U.S. patent application number 10/802765 was filed with the patent office on 2004-09-09 for aryl substituted thiazinidinones and the use thereof.
This patent application is currently assigned to Euro-Celtique S.A.. Invention is credited to Kyle, Donald J., Sun, Qun.
Application Number | 20040176364 10/802765 |
Document ID | / |
Family ID | 23179332 |
Filed Date | 2004-09-09 |
United States Patent
Application |
20040176364 |
Kind Code |
A1 |
Sun, Qun ; et al. |
September 9, 2004 |
Aryl substituted thiazinidinones and the use thereof
Abstract
This invention relates aryl substituted thiazolidinones of
Formula I: 1 or a pharmaceutically acceptable salt, or solvate
thereof, wherein R.sub.1 and R.sub.2, are defined 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: |
Sun, Qun; (Princeton,
NJ) ; Kyle, Donald J.; (Newtown, PA) |
Correspondence
Address: |
STERNE, KESSLER, GOLDSTEIN & FOX PLLC
1100 NEW YORK AVENUE, N.W.
WASHINGTON
DC
20005
US
|
Assignee: |
Euro-Celtique S.A.
122 Boulevard de la Petrusse, L-2330
Luxembourg
LU
|
Family ID: |
23179332 |
Appl. No.: |
10/802765 |
Filed: |
March 18, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10802765 |
Mar 18, 2004 |
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10195530 |
Jul 16, 2002 |
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60305099 |
Jul 16, 2001 |
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Current U.S.
Class: |
514/227.5 ;
514/326; 514/341; 514/369; 544/60; 546/209; 546/269.7; 548/182 |
Current CPC
Class: |
C07D 279/06 20130101;
C07D 417/06 20130101; A61P 25/24 20180101; A61P 21/00 20180101;
C07D 249/08 20130101; C07D 231/12 20130101; A61P 25/00 20180101;
C07D 277/14 20130101; A61P 23/02 20180101; A61P 25/08 20180101;
A61P 25/28 20180101; C07D 233/56 20130101; A61P 9/06 20180101; C07D
417/04 20130101; A61P 25/04 20180101 |
Class at
Publication: |
514/227.5 ;
514/326; 514/341; 514/369; 544/060; 546/209; 546/269.7;
548/182 |
International
Class: |
C07D 417/02; A61K
031/541; A61K 031/454; A61K 031/4439; A61K 031/426 |
Claims
What is claimed is:
1. A compound having the Formula I: 116or a pharmaceutically
acceptable salt, or solvate thereof, wherein: n is an integer from
1 to 2; R.sub.1 is selected from the group consisting of: 117 where
Y is alkylene, and R.sub.3 and R.sub.4 are the same or different
and are selected from hydrogen, alkyl, or aryl, or R.sub.3 and
R.sub.4 together form an alkylene chain having 4 to 5 carbon atoms
optionally interrupted by a nitrogen or oxygen; (ii) pyridylalkyl;
and (iii) piperidin-4-yl, optionally substituted by alkyl, aryl or
aralkyl; and R.sub.2 is selected from the group consisting of: (i)
optionally substituted phenoxyphenyl; (ii) optionally substituted
phenylthiophenyl; (iii) optionally substituted benzyloxyphenyl;
(iv) optionally substituted benzylthiophenyl; 118wherein R.sub.6
and R.sub.7 are independently hydrogen or alkyl; and p and q are
integers from 0 to 4; 119wherein R.sub.8 is hydrogen, halogen or
alkyl; 120wherein R.sub.9 is hydrogen or alkyl; and (viii)
naphthalenyl.
2. The compound according to claim 1, wherein R.sub.1 is 121and Y
is ethylene or propylene.
3. The compound according to claim 1, wherein R.sub.1 is 122where
R.sub.3 and R.sub.4 together form an alkylene chain having 4 to 5
carbon atoms; Y is an optionally substituted C.sub.1-6 alkylene
chain; and R.sub.2 is phenoxyphenyl or benzyloxyphenyl, wherein the
phenoxy moiety is optionally substituted with alkyl, halogen or
haloalkyl.
4. The compound according to claim 3, wherein R.sub.3 and R.sub.4
together form an alkylene chain of 5 carbon atoms; and Y is an
optionally substituted C.sub.2-4 alkylene chain.
5. The compound according to claim 3, wherein R.sub.3 and R.sub.4
together form an alkylene chain of 4 carbon atoms, and Y is an
optionally substituted C.sub.2-4 alkylene chain.
6. The compound according to claim 1, wherein R.sub.1 is 123where
R.sub.3 and R.sub.4 are independently hydrogen, alkyl or
alkylenylaryl, Y is an optionally substituted C.sub.1-4 alkylene
chain; and R.sub.2 is phenoxyphenyl or benzyloxyphenyl, wherein the
phenoxy moiety is optionally substituted with alkyl, halogen or
haloalkyl.
7. The compound according to claim 1, wherein R.sub.1 is
pyridyl(C.sub.1-4)alkyl.
8. The compound according to claim 7, wherein R.sub.2 is
phenoxyphenyl or benzyloxyphenyl, wherein the phenoxy moiety is
optionally substituted with alkyl, halogen or haloalkyl.
9. The compound of claim 8, wherein R.sub.1 is pyridylmethyl,
pyridylethyl or pyridylpropyl.
10. The compound according to claim 1, wherein R.sub.1 is an
optionally substituted piperidin-4-yl.
11. The compound according to claim 10, wherein R.sub.1 is
1-benzylpiperidin-4-yl.
