U.S. patent application number 11/750633 was filed with the patent office on 2007-10-04 for cyanoamidine p2x7 antagonists for the treatment of pain.
Invention is credited to William A. Carroll, Alan S. Florjancic, Sridhar Peddi, Arturo Perez-Medrano.
Application Number | 20070232686 11/750633 |
Document ID | / |
Family ID | 35219531 |
Filed Date | 2007-10-04 |
United States Patent
Application |
20070232686 |
Kind Code |
A1 |
Carroll; William A. ; et
al. |
October 4, 2007 |
Cyanoamidine P2X7 Antagonists for the Treatment of Pain
Abstract
Novel cyanoamidines compounds of formula (I) and (II) ##STR1##
and their derivatives wherein R.sub.1-R.sub.12 are as defined in
the specification act as antagonists of the P2X.sub.7 receptor.
These compounds are particularly useful in the treatment of pain,
inflammation and neurodegeneration states.
Inventors: |
Carroll; William A.;
(Evanston, IL) ; Perez-Medrano; Arturo;
(Grayslake, IL) ; Peddi; Sridhar; (Grayslake,
IL) ; Florjancic; Alan S.; (Kenosha, WI) |
Correspondence
Address: |
ROBERT DEBERARDINE;ABBOTT LABORATORIES
100 ABBOTT PARK ROAD
DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Family ID: |
35219531 |
Appl. No.: |
11/750633 |
Filed: |
May 18, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10909502 |
Aug 2, 2004 |
7241776 |
|
|
11750633 |
May 18, 2007 |
|
|
|
Current U.S.
Class: |
514/451 ;
514/579; 549/356; 558/300; 564/104 |
Current CPC
Class: |
C07D 215/12 20130101;
C07D 295/135 20130101; C07D 319/18 20130101; A61P 19/02 20180101;
A61P 25/28 20180101; A61P 29/00 20180101; C07C 261/04 20130101;
C07D 317/60 20130101; C07D 213/58 20130101 |
Class at
Publication: |
514/451 ;
514/579; 549/356; 558/300; 564/104 |
International
Class: |
A61K 31/16 20060101
A61K031/16; A61K 31/155 20060101 A61K031/155; A61K 31/17 20060101
A61K031/17; A61K 31/275 20060101 A61K031/275; C07C 255/00 20060101
C07C255/00; C07C 261/04 20060101 C07C261/04; C07C 277/02 20060101
C07C277/02; C07C 279/28 20060101 C07C279/28; C07D 309/00 20060101
C07D309/00 |
Claims
1. A method of a disorder selected from the group consisting of
pain, inflammation, arthritis, osteoarthritis, psoriasis, allergic
dermatitis, asthma, chronic obstructive pulmonary disease, airways
hyper-responsiveness, septic shock, glomerulonephritis, irritable
bowel disease, Crohn's disease, ulcerative colitis,
atherosclerosis, growth and metastases of malignant cells,
myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis,
osteoporosis, burn injury, ischemic heart disease, stroke,
neurodegeneration, and varicose veins in a mammal comprising
administering to the mammal a therapeutically effective amount of a
compound of formula (I) ##STR13## or a pharmaceutically acceptable
salt or prodrug thereof, wherein R.sub.1 is a bond or a chain
selected from the group consisting of alkyl, alkenyl, and alkynyl,
R.sub.2 is selected from the group consisting of aryl and
heteroaryl, wherein aryl and heteroaryl can be independently
substituted with 0, 1, 2, or 3 alkenyl, alkyl, alkynyl, halo,
haloalkyl, nitro, --C(O)--N--RaRb, --C(O)O--Ra, --C(O)--Ra,
--N--RaRb, alkyl-N--RaRb, --O--Ra, --OC(O)--Ra, alkyl-O--Ra,
--N--(Ra)--C(O)O--Rb, --N--(Ra)--C(O)N--RaRb, S--Ra, --S(O)--Ra,
--S(O).sub.2--Ra, S(O).sub.2--RaRb, wherein Ra and Rb are
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, aryl and arylalkyl; R.sub.3 is selected from the
group consisting of alkyl and haloalkyl, R.sub.4 is alkyl, and
R.sub.5 is selected from the group consisting of halogen, aryl, and
heteroaryl, wherein aryl, and heteroaryl can be independently
substituted with 0, 1, 2, 3 or 4 substituents independently
selected from alkenyl, alkyl, alkynyl, cyano, halo, haloalkyl,
nitro, ethylenedioxy, methylenedioxy, --C(O)NRaRb, --C(O)ORa,
--C(O)Ra, --NRaRb, alkylNRaRb, --ORa, --OC(O)Ra, alkylORa,
--N(Ra)C(O)ORb, --N(Ra)C(O)NRaRb, SRa, --S(O)Ra, --S(O).sub.2Ra,
S(O).sub.2RaRb, wherein Ra and Rb are independently selected from
the group consisting of hydrogen, alkyl, haloalkyl, aryl and
arylalkyl; and R.sub.6 and R.sub.7 are independently selected from
the group consisting of hydrogen and alkyl.
2. The method of claim 1, wherein the disorder is pain.
3. A compound of formula (II) ##STR14## or a pharmaceutically
acceptable salt or prodrug thereof, wherein R.sub.10 is a carbon
chain selected from the group consisting of alkyl, alkenyl, and
alkynyl, R.sub.11 is selected from the group consisting of aryl and
heteroaryl, wherein aryl and heteroaryl are independently
substituted with 0, 1, 2, 3 or 4 substituents independently
selected from alkenyl, alkyl, alkynyl, halo, haloalkyl, nitro,
--C(O)--N--RaRb, --C(O)O--Ra, --C(O)--Ra, --N--RaRb, alkyl-N--RaRb,
--O--Ra, --OC(O)--Ra, alkyl-O--Ra, --N--(Ra)--C(O)O--Rb,
--N--(Ra)--C(O)N--RaRb, S--Ra, --S(O)--Ra, --S(O).sub.2--Ra,
S(O).sub.2--RaRb, wherein Ra and Rb are independently selected from
the group consisting of hydrogen, alkyl, haloalkyl, aryl and
arylalkyl; R.sub.8 is a bond or a carbon chain selected from the
group consisting of alkyl, alkenyl, and alkynyl, wherein the carbon
chain can be substituted with 0, 1, or 2 substituents selected from
the group consisting of --NH.sub.2, --N(H)alkyl, --N(alkyl).sub.2,
and heterocycle; R.sub.9 is selected from the group consisting of
aryl and heteroaryl, wherein aryl and heteroaryl are independently
substituted with 0, 1, 2, 3 or 4 substituents independently
selected from alkenyl, alkyl, alkynyl, cyano, halo, haloalkyl,
nitro, heterocycle, --C(O)NRaRb, --C(O)ORa, --C(O)Ra, --NRaRb,
alkylNRaRb, --ORa, --OC(O)Ra, alkylORa, --N(Ra)C(O)ORb,
--N(Ra)C(O)NRaRb, SRa, --S(O)Ra, --S(O).sub.2Ra, S(O).sub.2RaRb,
wherein Ra and Rb are independently selected form the group
consisting of hydrogen, alkyl, haloalkyl, aryl and arylalkyl;
R.sub.12 is selected from the group consisting of hydrogen and
alkyl; alternatively, R.sub.12 and R.sub.8 together with the
nitrogen to which they are attached form a 4, 5, or 6 membered
heterocycle ring, or when R.sub.9 is aryl, R.sub.12 along with any
available carbon atom of R.sub.9 form a 5 or 6 membered heterocycle
ring, with the proviso that when R.sub.11 is unsubstituted aryl or
aryl substituted with 0, 1, 2, 3 or 4 halogen, and R.sub.12 is
selected from the group consisting hydrogen and alkyl, then R.sub.9
is not substituted pyridinyl.
4. The compound of claim 3, wherein R.sub.10 is alkyl, R.sub.11 is
aryl wherein aryl is phenyl substituted with 0, 1, 2, 3, or 4
substituents independently selected from the group consisting of
halo, alkyl, and haloalkyl. R.sub.8 is selected from the group
consisting of a bond and a carbon chain selected from the group
consisting of alkyl, alkenyl, and alkynyl, wherein the carbon chain
can be substituted with 0, 1, or 2 --NH.sub.2, --N(H)alkyl,
--N(alkyl).sub.2, or heterocycle, and R.sub.9 is aryl.
5. The compound of claim 3, wherein R.sub.8 is a carbon chain
selected from the group consisting of alkyl, alkenyl, and alkynyl,
wherein the carbon chain can be substituted with 0, 1, or 2
--NH.sub.2, --N(H)alkyl, --N(alkyl).sub.2, or morpholinyl, R.sub.9
is phenyl substituted with 0, 1, 2, 3, or 4, substituents
independently selected from the group of alkyl, halo and haloalkyl,
and, R.sub.11 is phenyl substituted with 0, 1, 2, 3, or 4,
substituents independently selected from the group of alkyl, halo
and haloalkyl.
6. The compound of claim 5, wherein the compound is selected from
the group consisting of
N'-cyano-2-(2-methylphenyl)-N-[(1R)-1-phenylethyl]ethanimidamide,
N'-cyano-2-(2-methylphenyl)-N-(1-methyl-1-phenylethyl)ethanimidamide,
N'-cyano-N-[(1R)-1-(4-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamid-
e,
N'-cyano-2-(2-methylphenyl)-N-[(1R)-1-phenylpropyl]ethanimidamide,
N'-cyano-N-[(1R)-1-(2-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamid-
e,
N'-cyano-N-[1-(3-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide,
N'-cyano-N-[1-(3,5-difluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamid-
e,
N'-cyano-N-[3-(4-methoxyphenyl)-1-methylpropyl]-2-(2-methylphenyl)etha-
nimidamide,
N'-cyano-2-(2-methylphenyl)-N-[(1R)-1-phenylpropyl]ethanimidamide,
N-[2-(2-chlorophenyl)-2-(dimethylamino)ethyl]-N'-cyano-2-(2-methylphenyl)-
ethanimidamide,
N'-cyano-N-[1-(4-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide,
N-[2-(2-chlorophenyl)ethyl]-N'-cyano-2-(2-methylphenyl)ethanimidamide,
N'-cyano-2-(2-methylphenyl)-N-(2-morpholin-4-yl-1-phenylethyl)ethanimidam-
ide,
N'-cyano-2-(2-methylphenyl)-N-[1-(2-morpholin-4-ylphenyl)ethyl]ethan-
imidamide, N'-cyano-N-(2-methylbenzyl)-3-phenylbutanimidamide, and
N'-cyano-N-[1-(3,5-difluorophenyl)ethyl]-2-[2-(trifluoromethyl)phenyl]eth-
animidamide.
7. The compound of claim 3, wherein R.sub.11 is aryl and, R.sub.9
is heteroaryl.
8. The compound of claim 7, wherein R.sub.9 is selected from the
group consisting of thienyl and pyridinyl.
9. The compound of claim 8, wherein the compound is selected from
the group consisting of
N'-cyano-2-(2-methylphenyl)-N-[(1R)-1-thien-2-ylethyl]ethanimidamide,
N'-cyano-2-(2-methylphenyl)-N-(1-pyridin-4-ylpentyl)ethanimidamide,
and
N'-cyano-2-(2-methylphenyl)-N-(1-pyridin-4-ylpropyl)ethanimidamide.
10. The compound of claim 3, wherein R.sub.11 is aryl, R.sub.8 is a
bond and, R.sub.9 is aryl.
11. The compound of claim 10 wherein R.sub.11 is phenyl substituted
with one alkyl group and R.sub.9 is selected from the group
consisting of 2,3-dihydro-indenyl, 1,2,3,4-tetrahydronaphthalenyl
and 1,2,3,4-tetrahydro-1,4-methanonaphthalenyl.
12. The compound of claim 11 wherein the compound is selected from
the group consisting of
N'-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(2-methylphenyl)ethanimidam-
ide,
N'-cyano-2-(2-methylphenyl)-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-y-
l]ethanimidamide,
N'-cyano-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(2-methylphenyl)ethanim-
idamide,
N'-cyano-N-(1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-
-methylphenyl)ethanimidamide,
N-(4-chloro-2,3-dihydro-1H-inden-1-yl)-N'-cyano-2-(2-methylphenyl)ethanim-
idamide,
N'-cyano-2-(2-methylphenyl)-N-[(1R,2R,4R)-1,2,3,4-tetrahydro-1,4-
-methanonaphthalen-2-yl]ethanimidamide,
N'-cyano-N-[(1S,2S,4S)-6,7-dimethoxy-1,2,3,4-tetrahydro-1,4-methanonaphth-
alen-2-yl]-2-(2-methylphenyl)ethanimidamide,
N'-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(2-fluorophenyl)ethanimidam-
ide, and
2-(2-chlorophenyl)-N'-cyano-N-(5-fluoro-2,3-dihydro-1H-inden-1-y-
l)ethanimidamide
13. The compound of claim 11, wherein
1,2,3,4-tetrahydronaphthalenyl can be substituted with 0, 1 or 2
substituents selected from the group consisting of alkyl and
alkoxy.
14. The compound of claim 3, wherein R.sub.11 is heteroaryl, and
R.sub.9 is aryl.
15. The compound of claim 14, wherein R.sub.11 is pyridinyl and
R.sub.9 is phenyl
16. The compound of claim 15, wherein the compound is selected from
the group consisting of
N'-cyano-2-(2-methylpyridin-3-yl)-N-[(1R)-1-phenylethyl]ethanimidamide,
N-[2-(2-chlorophenyl)ethyl]-N'-cyano-2-(2-methylpyridin-3-yl)ethanimidami-
de,
N'-cyano-2-(2-methylpyridin-3-yl)-N-[(1R)-1-phenylpropyl]ethanimidami-
de,
N'-cyano-N-[1-(3,5-difluorophenyl)ethyl]-2-(2-methylpyridin-3-yl)etha-
nimidamide, and
N'-cyano-N-[1-(3-fluorophenyl)ethyl]-2-(2-methylpyridin-3-yl)ethanimidami-
de.
17. The compound of claim 3, wherein R.sub.11 is heteroaryl,
wherein heteroaryl is pyridinyl, and R.sub.9 is aryl wherein aryl
is selected from the group consisting of 2,3-dihydro-indenyl and
1,2,3,4-tetrahydronaphthalenyl.
18. The compound of claim 17 wherein the compound is selected from
the group consisting of
N'-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(2-methylpyridin-3-yl)ethan-
imidamide,
N'-cyano-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(2-methylpyridin-3-yl)e-
thanimidamide, and
N'-cyano-2-(2-methylpyridin-3-yl)-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1--
yl]ethanimidamide.
19. The compound of claim 3, wherein R.sub.11 is heteroaryl wherein
heteroaryl is quinolinyl, and R.sub.9 is aryl, wherein aryl is
selected from the group consisting of 2,3-dihydro-indenyl and
1,2,3,4-tetrahydronaphthalenyl.
20. The compound of claim 19 wherein the compound is selected from
the group consisting of
N'-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-quinolin-5-ylethanimidamide
and
N'-cyano-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-2-quinolin-5-ylethanimid-
amide.
21. A method of treating a disorder selected from the group
consisting of pain, inflammation, rheumatoid arthritis,
osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic
obstructive pulmonary disease, airways hyper-responsiveness, septic
shock, glomerulonephritis, irritable bowel disease, Crohn's
disease, ulcerative colitis, atherosclerosis, growth and metastases
of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's
disease, meningitis, osteoporosis, burn injury, ischemic heart
disease, stroke, neurodegeneration and varicose veins in a mammal
comprising administering to the mammal a therapeutically effective
amount of a compound of formula (II) or a pharmaceutically
acceptable salt or prodrug thereof.
22. The method of claim 21 wherein the disorder is pain.
23. The method of claim 21 wherein the disorder is
inflammation.
24. The method of claim 21 wherein the disorder is
neurodegeneration
Description
[0001] This is a divisional of U.S. patent application Ser. No.
10/909,502, filed Aug. 2, 2004, incorporated herein by
reference.
TECHNICAL FIELD
[0002] The present invention relates to cyanoamidines of formula
(I) and (II) that are P2X.sub.7 antagonists and are useful for
treating pain, inflammation and neurodegeneration states.
BACKGROUND OF THE INVENTION
[0003] P2X receptors are ionotropic receptors activated by ATP. The
importance of P2X receptors in nociception is underscored by the
variety of pain states in which this endogenous ligand can be
released. Of the seven P2X receptors, the P2X.sub.7 is
distinguished by its ability to form a large pore upon prolonged or
repeated agonist stimulation. It is partially activated by
saturating concentrations of ATP, whereas it is fully activated by
the synthetic ATP analog benzoylbenzoic ATP (BzATP) (Bianchi et
al., Eur. J. Pharmacol. Vol. 376, pages 127-138, 1999). The
P2X.sub.7 receptor is expressed by presynaptic terminals in the
central and peripheral nervous systems, antigen-presenting cells
including macrophages, human epidermal Langerhans' cells,
microglial cells and a number of tumor cell lines of varying origin
(Jacobson K A, et al. "Adenosine and Adenine Nucleotides: From
Molecular Biology to Integrative Physiology". L. Belardinelli and
A. Pelleg (eds.), Kluwer, Boston, pages 149-166, 1995).
[0004] On glial cells, the P2X.sub.7 receptor has been shown to
mediate release of glutamate (Anderson C. et al., Drug Dev. Res.
Vol. 50 page 92, 2000). Since glutamate is known to be involved in
the neurotransmission of painful sensory signals, inhibition of
P2X.sub.7 may have therapeutic utility in the treatment of various
pain states. Furthermore, oxidized ATP (oATP), a nonselective and
irreversible P2X.sub.7 antagonist, was recently reported to possess
peripherally-mediated antinociceptive properties in inflamed rats
(Dell'Antonio et al., Neuroscience Lett. Vol. 327, pages 87-90,
2002). Thus, P2X.sub.7 antagonists may have utility in the
treatment of a variety of pain states.
[0005] Recent data also suggested a possible role for P2X.sub.7
receptor activation in neuroinflammation and neurodegeneration
(Collo G. et al., Neuropharmacology Vol. 36, pages 1277-1283,
1997). In the central nervous system, the P2X.sub.7 receptor is
predominately expressed by microglia, the resident macrophages of
the brain. Upregulation of the P2X.sub.7 receptor, most likely on
activated microglia, was reported at the site of cerebral ischemic
damage following middle cerebral artery occlusion in rat brain.
Thus, P2X.sub.7 antagonists may have utility in the treatment of
neurodegenerative conditions including stroke and Alzheimer's
disease.
