U.S. patent application number 10/961817 was filed with the patent office on 2005-09-08 for amide compounds as ion channel ligands and uses thereof.
Invention is credited to Janagani, Satyanarayana, Kelly, Michael G., Kincaid, John, Wu, Guoxian.
Application Number | 20050197364 10/961817 |
Document ID | / |
Family ID | 33457711 |
Filed Date | 2005-09-08 |
United States Patent
Application |
20050197364 |
Kind Code |
A1 |
Kelly, Michael G. ; et
al. |
September 8, 2005 |
Amide compounds as ion channel ligands and uses thereof
Abstract
Compounds are disclosed that have a formula represented by the
following: 1 The compounds may be prepared as pharmaceutical
compositions, and may be used for the prevention and treatment of a
variety of conditions in mammals including humans, including by way
of non-limiting example, pain, inflammation, traumatic injury, and
others.
Inventors: |
Kelly, Michael G.; (Thousand
Oaks, CA) ; Janagani, Satyanarayana; (Santa Clara,
CA) ; Wu, Guoxian; (Foster City, CA) ;
Kincaid, John; (Foster City, CA) |
Correspondence
Address: |
KLAUBER & JACKSON
411 HACKENSACK AVENUE
HACKENSACK
NJ
07601
|
Family ID: |
33457711 |
Appl. No.: |
10/961817 |
Filed: |
October 7, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60508865 |
Oct 7, 2003 |
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60575937 |
Jun 1, 2004 |
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Current U.S.
Class: |
514/337 ;
514/340; 514/341; 546/270.4; 546/271.4; 546/276.7 |
Current CPC
Class: |
A61P 11/02 20180101;
A61P 13/00 20180101; A61P 25/20 20180101; C07D 405/12 20130101;
C07D 417/14 20130101; A61P 27/00 20180101; C07D 213/75 20130101;
A61P 7/12 20180101; A61P 17/02 20180101; C07D 401/14 20130101; A61P
9/12 20180101; A61P 3/04 20180101; C07D 401/04 20130101; C07D
213/56 20130101; A61P 25/04 20180101; A61P 25/16 20180101; A61P
3/06 20180101; A61P 29/00 20180101; C07D 409/12 20130101; A61P
37/00 20180101; A61P 1/00 20180101; A61P 25/06 20180101; A61P 1/12
20180101; A61P 15/08 20180101; A61P 25/28 20180101; C04B 35/632
20130101; A61P 17/04 20180101; C07D 401/12 20130101; C07D 405/14
20130101; C07D 413/12 20130101; A61P 25/18 20180101; A61P 1/02
20180101; A61P 11/00 20180101; A61P 11/08 20180101; A61P 25/02
20180101; A61P 25/24 20180101; A61P 9/10 20180101; A61P 19/02
20180101; A61P 25/22 20180101; A61P 43/00 20180101; C07D 213/64
20130101; C07D 213/70 20130101; C07D 417/12 20130101; A61P 13/12
20180101; A61P 17/14 20180101; A61P 25/08 20180101; C07D 213/61
20130101; A61P 11/06 20180101; A61P 13/08 20180101; A61P 35/00
20180101; A61P 13/10 20180101; C07D 403/12 20130101; A61P 1/04
20180101; A61P 17/06 20180101; A61P 37/06 20180101; A61P 39/02
20180101; A61P 25/00 20180101 |
Class at
Publication: |
514/337 ;
546/276.7; 546/271.4; 546/270.4; 514/341; 514/340 |
International
Class: |
A61K 031/4439; C07D
417/02; C07D 413/02 |
Claims
1. A compound capable of modifying ion channels, in vivo, having a
formula: 446wherein: A is halogen or trihaloalkyl; each of W, X, Y
and Z is independently N or CR.sup.4; G is C.dbd.O, C.dbd.S or
SO.sub.2; R.sup.1 is substituted or unsubstituted heteroalkyl,
aryl, heteroaryl, aralkyl, or heteroaralkyl; and each R.sup.4 is
independently hydrogen, alkyl, substituted or unsubstituted alkyl,
acyl, acylamino, alkylamino, alkylthio, alkoxy, alkoxycarbonyl,
alkylarylamino, arylalkyloxy, amino, aryl, arylalkyl, sulfoxide,
sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid,
sulfuric acid ester, dihydroxyphosphoryl, aminohydroxyphosphoryl,
azido, carboxy, carbamoyl, carboxyl, cyano, cycloheteroalkyl,
dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl,
hydroxyl, nitro or thio; and n is an integer of from 1-3; or a
pharmaceutically acceptable salt, solvate or prodrug thereof; and
stereoisomers thereof.
2. (canceled)
3. A compound according to claim 1 wherein G is C.dbd.O; R.sup.1 is
substituted aryl or heteroaryl; provided that, when each of W, X, Y
and Z is CR.sup.4, then R.sup.1 is not substituted or unsubstituted
quinoline, isoguinoline, dihydroquinoline, dihydroisoguinoline,
tetrahydroquinoline or tetrahydroisoquinoline.
4. (canceled)
5. A compound according to claim 3 wherein each of W, X, Y and Z is
CR.sup.4.
6. A compound according to claim 3 wherein each of W, X, Y and Z is
independently selected from C--H, C-halogen and C-alkoxy.
7. A compound according to claim 3 wherein at least one of W, X, Y
and Z is C-halogen or C-alkoxy.
8. A compound according to claim 3 wherein at least one of W, X, Y
and Z is C-fluoro or C-methoxy.
9. A compound according to claim 3 wherein R.sup.1 is substituted
phenyl.
10. A compound according to claim 3 wherein R.sup.1 is substituted
or unsubstituted naphthyl.
11. A compound according to claim 1 wherein the compound is of the
formula: 447wherein R.sup.1' is elected from the group consisting
of cyano, trifluoroalkyl, halo, nitro, methoxy, trifluoromethoxy,
amino, alkylamino, and carboxy; x is selected from 1-5.
12. A compound according to claim 11 wherein A is Cl.
13. A compound according to claim 12 wherein x is 1.
14. A compound according to claim 13 wherein R.sup.' is
4-trifluoromethyl.
15. A compound according to claim 14 wherein the compound is of the
formula 448
16. A compound according to claim 1 wherein the compound is of
Table 1 and wherein the compound ID No. is 24, 25, 26, or 27, or a
pharmaceutically acceptable salt, solvate or prodrug thereof; and
stereoisomers thereof.
17. A compound according to claim 1 wherein the compound is of
Table 1 and wherein the compound ID No. is 2, 3, 5, 6, 12, 18, 20,
21, 22, 28, 43, 44, 45, 56, 57, 69, 71, 74, 79, 83, 84, 86, or 109,
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers thereof.
18. A compound according to claim 1 wherein the compound is of
Table 1 and wherein the compound ID No. is 11, 13, 15, 16, 23, 54,
67, 114, 116, 118, 119, 122, 124, 125, 127, 128, 132, 134, 135,
165, 166, 170, 172, 173, 175, 176, 177, 178, 183, 189, 190, 192,
193, 194, 195, 196, 199, 201, 204, 206, 210, 212, 213, 214, 240,
242, 246, 247, 248, 250, 252, 253, 254, 256, 258, 259, 260, 261,
265, 269, 271, 274, 276, 277, 278, 279, 281, or 284, or a
pharmaceutically acceptable salt, solvate or prodrug thereof; and
stereoisomers thereof.
19. A compound according to claim 11 wherein A is CF.sub.3.
20. A compound according to claim 1 wherein the compound is of
Table 1 and wherein the compound ID No. is 354, 355, 356, 357, 358,
359, 361, 362, 363, 364, 365, 366, 372, 373, 374, 375, 377, 378,
379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 395, 396,
397, or 398, or a pharmaceutically acceptable salt, solvate or
prodrug thereof; and stereoisomers thereof.
21. A compound according to claim 1 wherein the compound is of
Table 1 and wherein the compound ID No. is 366 or 389, or a
pharmaceutically acceptable salt, solvate or prodrug thereof; and
stereoisomers thereof.
22. A compound according to claim 3 wherein R.sup.1 is substituted
or unsubstituted heteroaryl.
23. A compound according to claim 3 wherein R.sup.1 is substituted
or unsubstituted pyrimidinyl, thiazolyl, or pyrazolyl.
24. A compound according to claim 3 wherein R.sup.1 is substituted
or unsubstituted 2-pyridyl, 4-pyridyl or 3-pyridyl.
25. A compound according to claim 24 wherein at least one of W, X,
Y and Z is C-fluoro or C-methoxy.
26. (canceled)
27. A compound according to any one of claims 24-25 wherein the
substitution on the heteroaryl is selected from the group
consisting of hydrogen, alkyl, trifluoromethyl, halo, methoxy,
trifluoromethoxy, amino and carboxy.
28. (canceled)
29. A compound according to claim 1 wherein the compound is of
Table 1 and wherein the compound Id No. is 7, 8, 9, 30, 31, 32, 33,
35, 37, 38, 48, 49, 62, 63, 95, 97, 98, 101, 103, 106, 139, 140,
145, 149, 152, 153, 156, 158, 217, 218, 219, 223, 225, 226, 230,
231, 232, 235, or a pharmaceutically acceptable salt, solvate or
prodrug thereof; and stereoisomers thereof.
30. A compound according to claim 3 wherein R.sup.1 is substituted
or unsubstituted benzodioxane, indole, indazole and carbazole.
31. (canceled)
32. A compound according to claim 30 wherein the substitution on
the heteroaryl is selected from the group consisting of hydrogen,
substituted or unsubstituted alkyl, halogen, cyano, nitro,
trihaloalkyl, alkoxy, and dialkylamino.
33. (canceled)
34. A compound according to claim 1 wherein the compound is of
Table 1 and wherein the compound Id. No. is 1, 36, or 55, or a
pharmaceutically acceptable salt, solvate or prodrug thereof; and
stereoisomers thereof.
35. A compound according to claim 1 wherein the compound is of
Table 1 and wherein the compound id # is 156, 160, 186, 233, 234,
236, 273, or 287 or a pharmaceutically acceptable salt, solvate or
prodrug thereof; and stereoisomers thereof.
36. A compound according to claim 3 wherein Y is N and each of W,
X, and Z is CR.sup.4.
37. A compound according to claim 36 wherein each of W, X, and Z is
selected from C--H, C-halogen and C-alkoxy.
38. (canceled)
39. A compound according to claim 36 wherein the substitution on
aryl or heteroaryl is selected from hydrogen, substituted or
unsubstituted alkyl, halogen, cyano, nitro, trihaloalkyl, alkoxy,
and dialkylamino.
40. (canceled)
41. A compound according to claim 36 wherein the compound is of
Table 1 and wherein the compound ID No. is 289, 292, 297, 299, 302,
303, 308, 311, 312, 313, 317, 318, 319, 324, 325, 326, 327, 328,
331, 332, 338, 339, 340, 341, 343, 344, 345, 346, or 347 or a
pharmaceutically acceptable salt, solvate or prodrug thereof; and
stereoisomers thereof.
42. A compound according to claim 3 wherein R.sup.1 is aryl, or
heteroaryl, substituted with 449wherein ring P is cycloheteroalkyl,
substituted cycloheteroalkyl, heteroaryl, or substituted
heteroaryl.
43-45. (canceled)
46. The compound of claim 42 wherein the ring P is selected from
substituted or un substituted 450wherein R.sup.2' is selected from
H and R.sup.1 and R.sup.1 is substituted or unsubstituted
alkyl.
47. (canceled)
48. A compound according to claim 1 wherein the compound is of
Table 1 and wherein the compound Id. No. is 400, 401, 402, or 403,
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers thereof.
49-55. (canceled)
56. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a pharmaceutically effective amount of a
compound of any of claims 1, 3, 11, 15, 22 or 42.
57. The pharmaceutical composition of claim 56 wherein the carrier
is a parenteral, oral or topical carrier.
58-59. (canceled)
60. A method for preventing, treating, ameliorating or managing a
disease or condition which comprises administering to a patient in
need of such prevention, treatment, amelioration or management, a
prophylactically or therapeutically effective amount of a compound
of any of claims 1, 3, 11, 15, 22 or 42, or the pharmaceutical
composition of any of claims 56-57.
61. The method of claim 60 wherein the disease or condition is a
pain condition.
62. The method of claim 60 wherein the disease or condition is an
autoimmune disease.
63. The method of claim 60 wherein the disease or condition is an
inflammatory disease or condition.
64. The method of claim 60 wherein the disease or condition is a
neurological or neurodegenerative disease or condition.
65. A method for preventing, treating, ameliorating or managing a
disease or condition, which comprises administering to a patient in
need of such prevention, treatment, amelioration or management a
prophylactically or therapeutically acceptable amount of a compound
of any of claims 1, 3, 11, 15, 22 or 42, or the pharmaceutical
composition of any of claims 56-57, wherein the disease or
condition is: pain including acute, inflammatory and neuropathic
pain; chronic pain; dental pain; headache including migraine,
cluster headache and tension headache; Parkinson's disease;
Alzheimer's disease; multiple sclerosis; diseases and disorders
mediated by or result in neuroinflammation, traumatic brain injury,
stroke, or encephalitis; centrally-mediated neuropsychiatric
diseases and disorders including depression, mania, bipolar
disease, anxiety, schizophrenia, eating disorders, sleep disorders
and cognition disorders; epilepsy and seizure disorders; prostate,
bladder and bowel dysfunction, urinary incontinence, urinary
hesitancy, rectal hypersensitivity, fecal incontinence, benign
prostatic hypertrophy and inflammatory bowel disease; respiratory
and airway disease and disorders including allergic rhinitis,
asthma and reactive airway disease and chronic obstructive
pulmonary disease; diseases and disorders mediated by or result in
inflammation including arthritis, rheumatoid arthritis and
osteoarthritis; myocardial infarction; autoimmune diseases and
disorders; uveitis and atherosclerosis; itch/pruritus, psoriasis;
alopecia (hair loss); obesity; lipid disorders; cancer; high blood
pressure; spinal cord injury; or renal disorders.
66. The method of claim 65 wherein the disease or condition is
Parkinson's disease.
67. The method of claim 65 wherein the disease or condition is
Alzheimer's disease.
68. The method of claim 65 wherein the disease or condition is
traumatic brain injury.
69. The method of claim 65 wherein the disease or condition is
stroke.
70. The method of claim 65 wherein the disease or condition is
pain.
71. The method of claim 65 wherein the disease or condition is
neuropathic pain.
72. (canceled)
73. A method of treating a mammal suffering from at least one
symptom selected from the group consisting of symptoms of exposure
to capsaicin, symptoms of burns or irritation due to exposure to
heat, symptoms of burns or irritation due to exposure to light,
symptoms of burns, bronchoconstriction or irritation due to
exposure to tear gas, and symptoms of burns or exposure irritation
due to exposure to acid which comprises administering to the mammal
an effective disease-treating or condition-treating amount of a
compound of claim 1, or the pharmaceutical composition of any of
claims 56-57.
74. The method of claim 73 wherein the pain is associated with a
condition selected from the group consisting of postmastectomy pain
syndrome, stump pain, phantom limb pain, oral neuropathic pain,
Charcot's pain, toothache, venomous snake bite, spider bite, insect
sting, postherpetic neuralgia, diabetic neuropathy, reflex
sympathetic dystrophy, trigeminal neuralgia, osteoarthritis,
rheumatoid arthritis, fibromyalgis, Guillain-Barre syndrome,
meralgia paresthetica, burning-mouth syndrome, bilateral peripheral
neuropathy, causalgia, sciatic neuritis, peripheral neuritis,
polyneuritis, segmental neuritis, Gombault's neuritis, neuronitis,
cervicobrachial neuralgia, cranial neuralgia, egniculate neuralgia,
glossopharyngial neuralgia, migranous neuralgia, idiopathic
neuralgia, intercostals neuralgia, mammary neuralgia, mandibular
joint neuralgia, Morton's neuralgia, nasociliary neuralgia,
occipital neuralgia, red neuralgia, Sluder's neuralgia,
splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia,
sinus headache, tension headache, labor, childbirth, intestinal
gas, menstruation, cancer, and trauma.
75-77. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the priority of co-pending
provisional applications U.S. Ser. No. 60/434,022, filed on Oct. 7,
2003, and U.S. Ser. No. 60/575,937, filed Jun. 1, 2004. The
disclosures of both applications are incorporated by reference
herein in their entireties. Applicants claim the benefits of both
applications under 35 U.S.C. .sctn.119(e).
FIELD OF THE INVENTION
[0002] This invention relates to novel compounds and to
pharmaceutical compositions containing such compounds. This
invention also relates to methods for preventing and/or treating
pain and inflammation-related conditions in mammals, such as (but
not limited to) arthritis, Parkinson's disease, Alzheimer's
disease, stroke, uveitis, asthma, myocardial infarction, the
treatment and prophylaxis of pain syndromes (acute and chronic or
neuropathic), traumatic brain injury, acute spinal cord injury,
neurodegenerative disorders, alopecia (hair loss), inflammatory
bowel disease and autoimmune disorders, using the compounds and
pharmaceutical compositions of the invention.
BACKGROUND OF THE INVENTION
[0003] Studies of signaling pathways in the body have revealed the
existence of ion channels and sought to explain their role. Ion
channels are integral membrane proteins with two distinctive
characteristics: they are gated (open and closed) by specific
signals such as membrane voltage or the direct binding of chemical
ligands and, once open, they conduct ions across the cell membrane
at very high rates.
[0004] There are many types of ion channels. Based on their
selectivity to ions, they can be divided into calcium channel,
potassium channel, sodium channel, etc. The calcium channel is more
permeable to calcium ions than other types of ions, the potassium
channel selects potassium ions over other ions, and so forth. Ion
channels may also be classified according to their gating
mechanisms. In a voltage-gated ion channel, the opening probability
depends on the membrane voltage, whereas in a ligand-gated ion
channel, the opening probability is regulated by the binding of
small molecules (the ligands). Since ligand-gated ion channels
receive signals from the ligand, they may also be considered as
"receptors" for ligands.
[0005] Examples of ligand-gated ion channels include nAChR
(nicotinic acetylcholine receptor) channel, GluR (glutamate
receptor) channel, ATP-sensitive potassium channel, G-protein
activated channel, cyclic-nucleotide-gated channel, etc.
[0006] Transient receptor potential (TRP) channel proteins
constitute a large and diverse family of proteins that are
expressed in many tissues and cell types. This family of channels
mediates responses to nerve growth factors, pheromones, olfaction,
tone of blood vessels and metabolic stress et al., and the channels
are found in a variety of organisms, tissues and cell types
including nonexcitable, smooth muscle and neuronal cells.
Furthermore, TRP-related channel proteins are implicated in several
diseases, such as several tumors and neurodegenerative disorders
and the like. See, for example, Minke, et al., APStracts 9:0006P
(2002).
