U.S. patent application number 10/700909 was filed with the patent office on 2004-05-13 for methods and therapeutic combinations for the treatment of autoimmune disorders.
This patent application is currently assigned to Schering Corporation. Invention is credited to Erbey, John R. II, Fine, Jay S., Veltri, Enrico P..
Application Number | 20040092499 10/700909 |
Document ID | / |
Family ID | 32314527 |
Filed Date | 2004-05-13 |
United States Patent
Application |
20040092499 |
Kind Code |
A1 |
Erbey, John R. II ; et
al. |
May 13, 2004 |
Methods and therapeutic combinations for the treatment of
autoimmune disorders
Abstract
The present invention provides methods for treating or
preventing an autoimmune disorder 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
autoimmune disorder treatment which can be useful for preventing or
treating an autoimmune disorder and associated conditions.
Inventors: |
Erbey, John R. II;
(Flemington, NJ) ; Fine, Jay S.; (Bloomfield,
NJ) ; Veltri, Enrico P.; (Princeton, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation
|
Family ID: |
32314527 |
Appl. No.: |
10/700909 |
Filed: |
November 4, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60493318 |
Aug 7, 2003 |
|
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60424165 |
Nov 6, 2002 |
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Current U.S.
Class: |
514/210.02 |
Current CPC
Class: |
A61P 9/04 20180101; A61P
19/08 20180101; A61P 9/08 20180101; A61K 45/06 20130101; A61P 21/04
20180101; A61P 37/00 20180101; A61P 1/04 20180101; A61K 31/397
20130101; A61P 11/00 20180101; A61K 31/40 20130101; A61P 19/02
20180101; A61P 3/10 20180101; A61K 31/397 20130101; A61P 17/06
20180101; A61P 25/00 20180101; A61P 29/00 20180101; A61P 7/06
20180101; A61P 17/14 20180101; A61P 1/16 20180101; A61K 31/40
20130101; A61K 31/366 20130101; A61K 31/366 20130101; A61P 17/00
20180101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/210.02 |
International
Class: |
A61K 031/397 |
Claims
Therefore, we claim:
1. A method of treating or preventing an autoimmune disorder 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.
2. The method according to claim 1, wherein the at least one sterol
absorption inhibitor is represented by Formula (I): 40or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein: Ar.sup.1 and Ar.sup.2 are independently selected from the
group consisting of aryl and R.sup.4-substituted aryl; Ar.sup.3 is
aryl or R.sup.5-substituted aryl; X, Y and Z are independently
selected from the group consisting of --CH.sub.2--, --CH(lower
alkyl)- and --C(dilower alkyl)-; R and R.sup.2 are independently
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.1 and R.sup.3 are
independently selected from the group consisting of hydrogen, lower
alkyl and aryl; 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; 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, --CH.dbd.CH--COOR.sup.6, --CF.sub.3, --CN,
--NO.sub.2 and halogen; 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.6, R.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.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.
3. The method according to claim 1, wherein the at least one sterol
absorption inhibitor is represented by Formula (II): 41or a
pharmaceutically acceptable salt or solvate thereof.
4. The method according to claim 1, wherein the at least one sterol
absorption inhibitor is represented by Formula (III): 42or 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 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.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.
5. The method according to claim 1, wherein the at least one sterol
absorption inhibitor is represented by Formula (IV): 43or 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 44and R.sup.1 is
selected from the group consisting of: 13 (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: 45R.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;
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)=CH--, a is 1; provided that when R.sup.7 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.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: 46where 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)al- kyl);
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, 3or 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)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 47and, 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, 48wherein 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.s- up.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.s- up.15, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.14, --CH.dbd.CH--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.
6. The method according to claim 1, wherein the at least one sterol
absorption inhibitor is represented by Formula (V): 49or 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)OR.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.su- p.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.
7. The method according to claim 1, where the at least one sterol
absorption inhibitor is represented by Formula (VI): 50or a
pharmaceutically acceptable salt thereof or a solvate thereof,
wherein: R.sub.1 is 51R.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)=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).s- ub.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 52B 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 53W 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.0-2NH.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 54for 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,
55--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.
8. The method according to claim 1, wherein the at least one sterol
absorption inhibitor is represented by Formula (VIIA) or (VIIB):
56or 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 57B' is 58D 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 59wherein 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.
9. The method according to claim 1, wherein the at least one sterol
absorption inhibitor is represented by Formula (VIII): 60or 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
61provided 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-C7)cycloalkyl and
R.sup.32-substituted-(C.sub.3-C7)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)alkylsulfa- nyl, (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-subs-
tituted 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 62and 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)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 63R.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)=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, R.sup.1 also can be: 64M 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.s-
up.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.s- up.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,
2or 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 65Ar.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.
10. The method according to claim 1, wherein the at least one
sterol absorption inhibitor is represented by Formula (IX): 66or 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, 67wherein 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.su- b.2-C.sub.4)alkenyl,
R.sup.32-substituted-(C.sub.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.3-C7)cycloalkyl and
R.sup.32-substituted-(C.s-
ub.3-C7)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)alkylsulfa- nyl,
(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)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: 68wherein 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-,
69R.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.2.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: 70wherein 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)
71wherein 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.2- 0, --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.s- up.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 0 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 72wherein R.sup.12 is 73R.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)=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 74then
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. 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.
12. The method according to claim 1, further comprising the step of
administering at least one other agent useful for the treatment of
an autoimmune disorder to the subject.
13. The method according to claim 12, wherein the other agent
useful for the treatment of an autoimmune disorder is selected from
the group consisting of: a) disease modifying antirheumatic drugs;
b) nonsteroidal anitinflammatory drugs; c) COX-2 selective
inhibitors; d) COX-1 inhibitors; e) immunosuppressives; p70.sup.S6
kinase inhibitors; and inosine monophosphate dehydrogenase
inhibitors; f) steroids; g) biological response modifiers; and h)
other agents useful for the treatment of autoimmune disorders.
14. The method according to claim 1, further comprising the step of
administering at least one HMG CoA reductase inhibitor to the
subject.
15. The method according to claim 14, wherein the at least one HMG
CoA reductase inhibitor is atorvastatin.
16. The method according to claim 14, wherein the at least one HMG
CoA reductase inhibitor is simvastatin.