12. The compound according to claim 1, wherein R.sub.2 is 124
13. The compound according to claim 12, wherein R.sub.1 is 125where
R.sub.3 and R.sub.4 together form an alkylene chain having 4 to 5
carbon atoms; Y is an optionally substituted C.sub.1-6 alkylene
chain.
14. The compound according to claim 12, wherein R.sub.1 is 126where
R.sub.3 and R.sub.4 are independently hydrogen, alkyl or
alkylenylaryl, and Y is an optionally substituted C.sub.1-6
alkylene chain.
15. The compound of claims 13 or 14, wherein p=0.
16. The compound according to claim 1, wherein R.sub.2 is 127
17. The compounds according to claim 16, wherein R.sub.1 is
128where R.sub.3 and R.sub.4 together form an alkylene chain having
4 to 5 carbon atoms; Y is an optionally substituted C.sub.1-6
alkylene chain.
18. The compound according to claim 16, wherein R.sub.1 is 129where
R.sub.3 and R.sub.4 are independently hydrogen, alkyl or
alkylenylaryl, and Y is an optionally substituted C.sub.1-6
alkylene chain.
19. The compound according to claim 16, wherein R.sub.8 is
hydrogen.
20. The compound according to claim 1, wherein R.sub.2 is 130
21. The compound according to claim 20, wherein R.sub.1 is 131where
R.sub.3 and R.sub.4 together form an alkylene chain having 4 to 5
carbon atoms; Y is an optionally substituted C.sub.1-6 alkylene
chain.
22. The compound according to claim 20, wherein R.sub.1 is 132where
R.sub.3 and R.sub.4 are independently hydrogen, alkyl or
alkylenylaryl, and Y is an optionally substituted C.sub.1-6
alkylene chain.
23. The compound according to claim 1, wherein R.sub.2 is
naphthalene.
24. The compound according to claim 23, wherein R.sub.1 is 133where
R.sub.3 and R.sub.4 together form an alkylene chain having 4 to 5
carbon atoms; Y is an optionally substituted C.sub.1-6 alkylene
chain.
25. The compound according to claim 23, wherein R.sub.1 is 134where
R.sub.3 and R.sub.4 are independently hydrogen, alkyl or
alkylenylaryl, and Y is an optionally substituted C.sub.1-6
alkylene chain.
26. The compound according to claim 1, wherein said compound is
selected from the group consisting of:
3-(2-piperidinylethyl)-2-(3-phenoxyphenyl) thiazolidin-4-one;
(.+-.)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
(+)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
(-)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(3-(4-tert-butylphenoxy)pheny- l)
thiazolidin-4-one; 3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazinidin-4-one;
3-(2-piperidinylethyl)-2-(2-(4-chlorophenyl)furanyl)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(3-(3,4-dichlorophenoxy)pheny- l)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(3-(3-trifluoromethylphenox- y)phenyl)
thiazolidin-4-one; 3-(2-piperidinylethyl)-2-(3-benzyloxyphenyl)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(3-(4-chlorophenoxy)phenyl)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(3-(3,5-dichlorophenoxy)pheny- l)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(4-(4-fluorophenoxy)phenyl)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(3-(4-methoxyphenoxy)phenyl)
thiazolidin-4-one; 3-(2-piperidinylethyl)-2-(N-ethylcarbozolyl)
thiazolidin-4-one; 3-(2-piperidinylethyl)-2-naphthyl
thiazolidin-4-one; 3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
3-(N,N-dimethylethylamino)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
3-(N,N-dimethylethylamino)-2-(3-(4-tert-butyl)phenoxy)phenyl)
thiazolidin-4-one;
3-(2-pyridinylmethyl)-2-(3-(4-tert-butyl)phenoxy)pheny- l)
thiazolidin-4-one; 3-(
N,N-dimethylethylamino)-2-(2,2-diphenylethenyl) thiazinidin-4-one;
3-(N-benzyl-4-piperidinyl)-2-(3-phenoxyphenyl) thiazolidin-4-one;
3-(3-imidazolylpropyl)-2-(3-benzyloxypheny) thiazolidin-4-one;
3-(2-pyridinylmethyl)-2-(3-(3-trifluoromethylphenoxy)p- henyl)
thiazolidin-4-one;
3-(N,N-dimethylethylamino)-2-(3-(3,5-dichlorophe- noxy)phenyl)
thiazolidin-4-one; 3-(N,N-dimethylpropylamino)-2-(3-(3,5-dich-
lorophenoxy)phenyl) thiazolidin-4-one;
3-(N-benzyl-4-piperidinyl)-2-(4-(4-- fluorophenoxy)phenyl)
thiazolidin-4-one; 3-(2-pyrrolidinylethyl)-2-(3-(3,4-
-dichlorophenoxy)phenyl) thiazolidin-4-one;
3-(2-pyrrolidinylethyl)-2-(3-(- 3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one; 3-(2-pyrrolidinylethyl)-2-(N-ethylcarbozole)
thiazolidin-4-one; 3-(2-pyrrolidinylethyl)-2-(3-benzyloxyphenyl)
thiazolidin-4-one; 3-(N-ethylmorpholinyl)-2-(3-(3
,4-dichlorophenoxy)phenyl) thiazolidin-4-one;
3-(N,N-dimethylethylamino)-2-(3-(3,4-dichlorophenoxy)p- henyl)
thiazolidin-4-one;
3-(N,N-dimethylethylamino)-2-(3-(3-trifluorometh- ylphenoxy)phenyl)
thiazolidin-4-one; 3-(3-imidazolylpropyl)-2-(3-(3-triflu-
oromethylphenoxy)phenyl) thiazolidin-4-one;
3-(N,N-dimethylpropylamino)-2--
(3-(3-tiifluoromethylphenoxy)phenyl) thiazolidin-4-one;
3-(N-ethylbenzylamino)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one;
3-(N,N-diisopropylethylamino)-2-(3-(3-trifluoromethylp-
henoxy)phenyl) thiazolidin-4-one;
3-(N,N-dimethyl-2,2-dimethylpropylamino)-
-2-(3-(3,4-dichlorophenoxy)phenyl) thiazolidin-4-one;
3-(2-methylpiperidinyl-N-propyl)-2-(3-(3,4-dichlorophenoxy)phenyl)
thiazolidin-4-one; 3-(N,N-dimethyl-2,2-dimethylpropyl
amino)-2-(3-(3-trifluoromethylphenoxy)phenyl) thiazolidin-4-one;
and
3-(2-methylpiperidinyl-N-propyl)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one.
