U.S. patent application number 15/254538 was filed with the patent office on 2016-12-22 for substituted amino triazoles useful as acidic mammalian chitinase inhibitors.
The applicant listed for this patent is OncoArendi Therapeutics Sp. z o.o.. Invention is credited to R. Paul Beckett, Wojciech J. Czestkowski, Adam A. Golebiowski, Robert Koralewski, Krzysztof Matyszewski, Jacek P. Olczak, Sylwia Olejniczak.
Application Number | 20160368894 15/254538 |
Document ID | / |
Family ID | 56120793 |
Filed Date | 2016-12-22 |
United States Patent
Application |
20160368894 |
Kind Code |
A1 |
Golebiowski; Adam A. ; et
al. |
December 22, 2016 |
SUBSTITUTED AMINO TRIAZOLES USEFUL AS ACIDIC MAMMALIAN CHITINASE
INHIBITORS
Abstract
Disclosed are amino triazole compounds substituted by a
carboxylate functional group or an bioisosteric polar functional
group. Compounds having the carboxylate moiety or carboxylate
bioisostere inhibit acidic mammalian chitinase. Also provided are
methods of using the compounds to treat asthma reactions caused by
allergens.
Inventors: |
Golebiowski; Adam A.;
(Madison, CT) ; Koralewski; Robert; (Lodz, PL)
; Czestkowski; Wojciech J.; (Pabianice, PL) ;
Matyszewski; Krzysztof; (Lodz, PL) ; Olejniczak;
Sylwia; (Lodz, PL) ; Olczak; Jacek P.; (Lodz,
PL) ; Beckett; R. Paul; (Yorktown Heights,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OncoArendi Therapeutics Sp. z o.o. |
Warsaw |
|
PL |
|
|
Family ID: |
56120793 |
Appl. No.: |
15/254538 |
Filed: |
September 1, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14959369 |
Dec 4, 2015 |
9440953 |
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15254538 |
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62094446 |
Dec 19, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 33/573 20130101;
G01N 2800/122 20130101; A61P 11/02 20180101; C07D 401/14 20130101;
A61P 37/08 20180101; G01N 2333/942 20130101; G01N 2500/04 20130101;
A61P 17/00 20180101; C07D 401/04 20130101; G01N 2800/52 20130101;
A61P 11/06 20180101; A61P 37/00 20180101 |
International
Class: |
C07D 401/04 20060101
C07D401/04; G01N 33/573 20060101 G01N033/573 |
Claims
1. A compound represented by formula (I) or a pharmaceutically
acceptable salt thereof: ##STR00138## wherein: X is N, and Z is
CR.sup.10; or X is CR.sup.11, and Z is N; R.sup.1 is selected from
the group consisting of Y, aryl substituted by Y, and alkyl
substituted by Y; Y is --CO.sub.2H, --C(O)O(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)OH, --C(O)N(H)CN, --C(O)NH.sub.2,
--C(O)NH((C.sub.1-C.sub.6)alkyl),
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
--C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), --C(O)N(aryl).sub.z,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl), --P(O)(OH).sub.2,
##STR00139## ##STR00140## R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, and R.sup.7 are each independently H,
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, or aryl; or
R.sup.2, taken together with R.sup.6 or R.sup.7, forms a 5- or
6-membered ring; R.sup.8 is selected from the group consisting of
halo, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl and
(C.sub.3-C.sub.6)cycloalkyl; R.sup.9 is selected from the group
consisting of OH, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, aryl(C.sub.1-C.sub.6)alkyl, aryl,
(C.sub.1-C.sub.6)alkoxyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)hydroxyalkyl, heteroaryl, and
heteroaryl(C.sub.1-C.sub.6)alkyl; R.sup.10 and R.sup.11 are each
independently selected from H and (C.sub.1-C.sub.6)alkyl; m is an
integer from 0-5; n is an integer from 0-2; further wherein any
occurrence of (C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl,
aryl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, or heteroaryl(C.sub.1-C.sub.6)alkyl is optionally and
independently substituted by one or more substituents selected from
the group consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, aryl, --NH.sub.2,
--NH((C.sub.1-C.sub.6)alkyl), --N((C.sub.1-C.sub.6)alkyl).sub.2,
--OH, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkoxyl, --SH, --S((C.sub.1-C.sub.6)alkyl),
(C.sub.1-C.sub.6)hydroxyalkyl, and
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, --CN, --CF.sub.3,
--C(O)NH.sub.2, --C(O)NH(R.sup.12), --C(O)N(R.sup.12).sub.2,
--N(H)C(O)(R.sup.12), --N(R.sup.12)C(O)(R.sup.12),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(R.sup.12),
--S(O).sub.2N(R.sup.12).sub.2, --N(H)S(O).sub.2(R.sup.12),
--N(R.sup.12)S(O).sub.2(R.sup.12), --NHC(O)NH.sub.2,
--NHC(O)NH(R.sup.12), and --NHC(O)N(R.sup.12).sub.2; and each
occurrence of R.sup.12 is independently selected from the group
consisting of (C.sub.1-C.sub.6)alkyl), aryl, and
aryl(C.sub.1-C.sub.6)alkyl.
2. The compound of claim 1, wherein R.sup.1 is Y.
3. The compound of claim 1, wherein R.sup.1 is aryl substituted by
Y.
4. The compound of claim 1, wherein R.sup.1 is
(C.sub.1-C.sub.6)alkyl substituted by Y.
5. The compound of any one of claims 1-4, wherein Y is --CO.sub.2H,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6)alkyl,
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl), or
1H-tetrazolyl.
6. The compound of claim 1, wherein R.sup.1 is selected from the
group consisting of: CO.sub.2H; C(O)NH.sub.2;
C(O)NH((C.sub.1-C.sub.6)alkyl); C(O)NH(aryl); 1H-tetrazolyl; aryl
substituted by --CO.sub.2H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6)alkyl, --C(O)NH(aryl),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl, or 1H-tetrazolyl; and
(C.sub.1-C.sub.6)alkyl substituted by CO.sub.2H,
--NHC(O)(C.sub.1-C.sub.6)alkyl, --NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)aryl, --NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl, --N(H)S(O).sub.2aryl,
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NH(C.sub.1-C.sub.6)haloalkyl, --S(O).sub.2NHaryl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl, or
--S(O).sub.2NHC(O)aryl.
7. The compound of claim 1, wherein R.sup.1 is selected from the
group consisting of: 1H-tetrazolyl; aryl substituted by
--CO.sub.2H, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NH.sub.2, --S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl, or 1H-tetrazolyl; and
(C.sub.1-C.sub.6)alkyl substituted by CO.sub.2H, --NHC(O)aryl,
--N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl, --N(H)S(O).sub.2aryl,
--S(O).sub.2NH(C.sub.1-C.sub.6)alkyl, or
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl.
8. The compound of any one of claims 1-7, wherein R.sup.2 and
R.sup.3 are each independently selected from the group consisting
of H and aryl.
9. The compound of claim 8, wherein R.sup.2 and R.sup.3 are both
H.
10. The compound of any one of claims 1-9, wherein X is N; and Z is
CH.
11. The compound of any one of claims 1-9, wherein X is CH; and Z
is N.
12. The compound of any one of claims 1-11, wherein R.sup.8 is
selected from the group consisting of halo,
(C.sub.1-C.sub.6)haloalkyl, and (C.sub.1-C.sub.6)alkyl.
13. The compound of claim 12, wherein R.sup.8 is halo.
14. The compound of any one of claims 1-13, wherein m is 1.
15. The compound of any one of claims 1-14, wherein R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are each independently selected from
the group consisting of H and (C.sub.1-C.sub.6)alkyl.
16. The compound of claim 15, wherein R.sup.4, R.sup.5, R.sup.6,
and R.sup.7 are each H.
17. The compound of any one of claims 1-16, wherein R.sup.9 is
selected from the group consisting of (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, and aryl(C.sub.1-C.sub.6)alkyl.
18. The compound of any one of claims 1-17, wherein n is 0.
19. The compound of claim 1, represented by any one of the
following structural formulae: ##STR00141## ##STR00142##
##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147##
##STR00148## ##STR00149##
20. A compound represented by formula (II) or a pharmaceutically
acceptable salt thereof: ##STR00150## wherein: X is NH or
N(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z is CR.sup.10; or X is
CHR.sup.11 or C(R.sup.11)(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z is
N; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and
R.sup.7 are each independently H, (C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkyl, or aryl; or R.sup.2, taken together
with R.sup.6 or R.sup.7, forms a 5- or 6-membered ring; R.sup.8 is
selected from the group consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, and (C.sub.3-C.sub.6)cycloalkyl;
R.sup.9 is selected from the group consisting of Y, aryl
substituted by Y, and (C.sub.1-C.sub.6)alkyl substituted by Y; Y is
--CO.sub.2H, --C(O)O(C.sub.1-C.sub.6)alkyl, --C(O)N(H)OH,
--C(O)N(H)CN, --C(O)NH.sub.2, --C(O)NH((C.sub.1-C.sub.6)alkyl),
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
--C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), --C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl), --P(O)(OH).sub.2,
##STR00151## ##STR00152## R.sup.10 and R.sup.11 are each
independently selected from H and (C.sub.1-C.sub.6)alkyl; m is an
integer from 0-5; n is 1 or 2; further wherein any occurrence of
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, aryl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, or heteroaryl(C.sub.1-C.sub.6)alkyl is optionally and
independently substituted by one or more substituents selected from
the group consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, aryl, --NH.sub.2,
--NH((C.sub.1-C.sub.6)alkyl), --N((C.sub.1-C.sub.6)alkyl).sub.2,
--OH, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkoxyl, --SH, --S((C.sub.1-C.sub.6)alkyl),
(C.sub.1-C.sub.6)hydroxyalkyl, and
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, --CN, --CF.sub.3,
--C(O)NH.sub.2, --C(O)NH(R.sup.12), --C(O)N(R.sup.12).sub.2,
--N(H)C(O)(R.sup.12), --N(R.sup.12)C(O)(R.sup.12),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(R.sup.1),
--S(O).sub.2N(R.sup.12).sub.2, --N(H)S(O).sub.2(R.sup.12),
--N(R.sup.12)S(O).sub.2(R.sup.12), --NHC(O)NH.sub.2,
--NHC(O)NH(R.sup.12), and --NHC(O)N(R.sup.12).sub.2; and each
occurrence of R.sup.12 is independently selected from the group
consisting of (C.sub.1-C.sub.6)alkyl), aryl, and
aryl(C.sub.1-C.sub.6)alkyl.
21. The compound of claim 20, wherein R.sup.9 is Y.
22. The compound of claim 20, wherein R.sup.9 is aryl substituted
by Y.
23. The compound of claim 20, wherein R.sup.9 is
(C.sub.1-C.sub.6)alkyl substituted by Y.
24. The compound of any one of claims 20-23, wherein Y is
--CO.sub.2H, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6)alkyl,
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl), or
1H-tetrazolyl.
25. The compound of claim 20, wherein R.sup.9 is selected from the
group consisting of: CO.sub.2H; C(O)NH.sub.2;
C(O)NH((C.sub.1-C.sub.6)alkyl); C(O)NH(aryl); 1H-tetrazolyl; aryl
substituted by --CO.sub.2H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6)alkyl, --C(O)NH(aryl),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl, or 1H-tetrazolyl; and
(C.sub.1-C.sub.6)alkyl substituted by CO.sub.2H,
--NHC(O)(C.sub.1-C.sub.6)alkyl, --NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)aryl, --NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl, --N(H)S(O).sub.2aryl,
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NH(C.sub.1-C.sub.6)haloalkyl, --S(O).sub.2NHaryl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl, or
--S(O).sub.2NHC(O)aryl.
26. The compound of any one of claims 20-25, wherein n is 1.
27. The compound of any one of claims 20-26, X is NH; and Z is
CH.
28. The compound of any one of claims 20-26, wherein X is
N(C(R.sup.1)(R.sup.2)(R.sup.3)); and Z is CH.
29. The compound of claim 28, wherein R.sup.2 and R.sup.3 are both
H.
30. The compound of claim 29, wherein R.sup.1 is H or
(C.sub.1-C.sub.6)alkyl.
31. The compound of any one of claims 20-26, wherein X is CH.sub.2;
and Z is N.
32. The compound of any one of claims 20-31, wherein R.sup.8 is
selected from the group consisting of halo,
(C.sub.1-C.sub.6)haloalkyl, and (C.sub.1-C.sub.6)alkyl.
33. The compound of claim 32, wherein R.sup.8 is halo.
34. The compound of any one of claims 20-33, wherein m is 1.
35. The compound of any one of claims 20-34, wherein R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are each independently selected from
the group consisting of H and (C.sub.1-C.sub.6)alkyl.
36. The compound of claim 35, wherein R.sup.4, R.sup.5, R.sup.6,
and R.sup.7 are each H.
37. A compound represented by formula (III) or a pharmaceutically
acceptable salt thereof: ##STR00153## wherein: X is NH or
N(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z is CR.sup.10; or X is
CHR.sup.11 or C(R.sup.11)(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z is
N; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.7 are
each independently H, (C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkyl, or aryl; or R.sup.1 or R.sup.2, taken
together with or R.sup.7, forms a 5- or 6-membered ring; R.sup.6 is
selected from the group consisting of Y, aryl substituted by Y, and
(C.sub.1-C.sub.6)alkyl substituted by Y; Y is --CO.sub.2H,
--C(O)O(C.sub.1-C.sub.6)alkyl, --C(O)N(H)OH, --C(O)N(H)CN,
--C(O)NH.sub.2, --C(O)NH((C.sub.1-C.sub.6)alkyl),
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
--C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), --C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl), --P(O)(OH).sub.2,
##STR00154## ##STR00155## R.sup.8 is selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, and (C.sub.3-C.sub.6)cycloalkyl;
R.sup.9 is selected from the group consisting of OH,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
aryl(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, and heteroaryl(C.sub.1-C.sub.6)alkyl; R.sup.10 and
R.sup.11 are each independently selected from H and
(C.sub.1-C.sub.6)alkyl; m is an integer from 0-5; n is an integer
from 0-2; further wherein any occurrence of (C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkoxyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)hydroxyalkyl, heteroaryl, or
heteroaryl(C.sub.1-C.sub.6)alkyl is optionally and independently
substituted by one or more substituents selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, aryl, --NH.sub.2,
--NH((C.sub.1-C.sub.6)alkyl), --N((C.sub.1-C.sub.6)alkyl).sub.2,
--OH, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkoxyl, --SH, --S((C.sub.1-C.sub.6)alkyl),
(C.sub.1-C.sub.6)hydroxyalkyl, and
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, --CN, --CF.sub.3,
--C(O)NH.sub.2, --C(O)NH(R.sup.12), --C(O)N(R.sup.12).sub.2,
--N(H)C(O)(R.sup.12), --N(R.sup.12)C(O)(R.sup.12),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(R.sup.12),
--S(O).sub.2N(R.sup.12).sub.2, --N(H)S(O).sub.2(R.sup.12),
--N(R.sup.12)S(O).sub.2(R.sup.12), --NHC(O)NH.sub.2,
--NHC(O)NH(R.sup.12), and --NHC(O)N(R.sup.12).sub.2; and each
occurrence of R.sup.12 is independently selected from the group
consisting of (C.sub.1-C.sub.6)alkyl), aryl, and
aryl(C.sub.1-C.sub.6)alkyl.
38. The compound of claim 37, wherein R.sup.6 is Y.
39. The compound of claim 37, wherein R.sup.6 is aryl substituted
by Y.
40. The compound of claim 37, wherein R.sup.6 is
(C.sub.1-C.sub.6)alkyl substituted by Y.
41. The compound of any one of claims 37-40, wherein Y is
--CO.sub.2H, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6)alkyl,
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl), or
1H-tetrazolyl.
42. The compound of claim 37, wherein R.sup.6 is selected from the
group consisting of: CO.sub.2H; C(O)NH.sub.2;
C(O)NH((C.sub.1-C.sub.6)alkyl); C(O)NH(aryl); 1H-tetrazolyl; aryl
substituted by --CO.sub.2H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6)alkyl, --C(O)NH(aryl),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)(SO.sub.2)aryl, --C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl, or 1H-tetrazolyl; and
(C.sub.1-C.sub.6)alkyl substituted by CO.sub.2H,
--NHC(O)(C.sub.1-C.sub.6)alkyl, --NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)aryl, --NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl, --N(H)S(O).sub.2aryl,
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NH(C.sub.1-C.sub.6)haloalkyl, --S(O).sub.2NHaryl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl, or
--S(O).sub.2NHC(O)aryl.
43. The compound of any one of claims 37-42, wherein n is 1.
44. The compound of any one of claims 37-43, X is NH; and Z is
CH.
45. The compound of any one of claims 37-43, wherein X is
N(C(R.sup.1)(R.sup.2)(R.sup.3)); and Z is CH.
46. The compound of claim 45, wherein R.sup.2 and R.sup.3 are both
H.
47. The compound of claim 46, wherein R.sup.1 is H or
(C.sub.1-C.sub.6)alkyl.
48. The compound of any one of claims 37-43, wherein X is CH.sub.2;
and Z is N.
49. The compound of any one of claims 37-48, wherein R.sup.8 is
selected from the group consisting of halo,
(C.sub.1-C.sub.6)haloalkyl and (C.sub.1-C.sub.6)alkyl.
50. The compound of claim 49, wherein R.sup.8 is halo.
51. The compound of any one of claims 37-50, wherein m is 1.
52. The compound of any one of claims 37-51, wherein R.sup.4,
R.sup.5, and R.sup.7 are each independently selected from the group
consisting of H and (C.sub.1-C.sub.6)alkyl.
53. The compound of claim 52, wherein R.sup.4, R.sup.5, and R.sup.7
are each H.
54. The compound of any one of claims 37-53, wherein R.sup.9 is
selected from the group consisting of (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, and aryl(C.sub.1-C.sub.6)alkyl.
55. The compound of any one of claims 37-54, wherein n is 0.
56. A pharmaceutical composition, comprising a compound of any one
of claims 1-55; and a pharmaceutically acceptable carrier.
57. A method for treating asthma, comprising administering to a
subject in need thereof a therapeutically effective amount of a
compound of any one of claims 1-55.
58. A method for treating a reaction caused by an allergen,
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of any one of claims
1-55.
59. The method of claim 58, wherein the reaction caused by an
allergen is allergic rhinitis or atopic dermatitis.
60. The method of claim 58 or 59, wherein the allergen is mold,
mammal dander, pollen, spores, fungus, dust mites, insects, or a
chemical.
61. A method for treating a fungal or parasitic infection,
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of any one of claims
1-55.
62. A method for assessing the efficacy of an agent for treating
asthma in a subject, comprising: a) detecting in a subject sample
collected at a first point in time, the expression level of acidic
mammalian chitinase protein; b) repeating step a) at one or more
subsequent points in time after administration of the agent; and c)
comparing expression level of acidic mammalian chitinase protein
detected in step a) with the expression level(s) detected in step
b), wherein a higher expression level of acidic mammalian chitinase
protein at the first point in time relative to at least one
subsequent point in time indicates that the agent is efficacious in
treating asthma.
63. A method of identifying an agent for treating asthma,
comprising: a) contacting a sample comprising acidic mammalian
chitinase protein with the agent; and b) determining the ability of
the agent to inhibit activity of acidic mammalian chitinase
protein, wherein decreased activity of acidic mammalian chitinase
protein identifies an agent for treating asthma.
64. The method of claim 63, wherein the activity of acidic
mammalian chitinase protein is assessed by fluorescence assay using
a reagent that is hydrolyzed by acidic mammalian chitinase
protein.
65. The method of claim 64, wherein the reagent is
4-methylumbelliferyl B-D-N,N'-diacetylchitobioside hydrate.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
Provisional Patent Application Ser. No. 62/094,446, filed Dec. 19,
2014.
BACKGROUND OF THE INVENTION
[0002] Acidic mammalian chitinase (AMCase; M.sub.r=.about.52.2 kD)
is a secreted enzyme, typically found in the stomach, salivary
gland, and lungs. The enzyme catalyzes the hydrolysis of artificial
chitin-like substrates, and is unique among mammalian enzymes in
that it has an acidic pH optimum. It is induced during Th2
inflammation through an IL-13-dependent mechanism. Chitinases are
believed to play a key role in the innate immunity to parasites and
other infectious agents. When produced in a dysregulated fashion,
the enzymes may also play an important role in the pathogenesis of
allergy and/or asthma.
[0003] Asthma is a chronic inflammatory disease of the airways
characterized by recurrent episodes of reversible airway
obstruction and airway hyperresponsiveness (AHR). Typical clinical
manifestations include shortness of breath, wheezing, coughing and
chest tightness that can become life threatening or fatal. While
existing therapies focus on reducing the symptomatic bronchospasm
and pulmonary inflammation, there is a growing awareness of the
role of long-term airway remodeling in the accelerated lung
deterioration in asthmatics. Airway remodeling refers to a number
of pathological features, including epithelial smooth muscle and
myofibroblast hyperplasia and/or metaplasia, subepithelial fibrosis
and matric deposition.
[0004] It is generally accepted that allergic asthma is initiated
by an inappropriate inflammatory reaction to airborne allergens.
The lungs of asthmatics demonstrate an intense infiltration of
lymphocytes, mast cells and, especially, eosinophils. AMCase is
prominently expressed in lungs from antigen-sensitized and
challenged and IL-13-transgenic mice. AMCase mRNA is not readily
detected in lung tissues from patients without known lung disease,
but has been detected, histologically and morphometrically, in the
epithelial cells and subepithelial cells in tissues from patients
with asthma.
[0005] Preliminary published studies (Zhu Z, Zheng T, Homer R J,
Kim Y K, Chen N Y, Cohn L, Hamid Q, and Elias J A. Acidic mammalian
chitinase in asthmatic Th2 inflammation and IL-13 pathway
activation. Science 304: 1678-1682, 2004; Matsumoto T, et al.
Demethylallosamidin, a chitinase inhibitor, suppresses airway
inflammation and hyperresponsiveness. Biochem Biophys Res Commun
390: 103-108, 2009) suggest that AMCase plays a role in the Th-2
driven inflammatory response in a murine model of allergic asthma.
Th-1 responses do not seem to be involved. No therapeutic effect
was observed in a mouse model that expresses Th-1, but not Th-2
(Fitz L J, et al. Acidic mammalian chitinase is not a critical
target for allergic airway disease. Am J Respir Cell Mol Biol 46:
71-9, 2011). This result would be expected since Th-1 cells are
primarily involved in host defense against pathogens.
[0006] There is a need to investigate the inhibition of AMCase, and
to discover treatments for conditions associated with elevated
expression of AMCase, such as asthma and allergic responses. In
particular, there is a need to explore new molecular scaffolds that
effectively inhibit AMCase and, therefore, can act as therapeutic
agents for the treatment of these conditions.
