U.S. patent application number 13/625508 was filed with the patent office on 2013-02-14 for substituted aryl sulfone derivatives as calcium channel blockers.
This patent application is currently assigned to Neuromed Pharmaceuticals Ltd.. The applicant listed for this patent is Merck Sharp & Dohme Corp., Neuromed Pharmaceuticals Ltd.. Invention is credited to Prasun K. Chakravarty, Yangbing Ding, Joseph L. Duffy, Hassan Pajouhesh, Pencheng Patrick Shao, Sriram Tyagarajan, Feng Ye.
Application Number | 20130040932 13/625508 |
Document ID | / |
Family ID | 40526515 |
Filed Date | 2013-02-14 |
United States Patent
Application |
20130040932 |
Kind Code |
A1 |
Chakravarty; Prasun K. ; et
al. |
February 14, 2013 |
SUBSTITUTED ARYL SULFONE DERIVATIVES AS CALCIUM CHANNEL
BLOCKERS
Abstract
A series of substituted aryl sulfone derivatives represented by
Formula I, or pharmaceutically acceptable salts thereof.
Pharmaceutical compositions comprise an effective amount of the
instant compounds, either alone, or in combination with one or more
other therapeutically active compounds, and a pharmaceutically
acceptable carrier. Methods of treating conditions associated with,
or caused by, calcium channel activity, including, for example,
acute pain, chronic pain, visceral pain, inflammatory pain,
neuropathic pain, urinary incontinence, itchiness, allergic
dermatitis, epilepsy, diabetic neuropathy, irritable bowel
syndrome, depression, anxiety, multiple sclerosis, sleep disorder,
bipolar disorder and stroke, comprise administering an effective
amount of the present compounds, either alone, or in combination
with one or more other therapeutically active compounds.
Inventors: |
Chakravarty; Prasun K.;
(Edison, NJ) ; Ding; Yangbing; (Richmond, CA)
; Duffy; Joseph L.; (Cranford, NJ) ; Pajouhesh;
Hassan; (West Vancouver, CA) ; Shao; Pencheng
Patrick; (Fanwood, NJ) ; Tyagarajan; Sriram;
(Edison, NJ) ; Ye; Feng; (Scotch Plains,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Merck Sharp & Dohme Corp.;
Neuromed Pharmaceuticals Ltd.; |
Rahway
Vancouver |
NJ |
US
CA |
|
|
Assignee: |
Neuromed Pharmaceuticals
Ltd.
Vancouver
NJ
Merck Sharp & Dohme Corp.
Rahway
|
Family ID: |
40526515 |
Appl. No.: |
13/625508 |
Filed: |
September 24, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12678454 |
Mar 16, 2010 |
8304434 |
|
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PCT/US08/11286 |
Sep 30, 2008 |
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13625508 |
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60997615 |
Oct 4, 2007 |
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Current U.S.
Class: |
514/210.18 ;
514/210.17; 514/249; 514/259.3; 514/300; 514/313; 514/318; 514/322;
514/326; 514/330; 514/423; 548/539; 548/953 |
Current CPC
Class: |
A61P 25/04 20180101;
C07D 401/10 20130101; A61P 13/10 20180101; A61P 35/00 20180101;
C07D 417/14 20130101; A61P 25/20 20180101; A61P 29/00 20180101;
C07D 401/14 20130101; A61P 9/12 20180101; C07D 205/04 20130101;
A61P 25/06 20180101; C07D 413/06 20130101; C07D 211/24 20130101;
C07D 413/04 20130101; A61P 9/00 20180101; A61P 25/22 20180101; A61P
15/00 20180101; A61P 43/00 20180101; A61P 25/16 20180101; C07D
211/98 20130101; C07D 417/04 20130101; C07D 487/04 20130101; A61P
17/04 20180101; C07D 207/08 20130101; A61P 3/10 20180101; C07D
417/06 20130101; A61P 37/08 20180101; C07D 401/06 20130101; A61P
17/00 20180101; C07D 471/04 20130101; C07D 401/12 20130101; A61P
25/18 20180101; C07D 473/04 20130101; A61P 25/24 20180101; A61P
25/08 20180101; C07D 401/08 20130101 |
Class at
Publication: |
514/210.18 ;
548/953; 514/210.17; 548/539; 514/423; 514/330; 514/318; 514/313;
514/326; 514/249; 514/322; 514/259.3; 514/300 |
International
Class: |
C07D 205/04 20060101
C07D205/04; C07D 207/08 20060101 C07D207/08; A61K 31/40 20060101
A61K031/40; A61K 31/445 20060101 A61K031/445; A61K 31/4545 20060101
A61K031/4545; A61P 25/20 20060101 A61P025/20; A61K 31/454 20060101
A61K031/454; A61K 31/498 20060101 A61K031/498; A61K 31/519 20060101
A61K031/519; A61K 31/4523 20060101 A61K031/4523; A61P 29/00
20060101 A61P029/00; A61P 25/08 20060101 A61P025/08; A61K 31/397
20060101 A61K031/397; A61K 31/4709 20060101 A61K031/4709 |
Claims
1-15. (canceled)
16. compound of structural formula I: ##STR00463## and
pharmaceutically acceptable salts thereof and individual
enantiomers and diastereomers thereof: X is a bond,
CR.sup.10R.sup.11, C.dbd.O, C.dbd.ONR.sup.10, CO.sub.2, SO.sub.2,
C.sub.6-10 aryl, or C.sub.5-10 heteroaryl; Y is CR.sup.10R.sup.11,
C.dbd.O or absent; Z is CR.sup.10R.sup.11, C.dbd.O or absent;
R.sup.1 is H, C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl, OR.sup.10,
C(O)R.sup.10, (CH.sub.2).sub.nC.sub.5-10 heterocycle,
(CH.sub.2).sub.nC.sub.6-10 aryl, (CH.sub.2).sub.nC.sub.5-10
heteroaryl, fused aryl or fused heteroaryl, wherein said alkyl,
cycloalkyl, heterocycle, aryl and heteroaryl is optionally
substituted with one to three groups of R.sup.a; R.sup.2 is H,
C.sub.1-4 alkyl and C.sub.1-4-perfluoroalkyl, C.sub.3-5-cycloalkyl,
C.sub.6-10 aryl, C.sub.5-10 heteroaryl, F, Cl, CN,
NR.sup.10R.sup.11, wherein said alkyl, cycloalkyl, aryl and
heteroaryl is optionally substituted with one to three groups of
R.sup.a; R.sup.3 and R.sup.4 are each and independently selected
from H, or C.sub.1-6 alkyl, C.sub.1-4-perfluoroalkyl,
C.sub.3-7-cycloalkyl, C.sub.6-10 aryl, C.sub.5-10 heteroaryl, F,
Cl, CN, OR.sup.10, NR.sup.10R.sup.11, SO.sub.2R.sup.10,
SO.sub.2NR.sup.10R.sup.11, CO.sub.2R.sup.10, CONHR.sup.10,
CONR.sup.10R.sup.11, or R.sup.3 and R.sup.4 join to form a 3-7
member carbocyclic or heterocyclic ring, wherein said alkyl,
cycloalkyl, heterocycle, aryl and heteroaryl is optionally
substituted with one to three groups of R.sup.a; R.sup.5 is
C.sub.6-10 aryl, C.sub.5-10 heteroaryl, C.sub.3-7 cycloalkyl,
C.sub.5-10 heterocycle, wherein said cycloalkyl, heterocycle, aryl
and heteroaryl is optionally substituted with one to three groups
of R.sup.a; R.sup.6, R.sup.7, R.sup.8, and R.sup.9 independently
represent H, C.sub.1-4alkyl and C.sub.1-4 perfluoroalkyl,
C.sub.3-6-cycloalkyl, C.sub.6-10 aryl, C.sub.5-10 heteroaryl, F,
Cl, CN, Ole, NR.sup.10R.sup.11, or R.sup.8 and R.sup.9 combined
with the carbon atom they are attached to can form C(O); R.sup.10
and R.sup.11 are each and independently selected from H, or
C.sub.1-6alkyl, (CH.sub.2).sub.nC.sub.1-4-fluoroalkyl,
C.sub.3-7cycloalkyl, C.sub.6-10 aryl, C.sub.5-10 heteroaryl, or
R.sup.10 and R.sup.11 join to form a 3-7 member carbocyclic or
heterocyclic ring with the atom to which they are attached; said
alkyl, aryl, or heteroaryl optionally substituted with 1 to 3
groups of R.sup.a, n represents 0 to 6, and R.sup.a represents
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4-fluoroalkyl,
C.sub.6-10 aryl, C.sub.5-10 heteroaryl, halogen, CN, --OCF.sub.3,
--OCHF.sub.2, --C(O)CF.sub.3, --C(OR.sup.10)(CF.sub.3).sub.2,
SR.sup.10, --OR.sup.10, NR.sup.10R.sup.11, SOR.sup.10,
SO.sub.2R.sup.10, NR.sup.10COR.sup.11, NR.sup.10COOR.sup.11,
NR.sup.10CONR.sup.10R.sup.11, NR.sup.10SO.sub.2NR.sup.10R.sup.11,
SO.sub.2NR.sup.10R.sup.11, NR.sup.10SO.sub.2R.sup.11,
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, said aryl and heteroaryl
optionally substituted with 1 to 3 groups of C.sub.1-6 alkyl,
C.sub.3-7 cycloalkyl, halogen, CF.sub.3, CN or OR.sup.10; with the
proviso that at least one of Y and Z is absent, and with the
proviso that when X.dbd.SO.sub.2, the compound of formula I cannot
be 4-[(4-Chlorobenzenesulfonyl)(2,5-difluorophenyl)methyl]-1-(trif-
luoromethanesulfonyl)piperidine; or
4-[(4-Chlorobenzenesulfonyl)(2,5-difluorophenyl)methyl]-1-(methanesulfony-
l)piperidine; or when X.dbd.C.dbd.O, the compound of formula I
cannot be
4-[[[4-[[5-[2-(2-Aminobenzothiazol-6-yl)vinyl]pyrimidin-2-yl]amino]phenyl-
]sulfonyl]-methyl]piperidine-1-carboxylic acid tert-butyl ester;
4-[[[4-[(5-Vinylpyrimidin-2-yl)amino]phenyl]sulfonyl]methyl]piperidine-1--
carboxylic acid tert-butyl ester; Piperidinecarboxylic acid,
4-[[[4-[[5-[(1E)-2-(3-methoxyphenyl)ethenyl]-2-pyrimidinyl]amino]phenyl]s-
ulfonyl]methyl]-,1,1-dimethylethyl ester;
4-[[(4-Bromophenyl)sulfonyl]methyl]piperidine-1-carboxylic acid
tert-butyl ester; Piperidinecarboxylic acid,
4-[[(4-fluorophenyl)sulfonyl]methyl]; Piperidinecarboxylic acid,
4-[[(2-fluorophenyl)sulfonyl]methyl]-,1,1-dimethylethyl ester;
Piperidinecarboxylic acid,
3-hydroxy-4-[[[4-(methylthio)phenyl]sulfonyl]methyl]-,1,1-dimethylethyl
ester, (3R,4S); tert-Butyl
4-[(4-chlorobenzenesulfonyl)(2,5-difluorophenyl)methyl]piperidine-1-carbo-
xylate;
4-[[(4-Fluorophenyl)sulfonyl]methyl]-1-piperidinecarboxylate
hydrochloride; tert-Butyl
4-[[(4-fluorophenyl)sulfonyl]methyl]-1-piperidinecarboxylate; or
Piperidine, 1-(bromoacetyl)-4-[[(4-methylphenyl)sulfonyl]methyl];
or when Y and Z are CH.sub.2, X is not CR.sup.10R.sup.11; or the
compound of formula I is not
piperidinyl-1-(bromoacetyl-4-[[4-methylphenyl)sulfonyl]methyl], or
benzonitrilyl-4-[4-[[(4-fluorophenyl)sulfonyl]methyl]-4-hydroxy-1-piperid-
inyl]-2-(trifluoromethyl).
17. The compound according to claim 16 wherein X is C.dbd.O,
R.sup.1 is (CH.sub.2).sub.nC.sub.5-10 heterocycle,
(CH.sub.2).sub.nC.sub.6-10 aryl, (CH.sub.2).sub.nC.sub.5-10
heteroaryl, fused aryl or fused heteroaryl, and R.sup.5 is
C.sub.6-10 aryl, C.sub.5-10 heteroaryl, or C.sub.5-10 heterocycle,
wherein said heterocycle, aryl and heteroaryl is optionally
substituted with one to three groups of R.sup.a.
18. The compound according to claim 17 wherein R.sup.1
(CH.sub.2).sub.nC.sub.6-10 aryl.
19. The compound according to claim 17 wherein R.sup.1 is
(CH.sub.2).sub.nC.sub.5-10 (CH.sub.2).sub.nC.sub.5-10
heteroaryl.
20. The compound according to claim 16 represented by structural
formula Ib: ##STR00464## wherein X is C.dbd.O and R.sup.2 is H, and
pharmaceutically acceptable salts thereof and individual
enantiomers and diastereomers thereof.
21. The compound according to claim 16 represented by structural
formula Ic: ##STR00465## wherein X is C.dbd.O and R.sup.2 is H, and
pharmaceutically acceptable salts thereof and individual
enantiomers and diastereomers thereof.
22. A compound which is:
1-[5-fluoro-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl-
)phenyl]-sulfonyl}ethyl)azetidine; tert-butyl
3-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine-1-carboxylate;
tert-butyl
3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine-1-carb-
oxylate;
1-[2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl]-3-({[3-(trifluo-
romethyl)phenyl]sulfonyl}-methyl)azetidine;
1-[2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl]-3-({[3-(trifluoromethyl-
)phenyl]sulfonyl}-methyl)azetidine;
1-[4-(methylsulfonyl)-2-(trifluoromethoxy)benzoyl]-3-({[3-(trifluoromethy-
l)phenyl]sulfonyl}-methyl)azetidine;
1-[2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl]-3-(1-methyl-1-{[3-(trif-
luoromethyl)phenyl]-sulfonyl}ethyl)azetidine;
1-[4-(difluoromethoxy)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-
sulfonyl}-ethyl)azetidine;
1-[2-(difluoromethoxy)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-
sulfonyl}ethyl)-azetidine;
1-[5-fluoro-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl-
)phenyl]sulfonyl}-ethyl)azetidine;
1-[3-(difluoromethoxy)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-
sulfonyl}ethyl)-azetidine;
1-[4-methoxy-3-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethy-
l)phenyl]sulfonyl}-ethyl)azetidine;
1-[4-(difluoromethoxy)-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trif-
luoromethyl)phenyl]-sulfonyl}ethyl) azetidine;
1-[4-(tert-butylsulfonyl)-2-chlorobenzoyl]-3-(1-methyl-1-{[3-(trifluorome-
thyl)phenyl]-sulfonyl}ethyl)azetidine;
1-[2-bromo-4-(tert-butylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromet-
hyl)phenyl]-sulfonyl}ethyl)azetidine;
1-[4-(tert-butylsulfonyl)-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(t-
rifluoromethyl)phenyl]-sulfonyl}ethyl)azetidine;
1-[2-chloro-4-(isopropylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromet-
hyl)phenyl]-sulfonyl}ethyl)azetidine;
1-[4-(isopropylsulfonyl)-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(tr-
ifluoromethyl)phenyl]-sulfonyl}ethyl)azetidine;
1-[4-methoxy-2,6-bis(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoro-
methyl)phenyl]-sulfonyl}ethyl)azetidine;
1-[4-(difluoromethoxy)-2,6-bis(methylsulfonyl)-benzoyl]-3-(1-methyl-1-{[3-
-(trifluoromethyl)-phenyl]sulfonyl}ethyl)azetidine;
1-[4-(cyclopropyloxy)-2,6-bis(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(-
trifluoromethyl)-phenyl]sulfonyl}ethyl)azetidine;
1-[2,6-bis(methylsulfonyl)-4-(trifluoromethoxy)benzoyl]-3-(1-methyl-1-{[3-
-(trifluoromethyl)-phenyl]sulfonyl}ethyl)azetidine;
(3R)-1-[4-(cyclopropyloxy)-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(-
trifluoromethyl)-phenyl]sulfonyl}ethyl)pyrrolidine;
(3R)-1-[4-(cyclopropyloxy)-2,6-bis(methylsulfonyl)benzoyl]-3-(1-methyl-1--
{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)pyrrolidine;
(3R)-1-[4-(cyclopropylsulfonyl)-2-methoxybenzoyl]-3-(1-methyl-1-{[3-(trif-
luoromethyl)phenyl]-sulfonyl}ethyl)pyrrolidine; or pharmaceutically
acceptable salts thereof and individual enantiomers and
diastereomers thereof.
23. A pharmaceutical composition comprising an inert carrier and an
effective amount of a compound according to claim 16.
24. A method for treating or preventing chronic or acute pain in a
mammalian patient in need thereof comprising administering to said
patient a therapeutically effective amount, or a prophylactically
effective amount, of a compound according structural formula I:
##STR00466## and pharmaceutically acceptable salts thereof and
individual enantiomers and diastereomers thereof: X is a bond,
CR.sup.10R.sup.11, C.dbd.O, C.dbd.ONR.sup.10, CO.sub.2, SO.sub.2,
C.sub.6-10 aryl, or C.sub.5-10 heteroaryl; Y is CR.sup.10R.sup.11,
C.dbd.O or absent; Z is CR.sup.10R.sup.11, C.dbd.O or absent;
R.sup.1 is C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl, OR.sup.10,
(CH.sub.2).sub.nC.sub.5-10 heterocycle, (CH.sub.2).sub.nC.sub.6-10
aryl, (CH.sub.2).sub.nC.sub.5-10 heteroaryl, fused aryl or fused
heteroaryl, wherein said alkyl, cycloalkyl, heterocycle, aryl and
heteroaryl is optionally substituted with one to three groups of
R.sup.a; R.sup.2 is H, C.sub.1-4 alkyl and
C.sub.1-4-perfluoroalkyl, C.sub.3-5-cycloalkyl, C.sub.6-10 aryl,
C.sub.5-10 heteroaryl, F, Cl, CN, NR.sup.10R.sup.11, wherein said
alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted
with one to three groups of R.sup.a; R.sup.3 and R.sup.4 are each
and independently selected from H, or C.sub.1-6 alkyl,
C.sub.1-4-perfluoroalkyl, C.sub.3-7-cycloalkyl, C.sub.6-10 aryl,
C.sub.5-10 heteroaryl, F, Cl, CN, OR.sup.10, NR.sup.10R.sup.11,
SO.sub.2R.sup.10, SO.sub.2NR.sup.10R.sup.11, CO.sub.2R.sup.10,
CONHR.sup.10, CONR.sup.10R.sup.11, or R.sup.3 and R.sup.4 join to
form a 3-7 member carbocyclic or heterocyclic ring, wherein said
alkyl, cycloalkyl, heterocycle, aryl and heteroaryl is optionally
substituted with one to three groups of R.sup.a; R.sup.5 is
C.sub.6-10 aryl, C.sub.5-10 heteroaryl, C.sub.3-7 cycloalkyl,
C.sub.5-10 heterocycle, wherein said cycloalkyl, heterocycle, aryl
and heteroaryl is optionally substituted with one to three groups
of R.sup.a; R.sup.6, R.sup.7, R.sup.8, and R.sup.9 independently
represent H, C.sub.1-4alkyl and C.sub.1-4 perfluoroalkyl,
C.sub.3-6-cycloalkyl, C.sub.6-10 aryl, C.sub.5-10 heteroaryl, F,
Cl, CN, OR.sup.10, NR.sup.10R.sup.11; R.sup.10 and R.sup.11 are
each and independently selected from H, or C.sub.1-6alkyl,
(CH.sub.2).sub.nC.sub.1-4-fluoroalkyl, C.sub.3-7cycloalkyl,
C.sub.6-10 aryl, C.sub.5-10 heteroaryl, or R.sup.10 and R.sup.11
join to form a 3-7 member carbocyclic or heterocyclic ring with the
atom to which they are attached; said alkyl, aryl, or heteroaryl
optionally substituted with 1 to 3 groups of R.sup.a, n represents
0 to 6, and R.sup.a represents C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, C.sub.1-4-fluoroalkyl, C.sub.6-10 aryl, C.sub.5-10
heteroaryl, halogen, CN, --OCF.sub.3, --OCHF.sub.2, --C(O)CF.sub.3,
--C(OR.sup.10)(CF.sub.3).sub.2, SR.sup.10, --OR.sup.10,
NR.sup.10R.sup.11, SO.sub.2R.sup.10, SO.sub.2NR.sup.10R.sup.11,
NR.sup.10SO.sub.2R.sup.11, CO.sub.2R.sup.10, CONR.sup.10R.sup.11,
said aryl and heteroaryl optionally substituted with 1 to 3 groups
of C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, halogen or OR.sup.10.
25. A method for treating or preventing chronic or acute pain in a
mammalian patient in need thereof comprising administering to said
patient a therapeutically effective amount, or a prophylactically
effective amount, of a compound according to claim 1, or a
pharmaceutically acceptable salt thereof.
26. A method for treating or controlling epilepsy in a mammalian
patient in need thereof which comprises administering to the
patient a therapeutically effective amount of the compound of claim
1, or a pharmaceutically acceptable salt thereof.
27. A method for enhancing the quality of sleep in a mammalian
patient in need thereof which comprises administering to the
patient a therapeutically effective amount of the compound of claim
1 or a pharmaceutically acceptable salt thereof.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a series of substituted aryl
sulfone derivatives. In particular, this invention relates to
substituted aryl sulfone derivatives that are N-type voltage-gated
calcium channel blockers useful for the treatment of a variety of
pain conditions including chronic and neuropathic pain. The
compounds of the present invention also display activity in
connection with blockage of T-type voltage-gated calcium channels.
The compounds described in this invention are useful for the
treatment of chronic and acute pain, including neuropathic,
inflammatory, and visceral pain. The compounds described in this
invention are also useful for the treatment of conditions including
disorders of bladder function, pruritis, itchiness, allergic
dermatitis and disorders of the central nervous system (CNS) such
as stroke, epilepsy, essential tremor, schizophrenia, Parkinson's
disease, manic depression, bipolar disorder, depression, anxiety,
sleep disorder, diabetic neuropathy, hypertension, cancer,
diabetes, infertility and sexual dysfunction.
BACKGROUND TO THE INVENTION
[0002] Ion channels control a wide range of cellular activities in
both excitable and non-excitable cells (Hille, Bertil--"Ion
Channels of Excitable Membranes", 3rd Edition, (2001), 814 pp;
Sinauer Associates, Sunderlan, Mass., USA). Ion channels are
attractive therapeutic targets due to their involvement in many
physiological processes. In excitable cells, the coordinated
function of the resident set of ion channels controls the
electrical behavior of the cell. Plasma membrane calcium channels
are members of a diverse superfamily of voltage gated channel
proteins. Calcium channels are membrane-spanning, multi-subunit
proteins that allow controlled entry of Ca2+ ions into cells from
the extracellular fluid. Excitable cells throughout the animal
kingdom, and at least some bacterial, fungal and plant cells,
possess one or more types of calcium channel. Nearly all
"excitable" cells in animals, such as neurons of the central
nervous system (CNS), peripheral nerve cells and muscle cells,
including those of skeletal muscles, cardiac muscles, and venous
and arterial smooth muscles, have voltage-gated calcium channels.
Voltage-gated calcium channels provide an important link between
electrical activity at the plasma membrane and cell activities that
are dependent on intracellular calcium, including muscle
contraction, neurotransmitter release, hormone secretion and gene
expression. Voltage-gated calcium channels serve to integrate and
transduce plasma membrane electrical activity into changes in
intracellular calcium concentration, and can do this on a rapid
time scale.
[0003] Multiple types of calcium channels have been identified in
mammalian cells from various tissues, including skeletal muscle,
cardiac muscle, lung, smooth muscle and brain. A major family of
this type is the L-type calcium channels, which include
Ca.sub.v1.1, Ca.sub.v1.2, Ca.sub.v1.3, and Ca.sub.v1.4, whose
function is inhibited by the familiar classes of calcium channel
blockers (dihydropyridines such as nifedipine, phenylalkylamines
such as verapamil, and benzothiazepines such as diltiazem).
Additional classes of plasma membrane calcium channels are referred
to as T (Ca.sub.v3.1, Ca.sub.v3.2, and Cav3.3), N (Ca.sub.v2.2),
P/Q (Ca.sub.v2.1) and R (Ca.sub.v2.3). The "T-type" (or "low
voltage-activated") calcium channels are so named because they open
for a shorter duration (T=transient) than the longer
(L=long-lasting) openings of the L-type calcium channels. The L, N,
P and Q-type channels activate at more positive potentials (high
voltage activated) and display diverse kinetics and
voltage-dependent properties.
[0004] Because of the crucial role in cell physiology, modulation
of calcium channel activity can have profound effects. Mutations in
calcium channel subunits have been implicated in a number of
genetic diseases including familial hemiplegic migraine,
spinocerebellar ataxia, Timothy Syndrome, incomplete congenital
stationary night blindness and familial hypokalemic periodic
paralysis. Modulation of voltage-gated calcium channels by
signaling pathways, including c-AMP-dependent protein kinases and G
proteins is an important component of signaling by hormones and
neurotransmitters (Catteall, W. A., Ann. Rev. Cell and Dev. Biol.
