U.S. patent application number 11/199464 was filed with the patent office on 2006-02-02 for compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same.
Invention is credited to Timothy Herpin, R. Michael Lawrence, John Macor, George C. Morton, Graham S. Poindexter, Edward H. Ruediger, Rejean Ruel, Carl Thibault, Guixue Yu.
Application Number | 20060025403 11/199464 |
Document ID | / |
Family ID | 26956008 |
Filed Date | 2006-02-02 |
United States Patent
Application |
20060025403 |
Kind Code |
A1 |
Yu; Guixue ; et al. |
February 2, 2006 |
Compounds useful as modulators of melanocortin receptors and
pharmaceutical compositions comprising same
Abstract
Compounds having the formula (I), and
pharmaceutically-acceptable salts, hydrates and prodrugs thereof,
##STR1## in which E is ##STR2## X is N or CH, W is
--NR.sub.16R.sub.17, --NR.sub.16C(.dbd.O)R.sub.22,
--NR.sub.16CO.sub.2R.sub.22, --OR.sub.23, or a heteroaryl or
heterocyclo group as defined in the specification, and R.sub.1
through R.sub.12, R.sub.16, R.sub.17, R.sub.22, R.sub.23, x, y, and
z are as defined in the specification, are useful as modulaters of
melanocortin receptors, particularly MC-1R and MC-4R.
Inventors: |
Yu; Guixue; (Lawrenceville,
NJ) ; Macor; John; (Guilford, CT) ; Herpin;
Timothy; (Princeton, NJ) ; Lawrence; R. Michael;
(Yardley, PA) ; Morton; George C.; (Collegeville,
PA) ; Ruel; Rejean; (Saint-Lambert, CA) ;
Poindexter; Graham S.; (Old Saybrook, CT) ; Ruediger;
Edward H.; (Greenfield Park, CA) ; Thibault;
Carl; (Mascouche, CA) |
Correspondence
Address: |
STEPHEN B. DAVIS;BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
26956008 |
Appl. No.: |
11/199464 |
Filed: |
August 8, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10090582 |
Mar 4, 2002 |
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11199464 |
Aug 8, 2005 |
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60273206 |
Mar 2, 2001 |
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60273291 |
Mar 2, 2001 |
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Current U.S.
Class: |
514/210.21 ;
514/310; 514/326; 514/422; 546/146; 546/207; 548/517 |
Current CPC
Class: |
A61P 17/14 20180101;
A61P 17/16 20180101; A61P 1/16 20180101; A61P 1/00 20180101; A61P
3/10 20180101; A61P 11/00 20180101; A61P 15/10 20180101; A61P 27/16
20180101; A61P 31/04 20180101; A61P 37/08 20180101; C07D 401/12
20130101; A61P 13/12 20180101; A61P 25/04 20180101; A61P 25/30
20180101; A61P 5/16 20180101; C07D 417/14 20130101; A61P 17/06
20180101; C07K 5/06191 20130101; A61P 43/00 20180101; A61P 25/00
20180101; A61P 25/18 20180101; A61P 25/06 20180101; A61P 3/02
20180101; A61P 7/02 20180101; A61P 9/12 20180101; A61P 11/02
20180101; A61P 17/04 20180101; C07D 413/14 20130101; A61K 38/00
20130101; C07D 487/04 20130101; A61P 7/00 20180101; A61P 9/10
20180101; A61P 11/06 20180101; A61P 35/00 20180101; C07D 409/14
20130101; Y02A 50/411 20180101; A61P 3/04 20180101; A61P 25/24
20180101; A61P 31/20 20180101; C07D 471/10 20130101; C07D 405/14
20130101; A61P 15/08 20180101; A61P 21/00 20180101; A61P 25/28
20180101; A61P 9/04 20180101; A61P 25/22 20180101; A61P 29/00
20180101; A61P 31/18 20180101; A61P 37/06 20180101; A61P 1/04
20180101; A61P 3/06 20180101; A61P 5/14 20180101; A61P 11/08
20180101; C07D 401/14 20130101; C07D 491/10 20130101; A61P 25/02
20180101; Y02A 50/30 20180101; A61P 15/00 20180101; C07K 5/06139
20130101; A61P 1/18 20180101; A61P 9/00 20180101; A61P 25/16
20180101; A61P 25/20 20180101; A61P 33/06 20180101; C07D 495/04
20130101; Y02A 50/463 20180101; A61P 19/02 20180101; A61P 19/10
20180101; A61P 31/06 20180101; A61P 17/00 20180101 |
Class at
Publication: |
514/210.21 ;
514/310; 514/326; 514/422; 546/146; 546/207; 548/517 |
International
Class: |
A61K 31/4709 20060101
A61K031/4709; A61K 31/454 20060101 A61K031/454; A61K 31/4025
20060101 A61K031/4025; C07D 43/02 20060101 C07D043/02 |
Claims
1. A compound according to formula (I), ##STR444## or a
pharmaceutically-acceptable salt, hydrate or prodrug thereof, in
which E is ##STR445## X is N or CH; R.sub.1 is hydrogen or
C.sub.1-6alkyl or is taken together with R.sub.2 or R.sub.3 to form
a monocyclic or bicyclic aryl, cycloalkyl, heteroaryl or
heterocycle; R.sub.2 is hydrogen, aryl, cycloalkyl, heteroaryl,
heterocyclo; or C.sub.1-6alkyl or C.sub.2-6alkenyl optionally
substituted with one to three of hydroxy, alkoxy, halogen, cyano,
nitro, trifluoromethyl, amino, alkylamino, aryl, cycloalkyl,
heteroaryl, and/or heterocyclo; or R.sub.2 is taken together with
R.sub.1 or R.sub.3 to form a monocyclic or bicyclic aryl,
cycloalkyl, heteroaryl or heterocycle; R.sub.3 is hydrogen or
C.sub.1-6alkyl or is taken together with R.sub.1 or R.sub.2 to form
a monocyclic or bicyclic aryl, cycloalkyl, heteroaryl or
heterocycle; R.sub.4, R.sub.5, R.sub.5a R.sub.5b, R.sub.6,
R.sub.6a, R.sub.6b, and R.sub.7 are independently selected from
hydrogen, alkyl, substituted alkyl, halogen, hydroxy, alkoxy, keto,
aryl, heteroaryl, cycloalkyl, and heterocyclo, or R.sub.5a and/or
R.sub.5b, R.sub.6a and/or R.sub.6b, are taken together with R.sub.8
or R.sub.9 to form a fused carbocyclic, heterocyclic or heteroaryl
ring; R.sub.8 and R.sub.9 are independently hydrogen, halogen,
cyano, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclo, aryl, heteroaryl, --OR.sub.13, --NR.sub.13R.sub.14,
--SR.sub.13--S(O).sub.pR.sub.14, --C(.dbd.O)R.sub.13,
--OC(.dbd.O)R.sub.13, --CO.sub.2R.sub.13,
--C(.dbd.O)NR.sub.13R.sub.14, --NR.sub.13C(.dbd.O)R.sub.14,
--OC(.dbd.O)NR.sub.13R.sub.14, --NR.sub.13CO.sub.2R.sub.14,
--NR.sub.13C(.dbd.O)NR.sub.14R.sub.15 or
--NR.sub.13SO.sub.2R.sub.14; or R.sub.8 and R.sub.9 taken together
form a monocyclic or bicyclic cycloalkyl or heterocyclo joined in a
spiro fashion to ring E at C*, provided that R.sub.8 and R.sub.9
are not both hydrogen, and provided further that when R.sub.8 is
--OR.sub.13, --(CH.sub.2).sub.k-aryl or
--(CH.sub.2).sub.k-heteroaryl, then R.sub.9 is not
--C(.dbd.O)NR.sub.18R.sub.19, --CO.sub.2R.sub.19,
--(CH.sub.2).sub.mNR.sub.18SO.sub.2R.sub.20,
--(CH.sub.2).sub.mNR.sub.18C(.dbd.O)R.sub.20,
--(CH.sub.2).sub.mOR.sub.19, (CH.sub.2).sub.mO(C.dbd.O)R.sub.20,
--CH(R.sub.18)R.sub.19, or
(CH.sub.2).sub.mNR.sub.18(C.dbd.O)NR.sub.19R.sub.21; R.sub.11 and
R.sub.12 are selected independently of each other from hydrogen,
alkyl, halogen, hydroxy, hydroxyalkyl, haloalkyl, amino,
aminoalkyl, alkylamino, arylalkyl, cycloalkylalkyl,
heteroarylalkyl, aryl, and cycloalkyl, and where y is at least 1,
then R.sub.11 and R.sub.12 may be heterocyclo or heterocycloalkyl,
or R.sub.11 and R.sub.12, when attached to the same carbon atom,
may join to form a spirocycloalkyl ring; R.sub.13, R.sub.14 and
R.sub.15 are independently hydrogen, alkyl, substituted alkyl,
cycloalkyl, aryl, heterocyclo, or heteroaryl; or R.sub.13 and
R.sub.14, or R.sub.14 and R.sub.15 may join together to form a
heterocyclo or heteroaryl, except R.sub.14 is not hydrogen when
joined to a sulfonyl group as in --S(O).sub.pR.sub.14 or
--NR.sub.13SO.sub.2R.sub.14; W is selected from: 1)
--NR.sub.16R.sub.17, --NR.sub.16C(.dbd.O)R.sub.22,
--NR.sub.16CO.sub.2R.sub.22, --OR.sub.23, amidino, and guanidino;
2) heteroaryl or heterocyclo groups selected from pyrrolyl, furyl,
thienyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl,
isothiazolyl, 3-azaisothiazolyl, pyridyl, pyrazinyl, pyridazinyl,
1,2-dihydropyridazinyl, and pyranyl, wherein said heteroaryl and
heterocyclo groups may be substituted or unsubstituted and may have
an optionally-substituted carbocyclic, heterocyclic or heteraryl
ring fused thereto; or 3) a ring selected from: ##STR446## and
where at least one of x and/or y is at least 1, W may be ##STR447##
wherein B is N, O or S; R.sub.16 and R.sub.17 are selected from
hydrogen, alkyl and substituted alkyl; R.sub.18, R.sub.19 and
R.sub.21 are independently hydrogen or C.sub.16alkyl optionally
substituted with halogen; R.sub.20 is C.sub.1-6alkyl, aryl, or
heteroaryl; R.sub.22 and R.sub.23 are independently selected from
hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl,
and heterocyclo; R.sub.24 and R.sub.25 at each occurrence are
attached to any available carbon or nitrogen atom of W and at each
occurrence are selected from hydrogen, C.sub.1-6alkyl, halogen,
substituted C.sub.1-6alkyl, amino, alkylamino, cyano, nitro,
trifluoromethoxy, --C(.dbd.O)R.sub.26, --CO.sub.2R.sub.26,
--SO.sub.2R.sub.26, --OR.sub.26, aryl, heteroaryl, heterocyclo, and
cycloalkyl, and/or two R.sub.25 attached to two adjacent carbon
atoms or adjacent carbon and nitrogen or carbon atoms may join to
form a fused optionally-substituted heteroaryl, heterocyclo or
cycloalkyl ring, and/or two R.sub.24 or two R.sub.25 when attached
to the same carbon atom may form keto (.dbd.O); R.sub.26 is
hydrogen, alkyl, substituted alkyl, aryl, heterocyclo, cycloalkyl,
or heteroaryl, except when joined to a sulphonyl group as in
SO.sub.2R.sub.26, then R.sub.26 is not hydrogen; k and m are
independently 0, 1, 2 or 3; p is 1, 2, or 3; r is 0 or 1; s is 0 or
1; u and v are 0, 1, 2, or 3; w is 0, 1, or 2; x and y are 0, 1, 2,
3, or 4; and z is 0 or 2.
2. (canceled)
3. A compound according to claim 1, or a
pharmaceutically-acceptable salt hydrate, or prodrug thereof, in
which W is --NR.sub.16R.sub.17, --NHC(.dbd.O)R.sub.22,
--NHCO.sub.2alkyl, OR.sub.23, or azetidinyl; R.sub.16 and R.sub.17
are independently selected from hydrogen, C.sub.1-8alkyl, and
(CH.sub.2).sub.q-J, wherein J is selected from napthyl, furanyl,
indolyl, imidazolyl, pyrimidinyl, benzothienyl, pyridinyl,
pyrrolyl, pyrrolidinyl, thienyl, and C.sub.3-7cycloalkyl, wherein
the alkyl, alkylene, and/or J groups of R.sub.16 and/or R.sub.17
are optionally substituted with up to three R.sub.32; R.sub.22 is
selected from C.sub.1-6alkyl, trifluoromethyl, alkoxyalkyl,
furylalkyl, alkylaminoethyl, phenyl, pyrollylalkyl, piperidinyl,
and piperidinylalkyl, wherein R.sub.22 in turn is optionally
substituted with one to two C.sub.1-4alkyl and/or
--CO.sub.2(C.sub.1-4alkyl); R.sub.23 is hydrogen or phenyl;
R.sub.32 is selected from C.sub.1-6alkyl, hydroxy, C.sub.1-4alkoxy,
amino, C.sub.1-4alkylamino, aminoC.sub.1-4alkyl, trifluoromethyl,
halogen, phenyl, benzyl, phenyloxy, benzyloxy,
--C(.dbd.O)(CH.sub.2)NH.sub.2, --CO.sub.2(C.sub.1-4alkyl),
--SO.sub.2(C.sub.1-4alkyl), tetrazolyl, piperidinyl, pyridinyl, and
indolyl, wherein when R.sub.32 is a ring, said ring in turn is
optionally substituted with one to two C.sub.1-4alkyl, hydroxy,
methoxy, and/or halogen; and q is 0, 1, 2 or 3.
4. A compound according to claim 1, or a
pharmaceutically-acceptable salt hydrate, or prodrug thereof, in
which W is a ring selected from: ##STR448## and where at least one
of x and/or y is at least 1, W may be ##STR449## wherein B is N, O
or S; R.sub.24 is selected from keto (.dbd.O), C.sub.1-6alkyl,
halogen, amino, aminoalkyl, alkylamino, hydroxy, C.sub.1-4alkoxy,
hydroxyC.sub.1-4alkyl, --C(.dbd.O)alkyl, --C(.dbd.O)aminoalkyl,
--C(.dbd.O)phenyl, --C(.dbd.O)benzyl, --CO.sub.2alkyl,
--CO.sub.2phenyl, --CO.sub.2benzyl, --SO.sub.2alkyl,
--SO.sub.2aminoalkyl, --SO.sub.2phenyl, --SO.sub.2benzyl, phenyl,
benzyl, phenyloxy, benzyloxy, pyrrolyl, pyrazolyl, piperidinyl,
pyridinyl, pyrimidinyl, and tetrazolyl, and each R.sub.24 in turn
is optionally substituted with one to two R.sub.31; R.sub.25 at
each occurrence is attached to any available carbon or nitrogen
atom of W and is selected from C.sub.1-6alkyl, halogen, amino,
aminoalkyl, alkylamino, hydroxy, C.sub.1-4alkoxy,
hydroxyC.sub.1-4alkyl, --C(.dbd.O)alkyl, --C(.dbd.O)aminoalkyl,
--C(.dbd.O)phenyl, --C(.dbd.O)benzyl, --CO.sub.2alkyl,
--CO.sub.2phenyl, --CO.sub.2benzyl, --SO.sub.2alkyl,
--SO.sub.2aminoalkyl, --SO.sub.2phenyl, --SO.sub.2benzyl, phenyl,
benzyl, phenyloxy, benzyloxy, pyrrolyl, pyrazolyl, piperidinyl,
pyridinyl, pyrimidinyl, and tetrazolyl, and/or two R.sub.25 when
attached to adjacent carbon atoms may be taken together to form a
fused benzo or pyrazolyl ring, and/or two R.sub.25 when attached to
the same carbon atom (in the case of a non-aromatic ring) may form
keto (.dbd.O), and each R.sub.25 in turn is optionally substituted
with up to two R.sub.31; R.sub.31 is selected from halogen,
trifluoromethyl, C.sub.1-4alkyl, hydroxy, and C.sub.1-4alkoxy; w is
selected from 0, 1, or 2; and u and v are selected from 0, 1, and
2.
5. A compound according to claim 1, or a
pharmaceutically-acceptable salt hydrate, or prodrug thereof, in
which R.sub.8 and R.sub.9 are selected independently from hydrogen,
alkyl, --(CH.sub.2).sub.j--C(.dbd.O)alkyl,
--(CH.sub.2).sub.j-phenyl, --(CH.sub.2).sub.j-napthyl,
--(CH.sub.2).sub.j--C.sub.4-7cycloalkyl,
--(CH.sub.2).sub.j-heterocyclo, and --(CH.sub.2).sub.j--
heteroaryl, or R.sub.8 and R.sub.9 together form a spirocycloalkyl
or spiroheterocyclic ring; and j is selected from 0, 1, 2 and
3.
6. A compound according to claim 1, or a
pharmaceutically-acceptable salt hydrate, or prodrug thereof, in
which E is ##STR450##
7. A compound according to claim 1, or a
pharmaceutically-acceptable salt thereof, in which R.sub.11 and
R.sub.12 are (i) at each occasion independently selected from: a)
hydrogen, b) C.sub.1-6alkyl, c) C.sub.1-6alkyl substituted with up
to two of hydroxy, alkoxy, amino, alkylamino, imidazolyl,
pyrazolyl, phenyl, napthyl, pyridinyl, indolyl, pyrimidyl, furyl,
thiazolyl, and thienyl, wherein said ringed substituents in turn
are optionally substituted with one to three R.sub.33 and/or have a
benzene ring fused thereto optionally substituted with one to two
R.sub.33; d) C.sub.3-7cycloalkyl optionally substituted with up to
two R.sub.33 and/or having a benzene ring fused thereto, wherein
said fused benzene ring is optionally substituted with up to two
R.sub.33; e) phenyl optionally substituted with up to three
R.sub.33; f) where y is at least one, R.sub.11 and R.sub.12 may
also be selected from piperidinyl, pyrrolidinyl, piperidinylalkyl,
and pyrrolidinylalkyl, in turn optionally substituted with up to
three R.sub.33; or ii) alternatively, one of R.sub.11 and one of
R.sub.12 attached to the same carbon atom may be taken together to
form a spirocycloalkyl ring; R.sub.33 is selected from
C.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy, halogen, nitro, phenyl,
benzyl, phenyloxy, benzyloxy, --C(.dbd.O)phenyl, amino, alkylamino,
and aminoalkyl, wherein when R.sub.33 includes a phenyl group said
phenyl group in turn is optionally substituted with one to two of
halogen, nitro, cyano, C.sub.1-4 alkyl, and/or C.sub.1-4
alkoxy.
8. A compound according to claim 1, or a
pharmaceutically-acceptable salt thereof, in which R.sub.2 is
selected from hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, biphenyl,
C.sub.2-6alkenylene-K, and --(CH.sub.2).sub.g--K; K is selected
from phenyl, napthyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl,
and C.sub.5-6cycloalkyl, wherein each group K in turn is optionally
substituted with one to three R.sub.30 or has a benzene ring fused
thereto, which also may be substituted with one to three R.sub.30;
R.sub.30 is selected from C.sub.1-4alkyl, hydroxy, alkoxy, halogen,
nitro, cyano, amino, alkylamino, phenyl, and acylphenyl; and g is
0, 1, 2 or 3.
9. A compound according to claim 1, or a
pharmaceutically-acceptable salt hydrate, or prodrug thereof, in
which
--X(R.sub.1)--CH(R.sub.2)--CH(R.sub.3).sub.r--(CH.sub.2).sub.s--,
taken together are selected from C.sub.1-4alkylene, ##STR451##
10. A compound according to claim 1, or a
pharmaceutically-acceptable salt thereof, in which X is N; R.sub.1
is hydrogen or C.sub.1-4alkyl; r is 0; and s is 0.
11. A compound according to claim 10, or a
pharmaceutically-acceptable salt hydrate, or prodrug thereof, in
which W is ##STR452## --NR.sub.16R.sub.17,
NR.sub.16C(.dbd.O)R.sub.22, OH, or imidazolyl; R.sub.16 and
R.sub.17 are selected from hydrogen and C.sub.1-4alkyl; R.sub.22 is
C.sub.1-4alkyl, phenyl or piperidinylC.sub.1-4alkyl; R.sub.24 is
C.sub.1-4alkyl; and u is 0 or 1.
12. A compound according to claim 11, or a
pharmaceutically-acceptable salt hydrate, or prodrug thereof, in
which R.sub.11 is hydrogen, C.sub.1-4alkyl, or
imidazolylC.sub.1-4alkyl; and R.sub.12 is hydrogen or
C.sub.1-4alkyl.
13. A compound according to claim 1, or a
pharmaceutically-acceptable salt hydrate, or prodrug thereof, in
which R.sub.16 and R.sub.17 are independently selected from
hydrogen, C.sub.1-8alkyl, and C.sub.1-8substituted alkyl, except
R.sub.16 and R.sub.17 are not alkyl substituted with pyridiyl,
imidazolyl, thiazolyl, pyrimidinyl, or piperazinyl, and W is not
morpholinyl.
14. (canceled)
15. (canceled)
16. (canceled)
17. (canceled)
18. A pharmaceutical composition comprising at least one compound
according to claim 1 or a pharmaceutically-acceptable salt hydrate,
or prodrug thereof; and a pharmaceutically-acceptable carrier or
diluent.