SUMMARY OF THE INVENTION
[0007] In one aspect, the invention provides a compound represented
by formula (I), or a pharmaceutically acceptable salt thereof:
##STR00001##
wherein: [0008] X is N, and Z is CR.sup.10; or X is CR.sup.11, and
Z is N; [0009] R.sup.1 is selected from the group consisting of Y,
aryl substituted by Y, and (C.sub.1-C.sub.6)alkyl substituted by Y;
[0010] Y is --CO.sub.2H, --C(O)O(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)OH, --C(O)N(H)CN, --C(O)NH.sub.2,
--C(O)NH((C.sub.1-C.sub.6)alkyl),
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
--C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), --C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl),
--P(O)(OH).sub.2,
[0010] ##STR00002## ##STR00003## [0011] R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are each independently H,
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, or aryl; or
R.sup.2, taken together with R.sup.6 or R.sup.7, forms a 5- or
6-membered ring; [0012] R.sup.8 is selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, and (C.sub.3-C.sub.6)cycloalkyl; [0013]
R.sup.9 is selected from the group consisting of OH,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
aryl(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, and heteroaryl(C.sub.1-C.sub.6)alkyl; [0014] R.sup.10
and R.sup.11 are each independently selected from H and
(C.sub.1-C.sub.6)alkyl; [0015] m is an integer from 0-5; [0016] n
is an integer from 0-2; [0017] further wherein any occurrence of
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, aryl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, or heteroaryl(C.sub.1-C.sub.6)alkyl is optionally and
independently substituted by one or more substituents selected from
the group consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, aryl, --NH.sub.2,
--NH((C.sub.1-C.sub.6)alkyl), --N((C.sub.1-C.sub.6)alkyl).sub.2,
--OH, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkoxyl, --SH, --S((C.sub.1-C.sub.6)alkyl),
(C.sub.1-C.sub.6)hydroxyalkyl, and
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, --CN, --CF.sub.3,
--C(O)NH.sub.2, --C(O)NH(R.sup.12), --C(O)N(R.sup.12).sub.2,
--N(H)C(O)(R.sup.12), --N(R.sup.12)C(O)(R.sup.12),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(R.sup.12),
--S(O).sub.2N(R.sup.12).sub.2, --N(H)S(O).sub.2(R.sup.12),
--N(R.sup.12)S(O).sub.2(R.sup.12), --NHC(O)NH.sub.2,
--NHC(O)NH(R.sup.12), and --NHC(O)N(R.sup.12).sub.2; and [0018]
each occurrence of R.sup.12 is independently selected from the
group consisting of (C.sub.1-C.sub.6)alkyl), aryl, and
aryl(C.sub.1-C.sub.6)alkyl.
[0019] In another aspect, the invention provides a compound
represented by formula (II) or a pharmaceutically acceptable salt
thereof:
##STR00004##
wherein: [0020] X is NH or N(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z
is CR.sup.10; or X is CHR.sup.11 or
C(R.sup.11)(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z is N; [0021]
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7
are each independently H, (C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkyl, or aryl; or R.sup.2, taken together
with R.sup.6 or R.sup.7, forms a 5- or 6-membered ring; [0022]
R.sup.8 is selected from the group consisting of halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl and
(C.sub.3-C.sub.6)cycloalkyl; [0023] R.sup.9 is selected from the
group consisting of Y, aryl substituted by Y, and
(C.sub.1-C.sub.6)alkyl substituted by Y; [0024] Y is --CO.sub.2H,
--C(O)O(C.sub.1-C.sub.6)alkyl, --C(O)N(H)OH, --C(O)N(H)CN,
--C(O)NH.sub.2, --C(O)NH((C.sub.1-C.sub.6)alkyl),
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
--C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), --C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl),
--P(O)(OH).sub.2,
[0024] ##STR00005## ##STR00006## [0025] R.sup.10 and R.sup.11 are
each independently selected from H and (C.sub.1-C.sub.6)alkyl;
[0026] m is an integer from 0-5; [0027] n is 1 or 2; [0028] further
wherein any occurrence of (C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkoxyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)hydroxyalkyl, heteroaryl, or
heteroaryl(C.sub.1-C.sub.6)alkyl is optionally and independently
substituted by one or more substituents selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, aryl, --NH.sub.2,
--NH((C.sub.1-C.sub.6)alkyl), --N((C.sub.1-C.sub.6)alkyl).sub.2,
--OH, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkoxyl, --SH, --S((C.sub.1-C.sub.6)alkyl),
(C.sub.1-C.sub.6)hydroxyalkyl, and
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, --CN, --CF.sub.3,
--C(O)NH.sub.2, --C(O)NH(R.sup.12), --C(O)N(R.sup.12).sub.2,
--N(H)C(O)(R.sup.12), --N(R.sup.12)C(O)(R.sup.12),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(R.sup.12),
--S(O).sub.2N(R.sup.12).sub.2, --N(H)S(O).sub.2(R.sup.12),
--N(R.sup.12)S(O).sub.2(R.sup.12), --NHC(O)NH.sub.2,
--NHC(O)NH(R.sup.12), and --NHC(O)N(R.sup.12).sub.2; and [0029]
each occurrence of R.sup.12 is independently selected from the
group consisting of (C.sub.1-C.sub.6)alkyl), aryl, and
aryl(C.sub.1-C.sub.6)alkyl.
[0030] In another aspect, the invention provides a compound
represented by formula (III), or a pharmaceutically acceptable salt
thereof,
##STR00007##
wherein: [0031] X is NH or N(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z
is CR.sup.10; or X is CHR.sup.11 or
C(R.sup.11)(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z is N; [0032]
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.7 are each
independently H, (C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkyl, or aryl; or R.sup.1 or R.sup.2, taken
together with R.sup.7, forms a 5- or 6-membered ring; [0033]
R.sup.6 is selected from the group consisting of Y, aryl
substituted by Y, and (C.sub.1-C.sub.6)alkyl substituted by Y;
[0034] Y is --CO.sub.2H, --C(O)O(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)OH, --C(O)N(H)CN, --C(O)NH.sub.2,
--C(O)NH((C.sub.1-C.sub.6)alkyl),
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
--C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), --C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl),
--P(O)(OH).sub.2,
[0034] ##STR00008## ##STR00009## [0035] R.sup.8 is selected from
the group consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl and (C.sub.3-C.sub.6)cycloalkyl; [0036]
R.sup.9 is selected from the group consisting of OH,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
aryl(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, and heteroaryl(C.sub.1-C.sub.6)alkyl; [0037] R.sup.10
and R.sup.11 are each independently selected from H and
(C.sub.1-C.sub.6)alkyl; [0038] m is an integer from 0-5; and [0039]
n is an integer from 0-2; [0040] further wherein any occurrence of
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, aryl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, or heteroaryl(C.sub.1-C.sub.6)alkyl is optionally and
independently substituted by one or more substituents selected from
the group consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, aryl, --NH.sub.2,
--NH((C.sub.1-C.sub.6)alkyl), --N((C.sub.1-C.sub.6)alkyl).sub.2,
--OH, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkoxyl, --SH, --S((C.sub.1-C.sub.6)alkyl),
(C.sub.1-C.sub.6)hydroxyalkyl, and
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, --CN, --CF.sub.3,
--C(O)NH.sub.2, --C(O)NH(R.sup.12), --C(O)N(R.sup.12).sub.2,
--N(H)C(O)(R.sup.12), --N(R.sup.12)C(O)(R.sup.12),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(R.sup.12),
--S(O).sub.2N(R.sup.12).sub.2, --N(H)S(O).sub.2(R.sup.12),
--N(R.sup.12)S(O).sub.2(R.sup.12), --NHC(O)NH.sub.2,
--NHC(O)NH(R.sup.12), and --NHC(O)N(R.sup.12).sub.2; and [0041]
each occurrence of R.sup.12 is independently selected from the
group consisting of (C.sub.1-C.sub.6)alkyl), aryl, and
aryl(C.sub.1-C.sub.6)alkyl.
[0042] Also provided herein are pharmaceutical compositions,
comprising a compound of the invention; and a pharmaceutically
acceptable carrier.
[0043] Also provided herein are methods for treating asthma,
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of the
invention.
[0044] Also provided herein are methods for treating a reaction
caused by an allergen, comprising administering to a subject in
need thereof a therapeutically effective amount of a compound of
the invention.
[0045] In another aspect, the invention provides methods for
treating a fungal or parasitic infection, comprising administering
to a subject in need thereof a therapeutically effective amount of
a compound of the invention.
[0046] In another aspect, the invention provides methods for
assessing the efficacy of an agent for treating asthma in a
subject, comprising:
[0047] a) detecting in a subject sample at a first point in time,
the expression level of acidic mammalian chitinase protein;
[0048] b) repeating step a) at one or more subsequent points in
time after administration of the agent; and
[0049] c) comparing expression level of acidic mammalian chitinase
protein detected in step a) with the expression level detected in
step b),
[0050] wherein a higher expression level of acidic mammalian
chitinase protein at the first point in time relative to at least
one subsequent point in time indicates that the agent is
efficacious in treating asthma.
[0051] The invention also provides methods for identifying an agent
for treating asthma, comprising:
[0052] a) contacting a sample comprising acidic mammalian chitinase
protein with the agent; and
[0053] b) determining the ability of the agent to inhibit activity
of acidic mammalian chitinase protein, wherein decreased activity
of acidic mammalian chitinase protein identifies an agent for
treating asthma.
DETAILED DESCRIPTION
[0054] The present invention is based on the unexpected discovery
that chemical modification of an amino triazole small molecule with
a carboxylate functional group or an bioisosteric polar functional
group produces a compound effective as an inhibitor of AMCase.
[0055] The amino triazole compounds having substitution by a
carboxylate functional group, or by an bioisosteric functional
group, effectively inhibit AMCase, and are useful in the treatment
of disorders associated with upregulated and dysregulated AMCase
activity, such as asthma and allergic reactions.
DEFINITIONS
[0056] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e., to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0057] The terms used herein may be preceded and/or followed by a
single dash "-", or a double dash "=", to indicate the bond order
of the bond between the named substituent and its parent moiety; a
single dash indicates a single bond and a double dash indicates a
double bond. In the absence of a single or double dash, it is
understood that a single bond is formed between the substituent and
its parent moiety; further, substituents are intended to be read
"from left to right," unless a dash indicates otherwise. For
example, (C.sub.1-C.sub.6)-alkoxycarbonyloxy and
--OC(O)(C.sub.1-C.sub.6)alkyl indicate the same functionality;
similarly arylalkyl and -alkylaryl indicate the same
functionality.
[0058] The term "heteroatom" is art-recognized and refers to an
atom of any element other than carbon or hydrogen. Illustrative
heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and
selenium.
[0059] The term "alkyl" as used herein is a term of art and refers
to saturated aliphatic groups, including straight-chain alkyl
groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups,
alkyl substituted cycloalkyl groups, and cycloalkyl substituted
alkyl groups. In certain embodiments, a straight-chain or
branched-chain alkyl has about 30 or fewer carbon atoms in its
backbone (e.g., C.sub.1-C.sub.30 for straight chain,
C.sub.3-C.sub.30 for branched chain), and alternatively, about 20
or fewer, 10 or fewer, or preferably 1-6 carbons. Representative
examples of alkyl include, but are not limited to, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,
n-pentyl, isopentyl, neopentyl, and n-hexyl.
[0060] The term "cycloalkyl" means mono- or bicyclic or bridged
saturated or partially saturated carbocyclic rings, each having
from 3 to 12 carbon atoms. Certain cycloalkyls have from 3-8, or
from 3-6 carbon atoms in their ring structure. Certain cycloalkyls
have from 5-12 carbon atoms in their ring structure, and may have
6-10 carbons in the ring structure. Examples of monocyclic
cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and
cyclooctyl. Bicyclic cycloalkyl ring systems include bridged
monocyclic rings and fused bicyclic rings. Bridged monocyclic rings
contain a monocyclic cycloalkyl ring where two non-adjacent carbon
atoms of the monocyclic ring are linked by an alkylene bridge of
between one and three additional carbon atoms (i.e., a bridging
group of the form --(CH.sub.2).sub.w--, where w is 1, 2, or 3).
Representative examples of bicyclic ring systems include, but are
not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,
bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane,
and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems
contain a monocyclic cycloalkyl ring fused to either a phenyl, a
monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic
heterocyclyl, or a monocyclic heteroaryl. The bridged or fused
bicyclic cycloalkyl is attached to the parent molecular moiety
through any carbon atom contained within the monocyclic cycloalkyl
ring. Cycloalkyl groups are optionally substituted. In certain
embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered
monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6
membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic
cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or
6 membered monocyclic heteroaryl, wherein the fused bicyclic
cycloalkyl is optionally substituted.
[0061] The term "heterocyclyl" as used herein refers to a radical
of a non-aromatic ring system, including, but not limited to,
monocyclic, bicyclic, and tricyclic rings, which can be completely
saturated or which can contain one or more units of unsaturation,
for the avoidance of doubt, the degree of unsaturation does not
result in an aromatic ring system, and having 3 to 14, or 3 to 12
atoms including at least one heteroatom, such as nitrogen, oxygen,
or sulfur. More preferred heterocycloalkyl groups have from 5-10
ring members where from 1-4 of the ring members are hetero atoms
selected from the group consisting of 0, N, and S, the remaining
ring atoms being C. For purposes of exemplification, which should
not be construed as limiting the scope of this invention, the
following are examples of heterocyclic rings: aziridinyl, azirinyl,
oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl,
1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,
imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,
isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl,
thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl,
dithietyl, furyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl,
isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl, tetrazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
tetrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl,
pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl,
benzothiazolyl, benzoxadiazolyl, benzthiadiazolyl, indolyl,
benztriazolyl, naphthyridinyl, azepines, azetidinyl, morpholinyl,
oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl,
oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl,
pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,
quinicludinyl, thiomorpholinyl, tetrahydropyranyl,
tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,
thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl,
and trithianyl. A heterocyclyl group is optionally substituted by
one or more substituents as described below.
[0062] As used herein, the term "heterocyclylene" refers to a
bivalent heterocyclyl (heterocycloalkyl) group, i.e., a cyclic
alkylene group, having from 3-10 members and from 1-4 hetero atoms
selected from S, O, and N. An example is
piperidine-2,3-dicarboxylic acid, i.e., in that compound, the
piperidine ring is a heterocyclyl group.
[0063] The term "heteroatom" is art-recognized, and includes an
atom of any element other than carbon or hydrogen. Illustrative
heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and
selenium, and alternatively oxygen, nitrogen or sulfur.
[0064] The term "cycloalkylalkyl" as used herein refers to an alkyl
group substituted with one or more cycloalkyl groups.
[0065] The term "heterocycloalkylalkyl" as used herein refers to an
alkyl group substituted with one or more heterocycloalkyl (i.e.,
heterocyclyl) groups.
[0066] The term "alkenyl" as used herein means a straight or
branched chain hydrocarbon radical containing from 2 to 10 carbons
and containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond(s) of the
alkenyl group can be located anywhere in the moiety and can have
either the (Z) or the (E) configuration about the double
bond(s).
[0067] The term "alkynyl" as used herein means a straight or
branched chain hydrocarbon radical containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0068] The term "alkylene" is art-recognized, and as used herein
pertains to a diradical obtained by removing two hydrogen atoms of
an alkyl group, as defined above. In one embodiment an alkylene
refers to a disubstituted alkane, i.e., an alkane substituted at
two positions with substituents such as halogen, azide, alkyl,
aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino,
nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido,
ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic
moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like.
That is, in one embodiment, a "substituted alkyl" is an
"alkylene".
[0069] The term "amino" is a term of art and as used herein refers
to both unsubstituted and substituted amines, e.g., a moiety that
may be represented by the general formulas:
##STR00010##
wherein R.sub.a, R.sub.b, and R.sub.c each independently represent
a hydrogen, an alkyl, an alkenyl, --(CH.sub.2).sub.x--R.sub.d, or
R.sub.a and R.sub.b, taken together with the N atom to which they
are attached complete a heterocycle having from 4 to 8 atoms in the
ring structure; R.sub.d represents an aryl, a cycloalkyl, a
cycloalkenyl, a heterocyclyl or a polycyclyl; and x is zero or an
integer in the range of 1 to 8. In certain embodiments, only one of
R.sub.a or R.sub.b may be a carbonyl, e.g., R.sub.a, R.sub.b, and
the nitrogen together do not form an imide. In other embodiments,
R.sub.a and R.sub.b (and optionally R.sub.c) each independently
represent a hydrogen, an alkyl, an alkenyl, or
--(CH.sub.2).sub.x--R.sub.d. In certain embodiments, the term
"amino" refers to NH.sub.2.
[0070] The term "amido", as used herein, means --NHC(.dbd.O)--,
wherein the amido group is bound to the parent molecular moiety
through the nitrogen. Examples of amido include alkylamido such as
CH.sub.3C(.dbd.O)N(H)-- and CH.sub.3CH.sub.2C(.dbd.O)N(H)--.
[0071] The term "acyl" is a term of art and as used herein refers
to any group or radical of the form RCO-- where R is any organic
group, e.g., alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl.
Representative acyl groups include acetyl, benzoyl, and
malonyl.
[0072] The term "aminoalkyl" as used herein refers to an alkyl
group substituted with one or more one amino groups. In one
embodiment, the term "aminoalkyl" refers to an aminomethyl
group.
[0073] The term "aminoacyl" is a term of art and as used herein
refers to an acyl group substituted with one or more amino
groups.
[0074] The term "aminothionyl" as used herein refers to an analog
of an aminoacyl in which the O of RC(O)-- has been replaced by
sulfur, hence is of the form RC(S)--.
[0075] The term "phosphoryl" is a term of art and as used herein
may in general be represented by the formula:
##STR00011##
wherein Q50 represents S or O, and R59 represents hydrogen, a lower
alkyl or an aryl; for example, --P(O)(OMe)- or --P(O)(OH).sub.2.
When used to substitute, e.g., an alkyl, the phosphoryl group of
the phosphorylalkyl may be represented by the general formulas:
##STR00012##
wherein Q50 and R59, each independently, are defined above, and Q51
represents O, S or N; for example, --O--P(O)(OH)OMe or
--NH--P(O)(OH).sub.2. When Q50 is S, the phosphoryl moiety is a
"phosphorothioate."
[0076] The term "aminophosphoryl" as used herein refers to a
phosphoryl group substituted with at least one amino group, as
defined herein; for example, --P(O)(OH)NMe.sub.2.
[0077] The term "azide" or "azido", as used herein, means an
N.sub.3 group.
[0078] The term "carbonyl" as used herein refers to
--C(.dbd.O)--.
[0079] The term "thiocarbonyl" as used herein refers to
--C(.dbd.S)--.
[0080] The term "alkylphosphoryl" as used herein refers to a
phosphoryl group substituted with at least one alkyl group, as
defined herein; for example, --P(O)(OH)Me.
[0081] The term "alkylthio" as used herein refers to alkyl-S--.
[0082] The term "carboxy", as used herein, means a --CO.sub.2H
group.
[0083] The term "aryl" is a term of art and as used herein refers
to includes monocyclic, bicyclic and polycyclic aromatic
hydrocarbon groups, for example, benzene, naphthalene, anthracene,
1,2,3,4-tetrahydronaphthalene, indene, 2,3-dihydroindene, and
pyrene. The aromatic ring may be substituted at one or more ring
positions with one or more substituents, such as halogen, azide,
alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
(cycloalkyl)alkoxyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl,
imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
ether, alkylthio, sulfonyl, aminosulfonyl, sulfonamido, ketone,
aldehyde, ester, heterocyclyl, heterocyclylalkyl, aromatic or
heteroaromatic moieties, aminoalkyl, haloalkyl, fluoroalkyl (such
as trifluoromethyl), haloalkoxyl, cyano, or the like. The term
"aryl" also includes polycyclic ring systems having two or more
cyclic rings in which two or more carbons are common to two
adjoining rings (the rings are "fused rings") wherein at least one
of the rings is an aromatic hydrocarbon, e.g., the other cyclic
rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,
heteroaryls, and/or heterocyclyls. Representative examples of the
polcyclic aryl ring systems include, but are not limited to,
azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl,
dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl,
2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl,
2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden-3-yl,
inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl,
dihydronaphthalen-4-yl, dihydronaphthalen-1-yl,
5,6,7,8-tetrahydronaphthalen-1-yl,
5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-4-yl,
2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl,
2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl,
benzo[d][1,3]dioxol-5-yl, 2H-chromen-2-on-5-yl,
2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl, 2H-chromen-2-on-8-yl,
isoindoline-1,3-dion-4-yl, isoindoline-1,3-dion-5-yl,
inden-1-on-4-yl, inden-1-on-5-yl, inden-1-on-6-yl, inden-1-on-6-yl,
2,3-dihydrobenzo[b][1,4]dioxan-5-yl,
2,3-dihydrobenzo[b][1,4]dioxan-6-yl,
2H-benzo[b][1,4]oxazin3(4H)-on-5-yl,
2H-benzo[b][1,4]oxazin3(4H)-on-6-yl,
2H-benzo[b][1,4]oxazin3(4H)-on-7-yl,
2H-benzo[b][1,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl,
benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl,
benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl,
quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl,
quinazolin-4(3H)-on-8-yl, quinoxalin-2(1H)-on-5-yl,
quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl,
quinoxalin-2(1H)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl,
benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and,
benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic
aryl is (i) naphthyl, or (ii) a phenyl ring fused to either a 5 or
6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic
cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein
the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are
optionally substituted. In certain embodiments, the term "aryl"
refers to a phenyl group.
[0084] The term "heteroaryl" is a term of art and as used herein
refers to a monocyclic, bicyclic, and polycyclic aromatic group
having 3 to 14, 5 to 14, or 3 to 12 total atoms including one or
more heteroatoms such as nitrogen, oxygen, or sulfur in the ring
structure. More preferred heteroaryl groups have from 5-10 ring
members where from 1-4 of the ring members are hetero atoms
selected from the group consisting of O, N, and S. Exemplary
heteroaryl groups include, for example, azaindolyl,
benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl,
benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl,
furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl,
indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl,
oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl,
pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl,
pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl,
thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl,
thienyl, thiomorpholinyl, triazolyl or tropanyl, and the like. The
"heteroaryl" may be substituted at one or more ring positions with
one or more substituents such as halogen, azide, alkyl, aralkyl,
alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl,
carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties,
fluoroalkyl (such as trifluromethyl), cyano, or the like. The term
"heteroaryl" also includes polycyclic ring systems having two or
more cyclic rings in which two or more carbons are common to two
adjoining rings (the rings are "fused rings") wherein at least one
of the rings is an aromatic group having one or more heteroatoms in
the ring structure, e.g., the other cyclic rings may be
cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls,
and/or heterocyclyls. Representative examples of bicyclic
heteroaryl include, but are not limited to, benzimidazolyl,
benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl,
benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl,
5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl,
isoquinolinyl, naphthyridinyl, quinolinyl, purinyl,
5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl,
5,6,7,8-tetrahydroquinolin-4-yl,
5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl,
4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, and
6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. Any heteroaryl or
bicyclic heteroaryl can be optionally substituted as detailed
below.