[0007] Nociceptors are specialized primary afferent neurons and the
first cells in a series of neurons that lead to the sensation of
pain. The receptors in these cells can be activated by different
noxious chemical or physical stimuli. The essential functions of
nociceptors include the transduction of noxious stimuli into
depolarizations that trigger action potentials, conduction of
action potentials from primary sensory sites to synapses in the
central nervous system, and conversion of action potentials into
neurotransmitter release at presynaptic terminals, all of which
depend on ion channels.
[0008] One TRP channel protein of particular interest is the
vanilloid receptor. Also known as VR1, the vanilloid receptor is a
non-selective cation channel which is activated or sensitized by a
series of different stimuli including capsaicin, heat and acid
stimulation and products of lipid bilayer metabolism (anandamide),
and lipoxygenase metabolites. See, for example Smith, et al.,
Nature, 418:186-190 (2002). VR1 does not discriminate among
monovalent cations, however, it exhibits a notable preference for
divalent cations with a permeability sequence of
Ca.sup.2+>Mg.sup.2+>Na.sup.+=K.sup.+=Cs.sup.+. Ca.sup.2+ is
especially important to VR1 function, as extracellular Ca.sup.2+
mediates desensitization, a process which enables a neuron to adapt
to specific stimuli by diminishing its overall response to a
particular chemical or physical signal. VR1 is highly expressed in
primary sensory neurons in rats, mice and humans, and innervates
many visceral organs including the dermis, bones, bladder,
gastrointestinal tract and lungs. It is also expressed in other
neuronal and non-neuronal tissues including the CNS, nuclei,
kidney, stomach and T-cells. The VR1 channel is a member of the
superfamily of ion channels with six membrane-spanning domains,
with highest homology to the TRP family of ion channels.
[0009] VR1 gene knockout mice have been shown to have reduced
sensory sensitivity to thermal and acid stimuli. See, for example,
Caterina, et al. Science, 14:306-313 (2000). This supports the
concept that VR1 contributes not only to generation of pain
responses but also to the maintenance of basal activity of sensory
nerves. VR1 agonists and antagonists have use as analgesics for the
treatment of pain of various genesis or etiology, for example
acute, inflammatory and neuropathic pain, dental pain and headache
(such as migraine, cluster headache and tension headache). They are
also useful as anti-inflammatory agents for the treatment of
arthritis, Parkinson's Disease, Alzheimer's Disease, stroke,
uveitis, asthma, myocardial infarction, the treatment and
prophylaxis of pain syndromes (acute and chronic [neuropathic]),
traumatic brain injury, spinal cord injury, neurodegenerative
disorders, alopecia (hair loss), inflammatory bowel disease and
autoimmune disorders, renal disorders, obesity, eating disorders,
cancer, schizophrenia, epilepsy, sleeping disorders, cognition,
depression, anxiety, blood pressure, lipid disorders, and
atherosclerosis.
[0010] Compounds, such as those of the present invention, which
interact with the vanilloid receptor can thus play a role in
treating or preventing or ameliorating these conditions.
[0011] A wide variety of Vanilloid compounds of different
structures are known in the art, for example those disclosed in
European Patent Application Numbers, EP 0 347 000 and EP 0 401 903,
UK Patent Application Number GB 2226313 and International Patent
Application, Publication Number WO 92/09285. Particularly notable
examples of vanilloid compounds or vanilloid receptor modulators
are capsaicin or trans 8-methyl-N-vanillyl-6-nonenamide which is
isolated from the pepper plant, capsazepine (Tetrahedron, 53, 1997,
4791) and olvanil or--N-(4-hydroxy-3-methoxybenzyl)oleamide (J.
Med. Chem., 36, 1993, 2595).
[0012] International Patent Application, Publication Number WO
02/08221 discloses diaryl piperazine and related compounds which
bind with high selectivity and high affinity to vanilloid
receptors, especially Type I Vanilloid receptors, also known as
capsaicin or VR1 receptors. The compounds are said to be useful in
the treatment of chronic and acute pain conditions, itch and
urinary incontinence.
[0013] International Patent Application, Publication Numbers WO
02/16317, WO 02/16318 and WO 02/16319 suggest that compounds having
a high affinity for the vanilloid receptor are useful for treating
stomach-duodenal ulcers.
[0014] WO04/56774 describe certain substituted
biphenyl-4-carboxylic acid arylamide analogues having possible
application as receptor modulators.
[0015] U.S. Pat. Nos. 3,424,760 and 3,424,761 both describe a
series of 3-Ureidopyrrolidines that are said to exhibit analgesic,
central nervous system, and pyschopharmacologic activities. These
patents specifically disclose the compounds
1-(1-phenyl-3-pyrrolidinyl)-3-phenyl urea and
1-(1-phenyl-3-pyrrolidinyl)-3-(4-methoxyphenyl) urea respectively.
International Patent Applications, Publication Numbers WO 01/62737
and WO 00/69849 disclose a series of pyrazole derivatives which are
stated to be useful in the treatment of disorders and diseases
associated with the NPY receptor subtype Y5, such as obesity. WO
01/62737 specifically discloses the compound
5-amino-N-isoquinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H--
pyrazole-3-carboxamide. WO 00/69849 specifically discloses the
compounds
5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carb-
oxamide,
5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-
-3-carboxamide,
5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H--
pyrazole-3-carboxamide,
N-isoquinolin-5-yl-5-methyl-1-[3-(trifluoromethyl)-
phenyl]-1H-pyrazole-3-carboxamide,
5-methyl-N-quinolin-5-yl-1-[3-(trifluor-
omethyl)phenyl]-1H-pyrazole-3-carboxamide,
1-(3-chlorophenyl)-N-isoquinoli-
n-5-yl-5-methyl-1H-pyrazole-3-carboxamide,
N-isoquinolin-5-yl-1-(3-methoxy-
phenyl)-5-methyl-1H-pyrazole-3-carboxamide,
1-(3-fluorophenyl)-N-isoquinol-
in-5-yl-5-methyl-1H-pyrazole-3-carboxamide,
1-(2-chloro-5-trifluoromethylp-
henyl)-N-isoquinolin-5-yl-5-methyl-1N-pyrazole-3-carboxamide,
5-methyl-N-(3-methylisoquinolin-5-yl)-1-[3-(trifluoromethyl)
phenyl]-1N-pyrazole-3-carboxamide,
5-methyl-N-(1,2,3,4-tetrahydroisoquino-
lin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.
[0016] German Patent Application Number 2502588 describes a series
of piperazine derivatives. This application specifically discloses
the compound N-[3-[2-(diethylamino)
ethyl]-1,2-dihydro-4-methyl-2-oxo-7-quino-
linyl]-4-phenyl-1-piperazinecarboxamide.
[0017] We have now discovered that certain compounds have
surprising potency and selectivity as VR-1 antagonists. The
compounds of the present invention are considered to be
particularly beneficial as VR-1 antagonists as certain compounds
exhibit improved aqueous solubility and metabolic stability.
SUMMARY OF THE INVENTION
[0018] It has now been found that compounds such as those set forth
herein, are capable of modifying mammalian ion channels such as the
VR1 cation channel. This finding leads to novel compounds having
therapeutic value. It also leads to pharmaceutical compositions
having the compounds of the present invention as active ingredients
and to their use to treat, prevent or ameliorate a range of
conditions in mammals such as but not limited to pain of various
genesis or etiology, for example acute, chronic, inflammatory and
neuropathic pain, dental pain and headache (such as migraine,
cluster headache and tension headache).
[0019] Accordingly, in a first aspect of the invention, compounds
are disclosed that are capable of modifying ion channels, in vivo,
having a formula: 2
[0020] wherein:
[0021] A is N, CR.sup.4, a carbon atom bound to L, or is not an
atom;
[0022] one of W, Z, B, Y and X is a carbon atom bound to L if A is
not an atom, another of W, Z, B, Y and X is a carbon atom bound to
G, and each of the remaining W, Z, B, Y and X is independently N or
CR.sup.4;
[0023] L is a bond or --CH.sub.2).sub.n--, wherein n is an integer
of 1-3;
[0024] G is C.dbd.O, C.dbd.S or SO.sub.2;
[0025] R.sup.1 is substituted or unsubstituted aliphatic, alkyl,
heteroalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
[0026] R.sup.2 is hydrogen or substituted or unsubstituted
alkyl;
[0027] R.sup.3 is substituted or unsubstituted aliphatic, alkyl,
heteroalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and each
R.sup.4 is independently hydrogen, alkyl, substituted or
unsubstituted alkyl, acyl, acylamino, alkylamino, alkylthio,
alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl,
arylalkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl,
arylsulfonyl, sulfuric acid, sulfuric acid ester,
dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxy,
carbamoyl, carboxyl, cyano, cycloheteroalkyl, dialkylamino, halo,
heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio, or
a pharmaceutically acceptable salt, solvate or prodrug thereof; and
isomers and stereoisomers thereof.
[0028] In a further embodiment of the invention, compounds are
capable of modifying ion channels, in vivo, having a formula IA
3
[0029] In compounds of formula I and IA, L will preferably be a
bond.
[0030] In certain specific compounds of formula I and IA, R.sup.3
is substituted or unsubstituted phenyl, benzo[1,3]dioxolyl,
morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl,
piperidinyl, pyridizinyl, thienyl, furyl, pyrazolyl, pyrrolyl,
triazolyl, indanyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl,
isothiazolyl, isooxazolyl or thiadiazolyl. In specific compounds
R.sup.3 is optionally substituted (i.e. substituted or
unsubstituted) pyridyl, or pyrimidine. In some preferred compounds
R.sup.3 is 2-pyridyl.
[0031] In certain specific compounds of formula IA, hereinafter
referred to as compounds of formula IA', L is a bond and R.sup.3 is
pyridyl substituted x times by moiety R.sup.5 wherein x represents
an integer 0 to 4 and R.sup.5 is independently selected from
substituted or unsubstituted alkyl, halo, hydroxy and alkoxy.
[0032] In a particular embodiment of the compounds of formula IA, L
is a bond, G is C.dbd.O, R.sup.1 is substituted aryl or heteroaryl,
R.sup.2 is hydrogen, and R.sup.3 is substituted heteroaryl.
[0033] In another particular embodiment of the invention compounds
are compounds of formula (IB) especially compounds of formula (IC):
4
[0034] wherein R.sup.5 is independently selected from substituted
or unsubstituted alkyl, halo, hydroxy and alkoxy and x is an
integer from 0 to 4.
[0035] In certain compounds of formula I, IA, IA', IB and IC,
R.sup.1 may for example represent alkyl, cycloalkyl, aryl or
aralkyl. In some preferred embodiments, R.sup.1 is a substituted
(eg a monosubstituted) aryl (eg substituted phenyl). A particular
R.sup.1 moiety is 3-alkoxyphenyl. In certain embodiments R.sup.1 is
substituted with alkyl, alkyl(OH), --COOH, --C(Me).sub.3,
--CH(Me).sub.2, halo, cyano or methoxy.
[0036] In certain preferred compounds of formula I, IA, IA', IB and
IC, R.sup.2 is hydrogen.
[0037] In compounds of formula I, IA, IA', IB and IC G will
preferably be CO.
[0038] In a further embodiment of the compounds of formula IA,
R.sup.3 is of the formula 5
[0039] wherein R.sup.4 is as described above; n is an integer of
from 1-3; and A is halogen or trihaloalkyl. In further embodiments,
each of W, X, Y and Z is CR.sup.4, or alternatively, each of W, X,
Y and Z is independently selected from C--H, C-halogen and
C-alkoxy. Further, at least one of W, X, Y and Z is C-halogen or
C-alkoxy, and may particularly, be C-fluoro or C-methoxy, and in a
particular embodiment, may all be C--H.
[0040] With respect to the compounds of formula IA, R.sup.1 may be
substituted phenyl, or alternatively, substituted or unsubstituted
naphthyl. Further, R.sup.1 may also be substituted or unsubstituted
heteroaryl, and in a particular embodiment, the heteroaryl may be
selected from the group consisting of pyrimidinyl, thiazolyl, and
pyrazolyl. More particularly, the heteroaryl may be 2-pyridyl,
3-pyridyl or 4-pyridyl. In a particular embodiment, the
substitution on the heteroaryl is selected from the group
consisting of hydrogen, alkyl, trifluoromethyl, halo, methoxy,
trifluoromethoxy, amino and carboxy. In a yet further particular
embodiment, the substitution on heteroaryl is selected from the
group consisting of tert-butyl, cyano, trifluoroalkyl, halo, nitro,
methoxy, amino and carboxy.
[0041] In a still further aspect of the invention derived from the
compounds of formula IA, additional compounds are disclosed that
are capable of modifying ion channels, in vivo, having a formula
II: 6
[0042] wherein R.sup.1' is selected from the group consisting of
cyano, trifluoroalkyl, halo, nitro, methoxy, trifluoromethoxy,
amino, alkylamino, and carboxy; x is selected from 1-5; or a
pharmaceutically acceptable salt, solvate or prodrug thereof; and
isomers and stereoisomers thereof. In particular embodiments of
these compounds, A may be Cl, x may be 1, and R.sup.1' may be
4-trifluoromethyl.
[0043] In a further particular embodiment, a compound capable of
modifying ion channels, in vivo, having a formula III: 7
[0044] wherein R.sup.1 is as stated with respect to the compound of
formula 1, above; or a pharmaceutically acceptable salt, solvate or
prodrug thereof; and isomers and stereoisomers thereof.
[0045] In a particular embodiment, a compound capable of modifying
ion channels, in vivo, having a formula IV: 8
[0046] wherein R.sup.1 is substituted or unsubstituted aryl or
heteroaryl. In a particular embodiment of the compounds of formula
IV, the substitution on aryl or heteroaryl may be selected from
hydrogen, substituted or unsubstituted alkyl, halogen, cyano,
nitro, trihaloalkyl, alkoxy, and dialkylamino. In a further
embodiment, the substitution on aryl or heteroaryl is selected from
the group consisting of tert-butyl, cyano, trifluoromethyl, halo,
nitro, alkoxy, amino and carboxy.
[0047] In a further embodiment of the invention, compounds based on
formula I may be prepared where R.sup.1 may be aliphatic, alkyl,
heteroalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl
substituted with 9
[0048] wherein ring P is cycloheteroalkyl, substituted
cycloheteroalkyl, heteroaryl, or substituted heteroaryl. In this
embodiment, L may be a bond, G may be C.dbd.O, and R.sup.2 may be
hydrogen, and R.sup.1 may be as just defined. A particular compound
within this scope has a formula V, as follows: 10
[0049] In this embodiment, the ring P is selected from substituted
or unsubstituted 11
[0050] wherein R.sup.2' is selected from H and R.sup.1, and R.sup.1
is as defined with respect to formula I.
[0051] In a particular embodiment, a compound capable of modifying
ion channels, vivo, having a formula VI: 12
[0052] wherein A is Cl, F, OMe, NMe.sub.2, CF.sub.3 or
SO.sub.2Me.
[0053] Examples of ring P include, but are not limited to,
substituted or unsubstituted: 13
[0054] wherein R.sup.2' is selected from H and R.sup.1, and R.sup.1
is as defined with respect to formula I.
[0055] In yet further particular embodiments, the compounds of the
invention are set forth and may be selected from a comprehensive
listing of such compounds, set forth later on herein in Table 1.
The Table contains in excess of 403 compounds that have been
synthesized and have as a group, demonstrated activity in their
capacity of modifying ion channels, in vivo, and thereby
functioning in the therapeutic applications set forth herein in
relation to capsaicin and the vanilloid receptor.
[0056] The compounds of the present invention are useful for the
treatment of inflammatory pain and associated hyperalgesia and
allodynia. They are also useful for the treatment of neuropathic
pain and associated hyperalgesis and allodynia (e.g. trigeminal or
herpetic neuralgia, diabetic neuropathy, causalgia, sympathetically
maintained pain and deafferentation syndromes such as brachial
plexus avulsion). The compounds of the present invention are also
useful as anti-inflammatory agents for the treatment of arthritis,
and as agents to treat Parkinson's Disease, Alzheimer's Disease,
stroke, uveitis, asthma, myocardial infarction, traumatic brain
injury, spinal cord injury, neurodegenerative disorders, alopecia
(hair loss), inflammatory bowel disease and autoimmune disorders,
renal disorders, obesity, eating disorders, cancer, schizophrenia,
epilepsy, sleeping disorders, cognition, depression, anxiety, blood
pressure, lipid disorders, and atherosclerosis.
[0057] In one aspect, this invention provides compounds which are
capable of modifying ion channels, in vivo. Representative ion
channels so modified include voltage-gated channels and
ligand-gated channels, including cation channels such as vanilloid
channels.
[0058] In a further aspect, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
and a pharmaceutical carrier, excipient or diluent. In this aspect
of the invention, the pharmaceutical composition can comprise one
or more of the compounds described herein.
[0059] In a further aspect of the invention, a method is disclosed
for treating mammals, including humans, as well as lower mammalian
species, susceptible to or afflicted with a condition from among
those listed herein, and particularly, such condition as may be
associated with e.g. arthritis, uveitis, asthma, myocardial
infarction, traumatic brain injury, acute spinal cord injury,
alopecia (hair loss), inflammatory bowel disease and autoimmune
disorders, which method comprises administering an effective amount
of one or more of the pharmaceutical compositions just described.
Correspondingly, the invention extends and includes the use of the
compounds of the invention for the treatment of the mentioned
maladies, as well as for the preparation of pharmaceutical
compositions and like medicaments, which include among their
applications and uses, the treatment of the stated maladies.
Likewise the invention extends to compounds of the invention for
use as pharmaceuticals and medicaments.
[0060] In yet another method of treatment aspect, this invention
provides a method of treating a mammal susceptible to or afflicted
with a condition that gives rise to pain responses or that relates
to imbalances in the maintenance of basal activity of sensory
nerves. Compounds have use as analgesics for the treatment of pain
of various geneses or etiology, for example acute, inflammatory
pain (such as pain associated with osteoarthritis and rheumatoid
arthritis); various neuropathic pain syndromes (such as
post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic
dystrophy, diabetic neuropathy, Guillian Barre syndrome,
fibromyalgia, phantom limb pain, post-masectomy pain, peripheral
neuropathy, HIV neuropathy, and chemotherapy-induced and other
iatrogenic neuropathies); visceral pain, (such as that associated
with gastroesophageal reflex disease, irritable bowel syndrome,
inflammatory bowel disease, pancreatitis, and various gynecological
and urological disorders), dental pain and headache (such as
migraine, cluster headache and tension headache).
