U.S. patent application number 12/113609 was filed with the patent office on 2008-08-28 for thiazole-amine compounds for the treatment of neurodegenerative disorders.
This patent application is currently assigned to PFIZER INC.. Invention is credited to Yuhpyng L. Chen, Lei Zhang.
Application Number | 20080207712 12/113609 |
Document ID | / |
Family ID | 34962046 |
Filed Date | 2008-08-28 |
United States Patent
Application |
20080207712 |
Kind Code |
A1 |
Chen; Yuhpyng L. ; et
al. |
August 28, 2008 |
THIAZOLE-AMINE COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE
DISORDERS
Abstract
The present invention relates to compounds of the Formula I
##STR00001## wherein R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.7 are as defined. Compounds of the Formula I have
activity inhibiting production of A.beta.-peptide. The invention
also relates to pharmaceutical compositions and methods of treating
disorders and diseases, for example, neurodegenerative and/or
neurological disorders, e.g., Alzheimer's disease, in a mammal
comprising compounds of the Formula I.
Inventors: |
Chen; Yuhpyng L.;
(Waterford, CT) ; Zhang; Lei; (Waterford,
CT) |
Correspondence
Address: |
PFIZER INC
10555 SCIENCE CENTER DRIVE
SAN DIEGO
CA
92121
US
|
Assignee: |
PFIZER INC.
|
Family ID: |
34962046 |
Appl. No.: |
12/113609 |
Filed: |
May 1, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11078880 |
Mar 11, 2005 |
7384968 |
|
|
12113609 |
|
|
|
|
60558902 |
Apr 1, 2004 |
|
|
|
Current U.S.
Class: |
514/371 ;
548/202 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 29/00 20180101; A61P 11/06 20180101; A61P 21/00 20180101; A61P
25/28 20180101; A61P 25/00 20180101; C07D 277/82 20130101; A61P
35/00 20180101; A61P 25/08 20180101; C07D 277/46 20130101; A61P
9/10 20180101; A61P 9/00 20180101; A61P 31/00 20180101; A61P 37/06
20180101; A61P 1/04 20180101; A61P 43/00 20180101; A61P 17/06
20180101 |
Class at
Publication: |
514/371 ;
548/202 |
International
Class: |
A61K 31/427 20060101
A61K031/427; C07D 277/20 20060101 C07D277/20 |
Claims
1.-24. (canceled)
25. A compound of the Formula I ##STR00006## wherein R.sup.1 is
selected from --C.sub.1-C.sub.20 alkyl, --C.sub.2-C.sub.20 alkenyl,
--C.sub.2-C.sub.20 alkynyl, and --C.sub.6-C.sub.14 aryl wherein
each hydrogen atom of said alkyl, alkenyl and alkynyl, of R.sup.1
is optionally replaced with a --F; wherein when R.sup.1 is alkyl,
alkenyl or alkynyl, R.sup.1 is optionally independently substituted
with from one to three substituents R.sup.1a, and wherein when
R.sup.1 is aryl, then R.sup.1 is optionally independently
substituted with from one to three substituents R.sup.1b; R.sup.1a
is in each instance independently selected from --C.sub.1-C.sub.6
alkyl, --C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --F, --Cl, --Br, --I, --CN, --NO.sub.2,
--OH, --NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--S(O).sub.2NR.sup.9R.sup.10, --C(.dbd.O)R.sup.11,
--S(O).sub.nR.sup.11, --C(.dbd.O)OR.sup.12, --C.sub.3-C.sub.8
cycloalkyl, --C.sub.4-C.sub.8 cycloalkenyl, --(C.sub.5-C.sub.11)bi-
or tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, -(3-8
membered) heterocycloalkyl, --C.sub.6-C.sub.14 aryl, -(5-14
membered) heteroaryl, --C.sub.6-C.sub.14 aryloxy and -(5-14
membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl,
alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.1a are each
optionally independently substituted with from one to three
substituents R.sup.1b; R.sup.1b is in each instance independently
selected from --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, --F, --Cl,
--Br, --I, --CN, --NO.sub.2, --OH, --NR.sup.9R.sup.10,
--C(.dbd.O)NR.sup.9R.sup.10, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.12, --S(O).sub.2NR.sup.9R.sup.10,
--S(O).sub.nR.sup.11, --C.sub.1-C.sub.6 hydroxyalkyl,
--C.sub.6-C.sub.14 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.14 aryloxy and -(5-14 membered) heteroaryloxy,
wherein said alkyl, alkenyl and alkynyl of R.sup.1b are each
optionally independently substituted with from one to six
substituents independently selected from --F, --Cl, --Br and --I;
R.sup.3 is selected from C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6
alkenyl, --C.sub.2-C.sub.6 alkynyl, --(C.sub.zero-C.sub.4
alkylene)-(C.sub.3-C.sub.6 cycloalkyl) and --(C.sub.zero-C.sub.4
alkylene)-(C.sub.3-C.sub.6 cycloalkenyl), wherein said alkyl,
alkenyl and alkynyl of R.sup.3 are each optionally independently
substituted with a substituent selected from --OH,
--C.sub.1-C.sub.4 alkoxy and --S--(C.sub.1-C.sub.4 alkyl); R.sup.4
is --H, --F or --C.sub.1-C.sub.4 alkyl; or R.sup.3 and R.sup.4
together with the carbon atom to which they are both attached may
optionally form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
morpholino, piperidino or perhydro-2H-pyran moiety, wherein said
moiety formed by R.sup.3 and R.sup.4 is optionally substituted with
from one to three substituents independently selected from methyl,
ethyl, allyl, methoxy, ethoxy, --F, --Cl, --OH, --CN, --CF.sub.3
and --OCF.sub.3; R.sup.5 is selected from --H, --C.sub.1-C.sub.6
alkyl and --C.sub.6-C.sub.10 aryl, wherein said alkyl and aryl of
R.sup.5 are optionally independently substituted with from one to
three substituents R.sup.1a; or R.sup.5 and R.sup.1 together with
the nitrogen atom to which they are both attached may optionally
form a -(5-8 membered) heterocycloalkyl, -(5-8 membered)
heterocycloalkenyl or -(5-14 membered) heteroaryl, wherein said
heterocycloalkyl and heterocycloalkenyl optionally contains one to
two further heteroatoms independently selected from N, O, and
S(O).sub.zero-2, and wherein said heteroaryl optionally contains
one to two further heteroatoms independently selected from N, O,
and S, and wherein said heterocycloalkyl, heterocycloalkenyl and
heteroaryl is optionally independently substituted with from one to
three substituents R.sup.1b; R.sup.6 is selected from --H,
--C.sub.1-C.sub.20 alkyl, --F, --Cl, --Br, --I, --CN, --CF.sub.3,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.nR.sup.11,
--C(.dbd.NR.sup.9)R.sup.15, --C.sub.3-C.sub.12 cycloalkyl,
--C.sub.5-C.sub.12 cycloalkenyl, and --C.sub.6-C.sub.10 aryl,
wherein said alkyl, cycloalkyl, cycloalkenyl and aryl of R.sup.6
are each optionally independently substituted with from one to
three substituents R.sup.1b; R.sup.7 is selected from H,
--C.sub.1-C.sub.20 alkyl, --C.sub.2-C.sub.20 alkenyl,
--C.sub.2-C.sub.20 alkynyl, --C.sub.1-C.sub.20 alkoxy,
--C.sub.2-C.sub.20 alkenoxy, --C.sub.2-C.sub.20 alkynoxy, --F,
--Cl, --Br, --I, --CN, --NO.sub.2, --CF.sub.3, --NR.sup.14R.sup.15,
--C(.dbd.O)R.sup.13, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)NR.sup.14R.sup.15, --C(.dbd.NR.sup.9)R.sup.15,
--S(O)R.sup.13, --S(O).sub.2NR.sup.14R.sup.15,
--(C.sub.zero-C.sub.4 alkylene)-(C.sub.3-C.sub.12 cycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-(C.sub.4-C.sub.12 cycloalkenyl),
--(C.sub.zero-C.sub.4 alkylene)-((C.sub.5-C.sub.20)bi- or
tricycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-((C.sub.7-C.sub.20)bi- or tricycloalkenyl),
--(C.sub.zero-C.sub.4 alkylene)-((3-12 membered) heterocycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-((7-20 membered) heterobi- or
heterotricycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.6-C.sub.14 aryl) and --(C.sub.zero-C.sub.4
alkylene)-((5-15 membered) heteroaryl), wherein each hydrogen atom
of said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy and alkynoxy of
R.sup.7 is optionally independently replaced with a --F, and
wherein said cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or
tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl of R.sup.7
are each optionally independently substituted with from one to six
--F, and wherein R.sup.7 is optionally independently substituted
with from one to three substituents independently selected from
R.sup.1a, --(CH.sub.2).sub.1-10NR.sup.9R.sup.10, --C.sub.3-C.sub.12
cycloalkyl, -(4-12 membered) heterocycloalkyl, --C.sub.6-C.sub.14
aryl, -(5-15 membered) heteroaryl, -(4-12 membered)
heterocycloalkoxy, --C.sub.6-C.sub.12 aryloxy and -(5-12 membered)
heteroaryloxy; or R.sup.6 and R.sup.7 together with the carbon
atoms to which they are respectively attached may optionally form a
--C.sub.6-C.sub.8 cycloalkyl, --C.sub.6-C.sub.8 cycloalkenyl,
--C.sub.10-C.sub.14 bicycloalkyl, --C.sub.10-C.sub.14
bicycloalkenyl, -(5-8 membered) heterocycloalkyl, -(5-8 membered)
heterocycloalkenyl, -(10-14 membered) heterobicycloalkyl, -(10-14
membered) heterobicycloalkenyl or --C.sub.6-C.sub.10 aryl fused to
the thiazole ring of Formula I, wherein said heterocycloalkyl and
heterocycloalkenyl contains from one to three heteroatoms
independently selected from N, O and S(O).sub.zero-2, and wherein
said heterobicycloalkyl and heterobicycloalkenyl contains from one
to five heteroatoms independently selected from N, O and
S(O).sub.zero-2, and wherein said cycloalkyl, cycloalkenyl,
bicycloalkyl, bicycloalkenyl, heterocycloalkyl, heterocycloalkenyl,
heterobicycloalkyl, heterobicycloalkenyl and aryl are each
optionally independently substituted with from one to three
substituents R.sup.1b; R.sup.9 and R.sup.10 are each independently
selected from --H, --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6
alkenyl, --C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy and --C.sub.2-C.sub.6 alkynoxy, --OH,
--C(.dbd.O)R.sup.11, --S(O).sub.nR.sup.11, --C(.dbd.O)OR.sup.12,
--S(O).sub.nNR.sup.11R.sup.12, --(C.sub.zero-C.sub.4
alkylene)-(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.4-C.sub.8 cycloalkenyl), --(C.sub.zero-C.sub.4
alkylene)-((C.sub.5-C.sub.11)bi- or tricycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-((C.sub.7-C.sub.11)bi- or
tricycloalkenyl), --(C.sub.zero-C.sub.4 alkylene)-((3-8 membered)
heterocycloalkyl)-(C.sub.zero-C.sub.4 alkylene)-(C.sub.6-C.sub.14
aryl), and --(C.sub.zero-C.sub.4 alkylene)-((5-14 membered)
heteroaryl), wherein each hydrogen atom of said alkyl, alkenyl,
alkynyl, alkoxy, alkenoxy and alkynoxy of R.sup.9 and R.sup.10 is
optionally independently replaced with a --F, and wherein said
cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or
tricycloalkenyl, heterocycloalkyl aryl, and heteroaryl of R.sup.9
and R.sup.10 are each optionally independently substituted with
from one to three substituents independently selected from
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, --F, --Cl,
--Br, --I, --CN, --NO.sub.2, --OH, --NR.sup.14R.sup.15,
--C(.dbd.O)NR.sup.14R.sup.15, C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.12, --S(O).sub.nR.sup.11,
--S(O).sub.2NR.sup.14R.sup.15, --C.sub.1-C.sub.6 hydroxyalkyl,
--(C.sub.zero-C.sub.4)--(C.sub.6-C.sub.14 aryl),
--(C.sub.zero-C.sub.4)-((5-14 membered) heteroaryl),
--C.sub.6-C.sub.14 aryloxy and -(5-14 membered) heteroaryloxy, and
wherein said --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl and
--C.sub.2-C.sub.6 alkynyl substituents of R.sup.9 and R.sup.10 are
each optionally independently substituted with from one to six
atoms independently selected from --F, --Cl, --Br and --I; or
NR.sup.9R.sup.10 may optionally form a (4-7 membered)
heterocycloalkyl or (4-7 membered) heterocycloalkenyl, wherein said
heterocycloalkyl and heterocycloalkenyl optionally independently
contain one or two further heteroatoms independently selected from
N, O, and S(O).sub.zero-2, and wherein said heterocycloalkyl and
heterocycloalkenyl are optionally independently substituted with
from one to three substituents independently selected from
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--C.sub.1-C.sub.6 hydroxyalkyl, --C.sub.2-C.sub.6 hydroxyalkenyl,
--C.sub.2-C.sub.6 hydroxyalkynyl, --F, --Cl, --Br, --I, --CN,
--NO.sub.2, --OH, --NR.sup.14R.sup.15,
--C(.dbd.O)NR.sup.14R.sup.15, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.12, --S(O).sub.nR.sup.11,
--S(O).sub.2NR.sup.12R.sup.14R.sup.15,
--(C.sub.zero-C.sub.4)--(C.sub.6-C.sub.14 aryl),
--(C.sub.zero-C.sub.4)-((5-14 membered) heteroaryl),
--C.sub.6-C.sub.14 aryloxy and -(5-14 membered) heteroaryloxy,
wherein said --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl and
--C.sub.2-C.sub.6 alkynyl substituents of the (4-7 membered)
heterocycloalkyl and (4-7 membered) heterocycloalkenyl of
NR.sup.9R.sup.10 are each optionally independently substituted with
from one to six atoms independently selected from --F, --Cl, --Br
and --I; R.sup.11 and R.sup.12 are each independently selected from
H, --C.sub.1-C.sub.6 alkyl, --(C.sub.zero-C.sub.4
alkylene)-(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.4-C.sub.8 cycloalkenyl), --(C.sub.zero-C.sub.4
alkylene)-((C.sub.5-C.sub.11)bi- or tricycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-((C.sub.7-C.sub.11)bi- or
tricycloalkenyl), --(C.sub.zero-C.sub.4 alkylene)-((3-8 membered)
heterocycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.6-C.sub.10 aryl) and --(C.sub.zero-C.sub.4
alkylene)-((5-14 membered) heteroaryl), wherein R.sup.11 and
R.sup.12 are optionally independently substituted with one to three
substitutents independently selected from --OH, --C.sub.1-C.sub.12
alkyl, --C.sub.2-C.sub.12 alkenyl, --C.sub.2-C.sub.12 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl, --F,
--Cl, --Br, --I, --CN, --NO.sub.2, --CF.sub.3, --NR.sup.14R.sup.15,
--C(.dbd.O)N NR.sup.14R.sup.15, --SO.sub.2NR.sup.14R.sup.15,
--C(.dbd.O)H, --C(.dbd.O)OH and --C(.dbd.O)O(C.sub.1-C.sub.6