[0006] Activation of the P2X.sub.7 receptor on cells of the immune
system (macrophages, mast cells and lymphocytes) leads to release
of interleukin-1.beta. (IL-1.beta.), giant cell formation,
degranulation, and L-selectin shedding. Compounds acting at the
P2X.sub.7 receptor may therefore have utility in the treatment of
various disease states and conditions such as rheumatoid arthritis,
osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic
obstructive pulmonary disease, airways hyper-responsiveness, septic
shock, glomerulonephritis, irritable bowel disease, Crohn's
disease, ulcerative colitis, atherosclerosis, growth and metastases
of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's
disease, meningitis, osteoporosis, burn injury, ischemic heart
disease, stroke and varicose veins.
[0007] Neuropathic pain is another type of pain different from pain
involved with inflammatory or neurodegenerative conditions.
Neuropathic pain is associated with any disorder affecting any
segment of the nervous system. Common causes of neuropathic pain
are, among others, alcoholism, amputation, cancer chemotherapy,
diabetes, trigeminal neuralgia, HIV infection, multiple sclerosis,
shingles and spine surgery. One of the most dramatic examples of
neuropathic pain is called "phantom limb syndrome" which occurs
when an arm or a leg have been removed, but the brain still gets
pain messages from the missing limb.
[0008] A recent study reported the localization of P2X.sub.7 on
presynaptic terminals in the central and peripheral nervous systems
(Deuchars et al., J. Neuroscience Vol. 21 pages 7143-7152, 2001)
where its activation was linked to release of the excitatory amino
acid neurotransmitter glutamate. A recent report suggests a link
between a P2X.sub.7 purinoceptor gene and chronic, inflammatory and
neuropathic pain (Hatcher et al., The 6th International Conference
on the Mechanisms and Treatment of Neuropathic Pain. San Fransisco,
Calif.--Sep. 18-20, 2003).
[0009] Overall, these findings indicate a role for the P2X.sub.7
receptor in the process of neuronal synaptic transmission and
therefore a potential role for P2X.sub.7 antagonists as novel
therapeutic tool to treat neuropathic pain.
[0010] In view of the above facts, there is a need for P2X.sub.7
antagonist that can be efficiently used in treating neuropathic
pain, chronic inflammatory pain, inflammation, and
neurodegenerative conditions (e.g. Alzheimer's disease).
SUMMARY OF THE INVENTION
[0011] The present invention discloses novel cyanoamidine compounds
that are P2X.sub.7 antagonists, a method of treating pain,
inflammation and neurodegeneration states, and pharmaceutical
compositions including these compounds. More particularly, the
present invention is directed to a compound having formula I,
##STR2## or a pharmaceutically acceptable salt or prodrug thereof,
wherein [0012] R.sub.1 is a bond or a chain selected from the group
consisting of alkyl, alkenyl, and alkynyl, [0013] R.sub.2 is
selected from the group consisting of substituted or unsubstituted
aryl and heteroaryl, [0014] R.sub.3 is selected from the group
consisting of alkyl and haloalkyl, [0015] R.sub.4 is alkyl, [0016]
R.sub.5 is selected from the group consisting of halogen, aryl, and
heteroaryl, and [0017] R.sub.6 and R.sub.7 are independently
selected from the group consisting of hydrogen and alkyl;
[0018] and to a compound having formula II, ##STR3## or a
pharmaceutically acceptable salt or prodrug thereof, wherein [0019]
R.sub.8 is a bond or a carbon chain selected from the group
consisting of alkyl, alkenyl, and alkynyl, [0020] R.sub.9 is
selected from the group consisting of aryl and heteroaryl, [0021]
R.sub.10 is a bond or a carbon chain selected from the group
consisting of alkyl, alkenyl, and alkynyl, [0022] R.sub.11 is
selected from the group consisting of aryl and heteroaryl, and
[0023] R.sub.12 is selected from the group consisting of hydrogen
and alkyl; alternatively, R.sub.12 and R.sub.8 together with the
nitrogen to which they are attached form a 4, 5, or 6 membered
heterocycle ring, or when R.sub.9 is aryl, R.sub.12 along with any
available carbon atom of R.sub.9 form a 5 or 6 membered heterocycle
ring, with the proviso that when R.sub.11 is unsubstituted aryl or
aryl substituted with 0, 1, 2, 3 or 4 halogen, and R.sub.12 is
selected from the group consisting hydrogen and alkyl, then R.sub.9
is not substituted pyridinyl.
DETAILED DESCRIPTION OF THE INVENTION
[0024] All patents, patent applications, and literature references
cited in the specification are herein incorporated by reference in
their entirety. In the case of inconsistencies, the present
disclosure, including definitions, will prevail.
[0025] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of use of the invention, may
be made without departing from the spirit and scope thereof.
(a) DEFINITION OF TERMS
[0026] As used throughout this specification and the appended
claims, the following terms have the following meanings.
[0027] The term "alkyl," as used herein, refers to a straight or
branched chain hydrocarbon containing from 1 to 10 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
1-ethylpropyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,
n-octyl, n-nonyl, n-decyl, and the like.
[0028] The term "alkenyl" as used herein, means a straight or
branched chain hydrocarbon containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0029] The term "alkynyl" as used herein, means a straight or
branched chain hydrocarbon group containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0030] The term "aryl" as used herein, refers to a phenyl group, or
a bicyclic hydrocarbon fused ring systems wherein one or more of
the rings is a phenyl group. Bicyclic fused ring systems have a
phenyl group fused to a monocyclic cycloalkenyl group, as defined
herein, a monocyclic cycloalkyl group, as defined herein, or
another phenyl group. Representative examples of aryl groups
include, but not limited to, indanyl (2,3-dihydro-indenyl),
indenyl, naphthalenyl, phenyl and tetrahydronaphthalenyl. The aryl
groups of the present invention can be connected to the parent
molecular moiety through any substitutable carbon atom of the
group. The aryl groups of the present invention can be substituted
with 0, 1, 2, 3 or 4 substituents independently selected from the
group consisting of alkenyl, --ORa, --C(O)ORa, alkylC(O)ORa, alkyl,
--C(O)Ra, alkylORa, --OC(O)Ra, alkylOC(O)Ra, --SRa, --S(O)Ra,
--S(O).sub.2Ra, --S(O).sub.2RaRb, alkynyl, --C(O)N RaRb, cyano,
ethylenedioxy, furyl, halo, haloalkyl, haloalkoxy, imidazolyl,
isothiazolyl, isoxazolyl, methylenedioxy, naphthyl, nitro, --NRaRb,
alkylNRaRb, --N(Ra)C(O)ORb, --N(Ra)C(O)NRaRb, oxadiazolyl,
oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl,
pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl,
thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl,
benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl,
benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl,
isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, and
quinolinyl, wherein said furyl, imidazolyl, isothiazolyl,
isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl,
pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl,
tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,
triazinyl, triazolyl, benzimidazolyl, benzothiazolyl,
benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl,
benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl,
isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl may be
substituted with 1 or 2 substituents independently selected from
alkenyl, --ORa, --C(O)ORa, alkylC(O)ORa, alkyl, --C(O)Ra,
--OC(O)Ra, alkylOC(O)Ra, --S(O)Ra, --S(O).sub.2Ra,
--S(O).sub.2NRaRb, alkynyl, --C(O)NRaRb, cyano, halo, haloalkyl,
haloalkoxy, nitro, --NRaRb, and (NRaRb)alkyl, wherein Ra and Rb are
independently selected from the group consisting of hydrogen,
alkyl, aryl, haloalkyl and arylalkyl. The bicyclic aryl ring
systems as defined herein may have two of the non-adjacent carbon
atoms connected by an alkylene bridge between one and three
additional carbon atoms. Representative examples of bicyclic aryl
ring systems that contain such connection between two non-adjacent
carbon atoms include, but not limited to,
1,2,3,4-tetrahydro-1,4-methanonaphthalenyl. The phenyl and bicyclic
aryl ring systems are connected to the parent molecular moiety
through any substitutable carbon atom of the system.
[0031] The term "arylalkyl," as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of arylalkyl include, but are not limited to, benzyl,
2-phenylethyl, 1,1-dimethyl-2-phenylethyl, 3-phenylpropyl,
2-naphth-2-ylethyl, and the like.
[0032] The term "cyano," as used herein, refers to a --CN
group.
[0033] The term "cycloalkyl," as used herein, refers to a
saturated, monocyclic hydrocarbon ring system having three to eight
carbon atoms and zero heteroatom. Examples of monocyclic ring
systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl.
[0034] The term "cycloalkenyl," as used herein, refers to a
non-aromatic, partially unsaturated, monocyclic, hydrocarbon ring
system, having four to seven carbon atoms and zero heteroatom. The
four-, five-, and six-membered rings have one or two double bonds,
the seven-membered rings have one, two or three double bonds.
Representative examples of cycloalkenyl groups include, but not
limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
[0035] The term "ethylenedioxy" as used herein, refers to a
--O(CH.sub.2).sub.2O-- group wherein the oxygen atoms of the
ethylenedioxy group are attached to the parent molecular moiety
through two adjacent carbon atoms of the parent molecular moiety,
forming a six membered ring.
[0036] The term "halo" or "halogen," as used herein, refers to
--Cl, --Br, --I or --F.
[0037] The term "haloalkyl," as used herein, refers to at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of haloalkyl include, but are not limited to, chloromethyl,
trichloromethyl, 1,1-dichloroethyl, 2-fluoroethyl, trifluoromethyl,
2,2,2-trifluoroethyl,
2,2,2-trifluoro-1-(trifluoromethyl)-1-(methyl)ethyl,
pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
[0038] The term "haloalkoxy," as used herein, refers to at least
one halogen, as defined herein, appended to the parent molecular
moiety through an alkoxy group, as defined herein.
[0039] The term "heteroaryl," as used herein, means an aromatic
monocyclic ring or an aromatic bicyclic ring. The aromatic
monocyclic rings are five or six membered rings containing 1, 2, 3,
or 4 heteroatoms independently selected from the group consisting
of N, O, and S. The nitrogen heteroatoms can be optionally
quaternized or oxidized to the N-oxide. The nitrogen containing
rings can be optionally N-protected. The five membered aromatic
monocyclic rings have two double bonds and the six membered
aromatic monocyclic rings have three double bonds. The aromatic
bicyclic rings are composed of an aromatic monocyclic ring fused to
a phenyl group. Alternatively, aromatic bicyclic rings are composed
of an aromatic monocyclic ring fused to another aromatic monocyclic
ring. The aromatic monocyclic rings and the aromatic bicyclic rings
are connected to the parent molecular moiety through a carbon or
nitrogen atom. Representative examples of heteroaryl include, but
are not limited to, benzothienyl, benzoxadiazolyl, cinnolinyl,
dibenzofuranyl, furopyridinyl, furyl, imidazolyl, indazolyl,
indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, pyrazolyl, pyridinium N-oxide, pyrrolyl, quinolinyl,
tetrazolyl, thiadiazolyl, thiazolyl, thienopyridinyl, thienyl,
triazolyl, and triazinyl.
[0040] The heteroaryl groups of the present invention are
substituted with 0, 1, 2, 3, or 4 substituents independently
selected from alkenyl, --ORa, alkylORa, --C(O)ORa, alkyl, --C(O)Ra,
--OC(O)Ra, --SRa, alkynyl, --C(O)O--, cyano, formyl, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,
--NR.sub.cR.sub.c and (NR.sub.cR.sub.d)carbonyl, wherein Rc and Rd
are independently selected from hydrogen, alkyl, --C(O)Ra, formyl,
aryl and arylalkyl. Representative examples include, but are not
limited to, 3-cyanopyridin-2-yl, 5-hydroxypyridin-2-yl, and
3-methylpyridin-2-yl.
[0041] The term "heterocycle" as used herein, refers to a
monocyclic or bicyclic, non-aromatic, saturated or partially
unsaturated ring system. Monocyclic ring systems are exemplified by
any 4-membered ring containing a heteroatom independently selected
from oxygen, nitrogen and sulfur; or a 5-, 6-, 7-, or 8-membered
ring containing one, two or three heteroatoms wherein the
heteroatoms are independently selected from nitrogen, oxygen and
sulfur. The 5-membered ring has 0 or 1 double bond. The 6-membered
ring has 0, 1 or 2 double bonds. The 7- or 8-membered ring has 0,
1, 2 or 3 double bonds. Representative examples of monocyclic ring
systems include, but are not limited to, azetidinyl, azepanyl,
azepinyl, diazepinyl, dioxolanyl, dioxanyl, dithianyl,
imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,
isoxazolinyl, isoxazolidinyl, morpholinyl, 3-oxo-morpholinyl,
oxadiazolinyl, oxadiazolidinyl, oxazolinyl, 2-oxo-oxazolinyl,
oxazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolinyl,
pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuryl,
tetrahydropyranyl, tetrahydropyridyl, tetrahydrothienyl,
thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,
thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine
sulfone), thiopyranyl, 1,4-diazepanyl and trithianyl. Bicyclic ring
systems are exemplified by any of the above monocyclic ring systems
fused to a phenyl group, a monocyclic cycloalkenyl group, as
defined herein, a monocyclic cycloalkyl group, as defined herein,
or an additional monocyclic heterocycle group, as defined herein.
Representative examples of bicyclic ring systems include but are
not limited to, benzodioxinyl, benzopyranyl, benzothiopyranyl,
2,3-dihydroindolyl, indolizinyl, pyranopyridinyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiopyranopyridinyl,
2-oxo-1,3-benzoxazolyl, 3-oxo-benzoxazinyl,
3-azabicyclo[3.2.0]heptyl, 3,6-diazabicyclo[3.2.0]heptyl,
octahydrocyclopenta[c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl,
and octahydropyrrolo[3,4-c]pyrrolyl. The monocyclic or bicyclic
ring systems as defined herein may have two of the non-adjacent
carbon atoms connected by a heteroatom selected from nitrogen,
oxygen or sulfur, or an alkylene bridge between one and three
additional carbon atoms. Representative examples of monocyclic or
bicyclic ring systems that contain such connection between two
non-adjacent carbon atoms include, but not limited to,
2-azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.2]octyl,
2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.1]heptyl,
2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl,
2-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl,
3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl,
8-azabicyclo [3.2.1]octyl, 3-azabicyclo[3.2.1]octyl,
1,4-diazabicyclo[3.2.2]nonyl,
1,4-diazatricyclo[4.3.1.1.sup.3,8]undecyl,
3,10-diazabicyclo[4.3.1]decyl, or 8-oxa-3-azabicyclo[3.2.1]octyl,
octahydro-1H-4,7-methanoisoindolyl, and
octahydro-1H-4,7-epoxyisoindolyl.
[0042] The heterocycle groups of this invention, including the
representative examples listed above, can be optionally substituted
with 1, 2, or 3 substituents independently selected from alkenyl,
--ORa, --C(O)ORa, -alkylC(O)ORa, alkyl, --CORa, --OC(O)Ra,
alkylOC(O)Ra, --S(O)Ra, --S(O).sub.2Ra, --S(O).sub.2NRaRb, alkynyl,
--C(O)NRaRb, cyano, halo, haloalkyl, haloalkoxy, nitro, --NRaRb,
and (NRaRb)alkyl, wherein Ra and Rb are independently selected from
the group consisting of hydrogen, alkyl, aryl, haloalkyl and
arylalkyl; furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl,
oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl,
pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl,
thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl,
benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl,
benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl,
naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl,
isoquinolinyl, and quinolinyl wherein said furyl, imidazolyl,
isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl,
pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl,
pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,
triazinyl, triazolyl, benzimidazolyl, benzothiazolyl,
benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl,
benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl,
isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl may be
substituted with 1 or 2 substituents independently selected from
alkenyl, --ORa, --C(O)ORa, alkylC(O)ORa, alkyl, --CORa, --OC(O)Ra,
alkylOC(O)Ra, --S(O)Ra, --SO.sub.2Ra, --SO.sub.2NRaRb, alkynyl,
--C(O)NRaRb, cyano, halo, haloalkyl, haloalkoxy, nitro, --NRaRb,
and (NRaRb)alkyl, wherein Ra and Rb are independently selected from
the group consisting of hydrogen, alkyl, aryl, haloalkyl and
arylalkyl. The heterocycle groups of this invention are connected
to the parent molecular moiety through any substitutable carbon or
nitrogen atom in the groups. The nitrogen heteroatom may or may not
be quaternized, and may or may not be oxidized to the N-oxide. In
addition, the nitrogen containing heterocyclic rings may or may not
be N-protected.
[0043] The term "hydroxyalkyl" as used herein means at least one
hydroxy group as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0044] The term "methylenedioxy" as used herein, refers to a
--O--CH.sub.2--O-- group wherein the oxygen atoms of the
ethylenedioxy group are attached to the parent molecular moiety
through two adjacent carbon atoms of the parent molecular moiety,
forming a five membered ring.
[0045] The term "nitro" as used herein, means a --NO.sub.2
group.
(b) EMBODIMENTS OF THE INVENTION
[0046] In its principal embodiment, the present invention discloses
a method for treating neuropathic pain in a mammal comprising
administering to the mammal a compound having formula (I) ##STR4##
or a pharmaceutically acceptable salt or prodrug thereof, in which
R.sub.1 is a bond or a chain selected from the group consisting of
alkyl, alkenyl, and alkynyl; R.sub.2 is selected from the group
consisting of aryl and heteroaryl, wherein aryl and heteroaryl can
be independently substituted with 0, 1, 2, or 3 alkenyl, alkyl,
alkynyl, halo, haloalkyl, nitro, --C(O)--N--RaRb, --C(O)O--Ra,
--C(O)--Ra, --N--RaRb, alkyl-N--RaRb, --O--Ra, --OC(O)--Ra,
alkyl-O--Ra, --N--(Ra)--C(O)O--Rb, --N--(Ra)--C(O)N--RaRb, S--Ra,
--S(O)--Ra, --S(O).sub.2--Ra, S(O).sub.2--RaRb, wherein Ra and Rb
are independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, aryl and arylalkyl; R.sub.3 is selected from the
group consisting of alkyl and haloalkyl; R.sub.4 is alkyl, and
R.sub.5 is selected from the group consisting of halogen, aryl, and
heteroaryl, wherein aryl, and heteroaryl can be independently
substituted with 0, 1, 2, 3 or 4 substituents independently
selected from alkenyl, alkyl, alkynyl, cyano, halo, haloalkyl,
nitro, ethylenedioxy, methylenedioxy, --C(O)NRaRb, --C(O)ORa,
--C(O)Ra, --NRaRb, alkylNRaRb, --ORa, --OC(O)Ra, alkylORa,
--N(Ra)C(O)ORb, --N(Ra)C(O)NRaRb, SRa, --S(O)Ra, --S(O).sub.2Ra,
S(O).sub.2RaRb, wherein Ra and Rb are independently selected from
the group consisting of hydrogen, alkyl, haloalkyl, aryl and
arylalkyl; and R.sub.6 and R.sub.7 are independently selected from
the group consisting of hydrogen and alkyl.