[0061] In additional method of treatment aspects, this invention
provides methods of treating a mammal susceptible to or afflicted
with neurodegenerative diseases and disorders such as, for example
Parkinson's disease, Alzheimer's disease and multiple sclerosis;
diseases and disorders which are mediated by or result in
neuroinflammation such as, for example traumatic brain injury,
stroke, and encephalitis; centrally-mediated neuropsychiatric
diseases and disorders such as, for example depression mania,
bipolar disease, anxiety, schizophrenia, eating disorders, sleep
disorders and cognition disorders; epilepsy and seizure disorders;
prostate, bladder and bowel dysfunction such as, for example
urinary incontinence, urinary hesitancy, rectal hypersensitivity,
fecal incontinence, benign prostatic hypertrophy and inflammatory
bowel disease; respiratory and airway disease and disorders such
as, for example, allergic rhinitis, asthma and reactive airway
disease and chronic obstructive pulmonary disease; diseases and
disorders which are mediated by or result in inflammation such as,
for example rheumatoid arthritis and osteoarthritis, myocardial
infarction, various autoimmune diseases and disorders, uveitis and
atherosclerosis; itch/pruritus such as, for example psoriasis;
alopecia (hair loss); obesity; lipid disorders; cancer; blood
pressure; spinal cord injury; and renal disorders method comprises
administering an effective condition-treating or
condition-preventing amount of one or more of the pharmaceutical
compositions just described.
[0062] In additional aspects, this invention provides methods for
synthesizing the compounds of the invention, with representative
synthetic protocols and pathways disclosed later on herein.
[0063] Other objects and advantages will become apparent to those
skilled in the art from a consideration of the ensuing detailed
description, in conjunction with the following illustrative
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0064] FIG. 1: A graph demonstrating the activity of Compounds 18
and 24 in inhibiting a capsaicin induced intracellular current. The
functional activity of compounds at a VR1 receptor may be
determined by measuring changes in intracellular calcium levels in
neurons such as those in the dorsal root ganglion (DRG
neurons).
[0065] FIG. 2: A graph showing that Compound 18 at a dose of 30
mg/kg significantly blocks capsaicin induced plasma extravasation
in rats. The results are expressed in .mu.g EB/mg tissue. The
results are represented for the delivery vehicle HPBCD, control
compound BCTC, compound 18 at two concentrations and capsaicin
alone in a delivery vehicle.
[0066] FIG. 3: A dose response curve demonstrating the increasing
effectiveness of Compound 18 in inhibiting a capsaicin induced
calcium ion influx at higher concentrations tested, namely 50 nM,
100 nM and 250 nM.
[0067] FIG. 4: A dose response curve demonstrating the increasing
effectiveness of Compound 24 in inhibiting a capsaicin induced
calcium ion influx at higher concentrations tested, namely 20 nM,
40 nM and 100 nM and 200 nM.
[0068] FIG. 5: A graph showing the times per second test subjects
lick their paw when a delivery vehicle is administered alone,
capsaicin is administered, capsaicin is administered with a control
compound, and capsaicin is administered with Compound 18 to the
affected area.
[0069] FIG. 6: A graph demonstrating that a dose of Compound 18 at
30 mg/kg significantly increases latency of paw withdrawal
demonstrating reversal of thermal hyperalgesia. The figure depicts
the time in seconds until animals withdraw from thermal stimulation
at baseline and two hours after administration of a delivery
vehicle, a control compound, and three concentrations of Compound
18.
DETAILED DESCRIPTION OF THE INVENTION
[0070] Definitions
[0071] When describing the compounds, pharmaceutical compositions
containing such compounds and methods of using such compounds and
compositions, the following terms have the following meanings
unless otherwise indicated. It should also be understood that any
of the moieties defined forth below may be substituted with a
variety of substituents, and that the respective definitions are
intended to include such substituted moieties within their scope.
By way of non-limiting example, such substituents may include e.g.
halo (such as fluoro, chloro, bromo), --CN, --CF.sub.3, --OH,
--OCF.sub.3, C.sub.2-6 alkenyl, C.sub.3-6 alkynyl, C.sub.1-6
alkoxy, aryl and di-C.sub.1-6 alkylamino.
[0072] "Acyl" refers to a radical --C(O)R, where R is hydrogen,
alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl, heteroarylalkyl as defined herein. Representative
examples include, but are not limited to, formyl, acetyl,
cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,
benzylcarbonyl and the like.
[0073] "Acylamino" refers to a radical --NR' C.(O)R, where R' is
hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,
heteroalkyl, heteroaryl, heteroarylalkyl and R is hydrogen, alkyl,
alkoxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl or heteroarylalkyl, as defined herein. Representative
examples include, but are not limited to, formylamino, acetylamino,
cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino,
benzoylamino, benzylcarbonylamino and the like.
[0074] "Acyloxy" refers to the group --OC(O)R where R is hydrogen,
alkyl, aryl or cycloalkyl.
[0075] "Substituted alkenyl" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
alkenyl group having 1 or more substituents, for instance from 1 to
5 substituents, and particularly from 1 to 3 substituents, selected
from the group consisting of acyl, acylamino, acyloxy, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro,
thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--.
[0076] "Alkoxy" refers to the group --OR where R is alkyl.
Particular alkoxy groups include, by way of example, methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
[0077] "Substituted alkoxy" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
alkoxy group having 1 or more substituents, for instance from 1 to
5 substituents, and particularly from 1 to 3 substituents, selected
from the group consisting of acyl, acylamino, acyloxy, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, hydroxyl,
keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,
thioketo, thiol, alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--.
[0078] "Alkoxycarbonylamino" refers to the group --NRC(O)OR' where
R is hydrogen, alkyl, aryl or cycloalkyl, and R' is alkyl or
cycloalkyl.
[0079] "Aliphatic" refers to hydrocarbyl organic compounds or
groups characterized by a straight, branched or cyclic arrangement
of the constituent carbon atoms and an absence of aromatic
unsaturation. Aliphatics include, without limitation, alkyl,
alkylene, alkenyl, alkenylene, alkynyl and alkynylene. Aliphatic
groups typically have from 1 or 2 to about 12 carbon atoms.
[0080] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl
groups particularly having up to about 11 carbon atoms, more
particularly as a lower alkyl, from 1 to 8 carbon atoms and still
more particularly, from 1 to 6 carbon atoms. The hydrocarbon chain
may be either straight-chained or branched. This term is
exemplified by groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and
the like. The term "lower alkyl" refers to alkyl groups having 1 to
6 carbon atoms. The term "alkyl" also includes "cycloalkyls" as
defined below.
[0081] "Substituted alkyl" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
alkyl group having 1 or more substituents, for instance from 1 to 5
substituents, and particularly from 1 to 3 substituents, selected
from the group consisting of acyl, acylamino, acyloxy, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, heteroaryl,
keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,
thioketo, thiol, alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2--, and
aryl-S(O).sub.2--.
[0082] "Alkylene" refers to divalent saturated aliphatic
hydrocarbyl groups particularly having up to about 11 carbon atoms
and more particularly 1 to 6 carbon atoms which can be
straight-chained or branched. This term is exemplified by groups
such as methylene (--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--),
the propylene isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and
--CH(CH.sub.3)CH.sub.2--) and the like.
[0083] "Substituted alkylene" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
alkylene group having 1 or more substituents, for instance from 1
to 5 substituents, and particularly from 1 to 3 substituents,
selected from the group consisting of acyl, acylamino, acyloxy,
alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino,
amino, substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen,
hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy,
thioaryloxy, thioketo, thiol, alkyl-S(O)--, aryl-S(O)--,
alkyl-S(O).sub.2-- and aryl-S(O).sub.2--.
[0084] "Alkenyl" refers to monovalent olefinically unsaturated
hydrocarbyl groups preferably having up to about 11 carbon atoms,
particularly, from 2 to 8 carbon atoms, and more particularly, from
2 to 6 carbon atoms, which can be straight-chained or branched and
having at least 1 and particularly from 1 to 2 sites of olefinic
unsaturation. Particular alkenyl groups include ethenyl
(--CH.dbd.CH.sub.2), n-propenyl (--CH.sub.2CH.dbd.CH.sub.2),
isopropenyl (--C(CH.sub.3).dbd.CH.sub.2), vinyl and substituted
vinyl, and the like.
[0085] "Alkenylene" refers to divalent olefinically unsaturated
hydrocarbyl groups particularly having up to about 11 carbon atoms
and more particularly 2 to 6 carbon atoms which can be
straight-chained or branched and having at least 1 and particularly
from 1 to 2 sites of olefinic unsaturation. This term is
exemplified by groups such as ethenylene (--CH.dbd.CH--), the
propenylene isomers (e.g., --CH.dbd.CHCH.sub.2-- and
--C(CH.sub.3).dbd.CH-- and --CH.dbd.C(CH.sub.3)--) and the
like.
[0086] "Alkynyl" refers to acetylenically unsaturated hydrocarbyl
groups particularly having up to about 11 carbon atoms and more
particularly 2 to 6 carbon atoms which can be straight-chained or
branched and having at least 1 and particularly from 1 to 2 sites
of alkynyl unsaturation. Particular non-limiting examples of
alkynyl groups include acetylenic, ethynyl (--C.ident.CH),
propargyl (--CH.sub.2C.ident.CH), and the like.
[0087] "Substituted alkynyl" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
alkynyl group having 1 or more substituents, for instance from 1 to
5 substituents, and particularly from 1 to 3 substituents, selected
from the group consisting of acyl, acylamino, acyloxy, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro,
thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--.
[0088] "Alkanoyl" or "acyl" as used herein refers to the group
R--C(O)--, where R is hydrogen or alkyl as defined above.
[0089] "Aryl" refers to a monovalent aromatic hydrocarbon group
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. Typical aryl groups include,
but are not limited to, groups derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexalene, as-indacene, s-indacene, indane, indene, naphthalene,
octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene and the like. Particularly, an aryl group comprises
from 6 to 14 carbon atoms.
[0090] "Substituted Aryl" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
aryl group that may optionally be substituted with 1 or more
substituents, for instance from 1 to 5 substituents, particularly 1
to 3 substituents, selected from the group consisting of acyl,
acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl,
alkynyl, substituted alkynyl, amino, substituted amino,
aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,
azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl,
halogen, hydroxyl, nitro, thioalkoxy, substituted thioalkoxy,
thioaryloxy, thiol, alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2--
and aryl-S(O).sub.2--.
[0091] "Fused Aryl" refers to an aryl having two of its ring carbon
in common with a second aryl ring or with an aliphatic ring.
[0092] "Alkaryl" refers to an aryl group, as defined above,
substituted with one or more alkyl groups, as defined above.
[0093] "Aralkyl" or "arylalkyl" refers to an alkyl group, as
defined above, substituted with one or more aryl groups, as defined
above.
[0094] "Aryloxy" refers to --O-aryl groups wherein "aryl" is as
defined above.
[0095] "Alkylamino" refers to the group alkyl-NR'R", wherein each
of R' and R" are independently selected from hydrogen and
alkyl.
[0096] "Arylamino" refers to the group aryl-NR'R", wherein each of
R' and R" are independently selected from hydrogen, aryl and
heteroaryl.
[0097] "Alkoxyamino" refers to a radical --N(H)OR where R
represents an alkyl or cycloalkyl group as defined herein.
[0098] "Alkoxycarbonyl" refers to a radical --C(O)-alkoxy where
alkoxy is as defined herein.
[0099] "Alkylarylamino" refers to a radical --NRR' where R
represents an alkyl or cycloalkyl group and R' is an aryl as
defined herein.
[0100] "Alkylsulfonyl" refers to a radical --S(O).sub.2R where R is
an alkyl or cycloalkyl group as defined herein. Representative
examples include, but are not limited to, methylsulfonyl,
ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
[0101] "Alkylsulfinyl" refers to a radical --S(O)R where R is an
alkyl or cycloalkyl group as defined herein. Representative
examples include, but are not limited to, methylsulfinyl,
ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like.
[0102] "Alkylthio" refers to a radical --SR where R is an alkyl or
cycloalkyl group as defined herein that may be optionally
substituted as defined herein. Representative examples include, but
are not limited to, methylthio, ethylthio, propylthio, butylthio,
and the like.
[0103] "Amino" refers to the radical --NH.sub.2.
[0104] "Substituted amino" includes those groups recited in the
definition of "substituted" herein, and particularly refers to the
group --N(R).sub.2 where each R is independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl,
cycloalkyl, substituted cycloalkyl, and where both R groups are
joined to form an alkylene group. When both R groups are hydrogen,
--N(R).sub.2 is an amino group.
[0105] "Aminocarbonyl" refers to the group --C(O)NRR where each R
is independently hydrogen, alkyl, aryl and cycloalkyl, or where the
R groups are joined to form an alkylene group.
[0106] "Aminocarbonylamino" refers to the group --NRC(O)NRR where
each R is independently hydrogen, alkyl, aryl or cycloalkyl, or
where two R groups are joined to form an alkylene group.
[0107] "Aminocarbonyloxy" refers to the group --OC(O)NRR where each
R is independently hydrogen, alkyl, aryl or cycloalky, or where the
R groups are joined to form an alkylene group.
[0108] "Arylalkyloxy" refers to an --O-arylalkyl radical where
arylalkyl is as defined herein.
[0109] "Arylamino" means a radical --NHR where R represents an aryl
group as defined herein.
[0110] "Aryloxycarbonyl" refers to a radical --C(O)--O-aryl where
aryl is as defined herein.
[0111] "Arylsulfonyl" refers to a radical --S(O).sub.2R where R is
an aryl or heteroaryl group as defined herein.
[0112] "Azido" refers to the radical --N.sub.3.
[0113] "Carbamoyl" refers to the radical --C(O)N(R).sub.2 where
each R group is independently hydrogen, alkyl, cycloalkyl or aryl,
as defined herein, which may be optionally substituted as defined
herein.
[0114] "Carboxy" refers to the radical --C(O)OH.
[0115] "Carboxyamino" refers to the radical --N(H)C(O)OH.
[0116] "Cycloalkyl" refers to cyclic hydrocarbyl groups having from
3 to about 10 carbon atoms and having a single cyclic ring or
multiple condensed rings, including fused and bridged ring systems,
which optionally can be substituted with from 1 to 3 alkyl groups.
Such cycloalkyl groups include, by way of example, single ring
structures such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,
2-methylcyclooctyl, and the like, and multiple ring structures such
as adamantanyl, and the like.
[0117] "Substituted cycloalkyl" includes those groups recited in
the definition of "substituted" herein, and particularly refers to
a cycloalkyl group having 1 or more substituents, for instance from
1 to 5 substituents, and particularly from 1 to 3 substituents,
selected from the group consisting of acyl, acylamino, acyloxy,
alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino,
amino, substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro,
thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--.
[0118] "Cycloalkoxy" refers to the group --OR where R is
cycloalkyl. Such cycloalkoxy groups include, by way of example,
cyclopentoxy, cyclohexoxy and the like.
[0119] "Cycloalkenyl" refers to cyclic hydrocarbyl groups having
from 3 to 10 carbon atoms and having a single cyclic ring or
multiple condensed rings, including fused and bridged ring systems
and having at least one and particularly from 1 to 2 sites of
olefinic unsaturation. Such cycloalkenyl groups include, by way of
example, single ring structures such as cyclohexenyl,
cyclopentenyl, cyclopropenyl, and the like.
[0120] "Substituted cycloalkenyl" includes those groups recited in
the definition of "substituted" herein, and particularly refers to
a cycloalkenyl group having 1 or more substituents, for instance
from 1 to 5 substituents, and particularly from 1 to 3
substituents, selected from the group consisting of acyl,
acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,
alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,
aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido,
carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,
hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy,
thioaryloxy, thioketo, thiol, alkyl-S(O)--, aryl-S(O)--,
alkyl-S(O).sub.2-- and aryl-S(O).sub.2--.
[0121] "Fused Cycloalkenyl" refers to a cycloalkenyl having two of
its ring carbon atoms in common with a second aliphatic or aromatic
ring and having its olefinic unsaturation located to impart
aromaticity to the cycloalkenyl ring.
[0122] "Cyanato" refers to the radical --OCN.
[0123] "Cyano" refers to the radical --CN.
[0124] "Dialkylamino" means a radical --NRR' where R and R'
independently represent an alkyl, substituted alkyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or
substituted heteroaryl group as defined herein.
[0125] "Ethenyl" refers to substituted or unsubstituted
--(C.dbd.C)--.
[0126] "Ethylene" refers to substituted or unsubstituted
--(C--C)--.
[0127] "Ethynyl" refers to --(C.ident.C)--.
[0128] "Halo" or "halogen" refers to fluoro, chloro, bromo and
iodo. Preferred halo groups are either fluoro or chloro.
[0129] "Hydroxy" refers to the radical --OH.
[0130] "Nitro" refers to the radical --NO.sub.2.
[0131] "Substituted" refers to a group in which one or more
hydrogen atoms are each independently replaced with the same or
different substituent(s). Typical substituents include, but are not
limited to, --X, --R.sup.14, --O.sup.-, .dbd.O, --OR.sup.14,
--SR.sup.14, --S.sup.-, .dbd.S, --NR.sup.14R.sup.15,
.dbd.NR.sup.14, --CX.sub.3, --CF.sub.3, --CN, --OCN, --SCN, --NO,
--NO.sub.2, .dbd.N.sub.2, --N.sub.3, --S(O).sub.2O.sup.-,
--S(O).sub.2OH, --S(O).sub.2R.sup.14, --OS(O.sub.2)O.sup.-,
--OS(O).sub.2R.sup.14, --P(O)(O.sup.-).sub.2,
--P(O)(OR.sup.14)(O.sup.-), --OP(O)(OR.sup.14)(OR.sup.15),
--C(O)R.sup.14, --C(S)R.sup.14, --C(O)OR.sup.14,
--C(O)NR.sup.14R.sup.15, --C(O)O.sup.-, --C(S)OR.sup.14,
--NR.sup.16C(O)NR.sup.14R.sup.15, --NR.sup.16C(S)NR.sup.14R.sup.15,
--NR.sup.17C(NR.sup.16)NR.sup.14R.sup.1- 5 and
--C(NR.sup.16)NR.sup.14R.sup.15, where each X is independently a
halogen; each R.sup.14, R.sup.15, R.sup.16 and R.sup.17 are
independently hydrogen, alkyl, substituted alkyl, aryl, substituted
alkyl, arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl, substituted heteroarylalkyl, --NR.sup.18R.sup.19,
--C(O)R.sup.18 or --S(O).sub.2R.sup.18 or optionally R.sup.18 and
R.sup.19 together with the atom to which they are both attached
form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and
R.sup.18 and R.sup.19 are independently hydrogen, alkyl,
substituted alkyl, aryl, substituted alkyl, arylalkyl, substituted
alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl.