alkyl), wherein said alkyl, alkenyl and alkynyl substituents of
R.sup.11 and R.sup.12 are each optionally independently further
substituted with from one to six --F, or with from one to two
substituents independently selected from --C.sub.1-C.sub.4 alkoxy,
or with an --OH; R.sup.13 is selected from H, --C.sub.1-C.sub.6
alkyl, --C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--(C.sub.zero-C.sub.4 alkylene)-(C.sub.3-C.sub.12 cycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-(C.sub.4-C.sub.12 cycloalkenyl),
--(C.sub.zero-C.sub.4 alkylene)-((C.sub.5-C.sub.20)bi- or
tricycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-((C.sub.7-C.sub.20)bi- or tricycloalkenyl),
--(C.sub.zero-C.sub.4 alkylene)-((3-12 membered) heterocycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-((7-20 membered) heterobi- or
heterotricycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.6-C.sub.14 aryl) and --(C.sub.zero-C.sub.4
alkylene)-((5-14 membered) heteroaryl), wherein each hydrogen atom
of said --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl and
--C.sub.2-C.sub.6 alkynyl of R.sup.13 is optionally independently
replaced with a --F, and wherein R.sup.13 is optionally
independently substituted with from one to three substitutents
independently selected from --OH, --C.sub.1-C.sub.12 alkyl,
--C.sub.2-C.sub.12 alkenyl, --C.sub.2-C.sub.12 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl, --F,
--Cl, --Br, --I, --CN, --NO.sub.2, --CF.sub.3, --NR.sup.14R.sup.15,
--C(.dbd.O)N NR.sup.14R.sup.15, --SO.sub.2NR.sup.14R.sup.15,
--C(.dbd.O)H, --C(.dbd.O)OH and --C(.dbd.O)O(C.sub.1-C.sub.6
alkyl), wherein said alkyl, alkenyl and alkynyl substituents of
R.sup.13 are each optionally independently further substituted with
from one to six --F, or with from one to two substituents
independently selected from --C.sub.1-C.sub.4 alkoxy, or with an
--OH; R.sup.14 and R.sup.15 are each independently selected from
--H, --C.sub.1-C.sub.20 alkyl, --C.sub.2-C.sub.20 alkenyl,
--C.sub.2-C.sub.20 alkynyl, --C(.dbd.O)R.sup.11,
--S(O).sub.nR.sup.11, --C(.dbd.O)OR.sup.12,
--S(O).sub.2NR.sup.11R.sup.12, --(C.sub.zero-C.sub.4
alkylene)-(C.sub.3-C.sub.12 cycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.4-C.sub.12 cycloalkenyl), --(C.sub.zero-C.sub.4
alkylene)-((C.sub.5-C.sub.20)bi- or tricycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-((C.sub.7-C.sub.20)bi- or
tricycloalkenyl), --(C.sub.zero-C.sub.4 alkylene)-((3-8 membered)
heterocycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.6-C.sub.14 aryl) and --(C.sub.zero-C.sub.4
alkylene)-((5-14 membered) heteroaryl), wherein each hydrogen atom
of said --C.sub.1-C.sub.20 alkyl, --C.sub.2-C.sub.20 alkenyl and
C.sub.2-C.sub.20 alkynyl of R.sup.14 and R.sup.15 is optionally
independently replaced with a --F, and wherein said cycloalkyl,
cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl,
heterocycloalkyl, aryl and heteroaryl of R.sup.14 and R.sup.15 are
each optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl,
--C.sub.2-C.sub.6 hydroxyalkenyl, --C.sub.2-C.sub.6 hydroxyalkynyl,
--F, --Cl, --Br, --I, --CN, --NO.sub.2, --OH, --NH.sub.2,
--C(.dbd.O)H, --S(O).sub.nH, --C(.dbd.O)OH, --C(.dbd.O)NH.sub.2,
--S(O).sub.2NH.sub.2, --(C.sub.zero-C.sub.4
alkylene)-(C.sub.6-C.sub.14 aryl), --(C.sub.zero-C.sub.4
alkylene)-((5-14 membered) heteroaryl), --C.sub.6-C.sub.14 aryloxy
and -(5-14 membered) heteroaryloxy, wherein each hydrogen atom of
said --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--C.sub.1-C.sub.6 hydroxyalkyl, --C.sub.2-C.sub.6 hydroxyalkenyl
and --C.sub.2-C.sub.6 hydroxyalkynyl substituent of R.sup.14 and
R.sup.15 is optionally independently replaced with a --F, and
wherein said --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl and
--C.sub.2-C.sub.6 alkynyl substituents of R.sup.14 and R.sup.15 are
optionally independently further substituted with from one to six
atoms independently selected from --Cl, --Br and --I; or
NR.sup.14R.sup.15 may optionally form a (4-7 membered)
heterocycloalkyl or (4-7 membered) heterocycloalkenyl, wherein said
heterocycloalkyl and heterocycloalkenyl optionally independently
contains one or two further heteroatoms independently selected from
N, O and S(O).sub.zero-2 and wherein said heterocycloalkyl and
heterocycloalkenyl is optionally independently substituted with
from one to three substituents independently selected from
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--C.sub.1-C.sub.6 hydroxyalkyl, --C.sub.2-C.sub.6 hydroxyalkenyl
and --C.sub.2-C.sub.6 hydroxyalkynyl, --F, --Cl, --Br, --I, --CN,
--NO.sub.2, --OH, --NH.sub.2, --C(.dbd.O)H, --C(.dbd.O)OH,
--C(.dbd.O)NH.sub.2, --S(O).sub.nH, --S(O).sub.nNH.sub.2,
--(C.sub.zero-C.sub.4 alkylene)-(C.sub.6-C.sub.14 aryl),
--(C.sub.zero-C.sub.4 alkylene)-((5-14 membered) heteroaryl),
--C.sub.6-C.sub.14 aryloxy and -(5-14 membered) heteroaryloxy,
wherein each hydrogen atom of said --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl,
--C.sub.2-C.sub.6 hydroxyalkenyl and --C.sub.2-C.sub.6
hydroxyalkynyl substituent of NR.sup.14R.sup.15 is optionally
independently replaced with a --F, and wherein said
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl and
--C.sub.2-C.sub.6 alkynyl substituent of NR.sup.14R.sup.15 is
optionally independently further substituted with from one to six
atoms independently selected from --Cl, --Br and --I; and n is in
each instance an integer independently selected from zero, 1, 2 and
3; or a pharmaceutically acceptable salt thereof.
26. A compound according to claim 25, wherein R.sup.3 is selected
from methyl, ethyl, n-propyl, n-butyl, i-butyl, s-butyl, allyl, and
--CH.sub.2CH.sub.2SCH.sub.3.
27. A compound according to claim 25, wherein R.sup.6 is selected
from --H, methyl, ethyl, --F, --Cl, --Br, and --CF.sub.3.
28. A compound according to claim 25, wherein R.sup.1 is selected
from --C.sub.2-C.sub.12 alkyl, and --C.sub.6-C.sub.14 aryl.
29. A compound according to claim 25, wherein R.sup.1 is
C.sub.1-C.sub.4 alkyl substituted with R.sup.1, wherein R.sup.1a is
--C.sub.6-C.sub.10 aryl or -(5-10 membered) heteroaryl.
30. A compound according to claim 25, wherein R.sup.1 is a
straight-chain C.sub.2-C.sub.20 alkyl or branched C.sub.3-C.sub.10
alkyl.
31. A compound according to claim 25, wherein R.sup.7 is selected
from --H, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.1-C.sub.20 alkoxy, --C.sub.2-C.sub.20 alkenoxy, --F, --Cl,
--Br, --I, --CN, --NO.sub.2, --C.sub.3-C.sub.12 cycloalkyl and
-(3-12 membered) heterocycloalkyl, C.sub.6-C.sub.14 aryl, -(5-15
membered) heteroaryl, --CHO, --C(.dbd.O)(C.sub.1-C.sub.15 alkyl),
--C(.dbd.O)((5-12 membered) heterocycloalkyl),
--C(.dbd.O)(C.sub.6-C.sub.14 aryl), --C(.dbd.O)(5-15 membered)
heteroaryl), --C(+O)(C.sub.5-C.sub.12 cycloalkyl),
--C(.dbd.O)(C.sub.1-C.sub.8 alkyl), --C(.dbd.O)N(C.sub.1-C.sub.10
alkyl)(C.sub.1-C.sub.10 alkyl), --C(.dbd.O)N(C.sub.1-C.sub.10
alkyl)(C.sub.6-C.sub.10 aryl), --C(.dbd.O)NH(C.sub.6-C.sub.10
aryl), --C(.dbd.O)N(C.sub.1-C.sub.10 alkyl)(5-10 membered)
heteroaryl), --C(.dbd.O)NH((5-10 membered)
heteroaryl)-C(.dbd.O)N(C.sub.1-C.sub.10 alkyl)-((5-10 membered
heterocycloalkyl), --C(.dbd.O)NH((5-10 membered) heterocycloalkyl),
--C(.dbd.O)N(C.sub.1-C.sub.10 alkyl)(C.sub.5-C.sub.10 cycloalkyl),
--C(.dbd.O)NH(C.sub.5-C.sub.10 cycloalkyl),
--S(O).sub.n(C.sub.1-C.sub.15 alkyl), --S(O).sub.n(C.sub.5-C.sub.12
cycloalkyl), --S(O).sub.n(C.sub.6-C.sub.15 aryl) and
--S(O).sub.n((5-10 membered) heteroaryl) wherein each hydrogen atom
of said alkyl, alkenyl, alkoxy and alkenoxy of R.sup.7 is
optionally independently replaced with a --F, and wherein said
cycloalkyl and heterocycloalkyl of R.sup.7 is optionally
independently substituted with from one to six --F, and wherein
said alkyl, alkenyl, cycloalkyl and heterocycloalkyl, aryl and
heteroaryl of R.sup.7 are each optionally independently substituted
with from one to three substituents independently selected from
--F, --Cl, --Br, --I, --OH, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--NR.sup.9R.sup.10, --(CH.sub.2).sub.1-10NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --S(O).sub.nR.sup.11, --C(.dbd.O)OR.sup.11,
--C(.dbd.O)NR.sup.9R.sup.10, --S(O).sub.2NR.sup.9R.sup.10,
--C.sub.3-C.sub.12 cycloalkyl, -(4-12 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl, -(4-12
membered) heterocycloalkoxy, --C.sub.6-C.sub.12 aryloxy and -(6-12
membered) heteroaryloxy.
32. A compound according to claim 25, wherein R.sup.7 is selected
from --C.sub.1-C.sub.12 alkyl --C.sub.1-C.sub.12 alkenyl,
--C.sub.3-C.sub.12 cycloalkyl and -(3-12 membered)
heterocycloalkyl, wherein each hydrogen atom of said alkyl and
alkenyl of R.sup.7 is optionally replaced with a --F, and wherein
said cycloalkyl and heterocycloalkyl of R.sup.7 are each optionally
independently substituted with from one to six --F, and wherein
said alkyl, alkenyl, cycloalkyl and heterocycloalkyl of R.sup.7 are
each optionally independently substituted with from one to three
substituents independently selected from --OH, --C.sub.1-C.sub.6
alkoxy, --C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--NR.sup.9R.sup.10, --(CH.sub.2).sub.1-6NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11,
--C(.dbd.O)NR.sup.9R.sup.10, --S(O).sub.2NR.sup.9R.sup.10,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl, -(4-12
membered) heterocycloalkoxy --C.sub.6-C.sub.12 aryloxy and -(6-12
membered) heteroaryloxy.
33. A compound according to claim 32, wherein R.sup.7 is a
--C.sub.1-C.sub.12 alkyl substituted with --NR.sup.9R.sup.10
morpholino, pyrrolidnyl or piperidinyl.
34. A compound according to claim 25, wherein R.sup.5 is
hydrogen.
35. A compound of claim 25 having the structure: ##STR00007##
36. A compound of claim 35, wherein R.sup.4 and R.sup.5 are H.
37. A compound according to claim 25 selected from the group
consisting of: 2-(S)-(1-Ethyl-propylamino)-pentanoic acid
[5-(1-ethyl-propyl)-thiazol-2-yl]-amide;
2-(S)-(1-Ethyl-propylamino)-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide;
2-(S)-(1-Propyl-butylamino)-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide;
2-(S)-(1-Ethyl-propylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide;
2-(S)-(1-Cyclopropyl-ethylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide;
2-(S)-(2-Cyclopentyl-1-methyl-ethylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; 2-(S)-Isopropylamino-pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide;
2-(S)-(1-Propyl-butylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; 2-(S)-Cyclohexylamino-pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide;
2-(S)-(2-Cyclohexyl-1-methyl-ethylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; and
2-(S)-(3,3-Dimethoxy-1-methyl-propylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; or a pharmaceutically acceptable
salt thereof.
38. A pharmaceutical composition, comprising an effective amount of
a compound according to claim 1, or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] The present application claims benefit of U.S. Ser. No.
60/558,902 filed on Apr. 1, 2004, which is incorporated by
reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the treatment of
neurodegenerative and/or neurological disorders, such as
Alzheimer's disease, in mammals, including humans. This invention
also relates to inhibiting, in mammals, including humans, the
production of A.beta.-peptides that can contribute to the formation
of neurological deposits of amyloid protein. More particularly,
this invention relates to thiazole-amine compounds, pharmaceutical
compositions comprising such compounds and methods of using such
compounds, i.e., for the treatment of neurodegenerative and/or
neurological disorders, such as Alzheimer's disease, related to
A.beta.-peptide production.
BACKGROUND OF THE INVENTION
[0003] Dementia results from a wide variety of distinctive
pathological processes. The most common pathological processes
causing dementia are Alzheimer's disease (AD), cerebral amyloid
angiopathy (CAA) and prion-mediated diseases. AD affects nearly
half of all people past the age of 85, the most rapidly growing
portion of the United States population. As such, the number of AD
patients in the United States is expected to increase from about 4
million to about 14 million by the middle of the next century.
[0004] Treatment of AD typically is the support provided by a
family member in attendance. Stimulated memory exercises on a
regular basis have been shown to slow, but not stop, memory loss. A
few drugs, for example Aricept.TM., provide treatment of AD.
[0005] A hallmark of AD is the accumulation in the brain of
extracellular insoluble deposits called amyloid plaques and
abnormal lesions within neuronal cells called neurofibrillary
tangles. Increased plaque formation is associated with an increased
risk of AD. Indeed, the presence of amyloid plaques, together with
neurofibrillary tangles, is the basis for definitive pathological
diagnosis of AD.
[0006] The major components of amyloid plaques are the amyloid
A.beta.-peptides, also called A.beta.-peptides, that consist of
several proteins including 38, 40, 42 or 43 amino acids, designated
as the A.beta..sub.1-38, A.beta..sub.1-40, A.beta..sub.1-42 and
A.beta..sub.1-43 peptides, respectively. The A.beta.-peptides are
thought to cause nerve cell destruction, in part, because they are
toxic to neurons in vitro and in vivo.