[0047] In another embodiment, the present invention relates to
compounds of formula (I), in which R.sub.1 is alkyl, and in which
both R.sub.2 and R.sub.5 are aryl.
[0048] In another embodiment, the present invention relates to
compounds of formula (I) in which R.sub.2 is phenyl and R.sub.5 can
be naphthyl, phenyl, 1,3-benzodioxolyl and
2,3-dihydro-1,4-benzodioxinyl. In a preferred embodiment R.sub.2 is
phenyl substituted with 0, 1, 2, or 3 alkyl, halo or haloalkyl
group. In a preferred embodiment, R.sub.5 is phenyl, which can be
independently substituted with 0, 1, 2, or 3, halo, --ORa,
methylenedioxy, ethylenedioxy, cyano, and --SRa group. In another
preferred embodiment, R.sub.5 is naphthyl. In yet another preferred
embodiment R.sub.5 is 1,3-benzodioxolyl or
2,3-dihydro-1,4-benzodioxinyl.
[0049] Another embodiment of the present invention relates to a
compound of formula (I) in which R.sub.1 is a bond, R.sub.2 is
phenyl substituted with 0, 1, 2, or 3 substituents selected from
the group consisting of alkyl, halo, and haloalkyl kyl. R.sub.5 can
be naphthyl or phenyl. In a preferred embodiment, R.sub.5 is
phenyl, which can be independently substituted with 0, 1, 2, 3, or
4 alkyl, halo, --ORa, --SRa, and cyano groups.
[0050] In yet another embodiment, the present invention relates to
a compound of formula (I) in which R.sub.1 is alkyl, R.sub.2 is
aryl and R.sub.5 is heteroaryl. In a preferred embodiment, R.sub.2
is phenyl substituted with 0, 1, 2, or 3 substituents selected from
the group consisting of alkyl, halo, and haloalkyl and R.sub.5 is
selected from the group of quinolinyl, thienyl and pyridinyl.
[0051] In yet another embodiment, the present invention discloses a
compound of formula (I) in which R.sub.1 is alkyl, R.sub.2 is aryl,
in which aryl is phenyl substituted with 0, 1, 2, or 3 substituents
selected from the group consisting of alkyl, halo, and haloalkyl,
R.sub.4 is alkyl and, R.sub.5 is halogen.
[0052] In yet another embodiment, the present invention discloses a
compound of formula (I) in which R.sub.2 is heteroaryl, wherein
heteroaryl can be selected form the group of pyridinyl and
quinolinyl, and R.sub.5 is aryl. In a preferred embodiment, R.sub.1
is alkyl, R.sub.2 is pyridinyl and R.sub.5 is aryl. In a most
preferred embodiment, R.sub.2 is pyridinyl substituted with 0, 1,
2, or 3 substituents independently selected from the group
comprising alkyl, halo, and haloalkyl, and R.sub.5 is phenyl, which
can be independently substituted with 0, 1, 2, 3, or 4 alkoxy and
halogen group.
[0053] Another embodiment of the present invention discloses a
compound of formula (I) in which R.sub.2 and R.sub.5 are both
heteroaryl groups. In a preferred embodiment, R.sub.1 is alkyl,
R.sub.2 is pyridinyl and R.sub.5 is quinolinyl. In a most preferred
embodiment, R.sub.2 is pyridinyl substituted with alkyl group.
[0054] In another preferred embodiment, the present invention
discloses a compound in which R.sub.1 is alkyl, R.sub.2 is
quinolinyl and R.sub.5 is phenyl, most preferably a phenyl
substituted with 0, 1, 2, 3, or 4 halogen group.
[0055] Another embodiment of the present invention relates to a
compound of formula (I) in which R.sub.1 is a bond, R.sub.2 is
quinolinyl and R.sub.5 is phenyl. In a most preferred embodiment,
R.sub.5 is phenyl substituted with 0, 1, 2, 3, or 4 alkoxy and
halogen group.
[0056] In yet another embodiment, the present invention relates to
a compound of formula (II) ##STR5## or a pharmaceutically
acceptable salt or prodrug thereof, wherein R.sub.10 is a carbon
chain selected from the group consisting of alkyl, alkenyl, and
alkynyl, R.sub.11 is selected from the group consisting of aryl and
heteroaryl, wherein aryl and heteroaryl are independently
substituted with 0, 1, 2, 3 or 4 substituents independently
selected from alkenyl, alkyl, alkynyl, halo, haloalkyl, nitro,
--C(O)--N--RaRb, --C(O)O--Ra, --C(O)--Ra, --N--RaRb, alkyl-N--RaRb,
--O--Ra, --OC(O)--Ra, alkyl-O--Ra, --N--(Ra)--C(O)O--Rb,
--N--(Ra)--C(O)N--RaRb, S--Ra, --S(O)--Ra, --S(O).sub.2--Ra,
S(O).sub.2--RaRb, wherein Ra and Rb are independently selected form
the group consisting of hydrogen, alkyl, haloalkyl, aryl and
arylalkyl; R.sub.8 is a bond or a carbon chain selected from the
group consisting of alkyl, alkenyl, and alkynyl, wherein the carbon
chain selected from the group consisting of alkyl, alkenyl, and
alkynyl, wherein the carbon chain can be substituted with 0, 1, or
2 substituents selected from the group consisting of --NH.sub.2,
--N(H)alkyl, --N(alkyl).sub.2, and heterocycle; R.sub.9 is selected
from the group consisting of aryl and heteroaryl, wherein aryl and
heteroaryl are independently substituted with 0, 1, 2, 3 or 4
substituents independently selected from alkenyl, alkyl, alkynyl,
cyano, halo, haloalkyl, nitro, heterocycle, --C(O)NRaRb, --C(O)ORa,
--C(O)Ra, --NRaRb, alkylNRaRb, --ORa, --OC(O)Ra, alkylORa,
--N(Ra)C(O)ORb, --N(Ra)C(O)NRaRb, SRa, --S(O)Ra, --S(O).sub.2Ra,
S(O).sub.2RaRb, wherein Ra and Rb are independently selected form
the group consisting of hydrogen, alkyl, haloalkyl, aryl and
arylalkyl; and R.sub.12 is selected from the group consisting of
hydrogen and alkyl; in an alternative embodiment, R.sub.12 and
R.sub.8 together with the nitrogen to which they are attached form
a 4, 5, or 6 membered heterocycle ring, or when R.sub.9 is aryl,
R.sub.12 along with any available carbon atom of R.sub.9 form a 5
or 6 membered heterocycle ring, with the proviso that when R.sub.11
is unsubstituted aryl or aryl substituted with 0, 1, 2, 3 or 4
halogen, and R.sub.12 is selected from the group consisting
hydrogen and alkyl, then R.sub.9 is not substituted pyridinyl.
[0057] In another embodiment of the present invention, a compound
of formula (II) is disclosed in which R.sub.10 is alkyl, R.sub.11
is aryl, and R.sub.8 is selected from the group consisting of a
bond and a carbon chain. In a preferred embodiment R.sub.10 is
phenyl substituted with 0, 1, 2, 3, or 4 substituents independently
selected from the group consisting of halo, alkyl, and haloalkyl.
In another preferred embodiment, R.sub.8 is a bond, and R.sub.9 is
aryl. In yet another embodiment, R.sub.8 is a carbon chain selected
from the group consisting of alkyl, alkenyl, and alkynyl, wherein
the carbon chain can be substituted with 0, 1, or 2 --NH.sub.2,
--N(H)alkyl, --N(alkyl).sub.2, or heterocycle, and R.sub.9 is
aryl.
[0058] In yet another embodiment, the present invention relates to
a compound of formula (II) in which R.sub.8 is a carbon chain
selected from the group consisting of alkyl, alkenyl, and alkynyl,
wherein the carbon chain can be substituted with 0, 1, or 2
--NH.sub.2, --N(H)alkyl, --N(alkyl).sub.2, or morpholinyl; R.sub.9
is phenyl substituted with 0, 1, 2, 3, or 4, substituents
independently selected form the group of alkyl, halo and haloalkyl,
and, R.sub.11 is phenyl substituted with 0, 1, 2, 3, or 4,
substituents independently selected form the group of alkyl, halo
and haloalkyl.
[0059] In yet another embodiment, the present invention relates to
a compound of formula (II) in which R.sub.9 is heteroaryl and
R.sub.11 is aryl. Most preferably, R.sub.9 is selected from the
group of thienyl and pyridinyl.
[0060] In another embodiment, the present invention relates to a
compound of formula (II), wherein R.sub.8 is a bond, R.sub.9 is
aryl and R.sub.11 is aryl. Most preferably, R.sub.9 is selected
from the group of 2,3-dihudro-indenyl,
1,2,3,4-tetrahydronaphthalenyl and
1,2,3,4-tetrahydro-1,4-methanopahthalenyl each independently
substituted with 1, 2, 3,or 4 halogen, alkyl, and alkoxy
groups.
[0061] In another embodiment, the present invention relates to a
compound of formula (II), wherein 1,2,3,4-tetrahydronaphthalenyl
can be substituted with 0, 1 or 2 substituents selected from the
group consisting of alkyl and alkoxy.
[0062] In another embodiment, the present invention relates to a
compound of formula (II) in which R.sub.11 is heteroaryl, and
R.sub.9 is aryl. In a preferred embodiment, R.sub.11 is pyridinyl
and R.sub.9 is phenyl In a most preferred embodiment, R.sub.11 is
pyridinyl substituted with alkyl, and R.sub.9 is phenyl substituted
with 0, 1, 2, 3, or 4 halogen, alkyl and alkoxy groups.
[0063] In yet another embodiment of the present invention relates
to a compound of formula (II) in which R.sub.8 is alkyl, R.sub.11
is quinolinyl and R.sub.9 is preferably selected from the group of
2,3-dihydro-indenyl and 1,2,3,4-tetrahydronaphthalenyl,
[0064] In another embodiment, the present invention relates to a
method of treating a disorder selected from the group consisting of
pain, rheumatoid arthritis, osteoarthritis, psoriasis, allergic
dermatitis, asthma, chronic obstructive pulmonary disease, airways
hyper-responsiveness, septic shock, glomerulonephritis, irritable
bowel disease, Crohn's disease, ulcerative colitis,
atherosclerosis, growth and metastases of malignant cells,
myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis,
osteoporosis, burn injury, ischemic heart disease, stroke and
varicose veins in a mammal comprising administering to the mammal a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt or prodrug thereof. In a most
preferred embodiment, the present invention relates to a method of
treating pain in a mammal comprising administering to the mammal a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt or prodrug thereof.
[0065] In yet another embodiment, the present invention relates to
a method of treating a disorder selected from the group consisting
of pain, rheumatoid arthritis, osteoarthritis, psoriasis, allergic
dermatitis, asthma, chronic obstructive pulmonary disease, airways
hyper-responsiveness, septic shock, glomerulonephritis, irritable
bowel disease, Crohn's disease, ulcerative colitis,
atherosclerosis, growth and metastases of malignant cells,
myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis,
osteoporosis, burn injury, ischemic heart disease, stroke and
varicose veins in a mammal comprising administering to the mammal a
therapeutically effective amount of a compound of formula (II) or a
pharmaceutically acceptable salt or prodrug thereof.
[0066] In yet another embodiment, the present invention relates to
a method of treating pain in a mammal comprising administering to
the mammal a therapeutically effective amount of a compound of
formula (II) or a pharmaceutically acceptable salt or prodrug
thereof.
(c) METHODS FOR PREPARING COMPOUNDS OF THE INVENTION
[0067] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes and methods, which illustrate a means by which the
compounds of the invention can be prepared.
[0068] The compounds of this invention may be prepared by a variety
of synthetic routes. Representative procedures are shown in Schemes
1-3. ##STR6##
[0069] Compounds of formula (3) can be prepared from the
corresponding carboxylic acids. Typically by reaction of compounds
of formula (1) with (a) thionyl chloride or oxalyl chloride,
optionally in the presence of dimethylformamide, at a temperature
from about 0.degree. C. to about 60.degree. C., in a solvent such
as, but is not limited to, dichloromethane, tetrahydrofuran,
chloroform or dioxane, for a period of about 1 hour to about 24
hours, and (b) reacting product from step (a) with an amine having
formula R.sub.7NH.sub.2 in a solvent such as, but not limited to,
tetrahydrofuran, dichloromethane, methanol, dioxane or water, at a
temperature from about 0.degree. C. to about 25.degree. C., for a
period of about 30 minutes to about 3 hours.
[0070] Alternatively, compounds of formula (3) can be prepared from
an ester having formula R.sub.5--R.sub.4--C(O)OR.sub.100, wherein
R.sub.100 is alkyl or aryl, preferably p-nitrophenyl, by reaction
with ammonia in a solvent such as, but is not limited to, methanol
or ethanol, at a temperature from about 20.degree. C. to about
80.degree. C., for a period of about 2 hours to about 120 hours.
The reaction is usually performed in a sealed container.
[0071] Alternatively, compounds of formula (3) can be prepared from
compounds of formula (1), by reaction with an amine of formula
R.sub.7NH.sub.2, in the presence of a coupling reagent, such as
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) or
dicyclohexyl carbodiimide (DCC) and hydroxybenzotriazole hydrate
(HOBT), and a base, such as diisopropylethylamine or triethylamine,
in an aprotic solvent, such as but not limited to, dichloromethane.
The reaction can be run at a temperature from about 0.degree. C. to
about 50.degree. C., for a period of about 1 hour to about 24
hours. ##STR7##
[0072] Compounds of formula (5) can be prepared from compounds of
formula (3) by reaction with aldehydes of formula (4) and
1H-1,2,3-benzotriazole in the presence of an acid such as, but not
limited to p-toluenesulfonic acid, pyridium p-toluensulfonate,
benzenesulfonic acid or camphorsulfonic acid in an organic solvent
such as, but not limited to, toluene, benzene or xylene. The
aforesaid reaction can be performed at about reflux temperature of
the solvent employed and preferably using Dean-Stark apparatus to
aid the removal of water. ##STR8##
[0073] Compounds of formula (6) can be converted to salts of imino
esters having formula (7) by reaction with dry hydrogen chloride
and an alcohol having formula R.sub.101OH, wherein R.sub.101 is
alkyl and preferably ethyl, in the absence of water. The reaction
can be performed neat or in the presence of an organic solvent such
as dichloromethane, at a temperature from about 0.degree. C. to
about 25.degree. C. for a period of about 12 hours to about 72
hours.
[0074] Compounds of formula (7) can be converted to compounds of
formula (8) by reaction with cyanamides of formula NH.sub.2CN, in
the presence of a base such as metal alkoxide having formula
MOR.sub.101 (for example sodium ethoxide, sodium methoxide,
potassium t-butoxide, and the like) wherein M is a monovalent
metal, in a solvent such as methanol or ethanol. The reaction can
be run at a temperature from about 20.degree. C. to about
60.degree. C. for a period of about 1 hour to about 24 hours.
[0075] Alternatively compounds of formula (8) can be prepared from
compounds of formula (6) directly by reaction with sodium cyanamide
in an alcoholic solvent having formula R.sub.101OH (for example
ethanol) at reflux temperature for about 1 hour to about 24 hours.
##STR9##
[0076] Compounds of formula (7A) can be prepared from compounds of
formula (7) by reaction with cyanamide and an alcohol having
formula R.sub.101OH in a solvent such as, but not limited to,
dichloromethane or diethyl ether, at a temperature from about
25.degree. C. to about 80.degree. C. for a period of about 1 hour
to about 24 hours. Compound of formula (7A) can be reacted with
amines of formula R.sub.6NH.sub.2 in an alcoholic solvent of
formula R.sub.101OH at a temperature from about 50.degree. C. to
about 100.degree. C. for a period of about 1 hour to about 24
hours, to afford compounds of formula (9). ##STR10##
[0077] Compounds of formula (10) can be prepared from compounds of
formula (9) by reaction with compounds of formula (5) in the
presence of an anhydrous base at a temperature from about
25.degree. C. to about 60.degree. C. for a period of about 5 hours
to about 24 hours. The reaction can be run in a solvent such as,
but not limited to dichloromethane, acetonitrile, toluene,
N,N,dimethyl formamide (DMF), dioxane, ethyl acetate or
dimethylsulfoxide. Examples of the anhydrous base include, but not
limited to, metal carbonates such as cesium carbonate, potassium
carbonate, organic amines such as imidazole, 1-methyl imidazole,
piperidine, pyrrolidine, triethylamine, diisopropylethyl amine, and
metal hydroxides such as lithium hydroxide. ##STR11##
[0078] Compounds of formula (12) wherein R.sub.101 is alkyl, can be
prepared from nitrites of formula (11) using the conditions for the
transformation of compounds of formula (6) to compounds of formula
(7) as described in Scheme 3.
[0079] Compounds of formula (13) can be prepared from compounds of
formula (12) by reaction with cyanamide and an alcohol having
formula R.sub.101OH in a solvent such as, but not limited to,
dichloromethane or diethyl ether, at a temperature from about
25.degree. C. to about 80.degree. C. for a period of about 1 hour
to about 24 hours. ##STR12##
[0080] Compound of formula (13) can be reacted with amines of
formula (14) in an alcoholic solvent of formula R.sub.101OH at a
temperature from about 50.degree. C. to about 100.degree. C. for a
period of about 1 hour to about 24 hours, to afford compounds of
formula (15).
(d) COMPOSITIONS OF THE INVENTION
[0081] The present invention provides pharmaceutical compositions,
which comprise compounds of the present invention formulated
together with one or more non-toxic pharmaceutically acceptable
carriers. The pharmaceutical compositions can be formulated for
oral administration in solid or liquid form, for parenteral
injection or for rectal administration.
[0082] The term "pharmaceutically acceptable carrier," as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as cocoa butter
and suppository waxes; oils such as peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil;
glycols; such a propylene glycol; esters such as ethyl oleate and
ethyl laurate; agar; buffering agents such as magnesium hydroxide
and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic
saline; Ringer's solution; ethyl alcohol, and phosphate buffer
solutions, as well as other non-toxic compatible lubricants such as
sodium lauryl sulfate and magnesium stearate, as well as coloring
agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of the
formulator.
[0083] The pharmaceutical compositions of this invention can be
administered to humans and other mammals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments or drops), bucally or as an
oral or nasal spray. The term "parenterally," as used herein,
refers to modes of administration that include intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous,
intraarticular injection and infusion.