27. A pharmaceutical composition, comprising the compound of claim
1, and a pharmaceutically acceptable carrier or diluent.
28. A method of making a compound according to claim 1 wherein said
method comprises reacting: (i) an amine having the Formula
II:R.sub.1--NH.sub.2 IIand (ii) an aldehyde having the Formula
III:R.sub.2--CHO IIIin the presence of a mercapto acid having the
Formula IV: 135wherein R.sub.1, R.sub.2 and n are as defined in
claim 1.
29. The method according to claim 28, wherein the reaction is
conducted in the presence of toluene.
30. The method according to claim 28, wherein the reaction is
conducted in the presence of at least one 4 Angstrom molecular
sieve.
31. The method according to claim 28, wherein the reaction is
conducted at a temperature of from about 50.degree. C. to about
110.degree. C.
32. The method according to claim 28, wherein the reaction is
conducted for about 2 hours to about 24 hours.
33. A method of treating, preventing or ameliorating a disorder
responsive to blockage of sodium channels in a mammal suffering
therefrom, comprising administering to a mammal in need of such
treatment an effective amount of a compound according to claim 1,
or pharmaceutically acceptable salt thereof.
34. The method according to claim 33, wherein said disorder is
selected from the group consisting of: neuronal damage; a
neurodegenerative condition, acute or chronic pain, depression, and
diabetic neuropathy.
35. The method according to claim 33, wherein said neuronal damage
is caused by focal or global ischemia.
36. The method according to claim 33, wherein said
neurodegenerative condition is amyotrophic lateral sclerosis
(ALS).
37. The method according to claim 33 wherein said mammal is a
human, dog or cat.
38. A pharmaceutical composition for treatment of a mammal having a
disorder or condition responsive to blockage of sodium channels,
which comprises an amount of the compound according to claim 1, or
a pharmaceutically effective salt thereof, that is effective for
treating said disorder or condition, and a pharmaceutically
acceptable carrier.
39. The compound according to claim 26, wherein said compound is
selected from the group consisting of:
3-(2-piperidinylethyl)-2-(3-phenoxyphenyl) thiazolidin-4-one;
(.+-.)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
(+)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
(-)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(3-(4-tert-butylphenoxy)pheny- l)
thiazolidin-4- one;
3-(2-piperidinylethyl)-2-(3-(3,4-dichlorophenoxy)ph- enyl)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(3-(3-trifluoromethylphe- noxy)phenyl)
thiazolidin-4-one; 3-(2-piperidinylethyl)-2-(3-benzyloxypheny- l)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(3-(4-chlorophenoxy)phenyl)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(3-(3,5-dichlorophenoxy)pheny- l)
thiazolidin-4-one;
3-(2-piperidinylethyl)-2-(4-(4-fluorophenoxy)phenyl)
thiazolidin-4-one; 3-(N-benzyl-4-piperidinyl)-2-(3-phenoxyphenyl)
thiazolidin-4-one;
3-(N-benzyl-4-piperidinyl)-2-(4-(4-fluorophenoxy)pheny- l)
thiazolidin-4-one;
3-(2-pyrrolidinylethyl)-2-(3-(3-trifluoromethylpheno- xy)phenyl)
thiazolidin-4-one; 3-(N-ethylbenzylamino)-2-(3-(3-trifluorometh-
ylphenoxy)phenyl) thiazolidin-4-one;
3-(N,N-diisopropylethylamino)-2-(3-(3-
-trifluoromethylphenoxy)phenyl) thiazolidin-4-one;
3-(N,N-dimethyl-2,2-dim-
ethylpropylamino)-2-(3-(3,4-dichlorophenoxy)phenyl)
thiazolidin-4-one; and
3-(N,N-dimethyl-2,2-dimethylpropylamino)-2-(3-(3-trifluoromethylphenoxy)p-
henyl) thiazolidin-4-one.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention is in the field of medicinal chemistry. In
particular, the invention relates to novel aryl substituted
thiazolidinones, and the discovery that these compounds are
blockers of sodium (Na+) channels.
[0003] 2. Related Art
[0004] 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.
[0005] 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)).
[0006] 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.
[0007] 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 similarities
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. Tips.
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)).
[0008] 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)).
[0009] A need exist in the art for novel compounds that are potent
blockers of sodium channels, and are therefore useful for treating
a variety of central nervous system conditions, including pain.
SUMMARY OF THE INVENTION
[0010] The present invention is related to the discovery that aryl
substituted thiazolidinones represented by Formula I act as
blockers of sodium (Na.sup.+) channels.
