U.S. patent application number 12/042640 was filed with the patent office on 2008-07-10 for methods and therapeutic combinations for the treatment of demyelination.
Invention is credited to Jay S. Fine, Eric McFee Parker.
Application Number | 20080166318 12/042640 |
Document ID | / |
Family ID | 32314527 |
Filed Date | 2008-07-10 |
United States Patent
Application |
20080166318 |
Kind Code |
A1 |
Fine; Jay S. ; et
al. |
July 10, 2008 |
METHODS AND THERAPEUTIC COMBINATIONS FOR THE TREATMENT OF
DEMYELINATION
Abstract
The present invention provides methods for treating
demyelination and associated conditions by administering at least
one sterol absorption inhibitor and compositions, therapeutic
combinations and methods including: (a) at least one sterol
absorption inhibitor; and (b) at least one demyelination treatment
which can be useful for preventing or treating demyelination and
associated conditions, such as multiple sclerosis.
Inventors: |
Fine; Jay S.; (Bloomfield,
NJ) ; Parker; Eric McFee; (Scotch Plains,
NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
32314527 |
Appl. No.: |
12/042640 |
Filed: |
March 5, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10701244 |
Nov 4, 2003 |
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12042640 |
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60493318 |
Aug 7, 2003 |
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60424165 |
Nov 6, 2002 |
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Current U.S.
Class: |
424/85.6 ;
514/210.02 |
Current CPC
Class: |
A61K 31/366 20130101;
A61P 1/04 20180101; A61P 19/08 20180101; A61K 31/397 20130101; A61P
7/06 20180101; A61P 37/00 20180101; A61P 3/10 20180101; A61P 21/04
20180101; A61K 45/06 20130101; A61K 31/40 20130101; A61P 19/02
20180101; A61P 17/00 20180101; A61P 1/16 20180101; A61P 9/04
20180101; A61K 31/366 20130101; A61P 17/14 20180101; A61P 11/00
20180101; A61P 9/08 20180101; A61K 31/397 20130101; A61P 17/06
20180101; A61P 25/00 20180101; A61P 29/00 20180101; A61K 31/40
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/85.6 ;
514/210.02 |
International
Class: |
A61K 31/397 20060101
A61K031/397; A61K 38/21 20060101 A61K038/21; A61P 25/00 20060101
A61P025/00 |
Claims
1. A method of treating demyelination in a subject, comprising the
step of administering to a subject in need of such treatment an
effective amount of at least one sterol absorption inhibitor or a
pharmaceutically acceptable salt or solvate thereof, wherein the at
least one sterol absorption inhibitor is selected from the group
consisting of sterol absorption inhibitors represented by the
following Formulae: (a) Formula (III): ##STR00041## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (III) above: Ar.sup.1 is R.sup.3-substituted
aryl; Ar.sup.2 is R.sup.4-substituted aryl; Ar.sup.3 is
R.sup.5-substituted aryl; Y and Z are independently selected from
the group consisting of --CH.sub.2--, --CH(lower alkyl)- and
--C(dilower alkyl)-; A is selected from --O--, --S--, --S(O)-- or
--S(O).sub.2--; R.sup.1 is selected from the group consisting of
--OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 and
--O(CO)NR.sup.6R.sup.7; R.sup.2 is selected from the group
consisting of hydrogen, lower alkyl and aryl; or R.sup.1 and
R.sup.2 together are .dbd.O; q is 1, 2 or 3; p is 0, 1, 2, 3 or4;
R.sup.5 is 1-3 substituents independently selected from the group
consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.9, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2-lower alkyl,
--NR.sup.6SO.sub.2-aryl, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6 R.sup.7, S(O).sub.0-2-alkyl, S(O).sub.0-2-aryl,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, o-halogeno, m-halogeno,
o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR.sup.6, and
--CH.dbd.CH--COOR.sup.6; R.sup.3 and R.sup.4 are independently 1-3
substituents independently selected from the group consisting of
R.sup.5, hydrogen, p-lower alkyl, aryl, --NO.sub.2, --CF.sub.3 and
p-halogeno; R.sup.6, R.sup.7 and R.sup.8 are independently selected
from the group consisting of hydrogen, lower alkyl, aryl and
aryl-substituted lower alkyl; and R.sup.9 is lower alkyl, aryl or
aryl-substituted lower alkyl; (b) Formula (IV): ##STR00042## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (IV) above: A is selected from the group
consisting of R.sup.2-substituted heterocycloalkyl,
R.sup.2-substituted heteroaryl, R.sup.2-substituted benzofused
heterocycloalkyl, and R.sup.2-substituted benzofused heteroaryl;
Ar.sup.1 is aryl or R.sup.3-substituted aryl; Ar.sup.2 is aryl or
R.sup.4-substituted aryl; Q is a bond or, with the 3-position ring
carbon of the azetidinone, forms the spiro group ##STR00043## and
R.sup.1 is selected from the group consisting of:
--(CH.sub.2).sub.q--, wherein q is 2-6, provided that when Q forms
a spiro ring, q can also be zero or 1;
--(CH.sub.2).sub.e-G-(CH.sub.2).sub.r--, wherein G is --O--,
--C(O)--, phenylene, --NR.sup.8-- or --S(O).sub.0-2--, e is 0-5 and
r is 0-5, provided that the sum of e and r is 1-6;
--(C.sub.2-C.sub.6 alkenylene)-; and
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6 cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6; R.sup.5 is selected from: ##STR00044##
R.sup.6 and R.sup.7 are independently selected from the group
consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-,
--C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--; or R.sup.5 together with an
adjacent R.sup.6, or R.sup.5 together with an adjacent R.sup.7,
form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero;
provided that when R.sup.6 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6
alkyl).dbd.CH--, a is 1; provided that when R.sup.7 is
--CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl).dbd.CH--, b is 1;
provided that when a is 2 or 3, the R.sup.6's can be the same or
different; and provided that when b is 2 or 3, the R.sup.7's can be
the same or different; and when Q is a bond, R.sup.1 also can be
selected from: ##STR00045## where M is --O--, --S--, --S(O)-- or
--S(O).sub.2--; X, Y and Z are independently selected from the
group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)- and
--C(di-(C.sub.1-C.sub.6) alkyl); R.sup.10 and R.sup.12 are
independently selected from the group consisting of --OR.sup.14,
--O(CO)R.sup.14, --O(CO)OR.sup.16 and --O(CO)NR.sup.14R.sup.15;
R.sup.11 and R.sup.13 are independently selected from the group
consisting of hydrogen, (C.sub.1-C.sub.6)alkyl and aryl; or
R.sup.10 and R.sup.11 together are .dbd.O, or R.sup.12 and R.sup.13
together are .dbd.O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0
or 1; t is 0 or 1; m, n and p are independently 0-4; provided that
at least one of s and t is 1, and the sum of m, n, p, s and t is
1-6; provided that when p is 0 and t is 1, the sum of m, s and n is
1-5; and provided that when p is 0 and s is 1, the sum of m, t and
n is 1-5; v is 0 or 1; j and k are independently 1-5, provided that
the sum of j, k and v is 1-5; R.sup.2 is 1-3 substituents on the
ring carbon atoms selected from the group consisting of hydrogen,
(C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkenyl, R.sup.17-substituted aryl,
R.sup.17-substituted benzyl, R.sup.17-substituted benzyloxy,
R.sup.17-substituted aryloxy, halogeno, --NR.sup.14R.sup.15,
NR.sup.14R.sup.15(C.sub.1-C.sub.6 alkylene)-,
NR.sup.14R.sup.15C(O)(C.sub.1-C.sub.6 alkylene)-, --NHC(O)R.sup.16,
OH, C.sub.1-C.sub.6 alkoxy, --OC(O)R.sup.16, --COR.sup.14,
hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, NO.sub.2,
--S(O).sub.0-2R.sup.16, --SO.sub.2NR.sup.14R.sup.15 and
--(C.sub.1-C.sub.6 alkylene)COOR.sup.14; when R.sup.2is a
substituent on a heterocycloalkyl ring, R.sup.2 is as defined, or
is .dbd.O or ##STR00046## and, where R.sup.2 is a substituent on a
substitutable ring nitrogen, it is hydrogen,
(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkoxy, aryloxy,
(C.sub.1-C.sub.6)alkylcarbonyl, arylcarbonyl, hydroxy,
--(CH.sub.2).sub.1-6CONR.sup.18R.sup.18, ##STR00047## wherein J is
--O--, --NH--, --NR.sup.18-- or --CH.sub.2--; R.sup.3 and R.sup.4
are independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --OR.sup.14, --O(CO)R.sup.14,
--O(CO)OR.sup.16, --O(CH.sub.2).sub.1-5OR.sup.14,
--O(CO)NR.sup.14R.sup.15, --NR.sup.14R.sup.15,
--NR.sup.14(CO)R.sup.15, --NR.sup.14(CO)OR.sup.16,
--NR.sup.14(CO)NR.sup.15R.sup.19, --NR.sup.14SO.sub.2R.sup.16,
--COOR.sup.14, --CONR.sup.14R.sup.15, --COR.sup.14,
--SO.sub.2NR.sup.14R.sup.15, S(O).sub.0-2R.sup.16,
--O(CH.sub.2).sub.1-10--COOR.sup.14,
--O(CH.sub.2).sub.1-10CONR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.14, --CH.dbd.CH--COOR.sup.14, --CF.sub.3, --CN,
--NO.sub.2 and halogen; R.sup.8 is hydrogen,
(C.sub.1-C.sub.6)alkyl, aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.14
or --COOR.sup.14; R.sup.9 and R.sup.17 are independently 1-3 groups
independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2,
--NR.sup.14R.sup.15, OH and halogeno; R.sup.14 and R.sup.15 are
independently selected from the group consisting of hydrogen,
(C.sub.1C.sub.6)alkyl, aryl and aryl-substituted
(C.sub.1-C.sub.6)alkyl; R.sup.16 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.17-substituted aryl; R.sup.18 is hydrogen or
(C.sub.1-C.sub.6)alkyl; and R.sup.19 is hydrogen, hydroxy or
(C.sub.1-C.sub.6)alkoxy; (c) Formula (V): ##STR00048## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (V) above: Ar.sup.1 is aryl,
R.sup.10-substituted aryl or heteroaryl; Ar.sup.2 is aryl or
R.sup.4-substituted aryl; Ar.sup.3 is aryl or R.sup.5-substituted
aryl; X and Y are independently selected from the group consisting
of --CH.sub.2--, --CH(lower alkyl)- and --C(dilower alkyl)-; R is
--OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 or
--O(CO)NR.sup.6R.sup.7; R.sup.1 is hydrogen, lower alkyl or aryl;
or R and R.sup.1 together are .dbd.O; q is 0 or 1; r is 0, 1 or 2;
m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum
of m, n and q is 1, 2, 3, 4 or 5; R.sup.4 is 1-5 substituents
independently selected from the group consisting of lower alkyl,
--OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, -(lower
alkylene)COOR.sup.6 and --CH.dbd.CH--COOR.sup.6; R.sup.5 is 1-5
substituents independently selected from the group consisting of
--OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, --CF.sub.3, --CN,
--NO.sub.2, halogen, -(lower alkylene)COOR.sup.6 and
--CH.dbd.CH--COOR.sup.6; R.sup.6, R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen, lower
alkyl, aryl and aryl-substituted lower alkyl; R.sup.9 is lower
alkyl, aryl or aryl-substituted lower alkyl; and R.sup.10 is 1-5
substituents independently selected from the group consisting of
lower alkyl, --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, --S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, --CF.sub.3, --CN,
--NO.sub.2 and halogen; (d) Formula (VI): ##STR00049## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein: R.sub.1 is ##STR00050## R.sub.2 and R.sub.3 are
independently selected from the group consisting of: --CH.sub.2--,
--CH(lower alkyl)-, --C(di-lower alkyl)-, --CH.dbd.CH-- and
--C(lower alkyl).dbd.CH--; or R.sub.1 together with an adjacent
R.sub.2, or R.sub.1 together with an adjacent R.sub.3, form a
--CH.dbd.CH-- or a --CH.dbd.C(lower alkyl)- group; u and v are
independently 0, 1, 2 or 3, provided both are not zero; provided
that when R.sub.2 is --CH.dbd.CH-- or --C(lower alkyl).dbd.CH--, v
is 1; provided that when R.sub.3 is --CH.dbd.CH-- or --C(lower
alkyl)=CH--, u is 1; provided that when v is 2 or 3, the R.sub.2's
can be the same or different; and provided that when u is 2 or 3,
the R.sub.3's can be the same or different; R.sub.4 is selected
from B--(CH.sub.2).sub.mC(O)--, wherein m is 0, 1, 2, 3, 4 or 5;
B--(CH.sub.2).sub.q--, wherein q is 0, 1, 2, 3, 4, 5 or 6;
B--(CH.sub.2).sub.e-Z-(CH.sub.2).sub.r--, wherein Z is --O--,
--C(O)--, phenylene, --N(R.sub.8)-- or --S(O).sub.0-2--, e is 0, 1,
2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided that the sum of
e and r is 0, 1, 2, 3, 4, 5 or 6; B--(C.sub.2-C.sub.6 alkenylene)-;
B--(C.sub.4-C.sub.6 alkadienylene)-;
B--(CH.sub.2).sub.t-Z-(C.sub.2-C.sub.6 alkenylene)-, wherein Z is
as defined above, and wherein t is 0, 1, 2 or 3, provided that the
sum of t and the number of carbon atoms in the alkenylene chain is
2, 3, 4, 5 or 6; B--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--,
wherein V is C.sub.3-C.sub.6 cycloalkylene, f is 1, 2, 3, 4 or 5
and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1,
2, 3, 4, 5 or 6; B--(CH.sub.2).sub.t--V--(C.sub.2-C.sub.6
alkenylene)- or B--(C.sub.2-C.sub.6
alkenylene)-V--(CH.sub.2).sub.t--, wherein V and t are as defined
above, provided that the sum of t and the number of carbon atoms in
the alkenylene chain is 2, 3, 4, 5 or 6;
B--(CH.sub.2).sub.a-Z-(CH.sub.2).sub.b--V--(CH.sub.2).sub.d--,
wherein Z and V are as defined above and a, b and d are
independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b
and d is 0, 1, 2, 3, 4, 5 or 6; or T-(CH.sub.2).sub.s--, wherein T
is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6;
or R.sub.1 and R.sub.4 together form the group ##STR00051## B is
selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl,
heteroaryl or W-substituted heteroaryl, wherein heteroaryl is
selected from the group consisting of pyrrolyl, pyridinyl,
pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl,
pyrazolyl, thienyl, oxazolyl and furanyl, and for
nitrogen-containing heteroaryls, the N-oxides thereof, or
##STR00052## W is 1 to 3 substituents independently selected from
the group consisting of lower alkyl, hydroxy lower alkyl, lower
alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower
alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower
alkanedioyl, allyloxy, --CF.sub.3, --OCF.sub.3, benzyl,
R.sub.7-benzyl, benzyloxy, R.sub.7-benzyloxy, phenoxy,
R.sub.7-phenoxy, dioxolanyl, NO.sub.2,--N(R.sub.8)(R.sub.9),
N(R.sub.8)(R.sub.9)-lower alkylene-, N(R.sub.8)(R.sub.9)-lower
alkylenyloxy-, OH, halogeno, --CN, --N.sub.3, --NHC(O)OR.sub.10,
--NHC(O)R.sub.10, R.sub.11O.sub.2SNH--,
(R.sub.11O.sub.2S).sub.2N--, --S(O).sub.2NH.sub.2,
--S(O).sub.0-2R.sub.8, tert-butyldimethyl-silyloxymethyl,
--C(O)R.sub.12, --COOR.sub.19, --CON(R.sub.8)(R.sub.9),
--CH.dbd.CHC(O)R.sub.12, -lower alkylene-C(O)R.sub.12,
R.sub.10C(O)(lower alkylenyloxy)-, N(R.sub.8)(R.sub.9)C(O)(lower
alkylenyloxy)- and ##STR00053## for substitution on ring carbon
atoms, and the substituents on the substituted heteroaryl ring
nitrogen atoms, when present, are selected from the group
consisting of lower alkyl, lower alkoxy, --C(O)OR.sub.10,
--C(O)R.sub.10, OH, N(R.sub.8)(R.sub.9)-lower
alkylene-,N(R.sub.8)(R.sub.9)-lower alkylenyloxy-,
--S(O).sub.2NH.sub.2 and 2-(trimethylsilyl)-ethoxymethyl; R.sub.7
is 1-3 groups independently selected from the group consisting of
lower alkyl, lower alkoxy, --COOH, NO.sub.2, --N(R.sub.8)(R.sub.9),
OH, and halogeno; R.sub.8 and R.sub.9 are independently selected
from H or lower alkyl; R.sub.10 is selected from lower alkyl,
phenyl, R.sub.7-phenyl, benzyl or R.sub.7-benzyl; R.sub.11 is
selected from OH, lower alkyl, phenyl, benzyl, R.sub.7-phenyl or
R.sub.7-benzyl; R.sub.12 is selected from H, OH, alkoxy, phenoxy,
benzyloxy, ##STR00054## --N(R.sub.8)(R.sub.9), lower alkyl, phenyl
or R.sub.7-phenyl; R.sub.13 is selected from --O--, --CH.sub.2--,
--NH--, --N(lower alkyl)- or --NC(O)R.sub.19; R.sub.15, R.sub.16
and R.sub.17 are independently selected from the group consisting
of H and the groups defined for W; or R.sub.15 is hydrogen and
R.sub.16 and R.sub.17, together with adjacent carbon atoms to which
they are attached, form a dioxolanyl ring;
R.sub.19 is H, lower alkyl, phenyl or phenyl lower alkyl; and
R.sub.20 and R.sub.21 are independently selected from the group
consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted
naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl,
heteroaryl, W-substituted heteroaryl, benzofused heteroaryl,
W-substituted benzofused heteroaryl and cyclopropyl, wherein
heteroaryl is as defined above; (e) Formula (VIIA) or (VIIB):
##STR00055## or a pharmaceutically acceptable salt or solvate
thereof, wherein: A is --CH.dbd.CH--, --C.ident.C-- or
--(CH.sub.2).sub.p-- wherein p is 0, 1 or 2; B is ##STR00056## B'
is ##STR00057## D is --(CH.sub.2).sub.mC(O)-- or
--(CH.sub.2).sub.q-- wherein m is 1, 2, 3 or 4 and q is 2, 3 or 4;
E is C.sub.10 to C.sub.20 alkyl or --C(O)--(C.sub.9 to
C.sub.19)-alkyl, wherein the alkyl is straight or branched,
saturated or containing one or more double bonds; R is hydrogen,
C.sub.1-C.sub.15 alkyl, straight or branched, saturated or
containing one or more double bonds, or B--(CH.sub.2).sub.r--,
wherein r is 0, 1, 2, or 3; R.sub.1, R.sub.2, R.sub.3, R.sub.1',
R.sub.2', and R.sub.3' are independently selected from the group
consisting of hydrogen, lower alkyl, lower alkoxy, carboxy,
NO.sub.2, NH.sub.2, OH, halogeno, lower alkylamino, dilower
alkylamino, --NHC(O)OR.sub.5, R.sub.6O.sub.2SNH-- and
--S(O).sub.2NH.sub.2; R.sub.4 is ##STR00058## wherein n is 0, 1, 2
or 3; R.sub.5 is lower alkyl; and R.sub.6 is OH, lower alkyl,
phenyl, benzyl or substituted phenyl wherein the substituents are
1-3 groups independently selected from the group consisting of
lower alkyl, lower alkoxy, carboxy, NO.sub.2, NH.sub.2, OH,
halogeno, lower alkylamino and dilower alkylamino; or a
pharmaceutically acceptable salt thereof or a prodrug thereof; (f)
Formula (VIII): ##STR00059## or a pharmaceutically acceptable salt
thereof or a solvate thereof, wherein, in Formula (VIII) above,
R.sup.26 is H or OG.sup.1; G and G.sup.1 are independently selected
from the group consisting of H, ##STR00060## and ##STR00061##
provided that when R.sup.26 is H or OH, G is not H; R, R.sup.a and
R.sup.b are independently selected from the group consisting of H,
--OH, halogeno, --NH.sub.2, azido,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)-alkoxy or --W--R.sup.30; W
is independently selected from the group consisting of
--NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--,
--NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--; R.sup.2 and
R.sup.6 are independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, aryl and aryl(C.sub.1-C.sub.6)alkyl;
R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.3a and R.sup.4a are
independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl,
--C(O)(C.sub.1-C.sub.6)alkyl and --C(O)aryl; R.sup.30 is selected
from the group consisting of R.sup.32-substituted T,
R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl,
R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl and
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl;
R.sup.31 is selected from the group consisting of H and
(C.sub.1-C.sub.4)alkyl; T is selected from the group consisting of
phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl
and pyridyl; R.sup.32 is independently selected from 1-3
substituents independently selected from the group consisting of
halogeno, (C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3,
--NO.sub.2, (C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo,
(C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2,
--C(O)--NH(C.sub.1-C.sub.4)alkyl,
--C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2,
--C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and
pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31,
the nitrogen to which it is attached and R.sup.32 form a
pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or
morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted
pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or
morpholinyl group; Ar.sup.1 is aryl or R.sup.10-substituted aryl;
Ar.sup.2 is aryl or R.sup.11-substituted aryl; Q is a bond or, with
the 3-position ring carbon of the azetidinone, forms the spiro
group ##STR00062## and R.sup.1 is selected from the group
consisting of --(CH.sub.2).sub.q--, wherein q is 2-6, provided that
when Q forms a spiro ring, q can also be zero or 1;
--(CH.sub.2).sub.e-E-(CH.sub.2).sub.r--, wherein E is --O--,
--C(O)--, phenylene, --NR.sup.22-- or --S(O).sub.0-2--, e is 0-5
and r is 0-5, provided that the sum of e and r is 1-6;
--(C.sub.2-C.sub.6)alkenylene-; and
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6 cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6; R.sup.12 is ##STR00063## R.sup.13 and
R.sup.14 are independently selected from the group consisting of
--CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-,