17. The method according to claim 1, wherein the subject has an
autoimmune disorder selected from the group consisting of: Alopecia
Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome,
Autoimmune Addison's Disease, Autoimmune Diabetes, Autoimmune
Hemolytic Anemia, Autoimmune Hepatitis, Behcet's Disease, Bullous
Pemphigoid, Cardiomyopathy, Celiac Sprue-Dermatitis, Chronic
Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic Inflammatory
Demyelinating Polyneuropathy, Churg-Strauss Syndrome, Cicatricial
Pemphigoid, CREST Syndrome, Cold Agglutinin Disease, Crohn's
Disease, Discoid Lupus, Essential Mixed Cryoglobulinemia,
Fibromyalgia-Fibromyositis, Good Pasture Syndrome, Graft Versus
Host Disease, Graves' Disease, Guillain-Barr, Hashimoto's
Thyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic
Thrombocytopenia Purpura (ITP), IgA Nephropathy, Insulin Dependent
Diabetes, Juvenile Arthritis, Lichen Planus, Lupus, Mnire's
Disease, Mixed Connective Tissue Disease, Multiple Sclerosis,
Myasthenia Gravis, Myositis, Pemphigus Vulgaris, Pernicious Anemia,
Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes,
Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary
Agammaglobulinemia, Primary Biliary Cirrhosis, Psoriasis, Raynaud's
Phenomenon, Reiter's Syndrome, Rheumatic Fever, Rheumatoid
Arthritis, Sarcoidosis, Scleroderma, Sjogren's Syndrome, Stiff-Man
Syndrome, Takayasu Arteritis, Temporal Arteritis/GianT-cell
Arteritis, Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo, and
Wegener's Granulomatosis.
18. The method according to claim 1, wherein said sterol absorption
inhibitor disrupts lipid raft formation and/or organization within
the cell membranes of leukocytes.
19. The method according to claim 18, wherein said lipid raft
disruption affects the pathogenesis of said autoimmune disorder by
affecting at least one immune response selected from the group
consisting of antigen presentation, T-cell activation, T-cell
receptor signaling, adhesion molecule function, chemokine receptor
signaling, and combinations thereof.
20. A method of treating or preventing an autoimmune disorder 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:
75or a pharmaceutically acceptable salt or solvate thereof.
21. The method according to claim 20, wherein the subject has an
autoimmune disorder selected from the group consisting of: Alopecia
Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome, aplastic
anemia, myelodysplastic syndromes, paroxysmal nocturnal
hemoglobulinemia, pure red cell aplasia, chronic neutropenias,
amegakaryocytic thrombocytopenia, antiphospholipid syndromes,
autoimmune thrombocytopenia, autoimmune hemolytic syndromes,
antiphospholipid syndromes, autoimmune gastritis, achlorhydria,
Autoimmune Addison's Disease, Autoimmune Diabetes, Autoimmune
Hemolytic Anemia, Autoimmune Hepatitis, Autoimmune hypophysitis,
Autoimmune orchiditis, autoimmune ovarian failure, Behcet's
Disease, Bullous Pemphigoid, Cardiomyopathy, Celiac
Sprue-Dermatitis, Cicatrical pemphigoid, Chronic Fatigue Immune
Dysfunction Syndrome (CFIDS), Chronic Inflammatory Demyelinating
Polyneuropathy, Interstitial cystitis, Churg-Strauss Syndrome,
Cicatricial Pemphigoid, CREST Syndrome, Cold Agglutinin Disease,
Crohn's Disease, Dermatitis herpetiformis, Discoid Lupus,
Drug-induced autoimmune disorders, Endometriosis, Epidermolysis
bullosa acquisita, Essential Mixed Cryoglobulinemia,
Fibromyalgia-Fibromyositis, Glomerulonephritis, Good Pasture
Syndrome, Graft Versus Host Disease, Graves' Disease,
Guillain-Barr, Hashimoto's Thyroiditis, Idiopathic Inflammatory
Myopathies, Idiopathic Pulmonary Fibrosis, Idiopathic
Thrombocytopenia Purpura (ITP), IgA Nephropathy, Insulin Dependent
Diabetes, Juvenile Arthritis, Lichen Planus, Systemic Lupus
Erythmatosus, Mnire's Disease, Metal-induced autoimmunity
disorders, Mixed Connective Tissue Disease, Multiple Sclerosis,
Myasthenia Gravis, Myocarditis, Myositis, Optic neuritis,
Painless/postpartum thyroiditis, Peripheral nerve vasculitis,
Pemphigus Foliaceus, Pemphigus Vulgaris, Pernicious Anemia,
Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes,
Polymyalgia Rheumatica, Polymyositis and Dermatomyositis,
Postinfectious autoimmune disorders, Primary Agammaglobulinemia,
Primary Biliary Cirrhosis, Psoriasis, Psoriatic Arthritis, Reactive
Arthritis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic
Fever, Rheumatoid Arthritis, Sarcoidosis, Scleritis, Scleroderma,
Sjogren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis,
Temporal Arteritis/Giant-cell Arteritis, Ulcerative Colitis,
Uveitis, Vasculitis, Vitiligo, and Wegener's Granulomatosis.
22. The method according to claim 20, further comprising the step
of administering to said subject at least one other agent useful
for the treatment of an autoimmune disorder.
23. The method according to claim 22, wherein the subject has
rheumatoid arthritis and wherein said other agent is selected from
the group consisting of COX-2 inhibitors, COX inhibitors,
immunosuppressives, steroids, PDE IV inhibitors, anti-TNF-.alpha.
compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors,
CB2-selective inhibitors and combinations thereof.
24. A method of treating or preventing rheumatoid arthritis 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.
25. A composition comprising: (a) at least one sterol absorption
inhibitor or a pharmaceutically acceptable salt or solvate thereof
and (b) at least one other agent useful for the treatment of an
autoimmune disorder.
26. 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 other agent useful for the treatment of an autoimmune
disorder, wherein the first amount and the second amount together
comprise a therapeutically effective amount for the treatment or
prevention of an autoimmune disorder in a subject.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority from U.S.
Provisional Patent Application Serial No. 60/493,318, filed Aug. 7,
2003 and U.S. Provisional Patent Application Serial No. 60/424,165,
filed Nov. 6, 2002.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to methods and therapeutic
combinations for treating and preventing an autoimmune disorder in
a subject comprising the administration of sterol absorption
inhibitor(s).
[0004] 2. Description
[0005] The pathogenesis of autoimmune diseases such as rheumatoid
arthritis, Crohn's disease, ulcerative colitis, psoriasis and
systemic lupus erythmatosus is mediated by the aberrant activation,
differentiation and trafficking of leukocytes in response to tissue
self-antigens. There are two main types of leukocytes: phagocytes
and lymphocytes. Lymphocytes, which include T-cells, B-cells and
natural killer (NK) cells, play a large role in autoimmune
reactions.
[0006] Plasma membranes of many cell types, including leukocytes
contain domains enriched in cholesterol, plant sterols and
sphingolipids called lipid rafts. The formation and organization of
lipid rafts within cell membranes of leukocytes has been
demonstrated to play a critical role in immune responses as diverse
as T-cell activation, antigen presentation, adhesion molecule
function and chemokine receptor signaling, as will now be discussed
in further detail below.
[0007] Both cholesterol and sterols derived from plants have been
shown to be essential to the structure and organization of lipid
rafts, and to the subsequent downstream signaling events mediated
by these rafts (see, Kabouridis, et al. (2002) Eur. J. Immunol. 30:
954-963; Bowen and London (2000) J. Biol. Chem. 275: 17221-17224;
Burack, et al. (2002) J. Immunol. 169: 2837-2841; and Vu, et al.
(2001) J. Biol. Chem. 276: 33540-33546).