[0011] Another aspect of the present invention is directed to the
use of novel compounds of Formula I as blockers of sodium
channels.
[0012] 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.
[0013] One aspect of the present invention is directed to the novel
aryl substituted thiazolidinones of Formula I.
[0014] 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 anesthetics and anti-arrhythmics,
and treating tinnitus by administering a compound of Formula I to a
mammal in need of such treatment or use.
[0015] 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.
[0016] 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.
[0017] 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
[0018] The present invention arises out of the discovery that aryl
substituted thiazolidinones 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.
[0019] Novel compounds of the present invention are aryl
substituted thiazolidinones represented by Formula I: 2
[0020] or a pharmaceutically acceptable salt, or solvate thereof,
wherein:
[0021] n is an integer from 1 to 2;
[0022] R.sub.1 is selected from the group consisting of: 3
[0023] where Y is alkylene, and
[0024] R.sub.3 and R.sub.4 are the same or different and are
selected from hydrogen, alkyl, or aryl, or R.sub.3 and R.sub.4
together form an alkylene chain having 4 to 5 carbon atoms
optionally interrupted by a nitrogen or oxygen;
[0025] (ii) pyridylalkyl; and
[0026] (iii) piperidin-4-ylalkyl, optionally substituted by alkyl,
aryl or aralkyl; and
[0027] R.sub.2 is selected from the group consisting of:
[0028] (i) optionally substituted phenoxyphenyl;
[0029] (ii) optionally substituted phenoxythiophenyl;
[0030] (iii) optionally substituted benzyloxyphenyl;
[0031] (iv) optionally substituted benzylthiophenyl; 4
[0032] wherein R.sub.6 and R.sub.7 are independently hydrogen,
alkyl, alkoxy, halo or haloalkyl; and p and q are independently
integers from 0 to 4; 5
[0033] wherein R.sub.8 is hydrogen, halogen or alkyl; 6
[0034] wherein R.sub.9 is hydrogen or alkyl; and
[0035] (viii) naphthalenyl.
[0036] Preferred compounds are those of Formula I wherein R.sub.1
is 7
[0037] and Y is ethylene or propylene.
[0038] Preferred compounds are additionally those of Formula I
wherein R.sub.1 is 8
[0039] where R.sub.3 and R.sub.4 together form an alkylene chain
having 4 to 5 carbon atoms;
[0040] Y is an optionally substituted C.sub.1-6 alkylene chain;
and
[0041] R.sub.2 is phenoxyphenyl or benzyloxyphenyl, wherein the
phenoxy moiety is optionally substituted with alkyl, halogen or
haloalkyl.
[0042] Preferred compounds also are those of Formula I wherein
R.sub.1 is pyridyl(C.sub.1-4)alkyl.
[0043] Preferred compounds are those of Formula I wherein R.sub.1
is 9
[0044] where R.sub.3 and R.sub.4 are independently hydrogen, alkyl
or alkenylaryl, Y is an optionally substituted C.sub.1-4 alkylene
chain; and
[0045] R.sub.2 is phenoxyphenyl or benzyloxyphenyl, wherein the
phenoxy moiety is optionally substituted with alkyl, halogen or
haloalkyl.
[0046] Preferred compounds also are those of Formula I wherein
R.sub.1 is 10
[0047] where R.sub.3 and R.sub.4 together form an alkylene chain
having 4 to 5 carbon atoms;
[0048] Y is an optionally substituted C.sub.1-6 alkylene chain;
and
[0049] R.sub.2 is 11
[0050] Preferred compounds also are those of Formula I wherein
R.sub.1 is 12
[0051] where R.sub.3 and R.sub.4 are independently hydrogen, alkyl
or alkylenylaryl, Y is an optionally substituted C.sub.1-4 alkylene
chain; and
[0052] R.sub.2 is 13
[0053] Additionally, preferred compounds also are those of Formula
I wherein R.sub.1 is 14
[0054] where R.sub.3 and R.sub.4 together form an alkylene chain
having 4 to 5 carbon atoms;
[0055] Y is an optionally substituted C.sub.1-6 alkylene chain;
and
[0056] R.sub.2 is 15
[0057] Additionally, preferred compounds also are those of Formula
I wherein R.sub.1 is 16
[0058] where R.sub.3 and R.sub.4 together form an alkylene chain
having 4 to 5 carbon atoms;
[0059] Y is an optionally substituted C.sub.1-6 alkylene chain;
and
[0060] R.sub.2 is 17
[0061] Preferred compounds also are those of Formula I wherein
R.sub.1 is 18
[0062] where R.sub.3 and R.sub.4 together form an alkylene chain
having 4 to 5 carbon atoms;
[0063] Y is an optionally substituted C.sub.1-6 alkylene chain; and
R.sub.2 is naphthalene.
[0064] For purposes of the present invention, the term "alkylene"
has the meaning --(CH.sub.2)m--, where m is an integer of from 1-6,
preferably 2-4. Suitable alkylene chains include but are not
limited to methylene, ethylene, propylene, butylene, pentylene and
hexylene. The alkylene chain may also be optionally
substituted.
[0065] The term "alkyl" means a linear or branched C.sub.1-10
carbon chain, preferably a C.sub.1-6 carbon chain. Suitable alkyl
groups include, but are not limited to, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl, hexyl
and octyl groups.
[0066] The term "optionally substituted alkyl" means replacement of
one or more alkyl hydrogens with aryl or halogen.