--C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--; or R.sup.12 together with an
adjacent R.sup.13 , or R.sup.12 together with an adjacent R.sup.14,
form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero;
provided that when R.sup.13 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6
alkyl).dbd.CH--, a is 1; provided that when R.sup.14 is
--CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl).dbd.CH--, b is 1;
provided that when a is 2 or 3, the R.sup.13's can be the same or
different; and provided that when b is 2 or 3, the R.sup.14's can
be the same or different; and when Q is a bond, R.sup.1 also can
be: ##STR00064## M is --O--, --S--, --S(O)-- or --S(O).sub.2--; X,
Y and Z are independently selected from the group consisting of
--CH.sub.2--, --CH(C.sub.1-C.sub.6)alkyl- and
--C(di-(C.sub.1-C.sub.6)alkyl); R.sup.10 and R.sup.11 are
independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --OR.sup.19, --O(CO)R.sup.19,
--O(CO)OR.sup.21, --O(CH.sub.2).sub.1-5OR.sup.19,
--O(CO)NR.sup.19R.sup.20, --NR.sup.19R.sup.20,
--NR.sup.19(CO)R.sup.20, --NR.sup.19(CO)OR.sup.21,
--NR.sup.19(CO)NR.sup.20R.sup.25, --NR.sup.19SO.sub.2R.sup.21,
--COOR.sup.19, --CONR.sup.19R.sup.20, --COR.sup.19,
--SO.sub.2NR.sup.19R.sup.20, S(O).sub.0-2R.sup.21,
--O(CH.sub.2).sub.1-10--COOR.sup.19,
--O(CH.sub.2).sub.1-10CONR.sup.19R.sup.20, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.19, --CH.dbd.CH--COOR.sup.19, --CF.sub.3, --CN,
--NO.sub.2 and halogen; R.sup.15 and R.sup.17 are independently
selected from the group consisting of --OR.sup.19, --O(CO)R.sup.19,
--O(CO)OR.sup.21 and --O(CO)NR.sup.19R.sup.20; R.sup.16 and
R.sup.18 are independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl and aryl; or R.sup.15 and R.sup.16 together
are .dbd.O, or R.sup.17 and R.sup.18 together are .dbd.O; d is 1, 2
or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is 0 or 1; m, n and p
are independently 0-4; provided that at least one of s and t is 1,
and the sum of m, n, p, s and t is 1-6; provided that when p is 0
and t is 1, the sum of m, s and n is 1-5; and provided that when p
is 0 and s is 1, the sum of m, t and n is 1-5; v is 0 or 1; j and k
are independently 1-5, provided that the sum of j, k and v is 1-5;
and when Q is a bond and R.sup.1 is ##STR00065## Ar.sup.1 can also
be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl,
pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R.sup.19 and R.sup.20 are independently selected from the group
consisting of H, (C.sub.1-C.sub.6)alkyl, aryl and aryl-substituted
(C.sub.1-C.sub.6)alkyl; R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.24-substituted aryl; R.sup.22 is H, (C.sub.1-C.sub.6)alkyl,
aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.19 or --COOR.sup.19;
R.sup.23 and R.sup.24 are independently 1-3 groups independently
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2, --NR.sup.19R.sup.20,
--OH and halogeno; and R.sup.25 is H, --OH or
(C.sub.1-C.sub.6)alkoxy; and (g) Formula (IX): ##STR00066## or a
pharmaceutically acceptable salt or solvate thereof, wherein in
Formula (IX): R.sup.1 is selected from the group consisting of H,
G, G.sup.1, G.sup.2, --SO.sub.3H and --PO.sub.3H; ##STR00067## G is
selected from the group consisting of: H, wherein R, R.sup.a and
R.sup.b are each independently selected from the group consisting
of H, --OH, halo, --NH.sub.2, azido,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy or --W--R.sup.30; W
is independently selected from the group consisting of
--NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--,
--NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--; R.sup.2 and
R.sup.6 are each independently selected from the group consisting
of H, (C.sub.1-C.sub.6)alkyl, acetyl, aryl and
aryl(C.sub.1-C.sub.6)alkyl; R.sup.3, R.sup.4, R.sup.5, R.sup.7,
R.sup.3a and R.sup.4a are each independently selected from the
group consisting of H, (C.sub.1-C.sub.6)alkyl, acetyl,
aryl(C.sub.1-C.sub.6)alkyl, --C(O)(C.sub.1-C.sub.6)alkyl and
--C(O)aryl; R.sup.30 is independently selected from the group
consisting of R.sup.32-substituted T,
R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl,
R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl and
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl;
R.sup.31 is independently selected from the group consisting of H
and (C.sub.1-C.sub.4)alkyl; T is independently selected from the
group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl,
pyrazolyl, imidazolyl and pyridyl; R.sup.32 is independently
selected from 1-3 substituents which are each independently
selected from the group consisting of H, halo,
(C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3, --NO.sub.2,
(C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo,
(C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2,
--C(O)--NH(C.sub.1-C.sub.4)alkyl,
--C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2,
--C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and
pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31,
the nitrogen to which it is attached and R.sup.32 form a
pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or
morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted
pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or
morpholinyl group; G.sup.1 is represented by the structure:
##STR00068## wherein R.sup.33 is independently selected from the
group consisting of unsubstituted alkyl, R.sup.34-substituted
alkyl, (R.sup.35)(R.sup.36)alkyl-, ##STR00069## R.sup.34 is one to
three substituents, each R.sup.34 being independently selected from
the group consisting of HOOC--, HO--, HS--, (CH.sub.3)S--,
H.sub.2N--, (NH.sub.2)(NH)C(NH)--, (NH.sub.2)C(O)-- and
HOOCCH(NH.sub.3.sup.+)CH.sub.2SS--; R.sup.35 is independently
selected from the group consisting of H and NH.sub.2--; R.sup.36 is
independently selected from the group consisting of H,
unsubstituted alkyl, R.sup.34-substituted alkyl, unsubstituted
cycloalkyl and R.sup.34-substituted cycloalkyl; G.sup.2 is
represented by the structure: ##STR00070## wherein R.sup.37 and
R.sup.38 are each independently selected from the group consisting
of (C.sub.1-C.sub.6)alkyl and aryl; R.sup.26 is one to five
substituents, each R.sup.26 being independently selected from the
group consisting of: a) H; b) --OH; c) --OCH.sub.3; d) fluorine; e)
chlorine; f) --O-G; g) --O-G.sup.1; h) --O-G.sup.2; i) --SO.sub.3H;
and j) --PO.sub.3H; provided that when R.sup.1 is H, R.sup.26 is
not H, --OH, --OCH.sub.3 or --O-G; Ar.sup.1 is aryl,
R.sup.10-substituted aryl, heteroaryl or R.sup.10-substituted
heteroaryl; Ar.sup.2 is aryl, R.sup.11-substituted aryl, heteroaryl
or R.sup.11-substituted heteroaryl; L is selected from the group
consisting of: a) a covalent bond; b) --(CH.sub.2).sub.q--, wherein
q is 1-6; c) --(CH.sub.2).sub.e-E-(CH.sub.2).sub.r--, wherein E is
--O--, --C(O)--, phenylene, --NR.sup.22-- or --S(O).sub.0-2--, e is
0-5 and r is 0-5, provided that the sum of e and r is 1-6; d)
--(C.sub.2-C.sub.6)alkenylene-; e)
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.9--, wherein V is
C.sub.3-C.sub.6cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6; and f) ##STR00071## wherein M is --O--,
--S--, --S(O)-- or --S(O).sub.2--; X, Y and Z are each
independently selected from the group consisting of --CH.sub.2--,
--CH(C.sub.1-C.sub.6)alkyl- and --C(di-(C.sub.1-C.sub.6)alkyl)-;
R.sup.8 is selected from the group consisting of H and alkyl;
R.sup.10 and R.sup.11 are each independently selected from the
group consisting of 1-3 substituents which are each independently
selected from the group consisting of (C.sub.1-C.sub.6)alkyl,
--OR.sup.19, --O(CO)R.sup.19, --O(CO)OR.sup.21,
--O(CH.sub.2).sub.1-5OR.sup.19, --O(CO)NR.sup.19R.sup.20,
--NR.sup.19R.sup.20, --NR.sup.19(CO)R.sup.20,
--NR.sup.19(CO)OR.sup.21, --NR.sup.19(CO)NR.sup.20R.sup.25,
--NR.sup.19SO.sub.2R.sup.21, --COOR.sup.19, --CONR.sup.19R.sup.20,
--COR.sup.19, --SO.sub.2NR.sup.19R.sup.20, S(O).sub.0-2R.sup.21,
--O(CH.sub.2).sub.1-10--COOR.sup.19,
--O(CH.sub.2).sub.1-10CONR.sup.19R.sup.20, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.19, --CH.dbd.CH--COOR.sup.19, --CF.sub.3, --CN,
--NO.sub.2 and halo; R.sup.15 and R.sup.17 are each independently
selected from the group consisting of --OR.sup.19, --OC(O)R.sup.19,
--OC(O)OR.sup.21, --OC(O)NR.sup.19R.sup.20; R.sup.16 and R.sup.18
are each independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl and aryl; or R.sup.15 and R.sup.16 together
are .dbd.O, or R.sup.17 and R.sup.18 together are .dbd.O; d is 1, 2
or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is 1 or 1; m, n and p
are each independently selected from 0-4; provided that at least
one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
provided that when p is 0 and t is 1, the sum of m, n and p is 1-5;
and provided that when p is 0 and s is 1, the sum of m, t and n is
1-5; v is 0 or 1; j and k are each independently 1-5, provided that
the sum of j, k and v is 1-5; Q is a bond, --(CH.sub.2).sub.q--,
wherein q is 1-6, or, with the 3-position ring carbon of the
azetidinone, forms the spiro group ##STR00072## wherein R.sup.12 is
##STR00073## R.sup.13 and R.sup.14 are each independently selected
from the group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6
alkyl)-, --C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--; or R.sup.12 together with an
adjacent R.sup.13, or R.sup.12 together with an adjacent R.sup.14,
form a
--CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)- group; a and
b are each independently 0, 1, 2 or 3, provided both are not zero;
provided that when R.sup.13 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6
alkyl).dbd.CH--, a is 1; provided that when R.sup.14 is
--CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl).dbd.CH--, b is 1;
provided that when a is 2 or 3, the R.sup.13's can be the same or
different; and provided that when b is 2 or 3, the R.sup.14's can
be the same or different; and when Q is a bond and L is
##STR00074## then Ar.sup.1 can also be pyridyl, isoxazolyl,
furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl,
pyrazinyl, pyrimidinyl or pyridazinyl; R.sup.19 and R.sup.20 are
each independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, aryl and aryl-substituted
(C.sub.1-C.sub.6)alkyl; R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.24-substituted aryl; R.sup.22 is H, (C.sub.1-C.sub.6)alkyl,
aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.19 or --COOR.sup.19;
R.sup.23 and R.sup.24 are each independently selected from the
group consisting of 1-3 substituents which are each independently
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2, --NR.sup.19R.sup.20,
--OH and halo; and R.sup.25 is H, --OH or
(C.sub.1-C.sub.6)alkoxy.
2. The method according to claim 1, wherein the at least one sterol
absorption inhibitor is administered to a subject in an amount
ranging from about 0.1 to about 1000 milligrams of sterol
absorption inhibitor per day.
3. The method according to claim 1, further comprising the step of
administering at least one antidemyelination agent to the
subject.
4. The method according to claim 3, wherein the antidemyelination
agent is selected from the group consisting of beta interferon,
glatiramer acetate and corticosteroids.
5. The method according to claim 1, further comprising the step of
administering at least one HMG CoA reductase inhibitor to the
subject.
6. The method according to claim 5, wherein the at least one HMG
CoA reductase inhibitor is atorvastatin.
7. The method according to claim 5, wherein the at least one HMG
CoA reductase inhibitor is simvastatin.
8. The method according to claim 1, wherein the subject has
multiple sclerosis.
9. A method of treating multiple sclerosis in a subject, comprising
the step of administering to a subject in need of such treatment an
effective amount of at least one sterol absorption inhibitor of
Formula (III) through (IX) of claim 1, or a pharmaceutically
acceptable salt or solvate thereof.
10. A composition comprising: (a) at least one sterol absorption
inhibitor or a pharmaceutically acceptable salt or solvate thereof
and (b) at least one antidemyelination agent, wherein the at least
one sterol absorption inhibitor is selected from the group
consisting of sterol absorption inhibitors represented by the
following Formulae: (a) Formula (III): ##STR00075## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (III) above: Ar.sup.1 is R.sup.3-substituted
aryl; Ar.sup.2 is R.sup.4-substituted aryl; Ar.sup.3 is
R.sup.5-substituted aryl; Y and Z are independently selected from
the group consisting of --CH.sub.2--, --CH(lower alkyl)- and
--C(dilower alkyl)-; A is selected from --O--, --S--, --S(O)-- or
--S(O).sub.2--; R.sup.1 is selected from the group consisting of
--OR.sup.6, --O(CO)R.sup.6, --O(OO)OR.sup.9 and
--O(CO)NR.sup.6R.sup.7; R.sup.2 is selected from the group
consisting of hydrogen, lower alkyl and aryl; or R.sup.1 and
R.sup.2 together are .dbd.O; q is 1, 2 or 3; p is 0, 1, 2, 3 or 4;
R.sup.5 is 1-3 substituents independently selected from the group
consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.9, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2-lower alkyl,
--NR.sup.6SO.sub.2-aryl, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2-alkyl, S(O).sub.0-2-aryl,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, o-halogeno, m-halogeno,
o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR.sup.6, and
--CH.dbd.CH--COOR.sup.6; R.sup.3 and R.sup.4 are independently 1-3
substituents independently selected from the group consisting of
R.sup.5, hydrogen, p-lower alkyl, aryl, --NO.sub.2, --CF.sub.3 and
p-halogeno; R.sup.6, R.sup.7 and R.sup.8 are independently selected
from the group consisting of hydrogen, lower alkyl, aryl and
aryl-substituted lower alkyl; and R.sup.9 is lower alkyl, aryl or
aryl-substituted lower alkyl; (b) Formula (IV): ##STR00076## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (IV) above: A is selected from the group
consisting of R.sup.2-substituted heterocycloalkyl,
R.sup.2-substituted heteroaryl, R.sup.2-substituted benzofused
heterocycloalkyl, and R.sup.2-substituted benzofused heteroaryl;
Ar.sup.1 is aryl or R.sup.3-substituted aryl; Ar.sup.2 is aryl or
R.sup.4-substituted aryl; Q is a bond or, with the 3-position ring
carbon of the azetidinone, forms the spiro group ##STR00077## and
R.sup.1 is selected from the group consisting of:
--(CH.sub.2).sub.q--, wherein q is 2-6, provided that when Q forms
a spiro ring, q can also be zero or 1;
--(CH.sub.2).sub.e-G-(CH.sub.2).sub.r--, wherein G is --O--,
--C(O)--, phenylene, --NR.sup.8-- or --S(O).sub.0-2--, e is 0-5 and
r is 0-5, provided that the sum of e and r is 1-6;
--(C.sub.2-C.sub.6 alkenylene)-; and
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6 cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6; R.sup.5 is selected from: ##STR00078##
R.sup.6 and R.sup.7 are independently selected from the group
consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-,
--C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--; or R.sup.5 together with an
adjacent R.sup.6, or R.sup.5 together with an adjacent R.sup.7,
form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero;
provided that when R.sup.6 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6
alkyl).dbd.CH--, a is 1; provided that when R.sup.7 is
--CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl).dbd.CH--, b is 1;
provided that when a is 2 or 3, the R.sup.6's can be the same or
different; and provided that when b is 2 or 3, the R.sup.7's can be
the same or different; and when Q is a bond, R.sup.1 also can be
selected from: ##STR00079## where M is --O--, --S--, --S(O)-- or
--S(O).sub.2--; X, Y and Z are independently selected from the
group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)- and
--C(di-(C.sub.1-C.sub.6) alkyl); R.sup.10 and R.sup.12 are
independently selected from the group consisting of --OR.sup.14,
--O(CO)R.sup.14, --O(CO)OR.sup.16 and --O(CO)NR.sup.14R.sup.15;
R.sup.11 and R.sup.13 are independently selected from the group
consisting of hydrogen, (C.sub.1-C.sub.6)alkyl and aryl; or
R.sup.10 and R.sup.11 together are .dbd.O, or R.sup.12 and R.sup.13
together are .dbd.O; d is 1,2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or
1; t is 0 or 1; m, n and p are independently 0-4; provided that at
least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
provided that when p is 0 and t is 1, the sum of m, s and n is 1-5;
and provided that when p is 0 and s is 1, the sum of m, t and n is
1-5; v is 0 or 1; j and k are independently 1-5, provided that the
sum of j, k and v is 1-5; R.sup.2 is 1-3 substituents on the ring
carbon atoms selected from the group consisting of hydrogen,
(C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkenyl, R.sup.17-substituted aryl,
R.sup.17-substituted benzyl, R.sup.17-substituted benzyloxy,
R.sup.17-substituted aryloxy, halogeno, --NR.sup.14R.sup.15,
NR.sup.14R.sup.15(C.sub.1-C.sub.6 alkylene)-,
NR.sup.14R.sup.15C(O)(C.sub.1-C.sub.6 alkylene)-, --NHC(O)R.sup.16,
OH, C.sub.1-C.sub.6 alkoxy, --OC(O)R.sup.16, --COR.sup.14,
hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-.sub.6)alkyl, NO.sub.2,
--S(O).sub.0-2R.sup.16, --SO.sub.2NR.sup.14R.sup.15 and
--(C.sub.1-C.sub.6 alkylene)COOR.sup.14; when R.sup.2 is a
substituent on a heterocycloalkyl ring, R.sup.2 is as defined, or
is .dbd.O or ##STR00080## and, where R.sup.2 is a substituent on a
substitutable ring nitrogen, it is hydrogen,
(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkoxy, aryloxy,
(C.sub.1-C.sub.6)alkylcarbonyl, arylcarbonyl, hydroxy,
--(CH.sub.2).sub.1-6CONR.sup.18R.sup.18, ##STR00081## wherein J is
--O--, --NH--, --NR.sup.18-- or --CH.sub.2--; R.sup.3 and R.sup.4
are independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --OR.sup.14, --O(CO)R.sup.14,
--O(CO)OR.sup.16, --O(CH.sub.2).sub.1-5OR.sup.14,
--O(CO)NR.sup.14R.sup.15, --NR.sup.14R.sup.15,
--NR.sup.14(CO)R.sup.15, --NR.sup.14(CO)OR.sup.16,
--NR.sup.14(CO)NR.sup.15R.sup.19, --NR.sup.14SO.sub.2R.sup.16,
--COOR.sup.14, --CONR.sup.14R.sup.15, --COR.sup.14,
--SO.sub.2NR.sup.14R.sup.15, S(O).sub.0-2R.sup.16,
--O(CH.sub.2).sub.1-10--COOR.sup.14,
--O(CH.sub.2).sub.1-10CONR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.14, --CH.dbd.CH--COOR.sup.14, --CF.sub.3, --CN,
--NO.sub.2 and halogen; R.sup.8 is hydrogen,
(C.sub.1-C.sub.6)alkyl, aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.14
or --COOR.sup.14; R.sup.9 and R.sup.17 are independently 1-3 groups
independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2,
--NR.sup.14R.sup.15, OH and halogeno; R.sup.14 and R.sup.15 are
independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, aryl and aryl-substituted
(C.sub.1-C.sub.6)alkyl; R.sup.16 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.17-substituted aryl; R.sup.18 is hydrogen or
(C.sub.1-C.sub.6)alkyl; and R.sup.19 is hydrogen, hydroxy or
(C.sub.1-C.sub.6)alkoxy; (c) Formula (V): ##STR00082## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (V) above: Ar.sup.1 is aryl,
R.sup.10-substituted aryl or heteroaryl; Ar.sup.2 is aryl or
R.sup.4-substituted aryl; Ar.sup.3 is aryl or R.sup.5-substituted
aryl; X and Y are independently selected from the group consisting
of --CH.sub.2--, --CH(lower alkyl)- and --C(dilower alkyl)-; R is
--OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 or
--O(CO)NR.sup.6R.sup.7; R.sup.1 is hydrogen, lower alkyl or aryl;
or R and R.sup.1 together are .dbd.O; q is 0 or 1; r is 0, 1 or 2;
m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum
of m, n and q is 1, 2, 3, 4 or 5; R.sup.4 is 1-5 substituents
independently selected from the group consisting of lower alkyl,
--OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, -(lower
alkylene)COOR.sup.6 and --CH.dbd.CH--COOR.sup.6; R.sup.5 is 1-5
substituents independently selected from the group consisting of
--OR.sup.5, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, --CF.sub.3, --CN,
--NO.sub.2, halogen, -(lower alkylene)COOR.sup.6 and
--CH.dbd.CH--COOR.sup.6; R.sup.6, R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen, lower
alkyl, aryl and aryl-substituted lower alkyl; R.sup.9 is lower
alkyl, aryl or aryl-substituted lower alkyl; and R.sup.10 is 1-5
substituents independently selected from the group consisting of
lower alkyl, --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.6, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, --S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, --CF.sub.3, --CN,
