U.S. patent application number 10/578950 was filed with the patent office on 2009-03-19 for substituted triazoles as sodium channel blockers.
Invention is credited to Prasun K. Chakravarty, Michael H. Fisher, Edward Gonzalez, Hyun Ok, Brenda Palucki, Min K. Park, William H. Parsons, Rosemary Sisco, Bishan Zhou, Louis L. Zuegner, III.
Application Number | 20090074890 10/578950 |
Document ID | / |
Family ID | 34590316 |
Filed Date | 2009-03-19 |
United States Patent
Application |
20090074890 |
Kind Code |
A1 |
Park; Min K. ; et
al. |
March 19, 2009 |
Substituted Triazoles as Sodium Channel Blockers
Abstract
Substituted triazole compounds represented by Formula I, II or
III, or pharmaceutically acceptable salts thereof. Pharmaceutical
compositions comprise an effective amount of the instant compounds,
either alone, or in combination with one or more other
therapeutically active compounds, and a pharmaceutically acceptable
carrier. Methods of treating conditions associated with, or caused
by, sodium channel activity, including, for example, acute pain,
chronic pain, visceral pain, inflammatory pain, neuropathic pain,
migraine, headache pain, migraine headache, epilepsy, irritable
bowel syndrome, diabetic neuropathy, multiple sclerosis, manic
depression and bipolar disorder, comprise administering an
effective amount of the present compounds, either alone, or in
combination with one or more other therapeutically active
compounds. A method of administering local anesthesia comprises
administering an effective amount of a compound of the instant
invention, either alone, or in combination with one or more other
therapeutically active compounds, and a pharmaceutically acceptable
carrier (I), (II), (III). ##STR00001##
Inventors: |
Park; Min K.; (Whippany,
NJ) ; Chakravarty; Prasun K.; (Edison, NJ) ;
Zhou; Bishan; (Hoboken, NJ) ; Gonzalez; Edward;
(Iselin, NJ) ; Ok; Hyun; (Colonia, NJ) ;
Palucki; Brenda; (Hillsborough, NJ) ; Parsons;
William H.; (Belle Mead, NJ) ; Sisco; Rosemary;
(Old Bridge, NJ) ; Fisher; Michael H.; (Ringoes,
NJ) ; Zuegner, III; Louis L.; (Flemington,
NJ) |
Correspondence
Address: |
MERCK AND CO., INC
P O BOX 2000
RAHWAY
NJ
07065-0907
US
|
Family ID: |
34590316 |
Appl. No.: |
10/578950 |
Filed: |
November 5, 2004 |
PCT Filed: |
November 5, 2004 |
PCT NO: |
PCT/US2004/037280 |
371 Date: |
May 5, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60518890 |
Nov 10, 2003 |
|
|
|
Current U.S.
Class: |
424/722 ;
514/383; 548/266.8 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 25/06 20180101; A61P 23/02 20180101; A61P 25/00 20180101; A61P
31/12 20180101; A61P 43/00 20180101; A61P 19/02 20180101; A61P 9/06
20180101; A61P 3/10 20180101; C07D 403/10 20130101; A61P 25/02
20180101; A61P 1/06 20180101; A61P 25/08 20180101; C07D 249/10
20130101; A61P 17/02 20180101; A61P 25/28 20180101; A61P 35/00
20180101; A61P 37/00 20180101; A61P 1/00 20180101; A61P 31/22
20180101; A61P 31/18 20180101; A61P 25/04 20180101; A61P 9/00
20180101 |
Class at
Publication: |
424/722 ;
548/266.8; 514/383 |
International
Class: |
C07D 249/08 20060101
C07D249/08; A61P 29/00 20060101 A61P029/00; A61P 9/00 20060101
A61P009/00; A61P 25/00 20060101 A61P025/00; A61K 33/00 20060101
A61K033/00; A61K 31/4196 20060101 A61K031/4196; A61P 1/00 20060101
A61P001/00; A61P 31/12 20060101 A61P031/12; A61P 37/00 20060101
A61P037/00 |
Claims
1. A compound represented by Formula (I) or (II): ##STR00118## or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 is (a) H,
(b) C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-alkynyl, any of which is optionally substituted
with one or more of the following substituents: NR.sup.aR.sup.b,
COOH, CONR.sup.aR.sup.b, or (c) --C(.dbd.O)R.sup.a, COOR.sup.a,
CONR.sup.aR.sup.b--; R.sup.a is: (a) H, (b) C.sub.1-C.sub.6-alkyl,
optionally substituted with one or more of halogen or CF.sub.3, or
(c) CF.sub.3; R.sup.b is (a) H, or (b) C.sub.1-C.sub.6-alkyl,
optionally substituted with one or more of halogen or CF.sub.3, or
(c) CF.sub.3; R.sup.2 is H or C.sub.1-4alkyl; R.sup.3 and R.sup.4
each independently is: (a) H, (b)
--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl or
--O--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl, (c)
halogen, or (d) --C.sub.1-C.sub.6 alkyl, optionally substituted
with one or more of halogen or CF.sub.3; and R.sup.5, R.sup.6 and
R.sup.7 each independently is: (a) H, (b)
--O--C.sub.1-C.sub.6-alkyl, --O--C.sub.1-C.sub.6-alkenyl,
--O--C.sub.1-C.sub.6-alkynyl, any of which is optionally
substituted with one or more of halogen or CF.sub.3, (c)
--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl, or
--O--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl, (d)
--O-phenyl, or --O--C.sub.1-C.sub.4-alkyl-phenyl, wherein phenyl is
optionally substituted with 1-3 substituents selected from i)
halogen, ii) --CN, iii) --NO.sub.2, iv) CF.sub.3, v) --OR.sup.a,
vi) --NR.sup.aR.sup.b, vii) --C.sub.0-4alkyl-CO--OR.sup.a,
viii)-(C.sub.0-4-alkyl) --CO--N(R.sup.a)(R.sup.b), ix) and x)
--C.sub.1-10 alkyl, wherein one or more of the alkyl carbons can be
replaced by a --NR.sup.a, C(O)--O--, or
--N(R.sup.a)--C(O)--N(R.sup.a)--, or (e) halogen, --OR.sup.a, or
phenyl wherein phenyl is optionally substituted with 1-3
substituents selected from i) halogen, ii) --CN, iii) --NO.sub.2,
iv) CF.sub.3, v) pyrazolyl, vi) --OR.sup.a, vii) --NR.sup.aR.sup.b,
viii) --C.sub.0-4alkyl-CO--OR.sup.a, ix)-(C.sub.0-4alkyl)
--CO--N(R.sup.a)(R.sup.b), and x) --C.sub.1-10alkyl, wherein one or
more of the alkyl carbons can be replaced by a --NR.sup.a,
C(O)--O--, or --N(R.sup.a)--C(O)--N(R.sup.a)--.
2. The compound of claim 1 described by the chemical Formula (I),
or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is
other than H and is attached at the ortho position.
3. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkyl.
4. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is optionally substituted phenyl.
5. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is --O--C.sub.1-C.sub.4-alkyl-phenyl,
wherein phenyl is optionally substituted.
6. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkenyl.
7. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein R.sup.6 is halogen.
8. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is halogen.
9. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 and R.sup.4 are halogen.
10. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3, R.sup.4 and R.sup.6 are halogen.
11. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is
--O--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl.
12. The compound of claim 1 described by the chemical Formula (II),
or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is
other than H and is attached at the ortho position.
13. The compound of claim 12, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkyl.
14. The compound of claim 12, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is optionally substituted phenyl.
15. The compound of claim 12, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is --O--C.sub.1-C.sub.4-alkyl-phenyl,
wherein phenyl is optionally substituted.
16. The compound of claim 12, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkenyl.
17. The compound of claim 12, or a pharmaceutically acceptable salt
thereof, wherein R.sup.6 is halogen.
18. The compound of claim 12, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is halogen.
19. The compound of claim 12, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 and R.sup.4 are halogen.
20. The compound of claim 12, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3, R.sup.4 and R.sup.6 are halogen.
21. The compound of claim 12, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is
--O--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl.
22. A compound represented by Formula (III) ##STR00119## or a
pharmaceutically acceptable salt thereof, wherein R.sup.1-R.sup.7
each is as defined in claim 1.
23. The compound of claim 22, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is other than H and is attached at the
ortho position.
24. The compound of claim 23, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkyl.
25. The compound of claim 23, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is optionally substituted phenyl.
26. The compound of claim 23, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is --O--C.sub.1-C.sub.4-alkyl-phenyl,
wherein phenyl is optionally substituted.
27. The compound of claim 23, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkenyl.
28. The compound of claim 23, or a pharmaceutically acceptable salt
thereof, wherein R.sup.6 is halogen.
29. The compound of claim 23, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is halogen.
30. The compound of claim 23, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 and R.sup.4 are halogen.
31. The compound of claim 23, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3, R.sup.4 and R.sup.6 are halogen.
32. The compound of claim 23, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is
--O--CO--C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl.
33. A compound represented by ##STR00120## ##STR00121##
##STR00122## ##STR00123## ##STR00124## ##STR00125## ##STR00126##
##STR00127## ##STR00128## ##STR00129## ##STR00130##
##STR00131##
34. A pharmaceutical composition comprising a therapeutically
effective amount of a compound according to claim 1, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
35. The pharmaceutical composition according to claim 34, further
comprising a second therapeutic agent selected from the group
consisting of: i) opiate agonists, ii) opiate antagonists, iii)
calcium channel antagonists, iv) 5HT receptor agonists, v) 5HT
receptor antagonists vi) sodium channel antagonists, vii) NMDA
receptor agonists, viii) NMDA receptor antagonists, ix) COX-2
selective inhibitors, x) NK1 antagonists, xi) non-steroidal
anti-inflammatory drugs, xii) selective serotonin reuptake
inhibitors, xiii) selective serotonin and norepinephrine reuptake
inhibitors, xiv) tricyclic antidepressant drugs, xv) norepinephrine
modulators, xvi) lithium, xvii) valproate, and xviii)
neurontin.
36. A method of treatment or prevention of pain comprising the step
of administering to a patient in need thereof a therapeutically
effective amount, or a prophylactically effective amount, of a
compound according to claim 1, or a pharmaceutically acceptable
salt thereof.
37. A method of treatment or prevention of chronic, visceral,
inflammatory and/or neuropathic pain syndromes comprising the step
of administering to a patient in need thereof a therapeutically
effective amount, or a prophylactically effective amount, of a
compound according to claim 1, or a pharmaceutically acceptable
salt thereof.
38. A method of treatment or prevention of pain resulting from, or
associated with, traumatic nerve injury, nerve compression or
entrapment, postherpetic neuralgia, trigeminal neuralgia, diabetic
neuropathy, cancer and/or chemotherapy, comprising the step of
administering to a patient in need thereof a therapeutically
effective amount, or a prophylactically effective amount, of a
compound according to claim 1, or a pharmaceutically acceptable
salt thereof.
39. A method of treatment or prevention of chronic lower back pain
comprising the step of administering to a patient in need thereof a
therapeutically effective amount, or a prophylactically effective
amount, of a compound according to claim 1, or a pharmaceutically
acceptable salt thereof.
40. A method of treatment or prevention of phantom limb pain
comprising the step of administering to a patient in need thereof a
therapeutically effective amount, or a prophylactically effective
amount, of a compound according to claim 1, or a pharmaceutically
acceptable salt thereof.
41. A method of treatment or prevention of HIV- and HIV
treatment-induced neuropathy, chronic pelvic pain, neuroma pain,
complex regional pain syndrome, chronic arthritic pain and/or
related neuralgias comprising the step of administering to a
patient in need thereof a therapeutically effective amount, or a
prophylactically effective amount, of a compound according to claim
1, or a pharmaceutically acceptable salt thereof.
42. A method of administering local anesthesia comprising the step
of administering to a patient in need thereof a therapeutically
effective amount, or a prophylactically effective amount, of a
compound according to claim 1, or a pharmaceutically acceptable
salt thereof.
43. A method of treatment or prevention of irritable bowel syndrome
and/or Crohn's disease comprising the step of administering to a
patient in need thereof a therapeutically effective amount, or a
prophylactically effective amount, of a compound according to claim
1, or a pharmaceutically acceptable salt thereof.
44. A method of treatment or prevention of epilepsy and/or partial
and generalized tonic seizures comprising the step of administering
to a patient in need thereof a therapeutically effective amount, or
a prophylactically effective amount, of a compound according to
claim 1, or a pharmaceutically acceptable salt thereof.
45. A method for neuroprotection under ischaemic conditions caused
by stroke or neural trauma comprising the step of administering to
a patient in need thereof a therapeutically effective amount, or a
prophylactically effective amount, of a compound according to claim
1, or a pharmaceutically acceptable salt thereof.
46. A method of treatment or prevention of multiple sclerosis
comprising the step of administering to a patient in need thereof a
therapeutically effective amount, or a prophylactically effective
amount, of a compound according to claim 1, or a pharmaceutically
acceptable salt thereof.
47. A method of treatment or prevention of bipolar disorder
comprising the step of administering to a patient in need thereof a
therapeutically effective amount, or a prophylactically effective
amount, of a compound according to claim 1, or a pharmaceutically
acceptable salt thereof.
48. A method of treatment or prevention of tachy-arrhythmias
comprising the step of administering to a patient in need thereof a
therapeutically effective amount, or a prophylactically effective
amount, of a compound according to claim 1, or a pharmaceutically
acceptable salt thereof.
49. A method of treatment or prevention of migraine, headache pain
and/or migraine headache comprising the step of administering to a
patient in need thereof a therapeutically effective amount, or a
prophylactically effective amount, of a compound according to claim
1, or a pharmaceutically acceptable salt thereof.
50. A pharmaceutical composition comprising a therapeutically
effective amount of a compound according to claim 22, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
51. The pharmaceutical composition according to claim 49, further
comprising a second therapeutic agent selected from the group
consisting of: i) opiate agonists, ii) opiate antagonists, iii)
calcium channel antagonists, iv) 5HT receptor agonists, v) 5HT
receptor antagonists vi) sodium channel antagonists, vii) NMDA
receptor agonists, viii) NMDA receptor antagonists, ix) COX-2
selective inhibitors, x) NK1 antagonists, xi) non-steroidal
anti-inflammatory drugs, xii) selective serotonin reuptake
inhibitors, xiii) selective serotonin and norepinephrine reuptake
inhibitors, xiv) tricyclic antidepressant drugs, xv) norepinephrine
modulators, xvi) lithium, xvii) valproate, and xviii)
neurontin.
52. A method of treatment or prevention of pain comprising the step
of administering to a patient in need thereof a therapeutically
effective amount, or a prophylactically effective amount, of a
compound according to claim 22, or a pharmaceutically acceptable
salt thereof.