[0007] The A.beta. peptides are derived from larger amyloid
precursor proteins (APP proteins), that consist of four proteins
containing 695, 714, 751 or 771 amino acids, designated as the
APP.sub.695, APP.sub.714, APP.sub.751 and APP.sub.771,
respectively. Proteases are believed to produce the A.beta.
peptides by cleaving specific amino acid sequences within the
various APP proteins. The proteases are named "secretases" because
the A.beta.-peptides they produce are secreted by cells into the
extracellular environment. These secretases are each named
according to the cleavage(s) they make to produce the
A.beta.-peptides. The secretase that forms the amino terminal end
of the A.beta.-peptides is called the beta-secretase. The secretase
that forms the carboxyl terminal end of the A.beta.-peptides is
called the gamma-secretase.
[0008] This invention relates to novel compounds that inhibit
A.beta.-peptide production, to pharmaceutical compositions
comprising such compounds, and to methods of using such compounds
to treat neurodegenerative and/or neurological disorders.
SUMMARY OF THE INVENTION
[0009] The present invention relates to compounds of the Formula
I
##STR00002##
wherein R.sup.1 is selected from --C.sub.1-C.sub.20 alkyl,
--C.sub.2-C.sub.20 alkenyl, --C.sub.2-C.sub.20 alkynyl,
--C.sub.3-C.sub.8 cycloalkyl, --C.sub.5-C.sub.8 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(3-8 membered) heterocycloalkyl, -(5-11
membered) heterobicycloalkyl, --C.sub.6-C.sub.14 aryl and -(5-15
membered) heteroaryl, wherein each hydrogen atom of said alkyl,
alkenyl and alkynyl, of R.sup.1 is optionally replaced with a
--F;
[0010] wherein when R.sup.1 is alkyl, alkenyl or alkynyl, R.sup.1
is optionally independently substituted with from one to three
substituents R.sup.1a, and wherein when R.sup.1 is cycloalkyl,
cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl,
heterocycloalkyl, heterobicycloalkyl, aryl or heteroaryl, then
R.sup.1 is optionally independently substituted with from one to
three substituents R.sup.1b;
[0011] R.sup.1a is in each instance independently selected from
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, --F, --Cl,
--Br, --I, --CN, --NO.sub.2, --OH, --NR.sup.9R.sup.10,
--C(.dbd.O)NR.sup.9R.sup.10, --S(O).sub.2NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --S(O).sub.nR.sup.11, --C(.dbd.O)OR.sup.12,
--C.sub.3-C.sub.8 cycloalkyl, --C.sub.4-C.sub.8 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(3-8 membered) heterocycloalkyl,
--C.sub.6-C.sub.14 aryl, -(5-14 membered) heteroaryl,
--C.sub.6-C.sub.14 aryloxy and -(5-14 membered) heteroaryloxy,
wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,
cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or
tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and
heteroaryloxy of R.sup.1a are each optionally independently
substituted with from one to three substituents R.sup.1b;
[0012] R.sup.1b is in each instance independently selected from
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, --F, --Cl,
--Br, --I, --CN, --NO.sub.2, --OH, --NR.sup.9R.sup.10,
--C(.dbd.O)NR.sup.9R.sup.10, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.12, --S(O).sub.2NR.sup.9R.sup.10,
--S(O).sub.nR.sup.11, --C.sub.1-C.sub.6 hydroxyalkyl,
--C.sub.6-C.sub.14 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.14 aryloxy and -(5-14 membered) heteroaryloxy,
wherein said alkyl, alkenyl and alkynyl of R.sup.1b are each
optionally independently substituted with from one to six
substituents independently selected from --F, --Cl, --Br and
--I;
[0013] R.sup.3 is selected from C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--(C.sub.zero-C.sub.4 alkylene)-(C.sub.3-C.sub.6 cycloalkyl) and
--(C.sub.zero-C.sub.4 alkylene)(C.sub.3-C.sub.6 cycloalkenyl),
wherein said alkyl, alkenyl and alkynyl of R.sup.3 are each
optionally independently substituted with a substituent selected
from --OH, --C.sub.1-C.sub.4 alkoxy and --S--(C.sub.1-C.sub.4
alkyl);
[0014] R.sup.4 is --H, --F or --C.sub.1-C.sub.4 alkyl;
[0015] or R.sup.3 and R.sup.4 together with the carbon atom to
which they are both attached may optionally form a cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, morpholino, piperidino or
perhydro-2H-pyran moiety, wherein said moiety formed by R.sup.3 and
R.sup.4 is optionally substituted with from one to three
substituents independently selected from methyl, ethyl, allyl,
methoxy, ethoxy, --F, --Cl, --OH, --CN, --CF.sub.3 and
--OCF.sub.3;
[0016] R.sup.5 is selected from --H, --C.sub.1-C.sub.6 alkyl and
--C.sub.6-C.sub.10 aryl, wherein said alkyl and aryl of R.sup.5 are
optionally independently substituted with from one to three
substituents R.sup.1a;
[0017] or R.sup.5 and R.sup.1 together with the nitrogen atom to
which they are both attached may optionally form a -(5-8 membered)
heterocycloalkyl, -(5-8 membered) heterocycloalkenyl or -(5-14
membered) heteroaryl, wherein said heterocycloalkyl and
heterocycloalkenyl optionally contains one to two further
heteroatoms independently selected from N, O, and S(O).sub.zero-2,
and wherein said heteroaryl optionally contains one to two further
heteroatoms independently selected from N, O, and S, and wherein
said heterocycloalkyl, heterocycloalkenyl and heteroaryl is
optionally independently substituted with from one to three
substituents R.sup.1b;
[0018] R.sup.6 is selected from --H, --C.sub.1-C.sub.20 alkyl, --F,
--Cl, --Br, --I, --CN, --CF.sub.3, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.12, --S(O).sub.2NR.sup.9R.sup.10,
--S(O).sub.nR.sup.11, --C(.dbd.NR.sup.9)R.sup.15,
--C.sub.3-C.sub.12 cycloalkyl, --C.sub.5-C.sub.12 cycloalkenyl, and
--C.sub.6-C.sub.10 aryl, wherein said alkyl, cycloalkyl,
cycloalkenyl and aryl of R.sup.6 are each optionally independently
substituted with from one to three substituents R.sup.1b;
[0019] R.sup.7 is selected from H, --C.sub.1-C.sub.20 alkyl,
--C.sub.2-C.sub.20 alkenyl, --C.sub.2-C.sub.20 alkynyl,
--C.sub.1-C.sub.20 alkoxy, --C.sub.2-C.sub.20 alkenoxy,
--C.sub.2-C.sub.20 alkynoxy, --F, --Cl, --Br, --I, --CN,
--NO.sub.2, --CF.sub.3, --NR.sup.14R.sup.15, --C(.dbd.O)R.sup.13,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)NR.sup.14R.sup.15,
--C(.dbd.NR.sup.9)R.sup.15, --S(O).sub.nR.sup.13,
--S(O).sub.2NR.sup.14R.sup.15, --(C.sub.zero-C.sub.4
alkylene)-(C.sub.3-C.sub.12 cycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.4-C.sub.12 cycloalkenyl), --(C.sub.zero-C.sub.4
alkylene)-((C.sub.5-C.sub.20)bi- or tricycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-((C.sub.7-C.sub.20)bi- or
tricycloalkenyl), --(C.sub.zero-C.sub.4 alkylene)-((3-12 membered)
heterocycloalkyl), --(C.sub.zero-C.sub.4 alkylene)-((7-20 membered)
heterobi- or heterotricycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.6-C.sub.14 aryl) and --(C.sub.zero-C.sub.4
alkylene)-((5-15 membered) heteroaryl), wherein each hydrogen atom
of said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy and alkynoxy of
R.sup.7 is optionally independently replaced with a --F, and
wherein said cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or
tricycloalkenyl, heterocycloalkyl, aryl and heteroaryl of R.sup.7
are each optionally independently substituted with from one to six
--F, and wherein R.sup.7 is optionally independently substituted
with from one to three substituents independently selected from
R.sup.1a, --(CH.sub.2).sub.1-10NR.sup.9R.sup.10, --C.sub.3-C.sub.12
cycloalkyl, -(4-12 membered) heterocycloalkyl, --C.sub.6-C.sub.14
aryl, -(5-15 membered) heteroaryl, -(4-12 membered)
heterocycloalkoxy, --C.sub.6-C.sub.12 aryloxy and -(5-12 membered)
heteroaryloxy;
[0020] or R.sup.6 and R.sup.7 together with the carbon atoms to
which they are respectively attached may optionally form a
--C.sub.6-C.sub.8 cycloalkyl, --C.sub.6-C.sub.8 cycloalkenyl,
--C.sub.10-C.sub.14 bicycloalkyl, --C.sub.10-C.sub.14
bicycloalkenyl, -(5-8 membered) heterocycloalkyl, -(5-8 membered)
heterocycloalkenyl, -(10-14 membered) heterobicycloalkyl, -(10-14
membered) heterobicycloalkenyl or --C.sub.6-C.sub.10 aryl fused to
the thiazole ring of Formula I, wherein said heterocycloalkyl and
heterocycloalkenyl contains from one to three heteroatoms
independently selected from N, O and S(O).sub.zero-2, and wherein
said heterobicycloalkyl and heterobicycloalkenyl contains from one
to five heteroatoms independently selected from N, O and
S(O).sub.zero-2, and wherein said cycloalkyl, cycloalkenyl,
bicycloalkyl, bicycloalkenyl, heterocycloalkyl, heterocycloalkenyl,
heterobicycloalkyl, heterobicycloalkenyl and aryl are each
optionally independently substituted with from one to three
substituents R.sup.1b;
[0021] R.sup.9 and R.sup.10 are each independently selected from
--H, --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy and --C.sub.2-C.sub.6 alkynoxy, --OH,
--C(.dbd.O)R.sup.11, --S(O).sub.nR.sup.11, --C(.dbd.O)OR.sup.12,
--S(O).sub.nNR.sup.11R.sup.12, --(C.sub.zero-C.sub.4
alkylene)-(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.4-C.sub.8 cycloalkenyl), --(C.sub.zero-C.sub.4
alkylene)-((C.sub.5-C.sub.11)bi- or tricycloalkyl),
--C.sub.zero-C.sub.4 alkylene)-((C.sub.7-C.sub.11)bi- or
tricycloalkenyl), --(C.sub.zero-C.sub.4 alkylene)-((3-8 membered)
heterocycloalkyl)-(C.sub.zero-C.sub.4 alkylene) (C.sub.6-C.sub.14
aryl), and --(C.sub.zero-C.sub.4 alkylene)-((5-14 membered)
heteroaryl), wherein each hydrogen atom of said alkyl, alkenyl,
alkynyl, alkoxy, alkenoxy and alkynoxy of R.sup.9 and R.sup.10 is
optionally independently replaced with a --F, and wherein said
cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or
tricycloalkenyl, heterocycloalkyl aryl, and heteroaryl of R.sup.9
and R.sup.10 are each optionally independently substituted with
from one to three substituents independently selected from
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, --F, --Cl,
--Br, --I, --CN, --NO.sub.2, --OH, --NR.sup.14R.sup.15,
--C(.dbd.O)NR.sup.14R.sup.15, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.12, --S(O).sub.nR.sup.11,
--S(O).sub.2NR.sup.14R.sup.15, --C.sub.1-C.sub.6 hydroxyalkyl,
--(C.sub.zero-C.sub.4)--(C.sub.6-C.sub.14 aryl),
--(C.sub.zero-C.sub.4)-((5-14 membered) heteroaryl),
--C.sub.6-C.sub.14 aryloxy and -(5-14 membered) heteroaryloxy, and
wherein said --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl and
--C.sub.2-C.sub.6 alkynyl substituents of R.sup.9 and R.sup.10 are
each optionally independently substituted with from one to six
atoms independently selected from --F, --Cl, --Br and --I;
[0022] or NR.sup.9R.sup.10 may optionally form a (4-7 membered)
heterocycloalkyl or (4-7 membered) heterocycloalkenyl, wherein said
heterocycloalkyl and heterocycloalkenyl optionally independently
contain one or two further heteroatoms independently selected from
N, O, and S(O).sub.zero-2, and wherein said heterocycloalkyl and
heterocycloalkenyl are optionally independently substituted with
from one to three substituents independently selected from
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--C.sub.1-C.sub.6 hydroxyalkyl, --C.sub.2-C.sub.6 hydroxyalkenyl,
--C.sub.2-C.sub.6 hydroxyalkynyl, --F, --Cl, --Br, --I, --CN,
--NO.sub.2, --OH, --NR.sup.14R.sup.15,
--C(.dbd.O)NR.sup.14R.sup.15, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.12, --S(O).sub.nR.sup.11,
--S(O).sub.2NR.sup.14R.sup.15,
--(C.sub.zero-C.sub.4)--(C.sub.6-C.sub.14 aryl),
--(C.sub.zero-C.sub.4)-((5-14 membered) heteroaryl),
--C.sub.6-C.sub.14 aryloxy and -(5-14 membered) heteroaryloxy,
wherein said --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl and
--C.sub.2-C.sub.6 alkynyl substituents of the (4-7 membered)
heterocycloalkyl and (4-7 membered) heterocycloalkenyl of
NR.sup.9R.sup.10 are each optionally independently substituted with
from one to six atoms independently selected from --F, --Cl, --Br
and --I;
[0023] R.sup.11 and R.sup.12 are each independently selected from
H, --C.sub.1-C.sub.6 alkyl, --(C.sub.zero-C.sub.4
alkylene)-(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.4-C.sub.8 cycloalkenyl), --(C.sub.zero-C.sub.4
alkylene)-((C.sub.5-C.sub.11)bi- or tricycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-((C.sub.7-C.sub.11)bi- or
tricycloalkenyl), --(C.sub.zero-C.sub.4 alkylene)-((3-8 membered)
heterocycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.6-C.sub.10 aryl) and --C.sub.zero-C.sub.4
alkylene)-((5-14 membered) heteroaryl), wherein R.sup.11 and
R.sup.12 are optionally independently substituted with one to three
substitutents independently selected from --OH, --C.sub.1-C.sub.12
alkyl, --C.sub.2-C.sub.12 alkenyl, --C.sub.2-C.sub.12 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl, --F,
--Cl, --Br, --I, --CN, --NO.sub.2, --CF.sub.3, --NR.sup.14R.sup.15,
--C(.dbd.O)N NR.sup.14R.sup.15, --SO.sub.2NR.sup.14R.sup.15,
--C(.dbd.O)H, --C(.dbd.O)OH and --C(.dbd.O)O(C.sub.1-C.sub.6
alkyl), wherein said alkyl, alkenyl and alkynyl substituents of
R.sup.11 and R.sup.12 are each optionally independently further
substituted with from one to six --F, or with from one to two
substituents independently selected from --C.sub.1-C.sub.4 alkoxy,
or with an --OH;
[0024] R.sup.13 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--(C.sub.zero-C.sub.4 alkylene)-(C.sub.3-C.sub.12 cycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-(C.sub.4-C.sub.12 cycloalkenyl),
--(C.sub.zero-C.sub.4 alkylene)-((C.sub.5-C.sub.20)bi- or
tricycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-((C.sub.7-C.sub.20)bi- or tricycloalkenyl),
--(C.sub.zero-C.sub.4 alkylene)-((3-12 membered) heterocycloalkyl),
--(C.sub.zero-C.sub.4 alkylene)-((7-20 membered) heterobi- or
heterotricycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.6-C.sub.14 aryl) and --(C.sub.zero-C.sub.4
alkylene)-((5-14 membered) heteroaryl), wherein each hydrogen atom
of said --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl and
--C.sub.2-C.sub.6 alkynyl of R.sup.13 is optionally independently
replaced with a --F, and wherein R.sup.13 is optionally
independently substituted with from one to three substitutents
independently selected from --OH, --C.sub.1-C.sub.12 alkyl,
--C.sub.2-C.sub.12 alkenyl, --C.sub.2-C.sub.12 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl, --F,