[0084] Pharmaceutical compositions of this invention for parenteral
injection comprise pharmaceutically acceptable sterile aqueous or
nonaqueous solutions, dispersions, suspensions or emulsions and
sterile powders for reconstitution into sterile injectable
solutions or dispersions. Examples of suitable aqueous and
nonaqueous carriers, diluents, solvents or vehicles include water,
ethanol, polyols (propylene glycol, polyethylene glycol, glycerol,
and the like), suitable mixtures thereof, vegetable oils (such as
olive oil) and injectable organic esters such as ethyl oleate.
Proper fluidity may be maintained, for example, by the use of a
coating such as lecithin, by the maintenance of the required
particle size in the case of dispersions, and by the use of
surfactants.
[0085] These compositions may also contain adjuvants such as
preservative agents, wetting agents, emulsifying agents, and
dispersing agents. Prevention of the action of microorganisms may
be ensured by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the
like. It may also be desirable to include isotonic agents, for
example, sugars, sodium chloride and the like. Prolonged absorption
of the injectable pharmaceutical form may be brought about by the
use of agents delaying absorption, for example, aluminum
monostearate and gelatin. In some cases, in order to prolong the
effect of a drug, it is often desirable to slow the absorption of
the drug from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the drug then depends upon its rate of dissolution
which, in turn, may depend upon crystal size and crystalline form.
Alternatively, delayed absorption of a parenterally administered
drug form is accomplished by dissolving or suspending the drug in
an oil vehicle. Suspensions, in addition to the active compounds,
may contain suspending agents, as, for example, ethoxylated
isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth, and mixtures thereof.
[0086] If desired, and for more effective distribution, the
compounds of the present invention can be incorporated into
slow-release or targeted-delivery systems such as polymer matrices,
liposomes, and microspheres. They may be sterilized, for example,
by filtration through a bacteria-retaining filter or by
incorporation of sterilizing agents in the form of sterile solid
compositions, which may be dissolved in sterile water or some other
sterile injectable medium immediately before use.
[0087] The active compounds can also be in micro-encapsulated form,
if appropriate, with one or more excipients as noted above. The
solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric
coatings, release controlling coatings and other coatings well
known in the pharmaceutical formulating art. In such solid dosage
forms the active compound can be admixed with at least one inert
diluent such as sucrose, lactose, or starch. Such dosage forms may
also comprise, as is normal practice, additional substances other
than inert diluents, e.g., tableting lubricants and other tableting
aids such a magnesium stearate and microcrystalline cellulose. In
the case of capsules, tablets and pills, the dosage forms may also
comprise buffering agents. They may optionally contain opacifying
agents and can also be of such composition that they release the
active ingredient(s) only, or preferentially, in a certain part of
the intestinal tract in a delayed manner. Examples of embedding
compositions that can be used include polymeric substances and
waxes.
[0088] Injectable depot forms are made by forming microencapsulated
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides) Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0089] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0090] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic,
parenterally acceptable diluent or solvent such as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, U.S.P. and isotonic
sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
are used in the preparation of injectables.
[0091] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or: a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; e) solution retarding agents such
as paraffin); f) absorption accelerators such as quaternary
ammonium compounds; g) wetting agents such as cetyl alcohol and
glycerol monostearate; h) absorbents such as kaolin and bentonite
clay; and i) lubricants such as talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, and
mixtures thereof. In the case of capsules, tablets and pills, the
dosage form may also comprise buffering agents.
[0092] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0093] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract in a delayed manner. Examples
of embedding compositions that can be used include polymeric
substances and waxes.
[0094] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0095] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0096] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, eye
ointments, powders and solutions are also contemplated as being
within the scope of this invention.
[0097] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0098] Powders and sprays can contain, in addition to the compounds
of this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants such as chlorofluorohydrocarbons.
[0099] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0100] Compounds of the present invention may also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable and metabolizable lipid capable of
forming liposomes may be used. The present compositions in liposome
form may contain, in addition to the compounds of the present
invention, stabilizers, preservatives, excipients, and the like.
The preferred lipids are the natural and synthetic phospholipids
and phosphatidylcholines (lecithins) used separately or together.
Methods to form liposomes are known in the art. See, for example,
Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press,
New York, N.Y., (1976), p 33 et seq.
[0101] The terms "pharmaceutically acceptable salts, esters and
amides," as used herein, refer to carboxylate salts, amino acid
addition salts, zwitterions, esters and amides of compounds of
formula I which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, are commensurate with a reasonable benefit/risk ratio,
and are effective for their intended use.
[0102] The term "pharmaceutically acceptable salt," as used herein,
refers to salts that are well known in the art. For example, S. M
Berge et al. describe pharmaceutically acceptable salts in detail
in J. Pharmaceutical Sciences, Vol. 66, pages 1-19 (1977). Examples
of pharmaceutically acceptable, nontoxic acid addition salts are
salts of an amino group formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid
and perchloric acid or with organic acids such as acetic acid,
oxalic acid, maleic acid, tartaric acid, citric acid, succinic
acid, or malonic acid or by using other methods used in the art
such as ion exchange. Other pharmaceutically acceptable salts
include nitrate, bisulfate, borate, formate, butyrate, valerate,
3-phenylpropionate, camphorate, adipate, benzoate, oleate,
palmitate, stearate, laurate, lactate, fumarate, ascorbate,
aspartate, nicotinate, p-toluenesulfonate, camphorsulfonate,
methanesulfonate, 2-hydroxyethanesulfonate, gluconate,
glucoheptonate, lactobionate, glycerophosphate, pectinate, lauryl
sulfate, and the like, metal salts such as sodium, potassium,
magnesium or calcium salts or amino salts such as ammonium,
triethylamine salts, and the like, all of which may be prepared
according to conventional methods.
[0103] The term "pharmaceutically acceptable ester," as used
herein, refers to esters of compounds of the present invention
which hydrolyze in vivo and include those that break down readily
in the human body to leave the parent compound or a salt thereof.
Examples of pharmaceutically acceptable, non-toxic esters of the
present invention include C.sub.1-to-C.sub.6 alkyl esters and
C.sub.5-to-C.sub.7 cycloalkyl esters, although C.sub.1-to-C.sub.4
alkyl esters are preferred.
[0104] The term "pharmaceutically acceptable amide," as used
herein, refers to non-toxic amides of the present invention derived
from ammonia, primary C.sub.1-to-C.sub.6 alkyl amines and secondary
C.sub.1-to-C.sub.6 dialkyl amines. In the case of secondary amines,
the amine may also be in the form of a 5- or 6-membered heterocycle
containing one nitrogen atom. Amides derived from ammonia,
C.sub.1-to-C.sub.3 alkyl primary amides and C.sub.1-to-C.sub.2
dialkyl secondary amides are preferred. Amides of the compounds of
formula I may be prepared according to conventional methods. It is
intended that amides of the present invention include amino acid
and peptide derivatives of the compounds of formula I, as well.
[0105] The term "pharmaceutically acceptable prodrug" or "prodrug,"
as used herein, represents those prodrugs of the compounds of the
present invention which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use. Prodrugs of the
present invention may be rapidly transformed in vivo to the parent
compound of the above formula, for example, by hydrolysis in blood.
A thorough discussion is provided in T. Higuchi and V. Stella,
"Pro-drugs as Novel Delivery Systems" V. 14 of the A.C.S. Symposium
Series, and in Edward B. Roche, ed., "Bioreversible Carriers in
Drug Design", American Pharmaceutical Association and Pergamon
Press (1987), hereby incorporated by reference.
[0106] When used in the above or other treatments, a
therapeutically effective amount of one of the compounds of the
present invention can be employed in pure form or, where such forms
exist, in pharmaceutically acceptable salt, ester, amide or prodrug
form. Alternatively, the compound can be administered as a
pharmaceutical composition containing the compound of interest in
combination with one or more pharmaceutically acceptable
excipients. The phrase "therapeutically effective amount" of the
compound of the invention means a sufficient amount of the compound
to treat disorders, at a reasonable benefit/risk ratio applicable
to any medical treatment. It will be understood, however, that the
total daily usage of the compounds and compositions of the present
invention will be decided by the attending physician within the
scope of sound medical judgment. The specific therapeutically
effective dose level for any particular patient will depend upon a
variety of factors including the disorder being treated and the
severity of the disorder; activity of the specific compound
employed; the specific composition employed; the age, body weight,
general health, sex and diet of the patient; the time of
administration, route of administration, and rate of excretion of
the specific compound employed; the duration of the treatment;
drugs used in combination or coincidental with the specific
compound employed; and like factors well known in the medical arts.
For example, it is well within the skill of the art to start doses
of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0107] The total daily dose of the compounds of this invention
administered to a human or lower animal may range from about 0.003
to about 50 mg/kg/day. For purposes of oral administration, more
preferable doses can be in the range of from about 0.01 to about 10
mg/kg/day. If desired, the effective daily dose can be divided into
multiple doses for purposes of administration; consequently, single
dose compositions may contain such amounts or submultiples thereof
to make up the daily dose.
(e) EXAMPLES OF THE PRESENT INVENTION
Example 1
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-phenylacetamide
Example 1A
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-phenylacetamide
[0108] A suspension of phenylacetamide (2.9 g, 21.45 mmol),
trimethylacetaldehyde (5.42 g, 63.00 mmol), and
1H-1,2,3-benzotriazole (2.56 g, 21.45 mmol) in toluene (75 mL) was
treated with p-toluenesulfonic acid (0.200 g, 1.00 mmol). The
solution was heated at reflux under Dean-Stark conditions for 10
hours, cooled gradually to ambient temperature. The mixture was
concentrated under reduced pressure and purified by flash
chromatography on silica gel (sequential elution with 10, 15, and
20% of ethyl acetate in methylene chloride) to provide 6.05 g of
the title compound. MS (ESI.sup.+) m/z 323 (M+H).sup.+.
Example 1B
ethyl 2-(2-methylphenyl)ethanimidoate hydrochloride
[0109] The title compound was prepared using the procedure as
described in Ife, R. J. et al. (WO 9315055).
Example 1C
N'-cyano-2-(2-methylphenyl)ethanimidamide
[0110] A solution of Example 1B (4 g, 18.72 mmol)) in absolute
ethanol (50 ml) was treated with a 21% sodium ethoxide solution in
ethanol (7 ml, 18.72 mmol) and the precipitated sodium chloride was
filtered off. The filtrate was then treated with a solution of
cyanamide (0.79 g, 18.72 mmol) in absolute ethanol (25 ml) and
stirred at room temperature for one hour. The solvent was
evaporated under reduced pressure. The residual oil was triturated
with ether to afford white crystals that were filtered and dried to
yield 2.5 g of product. MS (ESI.sup.+) m/z 174 (M+H).sup.+.
Example 1D
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-phenylacetamide
[0111] A solution of Example 1A (104 mg, 0.6 mmol) and Example 1C
(194 mg, 0.6 mmol) in CH.sub.3CN (4 mL) at about 23.degree. C. was
treated with finely powdered anhydrous Cs.sub.2CO.sub.3 (529 mg,
1.5 mmol). The reaction mixture was stirred for 10 hours. The
suspension was filtered through a pad of Celite and washed with
ethyl acetate. The filtrate was concentrated under reduced pressure
and purified by preparative HPLC on a Waters Symmetry C8 column (40
mm.times.100 mm, 7 .mu.m particle size) using a gradient of 10% to
100% of acetonitrile in a 10 mM aqueous solution of ammonium
acetate over 15 min at a flow rate of 70 mL/min to provided 136 mg
of the title compound. mp 182-183.degree. C.; MS (ESI.sup.+) m/z
377 (M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.92 (s, 9 H) 2.26 (s, 3 H) 3.53 (m, 2 H) 3.84 (s, 2 H) 5.64 (t,
J=8.59 Hz, 1 H) 7.04 (m, 2 H) 7.23 (m, 7 H) 8.15 (d, J=8.59 Hz, 1
H) 8.67 (d, J=8.59 Hz, 1 H); anal. calcd for
C.sub.23H.sub.28N.sub.4O: C, 73.37; H, 7.50; N, 14.88; Found: C,
73.00; H, 7.70; N, 14.81.
Example 2
2-(4-chlorophenyl)-N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,-
2-dimethylpropyl)acetamide
Example 2A
2-(4-chlorophenyl)acetamide
[0112] The title compound was prepared using the procedure as
described in Freudenreich, C et al., J. Amer. Chem. Soc., Vol. 106,
pages 3344-3553 (1984).
Example 2B
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-(4-chlorophenyl)ac-
etamide
[0113] The title compound was prepared using the procedure as
described in Example 1A, substituting 2-(4-chlorophenyl)acetamide
for phenylacetamide. MS (ESI.sup.+) m/z 357 (M+H).sup.+.
Example 2C
2-(4-chlorophenyl)-N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,-
2-dimethylpropyl)acetamide
[0114] The title compound was prepared according to the procedure
as described in Example 1D, substituting Example 2B for Example 1A.
mp 183-185.degree. C.; MS (ESI.sup.+) m/z 411 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.92 (s, 9 H) 2.26 (s, 3 H)
3.53 (s, 2 H) 3.83 (s, 2 H) 5.62 (t, J=8.65 Hz, 1 H) 7.01 (m, 2 H)
7.18 (m, 2 H) 7.31 (m, 4 H) 8.18 (d, J=8.48 Hz, 1 H) 8.66 (d,
J=8.48 Hz, 1 H). Anal. calcd for C.sub.23H.sub.27ClN.sub.4O: C,
67.22; H, 6.62; N, 13.63. Found: C, 66.87; H, 6.32; N, 13.51.
Example 3
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(3,4-dimethoxyphenyl)acetamide
Example 3A
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-(3,4-dimethoxyphen-
yl)acetamide
[0115] The title compound was prepared using the procedure as
described in Example 1A, substituting
2-(3,4-dimethoxyphenyl)acetamide for phenylacetamide. MS
(ESI.sup.+) m/z 383 (M+H).sup.+.
Example 3B
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(3,4-dimethoxyphenyl)acetamide
[0116] The title compound was prepared with the procedure as
described in Example 1D substituting Example 3A for Example 1A. mp
153-155.degree. C.; MS (ESI.sup.+) m/z 437 (M+H).sup.+; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 0.92 (s, 9 H) 2.27 (s, 3 H)
3.44 (m, 2 H) 3.71 (d, J=4.75 Hz, 6 H) 3.84 (s, 2 H) 5.64 (t,
J=8.65 Hz, 1 H) 6.77 (dd, J=8.31, 1.86Hz, 1 H) 6.86 (m, 2 H) 7.05
(m, 2 H) 7.19 (m, 2 H) 8.05 (d, J=8.48 Hz, 1 H) 8.63 (d, J=8.48 Hz,
1 H). Anal. calcd for C.sub.25H.sub.32N.sub.4O.sub.3: C, 68.78; H,
7.39; N, 12.83. Found: C, 68.55; H, 7.12; N, 12.75.
Example 4
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(4-methoxyphenyl)acetamide
Example 4A
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-(4-methoxyphenyl)a-
cetamide
[0117] The title compound was prepared using the procedure as
described in Example 1A, substituting 2-(4-methoxyphenyl)acetamide
for phenylacetamide. MS (ESI.sup.+) m/z 353 (M+H).sup.+;
Example 4B
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(4-methoxyphenyl)acetamide
[0118] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 4A for Example 1A. mp
199-201.degree. C.; MS (ESI.sup.+) m/z 407 (M+H).sup.+; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 0.91 (s, 9 H) 2.26 (s, 3 H)
3.44 (m, 2 H) 3.72 (s, 3 H) 3.83 (s, 2 H) 5.63 (t, J=8.65 Hz, 1 H)
6.85 (m, 2 H) 7.04 (m, 2 H) 7.18 (m, 4 H) 8.07 (d, J=8.81 Hz, 1 H)
8.66 (d, J=8.48 Hz, 1 H). Anal. calcd for
C.sub.24H.sub.30N.sub.4O.sub.2: C, 70.91; H, 7.44; N, 13.78. Found:
C, 70.56; H, 7.76; N, 13.81.
Example 5
2-(1,3-benzodioxol-5-yl)-N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]ami-
no}-2,2-dimethylpropyl)acetamide
Example 5A
2-(1,3-benzodioxol-5-yl)acetamide
[0119] The title compound was prepared using the procedure as
described in Mastagli et al; Bull. Soc. Chim. Fr., pages 662-665
(1948).
Example 5B
2-(1,3-benzodioxol-5-yl)-N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpro-
pyl]acetamide
[0120] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 5A for
phenylacetamide. MS (ESI.sup.+) m/z 367(M+H).sup.+;
Example 5C
2-(1,3-benzodioxol-5-yl)-N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]ami-
no}-2,2-dimethylpropyl)acetamide
[0121] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 5B for Example 1A. mp
167-169.degree. C.; MS (ESI.sup.+) m/z 421 (M+H).sup.+; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 0.91 (s, 9 H) 2.26 (s, 3 H)
3.42 (m, 2 H) 3.82 (m, 2 H) 5.63 (t, J=8.48 Hz, 1 H) 5.97 (s, 2 H)
6.71 (dd, J=7.80, 1.70 Hz, 1 H) 6.81 (m, 2 H) 7.03 (m, 2 H) 7.18
(m, 2 H) 8.12 (d, J=8.48 Hz, 1 H) 8.71 (d, J=8.14 Hz, 1 H). Anal.
calcd for C.sub.24H.sub.28N.sub.4O.sub.30.25 CH.sub.3OH: C, 67.97;
H, .6.82; N, 13.07. Found: C, 68.03; H, 7.22; N, 13.27.
Example 6
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(4-cyanophenyl)acetamide
Example 6A
2-(4-cyanophenyl)acetamide
[0122] The title compound was prepared using the procedure as
described in Mellinghoff, Chem. Ber., Vol. 22, page 3208
(1889).
Example 6B
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-(4-cyanophenyl)ace-
tamide
[0123] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 6A for
phenylacetamide. MS (ESI.sup.+) m/z 348 (M+H).sup.+.
Example 6C
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(4-cyanophenyl)acetamide
[0124] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 6C for Example 1A. mp
199-201.degree. C.; MS (ESI.sup.+) m/z 402 (M+H).sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.93 (s, 9 H) 2.26 (s, 3 H)
3.65 (s, 2 H) 3.83 (s, 2 H) 5.61 (t, J=8.59 Hz, 1 H) 7.01 (m, 2 H)
7.18 (m, 2 H) 7.46 (d, J=8.29 Hz, 2 H) 7.75 (dt, J=8.29, 1.84 Hz, 2
H) 8.28 (d, J=8.59 Hz, 1 H) 8.69 (d, J=8.28 Hz, 1 H) Anal. calcd
for C.sub.24H.sub.27N.sub.5O0.05 H.sub.2O: C, 71.63; H, 6.79; N,
17.40; Found: C, 71.26; H, 6.77; N, 17.28.