53. A method of treatment or prevention of chronic, visceral,
inflammatory and/or neuropathic pain syndromes comprising the step
of administering to a patient in need thereof a therapeutically
effective amount, or a prophylactically effective amount, of a
compound according to claim 22, or a pharmaceutically acceptable
salt thereof.
54. A method of treatment or prevention of pain resulting from
traumatic nerve injury, nerve compression or entrapment,
postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy,
cancer and/or chemotherapy comprising the step of administering to
a patient in need thereof a therapeutically effective amount, or a
prophylactically effective amount, of a compound according to claim
22, or a pharmaceutically acceptable salt thereof.
55. A method of treatment or prevention of chronic lower back pain
comprising the step of administering to a patient in need thereof a
therapeutically effective amount, or a prophylactically effective
amount, of a compound according to claim 22, or a pharmaceutically
acceptable salt thereof.
56. A method of treatment or prevention of phantom limb pain
comprising the step of administering to a patient in need thereof a
therapeutically effective amount, or a prophylactically effective
amount, of a compound according to claim 22, or a pharmaceutically
acceptable salt thereof.
57. A method of treatment or prevention of HIV- and HIV
treatment-induced neuropathy, chronic pelvic pain, neuroma pain,
complex regional pain syndrome, chronic arthritic pain and/or
related neuralgias comprising the step of administering to a
patient in need thereof a therapeutically effective amount, or a
prophylactically effective amount, of a compound according to claim
22, or a pharmaceutically acceptable salt thereof.
58. A method of administering local anesthesia comprising the step
of administering to a patient in need thereof a therapeutically
effective amount, or a prophylactically effective amount, of a
compound according to claim 22, or a pharmaceutically acceptable
salt thereof.
59. A method of treatment or prevention of irritable bowel syndrome
and/or Crohn's disease comprising the step of administering to a
patient in need thereof a therapeutically effective amount, or a
prophylactically effective amount, of a compound according to claim
22, or a pharmaceutically acceptable salt thereof.
60. A method of treatment or prevention of epilepsy and/or partial
and generalized tonic seizures comprising the step of administering
to a patient in need thereof a therapeutically effective amount, or
a prophylactically effective amount, of a compound according to
claim 22, or a pharmaceutically acceptable salt thereof.
61. A method for neuroprotection under ischaemic conditions caused
by stroke or neural trauma comprising the step of administering to
a patient in need thereof a therapeutically effective amount, or a
prophylactically effective amount, of a compound according to claim
22, or a pharmaceutically acceptable salt thereof.
62. A method of treatment or prevention of multiple sclerosis
comprising the step of administering to a patient in need thereof a
therapeutically effective amount, or a prophylactically effective
amount, of a compound according to claim 22, or a pharmaceutically
acceptable salt thereof.
63. A method of treatment or prevention of bipolar disorder
comprising the step of administering to a patient in need thereof a
therapeutically effective amount, or a prophylactically effective
amount, of a compound according to claim 22, or a pharmaceutically
acceptable salt thereof.
64. A method of treatment or prevention of tachy-arrhythmias
comprising the step of administering to a patient in need thereof a
therapeutically effective amount, or a prophylactically effective
amount, of a compound according to claim 22, or a pharmaceutically
acceptable salt thereof.
65. A method of treatment or prevention of migraine, headache pain
and/or migraine headache comprising the step of administering to a
patient in need thereof a therapeutically effective amount, or a
prophylactically effective amount, of a compound according to claim
22, or a pharmaceutically acceptable salt thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention is directed to a series of substituted
triazole compounds. In particular, this invention is directed to
substituted triazoles that are sodium channel blockers useful for
the treatment and prevention of chronic and neuropathic pain. The
compounds of the present invention are also useful for the
treatment of other conditions, including acute pain, inflammatory
pain, visceral pain, migraine, headache pain, migraine headache,
and disorders of the central nervous system (CNS) such as epilepsy,
manic depression, bipolar disorder and diabetic neuropathy.
BACKGROUND OF THE INVENTION
[0002] Voltage-gated ion channels allow electrically excitable
cells to generate and propagate action potentials and therefore are
crucial for nerve and muscle function. Sodium channels play a
special role by mediating rapid depolarization, which constitutes
the rising phase of the action potential and in turn activates
voltage-gated calcium and potassium channels. Voltage-gated sodium
channels represent a multigene family. Nine sodium channel subtypes
have been cloned and functionally expressed to date. [Clare, J. J.,
Tate, S. N., Nobbs, M. & Romanos, M. A. Voltage-gated sodium
channels as therapeutic targets. Drug Discovery Today 5, 506-520
(2000)]. They are differentially expressed throughout muscle and
nerve tissues and show distinct biophysical properties. All
voltage-gated sodium channels are characterized by a high degree of
selectivity for sodium over other ions and by their
voltage-dependent gating. [Catterall, W. A. Structure and function
of voltage-gated sodium and calcium channels. Current Opinion in
Neurobiology 1, 5-13 (1991)]. At negative or hyperpolarized
membrane potentials, sodium channels are closed. Following membrane
depolarization, sodium channels open rapidly and then inactivate.
Sodium channels only conduct currents in the open state and, once
inactivated, have to return to the resting state, favored by
membrane hyperpolarization, before they can reopen. Different
sodium channel subtypes vary in the voltage range over which they
activate and inactivate as well as in their activation and
inactivation kinetics.
[0003] Sodium channels are the target of a diverse array of
pharmacological agents, including neurotoxins, antiarrhythmics,
anticonvulsants and local anesthetics. [Clare, J. J., Tate, S. N.,
Nobbs, M. & Romanos, M. A. Voltage-gated sodium channels as
therapeutic targets. Drug Discovery Today 5, 506-520 (2000)].
Several regions in the sodium channel secondary structure are
involved in interactions with these blockers and most are highly
conserved. Indeed, most sodium channel blockers known to date
interact with similar potency with all channel subtypes.
Nevertheless, it has been possible to produce sodium channel
blockers with therapeutic selectivity and a sufficient therapeutic
window for the treatment of epilepsy (e.g. lamotrigine, phenyloin
and carbamazepine) and certain cardiac arrhythmias (e.g.
lignocaine, tocainide and mexiletine).
[0004] It is well known that the voltage-gated Na.sup.+ channels in
nerves play a critical role in neuropathic pain. Injuries of the
peripheral nervous system often result in neuropathic pain
persisting long after the initial injury resolves. Examples of
neuropathic pain include, but are not limited to, postherpetic
neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower
back pain, phantom limb pain, pain resulting from cancer and
chemotherapy, chronic pelvic pain, complex regional pain syndrome
and related neuralgias. It has been shown in human patients as well
as in animal models of neuropathic pain, that damage to primary
afferent sensory neurons can lead to neuroma formation and
spontaneous activity, as well as evoked activity in response to
normally innocuous stimuli. [Carter, G. T. and B. S. Galer,
Advances in the management of neuropathic pain. Physical Medicine
and Rehabilitation Clinics of North America, 2001. 12(2): p.
447-459]. The ectopic activity of normally silent sensory neurons
is thought to contribute to the generation and maintenance of
neuropathic pain. Neuropathic pain is generally assumed to be
associated with an increase in sodium channel activity in the
injured nerve. [Baker, M. D. and J. N. Wood, Involvement of Na
channels in pain pathways. TRENDS in Pharmacological Sciences,
2001. 22(1): p. 27-31.].
[0005] Indeed, in rat models of peripheral nerve injury, ectopic
activity in the injured nerve corresponds to the behavioral signs
of pain. In these models, intravenous application of the sodium
channel blocker and local anesthetic lidocaine can suppress the
ectopic activity and reverse the tactile allodynia at
concentrations that do not affect general behavior and motor
function. [Mao, J. and L. L. Chen, Systemic lidocaine for
neuropathic pain relief. Pain, 2000. 87: p. 7-17.]. These effective
concentrations were similar to concentrations shown to be
clinically efficacious in humans. [Tanelian, D. L. and W. G. Brose,
Neuropathic pain can be relieved by drugs that are use-dependent
sodium channel blockers: lidocaine, carbamazepine and mexiletine.
Anesthesiology, 1991. 74(5): p. 949-951.]. In a placebo-controlled
study, continuous infusion of lidocaine caused reduced pain scores
in patients with peripheral nerve injury, and in a separate study,
intravenous lidocaine reduced pain intensity associated with
postherpetic neuralgia (PHN). [Mao, J. and L. L. Chen, Systemic
lidocaine for neuropathic pain relief. Pain, 2000. 87: p. 7-17.
Anger, T., et al., Medicinal chemistry of neuronal voltage-gated
sodium channel blockers. Journal of Medicinal Chemistry, 2001.
44(2): p. 115-137.]. Lidoderm.RTM., lidocaine applied in the form
of a dermal patch, is currently the only FDA approved treatment for
PHN. [Devers, A. and B. S. Galer, Topical lidocaine patch relieves
a variety of neuropathic pain conditions: an open-label study.
Clinical Journal of Pain, 2000. 16(3): p. 205-208.].
[0006] In addition to neuropathic pain, sodium channel blockers
have clinical uses in the treatment of epilepsy and cardiac
arrhythmias. Recent evidence from animal models suggests that
sodium channel blockers may also be useful for neuroprotection
under ischaemic conditions caused by stroke or neural trauma and in
patients with multiple sclerosis (MS). [Clare, J. J. et. al. And
Anger, T. et. al.].
[0007] International Patent Publication WO 00/57877 describes aryl
substituted pyrazoles, imidazoles, oxazoles, thiazoles, and
pyrroles and their uses as sodium channel blockers. International
Patent Publication WO 01/68612 describes aryl substituted
pyridines, pyrimidines, pyrazines and triazines and their uses as
sodium channel blockers. International Patent Publication WO
99/32462 describes triazine compounds for the treatment for CNS
disorders. However, there remains a need for novel compounds and
compositions that therapeutically block neuronal sodium channels
with less side effects and higher potency than currently known
compounds.
SUMMARY OF THE INVENTION
[0008] The present invention is directed to substituted triazole
compounds which are sodium channel blockers useful for the
treatment and prevention of chronic and neuropathic pain. The
compounds of the present invention are also useful for the
treatment and prevention of other conditions, including disorders
of the CNS such as epilepsy, manic depression and bipolar disorder.
This invention also provides pharmaceutical compositions comprising
a compound of the present invention, either alone, or in
combination with one or more therapeutically active compounds, and
a pharmaceutically acceptable carrier.
[0009] This invention further comprises methods for the treatment
and prevention of acute pain, visceral pain, migraine, headache
pain, migraine headache, inflammatory pain, and disorders of the
CNS including, but not limited to, epilepsy, manic depression and
bipolar disorder comprising administering the compounds and
pharmaceutical compositions of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The present invention comprises compounds represented by
Formula (I) or (II):
##STR00002##
or pharmaceutically acceptable salts thereof, wherein
R.sup.1 is
(a) H,
[0011] (b) C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-alkynyl, any of which is optionally substituted
with one or more of the following substituents: NR.sup.aR.sup.b,
COOH, CONR.sup.aR.sup.b, or
(c) --C(.dbd.O)R.sup.a, COOR.sup.a, CONR.sup.aR.sup.b;
R.sup.a is
(a) H,
[0012] (b) C.sub.1-C.sub.6-alkyl, optionally substituted with one
or more of halogen or CF.sub.3, or
(c) CF.sub.3;
R.sup.b is
(a) H, or
[0013] (b) C.sub.1-C.sub.6-alkyl, optionally substituted with one
or more of halogen or CF.sub.3, or
(c) CF.sub.3;
[0014] R.sup.2 is H or C.sub.1-4 alkyl; R.sup.3 and R.sup.4 each
independently is
(a) H,
[0015] (b) --C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl
or --O--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl, (c)
halogen, or (d) --C.sub.1-C.sub.6 alkyl, optionally substituted
with one or more of halogen or CF.sub.3; and R.sup.5, R.sup.6 and
R.sup.7 each independently is
(a) H,
[0016] (b) --O--C.sub.1-C.sub.6-alkyl,
--O--C.sub.1-C.sub.6-alkenyl, --O--C.sub.1-C.sub.6-alkynyl, any of
which is optionally substituted with one or more of halogen or
CF.sub.3, (c)
--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl, or
--O--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl, (d)
--O-phenyl, or --O--C.sub.1-C.sub.4-alkyl-phenyl, wherein phenyl is
optionally substituted with 1-3 substituents selected from i)
halogen, ii)-CN, iii) --NO.sub.2, iv) CF.sub.3, v) --OR.sup.a, vi)
--NR.sup.aR.sup.b, vii) --C.sub.0-4alkyl-CO--OR.sup.a, viii)
--(C.sub.0-4alkyl)-CO--N(R.sup.a)(R.sup.b), ix) and x) --C.sub.1-10
alkyl, wherein one or more of the alkyl carbons can be replaced by
a --NR.sup.a, C(O)--O--, or --N(R.sup.a)--C(O)--N(R.sup.a)--, or
(e) halogen, --OR.sup.a, or phenyl wherein phenyl is optionally
substituted with 1-3 substituents selected from i) halogen, ii)-CN,
iii) --NO.sub.2, iv) CF.sub.3, v) pyrazolyl, vi) --OR.sup.a, vii)
--NR.sup.aR.sup.b, viii) --C.sub.0-4-alkyl-CO--OR.sup.a, ix)
--C.sub.0-4-alkyl) --CO--N(R.sup.a)(R.sup.b), and x)
--C.sub.1-10alkyl, wherein one or more of the alkyl carbons can be
replaced by a --NR.sup.a, C(O)--O--, or
--N(R.sup.a)--C(O)--N(R.sup.a)--.
[0017] The present invention further comprises compounds described
by Formula III:
##STR00003##
or pharmaceutical salts thereof, wherein R.sup.1-R.sup.7 each is as
defined above.
[0018] In a first aspect, the present invention provides a compound
described by the chemical Formula (I), or a pharmaceutically
acceptable salt thereof, wherein
[0019] R.sup.5 is other than H and is attached at the ortho
position.
[0020] In one embodiment of this first aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0021] R.sup.5 is optionally substituted phenyl.
[0022] In a second embodiment of this first aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0023] R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkyl.
[0024] In a third embodiment of this first aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0025] R.sup.5 is --O--C.sub.1-C.sub.4-alkyl-phenyl, wherein phenyl
is optionally substituted.
[0026] In another embodiment of this first aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0027] R.sup.6 is halogen.
[0028] In an additional embodiment of this first aspect, the
present invention provides a compound, or a pharmaceutically
acceptable salt thereof, wherein
[0029] R.sup.3 is halogen.
[0030] In a further embodiment of this first aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0031] R.sup.3 and R.sup.4 are halogen.