[0085] The term "aralkyl", "arylalkyl", or
"aryl(C.sub.1-C.sub.6)alkyl" is a term of art and as used herein
refers to an alkyl group, for example a C.sub.1-C.sub.6 alkyl
group, substituted with an aryl group, wherein the moiety is
appended to the parent molecule through the alkyl group.
[0086] The term "heteroaralkyl", "heteroarylalkyl", or
"heteroaryl(C.sub.1-C.sub.6)alkyl" is a term of art and as used
herein refers to an alkyl group, for example a C.sub.1-C.sub.6
alkyl group, substituted with a heteroaryl group, appended to the
parent molecular moiety through the alkyl group.
[0087] The term "alkoxy" or "alkoxyl" as used herein means an alkyl
group, as defined herein, appended to the parent molecular moiety
through an oxygen atom. Representative examples of alkoxy include,
but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy,
butoxy, tert-butoxy, pentyloxy, and hexyloxy.
[0088] The term "alkoxycarbonyl" means an alkoxy group, as defined
herein, appended to the parent molecular moiety through a carbonyl
group, represented by --C(.dbd.O)--, as defined herein.
Representative examples of alkoxycarbonyl include, but are not
limited to, methoxycarbonyl, ethoxycarbonyl, and
tert-butoxycarbonyl.
[0089] The term "alkylcarbonyl", as used herein, means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to, acetyl,
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and
1-oxopentyl.
[0090] The term "arylcarbonyl", as used herein, means an aryl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of arylcarbonyl include, but are not limited to, benzoyl
and (2-pyridinyl)carbonyl.
[0091] The term "alkylcarbonyloxy" and "arylcarbonyloxy", as used
herein, means an alkylcarbonyl or arylcarbonyl group, as defined
herein, appended to the parent molecular moiety through an oxygen
atom. Representative examples of alkylcarbonyloxy include, but are
not limited to, acetyloxy, ethylcarbonyloxy, and
tert-butylcarbonyloxy. Representative examples of arylcarbonyloxy
include, but are not limited to phenylcarbonyloxy.
[0092] The term "alkenoxy" or "alkenoxyl" means an alkenyl group,
as defined herein, appended to the parent molecular moiety through
an oxygen atom. Representative examples of alkenoxyl include, but
are not limited to, 2-propen-1-oxyl (i.e.,
CH.sub.2.dbd.CH--CH.sub.2--O--) and vinyloxy (i.e.,
CH.sub.2.dbd.CH--O--).
[0093] The term "aryloxy" as used herein means an aryl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom.
[0094] The term "heteroaryloxy" as used herein means a heteroaryl
group, as defined herein, appended to the parent molecular moiety
through an oxygen atom.
[0095] The term "carbocyclyl" as used herein means a monocyclic or
multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical
containing from 3 to 12 carbon atoms that is completely saturated
or has one or more unsaturated bonds, and for the avoidance of
doubt, the degree of unsaturation does not result in an aromatic
ring system (e.g., phenyl). Examples of carbocyclyl groups include
1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl,
3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl.
[0096] The terms "cyano" and "nitrile" is a term of art and as used
herein refers to --CN.
[0097] The term "nitro", as used herein, means --NO.sub.2.
[0098] The term "halo" is a term of art and as used herein refers
to --F, --Cl, --Br, or --I.
[0099] The term "haloalkyl" as used herein refers to an alkyl
group, as defined herein, wherein some or all of the hydrogens are
replaced with halogen atoms. The term "haloalkoxyl" refers to an
alkoxy group, as defined herein, wherein some or all of the
hydrogens are replaced with halogen atoms. An exemplary haloalkyl
group is trifluoromethyl.
[0100] The term "hydroxy" is a term of art and as used herein
refers to --OH.
[0101] The term "hydroxyalkyl", as used herein, means at least one
hydroxy group, as defined herein, is appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of hydroxyalkyl include, but are not
limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
[0102] The term "silyl", as used herein, includes hydrocarbyl
derivatives of the silyl (H.sub.3Si--) group (i.e.,
(hydrocarbyl).sub.3SH, wherein a hydrocarbyl groups are univalent
groups formed by removing a hydrogen atom from a hydrocarbon, e.g.,
ethyl, phenyl. The hydrocarbyl groups can be combinations of
differing groups which can be varied in order to provide a number
of silyl groups, such as trimethylsilyl (TMS),
tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl
(TBS/TBDMS), triisopropylsilyl (TIPS), and
[2-(trimethylsilyl)ethoxy]methyl (SEM).
[0103] The term "silyloxy", as used herein, means a silyl group, as
defined herein, is appended to the parent molecule through an
oxygen atom.
[0104] Certain compounds contained in compositions of the present
invention may exist in particular geometric or stereoisomeric
forms. In addition, compounds of the present invention may also be
optically active. The present invention contemplates all such
compounds, including cis- and trans-isomers, (R)- and
(S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, the
racemic mixtures thereof, and other mixtures thereof, as falling
within the scope of the invention. Additional asymmetric carbon
atoms may be present in a substituent such as an alkyl group. All
such isomers, as well as mixtures thereof, are intended to be
included in this invention.
[0105] If, for instance, a particular enantiomer of compound of the
present invention is desired, it may be prepared by asymmetric
synthesis, or by derivation with a chiral auxiliary, where the
resulting diastereomeric mixture is separated and the auxiliary
group cleaved to provide the pure desired enantiomers.
Alternatively, where the molecule contains a basic functional
group, such as amino, or an acidic functional group, such as
carboxyl, diastereomeric salts are formed with an appropriate
optically-active acid or base, followed by resolution of the
diastereomers thus formed by fractional crystallization or
chromatographic means well known in the art, and subsequent
recovery of the pure enantiomers.
[0106] It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, fragmentation, decomposition,
cyclization, elimination, or other reaction.
[0107] The term "substituted" is also contemplated to include all
permissible substituents of organic compounds. In a broad aspect,
the permissible substituents include acyclic and cyclic, branched
and unbranched, carbocyclic and heterocyclic, aromatic and
nonaromatic substituents of organic compounds. Illustrative
substituents include, for example, halogen, azide, alkyl, aralkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, (cycloalkyl)alkoxyl,
hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,
phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether,
alkylthio, sulfonyl, aminosulfonyl, sulfonamido, ketone, aldehyde,
ester, heterocyclyl, heterocyclylalkyl, aromatic or heteroaromatic
moieties, aminoalkyl, haloalkyl, fluoroalkyl (such as
trifluoromethyl), haloalkoxyl, cyano, or other substitutents
described above. The permissible substituents may be one or more
and the same or different for appropriate organic compounds. For
purposes of this invention, the heteroatoms such as nitrogen may
have hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valences of
the heteroatoms. This invention is not intended to be limited in
any manner by the permissible substituents of organic
compounds.
[0108] The phrase "protecting group", as used herein, means
temporary substituents which protect a potentially reactive
functional group from undesired chemical transformations. Examples
of such protecting groups include esters of carboxylic acids, silyl
ethers of alcohols, and acetals and ketals of aldehydes and
ketones, respectively. The field of protecting group chemistry has
been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2.sup.nd ed.; Wiley: New York, 1991). Protected
forms of the inventive compounds are included within the scope of
this invention.
[0109] A "saturated" or "fully saturated" compound means that the
referenced chemical structure does not contain any multiple
carbon-carbon bonds. For example, a saturated cycloalkyl group as
defined herein includes cyclohexyl, cyclopropyl, and the like.
[0110] A "unsaturated" or "partially saturated" compound means that
the referenced chemical structure may contains on or more multiple
carbon-carbon bonds, but is not aromatic. For example, a
unsaturated cycloalkyl group as defined herein includes
cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.
[0111] For purposes of the invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87,
inside cover.
[0112] Other chemistry terms herein are used according to
conventional usage in the art, as exemplified by The McGraw-Hill
Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill,
San Francisco, incorporated herein by reference). Unless otherwise
defined, all technical and scientific terms used herein have the
same meaning as commonly understood by one of ordinary skill in the
art to which this invention pertains.
[0113] It will be apparent to one skilled in the art that certain
compounds of this disclosure may exist in tautomeric forms, all
such tautomeric forms of the compounds being within the scope of
the disclosure. Unless otherwise stated, structures depicted herein
are also meant to include all stereochemical forms of the
structure; i.e., the R and S configurations for each asymmetric
center. Therefore, single stereochemical isomers as well as
enantiomeric and diastereomeric mixtures of the present compounds
are within the scope of the disclosure. Both the R and the S
stereochemical isomers, as well as all mixtures thereof, are
included within the scope of the disclosure.
[0114] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0115] The term "pharmaceutically acceptable salt" as used herein
includes salts derived from inorganic or organic acids including,
for example, hydrochloric, hydrobromic, sulfuric, nitric,
perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric,
succinic, tartaric, glycolic, salicylic, citric, methanesulfonic,
benzenesulfonic, benzoic, malonic, trifluoroacetic,
trichloroacetic, naphthalene-2-sulfonic, and other acids.
Pharmaceutically acceptable salt forms can include forms wherein
the ratio of molecules comprising the salt is not 1:1. For example,
the salt may comprise more than one inorganic or organic acid
molecule per molecule of base, such as two hydrochloric acid
molecules per molecule of compound of Formula I. As another
example, the salt may comprise less than one inorganic or organic
acid molecule per molecule of base, such as two molecules of
compound of Formula I per molecule of tartaric acid.
[0116] As used herein, a protic solvent is a solvent that has a
hydrogen atom bound to an oxygen (as in a hydroxyl group) or a
nitrogen (as in an amine group). In general terms, any solvent that
contains labile H.sup.+ is called a protic solvent. The molecules
of such solvents readily donate protons (H.sup.+) to reagents. In
contrast, an aprotic solvent is a solvent that does not have a
hydrogen atom bound to an oxygen (as in a hydroxyl group) or a
nitrogen (as in an amine group), and it cannot donate hydrogen.
[0117] As used herein, a polar protic solvent is a protic solvent
that will dissolve many salts. In general, these solvents have high
dielectric constants and high polarity. Non-limiting examples of
polar protic solvents include acetic acid, ammonia, ethanol, formic
acid, isopropanol, methanol, n-butanol, nitromethane, n-propanol,
t-butanol, and water.
[0118] As used herein, a polar aprotic solvent is a solvent that
will dissolve many salts, but lacks an acidic hydrogen; these
solvents generally have intermediate to high dielectric constants
and polarity. Non-limiting examples of polar aprotic solvents
include acetone, acetonitrile, dichloromethane (DCM), dimethyl
sulfoxide (DMSO), ethyl acetate, hexamethylphosphoric triamide
(HMPT), N,N-dimethylformamide (DMF), and tetrahydrofuran (THF).
[0119] As used herein, a nonpolar aprotic solvent is a solvent that
will dissolve many salts, but lacks an acidic hydrogen; these
solvents generally have low dielectric constants and polarity.
Non-limiting examples of nonpolar aprotic solvents include benzene,
chloroform, cyclohexane, diethyl ether, hexane, pentane, and
toluene.
[0120] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the therapeutically effective
amount of the pharmaceutical composition required. For example, the
physician or veterinarian could start doses of the pharmaceutical
composition or compound at levels lower than that required in order
to achieve the desired therapeutic effect and gradually increase
the dosage until the desired effect is achieved. By
"therapeutically effective amount" is meant the concentration of a
compound that is sufficient to elicit the desired therapeutic
effect. It is generally understood that the effective amount of the
compound will vary according to the weight, sex, age, and medical
history of the subject. Other factors which influence the effective
amount may include, but are not limited to, the severity of the
patient's condition, the disorder being treated, the stability of
the compound, the mode of administration, the bioavailability of
the particular compound, and, if desired, another type of
therapeutic agent being administered with the compound of the
invention. A larger total dose can be delivered by multiple
administrations of the agent. Methods to determine efficacy and
dosage are known to those skilled in the art (Isselbacher et al.
(1996) Harrison's Principles of Internal Medicine 13 ed.,
1814-1882, herein incorporated by reference).
[0121] "Modulating" or "modulate" refers to the treating,
prevention, suppression, enhancement or induction of a function,
condition or disorder.
[0122] The term "treating" includes prophylactic and/or therapeutic
treatments. The term "prophylactic or therapeutic" treatment is
art-recognized and includes administration to the host of one or
more of the subject compositions. If it is administered prior to
clinical manifestation of the unwanted condition (e.g., disease or
other unwanted state of the host animal) then the treatment is
prophylactic (i.e., it protects the host against developing the
unwanted condition), whereas if it is administered after
manifestation of the unwanted condition, the treatment is
therapeutic, (i.e., it is intended to diminish, ameliorate, or
stabilize the existing unwanted condition or side effects
thereof).
[0123] As used herein, "subject" refers to a warm blooded animal
such as a mammal, preferably a human, or a human child, which is
afflicted with, or has the potential to be afflicted with one or
more diseases and disorders described herein.
[0124] "EC.sub.50" refers to a dosage, concentration or amount of a
particular test compound that elicits a dose-dependent response at
50% of maximal expression of a particular response that is induced,
provoked or potentiated by the particular test compound.
[0125] "IC.sub.50" refers to an amount, concentration or dosage of
a particular test compound that achieves a 50% inhibition of a
maximal response in an assay that measures such response.
[0126] Compounds of the Invention
[0127] In certain embodiments, the invention relates to a compound
represented by formula (I), or a pharmaceutically acceptable salt
thereof,
##STR00013##
wherein: [0128] X is N, and Z is CR.sup.10; or X is CR.sup.11, and
Z is N; [0129] R.sup.1 is selected from the group consisting of Y,
aryl substituted by Y, and (C.sub.1-C.sub.6)alkyl substituted by Y;
[0130] Y is --CO.sub.2H, --C(O)O(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)OH, --C(O)N(H)CN, --C(O)NH.sub.2,
--C(O)NH((C.sub.1-C.sub.6)alkyl),
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
--C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), --C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl),
--P(O)(OH).sub.2,
[0130] ##STR00014## ##STR00015## [0131] R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are each independently H,
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, or aryl; or
R.sup.2, taken together with R.sup.6 or R.sup.7, forms a 5- or
6-membered ring; [0132] R.sup.8 is selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, and (C.sub.3-C.sub.6)cycloalkyl; [0133]
R.sup.9 is selected from the group consisting of OH,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
aryl(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, and heteroaryl(C.sub.1-C.sub.6)alkyl; [0134] R.sup.10
and R.sup.11 are each independently selected from H and
(C.sub.1-C.sub.6)alkyl; [0135] m is an integer from 0-5; [0136] n
is an integer from 0-2; [0137] further wherein any occurrence of
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, aryl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, or heteroaryl(C.sub.1-C.sub.6)alkyl is optionally and
independently substituted by one or more substituents selected from
the group consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, aryl, --NH.sub.2,
--NH((C.sub.1-C.sub.6)alkyl), --N((C.sub.1-C.sub.6)alkyl).sub.2,
--OH, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkoxyl, --SH, --S((C.sub.1-C.sub.6)alkyl),
(C.sub.1-C.sub.6)hydroxyalkyl, and
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, --CN, --CF.sub.3,
--C(O)NH.sub.2, --C(O)NH(R.sup.12), --C(O)N(R.sup.12).sub.2,
--N(H)C(O)(R.sup.12), --N(R.sup.12)C(O)(R.sup.12),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(R.sup.12),
--S(O).sub.2N(R.sup.12).sub.2, --N(H)S(O).sub.2(R.sup.12),
--N(R.sup.12)S(O).sub.2(R.sup.12), --NHC(O)NH.sub.2,
--NHC(O)NH(R.sup.12), and --NHC(O)N(R.sup.12).sub.2; and [0138]
each occurrence of R'.sup.2 is independently selected from the
group consisting of (C.sub.1-C.sub.6)alkyl), aryl, and
aryl(C.sub.1-C.sub.6)alkyl.
[0139] In certain embodiments, R.sup.1 is Y.
[0140] In certain embodiments, R.sup.1 is aryl substituted by
Y.
[0141] In certain embodiments, R.sup.1 is (C.sub.1-C.sub.6)alkyl
substituted by Y.
[0142] In certain embodiments, Y is --CO.sub.2H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6)alkyl,
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl), or
1H-tetrazolyl.
[0143] In certain embodiments, the invention relates to a compound
of formula (I), wherein R.sup.1 is selected from the group
consisting of: [0144] CO.sub.2H; [0145] C(O)NH.sub.2; [0146]
C(O)NH((C.sub.1-C.sub.6)alkyl); [0147] C(O)NH(aryl); [0148]
1H-tetrazolyl; [0149] aryl substituted by --CO.sub.2H,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6)alkyl, --C(O)NH(aryl),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl, or 1H-tetrazolyl; and [0150]
(C.sub.1-C.sub.6)alkyl substituted by CO.sub.2H,
--NHC(O)(C.sub.1-C.sub.6)alkyl, --NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)aryl, --NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl, --N(H)S(O).sub.2aryl,
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NH(C.sub.1-C.sub.6)haloalkyl, --S(O).sub.2NHaryl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl, or
--S(O).sub.2NHC(O)aryl.
[0151] In certain embodiments, R.sup.1 is selected from the group
consisting of: [0152] 1H-tetrazolyl; [0153] aryl substituted by
--CO.sub.2H, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NH.sub.2, --S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl, or 1H-tetrazolyl; and
[0154] (C.sub.1-C.sub.6)alkyl substituted by CO.sub.2H,
--NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --S(O).sub.2NH(C.sub.1-C.sub.6)alkyl, or
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl.
[0155] In certain embodiments, the invention relates to a compound
of formula (I), wherein R.sup.2 and R.sup.3 are each independently
selected from the group consisting of H and aryl. In certain
embodiments, R.sup.2 and R.sup.3 are both H.
[0156] In certain embodiments, R.sup.2, taken together with R.sup.6
or R.sup.7, forms a 5- or 6-membered ring, preferably, a 6-membered
ring.
[0157] In certain embodiments, X is N; and Z is CH. In alternative
embodiments, X is CH and Z is N.
[0158] In certain embodiments, R.sup.8 is selected from the group
consisting of halo, (C.sub.1-C.sub.6)haloalkyl, and
(C.sub.1-C.sub.6)alkyl. In certain embodiments, R.sup.8 is
halo.
[0159] In certain embodiments, there is one occurrence of R.sup.8
on the aromatic ring, i.e., m is 1.
[0160] In certain embodiments, R.sup.4, R.sup.5, R.sup.6, and
R.sup.7 are each independently selected from the group consisting
of H and (C.sub.1-C.sub.6)alkyl. In certain embodiments, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are each H.
[0161] In certain embodiments, R.sup.9 is selected from the group
consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
and aryl(C.sub.1-C.sub.6)alkyl.
[0162] In certain embodiments, n is 0.
[0163] In certain embodiments, the invention relates to a compound
of any one of the following structural formulae:
##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021## ##STR00022## ##STR00023## ##STR00024##
[0164] In certain embodiments, the invention relates to a compound
represented by formula (II), or a pharmaceutically acceptable salt
thereof,
##STR00025##
wherein: [0165] X is NH or N(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z
is CR.sup.10; or X is CHR.sup.11 or
C(R.sup.11)(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z is N; [0166]
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7
are each independently H, (C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkyl, or aryl; or R.sup.2, taken together
with R.sup.6 or R.sup.7, forms a 5- or 6-membered ring; [0167]
R.sup.8 is selected from the group consisting of halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, and
(C.sub.3-C.sub.6)cycloalkyl; [0168] R.sup.9 is selected from the
group consisting of Y, aryl substituted by Y, and
(C.sub.1-C.sub.6)alkyl substituted by Y; [0169] Y is --CO.sub.2H,
--C(O)O(C.sub.1-C.sub.6)alkyl, --C(O)N(H)OH, --C(O)N(H)CN,
--C(O)NH.sub.2, --C(O)NH((C.sub.1-C.sub.6)alkyl),
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
--C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), --C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl),
--P(O)(OH).sub.2,
[0169] ##STR00026## ##STR00027## [0170] R.sup.10 and R.sup.11 are
each independently selected from H and (C.sub.1-C.sub.6)alkyl;
[0171] m is an integer from 0-5; and [0172] n is 1 or 2; [0173]
further wherein any occurrence of (C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkoxyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)hydroxyalkyl, heteroaryl, or
heteroaryl(C.sub.1-C.sub.6)alkyl is optionally and independently
substituted by one or more substituents selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, aryl, --NH.sub.2,
--NH((C.sub.1-C.sub.6)alkyl), --N((C.sub.1-C.sub.6)alkyl).sub.2,
--OH, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkoxyl, --SH, --S((C.sub.1-C.sub.6)alkyl),
(C.sub.1-C.sub.6)hydroxyalkyl, and
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, --CN, --CF.sub.3,
--C(O)NH.sub.2, --C(O)NH(R.sup.12), --C(O)N(R.sup.12).sub.2,
--N(H)C(O)(R.sup.12), --N(R.sup.12)C(O)(R.sup.12),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(R.sup.12),
--S(O).sub.2N(R.sup.12).sub.2, --N(H)S(O).sub.2(R.sup.12),
--N(R.sup.12)S(O).sub.2(R.sup.12), --NHC(O)NH.sub.2,
--NHC(O)NH(R.sup.12), and --NHC(O)N(R.sup.12).sub.2; and [0174]
each occurrence of R.sup.12 is independently selected from the
group consisting of (C.sub.1-C.sub.6)alkyl), aryl, and
aryl(C.sub.1-C.sub.6)alkyl.
[0175] In certain embodiments, R.sup.9 is Y.
[0176] In certain embodiments, R.sup.9 is aryl substituted by
Y.
[0177] In certain embodiments, R.sup.9 is (C.sub.1-C.sub.6)alkyl
substituted by Y.
[0178] In certain embodiments, the invention relates to a compound
of formula (II), wherein Y is --CO.sub.2H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6)alkyl,
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl), or
1H-tetrazolyl.
[0179] In certain embodiments, the invention relates to a compound
of formula (II), wherein R.sup.9 is selected from the group
consisting of: [0180] CO.sub.2H; [0181] C(O)NH.sub.2; [0182]
C(O)NH((C.sub.1-C.sub.6)alkyl); [0183] C(O)NH(aryl); [0184]
1H-tetrazolyl; [0185] aryl substituted by --CO.sub.2H,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6)alkyl, --C(O)NH(aryl),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl, or 1H-tetrazolyl; and [0186]
(C.sub.1-C.sub.6)alkyl substituted by CO.sub.2H,
--NHC(O)(C.sub.1-C.sub.6)alkyl, --NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)aryl, --NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl, --N(H)S(O).sub.2aryl,
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NH(C.sub.1-C.sub.6)haloalkyl, --S(O).sub.2NHaryl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl, or
--S(O).sub.2NHC(O)aryl.