[0132] Examples of representative substituted aryls include the
following 14
[0133] In these formulae one of R.sup.6' and R.sup.7' may be
hydrogen and at least one of R.sup.6' and R.sup.7' is each
independently selected from alkyl, alkenyl, alkynyl,
cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy,
alkylamino, arylamino, heteroarylamino, NR.sup.10COR.sup.11,
NR.sup.10SOR.sup.11, NR.sup.10SO.sub.2R.sup.14, COOalkyl, COOaryl,
CONR.sup.10R.sup.11, CONR.sup.10OR.sup.11, NR.sup.10R.sup.11,
SO.sub.2NR.sup.10R.sup.11, S-alkyl, S-alkyl, SOalkyl,
SO.sub.2alkyl, Saryl, SOaryl, SO.sub.2aryl; or R.sup.6' and
R.sup.7' may be joined to form a cyclic ring (saturated or
unsaturated) from 5 to 8 atoms, optionally containing one or more
heteroatoms selected from the group N, O or S. R.sup.10, R.sup.11,
and R.sup.12 are independently hydrogen, alkyl, alkenyl, alkynyl,
perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, substituted
aryl, heteroaryl, substituted or hetero alkyl or the like.
[0134] "Hetero" when used to describe a compound or a group present
on a compound means that one or more carbon atoms in the compound
or group have been replaced by a nitrogen, oxygen, or sulfur
heteroatom. Hetero may be applied to any of the hydrocarbyl groups
described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g.
cycloheteroalkyl, aryl, e.g. heteroaryl, cycloalkenyl,
cycloheteroalkenyl, and the like having from 1 to 5, and especially
from 1 to 3 heteroatoms.
[0135] "Heteroaryl" refers to a monovalent heteroaromatic group
derived by the removal of one hydrogen atom from a single atom of a
parent heteroaromatic ring system. Typical heteroaryl groups
include, but are not limited to, groups derived from acridine,
arsindole, carbazole, .beta.-carboline, chromane, chromene,
cinnoline, furan, imidazole, indazole, indole, indoline,
indolizine, isobenzofuran, isochromene, isoindole, isoindoline,
isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,
oxazole, perimidine, phenanthridine, phenanthroline, phenazine,
phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,
pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine,
quinazoline, quinoline, quinolizine, quinoxaline, tetrazole,
thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.
Preferably, the heteroaryl group is between 5-20 membered
heteroaryl, with 5-10 membered heteroaryl being particularly
preferred. Particular heteroaryl groups are those derived from
thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,
quinoline, imidazole, oxazole and pyrazine.
[0136] Examples of representative heteroaryls include the
following: 15
[0137] wherein each Y is selected from carbonyl, N, NR.sup.4, O,
and S.
[0138] Examples of representative cycloheteroalkyls include the
following 16
[0139] wheerein each X is selected from CR.sup.4, NR.sup.4, O and
S; and each Y is selected from N, NR.sup.4, O and S, and where
R.sup.6' is R.sup.2.
[0140] Examples of representative cycloheteroalkenyls include the
following: 17
[0141] wherein each X is selected from CR.sup.4, NR.sup.4, O and S;
and each Y is selected from carbonyl, NH, NR.sup.4, O and S.
[0142] Examples of representative aryl having hetero atoms
containing substitution include the following: 18
[0143] wherein each X is selected from C.dbd.O, NR.sup.4, O and S;
and each Y is selected from carbonyl, NR.sup.4, O and S.
[0144] "Hetero substituent" refers to a halo, O, S or N
atom-containing functionality that may be present as an R.sup.4 in
a R.sup.4 C group present as substituents directly on A, B, W, X, Y
or Z of the compounds of this invention or may be present as a
substituent in the "substituted" aryl and aliphatic groups present
in the compounds.
[0145] Examples of hetero substituents include:
[0146] -halo,
[0147] --NO.sub.2, --NH.sub.2, --NHR, --N(R).sub.2,
[0148] --NRCOR, --NRSOR, --NRSO.sub.2R, OH, CN, CO.sub.2R,
[0149] --CO.sub.2H,
[0150] --R--OH, --O--R, --COOR,
[0151] --CON(R).sub.2, --CONROR,
[0152] --SO.sub.2H, --R--S, --SO.sub.2N(R).sub.2,
[0153] --S(O)R, --S(O).sub.2R, wherein each R is independently an
aryl or aliphatic, optionally with substitution. Among hetero
substituents containing R groups, preference is given to those
materials having aryl and alkyl R groups as defined herein.
Preferred hetero substituents are those listed above.
[0154] As used herein, the term "cycloheteroalkyl" refers to a
stable heterocyclic non-aromatic ring and fused rings containing
one or more heteroatoms independently selected from N, O and S. A
fused heterocyclic ring system may include carbocyclic rings and
need only include one heterocyclic ring. Examples of heterocyclic
rings include, but are not limited to, piperazinyl,
homopiperazinyl, piperidinyl and morpholinyl, and are shown in the
following illustrative examples: 19
[0155] optionally substituted with one or more groups selected from
the group consisting of acyl, acylamino, acyloxy, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro,
thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--. Substituting groups include carbonyl or
thiocarbonyl which provide, for example, lactam and urea
derivatives. In the examples, M is CR.sup.7, NR.sub.2, O or S; Q is
O, NR.sub.2 or S. R.sup.7 and R.sup.8 are independently selected
from the group consisting of acyl, acylamino, acyloxy, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro,
thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--.
[0156] "Dihydroxyphosphoryl" refers to the radical
--PO(OH).sub.2.
[0157] "Substituted dihydroxyphosphoryl" includes those groups
recited in the definition of "substituted" herein, and particularly
refers to a dihydroxyphosphoryl radical wherein one or both of the
hydroxyl groups are substituted. Suitable substituents are
described in detail below.
[0158] "Aminohydroxyphosphoryl" refers to the radical
--PO(OH)NH.sub.2.
[0159] "Substituted aminohydroxyphosphoryl" includes those groups
recited in the definition of "substituted" herein, and particularly
refers to an aminohydroxyphosphoryl wherein the amino group is
substituted with one or two substituents. Suitable substituents are
described in detail below. In certain embodiments, the hydroxyl
group can also be substituted.
[0160] "Thioalkoxy" refers to the group --SR where R is alkyl.
[0161] "Substituted thioalkoxy" includes those groups recited in
the definition of "substituted" herein, and particularly refers to
a thioalkoxy group having 1 or more substituents, for instance from
1 to 5 substituents, and particularly from 1 to 3 substituents,
selected from the group consisting of acyl, acylamino, acyloxy,
alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino,
amino, substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro,
thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--.
[0162] "Sulfanyl" refers to the radical HS--. "Substituted
sulfanyl" refers to a radical such as RS-- wherein R is any
substituent described herein.
[0163] "Sulfonyl" refers to the divalent radical --S(O.sub.2)--.
"Substituted sulfonyl" refers to a radical such as R--(O.sub.2)S--
wherein R is any substituent described herein. "Aminosulfonyl" or
"Sulfonamide" refers to the radical H.sub.2N(O.sub.2)S--, and
"substituted aminosulfonyl" "substituted sulfonamide" refers to a
radical such as R.sub.2N(O.sub.2)S-- wherein each R is
independently any substituent described herein.
[0164] "Sulfone" refers to the group --SO.sub.2R. In particular
embodiments, R is selected from H, lower alkyl, alkyl, aryl and
heteroaryl.
[0165] "Thioaryloxy" refers to the group --SR where R is aryl.
[0166] "Thioketo" refers to the group .dbd.S.
[0167] "Thiol" refers to the group --SH.
[0168] One having ordinary skill in the art of organic synthesis
will recognize that the maximum number of heteroatoms in a stable,
chemically feasible heterocyclic ring, whether it is aromatic or
non aromatic, is determined by the size of the ring, the degree of
unsaturation and the valence of the heteroatoms. In general, a
heterocyclic ring may have one to four heteroatoms so long as the
heteroaromatic ring is chemically feasible and stable.
[0169] "Pharmaceutically acceptable" means approved by a regulatory
agency of the Federal or a state government or listed in the U.S.
Pharmacopoeia or other generally recognized pharmacopoeia for use
in animals, and more particularly in humans.
[0170] "Pharmaceutically acceptable salt" refers to a salt of a
compound of the invention that is pharmaceutically acceptable and
that possesses the desired pharmacological activity of the parent
compound. Such salts include: (1) acid addition salts, formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-- 2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the like.
Salts further include, by way of example only, sodium, potassium,
calcium, magnesium, ammonium, tetraalkylammonium, and the like; and
when the compound contains a basic functionality, salts of non
toxic organic or inorganic acids, such as hydrochloride,
hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the
like. The term "pharmaceutically acceptable cation" refers to a non
toxic, acceptable cationic counter-ion of an acidic functional
group. Such cations are exemplified by sodium, potassium, calcium,
magnesium, ammonium, tetraalkylammonium cations, and the like.
[0171] The term "solvate" refers to forms of the compound that are
associated with a solvent, usually by a solvolysis reaction.
Conventional solvents include water, ethanol, acetic acid and the
like. The compounds of the invention may be prepared e.g. in
crystalline form and may be solvated or hydrated. Suitable solvates
include pharmaceutically acceptable solvates, such as hydrates, and
further include both stoichiometric solvates and non-stoichiometric
solvates.
[0172] "Pharmaceutically acceptable vehicle" refers to a diluent,
adjuvant, excipient or carrier with which a compound of the
invention is administered.
[0173] "Preventing" or "prevention" refers to a reduction in risk
of acquiring a disease or disorder (i.e., causing at least one of
the clinical symptoms of the disease not to develop in a subject
that may be exposed to or predisposed to the disease but does not
yet experience or display symptoms of the disease).
[0174] "Subject" includes humans. The terms "human," "patient" and
"subject" are used interchangeably herein.
[0175] "Therapeutically effective amount" means the amount of a
compound that, when administered to a subject for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" can vary depending on the
compound, the disease and its severity, and the age, weight, etc.,
of the subject to be treated.
[0176] "Treating" or "treatment" of any disease or disorder refers,
in one embodiment, to ameliorating the disease or disorder (i.e.,
arresting or reducing the development of the disease or at least
one of the clinical symptoms thereof). In another embodiment
"treating" or "treatment" refers to ameliorating at least one
physical parameter, which may not be discernible by the subject. In
yet another embodiment, "treating" or "treatment" refers to
modulating the disease or disorder, either physically, (e.g.,
stabilization of a discernible symptom), physiologically, (e.g.,
stabilization of a physical parameter), or both. In yet another
embodiment, "treating" or "treatment" refers to delaying the onset
of the disease or disorder.
[0177] "Prodrugs" refers to compounds, including derivatives of the
compounds of the invention, which have cleavable groups and become
by solvolysis or under physiological conditions the compounds of
the invention which are pharmaceutically active in vivo. Such
examples include, but are not limited to, choline ester derivatives
and the like, N-alkylmorpholine esters and the like.
[0178] It is also to be understood that compounds that have the
same molecular formula but differ in the nature or sequence of
bonding of their atoms or the arrangement of their atoms in space
are termed "isomers". Isomers that differ in the arrangement of
their atoms in space are termed "stereoisomers".
[0179] Stereoisomers that are not mirror images of one another are
termed "diastereomers" and those that are non-superimposable mirror
images of each other are termed "enantiomers". When a compound has
an asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0180] The compounds of this invention may possess one or more
asymmetric centers; such compounds can therefore be produced as
individual (R)-- or (S)-- stereoisomers or as mixtures thereof.
Unless indicated otherwise, the description or naming of a
particular compound in the specification and claims is intended to
include both individual enantiomers and mixtures, racemic or
otherwise, thereof. The methods for the determination of
stereochemistry and the separation of stereoisomers are well-known
in the art.
The Compounds
[0181] As set forth earlier herein, the compounds of the present
invention are useful for preventing and/or treating a broad range
of conditions, among them, arthritis, Parkinson's disease,
Alzheimer's disease, stroke, uveitis, asthma, myocardial
infarction, the treatment and prophylaxis of pain syndromes (acute
and chronic or neuropathic), traumatic brain injury, acute spinal
cord injury, neurodegenerative disorders, alopecia (hair loss),
inflammatory bowel disease and autoimmune disorders or conditions
in mammals.
[0182] In order that the invention described herein may be more
fully understood, the following structures representing compounds
typical of the invention are set forth. It should be understood
that these examples are for illustrative purposes only and are not
to be construed as limiting this invention in any manner.
[0183] Accordingly, additional groups of particular compounds are
provided. Thus, and as discussed earlier herein, suitable compounds
capable of modifying ion channels in vivo, may be selected from
those listed in Table 1, below, and may be prepared either as shown
or in the form of a pharmaceutically acceptable salt, solvate or
prodrug thereof; and isomers and stereoisomers thereof. All such
variants are contemplated herein and are within the scope of the
present invention.
[0184] In certain aspects, the present invention provides prodrugs
and derivatives of the compounds according to the formulae above.
Prodrugs are derivatives of the compounds of the invention, which
have cleavable groups and become by solvolysis or under
physiological conditions the compounds of the invention, which are
pharmaceutically active, in vivo. Such examples include, but are
not limited to, choline ester derivatives and the like,
N-alkylmorpholine esters and the like.
[0185] Other derivatives of the compounds of this invention have
activity in both their acid and acid derivative forms, but the acid
sensitive form often offers advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism (see,
Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives well know to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides and anhydrides derived
from acidic groups pendant on the compounds of this invention are
preferred prodrugs. In some cases it is desirable to prepare double
ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkyl- esters. Preferred are the C.sub.1 to
C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, aryl, C.sub.7-C.sub.12
substituted aryl, and C.sub.7-C.sub.12 arylalkyl esters of the
compounds of the invention.
Pharmaceutical Compositions
[0186] When employed as pharmaceuticals, the amide compounds of
this invention are typically administered in the form of a
pharmaceutical composition. Such compositions can be prepared in a
manner well known in the pharmaceutical art and comprise at least
one active compound.
[0187] Generally, the compounds of this invention are administered
in a pharmaceutically effective amount. The amount of the compound
actually administered will typically be determined by a physician,
in the light of the relevant circumstances, including the condition
to be treated, the chosen route of administration, the actual
compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0188] The pharmaceutical compositions of this invention can be
administered by a variety of routes including by way of non
limiting example, oral, rectal, transdermal, subcutaneous,
intravenous, intramuscular and intranasal. Depending upon the
intended route of delivery, the compounds of this invention are
preferably formulated as either injectable or oral compositions or
as salves, as lotions or as patches all for transdermal
administration.
[0189] The compositions for oral administration can take the form
of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Typical unit dosage forms include
prefilled, premeasured ampules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of
solid compositions. In such compositions, the furansulfonic acid
compound is usually a minor component (from about 0.1 to about 50%
by weight or preferably from about 1 to about 40% by weight) with
the remainder being various vehicles or carriers and processing
aids helpful for forming the desired dosing form.
[0190] Liquid forms suitable for oral administration may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, colorants, flavors and the like. Solid forms may
include, for example, any of the following ingredients, or
compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatin; an excipient such as starch
or lactose, a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate; a glidant
such as colloidal silicon dioxide; a sweetening agent such as
sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate, or orange flavoring.
[0191] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
carriers known in the art. As before, the active compound in such
compositions is typically a minor component, often being from about
0.05 to 10% by weight with the remainder being the injectable
carrier and the like.
[0192] Transdermal compositions are typically formulated as a
topical ointment or cream containing the active ingredient(s),
generally in an amount ranging from about 0.01 to about 20% by
weight, preferably from about 0.1 to about 20% by weight,
preferably from about 0.1 to about 10% by weight, and more
preferably from about 0.5 to about 15% by weight. When formulated
as a ointment, the active ingredients will typically be combined
with either a paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with, for example an oil-in-water cream base. Such transdermal
formulations are well-known in the art and generally include
additional ingredients to enhance the dermal penetration of
stability of the active ingredients or the formulation. All such
known transdermal formulations and ingredients are included within
the scope of this invention.
[0193] The compounds of this invention can also be administered by
a transdermal device. Accordingly, transdermal administration can
be accomplished using a patch either of the reservoir or porous
membrane type, or of a solid matrix variety.
[0194] The above-described components for orally administrable,
injectable or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's Pharmaceutical
Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa.,
which is incorporated herein by reference.
[0195] The compounds of this invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can be found in Remington's Pharmaceutical Sciences.
[0196] The following formulation examples illustrate representative
pharmaceutical compositions of this invention. The present
invention, however, is not limited to the following pharmaceutical
compositions.
Formulation 1--Tablets
[0197] A compound of formula I is admixed as a dry powder with a
dry gelatin binder in an approximate 1:2 weight ratio. A minor
amount of magnesium stearate is added as a lubricant. The mixture
is formed into 240-270 mg tablets (80-90 mg of active compound per
tablet) in a tablet press.
Formulation 2--Capsules
[0198] A compound of formula I is admixed as a dry powder with a
starch diluent in an approximate 1:1 weight ratio. The mixture is
filled into 250 mg capsules (125 mg of active compound per
capsule).
Formulation 3--Liquid
[0199] A compound of formula I (125 mg), sucrose (1.75 g) and
xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S.
sieve, and then mixed with a previously made solution of
microcrystalline cellulose and sodium carboxymethyl cellulose
(11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color
are diluted with water and added with stirring. Sufficient water is
then added to produce a total volume of 5 ml.
Formulation 4--Tablets
[0200] The compound of formula I is admixed as a dry powder with a
dry gelatin binder in an approximate 1:2 weight ratio. A minor
amount of magnesium stearate is added as a lubricant. The mixture
is formed into 450-900 mg tablets (150-300 mg of active compound)
in a tablet press.
Formulation 5--Injection
[0201] The compound of formula I is dissolved or suspended in a
buffered sterile saline injectable aqueous medium to a
concentration of approximately 5 mg/mi.
Formulation 6--Topical
[0202] Stearyl alcohol (250 g) and a white petrolatum (250 g) are
melted at about 75.degree. C. and then a mixture of a compound of
formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g),
sodium lauryl sulfate (10 g), and propylene glycol (120 g)
dissolved in water (about 370 g) is added and the resulting mixture
is stirred until it congeals.
Methods of Treatment
[0203] The present compounds are used as therapeutic agents for the
treatment of conditions in mammals. Accordingly, the compounds and
pharmaceutical compositions of this invention find use as
therapeutics for preventing and/or treating neurodegenerative,
autoimmune and inflammatory conditions in mammals including
humans.
[0204] In a method of treatment aspect, this invention provides a
method of treating a mammal susceptible to or afflicted with a
condition associated with arthritis, uveitis, asthma, myocardial
infarction, traumatic brain injury, acute spinal cord injury,
alopecia (hair loss), inflammatory bowel disease and autoimmune
disorders, which method comprises administering an effective amount
of one or more of the pharmaceutical compositions just
described.
[0205] In yet another method of treatment aspect, this invention
provides a method of treating a mammal susceptible to or afflicted
with a condition that gives rise to pain responses or that relates
to imbalances in the maintenance of basal activity of sensory
nerves. Compounds have use as analgesics for the treatment of pain
of various geneses or etiology, for example acute, inflammatory
pain (such as pain associated with osteoarthritis and rheumatoid
arthritis); various neuropathic pain syndromes (such as
post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic
dystrophy, diabetic neuropathy, Guillian Barre syndrome,
fibromyalgia, phantom limb pain, post-masectomy pain, peripheral
neuropathy, HIV neuropathy, and chemotherapy-induced and other
iatrogenic neuropathies); visceral pain, (such as that associated
with gastroesophageal reflex disease, irritable bowel syndrome,
inflammatory bowel disease, pancreatitis, and various gynecological
and urological disorders), dental pain and headache (such as
migraine, cluster headache and tension headache).