Example 7
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2.2-dimethylpropyl)-2-
-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide
Example 7A
2,3-Dihydro-1,4-benzodioxin-6-ylacetic acid
[0125] The title compound was prepared using the procedure as
described in Vazquez, et al., Farmaco Vol. 51 pages 215-218
(1996).
Example 7B
2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide
[0126] The title compound was prepared using the procedure as
described in Example 13A, substituting Example 7A for
2-(3,4-difluorophenyl)acetic acid. MS (ESI.sup.+) m/z 211
(M+NH.sub.3).sup.+.
Example 7C
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-(2,3-dihydro-1,4-b-
enzodioxin-6-yl)acetamide
[0127] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 7B for
phenylacetamide. MS (ESI.sup.+) m/z 381 (M+H).sup.+;
Example 7D
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide
[0128] The title compound was prepared according to the procedure
of Example 1D, substituting Example 7C for Example 1A. mp
180-181.degree. C.; MS (ESI+) m/z 435 (M+H).sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.91 (s, 9 H) 2.26 (s, 3 H) 3.39 (m,
2 H) 3.83 (s, 2 H) 4.20 (s, 4 H) 5.63 (t, J=8.59 Hz, 1 H) 6.70 (dd,
J=8.29, 1.84 Hz, 1 H) 6.76 (m, 2 H) 7.04 (m, 2 H) 7.18 (m, 2 H)
8.08 (d, J=8.59 Hz, 1 H) 8.68 (d, J=8.90 Hz, 1 H). Anal. calcd for
C.sub.25H.sub.30N.sub.4O.sub.30.075 H.sub.2O: C, 68.89; H, 6.97; N,
12.85; Found: C, 68.49; H, 7.23; N, 12.80.
Example 8
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-fluoroacetamide
Example 8A
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-fluoroacetamide
[0129] The title compound was prepared using the procedure as
described in Example 1A, substituting 2-fluoroacetamide for
phenylacetamide. MS (ESI.sup.+) m/z 265 (M+H).sup.+.
Example 8B
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-fluoroacetamide
[0130] The title compound was prepared using the procedure of
Example 1D, substituting Example 8A for Example 1A. mp
151-152.degree. C.; MS (ESI.sup.+) m/z 319 (M+H).sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.89 (s, 9 H) 2.29 (s, 3 H)
3.89 (m, 2 H) 4.81 (m, 1 H) 4.92 (m, 1 H) 5.73 (t, J=8.75 Hz, 1 H)
7.10 (m, 1 H) 7.20 (m, 3 H) 8.14 (d, J=8.90 Hz, 1 H) 8.45 (d,
J=8.28 Hz, 1 H). Anal. calcd for C.sub.17H.sub.23FN.sub.4O: C,
64.13; H, 7.28; N, 17.60; Found: C, 63.93; H, 7.49; N, 17.65.
Example 9
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(1-naphthyl)acetamide
Example 9A
N-[-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-(1-naphthyl)acetami-
de
[0131] The title compound was prepared using the procedure of
Example 1A, substituting 2-(1-naphthyl)acetamide for
phenylacetamide. MS (ESI.sup.+) m/z 373 (M+H).sup.+.
Example 9B
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(1-naphthyl)acetamide
[0132] The title compound was prepared using the procedure of
Example 1D, substituting Example 9A for Example 1A. mp
97-100.degree. C.; MS (ESI.sup.+) m/z 427 (M+H).sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.94 (s, 9 H) 2.27 (s, 3 H)
3.84 (s, 2 H) 4.01 (m, 2 H) 5.66 (t, J=8.59 Hz, 1 H) 7.00 (m, 2 H)
7.17 (m, 2 H) 7.43 (m, 2 H) 7.52 (m, 2 H) 7.83 (m, 1 H) 7.92 (m, 1
H) 8.07 (m, 1 H) 8.27 (d, J=8.29 Hz, 1 H) 8.68 (d, J=8.29 Hz, 1 H).
Anal. calcd for C.sub.27H.sub.30N.sub.4O: C, 76.03; H, 7.09; N,
13.13; Found: C, 75.73; H, 7.45; N, 13.04.
Example 10
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-quinolin-6-ylacetamide
Example 10A
2-(6-quinolinyl)acetamide
[0133] The title compound was prepared using the procedure as
described in Tsatsaronis, K., J. Org. Chem. Vol. 35 page 438
(1970).
Example 10B
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-quinolin-6-ylaceta-
mide
[0134] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 10A for
phenylacetamide. MS (ESI.sup.+) m/z 374 (M+H).sup.+;
Example 10C
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-quinolin-6-ylacetamide
[0135] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 10B for Example 1A.
mp 172-173.degree. C.; MS (ESI.sup.+) m/z 428 (M+H).sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.94 (s, 9 H) 2.25 (s, 3 H)
3.75 (s, 2 H) 3.83 (s, 2 H) 5.67 (t, J=8.44 Hz, 1 H) 6.92 (t,
J=6.90 Hz, 1 H) 7.01 (m, 1 H) 7.09 (td, J=7.29, 1.07 Hz, 1 H) 7.17
(m, 1 H) 7.50 (dd, J=8.29, 4.30 Hz, 1 H) 7.68 (dd, J=8.59, 1.84 Hz,
1 H) 7.81 (d, J=1.53 Hz, 1 H) 7.95 (d, J=8.90 Hz, 1 H) 8.27 (dd,
J=8.29, 1.23 Hz, 1 H) 8.37 (d, J=8.59 Hz, 1 H) 8.81 (d, J=8.59 Hz,
1 H) 8.86 (dd, J=4.30, 1.84 Hz, 1 H). Anal. calcd for
C.sub.26H.sub.29N.sub.5O0.5 H.sub.2O: C, 71.53; H, 6.93; N, 16.04;
Found: C, 71.27; H, 6.88; N, 15.96.
Example 11
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-quinolin-7-ylacetamide
Example 11A
7-Quinolinylacetic acid
[0136] The title compound was prepared using the procedure as
described in Meyer, M. D. et al., J. Med. Chem. Vol. 40, pages
1049-1062 (1997).
Example 11B
Methyl 7-quinolinylacetate
[0137] To a solution of example 11A (1.98 g, 10.59 mmol) in 40 mL
of anhydrous methanol was slowly added SOCl.sub.2 (1.5 mL, 31.7
mmol), and a drop of dimethylformamide as catalyst.
[0138] The mixture was refluxed for 5 his and then concentrated
under reduced pressure. The residue was dissolved in water (10 mL)
and neutralized with aqueous sodium bicarbonate to pH 8. The
product was extracted with methylene chloride, dried with anhydrous
sodium sulfate and concentrated under reduced pressure to afford
2.13 g of the title compound. MS (ESI.sup.+) m/z 202
(M+H).sup.+.
Example 11C
2-(7-quinolinyl)acetamide
[0139] Example 11B (2.128 g, 10.59 mmol) was dissolved in 7N
NH.sub.3 solution in MeOH (15 mL) and stirred at 60.degree. C. in a
sealed tube for 48 hr. The solvent and excess ammonia were removed
under reduced pressure to afford 1.026 g of the title compound. MS
(ESI.sup.+) m/z 187 (M+H).sup.+.
Example 11D
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-quinolin-7-ylaceta-
mide
[0140] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 11C for
phenylacetamide. MS (ESI.sup.+) m/z 374 (M+H).sup.+.
Example 11E
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-quinolin-7-ylacetamide
[0141] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 11D for Example 1A.
mp 165-166.degree. C.; MS (ESI.sup.+) m/z 428 (M+H).sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.93 (s, 9 H) 2.24 (s, 3 H)
3.77 (m, 2 H) 3.83 (s, 2 H) 5.68 (t, J=8.59 Hz, 1 H) 6.97 (m, 2 H)
7.09 (td, J=7.21, 1.53 Hz, 1 H) 7.16 (m, 1 H) 7.49 (dd, J=8.13,
4.14 Hz, 1 H) 7.54 (dd, J=8.44, 1.69 Hz, 1 H) 7.91 (d, J=8.59 Hz, 2
H) 8.34 (m, 2 H) 8.78 (d, J=8.59 Hz, 1 H) 8.88 (dd, J=4.14, 1.69
Hz, 1 H). Anal. calcd for C.sub.26H.sub.29N.sub.5O: C, 73.04; H,
6.84; N, 16.38; Found: C, 72.75; H, 6.88; N, 16.43.
Example 12
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-4-
-thien-2-ylbutanamide
Example 12A
4-(2-thienylbutanamide
[0142] The title compound was prepared using the procedure as
described in Blanchette et al., J. Amer. Chem. Soc., Vol. 74 page
1066 (1952).
Example 12B
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-4-thien-2-ylbutanami-
de
[0143] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 12A for
phenylacetamide. MS (ESI.sup.+) m/z 357 (M+H).sup.+;
Example 12C
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-4-
-thien-2-ylbutanamide
[0144] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 12B for Example 1A.
mp 154-155.degree. C.; MS (ESI.sup.+) m/z 411 (M+H).sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.92 (s, 9 H) 1.85 (m, 2 H)
2.23 (td, J=7.29, 2.30 Hz, 2 H) 2.28 (s, 3 H) 2.79 (t, J=7.52 Hz, 2
H) 3.84 (s, 2 H) 5.65 (t, J=8.59 Hz, 1 H) 6.82 (m, 1 H) 6.94 (dd,
J=5.22, 3.38 Hz, 1 H) 7.14 (m, 4 H) 7.31 (dd, J=5.22, 1.23 Hz, 1 H)
7.95 (d, J=8.59 Hz, 1 H) 8.59 (d, J=8.29 Hz, 1 H). Anal. calcd for
C.sub.23H.sub.30N.sub.4OS: C, 67.28; H, 7.36; N, 13.65; Found: C,
66.96; H, 7.70; N, 13.51.
Example 13
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(3,4-difluorophenyl)acetamide
Example 13A
2-(3,4-difluorophenyl)acetamide
[0145] To a solution of 2-(3,4-difluorophenyl)acetic acid (5.1 g,
30.33 mmol) in 50 mL of anhydrous dichloromethane was added
SOCl.sub.2 (4.33 g, 36.4 mmol), and a drop of dimethylformamide as
catalyst. The mixture was stirred at room temperature for 2 hr,
solvent and excess SOCl.sub.2 were removed under reduced pressure.
The crude product was dissolved in 50 mL of THF, cooled to
0.degree. C. and liquid ammonia was added dropwise through
condenser for 20 minutes. The reaction mixture was concentrated,
the product precipitated with 30 ml of water, filtered, and dried
to afford 4.55 g of title compound. MS (ESI.sup.+) m/z 172
(M+H).sup.+.
Example 13B
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-(3,4-difluoropheny-
l)acetamide
[0146] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 13A for
phenylacetamide. MS (ESI.sup.+) m/z 359 (M+H).sup.+.
Example 13C
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-(3,4-difluorophenyl)acetamide
[0147] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 13B for Example 1A.
mp 178-179.degree. C.; MS (ESI.sup.+) m/z 413 (M+H).sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.93 (s, 9 H) 2.26 (s, 3 H)
3.54 (s, 2 H) 3.83 (s, 2 H) 5.62 (t, J=8.59 Hz, 1 H) 7.04 (m, 3 H)
7.18 (m, 2 H) 7.32 (m, 2 H) 8.19 (d, J=8.28 Hz, 1 H) 8.66 (d,
J=8.29 Hz, 1 H). Anal. calcd for C.sub.23H.sub.26F.sub.2N.sub.4O:
C, 66.97; H, 6.35; N, 13.58; Found: C, 66.84; H, 6.60; N,
13.68.
Example 14
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-[4-(ethylthio)phenyl]acetamide
Example 14A
2-[4-(ethylthio)phenyl]acetamide
[0148] The title compound was prepared using the procedure as
described in Example 13A, substituting [4-(Ethylthio)phenyl]acetic
acid for 2-(3,4-difluorophenyl)acetic acid. MS (ESI.sup.+) m/z 213
(M+NH.sub.3).sup.+.
Example 14B
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-[4-(ethylthio)phen-
yl]acetamide
[0149] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 14A for
phenylacetamide. MS (ESI.sup.+) m/z 383.
Example 14C
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-[4-(ethylthio)phenyl]acetamide
[0150] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 14B for Example 1A.
mp 196-198.degree. C.; MS (ESI.sup.+) m/z 437 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.92 (s, 9 H) 1.22 (t,
J=7.29 Hz, 3 H) 2.26 (s, 3 H) 2.94 (q, J=7.46 Hz, 2 H) 3.49 (s, 2
H) 3.83 (s, 2 H) 5.63 (t, J=8.65 Hz, 1 H) 7.03 (m, 2 H) 7.22 (m, 6
H) 8.15 (d, J=8.82 Hz, 1 H) 8.67 (d, J=8.48 Hz, 1 H). Anal. calcd
for C.sub.25H.sub.32N.sub.4OS: C, 68.74; H, 7.39; N, 12.83; Found:
C, 68.35; H, 7.47; N, 12.77.
Example 15
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-[4-(methylthio)phenyl]acetamide
Example 15A
2-[4-(methylthio)phenyl]acetamide
[0151] The title compound was prepared using the procedure as
described in Ruechardt et al., Chem. Ber., Vol. 100 page 654
(1967).
Example 15B
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-[4-(methylthio)phe-
nyl]acetamide
[0152] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 15A for
phenylacetamide. MS (ESI.sup.+) m/z 369 (M+H).sup.+.
Example 15C
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-[4-(methylthio)phenyl]acetamide
[0153] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 15B for Example 1A.
mp 201-202.degree. C.; MS (ESI.sup.+) m/z 423 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.92 (s, 9 H) 2.26 (s, 3 H)
2.45 (s, 3 H) 3.48 (m, 2 H) 3.83 (s, 2 H) 5.63 (t, J=8.65 Hz, 1 H)
7.03 (m, 2 H) 7.18 (m, 6 H) 8.13 (d, J=8.82 Hz, 1 H) 8.66 (d,
J=8.81 Hz, 1 H). Anal. calcd for C.sub.24H.sub.30N.sub.4OS: C,
68.21; H, 7.16; N, 13.26; Found: C, 68.09; H, 7.43; N, 13.17.
Example 16
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-4-
-(4-methoxyphenyl)butanamide
Example 16A
4-(4-methoxyphenyl)butanamide
[0154] The title compound was prepared using the procedure as
described in Ganellin, et al., Arch. Pharm. Vol 331 pages 395-404
(1998).
Example 16B
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-4-(4-methoxyphenyl)b-
utanamide
[0155] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 16A for
phenylacetamide. MS (ESI.sup.+) m/z 381 (M+H).sup.+.
Example 16C
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-4-
-(4-methoxyphenyl)butanamide
[0156] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 16B for Example 1A.
mp 171-172.degree. C.; MS (ESI.sup.+) m/z 435 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.92 (s, 9 H) 1.76 (m, 2 H)
2.16 (t, J=7.12 Hz, 2 H) 2.27 (s, 3 H) 2.50 (m, 2 H) 3.72 (s, 3 H)
3.84 (s, 2 H) 5.64 (t, J=8.48 Hz, 1 H) 6.84 (m, 2 H) 7.08 (d,
J=8.48 Hz, 4 H) 7.18 (m, 2 H) 7.91 (d, J=8.81 Hz, 1 H) 8.58 (d,
J=8.81 Hz, 1 H). Anal. calcd for C.sub.26H.sub.34N.sub.4O.sub.2: C,
71.86; H, 7.89; N, 12.89; Found: C, 71.65; H, 8.19; N, 12.82.
Example 17
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl-5--
phenylpentanamide
Example 17A
5-phenylpentanamide
[0157] The title compound was prepared using the procedure as
described in De Tar et al., J. Amer. Chem. Soc. Vol. 68 pages
2025-2028 (1946).
Example 17B
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-5-phenylpentanamide
[0158] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 17A for
phenylacetamide. MS (ESI.sup.+) m/z 365 (M+H).sup.+.
Example 17C
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-5-
-phenylpentanamide
[0159] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 17B for Example 1A.
mp 151-152.degree. C.; MS (ESI.sup.+) m/z 419 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.91 (s, 9 H) 1.54 (m, 4 H)
2.18 (m, 2 H) 2.27 (s, 3 H) 2.57 (t, J=6.95 Hz, 2 H) 3.83 (s, 2 H)
5.63 (t, J=8.65 Hz, 1 H) 7.06 (m, J=2.71 Hz, 2 H) 7.17 (d, J=7.12
Hz, 5 H) 7.27 (m, 2 H) 7.89 (d, J=8.48 Hz, 1 H) 8.59 (d, J=8.82 Hz,
1 H). Anal. calcd for C.sub.26H.sub.34N.sub.4O: C, 74.61; H, 8.19,
N, 13.39; Found: C, 74.39; H, 8.52; N, 13.35.
Example 18
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-pyridin-3-ylacetamide
Example 18A
2-pyridin-3-yl-acetamide
[0160] The title compound was prepared using the procedure as
described in Mayer, Joachim M. et al., Helvetica Chimica Acta Vol.
65 pages 1868-84 (1982).
Example 18B
N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-pyridin-3-ylacetam-
ide
[0161] The title compound was prepared using the procedure as
described in Example 1A, substituting Example 18A for
phenylacetamide. MS (ESI.sup.+) m/z 324 (M+H).sup.+.
Example 18C
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-
-pyridin-3-ylacetamide
[0162] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 18B for Example 1A.
mp 84-86.degree. C; MS (ESI.sup.+) m/z 378 (M+H).sup.+; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 0.93 (s, 9 H) 2.26 (s, 3 H)
3.57 (s, 2 H) 3.83 (s, 2 H) 5.63 (t, J=8.48 Hz, 1 H) 7.02 (m, 2 H)
7.17 (m, 2 H) 7.33 (m, 1 H) 7.67 (dt, J=7.80, 2.03 Hz, 1 H) 8.27
(d, J=8.48 Hz, 1 H) 8.44 (d, J=1.70 Hz, 1 H) 8.46 (m, 1 H) 8.70 (d,
J=8.48 Hz, 1 H). Anal. calcd for C.sub.22H.sub.27N.sub.5O0.03
H.sub.2O: C, 69.90; H, 7.21; N, 18.53; Found: C, 69.50; H, 87.21,
N, 18.18.
Example 19
2-(4-chlorophenyl)-N-(1-{[(cyanoimino)(2-methylphenyl)methyl]amino}-2,2-di-
methylpropyl)acetamide
Example 19A
ethoxy(2-methylphenyl)methaniminium tetrafluoroborate
[0163] The title compound was prepared using the procedure as
described as in Weintraub, L. et al., J. Org. Chem., Vol. 33(4)
pages 1679-81 (1968). MS (ESI.sup.+) m/z 164 (M+H).sup.+.