[0008] It is known that lipid raft microdomains are important for
T-cell receptor (TCR)-mediated activation of T-cells. Signaling
proteins are associated with lipid rafts in T-cells and the TCR
itself associates with lipid rafts (see Hreisi V. (2003) Immunol.
Rev. 191: 1438-1464 and Janes et al. (2000) Immunology 12: 23-34).
Furthermore, it has been shown that the integrity of lipid rafts
containing the kinase Lck (a key signaling protein) is essential
for the initiation of peripheral blood T-cell lymphoblasts (PBT)
signal transduction through the TCR. It is also known that key
signaling proteins such as LcK and LAT are physically sequestered
into distinct lipid rafts in a resting T-cell. After activation,
these signaling molecules coinhabit the same region within the
plasma membrane, indicating that the sequestration of these
proteins may function to regulate the initiation of T-cell signal
transduction (Schade and Levine (2002) The Journal of Immunology
168: 2233-2239). Similarly, lipid rafts have been demonstrated to
be essential for B lymphocyte activation (Cheng et al (2001) Semin
Immunol 13:107-114), particularly in the context of Syk and CD45
tyrosine phosphatase colocalization (Gupta and De-Franco (2003) Mol
Biol Cell 14:432-444). Given the role of lipid rafts in both T-cell
and B-cell antigen receptor signaling, disrupting the formation
and/or organization of these rafts will likely inhibit the aberrant
activation of leukocytes in response to tissue self antigens that
occurs in autoimmune disorders.
[0009] The importance of lipid rafts on antigen presenting cells
(APCs) and their role in major histocompatability (MHC) Class
II--restricted antigen presentation is also known. T-cells use
their antigen-specific receptors (TCRs) to recognize antigens
(including self-antigens) bound to MHC molecules. MHC Class II
molecules are known to be present in raft-like microdomains on APCs
and perturbing APC raft integrity profoundly inhibits the ability
of APCs to stimulate antigen-specific T-cells. Moreover, the
localization of MHC Class II molecules into rafts on APCs allows
APCs to efficiently present antigens (including self-antigens) to
the TCR of antigen-specific T-cells, even at low concentrations of
the antigen (Anderson, et al. (2000) Nature Immunology 1: 156:162).
Furthermore, modification of a membrane cholesterol level has been
previously shown to affect expression and clustering of Class I HLA
molecules on the surface of JY human lymphoblasts (Bodnar, et al.
(1996) Immunol. Lett. 54: 221-226). In view of these studies, it is
likely that disrupting lipid rafts can inhibit the ability of APCs
to stimulate autoreactive T-cells with autoantigens, and would be
of benefit in treating/preventing autoimmune disorders.
[0010] Adhesion molecules, such as integrins, are molecules on the
surface of cells that assist leukocytes in interacting with their
environments through adherence. In particular, integrins are a
group of glycoproteins expressed on both leukocytes and endothelial
cells that are predominately involved in the aberrant leukocyte
trafficking and extravasation associated with autoimmune diseases.
Integrins promote adherence of leukocytes to the surface of
endothelial cells on the surface of blood vessels through which
leukocytes circulate. Studies have shown that lipid rafts play a
role in the regulation of integrin function (Leitinger and Hogg
(2002) J. Cell Sci. 115: 963-972). Moreover, it is known that
.alpha.5.beta.1 integrin functions can be modulated by the
phospholipid and cholesterol contents of cell membranes
(Gopalakrishna, et al. (2000) J. Cell. Biochem. 77: 517-528).
Therefore, it is likely that the aberrant leukocyte trafficking and
extravasation which occurs in autoimmune disorders can be inhibited
by disrupting lipid raft formation and/or organization in the
plasma membrane of leukocytes.
[0011] Chemokines are chemoattractant cytokines that mediate
chemotaxis of leukocytes involved in autoimmune diseases. Excess
levels of these cytokines are linked to autoimmune disorders. The
receptors for chemokines are mainly expressed on immune and
inflammatory cells, such as T and B lymphocytes, dendritic cells,
monocytes/macrophages and granulocytes, in which ligand-receptor
interactions lead to cell migration. Chemokine expression is either
induced at autoimmune disease sites to recruit T-cells that mediate
tissue destruction, or is constitutive in lymphoid organs (i.e.,
lymph nodes and spleen) to orchestrate the response to antigens,
including autoantigens, that drive autoimmune diseases. Studies
have indicated that cholesterol (a major component of lipid rafts)
is essential for macrophage inflammatory protein 1.beta. binding
and conformational integrity of CC chemokine receptor 5 (Nguyen and
Taub (2002) Blood 99: 4298-4306). This suggests that disrupting
lipid rafts in the plasma membranes of immune cells will likely
have an effect on ligand-chemokine receptor interactions that lead
to the chemotaxis of leukocytes associated with autoimmune
diseases.
[0012] Furthermore, reports have drawn a correlation between
cholesterol and the development of rheumatoid arthritis in human
populations (Heliovaara, et al. (1996) Br. J. Rheumatology 35:
255-257; Winyard, et al. (1993) Ann. Rheumatic Dis. 52: 677-680). A
correlation between cholesterol and rheumatoid arthritis has also
been shown in studies with pre-clinical rodent models (Hamer, et
al. (2002) J. Cell. Mol. Med. 6: 407-414; Nair, et al. (1998) Eur.
J. Oral. Sci. 106: 644-650). Studies have also established an
association between plant sterols and arthritis (Bhattacharyya
(1984) 136: 32-34; and Bjorkhem and Skrede In The Metabolic Basis
of Inherited Disease, 6.sup.th ed. Scriver, et al., eds.
McGraw-Hill, New York (1989), pp. 1283-1302). Moreover, a
relationship between plant sterols and lymphocyte activation has
also been observed (Bouic, et al. (1996) Int. J. Immunopharmacol.
18: 693-700).
[0013] There is a need in the art for compositions and treatments
which modulate cholesterol and plant sterol levels for the
treatment of autoimmune disorders by disrupting lipid raft
formation and organization within the plasma membranes of
leukocytes.
SUMMARY OF THE INVENTION
[0014] In one embodiment, there is provided a method of treating or
preventing autoimmune disorder 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.
[0015] A method of treating or preventing an autoimmune disorder in
a subject is further 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: 1
[0016] or a pharmaceutically acceptable salt or solvate
thereof.
[0017] 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 other agent useful for the treatment of an
autoimmune disorder.
[0018] 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 other agent useful for the treatment
of an autoimmune disorder, wherein the first amount and the second
amount together comprise a therapeutically effective amount for the
treatment or prevention of an autoimmune disorder in a subject.
[0019] Pharmaceutical compositions for the treatment or prevention
of an autoimmune disorder in a subject, comprising a
therapeutically effective amount of the above compounds,
compositions or therapeutic combinations and a pharmaceutically
acceptable carrier also are provided.
[0020] 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
[0021] As discussed above, the pathogenesis of autoimmune disorders
is mediated by the aberrant activation, differentiation and
trafficking of leukocytes in response to tissue self-antigens.