[0067] The term "optionally substituted alkylene chain" means
replacement of an alkylene hydrogen with one or more alkyl groups,
aryl groups or halogen atoms. Preferably, "optionally substituted
alkylene chain" will mean replacement with one or more alkyl groups
or halogen atoms, preferably alkyl groups.
[0068] The term "aryl" means a C.sub.6-14 mono- or polycyclic
aromatic ring system. Suitable carbocyclic aryl groups may be
selected from, but are not limited to, phenyl, naphthyl,
phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl
and fluorenyl groups. Particularly preferred carbocyclic aryl
groups are benzene and naphthalene.
[0069] The term "heteroaryl" means 3-7 membered monocyclic, or 7-14
membered polycyclic aromatic ring systems, independently containing
one or more nitrogen, oxygen or sulfur atoms. Suitable heteroaryl
groups may be selected from, but are not limited to, indole,
pyridine, carbazole imidizole furan and the like. Preferred
heteroaryl groups are pyridine, carbazol, furan and imidazole.
[0070] Non-aromatic heterocycles that are suitable for use in the
present invention include, but are not limited to, pyrrolidine,
piperidine and morpholine.
[0071] Exemplary preferred compounds that may be employed in this
method of invention include, without limitation:
[0072]
3-(2-piperidinylethyl)-2-(3-phenoxyphenyl)thiazolidin-4-one;
[0073]
(.+-.)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)thiazolidin-4--
one;
[0074]
(+)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)thiazolidin-4-one-
;
[0075]
(-)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)thiazolidin-4-one-
;
[0076]
3-(2-piperidinylethyl)-2-(3-(4-tert-butylphenoxy)phenyl)thiazolidin-
-4-one;
[0077]
3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)thiazinidin-4-one;
[0078]
3-(2-piperidinylethyl)-2-(2-(4-chlorophenyl)furanyl)thiazolidin-4-o-
ne;
[0079]
3-(2-piperidinylethyl)-2-(3-(3,4-dichlorophenoxy)phenyl)thiazolidin-
-4-one;
[0080]
3-(2-piperidinylethyl)-2-(3-(3-trifluoromethylphenoxy)phenyl)thiazo-
lidin-4-one;
[0081]
3-(2-piperidinylethyl)-2-(3-benzyloxyphenyl)thiazolidin-4-one;
[0082]
3-(2-piperidinylethyl)-2-(3-(4-chlorophenoxy)phenyl)thiazolidin-4-o-
ne;
[0083]
3-(2-piperidinylethyl)-2-(3-(3,5-dichlorophenoxy)phenyl)thiazolidin-
-4-one;
[0084]
3-(2-piperidinylethyl)-2-(4-(4-fluorophenoxy)phenyl)thiazolidin-4-o-
ne;
[0085]
3-(2-piperidinylethyl)-2-(3-(4-methoxyphenoxy)phenyl)thiazolidin-4--
one;
[0086]
3-(2-piperidinylethyl)-2-(N-ethylcarbozolyl)thiazolidin-4-one;
[0087] 3-(2-piperidinylethyl)-2-naphthylthiazolidin-4-one;
[0088]
3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)thiazolidin-4-one;
[0089]
3-(N,N-dimethylethylamino)-2-(2,2-diphenylethenyl)thiazolidin-4-one-
;
[0090]
3-(N,N-dimethylethylamino)-2-(3-(4-tert-butyl)phenoxy)phenyl)
thiazolidin-4-one;
[0091]
3-(2-pyridinylmethyl)-2-(3-(4-tert-butyl)phenoxy)phenyl)thiazolidin-
-4-one;
[0092] 3-(
N,N-dimethylethylamino)-2-(2,2-diphenylethenyl)thiazinidin-4-on-
e;
[0093]
3-(N-benzyl-4-piperidinyl)-2-(3-phenoxyphenyl)thiazolidin-4-one;
[0094]
3-(3-imidazolylpropyl)-2-(3-benzyloxypheny)thiazolidin-4-one;
[0095] 3-(2-pyridinylmethyl)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one;
[0096] 3-(N,N-dimethylethylamino)-2-(3-(3,5-dichlorophenoxy)phenyl)
thiazolidin-4-one;
[0097]
3-(N,N-dimethylpropylamino)-2-(3-(3,5-dichlorophenoxy)phenyl)thiazo-
lidin-4-one;
[0098]
3-(N-benzyl-4-piperidinyl)-2-(4-(4-fluorophenoxy)phenyl)thiazolidin-
-4-one;
[0099]
3-(2-pyrrolidinylethyl)-2-(3-(3,4-dichlorophenoxy)phenyl)thiazolidi-
n-4-one;
[0100]
3-(2-pyrrolidinylethyl)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one;
[0101]
3-(2-pyrrolidinylethyl)-2-(N-ethylcarbozole)thiazolidin-4-one;
[0102]
3-(2-pyrrolidinylethyl)-2-(3-benzyloxyphenyl)thiazolidin-4-one;
[0103] 3-(N-ethylmorpholinyl)-2-(3-(3,4-dichlorophenoxy)phenyl)
thiazolidin-4-one;
[0104] 3-(N,N-dimethylethylamino)-2-(3-(3,4-dichlorophenoxy)phenyl)
thiazolidin-4-one;
[0105]
3-(N,N-dimethylethylamino)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one;
[0106]
3-(3-imidazolylpropyl)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one;
[0107]
3-(N,N-dimethylpropylamino)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one;
[0108]
3-(N-ethylbenzylamino)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one;
[0109]
3-(N,N-diisopropylethylamino)-2-(3-(3-trifluoromethylphenoxy)phenyl-
)thiazolidin-4-one;
[0110]
3-(N,N-dimethyl-2,2-dimethylpropylamino)-2-(3-(3,4-dichlorophenoxy)-
phenyl)thiazolidin-4-one;
[0111] 3-(2-methylpiperidinyl-N-propyl)-2-(3-(3
,4-dichlorophenoxy)phenyl)- thiazolidin-4-one;
[0112]
3-(N,N-dimethyl-2,2-dimethylpropylamino)-2-(3-(3-trifluoromethylphe-
noxy)phenyl)thiazolidin-4-one; and
[0113]
3-(2-methylpiperidinyl-N-propyl)-2-(3-(3-trifluoromethylphenoxy)phe-
nyl)thiazolidin-4-one;
[0114] as well as pharmaceutically acceptable salts thereof.