Example 19B
N'-cyano-2-methylbenzenecarboximidamide
[0164] To a solution of Example 19A (2.5 g 10.00 mmol) in 10 ml of
absolute ethanol was added a solution of sodium ethoxide (681 mg,
10 mmol) in 3.7 ml of absolute ethanol. The precipitate was
filtered and the filtrate was treated with a solution of cyanamide
(420 mg, 10 mmol) in 10 ml of absolute ethanol. The reaction
mixture was refluxed for 3 days and the solvent removed under
reduced pressure. The crude mixture was purified by silica gel
chromatography, eluting with a gradient of 0-50% ethyl acetate in
methylene chloride to provide the 0.3 g of title compound. MS
(ESI.sup.+) m/z 160 (M+H).sup.+.
Example 19C
2-(4-chlorophenyl)-N-(1-{[(cyanoimino)(2-methylphenyl)methyl]amino}-2,2-di-
methylpropyl)acetamide
[0165] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 19B for Example 1C
and substituting Example 2B for Example 1A. mp 109-110.degree. C.;
MS (ESI.sup.+) m/z 397 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 0.97 (s, 9 H) 2.18 (br. s,3 H) 3.55 (s, 2
H) 5.66 (t, J=8.31 Hz, 1 H) 7.11 (br. s., 1 H) 7.36 (m, 7 H) 8.14
(d, J=8.48 Hz, 1 H) 9.06 (d, J=8.14 Hz, 1 H). Anal. calcd for
C.sub.22H.sub.25ClN.sub.4O: C, 66.57; H, 6.35; N, 14.12; Found: C,
66.45; H, 6.11; N, 14.26.
Example 20
2-(4-chlorophenyl)-N-(1-{[N-cyano-2-(2-methylpyridin-3-yl)ethanimidoyl]ami-
no}-2,2-dimethylpropyl)acetamide
Example 20A
(2-methylpyridin-3-yl)acetonitrile
[0166] The title compound was prepared using the procedure as
described in Sato, Y. et al. Chem. Phar. Bull., Vol. 8 pages
427-435 (1960). MS (ESI.sup.+) m/z 133 (M+H).sup.+.
Example 20B
ethyl 2-(2-methylpyridin-3-yl)ethanimidoate hydrochloride
[0167] Through a stirred solution of Example 20A (1.7 g, 12.86
mmol) in absolute ethanol (0.89 g, 19.35 mmol) and anhydrous
methylene chloride (25 ml) was bubbled with hydrogen chloride gas
for 20 min. The mixture was allowed to stand overnight in the
refrigerator. The product was precipitated with anhydrous ether and
filtered to obtain the title compound, which was immediately used
in the next step. MS (ESI.sup.+) m/z 180 (M+H).sup.+.
Example 20C
N'-cyano-2-(2-methylpyridin-3-yl)ethanimidamide
[0168] The title compound was prepared using the procedure as
described in Example 19B, substituting Example 20B for Example 19A
and using two equivalents of sodium ethoxide. MS (ESI.sup.+) m/z
175 (M+H).sup.+.
Example 20D
2-(4-chlorophenyl)-N-(1-{[N-cyano-2-(2-methylpyridin-3-yl)ethanimidoyl]ami-
no }-2,2-dimethylpropyl)acetamide
[0169] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 2B for Example 1A and
substituting Example 20C for Example 1C. mp 118-119.degree. C.; MS
(ESI.sup.+) m/z 412 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 0.94 (s, 9 H) 2.46 (s, 3 H) 3.53 (s, 2 H)
3.87 (m, 2 H) 5.58 (t, J=8.48 Hz, 1 H) 7.05 (dd, J=7.80, 4.75 Hz, 1
H) 7.32 (m, 5 H) 8.25 (d, J=8.14 Hz, 1 H) 8.32 (dd, J=4.92, 1.53
Hz, 1 H) 8.87 (d, J=8.48 Hz, 1 H). Anal. calcd for
C.sub.22H.sub.26ClN.sub.5O0.2 H.sub.2O: C, 63.59; H, 6.40; N,
16.85; Found: C, 63.21; H, 6.35; N, 16.73.
Example 21
N-(1-{[N-cyano-2-(2-methylpyridin-3-yl)ethanimidoyl]amino}-2,2-dimethylpro-
pyl)-2-(3,4-dimethoxyphenyl)acetamide
[0170] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 3A for Example 1A and
substituting Example 20C for Example 1C. mp 164-165.degree. C.; MS
(ESI.sup.+) m/z 438 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 0.93 (s, 9 H) 2.46 (s, 3 H) 3.44 (m, 2 H)
3.70 (s, 3 H) 3.72 (s, 3 H) 3.88 (br. s., 2 H) 5.59 (t, J=8.48 Hz,
1 H) 6.77 (dd, J=8.14, 2.03 Hz, 1 H) 6.86 (m, 2 H) 7.07 (dd,
J=7.80, 4.75 Hz, 1 H) 7.36 (dd, J=7.80, 1.36 Hz, 1 H) 8.08 (d,
J=8.14 Hz, 1 H) 8.32 (dd, J=4.92, 1.53 Hz, 1 H) 8.79 (d, J=8.14 Hz,
1 H). Anal. calcd for C.sub.24H.sub.31N.sub.5O.sub.3: C, 65.88; H,
7.14; N, 16.01; Found: C, 65.66; H, 7.24; N, 15.95.
Example 22
N-(1-{[N-cyano-2-(2-methylpyridin-3-yl)ethanimidoyl]amino}-2,2-dimethylpro-
pyl)-2-quinolin-6-ylacetamide
[0171] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 10B for Example 1A
and substituting Example 20C for Example 1C. mp 132-134.degree. C.;
MS (ESI.sup.+) m/z 434 (M+H.sup.+); .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 2.44 (s, 3 H) 3.76 (s, 2 H) 3.84 (d,
J=16.28 Hz, 1 H) 3.90 (d, J=15.00 Hz, 1 H) 5.62 (t, J=8.31 Hz, 1 H)
6.90 (dd, J=7.80, 4.75 Hz, 1 H) 7.33 (dd, J=7.63, 1.19 Hz, 1 H)
7.51 (dd, J=8.31, 4.24 Hz, 1 H) 7.67 (dd, J=8.48, 2.03 Hz, 1 H)
7.80 (d, J=1.36 Hz, 1 H) 7.95 (d, J=8.82 Hz, 1 H) 8.23 (dd, J=4.92,
1.53 Hz, 1 H) 8.27 (dd, J=8.48, 1.02 Hz, 1 H) 8.35 (d, J=8.14 Hz, 1
H) 8.86 (dd, J=4.41, 1.70 Hz, 1 H) 8.91 (m, 1 H).
Example 23
2-(4-chlorophenyl)-N-(1-{[N-cyano-2-quinolin-5-ylethanimidoyl]amino}-2,2-d-
imethylpropyl)acetamide
Example 23A
quinolin-5-ylacetonitrile
[0172] The title compound was prepared using the procedure as
described in Engler, T. et al., A.; Tetrahedron. Lett., Vol. 44
pages 2903-2905, (2003).
Example 23B
ethyl 2-quinolin-5-ylethanimidoate hydrochloride
[0173] The title compound was prepared using the procedure as
described in Example 20B, substituting Example 23A for Example 20A.
MS (ESI.sup.+) m/z 215 (M+H).sup.+.
Example 23C
N'-cyano-2-quinolin-5-ylethanimidamide
[0174] The title compound was prepared using the procedure as
described in Example 19B, substituting Example 23B for Example 19A
and using two equivalents of sodium ethoxide. MS (ESI.sup.+) m/z
211 (M+H).sup.+.
Example 23D
2-(4-chlorophenyl)-N-(1-{[N-cyano-2-quinolin-5-ylethanimidoyl]amino}-2,2-d-
imethylpropyl)acetamide
[0175] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 2B for Example 1A and
substituting Example 23C for Example 1C. mp 186-188.degree. C.; MS
(ESI.sup.+) m/z 448 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 0.93 (s, 9 H) 3.55 (s, 2 H) 4.35 (d,
J=16.27 Hz, 1 H) 4.42 (d, J=16.27 Hz, 1 H) 5.66 (t, J=8.48 Hz, 1 H)
7.28 (m, J=2.71 Hz, 1 H) 7.29 (d, J=8.82 Hz, 1 H) 7.35 (d, J=8.82
Hz, 1 H) 7.57 (m, 1 H) 7.60 (dd, J=5.09, 3.73 Hz, 1 H) 7.95 (d,
J=8.48 Hz, 1 H) 8.24 (d, J=8.48 Hz, 1 H) 8.55 (d, J=8.14 Hz, 1 H)
8.89 (d, J=8.14 Hz, 1 H) 8.95 (dd, J=4.24, 1.53 Hz, 1 H).
Example 24
N-(1-{[(cyanoimino)(quinolin-5-yl)methyl]amino}-2,2-dimethylpropyl)-2-(3,4-
-dimethoxyphenyl)acetamide
Example 24A
quinoline-5-carbonitrile
[0176] The title compound was prepared using the procedure as
described in Wagner, G. and Vieweg, H. Pharmazie Vol. 31 pages
145-148 (1976).
Example 24B
N'-cyanoquinoline-5-carboximidamide
[0177] A mixture of Example 24A (750 mg, 4.81 mmol) and sodium
cyanamide (312 mg, 4.81 mmol) in ethanol (10 mL) was heated at
reflux for 10 hours and cooled to ambient temperature. The solvent
was removed under reduced pressure and the crude mixture was
purified by silica gel chromatography, eluting with a gradient of
0-6% of methanol/methylene chloride to provide 0.3 g of the title
compound. MS (ESI.sup.+) m/z 197 (M+H).sup.+.
Example 24C
N-(1-{[(cyanoimino)(quinolin-5-yl)methyl]amino}-2,2-dimethylpropyl)-2-(3,4-
-dimethoxyphenyl)acetamide
[0178] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 3A for Example 1A and
substituting Example 24B for Example 1C. mp 203-205.degree. C.; MS
(ESI.sup.+) m/z 460 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.01 (s, 9 H) 3.50 (s, 2 H) 3.65 (s, 3 H)
3.72 (s, 3 H) 5.73 (t, J=8.14 Hz, 1 H) 6.83 (m, 3 H) 7.39 (m, 1 H)
7.62 (d, J=7.12 Hz, 1 H) 7.85 (dd, J=8.48, 7.12 Hz, 1 H) 8.07 (d,
J=8.14 Hz, 1 H) 8.17 (m, 2 H) 8.97 (m, 1 H) 9.38 (d, J=8.14 Hz, 1
H).
Example 25
2-(4-chlorophenyl)-N-(1-{[(cyanoimino)(quinolin-5-yl)methyl]amino}-2,2-dim-
ethylpropyl)acetamide
[0179] The title compound was prepared using the procedure as
described in Example 1D, substituting Example 2B for Example 1A and
substituting Example 24B for Example 1C. mp 218-220.degree. C.; MS
(ESI.sup.+) m/z 442 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.03 (s, 9 H) 3.60 (s, 2 H) 5.73 (t,
J=8.14 Hz, 1 H) 7.05 (m, 1 H) 7.34 (m, 4 H) 7.62 (d, J=7.80 Hz, 1
H) 7.87 (t, J=7.80 Hz, 1 H) 8.04 (d, J=8.14 Hz, 1 H) 8.17 (d,
J=8.14 Hz, 1 H) 8.32 (d, J=8.14 Hz, 1 H) 8.97 (m, 1 H) 9.40 (d,
J=9.15 Hz, 1 H).
Example 26
N'-cyano-2-(2-methylphenyl)-N-[(1R)-1-phenylethyl]ethanimidamide
Example 26A
ethyl 2-(2-methylphenyl)ethanimidoate hydrochloride
[0180] The title compound was prepared using the procedure as
described in Ife, R. J. et al. (WO 9315055).
Example 26B
ethyl N-cyano-2-(2-methylphenyl)ethanimidoate
[0181] A solution of Example 26A (15 g, 70.2 mmol) in absolute
ethanol (200 mL) was treated with a solution of cyanamide (2.95 g,
70.2 mmol) in dry ether (40 mL) and stirred at room temperature for
72 h. The resulting precipitate was filtered and the solution was
concentrated to dryness under reduced pressure to give 10.2 g of
the title compound.
Example 26C
N'-cyano-2-(2-methylphenyl)-N-[(1R)-1-phenylethyl]ethanimidamide
[0182] A solution of Example 26B (142 mg, 0.7 mmol) and
(R)-1-phenylethylamine (85 mg, 0.7 mmol) in absolute ethanol (1 mL
) was stirred at 60.degree. C. for 6 h. The mixture was
concentrated under reduced pressure and purified by preparative
HPLC on a Waters Symmetry C8 column (40 mm.times.100 mm, 7 .mu.m
particle size) using a gradient of 10% to 100% acetonitrile in 10
mM of aimnonium acetate over 15 min at a flow rate of 70 mL/min to
provide the title compound. MS (ESI+) m/z 277 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.46 (d, J=6.78 Hz, 3 H)
2.28 (s, 3 H) 3.83 (s, 2 H) 5.10 (m, 1 H) 6.95 (d, J=8.48 Hz, 1 H)
7.16 (m, 3 H) 7.29 (m, 1 H) 7.35 (m, 5 H) 9.37 (d, J=7.46 Hz, 1
H).
Example 27
N'-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(2-methylphenyl)ethanimidami-
de
[0183] The title compound was prepared using the procedure as
described in Example 26C, substituting
(1R)-2,3-dihydro-1H-inden-1-ylamine for (R)-1-phenylethylamine. MS
(ESI.sup.+) m/z 290 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.92 (m, 2 H) 2.31 (s, 3 H) 2.47 (m, 1 H)
2.88 (m, 1 H) 2.99 (m, 1 H) 3.86 (s, 2 H) 5.49 (q, J=7.46 Hz, 1 H)
7.12-7.32 (m, 8 H) 9.32 (d, J=7.46 Hz, 1 H).
Example 28
N'-cyano-2-(2-methylphenyl)-N-(1-methyl-1-phenylethyl)ethanimidamide
[0184] The title compound was prepared using the procedure as
described in Example 26C, substituting 1-methyl-1-phenylethylamine
for (R)-1-phenylethylamine. MS (ESI.sup.+) m/z 292 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 2.30 (s, 6 H) 3.82
(s, 2 H) 7.03 (m, 2 H) 7.20 (m, 4 H) 7.34 (d, J=4.07 Hz, 3 H) 9.11
(s, 1 H).
Example 29
N'-cyano-N-[(1R)-1-(4-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide
[0185] The title compound was prepared using the procedure as
described in Example 26C, substituting
(1R)-1-(4-fluorophenyl)ethanamine for (R)-1-phenylethylamine. MS
(ESI.sup.+) m/z 296 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.45 (d, J=6.78 Hz, 3 H) 2.28 (s, 3 H)
3.82 (s, 2 H) 5.10 (m, 1 H) 6.95 (m, 1 H) 7.19 (m, 5 H) 7.39 (dd,
J=8.48, 5.42 Hz, 2 H) 9.36 (d, J=7.46 Hz, 1 H).
Example 30
N'-cyano-2-(2-methylphenyl)-N-[(1R)-1-phenylpropyl]ethanimidamide
[0186] The title compound was prepared using the procedure as
described in Example 26C, substituting (1R)-1-phenylpropan-1-amine
for (R)-1-phenylethylamine. MS (ESI.sup.+) m/z 292 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.87 (t, J=7.29 Hz,
3 H) 1.81 (m, 2 H) 2.28 (s, 3 H) 3.84 (s, 2 H) 4.86 (m, 1 H) 6.92
(d, J=7.12 Hz, 1 H) 7.16 (m, 4 H) 7.34 (m, 4 H) 9.35 (d, J=7.80 Hz,
1 H).
Example 31
N'-cyano-2-(2-methylphenyl)-N-[1-thien-2-ylethyl]ethanimidamide
[0187] The title compound was prepared using the procedure as
described in Example 26C, substituting 1-thien-2-ylethanamine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 284 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.56 (d, J=6.78 Hz, 3 H)
2.28 (s, 3 H) 3.82 (m, 2 H) 5.40 (m, 1 H) 7.01 (m, 2 H) 7.06 (m, 2
H) 7.17 (m, 3 H) 7.46 (dd, J=5.09, 1.36 Hz, 1 H) 9.42 (d, J=7.80
Hz, 1 H).
Example 32
N'-cyano-N-[(1R)-1-(2-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide
[0188] The title compound was prepared using the procedure as
described in Example 26C, substituting
(1R)-1-(2-fluorophenyl)ethanamine for (R)-1-phenylethylamine. MS
(ESI.sup.+) m/z 296 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.47 (d, J=7.12 Hz, 3 H) 2.28 (s, 3 H)
3.83 (s, 2 H) 5.29 (m, 1 H) 6.95 (m, 1 H) 7.12 (m, 1 H) 7.19 (m, 3
H) 7.37 (m, 3 H) 9.43 (d, J=4.41 Hz, 1 H).
Example 33
N'-cyano-N-[1-(3-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide
[0189] The title compound was prepared using the procedure as
described in Example 26C, substituting 1-(3-fluorophenyl)ethanamine
for (R)-1-phenylethylamine. MS (ESI.sup.+) m/z 296 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.45 (d, J=7.12 Hz,
3 H) 2.29 (s, 3 H) 3.84 (s, 2 H) 5.12 (m, 1 H) 6.97 (m, 1 H) 7.13
(m, 3 H) 7.20 (m, 4 H) 7.42 (m, 1 H) 9.38 (d, J=7.12 Hz, 1 H).
Example 34
N'-cyano-N-[1-(3,5-difluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide
[0190] The title compound was prepared using the procedure as
described in Example 26C, substituting
1-(3,5-difluorophenyl)ethanamine for (R)-1-phenylethylamine. MS
(ESI.sup.+) m/z 314 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.44 (d, J=7.12 Hz, 2 H) 2.29 (s, 3 H)
3.85 (s, 2 H) 5.12 (m, 1 H) 6.98 (m, 1 H) 7.06 (m, 2 H) 7.17 (m, 2
H) 7.21 (m, 2 H) 9.37 (d, J=7.12 Hz, 1 H).
Example 35
N'-cyano-N-[3-(4-methoxyphenyl)-1-methylpropyl]-2-(2-methylphenyl)ethanimi-
damide
[0191] The title compound was prepared using the procedure as
described in Example 26C, substituting
3-(4-methoxyphenyl)-1-methylpropylamine for (R)-1-phenylethylamine.
mp 103-104.degree. C.; MS (ESI.sup.+) m/z 336 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.16 (d, J=6.44 Hz, 3 H)
1.73 (m, 2 H) 2.32 (s, 3 H) 2.54 (m, 2 H) 3.72 (s, 3 H) 3.80 (s, 2
H) 3.93 (m, 1 H) 6.85 (m, 2 H) 7.09 (m, 3 H) 7.21 (m, 3 H) 8.85 (d,
J=7.46 Hz, 1 H). Anal. calcd for C.sub.21H.sub.25N.sub.3O: C,
75.19; H, 7.51; N, 12.53; O, 4.77. Found: C, 74.96; H, 7.79; N:
12.34.
