U.S. patent application number 13/953213 was filed with the patent office on 2013-11-28 for new uses for amino acid anticonvulsants.
This patent application is currently assigned to RESEARCH CORPORATION TECHNOLOGIES, INC.. The applicant listed for this patent is Robert H. Harris. Invention is credited to Robert H. Harris.
Application Number | 20130316953 13/953213 |
Document ID | / |
Family ID | 22856332 |
Filed Date | 2013-11-28 |
United States Patent
Application |
20130316953 |
Kind Code |
A1 |
Harris; Robert H. |
November 28, 2013 |
NEW USES FOR AMINO ACID ANTICONVULSANTS
Abstract
The present invention is directed to the use of compounds of the
formula: ##STR00001## for treating pain, in particular neuropathic
pain, bipolar disease and migraine headaches.
Inventors: |
Harris; Robert H.; (Holmdel,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Harris; Robert H. |
Holmdel |
NJ |
US |
|
|
Assignee: |
RESEARCH CORPORATION TECHNOLOGIES,
INC.
Tucson
AZ
|
Family ID: |
22856332 |
Appl. No.: |
13/953213 |
Filed: |
July 29, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12829160 |
Jul 1, 2010 |
8519183 |
|
|
13953213 |
|
|
|
|
11651845 |
Jan 10, 2007 |
7772427 |
|
|
12829160 |
|
|
|
|
10688709 |
Oct 17, 2003 |
7186859 |
|
|
11651845 |
|
|
|
|
09938677 |
Aug 24, 2001 |
6884910 |
|
|
10688709 |
|
|
|
|
60228230 |
Aug 25, 2000 |
|
|
|
Current U.S.
Class: |
514/17.3 ;
514/17.6; 514/17.7; 514/18.3 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 38/04 20130101; A61P 25/18 20180101; A61K 31/16 20130101; A61K
31/165 20130101; A61K 31/195 20130101; A61K 31/40 20130101; A61P
29/00 20180101; A61K 31/44 20130101; A61K 38/05 20130101; A61P
25/14 20180101; A61P 25/04 20180101; A61P 25/28 20180101; A61P
43/00 20180101; A61P 25/06 20180101 |
Class at
Publication: |
514/17.3 ;
514/18.3; 514/17.7; 514/17.6 |
International
Class: |
A61K 38/05 20060101
A61K038/05 |
Claims
1. A method for alleviating pain in a patient suffering from
chronic pain comprising administering to said patient an analgesic
effective amount of a compound of the formula: ##STR00028## wherein
R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,
aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower
alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl,
and R is unsubstituted or is substituted with at least one electron
withdrawing group or electron donating group; R.sub.1 is hydrogen
or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl,
aryl, heterocyclic lower alkyl, heterocyclic, lower alkyl
heterocyclic, lower cycloalkyl, lower, cycloalkyl lower alkyl, each
unsubstituted or substituted with an electron donating group or an
electron withdrawing group; and R.sub.2 and R.sub.3 are
independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl,
aryl lower alkyl, halo, heterocyclic, heterocyclic lower alkyl,
lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower
alkyl, or Z--Y wherein R.sub.2 and R.sub.3 may be unsubstituted or
substituted with at least one electron withdrawing group or
electron donating group wherein the electron donating group or
electron withdrawing group is acyclic; and wherein heterocyclic in
R.sub.2 and R.sub.3 is furyl, thienyl, pyrazolyl, pyrrolyl,
imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl,
piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl,
tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl,
benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl,
indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl,
pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl,
pyrimidinyl, pyrazinyl, epoxy, aziridino, oxetanyl or azetidinyl; Z
is O, S, S(O).sub.a, NR.sub.6', or PR.sub.4; Y is hydrogen, lower
alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl,
heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted
or substituted with an electron donating group or an electron
withdrawing group, or ZY taken together is NR.sub.4NR.sub.5R.sub.7,
NR.sub.4OR.sub.5, ONR.sub.4R.sub.7, OPR.sub.4R.sub.5,
PR.sub.4OR.sub.5, SNR.sub.4R.sub.7, NR.sub.4SR.sub.7,
SPR.sub.4R.sub.5, PR.sub.4SR.sub.7, NR.sub.4PR.sub.5R.sub.6 or
PR.sub.4NR.sub.5R.sub.7, ##STR00029## R.sub.6' is hydrogen, lower
alkyl, lower alkenyl, or lower alkynyl and R.sub.4 may be
unsubstituted or substituted with an electron withdrawing group or
electron donating group; R.sub.4, R.sub.5 and R.sub.6 are
independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower
alkenyl, or lower alkynyl, wherein R.sub.4, R.sub.5 and R.sub.6 may
be unsubstituted or substituted with an electron withdrawing group
or an electron donating group; and R.sub.7 is COOR.sub.8,
COR.sub.8, hydrogen, lower alkyl, aryl, aryl lower alkyl, lower
alkenyl or lower alkynyl, which R.sub.7 may be unsubstituted or
substituted with an electron withdrawing group or electron donating
group; R.sub.8 is hydrogen or lower alkyl, or aryl lower alkyl, and
the aryl or alkyl group may be unsubstituted or substituted with an
electron withdrawing group or an electron donating group; and n is
1-4; and a is 1-3.
2. The method according to claim 1 wherein one of R.sub.2 and
R.sub.3 is hydrogen.
3. The method according to claim 1 wherein n is 1.
4. The method according to claim 1 wherein one of R.sub.2 and
R.sub.3 is hydrogen and n is 1.
5. The method according to claim 1 wherein R is aryl lower alkyl
and R.sub.1 is lower alkyl.
6. The method according to claim 1 wherein R.sub.2 and R.sub.3 are
independently hydrogen, lower alkyl, heterocyclic, heterocyclic
loweralkyl, or ZY; Z is O, NR.sub.4 or PR.sub.4; Y is hydrogen or
lower alkyl; or ZY is NR.sub.5R.sub.6R.sub.7, NR.sub.5OR.sub.6,
ONR.sub.5R.sub.7, ##STR00030##
7. The method according to claim 6 wherein R.sub.2 is hydrogen and
R.sub.3 is hydrogen, lower alkyl, heterocyclic, heterocyclic
loweralkyl or ZY; Z is O, NR.sub.4 or PR.sub.4; Y is hydrogen,
lower alkyl; or ZY is NR.sub.5NR.sub.6R.sub.7, NR.sub.5OR.sub.6,
ONR.sub.5R.sub.7, ##STR00031##
8. The method according to claim 6 wherein R.sub.2 is hydrogen and
R.sub.3 is lower alkyl, which may be unsubstituted or substituted
with an electron donating or electron withdrawing group,
NR.sub.4OR.sub.5, or ONR.sub.4R.sub.7.
9. The method according to claim 8 wherein R.sub.3 is lower alkyl
which is unsubstituted or substituted with hydroxy or loweralkoxy,
NR.sub.4OR.sub.6 or ONR.sub.4R.sub.7, wherein R.sub.4, R.sub.5 and
R.sub.7 are independently hydrogen or lower alkyl, R is aryl
loweralkyl, which aryl group may be unsubstituted or substituted
with an electron withdrawing group and R.sub.1 is lower alkyl.
10. The method according to claim 9 wherein aryl is phenyl.
11. The method according to claim 6 wherein one of R.sub.2 and
R.sub.3 is heterocyclic.
12. The method according to claim 11 wherein heterocyclic is
heteroaromatic.
13. The method according to claim 11 wherein R.sub.3 is furyl,
pyridyl, thienyl or thiazolyl.
14. The method according to claim 9 wherein aryl is phenyl and is
unsubstituted or substituted with halo.
15. The method according to claim 1 wherein the compound is
(R)--N-Benzyl-2-acetamide-3-methoxy-propionamide;
O-methyl-N-acetyl-D-serine-m-fluorobenzylamide;
O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;
N-acetyl-D-phenylglycinebenzylamide;
D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid
benzylamide; D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid
benzylamide.
16. The method according to claim 1 wherein the pain is neuropathic
pain.
17. The method according to claim 6 wherein the pain is neuropathic
pain.
18. The method according to claim 1 wherein the pain is nociceptive
pain.
19. The method according to claim 6 wherein the pain is nociceptive
pain.
20. A method for the prophylaxis or treatment of migraine headaches
in a subject, comprising administering to said patient a headache
relieving effective amount of a compound of the formula:
##STR00032## wherein R is hydrogen, lower alkyl, lower alkenyl,
lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic
lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower
cycloalkyl lower alkyl, and R is unsubstituted or is substituted
with at least one electron withdrawing group or electron donating
group; R.sub.1 is hydrogen or lower alkyl, lower alkenyl, lower
alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl,
heterocyclic, lower alkyl heterocyclic, lower cycloalkyl, lower
cycloalkyl lower alkyl, each unsubstituted or substituted with an
electron donating group or an electron withdrawing group; and
R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic,
heterocyclic lower alkyl, lower alkyl heterocyclic, lower alkyl
heterocyclic lower cycloalkyl, lower cycloalkyl lower alkyl, or
Z--Y wherein R.sub.2 and R.sub.3 may be unsubstituted or
substituted with at least one electron withdrawing group or
electron donating group; Z is O, S, S(O).sub.a, NR.sub.4, or
PR.sub.4; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower
alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, and
Y may be unsubstituted or substituted with an electron donating
group or an electron withdrawing group, or ZY taken together is
NR.sub.4NR.sub.5R.sub.7, NR.sub.4OR.sub.5, ONR.sub.4R.sub.7,
OPR.sub.4R.sub.5, PR.sub.4OR.sub.5, SNR.sub.4R.sub.7,
NR.sub.4SR.sub.7, SPR.sub.4R.sub.5 or PR.sub.4SR.sub.7,
NR.sub.4PR.sub.5R.sub.6 or PR.sub.4NR.sub.5R.sub.7, ##STR00033##
R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen, lower
alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl,
wherein R.sub.4, R.sub.5 and R.sub.6 may be unsubstituted or
substituted with an electron withdrawing group or an electron
donating group; and R, is COOR.sub.8 or COR.sub.8, hydrogen, lower
alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl,
which R.sub.7 may be unsubstituted or substituted with an electron
withdrawing group or electron donating group; R.sub.8 is hydrogen
or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group
may be unsubstituted or substituted with an electron withdrawing
group or an electron donating group; and n is 1-4; a is 1-3;
wherein heterocyclic contains from 3 up to 18 ring atoms and up to
a total of 17 ring carbon atoms containing 1 to 4 hetero ring atoms
selected from the group consisting of nitrogen, oxygen and
sulfur.
21. The method according to claim 20 wherein one of R.sub.2 and
R.sub.3 is hydrogen.
22. The method according to claim 20 wherein n is 1.
23. The method according to claim 20 wherein one of R.sub.2 and
R.sub.3 is hydrogen and n is 1.
24. The method according to claim 20 wherein R is aryl lower alkyl
and R.sub.1 is lower alkyl.
25. The method according to claim 20 wherein R.sub.2 and R.sub.3
are independently hydrogen, lower alkyl, aryl, aryllower alkyl,
heterocyclic, heterocyclic loweralkyl or ZY; Z is O, NR.sub.4 or
PR.sub.4; Y is hydrogen, lower alkyl, aryl, aryl loweralkyl,
heterocyclic or heterocyclic lower alkyl; or ZY taken together is
NR.sub.4NR.sub.5R.sub.7, NR.sub.4OR.sub.5, ONR.sub.4R.sub.7,
##STR00034## and R.sub.4, R.sub.5 and R.sub.7 are independently
hydrogen, lower alkyl, aryl or aryl lower alkyl.
26. The method according to claim 25 wherein R.sub.2 is hydrogen
and R.sub.3 is lower alkyl, aryl, aryllower alkyl, heterocyclic or
heterocyclic lower alkyl, or ZY; Z is O, NR.sub.4 or PR.sub.4; Y is
hydrogen, lower alkyl, aryl, aryl loweralkyl, heterocyclic or
heterocyclic lower alkyl; or ZY taken together is
NR.sub.4R.sub.5R.sub.7, NR.sub.4OR.sub.5, ONR.sub.4R.sub.7,
##STR00035## and R.sub.4, R.sub.5 and R.sub.7 are independently
hydrogen, lower alkyl, aryl or aryl lower alkyl.
27. The method according to claim 26 wherein R.sub.2 is hydrogen
and R.sub.3 is lower alkyl, which may be unsubstituted or
substituted with an electron donating or electron withdrawing
group, NR.sub.5OR.sub.6, or ONR.sub.5R.sub.7.
28. The method according to claim 26 wherein R.sub.3 is lower alkyl
which is unsubstituted or substituted with hydroxy or loweralkoxy,
NR.sub.4OR.sub.5 or ONR.sub.4R.sub.7, wherein R.sub.4, R.sub.5 and
R.sub.7 are independently hydrogen or lower alkyl, R is aryl
loweralkyl, which aryl group may be unsubstituted or substituted
with an electron withdrawing group and R.sub.1 is lower alkyl.
29. The method according to claim 26 wherein R.sub.3 is
heterocyclic.
30. The method according to claim 29 wherein heterocyclic is
heteroaromatic.
31. The method according to claim 30 wherein R.sub.3 is furyl,
pyridyl, thienyl or thiazolyl.
32. The method according to claim 28 wherein aryl is phenyl.
33. The method according to claim 28 wherein aryl is phenyl and is
unsubstituted or substituted with halo.
34. The method according to claim 20 wherein the compound is
(R)--N-Benzyl-2-acetamide-3-methoxy-propionamide;
O-methyl-N-acetyl-D-serine-m-fluorobenzylamide;
O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;
N-acetyl-D-phenylglycinebenzylamide;
D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid
benzylamide; or D-1,2-(O-methylhydroxylamino)-2-acetamido acetic
acid benzylamide.