Autoimmune reactions can often have fatal consequences. They can
cause the destruction of vital tissue which manifests in the
development of chronic autoimmune diseases. The driving forces in
the progression of these diseases are autoreactive immune cells. In
most cases, these autoreactive cells are CD4.sup.+ T-cells which
somehow escaped the self-tolerance control mechanisms of the immune
system. In non-pathogenic situations, CD4.sup.+ T-cells act as T
helper cells, which control or mediate the activation and
differentiation of other immune cells such as cytotoxic CD8.sup.+
T-cells, NK cells, granulocytes, macrophages and B-cells. However,
in the situation of chronic autoimmune diseases, CD4.sup.+ T-cells
are no longer just mediators, but are rather key players of the
autoimmune response. In particular, they are either directly or
indirectly responsible for the characteristic tissue destruction
that occurs in autoimmune diseases, which is triggered by the
recognition of autoantigens. These autoantigens are derived from
self-proteins of the attacked tissue and are presented to the
autoreactive CD4.sup.+ T-cells by antigen-presenting cells (APCs),
such as macrophages, dendritic cells or B-cells. In addition,
aberrant T cell-dependent or T cell-independent antibody production
by activated B cells plays a critical role in initiating and
amplifying tissue damage in autoimmune disorders.
[0022] As described above, the formulation and organization of
lipid rafts within the cell membranes of leukocytes has been
demonstrated to play a critical role in T-cell and B-cell
activation, antigen presentation, adhesion molecule function and
chemokine receptor signaling, each of which is associated with the
pathogenesis of autoimmune disorders. Both cholesterol and plant
sterols have been shown to be essential to the structure and
organization of lipid rafts, and to the subsequent downstream
signaling events mediated by these rafts. Therefore, depleting the
amount of cholesterol trafficked to cells will likely disrupt the
formation and organization of lipid rafts in the cell membranes of
autoreactive T-cells and other leukocytes involved in autoimmune
reactions. When cholesterol absorption in the intestines is reduced
by whatever means, less cholesterol is delivered to the liver. The
consequence of this action is a decreased hepatic lipoprotein
(VLDL) production and an increase in the hepatic clearance of
plasma cholesterol, mostly as LDL. Mammalian cells acquire a large
fraction of their cholesterol by receptor-mediated endocytosis of
serum lipoproteins, such as LDL. LDL particles carry cholesterol
predominantly as cholesteryl esters. Following endocytosis,
cholesteryl esters are transported to late endosomes and lysosomes
where they are hydrolyzed to release cholesterol for use by the
cell as an essential component of the lipid rafts of cell
membranes, for example. Thus, any means of reducing the intestinal
absorption of cholesterol (and/or plant sterols) will likely
disrupt the formation and organization of lipid rafts in the cell
membranes of leukocytes involved in autoimmune reactions.
Therefore, sterol absorption inhibitors can provide a
therapeutically effective method of treating and/or preventing
autoimmune disorders.
[0023] As used herein, the term "autoimmune disorders" is intended
to include any abnormal physical or mental condition, including
diseases, which are of an autoimmune etiology, as well as any
symptoms which are subject evidence of a disease or disorder.
[0024] "Lipid rafts," "raft-like microdomains," and the like as
defined herein refer to subdomains within the plasma membrane of
many cell types, including leukocytes, which are enriched in
cholesterol, sterols derived from plants and sphingolipids. They
exist as distinct, liquid-ordered regions of the membrane that are
resistant to extraction with non-ionic detergents and exhibit less
fluidity than the surrounding plasma membrane due to the presence
of cholesterol.
[0025] "Leukocytes" as defined herein are white blood cells
produced by the immune system to help defend the body against
infection. The different types of leukocytes include neutrophils,
lymphocytes (e.g. T-cells, B-cells and natural killer (NK cells),
monocytes, macrophages, eosinophils, and basophils.
[0026] U.S. Pat. Nos. 5,767,115, 5,624,920, 5,656,624 and 5,688,787
(each of which is incorporated by reference herein), 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 (both
incorporated by reference herein), 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.
[0027] According to the present invention, these and other sterol
absorption inhibitors discussed in detail below can be useful in
preventing or treating an autoimmune disorder and its associated
conditions. Such autoimmune disorders include, but are not limited
to, the following: Alopecia Areata, Ankylosing Spondylitis,
Antiphospholipid Syndrome, aplastic anemia, myelodysplastic
syndromes, paroxysmal nocturnal hemoglobulinemia, pure red cell
aplasia, chronic neutropenias, amegakaryocytic thrombocytopenia,
antiphospholipid syndromes, autoimmune thrombocytopenia, autoimmune
hemolytic syndromes, antiphospholipid syndromes, autoimmune
gastritis, achlorhydria, Autoimmune Addison's Disease, Autoimmune
Diabetes, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis,
Autoimmune hypophysitis, Autoimmune orchiditis, autoimmune ovarian
failure, Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy,
Celiac Sprue-Dermatitis, Cicatrical pemphigoid, Chronic Fatigue
Immune Dysfunction Syndrome (CFIDS), Chronic Inflammatory
Demyelinating Polyneuropathy, Interstitial cystitis, Churg-Strauss
Syndrome, Cicatricial Pemphigoid, CREST Syndrome, Cold Agglutinin
Disease, Crohn's Disease, Dermatitis herpetiformis, Discoid Lupus,
Drug-induced autoimmune disorders, Endometriosis, Epidermolysis
bullosa acquisita, Essential Mixed Cryoglobulinemia,
Fibromyalgia-Fibromyositis, Glomerulonephritis, Good Pasture
Syndrome, Graft Versus Host Disease, Graves' Disease,
Guillain-Barr, Hashimoto's Thyroiditis, Idiopathic Inflammatory
Myopathies, Idiopathic Pulmonary Fibrosis, Idiopathic
Thrombocytopenia Purpura (ITP), IgA Nephropathy, Insulin Dependent
Diabetes, Juvenile Arthritis, Lichen Planus, Systemic Lupus
Erythmatosus, Mnire's Disease, Metal-induced autoimmunity
disorders, Mixed Connective Tissue Disease, Multiple Sclerosis,
Myasthenia Gravis, Myocarditis, Myositis, Optic neuritis,
Painless/postpartum thyroiditis, Peripheral nerve vasculitis,
Pemphigus Foliaceus, Pemphigus Vulgaris, Pernicious Anemia,
Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes,
Polymyalgia Rheumatica, Polymyositis and Dermatomyositis,
Postinfectious autoimmune disorders, Primary Agammaglobulinemia,
Primary Biliary Cirrhosis, Psoriasis, Psoriatic Arthritis, Reactive
Arthritis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic
Fever, Rheumatoid Arthritis, Sarcoidosis, Scleritis, Scleroderma,
Sjogren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis,
Temporal Arteritis/Giant-cell Arteritis, Ulcerative Colitis,
Uveitis, Vasculitis, Vitiligo, and Wegener's Granulomatosis.
[0028] 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 and
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.