[0115] Particularly preferred compounds are selected from:
[0116] 3-(2-piperidinylethyl)-2-(3-phenoxyphenyl)
thiazolidin-4-one;
[0117] (.+-.)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
[0118] (+)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
[0119] (-)-3-(2-piperidinylethyl)-2-(2,2-diphenylethenyl)
thiazolidin-4-one;
[0120] 3-(2-piperidinylethyl)-2-(3-(4-tert-butylphenoxy)phenyl)
thiazolidin-4-one;
[0121] 3-(2-piperidinylethyl)-2-(3-(3,4-dichlorophenoxy)phenyl)
thiazolidin-4-one;
[0122]
3-(2-piperidinylethyl)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one;
[0123] 3-(2-piperidinylethyl)-2-(3-benzyloxyphenyl)
thiazolidin-4-one;
[0124] 3-(2-piperidinylethyl)-2-(3-(4-chlorophenoxy)phenyl)
thiazolidin-4-one;
[0125] 3-(2-piperidinylethyl)-2-(3-(3,5-dichlorophenoxy)phenyl)
thiazolidin-4-one;
[0126] 3-(2-piperidinylethyl)-2-(4-(4-fluorophenoxy)phenyl)
thiazolidin-4-one;
[0127] 3-(N-benzyl4-piperidinyl)-2-(3-phenoxyphenyl)
thiazolidin-4-one;
[0128] 3-(N-benzyl4-piperidinyl)-2-(4-(4-fluorophenoxy)phenyl)
thiazolidin-4-one;
[0129]
3-(2-pyrrolidinylethyl)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one;
[0130]
3-(N-ethylbenzylamino)-2-(3-(3-trifluoromethylphenoxy)phenyl)
thiazolidin-4-one;
[0131]
3-(N,N-diisopropylethylamino)-2-(3-(3-trifluoromethylphenoxy)phenyl-
) thiazolidin-4-one;
[0132]
3-(N,N-dimethyl-2,2-dimethylpropylamino)-2-(3-(3,4-dichlorophenoxy)-
phenyl) thiazolidin-4-one; and
[0133]
3-(N,N-dimethyl-2,2-dimethylpropylamino)-2-(3-(3-trifluoromethylphe-
noxy)phenyl) thiazolidin-4-one;
[0134] as well as pharmaceutically acceptable salts thereof.
[0135] The invention disclosed herein is meant to encompass all
pharmaceutically acceptable salts thereof of the disclosed
compounds. The pharmaceutically acceptable salts include, but are
not limited to, metal salts such as sodium salt, potassium salt,
cesium salt and the like; alkaline earth metals such as calcium
salt, magnesium salt and the like; organic amine salts such as
triethylamine salt, pyridine salt, picoline salt, ethanolamine
salt, triethanolamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt and the like; inorganic acid
salts such as hydrochloride, hydrobromide, sulfate, phosphate and
the like; organic acid salts such as formate, acetate,
trifluoroacetate, maleate, tartrate and the like; sulfonates such
as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the
like; amino acid salts such as arginate, asparginate, glutamate and
the like.
[0136] The invention disclosed herein is also meant to encompass
the in vivo metabolic products of the disclosed compounds. Such
products may result for example from the oxidation, reduction,
hydrolysis, amidation, esterification and the like of the
administered compound, primarily due to enzymatic processes.
Accordingly, the invention includes compounds produced by a process
comprising contacting a compound of this invention with a mammal
for a period of time sufficient to yield a metabolic product
thereof. Such products typically are identified by preparing a
radiolabelled compound of the invention, administering it
parenterally in a detectable dose to an animal such as rat, mouse,
guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur and isolating its conversion products from the
urine, blood or other biological samples.
[0137] The invention disclosed herein is also meant to encompass
the disclosed compounds being isotopically-labelled by having one
or more atoms replaced by an atom having a different atomic mass or
mass number.
[0138] Examples of isotopes that can be incorporated into the
disclosed compounds include isotopes of hydrogen, carbon, nitrogen,
oxygen, phosphorous, fluorine and chlorine, such as .sup.2H,
.sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O,
.sup.31P, .sup.32P, .sup.35S, .sup.18F, and .sup.36Cl,
respectively.
[0139] Some of the compounds disclosed herein may contain one or
more asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms. The present
invention is also meant to encompass all such possible forms as
well as their racemic and resolved forms and mixtures thereof. When
the compounds described herein contain olefinic double bonds or
other centers of geometric asymmetry, and unless specified
otherwise, it is intended to include both E and Z geometric
isomers. All tautomers are intended to be encompassed by the
present invention as well.