35. A method of treating a patient suffering from bipolar disease
comprising administering thereto a therapeutically effective amount
of a compound for treating bipolar disease, said compound having
the formula: ##STR00036## wherein R is hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic,
heterocyclic lower alkyl, lower alkyl heterocyclic, lower
cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or
is substituted with at least one electron withdrawing group or
electron donating group; R.sub.1 is hydrogen or lower alkyl, lower
alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower
alkyl, heterocyclic, lower alkyl heterocyclic, lower cycloalkyl,
lower cycloalkyl lower alkyl, each unsubstituted or substituted
with an electron donating group or an electron withdrawing group;
and R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo,
heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic,
lower cycloalkyl, lower cycloalkyl lower alkyl, or Z--Y wherein
R.sub.2 and R.sub.3 may be unsubstituted or substituted with at
least one electron withdrawing group or electron donating group; Z
is O, S, S(O).sub.a, NR.sub.4, or PR.sub.4; Y is hydrogen, lower
alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl,
heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted
or substituted with an electron donating group or an electron
withdrawing group, or ZY taken together is NR.sub.4NR.sub.5R.sub.7,
NR.sub.4OR.sub.5, ONR.sub.4R.sub.7, OPR.sub.4R.sub.5,
PR.sub.4OR.sub.5, SNR.sub.4R.sub.7, NR.sub.4SR.sub.7,
SPR.sub.4R.sub.5 or PR.sub.4SR.sub.7, NR.sub.4PR.sub.5R.sub.6 or
PR.sub.4NR.sub.5R.sub.7, ##STR00037## R.sub.4, R.sub.5 and R.sub.6
are independently hydrogen, lower alkyl, aryl, aryl lower alkyl,
lower alkenyl, or lower alkynyl, wherein R.sub.4, R.sub.5 and
R.sub.6 may be unsubstituted or substituted with an electron
withdrawing group or an electron donating group; and R.sub.7 is
COOR.sub.8, COR.sub.8, hydrogen, lower alkyl, aryl, aryl lower
alkyl, lower alkenyl or lower alkynyl wherein R.sub.7 may be
unsubstituted or substituted with an electron withdrawing group or
electron donating group; R.sub.8 is hydrogen or lower alkyl, or
aryl lower alkyl, and the aryl or alkyl group may be unsubstituted
or substituted with an electron withdrawing group or an electron
donating group; and n is 1-4; and a is 1-3.
36. The method according to claim 35 wherein one of R.sub.2 and
R.sub.3 is hydrogen.
37. The method according to claim 35 wherein n is 1.
38. The method according to claim 35 wherein one of R.sub.2 and
R.sub.3 is hydrogen and n is 1.
39. The method according to claim 35 wherein R is aryl lower alkyl
and R.sub.1 is lower alkyl.
40. The method according to claim 35 wherein R.sub.2 and R.sub.3
are independently lower alkyl, aryl, aryllower alkyl, heterocyclic,
heterocyclic lower alkyl, or ZY; Z is O, NR.sub.4 or PR.sub.4; Y is
hydrogen, lower alkyl, aryl, aryl loweralkyl, heterocyclic or
heterocyclic lower alkyl; or ZY taken together is
NR.sub.4NR.sub.5R.sub.7, NR.sub.4OR.sub.5, ONR.sub.4R.sub.7,
##STR00038## and R.sub.4, R.sub.5 and R.sub.7 are independently
hydrogen, lower alkyl, aryl or aryl lower alkyl.
41. The method according to claim 40 wherein R.sub.2 is hydrogen
and R.sub.3 is lower alkyl, aryl, aryllower alkyl, heterocyclic,
heterocyclic lower alkyl or ZY; Z is O, NR.sub.4 or PR.sub.4; Y is
hydrogen, lower alkyl, aryl, aryl loweralkyl, heterocyclic or
heterocyclic lower alkyl; or ZY taken together is
NR.sub.4NR.sub.5R.sub.7, NR.sub.4OR.sub.5, ONR.sub.4R.sub.7,
##STR00039## and R.sub.4, R.sub.5 and R.sub.7 are independently
hydrogen, lower alkyl, aryl or aryl lower alkyl.
42. The method according to claim 41 wherein R.sub.2 is hydrogen
and R.sub.3 is lower alkyl, which may be unsubstituted or
substituted with an electron donating or electron withdrawing
group, NR.sub.4OR.sub.5, or ONR.sub.4R.sub.7.
43. The method according to claim 41 wherein R.sub.3 is lower alkyl
which is unsubstituted or substituted with hydroxy or loweralkoxy,
NR.sub.4OR.sub.5 or ONR.sub.4R.sub.7, wherein R.sub.4, R.sub.5 and
R.sub.7 are independently hydrogen or lower alkyl, R is aryl
loweralkyl, which aryl group may be unsubstituted or substituted
with an electron withdrawing group and R.sub.1 is lower alkyl.
44. The method according to claim 41 wherein R.sub.3 is
heterocyclic.
45. The method according to claim 44 wherein heterocyclic is
heteroaromatic.
46. The method according to claim 45 wherein R.sub.3 is furyl,
pyridyl, thienyl or thiazolyl.
47. The method according to claim 43 wherein aryl is phenyl.
48. The method according to claim 43 wherein aryl is phenyl and is
unsubstituted or substituted with halo.
49. The method according to claim 35 wherein the compound is
(R)--N-Benzyl-2-acetamide-3-methoxy-propionamide;
O-methyl-N-acetyl-D-serine-m-fluorobenzylamide;
O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;
N-acetyl-D-phenylglycinebenzylamide;
D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid
benzylamide; D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid
benzylamide.
50. A method for treating a disorder in a mammal resulting from
abnormal activity at the glycine.sub.b site of the NMDA receptor in
neurons of said mammal comprising administering to said mammal a
therapeutically effective amount of a compound to interact with the
glycine.sub.b site of the NMDA receptor, said compound having the
formula: ##STR00040## wherein R is hydrogen, lower alkyl, lower
alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic,
heterocyclic lower alkyl, lower alkyl heterocyclic, lower
cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or
is substituted with at least one electron withdrawing group or
electron donating group; R.sub.1 is hydrogen or lower alkyl, lower
alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower
alkyl, heterocyclic, lower alkyl heterocyclic, lower cycloalkyl,
lower cycloalkyl lower alkyl, each unsubstituted or substituted
with an electron donating group or an electron withdrawing group;
and R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo,
heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic,
lower cycloalkyl, lower cycloalkyl lower alkyl, or Z--Y wherein
R.sub.2 and R.sub.3 may be unsubstituted or substituted with at
least one electron withdrawing group or electron donating group; Z
is O, S, S(O).sub.a, NR.sub.4, or PR.sub.4; Y is hydrogen, lower
alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl,
heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted
or substituted with an electron donating group or an electron
withdrawing group, or ZY taken together is NR.sub.4NR.sub.5R.sub.7,
NR.sub.4OR.sub.5, ONR.sub.4R.sub.7, OPR.sub.4R.sub.5,
PR.sub.4OR.sub.5, SNR.sub.4R.sub.7, NR.sub.4SR.sub.7,
SPR.sub.4R.sub.5 or PR.sub.4SR.sub.7, NR.sub.4PR.sub.5R.sub.6 or
PR.sub.4NR.sub.5R.sub.7, ##STR00041## R.sub.4, R.sub.5 and R.sub.6
are independently hydrogen, lower alkyl, aryl, aryl lower alkyl,
lower alkenyl, or lower alkynyl, wherein R.sub.4, R.sub.5 and
R.sub.6 may be unsubstituted or substituted with an electron
withdrawing group or an electron donating group; and R.sub.7 is
COOR.sub.8 or COR.sub.8, hydrogen, lower alkyl, aryl, aryl lower
alkyl, lower alkenyl or lower alkynyl, which R.sub.7 may be
unsubstituted or substituted with an electron withdrawing group or
electron donating group; R.sub.8 is hydrogen or lower alkyl, or
aryl lower alkyl, and the aryl or alkyl group may be unsubstituted
or substituted with an electron withdrawing group or an electron
donating group; and n is 1-4; and a is 1-3.
51. The method according to claim 1 wherein the electron
withdrawing group and electron donating group are selected from the
group consisting of halo, nitro, carboxy, lower alkenyl, lower
alkynyl, formyl, carboxyamido, trifluoromethyl, lower alkoxy
carbonyl, hydroxy, lower alkoxy, lower alkyl, amino, lower
alkylamino, diloweralkylamino, mercapto, loweralkylthio, and lower
alkyldithio.
52. The method according to claim 20 wherein the electron
withdrawing group and electron donating group are selected from the
group consisting of halo, nitro, carboxy, loweralkoxy carbonyl,
lower alkenyl, lower alkynyl, formyl, aryl, arylloweralkanoyl,
carboxyamido, hydroxy, loweralkoxy, lower alkyl, amino, lower
alkylamino, diloweralkylamino, aryl, aryl lower alkanoyl,
trifluoromethyl, aryloxy, lower alkylthio, mercapto, and lower
alkyldithio.
53. The method according to claim 35 wherein the electron
withdrawing group and electron donating group are selected from the
group consisting of halo, nitro, carboxy, loweralkoxy carbonyl,
lower alkenyl, lower alkynyl, formyl, aryl, arylloweralkanoyl,
carboxyamido, hydroxy, loweralkoxy, lower alkyl, amino, lower
alkylamino, diloweralkylamino, aryl, aryl lower alkanoyl,
trifluoromethyl, aryloxy, lower alkylthio, mercapto, and lower
alkyldithio.
54. The method according to claim 50 wherein the electron
withdrawing group and electron donating group are selected from the
group consisting of halo, nitro, carboxy, lower alkenyl, lower
alkynyl, formyl, carboxyamido, trifluoromethyl, lower alkoxy
carbonyl, hydroxy, lower alkoxy, lower alkyl, amino, lower
alkylamino, diloweralkylamino, mercapto, loweralkylthio, and lower
alkyldithio.
55. The method according to claim 1 wherein the carbon atom which
is substituted by R.sub.2 and R.sub.3 is in the D
configuration.
56. The method according to claim 20 wherein the carbon atom which
is substituted by R.sub.2 and R.sub.3 is in the D
configuration.
57. The method according to claim 35 wherein the carbon atom which
is substituted by R.sub.2 and R.sub.3 is in the D
configuration.
58. The method of claim 1 wherein the compound is of the formula:
##STR00042## wherein Ar is aryl which is unsubstituted or
substituted with an electron donating or electron withdrawing
group, and Q is loweralkoxy.
59. The method according to claim 56 wherein Ar is unsubstituted
aryl or aryl substituted with halo.
60. The method according to claim 56 wherein Q is methoxy.
61. The method according to claim 56 wherein Q is methoxy and Ar is
unsubstituted aryl or aryl substituted with halo.
62. The method according to claim 56 wherein the carbon atom which
is bonded to CH.sub.2Q is in the D configuration.
63. The method according to claim 20 wherein Ar is unsubstituted
aryl or aryl substituted with halo wherein the compound has the
formula: ##STR00043## and Q is lower alkoxy.
64. The method according to claim 63 wherein Q is methoxy.
65. The method according to claim 63 wherein Q is methoxy and Ar is
unsubstituted aryl or aryl substituted with halo.
66. The method according to claim 63 wherein the carbon atom which
is bonded to CH.sub.2Q is in the D configuration.
67. The method according to claim 63 wherein the carbon atom which
is bonded to CH.sub.2Q is in the D configuration.
68. The method of claim 35 wherein the compound is of the formula:
##STR00044## wherein Ar is aryl which is unsubstituted or
substituted with an electron donating or electron withdrawing
group, and Q is loweralkoxy.
69. The method according to claim 68 wherein Ar is unsubstituted
aryl or aryl substituted with halo.
70. The method according to claim 68 wherein Q is methoxy.
71. The method according to claim 68 wherein Q is methoxy and Ar is
unsubstituted aryl or aryl substituted with halo.
72. The method according to claim 68 wherein the carbon atom which
is bonded to CH.sub.2Q is in the D configuration.
Description
RELATED APPLICATION
[0001] The present application is claiming benefit of U.S. Ser. No.
60/228,230 filed on Aug. 25, 2000.
FIELD OF THE INVENTION
[0002] The present invention is directed to the novel uses of a
peptide class of compounds for treating bipolar disorders and
headaches, such as migraines and pain, especially neuropathic
pain.
BACKGROUND OF THE INVENTION
[0003] Bipolar disorders and headaches, such as migraines, and
pain, including neuropathic pain, are varied maladies that on its
face, are diverse.
[0004] A migraine headache is defined as a periodically occurring
vascular headache characterized by pain in the head (usually
unilateral), nausea, and vomiting, photophobia, phenophobia,
vertigo and general weakness. Migraine is the most common type of
vascular headache and affects as many as 15% of the world's
population. Of the different types of migraines, classical migraine
and common migraine are the two most prevalent. The major
difference between the two types of migraines is that classical
migraines are preceded by the appearance of neurological symptoms
before an attack whereas common migraines are not preceded by such
symptoms. Migraine is caused by intermittent brain dysfunction.
However, the precise pathophysiological mechanisms involved are not
understood. The head-pain is believed to involve blood vessel
dilation and a reduction in the brain's pain relieving
chemicals.
[0005] Neuropathic pain, on the other hand, can be described as
pain associated with damage or permanent alteration of the central
nervous system. Clinical manifestations of neuropathic pain include
a sensation of burning or electric shock, feelings of bodily
distortion, allodynia and hyperalgesia.
[0006] It results from injury to a nerve. In contrast to the
immediate pain caused by tissue injury, neuropathic pain can
develop days or months after a traumatic injury. Furthermore, while
pain caused by tissue injury is usually limited in duration to the
period of tissue repair, neuropathic pain frequently is long
lasting or chronic.
[0007] Moreover, neuropathic pain can occur spontaneously or as a
result of stimulation that normally is not painful.
[0008] The clinical causes of neuropathic pain are widespread and
include both trauma and disease. For example, traumatic nerve
compression, or crush, and traumatic injury to the brain or spinal
cord are common causes of neuropathic pain. Furthermore, most
traumatic nerve injuries also cause the formation of neuromas, in
which pain occurs as a result of aberrant nerve regeneration. In
addition, cancer-related neuropathic pain is caused when tumor
growth painfully compresses adjacent nerves, the brain or the
spinal cord. Neuropathic pain is associated with diseases such as
diabetes or alcoholism.