19. A pharmaceutical composition comprising (i) at least one
compound according to claim 1 or a pharmaceutically-acceptable salt
hydrate, or prodrug thereof; (ii) at least one second compound
effective for treating an inflammatory or immune disease, a
cardiovascular disease, or neurodegenerative disorder; and (iii) a
pharmaceutically-acceptable carrier or diluent.
20. The pharmaceutical composition according to claim 19 in which
the at least one second compound comprises a phosphodiesterase
inhibitor.
21. A method of treating a melanocortin-receptor associated
condition, the method comprising administering to a warm-blooded
species in need of such treatment a therapeutically-effective
amount of at least one compound according to claim 1.
22. The method of claim 21 in which the melanocortin-receptor
associated condition is an MC-1R or MC-4R associated condition.
Description
RELATED INVENTIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 10/090,582, filed Mar. 4, 2002 which claims
the benefit of priority of U.S. application Ser. Nos. 60/273,206,
and 60/273,291, filed Mar. 2, 2001, the entire contents of which
are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds useful in
treating diseases responsive to modulation of melanocortin
receptors, to methods of treating such diseases, and to
pharmaceutical compositions comprising same.
BACKGROUND OF THE INVENTION
[0003] Melanocortin peptides, particularly .alpha.-melanocyte
stimulating hormone (.alpha.-MSH), have a wide range of effects on
biological functions including feeding behavior, pigmentation, and
exocrine function. See Wikberg et al., "New Aspects on the
Melanocortins and their Receptors," Pharmacological Research, Vol.
42, No. 5 (2000), at pp. 393-420. The biological effects of
.alpha.-MSH are mediated by a sub-family of G protein-coupled
receptors, termed melanocortin receptors. See Wikberg et al.,
supra. There are four melanocortin receptors: MC-1R, MC-3R, MC-4R,
and MC-5R (MC-2R is not a receptor for .alpha.-MSH but is the
adrenocorticotropic hormone {ACTH} receptor). Activating any one of
these receptors results in stimulation of cAMP formation.
[0004] MC-1R was first found in melanocytes. Naturally occurring
inactive variants of MC-1R in animals were shown to lead to
alterations in pigmentation and a subsequent lighter coat color.
From these and other studies, it is evident that MC-1R is an
important regulator of melanin production and coat color in animals
(or skin color in humans). MC-3R is expressed in the brain and
peripheral tissues, and knock-out studies have revealed that MC-3R
is responsible for alterations in feeding behavior and body weight.
MC-4R is primarily expressed in the brain. Genetic knock-outs and
pharmacologic manipulation of MC-4R in animals have shown that
agonizing MC-4R causes weight loss and antagonizing MC-4R produces
weight gain. MC-5R is ubiquitously expressed in many peripheral
tissues and in the brain, but its expression is greatest in
exocrine glands. Genetic knock-out of this receptor in mice results
in altered regulation of exocrine gland function, leading to
changes in water repulsion and thermoregulation.
[0005] Much attention has been focused on the study of MC-3R and
MC-4R modulators and their use in treating body weight disorders,
such as obesity and anorexia. For example, WO 00/74679 to Merck
& Co., Inc., "Substituted Piperidines as
Melanocortin-4-Receptor Agonists," (Dec. 14, 2000), and WO 99/64002
also to Merck & Co Inc., "Spiropiperidine Derivatives as
Melanocortin Receptor Agonists," (Dec. 16, 1999), disclose
compounds that reportedly are selective agonists of MC-4R. Each of
the compounds of WO 00/74679 and WO 99/64002 has a bicyclic
terminal group, typically tetrahydroisoquinoline. Isoquinoline
compounds, more particularly tetrahydro-isoquinoline-based
compounds, useful as melanocortin (MC) receptor agonists and
antagonists are disclosed in U.S. Pat. No. 6,127,381, "Isoquinoline
Compound Melanocortin Receptor Ligands and Method of Using Same,"
issued Oct. 3, 2000 to Basu et al. See also WO 01/91752, WO
01/70708, and WO 01/70337 to Merck and WO 02/00654 to Pfizer
Products Inc., reportedly disclosing compounds for use as MC-4R
agonists. Individual compounds can bind to multiple MC receptors,
with different levels of affinity. Yet it may be advantageous in
treating diseases for compounds to be selective for one or more
particular MC receptors. See, e.g., WO 00/58361 to Proctor &
Gamble Co., "Melanocortin Receptor Ligands" (disclosing compounds
that reportedly are selective for MC3R and MC4R in preference to
MC-1R); and WO 99/54358 to Quadrant Holdings Cambridge Ltd.,
"Melanocortin Receptor Ligands" (disclosing compounds that
reportedly are selective for MC3R, MC4R and/or MC5R).
[0006] The melanocortin peptides have potent physiological effects
besides their role in regulating pigmentation, feeding behavior,
and exocrine function. In particular, .alpha.-MSH has been shown to
induce a potent anti-inflammatory effect in both acute and chronic
models of inflammatory diseases including inflammatory bowel
disease, renal ischemia/reperfusion injury, and endotoxin-induced
hepatitis. See Catania et al., "a-MSH in Normal Human Physiology
and Disease States," Trends in Endocrinology and Metabolism, Vol.
11, No. 8 (2000) at pp. 304-308. Administration of .alpha.-MSH
(either i.p. or i.v.) in these models results in substantial
lessening of inflammation-mediated tissue damage, a significant
decrease in leukocyte infiltration, and a dramatic reduction in
elevated levels of cytokines (e.g., TNF-.alpha.), chemokines (e.g.,
MCP-1, IL-8), and inflammatory mediators (e.g., i-NOS and ICAM-1),
to near baseline levels. Earlier studies had shown that .alpha.-MSH
acts as an "anti-cytokine" in many acute inflammatory models, in
effect antagonizing the pro-inflammatory actions of TNF-.alpha.,
IL-1.beta., and IL-6.
[0007] The anti-inflammatory actions of .alpha.-MSH are mediated by
MC-1R. MC-1R is expressed in cells that are important regulators of
the immune response: monocyte/macrophages, neutrophils,
endothelial, and mast cells. See Catania et al., cited above.
Stimulation with .alpha.-MSH results in a dampening of the
inflammatory response in these cells, including inhibition of
nitric oxide formation, decreased expression of co-stimulatory
molecules and adhesion receptors, and importantly, an increase in
the expression of IL-10, a cytokine with potent anti-inflammatory
actions. Studies have shown that MC-1R selective peptides are as
efficacious as .alpha.-MSH in eliciting an anti-inflammatory
response. See Wikberg, "Melanocortin Receptors: Perspectives for
Novel Drugs," European Journal of Pharmacology, Vol. 375 (1999), at
pp. 295-310, and WO 99/57148 to WA Pharma AB (1999), "Melanocortin
1 Receptor Selective Compounds."
[0008] The mechanism by which agonism of MC-1R results in an
anti-inflammatory response is likely through inhibition of the
pro-inflammatory transcription activator, NF-.kappa.B. NF-.kappa.B
is a pivotal component of the pro-inflammatory cascade, and its
activation is a central event in initiating many inflammatory
diseases. In a typical inflammatory response, NF-.kappa.B is
activated in response to an inflammatory stimulus and once
activated, induces expression of a wide array of pro-inflammatory
genes. See Tak and Firestein, "NF-.kappa.B: a Key Role in
Inflammatory Diseases," The Journal of Clinical Investigation, Vol.
107 (2001), pp. 7-11. Activation of MC-1R, and subsequent
generation of cAMP and/or decreased production of nitric oxide, has
been shown to inhibit activation of NF-.kappa.B. See Manna and
Aggarwal, ".alpha.-MSH Inhibits the Nuclear Transcription factor
NF-.kappa.B Activation Induced by Various Inflammatory Agents," The
Journal of Immunology, Vol. 161 (1998), pp. 2873-2880. Thus,
.alpha.-MSH exerts anti-inflammatory actions through stimulation of
MC-1R on cells involved in the inflammatory response and subsequent
inhibition of the activation of the pro-inflammatory transcription
factor NF-.kappa.B. Additionally, studies show that
anti-inflammatory actions of .alpha.-MSH may be, in part, mediated
by agonism of MC-3R and/or MC-5R. See WO 00/05263 to William Harvey
Research Limited (2000), "Compounds for Use in the Treatment of
Inflammation."
[0009] The present invention provides compounds useful as
modulators of the melanocortin receptors, including selective
modulators of MC-1R and/or MC-4R. Compounds that reportedly are
selective agonists of MC-1R are disclosed in WO 99/57148, cited
above, and selective antagonists of MC-1R are disclosed in WO
99/43709 to The Regents of the Univ. of Calif., "Melanocortin
Receptor Antagonists and Modulations of Melanocortin Receptor
Activity." Both WO 99/57148 and WO 99/43709 disclose large
polypeptides. Small molecule inhibitors are advantageous in
comparison to large polypeptides as they are less likely to induce
immune reactions in patients and are more amendable to oral
delivery. There remains a need for a small molecule useful as an
MC-1R agonist, which is provided by the present invention.
Melanocortin receptor modulators are also disclosed in U.S. patent
application Ser. No. ______, filed concomitantly herewith by the
same inventors herein and assigned to the present assignee,
claiming priority to U.S. patent application Ser. Nos. 60/273,206,
and 60/273,291, filed Mar. 2, 2001, the entire contents of which is
incorporated herein by reference. Also incorporated herein is WO
99/58501 to Novo Nordisk.
SUMMARY OF THE INVENTION
[0010] The present invention is directed to compounds having the
formula (I), useful as modulators of one or more melanocortin
receptors, ##STR3## [0011] and pharmaceutically-acceptable salts,
hydrates or prodrugs thereof, in which in which [0012] E is
##STR4## [0013] X is N or CH; [0014] R.sub.1 is hydrogen or
C.sub.1-6alkyl or is taken together with R.sub.2 or R.sub.3 to form
a monocyclic or bicyclic aryl, cycloalkyl, heteroaryl or
heterocycle; [0015] R.sub.2 is hydrogen, aryl, cycloalkyl,
heteroaryl, heterocyclo; or C.sub.1-6alkyl or C.sub.2-6alkenyl
optionally substituted with one to three of hydroxy, alkoxy,
halogen, cyano, nitro, trifluoromethyl, amino, alkylamino, aryl,
cycloalkyl, heteroaryl, and/or heterocyclo; or R.sub.2 is taken
together with R.sub.1 or R.sub.3 to form a monocyclic or bicyclic
aryl, cycloalkyl, heteroaryl or heterocycle; [0016] R.sub.3 is
hydrogen or C.sub.1-6alkyl or is taken together with R.sub.1 or
R.sub.2 to form a monocyclic or bicyclic aryl, cycloalkyl,
heteroaryl or heterocycle; [0017] R.sub.4, R.sub.5, R.sub.5a
R.sub.5b, R.sub.6, R.sub.6a, R.sub.6b, and R.sub.7 are
independently selected from hydrogen, alkyl, substituted alkyl,
halogen, hydroxy, alkoxy, keto, aryl, heteroaryl, cycloalkyl, and
heterocyclo, or R.sub.5a and/or R.sub.5b, R.sub.6a and/or R.sub.6b,
are taken together with R.sub.8 or R.sub.9 to form a fused
carbocyclic, heterocyclic or heteroaryl ring; [0018] R.sub.8 and
R.sub.9 are independently hydrogen, halogen, cyano, alkyl,
substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, --OR.sub.13, --NR.sub.13R.sub.14,
--SR.sub.13--S(O).sub.pR.sub.14, --C(.dbd.O)R.sub.13,
--OC(.dbd.O)R.sub.13, --CO.sub.2R.sub.13,
--C(.dbd.O)NR.sub.13R.sub.14, --NR.sub.13C(.dbd.O)R.sub.14,
--OC(.dbd.O)NR.sub.13R.sub.14, --NR.sub.13CO.sub.2R.sub.14,
--NR.sub.13C(.dbd.O)NR.sub.14R.sub.15 or
--NR.sub.13SO.sub.2R.sub.14; or R.sub.8 and R.sub.9 taken together
form a monocyclic or bicyclic cycloalkyl or heterocyclo joined in a
spiro fashion to ring E at C*, provided that R.sub.8 and R.sub.9
are not both hydrogen, and provided further that when R.sub.8 is
--OR.sub.13, --(CH.sub.2).sub.k-aryl or
--(CH.sub.2).sub.k-heteroaryl, then R.sub.9 is not
--C(.dbd.O)NR.sub.18R.sub.19, --CO.sub.2R.sub.19,
--(CH.sub.2).sub.mNR.sub.18SO.sub.2R.sub.20,
--(CH.sub.2).sub.mNR.sub.18C(.dbd.O)R.sub.20,
--(CH.sub.2).sub.mOR.sub.19, --(CH.sub.2).sub.mO(C.dbd.O)R.sub.20,
--CH(R.sub.18)R.sub.19, or
--(CH.sub.2).sub.mNR.sub.18(C.dbd.O)NR.sub.19R.sub.21; [0019]
R.sub.11 and R.sub.12 are selected independently of each other from
hydrogen, alkyl, halogen, hydroxy, hydroxyalkyl, haloalkyl, amino,
aminoalkyl, alkylamino, arylalkyl, cycloalkylalkyl,
heteroarylalkyl, aryl, and cycloalkyl, and where y is at least 1,
then R.sub.11 and R.sub.12 may be heterocyclo or heterocycloalkyl,
or R.sub.11 and R.sub.12, when attached to the same carbon atom,
may join to form a spirocycloalkyl ring; [0020] R.sub.13, R.sub.14
and R.sub.15 are independently hydrogen, alkyl, substituted alkyl,
cycloalkyl, aryl, heterocyclo, or heteroaryl; or R.sub.13 and
R.sub.14, or R.sub.14 and R.sub.15 may join together to form a
heterocyclo or heteroaryl, except R.sub.14 is not hydrogen when
joined to a sulfonyl group as in --S(O).sub.pR.sub.14 or
--NR.sub.13SO.sub.2R.sub.14; [0021] W is selected from: [0022] 1)
--NR.sub.16R.sub.17, --NR.sub.16C(.dbd.O)R.sub.22,
--NR.sub.16CO.sub.2R.sub.22, --OR.sub.23, amidino, and guanidino;
[0023] 2) heteroaryl or heterocyclo groups selected from pyrrolyl,
furyl, thienyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl,
isothiazolyl, 3-azaisothiazolyl, pyridyl, pyrazinyl, pyridazinyl,
1,2-dihydropyridazinyl, and pyranyl, wherein said heteroaryl and
heterocyclo groups may be substituted or unsubstituted and may have
an optionally-substituted carbocyclic, heterocyclic or heteraryl
ring fused thereto; or [0024] 3) a ring selected from: ##STR5##
[0025] and where at least one of x and/or y is at least 1, W may be
##STR6## [0026] wherein B is N, O or S; [0027] R.sub.16 and
R.sub.17 are selected from hydrogen, alkyl and substituted alkyl;
[0028] R.sub.18, R.sub.19 and R.sub.21 are independently hydrogen
or C.sub.1-6alkyl optionally substituted with halogen; [0029]
R.sub.20 is C.sub.1-6alkyl, aryl, or heteroaryl; [0030] R.sub.22
and R.sub.23 are independently selected from hydrogen, alkyl,
substituted alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;
[0031] R.sub.24 and R.sub.25 at each occurrence are attached to any
available carbon or nitrogen atom of W and at each occurrence are
selected from hydrogen, C.sub.1-6alkyl, halogen, substituted
C.sub.1-6alkyl, amino, alkylamino, cyano, nitro, trifluoromethoxy,
--C(.dbd.O)R.sub.26, --CO.sub.2R.sub.26, --SO.sub.2R.sub.26,
--OR.sub.26, aryl, heteroaryl, heterocyclo, and cycloalkyl, and/or
two R.sub.25 attached to two adjacent nitrogen or carbon atoms may
join to form a fused optionally-substituted heteroaryl, heterocyclo
or cycloalkyl ring, and/or two R.sub.24 or two R.sub.25 when
attached to the same carbon atom may form keto (.dbd.O); [0032]
R.sub.26 is hydrogen, alkyl, substituted alkyl, aryl, heterocyclo,
cycloalkyl, or heteroaryl, except when joined to a sulphonyl group
as in SO.sub.2R.sub.26, then R.sub.26 is not hydrogen; [0033] k and
m are independently 0, 1, 2 or 3; [0034] p is 1, 2, or 3; [0035] r
is 0 or 1; [0036] s is 0 or 1; [0037] u and v are 0, 1, 2, or 3;
[0038] w is 0, 1, or 2; [0039] x and y are 0, 1, 2, 3, or 4; and
[0040] z is 0, 1, or 2.
[0041] The invention is further directed to pharmaceutical
compositions comprising one or more compounds according to formula
(I). The invention is further directed to methods of treating
melanocortin-receptor associated conditions, as defined herein, as
well as methods of agonizing or antagonizing the melanocortin
receptors, more particularly, MC-1R and MC-4R. The invention is
also directed more generally to small molecule inhibitors of MC-1R,
and to methods of treating diseases responsive to inhibition of
MC-1R using a small molecule according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0042] The following are definitions of terms used in this
specification. The initial definition provided for a group or term
herein applies to that group or term throughout the present
specification, individually or as part of another group, unless
otherwise indicated.
[0043] The term "alkyl" refers to straight or branched chain
hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8
carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4
carbon atoms, are most preferred. When a subscript is used with
reference to an alkyl or other group, the subscript refers to the
number of carbon atoms that the group may contain.
[0044] The term "substituted alkyl" refers to an alkyl group as
defined above having one, two or three substituents selected from
the group consisting of halo, amino, cyano, keto (.dbd.O),
--OR.sub.a, --SR.sub.a, NR.sub.aR.sub.b, --(C.dbd.O)R.sub.a,
--CO.sub.2R.sub.a, --C(.dbd.O)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, NR.sub.aCO.sub.2R.sub.b,
--OC(.dbd.O)R.sub.a, --OC(.dbd.O)NR.sub.aR.sub.b,
--NR.sub.cC(.dbd.O)NR.sub.aR.sub.b, NR.sub.aSO.sub.2R.sub.d,
SO.sub.2R.sub.d, SO.sub.3R.sub.d, cycloalkyl, aryl, heteroaryl, or
heterocycle, wherein the groups R.sub.a, R.sub.b, and R.sub.c are
selected from hydrogen, C.sub.1-6alkyl, aryl, heteroaryl,
heterocycle, cycloalkyl, or C.sub.1-6alkyl substituted with
halogen, hydroxy, methoxy, nitro, amino, cyano, --(C.dbd.O)H,
--CO.sub.2H, --(C.dbd.O)alkyl, --CO.sub.2alkyl, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, carboxy, acyl, --C(.dbd.O)H,
--C(.dbd.O)phenyl, --CO.sub.2-alkyl, cycloalkyl,
--(C.dbd.O)NH.sub.2, --(C.dbd.O)NH(alkyl),
--(C.dbd.O)NH(cycloalkyl), --(C.dbd.O)N(alkyl).sub.2,
--C(.dbd.O)--(CH.sub.2).sub.1-2NH.sub.2,
--C(.dbd.O)--(CH.sub.2).sub.1-2NH(alkyl),
--C(.dbd.O)--(CH.sub.2).sub.1-2N(alkyl).sub.2,
--NH--CH.sub.2-carboxy, --NH--CH.sub.2--CO.sub.2-alkyl, phenyl,
benzyl, phenylethyl, or phenyloxy. The group R.sub.d may be
selected from the same groups as R.sub.a, R.sub.b and R.sub.c but
is not hydrogen. Alternatively, the groups R.sub.a and R.sub.b may
together form a heterocyclo or heteroaryl ring. It should be
understood that when a substituted alkyl group is substituted with
an aryl, cycloalkyl, heteroaryl, or heterocyclo, such rings are as
defined below and thus may have one to three substituents as set
forth below in the defintions for these terms.
[0045] When the term "alkyl" is used as a suffix following another
specifically named group, e.g., arylalkyl, heteroarylalkyl, the
term defines with more specificity at least one of the substituents
that the substituted alkyl will contain. For example, arylalkyl
refers to an aryl bonded through an alkyl, or in other words, a
substituted alkyl group having from 1 to 12 carbon atoms and at
least one substituent that is aryl (e.g., benzyl or biphenyl).
"Lower arylalkyl" refers to substituted alkyl groups having 1 to 4
carbon atoms and at least one aryl substituent.
[0046] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms and at least one
double bond. Alkenyl groups of 2 to 6 carbon atoms and having one
double bond are most preferred.
[0047] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms and at least one
triple bond. Alkynyl groups of 2 to 6 carbon atoms and having one
triple bond are most preferred. A substituted alkenyl or alkynyl
will contain one, two, or three substituents as defined above for
alkyl groups.
[0048] The term "alkylene" refers to bivalent straight or branched
chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1
to 8 carbon atoms, e.g., {--CH.sub.2--}.sub.n, wherein n is 1 to
12, preferably 1-8. Lower alkylene groups, that is, alkylene groups
of 1 to 4 carbon atoms, are most preferred. The terms "alkenylene"
and "alkynylene" refer to bivalent radicals of alkenyl and alknyl
groups, respectively, as defined above. Substituted alkylene,
alkenylene, and alkynylene groups may have substituents as defined
above for substituted alkyl groups.