Example 36
N'-cyano-2-(2-methylphenyl)-N-[(1R)-1-phenylpropyl]ethanimidamide
[0192] The title compound was prepared using the procedure as
described in Example 26C, substituting (R)-1-phenylpropylamine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 292 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.87 (t, J=7.12 Hz, 3 H)
1.78 (m, 2 H) 2.28 (s, 3 H) 3.84 (s, 2 H) 4.86 (m, 1 H) 6.92 (m, 2
H) 7.24 (m, 7 H) 9.35 (d, J=7.80 Hz, 1 H).
Example 37
N'-cyano-2-(2-methylphenyl)-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]etha-
nimidamide
[0193] The title compound was prepared using the procedure as
described in Example 26C, substituting
(1R)-1,2,3,4-tetrahydronaphthalen-1-amine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 304 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.86 (m, 4 H) 2.30 (s, 3 H)
2.75 (m, 2 H) 3.85 (s, 2 H) 5.18 (m, 1 H) 7.17 (m, 8 H) 9.31 (d,
J=7.80 Hz, 1 H).
Example 38
N-[2-(2-chlorophenyl)-2-(dimethylamino)ethyl]-N'-cyano-2-(2-methylphenyl)e-
thanimidamide
[0194] The title compound was prepared using the procedure as
described in Example 26C, substituting
1-(2-chlorophenyl)-N.sup.1,N.sup.1-dimethylethane-1,2-diamine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 355 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 2.15 (s, 6 H) 2.20 (s, 3 H)
3.59 (m, 1 H) 3.76 (s, 2 H) 3.84 (m, 1 H) 4.29 (t, J=6.78 Hz, 1 H)
6.85 (m, 1 H) 7.07 (m, 1 H) 7.16 (m, 2 H) 7.34 (m, 2 H) 7.46 (m, 2
H) 8.65 (m, 1 H).
Example 39
N'-cyano-N-[1-(4-fluorophenyl)ethyl]-2-(2-methylphenyl)ethanimidamide
[0195] The title compound was prepared using the procedure as
described in Example 26C, substituting 1-(4-fluorophenyl)ethanamine
for (R)-1-phenylethylamine. MS (ESI.sup.+) m/z 296 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.45 (d, J=7.12 Hz,
3 H) 2.28 (s, 3 H) 3.82 (s, 2 H) 5.10 (m, 1 H) 6.93 (m, 1 H) 7.16
(m, 5 H) 7.39 (m, 2 H) 9.37 (d, J=7.80 Hz, 1 H).
Example 40
N'-cyano-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(2-methylphenyl)ethanimi-
damide
[0196] The title compound was prepared using the procedure as
described in Example 26C, substituting
5-fluoro-2,3-dihydro-1H-inden-1-ylamine for (R)-1-phenylethylamine.
MS (ESI.sup.+) m/z 308 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.95 (m, 1 H) 2.30 (s, 3 H) 2.55 (m, 1 H)
2.86 (m, 1 H) 2.99 (m, 1 H) 3.84 (s, 2 H) 5.44 (m, 1 H) 7.04 (m, 1
H) 7.11 (m, 2 H) 7.20 (m, 3 H) 7.32 (m, 1 H) 9.31 (d, J=7.80 Hz, 1
H). Anal. calcd for C.sub.14H.sub.8ClN.sub.4: C, 74.25; H, 5.90; N,
13.67. Found: C, 74.19; H, 5.98; N, 13.87.
Example 41
N'-cyano-N-(1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-methylphe-
nyl)ethanimidamide
[0197] The title compound was prepared using the procedure as
described in Example 26C, substituting
1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 330 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.25 (s, 3 H) 1.29 (s, 3 H)
1.95 (m, 2 H) 2.30 (s, 3 H) 2.84 (m, 2 H) 3.90 (s, 2 H) 4.21 (m, 1
H) 7.13 (m, 7 H) 7.36 (m, 1 H) 8.76 (d, J=8.81 Hz, 1 H).
Example 42
N-[2-(2-chlorophenyl)ethyl]-N'-cyano-2-(2-methylphenyl)ethanimidamide
[0198] The title compound was prepared using the procedure as
described in Example 26C, substituting 2-(2-chlorophenyl)ethanamine
for (R)-1-phenylethylamine. MS (ESI.sup.+) m/z 312 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 2.25 (s, 3 H) 2.96
(t, J=7.12 Hz, 2 H) 3.54 (m, 2 H) 3.79 (s, 2 H) 6.99 (m, 1 H) 7.22
(m, 6 H) 7.44 (m, 1 H) 8.84 (br. s., 1 H).
Example 43
N-(4-chloro-2,3-dihydro-1H-inden-1-yl)-N'-cyano-2-(2-methylphenyl)ethanimi-
damide
[0199] The title compound was prepared using the procedure as
described in Example 26C, substituting
4-chloro-2,3-dihydro-1H-inden-1-ylamine for (R)-1-phenylethylamine.
MS (ESI.sup.+) m/z 322 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.96 (m, 1 H) 2.31 (s, 3 H) 2.56 (m, 1 H)
2.94 (m, 2 H) 3.85 (s, 2 H) 5.57 (m, 1 H) 7.24 (m, 7 H) 9.35 (d,
J=7.80 Hz, 1 H).
Example 44
N'-cyano-2-(2-methylphenyl)-N-(2-morpholin-4-yl-1-phenylethyl)ethanimidami-
de
[0200] The title compound was prepared using the procedure as
described in Example 26C, substituting
2-morpholin-4-yl-1-phenylethanamine for (R)-1-phenylethylamine. MS
(ESI.sup.+) m/z 363 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 2.32 (s, 3 H) 2.37 (m, 2 H) 2.51 (m, 2 H)
2.77 (m, 2 H) 3.58 (m, 4 H) 3.86 (ABq, 2H, J=15.60 Hz,
.DELTA..nu..sub.AB=26 Hz) 3.92 (d, J=15.60 Hz, 1 H) 5.20 (m, 1 H)
7.26 (m, 9 H) 9.30 (d, J=7.80 Hz, 1 H).
Example 45
N'-cyano-2-(2-methylphenyl)-N-[(1R,2R,4R)-1,2,3,4-tetrahydro-1,4-methanona-
phthalen-2-yl]ethanimidamide
[0201] The title compound was prepared using the procedure as
described in Example 26C, substituting
(1R,2R,4R)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-2-amine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 316 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.76 (m, 4 H) 2.33 (s, 3 H)
3.39 (s, 2 H) 3.69 (m, 1 H) 3.83 (s, 2 H) 7.07 (m, 3 H) 7.23 (m, 5
H) 9.21 (d, J=7.12 Hz, 1 H).
Example 46
N'-cyano-N-[(1S,2S,4S)-6,7-dimethoxy-1,2,3,4-tetrahydro-1,4-methanonaphtha-
len-2-yl]-2-(2-methylphenyl)ethanimidamide
[0202] The title compound was prepared using the procedure as
described in Example 26C, substituting
(1S,2S,4S)-6,7-dimethoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-2-amine
for (R)-1-phenylethylamine. MS (ESI.sup.+) m/z 376 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.71 (m, 4 H) 2.33
(s, 3 H) 3.29 (m, 2 H) 3.66 (m, 1 H) 3.71 (s, 3 H) 3.73 (s, 3 H)
3.83 (s, 2 H) 6.88 (m, 1 H) 6.96 (m, 1 H) 7.06 (m, 1 H) 7.20 (m, 3
H) 9.17 (d, J=6.44 Hz, 1 H).
Example 47
N'-cyano-2-(2-methylphenyl)-N-(1-pyridin-4-ylpentyl)ethanimidamide
[0203] The title compound was prepared using the procedure as
described in Example 26C, substituting 1-pyridin-4-ylpentan-1-amine
for (R)-1-phenylethylamine. MS (ESI.sup.+) m/z 321 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.84 (t, J=6.78 Hz,
3 H) 1.28 (m, 4 H) 1.74 (m, 2 H) 2.28 (s, 3 H) 3.87 (s, 2 H) 4.92
(m, 1 H) 6.93 (m, 1 H) 7.17 (m, 3 H) 7.33 (m, 2 H) 8.55 (m, 2 H)
9.41 (d, J=7.80 Hz, 1 H).
Example 48
N'-cyano-2-(2-methylphenyl)-N-(1-pyridin-4-ylpropyl)ethanimidamide
[0204] The title compound was prepared using the procedure as
described in Example 26C, substituting 1-pyridin-4-ylpropan-1-amine
for (R)-1-phenylethylamine. MS (ESI.sup.+) m/z 293 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.89 (t, J=7.12 Hz,
3 H) 1.79 (m, 2 H) 2.29 (s, 3 H) 3.88 (s, 2 H) 4.87 (m, 1 H) 6.94
(m, 1 H) 7.17 (m, 3 H) 7.33 (m, 2 H) 8.55 (m, 2 H) 9.43 (d, J=6.78
Hz, 1 H).
Example 49
N'-cyano-2-(2-methylphenyl)-N-[1-(2-morpholin-4-ylphenyl)ethyl]ethanimidam-
ide
Example 49A
1-(2-morpholin-4-ylphenyl)ethanone
[0205] The title compound was prepared using the procedure as
described in Moehrle, H.; et al., Chemical Sciences Vol. 53(11)
pages 1369-1378 (1998).
Example 49B
1-(2-morpholin-4-ylphenyl)ethanone O-methyloxime
[0206] A mixture of Example 49A (1.22 g, 5.94 mmol) and
methoxyamine hydrochloride (550 mg, 6.59 mmol) in pyridine (20 mL)
was stirred at room temperature for 12 h. The reaction was diluted
with ethyl acetate and washed sequentially with 3 N HCl, 1 N HCl
and brine. The organic layer was dried over anhydrous magnesium
sulfate, filtered and concentrated to dryness under reduced
pressure to give 1.3 g of the title compound. MS (ESI.sup.+) m/z
235 (M+H).sup.+.
Example 49C
1-(2-morpholin-4-ylphenyl)ethanamine
[0207] A mixture of Example 49B (1.3 g, 5.54 mmol) and Raney nickel
(14 g) in a mixture of 20% NH.sub.3 in methanol (140 mL) was
hydrogenated at 60 psi for 11 hrs. The reaction was filtered and
concentrated to dryness under reduced pressure to give 1.1 g of the
title compound. MS (ESI.sup.+) m/z 207 (M+H).sup.+.
Example 49D
N'-cyano-2-(2-methylphenyl)-N-[1-(2-morpholin-4-ylphenyl)ethyl]ethanimidam-
ide
[0208] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 49C for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 363 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.41 (d, J=6.78 Hz, 3 H)
2.28 (s, 3 H) 2.70 (m, 2 H) 3.00 (m, 2 H) 3.74 (m, 4 H) 3.82 (s, 2
H) 5.61 (m, 1 H) 6.98 (m, 1 H) 7.24 (m, 7 H) 9.29 (d, J=7.46 Hz, 1
H). Anal. calcd for C.sub.22H.sub.26N.sub.4O 0.15H.sub.2O: C,
72.41; H, 7.26; N, 15.35. Found: C, 72.11; H, 7.11; N, 15.33.
Example 50
N'-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(2-fluorophenyl)ethanimidami-
de
Example 50A
ethyl 2-(2-fluorophenyl)ethanimidoate hydrochloride
[0209] The title compound was prepared using the procedure as
described in Kelley, James L. et al., Journal of Medicinal
Chemistry Vol. 38(18) pages 3676-9 (1995).
Example 50B
ethyl N-cyano-2-(2-fluorophenyl)ethanimidoate
[0210] The title compound was prepared using the procedure as
described in Example 26B, substituting Example 50A for Example 26A.
MS (ESI/NH.sub.3) m/z 206 (M+H).sup.+.
Example 50C
N'-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(2-fluorophenyl)ethanimidami-
de
[0211] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 50B for Example 26B,
and substituting (1R)-2,3-dihydro-1H-inden-1-ylamine for
(R)-1-phenylethylamine. mp 141-142.degree. C.; MS (ESI.sup.+) m/z
294 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm
1.91 (m, 1 H) 2.49 (m, 1 H) 2.92 (m, 2 H) 3.93 (s, 2 H) 5.44 (m, 1
H) 7.28 (m, 8 H) 9.39 (d, J=6.44 Hz, 1 H). Anal. calcd for
C.sub.14H.sub.8ClN.sub.4: C, 73.70; H, 5.50; N, 14.32. Found: C,
73.86; H, 5.49; N, 14.24.
Example 51
2-(2-chlorophenyl)-N'-cyano-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)ethanimi-
damide
Example 51A
ethyl 2-(2-chlorophenyl)ethanimidoate hydrochloride
[0212] The title compound was prepared using the procedure as
described in Ife, R. et al. (WO 9315055).
Example 51B
ethyl 2-(2-chlorophenyl)-N-cyanoethanimidoate
[0213] The title compound was prepared using the procedure as
described in Example 26B, substituting Example 51A for Example 26A.
MS (ESI/NH.sub.3) m/z 222 (M+H).sup.+.
Example 51C
2-(2-chlorophenyl)-N'-cyano-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)ethanimi-
damide
[0214] The title compound was prepared using the procedure as
described in Example 26C, substituting
5-fluoro-2,3-dihydro-1H-inden-1-ylamine for (R)-1-phenylethylamine.
MS (ESI.sup.+) m/z 328 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.95 (m, 1 H) 2.52 (m, 1 H) 2.91 (m, 2H)
4.00 (s, 2 H) 5.44 (m, 1 H) 7.08 (m, 2 H) 7.40 (m, 5 H) 9.29 (br.
s., 1 H).
Example 52
N'-cyano-N-(2-methylbenzyl)-3-phenylbutanimidamide
Example 52A
3-phenylbutyronitrile
[0215] The title compound was prepared using the procedure as
described in Edwards, M. and Williams, J. Angewandte Chemie,
International Edition Vol. 41(24) pages 4740-4743 (2002).
Example 52B
ethyl 3-phenylbutanimidamide hydrochloride
[0216] Through a stirred solution of Example 52A (3.9 g, 26.8 mmol)
in absolute ethanol (30 mL) was bubbled with hydrogen chloride gas
for 20 min. The mixture was allowed to stand for overnight in the
refrigerator. The product was precipitated with anhydrous ether and
filtered to obtain 4.8g of the title compound. MS (ESI/NH.sub.3)
m/z 192 (M+H).sup.+.
Example 52C
ethyl N-cyano-3-phenylbutanimidoate
[0217] The title compound was prepared using the procedure as
described in Example 26B, substituting Example 52A for Example 26A.
MS (ESI/NH.sub.3) m/z 217 (M+H).sup.+.
Example 52D
N'-cyano-N-(2-methylbenzyl)-3-phenylbutanimidamide
[0218] A mixture of Example 52C (0.1 g, 0.44 mmol) and
2-methylbenzylamine (0.2 mL) was heated to 90.degree. C. for 2.5
hours. The mixture was cooled down to room temperature and purified
by flash chromatography (eluting with 35% ethyl acetate/hexaanes)
to give the title compound as a white solid. MS (ESI/NH.sub.3) m/z
292 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.24-1.26 (d, 3H) 2.17 (s, 3H) 2.79-2.82 (d, 2H) 3.38-3.40 (m, 1H)
4.25-4.29 (m, 2H) 7.08-7.32 (m, 9H) 9.01 (t, 1H).
Example 53
N'-cyano-2-(2-methylpyridin-3-yl)-N-[(1R)-1-phenylethyl]ethanimidamide
Example 53A
(2-methylpyridin-3-yl)acetonitrile
[0219] The title compound was prepared using the procedure as
described in Murata, et al. (WO 9206978).
Example 53B
ethyl 2-(2-methylpyridin-3-yl)ethanimidoate hydrochloride
[0220] Through a stirred solution of Example 53A (1.7 g, 12.86
mmol), absolute ethanol (0.89 g, 19.35 mmol) and anhydrous
methylene chloride (25 ml) was bubbled with hydrogen chloride gas
for 20 min. The mixture was allowed to stand overnight in the
refrigerator. The product was precipitated with anhydrous ether and
filtered to obtain the title compound, which was immediately used
in the next step. MS (ESI.sup.+) m/z 180 (M+H).sup.+.
Example 53C
ethyl N-cyano-2-(2-methylpyridin-3-yl)ethanimidoate
[0221] The title compound was prepared using the procedure as
described in Example 26B, substituting Example 53B for Example 26A.
MS (ESI.sup.+) m/z 175 (M+H).sup.+.
Example 53D
N'-cyano-2-(2-methylpyridin-3-yl)-N-[(1R)-1-phenylethyl]ethanimidamide
[0222] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 53C for Example 26B.
MS (ESI.sup.+) m/z 278 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 1.46 (d, J=7.12 Hz, 3 H) 2.47 (s, 3 H)
3.89 (s, 2 H) 5.09 (m, 1 H) 7.18 (dd, J=7.80, 4.75 Hz, 1 H) 7.35
(s, 6 H) 8.34 (dd, J=4.92, 1.53 Hz, 1 H) 9.43 (d, J=7.46 Hz, 1
H).
Example 54
N'-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(2-methylpyridin-3-yl)ethani-
midamide
[0223] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 53C for Example 26B,
and substituting (1R)-2,3-dihydro-1H-inden-1-ylamine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 290 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.90 (m, 1 H) 2.47 (m, 1 H)
2.48 (s, 3 H) 2.88 (m, 1 H) 2.99 (m, 1 H) 3.91 (s, 2 H) 5.48 (dd,
J=15.00, 7.35 Hz, 1 H) 7.27 (m, 5 H) 7.51 (dd, J=7.80, 1.70 Hz, 1
H) 8.36 (dd, J=4.75, 1.70 Hz, 1 H) 9.37 (d, J=6.10 Hz, 1 H).