[0032] In a still further embodiment of this first aspect, the
present invention provides a compound, or a pharmaceutically
acceptable salt thereof, wherein
[0033] R.sup.3, R.sup.4 and R.sup.6 are halogen.
[0034] In yet another embodiment of this first aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0035] R.sup.3 is
--O--CO--C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl.
[0036] In a yet still further embodiment of this first aspect, the
present invention provides a compound, or a pharmaceutically
acceptable salt thereof, wherein
[0037] R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkenyl.
[0038] In a second aspect, the present invention provides a
compound described by the chemical Formula (II), or a
pharmaceutically acceptable salt thereof, wherein
[0039] R.sup.5 is other than H and is attached at the ortho
position.
[0040] In one embodiment of this second aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0041] R.sup.5 is optionally substituted phenyl.
[0042] In a second embodiment of this second aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0043] R.sup.5 is --O--C.sub.1-C.sub.4-alkyl-phenyl, wherein phenyl
is optionally substituted.
[0044] In a third embodiment of this second aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0045] R.sup.5 is optionally substituted
--C.sub.1-C.sub.6-alkenyl.
[0046] In a fourth embodiment of this second aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0047] R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkyl.
[0048] In another embodiment of this second aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0049] R.sup.6 is halogen.
[0050] In an additional embodiment of this second aspect, the
present invention provides a compound, or a pharmaceutically
acceptable salt thereof, wherein
[0051] R.sup.3 is halogen.
[0052] In a further embodiment of this second aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0053] R.sup.3 and R.sup.4 are halogen.
[0054] In a still further embodiment of this second aspect, the
present invention provides a compound, or a pharmaceutically
acceptable salt thereof, wherein
[0055] R.sup.3, R.sup.4 and R.sup.6 are halogen.
[0056] In yet another embodiment of this second aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0057] R.sup.3 is
--O--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl.
[0058] In a third aspect, the present invention provides a compound
described by the chemical Formula (III), or a pharmaceutically
acceptable salt thereof, wherein
[0059] R.sup.5 is other than H and is attached at the ortho
position.
[0060] In one embodiment of this third aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0061] R.sup.5 is optionally substituted phenyl.
[0062] In a second embodiment of this third aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0063] R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkyl.
[0064] In a third embodiment of this third aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0065] R.sup.5 is --O--C.sub.1-C.sub.4-alkyl-phenyl, wherein phenyl
is optionally substituted.
[0066] In a fourth embodiment of this third aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0067] R.sup.5 is optionally substituted
--O--C.sub.1-C.sub.6-alkenyl.
[0068] In another embodiment of this third aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0069] R.sup.3 is halogen.
[0070] In a further embodiment of this third aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0071] R.sup.6 is halogen.
[0072] In a still further embodiment of this third aspect, the
present invention provides a compound, or a pharmaceutically
acceptable salt thereof, wherein
[0073] R.sup.3 and R.sup.4 are halogen.
[0074] In a yet still further embodiment of this third aspect, the
present invention provides a compound, or a pharmaceutically
acceptable salt thereof, wherein
[0075] R.sup.3, R.sup.4 and R.sup.6 are halogen.
[0076] In yet another embodiment of this third aspect, the present
invention provides a compound, or a pharmaceutically acceptable
salt thereof, wherein
[0077] R.sup.3 is
--O--C.sub.0-C.sub.4-alkyl-C.sub.1-C.sub.4-perfluoroalkyl.
[0078] As used herein, "alkyl" as well as other groups having the
prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, and
alkynyl means carbon chains which may be linear or branched or
combinations thereof. Examples of alkyl groups include methyl,
ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl,
hexyl, and heptyl. "Alkenyl," "alkynyl" and other like terms
include carbon chains containing at least one unsaturated C--C
bond.
[0079] The terms "C.sub.0-4alkyl" and "C.sub.0-C.sub.4-alkyl"
include alkyls containing 4, 3, 2, 1, or no carbon atoms. An alkyl
with no carbon atoms is a hydrogen atom substituent when the alkyl
is a terminal group and is a direct bond when the alkyl is a
bridging group.
[0080] The term "amine," unless specifically stated otherwise,
includes primary, secondary and tertiary amines substituted with
C.sub.0-6alkyl.
[0081] The term "carbonyl," unless specifically stated otherwise,
includes a C.sub.0-6alkyl substituent group when the carbonyl is
terminal.
[0082] The term "halogen" includes fluorine, chlorine, bromine and
iodine atoms.
[0083] The term "optionally substituted" is intended to include
both substituted and unsubstituted. Thus, for example, optionally
substituted phenyl could represent a pentafluorophenyl or a phenyl
ring. Further, optionally substituted multiple moieties such as,
for example, alkyl-phenyl are intended to mean that the alkyl and
the phenyl groups are optionally substituted. If only one of the
multiple moieties is optionally substituted then it will be
specifically recited such as "an --O--C.sub.1-C.sub.4-alkyl-phenyl,
wherein phenyl is optionally substituted with halogen."
[0084] Compounds described herein may contain one or more double
bonds and may thus give rise to cis/trans isomers as well as other
conformational isomers. The present invention includes all such
possible isomers as well as mixtures of such isomers unless
specifically stated otherwise. When the indicated site has only a
single bond, the presence of the required hydrogens is understood.
When the site is a double bond, then cis/trans isomers are formed
and are encompassed by this invention.
[0085] Compounds described herein can contain one or more
asymmetric centers and may thus give rise to diastereoisomers and
optical isomers. The present invention includes all such possible
diastereoisomers as well as their racemic mixtures, their
substantially pure resolved enantiomers, all possible geometric
isomers, and pharmaceutically acceptable salts thereof. The above
chemical Formulas are shown without a definitive stereochemistry at
certain positions. The present invention includes all stereoisomers
of the chemical Formulas and pharmaceutically acceptable salts
thereof. Further, mixtures of stereoisomers as well as isolated
specific stereoisomers are also included. During the course of the
synthetic procedures used to prepare such compounds, or in using
racemization or epimerization procedures known to those skilled in
the art, the products of such procedures can be a mixture of
stereoisomers.
[0086] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compound of the present invention is acidic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic bases, including inorganic
bases and organic bases. Salts derived from such inorganic bases
include aluminum, ammonium, calcium, copper (ic and ous), ferric,
ferrous, lithium, magnesium, manganese (ic and ous), potassium,
sodium, zinc and the like salts. Particularly preferred are the
ammonium, calcium, magnesium, potassium and sodium salts. Salts
derived from pharmaceutically acceptable organic non-toxic bases
include salts of primary, secondary, and tertiary amines, as well
as cyclic amines and substituted amines such as naturally occurring
and synthesized substituted amines. Other pharmaceutically
acceptable organic non-toxic bases from which salts can be formed
include ion exchange resins such as, for example, arginine,
betaine, caffeine, choline, N,N'-dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethylamine, trimethylamine, tripropylamine, and
tromethamine.
[0087] When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include, for example, acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
and tartaric acids.
[0088] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds of this invention which are
readily convertible in vivo into the required compound. Thus, in
the methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
conditions described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
Metabolites of these compounds include active species produced upon
introduction of compounds of this invention into the biological
milieu.
[0089] The pharmaceutical compositions of the present invention
comprise a compound represented by Formula I, II or III (or
pharmaceutically acceptable salts thereof) as an active ingredient,
a pharmaceutically acceptable carrier, and optionally one or more
additional therapeutic agents or adjuvants. Such additional
therapeutic agents can include, for example, i) opiate agonists or
antagonists, ii) calcium channel antagonists, iii) 5HT receptor
agonists or antagonists iv) sodium channel antagonists, v) NMDA
receptor agonists or antagonists, vi) COX-2 selective inhibitors,
vii) NK1 antagonists, viii) non-steroidal anti-inflammatory drugs
("NSAID"), ix) selective serotonin reuptake inhibitors ("SSRI")
and/or selective serotonin and norepinephrine reuptake inhibitors
("SSNRI"), x) tricyclic antidepressant drugs, xi) norepinephrine
modulators, xii) lithium, xiii) valproate, and xiv) neurontin
(gabapentin). The instant compositions include compositions
suitable for oral, rectal, topical, and parenteral (including
subcutaneous, intramuscular, and intravenous) administration,
although the most suitable route in any given case will depend on
the particular host, and nature and severity of the conditions for
which the active ingredient is being administered. The
pharmaceutical compositions may be conveniently presented in unit
dosage form and prepared by any of the methods well known in the
art of pharmacy.
[0090] The present compounds and compositions are useful for the
treatment and prevention of chronic, visceral, inflammatory and
neuropathic pain syndromes. The present compounds and compositions
are also useful for the treatment and prevention of other
conditions, including acute pain, migraine, headache pain, and
migraine headache. They are useful for the treatment and prevention
of pain resulting from traumatic nerve injury, nerve compression or
entrapment, postherpetic neuralgia, trigeminal neuralgia, and
diabetic neuropathy. The present compounds and compositions are
also useful for the treatment and prevention of chronic lower back
pain, phantom limb pain, chronic pelvic pain, neuroma pain, complex
regional pain syndrome, chronic arthritic pain and related
neuralgias, and pain associated with cancer, chemotherapy, HIV and
HIV treatment-induced neuropathy. Compounds of this invention may
also be utilized as local anesthetics. Compounds of this invention
are useful for the treatment and prevention of irritable bowel
syndrome and related disorders, as well as Crohns disease.
[0091] The instant compounds have clinical uses for the treatment
and prevention of epilepsy and partial and generalized tonic
seizures. They are also useful for neuroprotection under ischaemic
conditions caused by stroke or neural trauma and for treating
multiple sclerosis. The present compounds are useful for the
treatment and prevention of bipolar disorder and
tachy-arrhythmias.
[0092] It is understood that compounds of this invention can be
administered at prophylactically effective dosage levels to prevent
the above-recited conditions, as well as to prevent other
conditions associated with sodium channel activity.
[0093] Creams, ointments, jellies, solutions, or suspensions
containing the instant compounds can be employed for topical use.
Mouth washes and gargles are included within the scope of topical
use for the purposes of this invention.
[0094] Dosage levels from about 0.01 mg/kg to about 140 mg/kg of
body weight per day are useful in the treatment of inflammatory and
neuropathic pain, or alternatively about 0.5 mg to about 7 g per
patient per day. For example, inflammatory pain may be effectively
treated by the administration of from about 0.01 mg to about 75 mg
of the compound per kilogram of body weight per day, or
alternatively about 0.5 mg to about 3.5 g per patient per day.
Neuropathic pain may be effectively treated by the administration
of from about 0.01 mg to about 125 mg of the compound per kilogram
of body weight per day, or alternatively about 0.5 mg to about 5.5
g per patient per day.
[0095] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a formulation intended for the oral
administration to humans may conveniently contain from about 0.5 mg
to about 5 g of active agent, compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95 percent of the total composition. Unit dosage forms
will generally contain between from about 1 mg to about 1000 mg of
the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300
mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
[0096] It is understood, however, that the specific dose level for
any particular patient will depend upon a variety of factors. Such
patient-related factors include the age, body weight, general
health, sex, and diet of the patient. Other factors include the
time and route of administration, rate of excretion, drug
combination, and the severity of the particular disease undergoing
therapy.
[0097] In practice, the compounds represented by Formula I, II and
III or pharmaceutically acceptable salts thereof, can be combined
as the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending on the form of preparation desired for
administration, e.g., oral or parenteral (including intravenous).
Thus, the pharmaceutical compositions of the present invention can
be presented as discrete units suitable for oral administration
such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient. Further, the
compositions can be presented as a powder, as granules, as a
solution, as a suspension in an aqueous liquid, as a non-aqueous
liquid, as an oil-in-water emulsion or as a water-in-oil liquid
emulsion. In addition to the common dosage forms set out above, the
compounds represented by Formula I, II and III or pharmaceutically
acceptable salts thereof, may also be administered by controlled
release means and/or delivery devices. The compositions may be
prepared by any of the methods of pharmacy. In general, such
methods include a step of bringing into association the active
ingredient with the carrier that constitutes one or more necessary
ingredients. In general, the compositions are prepared by uniformly
and intimately admixing the active ingredient with liquid carriers
or finely divided solid carriers or both. The product can then be
conveniently shaped into the desired presentation.
[0098] Thus, the pharmaceutical compositions of this invention can
include a pharmaceutically acceptable carrier and compounds or
pharmaceutically acceptable salts of Formula I, II and/or III. The
compounds of Formula I, II and III, or pharmaceutically acceptable
salts thereof, can also be included in pharmaceutical compositions
in combination with one or more therapeutically active
compounds.
[0099] The pharmaceutical carrier employed can be, for example, a
solid, liquid, or gas. Examples of solid carriers include lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and stearic acid. Examples of liquid carriers are sugar
syrup, peanut oil, olive oil, and water. Examples of gaseous
carriers include carbon dioxide and nitrogen.
[0100] In preparing the compositions for oral dosage form, any
convenient pharmaceutical media may be employed. For example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like may be used to form oral liquid
preparations such as suspensions, elixirs and solutions; while
carriers such as starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents can be used to form oral solid preparations
such as powders, capsules and tablets. Because of their ease of
administration, tablets and capsules are the preferred oral dosage
units whereby solid pharmaceutical carriers are employed.
Optionally, tablets may be coated by standard aqueous or nonaqueous
techniques
[0101] A tablet containing the composition of this invention may be
prepared by compression or molding, optionally with one or more
accessory ingredients or adjuvants. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active or dispersing agent. Molded tablets may be made by molding
in a suitable machine, a mixture of the powdered compound moistened
with an inert liquid diluent. Each tablet preferably contains from
about 0.1 mg to about 500 mg of the active ingredient and each
cachet or capsule preferably containing from about 0.1 mg to about
500 mg of the active ingredient. Thus, a tablet, cachet, or capsule
conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200
mg, 300 mg, 400 mg, or 500 mg of the active ingredient taken one or
two tablets, cachets, or capsules, once, twice, or three times
daily.
[0102] Pharmaceutical compositions of the present invention
suitable for parenteral administration may be prepared as solutions
or suspensions of the active compounds in water. A suitable
surfactant can be included such as, for example,
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and mixtures thereof in
oils. Further, a preservative can be included to prevent the
detrimental growth of microorganisms.
[0103] Pharmaceutical compositions of the present invention
suitable for injectable use include sterile aqueous solutions or
dispersions. Furthermore, the compositions can be in the form of
sterile powders for the extemporaneous preparation of such sterile
injectable solutions or dispersions. In all cases, the final
injectable form must be sterile and must be effectively fluid for
easy syringability. The pharmaceutical compositions must be stable
under the conditions of manufacture and storage; thus, preferably
should 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 (e.g. glycerol, propylene glycol and liquid
polyethylene glycol), vegetable oils, and suitable mixtures
thereof.