16, 521-555 (2000)). Pharmacological modulation of calcium channels
can have significant therapeutic effects, including the use of
L-type calcium channel (Ca.sub.v1.2) blockers in the treatment of
hypertension (Hockerman, G. H et. al, Proc. Natl Acad Sci. (USA)
94, 14906-1491 (1997)) and more recently, use of Ziconitide, a
peptide blocker of N-type calcium channels (Ca.sub.v2.2), for the
treatment of intractable pain (Staals, P. S. et. al, Journal of the
American Medical Association 291, 63-70 (2004)). Zicontide is
derived from Conotoxin, a peptide toxin isolated from cone snail
venom, must be applied by intrathecal injection to allow its access
to a site of action in the spinal cord and to minimize exposure to
channels in the autonomic nervous system that are involved in
regulating cardiovascular function. Ziconotide has also been shown
to highly effective as a neuroprotective agent in rat models of
global and focal ischemia (Colborne et. Al., Stroke 30, 662-668
(1999)) suggesting that modulation of N-type calcium channels
(Ca.sub.v2.2) has implication in the treatment of stroke.
[0005] Clinical and preclinical experiments with ziconitide and
related peptides confirm a key role of N-type calcium channels in
transmitting nociceptive signals into the spinal cord.
Identification of N-type calcium channel blockers that can be
administered systemically, and effectively block N-type calcium
channels in the nociceptive signaling pathway, while sparing N-type
calcium channel function in the periphery would provide important
new tools for treating some forms of pain. The present invention
describes blockers of N-type calcium channels (Ca.sub.v2.2) that
display functional selectivity by blocking N-type calcium channel
activity needed to maintain pathological nociceptive signaling,
while exhibiting a lesser potency at blocking N-type calcium
channels involved in maintaining normal cardiovascular
function.
[0006] There are three subtypes of T-type calcium channels that
have been identified from various warm blooded animals including
rat [J Biol. Chem. 276(6) 3999-4011 (2001); Eur J Neurosci
11(12):4171-8 (1999); reviewed in Cell Mol Life Sci 56(7-8):660-9
(1999)]. These subtypes are termed .alpha.1G, .alpha.1H, and
.alpha.1I, and the molecular properties of these channels
demonstrate 60-70% homology in the amino acid sequences. The
electrophysiological characterization of these individual subtypes
has revealed differences in their voltage-dependent activation,
inactivation, deactivation and steady-state inactivation levels and
their selectivity to various ions such as barium (J Biol. Chem.
276(6) 3999-4011 (2001)). Pharmacologically, these subtypes have
shown differing sensitivities to blockade by ionic nickel. These
channel subtypes are also expressed in various forms due to their
ability to undergo various splicing events during their assembly (J
Biol. Chem. 276 (6) 3999-4011 (2001)).
[0007] U.S. Pat. Nos. 6,011,035; 6,294,533; and 6,617,322; and
publication numbers WO2007/075525, US2004/044004, JP2002/088073,
WO2007085357, W2007028638, WO94/22835, US20030408, and
WO2004/096217, describe calcium channel blockers in the treatment
of pain. See also WO2004/031138, WO2003084948, WO2003/075853,
WO2001/025200, WO2007056075, WO2005000798 and WO2002/055516.
[0008] T-type calcium channels have been implicated in pathologies
related to various diseases and disorders, including epilepsy,
essential tremor, pain, neuropathic pain, schizophrenia,
Parkinson's disease, depression, anxiety, sleep disorders, sleep
disturbances, psychosis, schizophrenia, cardiac arrhythmia,
hypertension, pain, cancer, diabetes, infertility and sexual
dysfunction (J Neuroscience, 14, 5485 (1994); Drugs Future 30(6),
573-580 (2005); EMBO J, 24, 315-324 (2005); Drug Discovery Today,
11, 5/6, 245-253 (2006)).
SUMMARY OF THE INVENTION
[0009] The present invention is directed to a series of substituted
aryl sulfone derivatives that are N-type calcium channel (Cav2.2)
blockers useful for the treatment of acute pain, chronic pain,
cancer pain, visceral pain, inflammatory pain, neuropathic pain,
post-herpetic neuralgia, diabatic neuropathy, trigeminal neuralgia,
migrane, fibromyalgia and stroke. The compounds of the present
invention also display activities on T-type voltage-activated
calcium channels (Cav 3.1 and Cav 3.2). The compounds described in
this invention are also useful for the treatment of other
conditions, including disorders of bladder function, pruritis,
itchiness, allergic dermatitis and disorders of the central nervous
system (CNS) such as stroke, epilepsy, essential tremor,
schizophrenia, Parkinson's disease, manic depression, bipolar
disorder, depression, anxiety, sleep disorder, hypertension,
cancer, diabetes, infertility and sexual dysfunction. This
invention also provides pharmaceutical compositions comprising a
compound of the present invention, either alone, or in combination
with one or more therapeutically active compounds, and a
pharmaceutically acceptable carrier. The compounds of the present
invention provide greater stability and maintain Cav2.2 potency and
efficacy than prior known sulfonamides.
[0010] This invention further comprises methods for the treatment
of acute pain, chronic pain, visceral pain, inflammatory pain,
neuropathic pain and disorders of the CNS including, but not
limited to, epilepsy, manic depression, depression, anxiety and
bipolar disorder comprising administering the compounds and
pharmaceutical compositions of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The compounds of this invention are represented by Formula
I:
##STR00001##
and pharmaceutically acceptable salts thereof and individual
enantiomers and diastereomers thereof: X is a bond,
CR.sup.10R.sup.11, C.dbd.O, C.dbd.ONR.sup.10, CO.sub.2, SO.sub.2,
C.sub.6-10 aryl, or C.sub.5-10 heteroaryl; Y is CR.sup.10R.sup.11,
C.dbd.O or absent; Z is CR.sup.10R.sup.11, C.dbd.O or absent;
R.sup.1 is H, C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl, OR.sup.10,
C(O)R.sup.10, (CH.sub.2).sub.nC.sub.5-10 heterocycle,
(CH.sub.2).sub.nC.sub.6-10 aryl, (CH.sub.2).sub.nC.sub.5-10
heteroaryl, fused aryl or fused heteroaryl, wherein said alkyl,
cycloalkyl, heterocycle, aryl and heteroaryl is optionally
substituted with one to three groups of R.sup.a; R.sup.2 is H,
C.sub.1-4 alkyl and C.sub.1-4-perfluoroalkyl, C.sub.3-5-cycloalkyl,
C.sub.6-10 aryl, C.sub.5-10 heteroaryl, F, Cl, CN,
NR.sup.10R.sup.11, wherein said alkyl, cycloalkyl, aryl and
heteroaryl is optionally substituted with one to three groups of
R.sup.a; R.sup.3 and R.sup.4 are each and independently selected
from H, or C.sub.1-6 alkyl, C.sub.1-4-perfluoroalkyl,
C.sub.3-7-cycloalkyl, C.sub.6-10 aryl, C.sub.5-10 heteroaryl, F,
Cl, CN, OR.sup.10, NR.sup.10R.sup.11, SO.sub.2R.sup.10,
SO.sub.2NR.sup.10R.sup.11, CO.sub.2R.sup.10, CONHR.sup.10,
CONR.sup.10R.sup.11, or R.sup.3 and R.sup.4 join to form a 3-7
member carbocyclic or heterocyclic ring, wherein said alkyl,
cycloalkyl, heterocycle, aryl and heteroaryl is optionally
substituted with one to three groups of R.sup.a; R.sup.5 is
C.sub.6-10 aryl, C.sub.5-10 heteroaryl, C.sub.3-7 cycloalkyl,
C.sub.5-10 heterocycle, wherein said cycloalkyl, heterocycle, aryl
and heteroaryl is optionally substituted with one to three groups
of R.sup.a; R.sup.6, R.sup.7, R.sup.8, and R.sup.9 independently
represent H, C.sub.1-4alkyl and C.sub.1-4 perfluoroalkyl,
C.sub.3-6-cycloalkyl, C.sub.6-10 aryl, C.sub.5-10 heteroaryl, F,
Cl, CN, OR.sup.10, NR.sup.10R.sup.11, or R.sup.8 and R.sup.9
combined with the carbon atom they are attached to can form C(O);
R.sup.10 and R.sup.11 are each and independently selected from H,
or C.sub.1-6alkyl, (CH.sub.2).sub.nC.sub.1-4-fluoroalkyl,
C.sub.3-7cycloalkyl, C.sub.6-10 aryl, C.sub.5-10 heteroaryl, or
R.sup.10 and R.sup.11 join to form a 3-7 member carbocyclic or
heterocyclic ring with the atom to which they are attached; said
alkyl, aryl, or heteroaryl optionally substituted with 1 to 3
groups of R.sup.a, n represents 0 to 6, and R.sup.a represents
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4-fluoroalkyl,
C.sub.6-10 aryl, C.sub.5-10 heteroaryl, halogen, CN, --OCF.sub.3,
--OCHF.sub.2, --C(O)CF.sub.3, --C(OR.sup.10)(CF.sub.3).sub.2,
SR.sup.10, --OR.sup.10, NR.sup.10R.sup.11, SOR.sup.10,
SO.sub.2R.sup.10, NR.sup.10COR.sup.11, NR.sup.10COOR.sup.11,
NR.sup.10CONR.sup.10R.sup.11, NR.sup.10SO.sub.2NR.sup.10R.sup.11,
SO.sub.2NR.sup.10R.sup.11, NR.sup.10SO.sub.2R.sup.11,
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, said aryl and heteroaryl
optionally substituted with 1 to 3 groups of C.sub.1-6 alkyl,
C.sub.3-7 cycloalkyl, halogen, CF.sub.3, CN or OR.sup.10; with the
proviso that when X.dbd.SO.sub.2, the compound of formula I cannot
be
4-[(4-Chlorobenzenesulfonyl)(2,5-difluorophenyl)methyl]-1-(trifluorometha-
nesulfonyl)piperidine; or
4-[(4-Chlorobenzenesulfonyl)(2,5-difluorophenyl)methyl]-1-(methanesulfony-
l)piperidine; or when X.dbd.C.dbd.O, the compound of formula I
cannot be
4-[[[4-[[5-[2-(2-Aminobenzothiazol-6-yl)vinyl]pyrimidin-2-yl]amino]phenyl-
]sulfonyl]-methyl]piperidine-1-carboxylic acid tert-butyl ester;
4-[[[4-[(5-Vinylpyrimidin-2-yl)amino]phenyl]sulfonyl]methyl]piperidine-1--
carboxylic acid tert-butyl ester; Piperidinecarboxylic acid,
4-[[[4-[[5-[(1E)-2-(3-methoxyphenyl)ethenyl]-2-pyrimidinyl]amino]phenyl]s-
ulfonyl]methyl]-,1,1-dimethylethyl ester;
4-[[(4-Bromophenyl)sulfonyl]methyl]piperidine-1-carboxylic acid
tert-butyl ester; Piperidinecarboxylic acid,
4-[[(4-fluorophenyl)sulfonyl]methyl]; Piperidinecarboxylic acid,
4-[[(2-fluorophenyl)sulfonyl]methyl]-,1,1-dimethylethyl ester;
Piperidinecarboxylic acid,
3-hydroxy-4-[[[4-(methylthio)phenyl]sulfonyl]methyl]-,1,1-dimethylethyl
ester, (3R,4S); tert-Butyl
4-[(4-chlorobenzenesulfonyl)(2,5-difluorophenyl)methyl]piperidine-1-carbo-
xylate;
4-[[(4-Fluorophenyl)sulfonyl]methyl]-1-piperidinecarboxylate
hydrochloride; tert-Butyl
4-[[(4-fluorophenyl)sulfonyl]methyl]-1-piperidinecarboxylate; or
Piperidine, 1-(bromoacetyl)-4-[[(4-methylphenyl)sulfonyl]methyl];
or when Y and Z are CH.sub.2, X is not CR.sup.10R.sup.11; or the
compound of formula I is not
piperidinyl-1-(bromoacetyl-4-[[4-methylphenyl)sulfonyl]methyl], or
benzonitrilyl-4-[4-[[(4-fluorophenyl)sulfonyl]methyl]-4-hydroxy-1-piperid-
inyl]-2-(trifluoromethyl).
[0012] One embodiment of the present invention is realized when X
is C.dbd.O and R.sup.1 is (CH.sub.2).sub.nC.sub.5-10 heterocycle,
(CH.sub.2).sub.nC.sub.6-10 aryl, (CH.sub.2).sub.nC.sub.5-10
heteroaryl, fused aryl or fused heteroaryl, wherein said
heterocycle, aryl and heteroaryl is optionally substituted with one
to three groups of R.sup.a and all other variables are as described
herein. A sub-embodiment of this invention is realized when R.sup.1
is phenyl, or pyridyl optionally substituted with 1 to 3 groups of
R.sup.a, and all other variables are as described herein. Still
another sub-embodiment of this invention is realized when R.sup.a
is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4-fluoroalkyl
halogen, CN, --OCF.sub.3, --OCHF.sub.2, OR.sup.10, or
SO.sub.2R.sup.10.
[0013] Another embodiment of the present invention is realized when
X is C.dbd.O and R.sup.1 is C.sub.1-6 alkyl, wherein said alkyl is
optionally substituted with one to three groups of R.sup.a and all
other variables are as described herein.
[0014] Another embodiment of the present invention is realized when
X is C.dbd.O and R.sup.5 is C.sub.6-10 aryl, C.sub.5-10 heteroaryl,
or C.sub.5-10 heterocycle, wherein said heterocycle, aryl and
heteroaryl is optionally substituted with one to three groups of
R.sup.a and all other variables are as described herein. A
sub-embodiment of this invention is realized when R.sup.5 is
phenyl, or pyridyl, optionally substituted with 1 to 3 groups of
R.sup.a, and all other variables are as described herein. Still
another sub-embodiment of this invention is realized when R.sup.a
is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4-fluoroalkyl
halogen, CN, --OCF.sub.3, --OCHF.sub.2, OR.sup.10, or
SO.sub.2R.sup.10.
[0015] In another embodiment of the present invention X is
C.sub.6-10 aryl, or C.sub.5-10 heteroaryl and all other variables
are as described herein.
[0016] In another embodiment of the present invention X is C.dbd.O
and all other variables are as described herein.
[0017] In another embodiment of the present invention Y is absent
and all other variables are as described herein.
[0018] In another embodiment of the present invention Y is
CR.sup.10R.sup.11, and all other variables are as described
herein.
[0019] In another embodiment of the present invention Y is C.dbd.O
and all other variables are as described herein.
[0020] In another embodiment of the present invention Z is C.dbd.O
and all other variables are as described herein.
[0021] In still another embodiment of the present invention Z is
absent and all other variables are as described herein.
[0022] In another embodiment of the present invention Z is
CR.sup.10R.sup.11 and all other variables are as described
herein.
[0023] In another embodiment of the present invention R.sup.1 is
phenyl optionally substituted with 1 to 3 groups of R.sup.a and all
other variables are as described herein.
[0024] In another embodiment of the present invention R.sup.1 is
pyridyl optionally substituted with 1 to 3 groups of R.sup.a and
all other variables are as described herein.
[0025] In another embodiment of the present invention R5 is phenyl
optionally substituted with 1 to 3 groups of R.sup.a and all other
variables are as described herein.
[0026] In another embodiment of the present invention R.sup.5 is
pyridyl optionally substituted with 1 to 3 groups of R.sup.a and
all other variables are as described herein.
[0027] In yet another embodiment of the present invention, both Y
and Z are CH.sub.2, and R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are
each H and all other variables are as described herein, as depicted
in
##STR00002##
[0028] A sub-embodiment of structural formula Ia is realized when X
is C.dbd.O and R.sup.2 is H. A further sub-embodiment is realized
when both R.sup.3 and R.sup.4 are H or CH.sub.3, or one of R.sup.3
and R.sup.4 is H and the other is CH.sub.3, with the resulting
stereocenter having either the R or S stereochemical configuration.
Still another sub-embodiment of this invention is realized when
R.sup.1 is C.sub.1-6 alkyl, phenyl, or pyridyl all optionally
substituted with 1 to 3 groups of R.sup.a. Yet another
sub-embodiment of this invention is realized when R.sup.5 is phenyl
or pyridyl optionally substituted with 1 to 3 groups of R.sup.a.
Another sub-embodiment of this invention is realized when both
R.sup.1 and R.sup.5 are phenyl, optionally substituted with 1 to 3
groups of R.sup.a. Another sub-embodiment of this invention is
realized one of R.sup.1 and R.sup.5 is phenyl and the other is
pyridyl, said phenyl and pyridyl optionally substituted with 1 to 3
groups of R.sup.a.
[0029] In still another embodiment of the present invention, Y is
CH.sub.2, Z is absent, and R.sup.6, R.sup.7, R.sup.8, and R.sup.9
are each H and all other variables are as described herein, as
depicted in formula Ib:
##STR00003##
[0030] A sub-embodiment of structural Ib is realized when X is
C.dbd.O and R.sup.2 is H.
A further sub-embodiment of this invention is realized when both
R.sup.3 and R.sup.4 are CH.sub.3. Still another sub-embodiment of
this invention is realized when R.sup.1 is C.sub.1-6 alkyl, phenyl,
or pyridyl all optionally substituted with 1 to 3 groups of
R.sup.a. Yet another sub-embodiment of this invention is realized
when R.sup.5 is phenyl or pyridyl optionally substituted with 1 to
3 groups of R.sup.a. Another sub-embodiment of this invention is
realized when both R.sup.1 and R.sup.5 are phenyl, optionally
substituted with 1 to 3 groups of R.sup.a. Another sub-embodiment
of this invention is realized when one of R.sup.1 and R.sup.5 is
phenyl and the other is pyridyl, said phenyl and pyridyl optionally
substituted with 1 to 3 groups of R.sup.a.
[0031] In still another embodiment of the present invention, both Y
and Z are absent, and R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are
each H and all other variables are as described herein, as depicted
in Ic:
##STR00004##
[0032] A sub-embodiment of structural Ic is realized when X is
C.dbd.O and R.sup.2 is H.
A further sub-embodiment of this invention is realized when both
R.sup.3 and R.sup.4 are H or CH.sub.3. Still another sub-embodiment
of this invention is realized when R.sup.1 is C.sub.1-6 alkyl,
phenyl, or pyridyl all optionally substituted with 1 to 3 groups of
R.sup.a. Yet another sub-embodiment of this invention is realized
when R.sup.5 is phenyl or pyridyl optionally substituted with 1 to
3 groups of R.sup.a. Another sub-embodiment of this invention is
realized when both R.sup.1 and R.sup.5 are phenyl, optionally
substituted with 1 to 3 groups of R.sup.a. Another sub-embodiment
of this invention is realized when one of R.sup.1 and R.sup.5 is
phenyl and the other is pyridyl, said phenyl and pyridyl optionally
substituted with 1 to 3 groups of R.sup.a.
[0033] In another embodiment of the compounds of the present
invention, Ar is aryl, both Y and Z are CH.sub.2, R.sup.2 is H, and
both R.sup.3 and R.sup.4 are CH.sub.3, and R.sup.6, R.sup.7,
R.sup.8, and R.sup.9 are each H and all other variables are as
described herein, as depicted in Id:
##STR00005##
A sub-embodiment of this invention is realized when Ar is phenyl
optionally substituted with 1 to 3 groups of R.sup.a. Yet another
sub-embodiment of this invention is realized when R.sup.5 is phenyl
or pyridyl optionally substituted with 1 to 3 groups of R.sup.a.
Another sub-embodiment of this invention is realized when both Ar
and R.sup.5 are phenyl, optionally substituted with 1 to 3 groups
of R.sup.a. Another sub-embodiment of this invention is realized
when Ar is phenyl and R.sup.5 is pyridyl, said phenyl and pyridyl
optionally substituted with 1 to 3 groups of R.sup.a.
[0034] In another embodiment of the present invention, Het is
heteroaryl, both Y and Z are CH.sub.2, R.sup.2 is H, both R.sup.3
and R.sup.4 are CH.sub.3, and R.sup.6, R.sup.7, R.sup.8, and
R.sup.9 are each H and all other variables are as described herein,
as depicted in Ie:
##STR00006##
A sub-embodiment of formula Ie invention is realized when Het is
pyridyl optionally substituted with 1 to 3 groups of R.sup.a. Yet
another sub-embodiment of this invention is realized when R.sup.5
is phenyl or pyridyl optionally substituted with 1 to 3 groups of
R.sup.a. Another sub-embodiment of this invention is realized when
R.sup.5 is phenyl, optionally substituted with 1 to 3 groups of
R.sup.a.
[0035] When any variable (e.g. aryl, heterocycle, R.sup.1, R.sup.5
etc.) occurs more than one time in any constituent, its definition
on each occurrence is independent at every other occurrence. Also,
combinations of substituents/or variables are permissible only if
such combinations result in stable compounds.
[0036] When R.sup.a is --O-- and attached to a carbon it is
referred to as a carbonyl group and when it is attached to a
nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it
is referred to a N-oxide and sulfoxide group, respectively.
[0037] As used herein, "alkyl" encompasses groups having the prefix
"alk" such as, for example, alkoxy, alkanoyl, alkenyl, and alkynyl
and means carbon chains which may be linear or branched or
combinations thereof. Examples of alkyl groups include methyl,
ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl,
hexyl, and heptyl. "Alkenyl" refers to a hydrocarbon radical
straight, branched or cyclic containing from 2 to 10 carbon atoms
and at least one carbon to carbon double bond. Preferred alkenyl
groups include ethenyl, propenyl, butenyl and cyclohexenyl.
Preferably, alkenyl is C.sub.2-C.sub.6 alkenyl. Preferred alkynyla
are C.sub.2-C.sub.6 alkynyl.
"Alkenyl," "alkynyl" and other like terms include carbon chains
containing at least one unsaturated C--C bond.
[0038] As used herein, "fluoroalkyl" refers to an alkyl substituent
as described herein containing at least one flurine
substituent.
[0039] The term "cycloalkyl" refers to a saturated hydrocarbon
containing one ring having a specified number of carbon atoms.
Examples of cycloalkyl include cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl.
[0040] The term "C.sub.1-6" includes alkyls containing 6, 5, 4, 3,
2, or 1 carbon atoms
[0041] The term "alkoxy" as used herein, alone or in combination,
includes an alkyl group connected to the oxy connecting atom. The
term "alkoxy" also includes alkyl ether groups, where the term
`alkyl` is defined above, and `ether` means two alkyl groups with
an oxygen atom between them. Examples of suitable alkoxy groups
include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy,
t-butoxy, methoxymethane (also referred to as `dimethyl ether`),
and methoxyethane (also referred to as `ethyl methyl ether`).
[0042] As used herein, "aryl" is intended to mean any stable
monocyclic or bicyclic carbon ring of up to 7 members in each ring,
wherein at least one ring is aromatic. Examples of such aryl
elements include phenyl, napthyl, tetrahydronapthyl, indanyl, or
biphenyl.
[0043] The term heterocycle, heterocyclyl, or heterocyclic, as used
herein, represents a stable 5- to 7-membered monocyclic or stable
8- to 11-membered bicyclic heterocyclic ring which is either
saturated or unsaturated, and which consists of carbon atoms and
from one to four heteroatoms selected from the group consisting of
N, O, and S, and including any bicyclic group in which any of the
above-defined heterocyclic rings is fused to a benzene ring. The
heterocyclic ring may be attached at any heteroatom or carbon atom
which results in the creation of a stable structure. The term
heterocycle or heterocyclic includes heteroaryl and
heterocycloalkyl moieties. Examples of such heterocyclic elements
include, but are not limited to, azepinyl, benzimidazolyl,
benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,
cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,
dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,
1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl,
indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl,
isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl,
naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl,
piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl,
pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl,
quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl. An
embodiment of the examples of such heterocyclic elements include,
but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl,
benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl,
dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl,
imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl,
isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,
isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl,
2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, 2-pyridinonyl,
pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl,
pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,
tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl,
thienofuryl, thienothienyl, thienyl and triazolyl.
[0044] In certain embodiments, the heterocyclic group is a
heteroaryl group. As used herein, the term "heteroaryl" refers to
groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring
atoms; having 6, 10, or 14.pi. electrons shared in a cyclic array;
and having, in addition to carbon atoms, between one and about
three heteroatoms selected from the group consisting of N, O, and
S. heteroaryl groups include, without limitation, thienyl,
benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl,
imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,
quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl,
thiazolyl, and isoxazolyl.
[0045] In certain other embodiments, the heterocyclic group is
fused to an aryl or heteroaryl group. Examples of such fused
heterocycles include, without limitation, tetrahydroquinolinyl and
dihydrobenzofuranyl.
[0046] The term "heteroaryl", as used herein except where noted,
represents a stable 5- to 7-membered monocyclic- or stable 9- to
10-membered fused bicyclic heterocyclic ring system which contains
an aromatic ring, any ring of which may be saturated, such as
piperidinyl, partially saturated, or unsaturated, such as
pyridinyl, and which consists of carbon atoms and from one to four
heteroatoms selected from the group consisting of N, O and S, and
wherein the nitrogen and sulfur heteroatoms may optionally be
oxidized, and the nitrogen heteroatom may optionally be
quaternized, and including any bicyclic group in which any of the
above-defined heterocyclic rings is fused to a benzene ring. The
heterocyclic ring may be attached at any heteroatom or carbon atom
which results in the creation of a stable structure. Examples of
such heteroaryl groups include, but are not limited to,
benzimidazole, benzisothiazole, benzisoxazole, benzofuran,
benzothiazole, benzothiophene, benzotriazole, benzoxazole,
carboline, cinnoline, furan, furazan, imidazole, indazole, indole,
indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine,
oxadiazole, oxazole, phthalazine, pteridine, purine, pyran,
pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,
quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole,
thiazole, thiophene, triazine, triazole, and N-oxides thereof.
[0047] Examples of heterocycloalkyls include azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one,
and thiomorpholinyl.
[0048] The term "heteroatom" means O, S or N, selected on an
independent basis.