[0029] In a preferred embodiment, sterol absorption inhibitors
useful in the compositions, therapeutic combinations and methods of
the present invention are represented by Formula (I) below: 2
[0030] or a pharmaceutically acceptable salt thereof or a solvate
thereof, wherein, in Formula (I) above:
[0031] Ar.sup.1 and Ar.sup.2 are independently selected from the
group consisting of aryl and R.sup.4-substituted aryl;
[0032] Ar.sup.3 is aryl or R.sup.5-substituted aryl;
[0033] X, Y and Z are independently selected from the group
consisting of --CH.sub.2--, --CH(lower alkyl)- and --C(dilower
alkyl)-;
[0034] R and R.sup.2 are independently 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;
[0035] R.sup.1 and R.sup.3 are independently selected from the
group consisting of hydrogen, lower alkyl and aryl;
[0036] 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;
[0037] 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.su- p.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;
[0038] R.sup.1 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.su- p.8, --NR.sup.6SO.sub.2R.sup.9,
--COOR.sup.6, --CONR.sup.6R.sup.7, --COR.sup.6,
--SO.sub.2NR.sub.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;
[0039] 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
[0040] R.sup.9 is lower alkyl, aryl or aryl-substituted lower
alkyl.
[0041] Preferably, R.sup.4 is 1-3 independently selected
substituents, and R.sup.5 is preferably 1-3 independently selected
substituents.
[0042] In a preferred embodiment, a sterol absorption inhibitor of
Formula (I) useful in the compositions, therapeutic combinations
and methods of the present invention is represented by Formula (II)
(ezetimibe) below: 3
[0043] or a pharmaceutically acceptable salt or solvate thereof.
The compound of Formula (II) can be in anhydrous or hydrated form.
The compound of Formula (II) is commercially available in a
pharmaceutical formulation ZETIA.RTM. from MSP Pharmaceuticals,
Inc.
[0044] 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.
[0045] "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.
[0046] 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.
[0047] 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 No. 02/079174 and PCT Patent
Application WO 93/02048, each of which is incorporated herein by
reference, and in the Example below.
[0048] Alternative sterol absorption inhibitors useful in the
compositions, therapeutic combinations and methods of the present
invention are represented by Formula (III) below: 4
[0049] or a pharmaceutically acceptable salt thereof or a solvate
thereof, wherein, in Formula (III) above:
[0050] Ar.sup.1 is R.sup.3-substituted aryl;
[0051] Ar.sup.2 is R.sup.4-substituted aryl;
[0052] Ar.sup.3 is R.sup.5-substituted aryl;
[0053] Y and Z are independently selected from the group consisting
of --CH.sub.2--, --CH(lower alkyl)- and --C(dilower alkyl)-;
[0054] A is selected from --O--, --S--, --S(O)-- or
--S(O).sub.2--;
[0055] 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;
[0056] q is 1, 2 or 3;
[0057] p is 0, 1, 2, 3 or 4;
[0058] 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.su- p.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;
[0059] 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;
[0060] 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.
[0061] 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.
[0062] In another embodiment, sterol absorption inhibitors useful
in the compositions, therapeutic combinations and methods of the
present invention are represented by Formula (IV): 5
[0063] or a pharmaceutically acceptable salt thereof or a solvate
thereof, wherein, in Formula (IV) above:
[0064] 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;
[0065] Ar.sup.1 is aryl or R.sup.3-substituted aryl;
[0066] Ar.sup.2 is aryl or R.sup.4-substituted aryl;
[0067] Q is a bond or, with the 3-position ring carbon of the
azetidinone, forms the spiro group 6
[0068] and
[0069] R.sup.1 is selected from the group consisting of:
[0070] --(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;
[0071] --(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;
[0072] --(C.sub.2-C.sub.6 alkenylene)-; and
[0073] --(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;
[0074] R.sup.5 is selected from: 7
[0075] 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;
[0076] 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)=CH--, a is 1; provided that when R.sup.7
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.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;
[0077] and when Q is a bond, R.sup.1 also can be selected from:
8
[0078] where M is --O--, --S--, --S(O)-- or --S(O).sub.2--;
[0079] 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)al- kyl);
[0080] 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;
[0081] 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;
[0082] d is 1, 2 or 3;
[0083] h is 0, 1, 2, 3 or 4;
[0084] 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;
[0085] v is 0 or 1;
[0086] j and k are independently 1-5, provided that the sum of j, k
and v is 1-5;
[0087] 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.6alkylene)-,
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)al- kyl, 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 9
[0088] 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,
10
[0089] wherein J is --O--, --NH--, --NR.sup.18-- or
--CH.sub.2--;
[0090] 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.1- 5, --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.s- up.15, --(C.sub.1-C.sub.6
alkylene)-COOR.sup.14, --CH.dbd.CH--COOR.sup.14,
--CH.dbd.CH--COOR.sup.14, --CF.sub.3, --CN, --NO.sub.2 and
halogen;
[0091] 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;
[0092] 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;
[0093] 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;
[0094] R.sup.16 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.17-substituted aryl;
[0095] R.sup.18 is hydrogen or (C.sub.1-C.sub.6)alkyl; and
[0096] R.sup.19 is hydrogen, hydroxy or
(C.sub.1-C.sub.6)alkoxy.
[0097] 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.
[0098] Is In another embodiment, sterol absorption inhibitors
useful in the compositions, therapeutic combinations and methods of
the present invention are represented by Formula (V): 11
[0099] or a pharmaceutically acceptable salt thereof or a solvate
thereof, wherein, in Formula (V) above:
[0100] Ar.sup.1 is aryl, R.sup.10-substituted aryl or
heteroaryl;
[0101] Ar.sup.2 is aryl or R.sup.4-substituted aryl;
[0102] Ar.sup.3 is aryl or R.sup.5-substituted aryl;
[0103] X and Y are independently selected from the group consisting
of --CH.sub.2--, --CH(lower alkyl)- and --C(dilower alkyl)-;
[0104] 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;
[0105] q is 0 or 1;
[0106] r is 0, 1 or 2;
[0107] 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;
[0108] 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.su- p.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;
[0109] R.sup.5 is 1-5 substituents independently selected from the
group consisting of --OR.sup.6, --O(CO)OR.sup.6, --O(CO)OR.sup.9,
--O(CH.sub.2).sub.1-5OR.sup.6, --O(CO)NR.sup.RR.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.su- p.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;
[0110] 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;
[0111] R.sup.9 is lower alkyl, aryl or aryl-substituted lower
alkyl; and
[0112] 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.su- p.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.
[0113] 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.