[0140] As used herein, the term "stereoisomers" is a general term
for all isomers of individual molecules that differ only in the
orientation of their atoms in space. It includes enantiomers and
isomers of compounds with more than one chiral center that are not
mirror images of one another (diastereomers).
[0141] The term "chiral center" refers to a carbon atom to which
four different groups are attached.
[0142] The term "enantiomer" or "enantiomeric" refers to a molecule
that is nonsuperimposeable on its mirror image and hence optically
active wherein the enantiomer rotates the plane of polarized light
in one direction and its mirror image rotates the plane of
polarized light in the opposite direction.
[0143] The term "racemic" refers to a mixture of equal parts of
enantiomers and which is optically inactive.
[0144] The term "resolution" refers to the separation or
concentration or depletion of one of the two enantiomeric forms of
a molecule. The phrase "enantiomeric excess" refers to a mixture
wherein one enantiomer is present is a greater concentration than
its mirror image molecule.
[0145] The invention is also directed to a method for treating
disorders responsive to the blockade of sodium channels in mammals
suffering thereof.
[0146] The thiazolidinone compounds of the invention may be used to
treat humans or companion animals, such as dogs and cats.
Particular preferred embodiments of the thiazolidinones of the
invention for use in treating such disorders are represented as
previously defined for Formula I.
[0147] The thiazolidinones of Formula I may be prepared using
methods known to those skilled in the art. Specifically, the
thiazolidones of the present invention were obtained by reacting
one equivalent of an aldehyde and one equivalent of amine, with one
equivalent of mercapto acid in toluene. The reaction was conducted
at 85.degree. C. for about 12 hours in the presence of 4-Angstrom
molecular sieves. Scheme 1 shows the method of making the
thiazolidinones of the invention, wherein R.sub.1, R.sub.2 and n
are as previously defined. 19
[0148] The resulting compounds were purified by flash column
chromatography.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] The present invention is directed to compounds of Formula I
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. Compounds of the present invention may be tested for their
Na.sup.+ channel blocking activity by the following binding and
electrophysiological assays.
[0153] In Vitro Binding Assay:
[0154] 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 are used
as sources of Na.sup.+ channel proteins. The binding assays are
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.
[0155] In Vivo Pharmacology:
[0156] 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 are 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 are restrained by gripping the loose skin on their
dorsal surface and saline-coated corneal electrodes were held
lightly against the two corneae. Rats are allowed free movement on
the bench top and ear-clip electrodes are used. Current is applied
and animals are observed for a period of up to 30 seconds for the
occurrence of a tonic hindlimb extensor response. A tonic seizure
is defined as a hindlimb extension in excess of 90 degrees from the
plane of the body. Results are treated in a quantal manner.
[0157] 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.) are
used in all experiments. Food is withdrawn on the day of
experiment. Mice are placed in Plexiglass jars for at least 1 hour
to accommodate to the environment. Following the accommodation
period mice are 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 are injected with formalin (20
.mu.L of 5% formaldehyde solution in saline) into the dorsal
surface of the right hind paw. Mice are transferred to the
Plexiglass jars and monitored for the amount of time spent licking
or biting the injected paw. Periods of licking and biting are
recorded in 5 minute intervals for 1 hour after the formalin
injection. All experiments are done in a blinded manner during the
light cycle. The early phase of the formalin response is measured
as licking/biting between 0-5 minutes, and the late phase is
measured from 15-50 minutes. Differences between vehicle and drug
treated groups are analyzed by one-way analysis of variance
(ANOVA). A P value .ltoreq.0.05 is considered significant. Activity
in blocking the acute and second phase of formalin-induced
paw-licking activity is indicative that compounds are considered to
be efficacious for acute and chronic pain.
[0158] 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 are anesthetized
with halothane (1-3% in a mixture of 70% air and 30% oxygen) and
their body temperature is controlled during anesthesia through use
of a homeothermic blanket. A 2-cm dorsal midline incision is then
made at the L5 and L6 level and the para-vertibral muscle groups
retracted bilaterally. L5 and L6 spinal nerves are then be exposed,
isolated, and tightly ligated with 6-0 silk suture. A sham
operation is performed exposing the contralateral L5 and L6 spinal
nerves as a negative control.
[0159] Tactile Allodynia: Rats are 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 are
applied to the plantar surface of the hindpaw to determine the
animal's withdrawal threshold. The first filament used possesses a
buckling weight of 9.1 g (0.96 log value) and is applied up to five
times to see if it elicited a withdrawal response. If the animal
has a withdrawal response then the next lightest filament in the
series is applied up to five times to determine if it can elicit a
response. This procedure is repeated with subsequent less filaments
until there is no response and the lightest filament that elicits a
response is recorded. If the animal does not have a withdrawal
response from the initial 9.1 g filament then subsequent filaments
of increased weight are applied until a filament elicits a response
and this filament is then recorded. For each animal, three
measurements are made at every time point to produce an average
withdrawal threshold determination. Tests are performed prior to
and at 1, 2, 4 and 24 hours post drug administration. Tactile
allodynia and mechanical hyperalgesia tests were conducted
concurrently.
[0160] Mechanical Hyperalgesia: Rats are transferred to an elevated
testing cage with a wire mesh floor and allowed to acclimate for
five to ten minutes. A slightly blunted needle is 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 produces a quick flinching reaction, too
short to be timed with a stopwatch and arbitrarily gives a
withdrawal time of 0.5 second. The operated side paw of neuropathic
animals exhibits an exaggerated withdrawal response to the blunted
needle. A maximum withdrawal time of ten seconds is used as a
cutoff time. Withdrawal times for both paws of the animals are
measured three times at each time point with a five-minute recovery
period between applications. The three measures are used to
generate an average withdrawal time for each time point. Tactile
allodynia and mechanical hyperalgesia tests are conducted
concurrently.