[0009] Bipolar disorder is a neuropsychiatric disorder. Also known
as bipolar affective disorder (BAD) or manic-depressive illness, it
is characterized by episodes of elevated mood (mania) and
depression. The most severe and clinically distinctive forms of BAD
are BP-I (severe bipolar affective (mood) disorder), which affects
2-3 million people in the U.S. and SAD-M (schizoaffective disorder
manic type). They are characterized by at least one full episode of
mania, with or without episodes of major depression (defined by
lower mood or depression, with associated disturbances in rhythmic
behaviors, such as sleeping, eating and sexual activity).
[0010] The therapies are varied. Analgesics are often used to treat
infrequent and mild migraines. Analgesics reduce the pain of a
migraine and in the case of aspirin also discourage clumping of
blood platelets. However, for moderate to severe migraines,
stronger medication is necessary, e.g., ergotamine or 5-H-T.sub.1
agonists, like sumatriptan.
[0011] On the other hand, for neuropathic pain, opioid compounds
(opiates) such as morphine may be utilized to treat the malady.
Although effective as an analgesic, it is not always effective in
treating neuropathic pain and may induce tolerance in patients.
When a subject is tolerant to opioid narcotics, increased doses are
required to achieve a satisfactory analgesic effect. At high doses,
these compounds produce side effects, such as respiratory
depression, which can be life threatening. In addition, opioids
frequently produce physical dependence in patients, which may be
related to the dose of opioid taken and the period of time over
which it is taken by the subject.
[0012] But neuropathic pain and bipolar disorder frequently are
resistant to available drug therapies. In addition, current
therapies have serious side-effects including, for example,
cognitive changes, sedation, nausea, and in the case of narcotic
drugs addictions. Many patients suffering from neuropathic pain are
elderly or have other medical conditions that particularly limit
their tolerance of the side-effects associated with available drug
therapy.
[0013] The inadequacy of current therapy in relieving neuropathic
pain and bipolar disorders without producing intolerable
side-effects frequently is manifested in the depression and
suicidal tendency of chronic pain sufferers. Moreover, the present
drugs are not effective for completely alleviating the pain from
those who have moderate to heavy migraine headaches.
[0014] U.S. Pat. No. 5,885,999 discloses compounds which are useful
for treating various maladies such as pain and headaches including
migraines. These compounds are serine derivatives of the
formula:
##STR00002##
wherein m is zero, 1 or 2; and n is zero or 1, with the proviso
that the sum total of m+n is 1 or 2;
[0015] R.sup.1 represents phenyl; naphthyl; benzohydryl; or benzyl,
where the naphthyl group or any phenyl moiety may be
substituted;
[0016] R.sup.2 represents hydrogen; phenyl; heteroaryl selected
from indazolyl, thienyl, furanyl, pyridyl, thiazolyl, tetrazolyl
and quinolinyl; naphthyl; benzohydryl; or benzyl; wherein each
heteroaryl, napthyl group and any phenyl moiety may be
substituted;
[0017] R.sup.3 and R.sup.4 each independently represents hydrogen
or C.sub.1-6alkyl or R.sup.3 and R.sup.4 together are linked so as
to form a C.sub.1-3alkylene chain;
[0018] Q represents CR.sup.5R.sup.6 or NR.sup.5;
[0019] X and Y each independently represents hydrogen, or together
form a group=0; and
[0020] Z represents a bond O, S, SO, SO.sub.2, NR.sup.c or
--(CR.sup.cR.sup.d)-m where R.sup.c and R.sup.d each independently
represent hydrogen or C.sub.1-6alkyl;
[0021] or a pharmaceutically acceptable salt thereof.
[0022] The compounds are alleged to be also useful in the treatment
or prevention of inflammation, emesis and postherapeutic
neuralgia.
[0023] In U.S. Pat. No. 6,228,825 to Tsai, et al., other amino
acids and derivatives thereof are alleged to be useful for treating
neuropsychiatric disorders, such as schizophrenia, Alzheimer's
Disease, depression, autism, closed head injury, benign
forgetfulness, childhood learning disorders, and attention deficit
disorders. These drugs include (i) D-alanine or modified form
thereof, provided that the composition is substantially free of
D-cycloserine and/or (ii) serine (or a modified from thereof),
and/or (iii) 105 to 500 mg of D-cycloserine (or a modified form
thereof); and/or (iv) N-methylglycine (or a modified form
thereof).
[0024] D-cycloserine, D-serine esters, D-serine or salts thereof
have been disclosed to be useful in treating spinocerebellar
degeneration. See, EP Application No. 1,084,704.
[0025] Peptides have also been alleged to be useful for treatment
of pain and neurosis. More specifically, EPO application 997,147
discloses compounds of the formula:
##STR00003##
wherein R.sup.1 is
[0026] 1) C1-15 alkyl,
[0027] 2) C1-8 alkoxy,
[0028] 3) phenyl,
[0029] 4) C3-8 cycloalkyl,
[0030] 5) hetero ring,
[0031] 6) C1-4 alkyl substituted by phenyl, C3-8 cycloalkyl, or
hetero ring,
[0032] 7) C1-4 alkoxy substituted by phenyl, C3-8 cycloalkyl, or
hetero ring, or
[0033] 8) C2-4 alkenyl substituted by phenyl, C3-8 cycloalkyl, or
hetero ring (with proviso that, all phenyl, C3-8 cycloalkyl and
hetero ring in R.sup.1 group may be substituted by 1-3 substituent
selected from the following (i)-(xi): [0034] (i) C1-4 alkyl, [0035]
(ii) C1-4 alkoxy, [0036] (iii) phenyl, [0037] (iv) phenoxy, [0038]
(v) benzyloxy, [0039] (vi) --SR.sup.5 (in which R.sup.5 is hydrogen
or C1-4 alkyl), [0040] (vii) C2-5 acyl, [0041] (viii) halogen,
[0042] (ix) C1-4 alkoxycarbonyl, [0043] (x) nitro, [0044] (xi)
--NR.sup.6R.sup.7 (in which R.sup.6 and R.sup.7 each independently,
is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R.sup.6 and
R.sup.7 taken together with the nitrogen atom to which they are
attached may represent 5-7 membered saturated hetero ring
containing another one nitrogen atom or one oxygen atom));
[0045] A is a bond, --CO-- or --SO.sub.2--;
[0046] R.sup.2 is hydrogen or C1-4 alkyl optionally substituted by
one phenyl;
[0047] D is C1-4 alkylene or C2-4 alkenylene;
[0048] E is [0049] 1) --COO--, [0050] 2) --OCO--, [0051] 3)
--CONR.sup.8 (in which R.sup.8 is hydrogen or C1-4 alkyl), [0052]
4) --NR.sup.9CO-- (in which R.sup.9 is hydrogen or C1-4 alkyl),
[0053] 5) --O--, [0054] 6) --S--, [0055] 7) --SO--, [0056] 8)
--SO.sub.2--, [0057] 9) --NR.sup.10-- (in which R.sup.10 is
hydrogen or C1-4 alkyl), [0058] 10) --CO--, [0059] 11)
--SO.sub.2NR.sup.11-- (in which R.sup.11 is hydrogen or C1-4 alkyl)
or [0060] 12) --NR.sup.12SO.sub.2-- (in which R.sup.12 is hydrogen
or C1-4 alkyl);
R.sup.3 is
[0061] 1) carbocyclic ring,
[0062] 2) hetero ring, or
[0063] 3) C1-4 alkyl substituted by carbocyclic ring or hetero ring
(with proviso that, all carbocyclic ring and hetero ring in R.sup.3
may be substituted by 1-3 substituents selected from the following
(i)-(xi); [0064] (i) C1-4 alkyl, [0065] (ii) C1-4 alkoxy, [0066]
(iii) phenyl, [0067] (iv) phenoxy, [0068] (v) benzyloxy, [0069]
(vi) --SR.sup.13 (in which R.sup.13 is hydrogen or C1-4 alkyl),
[0070] (vii) C2-5 acyl, [0071] (viii) halogen, [0072] (ix) C1-4
alkoxycarbonyl, [0073] (x) nitro, [0074] (xi) --NR.sup.14R.sup.15
(in which R.sup.14 and R.sup.15, each independently, is hydrogen,
C1-4 alkyl or C1-4 alkoxycarbonyl, or R.sup.14 and R.sup.15 taken
together with the nitrogen atom to which they are attached may
represent 5-7 membered saturated hetero ring containing another one
nitrogen atom or one oxygen atom); J is --O-- or --NR.sup.16-- (in
which R.sup.16 is hydrogen or C1-4 alkyl);
R.sup.4 is
[0075] 1) C1-8 alkyl,
[0076] 2) carbocyclic ring,
[0077] 3) hetero ring,
[0078] 4) C1-8 alkyl substituted by 1-3 of substituent selected
from the following (i)-(v); [0079] (i) carbocyclic ring, [0080]
(ii) hetero ring, [0081] (iii) COOR.sup.17 (in which R.sup.17 is
hydrogen or C1-4 alkyl substituted by one phenyl (in which phenyl
may be substituted by C1-4 alkoxy), [0082] (iv) SR.sup.18 (in which
R.sup.18 is hydrogen or C1-4 alkyl), [0083] (v) OR.sup.19 (in which
R.sup.19 is hydrogen or C1-4 alkyl), or when J represents
--NR.sup.16-- group, R.sup.4 and R.sup.16 taken together with the
nitrogen atom to which they are attached may represent hetero ring
(with proviso that, all carbocyclic ring and hetero ring, and
hetero ring represented by R.sup.4 and R.sup.16 taken together with
the nitrogen atom to which they are attached may be substituted by
1-3 of substituent selected from the following (i)-(xi); [0084] (i)
C1-4 alkyl, [0085] (ii) C1-4 alkoxy, [0086] (iii) phenyl, [0087]
(iv) phenoxy, [0088] (v) benzyloxy, [0089] (vi) --SR.sup.20 (in
which R.sup.20 is hydrogen or C1-4 alkyl), [0090] (vii) C2-5 acyl,
[0091] (viii) halogen, [0092] (ix) C1-4 alkoxycarbonyl, [0093] (x)
nitro, [0094] (xi) --NR.sup.21R.sup.22 (in which R.sup.21 and
R.sup.22 each independently, is hydrogen, C1-4 alkyl or C1-4
alkoxycarbonyl, or R.sup.21 and R.sup.22 taken together with the
nitrogen atom to which they are attached may represent 5-7 membered
saturated hetero ring containing another one nitrogen atom or one
oxygen atom), non-toxic salt thereof, or a hydrate thereof.
[0095] Other peptides are known to exhibit central nervous system
(CNS) activity and are useful in the treatment of epilepsy and
other CNS disorders. These peptides, which are described in U.S.
Pat. No. 5,378,729, to Kohn, et al., have the formula:
##STR00004##
wherein
[0096] R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,
aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl,
lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower
alkyl, and R is unsubstituted or is substituted with at least one
electron withdrawing group or electron donating group;
[0097] R.sub.1 is hydrogen or lower alkyl, lower alkenyl, lower
alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl,
heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each
unsubstituted or substituted with an electron donating group or an
electron withdrawing group; and
[0098] R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic,
heterocyclic lower alkyl, lower alkyl heterocyclic, lower
cycloalkyl, lower cycloalkyl lower alkyl, or Z--Y wherein R.sub.2
and R.sub.3 may be unsubstituted or substituted with at least one
electron withdrawing group or electron donating group;
[0099] Z is O, S, S(O).sub.a, NR.sub.4, PR.sub.4 or a chemical
bond;
[0100] Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower
alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower
alkyl, and Y may be unsubstituted or substituted with an electron
donating group or an electron withdrawing group, provided that when
Y is halo; Z is a chemical bond, or
[0101] ZY taken together is NR.sub.4NR.sub.5R.sub.7,
NR.sub.4OR.sub.5, ONR.sub.4R.sub.7, OPR.sub.4R.sub.5,
PR.sub.4OR.sub.5, SNR.sub.4R.sub.7, NR.sub.4SR.sub.7,
SPR.sub.4R.sub.5 or PR.sub.4SR.sub.7, NR.sub.4PR.sub.5R.sub.6 or
PR.sub.4NR.sub.5R.sub.7,
##STR00005##
[0102] R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen,
lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower
alkynyl, wherein R.sub.4, R.sub.5 and R.sub.6 may be unsubstituted
or substituted with an electron withdrawing group or an electron
donating group; and
[0103] R.sub.7 is R.sub.6 or COOR.sub.8 or COR.sub.8;
[0104] R.sub.8 is hydrogen or lower alkyl, or aryl lower alkyl, and
the aryl or alkyl group may be unsubstituted or substituted with an
electron withdrawing group or an electron donating group; and
[0105] n is 1-4; and
[0106] a is 1-3.
[0107] U.S. Pat. No. 5,773,475, the contents of which are
incorporated by reference, also discloses additional compounds
useful for treating CNS disorders. These compounds are
N-benzyl-2-amino-3-methoxy-propionamides having the formula:
##STR00006##
wherein
[0108] Ar is aryl which is unsubstituted or substituted with
halo;
[0109] Q is lower alkoxy; and
[0110] Q.sub.1 is CH.sub.3.