[0187] In certain embodiments, there is one occurrence of R.sup.9,
i.e., n is 1.
[0188] In certain embodiments, X is NH; and Z is CH.
[0189] In certain alternative embodiments, X is
N(C(R.sup.1)(R.sup.2)(R.sup.3)); and Z is CH. In certain such
embodiments, R.sup.2 and R.sup.3 are both H. In certain such
embodiments, R.sup.1 is H or (C.sub.1-C.sub.6)alkyl.
[0190] In certain embodiments, R.sup.2, taken together with R.sup.6
or R.sup.7, forms a 5- or 6-membered ring, preferably, a 6-membered
ring.
[0191] In other embodiments, X is CH.sub.2; and Z is N.
[0192] In certain embodiments, R.sup.8 is selected from the group
consisting of halo, (C.sub.1-C.sub.6)haloalkyl, and
(C.sub.1-C.sub.6)alkyl. In certain embodiments, R.sup.8 is
halo.
[0193] In certain embodiments, there is one occurrence of R.sup.8
on the aromatic ring, i.e., m is 1.
[0194] In certain embodiments, R.sup.4, R.sup.5, R.sup.6, and
R.sup.7 are each independently selected from the group consisting
of H and (C.sub.1-C.sub.6)alkyl. In certain embodiments, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are each H.
[0195] In certain embodiments, the invention relates to a compound
represented by formula (III), or a pharmaceutically acceptable salt
thereof,
##STR00028##
wherein: [0196] X is NH or N(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z
is CR.sup.10; or X is CHR.sup.11 or
C(R.sup.11)(C(R.sup.1)(R.sup.2)(R.sup.3)), and Z is N; [0197]
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.7 are each
independently H, (C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkyl, or aryl; or R.sup.1 or R.sup.2, taken
together with or R.sup.7, forms a 5- or 6-membered ring; [0198]
R.sup.6 is selected from the group consisting of Y, aryl
substituted by Y, and (C.sub.1-C.sub.6)alkyl substituted by Y;
[0199] Y is --CO.sub.2H, --C(O)O(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)OH, --C(O)N(H)CN, --C(O)NH.sub.2,
--C(O)NH((C.sub.1-C.sub.6)alkyl),
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
--C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), --C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl),
--P(O)(OH).sub.2,
[0199] ##STR00029## ##STR00030## [0200] R.sup.8 is selected from
the group consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, and (C.sub.3-C.sub.6)cycloalkyl; [0201]
R.sup.9 is selected from the group consisting of OH,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
aryl(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, and heteroaryl(C.sub.1-C.sub.6)alkyl; [0202] R.sup.10
and R.sup.11 are each independently selected from H and
(C.sub.1-C.sub.6)alkyl; [0203] m is an integer from 0-5; and [0204]
n is an integer from 0-2; [0205] further wherein any occurrence of
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, aryl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)hydroxyalkyl,
heteroaryl, or heteroaryl(C.sub.1-C.sub.6)alkyl is optionally and
independently substituted by one or more substituents selected from
the group consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, aryl, --NH.sub.2,
--NH((C.sub.1-C.sub.6)alkyl), --N((C.sub.1-C.sub.6)alkyl).sub.2,
--OH, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxyl,
(C.sub.1-C.sub.6)haloalkoxyl, --SH, --S((C.sub.1-C.sub.6)alkyl),
(C.sub.1-C.sub.6)hydroxyalkyl, and
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, --CN, --CF.sub.3,
--C(O)NH.sub.2, --C(O)NH(R.sup.12), --C(O)N(R.sup.12).sub.2,
--N(H)C(O)(R.sup.12), --N(R.sup.12)C(O)(R.sup.12),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(R.sup.12),
--S(O).sub.2N(R.sup.12).sub.2, --N(H)S(O).sub.2(R.sup.12),
--N(R.sup.12)S(O).sub.2(R.sup.12), --NHC(O)NH.sub.2,
--NHC(O)NH(R.sup.12), and --NHC(O)N(R.sup.12).sub.2; and [0206]
each occurrence of R'.sup.2 is independently selected from the
group consisting of (C.sub.1-C.sub.6)alkyl), aryl, and
aryl(C.sub.1-C.sub.6)alkyl.
[0207] In certain embodiments, R.sup.6 is Y.
[0208] In certain embodiments, R.sup.6 is aryl substituted by
Y.
[0209] In certain embodiments, R.sup.6 is (C.sub.1-C.sub.6)alkyl
substituted by Y.
[0210] In certain embodiments, the invention relates to a compound
of formula (III), wherein Y is --CO.sub.2H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6)alkyl,
--C(O)N((C.sub.1-C.sub.6)alkyl).sub.2, --C(O)NH(aryl),
C(O)N(aryl)((C.sub.1-C.sub.6)alkyl), C(O)N(aryl).sub.2,
--C(O)NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)S(O).sub.2aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)((C.sub.1-C.sub.6)alkyl),
--NHC(O)((C.sub.1-C.sub.6)haloalkyl), --NHC(O)(aryl),
--NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl,
C(O)N(H)S(O).sub.2((C.sub.1-C.sub.6)haloalkyl), or
1H-tetrazolyl.
[0211] In certain embodiments, the invention relates to a compound
of formula (III), wherein R.sup.6 is selected from the group
consisting of: [0212] CO.sub.2H; [0213] C(O)NH.sub.2; [0214]
C(O)NH((C.sub.1-C.sub.6)alkyl); [0215] C(O)NH(aryl); [0216]
1H-tetrazolyl; [0217] aryl substituted by --CO.sub.2H,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6)alkyl, --C(O)NH(aryl),
--S(O).sub.2NH.sub.2, --S(O).sub.2NH((C.sub.1-C.sub.6)alkyl),
--S(O).sub.2NH((C.sub.1-C.sub.6)haloalkyl), --S(O).sub.2NH(aryl),
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O).sub.2NHC(O)aryl, --N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--N(H)(SO.sub.2)aryl, --C(O)N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl,
--C(O)N(H)S(O).sub.2aryl, or 1H-tetrazolyl; and [0218]
(C.sub.1-C.sub.6)alkyl substituted by CO.sub.2H,
--NHC(O)(C.sub.1-C.sub.6)alkyl, --NHC(O)(C.sub.1-C.sub.6)haloalkyl,
--NHC(O)aryl, --NHC(O)NH(C.sub.1-C.sub.6)alkyl, --NHC(O)NHaryl,
--N(H)S(O).sub.2(C.sub.1-C.sub.6)alkyl, --N(H)S(O).sub.2aryl,
--S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6)alkyl,
--S(O).sub.2NH(C.sub.1-C.sub.6)haloalkyl, --S(O).sub.2NHaryl,
--S(O).sub.2NHC(O)(C.sub.1-C.sub.6)alkyl, or
--S(O).sub.2NHC(O)aryl.
[0219] In certain embodiments, n is 1.
[0220] In certain embodiments, X is NH; and Z is CH.
[0221] In certain alternative embodiments, X is
N(C(R.sup.1)(R.sup.2)(R.sup.3)); and Z is CH. In certain such
embodiments, R.sup.2 and R.sup.3 are both H. In certain such
embodiments, R.sup.1 is H or (C.sub.1-C.sub.6)alkyl.
[0222] In certain embodiments, or R.sup.1 or R.sup.2, taken
together with or R.sup.7, forms a 5- or 6-membered ring, preferably
a 6-membered ring.
[0223] In other embodiments, X is CH.sub.2; and Z is N.
[0224] In certain embodiments, R.sup.8 is selected from the group
consisting of halo, (C.sub.1-C.sub.6)haloalkyl, and
(C.sub.1-C.sub.6)alkyl. In certain embodiments, R.sup.8 is
halo.
[0225] In certain embodiments, there is one occurrence of R.sup.8
on the aromatic ring, i.e., m is 1.
[0226] In certain embodiments, R.sup.4, R.sup.5, and R.sup.7 are
each independently selected from the group consisting of H and
(C.sub.1-C.sub.6)alkyl. In certain embodiments, R.sup.4, R.sup.5,
and R.sup.7 are each H.
[0227] In certain embodiments, R.sup.9 is selected from the group
consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
and aryl(C.sub.1-C.sub.6)alkyl.
[0228] In certain embodiments, n is 0.
[0229] The compounds described herein are useful in treating
inflammatory diseases such as esophageal eosinophilic inflammation,
keratoconjunctivitis, seasonal allergic conjunctivitis, dry eye
syndrome, or chronic rhinosinusitis with nasal polyps. The
compounds can be used in treating diseases caused by infectious
agents, such as fungi, worms and parasites. The compounds can be
used in treating chronic obstructive pulmonary disease (COPD) or
autoimmune diseases including but not restricted to inflammatory
bowel disease or rheumatoid arthritis.
[0230] Pharmaceutical Compositions of the Invention
[0231] Another aspect of the invention provides a pharmaceutical
composition of a compound of the invention (e.g., a compound of any
of formulae (I), (II), or (III)), and a pharmaceutically acceptable
carrier.
[0232] The exact nature of the carrier, or, for example excipient
or diluent, will depend upon the desired use for the composition,
and may be suitable or acceptable for veterinary use and/or
suitable or acceptable for human use. The composition may
optionally include one or more additional compounds, including one
or more additional therapeutic agents.
[0233] Compounds of the invention can be combined with other
therapeutic agents. The compound of the invention and other
therapeutic agent may be administered simultaneously or
sequentially. When the other therapeutic agents are administered
simultaneously, they can be administered in the same or separate
formulations, but they are administered substantially at the same
time. The other therapeutic agents are administered sequentially
with one another and with compound of the invention, when the
administration of the other therapeutic agents and the compound of
the invention is temporally separated. The separation in time
between the administration of these compounds may be a matter of
minutes or it may be longer.
[0234] Examples of other therapeutic agents that may be
administered with the compounds of the invention include steroids,
membrane stabilizers, 5LO inhibitors, leukotriene synthesis and
receptor inhibitors, inhibitors of IgE isotype switching or IgE
synthesis, IgG isotype switching or IgG synthesis, .beta.-agonists,
tryptase inhibitors, aspirin, COX inhibitors, methotrexate,
anti-TNF drugs, retuxin, PD4 inhibitors, p38 inhibitors, PDE4
inhibitors, and antihistamines.
[0235] As stated above, an "effective amount" refers to any amount
that is sufficient to achieve a desired biological effect. Combined
with the teachings provided herein, by choosing among the various
active compounds and weighing factors such as potency, relative
bioavailability, patient body weight, severity of adverse
side-effects and preferred mode of administration, an effective
prophylactic or therapeutic treatment regimen can be planned which
does not cause substantial unwanted toxicity and yet is effective
to treat the particular subject. The effective amount for any
particular application can vary depending on such factors as the
disease or condition being treated, the particular compound of the
invention being administered, the size of the subject, or the
severity of the disease or condition. One of ordinary skill in the
art can empirically determine the effective amount of a particular
compound of the invention and/or other therapeutic agent without
necessitating undue experimentation. It is preferred generally that
a maximum dose be used, that is, the highest safe dose according to
some medical judgment. Multiple doses per day may be contemplated
to achieve appropriate systemic levels of compounds. Appropriate
systemic levels can be determined by, for example, measurement of
the patient's peak or sustained plasma level of the drug. "Dose"
and "dosage" are used interchangeably herein.
[0236] Generally, daily oral doses of active compounds will be, for
human subjects, from about 0.0001 milligrams/kg per day, 0.001
milligrams/kg per day, or 0.01 milligrams/kg per day to about 100
milligrams/kg per day or 1000 milligrams/kg per day. It is expected
that oral doses in the range of 0.5 to 50 milligrams/kg, in one or
several administrations per day, will yield the desired results.
Dosage may be adjusted appropriately to achieve desired drug levels
sufficient to achieve or maintain a desired therapeutic effect,
local or systemic, depending upon the mode of administration. For
example, it is expected that intravenous administration would be
from one order to several orders of magnitude lower dose per day.
In the event that the response in a subject is insufficient at such
doses, even higher doses (or effective higher doses by a different,
more localized delivery route) may be employed to the extent that
patient tolerance permits. Multiple doses per day are contemplated
to achieve appropriate systemic levels of compounds. The compounds
may be administered once per week, several times per week (e.g.,
every other day), once per day or multiple times per day, depending
upon, among other things, the mode of administration, the specific
indication being treated and the judgment of the prescribing
physician.
[0237] In one embodiment, intravenous administration of a compound
of the invention may typically be from 0.1 mg/kg/day to 20
mg/kg/day.
[0238] Determination of an effective dosage of a compound for a
particular use and mode of administration is well within the
capabilities of those skilled in the art. Effective dosages may be
estimated initially from in vitro activity and metabolism assays.
For example, an initial dosage of compound for use in animals may
be formulated to achieve a circulating blood or serum concentration
of the metabolite active compound that is at or above an IC.sub.50
of the particular compound as measured in as in vitro assay.
Calculating dosages to achieve such circulating blood or serum
concentrations taking into account the bioavailability of the
particular compound via the desired route of administration is well
within the capabilities of skilled artisans. Initial dosages of
compound can also be estimated from in vivo data, such as animal
models. For any compound described herein the therapeutically
effective amount can be initially determined from animal models. A
therapeutically effective dose can also be determined from human
data for compounds of the invention which have been tested in
humans and for compounds which are known to exhibit similar
pharmacological activities, such as other related active agents.
Higher doses may be required for parenteral administration. The
applied dose can be adjusted based on the relative bioavailability
and potency of the administered compound. Adjusting the dose to
achieve maximal efficacy based on the methods described above and
other methods as are well-known in the art is well within the
capabilities of the ordinarily skilled artisan.
[0239] The formulations of the invention can be administered in
pharmaceutically acceptable solutions, which may routinely contain
pharmaceutically acceptable concentrations of salt, buffering
agents, preservatives, compatible carriers, adjuvants, and
optionally other therapeutic ingredients.
[0240] Pharmaceutical compositions comprising the compound of the
invention may be manufactured by means of conventional mixing,
dissolving, granulating, dragee-making levigating, emulsifying,
encapsulating, entrapping or lyophilization processes. The
compositions may be formulated in conventional manner using one or
more physiologically acceptable carriers, diluents, excipients or
auxiliaries which facilitate processing of the compounds into
preparations which can be used pharmaceutically.
[0241] For use in therapy, an effective amount of the compound of
the invention can be administered to a subject by any mode that
delivers the compound of the invention to the desired surface.
Administering the pharmaceutical composition of the present
invention may be accomplished by any means known to the skilled
artisan. Routes of administration include but are not limited to
oral, buccal, nasal, rectal, vaginal, ocular, topical, intravenous,
intramuscular, intraperitoneal, subcutaneous, transdermal, direct
injection (for example, into an abscess), mucosal, inhalation, and
insufflation.
[0242] For oral administration, the compounds (i.e., compounds of
the invention, and other therapeutic agents) can be formulated
readily by combining the active compound(s) with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, lozenges, capsules, liquids, gels, syrups, slurries,
suspensions and the like, for oral ingestion by a subject to be
treated. Pharmaceutical preparations for oral use can be obtained
as solid excipient, optionally grinding a resulting mixture, and
processing the mixture of granules, after adding suitable
auxiliaries, if desired, to obtain tablets or dragee cores.
Suitable excipients are, in particular, binding agents, fillers,
lubricants, disintegrants, and wetting agents. Suitable fillers
include sugars, including lactose, sucrose, mannitol, or sorbitol;
cellulose preparations such as, for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth, methyl
cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If
desired, disintegrating agents may be added, such as the
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate. Optionally the oral formulations
may also be formulated in saline or buffers, e.g., EDTA for
neutralizing internal acid conditions or may be administered
without any carriers.
[0243] Also specifically contemplated are oral dosage forms of the
above component or components. The component or components may be
chemically modified so that oral delivery of the derivative is
efficacious. Generally, the chemical modification contemplated is
the attachment of at least one moiety to the component molecule
itself, where said moiety permits (a) inhibition of acid
hydrolysis; and (b) uptake into the blood stream from the stomach
or intestine. Also desired is the increase in overall stability of
the component or components and increase in circulation time in the
body. Examples of such moieties include: polyethylene glycol,
copolymers of ethylene glycol and propylene glycol, carboxymethyl
cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and
polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme
Adducts", In: Enzymes as Drugs, Hocenberg and Roberts, eds.,
Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et
al., J Appl Biochem 4:185-9 (1982). Other polymers that could be
used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. Preferred for
pharmaceutical usage, as indicated above, are polyethylene glycol
moieties.
[0244] For the component (or derivative) the location of release
may be the stomach, the small intestine (the duodenum, the jejunum,
or the ileum), or the large intestine. One skilled in the art has
available formulations which will not dissolve in the stomach, yet
will release the material in the duodenum or elsewhere in the
intestine. Preferably, the release will avoid the deleterious
effects of the stomach environment, either by protection of the
compound of the invention (or derivative) or by release of the
biologically active material beyond the stomach environment, such
as in the intestine.
[0245] To ensure full gastric resistance a coating impermeable to
at least pH 5.0 is essential. Examples of the more common inert
ingredients that are used as enteric coatings are cellulose acetate
trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP),
HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit
L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L,
Eudragit S, and shellac. These coatings may be used as mixed
films.
[0246] A coating or mixture of coatings can also be used on
tablets, which are not intended for protection against the stomach.
This can include sugar coatings, or coatings which make the tablet
easier to swallow. Capsules may consist of a hard shell (such as
gelatin) for delivery of dry therapeutic (e.g., powder); for liquid
forms, a soft gelatin shell may be used. The shell material of
cachets could be thick starch or other edible paper. For pills,
lozenges, molded tablets or tablet triturates, moist massing
techniques can be used.
[0247] The therapeutic can be included in the formulation as fine
multi-particulates in the form of granules or pellets of particle
size about 1 mm. The formulation of the material for capsule
administration could also be as a powder, lightly compressed plugs
or even as tablets. The therapeutic could be prepared by
compression.
[0248] Colorants and flavoring agents may all be included. For
example, the compound of the invention (or derivative) may be
formulated (such as by liposome or microsphere encapsulation) and
then further contained within an edible product, such as a
refrigerated beverage containing colorants and flavoring
agents.
[0249] One may dilute or increase the volume of the therapeutic
with an inert material. These diluents could include carbohydrates,
especially mannitol, .alpha.-lactose, anhydrous lactose, cellulose,
sucrose, modified dextrans and starch. Certain inorganic salts may
be also be used as fillers including calcium triphosphate,
magnesium carbonate and sodium chloride. Some commercially
available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and
Avicell.
[0250] Disintegrants may be included in the formulation of the
therapeutic into a solid dosage form. Materials used as
disintegrates include but are not limited to starch, including the
commercial disintegrant based on starch, Explotab. Sodium starch
glycolate, Amberlite, sodium carboxymethylcellulose,
ultramylopectin, sodium alginate, gelatin, orange peel, acid
carboxymethyl cellulose, natural sponge and bentonite may all be
used. Another form of the disintegrants are the insoluble cationic
exchange resins. Powdered gums may be used as disintegrants and as
binders and these can include powdered gums such as agar, Karaya or
tragacanth. Alginic acid and its sodium salt are also useful as
disintegrants.
[0251] Binders may be used to hold the therapeutic agent together
to form a hard tablet and include materials from natural products
such as acacia, tragacanth, starch and gelatin. Others include
methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl
cellulose (CMC). Polyvinyl pyrrolidone (PVP) and
hydroxypropylmethyl cellulose (HPMC) could both be used in
alcoholic solutions to granulate the therapeutic.
[0252] An anti-frictional agent may be included in the formulation
of the therapeutic to prevent sticking during the formulation
process. Lubricants may be used as a layer between the therapeutic
and the die wall, and these can include but are not limited to;
stearic acid including its magnesium and calcium salts,
polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and
waxes. Soluble lubricants may also be used such as sodium lauryl
sulfate, magnesium lauryl sulfate, polyethylene glycol of various
molecular weights, Carbowax 4000 and 6000.
[0253] Glidants that might improve the flow properties of the drug
during formulation and to aid rearrangement during compression
might be added. The glidants may include starch, talc, pyrogenic
silica and hydrated silicoaluminate.
[0254] To aid dissolution of the therapeutic into the aqueous
environment a surfactant might be added as a wetting agent.
Surfactants may include anionic detergents such as sodium lauryl
sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium
sulfonate. Cationic detergents which can be used and can include
benzalkonium chloride and benzethonium chloride. Potential
non-ionic detergents that could be included in the formulation as
surfactants include lauromacrogol 400, polyoxyl 40 stearate,
polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol
monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid
ester, methyl cellulose and carboxymethyl cellulose. These
surfactants could be present in the formulation of the compound of
the invention or derivative either alone or as a mixture in
different ratios.
[0255] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. Microspheres formulated for oral
administration may also be used. Such microspheres have been well
defined in the art. All formulations for oral administration should
be in dosages suitable for such administration.
[0256] Liquid preparations for oral administration may take the
form of, for example, elixirs, solutions, syrups or suspensions, or
they may be presented as a dry product for constitution with water
or other suitable vehicle before use. Such liquid preparations may
be prepared by conventional means with pharmaceutically acceptable
additives such as suspending agents (e.g., sorbitol syrup,
cellulose derivatives or hydrogenated edible fats); emulsifying
agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g.,
almond oil, oily esters, ethyl alcohol, or fractionated vegetable
oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates
or sorbic acid). The preparations may also contain buffer salts,
preservatives, flavoring, coloring and sweetening agents as
appropriate.
[0257] The pharmaceutical compositions may, if desired, be
presented in a pack or dispenser device which may contain one or
more unit dosage forms containing the compound(s). The pack may,
for example, comprise metal or plastic foil, such as a blister
pack. The pack or dispenser device may be accompanied by
instructions for administration.
[0258] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0259] For topical administration, the compound may be formulated
as solutions, gels, ointments, creams, suspensions, etc. as are
well-known in the art. Systemic formulations include those designed
for administration by injection, e.g., subcutaneous, intravenous,
intramuscular, intrathecal or intraperitoneal injection, as well as
those designed for transdermal, transmucosal oral or pulmonary
administration.