[0049] The term "alkoxy" refers to the group OR.sub.e wherein
R.sub.e is alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heterocycle, or cycloalkyl. Thus, an
alkoxy includes such groups as methoxy, ethoxy, cyclopropyloxy,
pyrrolidinyloxy, and so forth. The term "aryloxy" refers to the
groups O(aryl) or O(heteraryl), wherein aryl and heteroaryl are as
defined below.
[0050] The term "alkylthio" refers to an alkyl or substituted alkyl
group as defined above bonded through one or more sulfur (--S--)
atoms, e.g., --S (alkyl) or --S (alkyl-R.sub.a).
[0051] The term "alkylamino" refers to an alkyl or substituted
alkyl group as defined above bonded through one or more nitrogen
(--NR.sub.f--) groups, wherein R.sub.f is hydrogen, alkyl,
substituted alkyl, or cycloalkyl.
[0052] The term "acyl" refers to an alkyl or substituted alkyl
group as defined above bonded through one or more carbonyl
{--C(.dbd.O)--} groups. When the term acyl is used in conjunction
with another group, as in acylamino, this refers to the carbonyl
group {--C(.dbd.O)} linked to the second named group. Thus,
acylamino refers to --C(.dbd.O)NH.sub.2, substituted acylamino
refers to the group --C(.dbd.O)NRR, and acylaryl refers to
--C(.dbd.O)(aryl).
[0053] The term "aminoacyl" refers to the group
--NR.sub.fC(.dbd.O)R.sub.g, wherein R.sub.g is hydrogen, alkyl, or
substituted alkyl, and R.sub.f is as defined above for alkylamino
groups.
[0054] The term "halo" or "halogen" refers to chloro, bromo, fluoro
and iodo.
[0055] The term "carboxy" when used alone refers to the group
CO.sub.2H. Carboxyalkyl refers to the group CO.sub.2R, wherein R is
alkyl or substituted alkyl.
[0056] The term "sulphonyl" refers to a sulphoxide group (i.e.,
--S(O).sub.1-2--) linked to an organic radical including an alkyl,
alkenyl, alkynyl, substituted alkyl, substituted alkenyl, or
substituted alkynyl group, as defined above. The organic radical to
which the sulphoxide group is attached may be monovalent (e.g.,
--SO.sub.2-alkyl), or bivalent (e.g., --SO.sub.2-alkylene,
etc.)
[0057] The term "amidino" refers to the group ##STR7## and the term
"guanidino" refers to the group ##STR8## wherein for each of
amidino and guanidino R.sub.h, R.sub.i, and R.sub.j may be
hydrogen, alkyl, or substituted alkyl, or any two of R.sub.h,
R.sub.i, and R.sub.j may join to form a heterocyclo or heteroaryl
ring with the other of R.sub.h, R.sub.i, and R.sub.j comprising
hydrogen, alkyl, or substituted alkyl.
[0058] The term "cycloalkyl" refers to substituted and
unsubstituted monocyclic or bicyclic hydrocarbon groups of 3 to 9
carbon atoms which are, respectively, fully saturated or partially
unsaturated, including a fused aryl ring, for example, an indan. A
cycloalkyl group may be substituted by one or more (such as one to
three) substituents selected from alkyl, substituted alkyl,
aminoalkyl, halogen, cyano, nitro, trifluoromethyl, hydroxy,
alkoxy, alkylamino, sulphonyl, --SO.sub.2(aryl), --CO.sub.2H,
--CO.sub.2-alkyl, --C(.dbd.O)H, keto,
--C(.dbd.O)--(CH.sub.2).sub.1-2NH.sub.2,
--C(.dbd.O)--(CH.sub.2).sub.1-2NH(alkyl),
--C(.dbd.O)--(CH.sub.2).sub.1-2N(alkyl).sub.2, acyl, aryl,
heterocylcle, heteroaryl, or another cycloalkyl ring of 3 to 7
carbon atoms. The term "cycloalkylene" refers to a cycloalkyl
forming a link or spacer between two other groups, i.e., a
cycloalkylene is a cycloalkyl that is bonded to at least two other
groups. The term cycloalkyl includes saturated or partially
unsaturated carbocyclic rings having a carbon-carbon bridge of
three to four carbon atoms or having a benzene ring joined thereto.
When the cycloalkyl group is substituted with a further ring, said
further ring may have one to two substituents selected from
R.sub.k, wherein R.sub.k is lower alkyl, hydroxy, lower alkoxy,
amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro,
and lower alkyl substituted with one to two hydroxy, lower alkoxy,
amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, and/or
nitro.
[0059] The term "aryl" refers to substituted and unsubstituted
phenyl, 1-naphthyl and 2-naphthyl, with phenyl being preferred. The
aryl may have zero, one, two or three substituents selected from
the group consisting of alkyl, substituted alkyl, alkoxy,
alkylthio, halo, hydroxy, nitro, cyano, amino, trifluoromethyl,
trifluoromethoxy, sulphonyl, --SO.sub.2(aryl), --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, carboxy, acyl, --C(.dbd.O)H,
--C(.dbd.O)phenyl, --CO.sub.2-alkyl, cycloalkyl,
--(C.dbd.O)NH.sub.2, --(C.dbd.O)NH(alkyl),
--(C.dbd.O)NH(cycloalkyl), --(C.dbd.O)N(alkyl).sub.2,
--NH--CH.sub.2-carboxy, --NH--CH.sub.2--CO.sub.2-alkyl,
--C(.dbd.O)--(CH.sub.2).sub.1-2NH.sub.2,
--C(.dbd.O)--(CH.sub.2).sub.1-2NH(alkyl),
--C(.dbd.O)--(CH.sub.2).sub.1-2N(alkyl).sub.2, phenyl, benzyl,
phenylethyl, phenyloxy, phenylthio, heterocyclo, heteroaryl, or a
C.sub.3-7cycloalkyl ring. The term "arylene" refers to an aryl as
defined above forming a link or spacer between two other groups,
i.e., an arylene is an aryl that is bonded to at least two other
groups. When the aryl group is substituted with a further ring,
said further ring may have one to two substituents selected from
R.sub.k, wherein R.sub.k is defined as above.
[0060] The term "carbocyclo" or "carbocyclic" refers to a cyclic
group in which all ring atoms are carbon, including
optionally-substituted cycloalkyl and aryl groups, as defined
herein.
[0061] The term "heterocyclo" or "heterocycle" refers to
substituted and unsubstituted non-aromatic 3 to 7 membered
monocyclic groups, 7 to 11 membered bicyclic groups, and 10 to 15
membered tricyclic groups which have at least one heteroatom (O, S
or N) in at least one of the rings. Each ring of the heterocyclo
group containing a heteroatom can contain one or two oxygen or
sulfur atoms and/or from one to four nitrogen atoms provided that
the total number of heteroatoms in each ring is four or less, and
further provided that the ring contains at least one carbon atom.
The fused rings completing the bicyclic and tricyclic groups may
contain only carbon atoms and may be saturated, partially
saturated, or unsaturated. The nitrogen and sulfur atoms may
optionally be oxidized and the nitrogen atoms may optionally be
quaternized. The heterocyclo group may be attached at any available
nitrogen or carbon atom. The heterocyclo ring may contain one, two
or three substituents selected from the group consisting of halo,
amino, cyano, alkyl, substituted alkyl, trifluoromethyl,
trifluoromethoxy, sulphonyl, --SO.sub.2(aryl), --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, alkoxy, alkylthio, hydroxy,
nitro, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, carboxy,
--CO.sub.2-alkyl, cycloalkyl, --C(.dbd.O)H, acyl,
--(C.dbd.O)NH.sub.2, --(C.dbd.O)NH(alkyl),
--(C.dbd.O)NH(cycloalkyl), --(C.dbd.O)N(alkyl).sub.2,
--NH--CH.sub.2-carboxy, --NH--CH.sub.2--CO.sub.2-alkyl,
--C(.dbd.O)--(CH.sub.2).sub.1-2NH.sub.2,
--C(.dbd.O)--(CH.sub.2).sub.1-2NH(alkyl),
--C(.dbd.O)--(CH.sub.2).sub.1-2N(alkyl).sub.2, heterocyclo,
heteroaryl, a C.sub.3-7cycloalkyl ring. keto, .dbd.N--OH,
.dbd.N--O-lower alkyl, or a five or six membered ketal, i.e.,
1,3-dioxolane or 1,3-dioxane. The heterocyclo ring may have a
sulfur heteroatom that is substituted with one or more oxygen
(.dbd.O) atoms, as for example, in ##STR9## The term
"heterocyclene" refers to a heterocycle as defined above forming a
link or spacer between two other groups. When the heterocyclo group
is substituted with a further ring, said further ring may have one
to two substituents selected from R.sub.k, wherein R.sub.k is
defined as above.
[0062] Exemplary monocyclic groups include azetidinyl,
pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,
2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl,
morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, 1,3-dioxolane and
tetrahydro-1,1-dioxothienyl and the like. Exemplary bicyclic
heterocyclo groups include quinuclidinyl.
[0063] The term "heteroaryl" refers to substituted and
unsubstituted aromatic 5 or 6 membered monocyclic groups, 9 or 10
membered bicyclic groups, and 11 to 14 membered tricyclic groups
which have at least one heteroatom (O, S or N) in at least one of
the rings. Each ring of the heteroaryl group containing a
heteroatom can contain one or two oxygen or sulfur atoms and/or
from one to four nitrogen atoms provided that the total number of
heteroatoms in each ring is four or less and each ring has at least
one carbon atom. The fused rings completing the bicyclic and
tricyclic groups may contain only carbon atoms and may be
saturated, partially saturated, or unsaturated. The nitrogen and
sulfur atoms may optionally be oxidized and the nitrogen atoms may
optionally be quaternized. Heteroaryl groups which are bicyclic or
tricyclic must include at least one fully aromatic ring but the
other fused ring or rings may be aromatic or non-aromatic. The
heteroaryl group may be attached at any available nitrogen or
carbon atom of any ring. The heteroaryl ring system may contain
one, two or three substituents selected from the group consisting
of halo, amino, cyano, alkyl, substituted alkyl, trifluoromethyl,
trifluoromethoxy, sulphonyl, --SO.sub.2(aryl), --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, alkoxy, alkylthio, hydroxy,
nitro, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, carboxy,
--CO.sub.2-alkyl, cycloalkyl, --C(.dbd.O)H, acyl,
--(C.dbd.O)NH.sub.2, --(C.dbd.O)NH(alkyl),
--(C.dbd.O)NH(cycloalkyl), --(C.dbd.O)N(alkyl).sub.2,
--NH--CH.sub.2-carboxy, --NH--CH.sub.2--CO.sub.2-alkyl,
--C(.dbd.O)--(CH.sub.2).sub.1-2NH.sub.2,
--C(.dbd.O)--(CH.sub.2).sub.1-2NH(alkyl),
--C(.dbd.O)--(CH.sub.2).sub.1-2N(alkyl).sub.2, heterocylco,
heteroaryl, or a C.sub.3-7cycloalkyl ring. The heterocyclo ring may
have a sulfur heteroatom that is substituted with one or more
oxygen (.dbd.O) atoms, as for example, in ##STR10## The term
"heteroarylene" or "heterarylene" refers to a heteroaryl as defined
above forming a link or spacer between two other groups, i.e., it
is a heteroaryl that is bonded to at least two other groups. When
the heteroaryl group is substituted with a further ring, said
further ring may have one to two substituents selected from
R.sub.k, wherein R.sub.k is defined as above.
[0064] Exemplary monocyclic heteroaryl groups include pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl and the like.
[0065] Exemplary bicyclic heteroaryl groups include indolyl,
benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl,
quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl,
benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the
like.
[0066] Exemplary tricyclic heteroaryl groups include carbazolyl,
benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl
and the like.
[0067] When reference is made herein to a particularly-named
heterocyclic or heteroaryl group, such as azetidinyl, imidazolyl,
piperazinyl, and so forth, the named ring may optionally contain
one or more (preferably one to three) substituents selected from
the substituents recited above for heteroaryl and heterocyclo
groups, as appropriate. The term azetidinyl refers to an
optionally-substituted four membered ring having one nitrogen
heteroatom, i.e., ##STR11## wherein R can be any substituent
defined herein for heterocyclo groups and unless otherwise stated,
the azetidinyl ring can be attached to another group at any
available carbon atom or at the nitrogen atom.
[0068] When reference is made to a particularly-named group having
at least one heterocyclo, heteroaryl, or carbocyclic ring "joined"
thereto, it is meant that two substituents attached to the same,
adjacent, or non-adjacent atoms of the particularly-named group may
join to form a second or third ring (i.e., the further ring may be
fused, bridged or attached in a spiro fashion.) Each ring of these
bicyclic or tricyclic groups may be optionally substituted, wherein
the substituents are selected from those recited above for
cycloalkyl, aryl, heterocyclo and heteroaryl groups. Thus, an
imidazole having at least one ring joined thereto may include an
aryl-fused imidazole such as benzimidazole having one or more
(preferably one to three substituents), to an heteroaryl-fused
imidazole such as a pyridoimidazole having one or more (preferably
one to three) substituents, and so forth.
[0069] Accordingly, the above definitions and optional substituents
for cycloalkyl, heterocyclo, and heteroaryl groups include
spirocyclic ring systems. To illustrate, in compounds of formula
(I) above, R.sub.8 and R.sub.9 are recited as optionally forming a
spirocyclic ring. Thus, when z is 1, R.sub.8 and R.sub.9 together
with the piperidine to which they are attached may be selected from
the following exemplary groups, among others: ##STR12## ##STR13##
[0070] in which each R.sub.29 group is hydrogen or selected from
the above-recited substituents for aryl, cycloalkyl, heterocyclo
and heteroaryl groups.
[0071] Additionally, one skilled in the field may make appropriate
substitutions for the various groups of compounds of formula (I)
herein, without departing from the spirit and scope of the
invention. For example, it will be appreciated that in compounds of
formula (I), the group E can be replaced with other groups, such as
the groups E.sub.2, E.sub.3 and E.sub.4 shown in U.S. application
Ser. No. ______, filed concomitantly herewith and incorporated
herein, i.e., groups having the formula, --NR.sub.11R.sub.12,
##STR14## wherein the various groups R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, and R.sub.12 are as
defined in that application. Additionally, one may appreciate that
the group E as recited in compounds of formula (I) may be selected
from, or replaced with groups such as, ##STR15## as defined in WO
02/00654 and WO 01/91752, wherein the various groups R, A,
G.sub.1-3, Q, W, X, Y, Z, d, e, f, n and w, may be selected from
groups recited in WO 02/00654 and/or WO 01/91752, incorporated
herein by reference.
[0072] Throughout the specification, groups and substituents
thereof may be chosen to provide stable moieties and compounds.
[0073] The compounds of formula I form salts which are also within
the scope of this invention. Reference to a compound of the formula
I herein is understood to include reference to salts thereof,
unless otherwise indicated. The term "salt(s)", as employed herein,
denotes acidic and/or basic salts formed with inorganic and/or
organic acids and bases. In addition, when a compound of formula I
contains both a basic moiety, such as, but not limited to an amine
or a pyridine or imidazole ring, and an acidic moiety, such as, but
not limited to a carboxylic acid, zwitterions ("inner salts") may
be formed and are included within the term "salt(s)" as used
herein. Pharmaceutically acceptable (i.e., non-toxic,
physiologically acceptable) salts are preferred, although other
salts are also comtemplated as within the scope of the invention,
e.g., they may be useful in isolation or purification steps which
may be employed during preparation. Salts of the compounds of the
formula I may be formed, for example, by reacting a compound of the
formula I with an amount of acid or base, such as an equivalent
amount, in a medium such as one in which the salt precipitates or
in an aqueous medium followed by lyophilization.
[0074] The compounds of formula I which contain a basic moiety,
such as, but not limited to an amine or a pyridine or imidazole
ring, may form salts with a variety of organic and inorganic acids.
Exemplary acid addition salts include acetates (such as those
formed with acetic acid or trihaloacetic acid, for example,
trifluoroacetic acid), adipates, alginates, ascorbates, aspartates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, cyclopentanepropionates,
digluconates, dodecylsulfates, ethanesulfonates, fumarates,
glucoheptanoates, glycerophosphates, hemisulfates, heptanoates,
hexanoates, hydrochlorides (formed with hydrochloric acid),
hydrobromides (formed with hydrogen bromide), hydroiodides,
2-hydroxyethanesulfonates, lactates, maleates (formed with maleic
acid), methanesulfonates (formed with methanesulfonic acid),
2-naphthalenesulfonates, nicotinates, nitrates, oxalates,
pectinates, persulfates, 3-phenylpropionates, phosphates, picrates,
pivalates, propionates, salicylates, succinates, sulfates (such as
those formed with sulfuric acid), sulfonates (such as those
mentioned herein), tartrates, thiocyanates, toluenesulfonates such
as tosylates, undecanoates, and the like.
[0075] The compounds of formula I which contain an acidic moiety,
such as, but not limited to a carboxylic acid, may form salts with
a variety of organic and inorganic bases. Exemplary basic salts
include ammonium salts, alkali metal salts such as sodium, lithium,
and potassium salts, alkaline earth metal salts such as calcium and
magnesium salts, salts with organic bases (for example, organic
amines) such as benzathines, dicyclohexylamines, hydrabamines
[formed with N,N-bis(dehydro-abietyl)ethylenediamine],
N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and
salts with amino acids such as arginine, lysine and the like. Basic
nitrogen-containing groups may be quaternized with agents such as
lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl
chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl,
diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g.,
decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides), aralkyl halides (e.g., benzyl and phenethyl bromides),
and others.
[0076] Prodrugs and solvates of the compounds of this invention are
also contemplated herein. The term "prodrug", as employed herein,
denotes a compound which, upon administration to a subject,
undergoes chemical conversion by metabolic or chemical processes to
yield a compound of the formula I, and/or a salt and/or solvate
thereof. Solvates of the compounds of formula I are preferably
hydrates.
[0077] Compounds of the formula I and salts thereof may exist in
their tautomeric form (for example, as an amide or imino ether).
All such tautomeric forms are contemplated herein as part of the
present invention.
[0078] All stereoisomers of the present compounds, such as those,
for example, which may exist due to asymmetric carbons, including
enantiomeric forms (which may exist even in the absence of
asymmetric carbons) and diastereomeric forms, are contemplated and
within the scope of this invention. Individual stereoisomers of the
compounds of this invention may, for example, be substantially free
of other isomers, or may be admixed, for example, as racemates or
with all other or other selected, stereoisomers. The chiral centers
of the present invention can have the S or R configuration as
defined by the IUPAC 1974 Recommendations.
Methods of Preparation
[0079] The compounds of the present invention may be prepared by
methods such as those illustrated in the following Schemes I to
III. Starting materials are commercially available or can be
readily prepared by one of ordinary skill in the art using known
methods. For all of the schemes and compounds, the designated
groups such as E, W, R.sub.8, R.sub.9, etc., are as described above
for a compound of formula I, unless otherwise indicated.
[0080] Solvents, temperatures, pressures, and other reaction
conditions may readily be selected by one of ordinary skill in the
art. Starting materials are commercially available or readily
prepared by one of ordinary skill in the art. High Speed Analoging
(HSA) may be employed in the preparation of compounds, for example,
where the intermediates possess a carboxylic acid or amino group.
##STR16##
[0081] Compounds of formula (Ib) can be prepared from compounds
(Ia) [wherein P* is an amino protecting group, such as -Boc-,
-CBZ-, -Fmoc-, which can be present in Q as in formula (Ia) or
independently bonded to Q] via an appropriate amine deprotection
process in an inert solvent at a temperature in the range
-10.degree. C. to 100.degree. C. The choice of deprotection routes
can be chosen by one of ordinary skill in the art. They include,
but are not limited to TFA or hydrogen chloride acid for -Boc-,
hydrogenation with an appropriate metal catalyst (such as Pd), for
-CBZ-, or a base, such as NMM or DEA, for -Fmoc-. Inert solvents
include, but are not limited to methylene dichloride, alcoholic
solvents, THF, acetic acid, DMF, acetonitrile, and dioxane.
[0082] Compounds of formula (Ia) can be prepared by the coupling of
compounds of formula (5) with compounds (4) using an appropriate
carboxylic acid activating reagent in an inert solvent. Exemplary
carboxylic acid activating agents include carbonyldiimidazole,
dicyclohexylcarbodiimide, pentofluorophenol trifluoroacetate,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or other activating
agents known by one of ordinary skill in the art. Exemplary inert
solvents include ethers, including THF and dioxane, DMF,
acetonitrile, or CH.sub.2Cl.sub.2.
[0083] Compounds (4) can be prepared by the hydrolysis of compounds
(3) using a hydroxide source. Exemplary hydroxide sources include
NaOH or LiOH. Exemplary solvents include water, alcohols, and
mixtures of ethers/water.
[0084] Compounds (3) can be prepared by the coupling of compounds
(1) and (2) using an appropriate carboxylic acid activating reagent
in an inert solvent. Exemplary carboxylic acid activating agents
include carbonyldiimidazole, dicyclohexylcarbodiimide,
pentofluorophenol trifluoroacetate,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or other activating
agents known by one of ordinary skill in the art. Exemplary inert
solvents include ethers, including THF and dioxane, DMF,
acetonitrile, or CH.sub.2Cl.sub.2.
[0085] Compounds (1), (2) and (3) are either commercially available
or available by methods known to one of ordinary skill in the art.