[0206] In additional method of treatment aspects, this invention
provides methods of treating a mammal susceptible to or afflicted
with neurodegenerative diseases and disorders such as, for example
Parkinson's disease, Alzheimer's disease and multiple sclerosis;
diseases and disorders which are mediated by or result in
neuroinflammation such as, for example traumatic brain injury,
stroke, and encephalitis; centrally-mediated neuropsychiatric
diseases and disorders such as, for example depression mania,
bipolar disease, anxiety, schizophrenia, eating disorders, sleep
disorders and cognition disorders; epilepsy and seizure disorders;
prostate, bladder and bowel dysfunction such as, for example
urinary incontinence, urinary hesitancy, rectal hypersensitivity,
fecal incontinence, benign prostatic hypertrophy and inflammatory
bowel disease; respiratory and airway disease and disorders such
as, for example, allergic rhinitis, asthma and reactive airway
disease and chronic obstructive pulmonary disease; diseases and
disorders which are mediated by or result in inflammation such as,
for example rheumatoid arthritis and osteoarthritis, myocardial
infarction, various autoimmune diseases and disorders, uveitis and
atherosclerosis; itch/pruritus such as, for example psoriasis;
alopecia (hair loss); obesity; lipid disorders; cancer; blood
pressure; spinal cord injury; and renal disorders method comprises
administering an effective condition-treating or
condition-preventing amount of one or more of the pharmaceutical
compositions just described.
[0207] In further aspect of the invention there is provided the
present compounds for use in the treatment of the above mentioned
conditions; there is also provided use of the present compounds in
the treatment of the above mentioned conditions; there is also
provided use of the present compounds in the manufacture of a
medicament for the treatment of the above mentioned conditions.
[0208] Injection dose levels range from about 0.1 mg/kg/hour to at
least 10 mg/kg/hour, all for from about 1 to about 120 hours and
especially 24 to 96 hours. A preloading bolus of from about 0.1
mg/kg to about 10 mg/kg or more may also be administered to achieve
adequate steady state levels. The maximum total dose is not
expected to exceed about 2 g/day for a 40 to 80 kg human
patient.
[0209] For the prevention and/or treatment of long-term conditions,
such as neurodegenerative and autoimmune conditions, the regimen
for treatment usually stretches over many months or years so oral
dosing is preferred for patient convenience and tolerance. With
oral dosing, one to five and especially two to four and typically
three oral doses per day are representative regimens. Using these
dosing patterns, each dose provides from about 0.01 to about 20
mg/kg of the compound or its derivative, with preferred doses each
providing from about 0.1 to about 10 mg/kg and especially about 1
to about 5 mg/kg.
[0210] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses.
[0211] When used to prevent the onset of a neurodegenerative,
autoimmune or inflammatory condition, the compounds or their
derivatives of this invention will be administered to a patient at
risk for developing the condition, typically on the advice and
under the supervision of a physician, at the dosage levels
described above. Patients at risk for developing a particular
condition generally include those that have a family history of the
condition, or those who have been identified by genetic testing or
screening to be particularly susceptible to developing the
condition.
[0212] The compounds of this invention can be administered as the
sole active agent or they can be administered in combination with
other agents, including other active derivatives.
General Synthetic Procedures
[0213] The compounds of this invention can be prepared from readily
available starting materials using the following general methods
and procedures. It will be appreciated that where typical or
preferred process conditions (i.e., reaction temperatures, times,
mole ratios of reactants, solvents, pressures, etc.) are given,
other process conditions can also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular reactants
or solvent used, but such conditions can be determined by one
skilled in the art by routine optimization procedures.
[0214] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in T. W. Greene and P. G. M. Wuts, Protecting Groups in
Organic Synthesis, Second Edition, Wiley, New York, 1991, and
references cited therein.
[0215] The target compounds are synthesized by known reactions
outlined in the following schemes. The products are isolated and
purified by known standard procedures. Such procedures include (but
are not limited to) recrystallization, column chromatography or
HPLC. The target compounds, for example, may be prepared by the
reaction of an appropriately substituted halopyridine with an
appropriately functionalized carboxy boronic acid to obtain the
desired biaryl carboxylic acid. The carboxylic acid intermediate
thus obtained can be conveniently converted to its corresponding
amide by activation followed by reacting with an appropriately
substituted amine. The products are isolated and purified by known
standard procedures. Such procedures include (but are not limited
to) recrystallization, column chromatography or HPLC.
Synthesis of intermediate pyridin-2-yl-benzoic acids
Intermediate 1
Synthesis of 3-chloro-[2,3']bipyridinyl-6'-carboxylic acid
1a) Synthesis of 5-bis(hydroxyl)boron-2-methylpicoline
[0216] 20
[0217] 5-Hydroxy-2-methylpyridine (1.0 g, 9.2 mmol) was dissolved
in 20 ml of dichloromethane and stirred at 0.degree. C. To the
reaction mixture was added 1.10 ml of anhydrous pyridine (13.8
mmol), followed by 2.32 ml of triflic anhydride (13.8 mmol). The
reaction mixture was warmed to room temperature and allowed to stir
until completion (monitored by LC-MS/TLC). The mixture was poured
into a separatory funnel and washed with water three times. The
organic layer was washed with brine, dried over MgSO.sub.4,
filtered and evaporated under vacuum. The material was used as
crude material for the next step.
[0218] The triflate (4.6 mmol) was dissolved in acetonitrile (30
ml) and placed into a 5 ml microwave vessel. To the solution was
added 1.5 eq of bis(pinacolato)diboron (6.9 mmol; 1.71 g). The
mixture was stirred on a magnetic stir plate until dissolution. To
the mixture was added KOAc (13.8 mmol; 1.35 g) and 98 mg of
[1,1'-bis(diphenylphosphino)-ferrocene] dichloropalladium(II) (0.03
mol %). The reaction mixture was heated at 160.degree. C. for
2.times.600 s. After completion (monitored by LC-MS), the
acetonitrile was evaporated to give a black solid. The solid was
dissolved in DMSO, ms and purified by HPLC to give the boronic acid
(580 mg, 92%; 4.2 mmol).
[0219] MS: MH+=138
1b) Synthesis of 3-chloro-6'-methyl-[2,3']bipyridinyl
[0220] 21
[0221] The above boronic acid (4.2 mmol) was dissolved in
acetonitrile (2 ml) and added to a 5 ml microwave vessel. To the
solution was 6.9 mmol of 2,3-dichloropyridine (1.01 g), 53 mg of
tetrakis(triphenylphosphine)palla- dium(0). After stirring until
dissolution, 13.8 mmol of potassium carbonate (1.90 g) was added,
followed by 1 ml of water. The mixture was then heated at
160.degree. C. for 300 seconds. After reaction completion, the
solvents were evaporated under vacuum. The target compound was
purified by HPLC to give a yellow solid (800 mg; 85%).
[0222] MS: MH+=205
1c) Synthesis of 3-chloro-[2,3']bipyridinyl-6'-carboxylic acid
[0223] 22
[0224] The above 3-chloro-6'-methyl-[2,3']bipyridinyl (2.5 mmol)
was added to a 5 ml microwave vessel, followed by 3 ml of water.
3.75 mmol of potassium permanganate was added and the mixture was
heated at 120.degree. C. for 600 seconds. An additional 3.75 mmol
of potassium permanganate was added and the mixture was resubmitted
to microwave heating (same temperature) for 600 s. After completion
(monitored by LC-MS), the mixture was filtered through celite and
the manganese salts were washed with water. The water was
evaporated to .about.10 ml and the product was purified by HPLC to
give 293 mg as a white solid (51%).
[0225] MS: MH+=235
Intermediate 2
a) Synthesis of 4-(3-chloro-pyridin-2-yl)-3-methoxybenzoic acid
2a) Synthesis of 3-methoxy-4-boronicacid -benzoic acid methyl
ester
[0226] 23
[0227] 1.0 g of 4-hydroxy-3-methoxybenzoic acid methyl ester (5.5
mmol) was dissolved in 20 ml of dichloromethane and stirred at
0.degree. C. To the reaction mixture was added 0.66 ml of anhydrous
pyridine (8.25 mmol), followed by 1.39 ml of triflic anhydride
(8.25 mmol). The reaction mixture was warmed to room temperature
and allowed to stir until completion (monitored by LC-MS/TLC). The
mixture was poured into a separatory funnel and washed with water
three times. The organic layer was washed with brine, dried over
MgSO.sub.4, filtered and evaporated under vacuum to give the
triflate (used as crude for boronoic acid formation).
[0228] The triflate (5.5 mmol) was dissolved in acetonitrile (30
ml) and placed into an 80 ml microwave vessel. To the solution was
added 1.5 eq of Bis(pinacolato)diboron (8.25 mmol; 2.08 g). The
mixture was stirred on a magnetic stir plate until dissolution. To
the mixture was added KOAc (16.5 mmol; 1.62 g) and 134 mg of
[1,1'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.03
mol %). The reaction mixture was heated at 160.degree. C. for
2.times.600 s. After completion (monitored by LC-MS), the
acetonitrile was evaporated to give a black solid. The solid was
dissolved in EtOAc and washed with water, brine and dried over
MgSO.sub.4. After filtration, the solvent was evaporated under
vacuum. The solid material was then dissolved in chloroform and
filtered through silica. The chloroform was evaporated to give a
dark green solid (used as crude for the next reaction).
2b) Synthesis of 4-(3-chloro-pyridin-2-yl)-3-methoxybenzoic
acid
[0229] 24
[0230] Boronic acid 3 (5.5 mmol) was dissolved in acetonitrile (10
ml) and added to an 80 ml microwave vessel. To the solution was
8.25 mmol of 2,3-dichloropyridine (1.2 g), 63 mg of
tetrakis(triphenylphosphine)pallad- ium(0). After stirring until
dissolution, 5 ml of a 1 M potassium carbonate solution (aqueous)
was added and the mixture was heated at 160.degree. C. for 300 s.
After reaction completion, the acetonitrile was evaporated under
vacuum and 2 N KOH was added (20 ml), followed by 10 ml of THF. The
reaction was heated until hydrolysis was complete (15minutes). The
solution was acidified (CHCl) and extracted 3.times. with EtOAc.
After drying over MgSO.sub.4, the organic layer was filtered and
evaporated under vacuum. The compound was purified by HPLC to give
a yellow solid (263 mg, 18%).
[0231] MS: MH+=264
Intermediate 3
Synthesis of 4-(3-Trifluoromethylpyridin-2-yl)benzoic acid
[0232] 25
[0233] 4-Bis(hydroxyl)boron-1-methylbenzoate (2.8 mmol) was
dissolved in acetonitrile (2 ml) and added to a 5 ml microwave
vessel. To the solution was 3.5 mmol of
2-chloro-3-trifluoromethylpyridine (633 mg), 34 mg of
tetrakis(triphenylphosphine)-palladium(0). After stirring until
dissolution, 8.4 mmol of potassium carbonate (1.16 g) was added,
followed by 1 ml of water. The mixture was then heated at
160.degree. C. for 300 seconds. After reaction completion, the
solvents were evaporated under vacuum. The residue was dissolved in
2N KOH and THF and heated for 10 min. After hydrolysis, the THF was
evaporated and the basic layer was washed with EtOAC. The aqueous
layer was then acidified and extracted 3 times with EtOAc. The
organic layers were combined and washed with water and brine. After
drying, filtration and evaporation, the residue was purfied by HPLC
to give of the target compound as a white solid (602 mg; 81%).
[0234] MS: MH+=268
Intermediate 4
3-Fluoro-4-(3-trifluoromethylpyridin-2-yl)benzoic acid
[0235] 26
[0236] The 4-Bromo-3-fluorobenzoic acid methyl ester (700 mg; 2.45
mmol) was dissolved in acetonitrile (3.0 ml) and placed into a 2 ml
microwave vessel. To the solution was added 1.5 eq of
Bis(pinacolato)diboron (3.67 mmol; 1.08 g). The mixture was stirred
on a magnetic stir plate until dissolution. To the mixture was
added KOAc (7.33 mmol; 7.16 mg) and 60 mg of [1,1
'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.03 mol
%). The reaction mixture was heated at 160.degree. C. for
2.times.600 s. After completion (monitored by LC-MS), the
acetonitrile was evaporated to give a black solid. The solid was
dissolved in EtOAc and washed with water, brine and dried over
MgSO.sub.4. After filtration, the solvent was evaporated under
vacuum. The solid material was then dissolved in chloroform and
filtered through silica. The chloroform was evaporated to give a
dark green solid (used as crude for the next reaction).
[0237] The boronic acid (2.45 mmol) was dissolved in acetonitrile
(2.4 ml) and 3-(trifluoromethyl)-2-chloropyridine was added. After
mixing, tetrakis palladium was added (25 mg; 0.01 mol %), followed
by 0.8 ml of water and K.sub.2CO.sub.3 (912 mg; 3.0 mmol). The
reaction mixture was heated at 160.degree. C. in a Personal
Chemistry Emrys Microwave for 300 s. After reaction completion, the
solvents were evaporated and the residue was dissolved in EtOAc and
washed with water and brine. The organic layer was dried over
MgSO.sub.4, filtered and evaporated. The residue was then dissolved
in a 1:1 mixture of THF/2NKOH and heated until saponification was
complete. The basic layer was then extracted with EtOAc and
acidified with conc.HCl. The aqueos layer was then extracted three
times with EtOAc. The combined organic layers were dried over
MgSO.sub.4, filtered and evaporated to give the desired material as
a white solid (530 mg; 76%).
[0238] MS: MH+=286
Intermediate 5
4-(3-Trifluoromethylpyridin-2-yl)-3-methoxybenzoic acid
[0239] 27
[0240] The boronic acid was prepared as described in Intermediate 2
to give 410 mg (78%). The boronic acid (2.55 mmol) was dissolved in
acetonitrile (2.4 ml) and 3-(trifluoromethyl)-2-chloropyridine was
added. After mixing, tetrakis palladium was added (29 mg; 00.1 mol
%), followed by 0.8 ml of water and K.sub.2CO.sub.3 (912 mg; 6.6
mmol). The reaction mixture was heated at 160.degree. C. in a
Personal Chemistry Emrys Microwave for 300 s. After reaction
completion, the solvents were evaporated and the residue was
dissolved in EtOAc and washed with water and brine. The organic
layer was dried over MgSO.sub.4, filtered and evaporated. The
residue was then dissolved in a 1:1 mixture of THF/2NKOH and heated
until saponification was complete. The basic layer was then
extracted with EtOAc and acidified with conc.HCl. The aqueos layer
was then extracted three times with EtOAc. The combined organic
layers were dried over MgSO.sub.4, filtered and evaporated to give
the desired material as a white solid (495 mg; 68%).
[0241] MS: MH+=298
Intermediate 6
4-(3-Methoxypyridin-2-yl)-3-fluorobenzoic acid
[0242] 28
[0243] The boronic acid was prepared as described in Intermediate 4
to give 2.2 mmole. (quant.crude). The boronic acid (2.2 mmol) was
dissolved in acetonitrile (2.4 ml) and 3-methoxy-2-chloropyridine
(380 mg; 2.88 mmol) was added. After mixing, tetrakis palladium was
added (25 mg; 0.01 mol %), followed by 0.8 ml of water and
K.sub.2CO.sub.3 (912 mg; 6.6 mmol). The reaction mixture was heated
at 160.degree. C. in a Personal Chemistry Emrys Microwave for 300
s. After reaction completion, the solvents were evaporated and the
residue was dissolved in EtOAc and washed with water and brine. The
organic layer was dried over MgSO.sub.4, filtered and evaporated.
The residue was then dissolved in a 1:1 mixture of THF/2NKOH and
heated until saponification was complete. The basic layer was then
extracted with EtOAc and acidified with conc.HCl. The aqueos layer
was then extracted three times with EtOAc. The combined organic
layers were dried over MgSO.sub.4, filtered and evaporated to give
the desired material as a beige solid (312 mg; 57%).
[0244] MS: MH+=248
Intermediate 7
4-(3-Methoxypyridin-2-yl)benzoic acid
[0245] 29
[0246] 4-bis(hydroxyl)boron-1-methylbenzoate (2.8 mmol; 582 mg) was
dissolved in acetonitrile (2 ml) and added to a 5 ml microwave
vessel. To the solution was 3.5 mmol of 2-chloro-3-methoxypyridine
(482 mg), 34 mg of tetrakis(triphenylphosphine)palladium(0). After
stirring until dissolution, 8.4 mmol of potassium carbonate (1.16
g) was added, followed by 1 ml of water. The mixture was then
heated at 160.degree. C. for 300 seconds. After reaction
completion, the solvents were evaporated under vacuum. The residue
was dissolved in 2N KOH and THF and heated for 10 min. After
hydrolysis, the THF was evaporated and the basic layer was washed
with EtOAC. The aqueous layer was then acidified and extracted 3
times with EtOAc. The organic layers were combined and washed with
water and brine. After drying, filtration and evaporation, the
residue was triterated with ether to give the desired product as a
yellow solid (423 mg; 77%).
[0247] MS: MH+=230
Intermediate 8
4-(3-Trifluoromethylpyridin-2-yl)-3-chlorobenzoic acid
8a) 4-bromo-3-chloromethylbenzoate
[0248] 30
[0249] The 4-bromo-3chlorotoluene (4.0 g; 19.5 mmol) was added to a
250 ml round bottom flask, followed by 50 ml of water. To the
mixture was added 3.22 g of potassium permanganate (23.4 mmol) and
the reaction was refluxed until completion. After cooling, the
mixture was filtered through celite. The aqueous layer was
acidified and extracted three times with ethylacetate. The organic
layers were washed with brine, dried over MgSO.sub.4. After
filtration and evaporation, the resulting white solid was dissolved
in 1.0M HCl in ether and stirred overnight. The methanol was
removed under vacuum and the residue was dissolved in ethylacetate
and washed with saturated sodium bicarbonate. The organic layer was
dried over MgSO.sub.4, filtered and evaporated to give the desired
material as a clear oil (713 mg; 15%).
8b) 4-(3-Trifluoromethylpyridin-2-yl)-3-chlorobenzoic acid
[0250] 31
[0251] The boronic acid was prepared as described in Intermediate 4
to give 2.8 mmole. (quant.crude). The boronic acid (2.8 mmol) was
dissolved in acetonitrile (2.4 ml) and
2-chloro3-trifluoromethylpyridine (620 mg; 3.3 mmol) was added.