--Cl, --Br, --I, --CN, --NO.sub.2, --CF.sub.3, --NR.sup.14R.sup.15,
--C(.dbd.O)N NR.sup.14R.sup.15, --SO.sub.2NR.sup.14R.sup.15,
--C(.dbd.O)H, --C(.dbd.O)OH and --C(.dbd.O)O(C.sub.1-C.sub.6
alkyl), wherein said alkyl, alkenyl and alkynyl substituents of
R.sup.13 are each optionally independently further substituted with
from one to six --F, or with from one to two substituents
independently selected from --C.sub.1-C.sub.4 alkoxy, or with an
--OH;
[0025] R.sup.14 and R.sup.15 are each independently selected from
--H, --C.sub.1-C.sub.20 alkyl, --C.sub.2-C.sub.20 alkenyl,
--C.sub.2-C.sub.20 alkynyl, --C(.dbd.O)R.sup.11,
--S(O).sub.nR.sup.11, --C(.dbd.O)OR.sup.12,
--S(O).sub.2NR.sup.11R.sup.12, --(C.sub.zero-C.sub.4
alkylene)-(C.sub.3-C.sub.12 cycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.4-C.sub.12 cycloalkenyl), --(C.sub.zero-C.sub.4
alkylene)-((C.sub.5-C.sub.20)bi- or tricycloalkyl),
--C.sub.zero-C.sub.4 alkylene)-((C.sub.7-C.sub.20)bi- or
tricycloalkenyl), --(C.sub.zero-C.sub.4 alkylene)-((3-8 membered)
heterocycloalkyl), --(C.sub.zero-C.sub.4
alkylene)-(C.sub.6-C.sub.14 aryl) and --(C.sub.zero-C.sub.4
alkylene)-((5-14 membered) heteroaryl), wherein each hydrogen atom
of said --C.sub.1-C.sub.20 alkyl, --C.sub.2-C.sub.20 alkenyl and
C.sub.2-C.sub.20 alkynyl of R.sup.14 and R.sup.15 is optionally
independently replaced with a --F, and wherein said cycloalkyl,
cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl,
heterocycloalkyl, aryl and heteroaryl of R.sup.14 and R.sup.15 are
each optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl,
--C.sub.2-C.sub.6 hydroxyalkenyl, --C.sub.2-C.sub.6 hydroxyalkynyl,
--F, --Cl, --Br, --I, --CN, --NO.sub.2, --OH, --NH.sub.2,
--C(.dbd.O)H, --S(O).sub.nH, --C(.dbd.O)OH, --C(.dbd.O)NH.sub.2,
--S(O).sub.2NH.sub.2, --(C.sub.zero-C.sub.4
alkylene)-(C.sub.6-C.sub.14 aryl), --(C.sub.zero-C.sub.4
alkylene)-((5-14 membered) heteroaryl), --C.sub.6-C.sub.14 aryloxy
and -(5-14 membered) heteroaryloxy, wherein each hydrogen atom of
said --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--C.sub.1-C.sub.6 hydroxyalkyl, --C.sub.2-C.sub.6 hydroxyalkenyl
and --C.sub.2-C.sub.6 hydroxyalkynyl substituent of R.sup.14 and
R.sup.15 is optionally independently replaced with a --F, and
wherein said --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl and
--C.sub.2-C.sub.6 alkynyl substituents of R.sup.14 and R.sup.15 are
optionally independently further substituted with from one to six
atoms independently selected from --Cl, --Br and --I;
[0026] or NR.sup.14R.sup.15 may optionally form a (4-7 membered)
heterocycloalkyl or (4-7 membered) heterocycloalkenyl, wherein said
heterocycloalkyl and heterocycloalkenyl optionally independently
contains one or two further heteroatoms independently selected from
N, O and S(O).sub.2, and wherein said heterocycloalkyl and
heterocycloalkenyl is optionally independently substituted with
from one to three substituents independently selected from
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--C.sub.1-C.sub.6 hydroxyalkyl, --C.sub.2-C.sub.6 hydroxyalkenyl
and --C.sub.2-C.sub.6 hydroxyalkynyl, --F, --Cl, --Br, --I, --CN,
--NO.sub.2, --OH, --NH.sub.2, --C(.dbd.O)H, --C(.dbd.O)OH,
--C(.dbd.O)NH.sub.2, --S(O).sub.nH, --S(O).sub.nNH.sub.2,
--(C.sub.zero-C.sub.4 alkylene)-(C.sub.6-C.sub.14 aryl),
--(C.sub.zero-C.sub.4 alkylene)-((5-14 membered) heteroaryl),
--C.sub.6-C.sub.14 aryloxy and -(5-14 membered) heteroaryloxy,
wherein each hydrogen atom of said --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl,
--C.sub.2-C.sub.6 hydroxyalkenyl and --C.sub.2-C.sub.6
hydroxyalkynyl substituent of NR.sup.14R.sup.15 is optionally
independently replaced with a --F, and wherein said
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl and
--C.sub.2-C.sub.6 alkynyl substituent of NR.sup.14R.sup.15 is
optionally independently further substituted with from one to six
atoms independently selected from --Cl, --Br and --I; and
[0027] n is in each instance an integer independently selected from
zero, 1, 2 or 3;
[0028] or the pharmaceutically acceptable salts of such
compounds.
[0029] Compounds of the Formula I may have optical centers and
therefore may occur in different enantiomeric and diastereomeric
configurations. The present invention includes all enantiomers,
diastereomers, and other stereoisomers of such compounds of the
Formula I, as well as racemic compounds and racemic mixtures and
other mixtures of stereoisomers thereof.
[0030] Pharmaceutically acceptable salts of the compounds of
Formula I include the acid addition and base salts thereof.
[0031] Suitable acid addition salts are formed from acids which
form non-toxic salts. Examples include, but are not limited to, the
acetate, adipate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,
citrate, cyclamate, edisylate, esylate, formate, fumarate,
gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,
isethionate, lactate, malate, maleate, malonate, mandelates
mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate,
nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, pyroglutamate, salicylate,
saccharate, stearate, succinate, sulfonate, stannate, tartrate,
tosylate, trifluoroacetate and xinofoate salts.
[0032] Suitable base salts are formed from bases which form
non-toxic salts. Examples include, but are not limited to, the
aluminium, arginine, benzathine, calcium, choline, diethylamine,
diolamine, glycine, lysine, magnesium, meglumine, olamine,
potassium, sodium, tromethamine and zinc salts.
[0033] Hemisalts of acids and bases may also be formed, for
example, hemisulphate and hemicalcium salts.
[0034] For a review on suitable salts, see Handbook of
Pharmaceutical Salts: Properties, Selection, and Use by Stahl and
Wermuth (Wiley-VCH, 2002).
[0035] Pharmaceutically acceptable salts of compounds of Formula I
may be prepared by one or more of three methods:
[0036] (i) by reacting the compound of Formula I with the desired
acid or base;
[0037] (ii) by removing an acid- or base-labile protecting group
from a suitable precursor of the compound of Formula I or by
ring-opening a suitable cyclic precursor, for example, a lactone or
lactam, using the desired acid or base; or
[0038] (iii) by converting one salt of the compound of Formula I to
another by reaction with an appropriate acid or base or by means of
a suitable ion exchange column.
[0039] All three reactions are typically carried out in solution.
The resulting salt may precipitate out and be collected by
filtration or may be recovered by evaporation of the solvent. The
degree of ionization in the resulting salt may vary from completely
ionised to almost non-ionised.
[0040] The compounds of the invention may exist in a continuum of
solid states ranging from fully amorphous to fully crystalline. The
term `amorphous` refers to a state in which the material lacks long
range order at the molecular level and, depending upon temperature,
may exhibit the physical properties of a solid or a liquid.
Typically such materials do not give distinctive X-ray diffraction
patterns and, while exhibiting the properties of a solid, are more
formally described as a liquid. Upon heating, a change from solid
to liquid properties occurs which is characterised by a change of
state, typically second order (`glass transition`). The term
`crystalline` refers to a solid phase in which the material has a
regular ordered internal structure at the molecular level and gives
a distinctive X-ray diffraction pattern with defined peaks. Such
materials when heated sufficiently will also exhibit the properties
of a liquid, but the change from solid to liquid is characterised
by a phase change, typically first order (`melting point`).
[0041] The compounds of the invention may also exist in unsolvated
and solvated forms. The term `solvate` is used herein to describe a
molecular complex comprising the compound of the invention and one
or more pharmaceutically acceptable solvent molecules, for example,
ethanol. The term `hydrate` is employed when said solvent is
water.
[0042] A currently accepted classification system for organic
hydrates is one that defines isolated site, channel, or metal-ion
coordinated hydrates--see Polymorphism in Pharmaceutical Solids by
K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated
site hydrates are ones in which the water molecules are isolated
from direct contact with each other by intervening organic
molecules. In channel hydrates, the water molecules lie in lattice
channels where they are next to other water molecules. In metal-ion
coordinated hydrates, the water molecules are bonded to the metal
ion.
[0043] When the solvent or water is tightly bound, the complex will
have a well-defined stoichiometry independent of humidity. When,
however, the solvent or water is weakly bound, as in channel
solvates and hygroscopic compounds, the water/solvent content will
be dependent on humidity and drying conditions. In such cases,
non-stoichiometry will be the norm.
[0044] The compounds of the invention may also exist in a
mesomorphic state (mesophase or liquid crystal) when subjected to
suitable conditions. The mesomorphic state is intermediate between
the true crystalline state and the true liquid state (either melt
or solution). Mesomorphism arising as the result of a change in
temperature is described as `thermotropic` and that resulting from
the addition of a second component, such as water or another
solvent, is described as `lyotropic`. Compounds that have the
potential to form lyotropic mesophases are described as
`amphiphilic` and consist of molecules which possess an ionic (such
as --COO.sup.-Na.sup.+, --COO.sup.-K.sup.+, or
--SO.sub.3.sup.-Na.sup.+) or non-ionic (such as
--N.sup.-N.sup.+(CH.sub.3).sub.3) polar head group. For more
information, see Crystals and the Polarizing Microscope by N. H.
Hartshorne and A. Stuart, 4.sup.th Edition (Edward Arnold,
1970).
[0045] Hereinafter all references to compounds of Formula I include
references to salts, solvates, multi-component complexes and liquid
crystals thereof and to solvates, multi-component complexes and
liquid crystals of salts thereof.
[0046] The compounds of the invention include compounds of Formula
I as hereinbefore defined, including all polymorphs and crystal
habits thereof, prodrugs and isomers thereof (including optical,
geometric and tautomeric isomers) as hereinafter defined and
isotopically-labeled compounds of Formula I.
[0047] Unless otherwise indicated, as used herein, the terms
`halogen` and "halo" include F, Cl, Br and I.
[0048] Unless otherwise indicated, as used herein, the term "alkyl"
includes saturated monovalent hydrocarbon radicals having straight
or branched moieties. Examples of alkyl groups include, but are not
limited to, methyl, ethyl, n-propyl, isopropyl,
cyclopropylmethylene (--CH.sub.2-cyclopropyl) and t-butyl.
[0049] Unless otherwise indicated, as used herein, the term
`alkenyl` includes alkyl moieties having at least one carbon-carbon
double bond wherein alkyl is as defined above. Examples of alkenyl
include, but are not limited to, ethenyl and propenyl.
[0050] Unless otherwise indicated, as used herein, the term
"alkynyl" includes alkyl moieties having at least one carbon-carbon
triple bond wherein alkyl is as defined above. Examples of alkynyl
groups include, but are not limited to, ethynyl and 2-propynyl.
[0051] Unless otherwise indicated, as used herein, the term
"alkoxy", means "alkyl-O--", wherein "alkyl" is as defined above.
Examples of "alkoxy" groups include, but are not limited to,
methoxy, ethoxy, propoxy, butoxy, pentoxy and allyloxy.
[0052] Unless otherwise indicated, as used herein, the term
"alkenoxy", means "alkenyl-O--", wherein "alkenyl" is as defined
above.
[0053] Unless otherwise indicated, as used herein, the term
"alkynoxy", means "alkynyl-O--", wherein "alkynyl" is as defined
above.
[0054] Unless otherwise indicated, as used herein, the term
"cycloalkyl" includes non-aromatic saturated cyclic alkyl moieties
wherein alkyl is as defined above. Examples of cycloalkyl include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and cycloheptyl. "Bicycloalkyl" and "tricycloalkyl"
groups include non-aromatic saturated cyclic alkyl moieties
consisting of two or three rings respectively, wherein said rings
share at least one carbon atom. "Bicycloalkyl" and "tricycloalkyl"
groups also include cyclic moieties consisting of two or three
rings respectively, wherein one ring is aryl or heteroaryl and
wherein said rings share two carbon atoms. For purposes of the
present invention, and unless otherwise indicated, bicycloalkyl
groups include spiro groups and fused ring groups. Examples of
bicycloalkyl groups include, but are not limited to,
bicyclo-[3.1.0]-hexyl, bicyclo-2.2.1]-hept-1-yl, norbornyl,
spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl,
spiro[4.2]heptyl, indane, teralene (1,2,3,4-tetrahydronaphlene) and
6,7,8,9-tetrahydro-5H-benzocycloheptene. An example of a
tricycloalkyl group is adamantanyl. Other cycloalkyl, bicycloalkyl,
and tricycloalkyl groups are known in the art, and such groups are
encompassed by the definitions "cycloalkyl", "bicycloalkyl" and
"tricycloalkyl" herein. `Cycloalkenyl`, `bicycloalkenyl`, and
"tricycloalkenyl" refer to non-aromatic each cycloalkyl,
bicycloalkyl, and tricycloalkyl moieties as defined above, except
that they each include one or more carbon-carbon double bonds
connecting carbon ring members (an "endocyclic" double bond) and/or
one or more carbon-carbon double bonds connecting a carbon ring
member and an adjacent non-ring carbon (an "exocyclic" double
bond). Examples of cycloalkenyl groups include, but are not limited
to, cyclopentenyl, cyclobutenyl, and cyclohexenyl. A non-limiting
example of a bicycloalkenyl group is norbornenyl. Cycloalkyl,
cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include
groups that are substituted with one or more oxo moieties. Examples
of such groups with oxo moieties are oxocyclopentyl, oxocyclobutyl,
oxocyclopentenyl and norcamphoryl. Other cycloalkenyl,
bicycloalkenyl, and tricycloalkenyl groups are known in the art,
and such groups are included within the definitions "cycloalkenyl",
"bicycloalkenyl" and "tricycloalkenyl" herein.