[0104] Pharmaceutical compositions of the present invention can be
in a form suitable for topical use such as, for example, an
aerosol, cream, ointment, lotion, and dusting powder. Further, the
compositions can be in a form suitable for use in transdermal
devices. These formulations may be prepared, utilizing a compound
represented by Formula I, II or III, or a pharmaceutically
acceptable salt thereof, via conventional processing methods. As an
example, a cream or ointment is prepared by mixing hydrophilic
material and water, together with about 5 wt % to about 10 wt % of
the compound, to produce a cream or ointment having a desired
consistency.
[0105] Pharmaceutical compositions of this invention can be in a
form suitable for rectal administration wherein the carrier is a
solid. It is preferable that the mixture forms unit dose
suppositories. Suitable carriers include cocoa butter and other
materials commonly used in the art. The suppositories may be
conveniently formed by first admixing the composition with the
softened or melted carrier(s) followed by chilling and shaping in
moulds.
[0106] In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as
appropriate, one or more additional carrier ingredients such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, and preservatives (including
anti-oxidants). Furthermore, other adjuvants can be included to
render the formulation isotonic with the blood of the intended
recipient. Compositions containing a compound described by Formula
I, II or III, or a pharmaceutically acceptable salt thereof, can
also be prepared in powder or liquid concentrate form.
[0107] The compounds and pharmaceutical compositions of this
invention have been found to block sodium channels. Accordingly, an
aspect of the invention is the treatment in mammals of maladies
that are amenable to amelioration through blockage of neuronal
sodium channels, including, for example, acute pain, chronic pain,
visceral pain, inflammatory pain, and neuropathic pain by
administering an effective amount of a compound of this invention.
The term "mammals" includes humans, as well as other animals, such
as, for example, dogs, cats, horses, pigs, and cattle. Accordingly,
it is understood that the treatment of mammals other than humans
refers to the treatment of clinical conditions in non-human mammals
that correlate to the above-recited conditions.
[0108] Further, as described above, the instant compounds can be
utilized in combination with one or more therapeutically active
compounds. In particular, the inventive compounds can be
advantageously used in combination with i) opiate agonists or
antagonists, ii) calcium channel antagonists, iii) 5HT receptor
agonists or antagonists iv) sodium channel antagonists, v)
N-methyl-D-aspartate (NMDA) receptor agonists or antagonists, vi)
COX-2 selective inhibitors, vii) neurokinin receptor 1 (NK1)
antagonists, viii) non-steroidal anti-inflammatory drugs (NSAID),
ix) selective serotonin reuptake inhibitors (SSRI) and/or selective
serotonin and norepinephrine reuptake inhibitors (SSNRI), x)
tricyclic antidepressant drugs, xi) norepinephrine modulators, xii)
lithium, xiii) valproate, and xiv) neurontin (gabapentin).
[0109] The abbreviations used herein have the following tabulated
meanings. Abbreviations not tabulated below have their meanings as
commonly used unless specifically stated otherwise.
TABLE-US-00001 Ac Acetyl AIBN 2,2'-azobis(isobutyronitrile) BINAP
1,1'-bi-2-naphthol Bn Benzyl CAMP cyclic
adenosine-3',5'-monophosphate DAST (diethylamino)sulfur trifluoride
DEAD diethyl azodicarboxylate DBU
1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminum hydride
DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide Dppf
1,1'-bis(diphenylphosphino)-ferrocene EDCI
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Et.sub.3N Triethylamine GST glutathione transferase HMDS
Hexamethyldisilazide LDA lithium diisopropylamide m-CPBA
metachloroperbenzoic acid MMPP monoperoxyphthalic acid MPPM
monoperoxyphthalic acid, magnesium salt 6H.sub.2O Ms
methanesulfonyl = mesyl = SO.sub.2Me Ms0 methanesulfonate =
mesylate NBS N-bromo succinimide NSAID non-steroidal
anti-inflammatory drug o-Tol ortho-tolyl OXONE .RTM.
2KHSO.sub.5.cndot.KHSO.sub.4.cndot.K.sub.2SO.sub.4 PCC pyridinium
chlorochromate Pd.sub.2(dba).sub.3 Bis(dibenzylideneacetone)
palladium(0) PDC pyridinium dichromate PDE Phosphodiesterase Ph
Phenyl Phe Benzenediyl PMB para-methoxybenzyl Pye Pyridinediyl r.t.
room temperature Rac. Racemic SAM aminosulfonyl or sulfonamide or
SO.sub.2NH.sub.2 SEM 2-(trimethylsilyl)ethoxymethoxy SPA
scintillation proximity assay TBAF tetra-n-butylammonium fluoride
Th 2- or 3-thienyl TFA trifluoroacetic acid TFAA trifluoroacetic
acid anhydride THF Tetrahydrofuran Thi Thiophenediyl TLC thin layer
chromatography TMS-CN trimethylsilyl cyanide TMSI trimethylsilyl
iodide Tz 1H (or 2H)-tetrazol-5-yl XANTPHOS
4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene C.sub.3H.sub.5
Allyl
TABLE-US-00002 ALKYL GROUP ABBREVIATIONS Me = Methyl Et = ethyl
n-Pr = normal propyl i-Pr = isopropyl n-Bu = normal butyl i-Bu =
isobutyl s-Bu = secondary butyl t-Bu = tertiary butyl c-Pr =
cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex =
cyclohexyl
[0110] The following in vitro and in vivo assays were used in
assessing the biological activity of the instant compounds.
Compound Evaluation (In Vitro Assay):
[0111] The identification of inhibitors of the sodium channel is
based on the ability of sodium channels to cause cell
depolarization when sodium ions permeate through agonist-modified
channels. In the absence of inhibitors, exposure of an
agonist-modified channel to sodium ions will cause cell
depolarization. Sodium channel inhibitors will prevent cell
depolarization caused by sodium ion movement through
agonist-modified sodium channels. Changes in membrane potential can
be determined with voltage-sensitive fluorescence resonance energy
transfer (FRET) dye pairs that use two components, a donor coumarin
(CC.sub.2DMPE) and an acceptor oxanol (DiSBAC.sub.2(3)). Oxanol is
a lipophilic anion and distributes across the membrane according to
membrane potential. In the presence of a sodium channel agonist,
but in the absence of sodium, the inside of the cell is negative
with respect to the outside, oxanol is accumulated at the outer
leaflet of the membrane and excitation of coumarin will cause FRET
to occur. Addition of sodium will cause membrane depolarization
leading to redistribution of oxanol to the inside of the cell, and,
as a consequence, to a decrease in FRET. Thus, the ratio change
(donor/acceptor) increases after membrane depolarization. In the
presence of a sodium channel inhibitor, cell depolarization will
not occur, and therefore the distribution of oxanol and FRET will
remain unchanged.
[0112] Cells stably transfected with the PN1 sodium channel
(HEK-PN1) were grown in polylysine-coated 96-well plates at a
density of ca. 140,000 cells/well. The media was aspirated, and the
cells were washed with PBS buffer, and incubated with 100 .mu.L of
10 .mu.M CC.sub.2-DMPE in 0.02% pluronic acid. After incubation at
25.degree. C. for 45 min, media was removed and cells were washed
2.times. with buffer. Cells were incubated with 100 .mu.L of
DiSBAC.sub.2(3) in TMA buffer containing 20 .mu.M veratridine, 20
nM brevetoxin-3, and test sample. After incubation at 25.degree. C.
for 45 min in the dark, plates were placed in the VIPR instrument,
and the fluorescence emission of both CC.sub.2-DMPE and
DiSBAC.sub.2(3) recorded for 10 s. At this point, 100 .mu.L of
saline buffer was added to the wells to determine the extent of
sodium-dependent cell depolarization, and the fluorescence emission
of both dyes recorded for an additional 20 s. The ratio
CC.sub.2-DMPE/DiSBAC.sub.2(3), before addition of saline buffer
equals 1. In the absence of inhibitors, the ratio after addition of
saline buffer is >1.5. When the sodium channel has been
completely inhibited by either a known standard or test compound,
this ratio remains at 1. It is possible, therefore, to titrate the
activity of a sodium channel inhibitor by monitoring the
concentration-dependent change in fluorescence ratio.
Electrophysiological Assays (In Vitro Assays):
[0113] Cell preparation: A HEK-293 cell line stably expressing the
PN1 sodium channel subtype was established in-house. The cells were
cultured in MEM growth media (Gibco) with 0.5 mg/mL G418, 50
units/mL Pen/Strep and 1 mL heat-inactivated fetal bovine serum at
37.degree. C. and 10% CO.sub.2. For electrophysiological
recordings, cells were plated on 35 mm dishes coated with
poly-D-lysine.
[0114] Whole-cell recordings: HEK-293 cells stably expressing the
PN1 sodium channel subtype were examined by whole cell voltage
clamp (Hamill et. al. Pfluegers Archives 391:85-100 (1981)) using
an EPC-9 amplifier and Pulse software (HEKA Electronics, Lamprecht,
Germany). Experiments were performed at room temperature.
Electrodes were fire-polished to resistances of 2-4 M.OMEGA..
Voltage errors were minimized by series resistance compensation,
and the capacitance artefact was canceled using the EPC-9's
built-in circuitry. Data were acquired at 50 kHz and filtered at
7-10 kHz. The bath solution consisted of 40 mM NaCl, 120 mM NMDG
Cl, 1 mM KCl, 2.7 mM CaCl.sub.2, 0.5 mM MgCl.sub.2, 10 mM NMDG
HEPES, pH 7.4, and the internal (pipet) solution contained 110 mM
Cs-methanesulfonate, 5 mM NaCl, 20 mM CsCl, 10 mM CsF, 10 mM BAPTA
(tetra Cs salt), 10 mM Cs HEPES, pH 7.4.
[0115] The following protocols were used to estimate the
steady-state affinity of compounds for the resting and inactivated
state of the channel (K.sub.r and K.sub.i, respectively):
[0116] 1) 8 ms test-pulses to depolarizing voltages from -60 mV to
+50 mV from a holding potential of -90 mV were used to construct
current-voltage relationships (IV-curves). A voltage near the peak
of the IV-curve (typically -10 or 0 mV) was used as the test-pulse
voltage throughout the remainder of the experiment.
[0117] 2) Steady-state inactivation (availability) curves were
constructed by measuring the current activated during an 8 ms
test-pulse following 10 s conditioning pulses to potentials ranging
from -120 mV to -10 mV.
[0118] 3) Compounds were applied at a holding potential at which
20-50% of the channels was inactivated and sodium channel blockage
was monitored during 8 ms test pulses at 2 s intervals.
[0119] 4) After the compounds equilibrated, the voltage-dependence
of steady-state inactivation in the presence of compound was
determined according to protocol 2) above. Compounds that block the
resting state of the channel decrease the current elicited during
test-pulses from all holding potentials, whereas compounds that
primarily block the inactivated state shift the mid-point of the
steady-state inactivation curve. The maximum current at negative
holding potentials (I.sub.max) and the difference in the mid-points
of the steady-state inactivation curves (.DELTA.V) in control and
in the presence of a compound were used to calculate K.sub.r and
K.sub.i using the following equations:
K r = [ Drug ] * I Max , Drug I Max , Control - I Max , Drug
##EQU00001## K i = [ Drug ] ( 1 + [ Drug ] K r ) * - .DELTA. V k -
1 ##EQU00001.2##
[0120] In cases where the compound did not affect the resting
state, K.sub.i was calculated using the following equation:
K i = [ Drug ] - .DELTA. V k - 1 ##EQU00002##
Rat Formalin Paw Test (In Vivo Assay):
[0121] Compounds were assessed for their ability to inhibit the
behavioral response evoked by a 50 .mu.L injection of formalin
(5%). A metal band was affixed to the left hind paw of male
Sprague-Dawley rats (Charles River, 200-250 g) and each rat was
conditioned to the band for 60 min within a plastic cylinder (15 cm
diameter). Rats were dosed with either vehicle or a test compound
either before (local) or after (systemic) formalin challenge. For
local administration, compounds were prepared in a 1:4:5 vehicle of
ethanol, PEG400 and saline (EPEGS) and injected subcutaneously into
the dorsal surface of the left hind paw 5 min prior to formalin.
For systemic administration, compounds were prepared in either a
EPEGS vehicle or a Tween80 (10%)/sterile water (90%) vehicle and
were injected i.v. (via the lateral tail vein 15 min after
formalin) or p.o. (60 min before formalin). The number of flinches
was counted continuously for 60 min using an automated nociception
analyzer (UCSD Anesthesiology Research, San Diego, Calif.).
Statistical significance was determined by comparing the total
flinches detected in the early (0-10 min) and late (11-60 min)
phase with an unpaired t-test.
In Vivo Assay Using Rat CFA Model:
[0122] Unilateral inflammation was induced with a 0.2 ml injection
of complete Freund's adjuvant (CFA: Mycobacterium tuberculosis,
Sigma; suspended in an oil/saline (1:1) emulsion; 0.5 mg
Mycobacterium/mL) in the plantar surface of the left hindpaw. This
dose of CFA produced significant hind paw swelling but the animals
exhibited normal grooming behavior and weight gain over the course
of the experiment. Mechanical hyperalgesia was assessed 3 days
after tissue injury using a Randall-Selitto test. Repeated Measures
ANOVA, followed by Dunnett's Post Hoc test.
SNL: Mechanical Allodynia (In Vivo Assay):
[0123] Tactile allodynia was assessed with calibrated von Frey
filaments using an up-down paradigm before and two weeks following
nerve injury. Animals were placed in plastic cages with a wire mesh
floor and allowed to acclimate for 15 min before each test session.
To determine the 50% response threshold, the von Frey filaments
(over a range of intensities from 0.4 to 28.8 g) were applied to
the mid-plantar surface for 8 s, or until a withdrawal response
occurred. Following a positive response, an incrementally weaker
stimulus was tested. If there was no response to a stimulus, then
an incrementally stronger stimulus was presented. After the initial
threshold crossing, this procedure was repeated for four stimulus
presentations per animal per test session. Mechanical sensitivity
was assessed 1 and 2 hr post oral administration of the test
compound.
[0124] The compounds described in this invention displayed sodium
channel blocking activity of from about <0.1 .mu.M to about
<50 .mu.M in the in vitro assays described above. It is
advantageous that the compounds display sodium channel blocking
activity of <5 .mu.M in the in vitro assays. It is more
advantageous that the compounds display sodium channel blocking
activity of <1 .mu.M in the in vitro assays. It is even more
advantageous that the compounds display sodium channel blocking
activity of <0.5 .mu.M in the in vitro assays. It is still more
advantageous that the compounds display sodium channel blocking
activity of <0.1 .mu.M in the in vitro assays.