[0161] 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)).
[0162] 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)).
[0163] Electrophysiological Assay:
[0164] An electrophysiological assay was used to measure potencies
of compounds of the present invention rBIIa/beta 1 sodium channels
expressed in Xenopus oocytes.
[0165] Preparation of cRNA encoding cloned rat brain type IIa
(rBIIa) and beta 1 (.beta.1): cDNA clones encoding the rat brain
beta 1 subunit are cloned in house using standard methods, and mRNA
are prepared by standard methods. mRNA encoding rBIIa is provided
by Dr. A. Golden (UC Irvine). The mRNAs are diluted and stored at
-80.degree. C. in 1 .mu.L aliquots until injection.
[0166] Preparation of oocytes: Mature female Xenopus laevis are
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)).
[0167] Two to six ovarian lobes are surgically removed. Oocytes at
developmental stages V-VI are dissected from the ovary, wherein the
oocytes are still surrounded by enveloping ovarian tissues. Oocytes
are 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 are 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.
[0168] Micro-injection of oocytes: Defolliculated oocytes are
micro-injected using a Nanoject injection system (Drummond
Scientific Co., Broomall, Pa.). Injection pipettes are beveled to
minimize clogging. Tip diameter of injection pipettes is 15-35
.mu.m. Oocytes are microinjected with approximately 50 nL 1:10
ratio mixtures of cRNAs for rBIIa and beta 1 respectively.
[0169] Electrophysiology: Membrane current responses are 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 are made
using a conventional two-electrode voltage clamp (Dagan TEV-200)
over periods ranging between 1-7 days following injection. The
recording chamber is a simple gravity fed flow-through chamber
(volume 100-500 mL depending on adjustment of aspirator). Oocytes
are 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 are applied by bath perfusion.
[0170] Voltage protocols for evoking sodium channel currents: The
standard holding potential for whole oocyte clamp is -120 mV.
Standard current-voltage relationships are elicited by 40 ms
depolarizing steps starting from -60 mV to +50 mV in 10 mV
increments. Peak currents are measured as the maximum negative
current after depolarizing voltage steps. The voltage from maximum
current response is noted and used for the next voltage
protocol.
[0171] The purpose is 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 is used to measure a compounds affinity for the
inactivated state. Oocytes are held at a holding potential of -120
mV. At this membrane voltage, nearly all of the channels are in the
closed state. Then a 4 second depolarization is made to the voltage
where the maximum current is elicited. At the end of this
depolarization, nearly all the channels are in the inactivated
state. A 10 ms hyperpolarizing step is then made in order to remove
some channels from the inactivated state. A final depolarizing test
pulse is used to assay the sodium current after this prolonged
depolarization (see analysis below). Sodium currents are measured
at this test pulse before and after the application of the tested
compound. Data is acquired using PCLMP 8.0 software and analyzed
with CLAMPFIT software (Axon instruments).
[0172] Data analysis: Apparent inhibition constants (K.sub.i
values) for antagonists are 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
[0173] 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.
[0174] Drugs: Drugs are initially made up at concentrations of 2-10
mM in DMSO. Dilutions are 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 are made by 1000-3000
fold dilution of stocks into Ringer. At these dilutions DMSO alone
has little or no measurable effects on membrane current responses.
DMSO stocks of drugs are stored in the dark at 4.degree. C. Ringer
solutions of drugs are made up fresh each day of use.
[0175] 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 chronic pain. For intramuscular injection, the dose
is generally about one-half of the oral dose.
[0176] 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.
[0177] 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.
[0178] 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.
[0179] 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 thiazolidinones 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
thiazolidinone 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.
[0180] 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.
[0181] 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.
[0182] The pharmaceutical preparations of the present invention are
manufactured in a manner that is itself known, for example, by
means of conventional nixing, 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.
[0183] 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,
poly-ethylene 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.
[0184] 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.
[0185] 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.
[0186] 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.
[0187] 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.
[0188] The Ki values for compounds of the present invention are
provided in Table 1 below.
Inhibition Constants (Ki) for Preferred Thiazolidin-4-one
Compounds
[0189]
1 20 Ki (oocyte) NM R.sub.1 R.sub.2 n 430 21 22 1 290 23 24 1 180
25 26 1 3580 27 28 2 600 29 30 1 180 31 32 1 90 33 34 1 390 35 36 1
390 37 38 1 130 39 40 1 500 41 42 1 800 43 44 1 1120 45 46 1 330 47
48 1 760 49 50 1 11930 51 52 1 5350 53 54 1 8790 55 56 1 27310 57
58 1 18690 59 60 1 2830 61 62 1 70690 63 --CH.sub.3 1 3480 64 65 1
2600 66 67 1 840 68 69 1 1220 70 71 1 20030 72 73 2 250 74 75 1
6550 76 77 1 3400 78 79 1 840 80 81 1 1880 82 83 1 280 84 85 1 900
86 87 1 420 88 89 1 7400 90 91 1 3430 92 93 1 810 94 95 1 720 96 97
1 710 98 99 1 1150 100 101 1 2750 102 103 1 50 104 105 1 30 106 107
1 390 108 109 1 880 110 111 1 230 112 113 1 1320 114 115 1
[0190] 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.
[0191] 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.
[0192] All patents and publications cited herein are fully
incorporated by reference herein in their entirety.
* * * * *