[0055] Unless otherwise indicated, as used herein, the term "aryl"
includes an organic radical derived from an aromatic hydrocarbon by
removal of one hydrogen, such as phenyl (Ph), naphthyl, indenyl,
indanyl and fluorenyl. "Aryl" encompasses fused ring groups wherein
at least one ring is aromatic.
[0056] Unless otherwise indicated, as used herein, the terms
"heterocyclic" and "heterocycloalkyl" refer to non-aromatic cyclic
groups containing one or more heteroatoms, preferably from one to
four heteroatoms, each selected from O, S and N.
"Heterobicycloalkyl" groups include non-aromatic two-ringed cyclic
groups, wherein said rings share one or two atoms, and wherein at
least one of the rings contains a heteroatom (O, S, or N).
"Heterobicycloalkyl" groups also include two-ringed cyclic groups,
wherein said one ring is aryl or heteroaryl ring and wherein said
rings share one or two atoms, and wherein at least one of the rings
contains a heteroatom (O, S, or N). Unless otherwise indicated, for
purposes of the present invention, heterobicycloalkyl groups
include spiro groups and fused ring groups. In one embodiment, each
ring in the heterobicycloalkyl contains up to four heteroatoms
(i.e. from zero to four heteroatoms, provided that at least one
ring contains at least one heteroatom). The heterocyclic groups of
this invention can also include ring systems substituted with one
or more oxo moieties. Examples of non-aromatic heterocyclic groups
are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl,
piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl,
tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl,
pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.5]decyl,
1,4-dioxaspiro[4.4]nonyl, 1,4-dioxaspiro[4.3]octyl, and
1,4-dioxaspiro[4.2]heptyl.
[0057] Unless otherwise indicated, as used herein, "heteroaryl"
refers to aromatic groups containing one or more heteroatoms,
preferably from one to four heteroatoms, selected from O, S and N.
A multicyclic group containing one or more heteroatoms wherein at
least one ring of the group is aromatic is a "heteroaryl" group.
The heteroaryl groups of this invention can also include ring
systems substituted with one or more oxo moieties. Examples of
heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,
isoquinolyl, 1,2,3,4-tetrahydroguinolyl, tetrazolyl, furyl,
thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, triazinyl, 1,2,4-trizainyl,
1,3,5-triazinyl, isoindolyl, 1-oxoisoindolyl, purinyl, oxadiazolyl,
thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl,
dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl,
furopyridinyl, pyrolopyrimidinyl, and azaindolyl.
[0058] Unless otherwise indicated, as used herein, the term
"cycloalkoxy", means "cycloalkyl-O--", wherein "cycloalkyl" is as
defined above.
[0059] Unless otherwise indicated, as used herein, the term
"aryloxy", means "aryl-O--", wherein "aryl" is as defined
above.
[0060] Unless otherwise indicated, as used herein, the term
"heterocycloalkoxy", means "heterocycloalkyl-O--", wherein
"heterocycloalkyl" is as defined above.
[0061] Unless otherwise indicated, as used herein, the term
"heteroaryloxy", means "heteroaryl-O--", wherein "heteroaryl" is as
defined above.
[0062] The foregoing groups, as derived from the compounds listed
above, may be C-attached or N-attached where such is possible. For
instance, a group derived from pyrrole may be pyrrol-1-yl
(N-attached) or pyrrol-3-yl (C-attached). The terms referring to
the groups also encompass all possible tautomers.
[0063] In one aspect, the present invention relates to compounds of
the Formula I wherein R.sup.3 is selected from methyl, ethyl,
n-propyl, n-butyl, i-butyl, s-butyl, allyl and
--CH.sub.2CH.sub.2SCH.sub.3.
[0064] In another aspect, the present invention relates to
compounds of the Formula I wherein R.sup.5 is --H.
[0065] In another aspect, the present invention relates to
compounds of the Formula I wherein R.sup.6 is selected from --H,
methyl, ethyl, --F, --Cl, --Br and --F.sub.3.
[0066] In another aspect, the present invention relates to
compounds of the Formula I wherein R.sup.1 is selected from
--C.sub.2-C.sub.12 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.5-C.sub.8 cycloalkenyl, --(C.sub.5-C.sub.11)bi- or
tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, (38
membered) heterocycloalkyl, (7-11 membered) heterobicycloalkyl,
--C.sub.6-C.sub.14 aryl and -(5-15 membered) heteroaryl.
[0067] In another aspect, R.sup.1 is C.sub.1-C.sub.4 alkyl
substituted with R.sup.1a wherein R.sup.1a is --C.sub.6-C.sub.10
aryl or -(5-10 membered) heteroaryl.
[0068] In another aspect, R.sup.1 is a straight-chain
C.sub.2-C.sub.10 alkyl or branched C.sub.3-C.sub.10 alkyl.
[0069] In another aspect, R.sup.1 is selected from
--(C.sub.7-C.sub.11)bi- or tricycloalkyl and (7-11 membered)
heterobicycloalkyl.
[0070] In another aspect, R.sup.1 is 1,2,3,4-tetrahydronaphthalenyl
or indanyl optionally substituted with 1 to 3 fluorine or chlorine
atoms.
[0071] In another aspect, the present invention relates to
compounds of the Formula I, wherein R.sup.7 is selected from --H,
--C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.1-C.sub.20 alkoxy, --C.sub.2-C.sub.20 alkenoxy, --F, --Cl,
--Br, --I, --CN, --NO.sub.2, --C.sub.3-C.sub.12 cycloalkyl, -(3-12
membered) heterocycloalkyl, --C.sub.6-C.sub.14 aryl, -(5-15
membered) heteroaryl, --CHO, --C(.dbd.O)(C.sub.1-C.sub.15 alkyl),
--C(.dbd.O)((5-12 membered) heterocycloalkyl),
--C(.dbd.O)(C.sub.6-C.sub.14 aryl), --C(.dbd.O)((5-15 membered)
heteroaryl), --C(.dbd.O)(C.sub.5-C.sub.12 cycloalkyl),
--C(.dbd.O)O(C.sub.1-C.sub.8 alkyl), --C(.dbd.O)N(C.sub.1-C.sub.10
alkyl)(C.sub.1-C.sub.10 alkyl), --C(.dbd.O)N(C.sub.1-C.sub.10
alkyl)(C.sub.6-C.sub.10 aryl), --C(.dbd.O)NH(C.sub.6-C.sub.10
aryl), --C(.dbd.O)N(C.sub.1-C.sub.10 alkyl)-((5-10 membered)
heteroaryl), --C(.dbd.O)NH((5-10 membered) heteroaryl),
--C(.dbd.O)N(C.sub.1-C.sub.10 alkyl)-((5-10 membered)
heterocycloalkyl), --C(.dbd.O)NH((5-10 membered) heterocycloalkyl),
--C(.dbd.O)N(C.sub.1-C.sub.10 alkyl)(C.sub.5-C.sub.10 cycloalkyl),
--C(.dbd.O)NH(C.sub.5-C.sub.10 cycloalkyl),
--S(O).sub.n(C.sub.1-C.sub.15 alkyl), --S(O).sub.n(C.sub.5-C.sub.12
cycloalkyl), --S(O).sub.n(C.sub.6-C.sub.15 aryl) and
--S(O).sub.n((5-10 membered) heteroaryl), wherein each hydrogen
atom of said alkyl, alkenyl, alkoxy and alkenoxy of R.sup.7 is
optionally independently replaced with a --F, and wherein said
cycloalkyl and heterocycloalkyl of R.sup.7 is optionally
independently substituted with from one to six --F, and wherein
said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl of R.sup.7 are each optionally independently substituted
with from one to three substituents independently selected from
--F, --Cl, --Br, --I, --OH, --C.sub.1-C.sub.6 alkoxy,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--NR.sup.9R.sup.10, --(CH.sub.2).sub.1-10NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --S(O).sub.nR.sup.11, --C(.dbd.O)OR.sup.11,
--C(.dbd.O)NR.sup.9R.sup.10, --S(O).sub.2NR.sup.9R.sup.10,
--C.sub.3-C.sub.12 cycloalkyl, -(4-12 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl, -(4-12
membered) heterocycloalkoxy, --C.sub.6-C.sub.12 aryloxy and -(6-12
membered) heteroaryloxy.
[0072] In another aspect, R.sup.7 is selected from
--C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.3-C.sub.12 cycloalkyl and -(3-12 membered)
heterocycloalkyl, wherein each hydrogen atom of said alkyl and
alkenyl of R.sup.7 is optionally replaced with a --F, and wherein
said cycloalkyl and heterocycloalkyl of R.sup.7 are each optionally
independently substituted with from one to six --F, and wherein
said alkyl, alkenyl, cycloalkyl and heterocycloalkyl of R.sup.7 are
each optionally independently substituted with from one to three
substitutents independently selected from --OH, --C.sub.1-C.sub.6
alkoxy, --C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--NR.sup.9R.sup.10, --(CH.sub.2).sub.1-6NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11,
--C(.dbd.O)NR.sup.9R.sup.10, --S(O)NR.sup.9R.sup.10,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl, -(4-12
membered) heterocycloalkoxy, --C.sub.6-C.sub.12 aryloxy and -(6-12
membered) heteroaryloxy.
[0073] In another aspect, R.sup.7 is a --C.sub.1-C.sub.12 alkyl
substituted with --NR.sup.9R.sup.10 morpholino, pyrrolidnyl or
piperidinyl.
[0074] In another aspect, the compound of Formula I has the
following stereoisomeric structure:
##STR00003##
[0075] In another aspect, in the stereoisomeric compound above,
R.sup.4 and R.sup.5 are hydrogen. Specific embodiments of the
present invention include the following compounds of Formula I, all
pharmaceutically acceptable salts thereof, complexes thereof, and
derivatives thereof that convert into a pharmaceutically active
compound upon administration: [0076]
2-(S)-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid
[5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide; [0077]
2-(S)-(1-Ethyl-propylamino)-pentanoic acid
[5-(1-ethyl-propyl)-thiazol-2-yl]-amide [0078]
2-(S)-(1-Ethyl-propylamino)-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)thiazol-2-yl]-amide; [0079]
2-(S)-(1-Propyl-butylamino)-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide; [0080]
2-(S)-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide; [0081]
2-(S)-((1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0082]
2-(S)-(Indan-2-ylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)amide; [0083]
2-(S)-(1-Ethyl-propylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0084]
2-(S)-(1-Cyclopropyl-ethylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0085]
2-(S)-(2-Cyclopentyl-1-methyl-ethylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0086]
2-(S)-Isopropylamino-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0087]
2-(S)-(1-Propyl-butylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0088]
2-(S)-Cyclohexylamino-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0089]
2-(S)-(2-Cyclohexyl-1-methyl-ethylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0090]
2-(S)-(3,3-Dimethoxy-1-methyl-propylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0091]
2-(S)-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide; [0092]
2-(S)-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide; [0093]
2-(S)-(5-Chloro-indan-2-ylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0094]
2-(S)-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide; [0095]
2-(S)-(6,7,8,9-Tetrahydro-5H-benzocyclohepten-6-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide; [0096]
2-(S)-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide; [0097]
2-(S)-(5-Fluoro-indan-2-ylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide; [0098]
2-(S)-(6-Isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)amide; [0099]
2-(S)-(6-Methyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)amide; [0100]
2-(S)-(6-Chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide; [0101]
2-(S)-(8-Chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide; [0102]
2-(S)-(6,8-Dichloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)amide; [0103]
2-(S)-(5,8-Dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide; [0104]
2-(S)-(8-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide; [0105]
2-(S)-(6-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide; [0106]
2-(S)-(8-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide; [0107]
2-(S)-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)pentanoic
acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide; [0108]
2-(S)-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)pentanoic
acid [5-(5-methoxy-1,5-dimethyl-hexyl)thiazol-2-yl]-amide; [0109]
2-(S)-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide; [0110]
2-(S)-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide; [0111]
2-(S)-(8-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [5-(5-methoxy-1,5-dimethyl-hexyl)thiazol-2-yl]-amide; and
[0112]
2-(S)-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide.
[0113] As indicated, so-called `prodrugs` of the compounds of
Formula I are also within the scope of the invention. Thus certain
derivatives of compounds of Formula I which may have little or no
pharmacological activity themselves can, when administered into or
onto the body, be converted into compounds of Formula I having the
desired activity, for example, by hydrolytic cleavage. Such
derivatives are referred to as `prodrugs`. Further information on
the use of prodrugs may be found in Pro-drugs as Novel Delivery
Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella)
and Bioreversible Carriers in Drug Design, Pergamon Press, 1987
(Ed. E. B. Roche, American Pharmaceutical Association).
[0114] Prodrugs in accordance with the invention can, for example,
be produced by replacing appropriate functionalities present in the
compounds of Formula I with certain moieties known to those skilled
in the art as `pro-moieties` as described, for example, in Design
of Prodrugs by H. Bundgaard (Elsevier, 1985).
[0115] Some examples of prodrugs in accordance with the invention
include, but are not limited to,
[0116] (i) where the compound of Formula I contains a carboxylic
acid functionality
[0117] (--COOH), an ester thereof, for example, a compound wherein
the hydrogen of the carboxylic acid functionality of the compound
of Formula (I) is replaced by (C.sub.1-C.sub.8)alkyl;
[0118] (ii) where the compound of Formula I contains an alcohol
functionality (--OH), an ether thereof, for example, a compound
wherein the hydrogen of the alcohol functionality of the compound
of Formula I is replaced by (C.sub.1-C.sub.6)alkanoyloxymethyl;
and
[0119] (iii) where the compound of Formula I contains a primary or
secondary amino functionality (--NH.sub.2 or --NHR where
R.noteq.H), an amide thereof, for example, a compound wherein, as
the case may be, one or both hydrogens of the amino functionality
of the compound of Formula I is/are replaced by
(C.sub.1-C.sub.10)alkanoyl.
[0120] Further examples of replacement groups in accordance with
the foregoing examples and examples of other prodrug types may be
found in the aforementioned references.
[0121] Moreover, certain compounds of Formula I may themselves act
as prodrugs of other compounds of Formula I.
[0122] Also included within the scope of the invention are
metabolites of compounds of Formula I, that is, compounds formed in
vivo upon administration of the drug. Some examples of metabolites
in accordance with the invention include, but are not limited
to,
[0123] (i) where the compound of Formula I contains a methyl group,
an hydroxymethyl derivative thereof
(--CH.sub.3->--CH.sub.2OH):
[0124] (ii) where the compound of Formula I contains an alkoxy
group, an hydroxy derivative thereof (--OR->--OH);
[0125] (iii) where the compound of Formula I contains a tertiary
amino group, a secondary amino derivative thereof
(--NR.sup.1R.sup.2->--NHR.sup.1 or --NHR.sup.2);
[0126] (iv) where the compound of Formula I contains a secondary
amino group, a primary derivative thereof
(--NHR.sup.1->--NH.sub.2);
[0127] (v) where the compound of Formula I contains a phenyl
moiety, a phenol derivative thereof (-Ph->-PhOH); and
[0128] (vi) where the compound of Formula I contains an amide
group, a carboxylic acid derivative thereof
(--CONH.sub.2->COOH).