##STR17##
[0086] Compounds of formula (Ib) can be prepared from compounds of
formula (Ia) [wherein P* is an amino-protecting group as in Scheme
I] via an appropriate amine deprotection process in an inert
solvent at a temperature in the range from -10.degree. C. to
100.degree. C. The choice of deprotection routes can be chosen by
one of ordinary skill in the art. They include, but are not limited
to TFA or hydrogen chloride acid for -Boc-, hydrogenation with an
appropriate metal catalyst for -CBZ-, or a base, such as NMM or
DEA, for -Fmoc-. Inert solvents include, but are not limited to
methylene dichloride, alcoholic solvents, THF, acetic acid, DMF,
acetonitrile, and dioxane.
[0087] Compounds of formula (Ia) can be prepared by the coupling of
compounds (8) and (9) using an appropriate carboxylic acid
activating reagent in an inert solvent. Exemplary carboxylic acid
activating agents include carbonyldiimidazole,
dicyclohexylcarbodiimide, pentofluorophenol trifluoroacetate,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or other activating
agents known by on of ordinary skill in the art. Exemplary inert
solvents include ethers, including THF and dioxane, DMF,
acetonitrile, or CH.sub.2Cl.sub.2.
[0088] Compounds (8) [wherein P* is an amino-protecting group as
above] can be prepared from compounds (7) via an appropriate amine
deprotection process in an inert solvent at temperatures ranging
from -10.degree. C. to 100.degree. C. The choice of deprotection
routes can be chosen by one of ordinary skill in the art and
include those referenced above in Scheme I for -Boc-, -CBZ-, and
-Fmoc-. Inert solvents include, but are not limited to methylene
dichloride, alcoholic solvents, THF, acetic acid, DMF,
acetonitrile, and dioxane.
[0089] Compounds (7) can be prepared by the coupling of compounds
(5) and (6) using an appropriate carboxylic acid activating reagent
in an inert solvent. Exemplary carboxylic acid activating agents
include carbonyldiimidazole, dicyclohexylcarbodiimide,
pentofluorophenol trifluoroacetate,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or other activating
agents known by one of ordinary skill in the art. Exemplary inert
solvents include ethers, including THF and dioxane, DMF,
acetonitrile, or CH.sub.2Cl.sub.2.
[0090] Compounds (5) and (6) are either commercially available or
available by methods known to one of ordinary skill in the art.
##STR18##
[0091] Compounds of formula (If) can be prepared from compounds of
formula (Ie) [wherein P* is an amino protecting group as in Scheme
I] via an appropriate amine deprotection process chosen by one of
ordinary skill in the art, such as described above in Schemes I and
II.
[0092] Compounds of formula (Ie) can be prepared by the coupling of
compounds of formula (Id) with amines of the formula
R.sub.13R.sub.14NH using an appropriate carboxylic acid activating
reagent in an inert solvent. Exemplary carboxylic acid activating
agents include carbonyldiimidazole, dicyclohexylcarbodiimide,
pentofluorophenol trifluoroacetate,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or other activating
agents known by one of ordinary skill in the art. Exemplary inert
solvents include ethers, including THF and dioxane, DMF,
acetonitrile, or CH.sub.2Cl.sub.2.
[0093] Compounds of formula (Id) can be prepared by the hydrolysis
of compounds of formula (Ic) using a hydroxide source. Exemplary
hydroxide sources include NaOH or LiOH. Exemplary solvents include
water, alcohols, and mixtures of ethers/water.
[0094] Amines of the formula R.sub.13R.sub.14NH are either
commercially available or available by methods known to one of
ordinary skill in the art. Compounds of formula (Ic) can be
prepared as described above in Schemes I and II.
[0095] All documents cited in the present specification are
incorporated herein by reference in their entirety.
Preferred Compounds
[0096] Preferred compounds are those according to formula (I)
having the formula, ##STR19## [0097] and
pharmaceutically-acceptable salts, hydrates and prodrug thereof, in
which [0098] X is N or CH; [0099] R.sub.1 is hydrogen or
C.sub.1-6alkyl or is taken together with R.sub.2 or R.sub.3 to form
a monocyclic or bicyclic heteroaryl or heterocycle; [0100] R.sub.2
is hydrogen, aryl, cycloalkyl, heteroaryl, heterocyclo, or
C.sub.1-6alkyl or C.sub.2-6alkenyl optionally substituted with one
to three of hydroxy, halogen, aryl, cycloalkyl, heteroaryl, and/or
heterocyclo; or R.sub.2 is joined together with R.sub.1 or R.sub.3
to form a monocyclic or bicyclic aryl, cycloalkyl, heteroaryl or
heterocycle; [0101] R.sub.3 is hydrogen or C.sub.1-6alkyl or is
taken together with R.sub.2 to form a monocyclic or bicyclic aryl,
cycloalkyl, heteroaryl or heterocycle; [0102] R.sub.8 and R.sub.9
are independently selected from hydrogen, halogen, cyano, alkyl,
substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
and heteroaryl; [0103] R.sub.11 and R.sub.12 are selected
independently of each other from hydrogen, alkyl, halogen, hydroxy,
hydroxyalkyl, haloalkyl, amino, aminoalkyl, alkylamino, arylalkyl,
cycloalkylalkyl, heteroarylalkyl, aryl, and cycloalkyl, or R.sub.11
and R.sub.12, when attached to the same carbon atom, may join to
form a spirocycloalkyl ring; [0104] W is selected from: [0105] 1)
--NR.sub.16R.sub.17, --NR.sub.16C(.dbd.O)R.sub.22, or
--NR.sub.16CO.sub.2R.sub.22; or [0106] 2) heteroaryl or heterocyclo
groups selected from pyrrolyl, furyl, thienyl, imidazolyl,
pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, 3-azaisothiazolyl,
pyridyl, pyrazinyl, pyridazinyl, 1,2-dihydropyridazinyl, and
pyranyl, wherein said heteroaryl and heterocyclo groups may be
optionally substituted with one to three R.sub.36, and may have an
optionally-substituted carbocyclic, heterocyclic or heteroaryl ring
fused thereto; or [0107] 3) a carbocyclic, heterocyclic, or
heteroaryl ring selected from: ##STR20## [0108] in which W.sub.1
and W.sub.2 are NH, CH.sub.2, O or S, W.sub.3 is O or S, W.sub.4 is
N or CH, and W.sub.5 and W.sub.6 are NH or CH.sub.2, wherein when
W.sub.1, W.sub.2, W.sub.5 and W.sub.6 are NH or CH.sub.2, said
groups are optionally substituted with R.sub.24; [0109] R.sub.16
and R.sub.17 are hydrogen, C.sub.1-8alkyl or (CH.sub.2).sub.q-J,
[0110] wherein J is selected from aryl, heteroaryl, heterocyclo,
and cycloalkyl, wherein the alkyl, alkylene, and/or J groups of
R.sub.16 and/or R.sub.17 are optionally substituted with up to
three R.sub.32; [0111] R.sub.22 is selected from C.sub.1-6alkyl,
trifluoromethyl, alkoxyalkyl, furylalkyl, alkylaminoethyl, phenyl,
pyrollylalkyl, piperidinyl, and piperidinylalkyl, wherein R.sub.22
in turn is optionally substituted with one to two C.sub.1-4alkyl
and/or --CO.sub.2(C.sub.1-4alkyl); [0112] R.sub.24 and R.sub.25 at
each occurrence are attached to any available carbon or nitrogen
atom of W and at each occurrence are selected from hydrogen,
C.sub.1-6alkyl, halogen, substituted C.sub.1-6alkyl, amino,
alkylamino, hydroxy, C.sub.1-4alkoxy, --C(.dbd.O)R.sub.26,
--CO.sub.2R.sub.26, O--SO.sub.2R.sub.26, --OR.sub.26, aryl,
heteroaryl, heterocyclo, and cycloalkyl, and/or two R.sub.25
attached to two adjacent carbon atoms or adjacent carbon and
nitrogen atoms may join to form a fused optionally-substituted
heteroaryl, heterocyclo or cycloalkyl ring, and/or two R.sub.24 or
two R.sub.25 when attached to the same carbon atom may form keto
(.dbd.O); [0113] R.sub.26 is alkyl, phenyl, benzyl, or aminoalkyl;
[0114] R.sub.32 is selected from C.sub.1-6alkyl, hydroxy,
C.sub.1-6alkoxy, halogen, nitro, phenyl, benzyl, phenyloxy,
benzyloxy, --C(.dbd.O)phenyl, amino, alkylamino, and aminoalkyl,
wherein when R.sub.32 includes a phenyl group said phenyl group in
turn is optionally substituted with one to two of halogen, nitro,
cyano, C.sub.1-4 alkyl, and/or C.sub.1-4 alkoxy; [0115] R.sub.35
and R.sub.36 at each occurrence are selected from C.sub.1-6alkyl,
halogen, substituted C.sub.1-6alkyl, hydroxy, alkoxy, cyano,
trifluoromethyl, trifluoromethoxy, nitro, acyl, carboxyalkyl,
sulfonyl, aryl, heteroaryl, heterocyclo, and cycloalkyl; [0116] q
is selected from 0, 1, 2 and 3; [0117] r is 0 or 1; [0118] s is 0
or 1; [0119] u and v are 0, 1, or 2; [0120] w is 0, 1, or 2; and
[0121] x is 0, 1, 2, 3, or 4.
[0122] Also preferred are compounds according to the formula,
##STR21## in which [0123] K is aryl or heteroaryl (more preferably
phenyl or triazolyl), [0124] R.sub.8 and R.sub.9 are selected
independently from hydrogen, alkyl, substituted alkyl, heterocyclo,
heteroaryl, cycloalkyl, and aryl; [0125] R.sub.11 is hydrogen,
C.sub.1-6alkyl, or C.sub.1-6alkyl substituted with up to two of
hydroxy, alkoxy, amino, alkylamino, imidazolyl, pyrazolyl, phenyl,
napthyl, pyridinyl, indolyl, pyrimidyl, furyl, thiazolyl, and
thienyl, wherein when said ringed substituents in turn are
optionally substituted, [0126] W is [0127] a) OH,
--NR.sub.16R.sub.17, --NHC(.dbd.O)R.sub.22, or --NHCO.sub.2alkyl,
or [0128] b) a ring selected from: ##STR22## [0129] R.sub.16 and
R.sub.17 are independently selected from hydrogen, C.sub.1-8alkyl,
and (CH.sub.2).sub.q-J, wherein J is selected from napthyl,
furanyl, indolyl, imidazolyl, pyrimidinyl, benzothiophenyl,
pyridinyl, pyrrolyl, pyrrolidinyl, thiophenyl, and
C.sub.3-7cycloalkyl, wherein the alkyl, alkylene, and/or J groups
of R.sub.16 and/or R.sub.17 are optionally substituted; [0130]
R.sub.22 is selected from C.sub.1-6alkyl, trifluoromethyl,
alkoxyalkyl, furylalkyl, alkylaminoethyl, phenyl, pyrollylalkyl,
piperidinyl, and piperidinylalkyl, wherein R.sub.22 in turn is
optionally substituted with one to two C.sub.1-4alkyl and/or
--CO.sub.2(C.sub.1-4alkyl); [0131] R.sub.24 is selected from keto
(.dbd.O), C.sub.1-6alkyl, halogen, amino, aminoalkyl, alkylamino,
hydroxy, C.sub.1-4alkoxy, hydroxyC.sub.1-4alkyl, --C(.dbd.O)alkyl,
--C(.dbd.O)aminoalkyl, --C(.dbd.O)phenyl, --C(.dbd.O)benzyl,
--CO.sub.2alkyl, --CO.sub.2phenyl, --CO.sub.2benzyl,
--SO.sub.2alkyl, --SO.sub.2aminoalkyl, --SO.sub.2phenyl,
--SO.sub.2benzyl, phenyl, benzyl, phenyloxy, benzyloxy, pyrrolyl,
pyrazolyl, piperidinyl, pyridinyl, pyrimidinyl, and tetrazolyl, and
each R.sub.24 in turn is optionally substituted with one to two
R.sub.31; [0132] R.sub.25 at each occurrence is attached to any
available carbon or nitrogen atom of W and is selected from
C.sub.1-6alkyl, halogen, amino, aminoalkyl, alkylamino, hydroxy,
C.sub.1-4alkoxy, hydroxyC.sub.1-4alkyl, --C(.dbd.O)alkyl,
--C(.dbd.O)aminoalkyl, --C(.dbd.O)phenyl, --C(.dbd.O)benzyl,
--CO.sub.2alkyl, --CO.sub.2phenyl, --CO.sub.2benzyl,
--SO.sub.2alkyl, --SO.sub.2aminoalkyl, --SO.sub.2phenyl,
--SO.sub.2benzyl, phenyl, benzyl, phenyloxy, benzyloxy, pyrrolyl,
pyrazolyl, piperidinyl, pyridinyl, pyrimidinyl, and tetrazolyl,
and/or two R.sub.25 when attached to adjacent carbon and/or
nitrogen atoms may be taken together to form a fused benzo or
pyrazolyl ring, and each R.sub.25 in turn is optionally substituted
with up to two R.sub.31; [0133] R.sub.30 is selected from
C.sub.1-4alkyl, hydroxy, alkoxy, halogen, nitro, cyano, amino,
alkylamino, phenyl, and --C(.dbd.O)phenyl; [0134] R.sub.31 is
selected from halogen, trifluoromethyl, C.sub.1-4alkyl, hydroxy,
and C.sub.1-4alkoxy; [0135] w is selected from 0, 1, or 2; [0136] u
and v are selected from 0, 1, and 2; and [0137] t is 0, 1 or 2.
[0138] In compounds of formula (I), preferably W is ##STR23##
--NR.sub.16R.sub.17, or NR.sub.16C(.dbd.O)R.sub.22, wherein
R.sub.16, R.sub.17, and R.sub.22 are hydrogen, lower alkyl, phenyl,
or lower alkyl substituted with phenyl, heterocyclo, or heteroaryl.
More preferably W is NH.sub.2, NH(lower alkyl), or N(lower
alkyl).sub.2, or W is ##STR24## wherein R.sub.24 is hydrogen or
lower alkyl.
[0139] In compounds of formula (I), preferably R.sub.12 is hydrogen
or lower alkyl, and R.sub.11 is preferably hydrogen, alkyl,
heterocycloalkyl, heteroarylalkyl, or cycloalkylalkyl, more
preferably imidazolylalkyl.
[0140] In compounds of formula (I), preferably R.sub.2 is
arylalkyl, arylalkenyl, or heteroarylalkyl, more preferably
thiazolyl or benzyl optionally substituted in the para position
with lower alkyl, halogen, hydroxy, methoxy, cyano,
trifluoromethyl, trifluoromethoxy, or nitro, more preferably chloro
or fluoro.
[0141] In compounds of formula (I), preferably X is N, R.sub.1 is
hydrogen or lower alkyl, and r and s are preferably 0.
[0142] In compounds of formula (I), preferably E is ##STR25##
wherein R.sub.8 and R.sub.9 are selected independently from
hydrogen, alkyl, --(CH.sub.2).sub.j--C(.dbd.O)alkyl,
--(CH.sub.2).sub.j-phenyl, --(CH.sub.2).sub.j-napthyl,
--(CH.sub.2).sub.j--C.sub.4-7cycloalkyl,
--(CH.sub.2).sub.j-heterocyclo, and --(CH.sub.2).sub.j-heteroaryl,
or R.sub.8 and R.sub.9 together form a spirocycloalkyl or
spiroheterocyclic ring; and j is selected from 0, 1, 2 and 3. More
preferably, E is ##STR26##
[0143] Also preferred are compounds having the formulae: ##STR27##
##STR28## ##STR29## ##STR30## and pharmaceutically-acceptable
salts, hydrates and prodrugs thereof.
Utility
[0144] The inventive compounds are modulators of the melanocortin
receptors MC-1R, MC-3R, MC-4R, and/or MC-5R. The compounds are
useful in treating a wide range of condiitons responsive to
regulation of the melanocortin receptors, including inflammatory
and immune diseases, cardiovascular diseases, skin conditions,
neurodegenerative conditions, sexual dysfunction, bodyweight
disorders, and cancer. Certain compounds according to the invention
have selective affinity for one melanocortin receptor relative to
the other melanocortin receptors and thus are particularly useful
for treating those diseases responsive to regulation of that
receptor. For example, certain compounds have high selectivity for
binding to MC-1R relative to MC-3R, MC-4R, and MC-5R, and those
compounds are particularly useful in treating inflammatory or
immune conditions. Certain other compounds according to the
invention have high selective affinity for MC-4R and are
particularly useful in treating bodyweight and/or neurodegenerative
disorders. As used herein, the term "treating" or "treatment"
refers to prophylaxis measures designed to inhibit or delay the
onset of the disease or disorder and to responsive measures to
alleviate, ameliorate, lessen, or cure the disease or disorder
and/or its symptoms.
[0145] Compounds of the invention may be used to treat
inflammation, particularly inflammation characterized by the
activation of NF-.kappa.B and/or release of inflammatory cytokines.
The compounds can be immunomodulators and have multiple effects on
cells of the immune system. The compounds may be used to increase
the levels of cAMP in cells (with resultant anti-inflammatory
effects), decrease levels of the pro-inflammatory messenger nitric
oxide, decrease chemotactic ability, and alter the expression of
immune-related genes for such agents as cytokines, adhesion
molecules, and nitric oxide synthase.
[0146] In view of their effects on inhibiting NF-.kappa.B activity
and suppressing cytokine accumulation, the compounds will be useful
in treating consequences of many diseases associated with chronic
and acute inflammation and immune-modulation. Such diseases
include, but are not limited to, inflammatory bowel disease,
irritable bowel syndrome, gall bladder disease, Chrohn's disease,
rheumatoid arthritis, osteoarthritis, osteoporosis, traumatic
arthritis, rubella arthritis, muscle degeneration, pancreatis
(acute or chronic), psoriasis, glomerulonephritis, serum sickness,
lupus (systematic lupus erythematosis), urticaria, scleraclerma,
schleroderma, chronic thyroiditis, Grave's disease, dermatitis
(contact or atopic), dermatomyositis, alopecia, atopic eczemas,
ichthyosis, fever, sepsis, migraine, cluster headaches, Alzheimer's
Disease, Parkinson's disease, Creutzfeldt-Jacob disease, multiple
sclerosis, tuberculosis, dementia, and transplant or graft-host
rejections (e.g., kidney, liver, heart, lung, pancreas, bone
marrow, cornea, small bowel, skin allografts, skin homografts and
heterografts, etc.). The compounds may also be used to treat
respiratory allergies and diseases including asthma, acute
respiratory distress syndrome, hayfever, allergic rhinitis, and
chronic obstructive pulmonary disease; and inflammatory disorders
of the central nervous system, including HIV encephalitis, cerebral
malaria, meningitis, and ataxia telangiectasis. Additionally, the
compounds may be useful in treating pain, e.g., post-operative
pain, neuromuscular pain, headache, pain caused by cancer, dental
pain, and arthritis pain.
[0147] In view of their activity in inhibiting NF-.kappa.B
activity, the compounds may be used to treat viral and autoimmune
diseases including herpes simplex type 1 (HSV-1), herpes simplex
type 2 (HSV-2), cytomegalovirus, Epstein-Barr, human
immunodeficiency virus (HIV), Addison's disease (autoimmune disease
of the adrenal glands), idiopathic adrenal insufficiency,
autoimmune polyglandular disease (also known as autoimmune
polyglandular syndrome), chronic active hepatitis or acute
hepatitis infection (including hepatitis A, hepatits B, and
hepatitis C), autoimmune gastritis, autoimmune hemolytic anemia,
and autoimmune neutropenia. The compounds of the invention may also
be used to treat fungal infections such as mycosis fungoides.
[0148] In addition, the compounds of this invention are useful in
treating diseases of the cardiovascular system including those
diseases in which inflammation is an underlying component. These
diseases include but are not limited to atherosclerosis, transplant
atherosclerosis, peripheral vascular disease, inflammatory vascular
disease, intermittent claudication, restenosis, cerebrovascular
stroke, transient ischemic attack, myocardial ischemia and
myocardial infarction. The compounds also may be used to treat
hypertension, hyperlipidemia, coronary artery disease, unstable
angina, thrombosis, thrombin-induced platelet aggregation, and/or
consequences occurring from thrombosis and/or the formation of
atherosclerotic plaques.
[0149] Additionally, the compounds may be useful to treat stroke
and other ischemic brain diseases and/or neurodegeneration
associated therewith, and the neurodegeneration of, or consequences
of, traumatic brain injury.
[0150] In view of their ability to act as immunomodulators in the
skin and affect the production of melanin in the skin, the
compounds are useful in altering pigmentation in the skin and may
be used as photoprotective agents including agents for preventing,
treating, or ameliorating sunburn. The compounds also may be used
in treating acne, vitiligo, alopecia arreata, photosensitivity
disorders, albinism, and porphyria. Addditionally, the compounds
are useful to promote cosmetic as well as therapeutic tanning.
[0151] The compounds of the invention may also be used to treat
neurodegenerative disorders including depression, anxiety,
compulsion (obsessive-compulsive disorder), neuroses, psychosis,
insomnia/sleep disorder, sleep apnea, and drug or substance
abuse.