[0111] Harris in U.S. Pat. No. 6,133,261 describes a method of
treating or preventing stroke in a human by administering thereto
an effective amount of a compound of the formula:
R--NH--[--C(.dbd.O)--C(R.sub.2)(R.sub.3)--NH--].sub.n--C(=A)R.sub.1
wherein
[0112] R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,
aryl, aryl (lower alkyl), heterocyclic, heterocyclic (lower alkyl),
(lower alkyl) heterocyclic, lower cycloalkyl, lower cycloalkyl
(lower alkyl), and R is unsubstituted or is substituted with at
least one electron withdrawing group, or electron donating
group;
[0113] R.sub.1 is hydrogen or lower alkyl, lower alkenyl, lower
alkynyl, aryl (lower alkyl), aryl, heterocyclic, (lower alkyl)
heterocyclic, heterocyclic (lower alkyl), lower cycloalkyl, lower
cycloalkyl (lower alkyl), each unsubstituted or substituted with an
electron donating group or an electron withdrawing group and
[0114] R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, aryl (lower alkyl), aryl,
heterocyclic, heterocyclic (lower alkyl), (lower alkyl)
heterocyclic, lower cycloalkyl, lower cycloalkyl (lower alkyl),
SO.sub.3.sup.-, or Z--Y where R.sub.2 and R.sub.3 may be
unsubstituted or substituted with at least one electron withdrawing
group or electron donating group;
[0115] Z is O, S, S(O).sub.a, NR.sub.4, PR.sub.4 or a chemical
bond;
[0116] Y is hydrogen, lower alkyl, aryl, aryl(lower alkyl), lower
alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic (lower
alkyl), (lower alkyl)heterocyclic, cycloalkyl, cycloalkyl (lower
alkyl) and Y may be unsubstituted or substituted with an electron
donating group or an electron withdrawing group, provided that when
Y is halo, Z is a chemical bond;
[0117] or ZY taken together is NR.sub.4NR.sub.5R.sub.7,
NR.sub.4OR.sub.5, ONR.sub.4R.sub.7, OPR.sub.4R.sub.5,
PR.sub.4OR.sub.5, SNR.sub.4R.sub.7, NR.sub.4SR.sub.7,
SPR.sub.4R.sub.5, PR.sub.4SR.sub.7, NR.sub.4PR.sub.5R.sub.6,
PR.sub.4NR.sub.5R.sub.7, NR.sub.4C(O)R.sub.5, SC(O)R.sub.5,
NR.sub.4CO.sub.2R.sub.5, SCO.sub.2R.sub.5,
NR.sub.4C(O)R.sub.5R.sub.6, NR.sub.4C(O)NR.sub.5S(O).sub.aR.sub.6,
NR.sub.4C(S)R.sub.5R.sub.6, NR.sub.4C(=Q)MNR.sub.5C(=A)OR.sub.6, or
C(S)NH.sub.2;
[0118] R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen,
lower alkyl, aryl, aryl (lower alkyl), lower alkenyl, or lower
alkynyl, wherein R.sub.4, R.sub.5 and R.sub.6 may be unsubstituted
or substituted with an electron withdrawing group or an electron
donating group;
[0119] R.sub.7 is R.sub.6, COOR.sub.8, or C(O)R.sub.8;
[0120] R.sub.8 is hydrogen or lower alkyl, or aryl (lower alkyl),
and the aryl or alkyl group may be unsubstituted or substituted
with an electron withdrawing group or an electron donating
group;
[0121] A and Q are independently O or S;
[0122] M is an alkylene chain containing up to 6 carbon atoms or a
chemical bond;
[0123] n is 1-4; and
[0124] a is 1-3;
[0125] or a pharmaceutically acceptable salt thereof.
[0126] The present inventor has found that these peptides in U.S.
Pat. Nos. 5,378,729 and 5,773,475, are useful for treating pain,
including neuropathic pain, and headaches, including migraines and
bipolar disorders. Moreover, these compounds are not addictive and
do not exhibit the side effects of the commercially available drugs
described hereinabove.
SUMMARY OF THE INVENTION
[0127] Accordingly, the present invention is directed to the method
of treating bipolar disease in a patient suffering from same which
comprises administering thereto an amount effective to treat such
bipolar disease of a compound having Formula I:
##STR00007##
wherein
[0128] R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,
aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl,
lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower
alkyl, and R is unsubstituted or is substituted with at least one
electron withdrawing group, or electron donating group;
[0129] R.sub.1 is hydrogen or lower alkyl, lower alkenyl, lower
alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl,
heterocyclic, lower alkyl heterocyclic, lower cycloalkyl, lower
cycloalkyl lower alkyl, each unsubstituted or substituted with an
electron donating group or an electron withdrawing group; and
[0130] R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic,
heterocyclic lower alkyl, lower alkyl heterocyclic, lower
cycloalkyl, lower cycloalkyl lower alkyl, halo or Z--Y wherein
R.sub.2 and R.sub.3 may be unsubstituted or substituted with at
least one electron withdrawing group or electron donating
group;
[0131] Z is O, S, S(O).sub.a, NR.sub.4, or PR.sub.4;
[0132] Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower
alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower
alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl
lower alkyl, and Y may be unsubstituted or substituted with an
electron donating group or an electron withdrawing group, or
[0133] ZY taken together is NR.sub.4NR.sub.5R.sub.7,
NR.sub.4OR.sub.5, ONR.sub.4R.sub.7, OPR.sub.4R.sub.5,
PR.sub.4OR.sub.5, SNR.sub.4R.sub.7, NR.sub.4SR.sub.7,
SPR.sub.4R.sub.5 or PR.sub.4SR.sub.7, NR.sub.4PR.sub.5R.sub.6 or
PR.sub.4NR.sub.5R.sub.7,
##STR00008##
[0134] R.sub.4, R.sub.5, and R.sub.6 are independently hydrogen,
lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower
alkynyl, wherein R.sub.4, R.sub.5, and R.sub.6 may be unsubstituted
or substituted with an electron withdrawing group or an electron
donating group;
[0135] R.sub.7 is independently R.sub.6 or COOR.sub.8 or
COR.sub.8;
[0136] R.sub.8 is hydrogen or lower alkyl, or aryl lower alkyl, and
the aryl or alkyl group may be unsubstituted or substituted with an
electron withdrawing group or an electron donating group; and
[0137] n is 1-4; and
[0138] a is 1-3.
[0139] The present invention is also directed to the method of
treating pain in a patient suffering from same which comprises
administering to said patient a pain alleviating effective amount
of said compound to treat the pain.
[0140] In another aspect, the present invention is directed to a
method of treating headaches, including migraine headaches, in a
patient suffering from same which comprises administering to said
patient a headache alleviating effective amount of said
compound.
DETAILED DESCRIPTION OF THE INVENTION
[0141] As indicated hereinabove, the compounds of Formula I are
useful for treating pain, including neuropathic pain and headaches,
including migraine headaches, and bipolar disorders. These
compounds are described in U.S. Pat. No. 5,378,729, the contents of
which are incorporated by reference.
[0142] As defined herein, the "alkyl" groups when used alone or in
combination with other groups, are lower alkyl containing from 1 to
6 carbon atoms and may be straight chain or branched. These groups
include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
butyl, amyl, hexyl, and the like.
[0143] The "aryl lower alkyl" groups include, for example, benzyl,
phenethyl, phenpropyl, phenisopropyl, phenbutyl, diphenylmethyl,
1,1-diphenylethyl, 1,2-diphenylethyl, and the like.
[0144] The term "aryl", when used alone or in combination, refers
to an aromatic group which contains from 6 up to 18 ring carbon
atoms and up to a total of 25 carbon atoms and includes the
polynuclear aromatics. These aryl groups may be monocyclic,
bicyclic, tricyclic or polycyclic and are fused rings. A
polynuclear aromatic compound, as used herein, is meant to
encompass bicyclic and tricyclic fused aromatic ring systems
containing from 10-18 ring carbon atoms and up to a total of 25
carbon atoms. The aryl group includes phenyl, and the polynuclear
aromatics e.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and
the like. The aryl group also includes groups like ferrocyenyl.
[0145] "Lower alkenyl" is an alkenyl group containing from 2 to 6
carbon atoms and at least one double bond. These groups may be
straight chained or branched and may be in the Z or E form. Such
groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl,
1-pentenyl, (Z)-2-pentenyl, (E)-2-pentenyl,
(Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl,
e.g., 1,3- or 2,4-pentadienyl, and the like.
[0146] The term "lower alkynyl" is an alkynyl group containing 2 to
6 carbon atoms and may be straight chained as well as branched. It
includes such groups as ethynyl, propynyl, 1-butynyl, 2-butynyl,
1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl,
2-hexynyl, 3-hexynyl and the like.
[0147] The term "lower cycloalkyl" when used alone or in
combination is a cycloalkyl group containing from 3 to 18 ring
carbon atoms and up to a total of 25 carbon atoms. The cycloalkyl
groups may be monocyclic, bicyclic, tricyclic, or polycyclic and
the rings are fused. The cycloalkyl may be completely saturated or
partially saturated. Examples include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,
cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl,
decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl, adamantyl, and
the like. Cycloalkyl includes the cis or trans forms. Furthermore,
the substituents may either be in endo or exo positions in the
bridged bicyclic systems.
[0148] The term "electron-withdrawing and electron donating" refer
to the ability of a substituent to withdraw or donate electrons,
respectively, relative to that of hydrogen if the hydrogen atom
occupied the same position in the molecule. These terms are well
understood by one skilled in the art and are discussed in Advanced
Organic Chemistry, by J. March, John Wiley and Sons, New York,
N.Y., pp. 16-18 (1985) and the discussion therein is incorporated
herein by reference. Electron withdrawing groups include halo,
including bromo, fluoro, chloro, iodo and the like; nitro, carboxy,
lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl,
quaternary ammonium, trifluoromethyl, aryl lower alkanoyl,
carbalkoxy and the like. Electron donating groups include such
groups as hydroxy, lower alkoxy, including methoxy, ethoxy and the
like; lower alkyl, such as methyl, ethyl, and the like; amino,
lower alkylamino, di(loweralkyl)amino, aryloxy such as phenoxy;
mercapto, lower alkylthio, disulfide (lower alkyldithio) and the
like. One of ordinary skill in the art will appreciate that some of
the aforesaid substituents may be considered to be electron
donating or electron withdrawing under different chemical
conditions. Moreover, the present invention contemplates any
combination of substituents selected from the above-identified
groups.
[0149] The term "halo" includes fluoro, chloro, bromo, iodo and the
like.
[0150] The term "acyl" includes lower alkanoyl.
[0151] As employed herein, the heterocyclic substituent contains at
least one sulfur, nitrogen or oxygen ring atom, but also may
include one or several of said atoms in the ring, but preferably no
more than 4 heteroatoms in the ring. The heterocyclic substituents
contemplated by the present invention include heteroaromatics and
saturated and partially saturated heterocyclic compounds. These
heterocyclics may be monocyclic, bicyclic, tricyclic or polycyclic
and are fused rings. They may contain from 3 up to 18 ring atoms
and up to a total of 17 ring carbon atoms and a total of up to 25
carbon atoms. The heterocyclics are also intended to include the
so-called benzoheterocyclics. Representative heterocyclics include
furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl,
thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl,
pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl,
isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl,
tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl,
pyrazolindinyl, imidazolinyl, imadazolindinyl, pyrrolidinyl,
furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl,
pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, the
N-oxides of the nitrogen containing heterocycles, such as the
nitric oxides of pyridyl, pyrazinyl, and pyrimidinyl and the like.
The preferred heterocyclics are thienyl, furyl, pyrrolyl,
benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl,
pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, and pyridazinyl. The
preferred heterocyclic is a 5 or 6-membered heterocyclic compound.
The especially preferred heterocyclic is furyl, pyridyl, pyrazinyl,
imidazolyl, pyrimidinyl, and pyridazinyl. The most preferred
heterocyclic is furyl, pyridyl, thiazolyl and thienyl.
[0152] The preferred compounds are those wherein n is 1, but di,
tri and tetrapeptides are also contemplated to be within the scope
of the claims.
[0153] The preferred values of R is aryl lower alkyl, especially
benzyl, especially those wherein the phenyl ring thereof is
unsubstituted or substituted with electron donating groups or
electron withdrawing groups, such as halo (e.g., F).
[0154] The preferred R.sub.1 is H or lower alkyl. The most
preferred R.sub.1 group is methyl.
[0155] The most preferred electron donating substituents and
electron withdrawing substituents are halo, nitro, alkanoyl,
formyl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamido,
cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary
ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy,
lower alkoxy, lower alkyl, amino, lower alkylamino,
di(loweralkyl)amino, amino lower alkyl, mercapto, lower alkylthio,
and lower alkyldithio. The term "sulfide" encompasses mercapto, and
alkylthio, while the term disulfide encompasses alkyldithio. It is
more preferred that the electron donating groups and electron
withdrawing groups do not contain a cyclic group. The electron
donating and electron withdrawing groups may be substituted on any
one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 or R.sub.6,
R.sub.7 or R.sub.8 as defined herein.
[0156] The ZY groups representative of R.sub.2 and R.sub.3 include
hydroxy, alkoxy, such as methoxy, ethoxy, aryloxy, such as phenoxy;
thioalkoxy, such as thiomethoxy, thioethoxy; thioaryloxy such as
thiophenoxy; amino; alkylamino, such as methylamino, ethylamino;
arylamino, such as anilino; lower dialkylamino, such as,
dimethylamino; trialkyl ammonium salt; hydrazino; alkylhydrazino
and arylhydrazino, such as N-methylhydrazino, N-phenylhydrazino,
carbalkoxy hydrazino, aralkoxycarbonyl hydrazino, aryloxycarbonyl
hydrazino, hydroxylamino, such as N-hydroxylamino (--NH--OH), lower
alkoxy amino [(NHOR.sub.18) wherein R.sub.18 is lower alkyl],
N-lower alkylhydroxyl amino [(NR.sub.18)OH wherein R.sub.18 is
lower alkyl], N-lower alkyl-O-lower alkylhydroxyamino, i.e.,
[N(R.sub.18)OR.sub.19 wherein R.sub.18 and R.sub.19 are
independently lower alkyl] and o-hydroxylamino (--O--NH.sub.2);
alkylamido such as acetamido; trifluoroacetamido; lower
alkoxyamino, (e.g., NH(OCH.sub.3); and heterocyclicamino, such as
pyrazoylamino.
[0157] The preferred heterocyclic groups representative of R.sub.2
and R.sub.3 are monocyclic heterocyclic moieties of the
formula:
##STR00009##
or those corresponding partially or fully saturated form thereof
wherein n is 0 or 1; and
[0158] R.sub.50 is H or an electron withdrawing group or electron
donating group;
[0159] A, Z, L and J are independently CH, or a heteroatom selected
from the group consisting of N, O, S; and
[0160] G is CH, or a heteroatom selected from the group consisting
of N, O and S,
[0161] but when n is O, G is CH, or a heteroatom selected from the
group consisting of NH, O and S with the proviso that at most two
of A, E, L, J and G are heteroatoms.
[0162] When n is O, the above heteroaromatic moiety is a five
membered ring, while if n is 1, the heterocyclic moiety is a six
membered monocyclic heterocyclic moiety. The preferred heterocyclic
moieties are those aforementioned heterocyclics which are
monocyclic.
[0163] Thus, the most preferred monocyclic heterocyclic definition
of R.sub.2 and R.sub.3 is furyl thienyl, thiazolyl, and
pyridyl.