[0125] The present compounds can be prepared according to the
general schemes provided below as well as the procedures provided
in the Examples. The following schemes and Examples further
describe, but do not limit, the scope of the invention.
[0126] Unless specifically stated otherwise, the experimental
procedures were performed under the following conditions: All
operations were carried out at room or ambient temperature; that
is, at a temperature in the range of 18-25.degree. C. Evaporation
of solvent was carried out using a rotary evaporator under reduced
pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature
of up to 60.degree. C. The course of reactions was followed by thin
layer chromatography (TLC) and reaction times are given for
illustration only. Melting points are uncorrected and `d` indicates
decomposition. The melting points given are those obtained for the
materials prepared as described. Polymorphism may result in
isolation of materials with different melting points in some
preparations. The structure and purity of all final products were
assured by at least one of the following techniques: TLC, mass
spectrometry, nuclear magnetic resonance (NMR) spectrometry or
microanalytical data. When given, yields are for illustration only.
When given, NMR data is in the form of delta (.delta.) values for
major diagnostic protons, given in parts per million (ppm) relative
to tetramethylsilane (TMS) as internal standard, determined at 300
MHz, 400 MHz or 500 MHz using the indicated solvent. Conventional
abbreviations used for signal shape are: s. singlet; d. doublet; t.
triplet; m. multiplet; br. broad; etc. In addition, "Ar" signifies
an aromatic signal. Chemical symbols have their usual meanings; the
following abbreviations are used: v (volume), w (weight), b.p.
(boiling point), m.p. (melting point), L (liter(s)), mL
(milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol
(millimoles), eq (equivalent(s)).
Methods of Synthesis
[0127] Compounds of the present invention can be prepared according
to the Schemes provided below as well as the procedures provided in
the Reference Examples and Examples. The substituents are the same
as in the above Formulas except where defined otherwise or
otherwise apparent to the ordinary skilled artisan.
[0128] The novel compounds of the present invention can be readily
synthesized using techniques known to those skilled in the art,
such as those described, for example, in Advanced Organic
Chemistry, March, 4.sup.th Ed., John Wiley and Sons, New York,
N.Y., 1992; Advanced Organic Chemistry, Carey and Sundberg, Vol. A
and B, 3.sup.rd Ed., Plenum Press, Inc., New York, N.Y., 1990;
Protective groups in Organic Synthesis, Green and Wuts, 2.sup.nd
Ed., John Wiley and Sons, New York, N.Y., 1991; Comprehensive
Organic Transformations, Larock, VCH Publishers, Inc., New York,
N.Y., 1988; Handbook of Heterocyclic Chemistry, Katritzky and
Pozharskii, 2.sup.nd Ed., Pergamon, New York, N.Y., 2000 and
references cited therein. The starting materials for the present
compounds may be prepared using standard synthetic transformations
of chemical precursors that are readily available from commercial
sources, including Aldrich Chemical Co. (Milwaukee, Wis.); Sigma
Chemical Co. (St. Louis, Mo.); Lancaster Synthesis (Windham, N.H.);
Ryan Scientific (Columbia, S.C.); Maybridge (Cornwall, UK); Matrix
Scientific (Columbia, S.C.); Arcos, (Pittsburgh, Pa.) and Trans
World Chemicals (Rockville, N. Mex.).
[0129] The procedures described herein for synthesizing the
compounds may include one or more steps of protecting group
manipulations and of purification, such as, recrystallization,
distillation, column chromatography, flash chromatography,
thin-layer chromatography (TLC), radial chromatography and
high-pressure chromatography (HPLC). The products can be
characterized using various techniques well known in the chemical
arts, including proton and carbon-13 nuclear magnetic resonance
(.sup.1H and .sup.13C NMR), infrared and ultraviolet spectroscopy
(IR and UV), X-ray crystallography, elemental analysis and HPLC and
mass spectrometry (LC-MS). Methods of protecting group
manipulation, purification, structure identification and
quantification are well known to one skilled in the art of chemical
synthesis.
[0130] Appropriate solvents are those which will at least partially
dissolve one or all of the reactants and will not adversely
interact with either the reactants or the product. Suitable
solvents are aromatic hydrocarbons (e.g, toluene, xylenes),
halogenated solvents (e.g, methylene chloride, chloroform,
carbontetrachloride, chlorobenzenes), ethers (e.g, diethyl ether,
diisopropylether, tert-butyl methyl ether, diglyme,
tetrahydrofuran, dioxane, anisole), nitriles (e.g, acetonitrile,
propionitrile), ketones (e.g, 2-butanone, dithyl ketone, tert-butyl
methyl ketone), alcohols (e.g, methanol, ethanol, n-propanol,
iso-propanol, n-butanol, t-butanol), dimethyl formamide (DMF),
dimethylsulfoxide (DMSO) and water. Mixtures of two or more
solvents can also be used. Suitable bases are, generally, alkali
metal hydroxides, alkaline earth metal hydroxides such as lithium
hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide,
and calcium hydroxide; alkali metal hydrides and alkaline earth
metal hydrides such as lithium hydride, sodium hydride, potassium
hydride and calcium hydride; alkali metal amides such as lithium
amide, sodium amide and potassium amide; alkali metal carbonates
and alkaline earth metal carbonates such as lithium carbonate,
sodium carbonate, Cesium carbonate, sodium hydrogen carbonate, and
cesium hydrogen carbonate; alkali metal alkoxides and alkaline
earth metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide and magnesium ethoxide; alkali metal alkyls
such as methyllithium, n-butyllithium, sec-butyllithium,
t-bultyllithium, phenyllithium, alkyl magnesium halides, organic
bases such as trimethylamine, triethylamine, triisopropylamine,
N,N-diisopropylethylamine, piperidine, N-methyl piperidine,
morpholine, N-methyl morpholine, pyridine, collidines, lutidines,
and 4-dimethylaminopyridine; and bicyclic amines such as DBU and
DABCO.
[0131] As described previously, in preparing the compositions for
oral dosage form, any of the usual pharmaceutical media can be
employed. For example, in the case of oral liquid preparations such
as suspensions, elixirs and solutions, water, glycols, oils,
alcohols, flavoring agents, preservatives, coloring agents and the
like may be used; or in the case of oral solid preparations such as
powders, capsules and tablets, carriers such as starches, sugars,
microcrystalline cellulose, diluents, granulating agents,
lubricants, binders, disintegrating agents, and the like may be
included. Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit form in
which solid pharmaceutical carriers are employed. If desired,
tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, controlled
release means and/or delivery devices may also be used in
administering the instant compounds and compositions.
[0132] It is understood that the functional groups present in
compounds described in the Schemes below can be further
manipulated, when appropriate, using the standard functional group
transformation techniques available to those skilled in the art, to
provide desired compounds described in this invention.
[0133] Other variations or modifications, which will be obvious to
those skilled in the art, are within the scope and teachings of
this invention. This invention is not to be limited except as set
forth in the following claims.
##STR00004##
[0134] In accordance with Scheme 1,3-bromobenzoic acid 1 is coupled
with t-butyl carbazate by activation with HOBt
(hydroxybenzotriazole) in the presence of a suitable carbodiimide
such as EDC [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) and
diisopropylethylamine (DIEA) in dichloromethane or THF to give the
protected hydrazide 2. There are numerous other suitable methods to
activate carboxylic acids for coupling formation (see March J.,
Advanced Organic Chemistry, 5th ed., John Wiley & Sons, New
York, pp. 506-512 (2001)). Compound 2 can be converted to a variety
of unsymmetrical biphenyl intermediates 3 by means of a variety of
coupling reactions. One type is the Suzuki reaction wherein bromo,
iodo, or triflate compound 2 is reacted with an aryl boronic acid
in the presence of a palladium catalyst such as palladium acetate
with triphenyl phosphine and aqueous sodium carbonate in a solvent
such as toluene and a co-solvent such as n-propanol. (see Suzuki
et. al., Chem. Rev., 95, 2457, 1995). A variety of aryl boronic
acids are commercially available or can be prepared conveniently
from the corresponding aryl bromide or iodide by converting it to
an organolithium derivative [Baldwin, J. E. et al., Tetrahedron
Lett. 39, 707-710 (1998)], or a Grignard reagent followed by
treatment with trialkylborate Li, J. J. et al, J. Med. Chem., 38:
4570-4578 (1995) and Piettre, S. R. et al. J. Med. Chem. 40,
4208-4221 (1997)]. Aryl boronates can also be used as an
alternative to aryl boronic acids in these Pd-catalyzed coupling
reactions [Giroux, A. et. al., Tetrahedron Lett., 38, 3841 (1997)].
The boronates can be easily prepared from the aryl bromides,
iodides and trifluoromethane sulfonates using the method described
by [Murata, M. et. al., J. Org. Chem. 65: 164-168 (2000)]. The Boc
protecting group of compound 3 is removed by standard
conditions--trifluoroacetic acid in dichloromethane--to give the
TFA salt of hydrazide 4 which can be desalted with aqueous NaOH
solution.
##STR00005##
[0135] In Scheme 2, a method for preparing 5-biphenyl-3-substituted
1,2,4-triazole derivatives is described (Francis et. al.,
Tetrahedron Lett., 28(43), 5133-5136, 1987). Reaction of hydrazide
4 with a substituted amidine with a base such as sodium methoxide
in methanol gives intermediate 5 which, on heating neat (no
co-solvent), gives triazole 6.
##STR00006##
[0136] In Scheme 3, a method is described for preparing
5-biphenyl-3-substituted-1,2,4-triazole derivatives wherein the
substitution can be esters, acids, amides, etc. (Catarzi et. al.,
J. Med. Chem., 38, 2196-2201, (1995)). Reaction of hydrazide 4 with
carbethoxy-5-methyl-thioformimidium tetrafluoroborate and
triethylamine in dichloromethane gives oxamidrazonate 7 which is
cyclized to triazole ester .delta.. The reagent
carbethoxy-5-methyl-thioformimidium tetrafluoroborate is prepared
by reaction of ethyl-2-thiooxamate with trimethyl oxonium
tetrafluoroborate (see Catarzi et. al. above) in dichloromethane.
Ester 8 can be converted to a variety of amides simply by heating
it with the corresponding amine, in this case ammonia, in a solvent
such as methanol.
##STR00007##
[0137] In Scheme 4, a method is described for preparing an
unsubstituted 3-triazole ring system (Lin et.al, J. Org. Chem.,
44(23), 4160-4165, 1979). Ethyl-3-bromobenzoate 10 is reacted with
an aryl boronic acid as described in Scheme 1 to give biphenylester
11. The ester 11 provides a preformed biphenyl intermediate that
can be further elaborated to compound 4 and related derivatives as
described in earlier Schemes 1-3. In this Scheme 4, ester 11 is
converted to amide 12 under standard conditions. Specifically,
ester 11 is hydrolyzed to the corresponding acid which is then
activated with carbonyldiimidazole (CDI) in DMF, followed by the
addition of ammonia in the form of ammonium acetate to give amide
12. Amide 12 in dimethylformamide dimethylacetal is heated to give
intermediate 13 which, when heated with hydrazine in acetic acid,
gives triazole 14.
##STR00008##
[0138] In Scheme 5, alkylation of triazole 6 by using a base such
as sodium methoxide in a solvent such as methanol with an
alkylhalide or triflate gives a mixture of tautomeric products 15
and 15'.
##STR00009##
[0139] In Scheme 6, triazole ester 8 can be hydrolyzed to acid 16
under standard conditions (sodium hydroxide, methanol). Acid 16 can
be converted to amide 17 under a variety of conditions described in
Scheme 1. In this variation, activation of acid 16 with
carbonyldiimidazole (CDI) in dimethylformamide (DM) followed by
addition of an amine gives amide 17.
##STR00010##
[0140] In Scheme 7, triazole ester 8 can be converted to a
secondary alcohol 18 as the major product by reaction with a
mixture of lithium borohydride and a Grignard reagent in an aprotic
solvent such as THF. Alternatively, ester 8 can be reduced to
primary alcohol 20 by any of several reducing agents, which include
lithium aluminum hydride (LAH), diisobutylaluminum hydride
(DIBAL-H) and sodium borohydride (NaBH.sub.4). Either alcohol 18 or
20 can be further derivatized by any number of methods. In one
example, alcohol 18 can be oxidized to the ketone 19 by a variety
of oxidizing reagents which include chromium-based reagents, and
Swern type reagents (DMSO and oxalyl chloride).
##STR00011##
[0141] The alcohol 18 also can be converted to fluoride derivative
21 by reaction with diethylaminosulfurtrifluoride (DAST) in
dichlormethane at reduced temperatures, as described in Scheme
.delta..
SCHEME 9
[0142] In accordance with Scheme 9, bromoaniline 22, wherein the
amino group is protected with a Boc group, and an arylboronic acid
is converted to a variety of unsymmetrical biphenyl intermediates
23 as described in Scheme 1. The Boc protecting group of compound
23 is removed as described previously and converted to its
diazonium salt 24 by standard reaction with sodium nitrite and HCl
in water. Addition of compound 24 to a mixture of
methylisocyanoacetate and sodium acetate in methanol and water gave
the triazole ester 25. The key intermediate 25 can be then
converted to a variety of useful derivatives using the methods
described in Schemes 1-7.
##STR00012##
[0143] In Scheme 10, which is a variation to the protocols
described in Schemes 1, 4 and 9 above, the Boc-protected anline 26
containing a boronic acid group or boronate ester and an aryl
bromide, iodide or triflate is converted to a variety of
unsymmetrical biphenyl intermediates 23 as described in Scheme
1.
[0144] The following Reference Examples provide methods for
preparing certain compounds of the invention:
REFERENCE EXAMPLE 1
##STR00013##
[0145] 3-[3-(2-Trifluoromethoxyphenyl)-phenyl]-1,2,4-triazole
Step A: 2-Trinuoromethoxyphenylboronic acid
##STR00014##
[0147] To a stirred solution of 2 g (9.5 mmol) of
1-bromo-2-trifluoromethoxy benzene in 28 mL of tetrahydrofuran
(THF) at -78.degree. C., was carefully added 5.9 mL of a 1.7 M
solution of t-butyl lithium in hexanes (9.5 mmol). This reaction
mixture was stirred at -78.degree. C. for 45 min. To this reaction
mixture at -78.degree. C. was added 2.58 mL (11.1 mmol) of
tri-isopropyl borate, followed by slow warming of the mixture to
room temperature (RT) over a period of 16 h. The reaction mixture
was diluted with water and made basic with 2N NaOH solution. The
mixture was then washed with EtOAc. The aqueous fraction was
acidified with 2N HCl solution and stirred for 1 h at RT. The
reaction mixture was extracted with EtOAc and the organic fractions
were washed with water and saturated NaCl solution (brine), dried
over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated
to give the title compound as a white solid. .sup.1HNMR
(CDCl.sub.3) (.delta., ppm): 7.96 (dd, J=7.2, 1.6 Hz, 1H), 7.53
(ddd, J=9.1, 7.3, 1.8 Hz, 1H), 7.38 (td, J=7.3, 0.7 Hz, 1H), 7.28
(d, J=8.2 Hz, 1H), 5.25 (br s, 2H). MS (M+H): 206.9.