[0260] For administration by inhalation, the compounds for use
according to the present invention may be conveniently delivered in
the form of an aerosol spray presentation from pressurized packs or
a nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of e.g., gelatin for use in an inhaler or insufflator
may be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0261] Also contemplated herein is pulmonary delivery of the
compounds of the invention (or derivatives thereof). The compound
of the invention (or derivative) is delivered to the lungs of a
mammal while inhaling and traverses across the lung epithelial
lining to the blood stream. Other reports of inhaled molecules
include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int
J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et
al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989)
(endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989)
(.alpha.1-antitrypsin); Smith et al., 1989, J Clin Invest
84:1145-1146 (a-1-proteinase); Oswein et al., 1990, "Aerosolization
of Proteins", Proceedings of Symposium on Respiratory Drug Delivery
II, Keystone, Colo., March, (recombinant human growth hormone);
Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and
tumor necrosis factor alpha) and Platz et al., U.S. Pat. No.
5,284,656 (granulocyte colony stimulating factor). A method and
composition for pulmonary delivery of drugs for systemic effect is
described in U.S. Pat. No. 5,451,569, issued Sep. 19, 1995 to Wong
et al.
[0262] Contemplated for use in the practice of this invention are a
wide range of mechanical devices designed for pulmonary delivery of
therapeutic products, including but not limited to nebulizers,
metered dose inhalers, and powder inhalers, all of which are
familiar to those skilled in the art.
[0263] Some specific examples of commercially available devices
suitable for the practice of this invention are the Ultravent
nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the
Acorn II nebulizer, manufactured by Marquest Medical Products,
Englewood, Colo.; the Ventolin metered dose inhaler, manufactured
by Glaxo Inc., Research Triangle Park, N.C.; and the Spinhaler
powder inhaler, manufactured by Fisons Corp., Bedford, Mass.
[0264] All such devices require the use of formulations suitable
for the dispensing of compound of the invention (or derivative).
Typically, each formulation is specific to the type of device
employed and may involve the use of an appropriate propellant
material, in addition to the usual diluents, adjuvants and/or
carriers useful in therapy. Also, the use of liposomes,
microcapsules or microspheres, inclusion complexes, or other types
of carriers is contemplated. Chemically modified compound of the
invention may also be prepared in different formulations depending
on the type of chemical modification or the type of device
employed.
[0265] Formulations suitable for use with a nebulizer, either jet
or ultrasonic, will typically comprise compound of the invention
(or derivative) dissolved in water at a concentration of about 0.1
to 25 mg of biologically active compound of the invention per mL of
solution. The formulation may also include a buffer and a simple
sugar (e.g., for compound of the invention stabilization and
regulation of osmotic pressure). The nebulizer formulation may also
contain a surfactant, to reduce or prevent surface induced
aggregation of the compound of the invention caused by atomization
of the solution in forming the aerosol.
[0266] Formulations for use with a metered-dose inhaler device will
generally comprise a finely divided powder containing the compound
of the invention (or derivative) suspended in a propellant with the
aid of a surfactant. The propellant may be any conventional
material employed for this purpose, such as a chlorofluorocarbon, a
hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon,
including trichlorofluoromethane, dichlorodifluoromethane,
dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or
combinations thereof. Suitable surfactants include sorbitan
trioleate and soya lecithin. Oleic acid may also be useful as a
surfactant.
[0267] Formulations for dispensing from a powder inhaler device
will comprise a finely divided dry powder containing compound of
the invention (or derivative) and may also include a bulking agent,
such as lactose, sorbitol, sucrose, or mannitol in amounts which
facilitate dispersal of the powder from the device, e.g., 50 to 90%
by weight of the formulation. The compound of the invention (or
derivative) should advantageously be prepared in particulate form
with an average particle size of less than 10 micrometers (.mu.m),
most preferably 0.5 to 5 .mu.m, for most effective delivery to the
deep lung.
[0268] Nasal delivery of a pharmaceutical composition of the
present invention is also contemplated. Nasal delivery allows the
passage of a pharmaceutical composition of the present invention to
the blood stream directly after administering the therapeutic
product to the nose, without the necessity for deposition of the
product in the lung. Formulations for nasal delivery include those
with dextran or cyclodextran.
[0269] For nasal administration, a useful device is a small, hard
bottle to which a metered dose sprayer is attached. In one
embodiment, the metered dose is delivered by drawing the
pharmaceutical composition of the present invention solution into a
chamber of defined volume, which chamber has an aperture
dimensioned to aerosolize and aerosol formulation by forming a
spray when a liquid in the chamber is compressed. The chamber is
compressed to administer the pharmaceutical composition of the
present invention. In a specific embodiment, the chamber is a
piston arrangement. Such devices are commercially available.
[0270] Alternatively, a plastic squeeze bottle with an aperture or
opening dimensioned to aerosolize an aerosol formulation by forming
a spray when squeezed is used. The opening is usually found in the
top of the bottle, and the top is generally tapered to partially
fit in the nasal passages for efficient administration of the
aerosol formulation. Preferably, the nasal inhaler will provide a
metered amount of the aerosol formulation, for administration of a
measured dose of the drug.
[0271] The compounds, when it is desirable to deliver them
systemically, may be formulated for parenteral administration by
injection, e.g., by bolus injection or continuous infusion.
Formulations for injection may be presented in unit dosage form,
e.g., in ampoules or in multi-dose containers, with an added
preservative. The compositions may take such forms as sterile
suspensions, solutions, or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents.
[0272] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the active compounds in water-soluble
form. Additionally, suspensions of the active compounds may be
prepared as appropriate oily injection suspensions. Suitable
lipophilic solvents or vehicles include fatty oils such as sesame
oil, or synthetic fatty acid esters, such as ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions may
contain substances which increase the viscosity of the suspension,
such as sodium carboxymethylcellulose, sorbitol, or dextran.
Optionally, the suspension may also contain suitable stabilizers or
agents which increase the solubility of the compounds to allow for
the preparation of highly concentrated solutions.
[0273] Alternatively, the active compounds may be in powder form
for constitution with a suitable vehicle, e.g., sterile
pyrogen-free water, buffer, dextrose solution, before use. To this
end, the active compound may be dried by any art-known technique,
such as lyophilization, and reconstituted prior to use.
[0274] The compounds may also be formulated in rectal or vaginal
compositions such as suppositories or retention enemas, e.g.,
containing conventional suppository bases such as cocoa butter or
other glycerides.
[0275] For transmucosal administration, penetrants appropriate to
the barrier to be permeated are used in the formulation. Such
penetrants are known in the art.
[0276] For ocular administration, the compound(s) may be formulated
as a solution, emulsion, suspension, etc. suitable for
administration to the eye. A variety of vehicles suitable for
administering compounds to the eye are known in the art.
[0277] In addition to the formulations described above, for
prolonged delivery, the compounds may also be formulated as a depot
preparation for administration by, for example, implantation or
intramuscular injection. Such long acting formulations may be
formulated with suitable polymeric or hydrophobic materials (for
example as an emulsion in an acceptable oil) or ion exchange
resins, or as sparingly soluble derivatives, for example, as a
sparingly soluble salt. Alternatively, transdermal delivery systems
manufactured as an adhesive disc or patch which slowly releases the
compound for percutaneous absorption may be used. To this end,
permeation enhancers may be used to facilitate transdermal
penetration of the compound.
[0278] The pharmaceutical compositions also may comprise suitable
solid or gel phase carriers or excipients. Examples of such
carriers or excipients include but are not limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
[0279] Suitable liquid or solid pharmaceutical preparation forms
are, for example, aqueous or saline solutions for inhalation,
microencapsulated, encochleated, coated onto microscopic gold
particles, contained in liposomes, nebulized, aerosols, pellets for
implantation into the skin, or dried onto a sharp object to be
scratched into the skin. The pharmaceutical compositions also
include granules, powders, tablets, coated tablets,
(micro)capsules, suppositories, syrups, emulsions, suspensions,
creams, drops or preparations with protracted release of active
compounds, in whose preparation excipients and additives and/or
auxiliaries such as disintegrants, binders, coating agents,
swelling agents, lubricants, flavorings, sweeteners or solubilizers
are customarily used as described above. The pharmaceutical
compositions are suitable for use in a variety of drug delivery
systems. For a brief review of methods for drug delivery, see
Langer R, Science 249:1527-33 (1990), which is incorporated herein
by reference.
[0280] The compounds of the invention and optionally other
therapeutics may be administered per se (neat) or in the form of a
pharmaceutically acceptable salt. When used in medicine the salts
should be pharmaceutically acceptable, but non-pharmaceutically
acceptable salts may conveniently be used to prepare
pharmaceutically acceptable salts thereof. Such salts include, but
are not limited to, those prepared from the following acids:
hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic,
acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane
sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and
benzene sulphonic. Also, such salts can be prepared as alkaline
metal or alkaline earth salts, such as sodium, potassium or calcium
salts of the carboxylic acid group. Typically, such salts are more
soluble in aqueous solutions than the corresponding free acids and
bases, but salts having lower solubility than the corresponding
free acids and bases may also be formed.
[0281] The compounds may alternatively be formulated in the
pharmaceutical composition per se, or in the form of a hydrate,
solvate, or N-oxide.
[0282] Suitable buffering agents include: acetic acid and a salt
(1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a
salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v).
Suitable preservatives include benzalkonium chloride (0.003-0.03%
w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and
thimerosal (0.004-0.02% w/v).
[0283] Pharmaceutical compositions of the invention contain an
effective amount of a compound of the invention and optionally
therapeutic agents included in a pharmaceutically acceptable
carrier. The term "pharmaceutically acceptable carrier" means one
or more compatible solid or liquid filler, diluents or
encapsulating substances which are suitable for administration to a
human or other vertebrate animal. The term "carrier" denotes an
organic or inorganic ingredient, natural or synthetic, with which
the active ingredient is combined to facilitate the application.
The components of the pharmaceutical compositions also are capable
of being commingled with the compounds of the present invention,
and with each other, in a manner such that there is no interaction
which would substantially impair the desired pharmaceutical
efficiency.
[0284] The therapeutic agent(s), including specifically but not
limited to the compound of the invention, may be provided in
particles. Particles as used herein means nanoparticles or
microparticles (or in some instances larger particles) which can
consist in whole or in part of the compound of the invention or the
other therapeutic agent(s) as described herein. The particles may
contain the therapeutic agent(s) in a core surrounded by a coating,
including, but not limited to, an enteric coating. The therapeutic
agent(s) also may be dispersed throughout the particles. The
therapeutic agent(s) also may be adsorbed into the particles. The
particles may be of any order release kinetics, including
zero-order release, first-order release, second-order release,
delayed release, sustained release, immediate release, and any
combination thereof, etc. The particle may include, in addition to
the therapeutic agent(s), any of those materials routinely used in
the art of pharmacy and medicine, including, but not limited to,
erodible, nonerodible, biodegradable, or nonbiodegradable material
or combinations thereof. The particles may be microcapsules which
contain the compound of the invention in a solution or in a
semi-solid state. The particles may be of virtually any shape.
[0285] Both non-biodegradable and biodegradable polymeric materials
can be used in the manufacture of particles for delivering the
therapeutic agent(s). Such polymers may be natural or synthetic
polymers. The polymer is selected based on the period of time over
which release is desired. Bioadhesive polymers of particular
interest include bioerodible hydrogels described in Sawhney H S et
al. (1993) Macromolecules 26:581-7, the teachings of which are
incorporated herein. These include polyhyaluronic acids, casein,
gelatin, glutin, polyanhydrides, polyacrylic acid, alginate,
chitosan, poly(methyl methacrylates), poly(ethyl methacrylates),
poly(butylmethacrylate), poly(isobutyl methacrylate),
poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl
methacrylate), poly(phenyl methacrylate), poly(methyl acrylate),
poly(isopropyl acrylate), poly(isobutyl acrylate), and
poly(octadecyl acrylate).
[0286] The therapeutic agent(s) may be contained in controlled
release systems. The term "controlled release" is intended to refer
to any drug-containing formulation in which the manner and profile
of drug release from the formulation are controlled. This refers to
immediate as well as non-immediate release formulations, with
non-immediate release formulations including but not limited to
sustained release and delayed release formulations. The term
"sustained release" (also referred to as "extended release") is
used in its conventional sense to refer to a drug formulation that
provides for gradual release of a drug over an extended period of
time, and that preferably, although not necessarily, results in
substantially constant blood levels of a drug over an extended time
period. The term "delayed release" is used in its conventional
sense to refer to a drug formulation in which there is a time delay
between administration of the formulation and the release of the
drug there from. "Delayed release" may or may not involve gradual
release of drug over an extended period of time, and thus may or
may not be "sustained release."
[0287] Use of a long-term sustained release implant may be
particularly suitable for treatment of chronic conditions.
"Long-term" release, as used herein, means that the implant is
constructed and arranged to deliver therapeutic levels of the
active ingredient for at least 7 days, and preferably 30-60 days.
Long-term sustained release implants are well-known to those of
ordinary skill in the art and include some of the release systems
described above.
[0288] It will be understood by one of ordinary skill in the
relevant arts that other suitable modifications and adaptations to
the compositions and methods described herein are readily apparent
from the description of the invention contained herein in view of
information known to the ordinarily skilled artisan, and may be
made without departing from the scope of the invention or any
embodiment thereof.
[0289] Methods of the Invention
[0290] Another aspect of the invention is a method for treating
asthma, comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of the invention,
for example a compound of any one of formulae (I), (II), and
(III).
[0291] The invention also provides methods for treating a reaction
caused by an allergen, comprising administering to a subject in
need thereof a therapeutically effective amount of a compound of
the invention, for example a compound of any one of formulae (I),
(II), and (III).
[0292] In certain embodiments, the reaction caused by an allergen
is allergic rhinitis or atopic dermatitis.
[0293] In certain embodiments, the reaction caused by an allergen
is characterized by the occurrence of one or more symptoms, which
can include red eyes, itchiness, runny nose, eczema, impaired
hearing, hives, an asthma attack, increased mucus production in the
lungs, coughing, wheezing, and shortness of breath.
[0294] In certain embodiments, the allergen is mold, mammal dander,
pollen, spores, fungus, dust mites, insects (e.g., cockroaches), or
a chemical (e.g., an isocyanate).
[0295] In certain embodiments, the invention provides methods for
treating a fungal or parasitic infection, comprising administering
to a subject in need thereof a therapeutically effective amount of
a compound of the invention (e.g., a compound of any one of
formulae (I), (II), and (III)). In certain embodiments, the
infections treated in the methods of the invention include
infections caused by fungi, worms, or parasites.
[0296] In another aspect, the invention provides methods for
assessing the efficacy of an agent for treating asthma in a
subject, comprising the steps of:
[0297] a) detecting in a subject sample collected at a first point
in time, the expression level of acidic mammalian chitinase
protein;
[0298] b) repeating step a) at one or more subsequent points in
time after administration of the agent; and
[0299] c) comparing expression level of acidic mammalian chitinase
protein detected in step a) with the expression level(s) detected
in step b), wherein a higher expression level of acidic mammalian
chitinase protein at the first point in time relative to at least
one subsequent point in time indicates that the agent is
efficacious in treating asthma.
[0300] In certain embodiments, an agent identified by such a method
is efficacious in treating asthma, hay fever, allergic rhinitis,
atopic dermatitis, allergic reactions, or a disorder associated
with Th-2.
[0301] Alternatively, the efficacy of an agent for treating asthma
or an allergic reaction can be assessed via measuring the
expression level of an inflammatory mediator such as IL-13, IL-5,
IL-4, eotaxin, IgE, or measuring the amount of inflammatory cells
such as eosinophils, neutrophils, or lymphocytes in brocho-alveolar
washings, sputum, or tissues obtained from a mammal. In certain
such embodiments, the expression level can be measured prior to and
after administration of an agent. When the expression level of the
inflammatory mediator or the level of inflammatory cells decreases
after administration of an agent, such an agent is efficacious in
treating asthma, hay fever, allergic rhinitis, atopic dermatitis,
allergic reactions, or a disorder associated with Th-2.
[0302] Another aspect of the invention provides methods of
identifying an agent for treating asthma, comprising:
[0303] a) contacting a sample comprising acidic mammalian chitinase
protein with the agent; and
[0304] b) determining the ability of the agent to inhibit activity
of acidic mammalian chitinase protein, wherein decreased activity
of acidic mammalian chitinase protein identifies an agent for
treating asthma.
[0305] In certain embodiments, the activity of acidic mammalian
chitinase protein is assessed by fluorescence assay using a reagent
that is hydrolyzed by acidic mammalian chitinase protein. In
certain embodiments, the reagent is 4-methylumbelliferyl
B-D-N,N'-diacetylchitobioside hydrate.
EXAMPLES
[0306] The present invention is further illustrated by the
following examples, which in no way should be construed as limiting
the scope of the claimed invention.
Materials and Methods
Methods of Preparation and Characterization
[0307] The compounds of the present disclosure may be prepared by
use of known chemical reactions and procedures. Representative
methods for synthesizing compounds of the disclosure are presented
below. It is understood that the nature of the substituents
required for the desired target compound often determines the
preferred method of synthesis. All variable groups of these methods
are as described in the generic description if they are not
specifically defined below.
[0308] Those having skill in the art will recognize that the
starting materials and reaction conditions may be varied, the
sequence of the reactions altered, and additional steps employed to
produce compounds encompassed by the present disclosure, as
demonstrated by the following examples. Many general references
providing commonly known chemical synthetic schemes and conditions
useful for synthesizing the disclosed compounds are available (see,
e.g., Smith and March, March's Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, Fifth Edition,
Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic
Chemistry, Including Qualitative Organic Analysis, Fourth Edition,
New York: Longman, 1978).
[0309] The reactions are performed in a solvent appropriate to the
reagents and materials employed and suitable for the
transformations being effected. It will be understood by those
skilled in the art of organic synthesis that the functionality
present on the molecule should be consistent with the
transformations proposed. This will sometimes require a judgment to
modify the order of the synthetic steps or to select one particular
process scheme over another in order to obtain a desired compound
of the disclosure.
[0310] In some cases, protection of certain reactive
functionalities may be necessary to achieve some of the above
transformations. In general, the need for such protecting groups as
well as the conditions necessary to attach and remove such groups
will be apparent to those skilled in the art of organic synthesis.
An authoritative account describing the many alternatives to the
trained practitioner are J. F. W. McOmie, "Protective Groups in
Organic Chemistry," Plenum Press, London and New York 1973, in T.
W. Greene and P. G. M. Wuts, "Protective Groups in Organic
Synthesis," Third edition, Wiley, New York 1999, in "The Peptides;"
Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press,
London and New York 1981, in "Methoden der organischen Chemie,"
Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart
1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide,
Proteine," Verlag Chemie, Weinheim, Deerfield Beach, and Basel
1982, and/or in Jochen Lehmann, "Chemie der Kohlenhydrate:
Monosaccharide and Derivate," Georg Thieme Verlag, Stuttgart 1974.
The protecting groups may be removed at a convenient subsequent
stage using methods known from the art. The disclosures of all
articles and references mentioned in this application, including
patents, are incorporated herein by reference in their
entirety.
[0311] Representative synthetic procedures for the preparation of
compounds of the invention are outlined below. Substituents carry
the same meaning as defined above, unless otherwise noted.
[0312] Starting materials can be obtained from commercial sources
or prepared by well-established literature methods known to those
skilled in the art.
[0313] All solvents, substrates and reagents that were commercially
available were used without further purification. TLC analysis was
performed using pre-coated glass plates (0.2.+-.0.03 mm thickness,
GF-254, particle size 0.01-0.04 mm) from Fluorochem Ltd, UK. Column
chromatography was performed using high-purity grade silica gel
(pore size 60 .ANG., 220-440 mesh particle size, 35-75 .mu.m
particle size) from Fluka.
[0314] .sup.1H and .sup.13C NMR spectra were recorded on a 500 MHz
AVANCE DRX500 or 600 MHz AVANCE DRX600 Bruker NMR
spectrometers.
[0315] .sup.19F NMR spectra were recorded on a 200 MHz AVANCE
Bruker NMR spectrometer.
[0316] All spectra were recorded in appropriate deuterated solvents
(CDCl.sub.3, DMSO-d.sub.6, D.sub.2O, CD.sub.3OD, etc.) that were
commercially available.
[0317] Resonances are given in parts per million relative to
tetramethylsilane. Data are reported as follows: chemical shift,
multiplicity (s=singlet, d=doublet, t=triplet, m=multiplet,
bs=broad singlet), coupling constants (Hz) and integration.
[0318] ESI-MS spectra were obtained on a Waters Alliance 2695
separation module with a PDA 1996 UV detector and Waters Micromass
ZQ 2000 mass detector equipped with Kinetex 2.1/50 mm, 2.6 .mu.m
C18 column eluted with 0.3 mL/min flow of 3-100% gradient (over 6
min) of acetonitrile in water.
Human AMCase Activity Assay
[0319] An enzymatic assay with recombinant human AMCase was used in
order to establish inhibitory activity of the compounds (Boot et
al., 2001, JBC: 276). The assay was run in the 96-well plate
format, each reaction in the total volume of 100 .mu.L.
4-Methylumbelliferyl B-D-N,N'-diacetylchitobioside hydrate was used
as a substrate for the enzyme. Upon hydrolysis by AMCase, the
substrate releases 4-methylumbelliferyl (4MU) that, when ionized in
basic pH, emits fluorescence at 460 nm.
[0320] Briefly, 40 .mu.L of a substrate was added to each well,
followed by 10 .mu.L of compound dilution and 50 .mu.L of hAMCase
recombinant enzyme solution. The reaction was carried out in
citrate buffer, pH 5.2, in the dark, at 37.degree. C. for 60
minutes with shaking. After that time the reaction was stopped by
adding 195 .mu.l of Stop Buffer (pH 10.5) to each well. The
fluorescence of the reaction product was measured in Perkin Elmer
Envision fluorescent plate reader at an excitation wavelength of
355 nm.
[0321] The IC.sub.50 values (noted for compounds below as
"activity") were calculated using GraphPad Prism and divided into
the following groups: Activity hAMCase IC.sub.50:
A=1-10 nM; B=10-100 nM; C=0.1-1 .mu.M; D=1-10 .mu.M; E>10
.mu.M.
Example 1
General Synthetic Procedures
Procedure 1: Reductive Amination--Preparation of Compounds of the
General Formula:
##STR00031##
[0322] wherein: X.dbd.Cl or Br; R is an alkyl, substituted by a
polar functional group (e.g., carboxylic acid, ester, sulfonamide,
nitrile, tetrazole etc.)