[0152] The compounds of the invention may be used to treat male or
female sexual dysfunction. Male sexual dysfunction includes
impotence, loss of libido, and erectile dysfunction (including but
not limited to ejaculatory failure, premature ejaculation, or an
inability to achieve or maintain an erection or inability to
achieve an orgasm). Female sexual dysfunction may include sexual
arousal disorder or disorders relating to desire, sexual
receptivity, orgasm, and/or disturbances in trigger points of
sexual function. Female sexual dysfunction may also include sexual
pain, premature labor, dysmenorrhea, excessive menstruation, and
endometriosis.
[0153] The compounds of the invention may also be used to treat
bodyweight disorders including but not limited to obesity and
anorexia (e.g., by altering appetite, metabolic rate, fat intake or
carbohydrate craving); and diabetes mellitus (by enhancing glucose
tolerance and/or decreasing insulin resistance).
[0154] The compounds also may be used to treat cancer, more
particularly, cancer of the lung, prostate, colon, breast, ovaries,
and bone, or angiogenic disorders including the formation or growth
of solid tumors.
[0155] The compounds of the invention may also be used to treat
veterinary disease such as veterinary viral infections, including
feline immunodeficiency virus, bovine immunodeficiency virus, and
canine immunodeficiency virus.
[0156] The term "melanocortin-receptor associated condition" when
used herein refers to each of the above-referenced conditions,
disorders, or diseases that may be treated by agonizing or
antagonizing a melanocortin receptor, inhibiting NF-.kappa.B
activity and/or suppressing cytokine accumulation as if each of
these conditions, disorders and diseases were set forth herein at
length.
[0157] The inventive compounds may be used alone or in combination
with each other and/or other therapeutic agents such as
anti-inflammatory drugs, antibiotics, anti-viral agents,
anti-fungal agents, anti-diabetic agents, anti-osteoporosis agents,
anti-obesity agents or appetite suppressants, growth promoting
agents (including growth hormone secretagogues), anti-anxiety
agents, anti-depressants, anti-hypertensive agents,
cholesterol/lipid lowering agents, bone resorption inhibitors, and
anti-tumor agents including antiproliferative agents, or cytotoxic
drugs.
[0158] Examples of suitable other anti-inflammatory agents with
which the inventive compounds may be used include aspirin,
non-steroidal antiinflammatory drugs (NSAIDs) (such as ibuprofen
and naproxin), TNF-.alpha. inhibitors (such as tenidap and
rapamycin or derivatives thereof), or TNF-.alpha. antagonists
(e.g., infliximab, OR1384), prednisone, dexamethasone, Enbrel.RTM.,
cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors such
as Naproxen.RTM., Celebrex.RTM., or Vioxx.RTM.), CTLA4-Ig
agonists/antagonists, CD40 ligand antagonists, IMPDH inhibitors,
such as mycophenolate (CellCept.RTM.), integrin antagonists,
alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors,
interferon gamma antagonists, ICAM-1, prostaglandin synthesis
inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonists
(e.g., priliximab), p38 mitogen-activated protein kinase
inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK
inhibitors, therapies for the treatment of irritable bowel syndrome
(e.g., Zelmac.RTM. and Maxi-K.RTM. openers such as those disclosed
in U.S. Pat. No. 6,184,231 B1), or other NF-.kappa.B inhibitors,
such as corticosteroids, calphostin, CSAIDs, 4-substituted imidazo
[1,2-A]quinoxalines as disclosed in U.S. Pat. No. 4,200,750;
Interleukin-10, glucocorticoids, salicylates, nitric oxide, and
other immunosuppressants; and nuclear translocation inhibitors,
such as deoxyspergualin (DSG). To treat pain such as migraine and
other headaches, the inventive compounds may be used in combination
with aspirin, NSAIDs, or with 5-HT.sub.ID receptor agonists such as
sumitriptan, eletriptan or rizatriptan.
[0159] Examples of suitable other antibiotics with which the
inventive compounds may be used include .beta.-lactams (e.g.,
penicillins, cephalosporins and carbopenams); .beta.-lactam and
lactamase inhibitors (e.g., augamentin); aminoglycosides (e.g.,
tobramycin and streptomycin); macrolides (e.g., erythromycin and
azithromycin); quinolones (e.g., cipro and tequin); peptides and
deptopeptides (e.g. vancomycin, synercid and daptomycin)
metabolite-based anti-biotics (e.g., sulfonamides and
trimethoprim); polyring systems (e.g., tetracyclins and rifampins);
protein synthesis inhibitors (e.g., zyvox, chlorophenicol,
clindamycin, etc.); and nitro-class antibiotics (e.g., nitrofurans
and nitroimidazoles).
[0160] Examples of suitable other antifungal agents with which the
inventive compounds may be used include fungal cell wall inhibitors
(e.g., candidas), azoles (e.g., fluoconazole and vericonazole), and
membrane disruptors (e.g., amphotericin B).
[0161] Examples of suitable other antiviral agents for use with the
inventive compounds include nucleoside-based inhibitors,
protease-based inhibitors, and viral-assembly inhibitors.
[0162] Examples of suitable anti-diabetic agents for use in
combination with the compounds of the present invention include
biguanides (e.g., metformin or phenformin), glucosidase inhibitors
(e.g,. acarbose or miglitol), insulins (including insulin
secretagogues, sensitizers or mimetics), meglitinides (e.g.,
repaglinide), sulfonylureas (e.g., glimepiride, glyburide,
gliclazide, chlorpropamide and glipizide), biguanide/glyburide
combinations (e.g., Glucovance.RTM.), thiazolidinediones (e.g.,
troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists,
PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2
inhibitors, glycogen phosphorylase inhibitors, inhibitors of fatty
acid binding protein (aP2), glucagon-like peptide-1 (GLP-1),
dipeptidyl peptidase IV (DP4) inhibitors, Alistat.RTM.,
Meridia.RTM., and Zenacol.RTM..
[0163] Examples of suitable anti-osteoporosis agents for use in
combination with the compounds of the present invention include
alendronate, risedronate, PTH, PTH fragment, raloxifene,
calcitonin, RANK ligand antagonists, calcium sensing receptor
antagonists, TRAP inhibitors, selective estrogen receptor
modulators (SERM) and AP-1 inhibitors.
[0164] Examples of suitable anti-obesity agents for use in
combination with the compounds of the present invention include aP2
inhibitors, PPAR gamma antagonists, PPAR delta agonists, beta 3
adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355
(Merck), or CP331648 (Pfizer) or other known beta 3 agonists as
disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134,
5,776,983 and 5,488,064, a lipase inhibitor, such as orlistat or
ATL-962 (Alizyme), a serotonin, adrenergic (and dopamine) reuptake
inhibitor, such as sibutramine, topiramate (Johnson & Johnson)
or axokine (Regeneron), other thyroid receptor beta drugs, such as
a thyroid receptor ligand as disclosed in WO 97/21993 (U. Cal SF),
WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), and/or an
anorectic agent (such as dexamphetamine, phentermine,
phenylpropanolamine or mazindol). Additionally, the inventive
compounds may be used with an .alpha.-gluocosidase inhibitor, an
MHG-CoA reductase inhibitor, a sequestrant chlolestoral lowering
agent, a .beta.3 adrenergic receptor agonist, a neuropeptide Y
antagonist, or an .alpha.2-adrenergic receptor antagonist.
[0165] A still further use of the compounds of the invention is in
combination with estrogen, testosterone, a selective estrogen
receptor modulator, such as tamoxifen or raloxifene, or other
androgen receptor modulators.
[0166] A further use of the compounds of this invention is in
combination with steriodal or non-steroidal progesterone receptor
agonists ("PRA"), such as levonorgestrel, medroxyprogesterone
acetate (MPA).
[0167] Examples of suitable anti-anxiety agents for use in
combination with the compounds of the present invention include
benzodiazepines, diazepam, lorazepam, buspirone (Serzone.RTM.),
oxazepam, and hydroxyzine pamoate, or dopamine recetpor
agonists.
[0168] Examples of suitable anti-depressants for use in combination
with the compounds of the present invention include citalopram,
fluoxetine, nefazodone, sertraline, and paroxetine.
[0169] In treating skin disorders or diseases as described above,
the compounds may be used alone or in combination with a retinoid,
such as tretinoin, or a vitamin D analog.
[0170] Examples of suitable anti-hypertensive agents for use in
combination with the compounds of the present invention include
beta adrenergic blockers, calcium channel blockers (L-type and
T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and
mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide,
flumethiazide, hydroflumethiazide, bendroflumethiazide,
methylchlorothiazide, trichloromethiazide, polythiazide,
benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,
furosemide, musolimine, bumetanide, triamtrenene, amiloride, and
spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,
Vanlev.RTM., pravachol, zofenopril, fosinopril, enalapril,
ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,
lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan,
valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan
and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265),
Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389),
neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors
(dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat),
nitrates, and cardiac glycosides (e.g., digitalis and ouabain).
[0171] Examples of suitable cholesterol/lipid lowering agents for
use in combination with the compounds of the present invention
include HMG-CoA reductase inhibitors, squalene synthetase
inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP
inhibitors, lipooxygenase inhibitors, an ileal Na.sup.+/bile acid
cotransporter inhibitor, cholesterol absorption inhibitors, and
cholesterol ester transfer protein inhibitors (e.g.,
CP-529414).
[0172] In addition, the compounds may be used with other agents to
increase the levels of cAMP or cGMP in cells for a therapeutic
benefit. For example, applicants have discovered that MC-1R
agonists including the compounds of the invention have advantageous
effects when used in combination with phosphodiesterase inhibitors,
including PDE1 inhibitors (such as those described in Journal of
Medicinal Chemistry, Vol. 40, pp. 2196-2210 [1997]), PDE2
inhibitors, PDE3 inhibitors (such as revizinone, pimobendan, or
olprinone), PDE4 inhibitors (such as rolipram, cilomilast, or
piclamilast), and PDE7 inhibitors. The compounds of this invention
also may be used in combination with PDE5 inhibitors such as
sildenafil, sildenafil citrate, (e.g., when treating sexual
dysfunction) or IC-351.
[0173] The combination of the inventive compounds with other
therapeutic agents may prove to have additive and synergistic
effects. The combination may be advantageous to increase the
efficacy of the administration or decrease the dosage to reduce
possible side-effects.
[0174] The compounds of formula I may be administered by any means
suitable for the condition to be treated. The compounds may be
delivered orally such as in the form of tablets, capsules,
granules, powders, or with liquid formulations including syrups;
sublingually; bucally; transdermally; parenterally such as by
subcutaneous, intravenous, intramuscular, or intrasternal injection
or infusion (e.g., as sterile injectable aqueous or non-aqueous
solutions or suspensions); nasally such as by inhalation spray;
rectally such as in the form of suppositories; or liposomally.
Dosage unit formulations containing non-toxic, pharmaceutically
acceptable vehicles or diluents may be administered. The compounds
may be administered in a form suitable for immediate release or
extended release. Immediate release or extended release may be
achieved with suitable pharmaceutical compositions or, particularly
in the case of extended release, with devices such as subcutaneous
implants or osmotic pumps.
[0175] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The inventive compounds may be orally delivered
by sublingual and/or buccal administration, e.g., with molded,
compressed, or freeze-dried tablets. Exemplary compositions may
include fast-dissolving diluents such as mannitol, lactose,
sucrose, and/or cyclodextrins. Also included in such formulations
may be high molecular weight excipients such as celluloses
(AVICEL.RTM.) or polyethylene glycols (PEG); an excipient to aid
mucosal adhesion such as hydroxypropyl cellulose (HPC),
hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl
cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,
GANTREZ.RTM.); and agents to control release such as polyacrylic
copolymer (e.g., CARBOPOL 934.RTM.). Lubricants, glidants, flavors,
coloring agents and stabilizers may also be added for ease of
fabrication and use.
[0176] Exemplary compositions for nasal aerosol or inhalation
administration include solutions which may contain, for example,
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance absorption and/or bioavailability, and/or
other solubilizing or dispersing agents such as those known in the
art.
[0177] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides and fatty acids, including oleic acid.
[0178] Exemplary compositions for rectal administration include
suppositories which may contain, for example, suitable
non-irritating excipients, such as cocoa butter, synthetic
glyceride esters or polyethylene glycols, which are solid at
ordinary temperatures but liquefy and/or dissolve in the rectal
cavity to release the drug.
[0179] The effective amount of a compound of the present invention
may be determined by one of ordinary skill in the art. The specific
dose level and frequency of dosage for any particular subject may
vary and will depend upon a variety of factors, including the
activity of the specific compound employed, the metabolic stability
and length of action of that compound, the species, age, body
weight, general health, sex and diet of the subject, the mode and
time of administration, rate of excretion, drug combination, and
severity of the particular condition. An exemplary effective amount
of compounds of formula I may be within the dosage range of about
0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and
more preferably about 0.5 to about 25 mg/kg (or from about 1 to
about 2500 mg, preferably from about 5 to about 2000 mg) on a
regimen in single or 2 to 4 divided daily doses. Preferred subjects
for treatment include animals, most preferably mammalian species
such as humans, and domestic animals such as dogs, cats, horses,
and the like, subject to melanocortin-receptor associated
conditions.
[0180] Each of the inventive compounds exemplified herein has been
tested and shown activity at a measurable level for modulating a
melanocortin receptor, according to an assay described below and/or
an assay known in the field, such as, for example, assays described
in WO 00/74679 A1 and WO 01/91752.
Assays
MC1R
[0181] HBL cells, a human melanoma cell line licensed from Prof. G.
Ghanem (Lab. of Oncology & Exp. Surgery, Free University of
Brussels, Brussels, Belgium) were used as a source of the human
MC-1R. cAMP was measured using the cAMP SPA Direct Screening Assay
System from Amersham (RPA 559). 20,000 HBL cells were plated into
each well of a half-area 96 well white plate and were used between
16-48 hours after plating. Cells were incubated at 37.degree. C.
for 15 minutes in 25 uM IBMX to inhibit phosphodiesterase activity.
As per kit instructions, Assay Buffer Concentrate was diluted 1 to
50 with dH.sub.2O to prepare Assay Buffer (50 mM acetate buffer
containing 0.01% sodium azide). Vials containing rabbit
anti-succinyl cAMP serum and the tracer, adenosine 3',5'-cyclic
phosphoric acid 2'-0-succinyl-3-[.sup.125I] iodotyrosine methyl
ester, were resuspended with 7.5 ml Assay Buffer. SPA anti-rabbit
reagent (donkey anti-rabbit IgG coupled to SPA PVT beads) was
resuspended with 15 ml Assay Buffer. All reagents were stored at
4.degree. C. after reconstitution. Melanocortin ligands or
compounds were prepared in DMSO and added to the IBMX-treated cells
as 100.times. concentrated stocks. 50 nM .alpha.-MSH was used for
the maximum response and 1 ul DMSO was included in the negative
control wells. The final concentration of DMSO was 1% in all the
samples. After 15-30 minutes of stimulation, the reaction was
terminated by the aspiration of the contents of the well followed
by addition of 15 ul Assay Buffer containing 0.1 N HCl. Plates were
kept at room temperature for at least 30 minutes to effect
extraction of cAMP. Antiserum, Tracer, and SPA anti-rabbit reagent
solutions were mixed 1:1:1 just prior to use. 15 ul of SPA reagent
mixture was dispensed into each well and plates were incubated at
room temperature for a minimum of 5 hours. Plates were subsequently
counted for 6 minutes per sample in a TopCount scintillation reader
with background subtraction. Data was analyzed in relation to a
cAMP standard curve.
MC-4R
A. Binding Assay.
[0182] The membrane binding assay may be used to identify
competitive inhibitors of [.sup.125I]NDP-.alpha.-MSH binding to
cloned human MC4R expressed in Hi5 insect cells infected by a
baculovirus/human MC4R receptor construct.
[0183] Hi5 cells are grown in suspension in Express Five SFM Insect
Cell Media (Gibco, Cat. No. 10486-025) at 27.degree. C. with
constant shaking. Hi5 cells are infected using the following
protocol: [0184] Cells at a density of 1.times.10.sup.6 cells/mL
are spun down at 1000 rpm (Beckman GS-6KR centrifuge) for 10
minutes. [0185] Cells are resuspended in 10% of their original
volume in a sterile 50 mL conical centrifuge tube wrapped with
aluminum foil. Virus is added at a Multiplicity of Infection (MOI)
of 3 and incubated for 1 hour at room temperature with gentle
shaking. [0186] This cell/virus mix is added to the appropriate
volume of medium to attain the original volume and incubated at
27.degree. C. with constant shaking for 72 hours. [0187] Cells are
spun down in 50 mL conical centrifuge tubes at 1000 rpm for 10
minutes. Each of the resulting pellets are resuspended in 10 mL of
cold (4.degree. C.) membrane buffer (25 mM HEPES, pH 7.4, 140 mM
NaCl, 1.2 mM MgCl.sub.2, 2.5 mM CaCl.sub.2, 10 .mu.G/mL Aprotinin,
10 .mu.G/mL Leupeptin) and Dounce homogenized using 10-12 strokes.
Dilute to 30 mL with buffer and centrifuge at 18,000 rpm, 4.degree.
C., 15 minutes (Sorvall RC5C Centrifuge). The resulting pellet is
resuspended in cold membrane buffer in a total of 1/4 of the
original volume by vortexing and aspiration using a syringe and 27
gauge needle.
[0188] Protein content is determined (Bradford, Bio-Rad Protein
Assay). Membranes are aliquoted in microcentrifuge tubes and quick
frozen in liquid nitrogen. Store at -80.degree. C. until use.
[0189] The membrane binding buffer is composed of 25 mM HEPES, pH
7.4, 140 mM NaCl, 1.2 mM MgCl.sub.2, 2.5 mM CaCl.sub.2, 0.1% BSA.
160 .mu.L of membrane binding buffer containing 0.5 .mu.g membrane
protein is added to 20 .mu.L of 1.0 nM [.sup.125I]-NDP-.alpha.-MSH
(final concentration is 0.1 nM) and 20 .mu.L of competing drug or
buffer and incubated for 90 minutes at 37.degree. C.
[0190] The mixture is filtered with Brandel Microplate 96 filter
apparatus using 96-well GF/B filter presoaked in 1-%
polyethyleneimine (Sigma). The filter is washed (4 times with a
total of 1 mL per well) with cold wash buffer consisting of 20 mM
HEPES, pH 7.4, 5 mM MgCl.sub.2.
[0191] The filter is dried and punched into a 96 well sample plate
(Wallac, 1450-401). 100 .mu.l of Wallac Optiphase Supermix
scintillation fluid is added to each well. The top is sealed and
the plates are shaken to insure that the filters are thoroughly
soaked with fluid. Plates are then counted in a Wallac Microbeta
Trilux Scintillation and Luminescence Counter (Model 1450).
Dose-response curves are fitted by linear regression analyses and
IC.sub.50 values are calculated using ExcelFit.
[0192] B. Functional Assay.
[0193] Functional membrane based [.sup.35S]GTP.gamma.S binding
assays are developed to discriminate agonists and antagonists.
[0194] Membrane preparation. Cells (HEK-293 cells expressing the
human MC4R) are grown in Minimum Essential Medium with Earle's
salts and L-glutamate (Life Technologies, Cat. # 11095-080)
containing 10% heat-inactivated fetal bovine serum, 400 .mu.g/mL
geneticin and 100 mM sodium pyruvate in T175 flasks. Upon reaching
confluence, cells are dissociated from tissue culture flasks by
rinsing with Ca.sup.2+ and Mg.sup.2+ free phosphate buffered saline
(Life Technologies, Cat. # 14190-144) and detached following 5
minutes incubation at 37.degree. C. with enzyme free cell
dissociation buffer (Life Technologies, Cat. # 13151-014). Cells
are collected by centrifugation and resuspended in membrane
preparation buffer consisting of 20 mM HEPES, pH 7.4, 10 mM EDTA,
10 .mu.g/mL aprotinin and 10 .mu.g/mL leupeptin. The suspension is
homogenized by polytron PT3000 for 30 sec at 20,000 rpm, and
centrifuged at 35,000.times.g for 15 minutes at 4.degree. C. The
pellet is resuspended in membrane preparation buffer and the last
centrifugation is repeated. The final pellet is resuspended in
membrane storage buffer consisting of 20 mM HEPES, pH 7.4, 0.1 mM
EDTA, 10 .mu.g/mL aprotinin and 10 .mu.g/mL leupeptin. Protein
concentration is determined by the Bio-Rad method (Bio-Rad, Cat. #
500-0006) and the preparation is diluted to a final protein
concentration of 1 mg/mL. Aliquots are stored at -70.degree. C.
until used.
[0195] [.sup.35S]GTP.gamma.S membrane binding assay. Compounds are
dissolved at 10 mM concentration in DMSO and diluted to the
requited concentration into assay buffer. GTP.gamma.S to determine
nonspecific binding is prepared at 100 .mu.M concentration in assay
buffer. The final concentration of DMSO in the assay is 1%. The
assay buffer is consisting of 20 mM HEPES, pH 7.4, 100 mM NaCl, 5
mM MgCl.sub.2, 0.5 .mu.M GDP, 10 .mu.g/mL saponin, 10 .mu.g/mL
aprotinin and 10 .mu.g/mL leupeptin. The assay is composed by
adding 50 .mu.L 10.times. drug solution, 200 .mu.L membrane
preparation (containing 2-4 .mu.g protein), 50 .mu.L
[.sup.35S]GTP.gamma.S (100,000-150,000 CPM) and 200 .mu.L assay
buffer to achieve a total volume of 500 .mu.L. The assay mixture is
incubated at room temperature for exactly 30 minutes. The reaction
is terminated by rapid filtration under vacuum through Whatman GF/B
filters using a Brandel 96 wells cell harvester, followed by
washing four times with cold wash buffer consisting of 20 mM HEPES,
pH 7.4, and 5 mM MgCl.sub.2. The filters are air-dried and 200
.mu.L Wallac, Optiphase Super Mix, liquid scintillation cocktail is
added to each filter. The bound radioactivity (CPM) is determined
by Wallac Trilux 1450 MicroBeta liquid scintillation and
Luminescence counter after six hours.