[0164] If the ring depicted hereinabove contains a nitrogen ring
atom, then the N-oxide forms are also contemplated to be within the
scope of the invention.
[0165] When R.sub.2 or R.sub.3 is a heterocyclic of the above
formula, it may be bonded to the main chain by a ring carbon atom.
When n is O, R.sub.2 or R.sub.3 may additionally be bonded to the
main chain by a nitrogen ring atom.
[0166] Other preferred moieties of R.sub.2 and R.sub.3 are
hydrogen, aryl, e.g., phenyl, aryl alkyl, e.g., benzyl and
alkyl.
[0167] It is to be understood that the preferred groups of R.sub.2
and R.sub.3 may be unsubstituted or substituted with electron
donating or electron withdrawing groups. It is preferred that the
electron withdrawing group or electron donating group does not
contain a cyclic group, unless the electron withdrawing group or
electron donating group is a hydrocarbyl group that contains only
carbon and hydrogen atoms.
[0168] It is more preferred that R.sub.2 and R.sub.3 are
independently hydrogen, lower alkyl, which is either unsubstituted
or substituted with an electron withdrawing group or an electron
donating group, such as lower alkoxy (e.g., methoxy, ethoxy, and
the like), N-hydroxylamino, N-lower alkylhydroxyamino,
N-loweralkyl-O-loweralkyl and alkylhydroxyamino.
[0169] It is even more preferred that one of R.sub.2 and R.sub.3 is
hydrogen; while the other is one of the preferred group indicated
hereinabove.
[0170] It is preferred that n is one.
[0171] It is preferred that R.sub.2 is hydrogen and R.sub.3 is
hydrogen, an alkyl group which is unsubstituted or substituted by
at least an electron donating or electron withdrawing group or ZY.
In this preferred embodiment, it is more preferred that R.sub.3 is
hydrogen or an alkyl group such as methyl, which is unsubstituted
or substituted by an electron donating group, NR.sub.4OR.sub.5 or
ONR.sub.4R.sub.7, wherein R.sub.4, R.sub.5 and R.sub.7 are
independently hydrogen or lower alkyl. It is preferred that the
electron donating group is lower alkoxy, and especially methoxy or
ethoxy.
[0172] It is also preferred that R is aryl lower alkyl. The most
preferred aryl for R is phenyl. The most preferred R group is
benzyl. In a preferred embodiment, the aryl group may be
unsubstituted or substituted with an electron donating or electron
withdrawing group. If the aryl ring in R is substituted, it is most
preferred that it is substituted with an electron withdrawing
group, especially on the aryl ring. The most preferred electron
withdrawing group for R is halo, especially fluoro.
[0173] The preferred R.sub.1 is loweralkyl, especially methyl.
[0174] The more preferred compounds are compounds of formula I
wherein n is 1; R.sub.2 is hydrogen; R.sub.3 is hydrogen, an alkyl
group, especially methyl which is substituted by an electron
donating or electron withdrawing group or ZY; R is aryl, aryl lower
alkyl, such as benzyl, wherein the aryl group is unsubstituted or
substituted and R.sub.1 is lower alkyl. In this embodiment, it is
most preferred that R.sub.3 is hydrogen, an alkyl group, especially
methyl, substituted by electron donating group, such as lower
alkoxy, (e.g., methoxy, ethoxy and the like), NR.sub.4OR.sub.5 or
ONR.sub.4R.sub.7 wherein these groups are defined hereinabove.
[0175] The most preferred compounds utilized are those of the
formula:
##STR00010##
wherein
[0176] Ar is aryl, especially phenyl, which is unsubstituted or
substituted with at least one electron donating group or electron
withdrawing group;
[0177] R.sub.1 is lower alkyl; and
[0178] R.sub.3 is as defined herein, but especially hydrogen,
loweralkyl, which is unsubstituted or substituted by at least an
electron donating group or electron withdrawing group or ZY. It is
even more preferred that R.sub.3 is, in this embodiment, hydrogen,
an alkyl group which is unsubstituted or substituted by an electron
donating group, such as alkoxy, or NR.sub.4OR.sub.5 or
ONR.sub.4R.sub.7. It is most preferred that R.sub.3 is CH.sub.2-Q,
wherein Q is lower alkoxy, NR.sub.4OR.sub.5 or ONR.sub.4R.sub.7
wherein R.sub.4 is hydrogen or alkyl containing 1-3 carbon atoms,
R.sub.5 is hydrogen or alkyl containing 1-3 carbon atoms, and
R.sub.7 is hydrogen or alkyl containing 1-3 carbon atoms.
[0179] The preferred R.sub.1 is CH.sub.3.
[0180] The most preferred aryl is phenyl.
[0181] The most preferred compounds include: [0182] (R)
--N-Benzyl-2-acetamido-3-methoxy-propionamide,
[0182] ##STR00011## [0183]
O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide,
[0183] ##STR00012## [0184]
O-methyl-N-acetyl-D-serine-p-fluorobenzylamide,
[0184] ##STR00013## [0185] N-acetyl-D-phenylglycinebenzylamide;
[0185] ##STR00014## [0186]
D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid
benzylamide,
[0186] ##STR00015## [0187]
D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid
benzylamide,
##STR00016##
[0187] Some of the preferred compounds are described in U.S. Pat.
No. 5,773,475, the contents of which are incorporated by
reference.
[0188] It is to be understood that the various combinations and
permutations of the Markush groups of R.sub.1, R.sub.2, R.sub.3, R
and n described herein are contemplated to be within the scope of
the present invention. Moreover, the present invention also
encompasses compounds and compositions which contain one or more
elements of each of the various Markush groupings in R.sub.1,
R.sub.2, R.sub.3, n and R and the various combinations thereof.
Thus, for example, the present invention contemplates that R.sub.1
may be one or more of the substituents listed hereinabove in
combination with any and all of the substituents of R.sub.2,
R.sub.3, and R with respect to each value of n.
[0189] The compounds utilized in the present invention may contain
one (1) or more asymmetric carbons and may exist in racemic and
optically active forms. The configuration around each asymmetric
carbon can be either the D or L form. (It is well known in the art
that the configuration around chiral carbon atoms can also be
described as R or S in the Cahn-Prelog-Ingold nomenclature system).
All of the various configurations around each asymmetric carbon,
including the various enantiomers and diastereomers as well as
racemic mixtures and mixtures of enantiomers, diastereomers or both
are contemplated by the present invention.
[0190] In the principal chain, there exists asymmetry at the carbon
atom to which the groups R.sub.2 and R.sub.3 are attached. When n
is 1, the compounds of the present invention are of the formula
##STR00017##
wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, Z
and Y are as defined previously.
[0191] As used herein, the term configuration shall refer to the
configuration around the carbon atom to which R.sub.2 and R.sub.3
are attached, even though other chiral centers may be present in
the molecule. Therefore, when referring to a particular
configuration, such as D or L, it is to be understood to mean the D
or L stereoisomer at the carbon atom to which R.sub.2 and R.sub.3
are attached. However, it also includes all possible enantiomers
and diastereomers at other chiral centers, if any, present in the
compound.
[0192] The compounds of the present invention are directed to all
the optical isomers, i.e., the compounds of the present invention
are either the L-stereoisomer or the D-stereoisomer (at the carbon
atom to which R.sub.2 and R.sub.3 are attached). These
stereoisomers may be found in mixtures of the L and D stereoisomer,
e.g., racemic mixtures. The D stereoisomer is preferred.
[0193] Depending upon the substituents, the present compounds may
form addition salts as well. All of these forms are contemplated to
be within the scope of this invention, including mixtures of the
stereoisomeric forms.
The following three schemes of preparation are generally exemplary
of the process of which can be employed for the preparation of the
compounds utilized. These are described in U.S. Pat. Nos. 5,378,729
and 5,773,475, the contents of both of which are incorporated by
reference.
##STR00018##
##STR00019##
##STR00020##
wherein R.sub.1, R.sub.2, R.sub.3 and are as defined hereinabove
and R.sub.17 is lower alkyl, aryl or lowerarylalkyl.
[0194] More specifically, these compounds can be prepared by
art-recognized procedures from known compounds or readily
preparable intermediates. For instance, compounds of Formula I can
be prepared by reacting amines of Formula II with an acylating
derivative of a carboxylic acid of Formula III under amide forming
conditions:
##STR00021##
wherein R, R.sub.1, R.sub.2, R.sub.3 and n are as defined
hereinabove, although it is preferred that n is 1.
[0195] The amide forming conditions referred to herein involve the
use of known derivatives of the described acids, such as the acyl
halides, (e.g.
##STR00022##
wherein X is Cl, Br and the like), anhydrides (e.g.,
##STR00023##
mixed anhydrides, or lower alkyl esters, and the like.
[0196] It is preferred that the acylating derivative used is the
anhydride. When alkyl esters are employed, amide bond formation can
be effected by metal cyanides such as sodium or potassium
cyanides.
[0197] Another exemplary procedure for preparing compounds wherein
at least one of R.sub.2 and R.sub.3 is aromatic or heteroaromatic
is depicted in Scheme IV.
[0198] The ester (IV) is reacted with halogen and ultraviolet light
in the presence of a catalyst, e.g., AIBN, to form the halo
derivative (V). (V) is reacted in the presence of a Lewis acid,
such as zinc chloride, with an aromatic or heteroaromatic compound
to form the compound (VI). (VI) in turn is hydrolyzed and then
reacted with alkylhaolformate, such as alkylchloroformate, in the
presence of a tertiary amine to generate the mixed N-acyl amino
acid carbonic ester anhydride (VIII). This intermediate is reacted
with an amine under amide forming conditions to give the compound
of Formula I. Alternatively, (VI) can be reacted directly with an
amine (RNH.sub.2), optionally in the presence of a metal catalyst,
such as metal cyanides, e.g., potassium or sodium cyanide, under
amide forming conditions to form a compound of Formula I.
Alternatively, compound VIII can be prepared by an independent
method and converted to VI which is then reacted with an amine,
with or without catalyst, to form the compound of Formula I.
##STR00024##
wherein X=halogen (i.e., Cl, Br);
[0199] R.sub.17=lower alkyl, aryl, or aryl lower alkyl; and
[0200] M+=metal cation (i.e., Na.sup.+, K.sup.+)
[0201] Two additional synthetic routes may be employed for the
preparation of compounds wherein R.sub.2 or R.sub.3 is Z--Y as
defined hereinabove. In one scheme, for the preparation of these
complexes, a substitution reaction is used:
##STR00025##
In the above scheme, R.sub.9 is lower alkyl, R.sub.2 is Z--Y and Z,
Y, R, R.sub.3 and R.sub.1 are as defined hereinabove and M is a
metal.
[0202] The ether functionality on IX can be cleaved by treatment
with Lewis acids, such as BBr.sub.3, in an inert solvent such as
methylene chloride to form the corresponding halo (bromo)
derivative. Addition of either an excess of H--R.sub.2 or MR.sub.2
or the sequential addition of triethylamine and H--R.sub.2 to a THF
mixture containing the halo derivative furnishes the desired
product. For example, in the case wherein the compound of Formula
IX is 2-acetamido-N-benzyl-2-ethoxy acetamide, its treatment with
BBr.sub.2 in CH.sub.2Cl.sub.2 led to the formation of the
.alpha.-bromo derivative, 2-acetamido-N-benzyl-2-bromoacetamide.
Addition of an excess of HR.sub.2 or the sequential addition of
triethylamine and HR.sub.2 to the THF mixture containing the bromo
adduct furnishes the desired product.
[0203] In another procedure, the product wherein R.sub.2 or R.sub.3
is Z--Y can also be prepared by a substitution reaction on a
quaternary ammonium derivative of the compound of Formula I as
outlined below:
##STR00026##
In scheme VI, R, R.sub.1, R.sub.3 and R are as defined hereinabove,
R.sub.2 is Z--Y and R.sub.9 and R.sub.10 are independently lower
alkyl. In scheme VI, methylation of compound X with a methylation
reagent, such as trimethyloxonium tetrafluoroborate, provided the
corresponding ammonium derivative. Subsequent treatment of the
ammonium salt with HR.sub.2 furnishes the desired product. For
example, methylation of 2-acetamido-N-benzyl-2-(N,N-dimethylamino)
acetamide with trimethyloxonium tetrafluoroborate in nitromethane
furnished the quaternary ammonium derivative,
2-acetamido-N-benzyl-(N,N,N-trimethylammonium) acetamide
tetrafluoroborate in high yields. Subsequent treatment of the salt
with the HR.sub.2 reagent in the methanol leads to the production
of the desired product.
[0204] As in any organic reaction, inert solvents can be employed
such as methanol, ethanol, propanol, acetone, tetrahydrofuran,
dioxane, dimethylformamide, dichloromethane, chloroform and the
like. The reaction is normally effected at or near room
temperature, although temperatures from 0.degree. C. up to the
reflux temperature of the solvent can be employed.
[0205] As a further convenience, the amide forming reaction can be
effected in the presence of a base, such as a tertiary organic
amine, e.g., triethylamine, pyridine, 4-methyl-morpholine,
picolines and the like, particularly where hydrogen halide is
formed by the amide forming reaction, e.g., the reaction of an acyl
halide and the amine of Formula II. Of course, in those reactions
where hydrogen halide is produced, any of the commonly used
hydrogen halide acceptors can also be used.
[0206] The exact mineral acid or Lewis acid employed in the
reaction will vary depending on the given transformation, the
temperature required for the conversion and the sensitivity of the
reagent toward the acid in the reaction mixture.
[0207] The various substituents, e.g., as defined in R, R.sub.1,
R.sub.2, and R.sub.3, can be present in the starting compounds,
added to any one of the intermediates or added after formation of
the final products by the known methods of substitution or
conversion reactions. For example, the nitro groups can be added to
the aromatic ring by nitration and the nitro group converted to
other groups, such as amino by reduction, and halo by diazotization
of the amino group and replacement of the diazo group. Alkanoyl
groups can be substituted onto the aryl groups by Friedel-Crafts
acylation. The acyl groups can be then transformed to the
corresponding alkyl groups by various methods, including the
Woff-Kishner reduction or Clemmenson reduction. Amino groups can be
alkylated to form mono, dialkylamino and trialkylamino groups; and
mercapto and hydroxy groups can be alkylated to form corresponding
thioethers or ethers, respectively. Primary alcohols can be
oxidized by oxidizing agents known in the art to form carboxylic
acids or aldehydes, and secondary alcohols can be oxidized to form
ketones. Thus, substitution or oxidation reactions or a combination
thereof can be employed to provide a variety of substituents
throughout the molecule of the starting material, intermediates, or
the final product.