--NO.sub.2 and halogen; (d) Formula (VI): ##STR00083## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein: R.sub.1 is ##STR00084## R.sub.2 and R.sub.3 are
independently selected from the group consisting of: --CH.sub.2--,
--CH(lower alkyl)-, --C(di-lower alkyl)-, --CH.dbd.CH-- and
--C(lower alkyl).dbd.CH--; or R.sub.1 together with an adjacent
R.sub.2, or R.sub.1 together with an adjacent R.sub.3, form a
--CH.dbd.CH-- or a --CH.dbd.C(lower alkyl)- group; u and v are
independently 0, 1, 2 or 3, provided both are not zero; provided
that when R.sub.2 is --CH.dbd.CH-- or --C(lower alkyl).dbd.CH--, v
is 1; provided that when R.sub.3 is --CH.dbd.CH-- or --C(lower
alkyl).dbd.CH--, u is 1; provided that when v is 2 or 3, the
R.sub.2's can be the same or different; and provided that when u is
2 or 3, the R.sub.3's can be the same or different; R.sub.4 is
selected from B--(CH.sub.2).sub.mC(O)--, wherein m is 0, 1, 2, 3, 4
or 5; B--(CH.sub.2).sub.q--, wherein q is 0, 1, 2, 3, 4, 5 or 6;
B--(CH.sub.2).sub.e-Z-(CH.sub.2).sub.r--, wherein Z is --O--,
--C(O)--, phenylene, --N(R.sub.8)-- or --S(O).sub.0-2--, e is 0, 1,
2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided that the sum of
e and r is 0, 1, 2, 3, 4, 5 or 6; B--(C.sub.2-C.sub.6 alkenylene)-;
B--(C.sub.4-C.sub.6 alkadienylene)-;
B--(CH.sub.2).sub.t-Z-(C.sub.2-C.sub.6 alkenylene)-, wherein Z is
as defined above, and wherein t is 0, 1, 2 or 3, provided that the
sum of t and the number of carbon atoms in the alkenylene chain is
2, 3, 4, 5 or 6; B--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--,
wherein V is C.sub.3-C.sub.6 cycloalkylene, f is 1, 2, 3, 4 or 5
and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1,
2, 3, 4, 5 or 6; B--(CH.sub.2).sub.t--V--(C.sub.2-C.sub.6
alkenylene)- or B--(C.sub.2-C.sub.6
alkenylene)-V--(CH.sub.2).sub.t--, wherein V and t are as defined
above, provided that the sum of t and the number of carbon atoms in
the alkenylene chain is 2, 3, 4, 5 or 6;
B--(CH.sub.2).sub.a-Z-(CH.sub.2).sub.b--V--(CH.sub.2).sub.d--,
wherein Z and V are as defined above and a, b and d are
independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b
and d is 0, 1, 2, 3, 4, 5 or 6; or T-(CH.sub.2).sub.s--, wherein T
is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6;
or R.sub.1 and R.sub.4 together form the group ##STR00085## B is
selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl,
heteroaryl or W-substituted heteroaryl, wherein heteroaryl is
selected from the group consisting of pyrrolyl, pyridinyl,
pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl,
pyrazolyl, thienyl, oxazolyl and furanyl, and for
nitrogen-containing heteroaryls, the N-oxides thereof, or
##STR00086## W is 1 to 3 substituents independently selected from
the group consisting of lower alkyl, hydroxy lower alkyl, lower
alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower
alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower
alkanedioyl, allyloxy, --CF.sub.3, --OCF.sub.3, benzyl,
R.sub.7-benzyl, benzyloxy, R.sub.7-benzyloxy, phenoxy,
R.sub.7-phenoxy, dioxolanyl, NO.sub.2,--N(R.sub.8)(R.sub.9),
N(R.sub.8)(R.sub.9)-lower alkylene-, N(R.sub.8)(R.sub.9)-lower
alkylenyloxy-, OH, halogeno, --CN, --N.sub.3, --NHC(O)OR.sub.10,
--NHC(O)R.sub.10, R.sub.11O.sub.2SNH--,
(R.sub.11O.sub.2S).sub.2N--, --S(O).sub.2NH.sub.2,
--S(O).sub.0-2R.sub.8, tert-butyldimethyl-silyloxymethyl,
--C(O)R.sub.12, --COOR.sub.19, --CON(R.sub.8)(R.sub.9),
--CH.dbd.CHC(O)R.sub.12, -lower alkylene-C(O)R.sub.12,
R.sub.10C(O)(lower alkylenyloxy)-, N(R.sub.8)(R.sub.9)C(O)(lower
alkylenyloxy)- and ##STR00087## for substitution on ring carbon
atoms, and the substituents on the substituted heteroaryl ring
nitrogen atoms, when present, are selected from the group
consisting of lower alkyl, lower alkoxy, --C(O)OR.sub.10,
--C(O)R.sub.10, OH, N(R.sub.8)(R.sub.9)-lower
alkylene-,N(R.sub.8)(R.sub.9)-lower alkylenyloxy-,
--S(O).sub.2NH.sub.2 and 2-(trimethylsilyl)-ethoxymethyl; R.sub.7
is 1-3 groups independently selected from the group consisting of
lower alkyl, lower alkoxy, --COOH, NO.sub.2, --N(R.sub.8)(R.sub.9),
OH, and halogeno; R.sub.8 and R.sub.9 are independently selected
from H or lower alkyl; R.sub.10 is selected from lower alkyl,
phenyl, R.sub.7-phenyl, benzyl or R.sub.7-benzyl; R.sub.11 is
selected from OH, lower alkyl, phenyl, benzyl, R.sub.7-phenyl or
R.sub.7-benzyl; R.sub.12 is selected from H, OH, alkoxy, phenoxy,
benzyloxy, ##STR00088## --N(R.sub.8)(R.sub.9), lower alkyl, phenyl
or R.sub.7-phenyl; R.sub.13 is selected from --O--, --CH.sub.2--,
--NH--, --N(lower alkyl)- or --NC(O)R.sub.19; R.sub.15, R.sub.16
and R.sub.17 are independently selected from the group consisting
of H and the groups defined for W; or R.sub.15 is hydrogen and
R.sub.16 and R.sub.17, together with adjacent carbon atoms to which
they are attached, form a dioxolanyl ring;
R.sub.19 is H, lower alkyl, phenyl or phenyl lower alkyl; and
R.sub.20 and R.sub.21 are independently selected from the group
consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted
naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl,
heteroaryl, W-substituted heteroaryl, benzofused heteroaryl,
W-substituted benzofused heteroaryl and cyclopropyl, wherein
heteroaryl is as defined above; (e) Formula (VIIA) or (VIIB):
##STR00089## or a pharmaceutically acceptable salt or solvate
thereof, wherein: A is --CH.dbd.CH--, --C.ident.C-- or
--(CH.sub.2).sub.p-- wherein p is 0, 1 or 2; B is ##STR00090## B'
is ##STR00091## D is --(CH.sub.2).sub.mC(O)-- or
--(CH.sub.2).sub.q-- wherein m is 1, 2, 3 or 4 and q is 2, 3 or 4;
E is C.sub.10 to C.sub.20 alkyl or --C(O)--(C.sub.9 to
C.sub.19)-alkyl, wherein the alkyl is straight or branched,
saturated or containing one or more double bonds; R is hydrogen,
C.sub.1-C.sub.15 alkyl, straight or branched, saturated or
containing one or more double bonds, or B--(CH.sub.2).sub.r--,
wherein r is 0, 1, 2, or 3; R.sub.1, R.sub.2, R.sub.3, R.sub.1',
R.sub.2', and R.sub.3'are independently selected from the group
consisting of hydrogen, lower alkyl, lower alkoxy, carboxy,
NO.sub.2, NH.sub.2, OH, halogeno, lower alkylamino, dilower
alkylamino, --NHC(O)OR.sub.5, R.sub.6O.sub.2SNH-- and
--S(O).sub.2NH.sub.2; R.sub.4 is ##STR00092## wherein n is 0, 1, 2
or 3; R.sub.5 is lower alkyl; and R.sub.6 is OH, lower alkyl,
phenyl, benzyl or substituted phenyl wherein the substituents are
1-3 groups independently selected from the group consisting of
lower alkyl, lower alkoxy, carboxy, NO.sub.2, NH.sub.2, OH,
halogeno, lower alkylamino and dilower alkylamino; or a
pharmaceutically acceptable salt thereof or a prodrug thereof; (f)
Formula (VIII): ##STR00093## or a pharmaceutically acceptable salt
thereof or a solvate thereof, wherein, in Formula (VIII) above,
R.sup.26 is H or OG.sup.1; G and G.sup.1 are independently selected
from the group consisting of H, ##STR00094## provided that when
R.sup.26 is H or OH, G is not H; R, R.sup.a and R.sup.b are
independently selected from the group consisting of H, --OH,
halogeno, --NH.sub.2, azido,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)-alkoxy or --W--R.sup.30; W
is independently selected from the group consisting of
--NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--,
--NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--; R.sup.2 and
R.sup.6 are independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, aryl and aryl(C.sub.1-C.sub.6)alkyl;
R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.3a and R.sup.4a are
independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl,
--C(O)(C.sub.1-C.sub.6)alkyl and --C(O)aryl; R.sup.30 is selected
from the group consisting of R.sup.32-substituted T,
R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl,
R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl and
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl;
R.sup.31 is selected from the group consisting of H and
(C.sub.1-C.sub.4)alkyl; T is selected from the group consisting of
phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl
and pyridyl; R.sup.32 is independently selected from 1-3
substituents independently selected from the group consisting of
halogeno, (C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3,
--NO.sub.2, (C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo,
(C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2,
--C(O)--NH(C.sub.1-C.sub.4)alkyl,
--C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2,
--C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and
pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31,
the nitrogen to which it is attached and R.sup.32 form a
pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or
morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted
pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or
morpholinyl group; Ar.sup.1 is aryl or R.sup.10-substituted aryl;
Ar.sup.2 is aryl or R.sup.11-substituted aryl; Q is a bond or, with
the 3-position ring carbon of the azetidinone, forms the spiro
group ##STR00095## and R.sup.1 is selected from the group
consisting of --(CH.sub.2).sub.q--, wherein q is 2-6, provided that
when Q forms a spiro ring, q can also be zero or 1;
--(CH.sub.2).sub.e-E-(CH.sub.2).sub.r--, wherein E is --O--,
--C(O)--, phenylene, --NR.sup.22-- or --S(O).sub.0-2--, e is 0-5
and r is 0-5, provided that the sum of e and r is 1-6;
--(C.sub.2-C.sub.6)alkenylene-; and
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6 cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6; R.sup.12 is ##STR00096## R.sup.13 and
R.sup.14 are independently selected from the group consisting of
--CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-,
--C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl)=CH--; or R.sup.12 together with an
adjacent R.sup.13, or R.sup.12 together with an adjacent R.sup.14,
form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero;
provided that when R.sup.13 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6
alkyl).dbd.CH--, a is 1; provided that when R.sup.14 is
--CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl).dbd.CH--, b is 1;
provided that when a is 2 or 3, the R.sup.13's can be the same or
different; and provided that when b is 2 or 3, the R.sup.14's can
be the same or different; and when Q is a bond, R.sup.1 also can
be: ##STR00097## M is --O--, --S--, --S(O)-- or --S(O).sub.2--; X,
Y and Z are independently selected from the group consisting of
--CH.sub.2--, --CH(C.sub.1-C.sub.6)alkyl- and
--C(di-(C.sub.1-C.sub.6)alkyl); R.sup.10 and R.sup.11 are
independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of
(C.sub.l -C.sub.6)alkyl, --OR.sup.19, --O(CO)R.sup.19,
--O(CO)OR.sup.21, --O(CH.sub.2).sub.1-5OR.sup.19,
--O(CO)NR.sup.19R.sup.20, --NR.sup.19R.sup.20,
--NR.sup.19(CO)R.sup.20, --NR.sup.19(CO)OR.sup.21,
--NR.sup.19(CO)NR.sup.20R.sup.25, --NR.sup.19SO.sub.2R.sup.21,
--COOR.sup.19, --CONR.sup.19R.sup.20, --COR.sup.19,
--SO.sub.2NR.sup.19R.sup.20, S(O).sub.0-2R.sup.21,
--O(CH.sub.2).sub.1-10--COOR.sup.19,
--O(CH.sub.2).sub.1-10CONR.sup.19R.sup.20, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.19, --CH.dbd.CH--COOR.sup.19, --CF.sub.3, --CN,
--NO.sub.2 and halogen; R.sup.15 and R.sup.17 are independently
selected from the group consisting of --OR.sup.19, --O(CO)R.sup.19,
--O(CO)OR.sup.21 and --O(CO)NR.sup.19R.sup.20; R.sup.16 and
R.sup.18 are independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl and aryl; or R.sup.15 and R.sup.16 together
are .dbd.O, or R.sup.17 and R.sup.18 together are .dbd.O; d is 1, 2
or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is 0 or 1; m, n and p
are independently 0-4; provided that at least one of s and t is 1,
and the sum of m, n, p, s and t is 1-6; provided that when p is 0
and t is 1, the sum of m, s and n is 1-5; and provided that when p
is 0 and s is 1, the sum of m, t and n is 1-5; v is 0 or 1; j and k
are independently 1-5, provided that the sum of j, k and v is 1-5;
and when Q is a bond and R.sup.1 is ##STR00098## Ar.sup.1 can also
be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl,
pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R.sup.19 and R.sup.20 are independently selected from the group
consisting of H, (C.sub.1-C.sub.6)alkyl, aryl and aryl-substituted
(C.sub.1-C.sub.6)alkyl; R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.24-substituted aryl; R.sup.22 is H, (C.sub.1-C.sub.6)alkyl,
aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.19 or --COOR.sup.19;
R.sup.23 and R.sup.24 are independently 1-3 groups independently
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2, --NR.sup.19R.sup.20,
--OH and halogeno; and R.sup.25 is H, --OH or
(C.sub.1-C.sub.6)alkoxy; and (g) Formula (IX): ##STR00099## or a
pharmaceutically acceptable salt or solvate thereof, wherein in
Formula (IX): R.sup.1 is selected from the group consisting of H,
G, G.sup.1, G.sup.2, --SO.sub.3H and --PO.sub.3H; G is selected
from the group consisting of: H, ##STR00100## wherein R, R.sup.a
and R.sup.b are each independently selected from the group
consisting of H, --OH, halo, --NH.sub.2, azido,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy or --W--R.sup.30; W
is independently selected from the group consisting of
--NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--,
--NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--; R.sup.2 and
R.sup.6 are each independently selected from the group consisting
of H, (C.sub.1-C.sub.6)alkyl, acetyl, aryl and
aryl(C.sub.1-C.sub.6)alkyl; R.sup.3, R.sup.4, R.sup.5, R.sup.7,
R.sup.3a and R.sup.4a are each independently selected from the
group consisting of H, (C.sub.1-C.sub.6)alkyl, acetyl,
aryl(C.sub.1-C.sub.6)alkyl, --C(O)(C.sub.1-C.sub.6)alkyl and
--C(O)aryl; R.sup.30 is independently selected from the group
consisting of R.sup.32-substituted T,
R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl,
R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl and
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl;
R.sup.31 is independently selected from the group consisting of H
and (C.sub.1-C.sub.4)alkyl; T is independently selected from the
group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl,
pyrazolyl, imidazolyl and pyridyl; R.sup.32 is independently
selected from 1-3 substituents which are each independently
selected from the group consisting of H, halo,
(C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3, --NO.sub.2,
(C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo,
(C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2,
--C(O)--NH(C.sub.1-C.sub.4)alkyl,
--C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2,
--C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and
pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31,
the nitrogen to which it is attached and R.sup.32 form a
pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or
morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted
pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or
morpholinyl group; G.sup.1 is represented by the structure:
##STR00101## wherein R.sup.33 is independently selected from the
group consisting of unsubstituted alkyl, R.sup.34-substituted
alkyl, (R.sup.35)(R.sup.36)alkyl-, ##STR00102## R.sup.34 is one to
three substituents, each R.sup.34 being independently selected from
the group consisting of HOOC--, HO--, HS--, (CH.sub.3)S--,
H.sub.2N--, (NH.sub.2)(NH)C(NH)--, (NH.sub.2)C(O)-- and
HOOCCH(NH.sub.3.sup.+)CH.sub.2SS--; R.sup.35 is independently
selected from the group consisting of H and NH.sub.2--; R.sup.36 is
independently selected from the group consisting of H,
unsubstituted alkyl, R.sup.34-substituted alkyl, unsubstituted
cycloalkyl and R.sup.34-substituted cycloalkyl; G.sup.2 is
represented by the structure: ##STR00103## wherein R.sup.37 and
R.sup.38 are each independently selected from the group consisting
of (C.sub.1-C.sub.6)alkyl and aryl; R.sup.26 is one to five
substituents, each R.sup.26 being independently selected from the
group consisting of: a) H; b) --OH; c) --OCH.sub.3; d) fluorine; e)
chlorine; f) --O-G; g) --O-G.sup.1; h) --O-G.sup.2; i) --SO.sub.3H;
and j) --PO.sub.3H; provided that when R.sup.1 is H, R.sup.26 is
not H, --OH, --OCH.sub.3 or --O-G; Ar.sup.1 is aryl,
R.sup.10-substituted aryl, heteroaryl or R.sup.10-substituted
heteroaryl; Ar.sup.2 is aryl, R.sup.11-substituted aryl, heteroaryl
or R.sup.11-substituted heteroaryl; L is selected from the group
consisting of: a) a covalent bond; b) --(CH.sub.2).sub.q--, wherein
q is 1-6; c) --(CH.sub.2).sub.e-E-(CH.sub.2).sub.r--, wherein E is
--O--, --C(O)--, phenylene, --NR.sup.22-- or --S(O).sub.0-2--, e is
0-5 and r is 0-5, provided that the sum of e and r is 1-6; d)
--(C.sub.2-C.sub.6)alkenylene-; e)
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6; and f) ##STR00104## wherein M is --O--,
--S--, --S(O)-- or --S(O).sub.2--; X, Y and Z are each
independently selected from the group consisting of --CH.sub.2--,
--CH(C.sub.1-C.sub.6)alkyl- and --C(di-(C.sub.1-C.sub.6)alkyl)-;
R.sup.8 is selected from the group consisting of H and alkyl;
R.sup.10 and R.sup.11 are each independently selected from the
group consisting of 1-3 substituents which are each independently
selected from the group consisting of (C.sub.1-C.sub.6)alkyl,
--OR.sup.19, --O(CO)R.sup.19, --O(CO)OR.sup.21,
--O(CH.sub.2).sub.1-5OR.sup.19, --O(CO)NR.sup.19R.sup.20,
--NR.sup.19R.sup.20, --NR.sup.19(CO)R.sup.20,
--NR.sup.19(CO)OR.sup.21, --NR.sup.19(CO)NR.sup.20R.sup.25,
--NR.sup.19SO.sub.2R.sup.21, --COOR.sup.19, --CONR.sup.19R.sup.20,
--COR.sup.19, --SO.sub.2NR.sup.19R.sup.20, S(O).sub.0-2R.sup.21,
--O(CH.sub.2).sub.1-10--COOR.sup.19,
--O(CH.sub.2).sub.1-10CONR.sup.19R.sup.20, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.19, --CH.dbd.CH--COOR.sup.19, --CF.sub.3, --CN,
--NO.sub.2 and halo; R.sup.15 and R.sup.17 are each independently
selected from the group consisting of --OR.sup.19, --OC(O)R.sup.19,
--OC(O)OR.sup.21, --OC(O)NR.sup.19R.sup.20; R.sup.16 and
R.sup.18are each independently selected from the group consisting
of H, (C.sub.1-C.sub.6)alkyl and aryl; or R.sup.15 and R.sup.16
together are .dbd.O, or R.sup.17and R.sup.18 together are .dbd.O; d
is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is 1 or 1; m, n
and p are each independently selected from 0-4; provided that at
least one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
provided that when p is 0 and t is 1, the sum of m, n and p is 1-5;
and provided that when p is 0 and s is 1, the sum of m, t and n is
1-5; v is 0 or 1; j and k are each independently 1-5, provided that
the sum of j, k and v is 1-5; Q is a bond, --(CH.sub.2).sub.q--,
wherein q is 1-6, or, with the 3-position ring carbon of the
azetidinone, forms the spiro group ##STR00105## wherein R.sup.12 is
##STR00106## R.sup.13 and R.sup.14 are each independently selected
from the group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6
alkyl)-, --C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl)=CH--; or R.sup.12 together with an
adjacent R.sup.13, or R.sup.12 together with an adjacent R.sup.14,
form a --CH.dbd.CH-- or a --CH.dbd.
C(C.sub.1-C.sub.6 alkyl)- group; a and b are each independently 0,
1, 2 or 3, provided both are not zero; provided that when R.sup.13
is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl).dbd.CH--, a is 1;
provided that when R.sup.14 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6
alkyl).dbd.CH--, b is 1; provided that when a is 2 or 3, the
R.sup.13's can be the same or different; and provided that when b
is 2 or 3, the R.sup.14's can be the same or different; and when Q
is a bond and L is ##STR00107## then Ar.sup.1 can also be pyridyl,
isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl,
thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl; R.sup.19 and
R.sup.20 are each independently selected from the group consisting
of H, (C.sub.1-C.sub.6)alkyl, aryl and aryl-substituted
(C.sub.1-C.sub.6)alkyl; R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.24-substituted aryl; R.sup.22 is H, (C.sub.1-C.sub.6)alkyl,
aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.19 or --COOR.sup.19;
R.sup.23 and R.sup.24 are each independently selected from the
group consisting of 1-3 substituents which are each independently
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2, --NR.sup.19R.sup.20,
--OH and halo; and R.sup.25 is H, --OH or
(C.sub.1-C.sub.6)alkoxy.