[0196] Data interpretation. NDP-.alpha.-MSH is used as reference
compound and its maximal stimulation is measured at 1 .mu.M (Ref
CPM 100%). Total drug-independent binding (Total CPM) is measured
in the absence of compounds. Response triggered by compounds is
expressed as percent NDP-.alpha.-MSH response. Compound dose
response curves are generated by Excel XL Fit. The top of the curve
represents the compound's intrinsic activity expressed as % of
maximal stimulation.
[0197] C. Radioligand Binding Assays.
[0198] Binding of [.sup.125I]-(Nle.sup.4, D-Phe.sup.7)-.alpha.-MSH
to human melanocortin receptors was performed using membrane
homogenates from Hi5 cells that express recombinant MC4 receptors
(Hi5-MC4 cells) and from HEK-293 cells that express recombinant MC3
receptors (HEK-MC3 cells) or MC5 receptors (HEK-MC5 cells) as well
as from HBL cells expressing the human MC1R receptor. Homogenates
(.about.0.5 .mu.g protein/well) were incubated with
[.sup.125I]-(Nle.sup.4, D-Phe.sup.7)-.alpha.-MSH (100 pM for assays
with MC4 receptors and 50 pM for assays with MC3/5 receptors) and
increasing concentrations of competitors (final concentration of
DMSO=1%) for 90 min at 37.degree. C. in buffer consisting of 25 mM
HEPES (pH 7.4), 140 mM NaCl, 2.5 mM CaCl.sub.2, 1.2 mM MgCl.sub.2
and 0.1% BSA (10 .mu.g/ml aprotinin and 10 .mu.g/ml leupeptin were
added to assays with MC3/5 receptors). Assays were stopped by
addition of cold wash buffer (20 mM HEPES and 5 mM MgCl.sub.2 for
assays with MC4 receptors and 20 mM HEPES for assays with MC3/5
receptors). Filtration over glass fiber filters (Whatman GF/B
previously soaked in 1% PEI for assays with MC4 receptors or 0.5%
PEI for assays with MC3/5 receptors) was performed using a Brandel
cell harvester. Non-specific binding was defined with 1 .mu.M
NDP-.alpha.-MSH.
[0199] Abbreviations [0200] Boc=tert-butoxycarbonyl [0201]
CBZ=benzyloxycarbonyl [0202] DCE=1,2-dichloroethane [0203]
DCM=dichloromethane [0204] DEA=diethylamine [0205]
DMAP=4-dimethylaminopyridine [0206] DMF=N,N-dimethylformamide
[0207] DMSO=dimethylsulfoxide [0208] EDC or
EDCI=3-ethyl-3'-(dimethylamino)propyl-carbodiimide hydrochloride
[0209] Et=ethyl [0210] EtOH=ethanol [0211] EtOAc=ethyl acetate
[0212] Et.sub.3N=triethylamine [0213] EtOAc=ethyl acetate [0214]
Et.sub.2O=diethyl ether [0215] FMOC=fluorenylmethoxycarbonyl [0216]
HCl=hydrogen chloride [0217] HOBt or HOBT=hydroxybenzotriazole
hydrate [0218] LiOH=lithium hydroxide [0219]
Na.sub.2SO.sub.4=sodium sulfate [0220] NaOH=sodium hydroxide [0221]
NMM=N-methylmorpholine [0222] Me=methyl [0223] MeOH=methanol [0224]
Ph=phenyl [0225] THF=tetrahydrofuran [0226] TFA=trifluoroacetic
acid [0227] mp=melting point [0228] tlc=thin layer chromatography
[0229] RT=room temperature [0230] h=hours [0231] min.=minute or
minutes [0232] mmol=millimole [0233] sat'd=saturated [0234]
CH.sub.2Cl.sub.2=methylene chloride [0235] HPLC=high pressure
liquid chromatography [0236] LRMS=low resolution mass spectrometry
In the examples, when a letter is used in a parenthetical or
superscript following the term HPLC, MS, or HPLC/MS, as in "HPLC/MS
(A)", "LC/MS (B)", MS Data.sup.a, or following the data, such as
3.28.sup.a, the letter denotes the conditions used for the HLPC/MS,
as follows: [0237] Method A: Column Primesphere C18-HC 4.6.times.30
mm, gradient time: 2 min., Hold time: 1 min., Flow rate: 4 mL/min,
Detector Wavelength: 220 nM, Solvent A=10% AcCN/90% H.sub.2O/5 mM
NH.sub.4OAc, Solvent B=90% AcCN/10% H.sub.2O/5 mM NH.sub.4OAc,
Start % B=0/Finish % B=100; [0238] Method B: Column Primesphere
C18-HC 4.6.times.30 mm, gradient time: 2 min., Hold time: 1 min.,
Flow rate: 4 mL/min, Detector Wavelength: 220 nM, Solvent A: 10%
AcCN/90% H.sub.2O/0.1% TFA, Solvent B: 90% AcCN/10% H.sub.2O/0.1%
TFA, Start % B=0/Finish % B=100; [0239] Method C: Column
Primesphere C18-HC 4.6.times.30 mm, gradient time: 3 min., Hold
time: 1 min., Flow rate: 4 mL/min, Detector Wavelength: 220 nM,
Solvent A: 10% AcCN/90% H.sub.2O/0.1% TFA, Solvent B: 90% AcCN/10%
H.sub.2O/0.1% TFA, Start % B=0/Finish % B=100, Detector Wavelength:
220 nM; [0240] Method D: Column: Premisphere 5.mu.-C8 21.times.100
mm, acetonitrile-5 mM NH.sub.4OAc/water: 7 min. gradient from 20%
AcCN to 90% AcCN at 220 nm. Flow rate: 20 mL/min.); [0241] Method
E: Column: YMC ODS-A C18 4.6.times.150 mm; Flow rate: 1 mL/min,
Solvent system: 0-100% B in 30 min. Solvent A: 10% CH.sub.3CN-90%
H.sub.2O-5 mM NH.sub.4OAc; Solvent B: 90% CH.sub.3CN-10% H.sub.2O-5
mM NH.sub.4OAc; UV: 220 nm; [0242] Method F: Column: Combiscreen C8
S-5 4.6.times.50 mm; Flow rate: 4 mL/min, Solvent system: 0-100% B
in 2 min. Solvent A: 10% CH.sub.3CN-90% H.sub.2O-5 mM NH.sub.4OAc;
Solvent B: 90% CH.sub.3CN-10% H.sub.2O-5 mM NH.sub.4OAc; UV: 220
nm; [0243] Method G: Column: Combiscreen C8 S-5 4.6.times.50 mm;
Flow rate: 4 mL/min, Solvent system: 0-100% B in 4 min. Solvent A:
10% CH.sub.3CN-90% H.sub.2O-0.1% TFA; Solvent B: 90% CH.sub.3CN-10%
H.sub.2O-0.1% TFA; UV: 220 nm; [0244] Method H: Column: YMC ODS-A
C18 4.6.times.150 mm; Flow rate: 1 mL/min, Solvent system: 30-100%
B in 30 min. Solvent A: 10% CH.sub.3CN-90% H.sub.2O-0.1% TFA;
Solvent B: 90% CH.sub.3CN-10% H.sub.2O-0.1% TFA; UV: 220 nm; [0245]
Method I: Assignation from another HPLC analysis (with 0.1% TFA);
[0246] Method J: Column: Premisphere-5u C8 4.6.times.30 mm; Flow
rate: 4 mL/min, Solvent system: 0-100% (90% CH.sub.3CN-10%
H.sub.2O-5 mM NH.sub.4OAc), 2 min. gradient; UV: 220 nm; [0247]
Method K: Column: YMC S5 C18 4.6.times.150 mm, Flow rate: 1 mL/min,
Solvent system: 0-100% (90% CH.sub.3CN-10% H.sub.2O-5 mM
NH.sub.4OAc), 30 min. gradient; UV: 220 nm; [0248] Method L:
Column: Xterra-C8 4.6.times.30 mm; Flow rate: 4 mL/min, Solvent
system: 0-100% B in 2 min. Solvent A: 10% CH.sub.3CN-90% H.sub.2O-5
mM NH.sub.4OAc; Solvent B: 90% CH.sub.3CN-10% H.sub.2O-5 mM
NH.sub.4OAc; UV: 220 nm; [0249] Method M: Column: YMC-Pack S5
Phenyl 4.6.times.50 mm; Flow rate: 3 mL/min, Solvent system: 0-100%
B in 2 min. Solvent A: 10% CH.sub.3CN-90% H.sub.2O-0.05% TFA;
Solvent B: 90% CH.sub.3CN-10% H.sub.2O-0.05% TFA; UV: 220 nm.
EXAMPLE 1
[0250] ##STR31## ##STR32##
[0251] To a solution of N-Boc-L-histidine ##STR33## (3.1 g, 12.7
mmol), EDC (3.6 g, 19.1 mmol), HOBT (2.6 g, 19.1 mmol), DMAP (0.16
g, 1.3 mmol) in CH.sub.2Cl.sub.2, and DMF (1:1, 50 mL) were added
Et.sub.3N (8.8 mL, 64.0 mmol) and D-4-methoxyphenylalanine methyl
ester hydrochloride ##STR34## (2.9 g, 12.0 mmol), sequentially. The
reaction mixture was stirred at RT overnight. The reaction mixture
was diluted with EtOAc (200 mL) and washed with water (200 mL),
NaOH (0.5 N, 200 mL), and water (200 mL). The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, and the solvent was
subsequently removed under reduced pressure. The resulting compound
1A was >90% pure as judged by HPLC and used without further
purification in Step B. ##STR35##
[0252] To a solution of Compound 1A (12.0 mmol) in CH.sub.3OH (13
mL) was added NaOH (2N, 13 mL) to make the final concentration of
NaOH .about.1 N. This solution was stirred at RT for 2 h before
being diluted with water (100 mL). The aqueous layer was extracted
with Et.sub.2O (100 mL.times.2), and the organic matter was
discarded. The aqueous layer was acidified with HCl (6 N) to pH
.about.2, and extracted with EtOAc (100 mL.times.2). The combined
organic layers were dried over anhydrous Na.sub.2SO.sub.4, and the
solvent was subsequently removed under reduced pressure. The
resulting Compound 1B was a white solid with a purity >90% as
judged by HPLC. This intermediate was used without further
purification for Step C. ##STR36##
[0253] To a solution of Compound 1C (0.5 g, 1.1 mmol), EDC (0.3 g
g, 1.6 mmol), HOBT (0.22 g, 1.6 mmol), and DMAP (0.13 g, 1.1 mmol)
in CH.sub.2Cl.sub.2 (25 mL) were added Et.sub.3N (0.8 mL, 5.5 mmol)
and 4-butyryl-4-phenyl-piperidine hydrochloride (0.35 g, 1.3 mmol)
sequentially. The reaction mixture was stirred at RT overnight. The
reaction mixture was diluted with EtOAc (100 mL) and washed with
HCl (0.5 N, 100 mL), water (100 mL), NaOH (0.5 N, 100 mL), and
water (100 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, and the solvent was subsequently removed under
reduced pressure. The resulting Compound 1C was >90% pure as
judged by HPLC and used directly without further purification in
Step D.
Step D: Deprotection of Compound 1C
[0254] To a solution of the Boc-protected Compound 1C (1.1 mmol) in
wet CH.sub.2Cl.sub.2 (20 mL plus 1 mL water) was added TFA (10 mL).
The solution was stirred at RT for 1 h before the solvents were
removed. The crude reaction mixture was purified by preparative
HPLC to obtain Example 1 at >95% purity as judged by HPLC. HPLC
(min)=2.5, MS (M+H).sup.+=546.4.
EXAMPLES 2-84
[0255] ##STR37##
[0256] Compounds of formula (Ih), above, wherein the groups
R.sub.11 and W have the values listed in Table 1, were prepared
following the same or similar procedure described above for Example
1, using a different amino acid in place of N-Boc-L-histidine in
Step A. TABLE-US-00001 TABLE 1 HPLC Ret. Purity time Mass Ex No.
R.sub.11 W (%) (min) (M + H) 2 ##STR38## ##STR39## 89 3.3 572.49 3
--CH.sub.3 ##STR40## 90 3.2 480.46 4 --CH.sub.2--OH ##STR41## 89
3.2 496.49 5 --CH.sub.2CH.sub.3 ##STR42## 85 3.2 494.49 6 ##STR43##
##STR44## 92 3.0 522.33 7 ##STR45## ##STR46## 90 3.2 510.45 8
##STR47## ##STR48## 91 2.5 546.36 9 ##STR49## ##STR50## 81 3.3
508.46 10 ##STR51## ##STR52## 76 3.5 522.51 11 ##STR53## ##STR54##
95 2.7 636.21 12 ##STR55## ##STR56## 92 3.4 522.5 13 ##STR57##
##STR58## 80 3.3 542.41 14 ##STR59## ##STR60## 77 3.0 522.24 15
##STR61## ##STR62## 82 3.4 542.48 16 ##STR63## ##STR64## 89 3.0
586.19 17 ##STR65## ##STR66## 75 3.0 522.17 18 ##STR67## ##STR68##
90 2.8 636.26 19 ##STR69## ##STR70## 100 3.5 570.31 20 ##STR71##
##STR72## 92 2.5 560.39 21 ##STR73## ##STR74## 87 3.2 606.23 22
##STR75## ##STR76## 96 3.0 574.22 23 ##STR77## ##STR78## 95 2.5
557.3 24 ##STR79## ##STR80## 96 3.7 606.32 25 ##STR81## ##STR82##
94 2.5 560.15 26 ##STR83## ##STR84## 87 2.9 522.26 27 ##STR85##
##STR86## 93 3.7 632.32 28 ##STR87## ##STR88## 76 2.8 557.13 29
##STR89## ##STR90## 81 3.2 612.2 30 ##STR91## ##STR92## 88 3.1
536.29 31 --CH.sub.3 ##STR93## 96 2.7 480.04 32 ##STR94## ##STR95##
93 2.6 496.23 33 ##STR96## ##STR97## 85 2.9 522.39 34 ##STR98##
##STR99## 95 3.0 556.38 35 --CH.sub.3 ##STR100## 91 2.7 494.22 36
##STR101## ##STR102## 89 2.9 522.17 37 ##STR103## ##STR104## 83 2.7
510.28 38 ##STR105## ##STR106## 87 3.1 600.19 39 ##STR107##
##STR108## 92 3.1 600.14 40 ##STR109## ##STR110## 95 2.7 510.21 41
##STR111## ##STR112## 91 2.9 601.33 42 ##STR113## ##STR114## 89 2.8
522.3 43 ##STR115## ##STR116## 96 2.9 557.48 44 ##STR117##
##STR118## 89 3.1 590.09 45 ##STR119## ##STR120## 96 2.5 523.22 46
##STR121## ##STR122## 76 3.2 624.07 47 ##STR123## ##STR124## 82 2.9
570.14 48 ##STR125## ##STR126## 79 3.7 630.33 49 ##STR127##
##STR128## 86 3.1 633.88 50 ##STR129## ##STR130## 90 3.0 582 51
##STR131## ##STR132## 96 3.1 590.23 52 ##STR133## ##STR134## 87 3.2
590.06 53 ##STR135## ##STR136## 82 3.1 587.87 54 ##STR137##
##STR138## 89 3.0 574.28 55 ##STR139## ##STR140## 91 2.9 557.47 56
--CH.sub.3 ##STR141## 97 2.7 494.27 57 ##STR142## ##STR143## 90 3.7
662.07 58 ##STR144## ##STR145## 83 3.2 682.1 59 ##STR146##
##STR147## 95 3.7 662.24 60 ##STR148## ##STR149## 87 3.3 712.44 61
##STR150## ##STR151## 79 3.1 660.2 62 ##STR152## ##STR153## 92 3.9
730 63 ##STR154## ##STR155## 92 2.56 571.37 64 ##STR156##
##STR157## 92 2.51 571.32 65 ##STR158## ##STR159## 91 2.52 585.46
66 ##STR160## ##STR161## 82 3.07 605 67 ##STR162## ##STR163## 92
2.5 537.44 68 ##STR164## ##STR165## 90 4.3 595 69 ##STR166##
##STR167## 91 2.48 509.33 70 ##STR168## ##STR169## 94 2.51 571.35
71 ##STR170## ##STR171## 94 2.9 564.44 72 ##STR172## ##STR173## 93
2.71 547.28 73 ##STR174## ##STR175## 93 2.71 636.35 74 ##STR176##
##STR177## 93 2.47 495.29 75 ##STR178## ##STR179## 88 2.79 563.23
76 H ##STR180## 90 3.1 466.46 77 H ##STR181## 89 2.54 535.33 78
##STR182## ##STR183## 82 3.07 605 79 H ##STR184## 91 2.76 534.33 80
H ##STR185## 93 2.71 494.31 81 H ##STR186## 90 2.52 549.32 82 H
##STR187## 80 2.66 480.27 83 H ##STR188## 89 2.52 549.31 84 H
##STR189## 92 2.66 535.34
EXAMPLES 85-88
[0257] ##STR190##
[0258] Compounds of formula (Ii), above, wherein the group E has
the values shown in Table 2, were prepared following the same
procedures as described above for Example 1. TABLE-US-00002 TABLE 2
HPLC Ex. Purity RT Mass No. E (%) (min) (M + H) 85 ##STR191## 95
2.43 454 86 ##STR192## 98 1.96 532 87 ##STR193## 95 2.11 547 88
##STR194## 90 2.03 546
EXAMPLE 89
[0259] ##STR195##
[0260] Example 89 was prepared following the same or similar
procedure described herein for Example 1. Purity 86.0%, HPLC ret.
time=3.1, MS (M+H).sup.+=619.38.
EXAMPLE 90
[0261] ##STR196##
[0262] Example 90 was prepared following the same or similar
procedure described herein for Example 1. Purity 93%, HPLC ret.
time=3.8 min, MS (M+H).sup.+=635.42.
EXAMPLE 91
N-[1-(4-Chloro-benzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperid-
in-1-yl)-2-oxo-ethyl]-3-(pyrimidin-2-ylamino)-propionamide
[0263] ##STR197##
[0264] To a solution of Example 171 (35 mg, 0.07 mmol) and
2-bromopyrimidine (14 mg, 0.09 mmol) in EtOH (1.0 mL) at RT was
added potassium carbonate (14 mg, 0.1 mmol). The mixture was heated
to 60.degree. C. and stirred overnight at 60.degree. C. The mixture
was cooled to RT a sat'd solution of ammonium chloride (15 mL) was
added. The separated aqueous layer was extracted with DCM
(3.times.25 mL), and the combined organic layers were dried
(MgSO.sub.4 anh.), filtered, and evaporated to afford an oil
(>80% purity by LCMS). The residue was purified using
preparative HPLC and after evaporation, the residue was lyophilized
to afford 32 mg (80% yield) of Example 91. This semi-solid was
converted as its hydrochloride salt. HPLC/MS (A), ret. time=1.68
min, purity 98.4%, MS pos. m/z 579 (M+H).sup.+; HPLC/MS (E), ret.
time=24.13 min, purity 97.4% .sup.1H NMR (400 MHz, MeOH-d.sub.4)
.delta. ppm (two rotamers; 1:1.5 ratio) 8.45 (1H, s, minor
rotamer), 8.44 (1H, s, major rotamer), 8.28 (2H, t, J=4.6 Hz), 7.99
(1H, s, minor rotamer), 7.95 (1H, s, major rotamer), 7.31 (2H, d,
J=8.3 Hz, major rotamer), 7.27 (2H, d, J=8.4 Hz, minor rotamer),
7.24 (2H, d, J=8.6 Hz, major rotamer), 7.20 (2H, d, J=8.4 Hz, minor
rotamer), 6.63 (1H, t, J=4.8 Hz), 5.09 (1H, m), 4.30 (2H, s, major
rotamer), 4.26 (2H, s, minor rotamer), 3.64-3.45 (6H, m), 2.95 (2H,
m), 2.52 (2H, m), 1.81-0.88 (15H, m).
EXAMPLES 92-113
[0265] ##STR198##
[0266] Compounds of formula (Ij), above, wherein the group W has
the values listed in Table 3, were prepared following the same or
similar procedure described above for Example 1, using a different
amino acid in place of N-Boc-L-histidine in Step A. TABLE-US-00003
TABLE 3 HPLC Purity RT Mass Ex. No. W (%) (min) (M + H) 92
##STR199## 87 3.2 506.5 93 ##STR200## 91 3.2 522.45 94 ##STR201##
81 3.1 524.23 95 ##STR202## 82 2.8 520.25 96 ##STR203## 94 3.0
612.28 97 ##STR204## 96 2.7 520.43 98 ##STR205## 92 2.5 535 99
##STR206## 85 2.72 574 100 ##STR207## 93 2.73 520.41 101 ##STR208##
93 2.56 589.52 102 ##STR209## 96 2.54 583.38 103 ##STR210## 96 2.95
554.28 104 ##STR211## 85 4.31 521 105 ##STR212## 79 2.73 522.3 106
##STR213## 91 2.52 521.33 107 ##STR214## 92 2.5 521.33 108
##STR215## 80 2.82 531.28 109 ##STR216## 94 2.72 520.36 110
##STR217## 86 2.8 548.34 111 ##STR218## 86 2.8 563.27 112
##STR219## 80 2.74 520.33 113 ##STR220## 92 2.49 549.33
EXAMPLES 114-115
[0267] ##STR221##
[0268] Compounds of formula (Ik), above, wherein the groups
R.sub.11 and R.sub.12 have the values listed in Table 4, were
prepared following the same or similar procedure described above
for Example 1, using a different amino acid in place of
N-Boc-L-histidine in Step A. TABLE-US-00004 TABLE 4 HPLC Mass Ex.