[0049] A moiety that is substituted is one in which one or more
hydrogens have been independently replaced with another chemical
substituent. As a non-limiting example, substituted phenyls include
2-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl,
2,4-fluor-3-propylphenyl. As another non-limiting example,
substituted n-octyls include 2,4 dimethyl-5-ethyl-octyl and
3-cyclopentyloctyl. Included within this definition are methylenes
(--CH.sub.2--) substituted with oxygen to form carbonyl
(--CO--).
[0050] Unless otherwise stated, as employed herein, when a moiety
(e.g., cycloalkyl, hydrocarbyl, aryl, alkyl, heteroaryl,
heterocyclic, urea, etc.) is described as "optionally substituted"
it is meant that the group optionally has from one to four,
preferably from one to three, more preferably one or two,
non-hydrogen substituents. Suitable substituents include, without
limitation, halo, hydroxy, oxo (e.g., an annular --CH-- substituted
with oxo is --C(O)--), nitro, halohydrocarbyl, hydrocarbyl, aryl,
aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl,
arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl,
alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido,
aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido
groups. Preferred substituents, which are themselves not further
substituted (unless expressly stated otherwise) are:
[0051] (a) halo, cyano, oxo, carboxy, formyl, nitro, amino,
amidino, guanidino, and
[0052] (b) C.sub.1-C.sub.6 alkyl or alkenyl or arylalkyl imino,
carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl,
alkylaryl, arylalkyl, C.sub.1-C.sub.8 alkyl, SO.sub.2CF.sub.3,
CF.sub.3, SO.sub.2Me, C.sub.1-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkoxy, C.sub.1-C.sub.8 alkoxycarbonyl, aryloxycarbonyl,
C.sub.2-C.sub.8 acyl, C.sub.2-C.sub.8 acylamino, C.sub.1-C.sub.8
alkylthio, arylalkylthio, arylthio, C.sub.1-C.sub.8alkylsulfinyl,
arylalkylsulfnyl, arylsulfnyl, C.sub.1-C.sub.8 alkylsulfonyl,
arylalkylsulfonyl, arylsulfonyl, C.sub.0-C.sub.6 N-alkylcarbamoyl,
C.sub.2-C.sub.15 N,N dialkylcarbamoyl, C.sub.3-C.sub.7 cycloalkyl,
aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl
or heterocycle or another aryl ring, C.sub.3-C.sub.7 heterocycle,
or any of these rings fused or spiro-fused to a cycloalkyl,
heterocyclyl, or aryl, wherein each of the foregoing is further
optionally substituted with one more moieties listed in (a),
above.
[0053] "Halogen" refers to fluorine, chlorine, bromine and
iodine.
[0054] The term "mammal" "mammalian" or "mammals" includes humans,
as well as animals, such as dogs, cats, horses, pigs and
cattle.
[0055] Compounds described herein may contain one or more double
bonds and may thus give rise to cis/trans isomers as well as other
conformational isomers. The present invention includes all such
possible isomers as well as mixtures of such isomers unless
specifically stated otherwise.
[0056] The compounds of the present invention may contain one or
more asymmetric centers and may thus occur as racemates, racemic
mixtures, single enantiomers, diastereomeric mixtures, and
individual diastereomers.
[0057] It will be understood that, as used herein, references to
the compounds of structural formula I are meant to also include the
pharmaceutically acceptable salts, and also salts that are not
pharmaceutically acceptable when they are used as precursors to the
free compounds or in other synthetic manipulations.
[0058] The compounds of the present invention may be administered
in the form of a pharmaceutically acceptable salt. The term
"pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids. When the
compound of the present invention is acidic, its corresponding salt
can be conveniently prepared from pharmaceutically acceptable
non-toxic bases, including inorganic bases and organic bases. Salts
derived from such inorganic bases include aluminum, ammonium,
calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium,
manganese (ic and ous), potassium, sodium, zinc and the like salts.
Salts derived from pharmaceutically acceptable organic non-toxic
bases include salts of primary, secondary, and tertiary amines, as
well as cyclic amines and substituted amines such as naturally
occurring and synthesized substituted amines. Other
pharmaceutically acceptable organic non-toxic bases from which
salts can be formed include ion exchange resins such as, for
example, arginine, betaine, caffeine, choline,
N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethylamine, trimethylamine,
tripropylamine, and tromethamine.
[0059] When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include, for example, acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid and the like.
[0060] The pharmaceutical compositions of the present invention
comprise compounds of the invention (or pharmaceutically acceptable
salts thereof) as an active ingredient, a pharmaceutically
acceptable carrier, and optionally one or more additional
therapeutic agents or adjuvants. Such additional therapeutic agents
can include, for example, i) opiate agonists or antagonists, ii)
calcium channel antagonists, iii) 5HT receptor agonists or
antagonists, iv) sodium channel antagonists, v) NMDA receptor
agonists or antagonists, vi) COX-2 selective inhibitors, vii) NK1
antagonists, viii) non-steroidal anti-inflammatory drugs ("NSAID"),
ix) selective serotonin reuptake inhibitors ("SSRI") and/or
selective serotonin and norepinephrine reuptake inhibitors
("SSNRI"), x) tricyclic antidepressant drugs, xi) norepinephrine
modulators, xii) lithium, xiii) valproate, xiv) neurontin
(gabapentin), xv) pregabalin, and xvi) sodium channel blockers. The
instant compositions include compositions suitable for oral,
rectal, topical, and parenteral (including subcutaneous,
intramuscular, and intravenous) administration, although the most
suitable route in any given case will depend on the particular
host, and nature and severity of the conditions for which the
active ingredient is being administered. The pharmaceutical
compositions may be conveniently presented in unit dosage form and
prepared by any of the methods well known in the art of
pharmacy.
[0061] The present compounds and compositions are useful for the
treatment of chronic, visceral, inflammatory and neuropathic pain
syndromes. They are useful for the treatment of pain resulting from
traumatic nerve injury, nerve compression or entrapment,
postherpetic neuralgia, trigeminal neuralgia, small fiber
neuropathy, and diabetic neuropathy. The present compounds and
compositions are also useful for the treatment of chronic lower
back pain, phantom limb pain, chronic pelvic pain, neuroma pain,
complex regional pain syndrome, chronic arthritic pain and related
neuralgias, and pain associated with cancer, chemotherapy, HIV and
HIV treatment-induced neuropathy. Compounds of this invention may
also be utilized as local anesthetics. Compounds of this invention
are useful for the treatment of irritable bowel syndrome and
related disorders, as well as Crohn's disease.
[0062] The instant compounds have clinical uses for the treatment
of epilepsy and partial and generalized tonic seizures. They are
also useful for neuroprotection under ischaemic conditions caused
by stroke or neural trauma and for treating multiple sclerosis. The
present compounds are useful for the treatment of
tachy-arrhythmias. Additionally, the instant compounds are useful
for the treatment of neuropsychiatric disorders, including mood
disorders, such as depression or more particularly depressive
disorders, for example, single episodic or recurrent major
depressive disorders and dysthymic disorders, or bipolar disorders,
for example, bipolar I disorder, bipolar II disorder and
cyclothymic disorder; anxiety disorders, such as panic disorder
with or without agoraphobia, agoraphobia without history of panic
disorder, specific phobias, for example, specific animal phobias,
social phobias, obsessive-compulsive disorder, stress disorders
including post-traumatic stress disorder and acute stress disorder,
and generalised anxiety disorders.
[0063] In addition to primates, such as humans, a variety of other
mammals can be treated according to the method of the present
invention. For instance, mammals including, but not limited to,
cows, sheep, goats, horses, dogs, cats guinea pigs, or other
bovine, ovine, equine, canine, feline, rodent such as mouse,
species can be treated. However, the method can also be practiced
in other species, such as avian species (e.g., chickens).
[0064] It will be appreciated that for the treatment of depression
or anxiety, a compound of the present invention may be used in
conjunction with other anti-depressant or anti-anxiety agents, such
as norepinephrine reuptake inhibitors, selective serotonin reuptake
inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs),
reversible inhibitors of monoamine oxidase (RIMAs), serotonin and
noradrenaline reuptake inhibitors (SNRIs), .alpha.-adrenoreceptor
antagonists, atypical anti-depressants, benzodiazepines,
5-HT.sub.1A agonists or antagonists, especially 5-HT.sub.1A partial
agonists, neurokinin-1 receptor antagonists, corticotropin
releasing factor (CRF) antagonists, and pharmaceutically acceptable
salts thereof.
[0065] Further, it is understood that compounds of this invention
can be administered at prophylactically effective dosage levels to
prevent the above-recited conditions and disorders, as well as to
prevent other conditions and disorders associated with calcium
channel activity.
[0066] Creams, ointments, jellies, solutions, or suspensions
containing the instant compounds can be employed for topical use.
Mouth washes and gargles are included within the scope of topical
use for the purposes of this invention.
[0067] Dosage levels from about 0.01 mg/kg to about 140 mg/kg of
body weight per day are useful in the treatment of inflammatory and
neuropathic pain, or alternatively about 0.5 mg to about 7 g per
patient per day. For example, inflammatory pain may be effectively
treated by the administration of from about 0.01 mg to about 75 mg
of the compound per kilogram of body weight per day, or
alternatively about 0.5 mg to about 3.5 g per patient per day.
Neuropathic pain may be effectively treated by the administration
of from about 0.01 mg to about 125 mg of the compound per kilogram
of body weight per day, or alternatively about 0.5 mg to about 5.5
g per patient per day.
[0068] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a formulation intended for the oral
administration to humans may conveniently contain from about 0.5 mg
to about 5 g of active agent, compounded with an appropriate and
convenient amount of carrier material which may ary from about 5 to
about 95 percent of the total composition. Unit dosage forms will
generally contain between from about 1 mg to about 1000 mg of the
active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg,
400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
[0069] It is understood, however, that the specific dose level for
any particular patient will depend upon a variety of factors. Such
patient-related factors include the age, body weight, general
health, sex, and diet of the patient. Other factors include the
time and route of administration, rate of excretion, drug
combination, and the severity of the particular disease undergoing
therapy.
[0070] In practice, the compounds of the invention, or
pharmaceutically acceptable salts thereof, can be combined as the
active ingredient in intimate admixture with a pharmaceutical
carrier according to conventional pharmaceutical compounding
techniques. The carrier may take a wide variety of forms depending
on the form of preparation desired for administration, e.g., oral
or parenteral (including intravenous). Thus, the pharmaceutical
compositions of the present invention can be presented as discrete
units suitable for oral administration such as capsules, cachets or
tablets each containing a predetermined amount of the active
ingredient. Further, the compositions can be presented as a powder,
as granules, as a solution, as a suspension in an aqueous liquid,
as a non-aqueous liquid, as an oil-in-water emulsion or as a
water-in-oil liquid emulsion. In addition to the common dosage
forms set out above, the compounds of the invention, or
pharmaceutically acceptable salts thereof, may also be administered
by controlled release means and/or delivery devices. The
compositions may be prepared by any of the methods of pharmacy. In
general, such methods include a step of bringing into association
the active ingredient with the carrier that constitutes one or more
necessary ingredients. In general, the compositions are prepared by
uniformly and intimately admixing the active ingredient with liquid
carriers or finely divided solid carriers or both. The product can
then be conveniently shaped into the desired presentation.
[0071] Thus, the pharmaceutical compositions of this invention may
include a pharmaceutically acceptable carrier and a compound or a
pharmaceutically acceptable salt. The compounds of the invention,
or pharmaceutically acceptable salts thereof, can also be included
in pharmaceutical compositions in combination with one or more
therapeutically active compounds.
[0072] The pharmaceutical carrier employed can be, for example, a
solid, liquid, or gas. Examples of solid carriers include lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and stearic acid. Examples of liquid carriers are sugar
syrup, peanut oil, olive oil, and water. Examples of gaseous
carriers include carbon dioxide and nitrogen. As described
previously, in preparing the compositions for oral dosage form, any
of the usual pharmaceutical media can be employed. For example, in
the case of oral liquid preparations such as suspensions, elixirs
and solutions, water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents and the like may be used; or in the
case of oral solid preparations such as powders, capsules and
tablets, carriers such as starches, sugars, microcrystalline
cellulose, diluents, granulating agents, lubricants, binders,
disintegrating agents, and the like may be included. Because of
their ease of administration, tablets and capsules represent the
most advantageous oral dosage unit form in which solid
pharmaceutical carriers are employed. If desired, tablets may be
coated by standard aqueous or nonaqueous techniques. In addition to
the common dosage forms set out above, controlled release means
and/or delivery devices may also be used in administering the
instant compounds and compositions.
[0073] In preparing the compositions for oral dosage form, any
convenient pharmaceutical media may be employed. For example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like may be used to form oral liquid
preparations such as suspensions, elixirs and solutions; while
carriers such as starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents can be used to form oral solid preparations
such as powders, capsules and tablets. Because of their ease of
administration, tablets and capsules are advantageous oral dosage
units whereby solid pharmaceutical carriers are employed.
Optionally, tablets may be coated by standard aqueous or nonaqueous
techniques
[0074] A tablet containing the composition of this invention may be
prepared by compression or molding, optionally with one or more
accessory ingredients or adjuvants. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active or dispersing agent. Molded tablets may be made by molding
in a suitable machine, a mixture of the powdered compound moistened
with an inert liquid diluent. Each tablet advantageously contains
from about 0.1 mg to about 500 mg of the active ingredient and each
cachet or capsule advantageously containing from about 0.1 mg to
about 500 mg of the active ingredient. Thus, a tablet, cachet, or
capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100
mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient
taken one or two tablets, cachets, or capsules, once, twice, or
three times daily.
[0075] Pharmaceutical compositions of the present invention
suitable for parenteral administration may be prepared as solutions
or suspensions of the active compounds in water. A suitable
surfactant can be included such as, for example,
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and mixtures thereof in
oils. Further, a preservative can be included to prevent the
detrimental growth of microorganisms.
[0076] Pharmaceutical compositions of the present invention
suitable for injectable use include sterile aqueous solutions or
dispersions. Furthermore, the compositions can be in the form of
sterile powders for the extemporaneous preparation of such sterile
injectable solutions or dispersions. In all cases, the final
injectable form must be sterile and must be effectively fluid for
easy syringability. The pharmaceutical compositions must be stable
under the conditions of manufacture and storage, and thus should be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.
glycerol, propylene glycol and liquid polyethylene glycol),
vegetable oils, and suitable mixtures thereof.
[0077] Pharmaceutical compositions of the present invention can be
in a form suitable for topical use such as, for example, an
aerosol, cream, ointment, lotion, and dusting powder. Further, the
compositions can be in a form suitable for use in transdermal
devices. These formulations may be prepared, utilizing a compound
represented of the invention, or pharmaceutically acceptable salts
thereof, via conventional processing methods. As an example, a
cream or ointment is prepared by mixing hydrophilic material and
water, together with about 5 wt % to about 10 wt % of the compound,
to produce a cream or ointment having a desired consistency.
[0078] Pharmaceutical compositions of this invention can be in a
form suitable for rectal administration wherein the carrier is a
solid, such as, for example, where the mixture forms unit dose
suppositories. Suitable carriers include cocoa butter and other
materials commonly used in the art. The suppositories may be
conveniently formed by first admixing the composition with the
softened or melted carrier(s) followed by chilling and shaping in
moulds.
[0079] In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as
appropriate, one or more additional carrier ingredients such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, and preservatives (including
anti-oxidants). Furthermore, other adjuvants can be included to
render the formulation isotonic with the blood of the intended
recipient. Compositions containing a compound of the invention, or
pharmaceutically acceptable salts thereof, can also be prepared in
powder or liquid concentrate form.
[0080] The compounds and pharmaceutical compositions of this
invention have been found to block N-type, T-type, and L-type
calcium channels. Accordingly, an aspect of the invention is the
treatment and prevention in mammals of conditions that are amenable
to amelioration through blockage of said calcium channels by
administering an effective amount of a compound of this invention.
Such conditions include, for example, acute pain, chronic pain,
visceral pain, inflammatory pain and neuropathic pain. These
conditions may also include epilepsy, essential tremor,
schizophrenia, Parkinson's disease, depression, anxiety, sleep
disorders, sleep disturbances, psychosis, infertility, and sexual
dysfunction. These conditions may further include cardiac
arrhythmia and hypertension. The instant compounds and compositions
are useful for treating and preventing the above-recited
conditions, in humans and non-human mammals such as dogs and cats.
It is understood that the treatment of mammals other than humans
refers to the treatment of clinical conditions in non-human mammals
that correlate to the above-recited conditions.
[0081] Further, as described above, the instant compounds can be
utilized in combination with one or more therapeutically active
compounds. In particular, the inventive compounds can be
advantageously used in combination with i) opiate agonists or
antagonists, ii) other calcium channel antagonists, iii) 5HT
receptor agonists or antagonists, including 5-HT.sub.1A agonists or
antagonists, and 5-HT.sub.1A partial agonists, iv) sodium channel
antagonists, v) N-methyl-D-aspartate (NMDA) receptor agonists or
antagonists, vi) COX-2 selective inhibitors, vii) neurokinin
receptor 1 (NK1) antagonists, viii) non-steroidal anti-inflammatory
drugs (NSAID), ix) selective serotonin reuptake inhibitors (SSRI)
and/or selective serotonin and norepinephrine reuptake inhibitors
(SSNRI), x) tricyclic antidepressant drugs, xi) norepinephrine
modulators, xii) lithium, xiii) valproate, xiv) norepinephrine
reuptake inhibitors, xv) monoamine oxidase inhibitors (MAOIs), xvi)
reversible inhibitors of monoamine oxidase (RIMAs), xvii)
alpha-adrenoreceptor antagonists, xviii) atypical anti-depressants,
xix) benzodiazepines, xx) corticotropin releasing factor (CRF)
antagonists, xxi) neurontin (gabapentin) and xxii) pregabalin
[0082] The abbreviations used herein have the following meanings
(abbreviations not shown here have their meanings as commonly used
unless specifically stated otherwise): Ac (acetyl), Bn (benzyl),
Boc (tertiary-butoxy carbonyl), Bop reagent
(benzotriazol-1-yloxy)tris(dimethylamino)phosonium
hexafluorophosphate, CAMP (cyclic adenosine-3',5'-monophosphate),
DAST ((diethylamino)sulfur trifluoride), DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene), DIBAL (diisobutylaluminum
hydride), DIEA (diisopropylethyl amine), DMAP
(4-(dimethylamino)pyridine), DMF (N,N-dimethylformamide), DPPF
(1,1'-bisdiphenylphosphino ferrocene), EDC
(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride),
Et.sub.3N (triethylamine), GST (glutathione transferase), HOBt
(1-hydroxybenzotriazole), LAH (lithium aluminum hydride), Ms
(methanesulfonyl; mesyl; or SO.sub.2Me), MsO (methanesulfonate or
mesylate), MCPBA (meta-chloro perbenzoic acid), NaHMDS (sodium
hexamethyldisilazane), NBS (N-bromosuccinimide),
NCS(N-chlorosuccinimide), NSAID (non-steroidal anti-inflammatory
drug), PDE (Phosphodiesterase), Ph (Phenyl), r.t. or RT (room
temperature), Rac (Racemic), SAM (aminosulfonyl; sulfonamide or
SO.sub.2NH.sub.2), SPA (scintillation proximity assay), Th (2- or
3-thienyl), TFA (trifluoroacetic acid), THF (Tetrahydrofuran), Thi
(Thiophenediyl), TLC (thin layer chromatography), TMEDA
(N,N,N',N'-tetramethylethylenediamine), TMSI (trimethylsilyl
iodide), Tr or trityl (N-triphenylmethyl), C.sub.3H.sub.5 (Allyl),
Me (methyl), Et (ethyl), n-Pr (normal propyl), i-Pr (isopropyl),
n-Bu (normal butyl), i-Butyl (isobutyl), s-Bu (secondary butyl),
t-Bu (tertiary butyl), c-Pr (cyclopropyl), c-Bu (cyclobutyl), c-Pen
(cyclopentyl), c-Hex (cyclohexyl).
[0083] The present compounds can be prepared according to the
general Schemes provided below as well as the procedures provided
in the Examples. The following Schemes and Examples further
describe, but do not limit, the scope of the invention.
[0084] Unless specifically stated otherwise, the experimental
procedures were performed under the following conditions: All
operations were carried out at room or ambient temperature; that
is, at a temperature in the range of 18-25.degree. C. Inert gas
protection was used when reagents or intermediates were air and
moisture sensitive. Evaporation of solvent was carried out using a
rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30
mm Hg) with a bath temperature of up to 60.degree. C. The course of
reactions was followed by thin layer chromatography (TLC) or by
high-pressure liquid chromatography-mass spectrometry (HPLC-MS),
and reaction times are given for illustration only. The structure
and purity of all final products were assured by at least one of
the following techniques: TLC, mass spectrometry, nuclear magnetic
resonance (NMR) spectrometry or microanalytical data. When given,
yields are for illustration only. When given, NMR data is in the
form of delta (.delta.) values for major diagnostic protons, given
in parts per million (ppm) relative to tetramethylsilane (TMS) as
internal standard, determined at 300 MHz, 400 MHz or 500 MHz using
the indicated solvent. Conventional abbreviations used for signal
shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br.
Broad; etc. In addition, "Ar" signifies an aromatic signal.
Chemical symbols have their usual meanings; the following
abbreviations are used: v (volume), w (weight), b.p. (boiling
point), m.p. (melting point), L (liter(s)), mL (milliliters), g
(gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq
(equivalent(s)).
Assay Example 1
Fluorescent Assay for Cav2.2 Channels Using Potassium
Depolarization to Initiate Channel Opening
[0085] Human Cav2.2 channels were stably expressed in HEK293 cells
along with alpha2-delta and beta subunits of voltage-gated calcium
channels. An inwardly rectifying potassium channel (Kir2.3) was
also expressed in these cells to allow more precise control of the
cell membrane potential by extracellular potassium concentration.
At low bath potassium concentration, the membrane potential is
relatively negative, and is depolarized as the bath potassium
concentration is raised. In this way, the bath potassium
concentration can be used to regulate the voltage-dependent
conformations of the channels. Compounds are incubated with cells
in the presence of low (4 mM) potassium or elevated (12, 25 or 30
mM) potassium to determine the affinity for compound block of
resting (closed) channels at 4 mM potassium or affinity for block
of open and inactivated channels at 12, 25 or 30 mM potassium.
After the incubation period, Cav2.2 channel opening is triggered by
addition of higher concentration of potassium (70 mM final
concentration) to further depolarize the cell. The degree of
state-dependent block can be estimated from the inhibitory potency
of compounds after incubation in different potassium
concentrations.
[0086] Calcium influx through Cav2.2 channels is determined using a
calcium-sensitive fluorescent dye in combination with a fluorescent
plate reader. Fluorescent changes were measured with either a VIPR
(Aurora Instruments) or FLIPR (Molecular Devices) plate reader.
Protocol
[0087] 1. Seed cells in Poly-D-Lysine Coated 96- or 384-well plate
and keep in a 37.degree. C.-10% CO.sub.2 incubator overnight [0088]
2. Remove media.sup.1, wash cells with 0.2 ml (96-well plate) or
0.05 ml (384-well plate) Dulbecco's Phosphate Buffered Saline
(D-PBS) with calcium & magnesium (Invitrogen; 14040) [0089] 3.
Add 0.1 ml (96-well plate) or 0.05 ml (384-well plate) of 4 .mu.M
fluo-4 (Molecular Probes; F-14202) and 0.02% Pluronic acid
(Molecular Probes; P-3000) prepared in D-PBS with calcium &
magnesium (Invitrogen; 14040) supplemented with 10 mM Glucose &
10 mM Hepes/NaOH; pH 7.4 [0090] 4. Incubate in the dark at
25.degree. C. for 60-70 min [0091] 5. Remove dye.sup.2, wash cells
with 0.1 ml (96-well plate) or 0.06 ml (384-well plate) of 4, 12,
25, or 30 mM Potassium Pre-polarization Buffer. (PPB) [0092] 6. Add
0.1 ml (96-well plate) or 0.03 ml (384-well plate) of 4, 12, 25, 30
mM PPB. with or without test compound [0093] 7. Incubate in the
dark at 25.degree. C. for 30 min [0094] 8. Read cell plate on VIPR
instrument, Excitation=480 nm, Emission=535 nm [0095] 9. With VIPR
continuously reading, add 0.1 ml (96-well plate) or 0.03 ml
(384-well plate) of Depolarization Buffer, which is 2.times. the
final assay concentration, to the cell plate.
Assay Reagents:
TABLE-US-00001 [0096] 4 mM K Pre- 12 mM K Pre- 25 mM K Pre- 30 mM K
Pre- 140 mM K Polarization Polarization Polarization Polarization
Depolarization Buffer Buffer Buffer Buffer Buffer 146 mM NaCl 138
mM NaCl 125 mM NaCl 120 mM NaCl 10 mM NaCl 4 mM KCl 12 mM KCl 25 mM
KCl 30 mM KCl 140 mM KCl 0.8 mM CaCl.sub.2 0.8 mM CaCl.sub.2 0.8 mM
CaCl.sub.2 0.8 mM CaCl.sub.2 0.8 mM CaCl.sub.2 1.7 mM MgCl.sub.2
1.7 mM MgCl.sub.2 1.7 mM MgCl.sub.2 1.7 mM MgCl.sub.2 1.7 mM
MgCl.sub.2 10 mM HEPES 10 mM HEPES 10 mM HEPES 10 mM HEPES 10 mM
HEPES pH = 7.2 pH = 7.2 pH = 7.2 pH = 7.2 pH = 7.2
Assay Example 2
Electrophysiological Measurement of Block of Cav2.2 Channels Using
Automated Electrophysiology Instruments
[0097] Block of N-type calcium channels is evaluated utilizing the
IonWorks HT 384 well automated patch clamp electrophysiology
device. This instrument allows synchronous recording from 384 wells
(48 at a time). A single whole cell recording is made in each well.