[0208] In the above reactions, if the substituents themselves are
reactive, then the substituents can themselves be protected
according to techniques known in the art. A variety of protecting
groups known in the art may be employed. Examples of many of these
possible groups may be found in "Protective Groups in Organic
Synthesis," by T. W. Greene, John Wiley & Sons, 1981.
[0209] Resulting mixtures of isomers can be separated into the pure
isomers by methods known to one skilled in the art, e.g., by
fractional distillation, crystallization and/or chromatography.
[0210] The compounds obviously exist in stereoisomeric forms and
the products obtained thus can be mixtures of the isomers, which
can be resolved. Optically pure functionalized amino acid
derivatives can be prepared directly from the corresponding pure
chiral intermediate. Racemic products can likewise be resolved into
the optical antipodes, for example, by separation of diastereomeric
salts thereof, e.g., by fractional crystallization, by selective
enzymatic hydrolysis, e.g., papain digestion, or by use of a chiral
stationary phase in a chromatographic separation, such as by high
pressure liquid chromatography (HPLC). For a discussion of chiral
stationary phases for HPLC, See, DeCamp, Chirality, 1, 2-6 (1989),
which is incorporated herein by reference with the same force and
effect as is fully set forth herein.
[0211] For example, a racemic mixture of an intermediate in any of
the schemes depicted hereinabove has the formula:
##STR00027##
wherein R.sub.17 is H (which can be prepared according to the
procedures of Schemes 1, 2, 3 or 4) is reacted with an optically
active amine, RNH.sub.2, e.g., (R)(+).alpha.-methyl-benzylamine, to
form a pair of diastereomeric salts. Diastereomers can then be
separated by recognized techniques known in the art, such as
fractional recrystallization and the like.
[0212] In another method, a racemic mixture of final products or
intermediates can be resolved by using enzymatic methods. Since
enzymes are chiral molecules, it can be used to separate the
racemic modification, since it will preferentially act on one of
the compounds, without affecting the enantiomer. For example,
acylase, such as acylase I, can be used to separate the racemic
modification of an intermediate D, L
(.+-.).alpha.-acetamido-2-furanacetic acid. It acts on the
L(.+-.).alpha.-acetamido-2-furanacetic acid, but will not act on
the D enantiomer. In this way, the
D(-).alpha.-acetamido-2-furanacetic acid can be isolated. The
intermediate can then react with the amine (RNH.sub.2) under amide
forming conditions as described hereinabove to form the compound of
Formula I.
[0213] The compounds utilized in the present invention are useful
as such as depicted in the Formula I or can be employed in the form
of salts in view of its basic nature by the presence of the free
amino group. Thus, the compounds of Formula I form salts with a
wide variety of acids, inorganic and organic, including
pharmaceutically acceptable acids. The salts with therapeutically
acceptable acids are of course useful in the preparation of
formulations where enhanced water solubility is most
advantageous.
[0214] These pharmaceutically acceptable salts have also
therapeutic efficacy. These salts include salts of inorganic acids
such as hydrochloric, hydroiodic, hydrobromic, phosphoric,
metaphosphoric, nitric acid and sulfuric acids as well as salts of
organic acids, such as tartaric, acetic, citric, malic, benzoic,
perchloric, glycolic, gluconic, succinic, aryl sulfonic, (e.g.,
p-toluene sulfonic acids, benzenesulfonic), phosphoric, malonic,
and the like.
[0215] It is preferred that the compound utilized in the present
invention is used in therapeutically effective amounts.
[0216] The physician will determine the dosage of the present
therapeutic agents which will be most suitable and it will vary
with the form of administration and the particular compound chosen,
and furthermore, it will vary with the patient under treatment, the
age of the patient, and the type of malady being treated. He will
generally wish to initiate treatment with small dosages
substantially less than the optimum dose of the compound and
increase the dosage by small increments until the optimum effect
under the circumstances is reached. The compounds are useful in the
same manner as comparable therapeutic agents and the dosage level
is of the same order of magnitude as is generally employed with
these other therapeutic agents.
[0217] In a preferred embodiment, the compounds utilized are
administered in amounts ranging from about 1 mg to about 100 mg per
kilogram of body weight per day. This dosage regimen may be
adjusted by the physician to provide the optimum therapeutic
response. For example, several divided doses may be administered
daily or the dose may be proportionally reduced as indicated by the
exigencies of the therapeutic situation. The compounds of Formula I
may be administered in a convenient manner, such as by oral,
intravenous (where water soluble), intramuscular or subcutaneous
routes.
[0218] The compounds of Formula I may be orally administered, for
example, with an inert diluent or with an assimilable edible
carrier, or it may be enclosed in hard or soft shell gelatin
capsules, or it may be compressed into tablets, or it may be
incorporated directly into the food of the diet. For oral
therapeutic administration, the active compound of Formula I may be
incorporated with excipients and used in the form of ingestible
tablets, buccal tablets, troches, capsules, elixirs, suspensions,
syrups, wafers, and the like. Such compositions and preparations
should contain at least 1% of active compound of Formula I. The
percentage of the compositions and preparations may, of course, be
varied and may conveniently be between about 5 to about 80% of the
weight of the unit. The amount of active compound of Formula I in
such therapeutically useful compositions is such that a suitable
dosage will be obtained. Preferred compositions or preparations
according to the present invention contains between about 10 mg and
6 g of active compound of Formula I.
[0219] The tablets, troches, pills, capsules and the like may also
contain the following: a binder such as gum tragacanth, acacia,
corn starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, lactose or saccharin may be added
or a flavoring agent such as peppermint, oil of wintergreen, or
cherry flavoring. When the dosage unit form is a capsule, it may
contain, in addition to materials of the above type, a liquid
carrier.
[0220] Various other materials may be present as coatings or
otherwise modify the physical form of the dosage unit. For
instance, tablets, pills, or capsules may be coated with shellac,
sugar or both. A syrup or elixir may contain the active compound,
sucrose as a sweetening agent, methyl and propylparabens as
preservatives, a dye and flavoring such as cherry or orange flavor.
Of course, any material used in preparing any dosage unit form
should be pharmaceutically pure and substantially non-toxic in the
amounts employed. In addition, the active compound may be
incorporated into sustained-release preparations and formulations.
For example, sustained release dosage forms are contemplated
wherein the active ingredient is bound to an ion exchange resin
which, optionally, can be coated with a diffusion barrier coating
to modify the release properties of the resin.
[0221] The active compound may also be administered parenterally or
intraperitoneally. Dispersions can also be prepared in glycerol,
liquid polyethylene glycols, and mixtures thereof, and in oils.
Under ordinary conditions of storage and use, these preparations
contain a preservative to prevent the growth of microorganisms.
[0222] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions (where water soluble) or dispersions and
sterile powders for the extemporaneous preparation of sterile
injectable solutions or dispersions. In all cases, the form must be
sterile and must be fluid to the extent that easy syringability
exists. It must be stable under the conditions of manufacture and
storage and must be preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier can be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (for example, glycerol, propylene glycol, and
liquid polyethylene glycol, and the like), suitable mixtures
thereof, and vegetable oils. The proper fluidity can be maintained,
for example, by the use of a coating such as lecithin, by the
maintenance of the required particle size, in the case of
dispersions, and by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many cases, it will be preferable to include isotonic agents, for
example, sugars or sodium chloride. Prolonged absorption of the
injectable compositions can be brought about by the use in the
compositions of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0223] Sterile injectable solutions are prepared by incorporating
the active compound in the required amount in the appropriate
solvent with various other ingredients enumerated above, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredients into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are the use of vacuum drying and freeze-drying
techniques on the active ingredient plus any additional desired
ingredients from previously sterile-filtered solution(s)
thereof.
[0224] As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents for pharmaceutical active substances which are well
known in the art. Except insofar as any conventional media or agent
is incompatible with the active ingredient, its use in the
therapeutic compositions is contemplated. Supplementary active
ingredients can also be incorporated into the compositions.
[0225] It is especially advantageous to formulate parenteral
compositions in dosage unit form for ease of administration and
uniformity of dosage. Dosage unit form as used herein refers to
physically discrete units suited as unitary dosages for the
mammalian subjects to be treated; each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect in association with the required
pharmaceutical carrier. The specifics for the novel dosage unit
forms of the invention are dictated by and directly dependent on
(a) the unique characteristics of the active material and the
particular therapeutic effect to be achieved, and (b) the
limitations inherent in the art of compounding such as active
material for the treatment of disease in living subjects having a
diseased condition in which bodily health is impaired as herein
disclosed in detail.
[0226] The principal active ingredient is compounded for convenient
and effective administration in effective amounts with a suitable
pharmaceutically acceptable carrier in dosage unit form as
hereinbefore described. A unit dosage can, for example, contain the
principal active compound in amounts ranging from about 10 mg to
about 6 g. Expressed in proportions, the active compound is
generally present from about 1 to about 750 mg/ml of carrier. In
the case of compositions containing supplementary active
ingredients, the dosages are determined by reference to the usual
dose and manner of administration of the said ingredients.
[0227] As used herein the term "patient" or "subject" refers to a
warm blooded animal, preferably mammals, such as, for example,
cats, dogs, horses, cows, pigs, mice, rats and primates, including
humans. The preferred patient is human.
[0228] The term "treat" refers to either relieving the pain
associated with a disease or condition or alleviating the patient's
disease or condition.
[0229] The compounds of the present invention are useful for
treating chronic pain. As used herein, the term "chronic pain" is
defined as pain persisting for an extended period of time, for
example, greater than three to six months, although the
characteristic signs described hereinbelow can occur earlier or
later than this period. Vegetative signs, such as lassitude, sleep
disturbances, decreased appetite, loss of taste or food, weight
loss, diminished libido and constipation develop.
[0230] A type of chronic pain that the compounds of the present
invention are especially useful in treating is nociceptive pain and
neuropathic pain. As used herein, "nociceptive pain" is pain that
is judged to be commensurate with on-going activation of
pain-sensitive somatic or visceral nerve fibers. This pain is
typically experienced as aching or pressure-like when somatic
nerves are involved.
[0231] On the other hand, neuropathic pain is caused by damage to
nerve tissue. The pain may result from nervous system damage
involving reorganization of central somato-sensory processing,
i.e., differentiation pains (those due to partial or complete
interruption of peripheral or central afferent neural activity) and
those dependent on sympathetic-mediated pains (those dependent on
efferent sympathetic activity). Alternatively, the pain may result
from on-going peripheral processes or pathology, such as nerve
compression or neuroma formation.
[0232] The pain associated with these neuropathic pains is a deep
pain, i.e., a spontaneous burning pain often accompanied by a
superimposed lancinating component. Other pain sensations, such as
hyperesthesia, hyperalgesia, allodynia (pain from a non-noxious
stimulant) and hyperpathia (particularly unpleasant, exaggerated
pain response) may also be felt by the patient experiencing
neuropathic pain.
[0233] The compounds of the present invention are administered to a
patient suffering from neuropathic pain in an analgesic effective
amount. These amounts are equivalent to the therapeutically
effective amounts described hereinabove.
[0234] Another type of malady experienced by patients for which the
compounds of Formula I are useful in treating is headaches,
especially migraine headaches.
[0235] A migraine headache is a paroxysmal disorder characterized
by recurrent attacks of headaches, which may be associated with
visual or GI disturbances. In migraine headaches, the pain is
usually generalized, but it may also be a unilateral throbbing,
which begins around one of the eyes and then spreads through the
head to involve one or both sides.
[0236] In some severe cases, it is accompanied by anorexia, nausea
and vomiting and photophobia. In addition, the extremities are cold
and cyanosed, and the patient is irritable. Moreover, the scalp
arteries are prominent and their amplitude of pulsation is
increased.
[0237] The compounds of Formula I are useful in the prophylaxis and
the treatment of migraine headaches and alleviating the pain
associated therewith. They are administered to patients with
migraine headaches in pain relieving effective amounts. These
amounts are equivalent to the therapeutically effective amounts
described hereinabove. The discussions associated with therapeutic
effective amounts are applicable to the treatment and/or
prophylaxis of migraine headaches and are incorporated herein.
[0238] The compounds of the present invention are also useful in
treating patients with bipolar disorders. Bipolar disorders
commonly originate with depression and are characterized by at
least one elated period during the course of the illness. In
bipolar I disorder, major depressive episodes and full-blown manic
alternate. In bipolar II disorder, depressive episodes alternate
with hypomanias (i.e., mild, non-psychotic periods of excitement)
of relatively short duration. These disorders are typically
accompanied by the subject experiencing hypersomnia and overeating
and these traits may recur on a seasonal basis. Additionally, the
patient may suffer from insomnia and poor appetite.
[0239] In the full blown bipolar disorder, the mood of the person
suffering therefrom is usually elation, but irritability and frank
hostility and cantankerousness are also common. The patient is
morbid, yet the patient believes that he is in the best mental
state. He is psychotic, impatient, intrusive, meddlesome and
responds with aggressive irritability when challenged or crossed.
The patient may experience interpersonal friction and he may have
secondary paranoid delusional interpretations of being persecuted.
The patient usually suffers from delusions, especially grand
delusions, e.g., false belief of personal wealth, power,
inventiveness, genius or importance. The patient may believe that
he is being assaulted or persecuted by others. He may even suffer
from hallucinations. In the extreme, the psychomotor activity is so
frenzied that any understandable link between mood and behavior is
lost (delirious mania).
[0240] The present compounds are also useful for treating
cyclothymic disorders.
[0241] The term bipolar disorders, as used herein, also includes
mixed states which are rapid alternation between depression and
manic manifestations, as for example, momentary switching into
tearfulness and suicidal ideas.
[0242] The amounts effective for treating bipolar disorders are the
therapeutically effective amounts described hereinabove. The
discussions associated with therapeutic effective amounts are
applicable to the treatment of bipolar disorders and are
incorporated herein by reference.