No. R.sub.11 R.sub.12 Purity (%) RT (min) (M + H) 114 --CH.sub.3
--CH.sub.3 92 3.2 494.49 115 ##STR222## 95 2.7 492.25
EXAMPLES 116-117
[0269] ##STR223##
[0270] Compounds of formula (Il), above, wherein the integer y and
group W have the values listed in Table 5, were prepared following
the same or similar procedure described above for Example 1, using
a different amino acid in place of N-Boc-L-histidine in Step A.
TABLE-US-00005 TABLE 5 HPLC Purity RT Mass Ex. No. y W (%) (min) (M
+ H) 116 2 ##STR224## 96 2.79 548.34 117 4 ##STR225## 95 2.74
536.36
EXAMPLES 118-157
[0271] ##STR226##
[0272] Compounds of formula (Im), above, wherein R.sub.2 has the
values listed in Table 6, were prepared following the same
procedure described for Example 1, except a different methyl ester
hydrochloride was used in place of methoxyphenylalanine methyl
ester hydrochloride in Step A. TABLE-US-00006 TABLE 6 HPLC Mass Ex.
No. R.sub.2 Purity (%) RT (min) (M + H) 118 ##STR227## 76 3.0
482.36 119 ##STR228## 74 2.9 502.35 120 ##STR229## 75 3.0 482.36
121 ##STR230## 87 3.0 522.32 122 ##STR231## 86 3.0 561.3 123
##STR232## 93 3.3 566.33 124 ##STR233## 78 3.2 530.37 125
##STR234## 89 3.2 550.29 126 ##STR235## 85 3.3 566.34 127
##STR236## 84 3.1 534.35 128 ##STR237## 78 3.3 642.24 129
##STR238## 88 3.3 572.32 130 ##STR239## 87 3.3 522.43 131
##STR240## 90 3.4 584.26 132 ##STR241## 89 3.5 592.38 133
##STR242## 90 3.3 592.38 134 ##STR243## 84 3.2 620.38 135
##STR244## 92 3.3 594.25 136 ##STR245## 88 3.2 542.36 137
##STR246## 93 3.0 494.36 138 ##STR247## 92 3.2 550.29 139
##STR248## 84 3.1 552.31 140 ##STR249## 79 3.0 534.34 141
##STR250## 78 3.1 534.36 142 ##STR251## 76 3.1 552.33 143
##STR252## 89 3.0 690.16 144 ##STR253## 93 3.1 784.11 145
##STR254## 93 3.1 550.32 146 ##STR255## 84 3.2 572.38 147
##STR256## 88 2.3 517.4 148 ##STR257## 79 2.7 523.35 149 ##STR258##
90 2.3 517.4 150 ##STR259## 84 2.8 541.38 151 H 84 2.5 426.35 152
--CH.sub.3 85 2.5 440.35 153 ##STR260## 85 2.8 541.36 154
##STR261## 73 3.2 530.41 155 ##STR262## 83 3.2 542.4 156 ##STR263##
89 2.8 576.4 157 ##STR264## 77 3.5 536.46
EXAMPLES 158-167
[0273] ##STR265##
[0274] Compounds of formula (In), above, wherein A has the values
listed in Table 7 {wherein in compounds of formula (I),
A=X(R.sub.1)--CH(R.sub.2)--CH(R.sub.3).sub.r--(CH.sub.2).sub.s--},
were prepared following the same procedure described for Example 1,
except a different methyl ester hydrochloride was used in place of
methoxyphenylalanine methyl ester hydrochloride in Step A.
TABLE-US-00007 TABLE 7 Ex. Purity HPLC RT Mass No. A (%) (min) (M +
H) 158 --CH.sub.2CH.sub.2-- 82 2.6 440.32 159 ##STR266## 73 2.9
528.37 160 ##STR267## 88 2.8 488.33 161 ##STR268## 71 2.8 480.34
162 ##STR269## 84 2.7 480.36 163 ##STR270## 89 3.1 544.39 164
##STR271## 85 3.0 542.38 165 ##STR272## 74 3.1 542.39 166
##STR273## 90 3.1 542.4 167 ##STR274## 83 3.0 528.39
EXAMPLES 168-170
[0275] ##STR275##
[0276] Compounds of formula (Io), above, wherein the groups R.sub.1
and R.sub.30 have the values listed in Table 8, were prepared
following the same procedure as for Example 1, except a different
methyl ester hydrochloride was used in Step A. TABLE-US-00008 TABLE
8 Purity HPLC Mass Ex. No. R.sub.1 R.sub.30 (%) RT (min) (M + H)
168 H Cl 90 3.08 551 169 H H 86 2.88 515 170 CH.sub.3 Cl 85 3.26
565
EXAMPLE 171
[0277] ##STR276## ##STR277##
[0278] Compound 171A was prepared by coupling of commercially
available N-BOC D-4-chlorophenylalanine and
4-Cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidine, followed by
deprotection of the BOC group, as described in WO 00/74679,
incorporated herein by reference. ##STR278##
[0279] To a solution of .alpha.-amino amide from step A (1.1 g,
2.56 mmol) and N-Boc-.beta.-alanine (531 mg, 2.81 mmol) in DCM (12
mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (736
mg, 3.8 mmol) and HOBt (518 mg, 3.8 mmol) at RT. The mixture was
stirred at RT overnight and a sat'd solution of ammonium chloride
(15 mL) was added. The separated aqueous layer was extracted with
DCM (3.times.25 mL), and the combined organic layers were dried
(MgSO.sub.4 anh.), filtered, and evaporated to afford compound 171A
which was used in the next step without purification.
Step C: Example 171
[0280] To a solution of Compound 171B (1.0 g, 1.7 mmol) in DCM (10
mL) was added a 20% (v/v) solution of TFA in DCM (1.6 mL) at RT.
The mixture was stirred at RT for 8 h and evaporated under reduced
pressure. The residue was purified using preparative HPLC and after
evaporation, the residue was lyophilized to afford 0.9 g (47%
yield) of Example 171 as the TFA salt. HPLC/MS (A), ret. time=1.50
min, purity 86.9%, MS pos. m/z 501 (M+H).sup.+; HPLC/MS (E), ret.
time=10.81 min, purity 100%; ir (.nu..sub.max, KBr) cm.sup.-1
3600-2880, 1695, 1620; .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta.
ppm (two rotamers; 1:2 ratio) 8.43 (1H, s, minor rotamer), 8.42
(1H, s, major rotamer), 7.96 (1H, s, minor rotamer), 7.92 (1H, s,
major rotamer), 7.26 (2H, d, J=8.3 Hz, major rotamer), 7.23 (2H, d,
J=8.4 Hz, minor rotamer), 7.18 (2H, d, J=8.3 Hz, major rotamer),
7.15 (2H, d, J=8.6 Hz, minor rotamer), 4.98 (1H, t, J=7.8 Hz), 4.21
(2H, s, major rotamer), 4.18 (2H, s, minor rotamer), 3.60 (1H, m),
3.31 (3H, m), 3.08 (2H, m), 2.87 (2H, m), 2.54 (2H, t, J=6.5 Hz),
1.95-0.82 (15H, m). Anal. Calc'd for
C.sub.26H.sub.37ClN.sub.6O.sub.2.3CF.sub.3COOH.2H.sub.2O: C, 43.72;
H, 5.04; N, 9.56. Found: C, 43.90; H, 4.31; N, 9.16. Anal. Calc'd
for C.sub.26H.sub.37ClN.sub.6O.sub.2.3HCl.H.sub.2O: C, 49.69; H,
6.74; N, 13.37. Found: C, 49.96; H, 6.75; N, 12.88.
EXAMPLES 172 AND 173
3-Benzylamino-N-[1-(4-chloro-benzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-yl-
methyl-piperidin-1-yl)-2-oxo-ethyl]-propionamide (Ex. 172), and
3-diBenzylamino-N-[1-(4-chloro-benzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-
-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-propionamide (Ex. 173)
[0281] ##STR279##
[0282] At RT, benzaldehyde (13 .mu.L, 0.13 mmol) was added to a
solution of Example 171 (48.5 mg, 0.1 mmol) in DCE (1 mL). Sodium
triacetoxyborohydride (29 mg, 0.14 mmol) was added, the mixture was
stirred at RT for 24 hours, and a sat'd solution of ammonium
chloride (15 mL) was added. The separated aqueous layer was
extracted with DCM (3.times.25 mL) and the combined organic layers
were dried (MgSO.sub.4 anh.), filtered, and evaporated to afford 36
mg of an oil which consisted in a (1:1) mixture of Examples 172 and
173, as determined by HPLC/MS. The purification was performed using
preparative (Column: Premisphere 5.mu.-C8 21.times.100 mm) HPLC
(acetonitrile-5 mM NH.sub.4OAc/water: 7 min. gradient from 50% AcCN
to 90% AcCN at 220 nm. Flow rate: 20 mL/min.), and after
evaporation, the residue was lyophilized to afford 24 mg (42%
yield) of Ex. 172 along with 6 mg (9% yield) of Ex. 173.
[0283] Ex. 172: HPLC/MS (Column: Premisphere-C18 4.6.times.30 mm;
Flow rate: 4 mL/min, Solvent system: 0-100% B in 2 min. Solvent A:
10% CH.sub.3CN-90% H.sub.2O-5 mM NH.sub.4OAc; Solvent B: 90%
CH.sub.3CN-10% H.sub.2O-5 mM NH.sub.4OAc; UV: 220 nm; Micromass ZMD
2000, ESI): retention time 1.76 min, purity 100%, MS pos. m/z 591
(M+H).sup.+; HPLC/MS (Column: YMC ODS-A C 18 4.6.times.150 mm; Flow
rate: 1 mL/min, Solvent system: 30-100% B in 30 min., UV: 220 nm;):
retention time 12.13 min, purity 100% .sup.1H nmr (400 MHz,
MeOH-d.sub.4) .delta. ppm (two rotamers; 1:1.5 ratio) 8.47 (1H, s,
minor rotamer), 8.45 (1H, s, major rotamer), 8.02 (1H, s, minor
rotamer), 7.97 (1H, s, major rotamer), 7.41 (5H, m), 7.34 (2H, d,
J=8.4 Hz, major rotamer), 7.30 (2H, d, J=8.3 Hz, minor rotamer),
7.27 (2H, d, J=8.3 Hz, major rotamer), 7.23 (2H, d, J=8.6 Hz, minor
rotamer), 5.09 (1H, br. t, J=6.8 Hz), 4.31 (2H, s, major rotamer),
4.29 (2H, s, minor rotamer), 4.00 (2H, s, major rotamer), 3.96 (2H,
s, minor rotamer), 3.75-3.36 (4H, m), 3.00 (4H, m), 2.57 (2H, t,
J=6.8 Hz), 1.80-0.89 (15H, m).
[0284] Ex. 173: HPLC/MS (Column: Premisphere-C18 4.6.times.30 mm;
Flow rate: 4 mL/min, Solvent system: 0-100% B in 2 min. Solvent A:
10% CH.sub.3CN-90% H.sub.2O-5 mM NH.sub.4OAc; Solvent B: 90%
CH.sub.3CN-10% H.sub.2O-5 mM NH.sub.4OAc; UV: 220 nm; Micromass ZMD
2000, ESI): retention time 2.45 min, purity 96.7%, MS pos. m/z 681
(M+H).sup.+; .sup.1H nmr (400 MHz, MeOH-d.sub.4) .delta. ppm (two
rotamers present; 1:1.4 ratio) 8.46 (1H, s, minor rotamer), 8.42
(1H, s, major rotamer), 8.01 (1H, s, minor rotamer), 7.93 (1H, s,
major rotamer), 7.43-7.10 (14H, m), 5.10 (1H, m), 4.30 (2H, s,
major rotamer), 4.28 (2H, s, minor rotamer), 3.77 (1H, m), 3.70
(2H, s, minor rotamer), 3.66 (2H, s, major rotamer), 3.66-3.36 (7H,
m), 3.01-2.35 (5H, m), 1.90-0.79 (15H, m).
EXAMPLES 174-186
[0285] ##STR280##
[0286] Compounds of formula (Ip), above, wherein the group J has
the values listed in Table 9, were prepared following the same
procedure described for Examples 175-76, using with different
aldehydes in place of benzaldehyde. TABLE-US-00009 TABLE 9 HPLC
Retention MS Data.sup.b Ex. No. J Time (min).sup.b (M + H).sup.+
174 ##STR281## 1.84 650 175 ##STR282## 2.08 668 176 ##STR283## 1.80
580 177 ##STR284## 2.07 668 178 ##STR285## 2.05 668 179 ##STR286##
1.75 668 180 ##STR287## 1.96 660 181 ##STR288## 1.91 659 182
##STR289## 1.97 730 183 ##STR290## 1.84 626 184 ##STR291## 2.00 618
185 ##STR292## 1.92 629 186 ##STR293## 2.11 640
EXAMPLE 187
3-Amino-N-[1-(4-chloro-benzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-
-piperidin-1-yl)-2-oxo-ethyl]-2,2-dimethyl-propionamide
[0287] ##STR294## ##STR295##
[0288] Compound 187A was prepared following the procedure described
in Dhokte et al., Tetrahedron Lett., Vol. 39 (1998), at pp.
8771-8774.
Step B:
[0289] Example 187 was prepared following the procedure described
for the preparation of Example 171, using Compound (187A) in place
of Boc-.beta.-alanine in Step A. HPLC/MS (F), ret. time 1.64 min,
purity 95.7%, MS pos. m/z 529 (M+H).sup.+; HPLC/MS (H), ret.
time=12.12 min, purity 95.1%; .sup.1H NMR (400 MHz, MeOH-d.sub.4)
.delta. ppm (two rotamers; 1:1.4 ratio) 8.56 (1H, s, minor
rotamer), 8.53 (1H, s, major rotamer), 8.08 (1H, s, minor rotamer),
8.02 (1H, s, major rotamer), 7.36 (2H, d, J=8.4 Hz, major rotamer),
7.34 (2H, d, J=8.9 Hz, minor rotamer), 7.28 (2H, d, J=8.3 Hz, major
rotamer), 7.25 (2H, d, J=8.4 Hz, minor rotamer), 5.07 (1H, m), 4.32
(2H, s), 3.68-3.34 (4H, m), 3.02 (4H, m), 1.98-0.99 (15H, m), 1.34,
1.24 (6H, 2s, minor rotamer), 1.33, 1.28 (6H, 2s, major
rotamer).
EXAMPLE 188
[0290] ##STR296##
[0291] Example 188 was prepared using the same procedure as
described for the preparation of Example 171, starting with
.beta.-amino acid ##STR297## HPLC/MS (E), ret. time=2.04 min,
purity 98.7%, MS pos. m/z 647 (M+H).sup.+; HPLC (G), ret. time=2.75
min, purity 94.8%; MS (Finigan TSQ 7000, ESI) m/z 647 (M+H).sup.+;
HRMS calculated for C.sub.35H.sub.43ClN.sub.6O.sub.2S: 647.2925,
found: 647.2935 .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm
(two rotamers; ratio 1.6:1) 8.71 (1H, s, minor rotamer), 8.64 (1H,
s, major rotamer), 8.16 (1H, s, minor rotamer), 8.07 (1H, s, major
rotamer), 7.93 (1H, d, J=8 Hz), 7.82 (1H, t, J=8 Hz), 7.48-7.38
(3H, m), 7.26 (2H, d, J=8 Hz), 7.19 (2H, d, J=8 Hz), 7.18 (1H, d,
J=8 Hz), 5.03-4.95 (1H, m), 4.29 (2H, s), 4.18 (1H, m), 4.12 (1H,
m), 3.92-3.75 (1H, m), 3.69-3.59 (4H, m), 3.51-3.35 (1H, m),
3.20-3.06 (2H, m), 2.98-2.80 (2H, m), 2.63-2.48 (2H, m), 1.85-0.85
(14H, m).
EXAMPLES 189-217
[0292] ##STR298##
[0293] Compounds having the formula (Iq), and Core A and B as noted
in Table 10, wherein R.sub.11 has the values listed in Table 10,
were prepared using the same procedure described above for the
preparation of Example 171 starting with the appropriately
substituted .beta.-amino acid ##STR299## The compounds were
prepared via high-throughput synthesis. The crude product was
purified either by automated SPE-SCX using a Zymark BenchMate
Workstation or Shimadzu automated preparative HPLC system and
concentrated in vacuo. The SPE workstation was carried out as
follows: [0294] 1) Conditioned a SPE column (SCX cation exchange,
1.5 g of sorbent, 0.79 mequiv/g) with 10 mL of methanol (0.25
mL/sec) and 10 mL of a 1:1 mixture methanol/H.sub.2O; [0295] 2)
Loaded reaction contents onto the column (0.05 mL/sec); [0296] 3)
Washed column with 2.times.10 mL of methanol (0.20 mL/sec); [0297]
4) Eluted column with 2.times.8 mL of 2M ammonia in methanol and
collected the effluent into a tared receiving tube (0.10 mL/sec);
and [0298] 5) Concentrated the products using a Savant Speedvac
Plus SC210A.
[0299] Compounds purified by preparative HPLC were diluted in MeOH
(2 mL) and purified using a Shimadzu LC-10A automated preparative
HPLC system and the following conditions: initial gradient (80% A,
20% B) ramp to final gradient (0% A, 100% B) over 8 min., hold for
4 min. (0% A, 100% B), Solvent A: 10% AcCN/90% H.sub.2O/5 mM
NH.sub.4OAc, Solvent B: 90% AcCN/10% H.sub.2O/5 mM NH.sub.4OAc,
Column Primesphere C 18-HC 21.2.times.100 mm, Detector Wavelength:
220 nM. TABLE-US-00010 TABLE 10 HPLC Retention MS Data Ex. Core
R.sub.11 Time (min) (M + H).sup.+ 189 B ##STR300## 3.28.sup.c 641
190 A ##STR301## 3.21.sup.c 641 191 B ##STR302## 3.28.sup.c 641 192
A ##STR303## 3.22.sup.c 641 193 B ##STR304## 3.28.sup.c 647 194 B
##STR305## 1.70.sup.b 605 195 A ##STR306## 1.67.sup.b 605 196 B
##STR307## 1.37.sup.b 592 197 A ##STR308## 1.57.sup.b 577 198 A
##STR309## 1.60.sup.b 597 199 B ##STR310## 1.38.sup.b 592 200 B
##STR311## 1.59.sup.b 577 201 B ##STR312## 1.60.sup.b 597 202 B
##STR313## 1.62.sup.b 597 203 B ##STR314## 1.97.sup.b 667 204 A
##STR315## 1.77.sup.b 667 205 B ##STR316## 1.14.sup.b 581 206 A
##STR317## 0.44.sup.b 592 207 A ##STR318## 0.39.sup.b 592 208 B
##STR319## 0.30.sup.b 592 209 A ##STR320## 1.27.sup.b 581 210 A
##STR321## 1.51.sup.b 597 211 A ##STR322## 0.94.sup.b 592 212 A
##STR323## 1.56.sup.b 591 213 A (CH.sub.3).sub.2CHCH.sub.2--
1.79.sup.a 557 214 A (CH.sub.3).sub.2CH-- 1.71.sup.a 543 215 A
(S)--(C.sub.2H.sub.5)(CH.sub.3)C*H-- 1.76.sup.a 557 216 A
##STR324## 1.84.sup.a 630 217 A CH.sub.3-- 1.62.sup.a 515
EXAMPLES 218-237
[0300] ##STR325##
[0301] Compounds having the formula (Ir), wherein W has the values
listed in Table 11, were prepared using the same or similar
procedure described above for the preparation of Examples 187-217.
TABLE-US-00011 TABLE 11 HPLC Ret. MS Data Ex. W Time (min) (M +
H).sup.+ 218 ##STR326## 1.72.sup.a 543 219 ##STR327## 1.72.sup.a
541 220 ##STR328## 1.65.sup.a 541 221 ##STR329## 1.91.sup.a 555 222
##STR330## 1.65.sup.a 513 223 ##STR331## 1.94.sup.a 637 224
##STR332## 1.82.sup.a 6303 225 ##STR333## 1.82.sup.a 633 226
##STR334## 1.99.sup.a 671 227 ##STR335## 2.07.sup.a 637 228
##STR336## 1.94.sup.a 603 229 ##STR337## 1.91.sup.a 633 230
##STR338## 2.09.sup.a 671 231 ##STR339## 1.74.sup.a 555 232
##STR340## 1.67.sup.a 555 233 ##STR341## 1.80.sup.a 555 234
CH.sub.3NHCH.sub.2-- 1.83.sup.a 501 235 ##STR342## 1.89.sup.a 513
236 ##STR343## 1.82.sup.a 513 237 (CH.sub.3).sub.2NCH.sub.2--
1.84.sup.a 515
EXAMPLE 238
[0302] ##STR344##
[0303] Example 238 was prepared following the same procedure
described above for Examples 217-237. HPLC (A), ret. time=1.77,
(M+S).sup.+=541.