After mixing, tetrakis palladium was added (33 mg; 0.01 mol %),
followed by 0.8 ml of water and K.sub.2CO.sub.3 (1182 mg; 6.6
mmol). The reaction mixture was heated at 160.degree. C. in a
Personal Chemistry Emrys Microwave for 300 s. After reaction
completion, the solvents were evaporated and the residue was
dissolved in EtOAc and washed with water and brine. The organic
layer was dried over MgSO.sub.4, filtered and evaporated. The
residue was then dissolved in a 1:1 mixture of THF/2NKOH and heated
until saponification was complete. The basic layer was then
extracted with EtOAc and acidified with conc.HCl. The aqueos layer
was then extracted three times with EtOAc. The combined organic
layers were dried over MgSO.sub.4, filtered and evaporated to give
the desired material as a white solid (460 mg; 55%).
[0252] MS: MH+=303
Intermediate 9
4-(3-methoxypyridin-2-yl)-3-methoxybenzoic acid
[0253] 32
[0254] The boronic acid was prepared as described in Intermediate 5
(2.5 mmol; crude) and was dissolved in acetonitrile (2 ml) and
added to a 5 ml microwave vessel. To the solution was 3.0 mmol of
2-chloro-3-methoxypyrid- ine (432 mg), 29 mg of
tetrakis(triphenylphosphine)palladium(0). After stirring until
dissolution, 7.5 mmol of potassium carbonate (1.06 g) was added,
followed by 1 ml of water. The mixture was then heated at
160.degree. C. for 300 seconds. After reaction completion, the
solvents were evaporated under vacuum. The residue was dissolved in
2N KOH and THF and heated for 10 min. After hydrolysis, the THF was
evaporated and the basic layer was washed with EtOAC. The aqueous
layer was then acidified and extracted 3 times with EtOAc. The
organic layers were combined and washed with water and brine. After
drying, filtration and evaporation, the residue was triterated with
ether to give the desired product as a yellow solid (310 mg;
47%).
[0255] MS: MH+=260
Intermediate 10
4-(3-Methoxypyridin-2-yl)-3-chlorobenzoic acid
[0256] 33
[0257] The boronic acid was prepared as described in Intermediate 4
to give 2.8 mmole. (quant.crude). The boronic acid (2.14 mmol) was
dissolved in acetonitrile (2.4 ml) and 3-methoxy-2-chloropyridine
(368 mg; 2.6 mmol) was added. After mixing, tetrakis palladium was
added (25 mg; 0.01 mol %), followed by 0.8 ml of water and
K.sub.2CO.sub.3 (887 mg; 6.5 mmol). The reaction mixture was heated
at 160.degree. C. in a Personal Chemistry Emrys Microwave for 300
s. After reaction completion, the solvents were evaporated and the
residue was dissolved in EtOAc and washed with water and brine. The
organic layer was dried over MgSO.sub.4, filtered and evaporated.
The residue was then dissolved in a 1:1 mixture of THF/2NKOH and
heated until saponification was complete. The basic layer was then
extracted with EtOAc and acidified with conc. HCl. The aqueous
layer was then extracted three times with EtOAc. The combined
organic layers were dried over MgSO.sub.4, filtered and evaporated
to give the desired material as a yellow solid (425 mg; 76%).
[0258] MS: MH+=264
Intermediate 11
4-(3-Chloropyridin-2-yl)-3-fluorobenzoic acid
[0259] 34
[0260] The boronic acid was prepared as described in Intermediate 4
(2.45 mmol) was dissolved in acetonitrile (2.4 ml) and
2,3-dichloropyridine was added. After mixing, tetrakis palladium
was added (25 mg; 0.01 mol %), followed by 0.8 ml of water and
K.sub.2CO.sub.3 (912 mg; 3.0 mmol). The reaction mixture was heated
at 160.degree. C. in a Personal Chemistry Emrys Microwave for 300
s. After reaction completion, the solvents were evaporated and the
residue was dissolved in EtOAc and washed with water and brine. The
organic layer was dried over MgSO.sub.4, filtered and evaporated.
The residue was then dissolved in a 1:1 mixture of THF/2NKOH and
heated until saponification was complete. The basic layer was then
extracted with EtOAc and acidified with conc. HCl. The aqueos layer
was then extracted three times with EtOAc. The combined organic
layers were dried over MgSO.sub.4, filtered and evaporated to give
the desired material as a white solid (403 mg; 56%).
[0261] MS: MH+=252
Intermediate 12
4-(3-Chloropyridin-2-yl)-2-aminobenzoic acid
12a) 4-Bromo-2-aminomethylbenzoate
[0262] 35
[0263] 4-Bromo-2-nitromethylbenzoate (300 mg; 1.15 mmol) was
dissolved in 25 ml of methanol and shaken with 5% Pd(c) under
hydrogen atmosphere (50 PSI) for 1 hour. The reaction was filtered
through celite and evaporated to give the product as a white solid
(255 mg; 96%).
[0264] MS: MH+=230
12b) 4-(3-Chloropyridin-2-yl)-2-aminobenzoic acid
[0265] 36
[0266] The boronic acid was prepared as described in Intermediate 4
to give 3.4 mmole. (quant.crude). The boronic acid 656 mg (3.4
mmol) was dissolved in acetonitrile (2.4 ml) and
2,3-dichloropyridine (600 mg; 4.08 mmol) was added. After mixing,
tetrakis palladium was added (40 mg; 0.01 mol %), followed by 0.8
ml of water and K.sub.2CO.sub.3 (1.40 g; 10.8 mmol). The reaction
mixture was heated at 160.degree. C. in a Personal Chemistry Emrys
Microwave for 300 s. After reaction completion, the solvents were
evaporated and the residue was dissolved in EtOAc and washed with
water and brine. The organic layer was dried over MgSO.sub.4,
filtered and evaporated. The residue was then dissolved in a 1:1
mixture of THF/2NKOH and heated until saponification was complete.
The basic layer was then extracted with EtOAc and acidified with
conc.HCl. The aqueos layer was then extracted three times with
EtOAc. The combined organic layers were dried over MgSO.sub.4,
filtered and evaporated to give the desired material as a yellow
solid (466 mg; 55%).
[0267] MS: MH+=249
Intermediate 13
4-(3-Chloropyridin-2-yl)-2-N-methylaminobenzoic acid
13a)
4-(3-Chloropyridin-2-yl)-2-(trifluoromethylacetamide)methylbenzoate
[0268] 37
[0269] The 4-(3-Chloropyridin-2-yl)-2aminomethylbenzoate (1.43 mg;
0.55 mmol) was dissolved in 1,2-dichloroethane (5 ml). To the
mixture was added trifluoroacetic anhydride (7.2 mmol; 1.0 ml) and
pyridine (7.7 mmol; 0.63 ml) and the reaction was stirred for 2
hrs. The solution was diluted with dichloromethane and washed with
water. The organic layer was dried over MgSO.sub.4, filtered and
evaporated to give the desired product as a white solid (1.5 g;
79%).
[0270] MS: MH+=359
13b) 4-(3-Chloropyridin-2-yl)-2-N-methylaminobenzoic acid
[0271] 38
[0272]
4-(3-Chloropyridin-2-yl)-2-(trifluoromethylacetamide)methylbenzoate
(540 mg; 1.5 mmol) was dissolved in dry tetrahydrofuran.
Triphenylphosphine (446 mg; 1.7 mmol) and DIAD (0.36 ml; 1.7 mmol),
followed by anhydrous methanol (0.07 ml; 1.7 mmol). The THF was
evaporated and the residue was dissolved in EtOAc. The organic
layer was washed with water, brine, dried over MgSO.sub.4, filtered
and dried. The crude material was purified by flash chromatography
using 2:1 hexanes:ethylacetate to give 465 mg of the desired
product (83%).
[0273] The methylated product (464 mg; 1.24 mmol) was dissolved in
methanol (8 ml) and 4 ml of aqueous lithium hydroxide (4 ml; 10%).
The methanol was evaporated and the mixture was acidified and
extracted with EtOAc. The organic layer was washed with water,
dried over MgSO.sub.4, filtered and evaporated to give the desired
product as a yellow solid (338 mg; 91%).
[0274] MS: MH+=263
Intermediate 14
4-(3-Chloropyridin-2-yl)-2-N-methoxyethylaminobenzoic acid
[0275] 39
[0276] The
4-(3-Chloropyridin-2-yl)-2-(trifluoromethylacetamide)methylbenz-
oate (1.2 g; 3.3 mmol) was dissolved in dry tetrahydrofuran.
Triphenylphosphine (2.2 g; 8.3 mmol) and DIAD (1.7 ml; 8.3 mmol),
followed by anhydrous methoxyethanol (0.66 ml; 8.3 mmol). The THF
was evaporated and the residue was dissolved in EtOAc. The organic
layer was washed with water, brine, dried over MgSO.sub.4, filtered
and dried. The crude material was purified by flash chromatography
using 2:1 hexanes:ethylacetate to give 676 mg of the desired
product (66%).
[0277] The alkylated product (525 mg; 1.24 mmol) was dissolved in
methanol (8 ml) and 4 ml of aqueous lithium hydroxide (4 ml; 10%).
The methanol was evaporated and the mixture was acidified and
extracted with EtOAc. The organic layer was washed with water,
dried over MgSO.sub.4, filtered and evaporated to give the desired
product as a yellow solid (260 mg; 66%).
[0278] MS: M+=307
Intermediate 15
4-(3-Chloropyridin-2-yl)-2-N-benzylaminobenzoic acid
[0279] 40
[0280] The
4-(3-Chloropyridin-2-yl)-2-(trifluoromethylacetamide)methylbenz-
oate (436 m; 1.2 mmol) was dissolved in dry tetrahydrofuran.
Triphenylphosphine (349 mg; 1.33 mmol) and DIAD (0.28 ml; 1.33
mmol), followed by anhydrous benzylalcohol (0.14 ml; 1.33 mmol).
The THF was evaporated and the residue was dissolved in EtOAc. The
organic layer was washed with water, brine, dried over MgSO.sub.4,
filtered and dried. The crude material was purified by flash
chromatography using 2:1 hexanes:ethylacetate to give 435 mg of the
desired product (80%).
[0281] The alkylated product (68 mg; 0.15 mmol) was dissolved in
methanol (6 ml) and 4 ml of aqueous lithium hydroxide (2ml; 10%).
The methanol was evaporated and the mixture was acidified and
extracted with EtOAc. The organic layer was washed with water,
dried over MgSO.sub.4, filtered and evaporated to give the desired
product as a yellow solid (51 mg; 75%).
[0282] MS: M+=339
Intermediate 16
4-(3-Chloropyridin-2-yl)benzoic acid
[0283] 41
[0284] Tetrakis palladium (0.1 2 g, 0.1 mMol) was added to a
suspension of carboxybenzene boronic acid (0.33 g, 2.0 mMol) and
2,3-dichloropyridine (0.296 g, 2.0 mMol) in a mixture of 0.4M
K.sub.2CO.sub.3 (10 mL) and acetonitrile (10 mL) and the mixture
was heated at 90.degree. C. for 12 hrs under a blanket of nitrogen.
The hot suspension was filtered, the filtrate concentrated to about
half the original volume before being washed with methylene
chloride. The aq. layer was carefully acidified with conc. HCl and
the precipitate was collected, washed with water and vacuum dried
to obtain the product as a white solid.
[0285] MS: m/z=232 (M-1)
[0286] Following the procedure described above for Intermediate
1-16 and the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the other
benzoic acids, employed in synthesizing amide compounds of this
invention, were prepared.
[0287] Amidation of Carboxylic Acid
EXAMPLE 1
A Representative Synthesis of Benzamide
4-(3-Chloropyridin-2-yl)- N-(4-trifluoromethyl-phenyl)benzamide
(Compound 18)
[0288] 42
[0289] To a suspension of 4-(3-chloro-pyridin-2-yl)-benzoic acid
(5.0 g, 21.4 mmol) in methylene chloride (100 ml) at ambient
temperature was added oxalyl chloride (5.43 g, 42.79 mmol) followed
by two drops of DMF and the mixture was heated to reflux for 30
minutes. The clear solution was then concentrated to dryness,
dissolved in methylene chloride (100 ml) and was treated with
4-trifluoromethyl aniline (4.14 g, 25.68 mmol) followed by
triethylamine (2.6 g, 25.68 mmol) and the mixture was gently heated
to reflux for 30 minutes and agitated overnight at ambient
temperature. After treating the mixture with sat. Na.sub.2CO.sub.3,
the organic layer was separated, washed with water, dried and
concentrated to give the crude product which was chromatographed on
silicagel to obtain 4.0 g (49.6%) of the title compound as a white
solid.
[0290] MS: m/z=367 (M+1) .sup.1H NMR (DMSO-d6): .delta. 7.45-7.53
(m, 1H); 7.75 (d, 8.8 Hz, 2H); 7.86 (d, 5.2 Hz, 2H); 8.04-8.13 (m,
5H); 8.67 (dd, 4.8 Hz, 1.6 Hz, 1H); 10.72 (s, 1H).
EXAMPLE 2
A Representative Synthesis of Benzamides Using an Automated
Parallel Synthesis Method
[0291] The appropriate benzoic acid (2 mmol) was dissolved or
suspended in 15 ml of chloroform and treated with 20 mmol of
thionyl chloride. The reaction mixture was refluxed for fifteen
minutes and the solvents were removed under vacuum. The residue was
dissolved in 4 ml of anhydrous chloroform and 60 .mu.l (30 pmole)
of this solution was added to each well of the 96 well glass
plates. Appropriate amine was then added to the corresponding well
(60 .mu.mole), followed by N,N-diisopropylethylamine (120
.mu.mole). The plate was then heated at 65.degree. C. for 15
minutes. The solvents were removed using an HT-12 Genevac
centrifugal evacuator and 100 .mu.l of DMSO was added to each well
and the compounds were transferred to a 96-well polypropylene
reaction plate. The plates were then sealed using an ABgene plate
sealer and submitted to LC-MS purification.
General Method for Automated parallel LC-MS Purification of
Libraries
[0292] The libraries were purified using a Perkin Elmer API100 mass
spectrometer coupled to Shimadzu LC pumps. The chromatographic
method employed was 10-100% gradient of acetonitrile to water over
8 minutes at a flow rate of 6 ml per minute. The column used was a
10.times.50 mm YMC C18 and the compounds were collected using a
Gilson 204 fraction collector.
[0293] Following the procedure described above for Example 1 or 2
and the appropriate reagents, starting materials and purification
methods known to those skilled in the art, the amide compounds of
this invention were prepared.
[0294] The following synthetic and biological examples are offered
to illustrate this invention and are not to be construed in any way
as limiting the scope of this invention. In the examples below, all
temperatures are in degrees Celsius (unless otherwise indicated).
The compounds that have been prepared in accordance with the
invention, are presented in tabular form below. The syntheses of
these representative compounds were carried out in accordance with
the methods set forth above.
[0295] Exemplary Compounds of the Invention
[0296] The following compounds have been prepared according to the
methods of the invention.