Whole cell recording is established by perfusion of the internal
compartment with amphotericin B.
[0098] The voltage protocol is designed to detect use-dependent
block. A 2 Hz train of depolarizations (twenty 25 ms steps to +20
mV). The experimental sequence consists of a control train
(pre-compound), incubation of cells with compound for 5 minutes,
followed by a second train (post-compound). Use dependent block by
compounds is estimated by comparing fractional block of the first
pulse in the train to block of the 20th pulse.
Protocol
[0099] Parallel patch clamp electrophysiology is performed using
IonWorks HT (Molecular Devices Corp.) essentially as described by
Kiss and colleagues [Kiss et al. 2003; Assay and Drug Development
Technologies, 1:127-135]. Briefly, a stable HEK 293 cell line
(referred to as CBK) expressing the N-type calcium channel subunits
(alpha.sub.1B, alpha.sub.2-delta, beta.sub.3a,) and an inwardly
rectifying potassium channel (K.sub.ir2.3) is used to record barium
current through the N-type calcium channel. Cells are grown in T75
culture plates to 60-90% confluence before use. Cells are rinsed
3.times. with 10 ml PBS (Ca/Mg-free) followed by addition of 1.0 ml
1.times. trypsin to the flask. Cells are incubated at 37.degree. C.
until rounded and free from plate (usually 1-3 min). Cells are then
transferred to a 15 ml conical tube with 13 ml of CBK media
containing serum and antibiotics and spun at setting 2 on a table
top centrifuge for 2 min. The supernatant is poured off and the
pellet of cells is resuspended in external solution (in mM): 120
NaCl, 20 BaCl.sub.2, 4.5 KCl, 0.5 MgCl.sub.2, 10 HEPES, 10 Glucose,
pH=7.4). The concentration of cells in suspension is adjusted to
achieve 1000-3000 cells per well. Cells are used immediately once
they have been resuspended. The internal solution is (in mM): 100
K-Gluconate, 40 KCl, 3.2 MgCl.sub.2, 3 EGTA, 5 HEPES, pH 7.3 with
KOH. Perforated patch whole cell recording is achieved by added the
perforating agent amphotericin B to the internal solution. A 36
mg/ml stock of amphtericn B is made fresh in dimethyl sulfoxide for
each run. 166 .mu.l of this stock is added to 50 ml of internal
solution yielding a final working solution of 120 ug/ml.
[0100] Voltage protocols and the recording of membrane currents are
performed using the IonWorks HT software/hardware system. Currents
are sampled at 1.25 kHz and leakage subtraction is performed using
a 10 mV step from the holding potential and assuming a linear leak
conductance. No correction for liquid junction potentials is
employed. Cells are voltage clamped at -70 mV for 10 s followed by
a 20 pulse train of 25 ms steps to +20 mV at 2 Hz. After a control
train, the cells are incubated with compound for 5 minutes and a
second train is applied. Use dependent block by compounds is
estimated by comparing fractional block of the first pulse to block
of the 20th pulse. Wells with seal resistances less than 70 MOhms
or less than 0.1 nA of Ba current at the test potential (+20 mV)
are excluded from analysis. Current amplitudes are calculated with
the IonWorks software. Relative current, percent inhibition and
IC50s are calculated with a custom Excel/Sigmaplot macro.
[0101] Compounds are added to cells with a fluidics head from a
96-well compound plate. To compensate for the dilution of compound
during addition, the compound plate concentration is 3.times.
higher than the final concentration on the patch plate.
[0102] Two types of experiments are generally performed: screens
and titrations. In the screening mode, 10-20 compounds are
evaluated at a single concentration (usually 3 uM). The percent
inhibition is calculated from the ratio of the current amplitude in
the presence and absence of compound, normalized to the ratio in
vehicle control wells. For generation of IC50s, a 10-point
titration is performed on 2-4 compounds per patch plate. The range
of concentrations tested is generally 0.001 to 20 uM. IC50s are
calculated from the fits of the Hill equation to the data. The form
of the Hill equation used is: Relative
Current=Max-Min)/(1+(conc/IC50) slope))+Min. Vehicle controls
(dimethyl sulfoxide) and 0.3 mM CdCl.sub.2 (which inhibits the
channel completely) are run on each plate for normalization
purposes and to define the Max and Min.
Assay Example 3
Electrophysiological Measurement of Block of Cav2.2 Channels Using
Whole Cell Voltage Clamp and Using PatchXpress Automated
Electrophysiology Instrument
[0103] Block of N-type calcium channels is evaluated utilizing
manual and automated (PatchXpress) patch clamp electrophysiology.
Voltage protocols are designed to detect state-dependent block.
Pulses (50 ms) are applied at a slow frequency (0.067 Hz) from
polarized (-90 mV) or depolarized (-40 mV) holding potentials.
Compounds which preferentially block inactivated/open channels over
resting channels will have higher potency at -40 mV compared to -90
mV.
Protocol:
[0104] A stable HEK 293 cell line (referred to as CBK) expressing
the N-type calcium channel subunits (alpha.sub.1B,
alpha.sub.2-delta, beta.sub.3a,) and an inwardly rectifying
potassium channel (K.sub.ir2.3) is used to record barium current
through the N-type calcium channel. Cells are grown either on
poly-D-lysine coated coverglass (manual EP) or in T75 culture
plates (PatchXpress). For the PatchXpress, cells are released from
the flask using tryspin. In both cases, the external solution is
(in mM): 120 NaCl, 20 BaCl.sub.2, 4.5 KCl, 0.5 MgCl.sub.2, 10
HEPES, 10 Glucose, pH 7.4 with NaOH. The internal solution is (in
mM): 130 CsCl, 10 EGTA, 10 HEPES, 2 MgCl.sub.2, 3 MgATP, pH 7.3
with CsOH.
[0105] Barium currents are measured by manual whole-cell patch
clamp using standard techniques (Hamill et. al. Pfluegers Archiv
391:85-100 (1981)). Microelectrodes are fabricated from
borosilicate glass and fire-polished. Electrode resistances are
generally 2 to 4 MOhm when filled with the standard internal
saline. The reference electrode is a silver-silver chloride pellet.
Voltages are not corrected for the liquid junction potential
between the internal and external solutions and leak is subtracted
using the P/n procedure. Solutions are applied to cells by bath
perfusion via gravity. The experimental chamber volume is
.about.0.2 ml and the perfusion rate is 0.5-2 ml/min. Flow of
solution through the chamber is maintained at all times.
Measurement of current amplitudes is performed with PULSEFIT
software (HEKA Elektronik).
[0106] PatchXpress (Molecular Devices) is a 16-well whole-cell
automated patch clamp device that operates asynchronously with
fully integrated fluidics. High resistance (gigaohm) seals are
achieved with 50-80% success. Capacitance and series resistance
compensation is automated. No correction for liquid junction
potentials is employed. Leak is subtracted using the P/n procedure.
Compounds are added to cells with a pipettor from a 96-well
compound plate. Voltage protocols and the recording of membrane
currents are performed using the PatchXpress software/hardware
system. Current amplitudes are calculated with DataXpress
software.
[0107] In both manual and automated patch clamp, cells are voltage
clamped at -40 mV or -90 mV and 50 ms pulses to +20 mV are applied
every 15 sec (0.067 Hz). Compounds are added in escalating doses to
measure % Inhibition. Percent inhibition is calculated from the
ratio of the current amplitude in the presence and absence of
compound. When multiple doses are achieved per cell, IC50s are
calculated. The range of concentrations tested is generally 0.1 to
30 uM. IC50s are calculated from the fits of the Hill equation to
the data. The form of the Hill equation used is: Relative
Current=1/(1+(conc/IC50) slope)).
[0108] The intrinsic N-type calcium channel antagonist activity of
a compound which may be used in the present invention may be
determined by these assays.
[0109] In particular, the compounds of the following examples had
activity in antagonizing the N-type calcium channel in the
aforementioned assays, generally with an IC.sub.50 of less than
about 10 uM. Preferred compounds within the present invention had
activity in antagonizing the N-type calcium channel in the
aforementioned assays with an IC.sub.50 of less than about 1 uM.
Such a result is indicative of the intrinsic activity of the
compounds in use as antagonists of N-type calcium channel
activity.
Assay Example 4
Assay for Cav3.1 and Cav3.2 Channels
[0110] The T-type calcium channel blocking activity of the
compounds of this invention may be readily determined using the
methodology well known in the art described by Xia, et al., Assay
and Drug Development Tech., 1(5), 637-645 (2003).
[0111] In a typical experiment ion channel function from HEK 293
cells expressing the T-type channel alpha-1G, H, or I (CaV 3.1,
3.2, 3.3) is recorded to determine the activity of compounds in
blocking the calcium current mediated by the T-type channel
alpha-1G, H, or I (CaV 3.1, 3.2, 3.3). In this T-type calcium
(Ca.sup.2+) antagonist voltage-clamp assay calcium currents are
elicited from the resting state of the human alpha-1G, H, or I (CaV
3.1, 3.2, 3.3) calcium channel as follows. Sequence information for
T-type (Low-voltage activated) calcium channels are fully disclosed
in e.g., U.S. Pat. No. 5,618,720, U.S. Pat. No. 5,686,241, U.S.
Pat. No. 5,710,250,U.S. Pat. No. 5,726,035, U.S. Pat. No.
5,792,846, U.S. Pat. No. 5,846,757, U.S. Pat. No. 5,851,824, U.S.
Pat. No. 5,874,236, U.S. Pat. No. 5,876,958, U.S. Pat. No.
6,013,474, U.S. Pat. No. 6,057,114, U.S. Pat. No. 6,096,514, WO
99/28342, and J. Neuroscience, 19(6):1912-1921 (1999). Cells
expressing the t-type channels were grown in H3D5 growth media
which is comprised DMEM, 6% bovine calf serum (HYCLONE), 30
micromolar Verapamil, 200 microgram/ml Hygromycin B, 1.times.
Penicillin/Streptomycin. Glass pipettes are pulled to a tip
diameter of 1-2 micrometer on a pipette puller. The pipettes are
filled with the intracellular solution and a chloridized silver
wire is inserted along its length, which is then connected to the
headstage of the voltage-clamp amplifier. Trypsinization buffer was
0.05% Trypsin, 0.53 mM EDTA. The extracellular recording solution
consists of (mM): 130 mM NaCl, 4 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10
mM HEPES, 30 Glucose, pH 7.4. The internal solution consists of
(mM): 135 mM CsMeSO4, 1 MgCl2, 10 CsCl, 5 EGTA, 10 HEPES, pH 7.4,
or 135 mM CsCl, 2 MgCl2, 3 MgATP, 2 Na2ATP, 1 Na2GTP, 5 EGTA, 10
HEPES, pH 7.4. Upon insertion of the pipette tip into the bath, the
series resistance is noted (acceptable range is between 1-4
megaohm). The junction potential between the pipette and bath
solutions is zeroed on the amplifier. The cell is then patched, the
patch broken, and, after compensation for series resistance
(>=80%), the voltage protocol is applied while recording the
whole cell Ca2+ current response. Voltage protocols: (1) -80 mV
holding potential every 20 seconds pulse to -20 mV for 40 msec
duration; the effectiveness of the drug in inhibiting the current
mediated by the channel is measured directly from measuring the
reduction in peak current amplitude initiated by the voltage shift
from -80 mV to -20 mV; (2). -100 mV holding potential every 15
seconds pulse to -20 mV for 40 msec duration; the effectiveness of
the drug in inhibiting the current mediated by the channel is
measured directly from measuring the reduction in peak current
amplitude initiated by the shift in potential from -100 mV to -30
mV. The difference in block at the two holding potentials was used
to determine the effect of drug at differing levels of inactivation
induced by the level of resting state potential of the cells. After
obtaining control baseline calcium currents, extracellular
solutions containing increasing concentrations of a test compound
are washed on. Once steady state inhibition at a given compound
concentration is reached, a higher concentration of compound is
applied. % inhibition of the peak inward control Ca2+ current
during the depolarizing step to -20 mV is plotted as a function of
compound concentration.
[0112] The intrinsic T-type calcium channel antagonist activity of
a compound which may be used in the present invention may be
determined by these assays.
[0113] In particular, the compounds of the following examples had
activity in antagonizing the T-type calcium channel in the
aforementioned assays, generally with an IC.sub.50 of less than
about 10 uM. Preferred compounds within the present invention had
activity in antagonizing the T-type calcium channel in the
aforementioned assays with an IC.sub.50 of less than about 1 uM.
Such a result is indicative of the intrinsic activity of the
compounds in use as antagonists of T-type calcium channel
activity.
In Vivo Assay: (Rodent CFA Model):
[0114] Male Sprague Dawley rats (300-400 gm) were administered 200
microl CFA (Complete Freund's Adjuvant) three days prior to the
study. CFA is mycobacterium tuberculosis suspended in saline (1:1;
Sigma) to form an emulsion that contains 0.5 mg mycobacterium/ml.
The CFA was injected into the plantar area of the left hind
paw.
[0115] Rats are fasted the night before the study only for oral
administration of compounds. On the morning of test day using a Ugo
Basile apparatus, 2 baseline samples are taken 1 hour apart. The
rat is wrapped in a towel. Its paw is placed over a ball bearing
and under the pressure device. A foot pedal is depressed to apply
constant linear pressure. Pressure is stopped when the rat
withdraws its paw, vocalizes, or struggles. The right paw is then
tested. Rats are then dosed with compound and tested at
predetermined time points.
Compounds were prepared in dimethyl
sulfoxide(15%)/PEG300(60%)/Water(25%) and were dosed in a volume of
2 ml/kg.
[0116] Percent maximal possible effect (% MPE) was calculated as:
(post-treatment-pre-treatment)/(pre-injury
threshold-pre-treatment).times.100. The % responder is the number
of rats that have a MPE.30% at any time following compound
administration. The effect of treatment was determined by one-way
ANOVA Repeated Measures Friedman Test with a Dunn's post test.
Methods of Synthesis:
[0117] Compounds of the present invention can be prepared according
to the Schemes provided below as well as the procedures provided in
the Examples. The substituents are the same as in the above
Formulas except where defined otherwise or otherwise apparent to
the ordinary skilled artisan.
[0118] The novel compounds of the present invention can be readily
synthesized using techniques known to those skilled in the art,
such as those described, for example, in Advanced Organic
Chemistry, March, 5.sup.th Ed., John Wiley and Sons, New York,
N.Y., 2001; Advanced Organic Chemistry, Carey and Sundberg, Vol. A
and B, 3.sup.rd Ed., Plenum Press, Inc., New York, N.Y., 1990;
Protective groups in Organic Synthesis, Green and Wuts, 2.sup.nd
Ed., John Wiley and Sons, New York, N.Y., 1991; Comprehensive
Organic Transformations, Larock, VCH Publishers, Inc., New York,
N.Y., 1988; Handbook of Heterocyclic Chemistry, Katritzky and
Pozharskii, 2.sup.nd Ed., Pergamon, New York, N.Y., 2000 and
references cited therein. Other references used for synthesizing
novel compounds in the present invention include: Li, et al.,
Tetrahedron Lett., 2004, 45, 4257-4260; O'Shea, et al., J. Org.
Chem., 2005, 70, 3021-3030; Ishii, et al., J. Am. Chem. Soc., 2002,
124, 1590-1591; Vedso, et el., Org. Lett., 2001, 3, 1435-1437; Hwu
et el., Tetrahedron Lett., 1996, 37, 2035-2038; Buckwald et el,
Tetrahedron, 2004, 60, 7397-7403; Dessard et el., Org. Proc. Res.
Dev., 2001, 5, 572-574; Beaulieu et el, Tetrahedron lett., 2004,
45, 3233-3236; Schlosser et el., Tetrahedron, 2004, 60,
11869-11874; Meyers et el, Tetrahedron, 1984, 41, 837-860; Campos
et el., J. Org. Chem., 2005, 70, 268-274. The starting materials
for the present compounds may be prepared using standard synthetic
transformations of chemical precursors that are readily available
from commercial sources, including Aldrich Chemical Co. (Milwaukee,
Wis.); Sigma Chemical Co. (St. Louis, Mo.); Lancaster Synthesis
(Windham, N.H.); Ryan Scientific (Columbia, S.C.); Maybridge
(Cornwall, UK); Matrix Scientific (Columbia, S.C.); Arcos,
(Pittsburgh, Pa.) and Trans World Chemicals (Rockville, Md.).
[0119] The procedures described herein for synthesizing the
compounds may include one or more steps of protecting group
manipulations and of purification, such as, re-crystallization,
distillation, column chromatography, flash chromatography,
thin-layer chromatography (TLC), radial chromatography and
high-pressure chromatography (HPLC). The products can be
characterized using various techniques well known in the chemical
arts, including proton and carbon-13 nuclear magnetic resonance
(.sup.1H and .sup.13C NMR), infrared and ultraviolet spectroscopy
(IR and UV), X-ray crystallography, elemental analysis and HPLC and
mass spectrometry (HPLC-MS). Methods of protecting group
manipulation, purification, structure identification and
quantification are well known to one skilled in the art of chemical
synthesis.
[0120] Appropriate solvents are those which will at least partially
dissolve one or all of the reactants and will not adversely
interact with either the reactants or the product. Suitable
solvents are aromatic hydrocarbons (e.g, toluene, xylenes),
halogenated solvents (e.g, methylene chloride, chloroform,
carbontetrachloride, chlorobenzenes), ethers (e.g, diethyl ether,
diisopropylether, tert-butyl methyl ether, diglyme,
tetrahydrofuran, dioxane, anisole), nitriles (e.g, acetonitrile,
propionitrile), ketones (e.g, 2-butanone, dithyl ketone, tert-butyl
methyl ketone), alcohols (e.g, methanol, ethanol, n-propanol,
iso-propanol, n-butanol, t-butanol), N,N-dimethyl formamide (DMF),
dimethylsulfoxide (DMSO) and water. Mixtures of two or more
solvents can also be used. Suitable bases are, generally, alkali
metal hydroxides, alkaline earth metal hydroxides such as lithium
hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide,
and calcium hydroxide; alkali metal hydrides and alkaline earth
metal hydrides such as lithium hydride, sodium hydride, potassium
hydride and calcium hydride; alkali metal amides such as lithium
amide, sodium amide and potassium amide; alkali metal carbonates
and alkaline earth metal carbonates such as lithium carbonate,
sodium carbonate, cesium carbonate, sodium hydrogen carbonate, and
cesium hydrogen carbonate; alkali metal alkoxides and alkaline
earth metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide and magnesium ethoxide; alkali metal alkyls
such as methyllithium, n-butyllithium, sec-butyllithium,
t-bultyllithium, phenyllithium, alkyl magnaesium halides, organic
bases such as trimethylamine, triethylamine, triisopropylamine,
N,N-diisopropylethyl amine, piperidine, N-methyl piperidine,
morpholine, N-methyl morpholine, pyridine, collidines, lutidines,
and 4-dimethylaminopyridine; and bicyclic amines such as DBU and
DABCO.
[0121] It is understood that the functional groups present in
compounds described in the Schemes below can be further
manipulated, when appropriate, using the standard functional group
transformation techniques available to those skilled in the art, to
provide desired compounds described in this invention.
[0122] It is also understood that compounds listed in the Schemes
and Tables below that contain one or more stereocenters may be
prepared as single enantiomers or diastereomers, or as mixtures
containing two or more enantiomers or diastereomers in any
proportion.
[0123] Other variations or modifications, which will be obvious to
those skilled in the art, are within the scope and teachings of
this invention. This invention is not to be limited except as set
forth in the following claims.
##STR00007##
[0124] Amine intermediates 5 were synthesized as shown in Scheme 1.
Commercially available Boc protected amino alcohols 1 such as
tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (m, n=1),
tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (m=1, n=2)
and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (m, n=2)
were converted to mesylates 2 by treatment of methanesulfonyl
chloride or methanesulfonic anhydride and an appropriate base such
as triethylamine. The resulted mesylates 2 can be displaced by
selected thiols in present of a suitable base such as
K.sub.2CO.sub.3 to give desired thioether products 3, which were
oxidized with Oxone.TM. or meta chloroperbenzoic acid (MCPBA) to
give sulfone products 4. Deprotection of the Boc group with
trifluoroacetic acid gave desired aminesulfone products 5.
##STR00008##
[0125] To introduce substitutions such as methyl or gem dimethyl
groups at a position to the sulfone group, Boc protected amino
acids 6 such as 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid
(m, n=1), 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid
(m=1, n=2) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid
(m, n=2) were converted to their corresponding Weinreb amides 7
using procedures known to those of ordinary skill in the art.
Weinreb amides 7 were then treated with methyl Grignard reagent to
give methyl ketone intermediates which were sequentially reduced to
alcohols 8 with NaBH.sub.4. Alcohol compounds 8 were converted to
mesylates 9 by treatment of methanesulfonyl chloride or
methanesulfonic anhydride and an appropriate base such as
triethylamine. The resulted mesylates 9 can be displaced by
selected thiols in present of a suitable base such as
K.sub.2CO.sub.3 to give desired thioether products 10, which were
oxidized with Oxone.TM. or MCPBA to give sulfone products 11.
Deprotection of the Boc group with trifluoroacetic acid gave
desired amine products 12. To synthesize gem dimethyl compounds 13,
sulfone compounds 11 were treated with sodium
bis(trimethylsilyl)amide (NaHMDS) to generate sulfone anions which
were alkylated by addition of iodomethane (MeI). Boc protecting
group was then removed by treating with trifluoroacetic acid to
give desired aminesulfone compounds 14.
##STR00009##
[0126] Alternatively, thioethers such compounds 10 can be
synthesized following Scheme 3. Mesylates 9 were treated with
potassium ethanethiolate to give thioesters which were hydrolyzed
to give thio compounds 15. Palladium mediated coupling reaction
between 15 and selected aryl halides gave desired thioethers 10.
Thioethers 10 can be converted to amines 12 and 14 following the
reactions outlined in Scheme 2.
Example 1
1-benzoyl-4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperid-
ine
##STR00010##
[0127] Step 1:
tert-butyl-4-{[methoxy(methyl)amino]carbonyl}piperidine-1-carboxylate
##STR00011##
[0128] To a 500 ml round bottom flask was added 150 ml
tetrahydrofuran and 24.8 g
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (108 mmol).
Carbonyldiimidazole (CDI) (18.4 g, 114 mmol) was added in portions.
The reaction mixture was stirred at room temperature for 1 hour.
Methylmehoxy amine hydrochloride salt (14.8 g, 151 mmol) was added
followed by 22.6 ml triethylamine. The reaction mixture was heated
at 55.degree. C. for 1 hour. It was cooled with ice bath and
diluted with 200 ml ether. The resulting mixture was washed
sequentially twice with 150 ml of saturated ammonium chloride
solution, 150 ml 5% KOH solution and 100 ml brine. The organic
layers were dried over sodium sulfate, filtered and concentrated.
The residue was dissolved in 50 ml toluene and then reconcentrated
under vacuum to give 29 g colorless oil which was used for next
step without further purification.
[0129] .sup.1H-NMR (CDCl.sub.3): .delta. 4.17 (b, 2H), 3.74 (s,
3H), 3.21 (s, 3H), 2.8 (b, 3H), 1.7 (b, 4H), 1.49 (s, 9H)
[0130] Mass Spectra (m/e): 273 (M+1).
Step 2: tert-butyl 4-acetylpiperidine-1-carboxylate
##STR00012##
[0132] To a 500 ml round bottom flask was added
tert-butyl-4-{[methoxy(methyl)amino]carbonyl}piperidine-1-carboxylate
(29 g, 106 mmol) and 150 ml tetrahydrofuran. The resulting solution
was cooled with ice bath and methylmagnesium chloride
tetrahydrofuran solution (42.6 ml, 3M, 128 mmol) was added by a
syringe. The mixture was stirred at 0.degree. C. for 30 minutes. It
was diluted with 200 ml of ether and the resulting mixture was
washed twice with 150 ml saturated ammonium chloride solution. The
organics were dried over sodium sulfate, filtered and concentrated.
The crude product was used for next step without further
purification.
[0133] .sup.1H-NMR (CDCl.sub.3): .delta.4.12 (b, 2H), 2.8 (b, 2H),
2.48 (m, 1H), 2.19 (s, 3H), 1.85 (b, 2H), 1.5 (m, 2H), 1.48 (s,
9H).
Step 3: tert-butyl 4-(1-hydroxyethyl)piperidine-1-carboxylate
##STR00013##
[0135] tert-Butyl 4-acetylpiperidine-1-carboxylate from the
previous step was dissolved in 50 ml methanol. NaBH.sub.4 (2.01 g,
53 mmol) was added in batches at 0.degree. C. The resulting
reaction mixture was stirred at 0.degree. C. for 30 minutes. The
volatiles were removed under vacuum. The residue was partitioned
between 150 ml 10% KOH solution and 200 ml ether. The organic
layers were washed with 100 ml brine, dried over sodium sulfate and
concentrated to give 22.5 g colorless oil, which was azotropically
dried by addition of 50 ml toluene and reconcentration under
vacuum. This material was used for next step without further
purification.
[0136] .sup.1H-NMR (CDCl.sub.3): .delta.4.17 (b, 2H), 3.62 (m, 1H),
2.69 (b, 2H), 1.85 (m, 1H), 1.6 (m, 1H), 1.48 (s, 9H), 1.46 (m,
1H), 1.24 (m, 11H), 1.22 (d, J=6.2 Hz, 3H).
Step 4: tert-butyl
4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate
##STR00014##
[0138] To a 250 ml round bottom flask was added tert-butyl
4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate from the
previous step, triethylamine (27.4 ml, 196 mmol) and 100 ml
methylene chloride. Methanesulfonyl chloride was added via a
syringe at 0.degree. C. The resulting reaction mixture was stirred
at 0.degree. C. for 30 minutes. It was diluted with 300 ml ether,
washed sequentially with 150 ml 1N HCl, 100 ml saturated aqueous
Na.sub.2CO.sub.3 and 100 ml brine. The organic layers were dried
over sodium sulfate, filtered and concentrated to give 29 g light
yellow sticky material.