[0114] In another embodiment, sterol absorption inhibitors useful
in the compositions, therapeutic combinations and methods of the
present invention are represented by Formula (VI): 12
[0115] or a pharmaceutically acceptable salt thereof or a solvate
thereof, wherein:
[0116] R.sub.1 is 13
[0117] 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;
[0118] 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)=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;
[0119] 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)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).s- ub.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 0above 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
[0120] R.sub.1 and R.sub.4 together form the group 14
[0121] 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 15
[0122] 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 16
[0123] 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;
[0124] 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;
[0125] R.sub.8 and R.sub.9 are independently selected from H or
lower alkyl;
[0126] R.sub.10 is selected from lower alkyl, phenyl,
R.sub.7-phenyl, benzyl or R.sub.7-benzyl;
[0127] R.sub.11 is selected from OH, lower alkyl, phenyl, benzyl,
R.sub.7-phenyl or R.sub.7-benzyl;
[0128] R.sub.12 is selected from H, OH, alkoxy, phenoxy, benzyloxy,
17
[0129] --N(R.sub.8)(R.sub.9), lower alkyl, phenyl or
R.sub.7-phenyl;
[0130] R.sub.13 is selected from --O--, --CH.sub.2--, --NH--,
--N(lower alkyl)- or --NC(O)R.sub.19;
[0131] 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;
[0132] R.sub.19 is H, lower alkyl, phenyl or phenyl lower alkyl;
and
[0133] 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.
[0134] 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.
[0135] 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):
18
[0136] or a pharmaceutically acceptable salt or solvate
thereof,
[0137] wherein:
[0138] A is --CH.dbd.CH--, --C.ident.C-- or --(CH.sub.2).sub.p--
wherein p is 0, 1 or 2;
[0139] B is 19
[0140] B' is 20
[0141] 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;
[0142] 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;
[0143] 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;
[0144] 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;
[0145] R.sub.4 is 21
[0146] wherein n is 0, 1, 2 or 3;
[0147] R.sub.5 is lower alkyl; and
[0148] 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.
[0149] In another embodiment, sterol absorption inhibitors useful
in the compositions and methods of the present invention are
represented by Formula (VIII): 22
[0150] or a pharmaceutically acceptable salt thereof or a solvate
thereof, wherein, in Formula (VIII) above,
[0151] R.sup.26 is H or OG.sup.1;
[0152] G and G.sup.1 are independently selected from the group
consisting of 23
[0153] provided that when R.sup.26 is H or OH, G is not H;
[0154] 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;
[0155] 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)--;
[0156] 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)al- kyl;
[0157] 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;
[0158] 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.su- b.1-C.sub.6)alkyl,
R.sup.32-substituted-(C.sub.3-C.sub.7)cycloalkyl and
R.sup.32-substituted-(C.sub.3-C7)cycloalkyl(C.sub.1-C.sub.6)alkyl;
[0159] R.sup.31 is selected from the group consisting of H and
(C.sub.1-C.sub.4)alkyl;
[0160] T is selected from the group consisting of phenyl, furyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl,
benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and
pyridyl;
[0161] 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)alkylsulfa- nyl, (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-subs-
tituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl
or morpholinyl group;
[0162] Ar.sup.1 is aryl or R.sup.10-substituted aryl;
[0163] Ar.sup.2 is aryl or R.sup.11-substituted aryl;
[0164] Q is a bond or, with the 3-position ring carbon of the
azetidinone, forms the spiro group 24
[0165] and
[0166] R.sup.1 is selected from the group consisting of
[0167] --(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;
[0168] --(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;
[0169] --(C.sub.2-C.sub.6)alkenylene-; and
[0170] (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;
[0171] R.sup.12 is 25
[0172] 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;
[0173] a and b are independently 0, 1, 2 or 3, provided both are
not zero;
[0174] provided that when R.sup.13 is --CH.dbd.CH-- or
--C(C.sub.1-C.sub.6 alkyl)=CH--, a is 1;
[0175] provided that when R.sup.14 is --CH.dbd.CH-- or
--C(C.sub.1-C.sub.6 alkyl)=CH--, b is 1;
[0176] provided that when a is 2 or 3, the R.sup.13's can be the
same or different; and
[0177] provided that when b is 2 or 3, the R.sup.14's can be the
same or different;
[0178] and when Q is a bond, R.sup.1 also can be: 26
[0179] M is --O--, --S--, --S(O)-- or --S(O).sub.2--;
[0180] 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)alk- yl);
[0181] 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.2- 0, --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.s- up.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;
[0182] 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;
[0183] 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;
[0184] d is 1,2 or 3;
[0185] h is 0, 1, 2, 3 or 4;
[0186] s is 0 or 1; t is 0 or 1; m, n and p are independently
0-4;
[0187] provided that at least one of s and t is 1, and the sum of
m, n, p, s and t is 1-6;
[0188] 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;
[0189] v is 0 or 1;
[0190] j and k are independently 1-5, provided that the sum of j, k
and v is 1-5;
[0191] when Q is a bond and R.sup.1 is 27
[0192] Ar.sup.1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl,
thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl
or pyridazinyl;
[0193] 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;
[0194] R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.24-substituted aryl;
[0195] 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;
[0196] 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
[0197] R.sup.25 is H, --OH or (C.sub.1-C.sub.6)alkoxy.
[0198] 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.
[0199] In another embodiment, sterol absorption inhibitors useful
in the compositions and methods of the present invention are
represented by Formula (IX) below: 28
[0200] or a pharmaceutically acceptable salt or solvate thereof,
wherein in Formula (IX):
[0201] 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;
[0202] G is selected from the group consisting of: H, 29
[0203] (sugar derivatives)
[0204] 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(C1-C6)alkoxy or --W--R.sup.30;
[0205] 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)--;
[0206] 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;
[0207] 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;
[0208] 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.su- b.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(.sub.1-C.sub.6)alkyl;
[0209] R.sup.31 is independently selected from the group consisting
of H and (C.sub.1-C.sub.4)alkyl;
[0210] T is independently selected from the group consisting of
phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl
and pyridyl;
[0211] 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)alkylsulfa- nyl, (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-subs-
tituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl
or morpholinyl group;
[0212] G.sup.1 is represented by the structure: 30
[0213] 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-, 31
[0214] 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.2.sup.+)CH.sub.2SS--;
[0215] R.sup.35 is independently selected from the group consisting
of H and NH.sub.2--;
[0216] 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;
[0217] G.sup.2 is represented by the structure: 32
[0218] 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;
[0219] R.sup.26 is one to five substituents, each R.sup.26 being
independently selected from the group consisting of:
[0220] a) H;
[0221] b) --OH;
[0222] c) --OCH.sub.3;
[0223] d) fluorine;
[0224] e) chlorine;
[0225] f) --O-G;
[0226] g) --O-G.sup.1;
[0227] h) --O-G.sup.2;
[0228] i) --SO.sub.3H; and
[0229] j) --PO.sub.3H;
[0230] provided that when R.sup.1 is H, R.sup.26 is not H, --OH,
--OCH.sub.3 or --O-G;
[0231] Ar.sup.1 is aryl, R.sup.10-substituted aryl, heteroaryl or
R.sup.10-substituted heteroaryl;
[0232] Ar.sup.2 is aryl, R.sup.11-substituted aryl, heteroaryl or
R.sup.11-substituted heteroaryl;
[0233] L is selected from the group consisting of:
[0234] a) a covalent bond;
[0235] b) --(CH.sub.2).sub.q--, wherein q is 1-6;
[0236] 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;
[0237] d) --(C.sub.2-C.sub.6)alkenylene-;
[0238] 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
[0239] f) 33
[0240] wherein M is --O--, --S--, --S(O)-- or --S(O).sub.2--;
[0241] 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)-;
[0242] R.sup.8 is selected from the group consisting of H and
alkyl;
[0243] 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.s- up.19,
--O(CO)NR.sup.19R.sup.20, --NR.sup.19R.sup.20(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 halo;
[0244] 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;
[0245] 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;
[0246] or R.sup.15 and R.sup.16 together are .dbd.O, or R.sup.17and
R.sup.18 together are .dbd.O;
[0247] d is 1, 2 or 3;
[0248] h is 0, 1, 2, 3or 4;
[0249] s is 0 or 1;
[0250] t is 0 or 1;
[0251] m, n and p are each independently selected from 0-4;
[0252] 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;
[0253] v is 0 or 1;
[0254] j and k are each independently 1-5, provided that the sum of
j, k and v is 1-5;
[0255] 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 34
[0256] wherein R.sup.12 is 35
[0257] 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;
[0258] 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)=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;
[0259] and when Q is a bond and L is 36
[0260] then Ar.sup.1 can also be pyridyl, isoxazolyl, furanyl,
pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl,
pyrimidinyl or pyridazinyl;
[0261] 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;
[0262] R.sup.21 is (C.sub.1-C.sub.6)alkyl, aryl or
R.sup.24-substituted aryl;
[0263] 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;
[0264] 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
[0265] R.sup.25 is H, --OH or (C.sub.1-C.sub.6)alkoxy.