11. A therapeutic combination comprising: (a) a first amount of at
least one sterol absorption inhibitor or a pharmaceutically
acceptable salt or solvate thereof; and (b) a second amount of at
least one antidemyelination agent, wherein the first amount and the
second amount together comprise a therapeutically effective amount
for the treatment of demyelination in a subject and wherein the at
least one sterol absorption inhibitor is selected from the group
consisting of sterol absorption inhibitors represented by the
following Formulae: (a) Formula (III): ##STR00108## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (III) above: Ar.sup.1 is R.sup.3-substituted
aryl; Ar.sup.2 is R.sup.4-substituted aryl; Ar.sup.3 is
R.sup.5-substituted aryl; Y and Z are independently selected from
the group consisting of --CH.sub.2--, --CH(lower alkyl)- and
--C(dilower alkyl)-; A is selected from --O--, --S--, --S(O)-- or
--S(O).sub.2--; R is selected from the group consisting of
--OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 and
--O(CO)NR.sup.6R.sup.7; R.sup.2 is selected from the group
consisting of hydrogen, lower alkyl and aryl; or R.sup.1 and
R.sup.2 together are .dbd.O; q is 1, 2 or 3; p is 0, 1, 2, 3 or 4;
R.sup.5 is 1-3 substituents independently selected from the group
consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.9, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2-lower alkyl,
--NR.sup.6SO.sub.2-aryl, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2-alkyl, S(O).sub.0-2-aryl,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, o-halogeno, m-halogeno,
o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR.sup.6, and
--CH.dbd.CH--COOR.sup.6; R.sup.3 and R.sup.4 are independently 1-3
substituents independently selected from the group consisting of
R.sup.5, hydrogen, p-lower alkyl, aryl, --NO.sub.2, --CF.sub.3 and
p-halogeno; R.sup.6, R.sup.7 and R.sup.8 are independently selected
from the group consisting of hydrogen, lower alkyl, aryl and
aryl-substituted lower alkyl; and R.sup.9 is lower alkyl, aryl or
aryl-substituted lower alkyl; (b) Formula (IV): ##STR00109## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (IV) above: A is selected from the group
consisting of R.sup.2-substituted heterocycloalkyl,
R.sup.2-substituted heteroaryl, R.sup.2-substituted benzofused
heterocycloalkyl, and R.sup.2-substituted benzofused heteroaryl;
Ar.sup.1 is aryl or R.sup.3-substituted aryl; Ar.sup.2 is aryl or
R.sup.2-substituted aryl; Q is a bond or, with the 3-position ring
carbon of the azetidinone, forms the spiro group ##STR00110## and
R.sup.1 is selected from the group consisting of:
--(CH.sub.2).sub.q--, wherein q is 2-6, provided that when Q forms
a spiro ring, q can also be zero or 1;
--(CH.sub.2).sub.e-G-(CH.sub.2).sub.r--, wherein G is --O--,
--C(O)--, phenylene, --NR.sup.8-- or --S(O).sub.0-2, e is 0-5 and r
is 0-5, provided that the sum of e and r is 1-6; --(C.sub.2-C.sub.6
alkenylene)-; and --(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--,
wherein V is C.sub.3-C.sub.6 cycloalkylene, f is 1-5 and g is 0-5,
provided that the sum of f and g is 1-6; R.sup.5 is selected from:
##STR00111## R.sup.6 and R.sup.7 are independently selected from
the group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-,
--C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--; or R.sup.5 together with an
adjacent R.sup.6, or R.sup.5 together with an adjacent R.sup.7,
form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero;
provided that when R.sup.6 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6
alkyl).dbd.CH--, a is 1; provided that when R.sup.7 is
--CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl).dbd.CH--, b is 1;
provided that when a is 2 or 3, the R.sup.6's can be the same or
different; and provided that when b is 2 or 3, the R.sup.6's can be
the same or different; and when Q is a bond, R.sup.1 also can be
selected from: ##STR00112## where M is --O--, --S--, --S(O)-- or
--S(O).sub.2--; X, Y and Z are independently selected from the
group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)- and
--C(di-(C.sub.1-C.sub.6) alkyl); R.sup.10 and R.sup.12 are
independently selected from the group consisting of --OR.sup.14,
--O(CO)R.sup.14, --O(CO)OR.sup.16 and --O(CO)NR.sup.14R.sup.15;
R.sup.11 and R.sup.13 are independently selected from the group
consisting of hydrogen, (C.sub.1-C.sub.6)alkyl and aryl; or
R.sup.10 and R.sup.11 together are .dbd.O, or R.sup.12 and R.sup.13
together are .dbd.O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0
or 1; t is 0 or 1; m, n and p are independently 0-4; provided that
at least one of s and t is 1, and the sum of m, n, p, s and t is
1-6; provided that when p is 0 and t is 1, the sum of m, s and n is
1-5; and provided that when p is 0 and s is 1, the sum of m, t and
n is 1-5; v is 0 or 1; j and k are independently 1-5, provided that
the sum of j, k and v is 1-5; R.sup.2 is 1-3 substituents on the
ring carbon atoms selected from the group consisting of hydrogen,
(C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkenyl, R.sup.17-substituted aryl,
R.sup.17-substituted benzyl, R.sup.17-substituted benzyloxy,
R.sup.17-substituted aryloxy, halogeno, --NR.sup.14R.sup.15,
NR.sup.14R.sup.15(C.sub.1-C.sub.6
alkylene)-,--NR.sup.14R.sup.15C(O)(C.sub.1-C.sub.6alkylene)-,--NHC(O)R.su-
p.16, OH, C.sub.1-C.sub.6 alkoxy, --OC(O)R.sup.16, --COR.sup.14,
hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, NO.sub.2,
--S(O).sub.0-2R.sup.16, --SO.sub.2NR.sup.14R.sup.15 and
--(C.sub.1-C.sub.6 alkylene)COOR.sup.14; when R.sup.2 is a
substituent on a heterocycloalkyl ring, R.sup.2 is as defined, or
is .dbd.O or ##STR00113## and, where R.sup.2 is a substituent on a
substitutable ring nitrogen, it is hydrogen,
(C.sub.1-C.sub.6)alkyl, aryl, (C.sub.1-C.sub.6)alkoxy, aryloxy,
(C.sub.1-C.sub.6)alkylcarbonyl, arylcarbonyl, hydroxy,
--(CH.sub.2).sub.1-6CONR.sup.18R.sup.18, ##STR00114## wherein J is
--O--, --NH--, --NR.sup.18-- or --CH.sub.2--; R.sup.3 and R.sup.4
are independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --OR.sup.14, --O(CO)R.sup.14,
--O(CO)OR.sup.16, --O(CH.sub.2).sub.1-5OR.sup.14,
--O(CO)NR.sup.14R.sup.15,--NR.sup.14R.sup.15,
--NR.sup.14(CO)R.sup.15, --NR.sup.14(CO)OR.sup.16,
--NR.sup.14(CO)NR.sup.15R.sup.19, --NR.sup.14SO.sub.2R.sup.16,
--COOR.sup.14, --CONR.sup.14R.sup.15, --COR.sup.14,
SO.sub.2NR.sup.14R.sup.15, S(O).sub.0-2R.sup.16,
--O(CH.sub.2).sub.1-10--COOR.sup.14,
--O(CH.sub.2).sub.1-10CONR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.14, --CH.dbd.CH--COOR.sup.14, --CF.sub.3, --CN,
--NO.sub.2 and halogen; R.sup.8 is hydrogen,
(C.sub.1-C.sub.6)alkyl, aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.14
or --COOR.sup.14; R.sup.9 and R.sup.17 are independently 1-3 groups
independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2,
--NR.sup.14R.sup.15, OH and halogeno; R.sup.14 and R.sup.15 are
independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, aryl and aryl-substituted
(C.sub.1-C.sub.6)alkyl; R.sup.16 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.17-substituted aryl; R.sup.18 is hydrogen or
(C.sub.1-C.sub.6)alkyl; and R.sup.19 is hydrogen, hydroxy or
(C.sub.1-C.sub.6)alkoxy; (c) Formula (V): ##STR00115## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (V) above: Ar.sup.1 is aryl,
R.sup.10-substituted aryl or heteroaryl; Ar.sup.2 is aryl or
R.sup.4-substituted aryl; Ar.sup.3 is aryl or R.sup.5-substituted
aryl; X and Y are independently selected from the group consisting
of --CH.sub.2--, --CH(lower alkyl)- and --C(dilower alkyl)-; R is
--OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.6, or
--O(CO)NR.sup.6R.sup.7; R.sup.1 is hydrogen, lower alkyl or aryl;
or R and R.sup.1 together are .dbd.O; q is 0 or 1; r is 0, 1 or 2;
m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum
of m, n and q is 1, 2, 3, 4 or 5; R.sup.4 is 1-5 substituents
independently selected from the group consisting of lower alkyl,
--OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7,S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, -(lower
alkylene)COOR.sup.6 and --CH.dbd.CH--COOR.sup.6; R.sup.5 is 1-5
substituents independently selected from the group consisting of
--OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, --CF.sub.3, --CN,
--NO.sub.2, halogen, -(lower alkylene)COOR.sup.6 and
--CH.dbd.CH--COOR.sup.6; R.sup.6, R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen, lower
alkyl, aryl and aryl-substituted lower alkyl; R.sup.9 is lower
alkyl, aryl or aryl-substituted lower alkyl; and R.sup.10 is 1-5
substituents independently selected from the group consisting of
lower alkyl, --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, --S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, --CF.sub.3, --CN,
--NO.sub.2 and halogen; (d) Formula (VI): ##STR00116## or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein: R.sub.1 is ##STR00117## R.sub.2 and R.sub.3 are
independently selected from the group consisting of: --CH.sub.2--,
--CH(lower alkyl)-, --C(di-lower alkyl)-, --CH.dbd.CH-- and
--C(lower alkyl)=CH--; or R.sub.1 together with an adjacent
R.sub.2, or R.sub.1 together with an adjacent R.sub.3, form a
--CH.dbd.CH-- or a --CH.dbd.C(lower alkyl)- group; u and v are
independently 0, 1, 2 or 3, provided both are not zero; provided
that when R.sub.2 is --CH.dbd.CH-- or --C(lower alkyl).dbd.CH--, v
is 1; provided that when R.sub.3 is --CH--CH-- or --C(lower
alkyl).dbd.CH--, u is 1; provided that when v is 2 or 3, the
R.sub.2's can be the same or different; and provided that when u is
2 or 3, the R.sub.3's can be the same or different; R.sub.4 is
selected from B--(CH.sub.2).sub.mC(O)--, wherein m is 0, 1, 2, 3, 4
or 5; B--(CH.sub.2).sub.q--, wherein q is 0, 1, 2, 3, 4, 5 or 6;
B--(CH.sub.2).sub.e-Z-(CH.sub.2).sub.r--, wherein Z is --O--,
--C(O)--, phenylene, --N(R.sub.8)-- or --S(O).sub.0-2--, e is 0, 1,
2, 3, 4 or 5and r is 0, 1, 2, 3, 4 or 5, provided that the sum of e
and r is 0, 1, 2, 3, 4, 5 or 6; B--(C.sub.2-C.sub.6 alkenylene)-;
B--(C.sub.4-C.sub.6 alkadienylene)-;
B--(CH.sub.2).sub.t-Z-(C.sub.2-C.sub.6 alkenylene)-, wherein Z is
as defined above, and wherein t is 0, 1, 2 or 3, provided that the
sum of t and the number of carbon atoms in the alkenylene chain is
2, 3, 4, 5 or 6; B--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--,
wherein V is C.sub.3-C.sub.6 cycloalkylene, f is 1, 2, 3, 4 or 5
and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1,
2, 3, 4, 5 or 6; B--(CH.sub.2).sub.t--V--(C.sub.2-C.sub.6
alkenylene)- or B--(C.sub.2-C.sub.6
alkenylene)-V--(CH.sub.2).sub.t--, wherein V and t are as defined
above, provided that the sum of t and the number of carbon atoms in
the alkenylene chain is 2, 3, 4, 5 or 6;
B--(CH.sub.2).sub.a-Z-(CH.sub.2).sub.b--V--(CH.sub.2).sub.d--,
wherein Z and V are as defined above and a, b and d are
independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b
and d is 0, 1, 2, 3, 4, 5 or 6; or T-(CH.sub.2).sub.s--, wherein T
is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6;
or R.sub.1 and R.sub.4 together form the group ##STR00118## B is
selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl,
heteroaryl or W-substituted heteroaryl, wherein heteroaryl is
selected from the group consisting of pyrrolyl, pyridinyl,
pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl,
pyrazolyl, thienyl, oxazolyl and furanyl, and for
nitrogen-containing heteroaryls, the N-oxides thereof, or
##STR00119## W is 1 to 3 substituents independently selected from
the group consisting of lower alkyl, hydroxy lower alkyl, lower
alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower
alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower
alkanedioyl, allyloxy, --CF.sub.3, --OCF.sub.3, benzyl,
R.sub.7-benzyl, benzyloxy, R.sub.7-benzyloxy, phenoxy,
R.sub.7-phenoxy, dioxolanyl, NO.sub.2,--N(R.sub.8)(R.sub.9),
N(R.sub.8)(R.sub.9)-lower alkylene-, N(R.sub.8)(R.sub.9)-lower
alkylenyloxy-, OH, halogeno, --CN, --N.sub.3, --NHC(O)OR.sub.10,
--NHC(O)R.sub.10, R.sub.11O.sub.2SNH--,
(R.sub.11O.sub.2S).sub.2N--, --S(O).sub.2NH.sub.2,
--S(O).sub.0-2R.sub.8,tert-butyldimethyl-silyloxymethyl,
--C(O)R.sub.12, --COOR.sub.19, --CON(R.sub.8)(R.sub.9),
--CH.dbd.CHC(O)R.sub.12, -lower alkylene-C(O)R.sub.12,
R.sub.10C(O)(lower alkylenyloxy)-, N(R.sub.8)(R.sub.9)C(O)(lower
alkylenyloxy)- and ##STR00120## for substitution on ring carbon
atoms, and the substituents on the substituted heteroaryl ring
nitrogen atoms, when present, are selected from the group
consisting of lower alkyl, lower alkoxy, --C(O)OR.sub.10,
--C(O)R.sub.10, OH, N(R.sub.8)(R.sub.9)-lower
alkylene-,N(R.sub.8)(R.sub.9)-lower alkylenyloxy-,
--S(O).sub.2NH.sub.2 and 2-(trimethylsilyl)-ethoxymethyl; R.sub.7
is 1-3 groups independently selected from the group consisting of
lower alkyl, lower alkoxy, --COOH, NO.sub.2, --N(R.sub.8)(R.sub.9),
OH, and halogeno; R.sub.8 and R.sub.9 are independently selected
from H or lower alkyl; R.sub.10 is selected from lower alkyl,
phenyl, R.sub.7-phenyl, benzyl or R.sub.7-benzyl; R.sub.11 is
selected from OH, lower alkyl, phenyl, benzyl, R.sub.7-phenyl or
R.sub.7-benzyl; R.sub.12 is selected from H, OH, alkoxy, phenoxy,
benzyloxy, ##STR00121## --N(R.sub.8)(R.sub.9), lower alkyl, phenyl
or R.sub.7-phenyl; R.sub.13 is selected from --O--, --CH.sub.2--,
--NH--, --N(lower alkyl)- or --NC(O)R.sub.19; R.sub.15, R.sub.16
and R.sub.17 are independently selected from the group consisting
of H and the groups defined for W; or R
.sub.15 is hydrogen and R.sub.16 and R.sub.17, together with
adjacent carbon atoms to which they are attached, form a dioxolanyl
ring; R.sub.19 is H, lower alkyl, phenyl or phenyl lower alkyl; and
R.sub.20 and R.sub.21 are independently selected from the group
consisting of phenyl, W-substituted phenyl, naphthyl, W-substituted
naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl,
heteroaryl, W-substituted heteroaryl, benzofused heteroaryl,
W-substituted benzofused heteroaryl and cyclopropyl, wherein
heteroaryl is as defined above; (e) Formula (VIIA) or (VIIB):
##STR00122## or a pharmaceutically acceptable salt or solvate
thereof, wherein: A is --CH.dbd.CH--, --C.ident.C-- or
--(CH.sub.2).sub.p-- wherein p is 0, 1 or 2; B is ##STR00123## B'
is ##STR00124## D is --(CH.sub.2).sub.mC(O)-- or
--(CH.sub.2).sub.q-- wherein m is 1, 2, 3 or 4 and q is 2, 3 or 4;
E is C.sub.10 to C.sub.20 alkyl or --C(O)--(C.sub.9 to
C.sub.19)-alkyl, wherein the alkyl is straight or branched,
saturated or containing one or more double bonds; R is hydrogen,
C.sub.1-C.sub.15 alkyl, straight or branched, saturated or
containing one or more double bonds, or B--(CH.sub.2).sub.r--,
wherein r is 0, 1, 2, or 3; R.sub.1, R.sub.2, R.sub.3, R.sub.1',
R.sub.2', and R.sub.3' are independently selected from the group
consisting of hydrogen, lower alkyl, lower alkoxy, carboxy,
NO.sub.2, NH.sub.2, OH, halogeno, lower alkylamino, dilower
alkylamino, --NHC(O)OR.sub.5, R.sub.6O.sub.2SNH-- and
--S(O).sub.2NH.sub.2; R.sub.4 is ##STR00125## wherein n is 0, 1, 2
or 3; R.sub.5 is lower alkyl; and R.sub.6 is OH, lower alkyl,
phenyl, benzyl or substituted phenyl wherein the substituents are
1-3 groups independently selected from the group consisting of
lower alkyl, lower alkoxy, carboxy, NO.sub.2, NH.sub.2, OH,
halogeno, lower alkylamino and dilower alkylamino; or a
pharmaceutically acceptable salt thereof or a prodrug thereof; (f)
Formula (VIII): ##STR00126## or a pharmaceutically acceptable salt
thereof or a solvate thereof, wherein, in Formula (VIII) above,
R.sup.26 is H or OG.sup.1; G and G.sup.1 are independently selected
from the group consisting of H, ##STR00127## and ##STR00128##
provided that when R.sup.26 is H or OH, G is not H; R, R.sup.a and
R.sup.b are independently selected from the group consisting of H,
--OH, halogeno, --NH.sub.2, azido,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)-alkoxy or --W--R.sup.30; W
is independently selected from the group consisting of
--NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--,
--NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--; R.sup.2 and
R.sup.6 are independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, aryl and aryl(C.sub.1-C.sub.6)alkyl;
R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.3a and R.sup.4a are
independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl,
--C(O)(C.sub.1-C.sub.6)alkyl and --C(O)aryl; R.sup.30 is selected
from the group consisting of R.sup.32-substituted T,
R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl,
R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl and
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl;
R.sup.31 is selected from the group consisting of H and
(C.sub.1-C.sub.4)alkyl; T is selected from the group consisting of
phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl
and pyridyl; R.sup.32 is independently selected from 1-3
substituents independently selected from the group consisting of
halogeno, (C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3,
--NO.sub.2, (C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo,
(C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2,
--C(O)--NH(C.sub.1-C.sub.4)alkyl,
--C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2,
--C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and
pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31,
the nitrogen to which it is attached and R.sup.32 form a
pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or
morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted
pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or
morpholinyl group; Ar.sup.1 is aryl or R.sup.10-substituted aryl;
Ar.sup.2 is aryl or R.sup.11-substituted aryl; Q is a bond or, with
the 3-position ring carbon of the azetidinone, forms the spiro
group ##STR00129## and R.sup.1 is selected from the group
consisting of --(CH.sub.2).sub.q--, wherein q is 2-6, provided that
when Q forms a spiro ring, q can also be zero or 1;
--(CH.sub.2).sub.e-E-(CH.sub.2).sub.r--, wherein E is --O--,
--C(O)--, phenylene, --NR.sup.22-- or --S(O).sub.0-2--, e is 0-5
and r is 0-5, provided that the sum of e and r is 1-6;
--(C.sub.2-C.sub.6)alkenylene-; and
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6 cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6; R.sup.12 is ##STR00130## R.sup.13 and
R.sup.14 are independently selected from the group consisting of
--CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-,
--C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl)=CH--; or R.sup.12 together with an
adjacent R.sup.13, or R.sup.12 together with an adjacent R.sup.14,
form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)- group;
a and b are independently 0, 1, 2 or 3, provided both are not zero;
provided that when R.sup.13 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6
alkyl).dbd.CH--, a is 1; provided that when R.sup.14 is
--CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl).dbd.CH--, b is 1;
provided that when a is 2 or 3, the R.sup.13's can be the same or
different; and provided that when b is 2 or 3, the R.sup.14's can
be the same or different; and when Q is a bond, R.sup.1 also can
be: ##STR00131## M is --O--, --S--, --S(O)-- or --S(O).sub.2--; X,
Y and Z are independently selected from the group consisting of
--CH.sub.2--, --CH(C.sub.1-C.sub.6)alkyl- and
--C(di-(C.sub.1-C.sub.6)alkyl); R.sup.10 and R.sup.11 are
independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --OR.sup.19, --O(CO)R.sup.19,
--O(CO)OR.sup.21, --O(CH.sub.2).sub.1-5OR.sup.19,
--O(CO)NR.sup.19R.sup.20, --NR.sup.19R.sup.20,
--NR.sup.19(CO)R.sup.20, --NR.sup.19(CO)OR.sup.21,
--NR.sup.19(CO)NR.sup.20R.sup.25, --NR.sup.19SO.sub.2R.sup.21,
--COOR.sup.19, --CONR.sup.19R.sup.20, --COR.sup.19,
--SO.sub.2NR.sup.19R.sup.20, S(O).sub.0-2R.sup.21,
--O(CH.sub.2).sub.1-10--COOR.sup.19,--O(CH.sub.2).sub.1-10CONR.sup.19R.su-
p.20, --(C.sub.1-C.sub.6 alkylene)-COOR.sup.19,
--CH.dbd.CH--COOR.sup.19, --CF.sub.3, --CN, --NO.sub.2 and halogen;
R.sup.15 and R.sup.17 are independently selected from the group
consisting of --OR.sup.19, --O(CO)R.sup.19, --O(CO)OR.sup.21 and
--O(CO)NR.sup.19R.sup.20; R.sup.16 and R.sup.18 are independently
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl and
aryl; or R.sup.15 and R.sup.16 together are .dbd.O, or R.sup.17 and
R.sup.18 together are .dbd.O; d is 1,2 or 3; h is 0, 1, 2, 3 or 4;
s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4;
provided that at least one of s and t is 1, and the sum of m, n, p,
s and t is 1-6; provided that when p is 0 and t is 1, the sum of m,
s and n is 1-5; and provided that when p is 0 and s is 1, the sum
of m, t and n is 1-5; v is 0 or 1; j and k are independently 1-5,
provided that the sum of j, k and v is 1-5; and when Q is a bond
and R.sup.1 is ##STR00132## Ar.sup.1 can also be pyridyl,
isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl,
thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl; R.sup.19 and
R.sup.20 are independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, aryl and aryl-substituted
(C.sub.1-C.sub.6)alkyl; R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.24-substituted aryl; R.sup.22 is H, (C.sub.1-C.sub.6)alkyl,
aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.19 or --COOR.sup.19;
R.sup.23 and R.sup.24 are independently 1-3 groups independently
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2, --NR.sup.19R.sup.20,
--OH and halogeno; and R.sup.25 is H, --OH or
(C.sub.1-C.sub.6)alkoxy; and (g) Formula (IX): ##STR00133## or a
pharmaceutically acceptable salt or solvate thereof, wherein in
Formula (IX): R.sup.1 is selected from the group consisting of H,
G, G.sup.1, G.sup.2, --SO.sub.3H and --PO.sub.3H; ##STR00134## G is
selected from the group consisting of: H, wherein R, R.sup.a and
R.sup.b are each independently selected from the group consisting
of H, --OH, halo, --NH.sub.2, azido,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy or --W--R.sup.30; W
is independently selected from the group consisting of
--NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--,
--NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--; R.sup.2 and
R.sup.6 are each independently selected from the group consisting
of H, (C.sub.1-C.sub.6)alkyl, acetyl, aryl and
aryl(C.sub.1-C.sub.6)alkyl; R.sup.3, R.sup.4, R.sup.5, R.sup.7,
R.sub.3a and R.sup.4a are each independently selected from the
group consisting of H, (C.sub.1-C.sub.6)alkyl, acetyl,
aryl(C.sub.1-C.sub.6)alkyl, --C(O)(C.sub.1-C.sub.6)alkyl and
--C(O)aryl; R.sup.30 is independently selected from the group
consisting of R.sup.32-substituted T,
R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl,
R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl and
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl;
R.sup.31 is independently selected from the group consisting of H
and (C.sub.1-C.sub.4)alkyl; T is independently selected from the
group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl,
pyrazolyl, imidazolyl and pyridyl; R.sup.32 is independently
selected from 1-3 substituents which are each independently
selected from the group consisting of H, halo,
(C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3, --NO.sub.2,
(C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo,
(C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2,
--C(O)--NH(C.sub.1-C.sub.4)alkyl,
--C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2,
--C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and
pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31,
the nitrogen to which it is attached and R.sup.32 form a
pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or
morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted
pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or
morpholinyl group; G.sup.1 is represented by the structure:
##STR00135## wherein R.sup.33 is independently selected from the
group consisting of unsubstituted alkyl, R.sup.34-substituted
alkyl, (R.sup.35)(R.sup.36)alkyl-, ##STR00136## R.sup.34 is one to
three substituents, each R.sup.34 being independently selected from
the group consisting of HOOC--, HO--, HS--, (CH.sub.3)S--,
H.sub.2N--, (NH.sub.2)(NH)C(NH)--, (NH.sub.2)C(O)-- and
HOOCCH(NH.sub.3.sup.+)CH.sub.2SS--; R.sup.35 is independently
selected from the group consisting of H and NH.sub.2--; R.sup.36 is
independently selected from the group consisting of H,
unsubstituted alkyl, R.sup.34-substituted alkyl, unsubstituted
cycloalkyl and R.sup.34-substituted cycloalkyl; G.sup.2 is
represented by the structure: ##STR00137## wherein R.sup.37 and
R.sup.38 are each independently selected from the group consisting
of (C.sub.1-C.sub.6)alkyl and aryl; R.sup.26 is one to five
substituents, each R.sup.26 being independently selected from the
group consisting of: a) H; b) --OH; c) --OCH.sub.3; d) fluorine; e)
chlorine; f) --O-G; g) --O-G.sup.1; h) --O-G.sup.2; i) --SO.sub.3H;
and j) --PO.sub.3H; provided that when R.sup.1 is H, R.sup.26 is
not H, --OH, --OCH.sub.3 or --O-G; Ar.sup.1 is aryl,
R.sup.10-substituted aryl, heteroaryl or R.sup.10-substituted
heteroaryl; Ar.sup.2 is aryl, R.sup.11-substituted aryl, heteroaryl
or R.sup.11-substituted heteroaryl; L is selected from the group
consisting of: a) a covalent bond; b) --(CH.sub.2).sub.q--, wherein
q is 1-6; c) --(CH.sub.2).sub.e-E-(CH.sub.2).sub.r--, wherein E is
--O--, --C(O)--, phenylene, --NR.sup.22-- or --S(O).sub.0-2--, e is
0-5 and r is 0-5, provided that the sum of e and r is 1-6; d)
--(C.sub.2-C.sub.6)alkenylene-; e)
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6; and f) ##STR00138## wherein M is --O--,
--S--, --S(O)-- or --S(O).sub.2--; X, Y and Z are each
independently selected from the group consisting of --CH.sub.2--,
--CH (C.sub.1-C.sub.6)alkyl- and --C(di-(C.sub.1-C.sub.6)alkyl )-;
R.sup.8 is selected from the group consisting of H and alkyl;
R.sup.10 and R.sup.11 are each independently selected from the
group consisting of 1-3 substituents which are each independently
selected from the group consisting of (C.sub.1-C.sub.6)alkyl,
--OR.sup.19, --O(CO)R.sup.19, --O(CO)OR.sup.21,
--O(CH.sub.2).sub.1-5OR.sup.19, --O(CO)NR.sup.19R.sup.20,
--NR.sup.19R.sup.20, --NR.sup.19(CO)R.sup.20,
--NR.sup.19(CO)OR.sup.21, --NR.sup.19(CO)NR.sup.20R.sup.25,
--NR.sup.19SO.sub.2R.sup.21, --COOR.sup.19, --CONR.sup.19R.sup.20,
--COR.sup.19, --SO.sub.2NR.sup.19R.sup.20, S(O).sub.0-2R.sup.21,
--O(CH.sub.2).sub.1-10--COOR.sup.19,
--O(CH.sub.2).sub.1-10CONR.sup.19R.sup.20, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.19, --CH.dbd.CH--COOR.sup.19, --CF.sub.3, --CN,
--NO.sub.2 and halo; R.sup.15 and R.sup.17 are each independently
selected from the group consisting of --OR.sup.19, --OC(O)R.sup.19,
--OC(O)OR.sup.21, --OC(O)NR.sup.19R.sup.20; R.sup.16 and R.sup.18
are each independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl and aryl; or R.sup.15 and R.sup.16 together
are .dbd.O, or R.sup.17and R.sup.18 together are .dbd.O; d is 1, 2
or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is 1 or 1; m, n and p
are each independently selected from 0-4; provided that at least
one of s and t is 1, and the sum of m, n, p, s and t is 1-6;
provided that when p is 0 and t is 1, the sum of m, n and p is 1-5;
and provided that when p is 0 and s is 1, the sum of m, t and n is
1-5; v is 0 or 1; j and k are each independently 1-5, provided that
the sum of j, k and v is 1-5; Q is a bond, --(CH.sub.2).sub.q--,
wherein q is 1-6, or, with the 3-position ring carbon of the
azetidinone, forms the spiro group ##STR00139## wherein R.sup.12 is
##STR00140## R.sup.13 and R.sup.14 are each independently selected
from the group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6
alkyl)-, --C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1
-C.sub.6 alkyl).dbd.CH--; or R.sup.12 together with an adjacent
R.sup.13, or R.sup.12 together with an adjacent R.sup.14, form a
--CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)- group; a and
b are each independently 0, 1, 2 or 3, provided both are not zero;
provided that when R.sup.13 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6
alkyl).dbd.CH--, a is 1; provided that when R.sup.14 is
--CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl).dbd.CH--, b is 1;
provided that when a is 2 or 3, the R.sup.13's can be the same or
different; and provided that when b is 2 or 3, the R.sup.14's can
be the same or different; and when Q is a bond and L is
##STR00141## then Ar.sup.1 can also be pyridyl, isoxazolyl,
furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl,
pyrazinyl, pyrimidinyl or pyridazinyl; R.sup.19 and R.sup.20 are
each independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, aryl and aryl-substituted
(C.sub.1-C.sub.6)alkyl; R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.24-substituted aryl; R.sup.22 is H, (C.sub.1-C.sub.6)alkyl,
aryl (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.19 or --COOR.sup.19;
R.sup.23 and R.sup.24 are each independently selected from the
group consisting of 1-3 substituents which are each independently
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2, --NR.sup.19R.sup.20,
--OH and halo; and R.sup.25 is H, --OH or (C.sub.1-C.sub.6)alkoxy.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of co-pending
U.S. patent application Ser. No. 10/701,244, filed Nov. 4, 2003,
which is incorporated herein by reference. This application claims
the benefit of priority from U.S. Provisional Patent Application
Ser. No. 60/493,318, filed Aug. 7, 2003 and U.S. Provisional Patent
Application Ser. No. 60/424,165, filed Nov. 6, 2002, each of which
is incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to methods and therapeutic
combinations for treating and preventing demyelination in a subject
comprising the administration of sterol absorption
inhibitor(s).
