub.3 in methanol and the resulting solution was stirred
for 12 hours. The mixture was then concentrated to dryness and the
resulting solid was recrystalized in methanol to give 67 mg clean
4-methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide (18).
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.31 (d, 2H, J=8.9 Hz), 8.27
(bs, 1H, N--H), 7.70 (bs, 1H, N--H), 7.61 (d, 1H, J=2.3 Hz), 7.47
(d, 1H, J=2.3 Hz), 7.26 (t, 2H, 8.7 Hz), 7.13 (m, 2H), 7.03 (d, 2H,
J=9.0 Hz), 3.94 (s, 3H). MS: 339.2.
[0338] i)
4-Methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxylic acid
dimethylaminoethylamide (19): Excess of N,N-dimethyl ethylene
diamine was added to the solution of 200 mg (0.56 mmol) of compound
17 in 10 ml methanol, and the resulting solution was stirred at
room temperature for 4 days at which time the conversion was
complete. The reaction mixture was concentrated to dryness. HCl in
Et.sub.2O was added to the residue and the solid was recrystalized
to yield clean compound 19. .sup.1H NMR (CDCl.sub.3): .delta. 8.97
(bs, 1H, N--H), 8.10 (d, 2H, J=8.8 Hz), 7.61 (d, 1H, J=2.2 Hz),
7.32 (d, 1H, J=2.2 Hz), 7.05 (m, 6H), 4.00 (m, 1H), 3.96 (s, 3H),
3.78 (m, 1H), 3.63 (m, 1H), 3.45 (s, 3H), 3.27 (bs, 1H), 2.85 (s,
3H). MS: 410.2.
EXAMPLE 19
4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide as
Anticonvulsant
[0339] The ability of
4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxami- de to block
maximal electroshock-induced seizures (MES) was determined
according to the method above.
[0340] 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide was
administered p.o. to mice 30 minutes before the test procedure. The
compound exhibited protection against MES with an ED.sub.50 (the
dose protecting 50% of animals) of 1.6 mg/kg.
[0341] The following compounds on Table 1 were tested accordingly
after a p.o. administration and also after an i.v. injection. The
compounds were injected i.v. 15 minutes before the test
procedure.
1TABLE 1 Anticonvulsant Evaluation after Oral Administration to
Mice and Intravenous Injection into Mice MES MES p.o. i.v. Compound
name ED.sub.50/mg/kg ED.sub.50/mg/kg
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2- 1.6 0.7 carboxamide
4-[4-(4-fluorophenoxy)phenyl]pyrimidine- -2- 6.1 2.8 carboxylic
acid methylamide 4-[4-(4-trifluoromethylphenoxy)phenyl]- 2.5 0.5
pyrimidine-2-carboxamide 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-
5.7 2.3 pyrimidine-4-carboxamide 4-[4-(2,4-difluorophenoxy)-
phenyl]- 1.4 0.9 pyrimidine-2-carboxamide
4-[4-(nitrophenoxy)phenyl]pyrimidine-2- 10.0 3.1 carboxamide
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2- 5.0 1.5 carboxylic acid
hydroxymethyleneamide 2-[4-(4-fluorophenoxy)phenyl]pyrimidine- -4-
7.5 2.5 carboxamide 6-[4-(4-fluorophenoxy)phenyl]pyridin- e-2- 3.3
1.2 carboxamide 6-(4-phenoxyphenyl)pyridine-2-carbo- xamide 10.5
3.2 2-(4-phenoxyphenyl)-6-(dimethylamino)- 2.10
pyrimidine-4-carboxylic acid dimethylamide 2-[4-(4-chloro-2-fluoro-
phenoxy)phenyl]- 4.10 1.50 pyrimidine-4-carboxylic acid
dimethylamino- methyleneamide
EXAMPLE 20
[0342] Activity of
4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide as Sodium
Channel Blocker
[0343] 4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxamide was
tested in the electrophysiological assay 1 and binding assay as
described above and produced dose-dependent inhibition of
voltage-gated sodium currents recorded in HEK-293 cells stably
expressing the rBIIA isoform of Na.sup.+ channels. The blocking
effect of this compound on Na.sup.+ currents was highly sensitive
to the holding voltage, indicating that
4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxamide binds to
voltage-sensitive Na.sup.+ channels in their inactivated states and
has weak potency towards Na.sup.+ channels in their resting states
(Ragsdale et al., Mol. Pharmacol. 40:756-765 (1991); Kuo and Bean,
Mol. Pharmacol. 46:716-725 (1994)). The apparent antagonist
dissociation constant (K.sub.i) of this compound for inactivated
sodium channels is 0.49 .mu.M.
[0344] The K.sub.i (the concentration of a compound that produces
half maximal inhibition) value for
4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-- carboxamide and other
tested compounds are presented in Table 2.