[0266] 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.
[0267] An example of a useful compound of this invention is one
represented by the formula X: 37
[0268] wherein R.sup.1 is defined as above.
[0269] A more preferred compound is one represented by formula XI:
38
[0270] Another useful compound is represented by Formula XII:
39
[0271] 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. Pat. Publication Nos. 2002/0,039,774,
2002/0,128,252, 2002/0,128,253 and 2002/0,137,689, and WO
2002/066464, each of which is incorporated by reference herein.
[0272] 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.
[0273] 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.
[0274] 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.
[0275] 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.
[0276] 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.
[0277] 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).
[0278] 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).
[0279] 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.
[0280] 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.
[0281] The term "therapeutically effective amount" means that
amount of a therapeutic agent of the composition, such as a sterol
absorption inhibitor(s), or other agent useful for the treatment of
an autoimmune disorder 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 (autoimmune disorder and its
symptom(s)).
[0282] For example, a widely accepted composite index of
improvement in rheumatoid arthritis (RA) is the ACR20 score
proposed by the American College of Rheumatology (ACR). ACR20
refers to a composite improvement of 20% in swollen joint count,
tender joint count, and 3 or more of the following measures:
patient's own global assessment of RA disease activity; physician's
assessment of disease activity; patient's own assessment of pain
due to RA; acute-phase reactant (ESR, CRP); and disability (Health
Assessment Questionnaire). See "Guidelines for the Management of
Rheumatoid Arthritis, 2002 Update", Arthritis and Rheumatism 46(2):
328-346 (2002). The percentage of patients showing improvement in
ACR20 score is the generally accepted minimum criteria for all new
therapeutics for the treatment of RA.
[0283] 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.
[0284] As used herein, "combination therapy" or "therapeutic
combination" means the administration of two or more therapeutic
agents, such as sterol absorption inhibitor(s) and other agents
useful for the treatment of an autoimmune disorder, to prevent or
treat an autoimmune disorder or any of its associated conditions.
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
autoimmune 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
autoimmune 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.
[0285] 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 other agent or treatment useful for the treatment of an
autoimmune disorder, wherein the first amount and the second amount
together comprise a therapeutically effective amount for the
treatment or prevention of an autoimmune disorder or lessening or
amelioration of one or more symptoms of a condition associated with
the autoimmune disorder.
[0286] In another embodiment, the present invention provides a
pharmaceutical composition for the treatment or prevention of an
autoimmune disorder 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
other agent useful for the treatment of an autoimmune disorder and
(c) a pharmaceutically acceptable carrier.
[0287] In another embodiment, the present invention provides a
method of treating or preventing an autoimmune disorder 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 other agent useful for the
treatment of an autoimmune disorder to prevent or treat an
autoimmune disorder or any of its symptoms in the subject.
[0288] Useful agents for treating autoimmune disorders include: (a)
disease modifying antirheumatic drugs, including methotrexate, gold
salts, D-penicillamine, hydroxychloroquine, auranofin,
sulfsalazine; (b) nonsteroidal anitinflammatory drugs, including
indomethacin, naproxen, diclofenac, ibuprofen, aspirin and aspirin
analogs, acetaminophen; (c) COX-2 selective inhibitors, including
celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib; (d)
COX-1 inhibitors; (e) immunosuppressives, including calcineurin
inhibitors such as cyclosporin and FK506; p70.sup.S6 kinase
inhibitors such as sirolimus and rapamycin; inosine monophosphate
dehydrogenase inhibitors such as mycophenolate; leflunomide,
cyclophosphamide, azathioprine; (f) steroids, including prednisone,
betamethasone, budesonide and dexamethasone; (g) biological
response modifiers, including TNF.alpha. antagonists such as
infliximab, adalimmab and etanercept; IL-1 receptor antagonists
such as anakinra; humanized or chimeric antibodies or fusion
proteins such as alefacept, efalizumab, daclizumab; anti-chemokine
antibodies or interleukins; and (h) other agents useful for the
treatment of autoimmune disorders, including chemokine receptor
antagonists or modulators, cannabinoid receptor antagonists or
modulators, inhibitors of matrix metalloproteinases,
TNF.alpha.-converting enzymes, nitric oxide synthetases or
phosphodiesterase IV, such as roflumilast or cilomilast; inhibitors
of p38 MAP-kinase, the NF-kappa.beta., pathway or IL-1 receptor
associated kinase or inhibitors of interactions involving adhesion
molecules such as LFA-1, VLA-4, ICAM-1, VCAM-1,
.alpha..sub.4.beta..sub.7, MAdCAM-1, and .alpha..sub.v.beta..sub.3.
The amount of the respective agent for treating an autoimmune
disorder, which is to administered to the subject can be readily
determined by one skilled in the art.
[0289] 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.
[0290] 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,
CI-981, rivastatin (sodium
7-(4-fluorophenyl)-2,6-diisopropyl-5-methoxyme-
thylpyridin-3-yl)-3,5-dihydroxy-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.
[0291] 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.
[0292] 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.
[0293] 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. 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.
[0294] 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.
[0295] The compositions or treatments of the present invention can
further comprise one or more AcylCoA:Cholesterol O-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.
[0296] 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.
[0297] 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.
[0298] 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.
[0299] 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.
[0300] 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.
[0301] 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.
[0302] 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.
[0303] 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.