[0004] 2. Description
[0005] Nerve fibers are wrapped with many layers of insulation
known as the myelin sheath. Like insulation around an electrical
wire, the myelin sheath permits electrical impulses to be conducted
along the nerve fiber with speed and accuracy. When normal
development of the myelin is impaired (for example in subjects
having Tay-Sachs disease, Niemann-Pick disease, Gaucher's disease
and Hurler's syndrome), permanent, extensive neurological defects
can result. Also, the myelin sheath can be damaged by stroke,
inflammation, immune diseases, metabolic disorders, poison or
drugs. If the sheath is able to regenerate itself, normal nerve
function can be partially or fully restored. If demyelination is
extensive, the underlying nerve can die and cause irreversible
damage. Demyelination in the central nervous system (brain and
spinal cord) occurs in several primary demyelinating diseases, such
as multiple sclerosis, acute disseminated encephalomyelitis,
adrenoleukodystrophy, adrenomyeloneuropathy, Leber's hereditary
optic atrophy and HTLV-associated myelopathy.
[0006] Multiple sclerosis ("MS") is characterized by the loss of
patches of myelin in the nerves of the eye, brain and/or spinal
cord. It is believed that the body produces antibodies against its
own myelin that provoke inflammation and damage the myelin sheath.
Heredity and environment appear to play some role in the disease,
although it is believed that a virus or unknown antigen somehow
triggers the autoimmune process. Symptoms depend upon the area
affected. Demyelination in nerve pathways that bring signals to
muscles can produce problems with movement (motor symptoms), such
as weakness, clumsiness, difficulty in walking or maintaining
balance, tremor, double vision, problems with bladder or bowel
control, stiffness, unsteadiness or unusual tiredness.
Demyelination in nerve pathways that bring signals to the brain can
cause sensory symptoms, such as numbness, tingling, dysesthesias,
visual disturbances, sexual dysfunction, dizziness or vertigo.
Magnetic resonance imaging (MRI) can reveal areas of the brain that
have lost myelin, and may even distinguish areas of recent
demyelination from areas that occurred some time ago.
[0007] Treatments for multiple sclerosis include injection with
beta-interferon, which can decrease the frequency and occurrence of
flare-ups and slow the progression to disability; injection with
glatiramer acetate, which can reduce the frequency of relapses; or
administration of corticosteroids, such as prednisone, to relieve
acute symptoms. Recently, statins such as simvastatin and
atorvastatin (HMG CoA reductase inhibitors) have been studied for
their immunomodulatory effects in treating MS. C. Pelfrey,
"ACTRIMS-ECTRIMS 2002 (Part II)", IDDB Meeting Report, Sep. 18-21,
2002 Baltimore, Md., USA, (October 3, 2002).
[0008] There is a need in the art for improved compositions and
treatments for demyelination and associated diseases such as
multiple sclerosis.
SUMMARY OF THE INVENTION
[0009] In one embodiment, there is provided a method of treating or
preventing demyelination in a subject, comprising the step of
administering to a subject in need of such treatment an effective
amount of at least one sterol absorption inhibitor or a
pharmaceutically acceptable salt or solvate thereof.
[0010] In another embodiment, there is provided a method of
treating or preventing multiple sclerosis in a subject, comprising
the step of administering to a subject in need of such treatment an
effective amount of at least one sterol absorption inhibitor or a
pharmaceutically acceptable salt or solvate thereof.
[0011] A method of treating or preventing demyelination in a
subject is provided, comprising the step of administering to a
subject in need of such treatment an effective amount of at least
one sterol absorption inhibitor represented by Formula (II)
below:
##STR00001##
or a pharmaceutically acceptable salt or solvate thereof.
[0012] In another embodiment, the present invention provides a
composition comprising: (a) at least one sterol absorption
inhibitor or a pharmaceutically acceptable salt or solvate thereof
and (b) at least one antidemyelination agent.
[0013] Therapeutic combinations also are provided comprising: (a) a
first amount of at least one sterol absorption inhibitor or a
pharmaceutically acceptable salt or solvate thereof; and (b) a
second amount of at least one antidemyelination agent, wherein the
first amount and the second amount together comprise a
therapeutically effective amount for the treatment or prevention of
demyelination in a subject.
[0014] Pharmaceutical compositions for the treatment or prevention
of demyelination in a subject, comprising a therapeutically
effective amount of the above compounds, compositions or
therapeutic combinations and a pharmaceutically acceptable carrier
also are provided.
[0015] Other than in the operating examples, or where otherwise
indicated, all numbers expressing quantities of ingredients,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about."
DETAILED DESCRIPTION
[0016] According to F. Giubilei et al., "Blood Cholesterol and MRI
Activity in First Clinical Episode Suggestive of Multiple
Sclerosis", Acta Neurol Scand 2002: 106: 109-112, 111, a
significant correlation was found between MS disease activity and
both total and LDL (low density lipoprotein) cholesterol levels.
Lesions formed by demyelination are characterized by the presence
of foamy macrophages containing cholesterol esters. J. Newcombe et
al., "Low Density Lipoprotein Uptake by Macrophages in Multiple
Sclerosis Plaques: Implication for Pathogenesis", Neuropathol.
Appl. Neurobiol. 1994: 20:152-62, 152. There is evidence of early
involvement of LDL in the development of MS lesions. F. Giubilei at
111. A large proportion of the plasma LDL enters the parenchyma of
MS plaques as a result of blood-brain barrier damage and is
oxidatively modified in the lesion. Id. Lipid peroxidation and
oxidized LDL uptake by infiltrating macrophages or microglial cells
in early stages of MS plaque development may play an important role
in demyelination. Id.
[0017] U.S. Pat. Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624
and 5,688,787, respectively, disclose hydroxy-substituted
azetidinone compounds and substituted .beta.-lactam compounds
useful for inhibiting the absorption of cholesterol, thereby
lowering cholesterol levels and/or inhibiting the formation of
cholesterol-containing lesions in mammalian arterial walls. U.S.
Pat. Nos. 5,846,966 and 5,661,145, respectively, disclose
hydroxy-substituted azetidinone compounds or substituted
.beta.-lactam compounds in combination with HMG CoA reductase
inhibitors for preventing or treating atherosclerosis and reducing
plasma cholesterol levels. Such compounds can also be useful in
lowering C-reactive protein levels in subjects.
[0018] According to the present invention, these and other sterol
absorption inhibitors discussed in detail below can be useful in
preventing or treating demyelination and its associated conditions,
such as primary demyelinating diseases including but not limited to
multiple sclerosis, acute disseminated encephalomyelitis,
adrenoleukodystrophy, adrenomyeloneuropathy, Leber's hereditary
optic atrophy and HTLV-associated myelopathy, and other conditions
characterized by demyelination such as Tay-Sachs disease,
Niemann-Pick disease, Gaucher's disease and Hurler's syndrome; or
stroke, inflammation, immune diseases, metabolic disorders, poison
or drugs.
[0019] In one embodiment, the present invention is directed to
compositions, pharmaceutical compositions, therapeutic
combinations, kits and methods of treatment using the same
comprising at least one (one or more) sterol absorption
inhibitor(s). Suitable sterol absorption inhibitors include
substituted azetidinone sterol absorption inhibitors, substituted
.beta.-lactam sterol absorption inhibitors or combinations thereof
as discussed in detail below. As used herein, "sterol absorption
inhibitor" means a compound capable of inhibiting the absorption of
one or more sterols, including but not limited to cholesterol,
phytosterols (such as sitosterol, campesterol, stigmasterol and
avenosterol), when administered in a therapeutically effective
(sterol absorption inhibiting) amount to a subject, such as a
mammal or human. Other useful compositions, pharmaceutical
compositions, therapeutic combinations, kits and methods of
treatment using the same comprise at least one (one or more)
5.alpha.-stanol absorption inhibitor(s). As used herein,
"5.alpha.-stanol absorption inhibitor" means a compound capable of
inhibiting the absorption of one or more 5.alpha.-stanols (such as
cholestanol, 5.alpha.-campestanol, 5.alpha.-sitostanol), when
administered in a therapeutically effective (5.alpha.-stanol
absorption inhibiting) amount to a subject, such as a mammal or
human.
[0020] In a preferred embodiment, sterol or 5.alpha.-stanol
absorption inhibitors useful in the compositions, therapeutic
combinations and methods of the present invention are represented
by Formula (I) below:
##STR00002##
or a pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (I) above:
[0021] Ar.sup.1 and Ar.sup.2 are independently selected from the
group consisting of aryl and R.sup.4-substituted aryl;
[0022] Ar.sup.3 is aryl or R.sup.5-substituted aryl;
[0023] X, Y and Z are independently selected from the group
consisting of --CH.sub.2--, --CH(lower alkyl)- and --C(dilower
alkyl)-;
[0024] R and R.sup.2 are independently selected from the group
consisting of --OR, --O(CO)R.sup.6, --O(CO)OR.sup.9 and
--O(CO)NR.sup.6R.sup.7;
[0025] R.sup.1 and R.sup.3 are independently selected from the
group consisting of hydrogen, lower alkyl and aryl;
[0026] q is 0 or 1; r is 0 or 1; m, n and p are independently
selected from 0, 1, 2, 3 or 4; provided that at least one of q and
r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and
provided that when p is 0 and r is 1, the sum of m, q and n is 1,
2, 3, 4 or 5;
[0027] R.sup.4 is 1-5 substituents independently selected from the
group consisting of lower alkyl, --OR.sup.6, --O(CO)R.sup.6,
--O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5OR.sup.6,
--O(CO)NR.sup.6R.sup.7, --NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.9,
--NR.sup.6(CO)OR.sup.9, --NR.sup.6(CO)NR.sup.7R.sup.8,
--NR.sup.6SO.sub.2R.sup.9, --COOR.sup.6, --CONR.sup.6R.sup.7,
--COR.sup.6, --SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, -(lower
alkylene)COOR.sup.6, --CH.dbd.CH--COOR.sup.6, --CF.sub.3, --CN,
--NO.sub.2 and halogen;
[0028] R.sup.5 is 1-5 substituents independently selected from the
group consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, -(lower
alkylene)COOR.sup.6 and --CH.dbd.CH--COOR.sup.6;
[0029] R.sup.6, R.sup.7 and R.sup.8 are independently selected from
the group consisting of hydrogen, lower alkyl, aryl and
aryl-substituted lower alkyl; and
[0030] R.sup.9 is lower alkyl, aryl or aryl-substituted lower
alkyl.
[0031] Preferably, R.sup.4 is 1-3 independently selected
substituents, and R.sup.5 is preferably 1-3 independently selected
substituents.
[0032] In a preferred embodiment, a sterol or 5.alpha.-stanol
absorption inhibitor of Formula (I) useful in the compositions,
therapeutic combinations and methods of the present invention is
represented by Formula (II) (ezetimibe) below:
##STR00003##
or a pharmaceutically acceptable salt or solvate thereof. The
compound of Formula (II) can be in anhydrous or hydrated form.
[0033] As used herein, the term "alkyl" or "lower alkyl" means
straight or branched alkyl chains having from 1 to 6 carbon atoms
and "alkoxy" means alkoxy groups having 1 to 6 carbon atoms.
Non-limiting examples of lower alkyl groups include, for example
methyl, ethyl, propyl, and butyl groups. Where an alkyl chain joins
two other variables and is therefore bivalent, the term alkylene is
used.
[0034] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 6 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms, such as phenyl, naphthyl,
indenyl, tetrahydronaphthyl or indanyl.
[0035] The statements wherein, for example, R, R.sup.1, R.sup.2 and
R.sup.3 are said to be independently selected from a group of
substituents mean that R, R.sup.1, R.sup.2 and R.sup.3 are each
independently selected, but also that where an R, R.sup.1, R.sup.2
and R.sup.3 variable occurs more than once in a molecule, each
occurrence is independently selected (e.g., if R is --OR.sup.6,
wherein R.sup.6 is hydrogen, R.sup.2 can be --OR.sup.6 wherein
R.sup.6 is lower alkyl). Those skilled in the art will recognize
that the size and nature of the substituent(s) will affect the
number of substituents that can be present.
[0036] Compounds of Formula I can be prepared by a variety of
methods well known to those skilled in the art, for example such as
are disclosed in U.S. Pat. Nos. 5,631,365, 5,767,115, 5,846,966,
6,207,822, PCT patent application Ser. No. 02/079174 and PCT Patent
Application WO 93/02048, each of which is incorporated herein by
reference, and in the Example below.
[0037] Alternative sterol absorption inhibitors useful in the
compositions, therapeutic combinations and methods of the present
invention are represented by Formula (III) below:
##STR00004##
or a pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (III) above:
[0038] Ar.sup.1 is R.sup.3-substituted aryl;
[0039] Ar.sup.2 is R.sup.4-substituted aryl;
[0040] Ar.sup.3 is R.sup.5-substituted aryl;
[0041] Y and Z are independently selected from the group consisting
of --CH.sub.2--, --CH(lower alkyl)- and --C(dilower alkyl)-;
[0042] A is selected from --O--, --S--, --S(O)-- or
--S(O).sub.2--;
[0043] R.sup.1 is selected from the group consisting of --OR.sup.6,
--O(CO)R.sup.6, --O(CO)OR.sup.9 and --O(CO)NR.sup.6R.sup.7; R.sup.2
is selected from the group consisting of hydrogen, lower alkyl and
aryl; or R.sup.1 and R.sup.2 together are .dbd.O;
[0044] q is 1, 2 or 3;
[0045] p is 0, 1, 2, 3 or 4;
[0046] R.sup.5 is 1-3 substituents independently selected from the
group consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.9, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2-lower alkyl,
--NR.sup.6SO.sub.2-aryl, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2-alkyl, S(O).sub.0-2-aryl,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, o-halogeno, m-halogeno,
o-lower alkyl, m-lower alkyl, -(lower alkylene)-COOR.sup.6, and
--CH.dbd.CH--COOR.sup.6;
[0047] R.sup.3 and R.sup.4 are independently 1-3 substituents
independently selected from the group consisting of R.sup.5,
hydrogen, p-lower alkyl, aryl, --NO.sub.2, --CF.sub.3 and
p-halogeno;
[0048] R.sup.6, R.sup.7 and R.sup.8 are independently selected from
the group consisting of hydrogen, lower alkyl, aryl and
aryl-substituted lower alkyl; and R.sup.9 is lower alkyl, aryl or
aryl-substituted lower alkyl.
[0049] Methods for making compounds of Formula III are well known
to those skilled in the art. Non-limiting examples of suitable
methods are disclosed in U.S. Pat. No. 5,688,990, which is
incorporated herein by reference.