1 HPLC HPLC HPLC START END % MW MS RT TIME TIME Inhibition ID
STRUCTURE (calc) (Obs) (Min) (Min) (Min) @ 1 uM 1 43 366.81 367.09
3.04 2.95 3.62 + + 2 44 338.80 339.09 3.18 3.09 3.59 + 3 45 308.77
309.28 3.12 3.05 3.58 + 4 46 347.81 348.15 2.90 2.83 3.18 + + + + 5
47 338.80 339.11 3.05 2.92 3.43 + + 6 48 326.76 327.11 3.19 3.12
3.47 7 49 309.76 310.28 2.21 2.09 2.61 + + + + 8 50 309.76 310.28
2.09 2.02 2.46 + + + + 9 51 298.73 299.17 2.29 2.19 2.53 + 10 52
324.77 325.23 2.93 2.85 3.18 11 53 333.78 334.18 2.93 2.78 3.32 +
12 54 343.22 343.09 3.52 3.42 3.81 + 13 55 338.80 339.12 3.34 3.22
3.68 + + + + 14 56 350.85 351.29 3.45 3.34 3.91 15 57 343.22 343.09
3.41 3.33 3.81 + 16 58 377.66 377.16 3.79 3.71 4.14 + 17 59 373.24
373.03 3.33 3.22 3.66 + 18 60 376.77 377.26 3.67 3.54 3.89 + + + +
19 61 377.66 377.17 3.74 3.61 4.05 20 62 411.21 411.00 3.89 3.78
4.24 + + + 21 63 387.67 389.18 3.57 3.48 3.91 + 22 64 333.78 334.15
3.16 3.09 3.48 + 23 65 352.82 353.22 2.78 2.71 3.15 + + + 24 66
364.88 365.09 3.85 3.75 4.31 + + + + 25 67 350.85 351.29 3.71 3.62
4.05 + + + + 26 68 364.88 365.09 3.96 3.85 4.68 + + 27 69 390.92
391.32 4.19 3.99 4.57 + + + + 28 70 406.79 407.15 3.73 3.65 4.14 +
+ 29 71 336.82 337.34 3.29 3.16 3.59 + 30 72 344.20 344.08 2.90
2.83 3.32 + + 31 73 344.20 344.08 3.02 2.92 3.31 + 32 74 339.78
340.10 2.66 2.58 2.98 + 33 75 344.20 344.08 3.05 2.88 3.36 + + + +
34 76 352.78 353.15 3.05 2.90 3.48 + 35 77 338.80 339.13 2.29 2.22
2.51 + 36 78 396.88 397.10 3.83 3.53 4.24 + + 37 79 337.81 338.29
2.40 2.25 2.80 + 38 80 315.78 316.06 2.82 2.72 3.16 + 39 81 371.76
371.96 3.56 3.48 3.83 40 82 353.77 354.12 3.53 3.46 3.78 41 83
304.78 305.24 2.33 2.29 2.61 + 42 84 350.85 351.30 3.29 3.21 3.66
43 85 351.84 352.29 2.28 2.16 2.62 + + + + 44 86 379.89 380.27 2.39
2.19 2.82 + + + + 45 87 393.88 394.15 2.43 2.36 2.89 + 46 88 323.78
324.28 2.28 2.17 2.59 47 89 310.75 311.25 2.35 2.23 2.53 48 90
323.78 324.28 2.19 2.12 2.39 + + 49 91 388.65 390.14 3.42 3.35 3.63
+ + 50 92 377.76 378.19 3.56 3.51 3.82 + + 51 93 412.20 412.11 3.32
3.13 3.63 52 94 337.81 338.29 2.42 2.36 2.64 53 95 302.81 303.08
3.15 3.06 3.59 + 54 96 359.82 360.14 2.33 2.22 2.59 + 55 97 425.92
426.12 3.78 3.68 4.49 + + 56 98 353.77 354.15 3.39 3.31 3.56 + + +
+ 57 99 358.83 359.15 3.58 3.48 3.92 + + + + 58 100 355.80 356.12
2.50 2.38 2.93 59 101 306.77 307.22 3.25 3.18 3.46 60 102 326.76
327.10 3.35 3.28 3.59 61 103 356.79 357.01 3.28 3.19 3.75 62 104
327.75 328.19 2.25 2.13 2.58 + 63 105 327.75 328.21 2.18 2.12 2.53
+ 64 106 389.75 390.15 3.82 3.66 4.21 65 107 371.76 371.94 3.78
3.71 4.16 66 108 368.84 369.07 3.56 3.46 3.96 + 67 109 342.76
343.09 3.18 3.08 3.49 + 68 110 351.77 352.15 3.31 3.12 3.61 69 111
369.83 370.11 2.39 2.29 2.76 + 70 112 397.88 398.10 2.48 2.26 2.99
71 113 361.21 361.02 3.69 3.58 3.96 + 72 114 356.79 357.00 3.76
3.69 4.05 73 115 368.84 369.04 3.83 3.66 4.26 74 116 356.79 357.00
3.38 3.29 3.85 + 75 117 411.87 412.10 2.61 2.46 3.19 76 118 361.21
77 119 341.78 342.07 2.40 2.26 2.73 78 120 395.65 394.97 4.45 4.31
4.51 79 121 391.23 391.22 3.52 3.41 3.81 + + 80 122 394.76 395.00
3.81 3.68 4.05 81 123 395.65 396.95 4.34 4.24 4.61 82 124 429.20
428.97 4.02 3.88 4.31 83 125 405.66 406.99 3.75 3.66 4.09 + + + +
84 126 351.77 352.14 3.31 3.22 3.59 + + + + 85 127 370.81 371.01
2.89 2.82 3.22 86 128 382.87 383.16 4.05 3.95 4.26 + 87 129 368.84
369.07 3.91 3.82 4.30 88 130 382.87 382.86 3.80 3.72 4.02 89 131
408.91 409.21 4.44 4.31 4.85 90 132 424.79 424.96 3.86 3.76 4.21 91
133 354.81 355.19 3.63 3.56 3.95 92 134 384.80 385.11 3.22 3.15
3.55 93 135 365.80 366.10 3.09 3.02 3.59 94 136 328.74 329.16 2.60
2.50 2.85 95 137 341.78 342.06 2.32 2.23 2.70 + 96 138 406.64
408.06 3.76 3.69 3.99 97 139 395.75 396.06 3.84 3.71 4.07 + 98 140
430.19 430.12 3.55 3.49 3.88 + 99 141 355.80 356.13 2.58 2.46 2.76
100 142 320.80 321.12 3.46 3.36 4.02 101 143 362.19 362.15 3.44
3.11 3.62 + 102 144 362.19 362.14 3.18 3.11 3.45 103 145 357.77
358.10 2.88 2.79 3.23 + 104 146 362.19 362.19 2.70 2.65 2.80 105
147 370.77 370.99 3.23 3.15 3.49 106 148 356.79 357.07 2.40 2.29
2.73 107 149 377.81 378.17 2.40 2.32 2.78 + + 108 150 414.87 415.24
4.05 3.89 4.38 109 151 376.82 377.27 3.75 3.66 4.11 + + 110 152
306.77 307.22 3.06 2.95 3.46 + 111 153 368.84 369.10 3.36 3.28 3.73
112 154 326.76 327.10 3.21 3.12 3.52 113 155 356.79 357.09 3.13
3.03 3.63 114 156 344.75 344.97 3.28 3.12 3.53 + 115 157 351.77
352.22 2.99 2.86 3.29 116 158 361.21 361.13 3.53 3.41 3.88 + 117
159 356.79 357.04 3.35 3.09 3.73 118 160 368.84 369.10 3.49 3.35
4.02 + 119 161 356.79 357.09 3.24 2.89 3.79 + 120 162 361.21 361.09
3.39 3.12 3.79 121 163 395.65 394.98 3.74 3.49 4.12 122 164 395.65
394.97 3.66 3.46 4.06 + + + + 123 165 405.66 407.03 3.61 3.48 4.09
124 166 351.77 352.18 3.21 3.13 3.42 + + + + 125 167 382.87 383.17
3.87 3.77 4.24 + + + + 126 168 368.84 369.08 3.72 3.48 4.11 127 169
382.87 383.18 3.99 3.79 4.56 + + + + 128 170 354.81 355.20 3.33
3.22 3.79 + + + + 129 171 384.80 385.18 3.12 3.03 3.49 130 172
370.77 370.99 3.14 2.99 3.59 131 173 371.76 371.94 3.42 3.33 3.69
132 174 389.75 390.22 3.49 3.41 3.83 + + + + 133 175 371.76 372.00
3.49 3.41 3.92 134 176 391.23 391.22 3.38 3.21 3.73 135 177 394.76
395.03 3.68 3.51 3.91 + + 136 178 429.20 428.99 3.91 3.79 4.19 137
179 370.81 371.04 2.90 2.78 3.19 138 180 424.79 425.01 3.76 3.63
3.95 139 181 355.80 356.13 2.45 2.28 2.82 + 140 182 327.75 328.21
2.28 2.15 2.59 + + + + 141 183 327.75 328.23 2.17 2.07 2.49 142 184
369.83 370.13 2.39 2.25 2.63 143 185 397.88 398.14 2.43 2.30 2.99
144 186 411.87 412.11 2.56 2.35 2.98 145 187 341.78 342.08 2.33
2.15 2.60 + + + + 146 188 365.80 366.10 2.99 2.86 3.53 147 189
328.74 329.18 2.46 2.39 2.78 148 190 406.64 408.06 3.46 3.38 3.81
149 191 395.75 396.10 3.58 3.48 3.85 + + 150 192 430.19 430.13 3.35
3.15 3.75 151 193 355.80 356.14 2.48 2.26 2.85 152 194 362.19
362.16 3.12 2.95 3.46 + 153 195 357.77 358.11 2.79 2.65 3.18 + +
154 196 362.19 362.19 3.12 3.07 3.45 155 197 356.79 357.09 2.36
2.30 2.55 156 198 377.81 378.19 2.40 2.12 2.78 + + + + 157 199
443.91 158 200 316.72 317.08 2.42 2.33 2.83 + 159 201 333.77 334.13
2.91 2.84 3.29 160 202 376.82 377.26 3.61 3.45 4.12 + + + + 161 203
432.89 433.22 3.72 3.48 4.02 162 204 398.82 399.10 3.51 3.31 3.82
163 205 469.95 470.32 2.66 2.56 2.98 164 206 386.81 387.15 2.98
2.80 3.38 165 207 370.77 371.04 2.85 2.78 3.21 + 166 208 405.22
405.21 2.99 2.80 3.26 + + + + 167 209 398.82 399.10 3.45 3.36 3.91
168 210 383.81 384.11 2.65 2.52 3.03 169 211 361.21 361.12 3.52
3.41 3.78 170 212 372.79 373.05 2.78 2.68 3.06 + + 171 213 416.84
417.30 3.08 2.96 3.61 172 214 366.79 367.07 2.79 2.66 3.31 + + +
173 215 384.84 385.21 3.56 3.48 3.92 + + 174 216 394.76 395.06 3.65
3.51 3.96 175 217 410.76 411.04 3.71 3.62 3.96 + + 176 218 410.76
411.01 3.73 3.62 4.12 + 177 219 384.84 385.22 3.58 3.46 3.82 + 178
220 362.74 363.29 3.43 3.33 3.72 + + + 179 221 370.81 371.10 3.42
3.31 3.76 180 222 370.81 371.06 3.32 3.21 3.71 181 223 382.87
383.20 3.91 3.75 4.14 182 224 424.79 425.00 3.55 3.46 3.72 183 225
446.31 446.12 3.38 3.28 3.61 + + + + 184 226 393.81 394.10 3.16
3.08 3.48 185 227 441.27 441.01 2.26 2.20 2.56 186 228 395.87
396.11 2.61 2.11 3.01 + 187 229 318.81 319.00 2.76 2.68 3.26 + 188
230 380.88 381.24 3.11 2.98 3.46 189 231 338.80 339.12 2.95 2.79
3.33 + 190 232 368.82 369.09 2.89 2.75 3.36 + 191 233 356.79 357.09
3.02 2.95 3.26 192 234 363.81 364.29 2.76 2.65 2.90 + 193 235
373.24 373.02 3.31 3.19 3.69 + 194 236 368.82 369.10 3.09 2.96 3.51
+ + 195 237 380.88 381.25 3.23 3.11 3.75 + + 196 238 368.82 369.09
2.98 2.86 3.35 + + 197 239 373.24 373.01 3.14 2.95 3.65 198 240
407.69 407.09 3.49 3.39 3.93 199 241 407.69 409.01 3.42 3.36 3.83 +
+ + + 200 242 417.69 419.04 3.35 3.19 3.85 201 243 363.81 364.29
2.99 2.92 3.32 + + + + 202 244 394.90 395.14 3.61 3.46 4.08 203 245
380.88 381.26 3.49 3.38 3.95 204 246 394.90 395.14 3.73 3.58 4.15 +
+ 205 247 420.94 421.17 3.96 3.73 4.35 206 248 366.85 367.09 3.09
2.95 3.51 + + + + 207 249 396.83 397.07 2.88 2.72 3.26 208 250
382.81 383.10 2.90 2.69 3.39 209 251 383.79 384.08 3.19 3.12 3.41
210 252 401.78 402.12 3.31 3.16 3.65 + + + + 211 253 383.79 384.09
3.29 3.18 3.56 212 254 403.27 403.27 3.15 3.06 3.45 + + + 213 255
406.79 407.15 3.46 3.36 3.93 + + 214 256 441.24 441.09 3.69 3.56
4.01 + 215 257 382.85 383.14 2.65 2.49 3.01 216 258 436.82 437.12
3.54 3.42 3.89 217 259 367.84 368.13 2.36 2.28 2.70 + 218 260
339.78 340.09 2.16 2.03 2.55 + + + + 219 261 339.78 340.11 2.09
2.03 2.42 + 220 262 381.87 382.16 2.22 2.16 2.63 221 263 409.92
410.21 2.32 2.26 2.69 222 264 423.90 424.12 2.36 2.29 2.69 223 265
353.81 354.15 2.23 2.13 2.51 + + + + 224 266 377.83 378.20 2.76
2.68 3.31 225 267 340.77 340.96 2.32 2.13 2.70 + + 226 268 418.68
420.00 3.23 3.15 3.63 + 227 269 442.23 442.16 3.15 2.96 3.39 228
270 367.84 368.15 2.39 2.13 2.66 229 271 374.23 374.08 2.86 2.76
3.25 230 272 369.81 370.12 2.56 2.49 2.93 + + 231 273 374.23 374.09
2.89 2.70 3.38 + 232 274 368.83 369.14 2.23 2.12 2.46 + 233 275
389.84 390.25 2.26 2.20 2.83 + + + + 234 276 455.95 456.21 3.58
3.43 3.95 + 235 277 345.81 345.95 2.70 2.63 2.98 + 236 278 388.86
389.31 3.35 3.23 3.79 + + + + 237 279 444.92 445.29 3.49 3.32 3.99
238 280 410.86 411.14 3.26 3.16 3.45 239 281 481.98 482.22 2.50
2.39 2.66 240 282 398.85 399.10 2.73 2.55, 3.16 + 241 283 382.81
383.10 2.63 2.52 3.03 + 242 284 417.25 417.27 2.79 2.69 3.29 + + +
+ 243 285 410.86 411.14 3.22 3.13 3.61 244 286 395.85 396.09 2.46
2.39 2.83 245 287 373.24 373.04 3.28 3.13 3.75 246 288 428.88
429.25 2.85 2.73 3.19 + + + + 247 289 378.82 379.25 2.59 2.36 3.06
+ + 248 290 398.25 398.03 3.31 3.22 3.72 + + + + 249 291 396.88
397.14 3.33 3.22 3.92 250 292 406.79 407.15 3.44 3.21 3.82 + + 251
293 422.79 422.95 3.48 3.39 3.85 252 294 422.79 422.95 3.52 3.42
3.92 + 253 295 396.88 397.14 3.32 3.22 3.82 + 254 296 374.78 375.08
3.19 3.08 3.59 + + + 255 297 382.85 383.14 3.18 3.09 3.62 256 298
382.85 383.15 3.09 2.96 3.56 + 257 299 394.90 395.15 3.68 3.58 4.18
258 300 436.82 437.12 3.35 3.25 3.79 + + 259 301 458.35 458.26 3.18
3.03 3.63 + 260 302 405.84 406.22 2.90 2.55 3.25 + + + 261 303
453.30 452.96 2.09 1.94 2.38 + 262 304 407.90 408.13 2.32 2.13 2.39
263 305 414.90 415.27 3.59 3.51 4.22 264 306 380.83 381.22 3.41
3.25 4.02 265 307 451.96 452.15 2.53 2.36 2.88 + 266 308 368.82
369.10 2.83 2.72 3.34 267 309 352.78 353.17 2.71 2.63 2.83 268 310
387.23 387.06 2.85 2.79 3.06 269 311 380.83 381.22 3.33 3.23 3.99 +
270 312 365.82 366.14 2.52 2.45 2.89 271 313 354.80 355.20 2.61
2.51 2.84 + 272 314 398.85 399.10 2.93 2.82 3.39 273 315 348.79
349.24 2.66 2.52 3.03 + + 274 316 366.85 367.09 3.45 3.35 4.01 +
275 317 376.77 377.26 3.55 3.42 4.18 276 318 392.77 393.09 3.58
3.48 4.01 + 277 319 392.77 393.06 3.64 3.37 4.20 + 278 320 366.85
367.10 3.45 3.25 4.08 + 279 321 344.75 345.01 3.32 3.08 3.86 + 280
322 352.82 353.23 3.31 3.11 3.75 281 323 352.82 353.21 3.16 3.09
3.36 + 282 324 364.88 365.09 3.81 3.66 4.34 283 325 406.79 407.17
3.46 3.35 3.84 284 326 428.32 428.12 3.26 3.16 4.17 + + + 285 327
375.82 376.16 3.02 2.95 3.29 286 328 423.28 422.93 2.10 2.03 2.42
287 329 377.88 378.24 2.29 2.07 2.49 + 288 330 351.84 352.18 3.51
3.44 3.72 289 331 309.76 310.14 3.35 3.26 3.54 + + + + 290 332
339.78 340.07 3.31 3.21 3.39 291 333 327.75 328.18 3.41 3.29 3.65 +
292 334 334.77 335.24 3.41 3.25 3.75 + 293 335 344.20 344.05 3.72
3.66 3.91 294 336 339.78 340.07 3.58 3.45 3.75 295 337 351.84
352.16 3.98 3.88 4.48 296 338 339.78 340.08 3.38 3.29 3.63 297 339
344.20 344.04 3.95 3.86 4.22 + + + + 298 340 388.65 390.11 3.79
3.71 4.01 299 341 334.77 335.24 3.28 3.19 3.51 + + + + 300 342
365.87 365.89 4.11 4.02 4.22 301 343 351.84 352.15 3.98 3.78 4.28
302 344 365.87 366.11 4.11 3.99 4.44 + + + 303 345 391.90 392.13
4.52 4.36 4.89 + + + + 304 346 337.81 338.21 3.73 3.68 3.95 305 347
367.79 368.07 3.23 3.16 3.53 306 348 353.77 307 349 374.23 374.05
3.53 3.41 3.73 308 350 377.76 378.12 3.82 3.75 4.02 + 309 351
412.20 414.31 3.56 3.51 3.78 310 352 353.81 311 353 407.78 408.13
3.86 3.79 4.06 + 312 354 338.80 339.10 2.43 2.15 2.79 + 313 355
310.75 311.21 2.15 2.10 2.26 + + + 314 356 310.75 311.20 2.09 2.00
2.45 315 357 352.83 353.20 2.36 2.19 2.63 316 358 380.88 381.22
2.48 2.36 2.66 317 359 394.86 395.04 2.55 2.35 2.86 + 318 360
324.77 325.23 2.30 2.23 2.70 + 319 361 311.73 312.08 2.64 2.52 2.79
+ + + + 320 362 378.74 379.16 3.92 3.84 4.11 321 363 413.19 412.97
3.58 3.49 3.89 322 364 338.80 339.06 2.51 2.25 2.63 323 365 345.19
344.94 3.12 2.86 3.36 324 366 340.77 340.95 2.82 2.61 3.23 + + 325
367 345.19 344.92 3.18 2.98 3.41 + 326 368 339.79 340.08 2.36 2.13
2.79 + 327 369 360.81 361.08 2.38 2.07 2.66 + 328 370 426.91 426.98
4.08 3.99 4.49 + + + + 329 371 299.72 300.05 2.35 2.22 2.70 330 372
316.77 316.95 2.86 2.76 3.11
331 373 359.82 360.09 3.85 3.71 4.24 + + 332 374 415.88 416.23 3.88
3.78 4.28 + 333 375 381.82 382.10 3.65 3.55 3.86 + 334 376 452.94
453.04 2.69 2.52 2.78 335 377 369.81 370.08 3.08 2.88 3.79 336 378
381.82 382.11 3.59 3.48 3.88 337 379 366.81 366.98 2.69 2.49 3.12
338 380 355.78 356.10 2.82 2.55 3.12 + + 339 381 399.84 400.09 3.15
2.89 3.36 + 340 382 349.78 350.17 2.89 2.55 3.13 + + + + 341 383
367.84 368.10 3.75 3.58 4.08 + 342 384 377.76 378.12 3.79 3.51 4.02
343 385 393.76 394.08 3.83 3.73 4.05 + 344 386 393.76 394.06 3.86
3.73 4.24 + + 345 387 367.84 368.08 3.74 3.45 4.04 + 346 388 345.74
345.86 3.55 3.41 3.79 + + + + 347 389 353.81 354.12 3.61 3.45 3.95
+ + + + 348 390 353.81 354.11 3.51 3.36 3.85 349 391 365.87 366.11
4.16 3.95 4.51 350 392 407.78 408.09 3.66 3.43 3.95 351 393 429.31
429.06 3.58 3.39 3.79 352 394 424.26 423.90 2.20 2.12 2.39 353 395
378.86 379.24 2.68 2.28 3.03 354 396 342.32 343.10 3.19 2.99 3.58
355 397 413.45 414.14 2.49 2.20 2.96 356 398 372.35 373.06 3.22
3.01 3.75 357 399 427.43 428.13 2.53 2.38 2.93 358 400 376.77
377.25 3.51 3.25 3.92 359 401 406.79 407.16 3.38 3.21 3.88 360 402
410.32 411.07 3.65 3.51 3.95 361 403 444.77 445.18 3.83 3.56 4.26
362 404 398.43 399.18 3.79 3.59 4.15 363 405 384.40 385.26 3.68
3.55 4.15 364 406 398.43 399.17 3.91 3.78 4.35 365 407 440.35
441.22 3.70 3.55 4.07 366 408 400.36 401.10 3.13 3.00 3.66 367 409
422.21 421.94 3.43 3.19 3.82 368 410 411.31 412.10 3.53 3.31 3.91
369 411 377.76 378.16 3.11 2.98 3.52 370 412 373.34 374.11 2.78
2.55 3.19 371 413 377.76 378.15 3.15 2.93 3.65 372 414 410.32
411.07 3.63 3.42 3.96 373 415 426.32 426.99 3.67 3.52 4.01 374 416
398.43 399.16 3.86 3.55 4.38 375 417 440.35 441.20 3.53 3.33 3.99
376 418 395.39 377 419 360.31 361.22 3.31 3.11 3.62 378 420 431.44
432.27 2.59 2.17 2.99 379 421 390.34 391.27 3.35 3.23 3.53 380 422
445.42 446.16 2.66 2.53 3.08 381 423 394.76 395.03 3.58 3.45 3.91
382 424 424.79 424.99 3.45 3.11 3.92 383 425 428.31 429.13 3.72
3.33 4.01 384 426 462.76 463.12 3.93 3.66 4.19 385 427 416.42
417.32 3.86 3.65 4.42 386 428 402.40 403.31 3.78 3.62 4.26 387 429
416.42 417.32 4.01 3.85 4.68 388 430 458.34 459.23 3.78 3.59 4.21
389 431 418.35 419.13 3.21 3.08 3.42 390 432 440.20 442.12 3.55
3.24 3.87 391 433 429.30 430.15 3.63 3.26 4.05 392 434 395.75
396.07 3.22 3.05 3.56 393 435 391.33 392.11 2.93 2.63 3.33 394 436
395.75 396.07 3.22 3.02 3.69 395 437 428.31 429.12 3.68 3.55 4.04
396 438 444.31 445.19 3.73 3.61 4.18 397 439 416.42 417.31 3.93
3.66 4.55 398 440 458.34 459.22 3.58 3.32 3.99 399 441 413.38
414.12 3.34 3.18 3.46 400 442 441.94 401 443 457.94 402 444 459.91
403 445 441.48 For purposes of the Table 1, activity of each
compound is expressed as follows: "+" compound exhibited 0-25%
inhibition of calcium ion influx induced by capsaicin stimulation.