Step 5: tert-butyl
4-(1-{[3-(trifluoromethyl)phenyl]thio}ethyl)piperidine-1-carboxylate
##STR00015##
[0140] To a 250 ml round bottom flask was added tert-butyl
4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (11 g,
35.8 mmol), 3-(trifluoromethyl)benzenethiol (7.6 g, 43 mmol),
K.sub.2CO.sub.3 (9.9 g, 72 mmol) and 80 ml dimethylformamide. The
reaction mixture was heated at 50.degree. C. for 36 hr under
N.sub.2, then cooled down to room temperature, 150 ml ether was
added. The resulting mixture was sequentially washed with 250 ml
water, 100 ml 5% KOH solution and 75 ml brine. The organic layers
were dried over sodium sulfate, filtered and concentrated to give
13.7 g crude product. It was used for next step without further
purification.
[0141] .sup.1H-NMR (CDCl.sub.3): .delta.7.63 (s, 1H), 7.56 (d,
J=7.8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.43 (t, J=7.8, 1H), 4.2 (b,
2H), 3.23 (m, 1H), 2.66 (b, 2H), 1.83 (m, 2H), 1.66 (m, 1H), 1.49
(s, 9H), 1.34 (m, 1H), 1.31 (d, J=6.9 Hz, 3H).
Step 6: tert-butyl
4-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine-1-carboxylate
##STR00016##
[0143] To a 500 ml round bottom flask was loaded with tert-butyl
4-(1-{[3-(trifluoromethyl)phenyl]thio}ethyl)piperidine-1-carboxylate
(13.7 g, 35.2 mmol) from the previous step and 150 ml methanol.
Oxone.TM. (43.2 g, 70.4 mmol) in 150 ml water (pH was adjusted to 3
with addition of potassium carbonate solution). The reaction
mixture was stirred at room temperature for 30 minutes, followed by
the addition of another 5 g of Oxone.TM. in 30 ml water. The
reaction mixture was stirred at room temperature for an additional
20 minutes. The reaction mixture was diluted with 250 ml ether and
100 ml water and filtered. The organic layers were separated from
the filtrate and washed with 150 ml brine, dried over sodium
sulfate, filtered and concentrated. The residue was purified on
silica gel column eluted with 1:4 to 1:2 ethylacetate/hexane to
give 10.8 g colorless sticky material.
[0144] .sup.1H-NMR (CDCl.sub.3): .delta.8.18 (s, 1H), 8.12 (d,
J=7.8 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.77 (t, J=7.8, 1H), 4.2 (b,
2H), 3.0 (m, 1H), 2.75 (b, 2H), 2.45 (m, 1H), 1.95 (m, 1H), 1.48
(s, 9H), 1.4 (m, 2H), 1.23 (d, J=7.1 Hz, 3H).
Step 7: tert-butyl
4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine-1-car-
boxylate
##STR00017##
[0146] To a 100 ml round bottom flask was added tert-butyl
4-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine-1-carboxylate
(5.4 g, 12.8 mmol) and 30 ml tetrahydrofuran. The resulting
solution was cooled to -78.degree. C. Sodium
bis(trimethylsilyl)amide (NaHMDS) tetrahydrofuran solution (1M,
15.4 ml) was added via a syringe. The reaction mixture turned deep
orange-red. It was stirred at -78 C for 5 minutes. MeI (0.96 ml,
15.4 mmol) was then added dropwise with a syringe until reaction
mixture turned light yellow. More NaHMDS (1M, 3 ml tetrahydrofuran
solution) was added. The reaction mixture was stirred at
-78.degree. C. for 5 more minutes and 0.3 ml MeI was added.
NH.sub.4Cl (60 ml) was added at -78.degree. C. to quench the
reaction. The resulting mixture was diluted with 120 ml ether and
60 ml water. The layers were separated, and the organics were dried
over sodium sulfate, filtered and concentrated. The residue was
purified on silica gel column eluted with 1:4 to 1:2
ethylacetate/hexane to give desired product which was used for the
next directly.
[0147] .sup.1H-NMR (CDCl.sub.3): .delta.8.16 (s, 1H), 8.09 (d, J=8
Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.76 (t, J=7.8, 1H), 4.2 (b, 2H),
2.72 (b, 2H), 2.1 (m, 1H), 2.05 (m, 2H), 1.49 (s, 9H), 1.4 (m, 2H),
1.26 (s, 6H).
Step 8:
4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidin-
e
##STR00018##
[0149] To a 250 ml round bottom flask was added tert-butyl
4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine-1-car-
boxylate from the previous step, 60 ml ethyl acetate and 60 ml 3N
HCl. The reaction mixture was heated at reflux for 3 hours. NMR
showed complete conversion. The volatiles were removed and the
residue was dissolved in 50 ml water, washed with 50 ml ether. The
aqueous portion was basified with addition of KOH and extracted
twice with 60 ml ethyl acetate. The extracts were dried over sodium
sulfate, filtered and concentrated to give 3.5 g colorless
solid.
[0150] .sup.1H-NMR (CDCl.sub.3) (HCl salt): .delta.8.15 (s, 1H),
8.09 (d, J=8 Hz, 1H), 7.98 (d, J=8 Hz, 1H), 7.78 (t, J=7.8, 1H),
3.6 (m, 2H), 2.95 (m, 2H), 2.4 (m, 1H), 2.3 (m, 2H), 2.0 (m, 2H),
1.49 (s, 9H), 1.28 (s, 6H).
Step 9:
1-benzoyl-4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl-
)piperidine
##STR00019##
[0152] To a 10 ml vial was added
4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine
(33 mg, 0.098 mmol), benzoic acid (10 mg, 0.082 mmol), Bop reagent
(43.5 mg, 0.098 mmol), diisopropylethyl amine (0.029 ml, 0.164
mmol) and 2 ml dimethylformamide. The resulting solution was
stirred at room temperature for 10 minutes. LC-Mass showed clean
desired product. The reaction mixture was diluted with 1 ml
dimethyl sulfoxide, 1 ml water and 0.03 ml of trifluoroacetic acid.
This mixture was loaded on a reverse phase column and purified on
HPLC eluted with water/acetonitrile gradient solvent. Desired
fraction was collected and lyophilized to give the title compound
as a fluffy white solid.
[0153] .sup.1H-NMR (CDCl.sub.3): .delta.8.14 (s, 1H), 8.08 (d,
J=7.6 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.75 (t, J=7.8, 1H), 7.42
(m, 5H), 4.86 (b, 1H), 3.89 (b, 1H), 3.06 (b, 1H), 2.79 (b, 1H),
2.3 (m, 1H), 2.1 (b, 2H), 1.5 (b, 2H), 1.26 (s, 6H).
[0154] Mass Spectra (m/e): 440 (M+1).
Example 2
1-[2-(methylsulfonyl)-4-(trifluoromethoxy)benzoyl]-4-(1-methyl-1-{[3-(trif-
luoromethyl)phenyl]sulfonyl}ethyl)piperidine
##STR00020##
[0155] Step 1:
N-(2-hydroxy-1,1-dimethylethyl)-4-(trifluoromethoxy)benzamide
##STR00021##
[0157] To a 100 ml round bottom flask was loaded
4-(trifluoromethoxy)benzoic acid (4.85 g, 23.5 mmol). Thionyl
chloride (5.15 ml, 70.6 mmol) was added at 0.degree. C. The
reaction mixture was allowed to warm up to room temperature and
then heated at 80.degree. C. for 1 hour. After cooling down to room
temperature, the volatiles were removed. The residue was diluted
with 50 ml methylene chloride, and 2-amino-2-methylpropan-1-ol
(7.34 g, 82 mmol) was added at 0.degree. C. The reaction mixture
was allowed to warm up to room temperature. It was diluted with 150
ml ether, washed sequentially with 100 ml 1N HCl, 100 ml 5% KOH and
50 ml brine. The organics were dried over sodium sulfate, filtered
and concentrated to give 4.2 g desired product. It was used for the
next step directly without further purification.
[0158] .sup.1H-NMR (CDCl.sub.3): .delta.7.8 (d, J=8.7 Hz, 2H), 7.29
(d, J=8.1 Hz, 2H), 3.72 (s, 2H), 1.44 (s, 6H).
Step 2:
4,4-dimethyl-2-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,3-oxazol-
e
##STR00022##
[0160] To a 25 ml round bottom flask was added
N-(2-hydroxy-1,1-dimethylethyl)-4-(trifluoromethoxy)benzamide (4.2
g, 15.2 mmol). Thionyl chloride (3.32 ml, 45.5 mmol) was added. The
resulting reaction mixture was stirred at room temperature for 1
hour. The reaction mixture was poured into 100 g crushed ice. Solid
KOH was added until the mixture became strongly basic. The mixture
was extracted twice with 50 ml ethyl acetate. The extracts were
dried over sodium sulfate, filtered and concentrated. The crude
product was purified on silica gel column eluted with 1:10 ethyl
acetate/hexane to give 2.6 g colorless liquid.
[0161] .sup.1H-NMR (CDCl.sub.3): .delta.8.01 (d, J=9 Hz, 2H), 7.26
(d, J=8.3 Hz, 2H), 4.15 (s, 2H), 1.41 (s, 6H).
[0162] Mass Spectra (m/e): 260 (M+1).
Step 3:
2-[2-bromo-4-(trifluoromethoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,-
3-oxazole
##STR00023##
[0164] To a 50 ml round bottom flask was loaded
4,4-dimethyl-2-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,3-oxazole
(0.5 g, 1.93 mmol) and 7 ml tetrahydrofuran. The resulting solution
was cooled with dry ice acetone bath, and nbutyllithium (nBuLi)
(2.5 M hexane solution, 0.85 ml, 2.12 mmol) was added via a
syringe. The resulting reaction mixture was allowed to warm up to
-20.degree. C. and stirred at this temperature for 30 minutes. The
reaction mixture was cooled back to -78.degree. C. It was quenched
by addition of bromine (0.109 ml, 2.12 mmol), followed by 10 ml
saturated sodium carbonate and 10 ml sodium thiosulfate solution.
The resulting mixture was diluted with 30 ml ether. The layers were
separated, and the organics were dried over sodium sulfate,
filtered and concentrated to give 0.60 g light yellow liquid. It
was used for the next step without further purification.
[0165] .sup.1H-NMR (CDCl.sub.3): .delta.7.78 (d, J=8.5 Hz, 1H),
7.54 (s, 1H), 7.24 (d, J=8.7 Hz, 1H), 4.20 (s, 2H), 1.46 (s,
6H).
[0166] Mass Spectra (m/e): 340 (M+1).
Step 4: 2-bromo-4-(trifluoromethoxy)benzoic acid
##STR00024##
[0168] To a 50 ml round bottom flask fitted with a magnetic
stirring bar and a reflux condensor was loaded
2-[2-bromo-4-(trifluoromethoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazo-
le (0.56 g, 1.66 mmol) and 10 ml 5N HCl. The reaction mixture was
heated at 90.degree. C. overnight. After cooling to room
temperature, the reaction mixture was diluted with 20 ml water and
extracted with 40 ml ethyl acetate. The extracts were dried over
sodium sulfate, filtered and concentrated to give 0.42 g light
brown solid.
[0169] .sup.1H-NMR (CDCl.sub.3): .delta.8.10 (d, J=8.6 Hz, 1H),
7.61 (s, 1H), 7.30 (d, 1H).
Step 5: 2-(methylsulfonyl)-4-(trifluoromethoxy)benzoic acid
##STR00025##
[0171] To a 16 ml vial was loaded
2-bromo-4-(trifluoromethoxy)benzoic acid (225 mg, 0.79 mmol),
sodium methylsulfinate (161 mg, 1.58 mmol), CuI (301 mg, 1.58
mmol), KOH (44 mg, 0.79 mmol, in 0.1 ml water) and 4 ml dimethyl
sulfoxide. The reaction mixture was flushed with nitrogen, sealed
and heated at 120.degree. C. for 5 hours. After cooling to room
temperature, it was diluted with 40 ml ether/ethyl acetate (1:1),
30 ml brine and 10 ml 3N HCl. The mixture was filtered through a
pad of celite. The layers were separated, and the organic portion
was dried over sodium sulfate, filtered and concentrated. The
residue was purified with HPLC on a reverse phase column eluted
with water and acetonitrile gradient solvent to give desire product
as white solid.
[0172] .sup.1H-NMR (CDCl.sub.3): .delta.8.07 (s, 1H), 8.01 (d,
J=8.5 Hz, 1H), 7.59 (m, 1H), 3.47 (s, 3H).
Step 6:
1-[2-(methylsulfonyl)-4-(trifluoromethoxy)benzoyl]-4-(1-methyl-1-{-
[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine
##STR00026##
[0174] To a 10 ml vial was added
4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine
(70.8 mg, 0.211 mmol),
2-(methylsulfonyl)-4-(trifluoromethoxy)benzoic acid (50 mg, 0.176
mmol), Bop reagent (93 mg, 0.211 mmol), diisopropylethyl amine
(0.062 ml, 0.352 mmol) and 2 ml dimethylformamide. The resulting
solution was stirred at room temperature for 10 minutes. The
reaction mixture was diluted with 1 ml dimethyl sulfoxide, 1 ml
water and 0.03 ml of trifluoroacetic acid. This mixture was loaded
on a reverse phase column and purified with HPLC eluted with
water/acetonitrile gradient solvent. Desired fraction was collected
and lyophilized to give to give title compound as fluffy white
solid.
[0175] .sup.1H-NMR (CDCl.sub.3): .delta.8.15 (s, 1H), 8.1 (m, 1H),
7.95 (m, 2H), 7.75 (m, 1H), 7.4 (m, 1H), 4.8 (m, 1H), 3.5 (m, 1H),
3.34, 3.28 (s, 3H), 3.1 (m, 1H), 2.8 (m, 1H), 2.1-2.4 (m, 3H)
1.5-1.8 (m, 2H), 1.3, 1.27, 1.22 (s, 6H). Complicate .sup.1H NMR
spectrum indicating the compound exits as a pair of rotomers at
room temperature.
[0176] Mass Spectra (m/e): 602 (M+1).
Example 3
2-(cyclopropylsulfonyl)-3-{[4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulf-
onyl}ethyl)piperidin-1-yl]carbonyl}-6-(trifluoromethyl)pyridine
##STR00027##
[0177] Step 1: Magnesium Bromide Cyclopropanesulfinate
##STR00028##
[0179] To 250 ml round bottom flask was added cyclopropylmagnesium
bromide tetrahydrofuran solution (0.5 M, 25 ml, 12.5 mmol) and 20
ml tetrahydrofuran. The resulting solution was cooled to
-78.degree. C. Sulfor dioxide (SO.sub.2) gas was bubbled through
for 5 minutes. The resulting reaction mixture was allowed to warm
up to room temperature over 30 minutes. The volatiles were removed
under vacuum to give 3.5 g desired product as white solid (contains
tetrahydrofuran solvent).
[0180] .sup.1H-NMR (CD.sub.3OD): .delta.1.95 (m, 1H), 0.8 (m, 2H),
0.65 (m, 2H).
Step 2: 2-(cyclopropylsulfonyl)-6-(trifluoromethyl)nicotinic
acid
##STR00029##
[0182] To a 100 ml round bottom flask was loaded magnesium bromide
cyclopropanesulfinate (928 mg, 4.43 mmol),
2-chloro-6-(trifluoromethyl)nicotinic acid (250 mg, 1.11 mmol), CuI
(844 mg, 4.43 mmol), NaOH (44.3 mg, 1.11 mmol), 20 ml dimethyl
sulfoxide and 4 ml water. The resulting reaction mixture was
flushed with nitrogen gas and heated at 120.degree. C. for 18 hr.
After cooling down to room temperature, the reaction mixture was
diluted with 60 ml ethyl acetate and 60 ml water. It was filtered
through a pad of celite, which was then rinsed with 20 ml ethyl
acetate. The layers were separated from filtrates, and the organics
were dried over sodium sulfate, filtered and concentrated. The
residue was purified on reverse phase column eluted with
water/acetonitrile gradient solvent to give desired product was
white solid (152 mg, 0.52 mmol).
[0183] .sup.1H-NMR (CD.sub.3OD): .delta.8.43 (d, J=8.0 Hz, 1H),
8.18 (d, J=8.0 Hz, 1H), 3.14 (m, 1H), 1.31 (m, 2H), 1.17 (m,
1H).
Step 3:
2-(cyclopropylsulfonyl)-3-{[4-(1-methyl-1-{[3-(trifluoromethyl)phe-
nyl]sulfonyl}ethyl)piperidin-1-yl]carbonyl}-6-(trifluoromethyl)pyridine
##STR00030##
[0185] To a 50 ml round bottom flask was added
4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine
(1.64 g, 4.88 mmol),
2-(cyclopropylsulfonyl)-6-(trifluoromethyl)nicotinic acid (1.2 g,
4.06 mmol), Bop reagent (2.16 g, 4.88 mmol), diisopropylethyl amine
(1.42 ml, 8.13 mmol) and 10 ml dimethylformamide. The resulting
solution was stirred at room temperature 10 minutes. It was diluted
with 60 ml NH.sub.4Cl solution and extracted with 60 ml ethyl
acetate. The organics were dried over sodium sulfate, filtered and
concentrated. The sesidue was purified on silica gel column eluted
with 2:1 ethyl acetate/hexane. The desired fraction was collected
and concentrated. The residue was further purified on prep-TLC to
give title compound as a white solid.
[0186] .sup.1H-NMR (CDCl.sub.3): .delta.8.14 (s, 1H), 8.1 (m, 1H),
7.95 (m, 3H), 7.75 (m, 1H), 4.8 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H),
3.0 (m, 1H), 2.8 (m, 1H), 1.4-2.4 (m, 5H), 1.29, 1.28, 1.27, 1.23
(s, 6H) 1.1 (m, 2H). Complicate .sup.1H NMR spectrum indicating the
compound exits as a pair of rotomers at room temperature.
[0187] Mass Spectra (m/e): 613 (M+1).
Example 4
1-[4-(cyclopropyloxy)-2,6-bis(methylsulfonyl)benzoyl]-4-(1-methyl-1-{[3-(t-
rifluoromethyl)phenyl]sulfonyl}ethyl)piperidine
##STR00031##
[0188] Step 1: 3,5-difluorophenyl vinyl ether
##STR00032##
[0190] To a 100 ml round bottom flask was added 3,5-difluorophenol
(3.85 g, 29.6 mmol), vinylacetate (5.1 g, 59.2 mmol),
Na.sub.2CO.sub.3 (1.88 g, 17.8 mmol), chloro-1,5-cyclooctadiene
iridium (I) dimmer (199 mg, 0.296 mmol) and 10 ml toluene. The
resulting reaction mixture was flushed with nitrogen and heated at
100.degree. C. overnight. After cooling to room temperature, the
reaction mixture was diluted with 60 ml hexane and washed with 60
ml water. The organics were dried over sodium sulfate, filtered
through a pad of silica gel, rinsed with 60 ml hexane. The
filtrates were concentrated to give 3.25 g desired product as
colorless liquid.
[0191] .sup.1H-NMR (CDCl.sub.3): .delta.7.6 (m, 4H), 4.9 (dd,
J=13.5, 1.8 Hz, 1H), 4.6 (m, 1H).
Step 2: cyclopropyl 3,5-difluorophenyl ether
##STR00033##
[0193] To a nitrogen flushed 250 ml round bottom flask equipped
with magnetic stirring bar and septa was added 80 ml
dichloromethane and Et.sub.2Zn (7.18 g, 58.1 mmol). The resulting
solution was cooled with ice bath. Trifluoroacetic acid (4.23 ml,
55 mmol) was added by a syringe slowly (septa was opened slightly
to release pressure). The reaction mixture was stirred at 0.degree.
C. for 10 minutes after addition. Diiodomethane (4.88 ml, 60.4
mmol) was added by a syringe and the resulting reaction mixture was
stirred at 0.degree. C. for 10 minutes. A dichloromethane solution
of 3,5-difluorophenyl vinyl ether (3.3 g, 21.1 mmol in 10 ml
CH.sub.2Cl.sub.2) was added. The reaction mixture was allowed to
warm up to room temperature over 30 minutes, then quenched by
addition of 50 ml water and 50 ml 3N HCl. The layers were
separated. The aqueous portion was extracted with 50 ml ether. The
organics were combined, dried over sodium sulfate, filtered and
concentrated. The residue was purified on silica gel column eluted
with hexane to give 3.6 g desired product as light yellow
liquid.
[0194] .sup.1H-NMR (CDCl.sub.3): .delta.6.6 (dd, J=9, 2.1 Hz, 2H),
6.45 (m, 1H), 3.73 (m, 1H), 0.82 (m, 4H).
Step 3: ethyl 4-(cyclopropyloxy)-2,6-difluorobenzoate
##STR00034##
[0196] To a 250 ml round bottom flask was added cyclopropyl
3,5-difluorophenyl ether (3.6 g, 21.2 mmol) and 60 ml
tetrahydrofuran. n-Butyllithium (nBuLi) (2.5 M, 8.9 ml, 22.2 mmol)
was added via a syringe at -78.degree. C. The resulting solution
was stirred at -78.degree. C. for 20 minutes. Ethylchloroformate
(3.05 ml, 31.7 mmol) was added by a syringe. The resulting solution
was left stirring for 5 more minutes. The reaction mixture was
diluted with 100 ml ether and 60 ml brine. The layers were
separated, and the organic portion was dried over sodium sulfate,
filtered and concentrated. The crude product was purified on silica
gel column eluted with hexane to 1:9 ethyl acetate/hexane gradient
solvent to give 4.5 g desired product as yellow liquid.
[0197] .sup.1H-NMR (CDCl.sub.3): .delta.6.6 4 (dd, J=14.5, 3.6 Hz,
2H), 4.41 (q, J=7.1 Hz, 2H), 3.77 (m, 1H), 1.41 (t, J=7.1 Hz, 3H),
0.85 (m, 4H).
Step 4: 4-(cyclopropyloxy)-2,6-bis(methylthio)benzoic acid
##STR00035##
[0199] To a microwave heating vial was add ethyl
4-(cyclopropyloxy)-2,6-difluorobenzoate (1 g, 4.13 mmol) and DBU
(2.18 ml, 14.5 mmol). The reaction mixture was cooled with dry ice
acetone bath. Methanethiol (.about.1 ml) was condensed into the
vial. The vial was sealed and the resulting reaction mixture was
heated at 100.degree. C. with microwave for 1 hour. The volatiles
were removed by a stream of nitrogen. The residue was diluted with
60 ml ether, extracted with 2.times.30 ml 5% KOH. The aqueous
portion was acidified with concentrated HCl to cause precipitation.
The mixture was filtered and the precipitate was washed with 15 ml
water. The resulting solid was air dried to give 0.37 g desired
product as white solid. The organic portion was washed with 60 ml
1N HCl, dried over sodium sulfate, filtered and concentrated to
give 0.78 g oil which contains mostly ethyl
4-(cyclopropyloxy)-2,6-bis(methylthio)benzoate. It was dissolved in
20 ml methanol and 3 ml water. LiOH (2 g) was added. The resulting
reaction mixture was refluxed for 24 hours. The volatiles were
removed, and the residue was dissolved in 40 ml water, washed with
30 ml ether, acidified with concentrated HCl to cause
precipitation. It was filtered, washed with 20 ml water, air dried
to give 0.52 g desired product as light yellow solid.
[0200] .sup.1H-NMR (CDCl.sub.3): .delta.6.84 (s, 2H), 3.8 (m, 1H),
2.48 (s, 6H), 0.83 (m, 4H).
Step 5:
1-[4-(cyclopropyloxy)-2,6-bis(methylthio)benzoyl]-4-(1-methyl-1-{[-
3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine
##STR00036##
[0202] To a 16 ml vial was added
4-(cyclopropyloxy)-2,6-bis(methylthio)benzoic acid (375 mg, 1.39
mmol),
4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine
(465 mg, 1.39 mmol), Bop reagent (675 mg, 1.53 mmol),
diisopropylethyl amine (1.21 ml, 6.93 mmol) and 4 ml
dimethylformamide. The resulting solution was stirred at room
temperature for 1 hour. It was diluted with 30 ml ethyl acetate,
washed sequencially with 20 ml 1N HCl, 20 ml 5% KOH and 20 ml
brine. The organics were dried over sodium sulfate, filtered and
concentrated. The residue was purified on silica gel column eluted
with 1:2 to 1:1 ethyl acetate/hexane to give desired product as
sticky material.
[0203] Mass Spectra (m/e): 588 (M+1).
Step 6:
1-[4-(cyclopropyloxy)-2,6-bis(methylsulfonyl)benzoyl]-4-(1-methyl--
1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine
##STR00037##
[0205] To a 100 ml round bottom flask was added
1-[4-(cyclopropyloxy)-2,6-bis(methylthio)benzoyl]-4-(1-methyl-1-{[3-(trif-
luoromethyl)phenyl]sulfonyl}ethyl)piperidine (460 mg, 0.783 mmol),
meta-chloroperbenzoic acid (1.93 g, 7.83 mmol) and 30 ml methylene
chloride. The resulting reaction mixture was heated at 45.degree.
C. for 18 h. After cooling to room temperature, the reaction
mixture was washed with 40 ml saturated sodium carbonate and 20 ml
sodium thiosulfate. The organics were dried over sodium sulfate,
filtered and concentrated. The residue was purified on a reverse
phase column eluted with water and acetonitrile gradient solvent.
The fractions contain desired compound were collected and
lyophilized to give the title compound as fluffy white solid.