Step B: Ethyl-3-(2-Trifluoromethoxyphenyl)-benzoate
##STR00015##
[0149] To a solution of 0.94 g (4.58 mmol) of ethyl-3-bromobenzoate
in 14.5 mL of toluene at RT was added 0.25 g (0.218 mmol) of
tetrakis(triphenylphosphine) palladium(0), 0.94 g (4.58 mmol) of
2-trifluoromethoxyphenylboronic acid, 2.22 mL (4.45 mmol) of 2M
aqueous sodium carbonate solution and 7 mL of ethanol. The reaction
mixture was heated at reflux for 18 h. The reaction mixture was
cooled and diluted with ethyl acetate and water. The organic
fraction was separated and washed with saturated NaCl solution
(brine), dried over MgSO.sub.4, and filtered. The filtrate was
concentrated to an oil which was purified by chromatography
(silica, 1%, 5%, 30% successively ethyl acetate:hexanes) to give
the title compound. .sup.1H NMR (CD.sub.3OD) (.delta., ppm): 8.02
(s, 1H), 7.97 (dd, J=7.8, 1.2 Hz, 1H), 7.60 (dd, J=7.7, 1.3 Hz,
1H), 7.50-7.33 (m, 5H), 4.31 (q, 2H), 1.31 (t, 3H). Mass Spectrum
(ESI) m/e (M+1): 311.2.
Step C: 3-(2-Trifluoromethoxyphenyl)-benzoic acid
##STR00016##
[0151] A solution of 0.3 g (4.19 mmol) of
ethyl-3-(2-trifluoromethoxyphenyl)-benzoate and 8.3 mL (8.3 mmol)
of a 1N solution of NaOH in 12.5 mL of methanol was stirred 18 h at
RT. The reaction mixture was concentrated and the pH was adjusted
to pH of 2 with 1N HCl solution. The mixture was extracted with
ethyl acetate (EtOAc) and the organic fraction was dried over
MgSO.sub.4 and filtered. The filtrate was concentrated to give the
title compound as a white solid that was used without further
purification.
Step D: 3-(2-Trifluoromethoxyphenyl)-benzamide
##STR00017##
[0153] To a solution of 0.94 g (3.36 mmol) of
3-(2-trifluoromethoxyphenyl)-benzoic acid in 17 mL of DMF was added
0.55 g (3.36 mmol) of carbonyldiimidazole (CDI) and the reaction
was stirred at RT for 4 h. To the reaction mixture was added 2.6 g
(33.6 mmol) of ammonium acetate and the reaction mixture was
stirred over night at RT. The reaction mixture was partitioned
between ethyl acetate and water and the organic fraction was washed
with brine, dried over MgSO.sub.4, filtered and the filtrate was
concentrated. The residue was purified by chromatography (silica,
30%, 50% successively EtOAc: hexanes) to give the title
compound.
[0154] Mass Spectrum (ESI) m/e (M+1): 282.2.
Step E: 3-[3-(2-Trifluoromethoxyphenyl)-phenyl]-1,2,4-triazole
##STR00018##
[0156] A solution of 0.137 g (0.48 mmol) of
3-(2-trifluoromethoxyphenyl)-benzamide in 1 mL of
N,N-dimethylformamide dimethyl acetal was heated at 120.degree. C.
for 2 h at which time the reaction was concentrated in vacuo. To
this material in 2.3 mL of acetic acid was added 0.028 g (0.55
mmol) of hydrazine hydrate and the reaction mixture was heated at
90.degree. C. for 2 h. The reaction mixture was then concentrated
and partitioned between EtOAc and saturated NaHCO.sub.3 solution.
The organic fraction was washed with brine, dried over MgSO.sub.4,
filtered and the filtrate was concentrated. The residue was
purified by chromatography (silica, 30:1, 9:1, 3:1 successively
CH.sub.2Cl.sub.2: acetone) to give the title compound. .sup.1H NMR
(CD.sub.3OD) (.delta., ppm): 8.32 (s, 1H), 8.06 (s, 1H), 7.98 (m,
1H), 7.50 (m, 3H), 7.39 (m, 3H). Mass Spectrum (ESI) m/e (M+1):
306. 1.
REFERENCE EXAMPLE 2
##STR00019##
[0157]
5-Methyl-3-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole
Step A: 3-Bromophenylcarbonyl-(N-t-butoxycarbonyl)hydrazide
##STR00020##
[0159] A solution of 1 g (4.97 mmol) of 3-bromobenzoic acid, 0.59 g
(4.52 mmol) of t-butylcarbazate, 0.95 g (4.97 mmol) of EDC
[1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), 0.67 g (4.97 mmol)
of hydroxybenzotriazole (HOBt) and 3.15 mL (18.1 mmol) of
diisopropylethylamine in 23 mL of CH.sub.2Cl.sub.2 was stirred at
RT for 18 h. The reaction mixture was diluted with CH.sub.2Cl.sub.2
and washed with 1N HCl solution, saturated NaHCO.sub.3 solution and
brine. The solution was dried over MgSO.sub.4, filtered and the
filtrate was concentrated. The residue was purified by
chromatography (silica, 30:1, 9:1, 3:1 successively
CH.sub.2Cl.sub.2:acetone) to give the title compound.
[0160] Mass Spectrum (ESI) m/e (M): 314.0, (M+2): 316.0
Step B: 3-((2-Trifluoromethoxy)phenyl)-phenylhydrazide
##STR00021##
[0162] A solution of 0.22 g (1.07 mmol) of
2-trifluoromethoxyphenylboronic acid and 0.32 g (1.02 mmol) of
3-bromophenylcarbonyl-N-t-butoxycarbonylhydrazide in 5 mL of
toluene and 2.5 mL of n-propanol was stirred for 30 min. To this
reaction mixture was added 0.0007 g (0.003 mmol) of palladium
acetate, 0.0024 g (0.009 mmol) of triphenylphosphine and 0.61 mL
(1.2 mmol) of a 2M aqueous sodium carbonate solution and the
reaction mixture was heated at reflux for 18 h. The reaction
mixture was cooled and diluted with EtOAc and water. The organic
fraction was dried over MgSO.sub.4, filtered and the filtrate was
concentrated. The residue was purified by chromatography (silica,
30:1, 9:1 successively, CH.sub.2Cl.sub.2: acetone) to give the
protected hydrazide which was then dissolved in a mixture of 2.1 mL
of TFA and 2.1 mL of CH.sub.2Cl.sub.2. The reaction mixture was
stirred for 2 h whereupon it was concentrated, dissolved in
CH.sub.2Cl.sub.2 and washed with 1N NaOH solution. The organic
fraction was dried over MgSO.sub.4, filtered and the filtrate was
concentrated to give the tile compound as a white solid. Mass
Spectrum (ESI) m/e (M+1): 297.1.
Step C:
5-Methyl-3-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole
##STR00022##
[0164] To a solution of 0.093 g (0.98 mmol) of acetamidine
hydrochloride in 1.1 mL of ethanol was added 0.22 mL (0.98 mmol) of
a 25% solution of sodium methoxide in methanol and the reaction
mixture was stirred for 30 min. whereupon it was filtered. To the
filtrate was added 0.19 g (0.66 mmol) of
3-((2-trifluoromethoxy)phenyl)-bromophenylhydrazide and the
reaction mixture was stirred over night. The reaction mixture was
concentrated and purified by chromatography (silica, 3%, 10%, 30%
successively, methanol: CH.sub.2Cl.sub.2) to give a white solid.
The white solid was heated (neat) to its melting temperature for 30
min. The reaction was cooled to RT, dissolved in CH.sub.2Cl.sub.2
and concentrated. The residue was purified by chromatography
(silica, 3%, 10%, successively, methanol: CH.sub.2Cl.sub.2) to give
the title compound as a white solid. .sup.1H NMR (CD.sub.3OD)
(.delta., ppm): 8.00 (s, 1H), 7.93 (m, 1H), 7.49-7.34 (m, 6H), 2.41
(s, 3H). Mass Spectrum (ESI) m/e (M+1): 320.5.
REFERENCE EXAMPLE 3
##STR00023##
[0165]
3-[3-((2-Trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carboxa-
mide
Step A.
Ethyl-N.sup.1-3-(2-trifluoromethoxy)-benzoyl-N.sup.2-oxamidrazonat-
e
##STR00024##
[0167] To a solution of 0.45 g (1.54 mmol) of
3-(2-trifluoromethoxyphenyl)-bromophenylhydrazide (Example 9, Step
B) in 20 mL of CH.sub.2Cl.sub.2 was added 0.54 g (2.3 mmol) of
carbethoxy-5-methylthioformimidium tetrafluoroborate and 0.43 mL
(3.08 mmol) of triethylamine and the reaction was stirred at
refluxing temperatures for 4 hr. The reaction mixture was cooled to
RT, washed with water, dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated to a solid. Two mL of
CH.sub.2Cl.sub.2 was added and the resulting solid product was
recovered by filtration. Mass Spectrum (ESI) m/e (M+1): 396.1.
Step B.
5-Ethyl-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole--
5-carboxylate
[0168] The solid
Ethyl-N.sup.1-3-(2-trifluoromethoxy)-benzoyl-N.sup.2-oxamidrazonate
(0.25 g, 0.616 mmol) was heated in an oil bath above its melting
point for 20 min. After cooling to RT, the residue was dissolved in
CH.sub.2Cl.sub.2 and concentrated to give a yellow solid. It was
purified by chromatography (silica, 10%, 30%, 50% successively,
EtOAc: hexanes) to give a white solid.
[0169] Mass Spectrum (ESI) m/e (M+1): 378.1.
Step C.
3-[3-((2-Trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-5-carbox-
amide
[0170] A solution of 0.13 g (0.34 mmol) of
5-ethyl-3-[3-((2-trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole-5-carbox-
ylate in 2 mL of methanol in a tube was saturated with ammonia. The
tube was sealed and the reaction mixture was heated at 60.degree.
C. overnight. The reaction mixture was then concentrated and the
residue was purified by chromatography (silica, 3%, 10%, 20%
successively methanol: CH.sub.2Cl.sub.2) to give the title
compound. .sup.1H NMR (CD.sub.3OD) (.delta., ppm): 8.10 (s, 1H),
8.02 (m, 1H), 7.54-7.36 (m, 6H). Mass Spectrum (ESI) m/e (M+1):
349.2.
REFERENCE EXAMPLE 4
##STR00025##
[0171]
1-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-c-
arboxamide
Step A. 3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-aniline
##STR00026##
[0173] To a solution of 1.0 g (3.93 mmol) of
2-trifluoroethoxyphenyl bromide (Example 2, Step A) in 39 mL of
toluene was added 0.136 g (0.118 mmol) of
tetrakis(triphenylphosphine)palladium(0), 0.56 g (4.31 mol) of
3-aminophenylboronic acid, 47 mL (94.1 mmol) of a 2M solution of
sodium carbonate and 8 mL of ethanol and the reaction mixture was
heated at 90.degree. C. for 22 hr. The reaction mixture was cooled
to RT, and partitioned between water and EtOAc. The aqueous
fraction was extracted with EtOAc and the combined organic
fractions were washed with water and brine and dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
residue was purified by chromatography (silica, 4:1 hexanes: EtOAc)
to give the title compound. Mass Spectrum (ESI) m/e M+1 268.1.
Step B.
Methyl-1-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-phenyl]-1,2,4-tria-
zole-3-carboxylate
##STR00027##
[0175] To a solution of 0.923 g (3.45 mmol) of
3-((2-trifluoroethoxy)-phenyl)analine in 6 mL of a 1N solution of
HCl at 0.degree. C. was added 0.238 g (3.45 mmol) of sodium nitrite
and 1 mL of water and the reaction mixture was stirred for 20 min.
to give the diazonium salt solution.
[0176] To a solution of 0.27 g (2.76 mmol) of methylisocyanoacetate
in 15 mL of methanol and 2 mL of water at 0.degree. C. was added
1.8 g (22.08 mmol) of sodium acetate. To this reaction mixture was
added dropwise the diazonium salt solution and the reaction mixture
was stirred at 0.degree. C. for 1 h. The reaction mixture was then
diluted with methanol and concentrated. The residue was diluted
with EtOAc and 0.5N HCl solution. The aqueous layer was extracted
with EtOAc and the combined organic fractions were washed with 5%
NaHCO.sub.3 solution, brine, dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated. The residue was purified by
chromatography (silica, 1:1 EtOAc:hexanes) to give the title
compound. Mass Spectrum (ESI) m/e M+1 378.1.
Step C.
1-[3-((2-(2,2,2-Triuoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-ca-
rboxylic acid
##STR00028##
[0178] A solution of 0.29 g (0.769 mmol) of
methyl-1-[3-((2-trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-carboxy-
late and 2.2 mL (2.2 mmol) of a 1M solution of NaOH in water was
stirred for 18 hr at RT. The reaction mixture was concentrated. The
residue was diluted with water and the pH was adjusted to 2-4 with
1N HCl solution. The mixture was extracted with EtOAc and the
combined organic fractions were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to
give the title compound. Mass Spectrum (ESI) m/e M+1 363.9.
Step D.
1-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-phenyl]-1,2,4-triazole-3--
carboxamide
[0179] To a solution of 0.225 g (0.619 mmol) of
1-[3-((2-trifluoroethoxy)phenyl)-phenyl]-1,2,4-triazole-3-carboxylic
acid in 3.1 mL of DMF was added 0.1 g (0.19 mmol) of CDI and the
reaction mixture was stirred at RT for 4 hr. To the reaction
mixture was added 0.477 g (6.19 mmol) of ammonium acetate and the
reaction mixture was stirred for 19 hr. The reaction mixture was
diluted with water and EtOAc and the aqueous layer was extracted
with EtOAc. The combined organic fractions were washed with brine,
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. The residue was purified by chromatography (silica,
1:1 EtOAc: hexanes, 1% methanol: CH.sub.2Cl.sub.2, 10% methanol:
CH.sub.2Cl.sub.2) to give the title compound. Mass Spectrum (ESI)
m/e M+1 363.1.