Example 55
N-[2-(2-chlorophenyl)ethyl]-N'-cyano-2-(2-methylpyridin-3-yl)ethanimidamid-
e
[0224] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 53C for Example 26B,
and substituting 2-(2-chlorophenyl)ethanamine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 318 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 2.45 (s, 3 H) 2.96 (t,
J=7.12 Hz, 1 H) 3.52 (t, J=7.12 Hz, 1 H) 3.57 (t, J=7.12 Hz, 1 H)
3.85 (s, 2 H) 7.19 (dd, J=7.80, 4.75 Hz, 1 H) 7.29 (m, 3 H) 7.36
(dd, J=7.80, 1.36 Hz, 1 H) 7.44 (m, 1 H) 8.36 (dd, J=4.75, 1.70 Hz,
1 H) 8.91 (t, J=5.59 Hz, 1 H).
Example 56
N'-cyano-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-(2-methylpyridin-3-yl)et-
hanimidamide
[0225] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 53C for Example 26B,
and substituting 5-fluoro-2,3-dihydro-1H-inden-1-ylamine for
(R)-1-phenylethylamine. mp 148-149.degree. C.; MS (ESI.sup.+) m/z
310 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm
1.94 (m, 1 H) 2.50 (s, 3 H) 2.56 (m, 1 H) 2.92 (m, 2 H) 3.90 (s,
2H) 5.43 (m, 1 H) 7.08 (m, 2 H) 7.23 (m, 1 H) 7.33 (m, 1 H) 7.49
(m, 1 H) 8.36 (m, 1 H) 9.35 (d, J=7.80 Hz, 1 H). Anal. caled for
C.sub.14H.sub.8ClN.sub.4: C, 70.11; H, 5.56; N, 18.17. Found: C,
69.79; H, 5.57; N, 17.82.
Example 57
N'-cyano-2-(2-methylpyridin-3-yl)-N-[(1R)-1-phenylpropyl]ethanimidamide
[0226] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 53C for Example 26B,
and substituting (1R)-1-phenylpropan-1-amine for
(R)-1-phenylethylamine. mp 52-54.degree. C.; MS (ESI.sup.+) m/z 293
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 0.87
(t, J=7.46 Hz, 3 H) 1.78 (m, 2 H) 2.47 (s, 3 H) 3.90 (s, 2 H) 4.84
(m, 1 H) 7.16 (m, 1 H) 7.32 (m, 6 H) 8.34 (m, 1 H) 9.40 (m, 1 H)
Anal. calcd for C.sub.14H.sub.8ClN.sub.4: C, 73.94; H, 6.89; N,
19.16. Found: C, 73.57; H, 7.16; N, 18.96.
Example 58
N'-cyano-2-(2-methylpyridin-3-yl)-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-y-
l]ethanimidamide
[0227] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 53C for Example 26B,
and substituting (1R)-1,2,3,4-tetrahydronaphthalen-1-amine for
(R)-1-phenylethylamine. mp 193-194.degree. C.; MS (ESI.sup.+) m/z
305 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm
1.87 (m, 4 H) 2.49 (s, 3 H) 2.75 (m, 2 H) 3.91 (s, 2 H) 5.17 (m, 1
H) 7.19 (m, 5 H) 7.49 (m, 1 H) 8.35 (m, 1 H) 9.36 (d, J=7.46 Hz, 1
H). Anal. calcd for C.sub.14H.sub.8ClN.sub.4: C, 74.97; H, 6.62; N,
18.41. Found: C, 74.60; H, 6.55; N, 18.26.
Example 59
N'-cyano-N-[1-(3,5-difluorophenyl)ethyl]-2-(2-methylpyridin-3-yl)ethanimid-
amide
[0228] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 53C for Example 26B,
and substituting 1-(3,5-difluorophenyl)ethanamine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 315 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.44 (d, J=7.12 Hz, 3 H)
2.48 (s, 3 H) 3.92 (s, 2 H) 5.11 (m, 1 H) 7.08 (m, 2 H) 7.15 (m, 1
H) 7.20 (dd, J=7.80, 4.75 Hz, 1 H) 7.37 (dd, J=7.63, 1.53 Hz, 1 H)
8.36 (dd, J=4.75, 1.70 Hz, 1 H) 9.40 (d, J=7.46 Hz, 1 H).
Example 60
N'-cyano-N-[1-(3-fluorophenyl)ethyl]-2-(2-methylpyridin-3-yl)ethanimidamid-
e
[0229] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 53C for Example 26B,
and substituting 1-(3-fluorophenyl)ethanamine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 297 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.45 (d, J=7.12 Hz, 3 H)
2.48 (s, 3 H) 3.90 (s, 2 H) 5.11 (m, 1 H) 7.19 (m, 3 H) 7.40 (s, 2
H) 8.35 (dd, J=4.75, 1.70 Hz, 1 H) 9.42 (d, J=7.46 Hz, 1 H).
Example 61
N'-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-quinolin-5-ylethanimidamide
Example 61A
quinolin-5-ylacetonitrile
[0230] The title compound was prepared using the procedure as
described in Engler, T. A. et al., Tetrahedron Letters Vol. 44(14)
pages 2903-2905 (2003).
Example 61B
ethyl 2-quinolin-5-ylethanimidoate hydrochloride
[0231] The title compound was prepared using the procedure as
described in Example 53B, substituting Example 61A for Example 53A.
MS (ESI.sup.+) m/z 214 (M+H).sup.+.
Example 61C
ethyl N-cyano-2-quinolin-5-ylethanimidoate
[0232] The title compound was prepared using the procedure as
described in Example 26B, substituting Example 61B for Example 26A.
MS (ESI.sup.+) m/z 240 (M+H).sup.+.
Example 61D
N'-cyano-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-quinolin-5-ylethanimidamide
[0233] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 61C for Example 26B
and substituting (1R)-2,3-dihydro-1H-inden-1-ylamine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 327 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.89 (m, 1 H) 2.54 (m, 1 H)
2.89 (m, 1 H) 2.99 (m, 1 H) 4.41 (s, 2 H) 5.53 (dd, J=15.00, 7.35
Hz, 1 H) 7.28 (m, 4 H) 7.48 (d, J=7.80 Hz, 1 H) 7.62 (dd, J=8.65,
4.24 Hz, 1 H) 7.77 (dd, J=8.48, 7.12 Hz, 1 H) 7.99 (d, J=8.48 Hz, 1
H) 8.57 (m, 1 H) 8.96 (dd, J=4.07, 1.70 Hz, 1 H) 9.45 (d, J=7.46
Hz, 1 H).
Example 62
N'-cyano-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-2-quinolin-5-ylethanimidamide
[0234] The title compound was prepared using the procedure as
described in Example 26C, substituting Example 61C for Example 26B
and substituting (1S)-2,3-dihydro-1H-inden-1-ylamine for
(R)-1-phenylethylamine. MS (ESI.sup.+) m/z 327 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.91 (m, 1 H) 2.54 (m, 1 H)
2.89 (m, 1 H) 2.99 (m, 1 H) 4.41 (s, 1 H) 5.53 (dd, J=15.00, 7.46
Hz, 1 H) 7.29 (m, 4 H) 7.48 (dd, J=7.12, 0.68 Hz, 1 H) 7.62 (dd,
J=8.65, 4.24 Hz, 1 H) 7.77 (dd, J=8.48, 7.12 Hz, 1 H) 7.99 (d,
J=8.48 Hz, 1 H) 8.60 (m, 1 H) 8.96 (dd, J=4.07, 1.36 Hz, 1 H) 9.45
(d, J=8.14 Hz, 1 H).
Example 63
N'-cyano-N-[1-(3,5-difluorophenyl)ethyl]-2-[2-(trifluoromethylphenyl]ethan-
imidamide
Example 63A
ethyl 2-[2-(trifluoromethyl)phenyl]ethanimidoate hydrochloride
[0235] The title compound was prepared using the procedure as
described in Example 53B, substituting
[2-(trifluoromethyl)phenyl]acetonitrile for Example 53A. MS
(ESI/NH.sub.3) m/z 231 (M+H).sup.+.
Example 63B
[0236] ethyl N-cyano-2-[2-(trifluoromethyl)phenyl]ethanimidoate
[0237] The title compound was prepared using the procedure as
described in Example 26B, substituting Example 63A for Example 26A.
MS (ESI/NH.sub.3) m/z 256 (M+H).sup.+.
Example 63C
N'-cyano-N-[1-(3,5-difluorophenyl)ethyl]-2-[2-(trifluoromethyl)phenyl]etha-
nimidamide
[0238] The title compound from was prepared using the procedure as
described in Example 26C, substituting Example 63B for Example 26B
and substituting 1-(3,5-difluorophenyl)ethylamine for
(R)-1-phenylethylamine. MS (ESI/NH.sub.3) m/z 367 (M+H).sup.+;
.sup.1H NMR (DMSO-d.sub.6) .delta. 1.44-1.47 (d, 3H), 4.13 (s, 2H),
5.13-5.18 (m, 1H), 7.10-7.20 (m, 4H), 7.53-7.56 (t, 1H), 7.63-7.66
(t, 1H), 7.78-7.81 (d, 1H), 9.40-9.42 (d, 1H).
(f) DETERMINATION OF BIOLOGICAL ACTIVITY
1. In vitro Experiments
[0239] (a) Tissue Culture: Cells of the THP-1 monocytic cell line
(American Type Culture Collection, Rockville, Md.) were maintained
in the log phase of growth in RPMI medium containing high glucose
and 10% fetal calf serum (Invitrogen, Carlsbad, Calif.) according
to established procedures (Humphrey B D and Dubyak G R, J.
Immunology Vol. 157, pages 5627-37 (1996)). Fresh vials of frozen
THP-1 cells were initiated for growth every eight weeks. To
differentiate THP-1 cells into a macrophage phenotype, a final
concentration of 25 ng/ml of lipopolysaccharide (LPS) and 10 ng/ml
of IFN.gamma. were added to the cells either for 3 hours for
IL-1.beta. release assays.
[0240] (b) P2X.sub.7 Mediated IL-1.beta. Release: Activation of
P2X7 receptors also induces secretion of IL-1.beta. (Verhoef et
al., above; Brough et al., Molecular and Cellular Neuroscience,
Vol. 19, pages 272-280, 2002). THP-1 cells were plated in 24-well
plates at a density of 1.times.10.sup.6 cells/well/mL. On the day
of the experiment, cells were differentiated with 25 ng/ml LPS and
10 ng/mL final concentration of .gamma.IFN for 3 hours at
37.degree. C. Solutions of antagonist compounds were prepared by
serial dilutions of a 10 mM DMSO solution of the antagonist into
the PBS solution. In the presence of the differentiation media, the
cells were incubated with the antagonists of the present invention
for 30 minutes at 37.degree. C. followed by a challenge with 1 mM
BzATP for an additional 30 minutes at 37.degree. C. Supernatants of
the samples were collected after a 5 minute centrifugation in
microfuge tubes to pellet the cells and debris and to test for
mature IL-1.beta. released into the supernatant using either R
& D Systems Human IL-1.beta. ELISA assay or Endogen Human
IL-1.beta. ELISA, following the manufacturer's instructions. The
maximum IL-1.beta. release at each concentration of test compound
was normalized to that induced by BzATP alone to determine the
activity of the test compound. Antagonist compounds were tested for
activity over a concentration range from 0.001 to 100 .mu.M.
Antagonist potency was expressed as the concentration producing a
50% reduction in release of IL-1.beta. or IC.sub.50. For each
experiment, differentiated control cells were also measured over
the 60 min time course of the assay to assess background IL-1.beta.
accumulation. This non-specific background IL-1.beta. release,
typically averaged 3-8% of the maximum BzATP response, was
subtracted from the maximum BzATP-induced release and all release
values normalized to the BzATP-induced response. Representative
compounds of the present invention when tested with the above assay
demonstrated antagonist activity at the P2X.sub.7 receptor with
IC.sub.50's equal or less than 10 .mu.M.
[0241] (c) P2X.sub.7 Mediated Pore Formation. Activation of the
P2X.sub.7 receptor induces nonspecific pore formation and
eventually cell lysis (Verhoef et al., The Journal of Immunology,
Vol. 170, pages 5728-5738, 2003). Accordingly, the inhibitory
activity of the antagonists of the present invention was determined
by their capacity to inhibit the agonist-induced pore formation
using the fluorescent dye YO-PRO (MW=629) and Fluorometric Imaging
Plate Reader (FLIPR, Molecular Devices, Sunnydale, Calif.). Prior
to YO-PRO dye addition, the cells were rinsed once in PBS without
Mg.sup.2+ or Ca.sup.2+ ions, which have been shown to inhibit pore
formation (Michel et al, N--S Arch Pharmacol 359:102-109, 1999).
The YO-PRO iodide dye (1 mM in DMSO) was diluted to a final
concentration of 2 .mu.M in phosphate buffered saline (PBS without
Mg.sup.2+ or Ca.sup.2+) and then placed on the cells prior to the
addition of the agonist BzATP. Since the THP-1 cells are a
non-adherent cell line, the cells were washed in PBS and loaded
with the dye in a conical tube prior to spinning the cells onto
poly-lysine-coated black-walled 96-well plates, which were utilized
to reduce light scattering. After the addition of the agonist BzATP
(50 .mu.M, the EC.sub.70 value for agonist activation), the YO-PRO
dye uptake was observed in the FLIPR apparatus equipped with an
Argon laser (wavelength=488 nm) and a CCD camera. The intensity of
the fluorescence was captured by the CCD camera every 15 seconds
for the first 10 minutes of agonist exposure followed by every 20
seconds for an additional 50 minutes with the data being digitally
transferred to an interfaced PC. The exposure setting of the camera
was 0.25 sec with an f-stop setting of 2. Solutions of antagonist
compounds were prepared by serial dilutions of a 10 mM DMSO
solution of the antagonist into the buffer solution with the YO-PRO
dye. Antagonist compounds were tested for activity over a
concentration range from 0.003 to 100 .mu.M. The test compounds
were incubated for 10 minutes with the THP-1 cells at room
temperature, after which the cells were stimulated with BzATP and
fluorescence measured as described above in the absence of the
antagonist. For antagonist activity measurements, the percent
maximal intensity was normalized to that induced by 50 .mu.M BzATP
and plotted against each concentration of compound to calculate
IC.sub.50 values and account for plate-to-plate variability
2. In vivo Experiments--Determination of Analgesic Activity
[0242] Adult male Sprague-Dawley rats (250-300 g), Charles River
Laboratories, Portage, Mich. were used in this study. Animal
handling and experimental protocols were approved by the
Institutional Animal Care and Use Committee (IACUC) at Abbott
Laboratories. For all surgical procedures, animals were maintained
under halothane anesthesia (4% to induce, 2% to maintain), and the
incision sites were sterilized using a 10% povidone-iodine solution
prior to and after surgeries.
[0243] (a) Spinal Nerve ligation: A model of spinal nerve
ligation-induced neuropathic pain was produced using the procedure
originally described by Kim and Chung (Kim and Chung, Pain, Vol. 50
pages 355-363, 1992). The left L5 and L6 spinal nerves of the rat
were isolated adjacent to the vertebral column and tightly ligated
with a 5-0 silk suture distal to the DRG, and care was taken to
avoid injury of the L4 spinal nerve. Sham rats underwent the same
procedure, but without nerve ligation. All animals were allowed to
recover for at least 1 week and not more than 3 weeks prior to
assessment of mechanical allodynia. Mechanical allodynia in the
left hind paw was confirmed by comparing the paw withdrawal
threshold in grams for the injured left paw and the uninjured right
paw. Mechanical allodynia was measured using calibrated von Frey
filaments (Stoelting, Wood Dale, Ill.). Rats were placed into
inverted individual plastic containers (20.times.12.5.times.20 cm)
on top of a suspended wire mesh grid, and acclimated to the test
chambers for 20 min. The von Frey filaments were presented
perpendicularly to the plantar surface of the selected hind paw,
and then held in this position for approximately 8 sec with enough
force to cause a slight bend in the filament. Positive responses
included an abrupt withdrawal of the hind paw from the stimulus, or
flinching behavior immediately following removal of the stimulus. A
50% withdrawal threshold was determined using an up-down procedure
(Dixon, Ann. Rev. Pharmacol. Toxicol., Vol. 20, pages 441-462,
1980). Prior to compound administration, animals demonstrating
motor deficit or failure to exhibit subsequent mechanical allodynia
were excluded from further studies. The antinociceptive activity of
a test compound was determined by comparing its ability to increase
the paw withdrawal threshold of the injured left paw relative to
vehicle (0%) and the uninjured right paw (100%). Activity of test
compounds was determined 60 minutes after an oral dose or 30
minutes after an intraperitoneal dose. Dose-response curves as well
as single dose responses were performed. Representative compounds
had effective doses (ED.sub.50's) equal to or less than 500
.mu.mol/kg.
[0244] (b) Complete Freund's adjuvant-induced thermal hyperalgesia:
Unilateral inflammation was induced by injecting 150 .mu.L of a 50%
solution of complete Freund's adjuvant (CFA) (Sigma Chemical Co.,
St. Louis, Mo.) in physiological saline into the plantar surface of
the right hindpaw of the rat. The hyperalgesia to thermal
stimulation was determined 48 hr after CFA injections using a
commercially available paw thermal stimulator (UARDG, Department of
Anesthesiology, University of California, San Diego, La Jolla,
Calif.). Rats were placed individually in Plexiglass cubicles
mounted on a glass surface maintained at 30.degree. C., and allowed
a 30 min habituation period. A thermal stimulus, in the form of
radiant heat emitted from a focused projection bulb, was then
applied to the plantar surface of each hind paw. The stimulus
current was maintained at 4.5 Amp and the maximum time of exposure
was set at 20 sec to limit possible tissue damage. In each test
session, each rat was tested in 3 sequential trials at
approximately 5 min intervals. Paw withdrawal latencies were
calculated as the mean of the two shortest latencies. The
antinociceptive activity of a test compound was determined by
comparing its ability to increase the paw withdrawal threshold of
the injured right paw relative to vehicle (0%) and the uninjured
left paw (100%). Activity of test compounds was determined 60
minutes after an oral dose or 30 minutes after an intraperitoneal
dose. Dose-response curves as well as single dose responses were
performed. Representative compounds had effective doses
(ED.sub.50's) equal to or less than 500 .mu.mol/kg.
[0245] (c) Zymosan Method: Mice were dosed with experimental
compounds orally or subcutaneously 30 minutes prior to injection of
zymosan. Mice were then injected intraperitonealy with 2 mg/animal
of zymosan suspended in saline. Four hours later the animals were
euthanized by CO.sub.2 inhalation and the peritoneal cavities
lavaged with 2.times.1.5 mL of ice cold phosphate buffered saline
containing 10 units of heparin/ml. For IL-1.beta. determination the
samples were spun at 10,000.times.g in a refrigerated microfuge
(4.degree. C.), supernatants removed and frozen until ELISAs
(Enzyme Linked Immuno-Assay) were performed. ELISAs were performed
according to manufacture's instructions. IL-1.beta. was determined
relative to vehicle control (Perretti M. et al., Agents Actions Vol
35(1-2) pages 71-78 (1992); Torok K, et al., Inflamm Res. Vol 44(6)
pages 248-252 (1995)). A representative compound of this invention
exhibited inhibition of IL-1.beta. release in this assay with an
ED.sub.50 of 90 .mu.mol/kg, sc.
* * * * *