[0129] Compounds of Formula I containing one or more asymmetric
carbon atoms can exist as two or more stereoisomers. Where a
compound of Formula I contains an alkenyl or alkenylene group,
geometric cis/trans (or Z/E) isomers are possible. Where structural
isomers are interconvertible via a low energy barrier, tautomeric
isomerism (`tautomerism`) can occur. This can take the form of
proton tautomerism in compounds of Formula I containing, for
example, an imino, keto, or oxime group, or so-called valence
tautomerism in compounds which contain an aromatic moiety. It
follows that a single compound may exhibit more than one type of
isomerism.
[0130] Included within the scope of the present invention are all
stereoisomers, geometric isomers and tautomeric forms of the
compounds of Formula I, including compounds exhibiting more than
one type of isomerism, and mixtures of one or more thereof. Also
included are acid addition or base salts wherein the counterion is
optically active, for example, d-lactate or l-lysine, or racemic,
for example, dl-tartrate or dl-arginine.
[0131] Cis/trans isomers may be separated by conventional
techniques well known to those skilled in the art, for example,
chromatography and fractional crystallisation.
[0132] Conventional techniques for the preparation/isolation of
individual enantiomers include chiral synthesis from a suitable
optically pure precursor or resolution of the racemate
[0133] (or the racemate of a salt or derivative) using, for
example, chiral high pressure liquid chromatography (HPLC).
[0134] Alternatively, the racemate (or a racemic precursor) may be
reacted with a suitable optically active compound, for example, an
alcohol, or, in the case where the compound of Formula I contains
an acidic or basic moiety, a base or acid such as
1-phenylethylamine or tartaric acid. The resulting diastereomeric
mixture may be separated by chromatography and/or fractional
crystallization and one or both of the diastereoisomers converted
to the corresponding pure enantiomer(s) by means well known to a
skilled person.
[0135] Chiral compounds of the invention (and chiral precursors
thereof) may be obtained in enantiomerically-enriched form using
chromatography, typically HPLC, on an asymmetric resin with a
mobile phase consisting of a hydrocarbon, typically heptane or
hexane, containing from 0 to 50% by volume of isopropanol,
typically from 2% to 20%, and from 0 to 5% by volume of an
alkylamine, typically 0.1% diethylamine. Concentration of the
eluate affords the enriched mixture.
[0136] When any racemate crystallises, crystals of two different
types are possible. The first type is the racemic compound (true
racemate) referred to above wherein one homogeneous form of crystal
is produced containing both enantiomers in equimolar amounts. The
second type is the racemic mixture or conglomerate wherein two
forms of crystal are produced in equimolar amounts each comprising
a single enantiomer.
[0137] While both of the crystal forms present in a racemic mixture
have identical physical properties, they may have different
physical properties compared to the true racemate. Racemic mixtures
may be separated by conventional techniques known to those skilled
in the art--see, for example, Stereochemistry of Organic Compounds
by E. L. Eliel and S. H. Wilen (Wiley, 1994).
[0138] The present invention includes all pharmaceutically
acceptable isotopically-labelled compounds of Formula I wherein one
or more atoms are replaced by atoms having the same atomic number,
but an atomic mass or mass number different from the atomic mass or
mass number which predominates in nature.
[0139] Examples of isotopes suitable for inclusion in the compounds
of the invention include, but are not limited to, isotopes of
hydrogen, such as .sup.2H and .sup.3H, carbon, such as .sup.11C,
.sup.13C and .sup.14C, chlorine, such as .sup.36Cl, fluorine, such
as .sup.18F, iodine, such as .sup.123I and .sup.125I, nitrogen,
such as .sup.13N and .sup.15N, oxygen, such as .sup.15O, .sup.17O
and .sup.18O, phosphorus, such as .sup.32P, and sulphur, such as
.sup.35S.
[0140] Certain isotopically-labelled compounds of Formula I, for
example, those incorporating a radioactive isotope, are useful in
drug and/or substrate tissue distribution studies. The radioactive
isotopes tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection.
[0141] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0142] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy.
[0143] Isotopically-labeled compounds of Formula I can generally be
prepared by conventional techniques known to those skilled in the
art or by processes analogous to those described in the
accompanying Examples and Preparations using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
previously employed.
[0144] Pharmaceutically acceptable solvates in accordance with the
invention include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.6-DMSO.
[0145] Also within the scope of the invention are intermediate
compounds of Formula II as hereinbefore defined, all salts,
solvates and complexes thereof and all solvates and complexes of
salts thereof as defined hereinbefore for compounds of Formula I.
The invention includes all polymorphs of the aforementioned species
and crystal habits thereof.
[0146] When preparing compounds of Formula I in accordance with the
invention, it is open to a person skilled in the art to routinely
select the form of compound of Formula II which provides the best
combination of features for this purpose. Such features include,
but are not limited to, the melting point, solubility,
processability and yield of the intermediate form and the resulting
ease with which the product may be purified on isolation.
[0147] Compounds of the Formula I of this invention, and their
pharmaceutically acceptable salts, have useful pharmaceutical and
medicinal properties. The compounds of Formula I, and their
pharmaceutically acceptable salts inhibit the production of
A.beta.-peptide (thus, gamma-secretase activity) in mammals,
including humans. Compounds of the Formula I, and their
pharmaceutically acceptable salts, are therefore able to function
as therapeutic agents in the treatment of the neurodegenerative
and/or neurological disorders and diseases enumerated below, for
example Alzheimer's disease, in an afflicted mammal, including a
human.
[0148] The present invention also relates to a pharmaceutical
composition for treating a disease or condition selected from the
group consisting of Alzheimer's disease, hereditary cerebral
hemorrhage with amyloidosis, cerebral amyloid angiopathy, a
prion-mediated disease, inclusion body myositis, stroke, multiple
sclerosis and Down's Syndrome in a mammal, including a human,
comprising an amount of a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, that is effective in
inhibiting A.beta.-peptide production, and a pharmaceutically
acceptable carrier.
[0149] The present invention also relates to a pharmaceutical
composition for treating a disease or condition selected from the
group consisting of Alzheimer's disease and Down's Syndrome in a
mammal, including a human, comprising an amount of a compound of
the Formula I, or a pharmaceutically acceptable salt thereof, that
is effective in inhibiting A.beta.-peptide production, and a
pharmaceutically acceptable carrier.
[0150] The present invention also relates to a pharmaceutical
composition for treating a disease or a condition selected from the
group consisting of Alzheimer's disease, hereditary cerebral
hemorrhage with amyloidosis, cerebral amyloid angiopathy, a
prion-mediated disease, inclusion body myositis, stroke, multiple
sclerosis and Down's Syndrome in a mammal, including a human,
comprising an amount of a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, that is effective in
treating such disease or condition, and a pharmaceutically
acceptable carrier.
[0151] The present invention also relates to a pharmaceutical
composition for treating a disease or a condition selected from the
group consisting of Alzheimer's disease and Down's Syndrome in a
mammal, including a human, comprising an amount of a compound of
the Formula I, or a pharmaceutically acceptable salt thereof, that
is effective in treating such disease or condition, and a
pharmaceutically acceptable carrier.
[0152] The present invention also relates to a method of treating a
disease or condition selected from Alzheimer's disease, hereditary
cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy,
a prion-mediated disease, inclusion body myositis, stroke, multiple
sclerosis and Down's Syndrome in a mammal, including a human,
comprising administering to said mammal an amount of a compound of
the Formula I, or a pharmaceutically acceptable salt thereof, that
is effective in inhibiting A.beta.-production.
[0153] The present invention also relates to a method of treating a
disease or condition selected from Alzheimer's disease and Down's
Syndrome in a mammal, including a human, comprising administering
to said mammal an amount of a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, that is effective in
inhibiting A.beta.-production.
[0154] The present invention also relates to a method of treating a
disease or condition selected from Alzheimer's disease, hereditary
cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy,
a prion-mediated disease, inclusion body myositis, stroke, multiple
sclerosis and Down's Syndrome in a mammal, including a human,
comprising administering to said mammal an amount of a compound of
the Formula I, or a pharmaceutically acceptable salt thereof, that
is effective in treating such condition.
[0155] The present invention also relates to a method of treating a
disease or condition selected from Alzheimer's disease and Down's
Syndrome in a mammal, including a human, comprising administering
to said mammal an amount of a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, that is effective in
treating such condition.
[0156] Compounds of the Formula I may be used alone or used in
combination with any other drug, including, but not limited to, any
memory enhancement agent, e.g., Aricept.TM., antidepressant agent,
e.g., Zoloft.TM., anxiolytic, antipsychotic agent, e.g.,
Geodon.TM., sleep disorder agent, anti-inflammatory agent e.g.,
Celebrex.TM., Bextra.TM., etc., anti-oxidant agent, cholesterol
modulating agent (for example, an agent that lowers LDL or
increases HDL), e.g., Lipitor.TM., or anti-hypertension agent.
[0157] The present invention also relates to a pharmaceutical
composition for treating a disease or condition associated with
A.beta.-peptide production in a mammal, including a human,
comprising (a) a compound of the Formula I, or a pharmaceutically
acceptable salt thereof; (b) a memory enhancement agent,
antidepressant, anxiolytic, antipsychotic agent, sleep disorder
agent, anti-inflammatory agent, anti-oxidant agent, cholesterol
modulating agent or anti-hypertensive agent; and (c) a
pharmaceutically acceptable carrier; wherein the active agents "a"
and "b" above are present in amounts that render the composition
effective in treating such disease or condition.
[0158] The present invention also relates to a pharmaceutical
composition for treating a disease or condition selected from the
group consisting of Alzheimer's disease, hereditary cerebral
hemorrhage with amyloidosis, cerebral amyloid angiopathy, a
prion-mediated disease, inclusion body myositis, stroke, multiple
sclerosis and Down's Syndrome, in a mammal, including a human,
comprising (a) a compound of the Formula I, or a pharmaceutically
acceptable salt thereof; (b) a memory enhancement agent,
antidepressant, anxiolytic, antipsychotic agent, sleep disorder
agent, anti-inflammatory agent, anti-oxidant agent, cholesterol
modulating agent or anti-hypertensive agent; and (c) a
pharmaceutically acceptable carrier; wherein the active agents "a"
and "b" above are present in amounts that render the composition
effective in treating such disease or condition.
[0159] The present invention also relates to a pharmaceutical
composition for treating a disease or condition selected from the
group consisting of Alzheimer's disease and Down's Syndrome, in a
mammal, including a human, comprising (a) a compound of the Formula
I, or a pharmaceutically acceptable salt thereof; (b) a memory
enhancement agent, antidepressant, anxiolytic, antipsychotic agent,
sleep disorder agent, anti-inflammatory agent, anti-oxidant agent,
cholesterol modulating agent or anti-hypertensive agent; and (c) a
pharmaceutically acceptable carrier; wherein the active agents "a"
and "b" above are present in amounts that render the composition
effective in treating such disease or condition.
[0160] The present invention also relates to a method of treating a
disease or condition associated with A.beta.-peptide production in
a mammal, including a human, comprising administering to said
mammal (a) a compound of the Formula I, or a pharmaceutically
acceptable salt thereof; and (b) a memory enhancement agent,
antidepressant, anxiolytic, antipsychotic agent, sleep disorder
agent, anti-inflammatory agent, anti-oxidant agent, cholesterol
modulating agent or anti-hypertensive agent; wherein the active
agents "a" and "b" above are present in amounts that render the
composition effective in treating such disease or condition.
[0161] The present invention also relates to a method of treating a
disease or condition selected from the group consisting of
Alzheimer's disease, hereditary cerebral hemorrhage with
amyloidosis, cerebral amyloid angiopathy, a prion-mediated disease,
inclusion body myositis, stroke, multiple sclerosis and Down's
Syndrome, in a mammal, including a human, comprising administering
to said mammal (a) a compound of the Formula I, or a
pharmaceutically acceptable salt thereof; and (b) a memory
enhancement agent, antidepressant, anxiolytic, antipsychotic agent,
sleep disorder agent, anti-inflammatory agent, anti-oxidant agent,
cholesterol modulating agent or anti-hypertensive agent; wherein
the active agents "a" and "b" above are present in amounts that
render the composition effective in treating such disease or
condition.
[0162] The present invention also relates to a method of treating a
disease or condition selected from the group consisting of
Alzheimer's disease and Down's Syndrome, in a mammal, including a
human, comprising administering to said mammal (a) a compound of
the Formula I, or a pharmaceutically acceptable salt thereof; and
(b) a memory enhancement agent, antidepressant, anxiolytic,
antipsychotic agent, sleep disorder agent, anti-inflammatory agent,
anti-oxidant agent, cholesterol modulating agent or
anti-hypertensive agent; wherein the active agents "a" and "b"
above are present in amounts that render the composition effective
in treating such disease or condition.
[0163] The compounds of Formula I, or their pharmaceutically
acceptable salts may also be used to modulate or inhibit the Notch
signaling pathway in organisms, including humans. The Notch
signaling pathway is an evolutionarily conserved mechanism utilized
by organisms, ranging from worms through humans, to regulate fate
determination of various cell lineages. Notch belongs to the family
of epidermal growth factor-like homeotic genes, which encode
transmembrane proteins with variable numbers of epidermal growth
factor-like repeats in the extracellular domain. There is
increasing evidence for a role of the Notch pathway in human
disease. All of the components of the pathway have yet to be
identified, but among those identified to date, mutations that
affect their interaction with each other can lead to a variety of
syndromes and pathological conditions.
[0164] For example, Notch signaling is typically associated with
cell fate decision. The finding that Notch activation stimulates
capillary outgrowth suggests that Notch receptors must be activated
to allow this process to occur. Therefore, Notch modulation
provides a method for regulating angiogenesis. Specifically,
modulation of Notch signaling can be used to modulate angiogenesis
(e.g., by blocking Notch signaling to block angiogenesis). This
inhibition of angiogenesis in vivo can be used as a therapeutic
means to treat a variety of diseases, including but not limited to
cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis,
inflammatory bowel disease and arteriosclerosis.
[0165] The Notch pathway is also implicated in the development and
maturation of T cells, as described in Radtke, F. et al., Immunity
10:547-558, 1999. The compounds of Formula I, and their
pharmaceutically acceptable salts are therefore useful candidates
for modulating the immune system, including the treatment of
inflammation, asthma, graft rejection, graft versus host disease,
autoimmune disease and transplant rejection.
[0166] In addition, a number of studies published between 2002 and
2004 have provided convincing evidence that Notch signaling is
frequently elevated in a variety of human tumors (including, but
not limited to breast, prostate, pancreas and T-cell acute
lymphoblastic leukemia). One key study provides a strong genetic
link to Notch's role in important tumor types. Specifically,
Weijzen et al. demonstrated that Notch signaling maintains the
neoplastic phenotype in human Ras-transformed cells. Weijzen et al.
(2002) Nature Med 8: 979. Because 30% of human malignancies may
carry activating mutations in at least one of the three isoforms of
Ras, this finding raises the possibility that Notch inhibitors
would be a powerful addition to anti-cancer therapy. Another
study's findings support a central role for aberrant Notch
signaling in the pathogenesis of human T cell acute lymphoblastic
leukemia/lymphoma. Pear et al., Current Opinion in Hematology
(2004), 11 (6), 426-433.