[0206] .sup.1H-NMR (CDCl.sub.3): .delta.8.17 (d, J=7.5 Hz, 1H), 8.1
(m, 2H), 8.04 (m, 2H), 7.90 (t, J=7.8 Hz, 1H), 4.7 (m, 1H), 4.07
(m, 1H), 3.24, 3.19 (s, 6H), 3.05 (m, 1H), 3.15 (m, 1H), 2.75 (m,
1H), 2.15 (m, 1H), 1.8 (m, 1H), 1.65 (m, 1H), 1.28, 1.24 (s, 6H),
0.95 (m, 2H), 0.84 (m, 1H). Complicate .sup.1H NMR spectrum
indicating the compound exits as a pair of rotomer at room
temperature.
[0207] Mass Spectra (m/e): 651 (M+1).
Example 5
2-[(1-methyl-1-{1-[2-(methylsulfonyl)-4-(trifluoromethoxy)benzoyl]piperidi-
n-4-yl}ethyl)sulfonyl]-6-(trifluoromethyl)pyridine
##STR00038##
[0208] Step 1: tert-butyl
4-(1-mercaptoethyl)piperidine-1-carboxylate
##STR00039##
[0210] To a 500 ml round bottom flask was added tert-butyl
4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (19 g,
61.8 mmol), potassium thioacetate (8.47 g, 74.2 mmol) and 90 ml
dimethyl sulfoxide. The resulting reaction mixture was heated at
60.degree. C. under nitrogen for 2 hours then at 45.degree. C. for
18 hours. After cooling to room temperature, the reaction mixture
was diluted with 300 ml ether, washed with 400 ml water and then
150 ml brine. The organics were dried over sodium sulfate, filtered
and concentrated. The residue was purified on silica gel column
eluted with 1:20 to 1:10 ethyl acetate/hexane to give 15 g
tert-butyl 4-[1-(acetylthio)ethyl]piperidine-1-carboxylate as dark
yellow sticky material. This material was dissolved in 100 ml MeOH.
A solution of KOH (17.3 g, 309 mmol) in 150 ml water was added. The
reaction mixture was flushed with nitrogen and stirred at
50.degree. C. for 2 hours. After cooling to room temperature, the
volume of reaction was reduced to 150 ml. Hexane (300 ml) was
added. The layers were separated, and the aqueous portion was
poured into an Erlenmyer flask with 250 ml saturated NH.sub.4Cl,
and pH of the mixture was adjusted to 7 by addition of 3N HCl. This
solution was extracted with 250 ml ether. The extracts were washed
with 100 ml brine, dried over sodium sulfate, filtered and
concentrated. The residue was purified on silica gel column eluted
with 1:20 to 1:9 ethyl acetate/hexane to give 8.3 g desire product
as light yellow sticky material.
[0211] .sup.1H-NMR (CDCl.sub.3): .delta.4.2 (b, 2H), 2.9 (m, 1H),
2.7 (b, 2H), 1.8 (m, 2H) 1.49 (s, 9H), 1.37 (d, J=6.9 Hz, 3H), 1.3
(m, 2H).
Step 2: tert-butyl
4-(1-{[6-(trifluoromethyl)pyridin-2-yl]thio}ethyl)piperidine-1-carboxylat-
e
##STR00040##
[0213] To a 16 ml vial was added tert-butyl
4-(1-mercaptoethyl)piperidine-1-carboxylate (500 mg, 2.04 mmol),
2-bromo-6-(trifluoromethyl)pyridine (460 mg, 2.04 mmol),
Pd(dppf)Cl.sub.2 (42 mg, 0.051 mmol) and Cs.sub.2CO.sub.3 (996 mg,
3.06 mmol) and 4 ml toluene. The vial was flushed with nitrogen,
sealed and heated at 75.degree. C. for 36 hours. After cooling to
room temperature, the reaction mixture was diluted with 30 ml
ether, and washed with 30 ml water. The organics were dried over
sodium sulfate, filtered and concentrated. The residue was purified
on silica gel column eluted with 1:9 to 1:4 ethyl acetate/hexane to
give 750 mg desired product was light yellow oil.
[0214] .sup.1H-NMR (CDCl.sub.3): .delta.7.62 (t, J=7.8 Hz, 1H),
7.34 (d, J=7.3 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 4.2 (b, 3H), 2.7
(b, 2H), 1.8 (b, 3H), 1.48 (s, 9H), 1.40 (d, J=7.3 Hz, 3H) 1.35 (m,
1H).
[0215] Mass Spectra (m/e): 391 (M+1).
Step 3: tert-butyl
4-(1-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}ethyl)piperidine-1-carbox-
ylate
##STR00041##
[0217] To a 100 ml round bottom flask was added tert-butyl
4-(1-{[6-(trifluoromethyl)pyridin-2-yl]thio}ethyl)piperidine-1-carboxylat-
e (0.90 g, 2.31 mmol), meta-choroperbenzoic acid (MCPBA) (1.71 g,
6.91 mmol) and 20 ml dichloromethane. The resulting reaction
mixture was stirred at room temperature for 2 hours. It was diluted
with 50 ml ether, washed with 20 ml sodium carbonate and 20 ml
sodium thiosulfate saturated solution. The organics were dried over
sodium sulfate, filtered and concentrated. The residue was purified
on silica gel column eluted with 1:4 to 1:2 ethyl acetate/hexane to
give 0.78 g desired product as colorless sticky material.
[0218] .sup.1H-NMR (CDCl.sub.3): .delta.8.33 (d, J=7.8 Hz, 1H),
8.23 (t, J=7.8 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 4.2 (b, 2H), 3.83
(m, 1H), 2.74 (b, 2H), 2.43 (m, 1H), 2.0 (b, 1H), 1.85 (m, 1H),
1.3-1.6 (m, 2H), 1.48 (s, 9H), 1.26 (d, J=7.3 Hz, 3H).
Step 4: tert-butyl
4-(1-methyl-1-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}ethyl)piperidine-
-1-carboxylate
##STR00042##
[0220] To a 50 ml round bottom flask was added tert-butyl
4-(1-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}ethyl)piperidine-1-carbox-
ylate (0.78 g, 1.85 mmol) and tetrahydrofuran (10 ml). The
resulting solution was cooled with dry ice acetone bath. Sodium
bis(trimethylsilyl)amide (NaHMDS) tetrahydrofuran solution (1M,
2.58 ml, 2.58 mmol) was added via a syringe. The resulting reaction
solution was stirred at -78.degree. C. for 10 minutes. MeI (0.173
ml, 2.77 mmol) was added. The reaction mixture was allowed to warm
up to room temperature and quenched by addition of 50 ml saturated
NH.sub.4Cl solution. It was diluted with 30 ml ether. The layers
were separated, and the organics were dried over sodium sulfate,
filtered and concentrated. The residue was purified on silica gel
column eluted with 1:4 to 1:2 ethyl acetate/hexane to give 0.806 g
desired product (contains solvent).
[0221] .sup.1H-NMR (CDCl.sub.3): .delta.8.32 (d, J=7.8 Hz, 1H),
8.20 (t, J=7.9 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 4.2 (b, 2H), 2.7
(b, 2H), 2.16 (m, 1H), 2.0 (b, 2H), 1.3-1.6 (m, 2H), 1.48 (s, 9H),
1.39 (s, 6H).
[0222] Mass Spectra (m/e): 437 (M+1).
Step 5:
2-[(1-methyl-1-piperidin-4-ylethyl)sulfonyl]-6-(trifluoromethyl)py-
ridine
##STR00043##
[0224] To a 25 ml round bottom flask was added tert-butyl
4-(1-methyl-1-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}ethyl)piperidine-
-1-carboxylate (0.806 g, 1.85 mmol), trifluoroacetic acid (1.5 ml)
and dichloromethane (5 ml). The resulting solution was stirred at
room temperatuer for 1 hour. It was diluted with 50 ml ethyl
acetate, washed with 50 ml 10% KOH and then 30 ml brine. The
organics were dried over sodium sulfate, filtered and concentrated
to give 0.33 g desired product as cyrstalline solid.
[0225] .sup.1H-NMR (CDCl.sub.3): .delta.8.33 (d, J=8.0 Hz, 1H),
8.20 (t, J=7.8 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 3.17 (m, 2H), 2.64
(m, 2H), 2.15 (m, 1H), 2.0 (m, 2H), 1.45 (m, 2H), 1.42 (s, 6H).
[0226] Mass Spectra (m/e): 337 (M+1).
Step 6:
2-[(1-methyl-1-{1-[2-(methylsulfonyl)-4-(trifluoromethoxy)benzoyl]-
piperidin-4-yl}ethyl)sulfonyl]-6-(trifluoromethyl)pyridine
##STR00044##
[0228] To a 10 ml vial was added
2-(methylsulfonyl)-4-(trifluoromethoxy)benzoic acid (16.9 mg, 0.059
mmol),
2-[(1-methyl-1-piperidin-4-ylethyl)sulfonyl]-6-(trifluoromethyl)py-
ridine (20 mg, 0.059 mmol), Bop reagent (31.6 mg, 0.071 mmol),
diisopropylethyl amine (0.052 ml, 0.297 mmol) and 1 ml
dimethylformamide. The resulting solution was stirred at room
temperature for 1 hour. It was diluted with 1 m dimethyl sulfoxide,
0.5 ml water and 0.1 ml trifluoroacetic acid. This mixture was
loaded on to reverse phase column directly and eluted with water
acetonitrile gradient solvent to give the title compound as fluffy
white solid after lyophilizing.
[0229] .sup.1H-NMR (CDCl.sub.3): .delta.8.4 (m, 2H), 8.16 (d, J=7.5
Hz, 1H), 7.94 (m, 1H), 7.7 (m, 1H), 7.6 (m, 1H), 4.8 (m, 1H),
3.7-1.5 (m, 8H), 3.31 3.25 (s, 3H), 1.41, 1.38, 1.37, 1.32 (s, 6H).
Complicate .sup.1H NMR spectrum indicating the compound exits as a
pair of rotomers at room temperature.
[0230] Mass Spectra (m/e): 603 (M+1).
Example 6
1-[5-fluoro-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)-
phenyl]sulfonyl}ethyl)azetidine
##STR00045##
[0231] Step 1: tert-butyl
3-{[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate
##STR00046##
[0233] To a 100 ml round bottom flask was added
1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.75 g, 18.6
mmol) and 20 ml tetrahydrofuran, followed by CDI (3.63 g, 22.4
mmol). Vigorous gas evolution was observed. After gas evolution
stopped, the reaction mixture was stirred at room temperature for
additional 30 minutes. Methoxy(methyl)ammonium chloride (2.55 g,
26.1 mmol) was added, followed by diisopropylethyl amine (6.5 ml,
37.3 mmol). The resulting reaction mixture was stirred at room
temperature overnight. It was diluted with 120 ml ether and washed
with 60 ml saturated NH.sub.4Cl. The organics were dried over
sodium sulfate, filtered and concentrated. The residue was purified
on silica gel column, eluted with 1:2 to 3:2 ethyl acetate/hexane
to give 3.6 g desired product was colorless oil.
[0234] .sup.1H-NMR (CDCl.sub.3): .delta.4.17 (m, 2H), 4.08 (t,
J=8.7 Hz, 2H), 3.69 (s, 3H), 3.5 (b, 1H), 3.24 (s, 3H), 1.47 (s,
9H).
Step 2: tert-butyl 3-acetylazetidine-1-carboxylate
##STR00047##
[0236] To a 100 ml round bottom flask was added tert-butyl
3-{[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate (2.6 g,
10.6 mmol) and 20 ml tetrahydrofuran. The resulting solution was
cooled to 0.degree. C. and methylmagnesium chloride tetrahydrofuran
solution (4.3 ml, 3M, 12.8 mmol) was added by a syringe. The
reaction mixture was stirred at 0.degree. C. for 1 hour. It was
diluted with 100 ml ether, and the resulting mixture was washed
twice with 100 ml saturated ammonium chloride solution. The
organics were dried over sodium sulfate, filtered and concentrated.
The crude product was used for the next step without further
purification.
[0237] .sup.1H-NMR (CDCl.sub.3): .delta.4.05 (m, 4H), 3.43 (m, 1H),
2.20 (s, 3H), 1.45 (s, 9H).
Step 3: tert-butyl 3-(1-hydroxyethyl)azetidine-1-carboxylate
##STR00048##
[0239] To a 100 ml round bottom flask was added tert-butyl
3-acetylazetidine-1-carboxylate (2.06, 10.3 mmol) and 30 ml MeOH.
NaBH.sub.4 (0.403 g, 10.6 mmol) was added in portions. The
resulting reaction mixture was stirred at room temperature for 15
minutes. The volatiles were removed under vacuum. The residue was
treated with 50 ml 10% KOH and extracted with 2.times.50 ml ethyl
acetate. The organics were combined and dried over sodium sulfate,
filtered and concentrated. The residue was purified on silica gel
column eluted with 1:4 to 1:2 E/H to give 2.06 g desired product as
colorless oil.
[0240] .sup.1H-NMR (CDCl.sub.3): .delta.3.95 (m, 2H), 3.83 (m, 1H),
3.65 (m, 1H), 2.5 (m, 1H), 1.45 (s, 9H) 1.17 (d, J=6.5 Hz, 3H).
Step 4: tert-butyl
3-(1-{[3-(trifluoromethyl)phenyl]thio}ethyl)azetidine-1-carboxylate
##STR00049##
[0242] To 100 ml round bottom flask was added tert-butyl
3-(1-hydroxyethyl)azetidine-1-carboxylate (2.06 g, 10.2 mmol),
triethylamine (4.2 ml, 30.7 mmol) and 40 ml dichloromethane.
Methanesulfonyl chloride (0.955 ml, 12.3 mmol) was added at
0.degree. C. The reaction mixture was allowed to warm up to room
temperature and stirred for 1 hour. It was then diluted with 100 ml
ether, washed with 2.times.50 ml saturated sodium carbonate
solution. The organics were dried over sodium sulfate, filtered and
concentrated. The residue was dissolved in 30 ml dimethylformamide.
Potassium carbonate (3.75 g, 26.8 mmol) and
3-(trifluoromethyl)benzenethiol (1.91 g, 10.7 mmol) were added. The
resulting reaction mixture was heated at 75.degree. C. overnight.
It was diluted with 120 ml ether, washed sequentially with 150 ml
water, and 75 ml saturated sodium carbonate. The organics were
dried over sodium sulfate, filtered and concentrated. The residue
was purified on silica gel column eluted with hexane to 1:9 ethyl
acetate/hexane to give 2.65 g desired product as colorless oil.
[0243] .sup.1H-NMR (CDCl.sub.3): .delta.7.68 (s, 1H), 7.61 (d,
J=8.0 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 4.0
(m, 2H), 3.80 (m, 1H), 3.7 (m, 1H), 3.15 (m, 1H), 2.6 (m, 1H), 1.47
(s, 9H) 1.30 (d, J=6.7 Hz, 3H).
Step 5: tert-butyl
3-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine-1-carboxylate
##STR00050##
[0245] To 500 ml round bottom flask was added tert-butyl
3-(1-{[3-(trifluoromethyl)phenyl]thio}ethyl)azetidine-1-carboxylate
(2.65 g, 7.33 mmol) and 150 ml MeOH. Oxone.TM. in 75 ml water (pH
of the solution was adjusted to 3 with addition of potassium
carbonate solution) was added. The resulting reaction mixture was
stirred at room temperature for 2 hours. It was diluted with 100 ml
ethyl acetate and filtered through a pad of celite. The volatiles
were removed from the filtrate. The residue was partitioned between
100 ml ethyl acetate and 100 ml water. The organics were dried over
sodium sulfate, filtered and concentrated. The residue was purified
on silica gel column eluted with 1:4 to 1:2 ethyl acetate to give
2.5 g desired product was colorless sticky oil.
[0246] .sup.1H-NMR (CDCl.sub.3): .delta.8.17 (s, 1H), 8.11 (d,
J=8.0 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 4.05
(m, 2H), 3.90 (b, 1H), 3.75 (m, 1H), 3.4 (m, 1H), 2.95 (m, 1H),
1.46 (s, 9H) 1.29 (d, J=7.1 Hz, 3H).
Step 6: tert-butyl
3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine-1-carb-
oxylate
##STR00051##
[0248] To a 100 ml round bottom flask was added was added
tert-butyl
3-(1-{[3-(trifluoromethyl)phenyl]thio}ethyl)azetidine-1-carboxylate
(1.82 g, 4.63 mmol) and 20 ml tetrahydrofuran. Sodium
bis(trimethylsilyl)amide tetrahydrofuran solution (5.55 ml, 1M,
5.55 mmol) was added to this solution at -78.degree. C. The
resulting reaction solution was stirred at -78.degree. C. for 5
minutes. The reaction mixture turned deep orange red immediately.
Iodomethane was added dropwise via a syringe until reaction mixture
turned to light yellow. More sodium bis(trimethylsilyl)amide
tetrahydrofuran solution (2 ml, 1M, 2 mmol) was added, and the
resulting reaction mixture was stirred at -78.degree. C. for 5
minutes. More iodomethane (0.2 ml, 3.2 mmol) was added. After
stirring at -78.degree. C. for 10 minutes, it was quenched by
addition of 30 ml saturated NH.sub.4Cl. The reaction mixture was
diluted with 60 ml ether and 30 ml water. The layers were
separated, and the organics were dried over sodium sulfate,
filtered and concentrated. The residue was purified on silica gel
column eluted with 1:3 to 1:2 ethyl acetate/hexane to give 1.72 g
desired product as colorless sticky oil.
[0249] .sup.1H-NMR (CDCl.sub.3): .delta.8.14 (s, 1H), 8.07 (d,
J=8.3 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.78 (t, J=7.8 Hz, 1H), 3.98
(m, 2H), 3.90 (b, 1H), 3.11 (m, 1H), 1.46 (s, 9H) 1.37 (s, 6H).
Step 7:
3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine
##STR00052##
[0251] To a 100 ml round bottom flask equipped with a reflux
condenser was added tert-butyl
3-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine-1-carboxylate
(0.85 g, 2.09 mmol), ceric ammonium nitrate (1.37 g, 2.5 mmol) and
15 ml acetonitrile. The resulting reaction mixture was refluxed for
3 hours. The volatiles were removed. The residue was diluted with
60 ml ethyl acetate and 50 ml saturated sodium carbonate. It was
filtered through a pad of celite. The organic portion from the
filtrate was washed with 50 ml brine, dried over sodium sulfate,
filtered and concentrated. The residue was redissolved in
hexane/CH.sub.2Cl.sub.2 (9:1), filtered and concentrated to give
0.62 g yellow sticky solid. It is about 90% pure based on .sup.1H
NMR spectra. It was used for next step without further
purification.
[0252] .sup.1H-NMR (CD.sub.3OD): .delta.8.15 (d, J=8.4 Hz, 1H), 8.1
(m, 2H), 7.90 (m, 1H), 3.61 (t, J=8.8 Hz, 2H), 3.45 (t, J=8.9 Hz,
2H), 3.3 (m, 1H), 1.33 (s, 6H).
Step 8:
1-[5-fluoro-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluor-
omethyl)phenyl]sulfonyl}ethyl)azetidine
##STR00053##
[0254] To a 10 ml vial was added 5-fluoro-2-(methylsulfonyl)benzoic
acid (35.5 mg, 0.163 mmol),
3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine
(50 mg, 0.163 mmol), Bop reagent (79 mg, 0.179 mmol),
diisopropylethyl amine (0.142 ml, 0.813 mmol) and 1 ml
dimethylformamide. The resulting solution was stirred at room
temperature for 1 hour. It was diluted with 1 m dimethyl sulfoxide,
0.5 ml water and 0.1 ml trifluoroacetic acid. This mixture was
loaded on to reverse phase column directly eluted with water
acetonitrile gradient solvent to give the title compound as a
fluffy white solid after lyophilizing.
[0255] .sup.1H-NMR (CD.sub.3OD): .delta.8.15 (m, 4H), 7.90 (t,
J=7.5 Hz, 1H), 7.45 (m, 1H), 7.37 (m, 1H), 4.15 (m, 1H), 4.05 (m,
1H), 3.97 (m, 1H), 3.91 (m, 1H), 3.35, 3.28 (s, 3H), 1.37, 1.31 (s,
6H). Complicate .sup.1H NMR spectrum indicating the compound exits
as a pair of rotomer at room temperature.
[0256] Mass Spectra (m/e): 507 (M+1).
Example 7
3-[4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidin-1-yl-
]quinoline
##STR00054##
[0258] To a 10 ml vial was added
4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine
(30 mg, 0.089 mmol), quinolin-3-ylboronic acid (62 mg, 0.358 mmol),
copper acetate (32.5 mg, 0.179 mmol), diisopropylethyl amine (0.049
ml, 0.358 mmol) and 1 ml tetrahydrofuran. The resulting reaction
mixture was stirred at room temperature for one hour then
60.degree. C. 3 hours. After aqueous work up, the crude product was
purified on reverse phase column eluted with water/acetonitrile
gradient solvent to give 24 mg desired product as fluffy white
solid after lyophilizing.
[0259] .sup.1H-NMR (CD.sub.3OD): .delta.8.77 (s, 1H), 8.20 (d,
J=8.0 Hz, 1H), 8.15 (s, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.9 (m, 2H),
7.80 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.52 (m, 2H), 3.97 (m, 2H),
2.81 (m, 2H), 2.22 (m, 2H), 2.1 (m, 1H), 1.75 (m, 2H), 1.33 (s,
6H).
[0260] Mass Spectra (m/e): 463 (M+1).
Example 8
##STR00055##
[0261]
1-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-4-(1-methyl-1-{[3-(-
trifluoromethyl)phenyl]-sulfonyl}ethyl)piperidine
[0262] To a 10 ml vial was loaded
4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine
(60 mg, 0.179 mmol), diisoprpoylethylamine (0.093 ml, 0.54 mmol),
2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (87 mg, 0.27
mmol), N,N-dimethylaminopyridine (4.4 mg, 0.036 mmol) and 1 ml
methylene chloride. The resulting reaction solution was stirred at
room temperature for one hour. It was diluted with 20 ml ethyl
acetate, washed sequentially with 20 ml 1N HCl, 20 ml 10% KOH and
20 ml brine. Organics were dried over sodium sulfate, filtered and
concentrated to give 91 mg white solid. A fraction of this crude
product (20 mg) was further purified on a reverse phase column
eluted with water/acetonitrile gradient solvent to give 16 mg
desired product as fluffy white solid after lyophilizing.
[0263] .sup.1H-NMR (CDCl.sub.3): .delta.8.25 (d, J=8.0 Hz, 1H),
8.13 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.03 (s, 2H), 7.96 (d, J=8.2
Hz, 1H), 7.76 (m, 2H), 3.99 (d, J=10.8 Hz, 2H), 2.85 (t, J=12 Hz,
2H), 2.16 (m, 3H), 1.6 (m, 2H), 1.25 (s, 6H).
[0264] Mass Spectra (m/e): 622 (M+1).
[0265] Using the procedures described in EXAMPLES 1-8 with the
appropriate modifications, reagents and substrates the following
compounds of the current invention were prepared.