"+ +" compound exhibited 25-50% inhibition of calcium ion influx
induced by capsaicin stimulation. "+ + +" compound exhibited 50-75%
inhibition of calcium ion influx induced by capsaicin stimulation.
"+ + + +" compound exhibited 75% or greater inhibition of calcium
ion influx induced by capsaicin stimulation. Compounds with a
percent inhibition represented by "+ + + +" are of particular
interest. Compound 18 is especially of interest.
EXAMPLE 3
High Throughput Screening of VR1 Antagonists for Determination of
In Vitro Efficacy Using a Calcium Imaging Assay
[0297] VR1 protein is a heat-gated cation channel that exchanges
about 10 calcium ions for every sodium ion resulting in neuronal
membrane depolarization and elevated intracellular calcium ion
levels. Therefore the functional activity of compounds at the VR1
receptor may be determined by measuring changes in intracellular
calcium levels in 293 cells expressing capsaicin-insensitive VR1
receptor variants. A dual wavelength ratiometric dye, Fura2, was
used as an indicator of relative levels of calcium ions in a 96
well format using a bench top scanning fluorometer with integrated
fluidics and temperature control (Flex Station, Molecular
Devices).
[0298] A dual wavelength ratiometric dye, Fura2, was used as an
indicator of relative levels of [Ca2+] in a 96 well format using a
bench top scanning fluorometer with integrated fluidics and
temperature control (Flex Station, Molecular Devices).
[0299] 293 cells were grown on PDL coated 96-well black-walled
plates, in the presence of a DMEM medium containing 5% Penstrep, 5%
Glutamax, 200 ug/mL Hygromycin, 5 .mu.g/mL Blasticide and 10% heat
inactivated FBS. Prior to assay, the cells were loaded with 5
.mu.g/mL Fura2 in normal saline solution at 37.degree. C. for 40
minutes. Cells were then washed with normal saline to remove the
dye.
[0300] The assay consists of two stages; a pre-treatment phase
followed by a treatment phase.
[0301] 50 .mu.l of a compound solution was added to the cells
(Pre-treatment). Immediately following, 50 .mu.l of the test
compound in a saline solution at pH 5.1 was added. Fura2 was
excited at 340 and 380 nM to indicate relative calcium
concentration. Changes in wavelength measurements were made
throughout the course of the experiment in 4 second intervals over
a period of 3 minutes. Responses were measured as peak fluorescence
ratio after test compound addition minus baseline fluorescence
ratio prior to pre-treatment and were calculated using SoftMaxPro
softwareData were expressed as percentage inhibition calculated
using Excel as follows: 1 Percentage Inhibition = ( Compound
Response ) - ( Control Response ) ( Agonist Response - Control
Response ) .times. 100
[0302] All compounds with percentage inhibition values greater than
75% are considered hits and earmarked for further investigation at
lower concentrations. The relative strengths of the percentage
inhibition values are set forth in Table 1.
EXAMPLE 4
Whole-cell Patch Clamp Electrophysiology
[0303] Dorsal root ganglion (DRG) neurons were recovered from
either neonatal or adult rats and plated onto poly-D-lysine coated
glass coverslips. The plated neurons were transferred into a
chamber to allow drug solutions to be added to the cells using a
computer-controlled solenoid-valve based perfusion system. The
cells were imaged using standard DIC optics. Cells were patched
using finely-pulled glass electrodes. Voltage-clamp
electrophysiology experiments were carried out using an Axon
Instruments Multiclamp amplified controlled by pCLAMP8
software.
[0304] The cells were placed into a whole-cell voltage clamp and
help at a voltage of -80 mV while monitoring the membrane current
in gap-free recording mode. 500 nM capsaicin was added for 30
seconds as a control. Test compounds at various concentrations at
ranging from (10-1000 nM) were added to the cells for 1 minute
prior to a 30 second capsaicin application. Differences between
control experiments and drug positive capsaicin experiments were
used to determine the efficacy of each test compound. All compounds
that inhibited capsaicin induced current greater than 50% were
considered positives. The data obtained for compounds 24 and 18 are
set forth in Table 2, below. FIG. 3 represents a dose response
curve demonstrating the increasing effectiveness of compound 18 in
inhibiting a capsaicin induced calcium ion influx at higher
concentrations tested, namely 50 nM, 100 nM and 250 nM. Likewise,
FIG. 4 represents a dose response curve demonstrating the
increasing effectiveness of Compound 24 in inhibiting a capsaicin
induced calcium ion influx at higher concentrations tested, namely
20 nM, 40 nM, 100 nM and 200 nM.
2TABLE 2 % inhibition of Treatment time capsaicin induced Compound
ID Concentration (seconds) current 24 200 nM 25 100 18 100 nM 20
<75
[0305] FIG. 1 demonstrates the activity of the compounds tested in
inhibiting the capsaicin induced current.
EXAMPLE 5
Plasma Extravasation Study: A Measure of Neurogenic
Inflammation
[0306] The density of TRPV1 expression is enhanced during an
inflammatory condition. Therefore TRPV1 antagonists have been
investigated in three different models of inflammatory pain, namely
plasma extravasation, paw lick assay, and thermal hyperalgesia.
[0307] Methods
[0308] Sprague-Dawley male rats obtained from Charles River, San
Diego, Calif. were dosed with compound 18. Two hours later, they
were injected with Evan's Blue (10 ml/kg or 150 .mu.l). Thirty
minutes after I.V. injection, 10 .mu.l of 25 mM capsaicin in 100%
ethanol was applied to the left ear of the animal, followed by 10
.mu.l vehicle (100% EtOH) to the right ear of the mouse. Fifteen
minutes later, the animal was sacrificed using CO.sub.2. Each ear
was removed, placed into labeled tubes and weighed. The dye was
then extracted from the ears by drying the ears at 55-60.degree.
overnight. The following day, 250 .mu.l formamide was added and
left at 55-60.degree. overnight.
[0309] An Evans blue standard curve was first generated (2.5, 5,
10, 20, 40, and 80 mg/.mu.l). Samples (with ears) were spun for at
least 1 minute before addition of 100 .mu.l of each sample to
appropriate wells. Samples were analyzed in a plate holder by
SOFTmax PRO. Standards were graphed to generate a standard curve
and then used to extrapolate Evans Blue concentrations of
experimental samples.
[0310] Results
[0311] Compound 18 at a dose of 30 mg/kg significantly blocks
capsaicin induced plasma extravasation in rats. FIG. 2 demonstrates
the results in .mu.g EB/mg tissue (Evans Blue). The results are
represented for the delivery vehicle HPBCD, control compound BCTC,
Compound 18 at two concentrations and capsaicin alone in
vehicle.
EXAMPLE 6
Paw Lick Assay
[0312] This assay was performed to test the ability of Compound 18
to inhibit the response to capsaicin challenge.
[0313] Methods
[0314] Animals were acclimatized at least 2 days prior to testing
by placing them in a behavioral chamber for one hour. On the day of
testing, animals were trained for 30-60 minutes prior to dosing.
Animals were dosed with 30 mg/kg of Compound 18 at least 30 minutes
prior to testing and then placed in behavioral chambers for
acclimatization. Animals were then placed into a falcon tube
restrainer and injected with a 0.16 mg/ml capsaicin solution (or
vehicle) into the plantar surface of their paw. Animals were then
returned to the behavior chamber and monitored for paw licking
behavior (including paw and leg licking behavior) over the next 5
minute interval.
[0315] Results
[0316] Compound 18 (30 mg/kg) significantly inhibited pawlick
response induced by treatment with capsaicin. FIG. 5 demonstrates
the pawlick times per second when a delivery vehicle is
administered alone, capsaicin is administered, capsaicin is
administered with a control compound, and capsaicin is administered
with Compound 18.
EXAMPLE 7
Thermal Hyperalgesia
[0317] Sprague-Dawley male rats obtained from Charles River, San
Diego, Calif. were purchased at 150-175 g, and held for at least
one week before testing. Pain was induced by injecting 100 .mu.l of
2% carrageenan in 0.9% saline sub-Q into the right ventral hindpaw
while the animals were under isofluorane anesthesia. Animals were
then dosed one hour after with different concentrations of Compound
18 (3, 10, and 30 mg/kg). Two hours later, after acclimatizing in
testing chambers for 20-30 minutes, animals were tested on both
hindpaws for latency of paw withdrawal using a thermal testing
apparatus. 2-3 trials were conducted with 10 minutes between
trials. As demonstrated in FIG. 6, a dose of Compound 18 at 30
mg/kg significantly increased latency of paw withdrawal
demonstrating reversal of thermal hyperalagesia. The figure depicts
the time in seconds until animals withdraw from thermal stimulation
at baseline and two hours after administration of delivery vehicle,
control compound, and three concentrations of Compound 18.
EXAMPLE 8
Pharmacokinetic Profile
[0318] The pharmacokinetic profile of Compound 18 was evaluated
following intravenous and oral administration in rats.
Sprague-Dawley male rats obtained from Charles River, San Diego,
Calif. were acclimated for 24 hours.
[0319] Compound 18 was formulated at a concentration of 0.5 mg/mL
for IV administration at a 1 mg/kg dose and 1 mg/mL for oral
administration at a 5 mg/kg dose. All animals were weighed before
dosing. The body weight was used to calculate the actual dose for
each animal. The intravenous dose was administered through the
jugular vein catheter in less than 1 minute. The oral dose volume
was 1.5 ml for all PO rats administered through oral lavage.
[0320] For IV dosing, blood samples were collected using a
pre-heparinized syringe via the carotid artery catheter before
dosing and at t=2, 5, 15, 30, 60, 120, 180, 360, and 480 minutes
post dosing. For PO dosing, blood samples were collected using a
pre-heparinized syringe via the carotid artery catheter before
dosing and at t=5, 15, 30, 60, 120, 180, 360, and 480 minutes post
dosing. 250 uL of blood was obtained at each time point from each
animal. Equal volumes of 0.9% normal saline were replaced to
prevent dehydration. The whole blood samples were maintained on ice
until centrifugation. Blood samples were centrifuged at 14,000 rpm
for 10 minutes at 4.degree. C., and the upper plasma layer was
transferred into a clean vial and store at -80.degree. C.
[0321] The plasma was analyzed. Compound 18 demonstrates Oral
Bioavailability (%F) of 30.06%, a half life (t1/2) of 3.71 hours,
Clearance (Cl) of 0.53 L/h/Kg, a Volume of distribution (Vd) of
2.82 L/Kg, a Tmax of 180 minutes, and a Cmax of 1.75 mM.
EXAMPLE 9
Aqueous Solubility
[0322] Equilibrium solubility was measured in a pH 2.0 isotonic
solution of NaCl/HCl and a pH 7.4 aqueous buffer. The pH 2.0
solution was prepared by adjusting the saline solution to a pH of
2.0 using HCl. The pH 7.4 buffer was prepared by adjusting the pH
of a 0.07 M solution of NaH.sub.2PO.sub.4 to pH 7.4 with 10 N NaOH.
Each buffer had an ionic strength of 0.15. At least 1 mg of powder
was combined with 1 ml of buffer to make .gtoreq.1 mg/ml mixture.
This sample was shaken for .gtoreq.2 hours and left to stand
overnight at room temperature. The samples were then filtered
through a 0.45-.mu.m Nylon syringe filter that was first saturated
with the sample. The filtrate was sampled twice, consecutively. All
samples were assayed by LC/MS using electrospray ionization. The
typical range of the assay is greater than 1 mg/mL to less than
0.0002 mg/mL, depending on analytical sensitivity. The results
demonstrated solubility of <0.0002 mg/ml at pH 2.0 and low
solubility at pH 7.4.
[0323] The partition coefficient, Log(D), between water-saturated
1octanol and pH 7.4 buffer was determined for Compound 18. The pH
7.4 buffer was prepared by adjusting the pH of a 0.07 M solution of
NaH.sub.2PO.sub.4 to pH 7.4 with 10 N NaOH. 15 .mu.L of a 10 mM
stock solution of test article were pipetted in duplicate, into
test tubes containing 750 .mu.L each of 1-octanol and pH 7.4
buffer. Then 3 .mu.L of 50 mM testosterone was also added to each
tube. Then the tubes were rotated for about one hour using a
benchtop rotator. Following the rotation, the tubes sat on the
bench top for about 1 hour to allow the layers to separate.
[0324] Thereafter, 400 .mu.L of the octanol (top) layer was removed
and placed into a test tube. Next 400 .mu.L of the aqueous (bottom)
layer was removed and placed into a test tube. The following serial
dilutions were then made of each layer using 50% methanol as the
diluent: Octanol--100.times., 1000.times., and 10,000.times.
Aqueous--1.times., 10.times., & 100.times.. The 100.times.,
1000.times. and 10,000.times. diluted octanol samples and the
undiluted, 10.times. and 100.times. diluted aqueous samples were
then aliquoted into appropriate vials.
[0325] A standard curve of test article and testosterone was
prepared using 50% methanol at the following concentrations: 2,
0.6, 0.2, 0.06, 0.02, 0.006, and 0.002 .mu.M. The samples were
analyzed by LC/MS monitoring both test article and testosterone.
Log (D) was calculated for each duplicate sample by taking the
calculated concentration of the least diluted sample for each phase
that fell within the standard curve using the following equation:
Log(D)=Log10(Calc. Conc. in Organic Phase/Calc. Conc. in Aqueous
Phase). The results demonstrated Log (D) values at pH 7.4 of less
than 4.7 for Compound 18.
EXAMPLE 10
Analysis of Plasma Protein Binding
[0326] Membranes from Harvard/Amika with a molecular weight cutoff
of 5,000 were rinsed with dH.sub.2O then placed in pH 7.4 PBS
supplied by Gibco. The membranes were allowed to soak for 1 hour. A
stock of the test article was pooled with Warfarin, Atropine at 2
mM in DMSO. The test article was then dosed into human plasma in
sodium citrate, Rat Plasma, and Mouse Plasma to a final 10 .mu.M
concentration (0.5% DMSO v/v). The pre-soaked membranes were then
placed into dialysis chambers. 500 .mu.L of PBS was added to one
side of the chamber, and 500 .mu.L of the Matrix containing the
test article was added to the other side of the chamber.
[0327] The chambers were then placed into an enclosed, heated
rocker, which was pre-warmed to 37.degree. C. and allowed to reach
equilibrium for at least 22 hours. After 22 hours both sides were
sampled. 100 .mu.L of the donor side was added to 500 .mu.L of PBS.
100 .mu.L of the PBS side was added to 20 .mu.L of fresh matrix.
Samples then were crashed with 1:1 Acetonitrile and centrifuged at
10,000 RPM for 10 minutes. 100 .mu.L of supernatant was placed into
LC/MS vials for analysis.
[0328] Standards were prepared in a 1:5 plasma:PBS mixture at 5,
1.5, 0.5, 0.15, 0.05, 0.015 and 0.005 .mu.M concentrations. The
samples and standards were placed into HPLC vials and assayed by
LC/MS. Protein binding values were calculated as follows:
% Bound=[(Concentration in Donor-Concentration in
Receiver)/(Concentration in Donor)].times.100.
% Recovery=[(Concentration in donor+Concentration in
Receiver)]/(Concentration in Normal Initial)].times.100
[0329] Compound 18 had high human plasma protein binding of more
than 99.8%. Compound 18 protein binding in rat and mouse plasma
could not be established due to low recovery of the test
article.
EXAMPLE 11
Cytochrome p450 Inhibition Assessment
[0330] The ability of test compounds to inhibit five major human
cytochrome p450 isozymes was evaluated. Cytochrome p450 inhibition
assays were performed on 96-well microtiter assay plates according
to the protocols described in Gentest P450 inhibition instruction
manuals. The assays were performed in duplicate at 8 concentrations
with the upper concentration of 100 .mu.M followed by a 1:3 serial
dilution. Reactions were initiated by the addition of 100 .mu.L of
enzyme/substrate mix to 100 .mu.L of cofactor/serial dilution mix,
and terminated by addition of 75 .mu.L of a 4:1 acentonitrile: 0.5
M Tris base solution or by 2N NaOH for CYP3A4/DBF. Fluorescence was
measured using a fluorescence plate reader (FLUOstar model 403, BMG
Lab Technologies, Durham, N.C.). For reactions with inhibition
greater than 50%, IC.sub.50 values were determined by fitting the
data to the Hill equation using software GraphPad Prism (Version
4.02, GraphPad Software, San Diego, Calif.).
[0331] Known CYP inhibitors inhibited respective CYP enzymes in the
expected manners, indicating that CYP enzymes were active and
responsive. Compound 18 did not significantly inhibit 2C9, CYP2D6
and CYP3A4 activities in the concentration range tested. It
inhibited CYP2C19 activity. The IC.sub.50 value was estimated to be
26.85 .mu.M. It also inhibited CYP1A2 activity with an estimated
IC.sub.50 of 97.45 .mu.M.
[0332] From the foregoing description, various modifications and
changes in the compositions and methods of this invention will
occur to those skilled in the art. All such modifications coming
within the scope of the appended claims are intended to be included
therein.
[0333] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
* * * * *