[0167] Accordingly, the compounds of Formula I, and their
pharmaceutically acceptable salts, may be used for treating a
disease or condition selected from the group consisting of cancer,
arteriosclerosis, diabetic retinopathy, rheumatoid arthritis,
psoriasis, inflammatory bowel disease inflammation, asthma, graft
rejection, graft versus host disease, autoimmune disease and
transplant rejection.
[0168] Compounds of the Formula I, or any of the combinations
described in the preceding paragraphs, may optionally be used in
conjunction with a know P-glycoprotein inhibitor, such as
verapamil.
[0169] References herein to diseases and conditions "associated
with A.beta.-peptide production" relate to diseases or conditions
that are caused, at least in part, by A.beta.-peptide and/or the
production thereof. Thus, A.beta.-peptide is a contributing factor,
but not necessarily the only contributing factor, to "a disease or
condition associated with A.beta.-peptide production."
[0170] As used herein, the term "treating" refers to reversing,
alleviating or inhibiting the progress of a disease, disorder or
condition, or one or more symptoms of such disease, disorder or
condition, to which such term applies. As used herein, "treating"
may also refer to decreasing the probability or incidence of the
occurrence of a disease, disorder or condition in a mammal as
compared to an untreated control population, or as compared to the
same mammal prior to treatment. For example, as used herein,
"treating" may refer to preventing a disease, disorder or
condition, and may include delaying or preventing the onset of a
disease, disorder or condition, or delaying or preventing the
symptoms associated with a disease, disorder or condition. As used
herein, "treating" may also refer to reducing the severity of a
disease, disorder or condition or symptoms associated with such
disease, disorder or condition prior to a mammal's affliction with
the disease, disorder or condition. Such prevention or reduction of
the severity of a disease, disorder or condition prior to
affliction relates to the administration of the composition of the
present invention, as described herein, to a subject that is not at
the time of administration afflicted with the disease, disorder or
condition. As used herein "treating" may also refer to preventing
the recurrence of a disease, disorder or condition or of one or
more symptoms associated with such disease, disorder or condition.
The terms "treatment" and "therapeutically," as used herein, refer
to the act of treating, as "treating" is defined above.
DETAILED DESCRIPTION OF THE INVENTION
[0171] Compounds of the Formula I, and their pharmaceutically
acceptable salts, may be prepared as described in the following
reaction Schemes and discussion. Unless otherwise indicated, as
referred to in the reaction schemes and discussion that follow,
R.sup.1, R.sup.1a, R.sup.1b, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15 and n are as defined above.
[0172] The compounds of Formula I may have asymmetric carbon atoms
and may therefore exist as racemic mixtures, diastereoisomers, or
as individual optical isomers.
[0173] Separation of a mixture of isomers of compounds of Formula I
into single isomers may be accomplished according to conventional
methods known in the art. Enantiomers or diasteroisomers may be
separated by chiral column chromatography, or separated through
recrystallization of the corresponding salt prepared by addition of
an appropriate chiral acid or base.
[0174] The compounds of the Formula I may be prepared by the
methods described below, together with synthetic methods known in
the art of organic chemistry, or modifications and derivatisations
that are familiar to those of ordinary skill in the art. Preferred
methods include, but are not limited to, those described below.
[0175] The reactions described below are performed in solvents that
are appropriate to the reagents and materials employed and that are
suitable for use in the reactions described. In the description of
the synthetic methods described below, it is also to be understood
that all reaction conditions, whether actual or proposed, including
choice of solvent, reaction temperature, reaction duration time,
reaction pressure, and other reaction conditions (such as anhydrous
conditions, under argon, under nitrogen, etc.), and work up
procedures, are those conditions that are standard for that
reaction, as would be readily recognized by one of skill in the
art. Alternate methods may also be used.
##STR00004##
[0176] Referring to Scheme 1, compounds of formula I wherein
R.sup.1 is --C.sub.1-C.sub.20 alkyl, --C.sub.2-C.sub.20 alkenyl,
--C.sub.2-C.sub.20 alkynyl, --C.sub.3-C.sub.8 cycloalkyl,
--C.sub.5-C.sub.8 cycloalkenyl, --(C.sub.5-C.sub.11)bi- or
tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, -(3-8
membered) heterocycloalkyl, -(5-11 membered) heterobicycloalkyl or
R.sup.5 is C.sub.1-C.sub.6 alkyl, it can be prepared by using a
well-established reductive amination method by reacting compounds
in formula II with a ketone or aldehyde with or without acid
catalyst (such as acetic acid)/ammonium acetate/dry agents (such as
anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4), and a reducing agent
such as sodium triacetoxy borohydride (NaBH(OAc).sub.3, sodium
cyanoborohydride (NaCNBH.sub.3), sodium borohydride, or the
corresponding polymer bound-NaBH4, polymer bound-NaCNBH.sub.3,
polymer bound-NaBH(OAc).sub.3, or any reducing agent (e.g.,
hydrogenation) that is known in the literature for reducing the
imine bond to the corresponding amine in an appropriate solvent,
such as dichloroethane, chloroform, THF, MeOH, ethanol, about
iso-propanol, t-butanol or toluene, at a temperature between room
temperature to reflux, preferably at about room temperature to
about 65.degree. C. (For review, see, Baxter, Ellen W.; Reitz,
Allen B. Organic Reactions (New York) (2002), 59 1-714; Tarasevich,
Vladimir A.; Kozlov, Nikolai G. Russian Chemical Reviews (1999), 68
(1), 55-72). Alternatively, it can be prepared by well-established
alkylation method by reacting compound of formula II with an
alkyl-L.sub.1 wherein L.sub.1 is a leaving group, such as a halide
(I, Br, Cl) or tosylate (OTs), myslate (OMs), trifilate (OTf) in
the presence of an appropriate base selecting from a tertiary amine
(e.g., triethylamine, diisopropylamine, dimethylaminopyridine,
sodium hydroxide, potassium carbonate, cesium carbonate) in an
appropriate solvent selecting from C.sub.1-C.sub.4 alcohol, THF,
methylene chloride, dichloroethane, dimethylformamide, DMSO,
pyridine, N-methylpyrrolidone, toluene, xylene, acetonitrile,
acetone, proprionitrile at an appropriate temperature form room
temperature to refluxing. Compounds of formula I wherein R.sup.1 is
--C.sub.6-C.sub.14 aryl and -(5-15 membered) heteroaryl, it can be
prepared by reacting compound of formula II with aryl-L.sub.1 or
heteroaryl-L1, or well-established Pd-catalyzed amination
(References: J. Org. Chem., 2000, 65, 1158), wherein L.sub.1 is a
leaving group, such as a halide (I, Br, Cl) or tosylate (OTs),
myslate (OMs), trifilate (OTf) in the presence of an appropriate
base selecting from a tertiary amine (e.g., triethylamine,
diisopropylamine, dimethylaminopyridine, sodium hydroxide,
potassium carbonate, cesium carbonate, potassium or sodium alkoxide
(t-butoxide, methoxide), potassium or sodium hydride, with or
without an organometallics (e.g., Pd(OAc).sub.2, Pd(dba).sub.2,
Pd(PPh.sub.3).sub.4 and a ligand such as PPh.sub.3, BINAP,
PPh.sub.3 PCy.sub.3, P(t-Bu).sub.3, and related ligand know in
literature in an appropriate solvent selecting from C.sub.1-C.sub.4
alcohol, THF, methylene chloride, dichloroethane,
dimethylformamide, DMSO, N-methylpyrrolidone, xylene, toluene,
acetonitrile, pyridine, acetone, proprionitrile at an appropriate
temperature form room temperature to refluxing;
[0177] Compounds of formula II in turn can be synthesized by
reacting 2-amino-1,3-thiazole (Prepared using known literature
methods. Reference: Can. J. Chem., EN, 66 (1988), 1617-1624; Chem.
Heterocycl. Compd. (Engl. Transl.), EN, 5, (1969) 46-48; J. Org.
Chem. USSR (Engl. Transl.), EN, 6, (1970), 1196-1200; Hoekfelt, B.;
Joensson, A.; JMPCAS; J. Med. Pharm. Chem., EN, 5, (1962) 247-257.;
J. Chem. Soc., (1951), 2430, 2440; J. Amer. Chem. Soc., 72 (1950),
3722; J. Chem. Soc., (1945) 455, 457) with N-protected amino acids
using the standard coupling methods such as carbodiimide, i.e.
1,3-dicyclohexylcarbodiimide (DCC),
O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TPTU), 1,3-diisopropylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC or EDCl),
N-cyclohexylcarbodiimide, or N'-methylpolystyrene in the presence
or absence of 1-hydroxy-benzotriazole (HOBt) in a suitable solvent
such as dichloromethane (CH.sub.2Cl.sub.2), chloroform
(CHCl.sub.3), tetrahydrofuran (THF), diethyl ether (Et.sub.2O),
1,4-dioxane, acetonitrile (CH.sub.3CN), toluene,
N,N-dimethylformamide (DMF). Compounds of Formula II can then be
obtained by removing the N-protecting group: strong acid in the
case of t-butoxycarbonyl or through hydrogenolysis in the case of
carbobenzyloxycarbonyl.
[0178] The starting materials used in the procedures of the above
Schemes, the syntheses of which are not described above, are either
commercially available, known in the art or readily obtainable from
known compounds using methods that will be apparent to those
skilled in the art (e.g., WO2004/033439).
[0179] Alternatively, compounds in formula I may be prepared from
left to right as shown in Scheme II using the methods analogous to
that described in Scheme I.
##STR00005##
[0180] The starting materials used in the procedure of the above
Scheme II, the syntheses of which are not described above, are
either commercially available, known in the art or readily
obtainable from known compounds using methods that will be apparent
to those skilled in the art.
[0181] The compounds of Formula I, and the intermediates shown in
the above reaction schemes, may be isolated and purified by
conventional procedures, such as recrystallization or
chromatographic separation, such as on silica gel, either with an
ethyl acetate/hexane elution gradient, a methylene
chloride/methanol elution gradient, or a chloroform/methanol
elution gradient. Alternatively, a reverse phase preparative HPLC
or chiral HPLC separation technique may be used.
[0182] In each of the reactions discussed or illustrated above,
pressure is not critical unless otherwise indicated. Pressures from
about 0.5 atmospheres to about 5 atmospheres are generally
acceptable, and ambient pressure, i.e., about 1 atmosphere, is
preferred as a matter of convenience.
[0183] Pharmaceutically acceptable salts of the compounds of
Formula I may be prepared in a conventional manner by treating a
solution or suspension of the corresponding free base or acid with
one chemical equivalent of a pharmaceutically acceptable acid or
base. Conventional concentration or crystallization techniques may
be employed to isolate the salts. Suitable acids, include, but are
not limited to, acetic, lactic, succinic, maleic, tartaric, citric,
gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric,
phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic,
sulfonic acids such as methanesulfonic, benzene sulfonic,
p-toluenesulfonic and related acids. Suitable bases include, but
are not limited to, sodium, potassium and calcium.
[0184] A compound of the Formula I of the present invention may be
administered to mammals via either the oral, parenteral (such as
subcutaneous, intravenous, intramuscular, intrasternal and infusion
techniques), rectal, intranasal, topical or transdermal (e.g.,
through the use of a patch) routes. In general, these compounds are
most desirably administered in doses ranging from about 0.1 mg to
about 1000 mg per day, in single or divided doses (i.e., from 1 to
4 doses per day), although variations will necessarily occur
depending upon the species, weight, age and condition of the
subject being treated, as well as the particular route of
administration chosen. However, a dosage level that is in the range
of about 0.1 mg/kg to about 5 gm/kg body weight per day, preferably
from about 0.1 mg/kg to about 100 mg/kg body weight per day, is
most desirably employed. Nevertheless, variations may occur
depending upon the species of animal being treated and its
individual response to said medicament, as well as on the type of
pharmaceutical formulation chosen and the time period and interval
at which such administration is carried out. In some instances,
dosage levels below the lower limit of the aforesaid range may be
more than adequate, while in other cases still larger doses may be
employed without causing any harmful side effects, provided that
such higher dosage levels are first divided into several small
doses for administration throughout the day.
[0185] A compound of the Formula I of the present invention may be
administered alone or in combination with pharmaceutically
acceptable carriers or diluents by either of the routes previously
indicated, and such administration may be carried out in single or
multiple doses. Suitable pharmaceutical carriers include solid
diluents or fillers, sterile aqueous media and various non-toxic
organic solvents, etc. The pharmaceutical compositions formed by
combining a compound of the Formula I, or a pharmaceutically
acceptable salt thereof, with a pharmaceutically acceptable inert
carrier, can then be readily administered in a variety of dosage
forms such as tablets, capsules, lozenges, troches, hard candies,
powders, sprays, creams, salves, suppositories, jellies, gels,
pastes, lotions, ointments, aqueous suspensions, injectable
solutions, elixirs, syrups, and the like. Moreover, oral
pharmaceutical compositions may be suitably sweetened and/or
flavored.
[0186] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate and glycine may be employed
along with various disintegrants such as starch (preferably corn,
potato or tapioca starch), methylcellulose, alginic acid and
certain complex silicates, together with granulation binders such
as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often useful for tabletting purposes. Solid
compositions of a similar type may also be employed as fillers in
gelatin capsules. Preferred materials in this connection include
lactose or milk sugar as well as high molecular weight polyethylene
glycols. When aqueous suspensions and/or elixirs are desired for
oral administration, the active ingredient may be combined with
various sweetening or flavoring agents, coloring matter or dyes,
and, if so desired, emulsifying and/or suspending agents as well,
together with such diluents as water, ethanol, propylene glycol,
glycerin and various like combinations thereof.
[0187] For parenteral administration, solutions containing a
compound of the Formula I of the present invention in either sesame
or peanut oil or in aqueous propylene glycol may be employed. The
aqueous solutions should be suitably buffered (preferably pH
greater than 8) if necessary and the liquid diluent first rendered
isotonic with sufficient saline or glucose. These aqueous solutions
are suitable for intravenous injection purposes. The oily solutions
are suitable for intraarticular, intramuscular and subcutaneous
injection purposes. The preparation of all these solutions under
sterile conditions is readily accomplished by standard
pharmaceutical techniques well known to those skilled in the
art.
[0188] The compounds of Formula I of the present invention are
useful in inhibiting A.beta.-peptide production (thus,
gamma-secretase activity) in mammals, and therefore they are able
to function as therapeutic agents in the treatment of the
aforementioned disorders and diseases in an afflicted mammal.
[0189] The ability of compounds of the Formula I of this invention,
and their pharmaceutically acceptable salts, to inhibit
A.beta.-peptide production (thus, gamma-secretase activity) may be
determined using biological assays known to those of ordinary skill
in the art, for example the assays described below.
[0190] The activity of compounds of the Formula I of the present
invention in inhibiting gamma-secretase activity is determinable in
a solubilized membrane preparation generally according to the
description provided in McLendon et al. Cell-free assays for
.gamma.-secretase activity, The FASEB Journal (Vol. 14, December
2000, pp. 2383-2386). Compounds of the present invention were
determined to have an IC.sub.50 activity for inhibiting
gamma-secretase activity of less than about 100 micromolar.