EXAMPLE 239
N-[1-(4-Chloro-benzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperid-
in-1-yl)-2-oxo-ethyl]-3-methylamino-propionamide
[0304] ##STR345##
[0305] To a solution of Compound 171A (80 mg, 0.19 mmol) and
carbamate ##STR346## (45 mg, 0.22 mmol) in DCM was added EDCI (57
mg, 0.3 mmol) and HOBt (40 mg, 0.3 mmol). The mixture was stirred
at RT overnight and a sat'd solution of ammonium chloride (15 mL)
was added. The separated aqueous layer was extracted with DCM
(3.times.25 mL), and the combined organic layers were dried
(MgSO.sub.4 anh.), filtered and evaporated to afford a
tert-butylcarbamate intermediate. The tert-butylcarbamate
intermediate was dissolved in DCM (10 mL), and a 20% (v/v) solution
of TFA in DCM (1.6 mL) was added at RT. The mixture was stirred at
RT for 8 hours and evaporated under reduced pressure. The residue
was purified using HPLC and after evaporation, the residue was
lyophilized to afford Example 239 as the TFA salt. HPLC/MS (J),
ret. time=1.66 min, purity 100% Micromass ZMD 2000, ESI): MS pos.
m/z 515 (M+H).sup.+; HPLC (H), ret. time=18.78, 1915 min, purity
93.1%). .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm (two
rotamers; 1:1.7 ratio) 8.55 (1H, s, minor rotamer), 8.54 (1H, s,
major rotamer), 8.08 (1H, s, minor rotamer), 8.03 (1H, s, major
rotamer), 7.35 (2H, d, J=8.3 Hz, major rotamer), 7.29 (2H, d, J=8.4
Hz, minor rotamer), 7.28 (2H, d, J=8.3 Hz, major rotamer), 7.26
(2H, d, J=8.6 Hz, minor rotamer), 5.08 (1H, t, J=7.8 Hz), 4.32 (2H,
s, major rotamer), 4.29 (2H, s, minor rotamer), 3.60 (1H, m), 3.31
(3H, m), 3.08 (2H, m), 2.87 (2H, m), 2.54 (5H, m), 1.95-0.82 (15H,
m).
EXAMPLE 240
N-[1-(4-Chloro-benzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperid-
in-1-yl)-2-oxo-ethyl]-3-dimethylamino-propionamide
[0306] ##STR347##
[0307] To a vigorously stirred solution of Example 171 (45 mg, 0.09
mmol) and formaldehyde (37% w/w in water, 45 .mu.L, 0.5 mmol) in
DCE (1.0 mL) was added sodium triacetoxyborohydride (110 mg, 0.5
mmol) at RT. The mixture was stirred overnight at RT and a sat'd
solution of ammonium acetate (5 mL) was added. The separated
aqueous layer was extracted with methylene chloride (3.times.15
mL), and the combined organic layers were dried (Na.sub.2SO.sub.4),
filtered and evaporated under reduced pressure. The residue was
purified using preparative HPLC and after evaporation, the residue
was lyophilized to afford Example 240 as the TFA salt. HPLC/MS (A),
ret. time=1.74 min, purity 98.2% Micromass ZMD 2000, ESI): MS pos.
m/z 529 (M+H).sup.+; HPLC (K), ret. time=19.58 min, purity 84.3%.
.sup.1H NMR (400 MHz, MeOH-d.sub.4), .delta. ppm (two rotamers;
1:1.7 ratio) 8.56 (1H, s, minor rotamer), 8.53 (1H, s, major
rotamer), 8.08 (1H, s, minor rotamer), 8.03 (1H, s, major rotamer),
7.35 (2H, d, J=8.3 Hz, major rotamer), 7.29 (2H, d, J=8.4 Hz, minor
rotamer), 7.28 (2H, d, J=8.3 Hz, major rotamer), 7.26 (2H, d, J=8.6
Hz, minor rotamer), 5.00 (1H, m), 4.31 (2H, m), 3.70-2.85 (11H, m),
2.92 (6H, br. s), 2.74 (2H, m), 1.91-0.75 (15H, m).
EXAMPLE 241
3-Acetylamino-N-[1-(4-chloro-benzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-yl-
methyl-piperidin-1-yl)-2-oxo-ethyl]-propionamide
[0308] ##STR348##
[0309] Acetyl chloride (25 .mu.L, 3.3 mmol) was added to a solution
of Example 171 (150 mg, 3.0 mmol) and Et.sub.3N (50 .mu.L, 3.6
mmol) in DCM (7 mL) at 0.degree. C. The mixture was stirred at RT
overnight and quenched with sat'd ammonium chloride (10 mL). The
separated aqueous layer was extracted with methylene chloride
(3.times.15 mL), and the combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and evaporated under reduced pressure.
The residue was purified using preparative HPLC, and after
evaporation, the residue was lyophilized to afford Example 241 as
the TFA salt. HPLC/MS (A?), ret. time=1.60 min, purity 91.6%.
Micromass ZMD 2000, ESI): MS pos. m/z 543 (M+H).sup.+; HPLC (K),
ret. time=20.98 min, purity 92.6%. .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. ppm (two rotamers; 1:1.6 ratio) 8.56 (1H, s),
8.13 (1H, s), 7.35 (2H, d, J=8.1 Hz, major rotamer), 7.30 (2H, d,
J=8.1 Hz, minor rotamer), 7.28 (2H, d, J=8.1 Hz, major rotamer),
7.24 (2H, d, J=8.6 Hz, minor rotamer), 5.08 (1H, br. t, J=3.3 Hz),
4.34 (2H, s, major rotamer), 4.29 (2H, s, minor rotamer), 3.70-2.85
(11H, m), 2.74 (2H, m), 1.96 (3H, s, major rotamer), 1.94 (3H, s,
minor rotamer), 1.91-0.75 (15H, m).
EXAMPLES 242-251
[0310] ##STR349##
[0311] Compounds having the formula (Is), wherein R.sub.22 has the
values listed in Table 12, were prepared using EDCI-HOBt coupling
method described above for compound 171B, using an appropriate
amino acid in place of Boc-.beta.-alanine. TABLE-US-00012 TABLE 12
HPLC Retention MS Data Ex. R.sub.22 Time (min) (M + H).sup.+ 242
##STR350## 1.57.sup.a 594 243 ##STR351## 1.64.sup.a 604 244
CF.sub.3-- 1.66.sup.a 596 245 CH.sub.3CH.sub.2-- 1.50.sup.a 556 246
##STR352## 1.50 639 247 (Me).sub.2NCH.sub.2CH.sub.2-- 1.42 599 248
CH.sub.3OCH.sub.2-- 1.48 572 249 ##STR353## 1.64 607 250 ##STR354##
1.71 711 251 ##STR355## 1.72 711
EXAMPLE 252
2-Amino-N-[1-(4-chloro-benzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-
-piperidin-1-yl)-2-oxo-ethyl]-acetamide
[0312] ##STR356## ##STR357##
[0313] To a solution of compound 171A (83 mg, 0.19 mmol) and
N-Boc-glycine (86 mg, 0.49 mmol) in DMF (2 mL) was added EDCI (93
mg, 0.49 mmol), HOBt (66 mg, 0.49 mmol) and DIPEA (135 .mu.L, 0.78
mmol) at RT. The mixture was stirred at RT overnight and water (25
mL) was added. The aqueous layer was extracted with EtOAc
(3.times.25 mL) and the combined organic layers were washed with a
solution of sodium bicarbonate (25 mL), water (25 mL), brine (25
mL) dried (Na.sub.2SO.sub.4 anh.), filtered, and evaporated to
afford the compound 252A which was used in the next step without
purification.
Step B: Example 252
[0314] To a solution of compound 252A (111 mg, 0.19 mmol) in DCM (5
mL) was added TFA (2.5 mL) at RT. The mixture was stirred at RT for
15 min. and evaporated under reduced pressure. The residue was
purified using preparative HPLC and after evaporation, the residue
was purified by automated solid phase extraction and concentrated
in vacuo. The product was dissolved in a 4 M HCl solution in
dioxane and lyophilized to yield 70 mg of Example 252 as the
hydrochloride salt (66%). HPLC/MS (L), ret. time=1.41 min, purity
99%, MS pos. m/z 487 (M+H).sup.+; HPLC/MS (B), ret. time=1.43 min,
purity 97.8%, MS pos. m/z 487 (M+H).sup.+; MS (Finigan TSQ 7000,
ESI) m/z 487 (M+H).sup.+; IR (.nu..sub.max, KBr) cm.sup.-1
3600-2854, 1683, 1625, 1456; .sup.1H NMR (400 MHz, MeOH-d.sub.4)
.delta. ppm (two rotamers; 1:1.2 ratio) 9.33 (1H, s), 9.26 (1H, s),
8.53 (1H, s), 8.46 (1H, s), 7.22-7.10 (4H, m), 4.99 (1H, t, J=8.0
Hz), 4.32 (2H, s, major rotamer), 4.30 (2H, s, minor rotamer),
3.68-3.50 (2H, m), 3.40-3.34 (1H, m), 3.27-3.21 (1H, m), 2.92-2.75
(2H, m), 1.75-0.76 (15H, m).
EXAMPLES 253-54
4-Amino-N-[1-(4-chloro-benzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-
-piperidin-1-yl)-2-oxo-ethyl]-butyramide
[0315] ##STR358##
[0316] The procedure described for the preparation of Example 252
was used to prepare compounds of formula (It), wherein Q has the
values listed in Table 13, using N-Boc-3amino propionoic acid (Ex.
253) and ##STR359##
[0317] (Ex. 254), in place of N-Boc-glycine. Compounds were
prepared as the hydrochloride salt. In compounds of formula (I),
Q=(CR.sub.11R.sub.12).sub.y--(CH.sub.2).sub.x--W. TABLE-US-00013
TABLE 13 HPLC/MS Ex. Q Compound Name (ret. time) .sup.1H NMR 253
--(CH.sub.2).sub.3--NH.sub.2 4-Amino-N-[1-(4- 1.42.sup.L min; (400
MHz, MeOH-d.sub.4) .delta. ppm chloro-benzyl)-2-(4- 1.43.sup.b min;
(two rotamers; 1:2 ratio) 9.30 cyclohexyl-4- 1H, s, major rotamer),
9.25 (1H, s, [1,2,4]triazol-1- s, major rotamer), 9.23 (1H, s,
ylmethyl-piperidin-1- minor rotamer), 9.20 (1H, s,
yl)-2-oxo-ethyl]- minor rotamer), 8.51 (1H, s, butyramide major
rotamer), 8.47 (1H, s, minor rotamer), 8.45 (1H, s, major rotamer),
8.41 (1H, s, minor rotamer), 7.29-7.09 (4H, m, major and minor
rotamers), 4.91 (1H, t, J = 8.0 Hz), 4.31 (2H, s, major rotamer),
4.29 (2H, s, minor rotamer), 3.61-3.29 (2H, m), 3.40-3.35 (1H, m),
3.27-3.20 (1H, m), 3.05-2.74 (2H, m), 2.36 (1H, d, J = 4 Hz), 2.32
(1H, d, J = 8 Hz), 2.22 (2H, m), 1.95-0.82 (17H, m). 254 ##STR360##
1-Methyl-azetidine-2- carboxylic acid[1-(4- chloro-benzyl)-2-(4-
cyclohexyl-4- [1,2,4]triazol-1- ylmethyl-piperidin-1-
yl)-2-oxo-ethyl]-amide 1.55.sup.L min; 1.84.sup.m min; 400 MHz,
MeOH-d.sub.4) .delta. ppm (two rotamers, 1:2) 9.30 (m, 1H, broad),
8.52 (m, 1H, broad), 7.33 (d, 2H, J = 8Hz, major rotamer), 7.28 (d,
2H, J = 8Hz, minor rotamer), 7.24 (d, 2H, J = #8Hz, major rotamer),
7.22 (d, 2H, J =8Hz, minor rotamer), 5.10 (m, 1H), 4.41 (s, 2H),
4.07-3.93 (m, 2H), 3.72-3.67 (m, 1H), 3.55- 3.36 (m, 3H), 3.05-2.90
(m, 2H), 2.88 (s, 3H, major rotamer), 2.86 (s, 2H, minor rotamer),
2.77-2.65 (m, 1H), 2.40-2.19 (m, 1H), 1.80 (m, 3H), 1.68 (m, 3H),
1.54-0.90 (11H, m).
EXAMPLES 255-303
[0318] ##STR361##
[0319] Compounds having the formula (Iu), wherein W has the values
listed in Table 14, were prepared following the same or similar
procedure described above for Example 171. TABLE-US-00014 TABLE 14
HPLC Purity ret. time Mass Ex. No. W (%) (min) (M + H) 255
##STR362## 89.0% 3.9 627.43 256 ##STR363## 90.0% 3.7 643.44 257
##STR364## 90.0% 4.0 627.45 258 ##STR365## 86.0% 4.0 641.44 259
##STR366## 89.0% 4.0 645.4 260 ##STR367## 90.0% 3.7 641.41 261
##STR368## 87.0% 4.1 641.47 262 ##STR369## 90.0% 4.2 703.46 263
##STR370## 91.0% 3.5 553.36 264 ##STR371## 94.0% 4.0 565.36 265
##STR372## 93.0% 4.0 569.3 266 ##STR373## 97.0% 3.6 585.38 267
##STR374## 96.0% 3.8 552.38 268 ##STR375## 94.0% 3.9 614.42 269
##STR376## 91.0% 3.9 526.39 270 ##STR377## 91.0% 4.0 540.41 271
##STR378## 92.0% 3.9 615.38 272 ##STR379## 90.0% 3.4 542.36 273
##STR380## 92.0% 3.8 540.32 274 ##STR381## 93.0% 3.8 540.32 275
##STR382## 91.0% 3.6 583.42 276 ##STR383## 93.0% 3.9 570.33 277
##STR384## 86.0% 3.9 665.37 278 ##STR385## 98.0% 4.2 622.42 279
##STR386## 94.0% 4.0 677.37 280 ##STR387## 92.0% 3.9 566.4 281
##STR388## 92.0% 3.6 525.34 282 ##STR389## 93.0% 4.1 664.34 283
##STR390## 91.0% 3.8 556.33 284 ##STR391## 92.0% 4.0 661.43 285
##STR392## 92.0% 3.8 677.42 286 ##STR393## 92.0% 4.0 661.43 287
##STR394## 83.0% 3.2 541.41 288 ##STR395## 91.0% 3.6 569.39 289
##STR396## 88.0% 3.7 528.37 290 ##STR397## 93.0% 4.1 590.39 291
##STR398## 92.5% 4.0 601.37 292 ##STR399## 83.5% 3.3 601.38 293
##STR400## 87.0% .7 537.3 294 ##STR401## 78.8% 3.7 542.28 295
##STR402## 89.8% 3.6 552.33 296 ##STR403## 92.1% 3.9 617.34 297
##STR404## 90.6% 4.2 633.38 298 ##STR405## 92.6% 3.9 608.36 299
##STR406## 93.2% 4.4 651.3 300 ##STR407## 88.7% 4.3 634.33 301
##STR408## 92.8% 3.5 585.4 302 ##STR409## 93.4% 3.5 541.36 303
##STR410## 93.8% 3.9 611.45
EXAMPLES 304-319
[0320] ##STR411##
[0321] Compounds having the formula (Iv), wherein R.sub.11 and W
have the values listed in Table 15, were prepared following the
same or similar procedure described above for Example 171.
TABLE-US-00015 TABLE 15 HPLC Ex. Purity ret. time Mass No. R.sub.11
W (%) (min) (M + H) 304 --CH.sub.3 ##STR412## 92.0% 4.0 615.43 305
-isoPr ##STR413## 88.0% 4.2 643.46 306 ##STR414## ##STR415## 91.0%
4.2 677.45 307 ##STR416## ##STR417## 89.0% 4.3 691.48 308
##STR418## ##STR419## 90.0% 4.4 725.43 309 ##STR420## ##STR421##
90.0% 3.9 631.43 310 ##STR422## ##STR423## 82.0% 3.8 631.43 311
##STR424## ##STR425## 90.0% 4.2 657.49 312 ##STR426## ##STR427##
91.0% 4.1 570.41 313 ##STR428## ##STR429## 92.0% 4.0 570.41 314
##STR430## --OH 86.0% 3.7 600.36 315 -isoPr ##STR431## 91.0% 3.8
544.39 316 ##STR432## ##STR433## 91.0% 4.0 598.33 317 Et ##STR434##
92.0% 4.1 592.4 318 ##STR435## ##STR436## 85.0% 3.5 605.43 319
##STR437## ##STR438## 91.4% 3.9 631.43
EXAMPLES 320-322
[0322] ##STR439##
[0323] Compounds having the formula (Iw), wherein R.sub.11 and W
have the values listed in Table 16, were prepared following the
same or similar procedure described above for Example 171.
TABLE-US-00016 TABLE 16 HPLC Purity ret. time Mass Ex. No. R.sub.11
R.sub.12 W (%) (min) (M + H) 320 CH.sub.3 Et --OH 62.0% 3.7 530.38
321 CH.sub.3 Ph ##STR440## 94.0% 4.0 578.38 322 CH.sub.3 Ph
##STR441## 93.0% 3.8 578.38
EXAMPLE 323
1-Methyl-azetidine-2-carboxylic
acid[1-(4-chloro-benzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-pipe-
ridin-1-yl)-2-oxo-ethyl]-amide
[0324] ##STR442##
[0325] To a solution of
2-Amino-3-(4-chloro-phenyl)-1-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-p-
iperidin-1-yl)-propan-1-one (Compound 171A) (79 mg, 0.18 mmol) and
(R)-1-methyl-azetidine-2-carboxylic acid ##STR443## (32 mg, 0.28
mmol) in N,N-dimethylformamide (1.8 mL) was added
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (53 mg, 0.28 mmol),
1-hydroxybenzotriazole hydrate (37 mg, 0.28 mmol) and
N,N-diisopropylethylamine (97 .mu.L, 0.56 mmol) at rt. The mixture
was stirred 12 hours and then the solution was purified using
preparative HPLC (Column: Column S-5 Phenyl 20.times.100 mm.
Acetonitrile-0.05% TFA/water: 7 min. gradient from 10% AcCN to 90%
AcCN at 220 nm. Flow rate: 20 mL/min.) and collected fractions were
concentrated in vacuo. A second purification using preparative HPLC
was done (Column: Column X-Terra C-8 21.2.times.100 mm.
Acetonitrile-5 mM NH.sub.4OAc/water: 7 min. gradient from 10% AcCN
to 90% AcCN at 220 nm. Flow rate: 20 mL/min) and collected
fractions were concentrated in vacuo. The hydrochloride salt was
made using a solution of 4 M HCl in dioxane and the salt was
lyophilized to yield 30 mg of Example 323. (31%). HPLC/MS (Column:
Xterra-C8 4.6.times.30 mm; Flow rate: 4 mL/min, Solvent system:
0-100% B in 2 min. Solvent A: 10% CH.sub.3CN-90% H.sub.2O-5 mM
NH.sub.4OAc; Solvent B: 90% CH.sub.3CN-10% H.sub.2O-5 mM
NH.sub.4OAc; UV: 220 nm; Micromass ZMD 2000, ESI): retention time
1.55 min, purity 92.4%, MS pos. m/z 527 (M+H).sup.+; HPLC/MS
(Column: YMC-Pack S5 Phenyl 4.6.times.50 mm; Flow rate: 3 mL/min,
Solvent system: 0-100% B in 2 min. Solvent A: 10% CH.sub.3CN-90%
H.sub.2O-0.05% TFA; Solvent B: 90% CH.sub.3CN-10% H.sub.2O-0.05%
TFA; UV: 220 nm; Micromass ZMD 2000, ESI): retention time 1.83 min,
purity 97.5%, MS pos. m/z 527 (M+H).sup.+; MS (Finigan TSQ 7000,
ESI) m/z 527 (M+H).sup.+; HRMS calculated for:
C.sub.28H.sub.39ClN.sub.6O.sub.2 (M+H.sup.+)=527.290128;
Found=527.291621; .sup.1H nmr (400 MHz, MeOH-d.sub.4) .delta. ppm
(two rotamers, 1:2) 9.60 (s, 1H, broad, minor rotamer), 9.57 (s,
1H, broad, major rotamer), 8.81 (dd, 1H, J=4, 8 Hz), 8.74 (s, 1H,
broad, minor rotamer), 8.69 (s, 1H, broad, major rotamer),
7.34-7.23 (m, 4H), 5.08 (m, 1H), 4.46 (s, 2H, major rotamer), 4.44
(s, 2H, minor rotamer), 4.16-3.97 (m, 2H), 3.77-3.60 (m, 2H),
3.52-3.46 (m, 1H), 3.40-3.35 (m, 1H), 2.99 (d, 1H, J=8 Hz), 2.89
(s, 3H, major rotamer), 2.85 (s, 3H, minor rotamer), 2.80-2.71 (m,
1H), 2.54-2.45 (m, 1H), 1.80 (m, 3H), 1.68 (m, 3H), 1.54-0.90 (m,
11H).
* * * * *