Procedure 1A
##STR00032##
[0324] To the solution of N-Boc-piperid-4-one in dichloroethane
(DCE) (2 mL/mmol) or in DCE/AcOH (10:1 v/v, 2 mL/mmol), a primary
alkyl amine R--NH.sub.2 (1 equiv), substituted by a polar
functionality on the alkyl group (e.g., carboxylic acid, ester,
sulfonamide, nitrile, tetrazole, etc.), is added, followed by
addition of NaBH(OAc).sub.3 (2 equiv). The reaction mixture is
stirred for an appropriate period of time (typically 1-15 hours) at
room temperature, and (4-(halo)-phenyl)acetaldehyde (1.5 equiv) is
then added, followed by another portion of NaBH(OAc).sub.3 (2
equiv). The reaction mixture is stirred for another 5 hours at room
temperature after which time it is partitioned between 5%
NaHCO.sub.3 and EtOAc (10 mL/mmol). The organic layer is washed
once again with 5% NaHCO.sub.3, then brine (2.times.) and then is
dried over MgSO.sub.4. After filtration of the drying agent and
stripping the solvent, the desired product is purified either by
crystallization or by flash column chromatography over silica
gel.
Procedure 1B
##STR00033##
[0326] To the solution of N-Boc-piperid-4-one in DCE (2 mL/mmol),
2-(4-(halo)-phenyl)ethylamine (1 equiv) is added followed by
addition of NaBH(OAc).sub.3 (2 equiv). The reaction mixture is
stirred for an appropriate period of time (typically 1-15 hours) at
room temperature, after which time the aldehyde (1.5 equiv)
containing a polar functionality (e.g., carboxylic acid, ester,
sulfonamide, nitrile, tetrazole, etc.) is added, followed by
addition of NaBH(OAc).sub.3 (2 equiv). The reaction mixture is
stirred for another 5 hours at room temperature after which time it
is partitioned between 5% NaHCO.sub.3 and EtOAc (10 mL/mmol). The
organic layer is washed once again with 5% NaHCO.sub.3, then brine
(2.times.) and then is dried over MgSO.sub.4. After filtration of
the drying agent and stripping the solvent, the desired product is
purified either by crystallization or flash column chromatography
over silica gel.
Procedure 2: Deprotection--Preparation of Compounds of the General
Formula:
##STR00034##
[0328] The product of reductive amination described in Procedure 1
is treated with a 4 N solution of HCl (4 mL/mmol of starting
material) in appropriate organic solvent (e.g., EtOAc, 1,4-dioxane,
MeOH, DCM, etc.) for the time necessary for complete consumption of
the starting material (typically 30 min 2 hrs). The volatiles are
then removed in vacuo providing the desired compound in the form of
its hydrochloride salt that is directly taken to the next step
without any further purification.
Procedure 3: Preparation of the Triazolyl Compounds of the General
Formula:
##STR00035##
[0330] The product of the protecting group removal described in
Procedure 2, anhydrous K.sub.2CO.sub.3 (2 equiv) and
S,S'-dimethyl-N-cyano-dithioiminocarbonate (1.2 equiv) are added to
acetonitrile (2 mL/mmol of starting material) and the reaction is
refluxed for 1-7 hours (monitoring by TLC). Hydrazine monohydrate
(3-5 equiv) is then added and the mixture is further refluxed for
another 2-5 hours after which time it is cooled to room temperature
and solids are filtered off. The filtrate is concentrated in vacuo
and the crude product is purified either by crystallization from
appropriate solvent or chromatography over regular silica gel or a
reversed phase C-18 bed.
Example 2
2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)ami-
no-)methyl)benzoic acid
##STR00036##
[0331] Step 1: tert-butyl
4-((4-chlorophenethyl)(2-(methoxycarbonyl)benzyl)amino)piperidine-1-carbo-
xylate
##STR00037##
[0333] The title compound was obtained in a manner described in
Procedure 1B from N-Boc-piperid-4-one,
2-(4-chlorophenyl)ethylamine, and methyl 2-formylbenzoate. ESI MS
for C.sub.27H.sub.35ClN.sub.2O.sub.4: calculated 487.04. found
487.3/489.3 (M+1), 485.3/487.3 (M-1).
Step 2: methyl
2-(((4-chlorophenethyl)(piperidin-4-yl)amino)methyl)benzoate
hydrochloride
##STR00038##
[0335] tert-Butyl
4-((4-chlorophenethyl)(2-(methoxycarbonyl)benzyl)amino)piperidine-1-carbo-
xylate obtained in Step 1 was subjected to the deprotection
reaction as described in Procedure 2 (4 N HCl in AcOEt).
Step 3: Methyl
2-(((1-(5-amino-4H-1,2,4-triazol-3-yl)piperidin-4-yl)(4-chlorophenethyl)a-
mino)-methyl)benzoate
##STR00039##
[0337] Methyl
2-(((4-chlorophenethyl)(piperidin-4-yl)amino)methyl)benzoate
hydrochloride obtained in Step 2 was reacted with K.sub.2CO.sub.3
and S,S'-dimethyl-N-cyano-dithioiminocarbonate, followed by the
cyclization of the intermediate
(N-cyanopiperazine-1-carbimidothioate) with hydrazine monohydrate
in a manner described in Procedure 3. ESI MS for
C.sub.24H.sub.29ClN.sub.6O.sub.2: calculated 468.99. found
469.4/471.4 (M+1), 467.3/469.3 (M-1).
Step 4:
2-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophen-
ethyl)amino)methyl) benzoic acid
[0338] Methyl
2-(((1-(5-amino-4H-1,2,4-triazol-3-yl)piperidin-4-yl)(4-chlorophenethyl)a-
mino)-methyl)benzoate obtained in Step 3 was dissolved in methanol
(10 mL) and 3 mL of 1 N NaOH (aq) was added. The reaction mixture
was stirred for 5 hours at room temperature after which time the
starting material was no longer present. pH of the reaction mixture
was brought to 7 by means of careful addition of 1 N HCl and the
solvents were stripped off. The solid residue was passed through
the reversed phase C-18 column and the product containing fractions
were combined and freeze-dried to give the desired product in a
form of white solid (95 mg, 22% yield)
[0339] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 8.00 (d,
2H, J=7.5 Hz), 7.84 (d, 1H, J=7.5 Hz), 7.66 (t, 1H, J=7.5 Hz), 7.58
(t, 1H, J=7.5 Hz), 7.30 (d, 2H, J=8.5 Hz), 7.11 (d, 2H, J=8.0 Hz),
3.98 (m, 2H), 3.71 (t, 1H, J=11.5 Hz), 3.34 (q, 2H, J=7.0 Hz), 3.21
(brs, 3H), 3.00 (t, 2H, J=12.0 Hz), 2.90 (brs, 1H), 2.17 (d, 2H,
J=11.0 Hz), 1.91 (m, 2H), 1.05 (t, 1H, J=7.0 Hz).
[0340] ESI-MS for C.sub.23H.sub.27ClN.sub.6O.sub.2 expected 454.96.
found 455.3/457.3 (M+1), 453.3/455.3 (M-1).
TABLE-US-00001 Ex # Activity Structure 2 C ##STR00040##
Example 3
3-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl)ami-
no)-methyl)benzoic acid
##STR00041##
[0342] The title compound was prepared exactly in the same manner
as Example 2 (all steps) starting from N-Boc-piperid-4-one,
2-(4-bromophenyl)ethylamine, and methyl 3-formylbenzoate.
[0343] .sup.1H NMR (D.sub.2O, 500 MHz) .delta. [ppm]: 7.77 (s, 1H),
7.73 (d, 1H, J=7.5 Hz), 7.42 (d, 1H, J=7.7 Hz), 7.38 (d, 1H, J=7.9
Hz), 7.35 (d, 2H, J.sub.AA'BB'=8.3 Hz), 6.97 (d, 2H,
J.sub.AA'BB'=8.5 Hz), 3.75 (d, 2H, J=12.6 Hz), 3.71 (s, 2H),
2.73-2.78 (m, 1H), 2.62-2.73 (m, 4H), 2.55-2.59 (m, 2H), 1.90 (d,
2H, J=12.2 Hz), 1.56 (ddd, 2H, J=24.7 Hz, J=12.4 Hz, J=3.4 Hz).
[0344] ESI-MS for C.sub.23H.sub.27BrN.sub.6O.sub.2 calculated
499.41. found 499.2/501.3 (M+1), 497.2/499.3 (M-1).
TABLE-US-00002 Ex # Activity Structure 3 A ##STR00042##
Example 4
4-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl)-am-
ino)methyl)benzoic acid
##STR00043##
[0346] The title compound was prepared exactly in the same manner
as Example 2 (all steps) starting from N-Boc-piperid-4-one,
2-(4-bromophenyl)ethylamine, and methyl 4-formylbenzoate.
[0347] .sup.1H NMR (D.sub.2O, 500 MHz) .delta. [ppm]: 7.21 (d, 2H,
J.sub.AA'BB'=8.5 Hz); 6.78 (d, 2H, J.sub.AA'BB'=8.3 Hz); 6.58 (d,
2H, J.sub.AA'BB'=8.3 Hz); 6.17 (d, 2H, J.sub.AA'BB'=8.3 Hz); 3.80
(d, 1H, J=13.3 Hz); 3.55 (d, 1H, J=13.3 Hz); 3.02-3.07 (m, 2H),
2.90-2.94 (m, 1H); 2.66-2.69 (m, 1H); 2.52-2.55 (m, 1H); 2.26-2.35
(m, 2H); 2.12-2.18 (m, 1H), 1.92-1.99 (m, 1H), 1.40-1.45 (m, 2H),
1.14-1.22 (m, 2H).
[0348] ESI-MS for C.sub.23H.sub.27BrN.sub.6O.sub.2 calculated
499.41. found 499.0/501.0 (M+1), 497.1/499.1 (M-1).
TABLE-US-00003 Ex # Activity Structure 4 A ##STR00044##
Example 5
4-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)ami-
no)-methyl)-2-methylbenzoic acid
##STR00045##
[0350] The title compound was prepared exactly in the same manner
as Example 2 (all steps) starting from N-Boc-piperid-4-one,
2-(4-chlorophenyl)ethylamine, and methyl
4-formyl-2-methylbenzoate.
[0351] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 9.87
(brs, 1H), 7.84 (brs, 1H), 7.47 (brs, 1H), 7.33 (d, J.sub.AB=7.9
Hz, 2H), 7.18 (d, J.sub.AB=7.9 Hz, 2H), 4.53 (brs, 1H), 4.30 (brs,
1H), 3.90-3.80 (m, 2H), 3.57 (brs, 1H), 3.25 (brs, 1H), 3.16 (brs,
1H), 2.97 (brs, 1H), 2.93-2.86 (m, 2H), 2.80 (brs, 1H), 2.50 (s,
3H), 2.11 (brs, 2H), 1.82 (brs, 2H).
[0352] ESI-MS for C.sub.24H.sub.29ClN.sub.6O.sub.2 calculated
468.99. found 469.0/471.0 (M+1), 467.1/469.2 (M-1).
TABLE-US-00004 Ex # Activity Structure 5 A ##STR00046##
Example 6
5-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-am-
ino)methyl)-2-methylbenzoic acid
##STR00047##
[0354] The title compound was prepared exactly in the same manner
as Example 2 (all steps) starting from N-Boc-piperid-4-one,
2-(4-chlorophenyl)ethylamine, and methyl
5-formyl-2-methylbenzoate.
[0355] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 12.85
(brs, 1H), 9.75 (brs, 1H), 8.04 (brs, 1H), 7.62 (brs, 1H), 7.37 (d,
J=7.3 Hz, 1H), 7.32 (d, J.sub.AB=8.3 Hz, 2H), 7.16 (d, J.sub.AB=8.3
Hz, 2H), 4.59-4.50 (m, 1H), 4.34 (brs, 1H), 3.88-3.79 (m, 2H), 3.55
(brs, 1H), 3.25 (brs, 1H), 3.12 (brs, 1H), 2.97 (brs, 1H),
2.92-2.85 (m, 2H), 2.76 (brs, 1H), 2.51 (s, 3H), 2.11 (brs, 2H),
1.18 (brs, 2H).
[0356] ESI-MS for C.sub.24H.sub.29ClN.sub.6O.sub.2 calculated
468.99. found 469.0/471.0 (M+1), 467.2/469.2 (M-1).
TABLE-US-00005 Ex # Activity Structure 6 B ##STR00048##
Example 7
5-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)ami-
no)-methyl)-2-chlorobenzoic acid
##STR00049##
[0358] The title compound was prepared exactly in the same manner
as Example 2 (all steps) starting from N-Boc-piperid-4-one,
2-(4-chlorophenyl)ethylamine, and methyl
2-chloro-5-formylbenzoate.
[0359] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 13.19
(brs, 1H), 10.81 (brs, 1H), 8.09 (brs, 1H), 7.85 (brs, 1H), 7.62
(brs, 1H), 7.33 (d, J=7.5 Hz, 2H), 7.18 (d, J=7.5 Hz, 2H), 4.53
(brs, 1H), 4.37 (brs, 1H), 3.89 (brs, 1H), 3.21 (brs, 1H), 3.07
(brs, 1H), 2.90 (brs, 3H), 2.18 (brs, 2H), 1.89 (brs, 2H).
[0360] ESI-MS for C.sub.23H.sub.26Cl.sub.2N.sub.6O.sub.2 calculated
489.41. found 489.0/491.0 (M+1), 487.2/489.2 (M-1).
TABLE-US-00006 Ex # Activity Structure 7 A ##STR00050##
Example 8
5-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)ami-
no)-methyl)-2-fluorobenzoic acid
##STR00051##
[0362] The title compound was prepared exactly in the same manner
as Example 2 (all steps) starting from N-Boc-piperid-4-one,
2-(4-chlorophenyl)ethylamine, and methyl
2-fluoro-5-formylbenzoate.
[0363] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 10.60
(brs, 1H), 8.15 (brs, 1H), 7.94 (brs, 1H), 7.42-7.36 (m, 1H), 7.32
(d, J.sub.AB=8 Hz, 2H), 7.18 (d, J.sub.AB=8 Hz, 2H), 4.58-4.49
(brs, 1H), 4.41-4.32 (brs, 1H), 3.91-3.80 (brs, 2H), 3.58-3.49
(brs, 1H), 3.30-3.18 (brs, 1H), 3.14-3.00 (brs, 2H), 2.98-2.87
(brs, 2H), 2.87-2.78 (brs, 1H), 2.27-2.12 (brs, 2H), 1.92-1.80
(brs, 2H).
[0364] .sup.19F NMR (DMSO-d.sub.6, 500 MHz), -73.77 ppm.
[0365] ESI-MS for C.sub.23H.sub.26ClFN.sub.6O.sub.2 calculated
472.95. found 473.2/475.2 (M+1), 471.4/473.4 (M-1).
TABLE-US-00007 Ex # Activity Structure 8 B ##STR00052##
Example 9
N-(2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-
amino)-ethyl)benzamide
##STR00053##
[0366] Step 1: Allyl
4-((2-((tert-butoxycarbonyl)amino)ethyl)(4-chlorophenethyl)amino)piperidi-
ne-1-carboxylate
##STR00054##
[0368] To the solution of N-alloc-piperid-4-one in dichloroethane
(DCE) (2 mL/mmol), tert-butyl 2-aminoethylcarbamate
(N-Boc-ethylenediamine) (1 equiv) was added followed by addition of
NaBH(OAc).sub.3 (2 equiv). The reaction mixture was stirred for 5
hours at room temperature. (4-Chlorophenyl)acetaldehyde (1.5 equiv)
was then added, followed by another portion of NaBH(OAc).sub.3 (2
equiv). The reaction mixture was stirred for another 15 hours at
room temperature after which time it was taken between 5%
NaHCO.sub.3 and EtOAc (10 mL/mmol of starting
N-alloc-piperid-4-one). The organic layer was washed once again
with 5% NaHCO.sub.3, then brine (2.times.) and then it was dried
over MgSO.sub.4. After filtration of the drying agent and stripping
the solvent, the desired product was purified by flash column
chromatography over silica gel (yield 75%).
Step 2: Allyl
4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate
hydrochloride
##STR00055##
[0370]
1-Allyloxycarbonyl-N-[2-(tert-butoxycarbonylamino)ethyl]-N-[2-(4-ch-
lorophenyl)ethyl]-piperidin-4-amine obtained in Step 1 was
subjected to the deprotection reaction as described in Procedure 2
(4 N HCl in EtOAc). The crude product that was obtained in this
step was used in the synthesis of Examples 8-13 without any further
purification.
Step 3: Allyl
4-((2-benzamidoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate
##STR00056##
[0372] Allyl
4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate
hydrochloride obtained in Step 2 was suspended in dichloromethane
(4 mL/mmol), the suspension was cooled to -15.degree. C. and DIPEA
(2.2 equiv) followed by benzoyl chloride (1.05 equiv) were added
dropwise over 5 minutes. The cooling bath was removed and the
reaction mixture was allowed to warm to ambient temperature. After
2 h TLC revealed no presence of starting material. The reaction
mixture was diluted with EtOAc (10 mL/mmol of starting material),
washed with 1 M NaOH (2.times.), water (2.times.) and brine
(2.times.) and dried over anhydrous MgSO.sub.4. After filtration of
the drying agent the solvent was stripped off and the crude product
was purified by column chromatography.
Step 4:
N-(2-((4-chlorophenethyl)(piperidin-4-yl)amino)ethyl)benzamide
##STR00057##
[0374] The solution of allyl
4-((2-benzamidoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate,
PhSiH.sub.3 (5 equiv) in DCM (8 mL/mmol) was degassed for 10 min by
bubbling argon through the inserted needle, prior to the addition
of Pd(Ph.sub.3P).sub.4 (5 mol %). After 20 min TLC indicated
completion of reaction. The reaction was concentrated and was
purified by column chromatography in DCM/MeOH solvent system
(gradient 100:1 to 10:1) to give pure product in a form of an
off-white solid.
Step 5:
N-(2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chloroph-
enethyl)amino)-ethyl)benzamide
[0375]
N-(2-((4-Chlorophenethyl)(piperidin-4-yl)amino)ethyl)benzamide
obtained in Step 4 was reacted with K.sub.2CO.sub.3 and
S,S'-dimethyl-N-cyano-dithioiminocarbonate, followed by the
cyclization of the intermediate
(N-cyanopiperazine-1-carbimidothioate) with hydrazine monohydrate
in a manner described in Procedure 3. Purification over silica gel
provided pure product.
[0376] .sup.1H NMR (DMSO-d.sub.6, 600 MHz) .delta. [ppm]: 9.08
(brs, 1H), 7.94-7.91 (m, 2H), 7.54-7.5 (m, 1H), 7.47-7.43 (m, 2H),
7.35 (d, 2H, J=7.7 Hz), 7.32 (d, 2H, J=7.7 Hz), 3.9 (brs, 2H),
3.77-3.7 (m, 3H), 3.44 (brs, 1H), 3.36 (brs, 1H) 3.32-3.24 (m, 2H),
3.18-3.12 (m, 2H), 3.04-2.9 (m, 2H), 2.22-2.13 (m, 2H), 1.82-1.74
(m, 2H).
[0377] ESI-MS for C.sub.24H.sub.30ClN.sub.7O calculated 468.01.
found 468.2/470.1 (M+1), 466.3/468.3 (M-1).
TABLE-US-00008 Ex # Activity Structure 9 B ##STR00058##
Example 10
N-(2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-
-amino)ethyl)acetamide
##STR00059##
[0379] Allyl
4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate
hydrochloride described in Example 9, Step 2, was carried on to the
title compound in a similar manner as described for Example 9,
Steps 3-5, using acetyl chloride instead of benzoyl chloride in the
acylation step (Step 3).
[0380] .sup.1H NMR (DMSO-d.sub.6, 600 MHz) .delta. [ppm]: 8.41 (t,
1H, J=5.6 Hz), 7.39 (d, 2H, J=8.3 Hz), 7.35 (d, 2H, J=8.3 Hz),
3.98-3.92 (m, 2H), 3.71-3.64 (m, 1H), 3.52-3.47 (m, 2H), 3.39-3.23
(m, 3H), 3.2-3.1 (m, 3H), 3.03 (brs, 2H), 2.21-2.12 (m, 2H), 1.81
(s, 3H), 1.82-1.75 (m, 2H).
[0381] ESI-MS for C.sub.19H.sub.28ClN.sub.7O calculated 405.93.
found 406.1/408.1 (M+1), 404.3/406.3 (M-1).
TABLE-US-00009 Ex # Activity Structure 10 C ##STR00060##
Example 11
1-(2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-
-amino)ethyl)-3-methylurea
##STR00061##
[0383] Allyl
4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate
hydrochloride described in Example 9, Step 2, was carried on to the
title compound in a similar manner as described for Example 9,
Steps 3-5, using methyl isocyanate instead of benzoyl chloride in
the urea formation step (Step 3).
[0384] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): 10.78 (s, 1H), 7.40 (d,
2H, J=8.5 Hz), 7.37 (d, 2H, J=8.5 Hz), 6.95 (brs, 1H), 6.60 (brs,
1H), 6.42 (brs, 1H), 3.93 (d, 2H, J=12.5 Hz), 3.63 (t, 1H, J=11
Hz), 3.42-3.26 (m, 5H), 3.11-3.08 (m, 3H), 2.91 (t, 2H, J=12 Hz),
2.56 (s, 3H), 2.08 (t, 3H, J=8.5 Hz), 1.78-1.71 (m, 2H).
[0385] ESI-MS for C.sub.19H.sub.29ClN.sub.8O calculated 420.95.
found 421.2/423.1 (M+1), 419.4/421.4 (M-1).
TABLE-US-00010 Ex # Activity Structure 11 D ##STR00062##
Example 12
1-(2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-
-amino)ethyl)-3-isopropylurea
##STR00063##
[0387] Allyl
4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate
hydrochloride described in Example 9, Step 2, was carried on to the
title compound in a similar manner as described for Example 9,
Steps 3-5, using isopropyl isocyanate instead of benzoyl chloride
in the urea formation step (Step 3).
[0388] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 12.75 (br
s, 1H), 10.97 (s, 1H), 7.53 (br s, 1H), 7.40-7.36 (m, 4H), 6.47 (s,
2H), 3.96-3.93 (m, 2H), 3.68-3.64 (m, 3H), 3.24-3.04 (m, 11H),
2.15-2.08 (m, 2H), 1.01 (two doublets, 6H).
[0389] ESI-MS for C.sub.21H.sub.33ClN.sub.8O calculated 449.00.
found 449.1/451.1 (M+1), 447.4/449.4 (M-1).
TABLE-US-00011 Ex # Activity Structure 12 C ##STR00064##
Example 13
N-(2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-
-amino)ethyl)methanesulfonamide
##STR00065##
[0391] Allyl
4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate
hydrochloride described in Example 9, Step 2, was carried on to the
title compound in a similar manner as described for Example 9,
Steps 3-5, using methanesulfonyl chloride instead of benzoyl
chloride in the sulfonamide formation step (Step 3).
[0392] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 11.00 (s,
1H), 7.58 (s, 1H), 7.41 (d, 2H, J=10 Hz), 7.37 (d, 2H, J=10 Hz),
3.95-3.93 (m, 2H), 3.69-3.67 (m, 2H), 3.25-3.02 (m, 14H), 2.20-2.16
(m, 2H), 1.81-1.77 (m, 2H).