[0050] In another embodiment, sterol absorption inhibitors useful
in the compositions, therapeutic combinations and methods of the
present invention are represented by Formula (IV):
##STR00005##
or a pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (IV) above:
[0051] A is selected from the group consisting of
R.sup.2-substituted heterocycloalkyl, R.sup.2-substituted
heteroaryl, R.sup.2-substituted benzofused heterocycloalkyl, and
R.sup.2-substituted benzofused heteroaryl;
[0052] Ar.sup.1 is aryl or R.sup.3-substituted aryl;
[0053] Ar.sup.2 is aryl or R.sup.4-substituted aryl;
[0054] Q is a bond or, with the 3-position ring carbon of the
azetidinone, forms the spiro group
##STR00006##
and
[0055] R.sup.1 is selected from the group consisting of: [0056]
--(CH.sub.2).sub.q--, wherein q is 2-6, provided that when Q forms
a spiro ring, q can also be zero or 1; [0057]
--(CH.sub.2).sub.e-G-(CH.sub.2).sub.r--, wherein G is --O--,
--C(O)--, phenylene, --NR.sup.8-- or --S(O).sub.0-2--, e is 0-5 and
r is 0-5, provided that the sum of e and r is 1-6; [0058]
--(C.sub.2-C.sub.6 alkenylene)-; and [0059]
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6 cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6;
[0060] R.sup.5 is selected from:
##STR00007##
[0061] R.sup.6 and R.sup.7 are independently selected from the
group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-,
--C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl)=CH--; or R.sup.5 together with an
adjacent R.sup.6, or R.sup.5 together with an adjacent R.sup.7,
form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)-
group;
[0062] a and b are independently 0, 1, 2 or 3, provided both are
not zero; provided that when R.sup.6 is --CH.dbd.CH-- or
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--, a is 1; provided that when
R.sup.7 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl).dbd.CH--, b
is 1; provided that when a is 2 or 3, the R.sup.6's can be the same
or different; and provided that when b is 2 or 3, the R.sup.7's can
be the same or different;
[0063] and when Q is a bond, R.sup.1 also can be selected from:
##STR00008##
[0064] where M is --O--, --S--, --S(O)-- or --S(O).sub.2--;
[0065] X, Y and Z are independently selected from the group
consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)- and
--C(di-(C.sub.1-C.sub.6) alkyl);
[0066] R.sup.10 and R.sup.12 are independently selected from the
group consisting of --OR.sup.14, --O(CO)R.sup.14, --O(CO)OR.sup.16
and --O(CO)NR.sup.14R.sup.15;
[0067] R.sup.11 and R.sup.13 are independently selected from the
group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl and aryl; or
R.sup.10 and R.sup.11 together are .dbd.O, or R.sup.12 and R.sup.13
together are .dbd.O;
[0068] d is 1, 2 or 3;
[0069] h is 0, 1, 2, 3 or 4;
[0070] s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4;
provided that at least one of s and t is 1, and the sum of m, n, p,
s and t is 1-6; provided that when p is 0 and t is 1, the sum of m,
s and n is 1-5; and provided that when p is 0 and s is 1, the sum
of m, t and n is 1-5;
[0071] v is 0 or 1;
[0072] j and k are independently 1-5, provided that the sum of j, k
and v is 1-5;
[0073] R.sup.2 is 1-3 substituents on the ring carbon atoms
selected from the group consisting of hydrogen,
(C.sub.1-C.sub.10)alkyl, (C.sub.2-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkenyl, R.sup.17-substituted aryl,
R.sup.17-substituted benzyl, R.sup.17-substituted benzyloxy,
R.sup.17-substituted aryloxy, halogeno, --NR.sup.14R.sup.15,
NR.sup.14R.sup.15(C.sub.1-C.sub.6 alkylene)-,
NR.sup.14R.sup.15C(O)(C.sub.1-C.sub.6 alkylene)-, --NHC(O)R.sup.16,
OH, C.sub.1-C.sub.6 alkoxy, --OC(O)R.sup.16, --COR.sup.14,
hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, NO.sub.2,
--S(O).sub.0-2R.sup.16, --SO.sub.2NR.sup.14R.sup.15 and
--(C.sub.1-C.sub.6 alkylene)COOR.sup.14; when R.sup.2 is a
substituent on a heterocycloalkyl ring, R.sup.2 is as defined, or
is .dbd.O or
##STR00009##
and, where R.sup.2 is a substituent on a substitutable ring
nitrogen, it is hydrogen, (C.sub.1-C.sub.6)alkyl, aryl,
(C.sub.1-C.sub.6)aryloxy, (C.sub.1-C.sub.6)alkylcarbonyl,
arylcarbonyl, hydroxy, --(CH.sub.2).sub.1-6CONR.sup.18R.sup.18,
##STR00010##
[0074] wherein J is --O--, --NH--, --NR.sup.18-- or
--CH.sub.2--;
[0075] R.sup.3 and R.sup.4 are independently selected from the
group consisting of 1-3 substituents independently selected from
the group consisting of (C.sub.1-C.sub.6)alkyl, --OR.sup.14,
--O(CO)R.sup.14, --O(CO)OR.sup.16, --O(CH.sub.2).sub.1-5OR.sup.14,
--O(CO)NR.sup.14R.sup.15, --NR.sup.14R.sup.15,
--NR.sup.14(CO)R.sup.15, --NR.sup.14(CO)OR.sup.16,
--NR.sup.14(CO)NR.sup.15R.sup.19, --NR.sup.14SO.sub.2R.sup.16,
--COOR.sup.14, --CONR.sup.14R.sup.15, --COR.sup.14,
SO.sub.2NR.sup.14R.sup.15, S(O).sub.0-2R.sup.16,
--O(CH.sub.2).sub.1-10--COOR.sup.14,
--O(CH.sub.2).sub.1-10CONR.sup.14R.sup.15, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.14, --CH.dbd.CH--COOR.sup.14, --CF.sub.3, --CN,
--NO.sub.2 and halogen;
[0076] R.sup.8 is hydrogen, (C.sub.1-C.sub.6)alkyl, aryl
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.14 or --COOR.sup.14;
[0077] R.sup.9 and R.sup.17 are independently 1-3 groups
independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2,
--NR.sup.14R.sup.15, OH and halogeno;
[0078] R.sup.14 and R.sup.15 are independently selected from the
group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, aryl and
aryl-substituted (C.sub.1-C.sub.6)alkyl;
[0079] R.sup.16 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.17-substituted aryl;
[0080] R.sup.18 is hydrogen or (C.sub.1-C.sub.6)alkyl; and
[0081] R.sup.19 is hydrogen, hydroxy or
(C.sub.1-C.sub.6)alkoxy.
[0082] Methods for making compounds of Formula IV are well known to
those skilled in the art. Non-limiting examples of suitable methods
are disclosed in U.S. Pat. No. 5,656,624, which is incorporated
herein by reference.
[0083] In another embodiment, sterol absorption inhibitors useful
in the compositions, therapeutic combinations and methods of the
present invention are represented by Formula (V):
##STR00011##
or a pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (V) above:
[0084] Ar.sup.1 is aryl, R.sup.10-substituted aryl or
heteroaryl;
[0085] Ar.sup.2 is aryl or R.sup.4-substituted aryl;
[0086] Ar.sup.3 is aryl or R.sup.5-substituted aryl;
[0087] X and Y are independently selected from the group consisting
of --CH.sub.2--, --CH(lower alkyl)- and --C(dilower alkyl)-;
[0088] R is --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 or
--O(CO)NR.sup.6R.sup.7; R.sup.1 is hydrogen, lower alkyl or aryl;
or R and R.sup.1 together are .dbd.O;
[0089] q is 0 or 1;
[0090] r is 0, 1 or 2;
[0091] m and n are independently 0, 1, 2, 3, 4 or 5; provided that
the sum of m, n and q is 1, 2, 3, 4 or 5;
[0092] R.sup.4 is 1-5 substituents independently selected from the
group consisting of lower alkyl, --OR.sup.6, --O(CO)R.sup.6,
--O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5OR.sup.6,
--O(CO)NR.sup.6R.sup.7, --NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7,
--NR.sup.7(CO)OR.sup.9, --NR.sup.6(CO)NR.sup.7R.sup.8,
--NR.sup.6SO.sub.2R.sup.9, --COOR.sup.6, --CONR.sup.6R.sup.7,
--COR.sup.6, --SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, -(lower
alkylene)COOR.sup.6 and --CH.dbd.CH--COOR.sup.6;
[0093] R.sup.5 is 1-5 substituents independently selected from the
group consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.6R.sup.7,
--NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7, --NR.sup.6(CO)OR.sup.9,
--NR.sup.6(CO)NR.sup.7R.sup.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sup.6R.sup.7, S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, --CF.sub.3, --CN,
--NO.sub.2, halogen, -(lower alkylene)COOR.sup.6 and
--CH.dbd.CH--COOR.sup.6;
[0094] R.sup.6, R.sup.7 and R.sup.8 are independently selected from
the group consisting of hydrogen, lower alkyl, aryl and
aryl-substituted lower alkyl;
[0095] R.sup.9 is lower alkyl, aryl or aryl-substituted lower
alkyl; and
[0096] R.sup.10 is 1-5 substituents independently selected from the
group consisting of lower alkyl, --OR.sup.6, --O(CO)R.sup.6,
--O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5OR.sup.6,
--O(CO)NR.sup.6R.sup.7, --NR.sup.6R.sup.7, --NR.sup.6(CO)R.sup.7,
--NR.sup.6(CO)OR.sup.9, --NR.sup.6(CO)NR.sup.7R.sup.8,
--NR.sup.6SO.sub.2R.sup.9, --COOR.sup.6, --CONR.sup.6R.sup.7,
--COR.sup.6, --SO.sub.2NR.sup.6R.sup.7, --S(O).sub.0-2R.sup.9,
--O(CH.sub.2).sub.1-10--COOR.sup.6,
--O(CH.sub.2).sub.1-10CONR.sup.6R.sup.7, --CF.sub.3, --CN,
--NO.sub.2 and halogen.
[0097] Methods for making compounds of Formula V are well known to
those skilled in the art. Non-limiting examples of suitable methods
are disclosed in U.S. Pat. No. 5,624,920, which is incorporated
herein by reference.
[0098] In another embodiment, sterol absorption inhibitors useful
in the compositions, therapeutic combinations and methods of the
present invention are represented by Formula (VI):
##STR00012##
or a pharmaceutically acceptable salt thereof or a solvate thereof,
wherein:
[0099] R.sub.1 is
##STR00013##
[0100] R.sub.2 and R.sub.3 are independently selected from the
group consisting of: --CH.sub.2--, --CH(lower alkyl)-, --C(di-lower
alkyl)-, --CH.dbd.CH-- and --C(lower alkyl).dbd.CH--; or R.sub.1
together with an adjacent R.sub.2, or R.sub.1 together with an
adjacent R.sub.3, form a --CH.dbd.CH-- or a --CH.dbd.C(lower
alkyl)- group;
[0101] u and v are independently 0, 1, 2 or 3, provided both are
not zero; provided that when R.sub.2 is --CH.dbd.CH-- or --C(lower
alkyl).dbd.CH--, v is 1; provided that when R.sub.3 is
--CH.dbd.CH-- or --C(lower alkyl).dbd.CH--, u is 1; provided that
when v is 2 or 3, the R.sub.2's can be the same or different; and
provided that when u is 2 or 3, the R.sub.3's can be the same or
different;
[0102] R.sub.4 is selected from B--(CH.sub.2).sub.mC(O)--, wherein
m is 0, 1, 2, 3, 4 or 5; B--(CH.sub.2).sub.q--, wherein q is 0, 1,
2, 3, 4, 5 or 6; B--(CH.sub.2).sub.e-Z-(CH.sub.2).sub.r--, wherein
Z is --O--, --C(O)--, phenylene, --N(R.sub.8)-- or
--S(O).sub.0-2--, e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or
5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6;
B--(C.sub.2-C.sub.6 alkenylene)-; B--(C.sub.4-C.sub.6
alkadienylene)-; B--(CH.sub.2).sub.t-Z-(C.sub.2-C.sub.6
alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1,
2 or 3, provided that the sum of t and the number of carbon atoms
in the alkenylene chain is 2, 3, 4, 5 or 6;
B--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6 cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1,
2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or
6; B--(CH.sub.2).sub.t--V--(C.sub.2-C.sub.6 alkenylene)- or
B--(C.sub.2-C.sub.6 alkenylene)-V--(CH.sub.2).sub.t--, wherein V
and t are as defined above, provided that the sum of t and the
number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
B--(CH.sub.2).sub.a-Z-(CH.sub.2).sub.d--V--(CH.sub.2).sub.d--,
wherein Z and V are as defined above and a, b and d are
independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b
and d is 0, 1, 2, 3, 4, 5 or 6; or T-(CH.sub.2).sub.s--, wherein T
is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6;
or
[0103] R.sub.1 and R.sub.4 together form the group
##STR00014##
[0104] B is selected from indanyl, indenyl, naphthyl,
tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein
heteroaryl is selected from the group consisting of pyrrolyl,
pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl,
thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for
nitrogen-containing heteroaryls, the N-oxides thereof, or
##STR00015##
[0105] W is 1 to 3 substituents independently selected from the
group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy,
alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower
alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower
alkanedioyl, allyloxy, --CF.sub.3, --OCF.sub.3, benzyl,
R.sub.7-benzyl, benzyloxy, R.sub.7-benzyloxy, phenoxy,
R.sub.7-phenoxy, dioxolanyl, NO.sub.2, --N(R.sub.8)(R.sub.9),
N(R.sub.8)(R.sub.9)-lower alkylene-, N(R.sub.8)(R.sub.9)-lower
alkylenyloxy-, OH, halogeno, --CN, --N.sub.3, --NHC(O)OR.sub.10,
--NHC(O)R.sub.10, R.sub.11O.sub.2SNH--,
(R.sub.11O.sub.2S).sub.2N--, --S(O).sub.2NH.sub.2,
--S(O).sub.0-2R.sub.8, tert-butyldimethyl-silyloxymethyl,
--C(O)R.sub.12, --COOR.sub.19, --CON(R.sub.8)(R.sub.9),
--CH.dbd.CHC(O)R.sub.12, -lower alkylene-C(O)R.sub.12,
R.sub.10C(O)(lower alkylenyloxy)-, N(R.sub.8)(R.sub.9)C(O)(lower
alkylenyloxy)- and
##STR00016##
for substitution on ring carbon atoms, and the substituents on the
substituted heteroaryl ring nitrogen atoms, when present, are
selected from the group consisting of lower alkyl, lower alkoxy,
--C(O)OR.sub.10, --C(O)R.sub.10, OH, N(R.sub.8)(R.sub.9)-lower
alkylene-, N(R.sub.8)(R.sub.9)-lower alkylenyloxy-,
--S(O).sub.2NH.sub.2 and 2-(trimethylsilyl)-ethoxymethyl;
[0106] R.sub.7 is 1-3 groups independently selected from the group
consisting of lower alkyl, lower alkoxy, --COOH, NO.sub.2,
--N(R.sub.8)(R.sub.9), OH, and halogeno;
[0107] R.sub.8 and R.sub.9 are independently selected from H or
lower alkyl;
[0108] R.sub.10 is selected from lower alkyl, phenyl,
R.sub.7-phenyl, benzyl or R.sub.7-benzyl;
[0109] R.sub.11 is selected from OH, lower alkyl, phenyl, benzyl,
R.sub.7-phenyl or R.sub.7-benzyl;
[0110] R.sub.12 is selected from H, OH, alkoxy, phenoxy,
benzyloxy,
##STR00017##
--N(R.sub.8)(R.sub.9), lower alkyl, phenyl or R.sub.7-phenyl;
[0111] R.sub.13 is selected from --O--, --CH.sub.2--, --NH--,
--N(lower alkyl)- or --NC(O)R.sub.19;
[0112] R.sub.15, R.sub.16 and R.sub.17 are independently selected
from the group consisting of H and the groups defined for W; or
R.sub.15 is hydrogen and R.sub.16 and R.sub.17, together with
adjacent carbon atoms to which they are attached, form a dioxolanyl
ring;
[0113] R.sub.19 is H, lower alkyl, phenyl or phenyl lower alkyl;
and
[0114] R.sub.20 and R.sub.21 are independently selected from the
group consisting of phenyl, W-substituted phenyl, naphthyl,
W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl,
benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused
heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl,
wherein heteroaryl is as defined above.
[0115] Methods for making compounds of Formula VI are well known to
those skilled in the art. Non-limiting examples of suitable methods
are disclosed in U.S. Pat. No. 5,698,548, which is incorporated
herein by reference.
[0116] In another embodiment, sterol absorption inhibitors useful
in the compositions, therapeutic combinations and methods of the
present invention are represented by Formulas (VIIA) and
(VIIB):
##STR00018##
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
[0117] A is --CH.dbd.CH--, --C.ident.C-- or --(CH.sub.2).sub.p--
wherein p is 0, 1 or 2;
[0118] B is
##STR00019##
[0119] B' is
##STR00020##
[0120] D is --(CH.sub.2).sub.mC(O)-- or --(CH.sub.2).sub.q--
wherein m is 1, 2, 3 or 4 and q is 2, 3 or 4;
[0121] E is C.sub.10 to C.sub.20 alkyl or --C(O)--(C.sub.9 to
C.sub.19)-alkyl, wherein the alkyl is straight or branched,
saturated or containing one or more double bonds;
[0122] R is hydrogen, C.sub.1-C.sub.15 alkyl, straight or branched,
saturated or containing one or more double bonds, or
B--(CH.sub.2).sub.r--, wherein r is 0, 1, 2, or 3;
[0123] R.sub.1, R.sub.2, R.sub.3, R.sub.1', R.sub.2', and R.sub.3',
are independently selected from the group consisting of hydrogen,
lower alkyl, lower alkoxy, carboxy, NO.sub.2, NH.sub.2, OH,
halogeno, lower alkylamino, dilower alkylamino, --NHC(O)OR.sub.5,
R.sub.6O.sub.2SNH-- and --S(O).sub.2NH.sub.2;
[0124] R.sub.4 is
##STR00021##
wherein n is 0, 1, 2 or 3;
[0125] R.sub.5 is lower alkyl; and
[0126] R.sub.6 is OH, lower alkyl, phenyl, benzyl or substituted
phenyl wherein the substituents are 1-3 groups independently
selected from the group consisting of lower alkyl, lower alkoxy,
carboxy, NO.sub.2, NH.sub.2, OH, halogeno, lower alkylamino and
dilower alkylamino; or a pharmaceutically acceptable salt thereof
or a solvate thereof.
[0127] In another embodiment, sterol absorption inhibitors useful
in the compositions and methods of the present invention are
represented by Formula (VIII):
##STR00022##
or a pharmaceutically acceptable salt thereof or a solvate thereof,
wherein, in Formula (VIII) above,
[0128] R.sup.26 is H or OG.sup.1;
[0129] G and G are independently selected from the group consisting
of
[0130] H,
##STR00023##
[0131] and
##STR00024##
provided that when R.sup.26 is H or OH, G is not H;
[0132] R, R.sup.1 and R.sup.b are independently selected from the
group consisting of H, --OH, halogeno, --NH.sub.2, azido,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)-alkoxy or
--W--R.sup.30;
[0133] W is independently selected from the group consisting of
--NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--,
--NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--;
[0134] R.sup.2 and R.sup.6 are independently selected from the
group consisting of H, (C.sub.1-C.sub.6)alkyl, aryl and
aryl(C.sub.1-C.sub.6)alkyl;
[0135] R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.3a and R.sup.4a
are independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl,
--C(O)(C.sub.1-C.sub.6)alkyl and --C(O)aryl;
[0136] R.sup.30 is selected from the group consisting of
R.sup.32-substituted T,
R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl,
R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl,
R.sup.32-Substituted-(C.sub.3-C.sub.7)cycloalkyl and
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl;
[0137] R.sup.31 is selected from the group consisting of H and
(C.sub.1-C.sub.4)alkyl;
[0138] T is selected from the group consisting of phenyl, furyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl,
benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and
pyridyl;
[0139] R.sup.32 is independently selected from 1-3 substituents
independently selected from the group consisting of halogeno,
(C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3, --NO.sub.2,
(C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo,
(C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2,
--C(O)--NH(C.sub.1-C.sub.4)alkyl,
--C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2,
--C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and
pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31,
the nitrogen to which it is attached and R.sup.32 form a
pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or
morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted
pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or
morpholinyl group;
[0140] Ar.sup.1 is aryl or R.sup.10-substituted aryl;
[0141] Ar.sup.2 is aryl or R.sup.11-substituted aryl;
[0142] Q is a bond or, with the 3-position ring carbon of the
azetidinone, forms the spiro group
##STR00025##
and
[0143] R.sup.1 is selected from the group consisting of [0144]
--(CH.sub.2).sub.q--, wherein q is 2-6, provided that when Q forms
a spiro ring, q can also be zero or 1; [0145]
--(CH.sub.2).sub.e-E-(CH.sub.2).sub.r--, wherein E is --O--,
--C(O)--, phenylene, --NR.sup.22-- or --S(O).sub.0-2--, e is 0-5
and r is 0-5, provided that the sum of e and r is 1-6; [0146]
--(C.sub.2-C.sub.6)alkenylene-; and [0147]
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6 cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6;
[0148] R.sup.12 is
##STR00026##
[0149] R.sup.13 and R.sup.14 are independently selected from the
group consisting of
[0150] --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-,
--C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--; or R.sup.12 together with an
adjacent R.sup.13, or R.sup.12 together with an adjacent R.sup.14,
form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)-
group;
[0151] a and b are independently 0, 1, 2 or 3, provided both are
not zero;
[0152] provided that when R.sup.13 is --CH.dbd.CH-- or
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--, a is 1;
[0153] provided that when R.sup.14 is --CH.dbd.CH-- or
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--, b is 1;
[0154] provided that when a is 2 or 3, the R.sup.13's can be the
same or different; and
[0155] provided that when b is 2 or 3, the R.sup.14's can be the
same or different;
[0156] and when Q is a bond, R.sup.1 also can be:
##STR00027##
[0157] M is --O--, --S--, --S(O)-- or --S(O).sub.2--;
[0158] X, Y and Z are independently selected from the group
consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6)alkyl- and
--C(di-(C.sub.1-C.sub.6)alkyl);
[0159] R.sup.10 and R.sup.11 are independently selected from the
group consisting of 1-3 substituents independently selected from
the group consisting of (C.sub.1-C.sub.6)alkyl, --OR.sup.19,
--O(CO)R.sup.19, --O(CO)OR.sup.21, --O(CH.sub.2).sub.1-5OR.sup.19,
--O(CO)NR.sup.19R.sup.20, --NR.sup.19R.sup.20,
--NR.sup.19(CO)R.sup.20, --NR.sup.19(CO)OR.sup.21,
--NR.sup.19(CO)NR.sup.20R.sup.25, --NR.sup.19SO.sub.2R.sup.21,
--COOR.sup.19, --CONR.sup.19R.sup.20, --COR.sup.19,
--SO.sub.2NR.sup.19R.sup.20, S(O).sub.0-2R.sup.21,
--O(CH.sub.2).sub.1-10--COOR.sup.19,
--O(CH.sub.2).sub.1-10CONR.sup.19R.sup.20, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.19, --CH.dbd.CH--COOR.sup.19, --CF.sub.3, --CN,
--NO.sub.2 and halogen;
[0160] R.sup.15 and R.sup.17 are independently selected from the
group consisting of --OR.sup.19, --O(CO)R.sup.19, --O(CO)OR.sup.21
and --O(CO)NR.sup.19R.sup.20;
[0161] R.sup.16 and R.sup.18 are independently selected from the
group consisting of H, (C.sub.1-C.sub.6)alkyl and aryl; or R.sup.15
and R.sup.16 together are .dbd.O, or R.sup.17 and R.sup.18 together
are .dbd.O;
[0162] d is 1, 2 or 3;
[0163] h is 0, 1, 2, 3 or 4;
[0164] s is 0 or 1; t is 0 or 1; m, n and p are independently
0-4;
[0165] provided that at least one of s and t is 1, and the sum of
m, n, p, s and t is 1-6;
[0166] provided that when p is 0 and t is 1, the sum of m, s and n
is 1-5; and provided that when p is 0 and s is 1, the sum of m, t
and n is 1-5;
[0167] v is 0 or 1;
[0168] j and k are independently 1-5, provided that the sum of j, k
and v is 1-5;
[0169] and when Q is a bond and R.sup.1 is
##STR00028##
Ar.sup.1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyi,
thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl
or pyridazinyl;
[0170] R.sup.19 and R.sup.20 are independently selected from the
group consisting of H, (C.sub.1-C.sub.6)alkyl, aryl and
aryl-substituted (C.sub.1-C.sub.6)alkyl;
[0171] R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.24-substituted aryl;
[0172] R.sup.22 is H, (C.sub.1-C.sub.6)alkyl, aryl
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.19 or --COOR.sup.19;
[0173] R.sup.23 and R.sup.24 are independently 1-3 groups
independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --COOH, NO.sub.2,
--NR.sup.19R.sup.20, --OH and halogeno; and
[0174] R.sup.25 is H, --OH or (C.sub.1-C.sub.6)alkoxy.