REFERENCE EXAMPLE 5
##STR00029##
[0180]
1-[3-((2-Trifluoromethoxy)-phenyl)-phenyl]-1,2,4-triazole-3-carboxa-
mide
Step A. 1-N-t-butoxycarbonylamino-3-bromobenzene
##STR00030##
[0182] A solution of 10 g (58.13 mmol) of 3-bromoaniline and 15.2 g
(69.75 mmol) of Boc.sub.2O in 300 mL of toluene was heated
overnight at 70.degree. C. The reaction mixture was concentrated
and diluted with EtOAc and 0.5N HCl solution. The organic fraction
was washed with 0.5N HCl solution and brine. It was dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
residue was purified by chromatography (hexanes, 9:1 hexanes:EtOAc
successively) to give the title compound.
Step B.
1-N-t-butoxycarbonyl-3-((2-Trifluoromethoxy)-phenyl)analine
##STR00031##
[0183] 1-N-t-Butoxycarbonylamino-3-bromobenzene was coupled with
2-trifluoromethoxyphenylboronic acid according to procedures
described in Reference Example 4, Step A
Step C. 3-((2-Trifluoromethoxy)-phenyl)aniline
##STR00032##
[0185] A solution of 0.977 g (2.77 mmol) of
1-N-t-butoxycarbonyl-3-((2-Trifluoromethoxy)-phenyl)analine in 7 mL
of TFA and 7 mL of CH.sub.2Cl.sub.2 was stirred at RT for 1 hr. The
reaction mixture was concentrated and the residue was diluted with
1N NaOH solution and EtOAc. The organic fraction was washed with 1N
NaOH solution and brine, dried over Na.sub.2SO.sub.4 filtered and
the filtrate was concentrated to give the title compound. Mass
Spectrum (ESI) m/e M+1 254.1.
Step D.
1-[3-((2-Trifluoromethoxy)phenyl)-phenyl]-1,2,4-triazole-3-carboxa-
mide
[0186] The title compound was prepared from
3-((2-Trifluoromethoxy)phenyl)aniline according to procedures
described in Reference Example 4. Mass Spectrum (ESI) m/e M+1
349.1.
[0187] The following examples were prepared according to procedures
previously described and are provided to illustrate the present
invention are not to be construed as limiting the scope of the
invention in any manner.
EXAMPLE 1
##STR00033##
[0188]
5-[6-Fluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-yl]2H-1,2-
,4-triazole-3-carboxamide
[0189] Mass Spectrum (ESI) m/e (M+1): 431.1.
EXAMPLE 2
##STR00034##
[0190]
5-[5-Fluoro-2'-(trifluoromethoxy)biphenyl-3-yl]2H-1,2,4-triazole-3--
carboxamide
[0191] Mass Spectrum (ESI) m/e (M+1): 367.0.
EXAMPLE 3
##STR00035##
[0192]
5-[5-Fluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-yl]2H-1,2-
,4-triazole-3-carboxamide
[0193] Mass Spectrum (ESI) m/e (M+1): 431.0.
EXAMPLE 4
##STR00036##
[0194]
5-[4'-Fluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-yl]2H-1,-
2,4-triazole-3-carboxamide
[0195] Mass Spectrum (ESI) m/e (M+1): 431.0.
EXAMPLE 5
##STR00037##
[0196]
5-[5'-Fluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-yl]2H-1,-
2,4-triazole-3-carboxamide
[0197] Mass Spectrum (ESI) m/e (M+1): 431.1.
EXAMPLE 6
##STR00038##
[0198]
5-[2-Fluoro-2'-(trifluoromethoxy)biphenyl-3-yl]2H-1,2,4-triazole-3--
carboxamide
[0199] Mass Spectrum (ESI) m/e (M+1): 367.0.
EXAMPLE 7
##STR00039##
[0200]
5-[6-Fluoro-2'-(ethoxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxamid-
e
[0201] Mass Spectrum (ESI) m/e (M+1): 381.1.
EXAMPLE 8
##STR00040##
[0202]
5-[2,6-Difluoro-2'-(trifluoromethoxy)biphenyl-3-yl]2H-1,2,4-triazol-
e-3-carboxamide
[0203] Mass Spectrum (ESI) m/e (M+1): 385.0.
EXAMPLE 9
##STR00041##
[0204]
5-[2',6-Bis(trifluoromethoxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carb-
oxamide
[0205] Mass Spectrum (ESI) m/e (M+1): 432.9.
EXAMPLE 10
##STR00042##
[0206]
5-[5',6-Difluoro-2'-(trifluoromethoxy)biphenyl-3-yl]2H-1,2,4-triazo-
le-3-carboxamide
[0207] Mass Spectrum (ESI) m/e (M+1): 384.9.
EXAMPLE 11
##STR00043##
[0208]
5-[2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-yl]2H-1,2,4-triazo-
le-3-carboxamide
[0209] Mass Spectrum (ESI) m/e (M+1): 413.2.
EXAMPLE 12
##STR00044##
[0210]
5-[2,6-Difluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-yl]2H-
-1,2,4-triazole-3-carboxamide
EXAMPLE 13
##STR00045##
[0211]
5-[2,5',6-Trifluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-y-
l]2H-1,2,4-triazole-3-carboxamide
EXAMPLE 14
##STR00046##
[0212]
5-[5,6-Difluoro-2'-(trifluoromethoxy)biphenyl-3-yl]2H-1,2,4-triazol-
e-3-carboxamide
[0213] Mass Spectrum (ESI) m/e (M+1): 385.0.
EXAMPLE 15
##STR00047##
[0214]
5-[5,6-Difluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-yl]2H-
-1,2,4-triazole-3-carboxamide
EXAMPLE 16
##STR00048##
[0215]
5-[5,5',6-Trifluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-y-
l]2H-1,2,4-triazole-3-carboxamide
EXAMPLE 17
##STR00049##
[0216]
5-[6-Fluoro-2'-(allyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxam-
ide
[0217] Mass Spectrum (ESI) m/e (M+1): 339.1.
EXAMPLE 18
##STR00050##
[0218]
5-[5'-Fluoro-2'-(allyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxa-
mide
[0219] Mass Spectrum (ESI) m/e (M+1): 339.2.
EXAMPLE 19
##STR00051##
[0220]
5-[6-Fluoro-2'-(n-propyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carbo-
xamide
[0221] Mass Spectrum (ESI) m/e (M+1): 341.1.
EXAMPLE 20
##STR00052##
[0222]
5-[5'-Fluoro-2'-(n-propyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carb-
oxamide
EXAMPLE 21
##STR00053##
[0223]
1-[6-Fluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-yl]-1,2,4-
-triazole-3-carboxamide
[0224] Mass Spectrum (ESI) m/e (M+1): 430.9.
EXAMPLE 22
##STR00054##
[0225]
1-[2'-(2,2,3,3,3-Pentafluoropropyloxy)biphenyl-3-yl]-1,2,4-triazole-
-3-carboxamide
[0226] Mass Spectrum (ESI) m/e (M+1): 413.0.
EXAMPLE 23
##STR00055##
[0227]
1-[5'Fluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-yl]-1,2,4-
-triazole-3-carboxamide
[0228] Mass Spectrum (ESI) m/e (M+1): 431.0.
EXAMPLE 24
##STR00056##
[0229]
5-[2'-(Phenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxamide
Step A. Ethyl-5-[3-bromophenyl]2H-1,2,4-triazole-3-carboxylate
##STR00057##
[0231] The title compound was prepared from ethyl-3-bromobenzoate
according to procedures described in Reference Example 3.
Step B.
Ethyl-2-trimethylsilylethoxymethyl-5-[3-bromophenyl]-1,2,4-triazol-
e-3-carboxylate
##STR00058##
[0233] To a mixture of 0.79 g (19.8 mmol) of sodium hydride (60% in
oil) in 15 mL of THF at 0.degree. C. was added dropwise a solution
of 5.31 g (18 mmol) of
ethyl-5-[3-bromophenyl]2H-1,2,4-triazole-3-carboxylate in 80 mL of
THF. After stirring for 10 min at RT, the reaction mixture was
cooled to 0.degree. C. and to it was added dropwise 3 g (18 mmol)
of trimethylsilylethoxy methyl chloride (SEM-Cl). After stirring
for 2 hr, the reaction mixture was poured into water and extracted
with ethyl acetate. The combined organic fractions were washed with
brine, dried (MgSO.sub.4) filtered and the filtrate was
concentrated. The residue was purified by chromatography (silica,
ethyl acetate:hexanes, 10-25% gradient) to give the title compound
as a mixture of two regiosiomers.
Step C.
2-Trimethylsilylethoxymethyl-5-[3-bromophenyl]-1,2,4-triazole-3-ca-
rboxamide
##STR00059##
[0235] A solution of 4.39 g (10.3 mmol) of
ethyl-2-trimethylsilylethoxymethyl-5-[3-bromophenyl]-1,2,4-triazole-3-car-
boxylate in 10 mL of a 2N solution of ammonia in methanol was
stirred overnight at 60.degree. C. The reaction mixture was then
concentrated to give the title compound.
Step D.
2-Trimethylsilylethoxymethyl-5-[3-(pinicolboranyl)phenyl]-1,2,4-tr-
iazole-3-carboxamide
##STR00060##
[0237] To a mixture of 7.1 g (17.9 mmol) of 2-Trimethylsilyl
ethoxymethyl-5-[3-bromophenyl]-1,2,4-triazole-3-carboxamide and 9.1
g (35.8 mmol) of pinicolboron
(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in 150 mL of DMSO at RT
was added 7 g (71.5 mmol) of potassium acetate and the reaction was
stirred at 40.degree. C. for 15 min in a nitrogen atmosphere. To
the reaction mixture was added 2.92 g (3.58 mmol) of
PdCl.sub.2(dppf) and the reaction mixture was stirred for 18 hr at
95-100.degree. C. The reaction mixture was cooled and partitioned
between EtOAc and water. The organic fraction was washed with water
and brine, dried (MgSO.sub.4), filtered and the filtrate was
concentrated. The residue was purified by chromatography (silica,
ethyl acetate:hexanes, 0-25% gradient) to give the title
compound.
Step E.
2-Trimethylsilylethoxymethyl-5-[2'-(Phenyl)biphenyl-3-yl]-1,2,4-tr-
iazole-3-carboxamide
##STR00061##
[0239] To a mixture of 0.0385 g (0.082 mmol) of 2-Trimethylsilyl
ethoxymethyl-5-[3-(pinicolboranyl)phenyl]-1,2,4-triazole-3-carboxamide,
0.0297 g (0.128 mmol) of 2-bromobiphenyl, 0.128 mL (0.255 mmol) of
a 2M solution of sodium carbonate in 1.5 mL of toluene and 0.5 mL
of ethanol was added 0.013 g (0.011 mmol) of Pd (PPh.sub.3).sub.4
and the reaction mixture was stirred at 100.degree. C. for 6 hr.
The reaction mixture was cooled to RT and partitioned between EtOAc
and water. The organic fraction was washed with brine, dried
(MgSO.sub.4), filtered and the filtrate was concentrated. The
residue was purified by chromatography (silica, Hexanes: EtOAc,
0-50% gradient) to give the title compound.
Step F.
5-[2'-(Phenyl)biphenyl-3-yl]2H-1,24-triazole-3-carboxamide
##STR00062##
[0241] A mixture of 0.035 g of
2-Trimethylsilylethoxymethyl-5-[2'-(Phenyl)biphenyl-3-yl]-1,2,4-triazole--
3-carboxamide in 3 mL of acetonitrile and 9 mL of a 50% solution of
HF in water was stirred at rt for 6 hours. The reaction mixture was
then concentrated and the residue was purified by chromatography
(silica, CH.sub.3OH: CH.sub.2Cl.sub.2 0-5% gradient) to give the
title compound.
[0242] Mass Spectrum (ESI) m/e (M+1): 341.2.
EXAMPLE 25
##STR00063##
[0243]
5-[2'-(2-Fluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxamide
[0244] The title compound was prepared according to procedures
described in Example 24. 2'-Fluoro-2-bromobiphenyl was prepared
from 2-fluorophenylboronic acid and 2-bromophenyliodide according
to the procedure described in Example 24, Step D.
[0245] Mass Spectrum (ESI) m/e (M+1): 359.2.
[0246] The following Examples 26 to 33 were prepared according to
procedures described in Examples 24 and 25.
EXAMPLE 26
##STR00064##
[0247]
5-[2'-(3-Fluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxamide
[0248] Mass Spectrum (ESI) m/e (M+1): 359.2.
EXAMPLE 27
##STR00065##
[0249]
5-[2'-(4-Fluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxamide
[0250] Mass Spectrum (ESI) m/e (M+1): 359.2.
EXAMPLE 28
##STR00066##
[0251]
5-[6-Fluoro-2'-(3-fluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-ca-
rboxamide
[0252] Mass Spectrum (ESI) m/e (M+1): 377.2.
EXAMPLE 29
##STR00067##
[0253]
5-[5'-Fluoro-2'-(3-fluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-c-
arboxamide
[0254] Mass Spectrum (ESI) m/e (M+1): 377.2.
EXAMPLE 30
##STR00068##
[0255]
5-[3',5'-Difluoro-2'-(3-fluorphenyl)biphenyl-3-yl]2H-1,2,4-triazole-
-3-carboxamide
[0256] Mass Spectrum (ESI) m/e (M+1): 395.03.
EXAMPLE 31
##STR00069##
[0257]
5-[6-Fluoro-5'-fluoro-2'-(3-fluorophenyl)biphenyl-3-yl]2H-1,2,4-tri-
azole-3-carboxamide
[0258] Mass Spectrum (ESI) m/e (M+1): 395.23.
EXAMPLE 32
##STR00070##
[0259]
5-[6-Fluoro-3',5'-difluoro-2'-(3-fluorophenyl)biphenyl-3-yl]2H-1,2,-
4-triazole-3-carboxamide
[0260] Mass Spectrum (ESI) m/e (M+1): 413.16.
EXAMPLE 33
##STR00071##
[0261]
5-[6-Fluoro-4'-fluoro-2'-(3-fluorophenyl)biphenyl-3-yl]2H-1,2,4-tri-
azole-3-carboxamide
[0262] Mass Spectrum (ESI) m/e (M+1): 395.23.
EXAMPLE 34
##STR00072##
[0263]
5-[2'-(2-trifluoromethylphenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-ca-
rboxamide
Step A.
2-Trimethylsilylethoxymethyl-5-[2'-(bromo)biphenyl-3-yl]-1,2,4-tri-
azole-3-carboxamide
##STR00073##
[0265] The title compound was prepared from 2-Trimethylsilyl
ethoxymethyl-5-[3-(pinicolboranyl)phenyl]-1,2,4-triazole-3-carboxamide
(Example 24, Step D) and 2-bromophenyliodide according to
procedures described in Example 24, Step E.
Step B.