TABLE-US-00002 TABLE 1 MASS SPECTRAL EXAMPLE CHEMICAL DATA #
STRUCTURE NAME m/e (M + H) 9 ##STR00056## 1-[4-(methylsulfonyl)-2-
(trifluoromethoxy)benzoyl]- 4-({[3-(trifluoromethyl)-
phenyl]sulfonyl}methyl)- piperidine 574 10 ##STR00057##
1-[5-fluoro-2- (methylsulfonyl)benzoyl]-4- ({[3-(trifluoromethyl)-
phenyl]sulfonyl}methyl) piperidine 508 11 ##STR00058##
1-[2-(methylsulfonyl)-4- (trifluoromethyl)benzoyl]-4-
({[3-(trifluoromethyl)- phenyl]sulfonyl}methyl) piperidine 558 12
##STR00059## 1-[2-chloro-4- (methylsulfonyl)benzoyl]-4-
({[3-(trifluoromethyl)- phenyl]sulfonyl}methyl) piperidine 524 13
##STR00060## 1-[5-fluoro-2-(methyl- sulfonyl)benzoyl]-4-{[(4-
fluorophenyl)sulfonyl]- methyl}piperidinehyl} piperidine 458 14
##STR00061## 4-{[(4-fluorophenyl)- sulfonyl]methyl}-1-[4-
(methylsulfonyl)-2- (trifluoromethoxy)benzoyl] piperidine 524 15
##STR00062## 4-{[(4-chlorophenyl)- sulfonyl]methyl}-1-[5-
fluoro-2-(methyl- sulfonyl)benzoyl]piperidine 475 16 ##STR00063##
4-{[(4- chlorophenyl)sulfonyl] methyl}-1-[4-(methylsulfonyl)-
2-(trifluoromethoxy)benzoyl] piperidine 541 17 ##STR00064## 4-{[(3-
chlorophenyl)sulfonyl] methyl}-1-[4-(methylsulfonyl)-
2-(trifluoromethoxy)benzoyl] piperidine 541 18 ##STR00065##
1-(3,5-di-tert-butyl-4- methoxybenzoyl)-4-{[(4-
fluorophenyl)sulfonyl]methyl} piperidine 504 19 ##STR00066##
4-{[(4- chlorophenyl)sulfonyl] methyl}-1-(3,5-di-tert-butyl-4-
methoxybenzoyl)piperidine 520 20 ##STR00067##
1-[4-(difluoromethoxy)-2- (methylsulfonyl)benzoyl]-4-
({[3-(trifluoromethyl)- phenyl]sulfonyl}methyl) piperidine 556 21
##STR00068## 4-{[(4-fluorophenyl)- sulfonyl]methyl}-1-[2-
(methylsulfonyl)-4- (trifluoromethyl)benzoyl] piperidine 508 22
##STR00069## 1-[4-(difluoromethoxy)-2- (methylsulfonyl)benzoyl]-
4-{[(4- fluorophenyl)sulfonyl]methyl} piperidine 506 23
##STR00070## 4-{[(4- chlorophenyl)sulfonyl]methyl}-
1-[2-(methylsulfonyl)- 4-(trifluoromethyl)benzoyl] piperidine 524
24 ##STR00071## 4-{[(4- chlorophenyl)sulfonyl]methyl}-
1-[4-(difluoromethoxy)-2- (methylsulfonyl)benzoyl] piperidine 522
25 ##STR00072## 1-[2-(methylsulfonyl)-4-
(trifluoromethoxy)benzoyl]- 4-({[3- (trifluoromethyl)phenyl]
sulfonyl}methyl)piperidine 574 26 ##STR00073## 4-{[(4-
chlorophenyl)sulfonyl]methyl}- 1-[2-(methylsulfonyl)-4-
(trifluoromethoxy)benzoyl] piperidine 540 27 ##STR00074## 4-{[(4-
fluorophenyl)sulfonyl]methyl}- 1-[2-(methylsulfonyl)-4-
(trifluoromethoxy)benzoyl] piperidine 524
TABLE-US-00003 TABLE 2 MASS SPECTRAL EXAMPLE CHEMICAL DATA #
STRUCTURE NAME m/e (M + H) 28 ##STR00075## 1-[4-(methylsulfonyl)-2-
(trifluoromethoxy)benzoyl]- 4-(1-{[3-(trifluoromethyl)
phenyl]sulfonyl}ethyl) piperidine 588 29 ##STR00076##
1-[4-(methylsulfonyl)-2- (trifluoromethoxy)benzoyl]- 4-((1S)-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 588 30
##STR00077## 1-[4-(methylsulfonyl)-2- (trifluoromethoxy)benzoyl]-
4-((1R)-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
588 31 ##STR00078## 4-{1-[(4- fluorophenyl)sulfonyl]ethyl}-
1-[4-(methylsulfonyl)-2- (trifluoromethoxy)benzoyl] piperidine 538
32 ##STR00079## 4-{1-[(4- chlorophenyl)sulfonyl]ethyl}-
1-[4-(methylsulfonyl)-2- (trifluoromethoxy)benzoyl] piperidine 555
33 ##STR00080## 4-{1-[(4- chlorophenyl)sulfonyl]ethyl}-
1-[5-fluoro-2- (methylsulfonyl)benzoyl] piperidine 488 34
##STR00081## 1-[5-fluoro-2- (methylsulfonyl)benzoyl]- 4-(1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 522 35
##STR00082## 1-[2-(methylsulfonyl)-4- (trifluoromethyl)benzoyl]-
4-(1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 572 36
##STR00083## tert-butyl4-(1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine-1- carboxylate 422 37 ##STR00084##
1-[2-(methylsulfonyl)-4- (trifluoromethoxy)benzoyl]- 4-((1S)-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 588 38
##STR00085## 1-[4-(difluoromethoxy)-2- (methylsulfonyl)benzoyl]-
4-((1S)-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
570 39 ##STR00086## 1-[2-(methylsulfonyl)-4-
(trifluoromethoxy)benzoyl]- 4-((1R)-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 588 40 ##STR00087##
1-[4-(difluoromethoxy)-2- (methylsulfonyl)benzoyl]- 4-((1R)-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 570 41
##STR00088## 1-[4-(cyclopropyloxy)-2,6- bis(methylsulfonyl)
benzoyl]-4-((1S)-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 638 42 ##STR00089##
1-[4-(cyclopropyloxy)-2,6- bis(methylsulfonyl)benzoyl]-
4-((1R)-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
638 43 ##STR00090## 2-(cyclopropylsulfonyl)-6-
(trifluoromethyl)-3-{[4- ((1S)-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine-1- yl]carbonyl}pyridine 599 44
##STR00091## 2-(cyclopropylsulfonyl)-6- (trifluoromethyl)-3-{[4-
((1R)-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}pyridine 599 45 ##STR00092## 3-chloro-5-
(trifluoromethyl)-2-{[4- ((1S)-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine- 1-yl]carbonyl}pyridine 529 46
##STR00093## 3-chloro-5- (trifluoromethyl)-2-{[4- ((1S)-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-
1-yl]carbonyl}pyridine 529 47 ##STR00094## 3-(methylsulfonyl)-5-
(trifluoromethyl)-2-{[4- ((1S)-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyridine 573 48
##STR00095## 3-(methylsulfonyl)-5- (trifluoromethyl)-2-{[4-
((1S)-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}pyridine 573 49 ##STR00096## 3-(cyclopropylsulfonyl)-5-
(trifluoromethyl)-2-{[4- ((1S)-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyridine 599 50
##STR00097## 3-(cyclopropylsulfonyl)-5- (trifluoromethyl)-2-{[4-
((1S)-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}pyridine 599 51 ##STR00098## 4-(cyclopropyl{[3-
(trifluoromethyl)phenyl] sulfonyl}methyl)-1-[5-fluoro-
2-(methylsulfonyl)benzoyl] piperidine 548 52 ##STR00099##
4-(cyclopropyl{[3- (trifluoromethyl)phenyl] sulfonyl}methyl)-1-[4-
(methylsulfonyl)-2- (trifluoromethoxy)benzoyl] piperidine 514
TABLE-US-00004 TABLE 3 MASS SPECTRAL EXAMPLE CHEMICAL DATA #
STRUCTURE NAME m/e (M + H) 53 ##STR00100## 1-[4-(methylsulfonyl)-2-
(trifluoromethoxy)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 602 54
##STR00101## 1-[2-(methylsulfonyl)-4- (trifluoromethyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 586 55 ##STR00102## 1-[5-fluoro-2-
(methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 536 56
##STR00103## 1-(3-fluorobenzoyl)-4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 458 57
##STR00104## 1-(3-methylbenzoyl)-4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 454 58
##STR00105## 1-(3-methoxybenzoyl)-4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 470 59
##STR00106## 1-(4-isopropylbenzoyl)-4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 482 60
##STR00107## 1-(4-tert-butylbenzoyl)-4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 496 61
##STR00108## 4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-(1,3- oxazol-2-ylcarbonyl) piperidine 431 62
##STR00109## 2-chloro-3-{[4-(1-methyl- 1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}quinoxaline 526 63 ##STR00110## 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)-1-[2-
(trifluoromethoxy)benzoyl] piperidine 524 64 ##STR00111## 1-[2-
(difluoromethoxy)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 506 65
##STR00112## 1-[4- (difluoromethoxy)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 506 66
##STR00113## 1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-1H- benzimidazole 498 67
##STR00114## 4-(methylthio)-2-{[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}phenol 502 68 ##STR00115## 6-chloro-2-{[4-(1-methyl-
1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-1H- benzimidazole 514 69 ##STR00116##
1-(3,5-di-tert-butyl-4- methoxybenzoyl)-4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 582 70
##STR00117## 4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-[3-(1H- tetrazol-1- yl)benzoyl]piperidine 508 71
##STR00118## 1-(3-cyclopropylbenzoyl)- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 480 72
##STR00119## 4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-(1,3- thiazol-4-ylcarbonyl) piperidine 447 73
##STR00120## 1-[(2,4-dimethyl-1,3- thiazol-5-yl)carbonyl]-4-
(1-methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
475 74 ##STR00121## 3-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyrazolo[1,5- a]pyrimidine
481 75 ##STR00122## 2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyrazolo[1,5- a]pyridine
480 76 ##STR00123## 1-[4-(methylsulfonyl)-2-
(trifluoromethoxy)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethoxy)phenyl] sulfonyl}ethyl)piperidine 618 77
##STR00124## 1-[2-(methylsulfonyl)-4- (trifluoromethyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethoxy)phenyl]
sulfonyl}ethyl)piperidine 602 78 ##STR00125## 1-[5-fluoro-2-
(methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethoxy)phenyl] sulfonyl}ethyl)piperidine 552 79
##STR00126## 1-[4-chloro-2- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethoxy)phenyl]
sulfonyl}ethyl)piperidine 569 80 ##STR00127##
1-benzoyl-4-(1-methyl-1-{[3- (trifluoromethoxy)phenyl]
sulfonyl}ethyl)piperidine 456 81 ##STR00128##
1-(3-fluorobenzoyl)-4-(1- methyl-1-{[3- (trifluoromethoxy)phenyl]
sulfonyl}ethyl)piperidine 474 82 ##STR00129##
1-(3-methylbenzoyl)-4-(1- methyl-1-{[3- (trifluoromethoxy)phenyl]
sulfonyl}ethyl)piperidine 470 83 ##STR00130## 4-(1-methyl-1-{[3-
(trifluoromethoxy)phenyl] sulfonyl}ethyl)-1-[2-
(trifluoromethoxy)benzoyl] piperidine 540 84 ##STR00131## 1-[2-
(difluoromethoxy)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethoxy)phenyl] sulfonyl}ethyl)piperidine 522 85
##STR00132## 1-[3- (difluoromethoxy)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethoxy)phenyl] sulfonyl}ethyl)piperidine 522 86
##STR00133## 1-[4- (difluoromethoxy)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethoxy)phenyl] sulfonyl}ethyl)piperidine 522 87
##STR00134## 1-[3- (methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 518 88
##STR00135## 1-[4-methoxy-3- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethoxy)phenyl]
sulfonyl}ethyl)piperidine 564 89 ##STR00136##
1-[4-(difluoromethoxy)-3- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethoxy)phenyl]
sulfonyl}ethyl)piperidine 600 90 ##STR00137## 1-[4-methoxy-2-
(methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethoxy)phenyl] sulfonyl}ethyl)piperidine 564 91
##STR00138## 1-[4-methoxy-2- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 548 92 ##STR00139## 1-[4-methoxy-3-
(methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 548 93
##STR00140## 1-[4-(difluoromethoxy)-3- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 584 94 ##STR00141##
1-[5-(difluoromethoxy)-2- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethoxy)phenyl]
sulfonyl}ethyl)piperidine 600 95 ##STR00142## 1-[3-fluoro-2-
(methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 536 96
##STR00143## 1-[4-fluoro-2- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 536 97 ##STR00144## 1-[4,5-difluoro-2-
(methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 554 98
##STR00145## 1-[2-(ethylsulfonyl)-4,5- difluorobenzoyl]-4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
568 99 ##STR00146## 1-[5-(difluoromethoxy)-2-
(methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 584 100
##STR00147## 1-[4-(difluoromethoxy)-2- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethoxy)phenyl]
sulfonyl}ethyl)piperidine 600 101 ##STR00148##
1-[4-(difluoromethoxy)-2- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 584 102 ##STR00149## Methyl
4-{[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}benzoate 498 103
##STR00150## 2,2,2-trifluoro-1-(4-{[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}phenyl)ethanone 534 104 ##STR00151##
1,1,1,3,3,3-hexafluoro-2- (4-{[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}phenyl) propan-2-ol 606 105 ##STR00152##
N-methyl-4-{[4-(1-methyl- 1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}benzamide 497 106
##STR00153## N-cyclopropyl-4-{[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}benzamide 523 107 ##STR00154## N-tert-butyl)-4-{[4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}benzamide 539 108 ##STR00155## 1-[4-(azetidin-1-
ylcarbonyl)benzoyl]-4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 523 109 ##STR00156## 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)-1-[4- (pyrrolidin-1-
ylcarbonyl)benzoyl] piperidine 538 110 ##STR00157##
3-(methylsulfonyl)-2-{[4- (1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}quinoline 569 111
##STR00158## 1-[4-(tert- butylthio)benzoyl]-4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 528 112
##STR00159## 1-[4-(tert- butylsulfonyl)benzoyl]-4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 560 113
##STR00160## 4-(methylsulfonyl)-3-{[4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}phenol 534 114 ##STR00161## 4-{1-[(3-
chlorophenyl)sulfonyl]-1- methylethyl}-1-[4,5- difluoro-2-
(methylsulfonyl)benzoyl] piperidine 521 115 ##STR00162## 4-{1-[(3-
chlorophenyl)sulfonyl]-1- methylethyl}-1-[2- (methylsulfonyl)-4-
(trifluoromethyl)benzoyl] piperidine 553 116 ##STR00163## 4-{1-[(3-
chlorophenyl)sulfonyl]-1- methylethyl}-1-[4- (difluoromethoxy)-2-
(methylsulfonyl)benzoyl] piperidine 551 117 ##STR00164## 4-{1-[(3-
chlorophenyl)sulfonyl]-1- methylethyl}-1-[5- (difluoromethoxy)-2-
(methylsulfonyl)benzoyl] piperidine 551 118 ##STR00165## 4-{1-[(3-
chlorophenyl)sulfonyl]-1- methylethyl}-1-[5-fluoro-2-
(methylsulfonyl)benzoyl] piperidine 503 119 ##STR00166##
1-[4-(tert-butylthio)-2- chlorobenzoyl]-4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 562 120
##STR00167## 1-[4-(tert-butylsulfonyl)-2- chlorobenzoyl]-4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
595 121 ##STR00168## 1-[2-bromo-4-(tert- butylsulfonyl)benzoyl]-4-
(1-methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
639 122 ##STR00169## 1-[4-(tert-butylsulfonyl)-2-
(methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 638 123
##STR00170## 1-[(1-methyl-1H-pyrazol- 4-yl)carbonyl]-4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
444 124 ##STR00171## 2-chloro-4-methyl-6-{[4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}pyrimidine 490 125 ##STR00172##
3-chloro-6-{[4-(1-methyl- 1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyridazine 476 126
##STR00173## 2-methoxy-5-{[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}pyrazine 472 127 ##STR00174## 5-{[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-1,3- benzothiazole 497 128 ##STR00175##
1-[2-(1H-imidazol-2- yl)benzoyl]-4-(1-methyl-1- {[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 506 129
##STR00176## 4-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-1,3-dihydro-
2H-imidazol-2-one 446 130 ##STR00177## 5-{[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}quinoxaline 492 131 ##STR00178## 1-[4-hydroxy-2-
(methylsulfonyl)benzoyl]- 4-[1-methyl-1-[[3-
(trifluoromethyl)phenyl] sulfonyl]ethyl]piperidine 534 132
##STR00179## 1-[4-chloro-2- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 553 133 ##STR00180## 1-[4-bromo-2-
(methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 597 134
##STR00181## 1-{[4-fluoro-2- (methylsulfonyl)phenyl]
acetyl}-4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 550 135 ##STR00182## 1-{[2-
(methylsulfonyl)phenyl] acetyl}-4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 532 136
##STR00183## 1-{[5-chloro-2- (methylsulfonyl)phenyl]
acetyl}-4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 567 137 ##STR00184## 4-(1-{[3,5-
bis(trifluoromethyl)phenyl] sulfonyl}-1-methylethyl)- 1-[4-(tert-
butylsulfonyl)benzoyl] piperidine 628 138 ##STR00185## 4-(1-{[3,5-
bis(trifluoromethyl)phenyl] sulfonyl}-1-methylethyl)-
1-[4-(tert-butylsulfonyl)-2- chlorobenzoyl]piperidine 663 139
##STR00186## 4-(1-{[3,5- bis(trifluoromethyl)phenyl]
sulfonyl}-1-methylethyl)- 1-[4-(tert-butylsulfonyl)-2-
(methylsulfonyl)benzoyl] piperidine 706 140 ##STR00187##
2-methyl-6-{[4-(1-methyl- 1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-1H- benzimidazole 494 141
##STR00188## 1-[2-chloro-4- (isopropylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 581 142 ##STR00189##
1-[4-(isopropylsulfonyl)-2- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 624 143 ##STR00190##
2-methyl-6-{[4-(1-methyl- 1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-1,3- benzothiazole 511 144
##STR00191## 1-[4-(5-cyclopropyl-1,3,4- oxadiazol-2-yl)-2-
(methylsulfonyl)benzoyl]- 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 626 145
##STR00192## 1-(2,6-difluoro-4- methoxybenzoyl)-4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 506 146
##STR00193## 1-[4-methoxy-2,6- bis(methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 626 147 ##STR00194## 4-{1-[(3-
fluorophenyl)sulfonyl]-1- methylethyl}-1-[2- (methylsulfonyl)-4-
(trifluoromethoxy)benzoyl] piperidine 552 148 ##STR00195##
1-[4-(difluoromethoxy)-2- (methylsulfonyl)benzoyl]- 4-{1-[(3-
fluorophenyl)sulfonyl]-1- methylethyl}piperidine 534 149
##STR00196## 1-[4-(ethylsulfonyl)-2- (trifluoromethyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 600 150 ##STR00197## 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)-1-[2,4,6-
tris(methylsulfonyl)benzoyl] piperidine 674 151 ##STR00198##
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-[4-[(2,2,2- trifluoroethyl)sulfonyl]-2-
(trifluoromethyl)benzoyl] piperidine 654 152 ##STR00199##
5-[4-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-3-
(trifluoromethoxy)phenyl] pyrimidine 602 153 ##STR00200##
1-[4-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperid1-[4- {[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin- 2(1H)-one 617
154 ##STR00201## 5-(3-(methylsulfonyl)-4- {[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}phenyl) pyrimidine 596 155 ##STR00202##
1-[2,6-bis(methylsulfonyl)- 4-(trifluoromethoxy)
benzoyl]-4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 680 156 ##STR00203##
1-(3-(methylsulfonyl)-4- {[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}phenyl)pyridin- 2(1H)-one 611 157 ##STR00204##
2-[2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5-
(trifluoromethoxy)phenoxy] pyridine 617 158 ##STR00205##
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-[2-(1H- 1,2,4-triazol-1-yl)-4-
(trifluoromethoxy)benzoyl] piperidine 591 159 ##STR00206##
1-[2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5-
(trifluoromethoxy)phenyl] pyridin-2(1H)-one 617 160 ##STR00207##
1-[2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5-
(trifluoromethoxy)phenyl]- 1,2-dihydro-3H-1,2,4- triazol-3-one 607
161 ##STR00208## 1-[4-(cyclopropylsulfonyl)- 2-(trifluoromethoxy)
benzoyl]-4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 628 162 ##STR00209##
3-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}quinoxalin-2-ol 508 163
##STR00210## 1-[2,4- bis(cyclopropylsulfonyl)
benzoyl]-4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 648 164 ##STR00211##
1-[4-(cyclopropyloxy)-2- (methylsulfonyl)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 574 165 ##STR00212## 1-[4-
(cyclopropylsulfonyl) benzoyl]-4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 544 166
##STR00213## 1-(5-(cyclopropyloxy)-2- {[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}phenyl)-1,2- dihydro-3H-1,2,4-triazol- 3-one 579 167
##STR00214## 3-[(1-methyl-1-{1-[2- (methylsulfonyl)-4-
(trifluoromethoxy)benzoyl] piperidin-4- yl}ethyl)sulfonyl]-5-
(trifluoromethyl)pyridine 603 168 ##STR00215## 3-[(1-{1-[4-
(difluoromethoxy)-2- (methylsulfonyl)benzoyl] piperidin-4-yl}-1-
methylethyl)sulfonyl]-5- (trifluoromethyl)pyridine 585 169
##STR00216## 3-[(1-{1-[4- (cyclopropyloxy)-2-
(methylsulfonyl)benzoyl] piperidin-4-yl}-1-
methylethyl)sulfonyl]-5- (trifluoromethyl)pyridine 575 170
##STR00217## 1-[4-(cyclopropylsulfonyl)- 3-fluorobenzoyl]-4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
562 171 ##STR00218## 1-[4-bromo-2- (cyclopropylsulfonyl)
benzoyl]-4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 623 172 ##STR00219##
1-[4-(cyclopropylsulfonyl)- 2-fluorobenzoyl]-4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 562 173
##STR00220## 1-[4-(cyclopropylsulfonyl)- 2-methoxybenzoyl]-4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
574 174 ##STR00221## 2-chloro-3-{[4-(1-methyl- 1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-6- (trifluoromethyl)pyridine 543 175 ##STR00222##
2-[(1-methyl-1-{1-[2- (methylsulfonyl)-4-
(trifluoromethoxy)benzoyl] piperidin-4- yl}ethyl)sulfonyl]-6-
(trifluoromethyl)pyridine 603 176 ##STR00223## 2-[(1-{1-[4-
(difluoromethoxy)-2- (methylsulfonyl)benzoyl] piperidin-4-yl}-1-
methylethyl)sulfonyl]-6- (trifluoromethyl)pyridine 585 177
##STR00224## 2-[(1-{1-[4- (cyclopropyloxy)-2-
(methylsulfonyl)benzoyl] piperidin-4-yl}-1-
methylethyl)sulfonyl]-6- (trifluoromethyl)pyridine 575 178
##STR00225## 2-[(1-methyl-1-{1-[2- (methylsulfonyl)-4-
(trifluoromethoxy)benzoyl] piperidin-4- yl}ethyl)sulfonyl]-4-
(trifluoromethyl)pyridine 603 179 ##STR00226## 2-[(1-{1-[4-
(difluoromethoxy)-2- (methylsulfonyl)benzoyl] piperidin-4-yl}-1-
methylethyl)sulfonyl]-4- (trifluoromethyl)pyridine 585 180
##STR00227## 2-[(1-{1-[4- (cyclopropyloxy)-2-
(methylsulfonyl)benzoyl] piperidin-4-yl}-1-
methylethyl)sulfonyl]-4- (trifluoromethyl)pyridine 575 181
##STR00228## 3-[(1-methyl-1-{1-[4- [(2,2,2-
trifluoromethyl)sulfonyl]-2- (trifluoromethyl)benzoyl] piperidin-4-
yl}ethyl)sulfonyl]-5- (trifluoromethyl)pyridine 655 182
##STR00229## 2-(methylsulfonyl)-3-{[4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-6- (trifluoromethyl)pyridine 587 183 ##STR00230##
1-[4-(cyclopropyloxy)-2- (methylsulfonyl)benzoyl]-
4-(1-{[3-fluoro-5- (trifluoromethyl)phenyl] sulfonyl}-1-
methylethyl)piperidine 592 184 ##STR00231##
1-[4-(cyclopropylsulfonyl)- 2-(difluoromethoxy)
benzoyl]-4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 610 185 ##STR00232##
2-(cyclobutyloxy)-5-{[4- (1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyridine 511 186
##STR00233## 3-(methylsulfonyl)-2-{[4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl)pyridine 587 187 ##STR00234##
2-(cyclobutyloxy)-4- (methylsulfonyl)-5-{[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}pyridine 589 188 ##STR00235##
2-(cyclopropylsulfonyl)-3- {[4-(1-{[3-fluoro-5-
(trifluoromethyl)phenyl] sulfonyl}-1- methylethyl)piperidin-1-
yl]carbonyl}-6- (trifluoromethyl)pyridine 631 189 ##STR00236##
3-{[4-(1-{[3-fluoro-5- (trifluoromethyl)phenyl]
sulfonyl}-1- methylethyl)piperidin-1- yl]carbonyl}-2-
(methylsulfonyl)-6- (trifluoromethyl)pyridine 605 190 ##STR00237##
2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5-
(trifluoromethyl)pyridine 509 191 ##STR00238##
3-chloro-2-{[4-(1-methyl- 1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5-
(trifluoromethyl)pyridine 543 192 ##STR00239##
3-(cyclopropylsulfonyl)-2- {[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl)pyridine 613 193 ##STR00240##
2-{[4-(1-{[3-fluoro-5- (trifluoromethyl)phenyl] sulfonyl}-1-
methylethyl)piperidin-1- yl]carbonyl}-3- (methylsulfonyl)-5-
(trifluoromethyl)pyridine 605 194 ##STR00241## 631 195 ##STR00242##
1-[4-[(1- methylcyclopropyl)oxy]- 2,6-bis(methylsulfonyl)
benzoyl]-4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 666 196 ##STR00243##
3-chloro-2-{[4-(1-{[3- fluoro-5- (trifluoromethyl)phenyl]
sulfonyl}-1- methylethyl)piperidin-1- yl]carbonyl}-5-
(trifluoromethyl)pyridine 561 197 ##STR00244##
1-[2-(cyclopropylsulfonyl)-4- (trifluoromethoxy)benzoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 528 198 ##STR00245##
3-chloro-2-{[4-(1-methyl- 1-{[3- (trifluoromethoxy)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5-
(trifluoromethyl)pyridine 559 199 ##STR00246##
3-(methylsulfonyl)-2-{[4- (1-methyl-1-{[3-
(trifluoromethoxy)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl)pyridine 603 200 ##STR00247##
3-(cyclopropylsulfonyl)-2- {[4-(1-methyl-1-{[3-
(trifluoromethoxy)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl)pyridine 629 201 ##STR00248##
5-[2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5-
(trifluoromethyl)pyridin-3- yl]pyrimidine 587 202 ##STR00249##
2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-3-(1H- pyrazol-4-yl)-5-
(trifluoromethyl)pyridine 575 203 ##STR00250##
3-(1-methyl-1H-pyrazol-4- yl)-2-{[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl)pyridine 589 204 ##STR00251##
2'-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5'-
(trifluoromethyl)-3,3'- bipyridin-6-ol 602 205 ##STR00252##
6'-methoxy-2-{[4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5- (trifluoromethyl)-3,3'-
bipyridine 616 206 ##STR00253## 2'-methoxy-2-{[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl)-3,3'- bipyridine 616 207
##STR00254## 2'-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5'-
(trifluoromethyl)-2,3'- bipyridine 586 208 ##STR00255##
2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5- (trifluoromethyl)-3,4'-
bipyridine 586 209 ##STR00256## 6-methyl-2'-{[4-(1-methyl- 1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5'- (trifluoromethyl)-2,3'- bipyridine 600 210
##STR00257## 2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5- (trifluoromethyl)