[0175] Methods for making compounds of Formula VIII are well known
to those skilled in the art. Non-limiting examples of suitable
methods are disclosed in U.S. Pat. No. 5,756,470, which is
incorporated herein by reference.
[0176] In another embodiment, sterol absorption inhibitors useful
in the compositions and methods of the present invention are
represented by Formula (IX) below:
##STR00029##
or a pharmaceutically acceptable salt or solvate thereof, wherein
in Formula (IX):
[0177] R.sup.1 is selected from the group consisting of H, G,
G.sup.1, G.sup.2, --SO.sub.3H and --PO.sub.3H;
[0178] G is selected from the group consisting of: H,
##STR00030##
[0179] wherein R, R.sup.a and R.sup.b are each independently
selected from the group consisting of H, --OH, halo, --NH.sub.2,
azido, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy or
--W--R.sup.30;
[0180] W is independently selected from the group consisting of
--NH--C(O)--, --O--C(O)--, --O--C(O)--N(R.sup.31)--,
--NH--C(O)--N(R.sup.31)-- and --O--C(S)--N(R.sup.31)--;
[0181] R.sup.2 and R.sup.6 are each independently selected from the
group consisting of H, (C.sub.1-C.sub.6)alkyl, acetyl, aryl and
aryl(C.sub.1-C.sub.6)alkyl;
[0182] R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.3a and R.sup.4a
are each independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, acetyl, aryl(C.sub.1-C.sub.6)alkyl,
--C(O)(C.sub.1-C.sub.6)alkyl and --C(O)aryl;
[0183] R.sup.30 is independently selected from the group consisting
of R.sup.32-substituted T,
R.sup.32-substituted-T-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.2-C.sub.4)alkenyl,
R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl and
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloal
kyl(C.sub.1-C.sub.6)alkyl;
[0184] R.sup.31 is independently selected from the group consisting
of H and (C.sub.1-C.sub.4)alkyl;
[0185] T is independently selected from the group consisting of
phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl
and pyridyl;
[0186] R.sup.32 is independently selected from 1-3 substituents
which are each independently selected from the group consisting of
H, halo, (C.sub.1-C.sub.4)alkyl, --OH, phenoxy, --CF.sub.3,
--NO.sub.2, (C.sub.1-C.sub.4)alkoxy, methylenedioxy, oxo,
(C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, --N(CH.sub.3).sub.2,
--C(O)--NH(C.sub.1-C.sub.4)alkyl,
--C(O)--N((C.sub.1-C.sub.4)alkyl).sub.2,
--C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy and
pyrrolidinylcarbonyl; or R.sup.32 is a covalent bond and R.sup.31,
the nitrogen to which it is attached and R.sup.32 form a
pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or
morpholinyl group, or a (C.sub.1-C.sub.4)alkoxycarbonyl-substituted
pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or
morpholinyl group;
[0187] G.sup.1 is represented by the structure:
##STR00031##
wherein R.sup.33 is independently selected from the group
consisting of unsubstituted alkyl, R.sup.34-substituted alkyl,
(R.sup.35)(R.sup.36)alkyl-,
##STR00032##
[0188] R.sup.34 is one to three substituents, each R.sup.34 being
independently selected from the group consisting of HOOC--, HO--,
HS--, (CH.sub.3)S--, H.sub.2N--, (NH.sub.2)(NH)C(NH)--,
(NH.sub.2)C(O)-- and HOOCCH(NH.sub.3.sup.+)CH.sub.2SS--;
[0189] R.sup.35 is independently selected from the group consisting
of H and NH.sub.2--;
[0190] R.sup.36 is independently selected from the group consisting
of H, unsubstituted alkyl, R.sup.34-substituted alkyl,
unsubstituted cycloalkyl and R.sup.34-substituted cycloalkyl;
[0191] G.sup.2 is represented by the structure:
##STR00033##
wherein R.sup.37 and R.sup.38 are each independently selected from
the group consisting of (C.sub.1-C.sub.6)alkyl and aryl;
[0192] R.sup.26 is one to five substituents, each R.sup.26 being
independently selected from the group consisting of: [0193] a) H;
[0194] b) --OH; [0195] c) --OCH.sub.3; [0196] d) fluorine; [0197]
e) chlorine; [0198] f) --O-G; [0199] g) --O-G.sup.1; [0200] h)
--O-G.sup.2; [0201] i) --SO.sub.3H; and [0202] j) --PO.sub.3H;
provided that when R.sup.1 is H, R.sup.26 is not H, --OH,
--OCH.sub.3 or --O-G;
[0203] Ar.sup.1 is aryl, R.sup.10-substituted aryl, heteroaryl or
R.sup.10-substituted heteroaryl;
[0204] Ar.sup.2 is aryl, R.sup.11-substituted aryl, heteroaryl or
R.sup.11-substituted heteroaryl;
[0205] L is selected from the group consisting of: [0206] a) a
covalent bond; [0207] b) --(CH.sub.2).sub.q--, wherein q is 1-6;
[0208] c) --(CH.sub.2).sub.e-E-(CH.sub.2).sub.r--, wherein E is
--O--, --C(O)--, phenylene, --NR.sup.22-- or --S(O).sub.0-2--, e is
0-5 and r is 0-5, provided that the sum of e and r is 1-6; [0209]
d) --(C.sub.2-C.sub.6)alkenylene-; [0210] e)
--(CH.sub.2).sub.f--V--(CH.sub.2).sub.g--, wherein V is
C.sub.3-C.sub.6cycloalkylene, f is 1-5 and g is 0-5, provided that
the sum of f and g is 1-6; and [0211] f)
##STR00034##
[0211] wherein M is --O--, --S--, --S(O)-- or --S(O).sub.2--;
[0212] X, Y and Z are each independently selected from the group
consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6)alkyl- and
--C(di-(C.sub.1-C.sub.6)alkyl)-;
[0213] R.sup.8 is selected from the group consisting of H and
alkyl;
[0214] R.sup.10 and R.sup.11 are each independently selected from
the group consisting of 1-3 substituents which are each
independently selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --OR, --O(CO)R.sup.19, --O(CO)OR.sup.21,
--O(CH.sub.2).sub.1-5OR.sup.19, --O(CO)NR.sup.19R.sup.20,
--NR.sup.19R.sup.20, --NR.sup.19(CO)R.sup.20,
--NR.sup.19(CO)OR.sup.21,
--NR.sup.19(CO)NR.sup.20R.sup.25, --NR.sup.19SO.sub.2R.sup.21,
--COOR.sup.19, --CONR.sup.19R.sup.20,
--COR.sup.--SO.sub.2NR.sup.19R.sup.20, S(O).sub.0-2R.sup.21,
--O(CH.sub.2).sub.1-10--COOR.sup.19,
--O(CH.sub.2).sub.1-10CONR.sup.19R.sup.20, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.19, --CH.dbd.CH--COOR.sup., --CF.sub.3, --CN,
--NO.sub.2 and halo;
[0215] R.sup.15 and R.sup.17 are each independently selected from
the group consisting of --OR.sup.19, --OC(O)R.sup.19,
--OC(O)OR.sup.21, --OC(O)NR.sup.19R.sup.20;
[0216] R.sup.16 and R.sup.18are each independently selected from
the group consisting of H, (C.sub.1-C.sub.6)alkyl and aryl;
[0217] or R.sup.15 and R.sup.16 together are .dbd.O, or R.sup.17and
R.sup.18 together are .dbd.O;
[0218] d is 1, 2 or 3;
[0219] h is 0, 1, 2, 3 or 4;
[0220] s is 0 or 1;
[0221] t is 0 or 1;
[0222] m, n and p are each independently selected from 0-4;
[0223] provided that at least one of s and t is 1, and the sum of
m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the
sum of m, n and p is 1-5; and provided that when p is 0 and s is 1,
the sum of m, t and n is 1-5;
[0224] v is 0 or 1;
[0225] j and k are each independently 1-5, provided that the sum of
j, k and v is 1-5;
[0226] Q is a bond, --(CH.sub.2).sub.q--, wherein q is 1-6, or,
with the 3-position ring carbon of the azetidinone, forms the spiro
group
##STR00035##
[0227] wherein R is
##STR00036##
[0228] R.sup.13 and R.sup.14 are each independently selected from
the group consisting of --CH.sub.2--, --CH(C.sub.1-C.sub.6 alkyl)-,
--C(di-(C.sub.1-C.sub.6) alkyl), --CH.dbd.CH-- and
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--; or R.sup.12 together with an
adjacent R.sup.13, or R.sup.12 together with an adjacent R.sup.14,
form a --CH.dbd.CH-- or a --CH.dbd.C(C.sub.1-C.sub.6 alkyl)-
group;
[0229] a and b are each independently 0, 1, 2 or 3, provided both
are not zero; provided that when R.sup.13 is --CH.dbd.CH-- or
--C(C.sub.1-C.sub.6 alkyl).dbd.CH--, a is 1; provided that when
R.sup.14 is --CH.dbd.CH-- or --C(C.sub.1-C.sub.6 alkyl)=CH--, b is
1; provided that when a is 2 or 3, the R.sup.13's can be the same
or different; and provided that when b is 2 or 3, the R.sup.14's
can be the same or different;
and when Q is a bond and L is
##STR00037##
then Ar.sup.1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl,
thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl
or pyridazinyl;
[0230] R.sup.19 and R.sup.20 are each independently selected from
the group consisting of H, (C.sub.1-C.sub.6)alkyl, aryl and
aryl-substituted (C.sub.1-C.sub.6)alkyl;
[0231] R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.24-substituted aryl;
[0232] R.sup.22 is H, (C.sub.1-C.sub.6)alkyl, aryl
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.19 or --COOR.sup.19;
[0233] R.sup.23 and R.sup.24 are each independently selected from
the group consisting of 1-3 substituents which are each
independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --COOH,
NO.sub.2,--NR.sup.19R.sup.20, --OH and halo; and
[0234] R.sup.25 is H, --OH or (C.sub.1-C.sub.6)alkoxy.
[0235] Examples of compounds of Formula (IX) which are useful in
the methods and combinations of the present invention and methods
for making such compounds are disclosed in U.S. patent application
Ser. No. 10/166,942, filed Jun. 11, 2002, incorporated herein by
reference.
[0236] An example of a useful compound of this invention is one
represented by the formula X:
##STR00038##
wherein R.sup.1 is defined as above.
[0237] A more preferred compound is one represented by formula
XI:
##STR00039##
[0238] Another useful compound is represented by Formula XII:
##STR00040##
[0239] Other useful substituted azetidinone compounds include
N-sulfonyl-2-azetidinones such as are disclosed in U.S. Pat. No.
4,983,597, ethyl 4-(2-oxoazetidin-4-yl)phenoxy-alkanoates such as
are disclosed in Ram et al., Indian J. Chem. Sect. B. 29B, 12
(1990), p. 1134-7, and diphenyl azetidinones and derivatives
disclosed in U.S. Patent Publication Nos. 2002/0039774,
2002/0128252, 2002/0128253 and 2002/0137689, and WO 2002/066464,
each of which is incorporated by reference herein.
[0240] The compounds of Formulae I-XII can be prepared by known
methods, including the methods discussed above and, for example, WO
93/02048 describes the preparation of compounds wherein
--R.sup.1-Q- is alkylene, alkenylene or alkylene interrupted by a
hetero atom, phenylene or cycloalkylene; WO 94/17038 describes the
preparation of compounds wherein Q is a spirocyclic group; WO
95/08532 describes the preparation of compounds wherein
--R.sup.1-Q- is a hydroxy-substituted alkylene group;
PCT/US95/03196 describes compounds wherein --R.sup.1-Q- is a
hydroxy-substituted alkylene attached to the Ar.sup.1 moiety
through an --O-- or S(O).sub.0-2-- group; and U.S. Ser. No.
08/463,619, filed Jun. 5, 1995, describes the preparation of
compounds wherein --R.sup.1-Q- is a hydroxy-substituted alkylene
group attached the azetidinone ring by a --S(O).sub.0-2--
group.
[0241] Compounds of the invention have at least one asymmetrical
carbon atom and therefore all isomers, including enantiomers,
stereoisomers, rotamers, tautomers and racemates of the compounds
of Formulae I-XII are contemplated as being part of this invention.
The invention includes d and I isomers in both pure form and in
admixture, including racemic mixtures. Isomers can be prepared
using conventional techniques, either by reacting optically pure or
optically enriched starting materials or by separating isomers of a
compound of the Formulae I-XII. Isomers may also include geometric
isomers, e.g., when a double bond is present.
[0242] Those skilled in the art will appreciate that for some of
the compounds of the Formulas I-XII, one isomer will show greater
pharmacological activity than other isomers.
[0243] Compounds of the invention with an amino group can form
pharmaceutically acceptable salts with organic and inorganic acids.
Examples of suitable acids for salt formation are hydrochloric,
sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic,
malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and
other mineral and carboxylic acids well known to those in the art.
The salt is prepared by contacting the free base form with a
sufficient amount of the desired acid to produce a salt. The free
base form may be regenerated by treating the salt with a suitable
dilute aqueous base solution such as dilute aqueous sodium
bicarbonate. The free base form differs from its respective salt
form somewhat in certain physical properties, such as solubility in
polar solvents, but the salt is otherwise equivalent to its
respective free base forms for purposes of the invention.
[0244] Certain compounds of the invention are acidic (e.g., those
compounds which possess a carboxyl group). These compounds form
pharmaceutically acceptable salts with inorganic and organic bases.
Examples of such salts are the sodium, potassium, calcium,
aluminum, gold and silver salts. Also included are salts formed
with pharmaceutically acceptable amines such as ammonia, alkyl
amines, hydroxyalkylamines, N-methylglucamine and the like.
[0245] As used herein, "solvate" means a molecular or ionic complex
of molecules or ions of solvent with those of solute (for example,
one or more compounds of Formulae I-XII, isomers of the compounds
of Formulae I-XII, or prodrugs of the compounds of Formulae I-XII).
Non-limiting examples of useful solvents include polar, protic
solvents such as water and/or alcohols (for example methanol).
[0246] Prodrugs of the compounds of Formulae I-XII are contemplated
as being part of this invention. As used herein, "prodrug" means
compounds that are drug precursors which, following administration
to a patient, release the drug in vivo via some chemical or
physiological process (e.g., a prodrug on being brought to the
physiological pH or through enzyme action is converted to the
desired drug form).
[0247] The daily dose of the sterol absorption inhibitor(s)
administered to the subject can range from about 0.1 to about 1000
mg per day, preferably about 0.25 to about 50 mg/day, and more
preferably about 10 mg per day, given in a single dose or 2-4
divided doses. The exact dose, however, is determined by the
attending clinician and is dependent on the potency of the compound
administered, the age, weight, condition and response of the
patient.
[0248] For administration of pharmaceutically acceptable salts of
the above compounds, the weights indicated above refer to the
weight of the acid equivalent or the base equivalent of the
therapeutic compound derived from the salt.
[0249] The term "therapeutically effective amount" means that
amount of a therapeutic agent of the composition, such as a sterol
absorption inhibitor(s), antidemyelination agent and other
pharmacological or therapeutic agents described below, that will
elicit a biological or medical response of a tissue, system, or
subject that is being sought by the administrator (such as a
researcher, doctor or veterinarian) which includes alleviation of
the symptoms of the condition or disease being treated and the
prevention, slowing or halting of progression of the condition
(demyelination and its symptom(s)).
[0250] Examples of suitable subjects that can be treated according
to the methods of the present invention include mammals, such as
humans or dogs, and other animals.
[0251] As used herein, "combination therapy" or "therapeutic
combination" means the administration of two or more therapeutic
agents, such as sterol absorption inhibitor(s) and
antidemyelination agent(s), to prevent or treat demyelination or
any of its associated conditions, such as are discussed above. As
used herein, "demyelination" means insufficient or loss of myelin
on the nerves. Such administration includes coadministration of
these therapeutic agents in a substantially simultaneous manner,
such as in a single tablet or capsule having a fixed ratio of
active ingredients or in multiple, separate capsules for each
therapeutic agent. Also, such administration includes use of each
type of therapeutic agent in a sequential manner. In either case,
the treatment using the combination therapy will provide beneficial
effects in treating the demyelination condition. A potential
advantage of the combination therapy disclosed herein may be a
reduction in the required amount of an individual therapeutic
compound or the overall total amount of therapeutic compounds that
are effective in treating the demyelination condition. By using a
combination of therapeutic agents, the side effects of the
individual compounds can be reduced as compared to a monotherapy,
which can improve patient compliance. Also, therapeutic agents can
be selected to provide a broader range of complimentary effects or
complimentary modes of action.
[0252] In another embodiment, the present invention provides a
therapeutic combination comprising (a) a first amount of at least
one sterol absorption inhibitor or a pharmaceutically acceptable
salt thereof or a solvate thereof; and (b) a second amount of at
least one antidemyelination agent or treatment, wherein the first
amount and the second amount together comprise a therapeutically
effective amount for the treatment or prevention of demyelination
or lessening or amelioration of one or more symptoms of a condition
associated with demyelination.
[0253] In another embodiment, the present invention provides a
pharmaceutical composition for the treatment or prevention of
diabetes and/or lowering a concentration of a sterol in plasma of a
subject, comprising a therapeutically effective amount of a
composition comprising (a) a first amount of at least one sterol
absorption inhibitor or a pharmaceutically acceptable salt thereof
or a solvate thereof; (b) a second amount of at least one
antidemyelination agent and (c) a pharmaceutically acceptable
carrier.
[0254] In another embodiment, the present invention provides a
method of treating or preventing demyelination in a subject,
comprising the step of administering to a subject in need of such
treatment an effective amount of a composition comprising (a) a
first amount of at least one sterol absorption inhibitor or a
pharmaceutically acceptable salt thereof or a solvate thereof; and
(b) a second amount of at least one antidemyelination agent to
prevent or treat demyelination or any of its symptoms in the
subject.
[0255] Useful antidemyelination agents include beta-interferon
(such as AVONEX.RTM. which is available from Biogen, Inc. and
BETASERON.RTM. which is available from Berlex Laboratories), which
can decrease the frequency and occurrence of flare-ups and slow the
progression to disability, glatiramer acetate (such as
COPAXONE.RTM. which is available from Teva Neuroscience, Inc.),
which can reduce the frequency of relapses, and/or administration
of corticosteroids, such as prednisone (available from Roxane), to
relieve acute symptoms. The amount of respective antidemyelination
agent to be administered to the subject readily can be determined
by one skilled in the art from the Physician's Desk Reference
(56.sup.th Ed. 2002) at pages 1013-1016, 988-995, 3306-3310 and
3064-3066, incorporated herein by reference.
[0256] Also useful with the present invention are compositions or
therapeutic combinations that can further comprise one or more
pharmacological or therapeutic agents or drugs such as cholesterol
biosynthesis inhibitors and/or lipid-lowering agents discussed
below.
[0257] Non-limiting examples of cholesterol biosynthesis inhibitors
for use in the compositions, therapeutic combinations and methods
of the present invention include competitive inhibitors of HMG CoA
reductase, the rate-limiting step in cholesterol biosynthesis,
squalene synthase inhibitors, squalene epoxidase inhibitors and
mixtures thereof. Non-limiting examples of suitable HMG CoA
reductase inhibitors include statins such as atorvastatin (for
example LIPITOR.RTM. which is available from Pfizer), lovastatin
(for example MEVACOR.RTM. which is available from Merck & Co.),
pravastatin (for example PRAVACHOL.RTM. which is available from
Bristol Meyers Squibb), fluvastatin, simvastatin (for example
ZOCOR.RTM. which is available from Merck & Co.), cerivastatin,
Cl-981, rivastatin (sodium
7-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethylpyridin-3-yl)-3,5-dihyd-
roxy-6-heptanoate) and pitavastatin (such as NK-104 of Negma Kowa
of Japan). Preferred HMG CoA reductase inhibitors include
atorvastatin and simvastatin. Generally, a total daily dosage of
cholesterol biosynthesis inhibitor(s) can range from about 0.1 to
about 160 mg per day, and preferably about 0.2 to about 80 mg/day
in single or 2-3 divided doses.
[0258] Also useful with the present invention are compositions or
therapeutic combinations that can further comprise at least one
(one or more) activators for peroxisome proliferator-activated
receptors (PPAR), such as peroxisome proliferator-activated
receptor alpha (PPAR.alpha.), peroxisome proliferator-activated
receptor gamma (PPAR.gamma.) and peroxisome proliferator-activated
receptor delta (PPAR.delta.). PPAR.alpha. activator compounds are
useful for, among other things, lowering triglycerides, moderately
lowering LDL levels and increasing HDL levels. Useful examples of
PPAR.alpha. activators include fibrates, such as clofibrate,
gemfibrozil and fenofibrate. The PPAR activator(s) are administered
in a therapeutically effective amount to treat the specified
condition, for example in a daily dose preferably ranging from
about 50 to about 3000 mg per day.
[0259] The compositions, therapeutic combinations or methods of the
present invention can further comprise one or more bile acid
sequestrants such as cholestyramine, colestipol and colesevelam
hydrochloride. Generally, a total daily dosage of bile acid
sequestrant(s) can range from about 1 to about 50 grams per day,
and preferably about 2 to about 16 grams per day in single or 2-4
divided doses.
[0260] The compositions or treatments of the present invention can
further comprise one or more ileal bile acid transport ("IBAT")
inhibitors (or apical sodium co-dependent bile acid transport
("ASBT") inhibitors) coadministered with or in combination with the
peroxisome proliferator-activated receptor activator(s) and sterol
absorption inhibitor(s) discussed above. The IBAT inhibitors can
inhibit bile acid transport to reduce LDL cholesterol levels.
Non-limiting examples of suitable IBAT inhibitors include
benzothiepines such as are disclosed in PCT Patent Application WO
00/38727 which is incorporated herein by reference. Generally, a
total daily dosage of IBAT inhibitor(s) can range from about 0.01
to about 1000 mg/day, and preferably about 0.1 to about 50 mg/day
in single or 2-4 divided doses.