2-Trimethylsilylethoxymethyl-5-[2'-(2-trifluoromethylphenyl)
biphenyl-3-yl]-1,2,4-triazole-3-carboxamide
##STR00074##
[0267] The title compound was prepared from 2-trimethylsilyl
ethoxymethyl-5-[2'-(bromo)biphenyl-3-yl]-1,2,4-triazole-3-carboxamide
and 2-thrifluoromethylphenylboronic acid according to the Suzuki
conditions described in the preceding examples.
Step C. 5-[2'-(Trifluoromethylphenyl)
biphenyl-3-yl]-1,2,4-triazole-3-carboxamide
[0268] The title compound was prepared from 2-Trimethylsilyl
ethoxymethyl-5-[2'-(2-trifluoromethylphenyl)
biphenyl-3-yl]-1,2,4-triazole-3-carboxamide according to procedures
described in Example 24, Step F.
[0269] Mass Spectrum (ESI) m/e (M+1): 408.98.
The following Examples 35 to 42 were prepared according to
procedures described in Examples 24 and 34.
EXAMPLE 35
##STR00075##
[0270]
5-[2'-(3-Trifluoromethylphenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-ca-
rboxamide
[0271] Mass Spectrum (ESI) m/e (M+1): 408.98.
EXAMPLE 36
##STR00076##
[0272]
5-[2'-(4-Trifluoromethylphenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-ca-
rboxamide
[0273] Mass Spectrum (ESI) m/e (M+1): 408.98.
EXAMPLE 37
##STR00077##
[0274]
5-[2'-(2-Trifluoromethoxyphenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-c-
arboxamide
[0275] Mass Spectrum (ESI) m/e (M+1): 424.9.
EXAMPLE 38
##STR00078##
[0276]
5-[2'-(3-Trifluoromethoxyphenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-c-
arboxamide
[0277] Mass Spectrum (ESI) m/e (M+1): 425.2.
EXAMPLE 39
##STR00079##
[0278]
5-[2'-(4-Trifluoromethoxyphenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-c-
arboxamide
[0279] Mass Spectrum (ESI) m/e (M+1): 425.3.
EXAMPLE 40
##STR00080##
[0280]
5-[2'-(3-Carbomethoxyphenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carbo-
xamide
[0281] Mass Spectrum (ESI) m/e (M+1): 367.2 (M-OCH.sub.3)
EXAMPLE 41
##STR00081##
[0282]
5-[2'-(4-Carbomethoxyphenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carbo-
xamide
[0283] Mass Spectrum (ESI) m/e (M+1): 367.2 (M-OCH.sub.3)
EXAMPLE 42
##STR00082##
[0284]
5-[2'-(2-Fluoro-4-trifluoromethylphenyl)biphenyl-3-yl]2H-1,2,4-tria-
zole-3-carboxamide
[0285] Mass Spectrum (ESI) m/e (M+1): 427.1.
EXAMPLE 43
##STR00083##
[0286]
5-[2'-(3,5-Difluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxa-
mide
[0287] Mass Spectrum (ESI) m/e (M+1): 377.2.
EXAMPLE 44
##STR00084##
[0288]
5-[2'-(2,5-Difluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxa-
mide
[0289] Mass Spectrum (ESI) m/e (M+1): 377.18.
EXAMPLE 45
##STR00085##
[0290]
5-[2'-(2,4-Difluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxa-
mide
[0291] Mass Spectrum (ESI) m/e (M+1): 377.18.
EXAMPLE 46
##STR00086##
[0292]
5-[2'-(3,4-Difluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxa-
mide
[0293] Mass Spectrum (ESI) m/e (M+1): 377.0.
EXAMPLE 47
##STR00087##
[0294]
5-[2'-(3,4,5-Trifluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carb-
oxamide
[0295] Mass Spectrum (ESI) m/e (M+1): 396.15.
EXAMPLE 48
##STR00088##
[0296]
5-[2'-(2,3,4-Trifluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carb-
oxamide
[0297] Mass Spectrum (ESI) m/e (M+1): 396.2.
EXAMPLE 49
##STR00089##
[0298]
5-[2'-(3-Dimethylaminophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carb-
oxamide
[0299] Mass Spectrum (ESI) m/e (M+1): 384.3.
EXAMPLE 50
##STR00090##
[0300]
5-[2'-(4-Dimethylaminophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carb-
oxamide
[0301] Mass Spectrum (ESI) m/e (M+1): 383.9.
EXAMPLE 51
##STR00091##
[0302]
5-[2'-(3-Cyanophenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxamide
[0303] Mass Spectrum (ESI) m/e (M+1): 366.18.
EXAMPLE 52
##STR00092##
[0304]
5-[2'-(3-(pyrazol-1-yl)phenyl)biphenyl-3-yl]2H-1,2,4-triazole-3-car-
boxamide
[0305] Mass Spectrum (ESI) m/e (M+1): 408.17.
EXAMPLE 53
##STR00093##
[0306]
5-[6-Fluoro-2'-(4-dimethylaminophenyl)biphenyl-3-yl]2H-1,2,4-triazo-
le-3-carboxamide
Step A.
2-Trimethylsilylethoxymethyl-5-[3-bromo-6-fluorophenyl]-1,2,4-tria-
zole-3-carboxamide
##STR00094##
[0308] The title compound was prepared according to procedures
described in Example 24.
Step B.
2-Trimethylsilylethoxymethyl-5-[2'-(hydroxy)biphenyl-3-yl]-1,2,4-t-
riazole-3-carboxamide
##STR00095##
[0310] The title compound was prepared from 2-trimethylsilyl
ethoxymethyl-5-[3-(pinicolboranyl)phenyl]-1,2,4-triazole-3-carboxamide
(Example 24, Step D) and 2-bromophenyliodide according to
procedures described in Example 24, Step E.
Step C.
2-Trimethylsilylethoxymethyl-5-[2'-(trifluoromethylsulfonyloxyphen-
yl) biphenyl-3-yl]-1,2,4-triazole-3-carboxamide
##STR00096##
[0312] To a solution of 0.2 g (0.467 mmol) of 2-trimethylsilyl
ethoxymethyl-5-[2'-(hydroxy)biphenyl-3-yl]-1,2,4-triazole-3-carboxamide
and 0.106 mL (0.61 mmol) of diisopropylethylamine in 10 mL of
acetonitrile at 0.degree. C. was added 0.217 g (0.61 mmol) of
N-phenyltrifluoromethanesulfonamide and the reaction mixture was
stirred at RT for 18 hr. The reaction mixture was concentrated and
the residue was purified by chromatography (silica, CH.sub.3OH:
CH.sub.2Cl.sub.2, 0-6% gradient then 6% CH.sub.3OH:
CH.sub.2Cl.sub.2)
Step D.
5-[6-Fluoro-2'-(4-dimethylaminophenyl)biphenyl-3-yl]2H-1,2,4-triaz-
ole-3-carboxamide
##STR00097##
[0314] The title compound was prepared by first coupling
trimethylsilylethoxymethyl-5-[2'-(trifluoromethylphenyl)
biphenyl-3-yl]-1,2,4-triazole-3-carboxamide with
4-dimethylaminophenylboronic acid under standard Suzuki coupling
conditions. Then the trimethylsilylethoxymethyl protecting group
was removed as described in Example 24, Step F.
[0315] Mass Spectrum (ESI) m/e (M+1): 402
The following Examples 54 to 56 were prepared according to
procedures described in Example 53.
EXAMPLE 54
##STR00098##
[0316]
5-[6-Fluoro-2'-(4-trifluoromethoxyphenyl)biphenyl-3-yl]2H-1,2,4-tri-
azole-3-carboxamide
[0317] Mass Spectrum (ESI) m/e (M+1): 443.0.
EXAMPLE 55
##STR00099##
[0318]
5-[6-Fluoro-2'-(3,5-difluorophenyl)biphenyl-3-yl]2H-1,2,4-triazole--
3-carboxamide
[0319] Mass Spectrum (ESI) m/e (M+1): 395.18.
EXAMPLE 56
##STR00100##
[0320]
5-[6-Fluoro-2'-(3,4,5-trifluorophenyl)biphenyl-3-yl]12H-1,2,4-triaz-
ole-3-carboxamide
[0321] Mass Spectrum (ESI) m/e (M+1): 412.8.
EXAMPLE 57
##STR00101##
[0322]
5-[6-Fluoro-5'-2'-(2,2,3,3,4,4,4-heptafluorobutyloxy)biphenyl-3-yl]-
2H-1,2,4-triazole-3-carboxamide
[0323] Mass Spectrum (ESI) m/e (M+1): 481.2.
EXAMPLE 58
##STR00102##
[0324]
5-[5'-Fluoro-2'-(2,2,3,3,4,4,4-heptafluorobutyloxy)biphenyl-3-yl]2H-
-1,2,4-triazole-3-carboxamide
[0325] Mass Spectrum (ESI) m/e (M+1): 481.4.
EXAMPLE 59
##STR00103##
[0326]
5-[6-Fluoro-2'-(n-butyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carbox-
amide
[0327] Mass Spectrum (ESI) m/e (M+1): 355.3.
EXAMPLE 60
##STR00104##
[0328]
5-[5'-Fluoro-2'-(2,2,3,3,4,4,4-heptafluorobutyloxy)biphenyl-3-yl]2H-
-1,2,4-triazole-3-carboxylic acid
[0329] To a solution of 0.1 g (0.196 mmol) of ethyl
5-[5'-fluoro-2'-(2,2,3,3,4,4,4-heptafluorobutyloxy)biphenyl-3-yl]2H-1,2,4-
-triazole-3-carboxylate (prepared according to procedures described
in Reference Example 3, Step B) in 1.4 mL of methanol was added
0.59 mL (0.59 mmol) of a 1N aqueous solution of NaOH and the
reaction mixture was stirred at rt for 23 hr. The pH of the
reaction mixture was adjusted to pH=4-5 with 1N HCl solution and
the mixture was extracted with EtOAc. The organic fractions were
dried (Na.sub.2SO.sub.4), filtered and the filtrate was
concentrated. The residue was purified by chromatography (silica,
CH.sub.2Cl.sub.2: acetone 9:1, then CH.sub.3OH: CH.sub.2Cl.sub.2 1
to 10% linear gradient) to give the title compound.
[0330] Mass Spectrum (ESI) m/e (M+1): 482.1.
The following Examples 61-63 were prepared according to procedures
described in Reference Example 3, Step B.
EXAMPLE 61
##STR00105##
[0331]
5-[5'-Fluoro-2'-(2,2,3,3,3-pentafluoropropyloxy)biphenyl-3-yl]2H-1,-
2,4-triazole-3-carboxylate
[0332] Mass Spectrum (ESI) m/e (M+1): 432.1.
EXAMPLE 62
##STR00106##
[0333]
5-[5'-Fluoro-2'-(2,2,3,3,4,4,4-heptafluorobutyloxy)biphenyl-3-yl]2H-
-1,2,4-triazole-3-carboxylate
[0334] Mass Spectrum (ESI) m/e (M+1): 482.3.
EXAMPLE 63
##STR00107##
[0335]
5-[6-Fluoro-2'-(n-butyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carbox-
ylate
[0336] Mass Spectrum (ESI) m/e (M+1): 356.2.
[0337] The following Examples 64 to 65 were prepared according to
procedures described in Example 53.
EXAMPLE 64
##STR00108##
[0338]
5-[2'-(4-Fluorobenzyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxam-
ide
Step A.
2-Trimethylsilylethoxymethyl-5-[2'-(4-fluorobenzyloxy)biphenyl-3-y-
l]-1,2,4-triazole-3-carboxamide
##STR00109##
[0340] To a solution of 0.05 g (0.122 mmol) of
2-trimethylsilylethoxymethyl-5-[2'-(hydroxy)biphenyl-3-yl]-1,2,4-triazole-
-3-carboxamide (prepared according to procedures described in
Example 53) in 4 mL of DMSO was added 0.16 g (0.488 mmol) of cesium
carbonate and the reaction mixture was stirred at rt for 20 min. To
the reaction mixture was added 0.025 mL (0.244 mmol) of
4-fluorobenzylbromide and the reaction mixture was heated at
80.degree. C. for 18 hr. The reaction mixture was partitioned
between water and EtOAc. The organic fraction was washed with water
and brine, dried (MgSO.sub.4) and filtered. The filtrate was
concentrated and the residue was purified by chromatography
(silica, EtOAc: hexanes, 3:10) to give the title compound.
Step B.
5-[2'-(4-Fluorobenzyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxa-
mide
[0341] The title compound was prepared from
2-trimethylsilylethoxymethyl-5-[2'-(4-fluorobenzyloxy)biphenyl-3-yl]-1,2,-
4-triazole-3-carboxamide according to procedures previously
described. Mass Spectrum (ESI) m/e (M+1): 389.21.
The following Examples 65 to 72 were prepared according to
procedures described in Example 64.
EXAMPLE 65
##STR00110##
[0342]
5-[6-Fluoro-2'-(2,4,5-trifluorobenzyloxy)biphenyl-3-yl]2H-1,2,4-tri-
azole-3-carboxamide
[0343] Mass Spectrum (ESI) m/e (M+1): 443.31.
EXAMPLE 66
##STR00111##
[0344]
5-[6-Fluoro-2'-(2,4-difluorobenzyloxy)biphenyl-3-yl]2H-1,2,4-triazo-
le-3-carboxamide
[0345] Mass Spectrum (ESI) m/e (M+1): 425.35.
EXAMPLE 67
##STR00112##
[0346]
5-[6-Fluoro-2'-(2,5-difluorobenzyloxy)biphenyl-3-yl]2H-1,2,4-triazo-
le-3-carboxamide
[0347] Mass Spectrum (ESI) m/e (M+1): 425.35.
EXAMPLE 68
##STR00113##
[0348]
5-[2'-(2,4,5-Trifluorobenzyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-c-
arboxamide
[0349] Mass Spectrum (ESI) m/e (M+1): 424.91.
EXAMPLE 69
##STR00114##
[0350]
5-[2'-(2,5-Difluorobenzyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carb-
oxamide
[0351] Mass Spectrum (ESI) m/e (M+1): 406.99.
EXAMPLE 70
##STR00115##
[0352]
5-[2'-(2,4-Difluorobenzyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carb-
oxamide
[0353] Mass Spectrum (ESI) m/e (M+1): 407.16.
EXAMPLE 71
##STR00116##
[0354]
5-[2'-(2-Fluorobenzyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxam-
ide
[0355] Mass Spectrum (ESI) m/e (M+1): 389.21.
EXAMPLE 72
##STR00117##
[0356]
5-[2'-(Benzyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxamide
[0357] Mass Spectrum (ESI) m/e (M+1): 371.0.
* * * * *