[0393] ESI-MS for C.sub.18H.sub.28ClN.sub.7O.sub.2S calculated
441.99. found 441.9/444.0 (M+1), 441.4/443.4 (M-1).
TABLE-US-00012 Ex # Activity Structure 13 B ##STR00066##
Example 14
N-(2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-
-amino)ethyl)-2,2,2-trifluoroacetamide
##STR00067##
[0395] Allyl
4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate
hydrochloride described in Example 9, Step 2, was carried on to the
title compound in a similar manner as described for Example 9,
Steps 3-5, using trifluoroacetic anhydride instead of benzoyl
chloride in the acylation step (Step 3).
[0396] ESI-MS for C.sub.19H.sub.25ClF.sub.3N.sub.7O calculated
459.91. found 460.2/462.2 (M+1), 458.5/460.5 (M-1).
TABLE-US-00013 Ex # Activity Structure 14 C ##STR00068##
Example 15
4-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl)amin-
o)-methyl)benzenesulfonamide
##STR00069##
[0397] Step 1: tert-butyl
4-((4-bromophenethyl)(4-sulfamoylbenzyl)amino)piperidine-1-carboxylate
##STR00070##
[0399] The title compound was obtained in a manner described in
Procedure 1A from N-Boc-piperid-4-one, (4-bromophenyl)acetaldehyde,
and 4-aminomethylbenzenesulfonamide.
[0400] ESI-MS for C.sub.25H.sub.34BrN.sub.3O.sub.4S calculated
552.54. found 552.6/554.6 (M+1), 550.5/552.5 (M-1).
Step 2:
4-(((4-bromophenethyl)(piperidin-4-yl)amino)methyl)benzenesulfonam-
ide hydrochloride
##STR00071##
[0402] tert-Butyl
4-((4-bromophenethyl)(4-sulfamoylbenzyl)amino)piperidine-1-carboxylate
obtained in Step 1 was subjected to the deprotection reaction as
described in Procedure 2 (4 N HCl in AcOEt).
[0403] ESI-MS for C.sub.20H.sub.26BrN.sub.3O.sub.2S calculated
452.42. found 452.5/454.5 (M+1), 450.5/452.5 (M-1).
Step 3:
4-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophene-
thyl)amino)-methyl)benzenesulfonamide
[0404]
4-(((4-Bromophenethyl)(piperidin-4-yl)amino)methyl)benzenesulfonami-
de hydrochloride obtained in Step 2 was reacted with
K.sub.2CO.sub.3 and S,S'-dimethyl-N-cyano-dithioiminocarbonate,
followed by the cyclization of the intermediate
(N-cyanopiperazine-1-carbimidothioate) with hydrazine monohydrate
in a manner described in Procedure 3.
[0405] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 7.67 (d,
J.sub.AB=8.2 Hz, 2H), 7.39 (d, J.sub.AB=8.2 Hz, 2H), 7.38 (d,
J.sub.AB=8.2 Hz, 2H), 7.25 (s, 2H), 7.06 (d, J.sub.AB=8.2 Hz, 2H),
4.10-4.00 (m, 2H), 3.79-3.76 (brs, 2H), 3.69 (s, 2H), 2.65-2.56 (m,
5H), 1.63-1.60 (m, 2H), 1.43-1.34 (m, 2H).
[0406] ESI MS for C.sub.22H.sub.28BrN.sub.7O.sub.2S calculated
534.48. found 534.5/536.5 (M+1), 532.5/534.5 (M-1).
TABLE-US-00014 Ex # Activity Structure 15 A ##STR00072##
Example 16
N-((4-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl-
)-amino)methyl)phenyl)sulfonyl)acetamide
##STR00073##
[0407] Step 1: tert-butyl
4-((4-(N-acetylsulfamoyl)benzyl)(4-bromophenethyl)amino)piperidine-1-carb-
oxylate
##STR00074##
[0409] tert-Butyl
4-((4-bromophenethyl)(4-sulfamoylbenzyl)amino)piperidine-1-carboxylate
(see Example 15, step 1) was dissolved in anhydrous THF (5 mL/mmol)
under atmosphere of argon and the solution was cooled to 0.degree.
C. Sodium hydride (2 equiv) was then added in one portion and after
10 minutes acetyl chloride (2 equiv) was added dropwise by syringe
over 10 minutes. The cooling batch was removed and the reaction
mixture was allowed to stir for two days after which time the
starting material could no longer be detected. The reaction mixture
was then diluted with EtOAc (12 mL/mmol of starting material),
washed with 1 M NaOH (2.times.), water (2.times.) and brine
(2.times.) and dried over anhydrous MgSO.sub.4. After filtration of
the drying agent the solvent was stripped off and the crude product
was purified by column chromatography (yield 65%).
[0410] ESI MS for C.sub.27H.sub.36BrN.sub.3O.sub.5S calculated
594.57. found 594.8/596.8 (M+1), 592.7/594.7 (M-1).
Step 2:
N-((4-(((4-bromophenethyl)(piperidin-4-yl)amino)methyl)phenyl)sulf-
onyl)acetamide hydrochloride
##STR00075##
[0412] tert-Butyl
4-((4-(N-acetylsulfamoyl)benzyl)(4-bromophenethyl)amino)piperidine-1-carb-
oxylate obtained in Step 1 was subjected to the deprotection
reaction as described in Procedure 2 (4 N HCl in EtOAc). The crude
product was carried on to the next step without further
purification.
[0413] ESI MS for C.sub.22H.sub.28BrN.sub.3O.sub.3S calculated
494.45. found 494.7/496.7 (M+1), 492.6/494.4 (M-1).
Step 3:
N-((4-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromop-
henethyl)amino)-methyl)phenyl)sulfonyl)acetamide
[0414]
N-((4-(((4-Bromophenethyl)(piperidin-4-yl)amino)methyl)phenyl)sulfo-
nyl)acetamide hydrochloride obtained in Step 2 was reacted with
K.sub.2CO.sub.3 and S,S'-dimethyl-N-cyano-dithioiminocarbonate,
followed by the cyclization of the intermediate
(N-cyanopiperazine-1-carbimidothioate) with hydrazine monohydrate
in a manner described in Procedure 3.
[0415] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O, 500 MHz) .delta. [ppm]:
7.93 (d, 2H, J.sub.AA'BB'=6.2 Hz), 7.77 (brs, 2H,), 7.40 (d, 2H,
J.sub.AA'BB'=6.6 Hz), 7.01 (d, 2H, J.sub.AA'BB'=6.4 Hz), 4.41 (brs,
2H), 3.51 (brs, 1H), 3.10-3.14 (m, 2H), 2.73-2.90 (m, 4H), 2.08
(brs, 2H), 1.86 (s, 3H), 1.76-1.79 (m, 2H).
[0416] ESI-MS for C.sub.24H.sub.30BrN.sub.7O.sub.3S calculated
576.52. found 576.9/578.9 (M+1), 574.6/576.4 (M-1).
TABLE-US-00015 Ex # Activity Structure 16 A ##STR00076##
Example 17
N-((4-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl-
)-amino)methyl)phenyl)sulfonyl)isobutyramide
##STR00077##
[0418] The title compound was prepared in the same manner as
Example 16 (all steps) using isobutyryl chloride instead of acetyl
chloride in the acylation step (Step 2).
[0419] .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta. [ppm]: 7.91 (d,
2H, J.sub.AA'BB'=8.3 Hz), 7.50 (d, 2H, J.sub.AA'BB'=8.1 Hz), 7.37
(d, 2H, J.sub.AA'BB'=8.3 Hz), 7.01 (d, 2H, J.sub.AA'BB'=8.3 Hz),
3.89-3.91 (m, 4H), 2.82-2.90 (m, 3H), 2.76 (dd, 2H, J=11.9 Hz,
J=12.2 Hz), 2.65-2.68 (m, 2H), 2.39-2.45 (m, 1H), 1.83 (brd, 2H,
J=11.5 Hz), 1.59-1.66 (m, 2H), 1.00 (d, 6H, J=6.8 Hz).
[0420] ESI-MS for C.sub.26H.sub.34BrN.sub.7O.sub.3S calculated
604.57. found 604.2/606.2 (M+1), 602.3/604.3 (M-1).
TABLE-US-00016 Ex # Activity Structure 17 A ##STR00078##
Example 18
N-((3-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl-
)-amino)methyl)phenyl)sulfonyl)acetamide
##STR00079##
[0422] The title compound was prepared in the same manner as
Example 16 (all steps) starting from N-Boc-piperid-4-one,
(4-bromophenyl)acetaldehyde, and 3-aminomethylbenzene-sulfonamide
in reductive amination Step 1.
[0423] 1H NMR (DMSO-d.sub.6+D.sub.2O, 500 MHz) .delta. [ppm]: 7.75
(s, 1H), 7.58-7.60 (m, 1H), 7.37 (d, 2H, J.sub.AA'BB'=8.2 Hz),
7.29-7.32 (m, 2H), 7.07 (d, 2H, J.sub.AA'BB'=8.2 Hz), 3.76 (brd,
2H, J=11.9 Hz), 3.68 (s, 2H), 2.55-2.63 (m, 7H), 1.70 (s, 3H), 1.64
(brd, 2H, J=11.5 Hz), 1.34-1.42 (m, 2H).
[0424] ESI-MS for C.sub.24H.sub.30BrN.sub.7O.sub.3S calculated
576.52. found 576.0/578.1 (M+1), 574.1/576.2 (M-1).
TABLE-US-00017 Ex # Activity Structure 18 A ##STR00080##
Example 19
3-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)am-
ino)-methyl)-N-(2,2,2-trifluoroethyl)benzenesulfonamide
##STR00081##
[0426] The title compound was prepared as described for Example 15
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and
3-(aminomethyl)-N-(2,2,2-trifluoroethyl)benzenesulfonamide used in
the reductive amination step followed by Procedure 2 and Procedure
3 for N-Boc-deprotection and triazole ring installation,
respectively.
[0427] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 10.95
(brs, 1H), 8.62 (t, 1H, J=6.0 Hz), 7.80 (s, 1H), 7.67 (d, 1H, J=7.3
Hz), 7.46-7.52 (m, 2H), 7.27 (d, 2H, J.sub.AA'BB'=8.3 Hz), 7.15 (d,
2H, J.sub.AA'BB'=8.3 Hz), 5.51 (brs, 2H), 3.82 (brd, 2H, J=11.9
Hz), 3.75 (s, 2H), 3.63-3.70 (m, 2H), 2.61-2.66 (m, 5H), 2.50-2.57
(m, 2H), 1.65 (brd, 2H, J=10.9 Hz), 1.40-1.47 (m, 2H).
[0428] .sup.19F NMR (DMSO-d.sub.6, 500 MHz) -70.39 ppm.
[0429] ESI-MS for C.sub.24H.sub.29ClF.sub.3N.sub.7O.sub.2S
calculated 572.06. found 572.0/574.0 (M+1), 570.2/572.2 (M-1).
TABLE-US-00018 Ex # Activity Structure 19 B ##STR00082##
Example 20
2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)ami-
no)-N-methylacetamide
##STR00083##
[0431] The title compound was prepared as described for Example 15
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and 2-amino-N-methylacetamide used in
the reductive amination step followed by Procedure 2 and Procedure
3 for N-Boc-deprotection and triazole ring installation,
respectively.
[0432] .sup.1H NMR (DMSO-d.sub.6, 600 MHz) .delta. [ppm]: 8.8 (brs,
1H), 7.37 (d, 2H, J=8.3 Hz), 7.29 (d, 2H, J=8.3 Hz), 4.15-4.08 (m,
1H), 3.97 (brs, 1H), 3.95-3.89 (m, 2H), 3.66-3.59 (m, 1H), 3.34
(brs, 2H), 3.02-2.91 (m, 4H), 2.65 (d, 3H, J=4.7 Hz), 2.03 (brs,
2H). 1.76 (brs, 1H), 1.64 (brs, 1H).
[0433] ESI MS for C.sub.18H.sub.26ClN.sub.7O calculated 391.91.
found 392.0/394.0 (M+1), 390.2/392.2 (M-1).
TABLE-US-00019 Ex # Activity Structure 20 C ##STR00084##
Example 21
2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)ami-
no)-N-phenylacetamide
##STR00085##
[0435] The title compound was prepared as described for Example 15
in a manner disclosed in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and 2-amino-N-phenylacetamide used in
the reductive amination step followed by Procedure 2 and Procedure
3 for N-Boc-deprotection and triazole ring installation,
respectively.
[0436] .sup.1H NMR (DMSO-d.sub.6, 600 MHz) .delta. [ppm]: 9.2 (brs,
1H), 7.36 (d, 2H, J=7.9 Hz), 7.29-7.22 (d, 6H), 7.01 (t, 1H, J=7.3
Hz), 3.81 (brs, 1H), 3.79 (brs, 1H), 3.21 (s, 2H), 2.84-2.79 (m,
2H), 2.76-2.72 (m, 3H), 2.62-2.55 (m, 2H), 1.68-1.64 (m, 2H),
1.41-1.34 (m, 2H).
[0437] ESI MS for C.sub.23H.sub.28ClN.sub.7O calculated 453.98.
found 454.0/456.0 (M+1), 452.2/454.2 (M-1).
TABLE-US-00020 Ex # Activity Structure 21 C ##STR00086##
Example 22
2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)ami-
no)-N-isopropylacetamide
##STR00087##
[0439] The title compound was prepared as described for Example 15
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and 2-amino-N-isopropylacetamide,
followed by Procedure 2 and Procedure 3 for N-Boc-deprotection and
triazole ring installation, respectively.
[0440] .sup.1H NMR (DMSO-d.sub.6, 600 MHz) .delta. [ppm]: 8.76
(brs, 1H), 7.37 (d, 2H, J=8.3 Hz), 7.29 (d, 2H, J=8.3 Hz),
4.09-4.04 (m, 1H), 3.92 (brs, 2H), 3.88-3.83 (m, 1H), 3.65-3.59 (m,
2H), 3.4-3.3 (m, 2H), 3.02-2.09 (m, 4H), 2.1-1.99 (m, 2H), 1.8-1.72
(m, 1H), 1.67-1.58 (m, 1H), 1.06 (d, 6H, J=6.6 Hz).
[0441] ESI-MS for C.sub.20H.sub.30ClN.sub.7O calculated 419.96.
found 420.0/422.0 (M+1), 418.2/420.2 (M-1).
TABLE-US-00021 Ex # Activity Structure 22 C ##STR00088##
Example 23
N-(3-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl)--
amino)propyl)methanesulfonamide
##STR00089##
[0443] The title compound was prepared as described for Example 15
in a manner disclosed in Procedure 1A from N-Boc-piperid-4-one,
(4-bromophenyl)acetaldehyde, and
N-(3-aminopropyl)methanesulfonamide, followed by Procedure 2 and
Procedure 3 for N-Boc-deprotection and triazole ring installation,
respectively.
[0444] .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta. [ppm]: 8.38 (d,
2H, J=10 Hz), 8.15 (d, 2H, J=10 Hz), 4.85-4.83 (m, 2H), 4.61-4.56
(m, 1H), 4.32-4.25 (m, 4H), 4.10-4.07 (m, 2H), 3.98-3.94 (m, 4H),
3.84 (s, 3H), 3.07-3.05 (m, 2H), 2.93-2.92 (m, 2H), 2.83-2.75 (m,
2H).
[0445] ESI-MS for C.sub.19H.sub.30BrN.sub.7O.sub.2S calculated
500.46. found 500.1/502.1 (M+1), 498.2/500.2 (M-1).
TABLE-US-00022 Ex # Activity Structure 23 A ##STR00090##
Example 24
N-(3-(1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl)-a-
mino)propyl)-4-methylbenzenesulfonamide
##STR00091##
[0447] The title compound was prepared as described for Example 15
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-bromophenyl)acetaldehyde, and
N-(3-aminopropyl)-4-methylbenzenesulfonamide, followed by Procedure
2 and Procedure 3 for N-Boc-deprotection and triazole ring
installation, respectively.
[0448] .sup.1H NMR (D.sub.2O, 500 MHz) .delta. [ppm]: 7.60 (d, 2H,
10 Hz), 7.41 (d, 2H, 10 Hz), 7.28 (d, 2H, 10 Hz), 7.06 (d, 2H, 10
Hz), 3.69 (dd, 2H), 3.46-2.83 (m, 12H), 2.21 (s, 3H), 1.95-1.92 (m,
2H), 1.65-1.63 (m, 2H).
[0449] ESI-MS for C.sub.25H.sub.34BrN.sub.7O.sub.2S calculated
576.56. found 576.2/578.2 (M+1), 574.3/576.3 (M-1).
TABLE-US-00023 Ex # Activity Structure 24 A ##STR00092##
Example 25
2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-am-
ino)acetic acid
##STR00093##
[0451] The title compound was prepared as described for Example 1
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and glycine methyl ester followed by
Procedure 2 and Procedure 3 for N-Boc-deprotection and triazole
ring installation, respectively. The final hydrolysis of the methyl
ester and purification of the title compound were accomplished in a
manner similar to Example 2, Step 4.
[0452] .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta. [ppm]: 7.35 (d,
2H, J=8.5 Hz), 7.30 (d, 2H, J=8.5 Hz), 4.09 (s, 2H), 3.97 (brd, 2H,
J=13 Hz), 3.71-3.66 (m, 1H), 3.48-3.44 (m, 2H), 3.10-3.07 (m, 2H),
3.03 (t, 2H, J=12.5 Hz), 2.13 (brd, 2H, J=12 Hz), 1.91-1.83 (m,
2H).
[0453] ESI-MS for C.sub.17H.sub.23ClN.sub.6O.sub.2 calculated
378.86. found 379.1/381.1 (M+1), 377.3/379.4 (M-1).
TABLE-US-00024 Ex # Activity Structure 25 D ##STR00094##
Example 26
3-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-am-
ino)propanoic acid
##STR00095##
[0455] The title compound was prepared as described for Example 2
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and methyl 3-aminopropanoate,
followed by Procedure 2 and Procedure 3 for N-Boc-deprotection and
triazole ring installation, respectively. The final hydrolysis of
the methyl ester and purification of the title compound were
accomplished in a manner similar to Example 1, Step 4.
[0456] .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta. [ppm]: 7.33 (s,
4H), 3.99 (brd, 2H, J=13 Hz), 3.55-3.49 (m, 1H), 3.35-3.30 (m, 4H),
3.09-3.06 (m, 2H), 2.87-2.82 (m, 2H), 2.60-2.58 (m, 2H), 1.95 (brd,
2H, J=11.5 Hz), 1.84-1.76 (m, 2H).
[0457] ESI-MS for C.sub.18H.sub.25ClN.sub.6O.sub.2 calculated
392.89. found 393.2/395.2 (M+1), 391.3/393.3 (M-1).
TABLE-US-00025 Ex # Activity Structure 26 D ##STR00096##
Example 27
4-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-am-
ino)butanoic acid
##STR00097##
[0459] The title compound was prepared as described for Example 2
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and methyl 4-aminobutanoate followed
by Procedure 2 and Procedure 3 for N-Boc-deprotection and triazole
ring installation, respectively. The final hydrolysis of the methyl
ester and purification of the title compound were accomplished in a
manner similar to Example 2, Step 4.
[0460] .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta. [ppm]: 7.33 (s,
4H), 4.00 (brd, 2H, J=13 Hz), 3.49-3.44 (m, 1H), 3.24-3.21 (m, 2H),
3.18-3.15 (m, 2H), 3.09-3.05 (m, 2H) 2.88-2.83 (m, 2H), 2.53-2.50
(m, 2H), 2.02 (br d, 2H, J=11 Hz), 1.96-1.92 (m, 2H), 1.84-1.75 (m,
2H).
[0461] ESI-MS for C.sub.19H.sub.27ClN.sub.6O.sub.2 calculated
406.92. found 407.2/409.2 (M+1), 405.3/407.3 (M-1).
TABLE-US-00026 Ex # Activity Structure 27 C ##STR00098##
Example 28
3-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)ami-
no)-3-(4-chlorophenyl)propanoic acid
##STR00099##
[0463] The title compound was prepared as described for Example 2
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and methyl
3-amino-3-(4-chlorophenyl)propanoate, followed by Procedure 2 and
Procedure 3 for N-Boc-deprotection and triazole ring installation,
respectively. The final hydrolysis of the methyl ester and
purification of the title compound were accomplished in a manner
similar to Example 2, Step 4.
[0464] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O, 500 MHz) .delta. [ppm]:
7.60 (d, 2H, J=8.47 Hz), 7.46 (d, 2H, J=8.5 Hz), 7.24 (d, 2H, J=8
Hz), 6.99 (d, 2H, J=7.5 Hz), 4.76 (dd, 1H, J=4 Hz, J=10 Hz), 3.76
(d, 1H, J=12 Hz), 3.69 (d, 1H, J=12.8 Hz), 3.51-3.49 (m, 1H),
3.24-3.10 (m, 4H), 2.97-2.93 (m, 1H), 2.86-2.81 (m, 1H), 2.60-2.51
(m, 2H), 1.90 (d, 1H, J=11.67), 1.79-1.71 (m, 3H).
[0465] ESI-MS for C.sub.24H.sub.28Cl.sub.2N.sub.6O.sub.2 calculated
503.44. found 502.9/504.9 (M+1), 501.2/503.2 (M-1).
TABLE-US-00027 Ex # Activity Structure 28 D ##STR00100##
Example 29
3-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)ami-
no)-2-(4-chlorophenyl)propanoic acid
##STR00101##
[0467] The title compound was prepared as described for Example 2
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and methyl
3-amino-2-(4-chlorophenyl)propanoate, followed by Procedure 2 and
Procedure 3 for N-Boc-deprotection and triazole ring installation,
respectively. The final hydrolysis of the methyl ester and
purification of the title compound were accomplished in a manner
similar to Example 2, Step 4.
[0468] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 7.31 (d,
2H, J=9 Hz), 7.30 (d, 2H, J=9 Hz), 7.22 (d, 2H, J=8 Hz), 4.08-4.05
(m, 1H), 3.90 (dd, 1H, J=9.5 Hz, J=13.5 Hz), 3.76 (m, 2H),
3.59-3.54 (m, 1H), 3.29-3.19 (m, 3H), 2.98-2.82 (m, 4H), 1.93 (d,
2H, J=10 Hz), 1.83-1.75 (m, 1H), 1.66-1.57 (m, 1H).
[0469] ESI-MS for C.sub.24H.sub.28Cl.sub.2N.sub.6O.sub.2 calculated
503.44. found 503.1/505.1 (M+1), 501.3/503.3 (M-1).