[0243] The compounds of the present invention are useful in
treating various types of neuroses, especially obsessive-compulsive
neurosis.
[0244] The former, by definition, is a disorder characterized by
the presence of ideas and fantasies which are recurrent, in fact
obsessive and by repetitive impulses or actions (compulsions) that
the patient recognizes as morbid and toward which he feels a strong
inner resistance. The patient himself is anxious, but the anxiety
arises in response to internally derived thoughts and disorders
that the patient fears he may execute despite a desire to restrain
himself.
[0245] Again, the amounts described herein are therapeutically
effective amounts, which discussions are incorporated herein by
reference.
[0246] Without wishing to be bound, the compounds of the present
invention are believed to interact with the strychnine-insensitive
glycine site of the NMDA receptor. By "interact", it is meant that
the compounds may be NMDA antagonists, NMDA agonists or partial
agonists/antagonists.
[0247] The NMDA (N-methyl-D-aspartate) receptor is one of the three
major sub-types of glutamate receptors in the CNS. Glutamate, which
is believed to be the major excitatory neurotransmitter in the
brain, activates the NMDA receptor. The NMDA receptors are found in
the membranes of virtually every neuron in the brain. NMDA
receptors are ligand gated cation channels that allow Na.sup.+,
K.sup.+, and Ca.sup.+2 to permeate when they are activated by
glutamate, aspartate or NMDA.
[0248] However, glutamate alone cannot activate the NMDA receptor.
In order to become fully activated by glutamate, the NMDA receptor
channel must bind glycine at a specific, high affinity glycine
binding site that is separate from the glutamate/NMDA binding site
of the receptor protein. Glycine is therefore an obligatory
co-agonist at the NMDA receptor/channel complex.
[0249] In addition to the binding site for glutamate/NMDA and
glycine, the NMDA receptor carries a number of other functionally
important binding sites, e.g., Mg.sup.2+, Zn.sup.2+, polyamines,
arachidonic acid and phencyclidine (PCP).
[0250] Without wishing to be bound, it is thus believed that
functional modulation of the NMDA subclass of glutamate receptors
can be achieved through actions at different recognition sites such
as: the primary transmitter site (competitive), the phencyclidine
(PCP) site located inside the cation channel (uncompetitive), the
polyamine modulatory site, and the strychnine-insensitive glycine
site (glycine.sub.b).
[0251] Without wishing to be bound, it is believed that the
compounds of the present invention interact with the glycine
binding site of the NMDA receptor. For example, the compounds of
the present invention may be antagonists of the glycine binding
site of the NMDA receptor.
[0252] Glycine is a co-agonist at NMDA receptors and its presence
at moderate nM concentrations is a prerequisite for channel
activation by glutamate or NMDA. D-serine is also known as an
endogenous agonist for the glycine.sub.b receptors. In fact, the
D-isomers of serine and alanine are nearly as potent as glycine and
considerably more potent than the L-isomers; and these also
modulate the glycine.sub.b site. Larger amino acids are less
effective. Cycloserine shows up as a relatively potent glycine
agonist at the NMDA receptor complex site.
[0253] Although a number of uncompetitive and competitive NMDA
receptor antagonists are already used clinically or are at advanced
stages of development, less is known about the therapeutic
potential of antagonists at the glycine.sub.b site. Initial
preclinical evidence suggests that a different, perhaps more
promising, therapeutic profile can be expected from glycine.sub.b
antagonism. The glycine.sub.b antagonists have been reported to
lack many of the side effects classically associated with NMDA
receptor blockade such as: 1) lack of neurodegenerative changes in
the cingulate/retrosplenial cortex; 2) lack of psychotomimetic-like
effects, and 3) lack of learning impairing effects at
anticonvulsive doses. However, more recently some full
glycine.sub.b antagonists, have also been reported to have good
therapeutic indices following systemic administration as
neuroprotective agents in models of focal ischemia; and trauma, as
antiepileptics, even in models of partial complex seizures; as
anxiolytics; as antipsychotomimetics; in blocking spreading
depression; and in models of hyperalgesia.
[0254] The compounds of the present invention exhibit no specific
affinity for a standard battery of CNS and peripheral receptors,
including many subtypes of glutamate receptors. However, they do
exhibit affinity at the glycine strychnine-insensitive site of the
NMDA receptor complex. For example, utilizing a representative
compound, (R)-2-Acetamido-N-benzyl-3-methoxy propionamide, the
present inventor has determined that the affinity thereof at the
glycine-strychnine-insensitive site of the NMDA receptor complex
has a IC.sub.50 value of 5.3 uM using dichlorokynurenic acid as the
ligand. Moreover, other studies have indicated that the proactive
effects of this representative compound on threshold extension in
rats can be reversed by D-serine, a glycine agonist, in a dose
dependent fashion. Thus the compounds of the present invention are
believed, without wishing to be bound, to be mediated by its
interaction with the glycine.sub.b/D-serine site.
[0255] However, the compounds of the present invention exhibit
little or no side effects caused by non-selective binding with
other receptors, particularly the PCP binding site of the NMDA
receptor and the glutamate binding site of the NMDA receptor.
[0256] There is an endogenous ligand present that binds to the
glycine.sub.b site. Some believe that it is glycine, while others
believe that it is D-serine. See Snyder, et al., Am. J. Psychiatry,
2000, 157, 11 1738-1751; and Baranano, et al., Trends in
Nurosciences, 2001, 24, 99-106.
[0257] Without wishing to be bound, it is believed that the
compounds of the present invention modulate the activity of the
glycine.sub.b receptor. Moreover, without wishing to be bound, it
is believed that the compounds of the present invention are useful
for the treatment of conditions associated with or caused by
abnormal receptor activity at the glycine.sub.b receptor site.
Without wishing to be bound, it is believed that compounds of the
present invention interact with this glycine.sub.b receptor site on
the NMDA receptor.
[0258] Without wishing to be bound, it is believed that by
interacting at the strychnine-insensitive glycine site on the NMDA
receptors, the compounds of Formula I are useful in treating or
preventing neuronal loss, neurodegenerative diseases and chronic
pain. In addition they are also anti-psychotics.
[0259] Other neurodegenerative diseases which are treated with the
compounds of Formula I are Alzheimer's disease, Huntington's
disease and Down's syndrome.
[0260] The compounds described herein also are useful for treating
or preventing dementia.
[0261] Besides treating neuropathic pain, the compounds of the
present invention find utility in treating or preventing pain,
e.g., chronic pain. Such chronic pain can result from surgery,
trauma, headache, arthritis, pain associated with a terminal case
of cancer, or degenerative diseases. The compounds of Formula I
find utility in the treatment of phantom pain that results from
amputation of an extremity.
[0262] In addition, it is believed, without wishing to be bound,
that the strychnine-insensitive glycine site of the NMDA receptors
is involved in the development of persistent pain following nerve
and tissue injury. Tissue injury, such as that caused by injecting
a small amount of formalin subcutaneously into the hindpaw of a
test animal, has been shown to produce an immediate increase of
glutamate and aspartate in the spinal cord. Without wishing to be
bound, it is believed that the administration of the compounds of
the present invention reduces the response of spinal cord dorsal
horn neurons following formalin injection. These dorsal horn
neurons are critical in carrying the pain signal from the spinal
cord to the brain and a reduced response of these neurons is
indicative of a reduction in pain perceived by the test animal to
which pain has been inflicted by subcutaneous formalin
injection.
[0263] Because the compounds of the present intention block dorsal
horn neuron response induced by subcutaneous formalin injection,
they are useful for the treatment of chronic pain, such as pain
caused by surgery or by amputation (phantom pain) or by infliction
of other wounds (wound pain).
[0264] The degree of pain is determined by measuring the decrease
in the amount of time the animal spends licking the
formalin-injected paw after administration of the drug.
[0265] Compared to vehicle control, the intraperitoneal injection
of the putative glycine receptor modulators of the present
invention 30 minutes prior to formalin injection into the hindpaw
significantly inhibits formalin-induced chronic pain in a
dose-dependent manner as determined by the reduction of the time
spent by the mouse licking the formalin injected hindpaw. This is
shown in Example 2 hereinbelow.
[0266] In the following Examples 1-5, the following were used:
[0267] 1. Animals
[0268] Male or female ICR mice and male or female Long Evans rats
provided by animal breeding center of MDS Panlabs Taiwan, Ltd. were
used. Space allocation for animals was as follows:
45.times.23.times.15 cm for 10 mice, 45.times.23.times.15 cm for 6
rats. Mice and rats were housed in APEC.RTM. (Allentown Gaging,
Allentown, N.J. 08501, U.S.A.) cages in a positive pressure
isolator (NuAire.RTM., Mode: Nu-605, airflow velocity 50.+-.5
ft/min, HEPA Filter). All animals were maintained in a controlled
temperature (22.degree. C.-24.degree. C.) and humidity (60%-80%)
environment with 12 hour light dark cycles for at least one week in
MDS Panlabs Taiwan laboratory prior to being used. Free access to
standard lab chow for mice and rats (Fwusow Industry Co., Limited,
Taiwan) and tap water was granted. All aspects of this work
including housing, experimentation and disposal of animals were
performed in general accordance with the International Guiding
Principles for Biomedical Research Involving Animals (CIOMS
Publication No. ISBN 90360194, 1985).
[0269] 2. Chemicals
[0270] The chemicals used were Acetic Acid (Sigma, U.S.A.), Aspirin
(ICN Biomedicals Inc.), CGS-19755 (RBI, U.S.A.), Diazepam (Sigma,
U.S.A.), Formalin (Wako, Japan), Morphine (National Narcotics
Bureau of Taiwan), NMDA (Sigma, U.S.A.), Phenylquionone (Sigma,
U.S.A.) and Saline (Astar, Taiwan).
[0271] 3. (R)--N-Benzyl-3-Acetamido-3-methoxypropionamide was
prepared in accordance with the procedure in U.S. Pat. No.
5,773,475. In the following examples, it will be designated as
Compound I.
[0272] The following experiments illustrate the effectiveness of
the compounds in treating pain. In the first series of experiments,
a representative compound of the present invention,
(R)-2-Acetamido-N-benzyl-3-methoxypropionamide (CMPD I) was
utilized at different concentrations.
[0273] In the first animal study in Example 1, the degree of pain
experienced by the mice after injection by acetic acid is seen by
the number of writhes. If the mice experience no pain, there is no
writhing. As would be expected, if a pain reliever is not
administered to the mice prior to injection of acetic acid, the
mice will exhibit writhing.
[0274] The protocol is based on the acetic acid writhing test in
mice, developed by R. Koster, et al. Fed. Proc, 18, 412 (1939), and
referred to a Koster test and Hunskarai, S., et al., J.
Neuroscience Meth. 14: 69-76, 1985.
Example 1
[0275] Test substance was administered PO (30 or 100 mg/kg) to
groups of 3 ICR derived male or female mice weighing 22.+-.2 gms
one hour before injection of acetic acid (0.5%, 20 ml/kg IP).
Reduction in the number of writhes by 50 percent or more
(.gtoreq.50%) per group of animals observed during the 5 to 10
minute period after acetic acid administration, relative to a
vehicle treated control group, indicated analgesic activity.
[0276] The results are tabulated hereinbelow:
TABLE-US-00001 TABLE 1 Protocol #50390 Analgesia, Acetic Acid
Writhing % Inh. Compound Route Dose No. No. of Writhes Distilled
water PO 20 ml/kg 1 17 Distilled water PO 20 ml/kg 2 12 Distilled
water PO 20 ml/kg 3 18 0 X .+-. SEM 15.7 .+-. 1.9 Compound I PO 100
mg/kg 1 0 Compound I PO 100 mg/kg 2 0 Compound I PO 100 mg/kg 3 0
100 X .+-. SEM 0 .+-. 0 Compound I PO 30 mg/kg 1 18 Compound I PO
30 mg/kg 2 12 Compound I PO 30 mg/kg 3 15 4 X .+-. SEM 15 .+-. 1.7
Aspirin PO 100 mg/kg 1 0 Aspirin PO 100 mg/kg 2 0 Aspirin PO 100
mg/kg 3 0 100 X .+-. SEM 0 .+-. 0 Note: Compound I, at a dose of
100 mg/kg, 3 out of 3 animals showed slight convulsions 15 minutes
after oral administration.
[0277] As clearly shown, the administration of compound I at 100
mg/Kg was effective in reducing pain, as indicated by the number of
writhes. In fact, when compound I was administered at 100 mg/Kg,
the mice experienced no writhes after acetic acid administration.
The same result was seen with aspirin, a known analgesic.
[0278] This next experiment shows that the compounds of the present
invention are also effective in reducing pain resulting from tissue
injury, such as that caused by injecting a small amount of formalin
subcutaneously into the hindpaw of a mouse.
Example 2
[0279] Test substance was administered (30 or 100 mg/kg) to groups
of 5 ICR derived male or female mice weighing 22.+-.2 gms one hour
before subplantar injection of formalin (0.02 ml, 5%). Reduction of
the induced hind paw licking time recorded during the following 20
to 30 minutes period by 50 percent or more (.gtoreq.50%) indicated
analgesic activity.
[0280] The results are tabulated hereinbelow:
TABLE-US-00002 TABLE 2 Licking Time (sec.) Compound Route Dose N
Indiv. Ave. % Inh. Distilled water PO 20 ml/kg 1 146 Distilled
water PO 20 ml/kg 2 150 Distilled water PO 20 ml/kg 3 121 Distilled
water PO 20 ml/kg 4 134 Distilled water PO 20 ml/kg 5 88 128 0
Compound I PO 100 mg/kg 1 0 Compound I PO 100 mg/kg 2 0 Compound I
PO 100 mg/kg 3 0 Compound I PO 100 mg/kg 4 0 Compound I PO 100
mg/kg 5 0 0 100 Compound I PO 30 mg/kg 1 122 Compound I PO 30 mg/kg
2 125 Compound I PO 30 mg/kg 3 62 Compound I PO 30 mg/kg 4 127
Compound I PO 30 mg/kg 5 63 100 22 Aspirin PO 300 mg/kg 1 30
Aspirin PO 300 mg/kg 2 36 Aspirin PO 300 mg/kg 3 51 Aspirin PO 300
mg/kg 4 9 Aspirin PO 300 mg/kg 5 54 36 72 Note: Compound I, at a
dose of 100 mg/kg, 5 out of 5 animals showed slight convulsions at
15 minutes after oral administration.