2TABLE 2 Evaluation of the Tested Compounds as Sodium Channel
Blockers after an Electrophysiological in vitro Assay 1 RBIIA
Compound name K.sub.i/.mu.M
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxamide 0.49
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 13.50
dimethylamide 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic
acid tert- 0.18 butylamide 4-[4-(4-trifluoromethylphenoxy)p-
henyl]- 0.21 pyrimidine-2-carboxamide
2-[4-(4-chloro-2-fluorophenoxy)phenyl]- 0.22
pyrimidine-4-carboxamide 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-
-carboxylic acid 51
4-[4-(2,4-difluorophenoxy)phenyl]-pyrimidine-2-- carboxamide 0.36
2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxam- ide 0.10
6-[4-(4-fluorophenoxy)phenyl]pyridine-2-carboxamide 0.07
2-[4-(4-fluorophenoxy)phenyl]-4-[3-(1,2,4-triazolyl)]pyrimidine
20.00 3,5-diamino-6-(4-phenoxyphenyl)pyrazine-2-carboxamide
2.20
EXAMPLE 21
Activity of 6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid
N-piperidinylethylamide as Sodium Channel Blocker
[0345] 6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid
N-piperidinylethylamide was tested in the electrophysiological
assay 2 as described above. The result of
6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid
N-piperidinylethylamide and other compounds are represented in
Table 3.
3TABLE 3 Evaluation of the Tested Compounds as Sodium Channel
Blockers after an Electrophysiological in vitro Assay 2
RBIIA/.beta.1 Compound name K.sub.i/.mu.M
6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid N- 0.06
piperidinylethylamide (3) 6-(4-tert-butylphenyl)pyridine-2-carbo-
xamide (8a) 6.13 6-(4-n-butylphenyl)pyridine-2-carboxamide (8b)
10.53 6-(4-i-propylphenyl)pyridine-2-carboxamide (8c) 41.61
6-(4-thiomethylphenyl)pyridine-2-carboxamide (8d) 52.73
6-(4-ethoxyphenyl)pyridine-2-carboxamide (8e) 58.72
6-(4-methoxyphenyl)pyridine-2-carboxamide (8f) 23.87
2-methyl-4-dimethylamino-6-[4-(4- 0.33 fluorophenoxy)phenyl]pyridi-
ne (14) 4-methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridine-2- 3.43
carboxamide (18) 4-methoxy-6-[4-(4-fluorophenoxy)phenyl]pyridin-
e-2- 0.32 carboxylic acid dimethylaminoethylamide (19)
2-dimethylamino-4-[4-(4-fluorophenoxy)phenyl]pyrimidine 27.57
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 9.86
ethyl ester 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carbamate
8.70 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 2-
2.62 chloroethylamide 1-[4-[4-(4-fluorophenoxy)phenyl]pyrim-
idine-2-yl]-2,2- 10.63 dibromoethanone
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 11.36
methylaminomethyleneamide hydrochloride 2-[3-(1,2,4-triazolyl)]-4--
[4-(4- 5.91 fluorophenoxy)phenyl]pyrimidine
4-[4-(2,4-difluorophenoxy)phenyl]pyrimidine-2-carboxylic 139 acid
methyl ester 2-[4-(4-fluorophenoxy)phenyl]pyrimidine-4-carboxylic
71.53 acid methyl ester 6-[4-(4-fluorophenoxy)phenyl]pyridi-
ne-2,3-dicarboxamide 4.54
2-methyl-6-[4-(4-fluorophenoxy)phenyl]pyr- idine-3- 8.45
carboxamide 5-cyano-6-(4-phenoxyphenyl)pyridin- e-2-carboxamide
11.9 5-hydroxy-6-(4-phenoxyphenyl)pyridine-2-carbox- amide 99.3
2-(5-isoxazolyl)-4-[4-(4-fluorophenoxy)phenyl]pyrimidine 2.63
4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid 3.53
hydroxymethyleneamide 4-[4-(4-nitrophenoxy)phenyl]pyri-
midine-2-carboxamide 1.13
EXAMPLE 22
Activity of 6-[4-(4-fluorophenoxy)phenyl]pyridine carboxylic acid
N-piperidinylethylamide as Sodium Channel Blocker
[0346] The tactile antiallodynia effect of the compounds listed in
Table 4 was tested in the Chung model of neuropathic pain in rats
as described above and described by Kim and Chung (Pain 50:355-363
(1992)). The tested compounds showed activity in the Chung model.
The results for each tested compound are shown as minimal effective
dose (MED) in Table 4.
4TABLE 4 Evaluation of the Tested Compounds in Chung Model of
Neuropathic Pain in Rats MED Compound name Mg/kg p.o.
2-[4-(4-chloro-2-fluorophenoxy)ph- enyl]- 1.25
pyrimidine-4-carboxamide 2-[4-(4-fluorophenoxy)p-
henyl]pyrimidine-4-carboxamide 2.50
6-[4-(4-fluorophenoxy)phenyl]py- ridine-2-carboxamide 2.50
[0347] Having now fully described this invention, it will be
understood by those of ordinary skill in the art that the same can
be performed within a wide and equivalent range of conditions,
formulations and other parameters without affecting the scope of
the invention or any embodiment thereof.
[0348] Other embodiments of the invention will be apparent to those
skilled in the art from consideration of the specification and
practice of the invention disclosed herein. It is intended that the
specification and examples be considered as exemplary only, with a
true scope and spirit of the invention being indicated by the
following claims.
[0349] All patents and publications cited herein are fully
incorporated by reference herein in their entirety.
* * * * *