[0304] The compositions, therapeutic combinations or methods of the
present invention can further comprise one or more cardiovascular
agents or blood modifiers.
[0305] 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.
[0306] 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 an
autoimmune disorder 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.
[0307] 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 sterol absorption
inhibitor(s) and the other agent useful for the treatment of an
autoimmune disorder 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.
[0308] 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.
[0309] 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.
[0310] 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.
[0311] 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.
[0312] 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.
[0313] 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.
[0314] 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.
[0315] Preferably the compound is administered orally.
[0316] 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 an autoimmune disorder and
its associated conditions.
[0317] 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 l-XII described herein above and the term
"Active Compound II" designates at least one other agent useful for
the treatment of an autoimmune disorder (such as an
immunosuppressive medicament) described herein above.
Example Formulation
[0318]
1 Tablets No. Ingredient mg/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
[0319] 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
[0320] 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.
[0321] 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 at least one other agent
useful for the treatment of an autoimmune disorder, 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.
[0322] Since the present invention relates to treating an
autoimmune disorder 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 anti-autoimmune
disorder 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.
[0323] 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 an autoimmune disorder and associated conditions,
such as rheumatoid arthritis, in subjects, in particular in
mammals.
[0324] 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 and phytosterols
(such as sitosterol, campesterol, stigmasterol and avenosterol) 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 absorption inhibitor described above. The reduction in
plasma concentration of sterols or 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.
[0325] Illustrating the invention are the following examples which,
however, are 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.
EXAMPLES
Example 1
Preparation of Compound of Formula (II)
[0326] 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%), NaCl
(sat'd) and water. The organic layer was dried over MgSO.sub.4 and
concentrated to obtain a semicrystalline product.
[0327] 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.
[0328] 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)ac- etamide (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 (1 N),
NaHCO.sub.3 (1N) and NaCl (sat'd.), and the organic layer was dried
over MgSO.sub.4.
[0329] 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.
[0330] 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-hydroxyphen-
yl)-3(R)-(3-oxo-3-phenylpropyl)-2-azetidinone: HRMS calc'd for
C.sub.24H.sub.19F.sub.2NO.sub.3=408.1429, found 408.1411.
[0331] 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-(phenylmethoxy)phenyl]-2-azetid-
inone (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.
[0332] 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 CDCl3 d H3=4.69. J=2.3 Hz.
Cl (M.sup.+H) 500.
[0333] 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.degre- e. (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.
[0334] Similarly treat compound 6B-1 to obtain compound 6B.
[0335] Mp 129.5-132.5.degree. C.; Cl (M.sup.+H) 410. Elemental
analysis calc'd for C.sub.24H21F.sub.2NO.sub.3: C 70.41; H 5.17; N
3.42; found C 70.30; H 5.14; N 3.52.
[0336] 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.
Example 2
Hypothetical in vivo Evaluation of the Ability of the Compound of
Formula II to Treat Experimental Arthritis
[0337] The compound of Formula II (or any cholesterol absorption
inhibitor discussed above) is administered to rodents which have
been induced to develop experimental arthritis. Useful rodents can
include Balb/c, C57BL/6, B10.RIII or DBA/1 mice, or Lewis or Wistar
rats (available from Jackson Laboratory, Charles River Laboratories
or Taconic Laboratories).
[0338] In the present example, collagen-induced arthritis (CIA) in
DBA/1 or B10.RIII mice (from the Jackson Laboratory) are used as an
animal model of rheumatoid arthritis for in vivo evaluation of the
effect of the compound of Formula II on rheumatoid disease.
Typically, the highly susceptible parental strain DBA/1 or B10.RIII
develop 90-100% arthritis in males and 60-100% arthritis in
females. The disease is induced by immunization with
cartilage-specific type II collagen in Complete Freund's adjuvant
and in some cases animals are boosted with Type II collagen or
lipopolysaccharide on days 17-25 after immunization. The mice are
8-10 weeks old at the time of immunization. Rat type II collagen is
prepared as previously described (see Miller and Rhodes (1982)
Methods Enzymol. 82: 33). CIA is induced by intradermal
immunization in the base of the tail with 50-100 .mu.g type II
collagen emulsified in Complete Freund's adjuvant (as described in
Current Protocols in Immunology, Unit 15, John Wiley & Sons,
Inc. NY or in Holmdahl, et al. (1998) Genetic Analysis of Murine
Models for Rheumatoid Arthritis In Human Genome Methods, vol. 215,
CRC Press, NY).
[0339] The compound of Formula II (or any cholesterol absorption
inhibitor discussed above) is administered to mice that have been
induced to developed CIA. Typically, mice can be scored for
clinical disease starting at 14 days after immunization with rat
type II collagen. The compound of Formula II is administered at a
dosage of 0.1-100 mg/kg/day either in the diet or by systemic oral,
subcutaneous or intraperitoneal administration over a period of 3
days to 10 weeks. Animals are scored daily for clinical disease
score as described in Current Protocols in Immunology, Unit 15,
John Wiley & Sons, Inc., NY. At a specified period of time
after compound administration, animals are euthanized by isofurane
overdose and cytological, histological, immunological and
immunohistochemical parameters are assessed by standard techniques
well known to those skilled in the art. Serum lipoprotein and
cholesterol measurements will be made by methods well known to
those skilled in the art and, for example, including those
disclosed in PCT WO 99/38498 at page 11, incorporated by reference
herein.
Example 3
Hypothetical in vivo Evaluation of the Ability of the Compound of
Formula II to Treat Ulcerative Colitis
[0340] The compound of Formula II (or any cholesterol absorption
inhibitor discussed above) is administered to rodents which have
been induced to develop ulcerative colitis. Suitable rodents are
the same as those described in Example 2.
[0341] In the present example, the effect of the administration of
the compound of Formula II is investigated in 2,4,6-trinitrobenzene
sulfonic acid (TNBS)--induced colitis in mice. The compound of
Formula II is administered at a dosage of 0.1-100 mg/kg/day either
in the diet or by systemic oral, subcutaneous or intraperitoneal
administration over a period of 3 days to 10 weeks. Colitis is
induced in mice by intrarectal administration of TNBS (1.5 mg/mouse
in 50% ethanol) and disease severity is assessed clinically and by
histologic scoring of colon damage, including determination of
interleukin (IL)-2, IL-12, interferon (INF)-gamma and tumor
necrosis factor (TNF)-alpha (protein and mRNA) and myeloperoxidase
(MPO) activity in the colon. Cytokine production by the lamina
propia mononuclear cells (LPMC) and luminal bacteria are also
typically measured (see Fiorucci, et al. (2002) Digestion 66(4):
246-256). In particular, after a specified period of time after
Compound II administration, animals are euthanized by isofurane
overdose and the above-described parameters are assessed using
methods described in Current Protocols in Immunology, Unit 15, John
Wiley & Sons, Inc. NY and/or using the methods described by
Fiorucci, et al. (2002) in Digestion 66(4): 246-256. Serum
lipoprotein and cholesterol measurements will be made as described
in Example 2.
[0342] 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.
* * * * *