[0281] The results clearly show that at 100 mg/Kg, there was less
licking by the mice than when aspirin was administered at 300
mg/Kg. Therefore, this shows that the compounds of the present
invention are more effective than aspirin in reducing pain from
tissue damages.
[0282] The following example illustrates that the compounds of the
present invention are not antagonists of the opioid receptor.
Example 3
[0283] Groups of 4 male ICR mice weighing 22.+-.2 gms were
employed. A dose (30 mg/kg) of test compound dissolved in a vehicle
of saline was administered intraperitoneally. The control group
received vehicle alone. At pretreatment (0 minute) a focused beam
of radiant heat was applied to the middle dorsal surface of the
tail to elicit a tail flick response within 6-7.5 seconds in
pre-treated animals. A maximum cut-off time of 15 seconds was set.
The time required to elicit a pain response was recorded for each
animal at 0 and 30 minutes following administration of test
compound. Prolongation by 50 percent or more (.gtoreq.50%) of the
time required to elicit a tail flick indicated analgesic
activity.
[0284] The results are as indicated hereinbelow:
TABLE-US-00003 TABLE 3 Response Time Compound Route Dose N 0 Min.
30 Min. % Inh. Saline (Vehicle) IP 20 ml/kg 1 6.2 6.2 Saline
(Vehicle) IP 20 ml/kg 2 6.6 5.6 Saline (Vehicle) IP 20 ml/kg 3 7.0
5.3 Saline (Vehicle) IP 20 ml/kg 4 6.3 5.7 0 X 6.5 5.7 SEM 0.2 0.2
Compound I IP 30 mg/kg 1 6.4 5.8 Compound I IP 30 mg/kg 2 7.3 5.0
Compound I IP 30 mg/kg 3 6.4 6.0 Compound I IP 30 mg/kg 4 6.5 6.2 0
X 6.7 5.8 SEM 0.2 0.3 Morphine IP 10 mg/kg 1 7.4 >15 Morphine IP
10 mg/kg 2 6.5 >15 Morphine IP 10 mg/kg 3 6.4 >15 Morphine IP
10 mg/kg 4 7.4 >15 100 X 6.9 15.0 SEM 0.3 0.0
[0285] The data show that the radiant heat induced tail flick
response was unaffected by administration of the compound at 30
mg/Kg. On the other hand, morphine gave a positive response. This
data show that Compound I does not work by the same mechanism as
morphine does; i.e., Compound I does not function through an opioid
receptor.
[0286] The compounds of the present invention do not have affinity
for the serotonin 5-HT.sub.1A receptor as determined by a challenge
with the 5 HT.sub.1A agent, 5-methoxy-N,N-dimethyltryptamine, as
shown by the following example.
Example 4
[0287] Test substance was administered PO (30 mg/kg) to a group of
3 Long Evans derived male or female rats weighing 150.+-.20 gms one
hour before injection of 5-MeODMT
(5-methoxy-N,N-dimethyltryptamine, 3 mg/kg IP). Each animal
exhibiting more than 2 head twitches during the ensuing 1 to 5
minute observation period was considered positive. Positive
responses occurring in 2 or more (.gtoreq.2) of the 3 animals was
considered a significant effect
[0288] The results are tabulated hereinbelow:
TABLE-US-00004 TABLE 4 Compound Route Dose No Head Twitch Ave.
Distilled PO 10 ml/kg 1 0 water (Vehicle) Distilled PO 10 ml/kg 2 0
water (Vehicle) Distilled PO 10 ml/kg 3 0 0 water (Vehicle)
Compound I PO 30 mg/kg 1 2 Compound I PO 30 mg/kg 2 0 Compound I PO
30 mg/kg 3 0 1 Diazepam PO 10 mg/kg 1 3 Diazepam PO 10 mg/kg 2 0
Diazepam PO 10 mg/kg 3 2 2
[0289] No potentiation of 5-MeODMT-induced heat twitch was observed
utilizing 30 mg/Kg of the representative compound PO.
Example 5
[0290] Test substance was administered ICVT
(intracerebroventricular, 30 .mu.g in 5 .mu.l/mouse). The
appearance of convulsions/mortality in 2 or more (.gtoreq.2) of 3
ICR derived male or female mice weighing 22.+-.2 gms within the 5
minutes thereafter would indicate NMDA receptor agonism. At a dose
where no significant agonist activity was seen within 5 minutes,
ability to inhibit NMDA (60 mg/kg IV)--induced Tonic
convulsions/mortality in 2 or more (.gtoreq.2) of 3 ICR derived
male or female mice weighing 22.+-.gms within the following 5
minutes indicated NMDA receptor antagonist activity.
[0291] The results are tabulated hereinbelow:
TABLE-US-00005 TABLE 5 Compound Route Conc. N Agonism Antagonism
Vehicle ICVT 5 .mu.l/mouse 3 0 0 (Saline) Compound I ICVT 30
.mu.g/mouse 3 0 1 Cis-4- ICVT 0.2 .mu.g/mouse 3 0 3 Phosphono-
methyl-2- piperidine- carboxylic acid* NMDA ICVT 1 .mu.g/mouse 3 3
-- *a known potent antagonist at the glutamate site of the NMDA
receptor Note: Compound I, at a dose of 30 .mu.g/mouse, 2 out of 3
animals showed tremors without convulsions after
intracerebroventricular administration.
[0292] The data indicate that the compounds did not directly
inhibit the effects of NMDA activity when 30 ug/mouse was
administered intracerebrally.
[0293] The results hereinabove in the writhing test further
demonstrate that the compounds of the present invention have
analgesic activity for the treatment of pain, including
inflammatory pain, e.g., rheumatoid arthritis.
Example 6
NMDA Induced Hyperalgesia
[0294] Holtzman male rats weighing 275 to 325 grams were prepared
with lumbar intrathecal catheters under isoflurane anesthesia. The
catheters were externalized on the back of the head. Four to five
days after implant, the animals were employed.
[0295] NMDA administration was accomplished using a gear driven
microinjection syringe connected to the spinal catheter by a length
of calibrated PE-90 tubing. The catheter plug was immediately
replaced to avoid back flow and the rat was replaced in its testing
box.
[0296] A modified Hargreaves box was used which allows the
direction of a focused light beam on the underface of the paw
through a glass surface upon which the rat stands. Surface
temperature was maintained at 30.degree. C. Withdrawal of the paw
was taken as the response. Lack of response within twenty seconds
was cause to terminate the test and assign that score.
[0297] The rats were placed on the thermal escape box and allowed
to acclimate for 30 minutes prior to testing. A measurement was
taken for each hindpaw to establish an average baseline latency
(counted as time=0).
(2R)-2-(acetylamino)-N-[(4-fluorophenyl)methyl]-3-methoxypropana-
mide solution, that is, test product in this experiment, was given
at an intrathecal dose of 1 .mu.g/10 .mu.l 10 minutes prior to
intrathecal NMDA. A control group was given an identical amount of
saline 10 minutes prior to intrathecal NMDA. Measurements were then
made at 15, 30, 60, 120, 240 and 360 minutes after intrathecal NMDA
injection. General behavior assessments were made during each
period of observation and include: tactile allodynia
(vocalization/agitation induced by light touch applied to the body
surface), spontaneous vocalization, biting and chewing of body
surface, loss of hind limb placing and stepping reflex, loss of
hind limb weight bearing and loss of righting reflex.
[0298] The saline group (n=2) displayed a hyperalgesic effect with
a baseline latency of approximately 1-second dropping to about 7
seconds after about 45 minutes. The test product group (n=2)
maintained a normal baseline of about 14 second out to 20 minutes
post NMDA injection and then dropping in latency to approximately
10 seconds.
[0299] The preliminary data with the NMDA induced thermal
hyperalgesic suggest that the
2R-2-(acetylamino)-N-[(4-fluorophenyl)methyl]-3-methoxypropanamide
had measurable anti-hyperalgesic actions.
Example 7
[0300] Sprague Dawley male rats weighing 275 to 325 grams was used
in this experiment. In this experiment, the response to neuropathic
pain was determined. The neuropathic preparation used to induce an
allodynic state is the surgical procedure described by Kim and
Chung in Pain, 1992, 50, 355-363 (1992) and outlined in Chaplain,
et al. in J. Neurosci. Meth., 1994, 53, 355-363. Briefly, the left
L.sub.5 and L.sub.6 spinal nerves were isolated adjacent to the
vertebral column and ligated with 6-0 silk suture distal to the
dorsal root ganglion under isoflurane anesthesia. The rats were
allowed a minimum 7 day postoperative recovery period before
placement in the study.
[0301] Testing groups consisted of 6 rats per group. Each group
received test article,
(2R)-2-acetyl-amino)-N-[(4-fluorophenyl)methyl]-3-methoxypropanamide
(hereinafter "test article"), in one of three concentrations
delivered intraperitoneally; the high concentration was 50 mg/kg,
the medium concentration was 30 mg/kg and the low concentration was
20 mg/kg. One group of 6 rats received saline control solution at a
volume equal to that used for test article.
[0302] General behavioral assessments were made during each period
of observation and include: tactile allodynia
(vocalization/agitation induced by light touch applied to the body
surface), spontaneous vocalization, biting and chewing of body
surface, loss of hind limb placing and stepping reflex, loss of
hind limb weight bearing, and loss of righting reflex. All
assessments were noted as "present", "absent" or ranked according
to a graded scale.
[0303] To assess tactile thresholds, rats were placed in a clear
plastic, wire mesh-bottomed cage, divided into individual
compartments. Animals were allowed to accommodate and then baseline
thresholds were taken prior to drug treatment. To determine the 50%
mechanical threshold for paw withdrawal, von Frey hairs were
applied to the plantar mid-hindpaw, avoiding the tori (footpads).
The eight von Frey hairs used are designated by [log(10*force
required to bend hair, mg)] and range from 0.4-15.1 grams. Each
hair was pressed perpendicularly against the paw with sufficient
force to cause slight bending, and held for approximately 6-8
seconds. A positive response was noted if the paw was sharply
withdrawn. Flinching immediately upon removal of the hair was also
considered a positive response. Absence of a response ("-") was
cause to present the next consecutive stronger stimulus; a positive
response ("+") was caused to present the next weaker stimulus.
Stimuli were presented successively until either six data points
were collected, or the maximum or minimum stimulus was reached. If
a minimum stimulus was reached and positive response still
occurred, the threshold was assigned an arbitrary minimum value of
0.25 grams; if a maximum stimulus was presented and no response
occurred, a maximum threshold value of 15 grams was assigned. If a
change in response occurred, either "-" to "+" or "+" to "-",
causing a change in the direction of stimulus presentation from
descending to ascending or vice-versa, four additional data points
were collected subsequent to the change. The resulting pattern of
responses were tabulated and the 50% response threshold computer
using the formula:
log(threshold,mg.times.10)=Xf+kh
[0304] wherein:
[0305] Xf=value of the last von Frey hair applied;
[0306] k=correction factor based on response pattern (from
calibration table) [0307] h=mean distance in log units between
stimuli.
[0308] Based on observations on normal, -operated rats and
sham-operated rats, the cutoff of a 15.1-g hair is selected as the
upper limit for testing.
[0309] The test was performed to establish an average baseline
value, counted as time 0; then again at 15, 30, 60, 120 and 240
minutes after the dosing by the control saline solution or the test
article.
[0310] The results were as follows:
[0311] Four rats were examined at intraperitoneal (IP) doses of 30
to 100 mg/kg.
[0312] One rat was given 100 mg/kg of the test article and within
15 minutes the rat was laterally recumbent displaying seizures and
bleeding from the nose. The animal was euthanized.
[0313] A second rat was given 90 mg/kg of the test article and
within 15 minutes the animal became catatonic and unable to right
itself. The animal became flaccid and displayed severe exopthalmos.
Thirty minutes later there was no change and the animal was
euthanized.
[0314] A third animal was given 60 mg/kg of the test article and
within 15 minutes the animal became catatonic and displayed
abnormal ambulation. Severe exopthalmos was also noted. Thirty
minutes later, the animal's ambulation appeared worse and it was
subsequently euthanized.
[0315] A fourth rat was given 50 mg/kg of the test article. The rat
appeared slightly catatonic which lasted 60 minutes. No other
behavioral deficits were noted.
[0316] A fifth rat was given 30 mg/kg of the test article IP and it
displayed no behavioral deficit.
[0317] Fifteen mg/kg of the test article had previously been shown
to have no observable affect.
[0318] Using the Chung Model a dose dependent response was seen.
The effect lasted approximately 2 hours after injection. Rats given
the high dose of 50 mg/kg IP showed a threshold increase from 2 to
11 grams. Behaviorally 6 of 6 rats appeared sedated for
approximately 1 hour post injection. No other deficits were noted.
Rats given 20 mg and 30 mg/kg test article showed an increase in
threshold from approximately 2 to 5 grams. Four of 6 rats given 30
mg appeared sedated for approximately 1 hour. No other deficits
were noted. Previous study of 15 mg/kg showed no effect on the
Chung Model. Group comparisons using one-way ANOVA performed on
maximum effect, area under the curve and on specific time points
(15 and 30 minutes post injection) showed no significant difference
between groups. The nonparametric Jonckheere Test of ordered
alternatives was performed and showed a dose related difference at
the p<0.05 level.
[0319] Test Article delivered intraperitoneally resulted in a
significant reversal of tactile allodynia otherwise observed in the
Chung model of neuropathy. This model has historically been shown
to be affected by a number of clinically relevant agents, such as
alpha 2 adrenergic agonists, NMDA receptor antagonists and N-type
Ca channel blockers. Importantly, these observations occurred at
doses that were believed to be without significant effects upon
competing behaviors (e.g., sedation or motor impairment).
[0320] The above preferred embodiments and examples are given to
illustrate the scope and spirit of the present invention. The
embodiments and examples described herein will make apparent to
those skilled in the art other embodiments and examples. These
other embodiments and examples are within the contemplation of the
present invention. Therefore, the present invention should be
limited only by the appended claims.
* * * * *