[0261] The compositions or treatments of the present invention can
further comprise nicotinic acid (niacin) and/or derivatives
thereof, such as NIASPAN.RTM. (niacin extended-release tablets)
which are available from Kos. Generally, a total daily dosage of
nicotinic acid or a derivative thereof can range from about 500 to
about 10,000 mg/day, preferably about 1000 to about 8000 mg/day,
and more preferably about 3000 to about 6000 mg/day in single or
divided doses.
[0262] The compositions or treatments of the present invention can
further comprise one or more AcylCoA:Cholesterol 0-acyltransferase
("ACAT") Inhibitors, which can reduce LDL and VLDL levels.
Non-limiting examples of useful ACAT inhibitors include avasimibe.
Generally, a total daily dosage of ACAT inhibitor(s) can range from
about 0.1 to about 1000 mg/day in single or 2-4 divided doses.
[0263] The compositions or treatments of the present invention can
further comprise one or more Cholesteryl Ester Transfer Protein
("CETP") Inhibitors. CETP is responsible for the exchange or
transfer of cholesteryl ester carrying HDL and triglycerides in
VLDL. Non-limiting examples of suitable CETP inhibitors are
disclosed in PCT Patent Application No. WO 00/38721 and U.S. Pat.
No. 6,147,090, which are incorporated herein by reference.
Generally, a total daily dosage of CETP inhibitor(s) can range from
about 0.01 to about 1000 mg/day, and preferably about 0.5 to about
20 mg/kg body weight/day in single or divided doses.
[0264] The compositions or treatments of the present invention can
further comprise probucol or derivatives thereof, which can reduce
LDL levels. Generally, a total daily dosage of probucol or
derivatives thereof can range from about 10 to about 2000 mg/day,
and preferably about 500 to about 1500 mg/day in single or 2-4
divided doses.
[0265] The compositions or treatments of the present invention can
further comprise low-density lipoprotein (LDL) receptor activators
such as HOE-402, an imidazolidinyl-pyrimidine derivative that
directly stimulates LDL receptor activity. Generally, a total daily
dosage of LDL receptor activator(s) can range from about 1 to about
1000 mg/day in single or 2-4 divided doses.
[0266] The compositions or treatments of the present invention can
further comprise fish oil, which contains Omega 3 fatty acids
(3-PUFA), which can reduce VLDL and triglyceride levels. Generally,
a total daily dosage of fish oil or Omega 3 fatty acids can range
from about 1 to about 30 grams per day in single or 2-4 divided
doses.
[0267] The compositions or treatments of the present invention can
further comprise natural water soluble fibers, such as psyllium,
guar, oat and pectin, which can reduce cholesterol levels.
Generally, a total daily dosage of natural water soluble fibers can
range from about 0.1 to about 10 grams per day in single or 2-4
divided doses.
[0268] The compositions or treatments of the present invention can
further comprise plant sterols, plant stanols and/or fatty acid
esters of plant stanols, such as sitostanol ester used in
BENECOL.RTM. margarine, which can reduce cholesterol levels.
Generally, a total daily dosage of plant sterols, plant stanols
and/or fatty acid esters of plant stanols can range from about 0.5
to about 20 grams per day in single or 2-4 divided doses.
[0269] The compositions or treatments of the present invention can
further comprise antioxidants, such as probucol, tocopherol,
ascorbic acid, .beta.-carotene and selenium, or vitamins such as
vitamin B.sub.6 or vitamin B.sub.12. Generally, a total daily
dosage of antioxidants or vitamins can range from about 0.05 to
about 10 grams per day in single or 2-4 divided doses.
[0270] The compositions or treatments of the present invention can
further comprise monocyte and macrophage inhibitors such as
polyunsaturated fatty acids, gene therapy and use of recombinant
proteins such as recombinant apo E. Generally, a total daily dosage
of these agents can range from about 0.01 to about 1000 mg/day in
single or 2-4 divided doses.
[0271] The compositions, therapeutic combinations or methods of the
present invention can further comprise one or more cardiovascular
agents or blood modifiers.
[0272] Mixtures of any of the pharmacological or therapeutic agents
described above can be used in the compositions and therapeutic
combinations of these other embodiments of the present
invention.
[0273] The compositions and therapeutic combinations of the present
invention can be administered to a subject in need of such
treatment in a therapeutically effective amount to treat
demyelination and its associated conditions as discussed above. The
compositions and treatments can be administered by any suitable
means which produce contact of these compounds with the site of
action in the body, for example in the plasma, liver or small
intestine of a subject.
[0274] The daily dosage for the various compositions and
therapeutic combinations described above can be administered to a
subject in a single dose or in multiple subdoses, as desired.
Subdoses can be administered 2 to 6 times per day, for example.
Sustained release dosages can be used. Where the antidemyelination
agent and sterol absorption inhibitor(s) are administered in
separate dosages, the number of doses of each component given per
day may not necessarily be the same, e.g., one component may have a
greater duration of activity and will therefore need to be
administered less frequently.
[0275] The compositions, therapeutic combinations or medicaments of
the present invention can further comprise one or more
pharmaceutically acceptable carriers, one or more excipients and/or
one or more additives. The pharmaceutical compositions can comprise
about 1 to about 99 weight percent of active ingredient (such as
one or more compounds of Formula I-XII), and preferably about 5 to
about 95 percent active ingredient.
[0276] Useful pharmaceutically acceptable carriers can be either
solid, liquid or gas. Non-limiting examples of pharmaceutically
acceptable carriers include solids and/or liquids such as magnesium
carbonate, magnesium stearate, talc, sugar, lactose, ethanol,
glycerol, water and the like. The amount of carrier in the
treatment composition or therapeutic combination can range from
about 5 to about 99 weight percent of the total weight of the
treatment composition or therapeutic combination. Non-limiting
examples of suitable pharmaceutically acceptable excipients and
additives include non-toxic compatible fillers, binders such as
starch, polyvinyl pyrrolidone or cellulose ethers, disintegrants
such as sodium starch glycolate, crosslinked polyvinyl pyrrolidone
or croscarmellose sodium, buffers, preservatives, anti-oxidants,
lubricants, flavorings, thickeners, coloring agents, wetting agents
such as sodium lauryl sulfate, emulsifiers and the like. The amount
of excipient or additive can range from about 0.1 to about 95
weight percent of the total weight of the treatment composition or
therapeutic combination. One skilled in the art would understand
that the amount of carrier(s), excipients and additives (if
present) can vary. Further examples of pharmaceutically acceptable
carriers and methods of manufacture for various compositions can be
found in A. Gennaro (ed.), Remington: The Science and Practice of
Pharmacy, 20.sup.th Edition, (2000), Lippincott Williams &
Wilkins, Baltimore, Md.
[0277] Useful solid form preparations include powders, tablets,
dispersible granules, capsules, cachets and suppositories. An
example of a preparation of a preferred solid form dosage
formulation is provided below.
[0278] Useful liquid form preparations include solutions,
suspensions and emulsions. As an example may be mentioned water or
water-propylene glycol solutions for parenteral injection or
addition of sweeteners and opacifiers for oral solutions,
suspensions and emulsions. Liquid form preparations may also
include solutions for intranasal administration.
[0279] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[0280] Also useful are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0281] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0282] Preferably the compound is administered orally.
[0283] In another embodiment, the present invention provides the
use of at least one compound represented by Formulae (I-XII) for
manufacture of a medicament (such as one of the compositions
discussed above) for the treatment of demyelination and its
associated conditions.
[0284] The following formulation exemplifies one of the dosage
forms of this invention. In the formulation, the term "Active
Compound I" designates a sterol absorption inhibitor such as any of
the compounds of Formulas I-XII described herein above and the term
"Active Compound II" designates an antidemyelination agent
described herein above.
EXAMPLE
TABLE-US-00001 [0285] Tablets No. Ingredient mq/tablet 1 Active
Compound I 10 2 Lactose monohydrate NF 55 3 Microcrystalline
cellulose NF 20 4 Povidone USP (K29-32) 4 5 Croscarmellose sodium
NF 8 6 Sodium lauryl sulfate NF 2 7 Magnesium stearate NF 1 Total
100
[0286] In the present invention, the above-described tablet can be
coadministered with an injection, tablet, capsule, etc. comprising
a dosage of Active Compound II as described above.
Method of Manufacture
[0287] Mix Item No. 4 with purified water in suitable mixer to form
binder solution. Spray the binder solution and then water over
Items 1, 2 and 6 and a portion of item 5 in a fluidized bed
processor to granulate the ingredients. Continue fluidization to
dry the damp granules. Screen the dried granule and blend with Item
No. 3 and the remainder of Item No. 5. Add Item No. 7 and mix.
Compress the mixture to appropriate size and weight on a suitable
tablet machine.
[0288] For coadministration in separate tablets or capsules,
representative formulations comprising a sterol absorption
inhibitor such as are discussed above are well known in the art and
representative formulations comprising an antidemyelination agent
such as are discussed above are well known in the art. It is
contemplated that where the two active ingredients are administered
as a single composition, the dosage forms disclosed above for
sterol absorption inhibitors may readily be modified using the
knowledge of one skilled in the art.
[0289] Since the present invention relates to treating
demyelination by treatment with a combination of active ingredients
wherein the active ingredients may be administered separately, the
invention also relates to combining separate pharmaceutical
compositions in kit form. That is, a kit is contemplated wherein
two separate units are combined: a pharmaceutical composition
comprising at least one antidemyelination medication and a separate
pharmaceutical composition comprising at least one sterol
absorption inhibitor as described above. The kit will preferably
include directions for the administration of the separate
components. The kit form is particularly advantageous when the
separate components must be administered in different dosage forms
(e.g., oral and parenteral) or are administered at different dosage
intervals.
[0290] The treatment compositions and therapeutic combinations of
the present invention can inhibit the intestinal absorption of
sterols in subjects and can be useful in the treatment and/or
prevention of demyelination and associated conditions, such as
multiple sclerosis, in subjects, in particular in mammals.
[0291] The compositions and therapeutic combinations of the present
invention can reduce plasma concentration of at least one sterol
selected from the group consisting of cholesterol, phytosterols
(such as sitosterol, campesterol, stigmasterol and avenosterol),
and/or 5.alpha.-stanols (such as cholestanol, 5.alpha.-campestanol,
5.alpha.-sitostanol), and mixtures thereof. The plasma
concentration can be reduced by administering to a subject in need
of such treatment an effective amount of at least one treatment
composition comprising at least one sterol or 5.alpha.-stanol
absorption inhibitor described above. The reduction in plasma
concentration of sterols or 5.alpha.-stanols can range from about 1
to about 70 percent, and preferably about 10 to about 50 percent.
Methods of measuring serum total blood cholesterol and total LDL
cholesterol are well known to those skilled in the art and for
example include those disclosed in PCT WO 99/38498 at page 11,
incorporated by reference herein. Methods of determining levels of
other sterols in serum are disclosed in H. Gylling et al., "Serum
Sterols During Stanol Ester Feeding in a Mildly
Hypercholesterolemic Population", J. Lipid Res. 40: 593-600 (1999),
incorporated by reference herein.
[0292] These sterol absorption inhibitors can be useful in treating
or preventing vascular inflammation. Vascular stimuli to mammals,
such as cellular injury or inflammation, may lead to the production
of various proteins, commonly called acute response proteins, in
the body. One particular type of acute phase protein is C-reactive
protein (CRP). Manufactured in the liver and deposited in damaged
tissue, CRP is found in high levels in inflammatory fluids and in
both the intimal layer of the atherosclerotic artery and within the
lesions of atherosclerotic plaque. These sterol absorption
inhibitors can be useful for lowering or controlling c-reactive
protein blood levels in a subject to less than about 3.4 mg/dL.
Preferably, the C-reactive protein blood levels in a subject are
reduced or controlled to less than 1.0 mg/dL by the methods of the
present invention. More preferably, the C-reactive protein blood
levels in a subject are reduced or controlled to less than 0.4
mg/dL by the methods of the present invention. C-reactive protein
assays and methodologies for the same are available from Behring
Diagnostics Inc., of Somerville, N.J. Moreover, methods for
analyzing c-reactive proteins are described in U.S. Pat. Nos.
5,358,852; 6,040,147; and 6,277,584, whose contents are
incorporated herein by reference.
[0293] Illustrating the invention is the following example of
preparation of a compound of Formula II which, however, is not to
be considered as limiting the invention to their details. Unless
otherwise indicated, all parts and percentages in the following
examples, as well as throughout the specification, are by
weight.
Example
Preparation of Compound of Formula (II)
[0294] Step 1): To a solution of (S)-4-phenyl-2-oxazolidinone (41
g, 0.25 mol) in CH.sub.2Cl.sub.2 (200 ml), was added
4-dimethylaminopyridine (2.5 g, 0.02 mol) and triethylamine (84.7
ml, 0.61 mol) and the reaction mixture was cooled to 0.degree. C.
Methyl-4-(chloroformyl)butyrate (50 g, 0.3 mol) was added as a
solution in CH.sub.2Cl.sub.2 (375 ml) dropwise over 1 h, and the
reaction was allowed to warm to 22.degree. C. After 17 h, water and
H.sub.2SO.sub.4 (2N, 100 ml), was added the layers were separated,
and the organic layer was washed sequentially with NaOH (10%), NaCI
(sat'd) and water. The organic layer was dried over MgSO.sub.4 and
concentrated to obtain a semicrystalline product.
[0295] Step 2): To a solution of TiCl.sub.4 (18.2 ml, 0.165 mol) in
CH.sub.2Cl.sub.2 (600 ml) at 0.degree. C., was added titanium
isopropoxide (16.5 ml, 0.055 mol). After 15 min, the product of
Step 1 (49.0 g, 0.17 mol) was added as a solution in
CH.sub.2Cl.sub.2 (100 ml). After 5 min., diisopropylethylamine
(DIPEA) (65.2 ml, 0.37 mol) was added and the reaction mixture was
stirred at 0.degree. C. for 1 h, the reaction mixture was cooled to
-20.degree. C., and 4-benzyloxybenzylidine(4-fluoro)aniline (114.3
g, 0.37 mol) was added as a solid. The reaction mixture was stirred
vigorously for 4 h at -20.degree. C., then acetic acid was added as
a solution in CH.sub.2Cl.sub.2 dropwise over 15 min, the reaction
mixture was allowed to warm to 0.degree. C., and H.sub.2SO.sub.4
(2N) was added. The reaction mixture was stirred an additional 1 h,
the layers were separated, washed with water, separated and the
organic layer was dried. The crude product was crystallized from
ethanol/water to obtain the pure intermediate.
[0296] Step 3): To a solution of the product of Step 2 (8.9 g, 14.9
mmol) in toluene (100 ml) at 50.degree. C., was added
N,O-bis(trimethylsilyl)acetamide (BSA) (7.50 ml, 30.3 mmol). After
0.5 h, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction
mixture stirred at 50.degree. C. for an additional 3 h. The
reaction mixture was cooled to 22.degree. C., CH.sub.3OH (10 ml),
was added. The reaction mixture was washed with HCl (1N),
NaHCO.sub.3 (1N) and NaCl (sat'd.), and the organic layer was dried
over MgSO.sub.4.
[0297] Step 4): To a solution of the product of Step 3 (0.94 g, 2.2
mmol) in CH.sub.3OH (3 ml), was added water (1 ml) and
LiOH.H.sub.2O (102 mg, 2.4 mmole). The reaction mixture was stirred
at 22.degree. C. for 1 h and then additional LiOH.H.sub.2O (54 mg,
1.3 mmole) was added. After a total of 2 h, HCl (1N) and EtOAc was
added, the layers were separated, the organic layer was dried and
concentrated in vacuo. To a solution of the resultant product (0.91
g, 2.2 mmol) in CH.sub.2Cl.sub.2 at 22.degree. C., was added
ClCOCOCl (0.29 ml, 3.3 mmol) and the mixture stirred for 16 h. The
solvent was removed in vacuo.
[0298] Step 5): To an efficiently stirred suspension of
4-fluorophenylzinc chloride (4.4 mmol) prepared from
4-fluorophenylmagnesium bromide (1M in THF, 4.4 ml, 4.4 mmol) and
ZnCl.sub.2 (0.6 g, 4.4 mmol) at 4.degree. C., was added
tetrakis(triphenyl-phosphine)palladium (0.25 g, 0.21 mmol) followed
by the product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2
ml). The reaction was stirred for 1 h at 0.degree. C. and then for
0.5 h at 22.degree. C. HCl (1N, 5 ml) was added and the mixture was
extracted with EtOAc. The organic layer was concentrated to an oil
and purified by silica gel chromatography to obtain
1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3-phenylpropyl)-2-a-
zetidinone:
[0299] HRMS calc'd for C.sub.24H.sub.19F.sub.2NO.sub.3=408.1429,
found 408.1411.
[0300] Step 6): To the product of Step 5 (0.95 g, 1.91 mmol) in THF
(3 ml), was added
(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]
oxazaborole (120 mg, 0.43 mmol) and the mixture was cooled to
-20.degree. C. After 5 min, borohydride-dimethylsulfide complex (2M
in THF, 0.85 ml, 1.7 mmol) was added dropwise over 0.5 h. After a
total of 1.5 h , CH.sub.3OH was added followed by HCl (1 N) and the
reaction mixture was extracted with EtOAc to obtain
1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl
)-3-hydroxypropyl)]-4(S)-[4-(phenyl methoxy)phenyl]-2-azetidinone
(compound 6A-1) as an oil. .sup.1H in CDCl.sub.3 d H3=4.68. J=2.3
Hz. Cl (M.sup.+H) 500.
[0301] Use of (S)-tetra-hydro-1-methyl-3,3-diphenyl-1H
,3H-pyrrolo-[1,2-c][1,3,2] oxazaborole gives the corresponding
3(R)-hydroxypropyl azetidinone (compound 6B-1). .sup.1H in
CDCl.sub.3 d H3=4.69. J=2.3 Hz. Cl (M.sup.+H) 500.
[0302] To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol
(2 ml), was added 10% Pd/C (0.03 g) and the reaction mixture was
stirred under a pressure (60 psi) of H.sub.2 gas for 16 h. The
reaction mixture was filtered and the solvent was concentrated to
obtain compound 6A. Mp 164-166.degree. C.; Cl (M.sup.+H) 410.
[.alpha.].sub.D.sup.25=-28.1.degree. (c 3, CH.sub.3OH). Elemental
analysis calc'd for C.sub.24H.sub.21F.sub.2NO.sub.3: C 70.41; H
5.17; N 3.42; found C 70.25; H 5.19; N 3.54.
[0303] Similarly treat compound 6B-1 to obtain compound 6B. Mp
129.5-132.5.degree. C.; Cl (M.sup.+H) 410. Elemental analysis
calc'd for C.sub.24H.sub.21F.sub.2NO.sub.3: C 70.41; H 5.17; N
3.42; found C 70.30; H 5.14; N 3.52.
[0304] Step 6' (Alternative): To a solution of the product of Step
5 (0.14 g, 0.3 mmol) in ethanol (2 ml), was added 10% Pd/C (0.03 g)
and the reaction was stirred under a pressure (60 psi) of H.sub.2
gas for 16 h. The reaction mixture was filtered and the solvent was
concentrated to afford a 1:1 mixture of compounds 6A and 6B.
Hypothetical In Vivo Evaluation
[0305] The compound of Formula II (or any cholesterol absorption
inhibitor discussed above) is administered to rodents which have
been induced to develop experimental autoimmune encephalomyelitis
("EAE"), a model of human multiple sclerosis and demyelinating
disease. Useful rodents can include C57BL/6 mice (obtained from the
Jackson Laboratory or Charles River Laboratories) immunized with
myelin oligodendrocyte protein (MOG) 35-55 peptide, SJL/J (also
available from Jackson Laboratory or Charles River Laboratories)
mice immunized with proteolipid protein (PLP) peptides, or Lewis,
BN or DA rats (obtained from Charles River Laboratories or Harlan
Laboratories) immunized with guinea pig spinal cord homogenate or
myelin basic protein (MBP). All immunizations are performed by
emulsifying the inducing peptide in either incomplete Freund's
adjuvant or complete Freund's adjuvant, with or without pertussis
toxin administration (as described in Current Protocols in
Immunology, Unit 15, John Wiley & Sons, Inc. NY, or Tran et al,
Eur. J. Immunol. 30:1410, 2002 or H. Butzkeuven et al, Nat. Med.
8:613, 2002).
[0306] Alternatively, the compound of Formula II (or any
cholesterol absorption inhibitor discussed above) is administered
to anti-MBP T cell receptor transgenic mice (as in Grewal et al
Immunity 14:291, 2001), which naturally develop EAE disease.
[0307] Alternatively the compound of Formula II (or any cholesterol
absorption inhibitor discussed above) is administered to rodents
adoptively transferred with MBP-specific, PLP-specific or
MOG-specific T cell lines (as described in Current Protocols in
Immunology, Unit 15, John Wiley & Sons, Inc. NY).
[0308] Alternatively, the compound of Formula II (or any
cholesterol absorption inhibitor discussed above) is administered
to SJL/J or C57BL/6 mice which can be induced to develop a profound
demyelinating disease by intracerebral inoculation with Theiler's
murine encephalomyelitis virus (as described in Pope et al, J.
Immunol. 156:4050, 1994) or by intraperitoneal injection of Simliki
Forest virus (as described in Soilu-Hanninen et al, J. Virol.
68:6291,1994).
[0309] The compound is administered at a dosage of 0.1-50 mg/kg/day
either in the diet or by systemic oral, subcutaneous or
intraperitoneal administration over a period of 4-10 weeks. Animals
are scored daily for clinical disease score as described in Current
Protocols in Immunology, Unit 15, John Wiley & Sons, Inc. NY,
or Tran et al, Eur. J. Immunol. 30:1410, 2002 or H. Butzkeuven et
al, Nat. Med. 8:613, 2002). At a specified period of compound
administration, animals are euthanized by CO.sub.2 asphyxiation and
histological, immunohistochemical and immunological parameters
measured as in Tran et al, Eur. J. Immunol. 30:1410, 2002 or H.
Butzkeuven et al, Nat. Med. 8:613, 2002. Serum lipoprotein and
cholesterol measurements will be made by standard techniques well
known to those skilled in the art.
[0310] It will be appreciated by those skilled in the art that
changes could be made to the embodiments described above without
departing from the broad inventive concept thereof. It is
understood, therefore, that this invention is not limited to the
particular embodiments disclosed, but it is intended to cover
modifications that are within the spirit and scope of the
invention, as defined by the appended claims.
* * * * *