nicotinonitrile 534 211 ##STR00258## 3-(ethylsulfonyl)-2-{[4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl)pyridine 601 212 ##STR00259##
2-{[4-(1-{[3- (difluoromethoxy)phenyl] sulfonyl}-1-
methylethyl)piperidin-1- yl]carbonyl}-3- (ethylsulfonyl)-5-
(trifluoromethyl)pyridine 599 213 ##STR00260## 2-{[4-(1-{[3-
(difluoromethoxy)phenyl] sulfonyl}-1- methylethyl)piperidin-1-
yl]carbonyl}-3- (methylsulfonyl)-5- (trifluoromethyl)pyridine 585
214 ##STR00261## 3-(cyclopropylsulfonyl)-2- {[4-(1-{[3-
(difluoromethoxy)phenyl] sulfonyl}-1- methylethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl)pyridine 611
TABLE-US-00005 TABLE 4 MASS SPECTRAL DATA m/e EXAMPLE # STRUCTURE
CHEMICAL NAME (M + H) 215 ##STR00262## 1-[2-(methylsulfonyl)-4-
(trifluoromethyl)benzoyl]- 3-({[3-(trifluoromethyl)phenyl]
sulfonyl}methyl)azetidine 530 216 ##STR00263##
1-[2-(methylsulfonyl)-4- (trifluoromethyl)benzoyl]-
3-({[3-(trifluoromethyl)phenyl] sulfonyl}methyl)azetidine 496 217
##STR00264## 1-[4-(methylsulfonyl)-2- (trifluoromethoxy)benzoyl]-
3-({[3-(trifluoromethyl)phenyl] sulfonyl}methyl)azetidine 546 218
##STR00265## 1-[2-(methylsulfonyl)-4- (trifluoromethyl)benzoyl]-
3-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)azetidine 558 219 ##STR00266##
1-[4-(difluoromethoxy)benzoyl]- 3-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)azetidine 478 220
##STR00267## 1-[2-(difluoromethoxy)benzoyl]- 3-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)azetidine 478 221
##STR00268## 1-[5-fluoro-2- (methylsulfonyl)benzoyl]-
3-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)azetidine 508 222 ##STR00269##
1-[3-(difluoromethoxy)benzoyl]- 3-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)azetidine 478 223
##STR00270## 1-[4-methoxy-3- (methylsulfonyl)benzoyl]-
3-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)azetidine 520 224 ##STR00271##
1-[4-(difluoromethoxy)-2- (methylsulfonyl)benzoyl]-
3-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)azetidine 556 225 ##STR00272##
1-[4-(tert-butylsulfonyl)-2- chlorobenzoyl]-3-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)azetidine 567 226
##STR00273## 1-[2-bromo-4-(tert- butylsulfonyl)benzoyl]-3-
(1-methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)azetidine
611 227 ##STR00274## 1-[4-(tert-butylsulfonyl)-2-
(methylsulfonyl)benzoyl]- 3-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)azetidine 610 228
##STR00275## 1-[2-chloro-4- (isopropylsulfonyl)benzoyl]-
3-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)azetidine 553 229 ##STR00276##
1-[4-(isopropylsulfonyl)-2- (methylsulfonyl)benzoyl]-
3-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)azetidine 596 230 ##STR00277## 1-[4-methoxy-2,6-
bis(methylsulfonyl)benzoyl]- 3-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)azetidine 598 231
##STR00278## 1-[4-(difluoromethoxy)- 2,6-bis(methylsulfonyl)-
benzoyl]-3-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)azetidine 634 232 ##STR00279##
1-[4-(cyclopropyloxy)-2,6- bis(methylsulfonyl)benzoyl]-
3-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)azetidine 624 233 ##STR00280##
1-[2,6-bis(methylsulfonyl)-4- (trifluoromethoxy)benzoyl]-
3-(1-methyl-1-{[3- (trifluoromethyl)phenyl] sulonyl}ethyl)azetidine
652 234 ##STR00281## (3R)-1-[4-(cyclopropyloxy)-2-
(methylsulfonyl)benzoyl]- 3-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)pyrrolidine 560 235
##STR00282## (3R)-1-[4-(cyclopropyloxy)-2,6-
bis(methylsulfonyl)benzoyl]- 3-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)pyrrolidine 638 236
##STR00283## (3R)-1-[4-(cyclopropylsulfonyl)-
2-methoxybenzoyl]-3-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)pyrrolidine 560
TABLE-US-00006 TABLE 5 MASS SPECTRAL DATA m/e EXAMPLE # STRUCTURE
CHEMICAL NAME (M + H) 237 ##STR00284## 8-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1- yl]quinolinium
trifluoroacetate 463 238 ##STR00285## 5-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1- yl]quinolinium
trifluoroacetate 463 239 ##STR00286## 5-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]isoquinolinium trifluoroacetate 463 240 ##STR00287##
3-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]quinoline 463 241 ##STR00288##
4,6-dimethyl-2-[4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]pyrimidin-1-ium trifluoroacetate 443
242 ##STR00289## 4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-[4-(1H- pyrazol-1- yl)phenyl]piperidine 478 243
##STR00290## 3-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-1,2-benzisoxazole 453 244
##STR00291## 2-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]quinoxaline 464 245 ##STR00292##
2-chloro-3-[4-(1-methyl-1- 1-[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]quinoxaline 497 246 ##STR00293##
3-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]quinoxalin-2-ol 480 247 ##STR00294##
3-(methylsulfonyl)-2-[4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]quinoline 540 248 ##STR00295##
3-(methylsulfonyl)-2-[4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]quinoline 514 249 ##STR00296##
1-{[2-(methylsulfonyl)-4- (trifluoromethyl)phenyl]
sulfonyl}-4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 622 250 ##STR00297## 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)-1-{[4-
(trifluoromethyl)phenyl] sulfonyl}piperidine 544
TABLE-US-00007 TABLE 6 MASS SPECTRAL DATA m/e EXAMPLE # STRUCTURE
CHEMICAL NAME (M + H) 251 ##STR00298## 2-{[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl)pyridine 509 252 ##STR00299##
5-[2-{[4-(1-methyl-1-{[3- (trifluoromethyl) phenyl]sulfonyl}ethyl)
piperidin-1-yl]carbonyl}-5- (trifluoromethyl)
pyridin-3-yl]pyrimidine 587 253 ##STR00300## 2-{[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-3- (1H-pyrazol-4-yl)-5- (trifluoromethyl)pyridine 575
254 ##STR00301## 3-(1-methyl-1H-pyrazol-4-
yl)-2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl
ethyl)piperidin-1- yl]carbonyl}-5- (trifluoromethyl)pyridine 589
255 ##STR00302## 2'-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5'-
(trifluoromethyl)-3,3'- bipyridin-6-ol 602 256 ##STR00303##
2'-methoxy-2-{[4-(1-methyl- 1-{[3-(trifluoromethyl)
phenyl]sulfonyl}ethyl) piperidin-1-yl]carbonyl}-5-
(trifluoromethyl)-3,3'- bipyridine 616 257 ##STR00304##
6'-methoxy-2-{[4-(1-methyl- 1-{[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1-yl] carbonyl}-5- (trifluoromethyl)-3,3'-
bipyridine 616 258 ##STR00305## 3-(methylsulfonyl)-2-{[4-(1-
methyl-1- {[3(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}quinoline 569 259 ##STR00306##
2-chloro-4-methyl-6-{[4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyrimidine 490 260
##STR00307## 3-chloro-6-{[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}pyridazine 476 261 ##STR00308##
2-methoxy-5-{[4-(1-methyl- 1-{[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyrazine 472 262
##STR00309## 2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5- (trifluoromethyl)-3,4'-
bipyridine 586 263 ##STR00310## 2-{[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl) nicotinonitrile 534 264
##STR00311## 3-(ethylsulfonyl)-2-{[4-(1- methyl-1-
{[3(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-5- (trifluoromethyl)pyridine 601 265 ##STR00312##
2-{[4-(1-{[3- (difluoromethoxy)phenyl] sulfonyl}-1-
methylethyl)piperidin-1- yl]carbonyl}-3- (ethylsulfonyl)-5-
(trifluoromethyl)pyridine 599 266 ##STR00313##
3-(cyclopropylsulfonyl)-2- {[4-(1-{[3- (difluoromethoxy)phenyl]
sulfonyl}-1- methylethyl)piperidin-1- yl]carbonyl}-5-
(trifluoromethyl)pyridine 611 267 ##STR00314## 2-{[4-(1-{[3-
(difluoromethoxy)phenyl] sulfonyl}-1-methyl ethyl)piperidin-1-
yl]carbonyl}-3- (methylsulfonyl)-5- (trifluoromethyl)pyridine 585
268 ##STR00315## 2'-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5'-
(trifluoromethyl)-2,3'- bipyridine 586 269 ##STR00316##
6-methyl-2'-{[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-5'-
(trifluoromethyl)-2,3'- bipyridine 600 270 ##STR00317##
2-{[4-(1-{[3-fluoro-2-iodo- 5-(trifluoromethyl)phenyl] sulfonyl}-1-
methylethyl)piperidin-1- yl]carbonyl}-3- (methylsulfonyl)-5-
(trifluoromethyl)pyridine 731 271 ##STR00318##
2-{[4-(1-{[3-fluoro-5- (trifluoromethyl)phenyl] sulfonyl}-1-
methylethyl)piperidin-1- yl]carbonyl}-3- (methylsulfonyl)-5-
(trifluoromethyl)pyridine 605 272 ##STR00319##
tert-butyl{(1S)-1-benzyl-2- [4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxoethyl}carbamate 583 273 ##STR00320##
tert-butyl{(1S))-2-methyl-1- {[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-yl]
carbonyl}propyl)carbamate 535 274 ##STR00321##
tert-butyl{1,1-dimethyl-2-[4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxoethyl}carbamate 521 275 ##STR00322##
(2S)-1-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-1-oxo-3-phenylpropan-2- aminium
chloride 483 276 ##STR00323## (2S)-3-methyl-1-[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-1-oxobutan-2-aminium chloride 435 277 ##STR00324##
2-methyl-1-[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-1-oxopropan-2-aminium chloride 421
278 ##STR00325## 1-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}cyclobutanamine 433 279
##STR00326## (2R)-4-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-4-oxo-1-(2,4,5-
trifluorophenyl)butan-2- aminiumtrifluoroacetate 551 280
##STR00327## 1-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl} cyclopentanaminium
trifluoroacetate 447 281 ##STR00328## (2S,3R)-3-hydroxy-1-[4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-1-oxobutan-2-aminium trifluoroacetate 437 282 ##STR00329##
(1S)-1-cyclohexyl-2-[4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-2-oxoethanaminium trifluoroacetate
475 283 ##STR00330## 1-{[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1- yl]carbonyl}
cyclopropanaminium trifluoroacetate 419 284 ##STR00331##
(R)-1-(4-chlorophenyl)-3-[4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-yl]-
3-oxopropan-1-aminium trifluoroacetate 517 285 ##STR00332##
(2S)-2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyrrolidinium
trifluoroacetate 433 286 ##STR00333## (2R)-1-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-yl]-
1-oxo-3-phenylpropan-2- aminium trifluoroacetate 483 287
##STR00334## (1R)-3-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-3-oxo-1-phenylpropan-1- aminium
trifluoroacetate 483 288 ##STR00335## (1S)-1-(4-chlorophenyl)-3-
[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1-yl]- 3-oxopropan-1-aminium
trifluoroacetate 517 289 ##STR00336## (1R)-2-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-yl]-
2-oxo-1-phenylethanaminium trifluoroacetate 469 290 ##STR00337##
(1S)-2-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1-yl]- 2-oxo-1-phenylethanaminium
trifluoroacetate 469 291 ##STR00338## N-{3-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-3-oxopropyl} methanesulfonamide 485 292 ##STR00339##
N-((1S)-3-methyl-1-{[4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}butyl)methane sulfonamide
526 293 ##STR00340## N-{(1S-1-benzyl-2-[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxoethyl}methane sulfonamide 561 294 ##STR00341##
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-{[4-(1H- tetrazol-1- yl)phenyl]acetyl}piperidine
522 295 ##STR00342## 1-(2-methyl-2- phenylpropanoyl)-4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
482 297 ##STR00343## 4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-[(1- phenylcyclopropyl) carbonyl]piperidine 480
298 ##STR00344## 4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-{[1- (trifluoromethyl)cyclopropyl]
carbonyl}piperidine 472 299 ##STR00345## N-{(1)-3-[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-3-oxo_l-phenylpropyl} methanesulfonamide 561 300 ##STR00346##
N-{1,1-dimethyl-2-[4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-2-oxoethyl} methanesulfonamide 499
301 ##STR00347## N-((1S)-2-methyl-1-{[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}propyl)methane sulfonamide 513 302 ##STR00348##
N-{(1S)-1-(4-chlorophenyl)- 3-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-3-oxopropyl} methanesulfonamide 595 303 ##STR00349##
N-{(1R)-1-(4-chlorophenyl)- 3-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] ]sulfonyl}ethyl)piperidin-1-
yl]-3-oxopropyl} methanesulfonamide 595 304 ##STR00350##
N-{(1S)-1-benzyl-2-[4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-2-oxoethyl} cyclopropanesulfonamide
587 305 ##STR00351## 3-(1-{[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}cyclopentyl) pyridine 509 306 ##STR00352##
N-[(1S)-2-[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-2-oxo-1-(pyridin-2- ylmethyl)ethyl]
methanesulfonamide 562 307 ##STR00353## N-{(1S)-1-(4-cyanobenzyl)-
2-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-2-oxoethyl} methanesulfonamide 586
308 ##STR00354## N-{(1S)-1-(4-chlorobenzyl)- 2-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxoethyl} methanesulfonamide 595 309 ##STR00355##
N-{(1S)-2-[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-2-oxo-1-phenylethyl}
methanesulfonamide 547 310 ##STR00356## (1S)-2-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxo-1-phenylethanol 470 311 ##STR00357##
(2R)-1-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-1-oxo-3-phenylpropan- 2-ol 484 312
##STR00358## (2S)-1-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-1-oxo-3-phenylpropan- 2-ol 484 313
##STR00359## 2-{2-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-2-oxoethyl}imidazo
[1,2-a]pyridin-1-ium trifluoroacetate 494 314 ##STR00360##
N'-{(1S)-1-(4- chlorophenyl)-3-[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-3-oxopropyl}-N,N- dimethylurea 588 315 ##STR00361##
N'-{(1S)-1-(4-chlorobenzyl)- 2-4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxoethyl}-N,N- dimethylurea 588 316 ##STR00362##
N-{(1S)-1-(4-cyanobenzyl)- 2-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxoethyl} cyclopropanesulfonamide 612 317 ##STR00363##
N-{(1S)-2-[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-2-oxo-1-phenylethyl}
cyclopropanesulfonamide 573 318 ##STR00364##
N-{(1R)-1-(4-chlorophenyl)- 3-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-3-oxopropyl} cyclopropanesulfonamide 622 319 ##STR00365##
1-[(2S)-2-(6-methoxy-2- naphthyl)propanoyl]-4-(1 methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 548 320
##STR00366## 1-{[1-(3-bromophenyl)-5- methyl-1H-pyrazol-3-
yl]carbonyl}-4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 598 321 ##STR00367##
1-(3-bromo-4-fluorophenyl)- 2-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxoethanone 564 322 ##STR00368## 1-[(1,5-diphenyl-1H-pyrazol-
3-yl)carbonyl]-4-(1-methyl- 1-{[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 582 323 ##STR00369##
N-{(1S)-1-(4-chlorobenzyl)- 2-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxoethyl} cyclopropanesulfonamide 621 324 ##STR00370##
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-[(2-phenyl- 1H-imidazol-4- yl)carbonyl]piperidine
506 325 ##STR00371## 3-(5-bromo-2-chlorophenyl)-
5-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyrazin-2(1H)- one 647 326
##STR00372## 4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1- [(phenylsulfonyl)acetyl] piperidine 518 327
##STR00373## 2-methyl-3-{[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}imidazo[1,2-a] pyridine 494 328 ##STR00374##
7-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-1H-indole 479 329
##STR00375## 2-methyl-1-[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-1-oxopropan-2-ol 422 330 ##STR00376##
(2R)-1-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-1-oxo-2-phenylpropan- 2-ol 484 331
##STR00377## (2S)-1-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl}-1-oxo-2-phenylpropan- 2-ol 484 332
##STR00378## (2R)-2-(4-tert-butylphenyl)- 1-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-1-oxopropan-2-ol 540 333 ##STR00379##
2-methyl-3-{[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}imidazo[1,2-a]
pyridin-1-ium chloride 494 334 ##STR00380##
(2S)-3-(4-chlorophenyl)-1- [4-(1-methyl-1-{[3
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-1-oxopropan-2-ol 518 335 ##STR00381##
2,2-dimethyl-3-[4-(1-methyl- 1-{[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-3-oxo-1-phenylpropan- 1-ol 512 336
##STR00382## (2R)-2-(3-chlorophenyl)-1- [4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-1-oxopropan-2-ol 518 337 ##STR00383##
(1R)-2-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-2-oxo-1-phenylethanol 470 338
##STR00384## (1S,2R)-3-[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-3-oxo-1-phenylpropane- 1,2-diol 500
339 ##STR00385## (1R,2S)-3-[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-3-oxo-1-phenylpropane- 1,2-diol 500 340 ##STR00386##
(1R)-1-(4-chlorophenyl)-2- [4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxoethanol 504 341 ##STR00387## (2S)-1-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-1-oxo-3-[4- (trifluoromethyl)phenyl] propan-2-
aminiumtrifluoroacetate 552 342 ##STR00388##
(2S)-3-(2,5-difluorophenyl)- 1-[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-1-oxopropan-2-aminium trifluoroacetate 519 343 ##STR00389##
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-[(2R)- 3,3,3-trifluoro-2-methoxy-2-
phenylpropanoyl]piperidine 552 344 ##STR00390## 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)-1-({[3-
(trifluoromethyl)phenyl] sulfonyl}acetyl) piperidineuoromethyl)
phenyl]sulfonyl}acetyl) piperidine 586 345 ##STR00391##
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)-1-({[3-
(trifluoromethyl)phenyl] sulfinyl}acetyl)piperidine 570 346
##STR00392## 4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-[2- (phenylsulfonyl)propanoyl] piperidine 532 347
##STR00393## 5-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-1H- benzimidazole 480 348
##STR00394## 2-methyl-5-{[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}-1-phenyl-1H- benzimidazole 570 349 ##STR00395##
1-{2-[(4- chlorophenyl)sulfonyl]-2- methylpropanoyl}-4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
580 350 ##STR00396## 3-(1H-indol-3-yl)-1-[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-1-oxopropan-2-ol 523 351 ##STR00397##
1-cyclobutyl-2-[4-(1-methyl- 1-{[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-2-oxo-1-phenylethanol 524 352
##STR00398## 1-[2-methyl-2- (phenylsulfonyl)propanoyl]-
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 546 353 ##STR00399##
5-{(2S)-2-hydroxy-3-[4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-3-oxopropyl}-1H- imidazol-3-ium
trifluoroacetate 474 354 ##STR00400## 5-chloro-2-{[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}quinolin-4-ol 541 355 ##STR00401##
7-chloro-2-{[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}quinolin-4-ol 541 356
##STR00402## 6-chloro-2-{[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}quinolin-4-ol 541 357 ##STR00403##
(2R)-1,1,1-trifluoro-3-[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-3-oxo-2-phenylpropan- 2-ol 538 358 ##STR00404##
2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-6-
(trifluoromethyl)quinolin- 4-ol 575 359 ##STR00405##
(2R)-3-(1H-indol-3-yl)-1-[4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-1-oxopropan-2-amine 522 360 ##STR00406## 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)-1-(2-methyl-
2-{[3-(trifluoromethyl)phenyl] sulfonyl}propanoyl)piperidine 614
361 ##STR00407## 1-(3-chlorobenzoyl)-4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 474 362
##STR00408## 2-{1,1-dimethyl-2-[4-(1- methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]-2-oxoethoxy}-5- (trifluoromethyl)pyridine 567 363 ##STR00409##
6-chloro-3-{[4-(1-methyl-1- {[3-(truoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}quinolin-4-ol 541 364
##STR00410## 6-fluoro-3-{[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}quinolin-4-ol 525 365 ##STR00411##
7-chloro-3-{[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}quinolin-4-ol 541 366
##STR00412## 3-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-2-
(trifluoromethyl)quinoline 559 367 ##STR00413##
2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}quinolin-4-ol 507 368
##STR00414## 3-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}quinolin-4-ol 507 369
##STR00415## 1-[2-(4-chlorophenyl)-2- methylpropanoyl]-4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
516 370 ##STR00416## 2-{[4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}pyridin-4-ol 457 371 ##STR00417##
3-{5-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin- 1-yl]-,3,4-thiadiazol-2- yl}pyridine 497
372 ##STR00418## 2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}quinoline-4,8- diol 523 373
##STR00419## 4-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-3
(trifluoromethyl)benzonitrile 533 374 ##STR00420##
2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}quinolin-8-ol 507 375
##STR00421## 5-chloro-6-{[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]carbonyl}pyrimidine-2,4- diol 508 376 ##STR00422##
5-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyrimidin-4- amine 457 377
##STR00423## 2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-7-
(trifluoromethyl)quinolin- 4-ol 575 378 ##STR00424##
2-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-4-
(trifluoromethyl)pyridine 509 379 ##STR00425##
3-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-2-
(trifluoromethyl)pyridine 509 380 ##STR00426##
5-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}-2-
(trifluoromethyl)pyridine 509 381 ##STR00427## 4-(1-methyl-1-{[4-
(trifluoromethyl)phenyl] sulfonyl}ethyl)-1-[3-
(trifluoromethoxy)benzoyl] piperidine 524 382 ##STR00428##
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)-1-[3-
(trifluoromethoxy)benzoyl] piperidine 524 383 ##STR00429##
5-fluoro-2-{[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyridine 459
384 ##STR00430## 1-[(4-phenyl-1,2,3- thiadiazol-5-yl)carbonyl]-4-
(1-methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine
524 385 ##STR00431## 1-[(4-isopropyl-1,2,3-
thiadiazol-5-yl)carbonyl]-4- (1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 490 386
##STR00432## 1-(5-cyclopropyl-1,3,4- thiadiazol-2-yl)-4-(1-methyl-
1-{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 460 387
##STR00433## 1-(5-tert-butyl-1,3,4- thiadiazol-2-yl)-4-(1-methyl-
1-{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 476 388
##STR00434## 6-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]nicotinonitrile 438 389 ##STR00435##
4-(1-methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)-1-[5-
(trifluoromethyl)-1,3,4- thiadiazol-2-yl]piperidine 488 390
##STR00436## 2-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1-yl]- 5-(trifluoromethyl)pyridine 481 391
##STR00437## 1-[5-(4-fluorophenyl)-1,3,4-
oxadiazol-2-yl]-4-(1-methyl- 1-{[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 498 392 ##STR00438## 4-(1-methyl-1-{[3-
(trifluoromethyl)phenyl] sulfonyl}ethyl)-1-{5-[4-
(trifluoromethyl)phenyl]- 1,3,4-oxadiazol-2- yl}piperidine 548 393
##STR00439## 4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)-1-{5-[4- (trifluoromethoxy)phenyl]-
1,3,4-oxadiazol-2- yl}piperidine 563 394 ##STR00440##
1-[5-(2-chlorophenyl)-1,3,4- oxadiazol-2-yl]-4-(1-methyl-
1-{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidine 514 395
##STR00441## 5-{[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]carbonyl}pyridin-3-ol 457 396
##STR00442## 2-{6-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-7H-purin-7-yl}ethanol 498 397
##STR00443## 2-{6-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-9H-purin-9-yl}ethanol 498 398
##STR00444## 6-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin- 1-yl]-9H-purine 454 399 ##STR00445##
5-methyl-2-[4-(1-methyl-1- {[3-(trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]-4-phenoxypyrimidine 520 400
##STR00446## 2-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl}-1H-benzimidazol-3-ium
trifluoroacetate 452 401 ##STR00447## 4-chloro-6-[4-(1-methyl-1-
{[3-(trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]pyrimidine 448 402 ##STR00448## N-(1-methyl-1-phenylethyl)-
2-[4-(1-methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidin-1- yl]acetamide 511 403 ##STR00449##
1-[2-(cyclopropylamino)-2- oxoethyl]-4-(1-methyl-1-
{[3-(trifluoromethyl) phenyl]sulfonyl}ethyl) piperidinium
trifluoroacetate 433 404 ##STR00450## ethyl 2-methyl-2-[4-(1-
methyl-1-{[3- (trifluoromethyl)phenyl] sulfonyl}ethyl)piperidin-1-
yl]propanoate 450 405 ##STR00451## 1-[2-(4-
chlorophenoxy)ethyl]-4-(1- methyl-1-{[3- (trifluoromethyl)phenyl]
sulfonyl}ethyl)piperidine 490 406 ##STR00452##
1-[2-(tert-butylamino)-2- oxoethyl]-4-(1-methyl-1-{[3
(trifluoromethyl) phenyl]sulfonyl}ethyl) piperidinium
trifluoroacetate 449
[0266] The compounds of this invention were evaluated using the
various assays described above. The data for a representative set
of compounds of this invention obtained using the Assay Example 1
is provided in Table 7.
TABLE-US-00008 TABLE 7 STRUCTURE CaV2.2 IC.sub.50 (micromolar)
##STR00453## 0.15 ##STR00454## 0.83 ##STR00455## 0.49 ##STR00456##
0.79 ##STR00457## 1.4 ##STR00458## 0.49 ##STR00459## 1.17
##STR00460## 0.36 ##STR00461## 0.51 ##STR00462## 1.39
* * * * *