[0191] The following Examples illustrate the present invention. It
is to be understood, however, that the invention, as fully
described herein and as recited in the claims, is not intended to
be limited by the details of the following Examples.
EXPERIMENTAL PROCEDURES
General Procedure for Reductive Amination
a) Sodium triacetoxyborohydride
[0192] An amine (1-4 eq.) in dichloromethane, dichloroethane or THF
was added to a solution of a ketone or aldehyde (1 eq.),
NaBH(OAc).sub.3 (1-3 eq.) and acetic acid (1-3 eq.) in
dichloromethane, dichloroethane or THF. The mixture was stirred at
room temperature until product formation or disappearance of the
starting material. The mixture was quenched with diluted base,
extracted with methylene chloride or other appropriate solvent such
as chloroform or ethyl acetate. The organic layer was separated,
dried and concentrated to give the desired amine. Purification may
be necessary.
b) Sodium cyanoborohydride
[0193] A mixture of a ketone or aldehyde (1 eq.), an amine (1-4
eq.), sodium cyanoborohydride (1-5 eq.), with catalytic amount of
zinc chloride in an appropriate solvent such as Methanol, or THF
was stirred at room temperature to 60.degree. C. until product
formation or disappearance of the starting material. The mixture
was quenched with diluted base, extracted with methylene chloride
or other appropriate solvent such as chloroform or ethyl acetate.
The organic layer was separated, dried and concentrated to give the
desired amine. Purification may be necessary.
Example 1
2-(S)-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)pentanoic
acid (5-isopropyl-thiazol-2-yl)-amide
[0194] 3-Methyl-butyraldehyde (174 mmol) was dissolved in 400 mL of
anhydrous dioxane and cooled to 0.degree. C. under N.sub.2. In a
separate flask, bromine (174 mmol) was dissolved in 500 mL of
anhydrous dioxane. The bromine-dioxane solution was added drop wise
to the reaction solution, maintaining the 0.degree. C. temperature.
A colorless precipitate formed. Once the addition was complete, the
reaction was warmed to rt and stirred for 2 h. A slurry of thiourea
(244 mmol) in 80 mL of anhydrous ethanol was then added to the
reaction and the suspension was stirred at rt for an additional 16
h. The crude reaction was then filtered to remove solids and the
filtrated was concentrated under reduced pressure to give a
residual oil. This oil was partitioned between 200 mL of EtOAc and
200 mL of 1N NaOH aqueous solution and extracted. The organics were
further washed with 200 mL of water, and 200 mL of brine. The
organics were then dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give
5-Isopropyl-thiazol-2-ylamine as the desired product. The crude
material was purified through flash chromatography on silica gel
and used directly.
[0195] The thiazole amine (69 mmol) was combined with
2-(S)-tert-butoxycarbonylamino-pentanoic acid (69 mmol) in 170 mL
of anhydrous DMF under N.sub.2. Triethylamine (76 mmol) was added
to the reaction, followed by HOBT (76 mmol) and EDCl (76 mmol). The
resultant mixture was stirred at r.t. for 16 h. The reaction was
then diluted with 200 mL of EtOAc and washed with 200 mL of water
and brine. The organics were then dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give the
desired product,
[1-(5-Isopropyl-thiazol-2-ylcarbamoyl)-butyl]-carbamic acid
tert-butyl ester.
[0196] The product (10.2 mmol) was purified through flash
chromatography and dissolved in 15 mL of anhydrous 4.0 N HCl in
dioxane and stirred at rt for 2 h. The reaction was then
concentrated under reduced pressure and triturated in Et.sub.2O to
give the desired amine, 2-Amino-pentanoic acid
(5-isopropyl-thiazol-2-yl)amide.
[0197] The 5,7-difluoro-2-tetralone (0.3 mmol) was dissolved in 2.0
mL of anhydrous dichloromethane under N.sub.2 at rt.
2-(S)-Amino-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide (0.3
mmol) was then added to the reaction solution, followed by sodium
triacetoxy borohydride (0.3 mmol) and acetic acid (0.3 mmol). The
reaction was stirred at rt for 16 h. The crude solution was then
diluted with 20 mL of EtOAc and washed with 20 mL of aqueous 1N
NaOH solution and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude products were purified through flash chromatography to
give
2-(S)-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (5 isopropyl-thiazol-2)-ylamide. LC-MS (retention time, M+1):
2.2 min, 408 [M+1].
[0198] The following Examples in Table 1 were synthesized by
methods analogous to those described above.
TABLE-US-00001 TABLE 1 LC-MS (retention time, Example Name M + 1) 2
2-(S)-(5-Chloro-indan-2-ylamino)-pentanoic acid (5- 2.0 min, 392
isopropyl-thiazol-2-yl)-amide [M + 1] 3
2-(S)-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2- 2.0 min, 408
ylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1] 4
2-(S)-(6,7,8,9-Tetrahydro-5H-benzocyclohepten-6-ylamino)- 2.0 min,
387 pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1] 5
2-(S)-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)- 2.0 min,
390 pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1] 6
2-(S)-(5-Fluoro-indan-2-ylamino)-pentanoic acid (5- 2.0 min, 376
isopropyl-thiazol-2-yl)-amide [M + 1] 7
2-(S)-(6-Isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)- 2.5
min, 414 pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1] 8
2-(S)-(6-Methyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)- 2.2 min,
386 pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1] 9
2-(S)-(6-Chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)- 2.3 min,
406 pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1] 10
2-(S)-(8-Chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)- 2.2 min,
406 pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1] 11
2-(S)-(6,8-Dichloro-1,2,3,4-tetrahydro-naphthalen-2- 2.4 min, 440
ylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1] 12
2-(S)-(5,8-Dimethyl-1,2,3,4-tetrahydro-naphthalen-2- 2.3 min, 400
ylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1] 13
2-(S)-(8-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)- 2.1 min,
390 pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1] 14
2-(S)-(6-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)- 1.9 min,
402 pentanoic acid (5-isopropyl-thiazol-2-yl)-amide [M + 1]
[0199] The following Examples in Table 2 were prepared using
2-Amino-pentanoic acid
[5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide prepared from
7-Methoxy-3,7-dimethyl-octanal following procedures analogous to
those described above.
TABLE-US-00002 TABLE 2 LC-MS (retention time, Example Name M + 1)
15 2-(S)-(8-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)- 2.3
min, 490 pentanoic acid
[5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2- [M + 1] 16
2-(S)-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2- 2.4 min, 508
ylamino)-pentanoic acid [5-(5-methoxy-1,5-dimethyl-hexyl)- [M + 1]
17 2-(S)-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2- 2.4 min,
508 ylamino)-pentanoic acid [5-(5-methoxy-1,5-dimethyl-hexyl)- [M +
1] 18 2-(S)-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2- 2.3 min,
508 ylamino)-pentanoic acid [5-(5-methoxy-1,5-dimethyl-hexyl)- [M +
1] 19 2-(S)-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)- 2.2
min, 490 pentanoic acid
[5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2- [M + 1] 20
2-(S)-(8-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)- 2.2 min,
490 pentanoic acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2- [M
+ 1] 21 2-(S)-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2- 2.3
min, 508 ylamino)-pentanoic acid [5-(5-methoxy-1,5-dimethyl-hexyl)-
[M + 1]
Examples 22 and 23
2-(S)-(1.2.314-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid
[5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide and
2-(S)-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)thiazol-2-yl]-amide
[0200] A mixture of 2-(S)-amino-pentanoic acid
[5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide HCl salt (600
mg, 1.59 mmol) and 2-tetralone (253 mg, 2.07 mmol) in
dichloroethane was stirred at room temperature overnight. Sodium
triacetoxyborohydride (530 mg, 2.5 mmol) was added and the mixture
was stirred at room temperature overnight. The mixture was quenched
with water, adjusted pH to around 10 and extracted with methylene
chloride. The organic layer was concentrated to dryness. The
residue was purified by SCX column after eluting with 1M
NH3/methanol and concentrated to dryness to give 620 mg that was
purified by Shimadzu HPLC to give
2-(S)-(1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid
[5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide, LC-MS RT=2.2
min, M+1=472.5 as an oil and
2-(S)-(1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide, retention
time, LC-MS RT=1.9 min, M+1=458.4 as a beige glass form.
Example 24
2-(S)-(1-Ethyl-propylamino)-pentanoic acid
[5-(1-ethyl-propyl)-thiazol-2-yl]-amide
[0201] A mixture of 2-(S)amino-pentanoic acid
[5-(1-ethyl-propyl)-thiazol-2-yl]-amide (107 mg, 0.4 mmol) and
3-pentanone (34 mg, 0.4 mmol) in 3 mL of methylene chloride and 5
drops of acetic acid was treated with sodium triacetoxyborohydride
(131 mg, 0.62 mmol) and stirred at room temperature overnight. An
additional sodium triacetoxyborohydride (167 mg) was added and the
resulting mixture was stirred at room temperature for 4 hrs. The
mixture was quenched with ammonium hydroxide/water and extracted
with methylene chloride. The organic layer was separated, dried,
filtered and concentrated to dryness to give a yellow oil. The oil
was purified by Shimadzu HPLC to give
2-(S)-(1-Ethyl-propylamino)-pentanoic acid
[5-(1-ethyl-propyl)-thiazol-2-yl]-amide as a colorless oil, RT=1.88
min, M+1=340.4.
Example 25
2-(S)-(1-Ethyl-propylamino)-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide
[0202] A mixture of 2-(S)-amino-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide HCl salt (200
mg, 0.55 mmol) and 3-pentanone (237 mg, 2.76 mmol), 5 drops of
acetic acid, sodium acetate (100 mg), sodium sulfate (100 mg) and
sodium cyanoborohydride (222 mg, 2.75 mmol) in dichloroethane (15
mL) was stirred at 40.degree. C. overnight. The mixture was
quenched with water, and extracted with methylene chloride. The
organic layer was concentrated to dryness. The residue was purified
by Shimadzu HPLC to give 2-(S)-(1-ethyl-propylamino)pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)thiazol-2-yl]-amide as a colorless
oil, LC-MS, RT=1.6 min, M+1=398.6.
Example 26
2-(S)-(1-Propyl-butylamino)-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide
[0203] A mixture of 2-(S)-amino-pentanoic acid
[5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide HCl salt (100
mg, 0.265 mmol) and 3-heptanone (0.1 mL), acetic acid (0.2 mL),
sodium sulfate and sodium cyanoborohydride (100 mg) in
dichloroethane (2 mL) and methanol (1 mL) was stirred at 40.degree.
C. overnight. The mixture was quenched with water, basified by
dilute sodium hydroxide, and extracted with methylene chloride. The
organic layer was concentrated to dryness. The residue was purified
by Biotage silica gel column chromatography to isolate
2-(S)-(1-propyl-butylamino)-pentanoic acid
[5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide as a
colorless oil, LC-MS, RT=2.2 min, M+1=426.5.
Example 27
2-(S)-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide
[0204] A mixture of 2-(S)-amino-pentanoic acid
(5-isopropyl-thiazol-2-yl)amide (350 mg, 1.4 mmol) and 2-tetralone
(318 mg, 2.2 mmol) in 20 mL of methylene chloride and 5 drops of
acetic acid was treated with sodium triacetoxyborohydride (462 mg,
2.2 mmol) and stirred at room temperature overnight. The mixture
was concentrated and eluted through SPEC SCX cartridge and
concentrated to dryness. The residue was purified by silica gel
column chromatography to give
2-(S)-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide as a solid, LC-MS, RT=1.9 min,
M+1=372.
[0205] The following compounds were prepared by the method
analogous to that described in Example 27 of the synthesis of
2-(S)-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide starting from
2-(S)-amino-pentanoic acid (5-isopropyl-thiazol-2-yl)amide and an
appropriate ketone.
Example 28
2-(S)-(Indan-2-ylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide
[0206] 2-(S)-(Indan-2-ylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide, purified by silica gel column
chromatography using 1-3% methanol in methylene chloride to give
the title compound as a brown oil, LC-MS RT=1.9 min, M+1=358.
Example 29
2-(S)-(1-Ethyl-propylamino)-pentanoic acid
(5-isopropyl-thiazol-2-ylamide
[0207] 2-(S)-(1-Ethyl-propylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide, purified by HPLC to give the
title compound as a colorless oil, LC-MS RT=1.5 min, M+1=312.
Example 30
2-(S)-(1-Cyclopropyl-ethylamino)pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide
[0208] A mixture of 2-(S)-amino-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide (150 mg, 0.54 mmol) and
cyclopropyl methyl ketone (45 mg, 0.54 mmol) in 10 mL of methylene
chloride and 5 drops of acetic acid was treated with sodium
triacetoxyborohydride (172 mg, 0.8 mmol) and stirred at room
temperature overnight. The mixture was quenched with dilute
ammonium hydroxide and extracted with methylene chloride. The
organic layer was separated and concentrated to dryness. The
residue was purified by HPLC to give
2-(S)-(1-cyclopropyl-ethylamino)pentanoic acid
(5-isopropyl-thiazol-2-yl)amide as a colorless oil, LC-MS RT=1.4
min, M+1=310.
[0209] The following compounds were prepared by the method
analogous to that described in Example 27 of the synthesis of
2-(S)-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide starting from
2-(S)-amino-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide and an
appropriate ketone.
Example 31
2-(S)-(2-Cyclopentyl-1-methyl-ethylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide
[0210] 2-(S)-(2-Cyclopentyl-1-methyl-ethylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide, purified by HPLC to give a
colorless oil, LC-MS RT=2.0 min, M+1=352.
Example 32
2-(S)-Isopropylamino-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide
[0211] 2-(S)-Isopropylamino-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide, purified by HPLC to give a white
solid, LC-MS RT=1.2 min, M+1=284.
Example 33
2-(S)-(1-Propyl-butylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide
[0212] 2-(S)-(1-Propyl-butylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)amide, purified by HPLC to give a
colorless oil, LC-MS RT=1.7 min, M+1=340.
Example 34
2-(S)-Cyclohexylamino-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide
[0213] 2-(S)-Cyclohexylamino-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide, purified by HPLC to give a
colorless oil, LC-MS RT=1.8 min, M+1=324.
Example 35
2-(S)-(2-Cyclohexyl-1-methyl-ethylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide
[0214] 2-(S)-(2-Cyclohexyl-1-methyl-ethylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide, purified by HPLC to give a
colorless oil, LC-MS RT=2.3 min, M+1=366.
Example 36
2-(S)-(3,3-Dimethoxy-1-methyl-propylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)amide
[0215] 2-(S)-(3,3-Dimethoxy-1-methyl-propylamino)-pentanoic acid
(5-isopropyl-thiazol-2-yl)-amide, purified by HPLC to give a
colorless oil, LC-MS RT=1.6 min, M+1=358.
[0216] The invention described and claimed herein is not to be
limited in scope by the specific embodiments herein disclosed,
since these embodiments are intended as illustrations of several
aspects of the invention. Any equivalent embodiments are intended
to be within the scope of this invention. Indeed, 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. Such modifications are also
intended to fall within the scope of the appended claims.
* * * * *