TABLE-US-00028 Ex # Activity Structure 29 B ##STR00102##
Example 30
1-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)am-
ino)-methyl)cyclopropanecarboxylic acid
##STR00103##
[0471] The title compound was prepared in a similar manner to
Example 2, as described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and methyl
1-(aminomethyl)cyclopropanecarboxylate followed by Procedure 2 and
Procedure 3 for N-Boc-deprotection and triazole ring installation,
respectively. The final hydrolysis of the methyl ester and
purification of the title compound were accomplished in a manner
similar to Example 1, Step 4.
[0472] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O, 500 MHz) .delta. [ppm]:
7.31 (d, 2H, J=8 Hz), 7.24 (d, 2H, J=8 Hz), 3.73 (d, 2H, J=12 Hz,
3.61-3.57 (m, 1H), 3.32 (t, 2H), 2.98-2.94 (m, 2H), 2.88 (m, 2H),
2.51-2.48 (m, 2H), 1.91 (d, 2H, J=12.80 Hz), 1.70 (br s, 2H), 1.30
(s, 2H), 1.04 (brs, 2H).
[0473] ESI-MS for C.sub.20H.sub.27ClN.sub.6O.sub.2 calculated
418.93. found 419.1/421.1 (M+1), 417.4/419.3 (M-1).
TABLE-US-00029 Ex # Activity Structure 30 D ##STR00104##
Example 31
N-(2-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl-
)-amino)methyl)phenyl)methanesulfonamide
##STR00105##
[0475] The title compound was prepared as described for Example 15
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and
2-(methylsulfonylamino)benzylamine, followed by Procedure 2 and
Procedure 3 for N-Boc-deprotection and triazole ring installation,
respectively.
[0476] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. [ppm]: 7.42 (d,
2H, J=8 Hz), 7.31-7.28 (m, 2H), 7.19 (s, 1H), 7.10 (d, 2H, J=8 Hz),
7.05-7.02 (m, 2H), 6.95 (s, 1H), 4.51 (br s, 2H), 3.96-3.93 (m,
4H), 3.78 (s, 3H), 2.78-2.72 (m, 3H) 1.86-1.84 (m, 4H), 1.72-1.65
(m, 4H).
[0477] ESI-MS for C.sub.23H.sub.30ClN.sub.7O.sub.2S calculated
504.06. found 504.1/506.0 (M+1), 502.2/504.2 (M-1).
TABLE-US-00030 Ex # Activity Structure 31 B ##STR00106##
Example 32
N-(3-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl-
)-amino)methyl)phenyl)methanesulfonamide
##STR00107##
[0479] The title compound was prepared as described for Example 15
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and
3-(methylsulfonylamino)benzylamine, followed by Procedure 2 and
Procedure 3 for N-Boc-deprotection and triazole ring installation,
respectively.
[0480] .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta. [ppm]: 7.26 (s,
1H), 7.19 (t, 1H, J=8 Hz), 7.16 (d, 2H, J=8 Hz), 7.55 (d, 2H, J=8
Hz), 7.03 (m, 2H), 3.80 (m, 2H), 3.67 (s, 2H), 2.87 (s, 3H),
2.71-2.60 (m, 7H), 1.72 (m, 2H) 1.60 (m, 2H).
[0481] ESI-MS for C.sub.23H.sub.30ClN.sub.7O.sub.2S calculated
504.06. found 504.0/506.0 (M+1), 502.1/504.1 (M-1).
TABLE-US-00031 Ex # Activity Structure 32 A ##STR00108##
Example 33
N-(4-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl-
)-amino)methyl)phenyl)methanesulfonamide
##STR00109##
[0483] The title compound was prepared as described for Example 15
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and
4-(methylsulfonylamino)benzylamine, followed by Procedure 2 and
Procedure 3 for N-Boc-deprotection and triazole ring installation,
respectively.
[0484] .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta. [ppm]: 7.60 (d,
2H, J=10 Hz), 7.56 (d, 2H, J=10 Hz), 7.50 (d, 2H, J=10 Hz), 7.42
(d, 2H, J=10 Hz), 4.23-4.20 (m, 2H), 4.03 (s, 2H), 3.28 (s, 3H),
3.10-2.99 (m, 7H), 2.12 (m, 2H), 1.91 (m, 2H).
[0485] ESI-MS for C.sub.23H.sub.30ClN.sub.7O.sub.2S calculated
504.06. found 504.1/506.0 (M+1), 502.2/504.2 (M-1).
TABLE-US-00032 Ex # Activity Structure 33 A ##STR00110##
Example 34
4-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl)-am-
ino)methyl)benzamide
##STR00111##
[0487] The title compound was prepared as described for Example 15
in a manner described in Procedure 1A from N-Boc-piperid-4-one,
(4-bromophenyl)acetaldehyde, and 4-(aminomethyl)benzamide in the
reductive amination, followed by Procedure 2 and Procedure 3 for
N-Boc-deprotection and triazole ring installation,
respectively.
[0488] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 10.88
(brs, 1H), 7.86 (brs, 1H), 7.73 (d, J.sub.AB=8.2 Hz, 2H), 7.38 (d,
J.sub.AB=8.2 Hz, 2H), 7.28 (d, J.sub.AB=8.2 Hz, 2H), 7.25 (brs,
1H), 7.06 (d, J.sub.AB=8.2 Hz, 2H), 5.54 (brs, 2H), 3.80-3.73 (m,
2H), 3.66 (s, 2H), 2.65-2.54 (m, 6H), 2.52-2.48 (m, 1H), 1.63-1.56
(m, 2H), 1.44-1.35 (m, 2H).
[0489] ESI-MS for C.sub.23H.sub.28BrN.sub.7O calculated 498.43.
found 498.1/500.1 (M+1), 496.2/498.2 (M-1).
TABLE-US-00033 Ex # Activity Structure 34 A ##STR00112##
Example 35
4-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl)-am-
ino)methyl)-N-methylbenzamide
##STR00113##
[0491] The title compound was prepared as described for Example 15
in a manner disclosed in Procedure 1A from N-Boc-piperid-4-one,
(4-bromophenyl)acetaldehyde, and 4-(aminomethyl)-N-methylbenzamide
in the reductive amination, followed by Procedure 2 and Procedure 3
for N-Boc-deprotection and triazole ring installation,
respectively.
[0492] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 10.89
(brs, 1H), 8.36-8.30 (m, 1H), 7.68 (d, J.sub.AB=8.0 Hz, 2H), 7.37
(d, J.sub.AB=8.2 Hz, 2H), 7.28 (d, J.sub.AB=8.0 Hz, 2H), 7.06 (d,
J.sub.AB=8.2 Hz, 2H), 5.45 (brs, 1H), 3.81-3.75 (m, 2H), 3.67 (s,
2H), 2.73 (d, J=4.5 Hz, 3H), 2.66-2.55 (m, 5H), 2.53-2.48 (m, 2H),
1.65-1.58 (m, 2H), 1.46-1.36 (m, 2H).
[0493] ESI MS for C.sub.24H.sub.30BrN.sub.7O calculated 512.46.
found 512.2/514.2 (M+1), 510.3/512.4 (M-1).
TABLE-US-00034 Ex # Activity Structure 35 A ##STR00114##
Example 36
N-(3-(1H-tetrazol-5-yl)benzyl)-1-(3-amino-1H-1,2,4-triazol-5-yl)-N-(4-chlo-
rophenethyl)piperidin-4-amine
##STR00115##
[0494] Step 1: tert-Butyl
4-((4-chlorophenethyl)(3-cyanobenzyl)amino)piperidine-1-carboxylate
##STR00116##
[0496] The title compound was obtained in a manner described in
Procedure 1B from N-Boc-piperid-4-one,
2-(4-chlorophenyl)ethylamine, and methyl 3-formylbenzonitrile.
Step 2: tert-Butyl
4-((3-(1H-tetrazol-5-yl)benzyl)(4-chlorophenethyl)amino)piperidine-1-carb-
oxylate
##STR00117##
[0498] tert-Butyl
4-((4-chlorophenethyl)(3-cyanobenzyl)amino)piperidine-1-carboxylate
obtained in Step 1 was dissolved in toluene (5 mL/mmol) and sodium
azide (3 equiv) and triethylamine hydrochloride (0.1 equiv) were
added to this solution. The heterogeneous mixture was refluxed for
3 days after which time the starting material could no longer be
detected. After cooling down to ambient temperature the solids were
filtered off and the solvent was stripped off in vacuo. The crude
product was purified by silica gel chromatography (yield 60%).
Steps 3-4:
1-(3-amino-1H-1,2,4-triazol-5-yl)-N-[3-(2H-tetrazol-5-yl)benzyl-
]-N-[2-(4-chlorophenyl)ethyl]piperidin-4-amine
[0499] tert-Butyl
4-((3-(1H-tetrazol-5-yl)benzyl)(4-chlorophenethyl)amino)piperidine-1-carb-
oxylate obtained in Step 2 was subjected to the N-Boc-deprotection
followed by triazole ring formation as described in Procedure 2 and
Procedure 3 respectively to provide the title compound.
[0500] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O, 500 MHz) .delta. [ppm]:
8.20 (s, 1H), 8.05 (d, 1H, J=7.7 Hz), 7.67-7.73 (m, 2H), 7.25 (d,
2H, J.sub.AA'BB'=7.8 Hz), 7.12 (d, 2H, J.sub.AA'BB'=7.7 Hz), 4.48
(s, 2H), 3.86 (brd, 2H, J=11.7 Hz), 3.55-3.60 (m, 1H), 3.20-3.23
(m, 2H), 2.82-2.87 (m, 4H), 2.12 (brd, 2H, J=10.5 Hz), 1.77-1.85
(m, 2H).
[0501] ESI-MS for C.sub.23H.sub.27ClN.sub.10 calculated 478.99.
found 479.0/481.0 (M+1), 477.2/479.3 (M-1).
TABLE-US-00035 Ex # Activity Structure 36 A ##STR00118##
Example 37
2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)ami-
no)-N-methylethanesulfonamide
##STR00119##
[0503] The title compound was prepared as described for Example 15
in a manner disclosed in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and 2-amino-N-methylethanesulfonamide
in the reductive amination, followed by Procedure 2 and Procedure 3
for N-Boc-deprotection and triazole ring installation,
respectively.
[0504] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. [ppm]: 7.24 (d,
2H, J.sub.AA'BB'=8.3 Hz), 7.09 (d, 2H, J.sub.AA'BB'=8.3 Hz), 5.52
(brs, 1H), 3.85 (d, 2H, J=11.1 Hz), 2.99-3.01 (m, 2H), 2.92-2.93
(m, 2H), 2.61-2.75 (m, 10H), 1.65 (brd, 2H, J=10.9 Hz), 1.46-1.51
(m, 2H).
[0505] ESI MS for C.sub.18H.sub.28ClN.sub.7O.sub.2S calculated
441.99. found 442.1/444.0 (M+1), 440.3/442.3 (M-1).
TABLE-US-00036 Ex # Activity Structure 37 B ##STR00120##
Example 38
N-((2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl-
)-amino)ethyl)sulfonyl)acetamide
##STR00121##
[0506] Step 1: tert-butyl
4-((4-chlorophenethyl)(2-sulfamoylethyl)amino)piperidine-1-carboxylate
##STR00122##
[0508] The title compound was obtained in a manner described in
Procedure 1A from N-Boc-piperid-4-one,
2-(4-chlorophenyl)acetaldehyde, and 2-aminoethanesulfonamide.
Step 2: tert-butyl
4-((2-(N-acetylsulfamoyl)ethyl)(4-chlorophenethyl)amino)piperidine-1-carb-
oxylate
##STR00123##
[0510] The title compound was obtained by acetylation of the
sulfonamide group in a manner described for Example 16, Step 1.
Steps 3-4:
1-(3-amino-1H-1,2,4-triazol-5-yl)-N-{2-[(acetylamino)sulfonyl]e-
thyl}-N-[2-(4-chlorophenyl)ethyl]piperidin-4-amine
[0511] tert-Butyl
4-((2-(N-acetylsulfamoyl)ethyl)(4-chlorophenethyl)amino)piperidine-1-carb-
oxylate obtained in Step 2 was subjected to the N-Boc-deprotection
followed by triazole ring formation as described in Procedure 2 and
Procedure 3 respectively, to provide the title compound.
[0512] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O, 500 MHz) .delta. [ppm]:
7.29 (d, 2H, J.sub.AA'BB'=7.7 Hz), 7.22 (d, 2H, J.sub.AA'BB'=7.7
Hz), 3.75 (brd, 2H, J=12.6 Hz), 3.35-3.37 (m, 2H), 2.92-2.95 (m,
2H), 2.60-2.70 (m, 7H), 1.92 (brs, 3H), 1.65 (brd, 2H, J=10.9 Hz),
1.29-1.36 (m, 2H).
[0513] ESI-MS for C.sub.19H.sub.28ClN.sub.7O.sub.3S calculated
470.00. found 470.0/472.0 (M+1), 468.3/470.3 (M-1).
TABLE-US-00037 Ex # Activity Structure 38 B ##STR00124##
Example 39
4-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)-a-
mino)methyl)-N-(methylsulfonyl)benzamide
##STR00125##
[0514] Step 1: tert-Butyl
4-((4-chlorophenethyl)(4-(methoxycarbonyl)benzyl)amino)piperidine-1-carbo-
xylate
##STR00126##
[0516] The title compound was prepared according to Procedure 1B
starting from N-Boc-piperid-4-one, 2-(4-chlorophenyl)ethylamine,
and methyl 4-formylbenzoate.
Step 2:
4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)(4-chlorophenethyl)amin-
o)methyl)benzoic acid
##STR00127##
[0518] tert-Butyl
4-((4-chlorophenethyl)(4-(methoxycarbonyl)benzyl)amino)piperidine-1-carbo-
xylate obtained in Step 1 was dissolved in MeOH (5 mL/mmol), NaOH
(5 eqs) (as a 0.5 N aqueous solution) was added and the reaction
mixture was stirred at room temperature for 15 hours.). pH of the
reaction was made neutral by careful addition of 0.5 N HCl, and
methanol was removed in vacuo. The precipitated product was
filtered off, washed several times with acetone/diethyl ether
mixture (1:2 v/v) and dried in the air. It was found to be of
sufficient purity to be used in the next step without further
purification.
Step 3:
tert-Butyl-4-((4-chlorophenethyl)(4-((methylsulfonyl)carbamoyl)ben-
zyl)amino)-piperidine-1-carboxylate
##STR00128##
[0520]
4-(((1-(tert-Butoxycarbonyl)piperidin-4-yl)(4-chlorophenethyl)amino-
)methyl)benzoic acid synthesized in Step 2 was dissolved in DCM (5
mL/mmol) and DIPEA (3 equiv) and methanesulfonamide (2 eqs) were
added. The reaction mixture was cooled to 0.degree. C. and TFFH
(1.2 eq) was added in one portion. The reaction mixture was stirred
at 0.degree. C. for 6 hours and then for 15 hours at room
temperature. Ethyl acetate (15 mL/mmol) was added and the solution
was washed sequentially with 5% citric acid (2.times.), 5%
NaHCO.sub.3 (2.times.) and brine (2.times.) and was dried over
MgSO.sub.4. The drying agent was filtered off and the solvents were
evaporated in vacuo. The crude product was purified by silica gel
chromatography.
Steps 4-5:
1-(3-amino-1H-1,2,4-triazol-5-yl)-N-{[4-N-(methylsulfonyl)benza-
mido]methyl}-N-[2-(4-chlorophenyl)ethyl]piperidin-4-amine
[0521] tert-Butyl
4-((4-chlorophenethyl)(4-((methylsulfonyl)carbamoyl)benzyl)amino)-piperid-
ine-1-carboxylate obtained in Step 3 was subjected to the
N-Boc-deprotection followed by triazole ring formation as described
in Procedure 2 and Procedure 3 respectively, to provide the title
compound.
[0522] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O, 500 MHz) .delta. [ppm]:
7.89 (d, 2H, J.sub.AA'BB'=7.5 Hz), 7.45 (d, 2H, J.sub.AA'BB'=7.5
Hz), 7.25 (d, 2H, J.sub.AA'BB'=8.3 Hz), 7.08 (d, 2H,
J.sub.AA'BB'=8.5 Hz), 4.24 (brs, 2H), 3.81 (brd, 2H, J=11.9 Hz),
3.30-3.35 (m, 1H), 3.02-3.05 (m, 2H), 2.95 (s, 3H), 2.72-2.75 (m,
2H), 2.63-2.68 (m, 2H), 1.95-1.97 (m, 2H), 1.63-1.67 (m, 2H).
[0523] ESI-MS for C.sub.24H.sub.30ClN.sub.7O.sub.3S calculated
532.07. found 532.1/534.1 (M+1), 530.3/532.1 (M-1).
TABLE-US-00038 Ex # Activity Structure 39 A ##STR00129##
Example 40
3-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)am-
ino)-methyl)-N-(methylsulfonyl)benzamide
##STR00130##
[0525] The title compound was prepared exactly in the same manner
as Example 38 (all steps) starting from N-Boc-piperid-4-one,
2-(4-chlorophenyl)ethylamine, and methyl 3-formylbenzoate.
[0526] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O, 500 MHz) .delta. [ppm]:
7.95 (s, 1H), 7.81 (d, 1H, J=7.3 Hz), 7.37 (d, 1H, J=6.2 Hz), 7.30
(d, 1H, J=7.3 Hz), 7.26 (d, 2H, J.sub.AA'BB'=8.3 Hz), 7.14 (d, 2H,
J.sub.AA'BB'=8.3 Hz), 3.79-3.85 (m, 4H), 2.91 (s, 3H), 2.52-2.77
(m, 7H), 1.75-1.77 (m, 2H), 1.47-1.50 (m, 2H).
[0527] ESI-MS for C.sub.24H.sub.30ClN.sub.7O.sub.3S calculated
532.07. found 532.1/534.1 (M+1), 530.2/532.2 (M-1).
TABLE-US-00039 Ex # Activity Structure 40 A ##STR00131##
Example 41
5-(((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-chlorophenethyl)am-
ino)-methyl)-2-chloro-N-(methylsulfonyl)benzamide
##STR00132##
[0529] The title compound was prepared exactly in the same manner
as Example 38 (all steps) starting from N-Boc-piperid-4-one,
2-(4-chlorophenyl)ethylamine, and methyl
2-chloro-5-formylbenzoate.
[0530] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. [ppm]: 9.85
(brs, 1H), 7.80 (brs, 1H), 7.69 (brs, 1H), 7.64 (brs, 1H), 7.33 (d,
J=7.6 Hz, 2H), 7.20 (d, J=7.6 Hz, 2H), 4.55 (brs, 1H), 4.34 (brs,
1H), 3.82 (brs, 2H), 3.61 (brs, 2H), 3.35 (s, 3H), 3.29-3.12 (m,
2H), 2.90 (brs, 3H), 2.77 (brs, 1H), 2.10 (brs, 2H), 1.81 (brs,
2H).
[0531] ESI-MS for C.sub.24H.sub.29Cl.sub.2N.sub.7O.sub.3S
calculated 566.51. found 566.1/568.1 (M+1), 564.3/566.3 (M-1).
TABLE-US-00040 Ex # Activity Structure 41 B ##STR00133##
Example 42
N-(2-((1-(3-amino-1H-1,2,4-triazol-5-yl)piperidin-4-yl)(4-bromophenethyl)--
amino)ethyl)-4-methylbenzenesulfonamide
##STR00134##
[0533] The title compound was prepared as described for Example 14
in a manner disclosed in Procedure 1A from N-Boc-piperid-4-one,
(4-bromophenyl)acetaldehyde, and
N-(2-aminoethyl)-4-methylbenzenesulfonamide in reductive amination
step followed by Procedure 2 and Procedure 3 for N-Boc-deprotection
and triazole ring installation, respectively.
[0534] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. [ppm]: 7.68 (d,
2H, J=10 Hz), 7.37 (d, 2H, J=10 Hz), 7.28 (d, 2H, J=10 Hz), 6.92
(d, 2H, J=10 Hz), 5.03 (br s, 1H), 4.45 (br s, 2H), 3.48 (s, 1H),
2.83-2.81 (m, 2H), 2.73-2.68 (m, 2H), 2.56-2.47 (m, 7H), 2.39 (s,
3H), 1.59-1.56 (m, 2H), 1.47-1.40 (m, 2H), 1.39-1.37 (m, 2H).
[0535] ESI-MS for C.sub.24H.sub.32BrN.sub.7O.sub.2S calculated
562.54. found 562.1/564.1 (M+1), 560.2/562.2 (M-1).
TABLE-US-00041 Ex # Activity Structure 42 A ##STR00135##
Example 43
N-((1H-tetrazol-5-yl)methyl)-1-(3-amino-1H-1,2,4-triazol-5-yl)-N-(4-chloro-
phenethyl)piperidin-4-amine
##STR00136##
[0537] The title compound was prepared as described for Example 15
in a manner disclosed in Procedure 1A from N-Boc-piperid-4-one,
(4-chlorophenyl)acetaldehyde, and (1H-tetrazol-5-ylmethyl)amine in
reductive amination step followed by Procedure 2 and Procedure 3
for N-Boc-deprotection and triazole ring installation,
respectively.
[0538] .sup.1H NMR (DMSO-d.sub.6+D.sub.2O, 500 MHz) .delta. [ppm]:
7.30 (d, 2H, J.sub.AA'BB'=8.1 Hz), 7.20 (d, 2H, J.sub.AA'BB'=8.1
Hz), 4.44 (s, 2H), 3.77 (brd, 2H, J=12.4 Hz), 3.24-3.29 (m, 1H),
3.09-3.14 (m, 2H), 2.82-2.86 (m, 2H), 2.79 (t, 2H, J=12.2 Hz), 2.00
(brd, 2H, J=10.9 Hz), 1.57-1.64 (m, 2H).
[0539] ESI-MS for C.sub.17H.sub.23ClN.sub.10 calculated 402.89.
found 403.1/405.1 (M+1), 401.3/405.3 (M-1).
TABLE-US-00042 Ex # Activity Structure 43 B ##STR00137##
INCORPORATION BY REFERENCE
[0540] All U.S. patents, U.S. published patent applications, and
PCT published patent applications designating the U.S. mentioned
herein are hereby incorporated by reference in their entirety as if
each individual publication or patent was specifically and
individually indicated to be incorporated by reference. In case of
conflict, the present application, including any definitions
herein, will control.
EQUIVALENTS
[0541] The foregoing written specification is considered to be
sufficient to enable one skilled in the art to practice the
invention. The present invention is not to be limited in scope by
examples provided, since the examples are intended as a single
illustration of one aspect of the invention and other functionally
equivalent embodiments are within the scope of the invention.
Various modifications of the invention in addition to those shown
and described herein will become apparent to those skilled in the
art from the foregoing description and fall within the scope of the
appended claims. The advantages and objects of the invention are
not necessarily encompassed by each embodiment of the
invention.
* * * * *